Document RJJO6nyjZQxyEdJVa5jn9086k

IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO GLOBAL STRATEGY FOR ASTHMA MANAGEMENT AND PREVENTION Updated 2022 2022 Global Initiative for Asthma IBUTE Global Strategy for Asthma Management and Prevention DISTR (2022 update)Y OR COP T NO AL - DO ATERI ED M Tthheeurseeadoef rhaecakltnhopwrloefdegsseisonthaalstItGahniHsdTrpeoploicryt -ismiankteenrsd.eIdt as an evidence-based is based, to the best of asthma management strategy, for our knowledge, on current best ehveiadlethncperoafensdsmioendailcsaalrkensoPtwroYlenRdgglyeaadnvdisperdatcoticueseatththeeir date own of publication. When assessing and treating patients, professional judgment, and to take into account local and national regulationCsOand guidelines. GINA cannot be held liable or responsible for inappropriate healthcare associated with the use of this document, including any use which is not in accordance with applicable local or national regulations or guidelines. This document should be cited as: Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention, 2022. Available from: www.ginasthma.org 1 Table of contents Tables and figures .............................................................................................................................................................5 Preface ................................................................................................................................................................................7 Members of GINA committees (2019-20) .........................................................................................................................8 Methodology ..................................................................................................................................................................... 10 What's new in GINA 2022?..............................................................................................................................................14 Advice on asthma management during the COVID-19 pandemic...............................................................................17 SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER ...........................................................19 Chapter 1. Definition, description, and diagnosis of asthma....................................................................................19 DDeefsincritiipotnionofoafsathsmtham.a............................................................................................................................................................................................................U....T......E............................................................................2200 Making the initial diagnosis ....................................................................................T..R...I.B..............................................21 Confirming the diagnosis of asthma in patients already taking controller treatDmISent .................................................26 Differential diagnosis.................................................................................O...R..............................................................27 How to make the diagnosis of asthma in other contexts .................O...P...Y....................................................................28 Chapter 2. Assessment of asthma ................................................T...C.............................................................................31 Overview ...............................................................................N..O...................................................................................32 Assessing asthma symptom control ............................-..D...O.........................................................................................34 ARsosleesosfilnugngfuftuunrectrioisnk ionf aasdsveesrssiengouatsctohmmeasc.o..n..t.r.R.o..lI..A....L....................................................................................................................................................................................................3398 Assessing asthma severity .........................A..T...E..........................................................................................................40 Chapter 3. Treating asthma to control sEyDmMptoms and minimize risk .......................................................................45 Part A. General principles of asthmIGaHmTanagement .......................................................................................................46 LTohnegp-atetriemntg-hoeaalslthofcaasrtehmpraoPvmYidaRenrapgaermtneenrst h..i.p............................................................................................................................................................................................................................4477 Personalized control-baCsOed asthma management ....................................................................................................48 Part B. Medications and strategies for symptom control and risk reduction..................................................................51 Asthma medications...................................................................................................................................................52 Asthma treatment tracks for adults and adolescents.................................................................................................54 Step 1 .........................................................................................................................................................................64 Step 2 .........................................................................................................................................................................66 Step 3 .........................................................................................................................................................................69 Step 4 .........................................................................................................................................................................70 Step 5 .........................................................................................................................................................................72 Reviewing response and adjusting treatment ............................................................................................................73 Treating other modifiable risk factors.........................................................................................................................76 2 Other therapies .......................................................................................................................................................... 77 Non-pharmacological strategies ................................................................................................................................ 79 Indications for referral for expert advice .................................................................................................................... 87 Part C. Guided asthma self-management education and skills training........................................................................88 Skills training for effective use of inhaler devices ...................................................................................................... 88 Adherence with medications and other advice ..........................................................................................................89 Asthma information .................................................................................................................................................... 91 Training in guided asthma self-management ............................................................................................................ 92 Part D. Managing asthma with multimorbidity and in specific populations....................................................................94 Managing comorbidities ............................................................................................................................................. 94 Managing asthma in specific populations or settings ................................................U..T...E........................................... 97 Part E. Difficult-to-treat and severe asthma in adults and adolescents.................T..R...I.B................................................104 Definitions: uncontrolled, difficult-to-treat and severe asthma....................D..I..S.........................................................105 Prevalence: how many people have severe asthma? .........................O...R.................................................................105 IImnvpeosrttiagnactee:atnhde mimapnaacgteodf isffeicvuelrte-toa-strthemataa.s..t.h..m...a...i.n...A...D..U...L..T..S....AC..N.O..D.P..A.Y..D..O...L..E..S...C...E..N...T..S............................................................................................111016 AMsasneasgseaannddtrmeaotnsiteovr esreeveasrethamsathpmhaentroetaytpmeesn..t...............................N....O......T......................................................................................................................................................................112103 Chapter 4. Management of worsening asthma and e- xDaOcerbations .........................................................................123 Overview .......................................................R...I.A..L.....................................................................................................125 Diagnosis of exacerbations....................A..T...E.............................................................................................................126 SMealnf-amgaenmaegnetmoef natsothf mexaaecxearbcaetriboanEtsioDwnsiMthinapwrirmittaerny asthma action plan ................................................................... care (adults, adolescents, chldren 6-11 years) ....................... 126 130 Management of asthma exaIcGeHrbTations in the emergency department (adults, adolescents, children 6-11 years)133 Covhearplatepr')5......D..i.a..g..n...o..s..i.s...a..n..d...Pi.n.Y..i.tR.i.a..l..t.r.e...a..t.m...e..n..t..o...f..a..d..u..l.t.s....w..i.t..h...f.e..a..t.u..r..e..s...o..f..a..s..t..h..m...a..,..C...O..P...D...o...r..b..o..t..h...(.`.a..s..t.h...m...a..-.C...O...P..D.... 141 Objectives ..............C...O............................................................................................................................................... 143 Background to diagnosing asthma and/or COPD in adult patients .........................................................................143 Assessment and management of patients with chronic respiratory symptoms.......................................................144 Future research........................................................................................................................................................149 SECTION 2. CHILDREN 5 YEARS AND YOUNGER ......................................................................................................... 151 Chapter 6. Diagnosis and management of asthma in children 5 years and younger...........................................151 Part A. Diagnosis ......................................................................................................................................................... 152 Asthma and wheezing in young children ................................................................................................................152 Clinical diagnosis of asthma....................................................................................................................................153 Tests to assist in diagnosis ...................................................................................................................................... 156 Differential diagnosis ............................................................................................................................................... 157 3 Part B. Assessment and management ........................................................................................................................159 Goals of asthma management.................................................................................................................................159 Assessment of asthma ............................................................................................................................................159 Medications for symptom control and risk reduction................................................................................................161 Asthma treatment steps for children aged 5 years and younger .............................................................................163 Reviewing response and adjusting treatment .........................................................................................................166 Choice of inhaler device ..........................................................................................................................................166 Asthma self-management education for carers of young children .........................................................................167 Part C. Management of worsening asthma and exacerbations in children 5 years and younger ...............................168 Diagnosis of exacerbations ......................................................................................................................................168 Initial home management of asthma exacerbations .......................................................U..T...E....................................169 Primary care or hospital management of acute asthma exacerbations in childrenT5RyIBears or younger..................171 Chapter 7. Primary prevention of asthma ..........................................................D..I..S....................................................175 Factors contributing to the development of asthma in children ................O...R............................................................176 Factors associated with increased or decreased risk of asthma in chPildYren............................................................176 Advice about primary prevention of asthma .................................C...O........................................................................179 SECChTaIOptNer38. T. RImApNlSeLmAeTnItOinNgIaNsTtOhmCaLmINaICnAagLePmReAnCt TstICraEte..g..i.e..s...i.n..Nt..oO...hT..e..a..l.t.h....s..y..s..t.e..m...s..........................................................................................................118811 Introduction ..................................................................-..D...O.......................................................................................182 Adapting and implementing asthma clinical pracRtiIcAeLguidelines..............................................................................182 Barriers and facilitators ...............................A..T...E........................................................................................................184 EExvaamluaptlieosnooffhthigehimimppleacmteimntpalteiomnepnrtoacEtieoDsnsMin..t..e..r.v..e..n..t.io..n..s........................................................................................................................................................................................118844 How can GINA help with implemIGeHntTation? ..............................................................................................................185 REFERENCES .......................C...O...P..Y...R..................................................................................................................................186 4 Tables and figures DIAGNOSIS Box 1-1. Diagnostic flowchart for clinical practice 22 Box 1-2. Diagnostic criteria for asthma in adults, adolescents, and children 6-11 years 23 Box 1-3. Steps for confirming the diagnosis of asthma in a patient already taking controller treatment 26 Box 1-4. How to step down controller treatment to help confirm the diagnosis of asthma 27 Box 1-5. Differential diagnosis of asthma in adults, adolescents and children 6-11 years 27 ASSESSMENT Box 2-1. Assessment of asthma in adults, adolescents, and children 6-11 years 33 Box 2-2. GINA assessment of asthma control in adults, adolescents and children 6-11 years 36 Box 2-3. Specific questions for assessment of asthma in children 6-11 years 37 Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment 43 ASTHMA MANAGEMENT UTE Box 3-1. Box 3-2. Communication strategies for health care providers The asthma management cycle for personalized asthma care TRIB 47 48 Box 3-3. Population level versus patient level decisions about asthma treatDmIeSnt 50 Initial treatment choices OR Box 3-4A. Box 3-4Bi. Initial asthma treatment Selecting initial controller rterecaotmmmenetnidneaddoupltstioannsdfoardaodleuslOctsePnaYtnsdwaitdhoalesdciaegnntsosis of asthma (V1) 55 56 Box 3-4Bii. Box 3-4C. Selecting initial controller Initial asthma treatment - rterecaotmmmenetnidneaddoupltstioannsdfoaOrdcoThleCilsdcreenntsagweidth6a-1d1iagyenaorssis of asthma (V2) 57 58 Box 3-4Di. Box 3-4Dii. Selecting Selecting initial initial controller controller treatment treatment in in cchhiillddrreeDnnOaaggNeedd 6-11 6-11 years years with with a a diagnosis diagnosis of of asthma asthma (V1) (V2) 59 60 Main treatment figures IAL - Box 3-5A. Box 3-5B. Personalized Personalized management management for for achdiulTdltErseRnan6d-1ad1oyleesacrsentotsctoonctroonl tsroylmspytmomptsomansdamndinmiminizime ifzuetufrueturrisekrisk 61 62 Box 3-6. Low, medium and high daily mMetAered doses of inhaled corticosteroids (alone or with LABA) 63 Ongoing Box 3-7. management Options for stepping downTEtrDeatment once asthma is well controlled 75 Box 3-8. Treating potentially mIGodHifiable risk factors to reduce exacerbations 76 Box 3-9. Non-pharmacoloPgYicRal interventions - summary 79 Box 3-10. Box 3-11. EInfdfeiccatitvioennsesfosCroOcfoanvsoididearnincgermefeearrsaul rfeosr for indoor allergens expert advice, where available 83 87 Box 3-12. Strategies to ensure effective use of inhaler devices 89 Box 3-13. Poor medication adherence in asthma 90 Box 3-14. Asthma information 91 Difficult-to-treat and severe asthma Box 3-15. What proportion of adults have difficult-to-treat or severe asthma? 105 Box 3-16A. Decision tree - investigate and manage difficult to treat asthma in adult and adolescent patients 107 Box 3-16B. Decision tree - assess and treat severe asthma phenotypes 108 Box 3-16C. Decision tree - consider add-on biologic Type 2-targeted treatments 109 Box 3-16D. Decision tree - monitor and manage severe asthma treatment 110 5 EXACERBATIONS Box 4-1. Factors that increase the risk of asthma-related death 125 Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan 129 Box 4-3. Management of asthma exacerbations in primary care (adults, adolescents, children 6-11 years) 131 Box 4-4. Management of asthma exacerbations in acute care facility, e.g. emergency department 135 Box 4-5. Discharge management after hospital or emergency department care for asthma 139 ASTHMA, COPD AND ASTHMA+COPD Box 5-1. Current definitions of asthma and COPD, and clinical description of asthma-COPD overlap 144 Box 5-2. Approach to initial treatment in patients with asthma and/or COPD 145 Box 5-3. Spirometric measures in asthma and COPD 146 Box 5-4. Specialized investigations sometimes used in distinguishing asthma and COPD 148 Box 6-1. Probability of asthma diagnosis in children 5 years and younger 153 CHILDREN 5 YEARS AND YOUNGER Box 6-2. Features suggesting a diagnosis of asthma in children 5 years and younger UTE 154 Box 6-2A. Box 6-3. Questions that can be used to elicit features Common differential diagnoses of asthma in scuhgildgreesntiv5eyoefaarsstahnmdayoungeTrRIB 155 157 Box 6-4. GINA assessment of asthma control in children 5 years and younger DIS 160 Box 6-5. Box 6-6. PLoewrsodnaailylizdeodsmesaonfaignehmaleendt coofratisctohsmtearoinidcshfioldrrcehnild5ryeena5rsyaenadrsyaonuOdnRgyeorunger 165 166 Box 6-7. Box 6-8. CMhaonoasgienmg eanntinofhaacleurtedeavsicthemfoarocrhwildhreeenz5ingyeinarcshailnddreyno5unygeeaOrrsPYand younger 167 170 Box 6-9. Initial assessment of acute asthma exacerbations in chiTldrCen 5 years and younger 171 Box 6-10. Indications for immediate transfer to hospital for chilNdrOen 5 years and younger 172 Box 6-11. PRIMARY Initial emergency department management PREVENTION OF ASTHMA IN CHILDREN of -asDtOhma exacerbations in children 5 years and younger 173 Box 7-1. Advice about primary prevention of asthmRaIAiLn children 5 years and younger 179 IMPLEMENTATION STRATEGIES AlTobEal Strategy for Asthma Management and Prevention 183 Box 8-1. Approach to implementation of theMG Box 8-2. Essential elements required toEiDmplement a health-related strategy 183 BBooxx 88--34.. EExxaammpplleess ooff bhaigrhri-eimrspYtaoRcttIhGienHtiemTrvpelenmtioennstaitnioansothfmevaidmeanncaeg-beamseendt recommendations 118844 COP 6 Preface Asthma is a serious global health problem affecting all age groups. Its prevalence is increasing in many countries, especially among children. Although some countries have seen a decline in hospitalizations and deaths from asthma, asthma still imposes an unacceptable burden on health care systems, and on society through loss of productivity in the workplace and, especially for pediatric asthma, disruption to the family. The Global Initiative for Asthma was established in 1993 by the National Heart, Lung, and Blood Institute and the World Health Organization, with the aim of increasing awareness about asthma and providing a mechanism to translate scientific evidence into improved asthma care worldwide. In 2001, GINA initiated an annual World Asthma Day, raising awareness about the burden of asthma, and becoming a focus for local and national activities to educate families and health care professionals about effective methods to manage and control asthma. GINA"s flagship publication, the Global Strategy for Asthma Management and Prevention (`GINA report'), first published in 1995,1 has been updated annually since 2002, with pivotal changes in 2006, 2014 and 2019. The main GINA report contains recommendations for clinical practice and brief supporting evidence, while additional resources and Publications and resources based on the GINA reports supporting material have been translated are into mpraonvyidleaUdngTouEnalginees. at www.ginasthma.org. GINA is independent of industry. Its work is supported only by income generated from the sale and licensingToRf IiBts resources. We acknowledge the superlative work of all who have contributed to the success DofISthe GINA program, and the many people who have participated Director and Claude in it. Lenf In particular, we ant as Executiv recognize e Director the outstanding over the many aynedadrseOdsiRcinacteedGwIoNrAk of Drs was f Suzanne Hurd as Scientific irst established, until their retirement in 2015. GINA. In 2016, we TwheroreugdheltihgehitretdiretoleswseclcoonmtreibuMtisonRse, bDercHcaurDd eacnkdeDr,OrBLPSeY,nMfaSntJf,oasstetrheed and facilitated the Program Director development of (now Executive Director) for GINA, and we appreciate the commitment and skills thaTt Cshe has brought to this demanding role. The members of the GINA Committees are solely responsible for the statemNeOnts and conclusions presented in this publication. They rmeeceetivinegsn.oThheonGoIrNaAriaAdorvorceaimtebsuarsnedmAesnstemofbelyx,pdeendsiceastefod-raDtshOtehimr amcaanrye hours of work in reviewing evidence or attending experts from many countries, work with the Science Cproommmotietteinet,ertnhaetioBnoaalrdcoollaf bDoirraetciotonrsanadnddistsheemDiniastsioeRnmIAoinLfaintifoonrmaantdionImapbloeumt eansttahtmioan. Committee to We share the sadness that the global asthmaATcEommunity feels at the loss of Mark FitzGerald (18 June 1955-18 leader and strong aJadnvoucaaryte2f0o2r2i)m. pInrohvisingE25DaysMethamrsaodf iwagonrkoswisithanGdINmAa,nMaagrekmweanst. a compassionate Mark's guidance wreimll baeinmaisgsueiddindgeaforlryceb.utInhiMs arerks'esahrcoIGhn,oHlreT,gGaIcNyA, ainsdecsotambmlisihtminegnat tsochheollpairnsghitphefowr ojurnldiobrrereastheearbcehtetersr from low- or middle-income couPnYtrRies. In spite of all of the above eCffOorts, and the availability of effective therapies, international data provide ongoing evidence for suboptimal asthma control in many countries. The majority of the burden of asthma morbidity and mortality occurs in low- and middle-income countries, and is avoidable. It is clear that if recommendations contained within this report are to improve care of people with asthma, every effort must be made to encourage health care leaders to assure availability of, and access to, effective quality-assured medications, and to develop means to implement and evaluate effective asthma management programs. We hope you find this report to be a useful resource in the management of asthma and that, in using it, you will recognize the need to individualize the care of each and every asthma patient you see. Helen K Reddel, MBBS PhD Chair, GINA Science Committee Louis-Philippe Boulet, MD Chair, GINA Board of Directors 7 Members of GINA committees (2019-20) GINA SCIENTIFIC COMMITTEE Fanny Wai-san Ko, MD Helen K. Reddel, MBBS PhD, Chair Woolcock Institute of Medical Research, University of The Chinese University of Hong Kong Hong Kong Sydney Jerry A. Krishnan, MD PhD (to November 2021) Sydney, Australia University of Illinois Hospital & Health Sciences System Leonard B. Bacharier, MD Chicago, IL, USA Vanderbilt University Medical Center Kevin Mortimer, BA/MA, MB/BChir, PhD Nashville, TN, USA Liverpool School of Tropical Medicine Eric D. Bateman, MD University of Cape Town Lung Institute Liverpool, UK Paulo Pitrez, MD, PhD TE Cape Town, South Africa Hospital Moinhos de Porto Alegre, Brazil VenRtoIBU Louis-Philippe Boulet, MD Universit Laval Aziz Sheikh, BSc, MDBISBTS, MSc, MD Qubec, QC, Canada TEhdeinUbunrigvhe,rsUitYnyitoOefdREKdiinngbduorgmh Christopher Brightling, FMedSci, PhD Leicester NIHR Biomedical Research Centre, GINA BCOOAPRD OF DIRECTORS University of Leicester Leicester, UK LUonNuiviOse-TrPshitilipLpaevaBl oulet, MD, Chair Guy Brusselle, MD, PhD Ghent University Hospital - DOQubec, QC, Canada Ghent, Belgium RIAL Eric D. Bateman, MD University of Cape Town Lung Institute Roland Buhl, MD PhD Mainz University Hospital ATE Cape Town, South Africa Mainz, Germany Jeffrey M. Drazen ED M GHT Guy Brusselle, MD, PhD Ghent University Hospital Ghent, Belgium Brigham and Woman's Hospital Boston, MA, USA PYRI Alvaro A. Cruz, MD Federal University of Bahia LUineisvbeersthityDMuiejtsd,icMalDCMenStcerPhd CO Salvador, BA, Brazil J. Mark FitzGerald, MD Rotterdam, The Netherlands University of British Columbia J. Mark FitzGerald, MD Vancouver, BC, Canada University of British Columbia Vancouver, BC, Canada Hiromasa Inoue, MD Kagoshima University Louise Fleming, MBChB MD Kagoshima, Japan Royal Brompton Hospital London, United Kingdom Jerry A. Krishnan, MD PhD University of Illinois Hospital & Health Sciences System Hiromasa Inoue, MD Chicago, IL, USA Kagoshima University Kagoshima, Japan Mark L. Levy, MD Locum GP Deceased London, UK 8 Members of GINA Board (continued) GINA PROGRAM Jiangtao Lin, MD (to 2021) Rebecca Decker, BS, MSJ China-Japan Friendship Hospital Peking University Kristi Rurey, AS Beijing, China EDITORIAL ASSISTANCE Helen K. Reddel, MBBS PhD Woolcock Institute of Medical Research, University of Sydney Ruth Hadfield, BSc, DPhil, GCBiostat Jenni Harman, BVSc, BA Sydney, Australia Arzu Yorgancioglu, MD Celal Bayar University GRAPHICS ASSISTANCE Kate Chisnall Department of Pulmonology Manisa, Turkey ITNoFmOokRoMIcAhTikIaOwNa,DMESSIGUNTE GINA DISSEMINATION AND IMPLEMENTATION Hugh Musick, MBA TRIB COMMITTEE Institute for HealDthIcSare Delivery Design Mark L. Levy, MD (Chair) Locum GP University ofOIlRlinois, Chicago, USA PY London, UK Arzu Yorgancioglu, MD T CO Celal Bayar University NO Department of Pulmonology Manisa, Turkey - DO Alvaro A. Cruz, MD RIAL Federal University of Bahia Salvador, BA, Brazil ATE Louis-Philippe Boulet, MD ED M Universit Laval Qubec, QC, Canada Hiromasa Inoue, MD IGHT PYR Kagoshima University Kagoshima, Japan CO Jerry A. Krishnan, MD PhD University of Illinois Hospital & Health Sciences System Chicago, IL, USA Disclosures for members of GINA Board of Directors and Science Committee can be found at www.ginasthma.org 9 Methodology GINA SCIENCE COMMITTEE The GINA Science Committee was established in 2002 to review published research on asthma management and prevention, to evaluate the impact of this research on recommendations in GINA documents, and to provide yearly updates to these documents. The members are recognized leaders in asthma research and clinical practice with the scientific expertise to contribute to the task of the Committee. They are invited to serve for a limited period and in a voluntary capacity. The Committee is broadly representative of adult and pediatric disciplines as well as from diverse geographic regions. The Science Committee normally meets twice yearly in conjunction with the American Thoracic Society (ATS) and European Respiratory Society (ERS) international conferences, to review asthma-related scientific literature. During COVID-19, meetings of the Science Committee were held online each month. Statements of interest for Committee members are found on the GINA website www.ginasthma.org. PROCESSES FOR UPDATES AND REVISIONS OF THE GINA REPORT UTE Literature search TRIB A PubMed search is Science Committee. performed twice a The search terms iynecalurd, eeaacshthcmovae, rainllgagthees,porenvlyioiutesm1s8wmitohnathDbssI,Struascitnsg, filters established by the clinical trial or meta-analysis or systematic review, and human. The search is not limited to specific PICOTOqRuestions (Population, Intervention, Comparison, Outcomes, Time). The `clinical trial' publication trials, but also pragmatic, real-life and observational studies. tSyypseteinmcalutidcOersePvnYioetwosnilnyccluodnev,ebntuiot naarel randomized controlled not limited to, those conducted using GRADE methodology2 including, where relevant, gTuidCelines documents published by other international organizations. The respiratory community is also invited to submNit Oany other fully published peer-reviewed publications that they because believe should be considered, of the comprehensive process pforor vlitideirnagtutrheerfeuvlliepwa-,pDseuOrcish submitted in (or translated ad hoc submissions have into) English; however, rarely resulted in substantial changes to the report. Systematic reviews RIAL Unique among evidence-based recommendationAsTinE asthma, and most other therapeutic areas, GINA conducts an oonwgnoGinRgAtwDiEce-b-yaesaerdlyreuvpideawtse,obfetchaeuesveidoefnthcEeeDcbuaMrsreenfot rciotsstroefcosumcmherenvdiaetwiosn,st.hGe IlNarAgedoneusmnboetrcoafrrPyICoOutToqr uceomstimonisssitohnatits would be necessary for a comprehenIsGivHeTpractical report of this scope, and because it would limit the responsiveness of the GINA report to emerging Committee includes relevant esyvisPdteeYnmRcaeticanrdevnieewwsdceovnedloupcmteednwtsithin asthma GRADE management. However, the Science methodology as part of its normal review process, once such reviews CarOe published. GINA recommendations are constantly being reviewed and considered for update as new evidence (including GRADE-based systematic reviews on specific topics) is identified and indicates the need. Literature screening and review Each article identified by the literature search, after removal of duplicates and those already reviewed, is pre-screened in Covidence for relevance and major quality issues by the Editorial Assistant (a medical librarian) and by at least two nonconflicted members of the Science Committee. Each publication selected from screening is allocated to be reviewed for quality and for relevance to the GINA strategy by at least two members of the Science Committee, neither of whom may be an author (or co-author) or declare a conflict of interest in relation to the publication. Articles that have been accepted for publication and are online in advance of print are eligible for full text review provided the approved/corrected copyedited proof is available. All members receive a copy of all of the abstracts and full text publication, and non-conflicted members have the opportunity to provide comments during the pre-meeting review period. Members evaluate the abstract and the full text publication, and answer written questions in a review template about whether the scientific data impact on GINA recommendations, and if so, what specific changes should be made. In 2020, the CASP checklist was 10 Methodology provided in the review template to assist in evaluation of systematic reviews. A list of all publications reviewed by the Committee is posted on the GINA website (www.ginasthma.org). Discussion and decisions during Science Committee meetings Each publication that is assessed by at least one reviewer to potentially impact on the GINA report is discussed in a Science Committee meeting (virtual or face-to-face). This process comprises three parts, as follows: 1. Quality and relevance of original research and systematic review publications. First, the Committee considers the relevance of the publication to the GINA report, the quality of the study, the reliability of the findings and the interpretation of the results, based on the responses from reviewers and discussion by members of the Committee. For systematic reviews, GRADE assessments, if available, are taken into account. However, for any systematic review, GINA members also independently consider the clinical relevance of the question addressed by the review, and the scientific and clinical validity of the included populations and study design. During this discussion, an author (or member with a conflict) may be requested to provide clarification or respond to questions relating to the study, but they may not otherwise take part in this discussion about the quality and relevance of the publication.UTE f2in. dDiencgissiaofnfeacbt oGuItNiAncrleucsoiomnmofetnhdeaetiovindsenocr es.taDteumrinegnttshiasnpdhsahsoeu, ltdhebeCoinmclmuditetedeindethcTeidRGeIsIBNwAherethpeorrtt.hTehpeusbelicdaetcioisnioonrsittso mwiothdiafyctohneflricetpoofrtinotreirtessrteifsereexnccluedseadrefrommadtheebsye cdoencsiseinosnuss. Ibf ythCeocmhamirittiseeanmaeumtDhbIoeSrrsonpraespeunbtliacnadti,oangbaeinin,ganreyvmieewmedb,ear n alternative chair is appointed to lead the discussion in part 1 and the decisOioRn in part 2 for that publication. 3. Discussion about related changes to the GINA report. If the commOittPeYe resolves to include the publication or its findings in about and the report, an author or conflicted member, if decisions on changes to the report, including tphreespeonsOti,tTiiosnCpinegrmoiftttehde to take part in the subsequent discussions study findings in the report and the way tdhisact uthsesyiownsoumldaybetaiknetepglaracteedimwmitehdeiaxtisetliyn,go(roorvoetrhtehrenceowu)rDscOeomoNfptohneeynetsarofatshneeGwINeAvidmeanncaegeemmeerngtesstroarteagsyo. tThheer scehanges to the GINA report Board awrheoaegxre-oefdficaiondatitmenpdlemGIeNnAteSd.cTiehneceabCooIvAmeLmc-oitntefleicmt oefeitnintegrse.st considerations also apply to members of the As with all previous GINA reports, levels of evidTeEnRce are assigned to management recommendations where appropriate. A description of the current criteria is foundMinATable A (p.12), which was developed by the National Heart Lung and Blood Institute. From consistent pattern of 2019, finding GINA s in th h e apsoTpinEuclDalutdioendfoinr Evidence which the L r ev ec el A strong observational evidence that provides a ommendation is made and has also described the v a lues aanvodidpraemfebreignuciteysatbhaotuwt tehreeptaokseitinoRniInGintoHgaocfcoobusnetrivnamtioankainl gdamtaajaonrdneswysrteemcoamticmreenvdieawtiosn. s. The table was updated in 2021 to New therapies and indicatioOnPsY The GINA report is a globCal strategy document. Since regulatory approvals differ from country to country, and manufacturers do not necessarily make regulatory submissions in all countries, some GINA recommendations are likely to be off-label in some countries. This is a particular issue for pediatrics, where across different diseases, many treatment recommendations for pre-school children and for children aged 6-11 years are off-label. For new therapies, GINA's aim is to provide clinicians with evidence-based guidance about new therapies and their positioning in the overall asthma treatment strategy as soon as possible, as the gap between regulatory approval and the periodic update of many national guidelines is otherwise filled only by advertising or educational material produced by the manufacturer or distributor. For new therapies, the GINA Science Committee generally makes recommendations after approval for asthma by at least one major regulatory agency (e.g. European Medicines Agency or Food and Drug Administration), since regulators often receive substantially more safety and/or efficacy data on new medications than are available to GINA through peer-reviewed literature. However, decisions by GINA to make or not make a recommendation about any therapy, or about its use in any particular population, are based on the best available peerreviewed evidence and not on labeling directives from regulators. Methodology 11 Table A. Description of levels of evidence used in this report Evidence level Sources of evidence Definition A Randomized controlled Evidence is from endpoints of well designed RCTs, systematic reviews of relevant trials (RCTs), systematic studies or observational studies that provide a consistent pattern of findings in the reviews, observational population for which the recommendation is made. Category A requires substantial evidence. Rich body of numbers of studies involving substantial numbers of participants. data. B Randomized controlled Evidence is from endpoints of intervention studies that include only a limited trials and systematic number of patients, post hoc or subgroup analysis of RCTs or systematic reviews reviews. Limited body of data. othfesyuachreRsCmTasll. iInn sgizeen,etrhael,yCwaeteregournydBerptaekrteaninisn wahpeonpufUelawTtEioranntdhoamt dizifefedrtsrifarolsmexthiset, C Nonrandomized trials or target population Evidence is from noof nth-rearnedcoommimzeedntdraiatlisono,roorbtsheerTvreaRstIiuoBlntsalasretusdoiems.ewhat inconsistent. observational studies. DIS D Panel consensus This category is used only in cases wheOreRthe provision of some guidance was judgment. djuesetimfyepdlavcaelumaebnlet ibnuotntheeocf ltihneicaolthlietOerrPcaaYtuteregoardiedsre. sTshiengPtahneesl uCbojencstewnsaussinissubfafisceiednot nto clinical experience or knowledgTeCthat does not meet the above listed criteria. NO For existing therapies with evidence for new regimens or in- dDifOferent populations than are covered by existing regulatory labels, the Science dose macrolides in Committee and Board agreed moderate-severe asthma, that itnheMRCaIAyoLm20m1i8tt,eien the context may, where of new evidence for use of relevant, consider making long-term low recommendations that are not necessarily covereAdTEby regulatory indications in any country at the time, provided the Committee is satisfied with the available evidenMce around safety and efficacy/effectiveness. The same approach was afograminottearkoel nanind2ta0k1i9ngwIiCthSrewchoemnmeveenrdSatAioBnTAsEifDsortamkeildn asthma about treatment rather than regularly. with as-needed inhaled corticosteroid (ICS)- Since the GINA report represents a gIlGobHal strategy, the report does not refer to recommendations being `off-label'. However, readers are advised thPaYt Rwhen assessing and treating patients, they should use their own professional judgment doses. and should also takCeOinto account local and national guidelines and eligibility criteria, as well as licensed drug External review Prior to publication each year, the GINA report undergoes extensive external review by patient advocates and by asthma care experts from primary and specialist care in multiple countries. There is also continuous external review throughout the year in the form of feedback from end-users and stakeholders through the contact form on the GINA website. LITERATURE REVIEWED FOR GINA 2022 UPDATE The GINA report has been updated in 2022 following the routine twice-yearly review of the literature by the GINA Science Committee. The literature searches for `clinical trial' publication types (see above) and systematic reviews identified a total of 3,864 publications, of which 3,054 duplicates/animal studies/non-asthma/pilot studies and protocols were removed. 810 publications underwent screening in Covidence by at least two reviewers, and 663 were screened out for relevance and/or quality. A total of 147 publications underwent full-text review by at least two members of the 12 Methodology Science Committee (including 16 systematic reviews that had used GRADE methodology), and 76 publications were subsequently discussed at meetings of the Science Committee, which in 2021 were held virtually rather than face to face because of the COVID-19 pandemic. A list of key changes in GINA 2022 can be found starting on p.14, and a tracked changes copy of the report is archived on the GINA website at www.ginasthma.org/archived-reports/. FUTURE CHALLENGES In spite of laudable efforts to improve asthma care over the past 30 years, and the availability of effective medications, many patients globally have not benefited from advances in asthma treatment and often lack even the rudiments of care. Many of the world's population live in areas with inadequate medical facilities and meager financial resources. The GINA Board of Directors recognizes that `fixed' international guidelines and `rigid' scientific protocols will not work in many locations. Thus, the recommendations found in this report must be adapted to fit local practices and the availability of health care resources. Timopilmempreonvteedasntahtmioanaclalyreaannddlopcaatlileynatnoduticnotemgerast,eedviindteonhceea-bltahsseydsrteecmosmamnedncdliantiicoanlspmraucstitceaT.lEsIombpeledmisesnetamtiionnatreedquainreds an evidence-based strategy involving professional groups and socioeconomic conditions. A challenge for the GINA Board ostfaDkierehcotlodresrsfoarntdheconnesxitdRseeIrBivneUgralol cyaelacrsulitsurtaol and continue working with primary health care providers, public health officials and patient support oDrgIaSnTizations to design, implement, and evaluate asthma care programs to meet implementation of asthma management rleoccoaml nmeeednsdaintiovnasri,oeusspceocuianlltyrieins.pTOrihmReaBryocaardrecsoentttiinnugessatnodeixnadmeivneelobpairnrgiers to countries, GINA is a and to examine new partner organization and in a innovative approaches that program launched in March w20il0l e6OnbsPyuYrWe HthOe,dtheelivGerloyboafltAhelliabnecset possible asthma against Chronic care. Respiratory Diseases (GARD). Through the work of GINA, and inTcCooperation with GARD, substantial progress toward better care for all patients with asthma should be achieved inNthOe next decade. At the which most fundamental level, patients in many areas are the cornerstone of care for asthma patients od-foaDnllOostehvaevreitya. cMceosres even to broadly, low dose inhaled corticosteroids, medications remain the major contributor to the overall costs of asthma manageRmIeAnLt, so the access to and pricing of high quality asthma medications continues approach to to absethamn aistsrueeatomfeunrtgeinnat dnoeleedscaenndtsaAaTgnrEdowaidnugltasr,ewahoicfhreaslseoaracvhoiindtsertehset.c3oTnhseeqsuaefenscteasnodf most effective starting treatment with SABA on the alone, World depends on access Health Organization t(oWICHSOE-)DfeoMsrmseontetiraollmaecrdoicsisneasll asthma list, the severity levels.4 With budesonide-formoterol now fundamental changes to treatment of mild asthma first included in the 2019 very low dose treatment. GINA repIGorHt Tmay provide a feasible solution to reduce the risk of severe exacerbations with The urgent need to ensure acPcYeRss to affordable, quality-assured inhaled asthma medications as part of universal health ccoovllaebraograetimnguswt inthowthebeInpterCironOraittiizoendabl Uy nailol nreAlegvaainntststTaukbeehrocludleorssi,spaanrdticLuulanrglyDmisaenausfeasct(uIUreArsTLoDf r,e`TlehveanUtniniohna')letros.wGoIrNk A is towards a World Health Assembly Resolution on equitable access to affordable care, including inhaled medicines, for children, adolescents and adults with asthma. Methodology 13 What's new in GINA 2022? The GINA report has been updated in 2022 following the routine twice-yearly cumulative review of the literature by the GINA Scientific Committee. Full details of the changes can be found in the tracked version archived on the GINA website. In summary, the key changes are: GINA methodology: the description of the methodology used in preparing annual updates of the GINA report has been expanded and clarified, including that relevant GRADE-based reviews are included when available, and that the GINA report undergoes extensive external review prior to publication (p.10). Guidance about asthma and COVID-19 (p.17) has been updated. Further evidence confirms that patients with well- controlled mild to moderate asthma are not at increased risk of severe COVID-19, but the risk is higher in patients requiring oral corticosteroids (OCS) for their asthma and in hospitalized patients with severe asthma. Advice about aerosol-generating procedures has been updated. While use of an in-line filter minimizes the risk of transmission during spirometry, precautions are still needed since many patients cough after performing spirometry. Updated advice is provided about COVID-19 vaccinations (including boosters) and influenza vaccination. UTE Diagnosis of asthma: The flow-chart (Box diagnostic testing is different depending on 1-1, p.22) and text whether the patient have been is already omnocdoifnietrdoTltloeRreItBmrepahtmaseiznet, that and the approach to clarify the to considerations for testing. DIS aAsstthhmmaamdoiarbgindiotysiasnadnmdomrtaalnitaygisemexepnetriiennlcoewd-inanlodwm- aidnddlme-iidndcloe-minecocmouenctoOriueRnstr(ieLsM, IaCnsd):mTohset majority of the of this burden burden is of avoidable. Additional detail has been included about diagnosis (p.30) OanPdYmanagement (p.97) of asthma in low resource settings, where differential diagnoses tuberculosis and HIV/AIDS. Advice is provided often about itnrcelautdmeeennt doepTmtioiCcnsreisnpLirMatIoCr.yGdIisNeAassetrsonagnldy infections including supports the current initiatives working towards a World Health Assembly resolutionNoOn equitable access to affordable care for asthma. Assessment of symptom control: further details have b- eDeOn provided (p.34) about the rationale for the exclusion of use of as-needed ICS-formoterol relevant data to clarify this issue. >2 or In the m2etaimnteims ep,etrhIweAeLaevkefrraogme the assessment of symptom control. GINA is seeking frequency of use of as-needed ICS-formoterol should still be considered in treatment decisions. This rTelEieRver is already providing the patient with additional controller treatment, and higher use significantly reducMesAthe risk of severe exacerbations. The definition of mild discussion. The current adsetfhinmitiao:nTohfeasstTehcEmtDioansoenvearsittyhims abasseevderoitny (p.40) has been rewritten following extensive the concept of `difficulty to treat'. The definition of severe asthma is widely corresponding definition oafccmeipldteadRs,tIhGamnHdarieslemvuacnht for use in clinical practice. However, the utility and relevance of the less clear. Patients and clinicians often assume that `mild asthma' msyemapntsomnos.riGskINaAndprnooponseeesd hOfooPrldYcionngtraoslletarkterehaotlmdeerndt,isbcuutsuspiotno, 3to0%obotafinasathgmreaemdeeantthasbaoruet iwnhpeetohpelre/hwowith`miniflrdeqaustehnmt a' should be defined and useCd in future. In the meantime, GINA suggests that the term `mild asthma' should generally be avoided in clinical practice where possible, but if used, it should be qualified with a reminder about the risks of severe exacerbations and the need for ICS-containing treatment. GINA treatment figure for adults and adolescents (Box 3-5A): The rationale for showing two treatment tracks in this figure (p.61) has been reinforced: Track 1, with as-needed ICS-formoterol as reliever across treatment steps, is preferred based on evidence for lower risk of exacerbation and similar or better symptom control compared with using SABA as reliever (p.54). The figure has been updated to include anti-thymic stromal lymphopoietin (anti-TSLP) as a new biologic therapy for severe asthma in Step 5, and to point to the severe asthma guide for more detail. About Step 5 options. The `other controller options' have been clarified as those that either have specific indications or have less evidence for safety and/or efficacy than the treatments in Track 1 or Track 2. Steps 1-2: as-needed low-dose ICS-formoterol: Additional evidence has been added, including a systematic review showing significant reduction in ED visits/hospitalizations with as-needed ICS-formoterol compared with daily ICS plus as-needed SABA; greater reduction in severe exacerbations in adults and adolescents previously taking 14 Methodology SABA alone with as-needed ICS-formoterol compared with daily ICS plus as-needed SABA; similar findings in adolescents as adults; and additional safety data (p.64, p.66). Treatment figure for children 6-11 years (Box 3-5B): the figure (p.62) has been updated to explain the `other controller options' and to add anti-IL4R (dupilumab) to the Step 5 options for this age-group based on a randomized controlled trial. Maintenance OCS should be considered only as a last resort. Chromone pressurized metered dose inhalers have been discontinued globally: These medications have had little place in management of asthma in recent years, because of their lack of efficacy compared with even low-dose inhaled corticosteroids, and the burdensome requirements for inhaler maintenance (p.69). LAMAs should not be used as monotherapy (i.e. without ICS) in asthma: Just as LABA monotherapy is not safe in asthma, there is an increased risk of severe exacerbations in patients receiving LAMA without any ICS (p.66). Adding LAMA to ICS-LABA for adults and adolescents (Step 5): A meta-analysis of studies adding LAMA to ICS- LABA confirmed a modest increase in lung function, and a modest overall reduction in severe exacerbations, but without clinically important benefits for symptoms or quality of patients with persistent dyspnea. Patients with exacerbations dliefes.pEitveidICenSc-LeAdBoAessnhootuUsldTuEprepcoeritvaedadtinlegaLsAt mMeAdfiourm dose ICS-LABA before GINA Guide and considering add-on LAMA (p.72). decision tree for difficult-to-treat and severe asthma in adTuRltIsBand adolescents: The GINA Pocket Guide for assessment and management of difficult-to-treat and seveDreISasthma in adults and adolescents, has been revised and increased to full letter size. The decision tree itself, whOicRh is included in the GINA report as Boxes 3- 1A6ddAit-ioDn(aslttarretaintgmpe.n1t0o7p)t,iohnass (baesebneulopwd)ataerde tioncinlucdlueddeinanfotir-TpSatLiePnatsOswaPitYnhenwocelavsidseonfcbeioolfoTgyicpeth2erianpflyamfomr tahtiisonagoen-group. repeated testing. T C Investigations for patients with elevated blood eosinopNhOils: For patients with difficult-to-treat asthma and blood eosinophils 300/l, investigate therapy; Strongyloides infection fisoronftoenn-aasstyhmmpatocmauastie-csD(piOn.1c1lu4d)i.nFgotresptaintigenfotsr Strongyloides before considering with hypereosinophilia (e.g. blood biologic eosinophils 1500/l), causes such and anti-IL4R is preferably avoided as as seuocshinpoapthRieilIniActLsgrwaenrueloemxcaltuodseisdwfriothmptohleyaPnhgaiisties (EGPA) should be III studies (p.114). considered, Add-on anti-thymic stromal lymphopoieAtiTnE(anti-TSLP) for adults and adolescents: Tezepelumab is an add-on biologic therapy for patients exacerbations in those with haiggehdblo1o2EdDyeeoMasrisnowpithhilsseovrehreigahsFthemNaO, with the greatest benefit (p.119 and decision tree in reduction of severe p.109). A trial of anti-TSLP hoansrebpeeeanteadddteesdtintogt,hbeuot tphteiornesisIfGoinrHscTuofnfisciideenrtaetivoindeinncpeatinienthtsose12taykeinagrsmwahinotehnaavnecneoOeCvSide(Bncoex of Type 2 inflammation 3-16B, p.108). oAnddre-poenaatendti-teILs4tiRngfoarnaddruePqltuYsiRraenmdaaidntoelneasncceentOsC: fSo,r patients a trial of 12 years who have no evidence of Type 2 anti-IL4R has been added to the options for inflammation consideration (Box 3-16CBO, p.108). Add-on anti-IgE in pregnancy: Evidence about treatment of severe asthma in pregnancy is scarce, and the risks of biologic therapy in pregnancy need to be balanced against the risks for mother and baby from uncontrolled asthma. A registry study found no increased risk of congenital malformations with use of omalizumab in pregnancy (p.117). Add-on anti-IL4R for children 6 years: add-on dupilumab by SC injection has been approved for children 6 years with severe eosinophilic/Type 2 asthma (Box 3-5B, p.62 and Step 5, p.72). Add-on anti-IgE, anti-IL5/5R, anti-IL4R: results of systematic reviews and meta-analyses in patients with eosinophilic/Type 2 severe asthma have been included Consider maintenance OCS as last resort: Because of the risk of serious long-term adverse effects, maintenance OCS should be considered only as a last resort in any age-group if other treatments have been optimized and no alternative is available. Methodology 15  Written asthma action plans: The term `written' has been clarified as including printed, digital or pictorial plans. Give patients documented instructions about how to change their reliever and controller medications when their asthma worsens, and when to seek medical advice, rather than only verbal instructions (p.126). Management of wheezing episodes in pre-school children: In children 5 years with intermittent viral wheezing and no or few interval respiratory symptoms, consideration of intermittent short course ICS has been added to the treatment figure (Box 6-5, p.165) for consistency with the existing text. Because of the risk of side-effects, this treatment should only be considered if the physician is confident that it will be used appropriately. Management of acute asthma in healthcare settings: At present, salbutamol (albuterol) is the usual bronchodilator in acute asthma management. Several emergency department studies of formoterol and one study of budesonideformoterol have shown similar safety and efficacy as salbutamol (p.133); more primary care and emergency department studies with ICS-formoterol are needed. Other changes include the following: o o Use of e-cigarettes is associated Air filters can reduce fine particle with an increased risk exposure, but there is of respiratory no consistent seyffmecpttoomn sasatnhdmUaasTotEhumtcaomexeasc(epr.b8a5t)ions (p.81) o Updated evidence about the association between air pollution and urgent healthTcRaIrBe utilization for asthma (p.85) o Electronic inhaler monitoring can identify poor adherence in patients with difDficISult-to-treat asthma (p.89) o eInospiantoiepnhtislswainthduhnigcohentrrFoleleNdOsyamrepatosmsoscdiaetsepditweitmhegdreiuamtetrorihsikgho-fdsoesveerIeCOSeRx-caocnetrabiantiniognstre(pa.t1m1e4n)t, higher blood o A reminder that patients admitted to hospital for an asthma exacerObaPtYion should continue on, or be prescribed, ICS-containing therapy (p.136). Topics to be addressed in future GINA reports: NOT C Review of these topics was delayed during 2021 due to the - CDOOVID-19 pandemic. Einvcidheilndcreeninwcillul dbeedreinvitehweeEdudrouprienagn2R02e2spwirhaetonrythSeoficnIieAatlLyfuglul pidueblilniceastiofonr diagnosis of is available. asthma in adults/adolescents and Recommendations about the definition of mild aTsEthRma, and references to mild asthma, will be updated following the proposed stakeholder discussion describedMonAp.40. EGvINidAenisceseoenksinugbceuvtiadneencoeusrealellevragnetntoimtThmEeuDansostehsesrampeyn(tSoCf IsTy)mapntdomsucbolinntgroulailnimpamtiuennotsthwerhaopsye(rSeLliIeTv)efroirspIaCtSie-nfotsrmwoittherol asthma is under review. IGH Chapter 6, diagnosis, assessmPYenRt and management of asthma in children 5 years and younger, is under review. A pocket guide on managCemOent of severe asthma in children 6-11 years is in development. The use of digital tools and communication in asthma management Advice about COVID-19 will be updated on the GINA website in a timely manner as relevant new information becomes available. NOTE: minor edits 30 June 2022 Page 118: in the eligibility criteria for anti-IL4R (dupilumab), the example of blood eosinophil count for dupilumab treatment has been updated to "150 to 1500 cells/L", for consistency with the example in the decision tree. The dupilumab regimens for children have been clarified as "with dose and frequency depending on weight". As for all medications, particularly biologic therapies for severe asthma, clinicians should check local regulatory and payer criteria since they may vary from the examples given. Footnotes have been added in the section on biologic therapies to further emphasize this. 16 Methodology Advice on asthma management during the COVID-19 pandemic COVID-19 and asthma People with asthma do not appear to be at increased risk of acquiring COVID-19, and systematic reviews have not shown an increased risk of severe COVID-19 in people with well-controlled mild to moderate asthma. Overall, studies to date indicate that people with well-controlled asthma are not at increased risk of COVID-19-related death,5,6 and in one meta-analysis, mortality appeared to be lower than in people without asthma.7 However, the risk of COVID-19 death was increased in people who had recently needed oral corticosteroids (OCS) for their asthma,5,8 and in hospitalized patients with severe asthma.9 Therefore, it is important to continue good asthma management (as described in the GINA report), with strategies to maintain good symptom control, reduce the risk of severe OCS. In one study of hospitalized patients aged 50 years with COVID-19, mexoartcaelirtbyawtiaosnslToaEwnedr minimize the need among those with for asthma who were using inhaled corticosteroid (ICS) than in patients without an undeRrlIyBinUg respiratory condition.9 In 2020, many countries saw precisely known, but may be daureedtouchtaionndwinaasshtihnmg,ameaxsakcserabnadtiosonsciaaln/pdhiynsfliuceanl zdDais-ItSraeTnlactiendg illness. The reasons are not that reduced the incidence of other respiratory infections, including influenza.10 OR Advise patients with asthma to continue taking their prescribed aOstPhYma medications, particularly inhaled corticosteroid (ICS)-containing medications, and oral corticosTteCroids (OCS) if prescribed pItaisndimempoicrt.aTnhtisfoirnpcalutideenstsICtoSc-coonntitnauineintagkminegdtihceaitriopnrses(carloibneedoaNrsiOtnhmcoammbeindaictiaotniownisthaas usual during the long-acting beta COVID-19 -agonist [LABA]), and add-on therapy including biologic therapy for severe- aDsOthma. Stopping ICS often leads to 2 potentially dangerous wphoarsrmenaicnogloogf iacsstthrmatae.gSieese, aCnhdaCpthearp3tBer(3pC.51(p).f8o8r)infRoforIArgmLuaidtieodn aasbtohumt aasstehlmf-ma amneadgiecmateionntseadnudcarteiognimaenndssaknildlsntroanin- ing. For a small proportion of patients with severeAaTstEhma, long-term OCS may sometimes be needed, and it is very dtoa-ntrgeeartoaunsdtosesvtoeprethaessthemsau,didnecnlulyd.inSgeaedECdDhitaioMpnteorf 3E (p.104) for advice about investigation and biologic therapy for minimizing use of OCS. management of difficult- Advise patients to discuss with youIGbHeTfore stopping any asthma medication. Make sure that all patients haPvYeRa written asthma action plan A written action plan (prinCteOd, digital or pictorial) tells the patient how to recognize worsening asthma, how to increase their reliever and controller medications, and when to seek medical help. A short course of OCS may be needed during severe asthma flare-ups (exacerbations). See Box 4-2 (p.129) for more information about specific action plan options for increasing both controller and reliever medications, depending on the patient's usual therapeutic regimen. At present, there is no clear evidence about how to distinguish between worsening asthma due to respiratory viral infections such as rhinovirus and influenza, and COVID-19. When COVID-19 is confirmed or suspected, or local risk is moderate or high, avoid use of nebulizers where possible due to the risk of transmitting infection to other patients/family and to healthcare workers Nebulizers can transmit respiratory viral particles for at least 1 meter. Use of nebulizers for delivering bronchodilator therapy is mainly restricted to management of life-threatening asthma in acute care settings. Instead, to deliver shortacting beta2-agonist for acute asthma in adults and children, use a pressurized metered-dose inhaler and spacer, with a mouthpiece or tightly fitting face mask, if required. Check the manufacturer's instructions about whether a spacer can be autoclaved. If not (as is the case for many types of spacers), or if in doubt, spacers should be restricted to single patient Advice about COVID-19 and asthma 17 use. If use of a nebulizer is needed in settings where COVID-19 infection is possible, strict infection control procedures should be followed. Remind patients not to share inhaler devices or spacers with family members, to avoid transmitting infection. Avoid spirometry in patients with confirmed/suspected COVID-19 In healthcare facilities, follow local COVID-19 testing recommendations and infection control procedures if spirometry or peak flow measurement is needed.11 Use of an in-line filter minimizes the risk of transmission during spirometry, but many patients cough after performing spirometry; before performing spirometry, coach the patient to stay on the mouthpiece if they feel the need to cough. The U.S. Centers for Disease Control and Prevention (CDC) recommendations are found here. If spirometry is not available due to local infection control restrictions, and information about lung function is needed, consider asking patients to monitor lung function at home. Follow infection control recommendations if other aerosol-generating procedures are UneTeEded Other aerosol-generating procedures include oxygen therapy (including with nasal proTnRgsIB), sputum induction, manual vaebnotuiltahtiyogni,ennoens-tinravtaesgivieesvaenndtiluastieonofapnedrsinotnuablaptiroonte. cCtiDveC ereqcuoipmmmeennt,daastionneswainrefofromuDanItdSiohnebree.cFomolleoswalvoacialal bhleeailnthyaoduvr ice country or region. OR The CDC website provides up-to-date information about COVID-19 for hOeaPlYth professionals here, and for patients here. The website of the World Health Organization (WHO) provides compTreChensive advice for health professionals and health systems about prevention and management of COVID-19NhOere. Asthma and COVID-19 vaccines - DO Many types people with of COVID-19 vaccines have been asthma, will emerge over time. In studied general, aIaAnllLderagrice in use. New reactions to evidence about the vaccines, including in the vaccines are rare. Patients with a history of severe allergic reaction to a COVID-19 vaccineTinEgRredient (e.g. polyethylene glycol for Pfizer/BioNTech or Moderna, or polysorbate anaphylaxis to 80 for foods, AinsstreacZt evneencoamo,roJr&oJth/JearnmsMseedAnic)astihoonusldcarencseaivfeelya different COVID-19 vaccine. receive COVID-19 vaccines. However, people More details from with the U.S. Advisory Committee on ImmunizatioTnEPDractices (ACIP) are here. As always, patients should speak to their healthcare provider if they have concIeGrnHs. Follow local advice about monitoring patients after COVID-19 vaccination. Usual vaccine vaccine, and if pthreecpaauttiieonntshaapspalyPf.eYFvRoerr example, ask if the patient or another infection, delay has a history of allergy to vaccination until they are any components well. of the At present, based on the benCeOfits and risks, and with the above caution, GINA recommends people with asthma should be up to date with COVID-19 vaccination, including booster doses if available For people with severe asthma, GINA suggests that, if possible, the first dose of biologic therapy and COVID-19 vaccine should not be given on the same day, to allow adverse effects of either to be more easily distinguished. Remind people with asthma to have an annual influenza vaccination (p.78). CDC (advice here) now advises that influenza vaccine and COVID-19 vaccine can be given on the same day. Current advice from the CDC is that where there is substantial transmission of COVID-19, people will be better protected, even if they are fully vaccinated, if they wear a mask in indoor public settings. Further details are here. Additional advice about management of asthma in the context of COVID-19 will be posted on the GINA website (www.ginasthma.org) as it becomes available. Global Initiative for Asthma, April 30, 2022 18 Advice about COVID-19 and asthma SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER IBUTE DISTR Y OR Chapter 1. COP T NO O Definition, IAL - D description, and diagnosis MATER of asthma GHTED PYRI CO KEY POINTS What is asthma? Asthma is a heterogeneous disease, usually characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms, such as wheeze, shortness of breath, chest tightness and cough, that vary over time and in intensity, together with variable expiratory airflow limitation. Airflow limitation may later become persistent. Asthma is usually associated with airway hyperresponsiveness and airway inflammation, but these are not necessary or sufficient to make the diagnosis. Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called `asthma phenotypes'; however, these do not correlate strongly with specific pathological processes or treatment responses. How is asthma diagnosed? The diagnosis of asthma is based on the history of characteristic symptom patternUs TaEnd evidence of variable expiratory airflow limitation. This should be documented from bronchodilator TreRvIeBrsibility testing or other tests. Test before treating, controller treatment, wherever possible, i.e. document the evidence for as it is often more difficult to confirm the diagnosis tahDfeteISdrwiaagrndoss. is of asthma before starting Additional or alternative strategies may be needed to confirm the diaOgnRosis of asthma in particular populations, including patients already on controller treatment, the elderly,CaOndPYthose in low-resource settings. DEFINITION OF ASTHMA NOT Aofsrtehmspairaistoaryhestyemropgtoemneso, ussucdhisaesasweh,eueszuea,llsyhcohrtanreascsteorifzb-erdDeaObythc, hcrhoensict taigirhwtnaeysisnfalanmd mcoautigohn,. It is that defined by the vary over time history and in intensity, together with variable expiratory airflow liRmIiAtaLtion. This definition was reached by consensus, basedAaTotEndcisotinnsgiduiesrhatiitofnroomf the characteristics that are typical of asthma other respiratory conditions. However, airflow before controller treatment is commenced, andMth limitation may become persistent later in thEeDcourse of the disease. DESCRIPTION OF ASTHMA IGHT Asthma Chapter is a common, 1). Asthma is cchhraornaicctererPiszpYeidRrabtoyrvyadriiasebalesesyamffpetcotmings 1-18% of the population in different countries (Appendix of wheeze, shortness of breath, chest tightness and/or cough, and by variable expiraCtOory airflow limitation. Both symptoms and airflow limitation characteristically vary over time and in intensity. These variations are often triggered by factors such as exercise, allergen or irritant exposure, change in weather, or viral respiratory infections. Symptoms and airflow limitation may resolve spontaneously or in response to medication, and may sometimes be absent for weeks or months at a time. On the other hand, patients can experience episodic flare-ups (exacerbations) of asthma that may be life-threatening and carry a significant burden to patients and the community (Appendix Chapter 1). Asthma is usually associated with airway hyperresponsiveness to direct or indirect stimuli, and with chronic airway inflammation. These features usually persist, even when symptoms are absent or lung function is normal, but may normalize with treatment. Asthma phenotypes Asthma is a heterogeneous disease, with different underlying disease processes. Recognizable clusters of demographic, clinical and/or pathophysiological characteristics are often called `asthma phenotypes'.12-14 In patients with more severe asthma, some phenotype-guided treatments are available. However, no strong relationship has been found 20 1. Definition, description and diagnosis of asthma between specific pathological features and particular clinical patterns or treatment responses. More research is needed to understand the clinical utility of phenotypic classification in asthma. Many clinical phenotypes of asthma have been identified.12-14 Some of the most common are: Allergic asthma: this is the most easily recognized asthma phenotype, which often commences in childhood and is associated with a past and/or family history of allergic disease such as eczema, allergic rhinitis, or food or drug allergy. Examination of the induced sputum of these patients before treatment often reveals eosinophilic airway inflammation. Patients with this asthma phenotype usually respond well to inhaled corticosteroid (ICS) treatment. Non-allergic asthma: some patients have asthma that is not associated with allergy. The cellular profile of the sputum of these patients may be neutrophilic, eosinophilic or contain only a few inflammatory cells (paucigranulocytic). Patients with non-allergic asthma often demonstrate less short-term response to ICS. Adult-onset (late-onset) asthma: some adults, particularly women, present with asthma for the first time in adult life. These patients tend to be non-allergic, and often require higher doses of ICS or are relatively refractory to corticosteroid treatment. Occupational asthma (i.e. asthma due to exposures at work) should be ruled out in patients presenting with adult-onset asthma. Asthma with persistent airflow limitation: some patients with long-standing asthma deUvTeElop airflow limitation that is persistent or incompletely reversible. This is thought to be due to airway wall reTmRoIdBeling. Asthma with obesity: airway inflammation. some obese patients with asthma have prominent resDpiIrSatory symptoms and little eosinophilic There are limited data about the natural history of asthma after diagnosis, ObuRt one longitudinal study showed that approximately 16% of adults with recently diagnosed asthma may exOpePrYience clinical remission (no symptoms or asthma medication for at least 1 year) within 5 years.15 T C Additional information can be found in Appendix Chapter and in Appendix Chapter 3 about pathophysiological and 2ceallbuNolaOurt factors predisposing to the mechanisms of asthma. development of asthma, - DO MAKING Making THE INITIAL the diagnosis DIAGNOSIS of asthma in a patient not onRcIAoLntroller treatment, as shown in Box 1-1 (p.22) is based on identifying both a characteristic pattern of resApiTraEtory symptoms such as wheezing, shortness of breath (dyspnea), chest tsigymhtpnteosmssormcaoyubgeh,daunedtovaarciaubteleoerxcphirraotEnoiDrcycMaoirnfdloitwiolnims iotathtieornt.h16aTnhaestphamttaer(nseoef sByomxp1to-3m(sp.is27im).pIfoprtoasnst,ibales,rtehsepeirvaitdoerynce sthuaptpaorretincghaaradciategrnisotsicisoof faassththmmaamI(GBaHyoxTim1p-2ro, vpe.2s3p)osnhtoaunledobueslydoocruwmitehnttreedatwmheennt;thaes patient first presents, as the features a result, it is often more difficult to confirm a diagnosis of asthmPa YoRnce the patient has been started on controller treatment. Patterns of respiratory syCmOptoms that are characteristic of asthma The following features are typical of asthma and, if present, increase the probability that the patient has asthma:16 Respiratory symptoms of wheeze, shortness of breath, cough and/or chest tightness: Patients (especially adults) experience more than one of these types of symptoms. Symptoms are often worse at night or in the early morning. Symptoms vary over time and in intensity. Symptoms are triggered by viral infections (colds), exercise, allergen exposure, changes in weather, laughter, or irritants such as car exhaust fumes, smoke or strong smells. The following features decrease the probability that respiratory symptoms are due to asthma: Isolated cough with no other respiratory symptoms (see p.28) Chronic production of sputum Shortness of breath associated with dizziness, light-headedness or peripheral tingling (paresthesia) Chest pain Exercise-induced dyspnea with noisy inspiration. 1. Definition, description and diagnosis of asthma 21 Box 1-1. Diagnostic flowchart for clinical practice IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO ICS: inhaled corticosteroids; PEF: peak expiratory flow (highest of three readings). When measuring PEF, use the same meter each time as the value may vary by up to 20% between different meters; prn: as-needed; SABA: short-acting beta2-agonist. Bronchodilator responsiveness (reversibility) may be lost during severe exacerbations or viral infections, and in long-standing asthma, and it usually decreases with inhaled corticosteroid treatment. If bronchodilator responsiveness is not found at initial presentation, the next step depends on the availability of tests and the clinical urgency of need for treatment. 22 1. Definition, description and diagnosis of asthma Box 1-2. Diagnostic criteria for asthma in adults, adolescents, and children 6-11 years 1. HISTORY OF VARIABLE RESPIRATORY SYMPTOMS Feature Symptoms or features that support the diagnosis of asthma Wheeze, shortness of breath, chest tightness and cough (Descriptors may vary between cultures and by age) More than one type of respiratory symptom (in adults, isolated cough is seldom due to asthma) Symptoms occur variably over time and vary in intensity Symptoms are often worse at night or on waking Symptoms are often triggered by exercise, laughter, allergens, cold air Symptoms often appear or worsen with viral infections 2. CONFIRMED VARIABLE EXPIRATORY AIRFLOW LIMITATION Feature 2.1 Documented* expiratory Considerations, definitions, criteria At a time when FEV is reduced, confirm that FEV /FUVTCEis reduced compared with airflow limitation the lower limit of 1 normal (it is usually >0.75-0.80TRin1IBadults, >0.90 in children17) AND DIS 2.2 Documented* excessive variability in lung function* Tcohnefigdreenattethrethdeiavganroiastiiso.nIsf,inoirtitahlley mneogrYeatOoivcRec,atseisotnssceaxncbeessrevpaeriaatteiodndiusrsinegensy, mthpetommosre (one or more of the following): or in the early morning. COP Positive bronchodilator (BD) responsiveness (reversibility) Adults: increase >15% and >400 minLF).ECVh1 ioldfNr>eO1nT2: %incarenads>e2i0n0FmEVL1(gorfe>a1te2r%copnrefiddiecntecde if increase is test Meqeuaivsaulreenct,hcaonmgepa1r0e-d-1Dw5Oitmhinpurete-BsDafrteerad2i0n0g-s4. 0P0osmitcivgestaelsbtumtaomreolli(kaelblyuitfeBroDl) woirthheld before test: SARBAIAL4 hours, twice-daily LABA 24 hours, once-daily LABA 36 hours Excessive variability in twicedaily PEF over 2 weeks ACdhuildltsre: na:vaeAvrTaegEraegdeadilayildyiudrinuarnl aPlEPFEvFavriaarbiailbityilit>y1>01%3*%* Significant increase in lung function after 4 weeks of aAfHdteuTrlEt4sD:winMecerkesasoef tirneFatEmVe1nbt,yo>u1ts2i%dearnedsp>i2ra0t0ormy Lin(feocr tPioEnFs by >20%) from baseline anti-inflammatory Positive exercise treatment challenge tesYtRIGAdults: fall in FEV of >10% and >200 mL from baseline P 1 CO Children: fall in FEV1 of >12% predicted, or PEF >15% Positive bronchial challenge test Fall in FEV1 from baseline of 20% with standard doses of methacholine, or 15% (usually only for adults) with standardized hyperventilation, hypertonic saline or mannitol challenge Excessive variation in lung function between visits (good specificity but poor sensitivity) Adults: variation in FEV1 of >12% and >200 mL between visits, outside of respiratory infections Children: variation in FEV1 of >12% in FEV1 or >15% in PEF between visits (may include respiratory infections) BD: bronchodilator (SABA or rapid-acting LABA); FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid; LABA: long-acting beta2agonist; PEF: peak expiratory flow (highest of three readings); SABA: short-acting beta2-agonist. See Box 1-3 (p.26) for how to confirm the diagnosis in patients already taking controller treatment. *Daily diurnal PEF variability is calculated from twice daily PEF as (day's highest minus day's lowest) divided by (mean of day's highest and lowest), averaged over one week. For PEF, use the same meter each time, as PEF may vary by up to 20% between different meters. BD responsiveness may be lost during severe exacerbations or viral infections,18 and airflow limitation may become persistent over time. If reversibility is not present at initial presentation, the next step depends on the availability of other tests and the urgency of the need for treatment. In a situation of clinical urgency, asthma treatment may be commenced and diagnostic testing arranged within the next few weeks (Box 1-4, p.27), but other conditions that can mimic asthma (Box 1-5) should be considered, and the diagnosis confirmed as soon as possible. 1. Definition, description and diagnosis of asthma 23 Why is it important to confirm the diagnosis of asthma? This is important to avoid unnecessary treatment or over-treatment, and to avoid missing other important diagnoses. In adults with an asthma diagnosis in the last 5 years, one-third could not be confirmed as having asthma after repeated testing over 12 months and staged withdrawal of controller treatment. The diagnosis of asthma was less likely to be confirmed in patients who had not had lung function testing performed at the time of initial diagnosis. Some patients (2%) had serious cardiorespiratory conditions that had been misdiagnosed as asthma.19 History and family history Commencement of respiratory symptoms in childhood, a history of allergic rhinitis or eczema, or a family history of asthma or allergy, increases the probability that the respiratory symptoms are due to asthma. However, these features are not specific for asthma and are not seen in all asthma phenotypes. Patients with allergic rhinitis or atopic dermatitis should be asked specifically about respiratory symptoms. Physical examination UTE Physical (rhonchi) examination in people with asthma is often on auscultation, but this may be absent or onnolrymhael.aTrdheonmfoosrct efrdeqeuxpeinrat taiobnn.oWrTmRhaeIlBietyziinsgemxpaiyraatolsroy wheezing be absent during severe asthma exacerbations, due to severely reduced airflow (so called `sDileISnt chest'), but at such times, other pohbysstriuccatliosnig,ncshroofnriecsopbirsattrourcytifvaeilupruelmaroenausryuadlilsyeparseese(CnOt. PWDh)e, erezsinpgiramtoaryyainlsfoecbtOeioRnhes,atrrdacwhitehoimndaulaccibiale, laryngeal or inhaled foreign body. Crackles (crepitations) and inspiratory wheezing are not features OofPaYsthma. Examination of the nose may reveal signs of allergic rhinitis or nasal polyposis. T C Lung function testing to document variable expiratory airflowNliOmitation Asthma is characterized by variable expiratory airflow limita-tDioOn, i.e. expiratory lung function varies over time and in magnitude, normal and to a greater extent than in severely obstructed in the hsaeamltehypaptoiepnutl.aPRtiooIAonsLrl.yIcnoanstrthomllead, lung function may vary between completely asthma is associated with greater variability in lung function than well-controlled asthma.18 ATE Lung function testing equipment,20 with an should be inline filter ctoarprireodteocut taEbgDyaiMwnsetllt-rtaranisnmedisosipoenraotfoirnsfewcittihonw.e11llF-moracinetdaienxepdiraantodryrevgoululamrley calibrated in 1 second e(FaEcVh 1t)imfreo,masspmireoamseutrreymisemntosrme areylidaibfIflGeerHtfhrTaonmpmeaekteer xtopimraetoteryr flow (PEF). If PEF by up to 20%.21 is used, the same meter should be used A reduced FEV1 may be found wPitYhRmany other lung diseases (or poor spirometric technique), but a reduced ratio of FEV1 Many tsopfiororcmeedtevristanl ocawpiancciltuydC(eFOEmVu1l/tFi-eVtChn),iccoamgep-asrpeedcwifiicthptrheediclotwedervlaimluiet so.f17normal, indicates expiratory airflow limitation. In clinical practice, once an obstructive defect has been confirmed, variation in airflow limitation is generally assessed from variation in FEV1 or PEF. `Variability' refers to improvement and/or deterioration in symptoms and lung function. Excessive variability may be identified over the course of one day (diurnal variability), from day to day, from visit to visit, or seasonally, or from a reversibility test. `Reversibility' (now called `responsiveness')20 generally refers to rapid improvements in FEV1 (or PEF), measured within minutes after inhalation of a rapid-acting bronchodilator such as 200-400 mcg salbutamol,22 or more sustained improvement over days or weeks after the introduction of effective controller treatment such as ICS.22 In a patient with typical respiratory symptoms, obtaining evidence of excessive variability in expiratory lung function is an essential component of the diagnosis of asthma. Some specific examples are: An increase in lung function after administration of a bronchodilator, or after a trial of controller treatment A decrease in lung function after exercise or during a bronchial provocation test Variation in lung function beyond the normal range when it is repeated over time, either on separate visits, or on home monitoring over at least 1-2 weeks 24 1. Definition, description and diagnosis of asthma Specific criteria for demonstrating excessive variability in expiratory lung function are listed in Box 1-2 (p.23). A decrease in lung function during a respiratory infection, while commonly seen in asthma, does not necessarily indicate that a person has asthma, as it may also be seen in otherwise healthy individuals or people with COPD. Additional information about tests for diagnosis of asthma can be found in Appendix Chapter 4. How much variation in expiratory airflow is consistent with asthma? There is overlap in bronchodilator reversibility and other measures of variation between health and disease.23 In a patient with respiratory symptoms, the greater the variations in their lung function, or the more times excess variation is seen, the more likely the diagnosis is to be asthma (Box 1-2, p.23). Generally, in adults with respiratory symptoms typical of asthma, an increase or decrease in FEV1 of >12% and >200 mL from baseline, or (if spirometry is not available) a change in PEF of at least 20%, is accepted as being consistent with asthma. Diurnal PEF variability is calculated from twice daily readings as the daily amplitude percent mean, i.e. ([Day's highest - day's lowest]/mean of day's highest and lowest) x weeks. The upper 95% confidence limit of diurnal 100, then variability the average of each day's (amplitude percent mean) fvroaTmluEetwisicceadlcauillyatreedadoivnegrs1i-s29% in healthy adults,24 and 12.3% is regarded as excessive. in healthy children,25 so in general, diurnal variability >1R0I%BUfor adults and >13% for children If FEV1 is within the predicted normal range when the patient is experiencing sDymISpTtoms, this reduces the probability that timheposyrtmanpttoinmcsreaarseedinuelutnogafsutnhcmtiao.nHwoiwthebvreorn, cphaotideinlatstowr hoor sceonbtaroslelelirnetreFaEtmV1eOnisRt.>P8r0e%dicptreeddincotermd aclarnanhgaeves a clinically (especially for PEF) have limitations, so the patient's own best reading (`personal beOsPt'Y) is recommended as their `normal' value. When can variable expiratory airflow limitation be documentedT?C If possible, evidence of variable expiratory airflow limitation shNoOuld be documented before treatment is started. This is because variability usually decreases with function after initiating controller treatment ICS can threelaptmtoecn-otDnafOsirmlunthgefudniacgtionnosimis porfoavsetsh.mIna.aBdrdoitniocnh,oadnilyationrcrreesapsoeninsivluenngess may not be present previous few hours; baentdwienesnosmyemppatotimenst,sd, uariirnflgowvirRlaimIlAiintLafetioctniomnsayorbeifctohempeapteiernstishteanstuosreidrreavbeerstaib2l-eagoovneirsttimwieth. in the If spirometry is not available, or variable expirAaTtoEry airflow limitation is not documented, a decision about whether to investigate further or start controller 1-3 (p.27) describes how to confirm tthreeaEdtDmiaegMnntoismismoefdaiasttehlmy adeinpeanpdastioenntcalilnreicaadl yurtgaekinncgycaonndtraocllecrestrseatotmoethnet.r tests. Box Other tests IGHT Bronchial provocation tests PYR One option for documentiCngOvariable expiratory airflow limitation is to refer the patient for bronchial provocation testing to assess airway hyperresponsiveness. Challenge agents include inhaled methacholine,26 histamine, exercise, 27 eucapnic voluntary hyperventilation or inhaled mannitol. These tests are moderately sensitive for a diagnosis of asthma but have limited specificity.26,27 For example, airway hyperresponsiveness to inhaled methacholine has been described in patients with allergic rhinitis,28 cystic fibrosis,29 bronchopulmonary dysplasia30 and COPD.31 This means that a negative test in a patient not taking ICS can help to exclude asthma, but a positive test does not always mean that a patient has asthma - the pattern of symptoms (Box 1-2, p.23) and other clinical features (Box 1-3, p.26) must also be considered. Allergy tests The presence of atopy increases the probability that a patient with respiratory symptoms has allergic asthma, but this is not specific for asthma nor is it present in all asthma phenotypes. Atopic status can be identified by skin prick testing or by measuring the level of specific immunoglobulin E (sIgE) in serum. Skin prick testing with common environmental allergens is simple and rapid to perform and, when performed by an experienced tester with standardized extracts, is inexpensive and has a high sensitivity. Measurement of sIgE is no more reliable than skin tests and is more expensive, but may be preferred for uncooperative patients, those with widespread skin disease, or if the history suggests a risk of 1. Definition, description and diagnosis of asthma 25 anaphylaxis.32 The presence of a positive skin test or positive sIgE, however, does not mean that the allergen is causing symptoms - the relevance of allergen exposure and its relation to symptoms must be confirmed by the patient's history. Does exhaled nitric oxide have a role in the diagnosis of asthma? The fractional concentration of exhaled nitric oxide (FeNO) is modestly associated with levels of sputum and blood eosinophils.33 FeNO has not been established as useful for ruling in or ruling out a diagnosis of asthma, as defined on p.20, because while FeNO is higher in asthma that is characterized by Type 2 airway inflammation,34 it is also elevated in non-asthma conditions (e.g. eosinophilic bronchitis, atopy, allergic rhinitis, eczema), and it is not elevated in some asthma phenotypes (e.g. neutrophilic asthma). FeNO is lower in smokers and during bronchoconstriction35 and the early phases of allergic response;36 it may be increased or decreased during viral respiratory infections.35 See Chapter 3B, p.53 for discussion about FeNO in the context of decisions about initial asthma treatment. CONFIRMING THE DIAGNOSIS OF ASTHMA IN PATIENTS ALREADY TAKING CONTROLLER TREATMENT If the basis of a patient's should be sought. Many diagnosis of asthma has patients (25-35%) with a ndoiatgpnroesviisouosflyasbtehemnadinocpurmimeanrtyedca, rceoncfairnmnUaoTttiEobne with objective confirmed as testing having asthma.19,37-40 TRIB The and process for confirming lung function (Box 1-3, the diagnosis in patients p.26). In some patients, tahlirseamdayyoinnccluodnetroallterriatlreoaf temitehneDrtISdaelpowenedrsorona the patient's higher dose symptoms of controller treatment. If the diagnosis of asthma cannot be confirmed, refer the patient foOr eRxpert investigation and diagnosis. For some patients, The process is it may be necessary to step described in Box 1-4, p.27. down the controller treatmenOt PinYorder to confirm the diagnosis of asthma. Box 1-3. Steps for confirming the diagnosis of asthma in a patOieTntCalready taking controller treatment Current status Steps toOcNonfirm the diagnosis of asthma Variable respiratory Diagnosis of asthma is confirmedL.-ADssess the level of asthma control (Box 2-2, p.36) and review symptoms and variable airflow limitation controller treatment (Box 3-E5R, pIA.61). Variable respiratory Consider repeating spMiroAmTetry after withholding BD (4 hrs for SABA, 24 hrs for twice-daily ICS- symptoms but no variable airflow LABA, FEV1, a3n6dhrbsrofonrcThoonEdcDeila-dtoari ly ICS-LABA) or responsiveness during . If still symptoms. Check between-visit normal, consider other diagnose v s ariab (Box ility of 1-5, p .27). limitation If FEV1 is >7I0G%Hpredicted: consider stepping down controller treatment (see Box 1-5) and reassesPsYinR2-4 weeks, then consider bronchial provocation test or repeating BD responsiveness. IrfeFaEsCsVeO1siss <70% predicted: consider stepping up controller treatment for symptoms and lung function. If no response, resume previous 3 months treatment (Box 3-5), and refer then patient for diagnosis and investigation. Few respiratory symptoms, normal lung function, and no variable airflow limitation Consider repeating BD responsiveness test again after withholding BD as above or during symptoms. If normal, consider alternative diagnoses (Box 1-5, p.27). Consider stepping down controller treatment (see Box 1-5): If symptoms emerge and lung function falls: asthma is confirmed. Step up controller treatment to previous lowest effective dose. If no change in symptoms or lung function at lowest controller step: consider ceasing controller, and monitor patient closely for at least 12 months (Box 3-7). Persistent shortness of Consider stepping up controller treatment for 3 months (Box 3-5, p.61), then reassess symptoms breath and persistent and lung function. If no response, resume previous treatment and refer patient for diagnosis and airflow limitation investigation. Consider asthma-COPD overlap (Chapter 5, p.141). BD: bronchodilator; LABA: long-acting beta2-agonist; SABA: short-acting beta2-agonist. `Variable airflow limitation' refers to expiratory airflow. 26 1. Definition, description and diagnosis of asthma Box 1-4. How to step down controller treatment to help confirm the diagnosis of asthma 1. ASSESS Document the patient's current status including asthma control (Box 2-2, p.36) and lung function. If the patient has risk factors for asthma exacerbations (Box 2-2B), do not step down treatment without close supervision. Choose a suitable time (e.g. no respiratory infection, not going away on vacation, not pregnant). Provide a written asthma action plan (Box 4-2, p.129) so the patient knows how to recognize and respond if symptoms worsen. Ensure they have enough medication to resume their previous dose if their asthma worsens. 2. ADJUST Show the patient how to reduce their ICS dose by 25-50%, or stop extra controller (e.g. LABA, leukotriene receptor antagonist) if being used (Box 3-7, p.75). Schedule a review visit for 2-4 weeks. UTE 3. REVIEW RESPONSE TRIB Repeat assessment of asthma control and lung function tests in 2-4 weeksD(ISBox 1-2, p.23). If symptoms increase and variable expiratory airflow limitation is confirOmRed after stepping down treatment, the diagnosis of asthma is If, after stepping down tcooanfliormweddo. sTehecocnotrnotrlloelrletrredaotsmeesnht,osuyldmbpetoOrmePtsuYrdnoendottowthoersleonwaenstdptrheevrieouiss effective dose. still no evidence of variable expiratory airflow limitation, consider ceasing controlTlerCtreatment and repeating asthma control assessment and lung function tests in 2-3 weeks, but follNowOthe patient for at least 12 months AL - DO DIFFERENTIAL DIAGNOSIS ERI The differential diagnosis in a patient with susApTected asthma varies with age (Box 1-5). Any of these alternative diagnoses may also be found together wEiDthMasthma. Box 1-5. Differential diagnosis oIfGaHsTthma in adults, adolescents and children 6-11 years Age PYR Symptoms Condition 6-11 years Sneezing, itchinCg,Oblocked nose, throat-clearing Chronic upper airway cough syndrome Sudden onset of symptoms, unilateral wheeze Inhaled foreign body Recurrent infections, productive cough Bronchiectasis Recurrent infections, productive cough, sinusitis Primary ciliary dyskinesia Cardiac murmurs Congenital heart disease Pre-term delivery, symptoms since birth Bronchopulmonary dysplasia Excessive cough and mucus production, gastrointestinal symptoms Cystic fibrosis (continued next page) 1. Definition, description and diagnosis of asthma 27 Box 1-5 (continued). Differential diagnosis of asthma in adults, adolescents and children 6-11 years Age Symptoms Condition 12-39 years Sneezing, itching, blocked nose, throat-clearing Dyspnea, inspiratory wheezing (stridor) Chronic upper airway cough syndrome Inducible laryngeal obstruction Dizziness, paresthesia, sighing Hyperventilation, dysfunctional breathing Productive cough, recurrent infections Bronchiectasis Excessive cough and mucus production Cystic fibrosis Cardiac murmurs Congenital heart disease Shortness of breath, family history of early emphysema Alpha1-antitrypsin deficiency Sudden onset of symptoms Inhaled foreign body 40+ Dyspnea, inspiratory wheezing (stridor) Inducible laryngeal obstruction years Dizziness, paresthesia, sighing Cough, sputum, dyspnea on exertion, smoking or noxious HCOypPeDrv*entilatioTnE, dysfunctional breathing exposure RIBU Productive cough, recurrent infections Dyspnea with exertion, nocturnal symptoms, ankle edema BCraorDndciIaShcTiefcatialusries Treatment with angiotensin converting enzyme (ACE) inhibitor OMRedication-related cough Dyspnea with exertion, non-productive cough, finger clubbing PY Parenchymal lung disease Pulmonary embolism Sudden onset of dyspnea, chest pain Dyspnea, unresponsive to bronchodilators T CO Central airway obstruction All Chronic cough, hemoptysis, dyspnea; and/or fatigue, feNvOer, (night) Tuberculosis ages *For more sweats, anorexia, weight detail, see Chapter 5 (p.141). Any loss of the above conditions may - DO also contribute to respiratory symptoms in patients with confirmed asthma. RIAL HOW TO MAKE THE DIAGNOSIS OF ASTHMA IANTOETHER CONTEXTS Patients presenting with persistent non-pEroDdMuctive cough as the only respiratory symptom Diagnoses to be considered are chroInGicHuTpper airway cough syndrome (often called `postnasal drip'), cough induced by aonbgstiorutectniosnin.4c1o,42nvPearttiienngtsenwziythmseo(-PAcYaClRlEe)din`choiubgitohr-sv,agriaasnttroaestshomphaa' hgaevael rpeeflrusxis, tcehnrtocnoicugsihnuassittihse, iarnpdrinincdipuacliboler olanrlyynsgyemapl tom, associated with airway hyperCreOsponsiveness. It is often more problematic at night. Lung function may be normal, and for these patients, documentation of variability in lung function (Box 1-2, p.23) is important.43 Cough-variant asthma must be distinguished from eosinophilic bronchitis in which patients have cough and sputum eosinophilia but normal spirometry and airway responsiveness.43 Occupational asthma and work-exacerbated asthma Asthma acquired in the workplace is frequently missed. Asthma may be induced or (more commonly) aggravated by exposure to allergens or other sensitizing agents at work, or sometimes from a single, massive exposure. Occupational rhinitis may precede asthma by up to a year and early diagnosis is essential, as persistent exposure is associated with worse outcomes.44,45 An estimated 5-20% of new cases of adult-onset asthma can be attributed to occupational exposure.44 Adult-onset asthma requires a systematic inquiry about work history and exposures, including hobbies. Asking patients whether their symptoms improve when they are away from work (weekends or vacation) is an essential screening question.46 It is important to confirm the diagnosis of occupational asthma objectively as it may lead to the patient changing their 28 1. Definition, description and diagnosis of asthma occupation, which may have legal and socioeconomic implications. Specialist referral is usually necessary, and frequent PEF monitoring at and away from work is often used to help confirm the diagnosis. Further information about occupational asthma is found in Chapter 3 (p.101) and in specific guidelines.44 Athletes The diagnosis of asthma in athletes should be confirmed by lung function tests, usually with bronchial provocation testing.47 Conditions that may either mimic or be associated with asthma, such as rhinitis, laryngeal disorders (e.g. inducible laryngeal obstruction42), dysfunctional breathing, cardiac conditions and over-training, must be excluded.48 Pregnant women Pregnant women and women planning a pregnancy should be asked whether they have asthma so that appropriate advice about asthma management and medications can be given (see Chapter 3: Managing asthma with multimorbidity and in specific populations, p.100).49 If objective confirmation of carry out a bronchial provocation test or to step down controller ttrheeatdmiaegnntousnistilisafnteereddeeldiv,eTitrEyw.ould not be advisable to The elderly RIBU Asthma is frequently undiagnosed in the elderly,50 due to poor perception of aiDrflIoSwTlimitation; acceptance of dyspnea as being `normal' the diagnosis. in In aoldlaraggee;ploapcuklaotfiofintnbeassse; dansdurrveedyucoef daspthhymsaicpaal aticetnivtsityo.ldTehreOthpRarens6e5ncyeeaorfsm, fualctitmorosrbaisdsitoycaialsteodcowmithplaicates history of asthma hospitalization included co-diagnosis of COPD, corOonPaYry artery disease, depression, diabetes mellitus, and difficulty accessing medications cough that are worse on exercise or or at ncilginhict aclacnaarelsboebceaucsaeusoefdcTobsyCt.c5a1 rSdyiomvpatsocmulsarodf iwsehaeseezinogr ,lebfrtevaetnhtlreicsusnlaersfsaialunrde, which are common in this age group. A careful history and phNysOical examination, combined with an electrocardiogram aanssdecshsemset nXt-roafyc,awrdililaacsfsuisntcitniotnhewidthiaegcnhooscisa.5rd2 iMogeraaspuhryemm- eDanyOtaolsf oplabsemhaelbprfuali.n53nIantroiuldreetricpepooplylepewpittihdea (BNP) and history of smoking or biomass (Chapter fuel exposure, 5, p.141). COPD and overlapping asRthIAmLa and COPD (asthma-COPD overlap) should be considered ATE Smokers Asthma and and ex-smokers COPD may be difficult to dEisDtinMguish in clinical practice, particularly in older patients and smokers and ex- samndokPerersv,eanntidonthoefsCe OcoPnDdi(tGioOnsLDm)a5IG4y dHoevTfeinrleasp (asthma-COPD overlap). The COPD on the basis of chronic Global Strategy for Diagnosis, Management respiratory symptoms, exposure to a risk factor such as smoking, and PpoYsRt-bronchodilator FEV1/FVC <0.7. Clinically important bronchodilator reversibility (>12% and >200 pattern of msyLm) pistoomftsenanfoduCpnaOdsitnreCcOoPrdDs.5c5aLnohweldpiftfousdioisntincgaupiaschittyhiessme opraetieconmtsmfroonminthCosOePwDitthhalonnga-ssthtamnad.inTghaeshthismtoarywahnod have developed persistent airflow limitation (see Chapter 5, p.141). Uncertainty in the diagnosis should prompt early referral for specialized investigation and treatment recommendations, as patients with asthma-COPD overlap have worse outcomes than those with asthma or COPD alone.56 Obese patients While asthma is more common in obese than non-obese people,57 respiratory symptoms associated with obesity can mimic asthma. In obese patients with dyspnea on exertion, it is important to confirm the diagnosis of asthma with objective measurement of variable expiratory airflow limitation. One study found that non-obese patients were just as likely to be over-diagnosed with asthma as obese patients (around 30% in each group).37 Another study found both over- and under-diagnosis of asthma in obese patients.58 1. Definition, description and diagnosis of asthma 29 Low- and middle-income countries As described above, asthma is a clinical diagnosis, based on the history of characteristic symptom patterns and evidence of variable expiratory airflow limitation. However, in low- and middle-income countries (LMICs), access to lung function testing is often very limited, and even when available, may be substantially underused (e.g. unaffordable for the patient or health system,59 too time-consuming in a busy clinic, or impractical because requiring repeated visits of indigent patients.60 In addition, in LMICs, the differential diagnosis of asthma may include other endemic respiratory disease (e.g. tuberculosis, HIV/AIDS-associated lung diseases, and parasitic or fungal lung diseases), so clinicians tend to place greater reliance on clinical findings and often use a syndromic approach to diagnosis and initial management.61 This comes at the cost of precision but is based on the assumption (valid in most LMICs) that under-diagnosis and undertreatment of asthma is more likely62 than the overdiagnosis and overtreatment often seen in high income countries.19,63 Although acknowledging that poor access to lung function testing is a common barrier to asthma diagnosis in LMICs, GINA does not recommend that diagnosis should be available, the presence of variable expiratory airflow lsimolietalytiobnas(iendcloundinsygnrdervoemrsicibclelinoicbasltrpuactUttieoTrnEn)sc.aWn hbeencsopnifriormmeedtrybyis not iPnEteFrv(eBnotxio1n-s2f,opr.p2r3im). aTrhyecWaroer6l4dliHstesatlhthe OPrEgFanmizeatteior nas(WanHeOs)sPeanctikaal gtoeool ifnetshseenmtiaanl angoenTmcRoeImnBtmoufncihcraobnleic(rPeEspNi)radtiosreyase diseases. WHO-PEN proposes use of PEF in support of a clinical diagnosis: a 20D%ISimprovement in PEF 15 minutes after giving 2 puffs of albuterol increases the likelihood of a diagnosis of asthmOaRversus COPD and other diagnoses.64 GINA also suggests that improvement therapy, with a 1-week course of OCS in symptoms if necessary, and can PEF help taoftceornafi4rm-wOtehPeekYdtihaegrnaopseisutoicf trial with anti-inflammatory asthma (or prompt investigation for alternative diagnoses) before starting long-term controller treatmTenCt. A structured algorithmic approach to patients presenting with resNpiOratory symptoms forms part of several strategies developed for where, owing improving to the high respiratory disease management prevalence of tuberculosis, large in-nuDLmOMbIeCrss.o60f These strategies are of particular use in countries patients with respiratory symptoms present for assessment at tuberculosis clinics. RIAL Tushee,retoisbea spurebssstainngtianlelyesdcfaolreadcucpesins LtoMaICffosr.dabMleAdTiEagnostic tools (peak flow meters and spirometry), and training in their TED IGH COPYR 30 1. Definition, description and diagnosis of asthma SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER IBUTE DISTR Y OR Chapter 2. COP T NO L - DO Assessment of TERIA asthma MA GHTED PYRI CO KEY POINTS Asthma control The level of asthma control is the extent to which the features of asthma can be observed in the patient, or have been reduced or removed by treatment. Asthma control is assessed in two domains: symptom control and risk of adverse outcomes. Poor symptom control is burdensome to patients and increases the risk of exacerbations, but patients with good symptom control can still have severe exacerbations. Asthma severity The current definition of asthma severity is based on retrospective assessment, after at least 2-3 months of controller treatment, from the treatment required to control symptoms and exacerbations. This definition is clinically useful for severe asthma, as it identifies patients whose asthma is relatively refractory to therapy. It is conventional high dose important to distinguish ICS-LABA and who may between severe asthma benefit from and asthma tahdadtiitsiounUnaclTotErnetarotmlleedntdsuuecthoamsobdioifliaogbliec factors such as incorrect inhaler technique and/or poor adherence. TRIB However, the often used in clinical clinical utility of practice the retrospective definition to mean infrequent or mild soyfm`mpitlodmass,thamnda'DpisaIStlieesnstscolefatern. In particular, the term is incorrectly assume that it means they are not at risk and do not need controller treatment. OR For these reasons, GINA suggest that the term `mild asthma' shOoPuYld generally be avoided in clinical practice or, if used, qualified with a reminder that patients with infrequent exacerbations, and that this risk is substantially reduced witTh Csymptoms can ICS-containing still have severe treatment. or fatal GINA proposes holding a stakeholder discussion about NthOe definition of mild asthma, to obtain agreement about the implications for clinical practice and clini-caDlOresearch of the changes in knowledge about asthma How to pathophysiology and treatment assess a patient with asthma since the curreIAntLdefinition of asthma severity was published. Assess symptom control from the frequenTcEyRof daytime and night-time asthma symptoms, night waking and activity limitation and, for patients usinMgAshort-acting beta2 agonist (SABA) reliever, their frequency of SABA use. Other symptom Assess the patient's fcuotunrterorlitsokoflosTrEineDcxlaucdeerbAasttihomnsa, Control Test and Asthma Control Questionnaire. even when symptom control is good. Risk factors for exacerbations that are indepIeGnHdent of symptom control include a history of 1 exacerbation in the previous yseeacor,nsdo(cFioEeVco)n, osmmoickpinrgPo,bYalRenmdsb,lopoodoreaodshineorepnhciliea,.incorrect inhaler technique, low forced expiratory volume in 1 Also assess 1 risk facCtoOrs for persistent airflow limitation and medication side-effects, treatment issues such as inhaler technique and adherence, and comorbidities, and ask the patient about their asthma goals. Once the diagnosis of asthma has been made, the main role of lung function testing is in the assessment of future risk. It should be recorded at diagnosis, 3-6 months after starting treatment, and periodically thereafter. Investigate further if there are few symptoms but impaired lung function, or frequent symptoms and good lung function. OVERVIEW For every patient, assessment of asthma should include the assessment of asthma control (both symptom control and future risk of adverse outcomes), treatment issues particularly inhaler technique and adherence, and any comorbidities that could contribute to symptom burden and poor quality of life (Box 2-1, p.33). Lung function, particularly FEV1 as a percentage of predicted, is an important part of the assessment of future risk. 32 2. Assessment of asthma The use of digital technology, telemedicine and telehealthcare in the monitoring of patients with asthma is rapidly increasing, particularly during the COVID-19 pandemic. However, the types of interactions are diverse, and high-quality studies are needed to evaluate their utility and effectiveness. See Appendix section on Telehealthcare. What is meant by `asthma control'? The level of asthma control is the extent to which the manifestations of asthma can be observed in the patient, or have been reduced or removed by treatment.24,65 It is determined by the interaction between the patient's genetic background, underlying disease processes, the treatment that they are taking, environment, and psychosocial factors.65 Asthma control has two domains: symptom control and future risk of adverse outcomes (Box 2-2, p.36). Both should always be assessed. Lung function is an important part of the assessment of future risk; it should be measured at the start of treatment, after 3-6 months of treatment (to identify the patient's personal best), and periodically thereafter for ongoing risk assessment. How to describe a patient's asthma control TE Asthma control Ms X has good should be described in terms asthma symptom control, but oshf eboisthastyinmcpretoamsecdornistrkoloaf nfudtufuretuerexaricseRkrbIdBaoUtmioanisnsb.eFcoaruesexasmhepleh:as had a severe factors exacerbation within the last year. for future exacerbations including Mr Y has low lung fpuonocrtioans,thcmuraresnytmspmtoomkincgo,natDrnodIlS.pHToeoramlsoedhicaastisoenveardahleardednictieo.nal risk What does the term `asthma control' mean to patients? OR Many studies describe discordance between the patient's and healthOpProYvider's assessment of the patient's level of asthma control. This does not necessarily severity, but that patients understand and umseeatnhethwatoprdat`iceonntstro`olO'vdeTirf-Cfeersetinmtlaytefr'otmhehirelaelvthelporfocfeosnstrioonl aolrs`,uen.dge. rb-aessteimd aotne'hiotsw quickly their symptoms resolve the meaning should always be when they explained. take reliever mDeOdicNation.65,66 If the term `asthma control' is used with patients, Box 2-1. Assessment of asthma in adults, adolesIAceLn-ts, and children 6-11 years 1. Assess asthma control = symptom controTl EanRd future risk of adverse outcomes Assess symptom control over the last 4MwAeeks (Box 2-2A). MIdeeantsiufyreanluynogthfuenrcrtiisoknfaact tdoirasgfnoorseisTx/aEsctDaerrtboaftitornesa,tmpeernsti,s3te-n6t maiorfnlothwsliamftietartsiotanrotinr gsidcoen-etrfofellcetrst(rBeaotxm2e-n2tB, )t.hen periodically, e.g. at least onceIGevHery 1-2 years, but more often in at-risk patients and those with severe asthma. 2. Assess treatment issues PYR Document the patientC'sOcurrent treatment step (Box 3-5, p.61). Watch inhaler technique (Box 3-12, p.89), assess adherence (Box 3-13, p.90) and side-effects. Check that the patient has a written asthma action plan. Ask about the patient's attitudes and goals for their asthma and medications. 3. Assess comorbidities Rhinitis, rhinosinusitis, gastroesophageal reflux, obesity, obstructive sleep apnea, depression and anxiety can contribute to symptoms and poor quality of life, and sometimes to poor asthma control. 2. Assessment of asthma 33 ASSESSING ASTHMA SYMPTOM CONTROL Asthma symptoms such as wheeze, chest tightness, shortness of breath and cough typically vary in frequency and intensity, and contribute to the burden of asthma for the patient. Poor symptom control is also strongly associated with an increased risk of asthma exacerbations.67-69 Asthma symptom control should be assessed at every opportunity, including during routine prescribing or dispensing. Directed questioning is important, as the frequency or severity of symptoms that patients regard as unacceptable or bothersome may vary from current recommendations about the goals of asthma treatment, and may differ from patient to patient. For example, despite having low lung function, a person with a sedentary lifestyle may not experience bothersome symptoms and so may appear to have good symptom control. To assess symptom control (Box 2-2A) ask about the following in the past four weeks: frequency of asthma symptoms (days per week), any night waking due to asthma or limitation of activity and, for patients using a SABA reliever, frequency of its use for relief of symptoms. In general, do not include reliever taken before exercise, because some people take this routinely without knowing whether they need it. UTE Frequency of reliever use TRIB Historically, frequency symptom control. This of SABA reliever use (<2 or 2 distinction was arbitrary, based doanytsh/we eaesks)uhmapstiboenetnhaint cifluSdDAeBIdSAinwtahse composite assessment of used on >2 days in a week, the patient needed to start controller therapy or increase the dose. In additionO, hRigher average use of SABA over a year is is associated associated with with a higher risk of severe exacerbations,70,71 and in an increased likelihood of a severe exacerbation tihnessuOhbPosreYtqeur etenrtmd,aiynscroerawsienegkuss.7e2 of as-needed SABA However, if a patient who is prescribed as-needed ICS-formoterol asTtCheir reliever (Track 1 in Box 3-5A, p.61) uses it on average more than 2 days/week, this is already providing additioNnaOl controller therapy, so further dose escalation may not be needed. exacerbation in Increasing use of subsequent days aosr -wneeeekdsedcoICmSp-aforermd owtiethro-ilfDitshOeasrseoliecivaeter diswSiAthBaAs,7i3g,7n4ifoicracnotlmy ploawreedr risk of with if severe the patient is using SABA alone.75 RIAL For these reasons, use composite assessment of of sICymS-pfotormmoctoenrotrlorle. lHieovweAredTveiEvri,dtehde categorically as 2 versus >2 days/week is not included in patient's average frequency of as-needed ICS-formoterol the use over the past 4 reviewed. This iwsseueekswsilhl boeuldrebveiewasesdeassgeadinE, DwanhMdentafkuertnhienrtodaatcacaoruentawvahielanblteh.e patient's maintenance controller dose is Asthma symptom control tools for aIdGuHltTs and adolescents Simple screening tools: these caPnYbRe used in primary care to quickly identify patients who need more detailed assessment. Examples incluCdeOthe consensus-based GINA symptom control tool (Part A, Box 2-2A). This classification correlates with assessments made using numerical asthma control scores.76,77 It can be used, together with a risk assessment (Box 2-2B), to guide treatment decisions (Box 3-5, p.61). Other examples are the Primary Care Asthma Control Screening Tool (PACS),78 and the 30-second Asthma Test, which also includes time off work/school.79 Categorical symptom control tools: e.g. the consensus-based `Royal College of Physicians (RCP) Three Questions' tool,80 which asks about difficulty sleeping, daytime symptoms and activity limitation due to asthma in the previous month. The Asthma APGAR tool includes a patient-completed asthma control assessment covering 5 domains: activity limitations, daytime and nighttime symptom frequency (based on US criteria for frequency of night waking), triggers, adherence, and patient-perceived response to treatment. This assessment is linked to a care algorithm for identifying problems and adjusting treatment up or down. A study in the US showed that introduction of the Asthma APGAR tools for patients aged 5-45 in primary care improved rates of asthma control; reduced asthma-related urgent care, and hospital visits; and increased practices' adherence to asthma management guidelines.81 Numerical `asthma control' tools: these tools provide scores and cut points to distinguish different levels of symptom control, validated against health care provider assessment. Many translations are available. These scores may be useful 34 2. Assessment of asthma for assessing patient progress; they are commonly used in clinical research, but may be subject to copyright restrictions. Numerical asthma control tools are more sensitive to change in symptom control than categorical tools.76 Examples of numerical asthma control tools for assessing symptom control are: Asthma Control Questionnaire (ACQ):82,83 Scores range from 0-6 (higher is worse). The ACQ score is the average of 5, 6 or 7 items: all versions include five symptom questions; ACQ-6 includes SABA reliever use; and ACQ-7, pre- bronchodilator FEV1. The authors stated that ACQ 0.75 indicated a high probability that asthma was well-controlled; 0.75-1.5 as a `grey zone'; and 1.5 a high probability that asthma was poorly controlled, based on concepts of asthma control at the time; the authors later added that the crossover point between `well-controlled' and `not well- controlled' asthma was close to 1.00.84 The minimum clinically important difference for all three versions of ACQ is 0.5.85 GINA prefers ACQ-5 over ACQ-6 or 7 because the reliever question assumes regular rather than as-needed use of SABA, and ACQ has not been validated with ICS-formoterol as the reliever. If ACQ is used in adjustment of treatment, inclusion of FEV1 in the composite score could lead to repeated step-up in ICS dose for patients with persistent airflow limitation. Asthma Control Test controlled; 16-19 as (ACT):77,86,87 Scores range from not well-controlled; and 5-15 as 5ve-r2y5p(ohoigrhlyecroisntbroeltlteedr).aSstchomreas.UToThf eE20A-C2T5 are has classified as wellfour symptom/ reliever questions plus patient self-assessed control. The minimum clinically imTpRorItBant difference is 3 points.87 When different tools are used for assessing asthma symptom control, the resuDltsIScorrelate broadly with each other, but aimreponrotat nidtetontciclaarl.ifRy ethsaptirsaytomryptsoymmspatoremdsumeatoy absethnmona-.specific so, when aYssOeRssing changes in symptom control, it is Asthma symptom control tools for children 6-11 years of age COP In children, as in adults, assessment of asthma symptom controOlTis based on symptoms, limitation of activities and use oliffer,easncdueonmsecdhicoaotlioanb.sCeantreeefuisl mre,viisewimopfotrhtaenitm. pMaacntyocf haisldthrDemOnawNointhapcohoirldly'scodnatilryolalecdtivaitsiethsm, iancalvuodiidngstsrepnourtosu, spleaxyearncidsesoscoial their asthma may appear to be well controlled. ThisImALay- lead to poor fitness and a higher risk of obesity. Children vary considerably in reliever therapy, and marked rtehdeudcetigorneeinoluf nagirfTfluoEnwRcltiimonitaistioonfteonbsseerevnedbebfeofroereit they complain of is recognized by dyspnea or use their the parents. Parents may report irritability, tiredness, and changes in MmAood in their child as the main problems when the child's asthma is not controlled. Parents have important to include both athleonpgaerer nret'csaTallEnpdDecrihoidldt'shainnfocrhmildarteionn, who may when the recall only the last few days; therefore, it is level of symptom control is being assessed. Several numeric asthma control sIcGoHres have been developed for children. These include: Childhood Asthma CPonYtRrol Test (c-ACT)88 with separate sections for parent and child to complete Asthma Control QCuOestionnaire (ACQ)89,90 Some asthma control scores for children include exacerbations with symptoms. These include: Test for Respiratory and Asthma Control in Kids (TRACK)91-93 Composite Asthma Severity Index (CASI)94 The results of these various tests correlate to some extent with each other and with the GINA classification of symptom control. Box 2-3 (p.37) provides more details about assessing asthma control in children. 2. Assessment of asthma 35 Box 2-2. GINA assessment of asthma control in adults, adolescents and children 6-11 years A. Asthma symptom control Level of asthma symptom control In the past 4 weeks, has the patient had: Daytime asthma symptoms more than twice/week? Any night waking due to asthma? SABA reliever for symptoms more than twice/week?* Any activity limitation due to asthma? Well controlled Yes No Yes No Yes No None of these Yes No Partly controlled 1-2 of these Uncontrolled 3-4 of these B. Risk factors for poor asthma outcomes Assess risk factors at diagnosis and periodically, particularly for patients experiencing exacerbations. Measure FEV1 at start of treatment, after 3-6 months of controller treatment to record the patient's personal best lung function, then periodically for ongoing risk assessment. Having uncontrolled asthma symptoms is an important risk factor for exacerbationsU.9T5 E Additional potentially modifiable risk factors for flare-ups (exacerbations), even iTnRpIaBtients with few symptoms include: DIS Mofeedxiaccaetirobnatsio: nhsig;1h23S,9A6 iBnAcreuasese(d3mxor2t0a0lit-ydopsaerticcaunlaisrltyerisf /y1eacraansisstoecr ipaeterdmwoOinthRthi7n1c,9r7e);ased risk inadequate ICS: not prescribed ICS; poor adherence;98 incorrect inhOalPeYr technique99 Having any of Other medical conditions: obesity;100,101 chronic rhinosinusitis;101 GERD;101 confirmed T C food allergy;102 pregnancy103 NOsensitized;104 air pollution106-108 these risk factors increases the patient's risk of ECxopnotesxutr:ems:asjomr opksiyncgh;1o0l4ogei-ccaigl aorresttoecsi;o1e05coanlleormgeicnperoxpbolesm-urDse1O0i9f exacerbations Lung function: low FEV1, responsiveness101,111,112 especially <60% predicRteIAd;L104,110 high BD even if they have few asthma symptoms Type 2 inflammatory markers: higher ATE blood eosinophils;101,113,114 elevated FeNO (in adults with allergic asthma taking ICSE)D11M5 O theEr vmear jionrtuinbdaetepdenodreinntinritseknsfaivcetocrasrfeoIGrufnHlaitTrfeo-ruapssth(emxaa1c1e6rbations) 1 severe exacerbation in PYR last 12 months117,118 Risk factors for developing peCrsOistent airflow limitation History: preterm birth, low birth weight and greater infant weight gain;119 chronic mucus hypersecretion120,121 Medications: lack of ICS treatment in patients who had a severe exacerbation122 Exposures: tobacco smoke;120 noxious chemicals; occupational exposures44 Investigations: low initial FEV1;121 sputum or blood eosinophilia121 Risk factors for medication side-effects Systemic: frequent OCS; long-term, high dose and/or potent ICS; also taking P450 inhibitors123 Local: high dose or potent ICS;123,124 poor inhaler technique125 BD: bronchodilator; FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid; OCS: oral corticosteroid; P450 inhibitors: cytochrome P450 inhibitors such as ritonavir, ketoconazole, itraconazole; SABA: short-acting beta2-agonist. *Based on SABA (as-needed ICS-formoterol reliever not included); excludes reliever taken before exercise. For children 6-11 years, also refer to Box 2-3, p.37. See Box 3-8, p.76 for specific risk reduction strategies. `Independent' risk factors are those that are significant after adjustment for the level of symptom control. 36 2. Assessment of asthma Box 2-3. Specific questions for assessment of asthma in children 6-11 years Asthma symptom control Day symptoms Ask: How often does the child have cough, wheeze, dyspnea or heavy breathing (number of times per week or day)? What triggers the symptoms? How are they handled? Night symptoms Cough, awakenings, tiredness during the day? (If the only symptom is cough, consider other diagnoses such as rhinitis or gastroesophageal reflux disease). Reliever use How often is reliever medication used? (check date on inhaler or last prescription) Distinguish between pre-exercise use (sports) and use for relief of symptoms. Level of activity What sports/hobbies/interests does the child have, at school and in their spare time? How does the child's level of activity compare with their peers or siblings? How many days is the child absent from school? Try to get an accurate picture of the child's day from the child without interruption from the parent/carer. Risk factors for adverse outcomes Exacerbations Ask: How How long do do viral infections the symptoms affect the child's last? How many asthma? episodes DhaovseyomcpctuoIBrmrUesdTiEnstinercfeertehewiritlhasstcmhoeodlicoar lsports? rfaecvtieorws?foArneyxuarcgeerbntadtioonctsoirn/ecmluedregaenhcisytodreypoafrtemxeanctevrbisaittsio?nIssI,StpThoReorer a written symptom action plan? control, poor Risk adherence and poverty,118 and persistent bronchodilator reversibiliRtyDeven if the child has few symptoms.112 Lung function Check curves and percent predicted technique. Main focus is to see trends over time. on FEPVY1 aOnd FEV1/FVC ratio. Plot these values as Side-effects Check the child's height at least yearly, as pooCrlOy controlled asthma can affect growth,126 and growth velocity may be lower in the first 1N-2OyTears of ICS treatment.127 Ask about frequency and dose of ICS and OCS. Treatment factors - DO Inhaler Ask the child to show how theRy IuAsLe their inhaler. Compare with a device-specific checklist. technique Adherence Is there any controller meAdTicEation in the home at present? On how many days does the child use their controller in evening? Where a is EwinDeheaMkle(rek.ge.p0t ,-2i,s4it, 7 in days)? Is it easier to plain view to reduce remember forgetting? to use it in the morning Check date on inhaler. or Goals/concerns Does the childIGorHtTheir parent/carer have any concerns about their asthma (e.g. fear of medication, Comorbidities side-eCffeOcPtsY,Rinterference with activity)? What are the child's/parent's/carer's goals for treatment? Allergic rhinitis Itching, sneezing, nasal obstruction? Can the child breathe through their nose? What medications are being taken for nasal symptoms? Eczema Sleep disturbance, topical corticosteroids? Food allergy Is the child allergic to any foods? (confirmed food allergy is a risk factor for asthma-related death102) Obesity Check age-adjusted BMI. Ask about diet and physical activity. Other investigations (if needed) 2-week diary Exercise challenge (laboratory) If no clear assessment can be made based on the above questions, ask the child or parent/carer to keep a daily diary of asthma symptoms, reliever use and peak expiratory flow (best of three) for 2 weeks (Appendix Chapter 4). Provides information about airway hyperresponsiveness and fitness (Box 1-2, p.23). Only undertake a challenge if it is otherwise difficult to assess asthma control. FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; ICS: inhaled corticosteroids; OCS: oral corticosteroids. 2. Assessment of asthma 37 ASSESSING FUTURE RISK OF ADVERSE OUTCOMES The second component of assessing asthma control (Box 2-2B, p.36) is to identify whether the patient is at risk of adverse asthma outcomes, particularly exacerbations, persistent airflow limitation, and side-effects of medications (Box 2-2B). Asthma symptoms, although an important outcome for patients, and themselves a strong predictor of future risk of exacerbations, are not sufficient on their own for assessing asthma because: Asthma symptoms can be controlled by placebo or sham treatments128,129 or by inappropriate use of longacting beta2-agonist (LABA) alone,130 which leaves airway inflammation untreated. Respiratory symptoms may be due to other conditions such as lack of fitness, or comorbidities such as inducible laryngeal obstruction.42 Anxiety or depression may contribute to symptom reporting. Some patients have impaired perception of bronchoconstriction, with few symptoms despite low lung function.131 Asthma symptom control and exacerbation risk should not be simply combined numerically, as poor control of symptoms and of exacerbations may have different causes and may need different treatment approaches. Risk factors for exacerbations UTE Poor asthma independent symptom control itself risk factors have been substantially increases the identified, i.e. factors, that, wrishkenofperexasecenrt,biantciorenTas.Rs6e7I-B6t9heHopwateievnetr',ssreisvkeroafl additional exacerbations even if symptoms are few. These risk factors (Box 2-2B) includeDaIShistory of 1 exacerbation in the previous year, poor adherence, incorrect inhaler technique, chronic sinusitisOaRnd smoking, all of which can be assessed in pr SABA use, ind imary care.132 ependent of tr The risk eatment of severe exacerbations step.71 Prescribing of thr eaendormmoOortrPaelYi2ty0 increas 0-dose es incr SABA ementally with high inhalers in a year, er corresponding to more than daily use, is associated with an increaTseCd risk of severe exacerbations71,133 and, in one study, increased mortality.71 Risk factors that are modifiable arNe Osometimes called `treatable traits'.134 In children, the increased with priosokrosfyemxpatcoemrbcaotinotnrsol,issgurbeoapttlyiminacl rderausgerde-gifiDmthOeenre, is a history of previous exacerbations; it is comorbid allergic disease and poverty.118 also Risk factors for development of persistent airflowRliImALitation The average rate of decline in FEV1 in non-smoAkTinEg healthy adults is 15-20 mL/year.135 People with asthma may haassvoecaianteadccweiltehramteodredpeecrlsiniseteinntludnygspfunnecat.EioIDnndaMenpdednedveenltorpisakirffalocwtorlsimthitaattiohnavtheabteisennoidtefunltliyfieredvfeorrspibelres.isTtheinstisaiorffltoewn limitation include exposure to cigareItGteHsTmoke or noxious agents, chronic mucus hypersecretion, and asthma exacerbations growth in lung finunpcatitoienn,tsanndotstoamPkYienRgarIeCaSt12r2is(kseoef Box 2-2B, p.36). Children with persistent asthma accelerated decline in lung function in early adult may have life.136 reduced CO Risk factors for medication side-effects Choices with any medication are based on the balance of benefit and risk. Most people using asthma medications do not experience any side-effects. The risk of side-effects increases with higher doses of medications, but these are needed in few patients. Systemic side-effects that may be seen with long-term, high dose ICS include easy bruising; an increase beyond the usual age-related risk of osteoporosis,137 cataracts and glaucoma; and adrenal suppression. Local side effects of ICS include oral thrush and dysphonia. Patients are at greater risk of ICS side-effects with higher doses or more potent formulations,123,124 and, for local side-effects, with incorrect inhaler technique.125 38 2. Assessment of asthma ROLE OF LUNG FUNCTION IN ASSESSING ASTHMA CONTROL Does lung function relate to other asthma control measures? Lung function does not correlate strongly with asthma symptoms in adults138 or children.139 In some asthma control tools, lung function is numerically averaged or added with symptoms,82,140 but if the tool includes several symptom items, these can outweigh clinically important differences in lung function.141 In addition, low FEV1 is a strong independent predictor of risk of exacerbations, even after adjustment for symptom frequency. Lung function should be assessed at diagnosis or start of treatment; after 3-6 months of controller treatment to assess the patient's personal best FEV1; and periodically thereafter. For example, in most adult patients, lung function should be recorded at least every 1-2 years, but more frequently in higher risk patients including those with exacerbations and those at risk of decline in lung function (see Box 2-2B, p.36). Lung function should also be recorded more frequently in children based on asthma severity and clinical course (Evidence D). Once the diagnosis of asthma has been confirmed, it is not generally necessary to ask patients to withhold their regular or as-needed medications before visits,24 but preferably the same conditions should apply at each visit. How to interpret lung function test results in asthma UTE A low FEV1 percent predicted: TRIB Identifies patients at risk of <60% predicted104,110,142,143 asthma exacerbations, independent of sDymISptom levels, especially if FEV1 is Is a risk factor for lung function decline, independent of symptomORlevels121 If symptoms are due to untreated few, suggests limitation airway inflammation.131 of lifestyle, or pooOr PpeYrception of airflow limitation,144 which may be A `normal' or near-normal FEV1 in a patient with frequent respOirTatCory symptoms (especially when symptomatic): Pnarosmalpdtrsipcoonr sgiadsetrraoteiosnopohf aaglteearnl aretifvluexcaduisseeassefo(rDBtOhoexNs1y-3m, ppt.o2m6)s.; e.g. cardiac disease, or cough due to post- Persistent bronchodilator responsiveness: IAL - Fainpdatiniegnst itgankiifnicgacnot nbtrroonllechr otrdeialatmtorenret,soTproEwnRshivoehnaesssta(kinecnreaassheoirnt-aFcEtVin1g>b1e2ta%2-aangdon>is2t0w0 imthLinfr4ohmoubrass,eolirnae2L2)AiBnA within 12 hours (or 24 hours for aMonAce-daily LABA), suggests uncontrolled asthma. In children, spirometry cannot be reliTaEblDy obtained until age 5 years or more, and it is less useful than in adults. Many children with uncontrolled IaGsHthma have normal lung function between flare-ups (exacerbations). How to interpret changes inPlYunRg function in clinical practice With regular ICS treatmeCnOt, FEV1 starts to improve within days, and reaches a plateau after around 2 months.145 The patient's highest FEV1 reading (personal best) should be documented, as this provides a more useful comparison for clinical practice than FEV1 percent predicted. If predicted values are used in children, measure their height at each visit. Some patients may have a faster than average decrease in lung function, and develop persistent (incompletely reversible) airflow limitation. While a trial of higher dose ICS-LABA and/or systemic corticosteroids may be appropriate to see if FEV1 can be improved, high doses should not be continued if there is no response. The between-visit variability of FEV1 (up to 12% week to week or 15% year to year in healthy individuals22) limits its use in adjusting asthma treatment or identifying accelerated decline in clinical practice. The minimal important difference for improvement and worsening in FEV1 based on patient perception of change has been reported to be about 10%.146,147 The role of short-term and long-term PEF monitoring Once the diagnosis of asthma is made, short-term peak expiratory flow (PEF) monitoring may be used to assess response to treatment, to evaluate triggers (including at work) for worsening symptoms, or to establish a baseline for action plans. After starting ICS, personal best PEF (from twice daily readings) is reached on average within 2 2. Assessment of asthma 39 weeks.148 Average PEF continues to increase, and diurnal PEF variability to decrease, for about 3 months.138,148 Excessive variation in PEF suggests suboptimal asthma control, and increases the risk of exacerbations.149 Long-term PEF monitoring is now generally only recommended for patients with severe asthma, or those with impaired perception of airflow limitation131,150-153 (Appendix Chapter 4). For clinical practice, displaying PEF results on a standardized chart may improve accuracy of interpretation.154 ASSESSING ASTHMA SEVERITY The currently accepted definition of asthma severity is based on `difficulty to treat' The current definition of asthma severity, recommended by an ATS/ERS Task Force24,65 and included in most asthma guidelines, is that severity should be assessed retrospectively from the level of treatment required to control the patient's symptoms and exacerbations, i.e. after at least several months of treatment.24,65,155 Hence: Severe asthma is defined as asthma that remains uncontrolled despite optimized treatment with high dose ICS-LABA, or that requires high dose ICS-LABA to prevent it from becoming uncontrolled. Severe asthma must be distinguished from asthma that is difficult to treat due to inadequate or inappropriate treatment, or persistent problems with adherence very different treatment implications or comorbidities such as compared with if asthma cishrroenlaictivrehliynoresfinraucstiUotirTsyEotor obesity,155 high dose as there are ICS-LABA or even OCS.155 See Box 3E (p.104) for more detail 2-4 (p.43) for how to distinguish about assessment, referral and difficult-to-treat treatment. aTnRdIBsevere asthma, and Chapter Moderate asthma is currently defined as asthma that is well controlled wDiItSh Step 3 or Step 4 treatment e.g. with low or medium dose ICS-LABA in either treatment track. OR dMoilsdeaIsCthSmpaluiss acsu-rnreenetdlyeddeSfiAnBedA.as asthma that is well contrColOlePdYwith as-needed ICS-formoterol, or with low d after good asthma control has been achieved Banydthtrisearetmtreonspt estcetipvpeeddedfionwitinonto, afisntdhmthaespeavteiernityt'scamninoimnluymbeefafseNscetOivsTesedose (p.75), or if asthma remains uncontrolled despite at least several months of optimized maximal the-raDpOy. The In terms `severe the community aansdthimn ap'riamnadry`mcailrde,atshtehtmeram' sar`eseoRvfeItAereLn' used with different or `mild' asthma are meanings than more commonly this based on the frequency or severity of their symptoms or exacAeTrEbations, irrespective of treatment. For example, `severe asthma' is commonly asthma' is cuosmedmifopnalytiuesnetsdhifapvaetiferenqtsuednotnEooDrttrhMoauvbeledsaoilmy esyamstphtmomassyomr ipf tsoymmsp,troemgsaradrleesqsuoicfktlhyerier ltireevaetdm.ent, and `mild In population-level studies, asthma iIsGoHfTten classified as `mild', `moderate' or `severe' based only on the prescribed treatment treatment by GINA or BTS was appropriate fSotretphP,eYreRpgaatirednlet'sssnoefepdas,tiewnhtesr' eleavseal sotfhamsathims aofcteonnturonld. eTrh-tirseaastesdumoreosvtehra-ttrtehaetepdre. scribed Most clinical trials of biologiCc Otherapy, although requiring patients to have uncontrolled asthma despite taking medium- or high-dose ICS-LABA, do not require contributory factors such as incorrect inhaler technique, poor adherence, or untreated comorbidities to have been addressed, and asthma control re-checked, prior to considering the patient's eligibility for enrolment.156,157 Some patients may therefore have `difficult-to-treat' rather than severe asthma. Some guidelines158,159 retain a second, older, classification of asthma severity based on symptom and SABA frequency, night waking, lung function and exacerbations before controller treatment is started.24,65 The classification distinguishes between `intermittent' and `mild persistent' asthma, but this historical distinction was arbitrary: it was not evidence-based, but was based on an untested assumption that patients with symptoms 2 days/week were not at risk, would not benefit from ICS, and should be treated with SABA alone. However, it is now known that patients with so-called `intermittent' asthma can have severe or fatal exacerbations,160,161 and that their risk is substantially reduced by ICS-containing treatment compared with SABA alone.162-164 Although this symptom-based classification is stated to apply to patients not on controller treatment,158,159 it is often used more broadly. This can cause confusion, as a patient's asthma may be classified differently, and be prescribed different treatment, depending on which definition the clinician uses. 40 2. Assessment of asthma For low resource countries that do not currently have access to medications such as ICS, the World Health Organization definition of severe asthma165 includes a category of `untreated severe asthma'. This category corresponds to uncontrolled asthma in patients not taking controller treatment. The patient's view of asthma severity Patients may perceive their asthma as severe if they have intense or frequent symptoms, but this does not necessarily indicate underlying severe disease, as symptoms and lung function can rapidly become well controlled with commencement of ICS-containing treatment, or improved inhaler technique or adherence.24,65 Likewise, patients often perceive their asthma as mild if they have symptoms that are easily relieved by SABA, or that are infrequent.24,65 Of concern, patients often interpret the term `mild asthma' to mean that they are not at risk of severe exacerbations and do not need to take controller treatment. This is often described as patients `underestimating' their asthma severity, but instead it reflects their different interpretation of the words `severity' and `mild'.24,65 How useful is the current retrospective definition of asthma severity? The retrospective definition of severe asthma based on `difficulty to treat' has been widely accepted in guidelines and in specialist clinical practice. It has obvious clinical utility as it identifies patients who, because of their burden of disease and incomplete respiratory physician (if response available) to optimized conventional ICS-based for further investigation, phenotyping, tarenadtmcoennsti,dmerUaayTtioEbnenoeffaitdfdroitmionreafletrreraalttmoeant such as biologic therapy (See Chapter 3E, p.104). Classifying patients who haveTRmIBodifiable factors, such as incorrect inhaler `severe' asthma itsecahpnpirqouper,iapteo,obr eacdahuesreenthceeirorasutnhtmreaatmedaycobmecoorbmideitwieesl,l-acsonhDtaroIvSlilnegd `difficult-to-treat' rather when such issues are than addressed.24,65,155 OR By contrast, the clinical utility of the retrospective definition of mild OasPtYhma is much less clear. By this definition, asthma can be classified as low-dose ICS or as-needed `mild' only after ICS-formoterol. several months However, many opOfaTttrieeCnattsmwenitth, and if asthma remains well-controlled asthma well-controlled on have not had their treatment stepped down. In for example whether occurr addition, academic ence of an isolated s have exacer bdDaiftOfieornNin(ge.ogp. inions virus- about trigger the ed) specific criteria precludes class for mild ification asthma, of a poaf tliitetlnet'vsaalusethimn adeacsid`minigldo' fnorfutthuerenetrxeta1tm2 emnot.nItnhsst.e1I6aA6dLF, -udrethciesri,obnescaabuosuet `mild asthma' is assessed ongoing treatment should retrospectively, be based upon it is an individualized assessment of symptom controTl,EeRxacerbation risk, predictors of response, and patient preferences. However, the most urgent problem with thMe Aterm `mild asthma', regardless of how it is defined, is that it encourages caonmd pdloaecsenncoyt,nseinecdecboontthropllaetrietrnetastmaneTdnEtc.DliHnoicwiaenvseor,ftuepn tiont3e0rp%reot f`masiltdhmasathemxaac' etorbmateioannsthaantdthdeeaptahtsieonct cisuraitnlopweoripslke with infrequent symptoms, for exIaGmHple, less than weekly or only on strenuous exercise.160,161 Interim advice about asthmaPYseRverity descriptors 1. Severe asthma: GINCAOcontinues to support the current definition of severe asthma as asthma that remains uncontrolled despite optimized treatment with high dose ICS-LABA, or that requires high dose ICS-LABA to prevent it from becoming uncontrolled; and the clinically important distinction between difficult-to-treat and severe asthma. See Box 2-4 (p.43) and Chapter 3E (p.104) for more detail about assessment and treatment. 2. `Mild' asthma, in clinical practice We suggest that the term `mild asthma' should generally be avoided in clinical practice, because of the common assumption by patients and clinicians that it equates to low risk. Instead, describe the patient's symptom control and risk factors on their current treatment (p.33). If the term `mild asthma' needs to be used in clinical practice, qualify it with a reminder that patients with infrequent or mild asthma symptoms can still have severe or fatal exacerbations,160,161 and that this risk is reduced by half to two-thirds with low dose ICS or as-needed low-dose ICS-formoterol.162,163 3. For population-level observational studies, if clinical details are not available, describe the prescribed (or dispensed) treatment, without imputing severity, e.g. `patients prescribed SABA with no ICS' rather than `mild asthma'. Since treatment options change over time, and may differ between guidelines, state the actual treatment, rather than a treatment Step (e.g. `low dose maintenance and reliever therapy with ICS-formoterol rather than `Step 3 treatment'). 2. Assessment of asthma 41 4. For clinical trials, describe the patient population by their level of asthma control and treatment, e.g. `patients with uncontrolled asthma despite medium-dose ICS-LABA plus as-needed SABA' rather than `moderate asthma' 5. Further discussion is clearly needed. Given the importance of the issues around mild asthma, GINA proposes holding a stakeholder discussion about the concept of asthma severity and the definition of mild asthma. The aim will be to obtain agreement among health professionals, researchers, industry and regulators about the implications for clinical practice and clinical research of current knowledge about asthma pathophysiology and treatment,24,65 and whether/how the term `mild asthma' should be used in the future. Pending this discussion, no change has been made to use of the term `mild asthma' elsewhere in this GINA report. HOW TO DISTINGUISH BETWEEN UNCONTROLLED ASTHMA AND SEVERE ASTHMA Although good symptom control and minimal exacerbations can usually be achieved with ICS-containing treatment, some patients will not achieve one or both of these goals even with a long period of high-dose therapy.140,155 In some patients this is due to truly refractory severe asthma, but in many others, it is due to incorrect inhaler technique, poor adherence, over-use of SABA, comorbidities, persistent environmental exposures, or psychosocial factors. It is important to distinguish between severe asthma and uncontrolled asthma, as the latter is a much more common rineiatisaol nstfeoprsptehrastisctaenntbseymcaprtroiemdsoaunt dtoeixdaecnetirfbyactoiomnsm,oanndcamusaeysboefmunocreonetaroslilleydimapsrthomvead..MBUooTrxeE2d-e4ta(pil.s43a)reshgoivwesn tihne Section 3E (p.104) about investigation and management of difficult-to-treat and sevTeRreIBasthma, including referral to a respiratory therapy. The physician or severe asthma clinic where most common problems that need to be possible, excluded abnedfouresemoafkaindgd-aDoIdnSiatrgenaotmsiesnotfinseclvuedriengasbtihomloagiacre: Poor inhaler technique (up to 80% of community patients)99 (BoxY3-O1R2, p.89) Poor medication adherence167,168 (Box 3-13, p.90) Incorrect diagnosis of asthma, with symptoms due to alternaCtiOvePconditions such as inducible laryngeal obstruction, cardiac failure or lack of fitness (Box 1-5, pN.O27T) MOnugltoiminogrbeidxpityossuurcehtoasserhnisniotizsiinngusoitrisir,rGitaEnRt Dag, eonbtes-siDintyOthaendhoombsetrourctwivoerksleenevpiraopnnmeean10t.1,169 (Chapter 3D, p.94) RIAL MATE TED IGH COPYR 42 2. Assessment of asthma Box 2-4. Investigating a patient with poor symptom control and/or exacerbations despite treatment IBUTE DISTR Y OR COP T NO - DO See Chapter 3E (p.104) for more details about assessment anRdIAmLanagement of difficult-to-treat and severe asthma. MATE TED IGH COPYR 2. Assessment of asthma 43 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER IBUTE DISTR Y OR Chapter 3. COP NOT - DO Treating asthma to ERIAL control symptoms MAT D and minimize risk IGHTE COPYR This chapter is divided into five parts: Part A. Part B. Part C. Part D. Part E. General principles of asthma management (p.46) Medications and strategies for asthma symptom control and risk reduction Medications, including treatment steps (p.51) Treating modifiable risk factors (p.76) Non-pharmacological therapies and strategies (p.76) Guided asthma self-management education and skills training (p.88) Information, inhaler skills, adherence, written asthma action plan, self-monitoring, regular review Managing asthma with multimorbidity and in specific populations (p.94) Difficult-to-treat and severe asthma in adults and adolescents (including decision tree) (p.104) Management of worsening and acute asthma is described in Chapter 4 (p.123). PART A. GENERAL PRINCIPLES OF ASTHMA MANAGEMENT KEY POINTS UTE TRIB Goals of asthma management DIS The long-term goals of asthma management are to achieve good sympOtoRm control, and to minimize future risk of asthma-related mortality, exacerbations, persistent own goals regarding their asthma and its treatment airflow should laimlsiotabtiOeonPidaYenndtifsieidde.-effects of treatment. The patient's The patient-health professional partnership T C Effective asthma management requires a partnership betwNeOen the person with asthma (or the parent/carer) and their health care providers. Teaching communication skills to health care provide- rDsOmay lead to increased patient satisfaction, better health outcomes, and reduced use of healthcare resoRuIrAceLs. The patient's `health information to make alipteprraocpyr'ia-tethhaet aislt,hthdeeAcpiTasEtioiennst's- ability to obtain, should be taken process and understand into account. basic health Making decisions about asthma treatmEenDt M Ainsbthomthastyrmeapttmomenct oisnatrdojluasnteddfuiInGtuaHrecTorinstkin(uoaf lecxyaccleerboaf taiosnsessasnmdesnidt,et-reeafftemctesn),t,aannddorfepvaietwienotfpthreefepraetniecnets's. response For population-level treatments for most pdaetcieisnPitosYn,RsbaasbeodutoansethvmidaentrceeatfmroemntrainndSotempisze1d-4co, nthtreo`lplerdefterirarelsd,'mopettiao-nasnarelypsreesseanntdthe best observational studies CabOout safety, efficacy and effectiveness, with a particular emphasis on symptom burden and exacerbation risk. For Steps 1-5, there are different population-level recommendations for different age- groups (adults/adolescents, children 6-11 years, children 5 years and younger). In Step 5, there are also different population-level recommendations depending on the inflammatory phenotype, Type 2 or non-Type 2. For individual patients, treatment decisions should also take into account any patient characteristics or phenotype that predict the patient's likely response to treatment, together with the patient's goals or concerns and practical issues (inhaler technique, adherence, medication access and cost to the patient). 46 3. Treating to control symptoms and minimize future risk LONG-TERM GOALS OF ASTHMA MANAGEMENT The long-term goals of asthma management from a clinical perspective are: To achieve good control of symptoms and maintain normal activity levels To minimize the risk of asthma-related death, exacerbations, persistent airflow limitation and side-effects. It is also important to elicit the patient's own goals regarding their asthma, as these may differ from conventional medical goals. Shared goals for asthma management can be achieved in various ways, taking into account differing health care systems, medication availability, and cultural and personal preferences. THE PATIENT-HEALTH CARE PROVIDER PARTNERSHIP Effective asthma management requires the development of a partnership between the person with asthma (or the parent/carer) and health care providers.170 This should enable the person with asthma to gain the knowledge, confidence and skills to assume a major role in the management of their asthma. Self-management education reduces asthma morbidity in both adults171 (Evidence A) and children172 (Evidence A). UTE There is emerging evidence encouraged to participate in that shared decision-making is associated decisions about their treatment, and given twhiethoipmpporrotuvTneRidtIyBotuotceoxmpreess.s173thPeairtieexnptsecsthaotiuolndsbaend csoenlf-cmerannsa.gTehmisepnat rmtnaeyrsvhairpyndeeepdesntdoinbgeoinndfiavcidtourasliszuecdhtoaseaecthhnpicaittiye,nlitt.eArapceyr,suonnDd'sIeSrwsitlalinndginnegsosfahnedalathbiclitoyntcoeepntsga(hgeeailnth literacy), numeracy, beliefs about asthma and medications, desire for autoOnoRmy, and the health care system. Good communication OPY Good communication by health care providers is essential as theTbCasis for good outcomes174-176 (Evidence B). Teaching health care providers to improve their communication skills (BNoOx 3-1) can result in increased patient satisfaction, better health outcomes, and reduced enhance patient adherence.177 uTsraeinoifnhgepaaltthiecnatsretoregsivoeu-ricnDefoOsr1m74a-1t7i6own icthleoaurtlyle, nsgetehkeinnifnogrmcoantisounl,taatniodncthimeceks.t1h7e7 iIrt can also understanding of information provided is also assoRcIiAatLed with improved adherence with treatment recommendations.177 Box 3-1. Communication strategies for heAaTltEh care providers Key strategies to facilitate good ED M communication175,176 AAllcoownignegntihael dpeamtieenatntoore(xfrpiernedsIslGintHehseTsir, ghouamlso,rbaenlidefasttaenndtivceonnecsesrn) s Empathy, reassurance, aPnYdRprompt handling of any concerns Giving encouragemeCntOand praise Giving appropriate (personalized) information Providing feedback and review How to reduce the impact of low health literacy178 Order information from most to least important. Speak slowly and use simple words (avoid medical language, if possible). Simplify numeric concepts (e.g. use numbers instead of percentages). Frame instructions effectively (use illustrative anecdotes, drawings, pictures, table or graphs). Confirm understanding by using the `teach-back' method (ask patients to repeat instructions). Ask a second person (e.g. nurse, family member) to repeat the main messages. Pay attention to non-verbal communication by the patient. Make patients feel comfortable about asking questions. 3. Treating to control symptoms and minimize future risk 47 Health literacy and asthma There is increasing recognition of the impact of low health literacy on health outcomes, including in asthma.178,179 Health literacy means much more than the ability to read: it is defined as `the degree to which individuals have the capacity to obtain, process and understand basic health information and services to make appropriate health decisions'.178 Low health literacy is associated with reduced knowledge and worse asthma control.180 In one study, low numeracy among parents of children with asthma was associated with higher risk of exacerbations.179 Interventions adapted for cultural and ethnicity perspectives have been associated with improved knowledge and significant improvements in inhaler technique.181 Suggested communication strategies for reducing the impact of low health literacy are shown in Box 3-1. PERSONALIZED CONTROL-BASED ASTHMA MANAGEMENT Asthma control has two domains: symptom control and risk reduction (see Box 2-2, p.36). In control-based asthma management, pharmacological and non-pharmacological treatment is adjusted in a continual cycle that involves aimspserosvsemaefntet,rttrheeatimnterondt uacntdiorneovifecwonbtyroal-pbparsoepdriagtueildyetlrianiense1d82p,1e83rsoornpnrealc(tiBcoaxl t3o-o2ls).fAorstihmmpalemouetncTotEamtioens have been shown of control-based to management randomized c strategies.173,184 The ontrolled medication concept trials, wit of controlh patients based management is identified for a change ainlsaossthumppaoRtrrtIeeBadUtmbyenthteondethsiegnbaosf i mos s of t features of poor symptom control with or without other risk factors such as low lunDgISfuTnction or a history of exacerbations. From 2014, personalized management GINA of the asthma management has focused patient's modifiable risk factors for neoxat coenrlybaoOtniRoansst,homthaesr yamdvpetorsme control, but also outcomes and on comorbidities, and taking into account the patient's preferences and goaOlsP. Y Box 3-2. The asthma management cycle for personalized asthmTa C care NO AL - DO ATERI HTED M PYRIG CO For many patients in primary care, symptom control is a good guide to a reduced risk of exacerbations.185 When inhaled corticosteroids (ICS) were introduced into asthma management, large improvements were observed in symptom control and lung function, and exacerbations and asthma-related mortality decreased. However, with other asthma therapies (including ICS-long-acting beta2-agonists [LABA]186,187) or different treatment regimens (such as as-needed ICS-formoterol in mild asthma188-191 and ICS-formoterol maintenance and reliever therapy192,193), and in patients with mild or severe asthma, there may be discordance between responses for symptom control and exacerbations. 48 3. Treating to control symptoms and minimize future risk In particular, patients with apparently mild asthma and few or intermittent symptoms may be still at risk of severe exacerbations162 (Box 2-2B, p.36). In addition, some patients continue to have exacerbations despite wellcontrolled symptoms, and for patients with ongoing symptoms, side-effects may be an issue if ICS doses continue to be stepped up. Therefore, in control-based management, both domains of asthma control (symptom control and future risk - see Box 2-2, p.36) should be taken into account when choosing asthma treatment and reviewing the response.24,65 Alternative strategies for adjusting asthma treatment Some alternative strategies have been evaluated for adjusting asthma treatment: Treatment guided by sputum eosinophil count: in adults, this approach, when compared with guidelines-based treatment, leads to a reduced risk of exacerbations and similar levels of symptom control and lung function.194 The benefits have primarily been seen in patients with frequent exacerbations and severe asthma.194 However, only a limited number of centers have routine children to assess this approach.194 access to induced sputum analysis. ThereUaTreEinsufficient data available in Treatment treatment, guided by fractional concentration of exhaled nitric problems with the design of the intervention and/or ocxoindtero(lFaelNgoOri)t:ThImRn IssBemvaekrael studies of FeNO-guided comparisons and conclusions difficult.195 Results of FeNO measurement at a single point iDn ItSime should be interpreted with caution (see p.26).35,196 In children and young adults with asthma, FeNO-guiOdeRd treatment was associated with a significant reduction in the number of patients with exacerbation rate (mean difference -0.27 [-0.49 to -01.0e6x]apceerrbyeaOatPior)Ync(oOmRpa0r.e6d7 [95% CI 0.51-0.90]) and in with guidelines-based treatment197 (Evide based nce A) algorit ; similar hms.197 differences However, in were non- seen in smoking caodmupltsarwisiotOhnsTasbCtehtmwae,ennoFseiNgnOif-igcaunidterdedtruecatitomneinnt and risk non-guidelinesof exacerbations and in exacerbation difference was only r s ates een w in as observed studies with w ot hitherF(enNonOD--tygOpuiiNcdaeld) treatment c comparator ompared to guideline-based tr approaches.198 No significant eatment; differenc a es were seen in symptoms or ICS dose with FeNIAOL-g-uided treatment compared with other strategies.197,198 Sputum-guided can be referred treatment is recommended for to) centers experienced in this TtaeEdcuRhltnipqauteie1n94t,s19w9 i(tEhvmidoednecreatAe).oIrnscehvieldrereans, tFhemNaOw-ghuoidaered managed treatment in (or significantly reduces exacerbation rates comMpAared with guidelines-based treatment (Evidence A).197 However, further strteuadtimesenatr,e19n7,e19e8daenddtothiedeonpttiifmy athl efrepqoupeTunlEacDtyioonfsFmeNosOt likely to benefit monitoring. from sputum-guided194 or FeNO-guided There is a need for evidence-baseIGd Hcorticosteroid de-escalation strategies in patients with asthma. In a randomized controlled trial (RCT) only vs. an algorithm boaf speadtieoPnntYsARtCakQin-7g high dose ICS-LABA, a strategy based and history of recent exacerbation was on a composite of Type inconclusive because a 2 biomarkers substantial proportion of patients did CnoOt follow recommendations for treatment change.200 Until more definitive evidence for a specific strategy is available, GINA continues to recommend a clinical evaluation that includes patient-reported symptoms as well as modifiable risk factors, comorbidities and patient preferences when making treatment decisions. Further evidence on the role of biomarkers in such decisions in Steps 1-4 is needed. Choosing between asthma treatment options At each treatment step in asthma management, different medication options are available that, although not of identical efficacy, may be alternatives for controlling asthma. Different considerations apply to recommendations or choices made for broad populations compared with those for individual patients (Box 3-3, p.50), as follows: Population-level medication choices: Population-level medication choices are often applied by bodies such as national formularies or managed care organizations. Population-level recommendations aim to represent the best option for most patients in the particular population. At each treatment step, `preferred' medications (controller and/or reliever) are recommended that provide the best benefit-to-risk ratio for both symptom control and risk reduction. Choice of the preferred controller and preferred reliever is based on evidence from efficacy studies 3. Treating to control symptoms and minimize future risk 49 (highly controlled studies in well-characterized populations) and effectiveness studies (from pragmatically controlled studies, or studies in broader populations, or strong observational data),201 with a particular focus on symptoms and exacerbation risk. Safety and relative cost are also taken into account. In Step 5, there are different population-level recommendations depending on the inflammatory phenotype, Type 2 or non-Type 2. In GINA 2021, the recommendations for adults and adolescents have been clarified in the treatment figure (Box 3-5A, p.61) by showing treatment options in two `tracks' based on the choice of reliever. Track 1, with as-needed low dose ICS-formoterol as the reliever, is the preferred approach for most patients, based on evidence of overall lower exacerbation risk and similar symptom control compared with treatments in Track 2 in which the reliever is short-acting beta2 agonist (SABA) (for more details, see Chapter 3B, p.51). Patient-level medication choices: Choices at this level also take into account any patient characteristics or phenotype that may predict a clinically important difference in their response compared with other patients, together with the patient's goals and practical issues (cost, ability to use the medication and adherence). The extent to on the health which asthma treatment can be system, the clinical context, the pinodteivnidtiuaal lmizaegdnaitcucdoerdoifndgiftfoerpeantcieenitncohuatrcaocmteeriss,tTiccEossotrapnhdeanvoatyilpaebsledepends resources. At present, most evidence and asthma202,203 (see Chapter 3E, p.104). research activity about individualized treatmeRnItBiUs focused on severe Box 3-3. Population level versus patient level decisions about asthma treatmDIeSnTt OR Choosing between treatment options at a population level (e.g. national formularies, health maintenance organizations, national gOuiPdeYlines) The `preferred' medication at each step is the best treatment for moTstCpatients, based on: Efficacy NO Effectiveness Mainly based on evidence abou-t sDyOmptoms and exacerbations (from Safety randomized controlled triaRlsI,ApLragmatic studies and strong observational data) Availability and cost at the For Steps 1-5, there are different ppooppuullaattiioonn-lleevvAeeTll rEecommendations by age-group (adults/adolescents, children 6-11 years, children recommendations depending 5onyethaersinafnladmEymoDuaMntogreyr)p.hInenSotteyppe5,, there are Type 2 or also different non-Type 2. population-level Choosing between controller optioIGnHs Tfor individual patients Use shared decision-making wiPthYtRhe patient/parent/carer to discuss the following: 1. Preferred treatment (asCaObove) based on evidence for symptom control and risk reduction 2. Patient characteristics or phenotype Does the patient have any features that predict differences in their future risk or treatment response compared with other patients (e.g. smoker; history of exacerbations, blood eosinophilia)? Are there any modifiable risk factors or comorbidities that may affect outcomes? 3. Patient views What are the patient's goals, beliefs and concerns about asthma and medications? 4. Practical issues Inhaler technique - can the patient use the inhaler correctly after training? Adherence - how often is the patient likely to take the medication? Cost to patient - can the patient afford the medication? 50 3. Treating to control symptoms and minimize future risk PART B. MEDICATIONS AND STRATEGIES FOR SYMPTOM CONTROL AND RISK REDUCTION KEY POINTS For safety, GINA no longer recommends treatment of asthma in adults and adolescents with SABA alone. All adults and adolescents with asthma should receive ICS-containing controller treatment to reduce their risk of serious exacerbations and to control symptoms. ICS-containing controller can be delivered either with regular daily treatment or, in mild asthma, with as-needed ICS-formoterol taken whenever needed for symptom relief. Treatment tracks for adults and adolescents For clarity, the treatment figure for adults and adolescents now shows two `tracks', based on the choice of reliever. Treatment may be stepped up or down within a track using the same reliever at each step, or treatment may be switched between tracks, according to the individual patient's needs. Track 1, in which the reliever is low dose ICS-formoterol, is the preferred approach recommended by GINA. When a patient at any step has asthma symptoms, they use Steps 3-5, they also take ICS-formoterol as regular dloawilydtoreseatImCeSn-fto. rTmhiostearpopl raosancheeisdepdrefTfoeErrrseydmbpetocmaurseelieitfr.eIdnuces the risk of severe exacerbations compared with using a SABA reliever, with similar RsyIBmUptom control. Track 2, in adherence which the reliever is a and no exacerbations SABA, is an alternative in the past year on their if Track current t1heisranpoyt.pIonsSsDtibeISlpeT,1o, rthifeappaatiteiennt ttaiskesstaablSe,AwBiAthagnodoad low the dose ICS reliever is together a SABA. for symptom relief (in Before considering a combination, or with the SABA reliever, consider IwChSetOthaeRkretnhreigphattaiefntetristhleikeSlyABtoAb).eInadShteerpesn2t -w5it,h their ICS-containing controller therapy, as otherwise they would be aOt PhiYgher risk of exacerbations. Steps 1 and 2 T C In adults and adolescents with mild asthma, treatment with asN-Oneeded-only low dose ICS-formoterol reduces the risk of severe dose ICS efoxrasceevrberaetioenxsacbeyrbaabtoiount stw, wo-itthhirndoscclionmicpaallyreidm-wpDoitrhOtaSnAt BdiAff-eornelnyctereinatsmyemnpt,toamndciosnntroonl.-iTnhfeeriorisr ktoodf aeimlyelorgwency dperepvaiortumselyntusviisnigtsSaAnBdAhoaslopnitea,liazsa-tnioenesdiesdreICduSc-feodrmRwoIiAttheLraosl-sniegendifeicdanICtlyS-rfeodrmucoetdertohlecorimskpoafresdevweirteh daily ICS. In patients exacerbations compared with daily ICS. ATE aTnredartemdeunctinwgitthhreergisuklaor fdaasiltyhmloaw-rdeolasteedIECeDSx,aMwceithrbaasti-onnese,dheodspSitAaBlizAa,tiisonhiagnhdlydeeffaetcht.ivHeoiwnerveedru,caindghearsetnhcmeawsiythmIpCtSomins Stepthpeincgomupmiufnaitsythismpaoorer,mleaaivnisngunpacItoGienHntrTtsoltlaekdindgeSsApiBteA alone good and at increased risk of adherence and inhaler exacerbations. technique Before considering any step PuYp,Rfirst confirm that the symptoms are due to asthma and identify and address common problems such as inhalerCteOchnique, adherence, allergen exposure and multimorbidity; provide patient education. For adults and adolescents, the preferred Step 3 treatment is low dose ICS-formoterol as maintenance and reliever therapy (MART). This reduces the risk of severe exacerbations compared with maintenance ICS-LABA controller plus as-needed SABA, with similar or better symptom control. If needed, the maintenance dose of ICS-formoterol can be increased to medium (i.e. Step 4). MART is also a preferred treatment option for children 6-11 years. Other Step 3 options for adults, adolescents and children include maintenance ICS-LABA plus as-needed SABA or, for children 6-11 years, medium dose ICS plus as-needed SABA. For children, try other controller options at the same step before stepping up. ICS-formoterol should not be used as the reliever for patients taking a different ICS-LABA maintenance treatment, since clinical evidence for safety and efficacy is lacking. 3. Treating to control symptoms and minimize future risk 51 Stepping down to find the minimum effective dose Once good asthma control has been achieved and maintained for 2-3 months, consider stepping down gradually to find the patient's lowest treatment that controls both symptoms and exacerbations Provide the patient with a written asthma action plan, monitor closely, and schedule a follow-up visit. Do not completely withdraw ICS unless this is needed temporarily to confirm the diagnosis of asthma. For all patients with asthma, provide asthma education and training in essential skills Provide inhaler skills training: this is essential for medications to be effective, but technique is often incorrect Encourage adherence with controller medication, even when symptoms are infrequent. Provide training in asthma self-management (self-monitoring of symptoms and/or PEF, written asthma action plan and regular medical review) to control symptoms and minimize the risk of exacerbations. For patients with one or more risk factors for exacerbations Prescribe provide a ICS-containing written asthma medication, action plan; preferably from Track 1 options, i.e. and arrange review more frequently with than afosr-nloeUweT-drEeisdk ICS-formoterol patients. as reliever; Identify and address modifiable risk factors (e.g. smoking, low lung function, ovTeRr-IuBse of SABA). Consider non-pharmacological strategies and interventions (e.g. smoking cessation advice, breathing exercises, some atovoaidssainsct ewsitthrastyDemgISipetso)m. control and risk reduction, Difficult-to-treat and severe asthma (see section 3E, p.104) OR Patients with poor symptom control and/or exacerbations despiteOmPeYdium or high dose ICS-LABA treatment should be assessed for contributing factors, and asthma treatment oTptiCmized. If the problems continue or diagnosis is uncertain, refer consideration of add-on therapy including biologics. toNaOspecialist center for phenotypic assessment and For all patients, use your own professional judgmen-t,DaOnd always check local eligibility and payer criteria ASTHMA MEDICATIONS RIAL ATE Categories of asthma When compared with medications medications usedEfDor M other chronic diseases, most of the medications used for treatment of asthma have very favorable theraIpGeHutTic ratios (Appendix Chapter 5). The pharmacological options for long-term treatmCenotnotrfoallsetrhmmeadfiacalltiinotnost:PhtYeheRfosellomweindgictahtrieoensmcaoinntacainteICgoSriaens:d are used to reduce airway inflammation, control symptoms, and redCucOe future risks such as exacerbations and related decline in lung function.122 In patients with mild asthma, controller treatment may be delivered through as-needed low dose ICS-formoterol, taken when symptoms occur and before exercise. The dose and regimen of controller medications should be optimized to minimize the risk of medication side-effects, including risks of needing oral corticosteroids (OCS). Reliever medications: these are provided to all patients for as-needed relief of breakthrough symptoms, including during worsening asthma or exacerbations. They are also recommended for short-term prevention of exerciseinduced bronchoconstriction (EIB). Relievers are divided into as-needed low dose ICS-formoterol (the preferred reliever, but not if the maintenance controller contains a different ICS-LABA), or as-needed SABA. Over-use of SABA (e.g. dispensing of three or more 200-dose canisters in a year, corresponding to average use more than daily) increases the risk of asthma exacerbations.123,71 Reducing and, ideally, eliminating the need for SABA reliever is both an important goal in asthma management and a measure of the success of asthma treatment. 52 3. Treating to control symptoms and minimize future risk  Add-on therapies for patients with severe asthma (Section 3E, p.104): these may be considered when patients have persistent symptoms and/or exacerbations despite optimized treatment with high dose controller medications (usually a high dose of ICS plus a LABA) and treatment of modifiable risk factors (see Box 3-8, p.76). Initial controller treatment For the best outcomes, ICS-containing controller treatment should be initiated as soon as possible after the diagnosis of asthma is made, as the evidence suggests that: Early initiation of low dose ICS in patients with asthma leads to a greater improvement in lung function than if symptoms have been present for more than 2-4 years.204,205 One study showed that after this time, higher ICS doses were required, and lower lung function was achieved.206 Patients not taking ICS who experience a severe exacerbation have a greater long-term decline in lung function than those who are taking ICS.122 For patients with occupational asthma, early removal from exposure to the sensitizing agent and early controller treatment increase the probability hyperresponsiveness.44,45 of resolution of symptoms, and improvement of lungTfuEnction and airway Starting treatment increases the risk with SABA alone encourages of poor adherence when daily pICaStieisntssutbosreeqguaerdntiltyapsrethsecirribmeadi.nRIaBsUthma treatment, and Recommended options for initial controller treatment in adults and adolescents, baDsISedTon evidence (where available) and consensus, are listed in 6-11 years are on p.58 and Box 3-4A p.59. The p(pa.t5ie5n)ta'snrdessphoonwsneinshBoouxld3b-4eBre(pvi.e5w6)e.dT,OhaRendcotrrreeastpmoenndtinsgterpepseodurdcoewsnfoornccheildgroeond control is achieved. Recommendations for a stepwise approach to ongoOinPgYtreatment are found in Box 3-5 (p.61). Does FeNO help in deciding whether to commence ICS? T C In studies mainly limited to non-smoking patients, FeNO >50 parNtsOper billion (ppb) has been associated with a good sehviodret-ntecremthreersepfoonresedotoesICnSo.t19m6,e20a7nHtohwateivteisr,stahfeesewisthturdeiegsardd-idDtonOeoxt aecxearmbaintieonthsetolowngitehrh-oteldrmICrSiskinopf aetxieanctesrbwaitthionlosw. Sinuitciahl fFoermNOot.eMrool rveerresucesnatsly-,nienetdweod1S2A-mBAonathndstvuedriseussinmmaiinldtReaInAsatLhnmceaI,CsSev, einredeepxeancdeerbnat toiof nbsasweelirneereindfluacmemd awtiothryacsh-naeraecdteedrisICticSs- including FeNO.190,191 ATE Consequently, in patients with a decision to start ICS, but cannot dbieagunsoesdistoEoDdr esMcuisdpeeacgteadindsitatgrenaotsmiseonft asthma, measurement of FeNO can with ICS. Based on past and current support the evidence, GINA recommends treatment with daIiGlyHloTw dose ICS or as-needed low dose ICS-formoterol for all patients with mild asthma, to reduce the risk of serPioYuRs exacerbations.188-190,208,209 Personalized approach for adCjOusting asthma treatment in adults, adolescents and children 6-11 years old Once asthma treatment has been commenced (Boxes 3-4A-D), ongoing treatment decisions are based on a personalized cycle of assessment, adjustment of treatment, and review of the response. For each patient, in addition to treatment of modifiable risk factors, controller medication can be adjusted up or down in a stepwise approach (Box 3-5A- B) to achieve good symptom control and minimize future risk of exacerbations, persistent airflow limitation and medication side-effects. Once good asthma control has been maintained for 2-3 months, treatment may be stepped down in order to find the patient's minimum effective treatment (Box 3-7, p.75). People's ethnic and racial backgrounds may be associated with different responses to treatment. These are not necessarily associated with genetic differences.210 The contributors are likely to be multifactorial, including differences in exposures, social disadvantage, diet and health-seeking behavior. If a patient has persisting uncontrolled symptoms and/or exacerbations despite 2-3 months of controller treatment, assess and correct the following common problems before considering any step up in treatment: Incorrect inhaler technique 3. Treating to control symptoms and minimize future risk 53  Poor adherence Persistent exposure at home/work to agents such as allergens, tobacco smoke, indoor or outdoor air pollution, or to medications such as beta-blockers or (in some patients) nonsteroidal anti-inflammatory drugs (NSAIDs) Comorbidities that may contribute to respiratory symptoms and poor quality of life Incorrect diagnosis. ASTHMA TREATMENT TRACKS FOR ADULTS AND ADOLESCENTS In the main treatment figure for adults and adolescents (Box 3-5A, p.61), the options for ongoing treatment are shown as two treatment `tracks', with the key difference being the medication that is used for symptom relief: as-needed low dose ICS-formoterol in Track 1 (preferred), and as-needed SABA in Track 2. The reasons for showing treatment in two tracks are, first, to show clinicians how treatment can be stepped up and down using the same reliever at each step, and second, to show that SABA is the appropriate reliever for patients prescribed ICS-non-formoterol-LABA maintenance treatment. Track 1: The reliever is as-needed low dose ICS-formoterol. This is the preferred appUrToaEch recommended by GINA for adults and adolescents, because using reliever' or AIR) reduces the risk of severe eloxwacdeorsbeatIiConSs-fcoormmoptaerreodl awsitrhelrieegviemr e(snosmTweRittIhiBmSeAsBcAallaesdr`ealnietiv-einrf,lawmithmsaitmoriylar symptom control. DIS With this approach, when a patient at any treatment step has asthmaOsRymptoms, they use low dose ICS- fIonrSmtoetpesro3l-in5,apsaitniegnletsinahlsaoletrafkoer IsCySm-pfotormmorteelrioefl aasndthteoirpdroaviliydCecoOthnPetrYiorlalenrtti-rienafltammemnta; ttoorgyetthheerra, pthyi.s is called `maintenance and reliever therapy' or `MART'. NOT Tasrathcmka2:isTshteabrleeliwevitehrgiosoadsa-ndeheedreendceSAanBdAn. oTheixsaicsearbnaat-iltoeDnrOsnaotnivteheapirpcruorarcehntifthTerraacpky1. Hisonwoetvpeor,ssbiebfloer,eopr rifeascpriabtiinegnta's regimen therapy, with SABA reliever, consider whether the as otherwise they will be at higher risk of eRpxaIaAticLeenrtbiastiloiknesly. to be adherent with their ICS-containing controller In Step 1, the patient takes a SABA andAaTElow dose ICS together for symptom relief when symptoms occur (in a cInomStbeipnsat2io-n5,inahSalAerB,Aor(awloithneth) eisIuCEsSDedtaMfkoernsyrimghpttoamfterretlhieef,SaAnBdAth).e patient takes ICS-containing controller medication regularly every dIaGyH. T Doruirtincganonbgeosinwgitctrheeadtmbeentwt,eterenPattYrmaRceknst,caacncoberdsintegptpoetdheupinodirvdidouwanl along one track, using the same patient's needs and preferences. reliever at each step, CO Before stepping up, check for common problems such as incorrect inhaler technique, poor adherence, and environmental exposures, and confirm that the symptoms are due to asthma (Box 2-4, p.43). Underneath the two treatment tracks for adults and adolescents are some additional controller options, that either have limited indications, or for which there is less evidence for their safety and/or efficacy, compared with the treatments in Tracks 1 and 2. 54 3. Treating to control symptoms and minimize future risk Box 3-4A. Initial asthma treatment - recommended options for adults and adolescents Presenting symptoms Preferred INITIAL treatment (Track 1) Alternative INITIAL treatment (Track 2) Infrequent asthma symptoms, e.g. less than twice a month and no risk factors for exacerbations, including no exacerbations in the last 12 months (Box 2-2B, p.36) As-needed low dose ICSformoterol (Evidence B) Low dose ICS taken whenever SABA is taken, in combination or separate inhalers (Evidence B) Asthma symptoms or need for reliever twice a month or more As-needed low dose ICSformoterol (Evidence A) Low dose ICS with as-needed SABA (Evidence A). Before choosing this option, consider likely adherence with daily ICS. Troublesome asthma symptoms most days (e.g. 4-5 days/week); Low dose ICS-formoterol maintenance and reliever therapy SLoAwBAdo(EsevidICeSnUc-LTeAEAB),AOwRith as-needed or waking due to asthma once a (Evidence A) Medium dToRsIeBICS with as-needed SABA week or more, especially if any risk factors exist (Box 2-2B, p.36) (wEitvhiddDeanIiSclyecAo)n.trCoollnesr.ider likely adherence Initial asthma presentation is with Medium dose ICS-formoterol YMOeRdium or high dose ICS-LABA severely uncontrolled asthma, or with an acute exacerbation maintenance (Evidence D). AansdhorertliceovuerrsethoefroarpCayOl P (Evidence D) with as-needed SABA. Consider likely adherence with daily corticosteroids may also be NneOeTded. controller. A short course of oral corticosteroids may also be needed. High - DO dose ICS with as-needed SABA is another option (Evidence A) but adherence is poor RIAL compared with combination ICS-LABA. Before starting initial controller treatment ATE Record Record evidence for the patient's ltehveedl ioafgsnyomsipstoomf EacDsothnMmtroal. and risk factors, including lung function (Box 2-2, p.36). Consider factors influencing choIGiceHTbetween available treatment options (Box 3-3, p.50), including likely adherence with Ensure that the pdaatiliyenctocnatrnoPlulYesRre, particularly the inhaler if the reliever correctly. is SABA. Schedule an appointmeCnOt for a follow-up visit. After starting initial controller treatment Review patient's response (Box 2-2, p.36) after 2-3 months, or earlier depending on clinical urgency. See Box 3-5 (p.61) for recommendations for ongoing treatment and other key management issues. Check adherence and inhaler technique frequently. Step down treatment once good control has been maintained for 3 months (Box 3-7, p.75). ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; SABA: short-acting beta2-agonist. This table is based on evidence from available studies and consensus, including considerations of cost and likely adherence with controller therapy. See also Box 3-4B (p.56) for where to start on the main treatment figure for adults and adolescents. See Box 3-6, p.63 for low, medium and high ICS doses for adults and adolescents. 3. Treating to control symptoms and minimize future risk 55 Box 3-4Bi. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma (V1) IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: shortacting beta2-agonist. See Box 3-6, p.63 for low, medium and high ICS doses for adults and adolescents. 56 3. Treating to control symptoms and minimize future risk Box 3-4Bii. Selecting initial controller treatment in adults and adolescents with a diagnosis of asthma (V2) IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist See Box 3-6, p.63 for low, medium and high ICS doses for adults and adolescents. 3. Treating to control symptoms and minimize future risk 57 Box 3-4C. Initial asthma treatment - recommended options for children aged 6-11 years Presenting symptoms Preferred INITIAL treatment Infrequent asthma symptoms, e.g. less than twice a month and no risk factors for exacerbations (Box 22B, p.36) As-needed SABA Other options include taking ICS whenever SABA is taken, in combination or separate inhalers. Asthma symptoms or need for reliever twice a month or more, but less than daily Low dose ICS with as-needed SABA (Evidence A), or Other options include daily LTRA (less effective than ICS, Evidence A), or taking ICS whenever SABA is taken in combination or separate inhalers (Evidence B). Consider likely adherence with controller if reliever is SABA. Troublesome asthma symptoms most Low dose ICS-LABA with as needed SABA (Evidence A), OR days (e.g. 4-5 days/week); or waking due to asthma once a week or more, Medium dose ICS with as-needed SABA (EvUidTeEnce A), OR especially if any risk factors exist (Box 2-2B) VeryOltohwer dooptsioenIsCiSn-cflourdmeolotewrodlomseaIiCntSenwaTitnRhcIdeBaailny dLTreRlAie,vweirth(EavsidneenecdeeBd )SABA. DIS Initial asthma presentation is with severely uncontrolled asthma, or with Start regular SABA or low cdoonsteroIlCleSr -tfroeramtmoteenrot lOwmiRthaimnteedniaunmcedoasned ICS-LABA with as-needed reliever (MART). A short an acute exacerbation course of OCS may also beOnPeeYded. Before starting initial controller treatment T C Record evidence for the diagnosis of asthma, if possibleN. O Record the child's level of symptom control and ris-kDfaOctors, including lung function (Box 2-2, p.36, Box 2-3, p.37). CEnosnusrideetrhfaatctthoerschinilfdluecanncinugsechthoeicienhbaeltewreceonrRraeIvcAatlLyila. ble treatment options (Box 3-3, p.50). Schedule an appointment for a follow-upAvTiEsit. After starting initial controller treatmEenDt M Review child's response (BoIxG2H-2T, p.36) after 2-3 months, or earlier depending on clinical urgency. See Box 3-5B (p.62) Step down treatment foonrPcrYeecRgoomomd ecnodntartoiol nhsasfobreoenngmoinaginttareinaetmd efonrt and other 3 months key management (Box 3-7, p.75). issues. CO ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta2-agonist. This table is based on evidence from available studies and consensus, including considerations of cost. See also Box 3-4D (p.59) for where to start on the main treatment figure for children 6-11 years. See Box 3-6, p.63 for low, medium and high ICS doses in children. 58 3. Treating to control symptoms and minimize future risk Box 3-4Di. Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V1) IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist. See Box 3-6, p.63 for low, medium and high ICS doses in children. 3. Treating to control symptoms and minimize future risk 59 Box 3-4Dii. Selecting initial controller treatment in children aged 6-11 years with a diagnosis of asthma (V2) IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist. See Box 3-6, p.63 for low, medium and high ICS doses in children. 60 3. Treating to control symptoms and minimize future risk Box 3-5A. Personalized management for adults and adolescents to control symptoms and minimize future risk IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO HDM: house dust mite; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: shortacting beta2-agonist; SLIT: sublingual immunotherapy. For recommendations about initial asthma treatment in adults and adolescents, see Box 3-4A (p.55) and 3-4B (p.56). See Box 3-6, p.63 for low, medium and high ICS doses for adults and adolescents. 3. Treating to control symptoms and minimize future risk 61 Box 3-5B. Personalized management for children 6-11 years to control symptoms and minimize future risk IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO BUD-FORM: budesonide-formoterol; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; MART: maintenance and reliever therapy with ICS-formoterol; OCS: oral corticosteroids; SABA: short-acting beta2-agonist. For initial asthma treatment in children aged 6-11 years, see Box 3-4C (p.58) and Box 3-4D (p.59) See Box 3-6, p.63 for low, medium and high ICS doses in children. 62 3. Treating to control symptoms and minimize future risk Box 3-6. Low, medium and high daily metered doses of inhaled corticosteroids (alone or with LABA) This is not a table of equivalence, but instead, suggested total daily doses for `low', `medium' and `high' dose ICS options for adults/adolescents (Box 3-5A, p.61) and children 6-11 years (Box 3-5B, p.62), based on product information. Few data are available for comparative potency, so this table does NOT imply potency equivalence. Doses may differ by country, depending on local products, regulatory labelling and clinical guidelines or, for one product, with addition of a LAMA to an ICS-LABA.211 Low dose ICS provides most of the clinical benefit of ICS for most patients with asthma. However, ICS responsiveness varies between patients, so some patients may need medium dose ICS if their asthma is uncontrolled, or they have ongoing exacerbations, despite good adherence and correct technique with low dose ICS (with or without LABA). High dose ICS (in combination with LABA or separately) is needed by very few patients, and its long-term use is associated with an increased risk of local and systemic side-effects, which must be balanced against the potential benefits. Daily doses in this table are shown as metered doses. See product information for deliveUreTdEdoses. Adults and adolescents (12 years and older) TRIB Inhaled corticosteroid TotaLlodwaiDlyISICS dose (mcg) Medium - see notes above High Beclometasone dipropionate (pMDI, standard particle, HFA) 200O-5R00 >500-1000 >1000 Beclometasone dipropionate (DPI or pMDI, extrafine particle, HFA) COP1Y00-200 200-400 >200-400 >400-800 >400 >800 Budesonide (DPI, or pMDI, standard particle, HFA) Ciclesonide (pMDI, extrafine particle, HFA) NOT 80-160 >160-320 >320 Fluticasone furoate (DPI) - DO 100 200 Fluticasone Fluticasone propionate propionate (DPI) (pMDI, standard particle, HRFIAAL) 100-250 100-250 >250-500 >250-500 >500 >500 Mometasone furoate (DPI) ATE Depends on DPI device - see product information Mometasone furoate (pMDI, standard pEaDrticMle, HFA) 200-400 >400 CBheicldlormenet6a-s1o1neyedaiprrsop-iosneaeteno(pteMsDIGaI,bHsoTtvaend(faorrdcphailrdtircelne,5HyFeAa)rs and younger, see 100-200 Box 6-6, p.166) >200-400 >400 Beclometasone dipropionateP(pYMRDI, extrafine particle, HFA) 50-100 >100-200 >200 Budesonide (DPI) CO 100-200 >200-400 >400 Budesonide (nebules) 250-500 >500-1000 >1000 Ciclesonide (pMDI, extrafine particle*, HFA) 80 >80-160 >160 Fluticasone furoate (DPI) 50 n.a. Fluticasone propionate (DPI) 50-100 >100-200 >200 Fluticasone propionate (pMDI, standard particle, HFA) 50-100 >100-200 >200 Mometasone furoate (pMDI, standard particle, HFA) 100 200 DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled corticosteroid; LABA: long-acting beta2-agonist; LAMA: long-acting muscarinic antagonist; n.a. not applicable; pMDI: pressurized metered dose inhaler; ICS by pMDI should preferably be used with a spacer. For new preparations, including generic ICS, the manufacturer's information should be reviewed carefully, as products containing the same molecule may not be clinically equivalent. For more detailed discussion see Raissy et al.123 Combination inhalers that include a long-acting muscarinic antagonist (LAMA) may have different ICS dosing - see product information. 3. Treating to control symptoms and minimize future risk 63 Choice of medication, device and dose In clinical practice, the choice of medication, device and dose for controller and reliever should be based for each individual patient on assessment of symptom control, risk factors, patient preference, and practical issues (cost, ability to use the device, and adherence) (Box 3-3, p.50). It is important to monitor the response to treatment and any sideeffects, and to adjust the dose accordingly (Box 3-5, p.61). Once good symptom control has been maintained for 2-3 months, the ICS dose should be carefully titrated to the minimum dose that will maintain good symptom control and minimize exacerbation risk, while reducing the potential for side-effects (Box 3-7, p.75). Patients who are being considered for a high daily dose of ICS (except for short periods) should be referred for expert assessment and advice, where possible (Chapter 3E, p.104). There is currently insufficient good quality evidence to support use of extra-fine particle ICS aerosols over others.212 More detail about asthma medications is provided in Appendix Chapter 5 (adults and adolescents: Part 5A; children 6-11 years: Part 5B). Below is more detail about the evidence for each of the treatments shown in Box 3-5A and 3-5B. Clinicians should check laodcoalleeslcigeinbtislitsyhaonudldpraeyceerivceritaenriaICbSe-fcoorentpariensincgribcionngt.roAllsers,hinocwonrpinortahteesdeafsigupraerts,oGf tIhNeApraetcieonmtU'msTpeEenrdssotnhaalitzaeldl aadsuthltms aand amsa-nnaeegdeemdenlotw. TdhoeseICISC-Sc-ofnotraminoitnegroml feodricsaymtiopntosmhoruelldiebf.eBtoaxke3n-6e(vpe.r6y3d) aliystosrs, uinggmeisldteadsTtlRohwmIB,am, aendiaulmterannadtivheigihs to take doses for several different ICS formulations. DIS ASTHMA TREATMENT STEPS OR GINA treatment recommendations for adults, adolescents and children wOePrYe updated in 2021 after a review of evidence for Steps 1-5. The treatment figure with the key difference between the for adults and `tracks' being tahdeotlyepsceeonftsre(lBieovOxeTr3(-Cl5oAw, p.61) dose shows treatment ICS-formoterol or options SABA; in two `tracks', see p.54). Track 1, efficacy, with as-needed low dose ICS-formoterol effectiveness and safety for lower risk of assevtheerereelxieaDvcOeerr,bNiastitohnesp, rweiftehrrseimd ialaprpsroymacphto, bmacsoendtoronl evidence for compared with controller medications plus as-needed SABA in TraEckR2IA. L - STEP 1 MAT Preferred Step 1 treatment for adults andTEaDdolescents: low dose combination ICS-formoterol taken as needed for relief of symptoms, and if needed beIfGoHre exercise (Track 1) GINA Step 1 recommendations ParYeRfor: Ignriotiuapl athstahtmisaratrreealytmsCetunOdtieindpatients with symptoms less than twice a month and no exacerbation risk factors, a Step-down treatment for patients whose asthma is well-controlled on regular ICS or LTRA Use of low dose ICS-formoterol as needed for symptom relief in Step 1 for adults and adolescents (Evidence B) is supported by indirect evidence for a reduction in risk of severe exacerbations compared with as-needed SABA alone, from a large double-blind study188 and an open-label study190 in patients who were eligible for Step 2 therapy (see below), and by direct evidence from two studies for stepping down from maintenance controller treatment.213 Four large studies showed a similar or greater reduction in severe exacerbations compared with daily ICS, with no clinically important difference in symptom control or lung function.173,174,180,182 For patients previously taking SABA alone, the risk of severe exacerbations was 26% lower with as-needed ICS-formoterol compared with daily ICS;213 it was also significantly lower than with daily ICS in an open-label study in patients previously taking SABA alone.190 Among patients stepping down from regular ICS or LTRA, as-needed ICS-formoterol was associated with a similar213 or greater209 reduction in severe exacerbations compared with taking daily ICS. Findings were similar in the adolescent subgroup.214 No new safety signals were seen with as-needed budesonide-formoterol in mild asthma.189-191,215,216 64 3. Treating to control symptoms and minimize future risk The most important considerations for GINA in extending the recommendation for as-needed low dose ICS- formoterol to Step 1 were: Patients with few interval asthma symptoms can still have severe or fatal exacerbations.160 GINA recommends assessing and addressing risk factors for exacerbations as well as symptom control (Box 2-2). The historic distinction between so-called `intermittent' and `mild persistent' asthma is arbitrary, with no evidence of difference in response to ICS.162 A large reduction in risk of severe exacerbations with as-needed ICS- formoterol compared with as-needed SABA was seen even in patients with SABA use twice a week or less at baseline.190 A post hoc analysis of one study found that a single day with increased as-needed budesonide-formoterol reduced the short-term (21-day) risk of severe exacerbations compared to as needed SABA alone, suggesting that timing of use of ICS-formoterol is important.75 In patients with infrequent symptoms, adherence with prescribed daily ICS is very poor,217 exposing them to risks of SABA-only treatment if they are prescribed daily ICS plus as-needed SABA There is a lack of evidence SABA-only treatment were for the based safety on the or efficacy of SABA-only assumption that patients wtreithatmmieldnta. sHthiUsmtToaEricworeucldomnomtebnednaetfioitnfrsofmorICS Taking airway SABA regularly for as little as one week significantly increases hyperresponsiveness and airway inflammation, and decreases ebxroenTrccRihsIoBed-iinladtuocr eredsbproonnsceh.o21c8onstriction, Even modest over-use of SABA (indicated by dispensing of 3 or more D20IS0-dose canisters a year) is associated with increased risk of severe exacerbations123 and, in one study, aOstRhma mortality.71 An important consideration avoid conflicting messages finoraGstIhNmAaweadsutcoaatiovoni.dPerestvaiobulisshlyin,OpgPaptYaietnietsntwreelrieanincietiaolnly SABA, and the priority to provided only with SABA for symptom relief, but later, despite this treatment in order to reduce their SABA use, they needed btoeitnagkeeOfafTedcCativilye from the patient's perspective, controller even when they had they were told no symptoms. that Recommending that all patients should be providedOwNith a controller from the start of therapy (including, in mild raesltiehfmaan,dthreiskopretidouncotifoans,-annededmeadyICavSo-fidoremsotatebLrlios-lh)Dianlglopwasticeonnt sreislitaennct emoenssSaAgBinAg about the need for both symptom as their main asthma treatment. Practice points for as-needed ICS-formoterol in mERildIAasthma T16h0e/4u.s5u),atladkoesnewohfeanse-vneerendeeeddbeuddfeosrosnyimdep-MtfoomArmTroetleierof.lTinhemmildaaxsimthumma is a single inhalation of 200/6 mcg (delivered dose recommended dose of as-needed budesonide- formoterol in a single day correspondsTtEoDa total of 72 mcg formoterol (54 mcg delivered dose). However, in RCTs in mild asthma, Chapter 5 for such high usage an illustration of rwealesIvGraaHnrtemlyesdeiecant,iownitshaanvderdaogseesu.se around 3-4 doses per week.188-190 See Appendix Rinsing the mouth is not gePnYeRrally needed after as-needed use of low dose ICS-formoterol, as this was not required in any of the mild asthmaCsOtudies (or in MART studies), and there was no increase in risk of oral thrush.216 ICS-formoterol formulations other than budesonide-formoterol have not been studied for as-needed-only use, but beclometasone-formoterol may also be suitable. Both of these medications are well-established for as-needed use within maintenance and reliever therapy in GINA Steps 3-5.193 For pre-exercise use in patients with mild asthma, one 6-week study showed that use of low dose budesonideformoterol for symptom relief and before exercise reduced exercise-induced bronchoconstriction to a similar extent as regular daily low dose ICS with SABA for symptom relief and before exercise.219 More studies are needed, but this study suggests that patients with mild asthma who are prescribed as-needed ICS-formoterol to prevent exacerbations and control symptoms can use the same medication prior to exercise, if needed, and do not need to be prescribed a SABA for pre-exercise use (Evidence B). Alternative Step 1 treatment options for adults and adolescents (Track 2) Low dose ICS taken whenever SABA is taken (Evidence B): There is much less evidence about the safety and efficacy of this approach than for as-needed ICS-formoterol, but it may be an option in countries where ICS-formoterol is not available or affordable. In Step 1, the evidence for this strategy is indirect, from studies with separate or combination ICS 3. Treating to control symptoms and minimize future risk 65 and SABA inhalers in patients eligible for Step 2 treatment (see below).220-223 In making this recommendation, the most important considerations were reducing the risk of severe exacerbations, and the difficulty of achieving good adherence with regularly prescribed ICS in patients with infrequent symptoms. Regular daily low dose ICS has been suggested by GINA since 2014 for consideration in Step 1, for patients with symptoms less than twice a month, to reduce the risk of exacerbations. This was based on indirect evidence from studies in patients eligible for Step 2 treatment162,215,224 (Evidence B). However, patients with symptoms less than twice a month are extremely unlikely to take ICS regularly even if prescribed, leaving them exposed to the risks of SABA-only treatment, so for feasibility reasons, this regimen is no longer recommended for general use in such patients. Step 1 treatment options for children 6-11 years Possible controller options for this age-group include taking ICS whenever SABA is taken, based on indirect evidence from Step 2 studies with separate inhalers in children and adolescents. One of these studies showed substantially fewer exacerbations compared with SABA-only treatment,221 and another showed similar outcomes as physician-adjusted treatment but for this age-gr with oup lower average ICS dose223 (Evi (Evidence B), but the likelihood dence B). Regular of poor adherence ICS in c with as hildren -wniethedinefdreSqUuAeBTnEAt is sy also a possible mptoms should opti be on taken into account. TRIB There have been no studies of as needed-only ICS-formoterol in SABA-only treatment are also relevant to children and should be cchoinldsrideenraegdewdh6e-nD1iI1nSiytieaatirnsg. However, concerns around Step 1 treatment (see other controller options for children below). OR Not recommended OPY GINA no longer recommends SABA-only treatment of asthma inTaCdults or adolescents. Although inhaled SABAs are highly effective for the quick relief of asthma symptoms,225 paNtiOents whose asthma is treated with SABA alone (compared healthcare with ICS) are at (Evidence A),227 increas even if ethderyishkaovfeagsothomd as-yrmelpattoe-mdDdcOeoantthro(lE.2v28idTehnec e r A) isk 71,2 of 26 and urgent asthma-r asthma exacerbations elated and m ortal ity increases incrementally with higher SABA use, regular SABA in patients with newly diagnosed iansctlhumdRianIAgsLhinowpaetdiewntosrstreeoatuetdcowmitehsSaAnBdAloawloenr elu.7n1gOfunnecltoionng-tthearmn instupdaytieonfts who were treated with daily low dose ICS from thAeTsEtart.229 Isnymadputoltms,sin; hhoawleedvaenr,titchheoslienearggeicntasgheanvtse laikEselDoipwrMaetrroopnisuemt oafraecptiootnenthtiaanl ainlthearnleadtivSeAsBtoA.SOArBaAl SfoArBrAouatinndetrheelioepf hoyflalinsethhmaave raishkigohfesrervisekreoef xsaidcee-rebfafeticotnssawndithartheensIoGetHrreeTlcieovmemr meneddeicda.tNioonsloinngp-atetiremntssanfeottyaslstuodtiaeksinhgavICe Sb.eUensepeorffolornmge-adcttoinagssess the mexuasccearrbinaitcioannst.a23g0onists (LAMCAO) PinYaRsthma without concomitant ICS is associated with an increased risk of severe The rapid-onset LABA, formoterol, is as effective as SABA as a reliever medication in adults and children,231 and reduces the risk of severe exacerbations by 15-45% compared with as-needed SABA,232-234 but use of regular or frequent LABA without ICS is strongly discouraged because of the risk of exacerbations130,235 (Evidence A). STEP 2 Preferred Step 2 treatment for adults and adolescents: low dose ICS-formoterol, taken as-needed for relief of symptoms and, if needed, before exercise (Track 1) The current evidence for this combination controller + reliever treatment is with low dose budesonide-formoterol: A large double-blind study in mild asthma found a 64% reduction in severe exacerbations compared with SABAonly treatment,188 with a similar finding in an open-label study in patients with mild asthma previously taking SABA alone.190 (Evidence A). 66 3. Treating to control symptoms and minimize future risk  Two large double-blind studies in mild asthma showed as-needed budesonide-formoterol was non-inferior for severe exacerbations compared with regular ICS.188,189 In two open-label randomized controlled trials, representing the way that patients with mild asthma would use as-needed ICS-formoterol in real life, as-needed budesonide-formoterol was superior to maintenance ICS in reducing the risk of severe exacerbations190,191 (Evidence A). In all four studies, the as-needed ICS-formoterol strategy was associated with a substantially lower average ICS dose than with maintenance low dose ICS.173,174,180,182 Clinical outcomes with as-needed ICS-formoterol were similar in adolescents as in adults.214 A post hoc analysis of one study188 found that a day with >2 doses of as-needed budesonide-formoterol reduced the short-term (21 day) risk of severe exacerbations compared to as needed terbutaline alone, suggesting that timing of use of ICS-formoterol is important.75 A Cochrane review provided moderate to high certainty evidence that as-needed ICS-formoterol was clinically effective in adults and adolescents with mild asthma, significantly reducing important clinical outcomes including need for oral corticosteroids, severe admissions compared with daily ICS exacerbation rates, (Evidence A).163,216 and emergency departUmTeEnt visits or hospital No new safety signals were seen with as-needed budesonide-formoterol inTRmIiBld asthma.189-191,215 ThemosTthiemnpeoerdtatontpcreovnesnidt seeravteiroenesxfaocreGrbIaNtAionins minapkaintigenthtsiswreithcommilmdeonrdinaftrioeDnqIuSfoerntassy-nmepetdoemdsI;CthSe-fsoermcaonteoroclc,uwrewreit:h unpredictable triggers such as viral infection, allergen exposure, pOolRlution or stress. The desire to adherent with avoid the need for daily prescribed ICS, leaving ICS in patients them exposed twoitthhemriOilsdkPasYsothf mSAa,BwAh-oonilny clinical practice treatment. are often poorly The greater reduction in severe exacerbations with as-neTedCed ICS-formoterol compared with daily ICS among patients previously taking SABA alone; with no signifiNcaOnt difference for patients with well-controlled asthma on ICS The or LTRA at baseline.190,213 very small differences in FEV1, (~30-50 mL-)D, sOymptom control (difference in ACQ-5 of ~0.15 vs minimal cwliitnhicraelglyuilmarpIoCrStanwtedreiffecorennscidee0re.5d),toanbde sleyRsmsIpAitmLompo-rfrtaenet.dTayhses(me edaiffnerdeifnfecreesnwceer1e0n.6otdcauyms upleartiyveeaor)v1e88r,1t8h9ecompared 12-month studies. The primary outcoAmTeEvariable of one study188 was `well-controlled asthma weeks', but this osyustcteommaetiwcaalslynboitacseodnsaidgearinesdtrtehEleiaDabMsle-nbeeecdaeudseICitSw-faosrmboatseerdolotrneaantmeeanrtliegrrocuopncbeepctaoufsaesmthumcah cleosnstrIoCl,Sawndaswas permitted classified ainsanowteweekllf-ocropnatIrGtoielHlneTtds. on ICS-formoterol than those on maintenance ICS before the week was FweaNs Onowsaigsnsifigicnaifnict adnifPtfleyYrerRendcueciendtrweaithtmbeontht eafsfe-ncet ewditehdabsu-ndeeesdoendidbeu-fdoermsoonteidreo-lfaonrmd omtearionltebnyabnacseeIlCinSe,eaonsdintohpehreils or baseline CO FeNO.190,191 Because as-needed ICS-formoterol is the preferred treatment for both Steps 1 and 2 in adults and adolescents, these steps have been combined in the treatment figure (Box 3-5A, p.61) to avoid confusion. Practice points for as-needed ICS-formoterol in mild asthma The usual dose of as-needed budesonide-formoterol in mild asthma is a single inhalation of 200/6 mcg (delivered dose 160/4.5), taken whenever needed for symptom relief. Based on product information, the maximum recommended dose of budesonide-formoterol in a single day is a total of 72 mcg formoterol (54 mcg delivered dose). However, in the randomized controlled trials in mild asthma, such high usage was rarely seen, and average use of as-needed ICSformoterol was around 3-4 doses per week.188-191 Rinsing the mouth is not generally needed after as-needed use of low dose ICS-formoterol, as this was not required in any of the mild asthma studies (or MART studies), and there was no increase in risk of oral thrush. Other ICS-formoterol formulations have not been studied for as-needed-only use, but beclometasone-formoterol may also be suitable. Both of these medications are well-established for as-needed use within maintenance and reliever 3. Treating to control symptoms and minimize future risk 67 therapy (MART) in GINA Steps 3-5.193 No new safety signals were seen in four studies with as-needed budesonideformoterol in mild asthma.189-191,215 For pre-exercise use in patients with mild asthma, one study showed that budesonide-formoterol taken as-needed and before exercise had similar benefit in reducing exercise-induced bronchoconstriction as daily ICS with SABA as-needed and pre-exercise.219 More studies are needed, but this suggests that patients with mild asthma who are prescribed asneeded ICS-formoterol to prevent exacerbations and control symptoms can use the same medication prior to exercise, if needed, and do not need to be prescribed a SABA for pre-exercise use (Evidence B). Alternative Step 2 treatment for adults and adolescents: daily low dose ICS plus as-needed SABA (Track 2) For regular daily low dose ICS plus as-needed SABA in patients with mild asthma, the burden of symptoms is low, so the most important consideration was to reduce the risk of severe exacerbations. There is a large body of evidence from RCTs and observational studies showing that the risks of severe exacerbations, hospitalizations and mortality are substantially reduced with reduced215,224,226,236,237 (Ev regular low dose ICS; symptoms idence A). Severe exacerbations and exercise-induc are halved with low eddosberoInCcShoecvoeTnnEsitnricptaiotnie are nts also with symptoms 0-1 days increase in pre- and paowste-ebkro.1n6c2 hInodailmateotraF-aEnValy%sisproefdliocntegdit,uidninaadluslttusdbiuets,nroetginulcahr iIlCdrSenwR,acIsBomUaspsaorceidatwedithwSithABaAvearlyonsem.2a3l8l However, when prescribing daily ICS for a 1 patient with mild asthma, clinicians shoDuIldSTbe aware that adherence with maintenance ICS in the adherent with daily ICS, ceoxmpomsuinngitythiesmexttoretmheelryislkoswo. fTShAeyBAsh-oonullydtcreoantsmideenrt.thOe Rlikelihood that the patient will be poorly Over-use of SABA, indicated by dispensing of three or more 200-dose cOanPiYsters of SABA in a year (i.e. average use more than daily), is associated with an increased risk of severe T C exacerbations71,133 and, in one study, with increased mortality,71 even in patients also taking ICS-containing controllerN. O Other Step 2 treatment options for adults and adolescents - DO Low dose formoterol ICS taken whenever is not available, and SthAeBpAatiisenutseisdu(ninlikceolymRtboIinAtaaLktieonreogruslaerpaICraSt.eTinhheaelevrisd)eniscaenisotfhroemr otpwtioonstiuf daise-sneineaddeudltIsCaSn-d two studies in children and difference in exacerbations acdoomlepsacreendtsw,itwhitdhasileypAIaCTrSaE.te or combination ICS and SABA inhalers,220-222,239 showing no Leukotriene receptor antagonists (LTRA) aEreDleMss effective than ICS,240 particularly for exacerbations (Evidence A). Bcoeufonrseelpleredsacbriobuintgthmeornistkeloufkanestu,rhoepaslyIthGchHpiarTotrfiecsesvioennatsls. should consider In 2020, the US its benefits and Food and Drug risks, and patients should be Administration (FDA) required a boxed warning to be added abouPtYthRe risk of serious mental health adverse effects with montelukast.241 For adult or as the initial amdaoilnetsecneanntcpeactioeCnnttOrsonlleort previously using controller treatment, regular daily combination low dose treatment reduces symptoms and improves lung function compared with ICS-LABA low dose ICS alone.242 However, it is more expensive and does not further reduce the risk of exacerbations compared with ICS alone242 (Evidence A). No comparison between regular and as-needed ICS-formoterol has been studied in patients eligible for Step 2 treatment. For patients with purely seasonal allergic asthma, e.g. with birch pollen, with no interval asthma symptoms, regular daily ICS or as-needed ICS-formoterol should be started immediately symptoms commence, and be continued for four weeks after the relevant pollen season ends (Evidence D). Preferred Step 2 treatment for children 6-11 years The preferred controller option for children at Step 2 is regular low dose ICS with as-needed SABA (see Box 3-6, p.63 for ICS dose ranges in children). 68 3. Treating to control symptoms and minimize future risk Alternative Step 2 treatment for children 6-11 years Another controller option for children is taking low dose ICS whenever SABA is taken, based on the results of two studies with separate ICS and SABA inhalers in patients aged between 5 years and 17 or 18 years.221,223 Interviews with parents indicated that those whose children were randomized to as-needed ICS+SABA felt more in control of their child's asthma than those whose children were randomized to physician-based adjustment.223 Another option is daily LTRA, which overall is less effective than ICS.240 The FDA warning about montelukast (above) also applies to its use in children.241 Not recommended Sustained-release theophylline has only weak efficacy in asthma243-245 (Evidence B) and side-effects are common, and may be life-threatening at higher doses.246 Use of long-acting muscarinic antagonists (LAMA) in asthma without concomitant ICS is associated with an increased risk of severe exacerbations.230 Chromones (nedocromil sodium and sodium cromoglycate) had burdensome daily washing a favorable safety profile to avoid blockage; these bmuetdloicwateioffnicsahcayv24e7-b24e9e(nEvdiidseconncetinAu)e, daTngEdlotbhaelliry.pMDI inhalers required RIBU STEP 3 DIST Before considering a step up, check for common problems such as incoYrreOcRt inhaler technique, poor adherence, and environmental exposures, and confirm that the symptoms are due tCoOaPsthma (Box 2-4, p.43). Preferred (Track 1) Step 3 treatment for adults and adolescents: lowNdOosTe ICS-formoterol maintenance and reliever therapy Ftreoar tamdeunltts(aMnAdRaTd)o.lIensctheinstsre,gthimee`pnr,elfoewrreddo'sSetIeCpS3-foorpmtioon-teDirsoOll,oewitdhoesr ebuICdeSs-foonrimdeo-tfeorroml aostebroolthormbaeicnltoemnaentacseoanned-forermlieovteerrol, is used as both the maintenance treatment and foRr sIAymL ptom relief. In adult therapy arendduacdeodleesxcaecnetrbpaattiioennstsawnidthpro1veidxeadcAesrTimbEailtaiornleivnetlhseopf raesvtihomusa year, ICS-formoterol maintenance and reliever control at relatively low doses of ICS, compared w(EitvhidaenfixceedAd).oIsneoopfeInC-Sla-bLeAlBsAtuadsiems tahinattEedDnidaMnncoet treatment or a higher dose require a history of severe of ICS, both with as-needed exacerbations, maintenance SABA250-255 and reliever therapy with ICS-formoterol also sIiGgnHifTicantly reduced severe exacerbations, with a lower average dose of ICS.250,256 Ffoormr poatetieronltsinparessincgrilbeeddaIyC,Sb-afPosreYmdRootnerporlomduacintteinnfoarnmceataionnd, reliever therapy, the maximum recommended dose of is 72 mcg metered dose (54 mcg delivered dose) for budesonide-formoterol anCdO48 mcg metered dose (36 mcg delivered dose) for beclometasone-formoterol. ICS-formoterol should not be used as the reliever for patients taking a different ICS-LABA maintenance treatment, since clinical evidence for safety and efficacy is lacking. Alternative Step 3 treatment for adults and adolescents: maintenance ICS-LABA plus as-needed SABA (Track 2) Maintenance ICS-LABA with as-needed SABA: This is an alternative approach if MART is not possible, or if a patient's asthma is stable with good adherence and no exacerbations on their current therapy. For patients receiving maintenance ICS with as-needed SABA, adding LABA in a combination inhaler provides additional improvements in symptoms and lung function with a reduced risk of exacerbations compared with the same dose of ICS,257,258 (Evidence A) but there is only a small reduction in reliever use.259,260 However, before prescribing a regimen with SABA reliever, consider whether the patient is likely to be adherent with their ICS-containing controller therapy, as otherwise they will be at higher risk of exacerbations. Currently approved combination ICS-LABA inhalers for Step 3 maintenance treatment of asthma include low doses of fluticasone propionate-formoterol, fluticasone furoate-vilanterol, fluticasone propionate-salmeterol, beclometasone- 3. Treating to control symptoms and minimize future risk 69 formoterol, budesonide-formoterol, mometasone-formoterol and mometasone-indacaterol (see Box 3-6, p.63). Effectiveness of fluticasone furoate-vilanterol over usual care was demonstrated for asthma symptom control in a large real-world study; there was no difference in risk of exacerbations.261,262 Other Step 3 controller options for adults and adolescents For adult patients with allergic rhinitis and sensitized to house dust mite, with suboptimally controlled asthma despite low to high dose ICS, consider adding sublingual allergen immunotherapy (SLIT), provided FEV1 is >70% predicted.263,264 (see p.77). Another option for adults and adolescents is to increase ICS to medium dose146 (see Box 3-6, p.63), but at a group level this is less effective than adding a LABA265,266 (Evidence A). Other less efficacious options are low dose ICS-containing therapy plus either LTRA267 (Evidence A) or low dose, sustained-release theophylline268 (Evidence B). See note above about the FDA warning for montelukast.241 Preferred Step 3 treatment for children 6-11 years TE Ipnrecfheirlrderedno,patfiotenrscahteackpinogpuinlahtaiolenrletevcehl:ntioquinecarenadsaedIhCeSretnocme,eadniudmtredoastieng(smeeodBifoiaxb3le-6r,ispRk.6IfBa3cU),t2o6r9s(,Ethveidreenacree Ath)roerechange to combination low dose and reliever therapy with ICS-LABA a very low (Evidence A),270 both with as-needed SABA dose of ICS-formoterol (Evidence B).271 In a rleaDlriIgeSevTesrt,uodrytoofscwhiitlcdhretno maintenance aged 4-11 years waliothnea fhoirsstoervyeoref aenxaecxearcbeartbioantiso,nwiniththneopdreiffveioreunscyeeianr,scyommpbtoinmatcioonntIrColSo-rLAreBliAeOvweRar susneo.n27-2inIfnercihoirldtoretnh,eassaimngeledostsuedoyfoIfCS maintenance and reliever therapy with very low dose budesonide-formoOteProYl (100/6 metered dose, 80/4.5 mcg delivered dose for both maintenance and reliever) showed a large budesonide-formoterol with SABA reliever, or compared wreidthuchtiigohneOirnTdeoCxsaecIeCrbSa.2ti7o1ns compared with the same dose of Individual children's responses vary, so the other controller opOtioNns above should be tried before considering Step 4 treatment.273 L - D Other Step 3 In children, ttrheeartemiesnlitttolepteiovnidsefnocrechfoilrdaredndi6n-g1L1TyReAarEtsoRloIAw dose ICS.267 The FDA warning about montelukast (above) also applies to its use in children.241 MAT STEP 4 TED IGH Although at a group level most bPeYneRfit from ICS is obtained at low dose, individual ICS responsiveness varies, and some patients whose asthma is unCcoOntrolled on low dose ICS-LABA despite good adherence and correct inhaler technique may benefit from increasing the maintenance dose to medium. High dose ICS is no longer recommended at Step 4. Before stepping up, check for common problems such as incorrect inhaler technique, poor adherence, and environmental exposures, and confirm that the symptoms are due to asthma (Box 2-4, p.43). Preferred Step 4 treatment for adults and adolescents: medium dose ICS-formoterol maintenance and reliever therapy (Track 1) For adult and adolescent patients, combination ICS-formoterol as maintenance and reliever treatment is more effective in reducing exacerbations than the same dose of maintenance ICS-LABA or higher doses of ICS254 (Evidence A). The greatest reduction in risk was seen in patients with a history of severe exacerbations,193 but MART was also significantly more effective than conventional best practice in open label studies in which patients were not selected for greater exacerbation risk.223 In Step 4, the MART regimen can be prescribed with medium dose budesonide-formoterol or beclometasone-formoterol maintenance treatment, but the reliever remains low dose ICS-formoterol. Based on product information, the maximum recommended total dose of formoterol in a single day is 72 mcg metered dose (54 mcg 70 3. Treating to control symptoms and minimize future risk delivered dose) for budesonide-formoterol and 48 mcg metered dose (36 mcg delivered dose) for beclometasoneformoterol). Alternative Step 4 treatment for adults and adolescents: medium or high dose ICS-LABA with as-needed SABA (Track 2) This is an alternative approach if MART is not possible, or if a patient's asthma is stable with good adherence and no exacerbations on their current therapy. As above, individual ICS responsiveness varies, and some patients whose asthma is uncontrolled or who have frequent exacerbations on low dose ICS-LABA despite good adherence and correct inhaler technique may benefit from medium dose ICS-LABA187 (Evidence B) with as-needed SABA, if maintenance and reliever therapy is not available. However, before prescribing a regimen with SABA reliever, consider whether the patient is likely to be adherent with their ICS-containing controller therapy, as otherwise they will be at higher risk of exacerbations. Occasionally, high dose ICS-LABA may be needed. Other Step 4 controller options for adults and adolescents Long-acting muscarinic antagonists (LAMA) may be considered as add-on therapy in a UseTpEarate inhaler for patients agglyecdopy6rryoenaiursm(;tifolutrtoicpaiusomn)e, ofur rionaatec-ovmilabnitneartoiol-num(`tericplildei'n) iiunmha;lmerofmoreptaastioennets-inadgaecdate1Tr8RolyI-Bgelayrcso(pbyercrolonmiuemta)sifoanset-hfomrma oisterol- persistently uncontrolled despite medium or modestly improved lung function211,274-277,252 high dose (Evidence ICS-LABA. A) but with nAodddiinffgerLeAnMcDeAIiSntosmymedpituommso.rInhigsohmdeossetuIdCiSes-L, AadBdAing LAMA to ICS-LABA modestly reduced exacerbations compared with someOmRedium or high dose ICS-LABA comparators.211,274,275,278,279 of LAMA to medium or high In a meta-analysis, dose ICS-LABA.279 there was a 17% reduOcPtiYon in risk of severe exacerbations with addition However, for patients experiencing exacerbations despite low dOoTseCICS-LABA, the ICS dose should be increased to at laeaLsAtMmAe.dIinumon, eorsttruedayt,mtheentssewveitcreheedxatocemrbaaintitoennarantceewaansdDloreOwlieeNrveinr therapy patients with ICS-formoterol, receiving high dose before considering fluticasone furoate- adding vpialatinetnetrsopl (rIeCsScr-iLbAeBdAa)nthICaSn-wLAithBAlo-wL-AmMeAdiwumithdaosneonfl-IuAfotiLcrma-sootenreolfuLrAoBatAe,-vthilaenateprporlo-upmriaetcelirdeinlieiuvmer(iIsCSSA-LBAAB.A-LAMA).276 For In Step 4, there is insufficient evidence to suppToErtRICS-LAMA over low or medium dose ICS-LABA combination; all studies were with ICS and tiotropium in sepMarAate inhalers.274 In one analysis, response to adding LAMA to medium dose ICS, as assessed by FEV1, FEV1, FEV1 reversibility, or pAaCsQt v, sa.nndeTevExeDar csemrboaktiniogn.s28,0was not modified by baseline demographics, body-mass index, Consider adding sublingual allergeIGnHimmunotherapy (SLIT) for adult patients with allergic rhinitis and sensitization to h(soeuesep.d7u7s).t mite, with subCopOtPimYaRlly controlled asthma despite low-high dose ICS, provided FEV1 is >70% predicted.263,264 For medium or high dose budesonide, efficacy may be improved with dosing four times daily281,282 (Evidence B), but adherence may be an issue. For other ICS, twice-daily dosing is appropriate (Evidence D). Other options for adults or adolescents that can be added to a medium or high dose ICS, but that are less efficacious than adding LABA, include LTRA283-287 (Evidence A), or low dose sustained-release theophylline244 (Evidence B), but neither of these has been compared with maintenance and reliever therapy with ICS-formoterol. See note above about the FDA warning for montelukast.241 Preferred Step 4 treatment for children 6-11 years For children whose asthma is not adequately controlled by low dose maintenance ICS-LABA with as-needed SABA, treatment may be increased to medium dose ICS-LABA272 (Evidence B). For maintenance and reliever therapy with budesonide-formoterol, the maintenance dose may be increased to 100/6 mcg twice daily (metered dose; 80/4.5 mcg delivered dose) (Evidence D); this is still a low dose regimen. If asthma is not well controlled on medium dose ICS (see Box 3-6B, p.63), the recommendation is to refer the child for expert assessment and advice. 3. Treating to control symptoms and minimize future risk 71 Other Step 4 options for children 6-11 years Other controller options include increasing to high pediatric dose ICS-LABA (Box 3-6B, p.63), but adverse effects must be considered. Tiotropium (long-acting muscarinic antagonist) by mist inhaler may be used as add-on therapy in children aged 6 years and older; it modestly improves lung function and reduces exacerbations288 (Evidence A) largely independent of baseline IgE or blood eosinophils.289 If not trialed before, LTRA could be added (see note above about FDA warning).241 Add-on theophylline is not recommended for use in children due to lack of efficacy and safety data. STEP 5 Preferred treatment at Step 5 in adults, adolescents and children: refer for expert assessment, phenotyping, and add-on therapy PwaitthieSnttespo4f atrneyaatmgeenwt iathndpeinrswishteonmt soythmeprtocomnstroorlleerxaocpetirobnastihoansvedbesepeinteccoonrsriedcetriendh,aslheor uteldchbUneiTqrEueefearrnedd gtoooadsapdehceiarleisntcweith expertise in investigation and management of severe asthma199 (Evidence D). TRIB In of severe asthma, patients seen in acslininicmalilpdr-amcoticdee.raFtoeraesxtahmmpal,e29,0apraergtiicsitpraynsttsudinyrfaonudnodmthizaetdocvoenr t8Dro0ISl%ledoftrpiaaltsiemntasywniotht be representative severe asthma would have been excluded from major regulatory studies evaluating biologic tOheRrapy.291 The contents of the GINA Guide and decision tree on Diagnosis and MOaPnYagement of difficult-to-treat and severe asthma in adolescent and adult patients is included in Chapter after optimization of existing therapy may include the following (3aElwO(paT.y1sC04c)h.eTcrkealotmcaelnet oligptiiboinlistythaantdmpaayybeer considered criteria): Combination high dose ICS-LABA: this may be considOerNed in adults and adolescents, but for most patients, the irnisckreoafsseidien-IeCffSecdtso,siencgleundeinrgallaydpreronvaildseusplpitrtleesasidodnit.2iLo92n-aADl hbiegnhedfiot1s4e0,1i4s6,r2e66c(oEmvmideenndceedAo),nalynodnthaetrreiaisl baansiisncforera3s-e6d months when good asthma control cannot beEaRchIAieved with medium dose ICS plus LABA and/or a third controller A(ed.gd.-LoTnRloAnogr-asucstitnaginemdu-rsecleaarisneicthaenotpahgyoMllniAniseTt2s44,(2L86AEMvAid)ecnacne B). be prescribed in a separate inhaler for patients aged 6 years (tiotropium), or in a combiTnEatDion (`triple') inhaler for patients aged 18 years (beclometasone-formoterol- gnloytcwopeyllrcroonnituromll;efdluwticitahsmoneedifuumrIoGaoHtreh-vigilhandtoesroel-IuCmSe-LcAlidBinAi.uAmd;dminogmLeAtaMsAontoe-IiCndSa-LcaAtBeArolm-golydceosptlyyrrimonpiruomve) sif asthma lung is function,211,274-277,279,280,288 P(EYvRidence A) but not quality of life, with no clinically important change in symptoms.279 CO Some studies showed a reduction in exacerbation risk; in meta-analysis, overall, there was a 17% reduction of severe exacerbations requiring oral corticosteroids (Evidence A).211,274,275,279,288,293 For patients with in risk exacerbations despite ICS-LABA, it is essential that sufficient ICS is given, i.e. at least medium dose ICS-LABA, before considering adding a LAMA. For patients prescribed an ICS-LABA-LAMA with a non-formoterol LABA, the appropriate reliever is SABA; patients prescribed ICS-formoterol-LAMA can continue ICS-formoterol reliever. Add-on azithromycin (three times a week) can be considered after specialist referral for adult patients with persistent symptomatic asthma despite high dose ICS-LABA. Before considering add-on azithromycin, sputum should be checked for atypical mycobacteria, ECG should be checked for long QTc (and re-checked after a month on treatment), and the risk of increasing antimicrobial resistance should be considered.294 Diarrhea is more common with azithromycin 500 mg 3 times a week.295 Treatment for at least 6 months is suggested, as a clear benefit was not seen by 3 months in the clinical trials.295,505 The evidence for this recommendation includes a meta-analysis of two clinical trials295,505 in adults with persistent asthma symptoms that found reduced asthma exacerbations among those taking medium or high dose ICS-LABA who had either an eosinophilic or noneosinophilic profile and in those taking high dose ICS-LABA296 (Evidence B) The option of add-on azithromycin for 72 3. Treating to control symptoms and minimize future risk adults is recommended only after specialist consultation because of the potential for development of resistance at the patient or population level.295 Add-on biologic therapy for severe asthma o Add-on anti-immunoglobulin E (anti-IgE) (omalizumab) treatment: for patients aged 6 years with moderate or severe allergic asthma that is uncontrolled on Step 4-5 treatment (Evidence A).297 o Add-on anti-interleukin-5/5R treatment (subcutaneous mepolizumab for patients aged 6 years; intravenous reslizumab for ages 18 years or subcutaneous benralizumab for ages 12 years), with severe eosinophilic asthma that is uncontrolled on Step 4-5 treatment (Evidence A).297-300 Efficacy data for mepolizumab in children 6-11 years are limited to one very small open label uncontrolled study.301 o Add-on anti-interleukin-4R treatment (subcutaneous dupilumab) for patients aged 6 years with severe eosinophilic/Type 2 asthma,302 or for adults or adolescents requiring treatment with maintenance OCS (Evidence A).297,303,304 o Add-on anti-thymic stromal lymphopoietin (anti-TSLP) (subcutaneous tezepelumab): for patients aged 12 years with severe asthma (Evidence A).305 UTE ISCpSu-tLuAmB-Ag,utirdeeadtmterenat tmmaeynbt:efoardajudsutletsd wbaithsepdeorsnisetionsginsoypmhpiltiaom(>s3a%n)di/norinedxuaccTeeRdrbIsBaptuiotnusmd. eInspsietevehrieghasdtohsmeaI,CtShisor strategy leads to reduced exacerbations and/or lower doses of ICS194 (EDviIdSence A), but few clinicians currently have access to routine sputum testing. OR aAsdthdm-oan19t9r,e30a6t(mEevnidtewncitehBb)r.oEnvcidheianlctehiesrmlimoipteldasatnyd: minasyebleeccteodnOspiPadtYeierendtsfo(sreseomp.e78a)d. uTlht epalotinegn-ttsewrmithefsfeevcetsre compared with control patients, including for lung function,TarCe not known. As a last resort, add-on low dose oral corticosteroidNsO(7.5 mg/day prednisone equivalent): this may be csoidneseidfeferectds3f0o7r-3s10om(Eeviaddeunlctse wAi)t.hTsheevyersehoausltdhmonal1y99-b(DeEOcvoidnesnidceerDed),fbour tatdhuelytsawreithofpteonorassysmocpiatotemdcwointhtrosluabnsdta/onrtial ofrfeoqtuheenrtceoxnatrciebrubtoartiyonfascdtoersspaitnedgootohderinahdadle-orRntIeAtcrLehantimqueentasnidncaludhdienrgenbcioelowgitichsSwtehper5etarevaatimlabelnet,aannddaafffoterdr aebxlcelu. sion Patients should be counseled about poAteTnEtial side-effects.308,310 They should be assessed and monitored for risk sohf oaudlrdenbael psruopvpidreesdswiointharnedlecvoarntitcEloifDsetseMtryoleidc-ionudnusceeldinogsatenodpporreosscisri,patinodn tohfotsheereaxppyefcotredprteovbeenttiorenaotefdosfoter op3omroosnisths (where appropriate).311 IGHT MMAaiRnTteinnapnacteienatnsdrereceliiePvviYneRgr athdedr-aopnytr(eMaAtmReTn)t wsuitchhIaCsSL-fAoMrmAooter rboiol:lothgeicrethiesrnaopyd,irbeucttsewviitdcehnincge aabpoautiteinntitfiraotimng MART to conventioCnaOl ICS-LABA plus as-needed SABA may increase the risk of exacerbations. REVIEWING RESPONSE AND ADJUSTING TREATMENT How often should asthma be reviewed? Patients with asthma should be reviewed regularly to monitor their symptom control, risk factors and occurrence of exacerbations, as well as to document the response to any treatment changes. For most controller medications, improvement begins within days of initiating treatment, but the full benefit may only be evident after 3-4 months.312 In severe and chronically under-treated disease, it may take longer.313 All health care providers should be encouraged to assess asthma control, adherence and inhaler technique at every visit, not just when the patient presents because of their asthma.314 The frequency of visits depends upon the patient's initial level of control, their response to treatment, and their level of engagement in self-management. Ideally, patients should be seen 1-3 months after starting treatment and every 3-12 months thereafter. After an exacerbation, a review visit within 1 week should be scheduled315 (Evidence D). 3. Treating to control symptoms and minimize future risk 73 Stepping up asthma treatment Asthma is a variable condition, and periodic treatment adjustments by the clinician and/or the patient may be needed.316 Day-to-day adjustment: For patients whose reliever inhaler is combination budesonide-formoterol or beclometasone-formoterol (with or without maintenance ICS-formoterol), the patient adjusts the number of as-needed doses of ICS-formoterol from day to day according to their symptoms. This strategy reduces the risk of developing a severe exacerbation requiring oral corticosteroids within the next 3-4 weeks.74,75,317 Short-term step up (for 1-2 weeks): A short-term increase in maintenance ICS dose for 1-2 weeks may be necessary; for example, during viral infections or seasonal allergen exposure. This may be initiated by the patient according to their written asthma action plan (Box 4-2, p.61), or by the health care provider. Sustained step up (for at least 2-3 months): Although at a group level most benefit from ICS is obtained at low dose, individual ICS responsiveness varies, and some patients whose asthma is uncontrolled on low dose ICS- LABA despite good adherence and correct technique may benefit from increasing the maintenance dose to medium. A step up in treatment may be recommended (Box 3-5, p.31) if the symptoms are confirmed to be due to asthma; inhaler addressed (Box technique and adherence are satisfactory; and 3-8, p.38). Any step-up should be regarded as amothdeifriaapbeleutriicsktrfiaalc.tIofrtsUhesTruEechisansosrmesopkoinngsehaavfteerbe2e-n3 months, treatment should be reduced to the previous level, and alternative treatTmReInBts or referral considered. Stepping down treatment when asthma is well controlled DIS Once good asthma control has been achieved and maintained for 2-3 monthsOaRnd lung function has reached a plateau, treatment can often be successfully reduced, without loss To find the patient's minimum effective treatment, oi.fea. stothmmaainctoaniOntrPgooYl.oTdhceoanitmrosl of of stepping down symptoms and are: exacerbations, and to minimize the costs of treatment and potential for sideT-eCffects To encourage the patient to continue controller treatmenNt.OPatients often experiment with intermittent treatment through concern about the risks or SABA-only treatment. For patients wcohsotsseoaf sdtahilmy atrei-saDwtmOeelln-ct,o3n18trboullet dthoisnlemaavienstetnhaenmceexlopwosdeodsteoItChSe risks with of as-needed SABA, an alternative is to cease mRaIAinLtenance ICS and switch to as-needed ICS-formoterol.188,189 Before stepping down ATE The approach to stepping down preferences. There are few data will on tdhieffeorpftEriomDmaMlptaimtieinngt,tosepqauteiennctedaenpdenmdainggnoitundteheoifr current treatment, risk factors and treatment reductions in asthma. Factors associated with emergency department vaisgitrefoartearsrthismkIGaoHfineTxthaeceprrbeavtiioounsa1ft2ermsotenpth-ds,o3w19n,32i0ncalnuddea a history of exacerbations and/or low baseline FEV1.320 Other predictors of loss of control are not readily during dose available in preridmuacPrtyiYoRcnairnec.lude airway hyperresponsiveness and sputum eosinophilia,321 but these tests Any treatment step-down shoCuOld be considered as a therapeutic trial, with the response evaluated in terms of both symptom control and exacerbation frequency. Prior to stepping down, the patient should be provided with a written asthma action plan and instructions for how and when to resume their previous treatment if their symptoms worsen. How to step asthma treatment down Decisions about treatment step-down should be made on an individual patient level. In one study of patients with wellcontrolled asthma on medium dose ICS-LABA, reducing the ICS dose and removing the LABA had similar effects on a composite treatment failure outcome. However, stopping LABA was associated with lower lung function and more hospitalizations; and decreasing the ICS dose was inferior to maintaining a stable dose of ICS-LABA.322 If treatment is stepped down too far or too quickly, exacerbation risk may increase even if symptoms remain reasonably controlled323 (Evidence B). To date, higher baseline FeNO has not been found to be predictive of exacerbation following step-down of ICS dose.324, 325 A meta-analysis suggested that greater reduction in ICS dose may be able to be achieved in patients with baseline FeNO <50 ppb, but the findings point to the need for further research.325 Complete cessation of ICS is associated with a significantly increased risk of exacerbations326 (Evidence A). Step-down strategies for different 74 3. Treating to control symptoms and minimize future risk controller treatments are summarized in Box 3-7, p.75; these are based on current evidence, but more research is needed. Only a small number of step-down studies have been performed in children. Box 3-7. Options for stepping down treatment once asthma is well controlled General principles of stepping down asthma treatment Consider stepping down when asthma symptoms have been well controlled and lung function has been stable for 3 or more months (Evidence D). If the patient has risk factors for exacerbations (Box 2-2, p.36), for example a history of exacerbations in the past year,319 or persistent airflow limitation, step down only with close supervision. Choose an appropriate time (no respiratory infection, patient not travelling, not pregnant). Approach each step as a therapeutic trial. Engage the patient in the process; document their asthma status (symptom control, lung function and risk factors, Box 2-2, p.36); provide clear instructions; provide a written asthma action plan (Box 4-2, p.129) and ensure the patient has sufficient medication to resume their previous E dose if necessary; monitor symptoms and/or PEF; and schedule a follow-up visit (Evidence D). UT Stepping down ICS doses by 25-50% at 3 month intervals is feasible and safe for most patients327 (Evidence A). TRIB Current IS step Current medication and dose Options for stepping down Evidence R D Step 5 High dose ICS-LABA plus Continue high dose ICS-LABA and reduce OCS dose D O oral corticosteroids (OCS) Use sputum-guided approach to reducing OCS B PY Alternate-day OCS treatment D CO Replace OCS with high dose ICS D OT High dose ICS-LABA plus Refer for expert advice D N other add-on agents - DO Step 4 Moderate to high dose ICS- Continue combination ICS-LABA with 50% reduction in ICS component, by B L LABA maintenance treatment using available formulations IA Discontinuing LABA may lead to deterioration328 A TER Medium dose ICS-formoterol* Reduce maintenance ICS-formoterol* to low dose, and continue as-needed D MA as maintenance and reliever low dose ICS-formoterol* reliever ED High dose ICS plus second Reduce ICS dose by 50% and continue second controller327 B T controller IGH Step 3 Low dose ICS-LABA Reduce ICS-LABA to once daily D YR maintenance Discontinuing LABA may lead to deterioration328 A COP Low dose ICS-formoterol* as Reduce maintenance ICS-formoterol* dose to once daily and continue C maintenance and reliever as-needed low dose ICS-formoterol* reliever Medium or high dose ICS Reduce ICS dose by 50%327 A Adding LTRA may allow ICS dose to be stepped down329 B Step 2 Low dose ICS Once-daily dosing (budesonide, ciclesonide, mometasone)330,331 A Switch to as-needed low dose ICS-formoterol188,189,191,213 A Switch to taking ICS whenever SABA is taken220,221,223 222 B Low dose ICS or LTRA Switch to as-needed low dose ICS formoterol188-191,213 A Complete cessation of ICS in adults and adolescents is not advised as the A risk of exacerbations is increased with SABA-only treatment213,326 BDP: beclometasone dipropionate; ICS: inhaled corticosteroids; LABA: long-acting beta2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids. *ICS-formoterol maintenance and reliever treatment can be prescribed with low dose budesonide-formoterol or BDP-formoterol. Note FDA warning on neuropsychiatric effects with montelukast.241 3. Treating to control symptoms and minimize future risk 75 TREATING OTHER MODIFIABLE RISK FACTORS Some patients continue to experience exacerbations even with maximal doses of current treatment. Having even one exacerbation increases the risk that a patient will have another within the next 12 months.117 There is increasing research interest in identifying at-risk patients (Box 2-2B, p.36), and in investigating new strategies to further reduce exacerbation risk. In clinical practice, exacerbation risk can be reduced both by optimizing asthma medications, and by identifying and treating modifiable risk factors (Box 3-8). Not all risk factors require or respond to a step up in controller treatment. Box 3-8. Treating potentially modifiable risk factors to reduce exacerbations Risk factor Any patient with 1 risk factor for exacerbations (including poor symptom control) 1 severe exacerbation in last year Exposure to tobacco smoke Low FEV1, especially if <60% predicted Obesity Major psychological problems Major socioeconomic problems Confirmed food allergy Allergen exposure if sensitized Sputum eosinophilia (limited centers) Treatment strategy Ensure patient is prescribed an ICS-containing controller. Maintenance and reliever therapy (MART) severe exacerbations compared with if the wreitlihevICeSr i-sfoSrmABotAe.roUl rTeEduces risk of Ensure Review patient patient has a more written action plan appropriate for frequently than low-risk patients. tThReiIrBhealth literacy. Check inhaler technique and adherence frequently. DIS Identify any modifiable risk factors (Box 2-2, p.36O)R. IeCxSac-feorrbmaotitoenroslcmomaipnaterneadnwciethainf dthreelrieelvieevr ererOgiPsimYSeAnBrAe.duces risk of severe Consider stepping up treatment if no mTodCifiable risk factors. Identify any avoidable triggers for eNxaOcerbations. Encourage smoking cessation Consider higher dose of ICS i-f bDyOpatient/family; provide asthma poorly controlled. advice and resources. Consider trial of 3 monthRsI'AtLreatment with high dose ICS. Consider 2 weeks' Exclude other lung AOdTiCsEeSa,sbeu,teta.gk.eCsOhPorDt-. and long-term risks into account Refer for expeErDt aMdvice if no improvement. SDtisratitnegguiIeiGsshHfoaTrstwhemigahst yrmedputcotmiosnfrom symptoms due to deconditioning, AmrerPachnYgaRenicmael nretasltrhicetaioltnh, and/or sleep assessment. apnea. CHOelp patient to distinguish between symptoms of anxiety and asthma; provide advice about management of panic attacks. Identify most cost-effective ICS-based regimen. Appropriate food avoidance; injectable epinephrine. Consider trial of simple avoidance strategies; consider cost. Consider step up of controller treatment. Consider adding SLIT in symptomatic adult HDM-sensitive patients with allergic rhinitis despite ICS, provided FEV1 is >70% predicted. Increase ICS dose independent of level of symptom control. Evidence A A A A A D A A C A B B B D D B D D D D A C D B A* COPD: chronic obstructive pulmonary disease; FEV1: forced expiratory volume in 1 second; HDM: house dust mite; ICS: inhaled corticosteroids; OCS: oral corticosteroids; SLIT: sublingual immunotherapy. * Based on evidence from relatively small studies in selected populations. Also see Box 3-9 and p.79 for more information about non-pharmacological interventions. 76 3. Treating to control symptoms and minimize future risk The potential for local and/or systemic side-effects of medications can be minimized by ensuring correct inhaler technique (Box 3-12, p.89), by reminding patients to rinse and spit out after using ICS, and, after good asthma control has been maintained for 3 months, by finding each patient's minimum effective dose (the lowest dose that will maintain good symptom control and minimize exacerbations, Box 3-7, p.75). OTHER THERAPIES Allergen immunotherapy Allergen-specific immunotherapy may be a treatment option where allergy plays a prominent role, including asthma with allergic rhinoconjunctivitis.332,333 There are currently two approaches: subcutaneous immunotherapy (SCIT) and sublingual immunotherapy (SLIT). In the past, few studies in asthma have compared immunotherapy with pharmacological therapy, or used standardized outcomes such as exacerbations, and most studies have been in patients with mild asthma. The allergens most commonly included in allergen immunotherapy studies have been house dust mite and grass pollens. There patients sensitized to mold.334 is insufficient evidence about safety and efficacy of aUllTeErgen immunotherapy in GINA plans to review evidence about allergen immunotherapy for asthma, and willTuRpIdBate its advice based on the findings. DIS Subcutaneous immunotherapy (SCIT) OR ShiCghITerindvooslveesstothiendiduecnetidfiecsaetinosnitaiznadtiounseanodf /colirnticoalellryanreclee.vEanutroaplleeargnepnOhsy,PsaYincidanasdmteinndisttroaftaiovnorofseinxgtrleacatlsleirngpernogressively immunotherapy whereas Northern American physicians often preTscCribe multiple allergens for treatment.335 In people wreiqthuiaresmthmenatsa,nadndalilmerpgricovseednsailtliezragteionn-,sSpeCcITificisaansdsnocoina-tsepdewciiftihNc Oaairrewdauychtiyopneirnressypmopntsoimvensceosrse.3s35and medication For SCIT, analysis of pooled safety data from clinical tri-alDs Oand post-marketing surveillance in house dust mite allergic rtheastpsireartoioruysdaisdevaesresesuegffgeecststsotfhSeCinITcidareencuencoofmadmvoRenrIs,AebLudtrumgaryeiancctliuodnes is approximately 0.5%.336 Studies to date life-threatening anaphylactic reactions. suggest Advice ATE Cadovmeprsaereedffteoctpshaanrmd athceoliongciocnavl eannidenaEcveDoiadMnadncceosotpotifotnhse, potential benefits prolonged course of of SCIT must be weighed against the risk of therapy, including the minimum half-hour wait required after each injectioIGn H(ETvidence D). Sublingual immunotherapy (SPLYIRT) Modest effects concern about twheerdeeisdiegnntCiofOifemd ainnya systematic review of SLIT for asthma in adults and children,333,337,338 but there of the studies.339 The evidence for important outcomes such as exacerbations was and quality of life remains limited.339 There are few studies comparing SLIT with pharmacological therapy for asthma.340 A trial of SLIT for house dust mites (HDM) in patients with asthma and HDM allergic rhinitis demonstrated a modest reduction of ICS with high dose SLIT.264 In another study in patients with asthma and HDM allergic rhinitis, SLIT added to low or medium dose ICS showed increased time to exacerbation during ICS reduction in suboptimally controlled asthma.263 Side effects341-343 from SLIT for inhalant allergens are predominantly limited to oral and gastrointestinal symptoms.333 Advice For adult patients with allergic rhinitis and sensitized to house dust mite, with persisting asthma symptoms despite low-medium dose ICS-containing therapy, consider adding SLIT, provided FEV1 is >70% predicted (Evidence B) As for any treatment, potential benefits of SLIT for individual patients should be weighed against the risk of adverse effects, and the cost to the patient and health system. 3. Treating to control symptoms and minimize future risk 77 Vaccinations Influenza causes significant morbidity and mortality in the general population, and contributes to some acute asthma exacerbations. In 2020, many countries saw a reduction in influenza-related illness, likely due to the handwashing, masks and social/physical distancing introduced because of the COVID-19 pandemic. The risk of influenza infection itself can be reduced by annual vaccination. A systematic review of placebo-controlled randomized controlled trials of influenza vaccination showed no reduction in asthma exacerbations,344 but no such studies had been performed since 2001. However, a systematic review and meta-analysis that included observational studies with a wide range of study designs suggested that influenza vaccination reduced the risk of asthma exacerbations, although for most of the studies, bias could not be excluded.345 There is no evidence for an increase in asthma exacerbations after influenza vaccination compared to placebo.345 Limited evidence exists with respect to the efficacy of live attenuated intranasal vaccination in children; from a safety perspective, an open-label study in children 2- 18 years with moderate-severe asthma showed no short-term effects on asthma symptoms or asthma control.346 People with asthma, insufficient evidence particularly children and the elderly, are at higher to recommend routine pneumococcal vaccination riinskpeoof pplneewumithoacostchcmaUlaTd.3Ei4s8ease,347 but there is Advice TRIB Advise patients with moderate to severe asthma to receive vaccination of the general population is advised (Evidence an C). influenza vaccinDaItSion every year, or at least when There is insufficient evidence to recommend routine pneumococcal vaccinOatRion in people with asthma (Evidence D). Advice about COVID-19 vaccination COVID-19 vaccination and influenza is on p.18. vaccination may be given on theOPsaYme day. Bronchial thermoplasty NOT C Bronchial thermoplasty is a potential treatment option at St-epDO5 in some countries for adult patients whose asthma rBermonacinhsiaul nthceornmtroopllleadstdyeisnpviotelveospttirmeaiztemdetnhteoraf ptheeutaicirwreagyIiAmsLdeunrsinagntdhrreeefesrreapl atoraaten asthma specialty center (Evidence bronchoscopies with a localized B). radiofrequency pulse.129 The treatment is associatTeEdRwith a large placebo effect.129 In patients taking high dose ICS- LpAerBioAd,,barnodncahsiaulbtsheeqrmueonptladsetcyrweaasseaisnseoxcaiacteerdbMwatAiitohnasn, binuct rneoasbeeninefaicsitahlmeaffeecxtaocnerlubnagtiofnusncdtuiorninogrthaesth3mmaosnythmtpretoamtmsent compared with sham-controlled patients.1T29EEDxtended follow up of some treated patients reported a sustained reduction einffeexcaticveernbeastsioannsdcosamfeptayr,eidncwluitdhinpgrefo-tIrrGeluaHntmg efunnt.c34ti9oHn,oiwnebvoetrh, longer-term follow up of larger cohorts comparing active and sham-treated patients is needed. Advice PYR For adult patients whose CasOthma remains uncontrolled despite optimization of asthma therapy and referral to a severe asthma specialty center, bronchial thermoplasty is a potential treatment option at Step 5 in some countries (Evidence B). Caution should be used in selecting patients for this procedure. The number of studies is small, people with chronic sinus disease, frequent chest infections or FEV1 <60% predicted were excluded from the pivotal sham-controlled study, and patients did not have their asthma treatment optimized before bronchial thermoplasty was performed. Bronchial thermoplasty should be performed in adults with severe asthma only in the context of an independent Institutional Review Board-approved systematic registry or a clinical study, so that further evidence about effectiveness and safety of the procedure can be accumulated.199 Vitamin D Several cross-sectional studies have shown that low serum levels of Vitamin D are linked to impaired lung function, higher exacerbation frequency and reduced corticosteroid response.350 Vitamin D supplementation may reduce the rate of asthma exacerbation requiring treatment with systemic corticosteroids or may improve symptom control in asthma patients with baseline 25(OH)D of less than approximately 25-30 nmol/L.351,352 In a meta-analysis, benefit for worsening 78 3. Treating to control symptoms and minimize future risk asthma was seen in some studies, but to date, there is no good-quality evidence that Vitamin D supplementation leads to improvement in asthma control or reduction in exacerbations.353-355 More studies are needed. NON-PHARMACOLOGICAL STRATEGIES In addition to pharmacological treatments, other strategies may be considered where relevant, to assist in improving symptom control and/or reducing future risk. The advice and evidence level are summarized in Box 3-9, with brief text on the following pages. Box 3-9. Non-pharmacological interventions - summary Intervention Advice/recommendation (continued on next page) Evidence Cessation of At every visit, strongly encourage people with asthma who smoke to quit. Provide access to A TE smoking and ETS counseling and smoking cessation programs (if available). U exposure IB Advise parents/carers of children with asthma not to smoke and not to allow smoking in rooms or A TR cars that their children use. DIS Strongly encourage people with asthma to avoid environmental smoke exposure. B OR Assess smokers/ex-smokers for COPD or overlapping features of asthma and COPD (asthma- D Y COPD overlap, ACO, Chapter 5, p.141), as additional treatment strategies may be required. OP Physical activity Encourage people with asthma to engage in regular physical activity for its general health benefits. A T C Provide advice about prevention of exercise-induced bronchoconstriction with regular ICS. A NO Provide advice about prevention of breakthrough exercise-induced bronchoconstriction with DO o warm-up before exercise A L - o SABA before exercise A RIA o low dose ICS-formoterol before exercise. B TE Regular physical activity improves cardiopulmonary fitness, and can have a small benefit for B MA asthma control and lung function, including with swimming in young people with asthma. ED There is little evidence to recommend one form of physical activity over another. D HT Avoidance of Ask all patients with adult-onset asthma about their work history and other exposures. D IG occupational YR exposures In management of occupational asthma, identify and eliminate occupational sensitizers as soon as A P possible, and remove sensitized patients from any further exposure to these agents. CO Patients with suspected or confirmed occupational asthma should be referred for expert A assessment and advice, if available. Avoidance of Always ask about asthma before prescribing NSAIDs, and advise patients to stop using them if D medications that asthma worsens. may make asthma worse Always ask people with asthma about concomitant medications. D Aspirin and NSAIDs (non-steroidal anti-inflammatory drugs) are not generally contraindicated A unless there is a history of previous reactions to these agents (see p.102). Decide about prescription of oral or ophthalmic beta-blockers on a case-by-case basis. Initiate D treatment under close medical supervision by a specialist. If cardioselective beta-blockers are indicated for acute coronary events, asthma is not an absolute D contra-indication, but the relative risks/benefits should be considered. Healthy diet Encourage patients with asthma to consume a diet high in fruit and vegetables for its general A health benefits. 3. Treating to control symptoms and minimize future risk 79 Box 3-9 (continued) Non-pharmacological interventions - Summary Intervention Avoidance of indoor allergens Advice/recommendation Allergen avoidance is not recommended as a general strategy in asthma. For sensitized patients, there is limited evidence of clinical benefit for asthma in most circumstances with single-strategy indoor allergen avoidance. Evidence A A Remediation of dampness or mold in homes reduces asthma symptoms and medication use in A adults. For patients sensitized to house dust mite and/or pets, there is limited evidence of clinical benefit B for asthma with avoidance strategies (only in children) . Allergen avoidance strategies are often complicated and expensive, and there are no validated D methods for identifying those who are likely to benefit. TE Weight reduction Include weight reduction in the treatment plan for obese patients with asthma. B IBU For obese adults with asthma a weight reduction program plus twice-weekly aerobic and strength B R exercises is more effective for symptom control than weight reduction alone. IST Breathing D exercises Breathing exercises may be a useful supplement to asthma pharmacotherapy for symptoms and A quality of life, but they do not reduce exacerbation risk or have consistent effects on lung function. Y OR Avoidance of Encourage people with asthma to use non-polluting heating and cooking sources, and for sources B P indoor air of pollutants to be vented outdoors where possible. CO pollution OT Avoidance of For sensitized patients, when pollen and mold counts are highest, closing windows and doors, D N outdoor allergens remaining indoors, and using air conditioning may reduce exposure to outdoor allergens. - DO Dealing with Encourage patients to identify goals and strategies to deal with emotional stress if it makes their D IAL emotional stress asthma worse. ER There is insufficient evidence to support one stress-reduction strategy over another, but relaxation B T strategies and breathing exercises may be helpful. D MA Arrange a mental health assessment for patients with symptoms of anxiety or depression. D HTE Avoidance of During unfavorable environmental conditions (very cold weather or high air pollution) it may be D IG outdoor air helpful to stay indoors in a climate-controlled environment, and to avoid strenuous outdoor physical YR pollutants/weather activity; and to avoid polluted environments during viral infections, if feasible. OP conditions C Avoidance of Food avoidance should not be recommended unless an allergy or food chemical sensitivity has D foods and food been clearly demonstrated, usually by carefully supervised oral challenges. chemicals For confirmed food allergy, food allergen avoidance may reduce asthma exacerbations. D If food chemical sensitivity is confirmed, complete avoidance is not usually necessary, and D sensitivity often decreases when asthma control improves. NSAID: non-steroidal anti-inflammatory drugs; SABA: short-acting beta2-agonist. Interventions with highest level evidence are shown first. 80 3. Treating to control symptoms and minimize future risk Smoking cessation and avoidance of environmental tobacco smoke Cigarette smoking has multiple deleterious effects in people with established asthma, in addition to its other well-known effects such as increased risk of lung cancer, chronic obstructive pulmonary disease (COPD) and cardiovascular disease; and, with exposure in pregnancy, increased risk of asthma and lower respiratory infections in children. In people with asthma (children and adults), exposure to passive smoke increases the risk of hospitalization and poor asthma control. Active smoking is associated with increased risk of poor asthma control, hospital admissions and, in some studies, death from asthma; it increases the rate of decline of lung function and may lead to COPD; and it reduces the effectiveness of inhaled and oral corticosteroids.356 After smoking cessation, lung function improves and airway inflammation decreases.357 Reduction of passive smoke exposure improves asthma control and reduces hospital admissions in adults and children.358 Use of e-cigarettes is associated with an increased risk of asthma symptoms or diagnosis, and an increased risk of asthma exacerbations.105,359 Advice At every visit, strongly encourage people with asthma who smoke to quit. They counseling and, if available, to smoking cessation programs (Evidence A). shouUldTbEe provided with access to Strongly encourage people with asthma to avoid environmental smoke exposurTeR(IEBvidence B). Advise parents/carers of children children use (Evidence A). with asthma not to smoke and not to allowDsISmoking in rooms or cars that their Assess patients with a >10 pack-year smoking history for COPD or asthOmRa-COPD overlap, as additional treatment strategies may be required (see Chapter 5, p.141). PY Physical activity T CO For people with asthma, as in the general population, regularNmOoderate physical activity has important health benefits including can have reduced cardiovascular a small beneficial effect roisnkaasnthdmimapsryomvepdtoqmuac-loiDtnyOtoroflliafen.dTlhuenrgefuisnscotimone, evidence although that aerobic exercise training not airway inflammation.360 Improved attributed cardiopulmonary fitness to asthma. In one study omf anyonre-odbuecseethpeaRtrIiieAsnkLtsofwdiythspansethamuan,rehliagthedintteonasiirtfyloiwntelimrviatal ttiroaninbinegintgogmeitshtearkewnitlhy a diet with high protein and low glycemic index imprAoTveEd asthma symptom control, although no benefit on lung function was seen.361 In young cardio-pulmonary people with asthma, fitness;362 however, tshEweDrimeMmariengsotrmaienicnognicsewrnesll tolerated and leads to increased about exposure to chlorine and tr lung function and ichloramine with indoor pools.47 Exercise is an important cause of IaGsHthTma symptoms for many asthma patients, but EIB can usually be reduced with maintenance ICS.47 BreakthrPouYgRh exercise-related symptoms can be managed with warm-up before exercise,47 and/or by taking SABA47 or low dCoOse ICS-formoterol219 before or during exercise. Advice Encourage people with asthma to engage in regular physical activity because of its general health benefits (Evidence A). However, regular physical activity confers no specific benefit on lung function or asthma symptoms per se, with the exception of swimming in young people with asthma (Evidence B). There is insufficient evidence to recommend one form of physical activity over another (Evidence D). Provide patients with advice about prevention and management of exercise-induced bronchoconstriction including with daily treatment with ICS (Evidence A) plus SABA as-needed and pre-exercise (Evidence A), or with low dose ICS-formoterol as-needed and before exercise (Evidence B), with warm-up before exercise if needed (Evidence A). Avoidance of occupational exposures Occupational exposures to allergens or sensitizers account for a substantial proportion of the incidence of adult-onset asthma.363 Once a patient has become sensitized to an occupational allergen, the level of exposure necessary to induce symptoms may be extremely low, and resulting exacerbations become increasingly severe. Attempts to reduce 3. Treating to control symptoms and minimize future risk 81 occupational exposure have been successful, especially in industrial settings.44 Cost-effective minimization of latex sensitization can be achieved by using non-powdered low-allergen gloves instead of powdered latex gloves.44 Advice Ask all patients with adult-onset asthma about their work history and other exposures (Evidence D). In management of occupational asthma, identify and eliminate occupational sensitizers as soon as possible, and remove sensitized patients from any further exposure to these agents (Evidence A). Patients with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if available, because of the economic and legal implications of the diagnosis (Evidence A) Avoidance of medications that may make asthma worse Aspirin and other NSAIDs can cause severe exacerbations.364 Beta-blocker drugs, including topical ophthalmic preparations, may cause bronchospasm365 and have been implicated in some asthma deaths. However, beta-blockers hcoarvoenaarpyroevveenntbaenndefriet cineitvheedmbaetnaa-gbelomckeenrtsowf citahrindio2v4ahsocuurlsarodf ihseosapsieta. lPaedompliesswioitnhhaasvthembaeewnUhTfooEuhnadvetohhaadvaenloawcuetrein- hospital mortality rates than those who did not receive beta-blockers.366 Advice TRIB Always ask people with asthma about concomitant medications, including eyedDrIoSps (Evidence D). Always ask about asthma and previous reactions before prescribing NSAIDOsR, and advise patients to stop using these medications if asthma worsens. Aspirin and NSAIDs are not generally contraindicated in asthma unleOssPYthere is a history of previous reactions to these agents (Evidence A). (See `Aspirin-exacerbated respiratoryTdCisease', p.102) tFhoerspeemopeldeicwaittihonasstshhmoaulwd hboe mmaaydebeonneafitcfarosme-boyra-cl aosreobpahsthisa,lmNanOicdbtreetaa-tmbloecnkt esrhtorueladtmonelnyt,bae dineitciaistieodn utondperer scclorisbee medical supervision by a specialist (Evidence D). - DO Asthma should not indicated for acute cboerorengaaryrdeevdeanstsa, nbuatbtshoeluretelactiovRneItrAraisLinksdiacantdiobnetnoeufistseschaorudlidosbeeleccotinvseidbeertead-b(lEovcikdeernscwehDe)n. they The are prescribing physician and patient should be aAwTaEre of the risks and benefits of treatment.367 Avoidance of indoor allergens ED M Bcoemcapulesteelmy aisnuysausathllymiampparaticetnictsalraenadctIvGteoHrymTbuultirpdleenfsaocmtoersfothratht earpeautibeinqtu. iMtoeudsicinattihoensentovimroanimnteanint,gaovoodidainsgthtmheasceofnatcrotolrs have an important controlled. role because PpYatRients are often less affected by environmental factors when their asthma is well- There is conflicting evidenceCaObout whether measures to reduce exposure to indoor allergens are effective at reducing asthma symptoms.368,369 The majority of single interventions have failed to achieve a sufficient reduction in allergen load to lead to clinical improvement.368,370,371 It is likely that no single intervention will achieve sufficient benefits to be cost effective (Box 3-10, p.83). One study of insecticidal bait in homes eradicated cockroaches for a year and led to a significant decrease in symptoms, improvement in pulmonary function, and less health care use for children with moderate to severe asthma.372 Domestic mites: these mites live and thrive in many sites throughout the house so they are difficult to reduce and impossible to eradicate. A systematic review of multi-component interventions to reduce allergens including house dust mite showed no benefit for asthma in adults and a small benefit for children.373 One study that used a rigorously applied integrated approach to dust mite control led to a significant decrease in symptoms, medication use and improvement in pulmonary function for children with dust mite sensitization and asthma.374 However, this approach is complicated and expensive and is not generally recommended. A study in mite-sensitized children recruited after emergency department presentation showed a decrease in emergency department visits, but not oral corticosteroids, with the use of miteimpermeable encasement of the mattress, pillow and duvet.375 82 3. Treating to control symptoms and minimize future risk Furred pets: complete avoidance of pet allergens is impossible for sensitized patients as these allergens are ubiquitous outside the home376 in schools,377 public transport, and even cat-free buildings, probably transferred on clothes.377 Although removal of such animals from the home of a sensitized patient is encouraged,378 it can be many months before allergen levels decrease,379 and the clinical effectiveness of this and other interventions remains unproven.380 Pest rodents: symptomatic patients suspected of domestic exposure to pest rodents should be evaluated with skin prick tests or specific IgE, as exposure may not be apparent unless there is an obvious infestation.381 High level evidence for the effectiveness of removing rodents is lacking, as most integrated pest management interventions also remove other allergen sources;381 one non-sham-controlled study showed comparable clinical improvement with pest reduction education and integrated pest management.382 Box 3-10. Effectiveness of avoidance measures for indoor allergens Measure House dust mites Encase bedding in impermeable covers Wash bedding on hot cycle (55-60C) Replace carpets with hard flooring Acaricides and/or tannic acid Minimize objects that accumulate dust Vacuum cleaners with integral HEPA filter and double- thickness bags Remove, hot wash, or freeze soft toys - DO Pets RIAL Remove cat/dog from the home ATE Keep pet from HEPA-filter air the main cleaners living areasE/bDedMrooms Wash pet IGHT Replace Vacuum ccalerapneetsrswwitihthhianrtPdegYflroRaol rHinEgPA filter and double- thickness bags CO Cockroaches NOT Evidence of effect Evidence of clinical on allergen levelsUTE benefit Some (A)TRIB Adults - none (A) DIS Children - some (A) SSOoomRmee (C) (B) PYWeak (C) None (D) None (D) None (D) CO None (D) None (D) Weak (C) None (D) None (D) None Weak (C) Weak (C) Some (B) Weak (C) None (D) None (D) None (D) None (D) None (A) None (D) None (D) None (D) Bait plus professional extermination of cockroaches Minimal (D) None (D) Baits placed in households Some (B) Some (B) Rodents Integrated pest management strategies Some (B) Some (B) Fungi Remediation of dampness or mold in homes A A Air filters, air conditioning Some (B) None (D) This table is adapted from Custovic et al383 3. Treating to control symptoms and minimize future risk 83 Cockroaches: avoidance measures for cockroaches are only partially effective in removing residual allergens384 and evidence of clinical benefit is lacking. Fungi: fungal exposure has been associated with asthma exacerbations. The number of fungal spores can best be reduced by removing or cleaning mold-laden objects.385 Air conditioners and dehumidifiers may be used to reduce humidity to less than 50% and to filter large fungal spores. However, air conditioning and sealing of windows have also been associated with increases in fungal and house dust mite allergens.386 Advice Allergen avoidance is not recommended as a general strategy for people with asthma (Evidence A). For sensitized patients, although it would seem logical to attempt to avoid allergen exposure in the home, there is some evidence for clinical benefit with single avoidance strategies (Evidence A) and only limited evidence for benefit with multi-component avoidance strategies (in children) (Evidence B). Although allergen avoidance strategies may be beneficial for some sensitized patients (Evidence B), they are often c(EovmidpelincaceteDd )a. nd expensive, and there are no validated methods for identifying those IwBhUoTaEre likely to benefit Healthy diet ISTR In the general population, a diet high in fresh fruit and vegetables has many healthDbenefits, including prevention of many chronic diseases and forms of cancer. Many epidemiological studies reOpoRrt that a high fruit and vegetable diet is associated with a lower risk of asthma and lung function decline. vegetable intake leads to an improvement in asthma control and aThreedreucOisePdsYorimske evidence that increasing of exacerbations.387 fruit and Advice T C Encourage patients with asthma to consume a diet high in fruNit Oand vegetables for its general health benefits (Evidence A). - DO Weight reduction for obese patients RIAL Asthma can ICS may be rbeedmucoerde.3d9i1ffTichueltretoiscolinmtritoeldineovibdeesneceApaTatEbieonutts,t3h8e8-3e9f0fethcet risk of exacerbations is greater,100,101 and of weight loss on asthma control. Studies response have to ranged from dietary restriction to populations have generally been msmualtilfl,aactnodEriDainltMienrtveervnetinotniosnasnwd irtheseuxltesrchiasevetrbaeineinnghaentedrocgoegnneitoivues.b3e92hIanvsioormalethseturadpieys, ,but wpaetiigehnttslowssithhaasstihmmparo.3v9e3,3d94aTsthhemma ocsotnIsGtrtroHikl,Tinlugnrgefsuunltcstihoanvaenbdeheenaoltbhssetravteuds,aafntedr reduced bariatric medication needs surgery,395,396 but in obese even 5-10% Adwveicigeht loss with diet, with or CwOithPoYuRt exercise, can lead to improved asthma control and quality of life.397 Include weight reduction in the treatment plan for obese patients with asthma (Evidence B). Increased exercise alone appears to be insufficient (Evidence B). Breathing exercises A systematic review of studies of breathing and/or relaxation exercises in adults with asthma and/or dysfunctional breathing, including the Buteyko method and the Papworth method, reported improvements in symptoms, quality of life and/or psychological measures, but with no consistent effect on lung function and no reduction in risk of exacerbations.398 In order for studies of non-pharmacological strategies such as breathing exercises to be considered high quality, control groups should be appropriately matched for level of contact with health professionals and for asthma education. A study of two physiologically contrasting breathing exercises, which were matched for contact with health professionals and instructions about rescue inhaler use, showed similar improvements in reliever use and ICS dose after down-titration in both groups.399 This suggests that perceived improvement with breathing exercises may be largely due to factors such 84 3. Treating to control symptoms and minimize future risk as relaxation, voluntary reduction in use of rescue medication, or engagement of the patient in their care. The cost of some commercial programs may be a potential limitation. Breathing exercises used in some of these studies are available at www.breathestudy.co.uk400 and www.woolcock.org.au/moreinfo.399 Advice Breathing exercises may be considered as a supplement to conventional asthma management strategies for symptoms and quality of life, but they do not improve lung function or reduce exacerbation risk (Evidence A). Avoidance of indoor air pollution In addition to passive and active smoking, other major indoor air pollutants that are known to impact on respiratory health include nitric oxide, nitrogen oxides, carbon monoxide, carbon dioxide, sulfur dioxide, formaldehyde, and biologicals (endotoxin).401,402 Sources include cooking and heating devices, particularly if they are not externally flued (vented). Installation children with asthma odfoneosnn-potolsluigtinnigfic, amnotlryeimefpferoctviveeluhnegatfiunngc(thioenabt uptusmigpn, iwficoaondtlyperleledtubcueUrsnTseEyr,mflputeodmgsaosf)ainstthhmeah,odmaeyss of off sccohnosoislt,ehnetaeltffheccatroenuatilsizthamtioano, uatncdompheasr.m404a,4c0i5st visits.403 Air filters can reduce fineIpSaTrRticIBle exposure, but there is no Advice R D Encourage people with asthma to use non-polluting heating and cookinOg sources, and for sources of pollutants to be vented outdoors where possible (Evidence B). Strategies for dealing with emotional stress OPY T C Emotional stress may lead to asthma exacerbations in childreNnO406 and adults. Hyperventilation associated with laughing, crying, anger, or fear important to note that can cause asthma is naoirtwparyimnaarrirlyowainpgsy.4c07h,4o0s8-oPmDaOantiicc attacks have a similar effect.409,410 However, disorder. During stressful times, medication it is adherence may also decrease. RIAL Advice Encourage patients to identify goals and sAtrTatEegies to deal with emotional stress if it makes their asthma worse (Evidence D). ED M Tmhaeyrebeishineslpuffufilcinienret deuvcidinegncaestthIoGmsHauTpspyomrpt toonmess(trEavteidgeynoceveBr)a. nother, but relaxation strategies and breathing exercises Arrange a mental health aPsYseRssment for patients with symptoms of anxiety or depression (Evidence D). Avoidance of outdoor alleCrgOens For patients sensitized to outdoor allergens such as pollens and molds, these are impossible to avoid completely. Advice For sensitized patients, closing windows and doors, remaining indoors when pollen and mold counts are highest, and using air conditioning may reduce exposure (Evidence D). The impact of providing information in the media about outdoor allergen levels is difficult to assess. Avoidance of outdoor air pollution Meta-analysis of epidemiological studies showed a significant association between air pollutants such as ozone, nitrogen oxides, acidic aerosols, and particulate matter and symptoms or exacerbations of asthma, including emergency department visits and hospitalizations.107 Proximity to main roads at home and school is associated with greater asthma morbidity.411 Certain weather and atmospheric conditions like thunderstorms412,413 may trigger asthma exacerbations by a variety of mechanisms, including dust and pollution, by increasing the level of respirable allergens, and causing changes in temperature and/or humidity. Reduction of outdoor air pollutants usually requires national or local policy 3. Treating to control symptoms and minimize future risk 85 changes. For example, short-term traffic restrictions imposed in Beijing during the Olympics reduced pollution and was associated with a significant fall in asthma outpatient visits.414 Advice In general, when asthma is well-controlled, there is no need for patients to modify their lifestyle to avoid unfavorable outdoor conditions (air pollutants, weather). It may be helpful, where possible, during unfavorable environmental conditions (very cold weather, low humidity or high air pollution) to avoid strenuous outdoor physical activity and stay indoors in a climate-controlled environment; and to avoid polluted environments during viral infections (Evidence D) Avoidance of food and food chemicals Food allergy as an exacerbating factor for asthma is uncommon and occurs primarily in young children. Confirmed food allergy is a risk factor for asthma-related mortality.102 Food when chemicals, either asthma is poorly naturally occurring controlled. Sulfites or added (common during processing, may also food and drug preservatives trigger found inasstUuhTcmhEafosoymdspatosmpsroecsepsesceiadlly potatoes, However, shri the mp, like dried lihood fru of its, beer, a a reaction nd wine) is depen have often dent on the been natur impl e of icated in the food, caus the l einvgeslTaeRnvedIBrfeoarmst hma exacerbations.415 of residual sulfite, the sensitivity of the patient, and the mechanism of the sulfite-induced reaction.415 TheDrIeSis little evidence to support any general role for other dietary substances including benzoate, the yellow dye, tOarRtrazine, and monosodium glutamate in worsening asthma. PY Advice CO Ask people with asthma about symptoms associated with any spTecific foods (Evidence D). Food avoidance should not be recommended unless an allergNyOor food chemical sensitivity has been clearly demonstrated If food allergy i(sEcvoidnefinrmceedD,),fouosduaallllyerbgyecnaarevofuidllyanscuepecravn-isrDeedOduocrael challenges.102 asthma exacerbations (Evidence D). Idfefocroedacsheesmwihceanl soevnesriatilvl iatystihsmcoancfiormnterodl,icmopmropvleetseR(aEIvAvoiLdideanncceeDis).not usually necessary, and sensitivity often MATE TED IGH COPYR 86 3. Treating to control symptoms and minimize future risk INDICATIONS FOR REFERRAL FOR EXPERT ADVICE While the majority of people with asthma can usually be managed in primary care, some clinical situations warrant referral for expert advice regarding diagnosis and/or management (Box 3-10). This list is based on consensus, and indications for referral may vary, as there is substantial variation between health systems in the delivery of the majority of asthma care: by primary health care providers in some countries, and by specialists in others. Box 3-11. Indications for considering referral for expert advice, where available Difficulty confirming the diagnosis of asthma Patient has symptoms of chronic infection, or features suggesting a cardiac or other nonpulmonary cause (Box 1-3, p.26) (immediate referral recommended) Diagnosis is unclear even after a trial of therapy with ICS or systemic corticosteroids Patients with features of both Suspected occupational asthma asthma and COPD, if there is doubt about priorities fUorTtEreatment Refer for confirmatory testing and identification of sensitizing or irritant agent,TsRpIeBcific advice about eliminating exposure and pharmacological treatment. See specific guidelines44 for deDtaIiSls. Persistent or severely uncontrolled asthma or frequent exacerbations OR Patient's symptoms remain inhaler technique and good uncontrolled, or adherence with patient Step 4 threaastmonegnotin(mgOeePdxiYaucmerdboastieonICsSo-rLlAowBAlu, nBgoxfu3n-c5ti,opn.6d1e)s.pBiteefocroerrect referral, depending on the clinical context, identify and treatTmCodifiable risk factors (Box 2-2, p.36; Box 3-8, p.76) and comorbidities (p.94). NO PSaeteieSnet chtaiosnfr3eEqu(pe.n1t0a4s)thomn ad-ifrfeiclautlet dtohtereaaltthacnadreseuvt-ielirDzeaOtaiosnth(me.ag,.inmculultdipinlegEaDdevicsiistsioonrtruereg.ent primary care visits). Any risk factors for asthma-related death (see BoRxIA4-L1, p.125) Near-fatal asthma attack (ICU admissionA,ToEr mechanical ventilation for asthma) at any time in the past Suspected Evidence of, or orirsckoonff,irsmigendifiacnaanpt htryelaatxEmisDeonMrt fsoidoed-eafllfeercgtsy in a patient with asthma Patients with significant side-IeGfHfeTcts from treatment Need for long-term oral PcoYrRticosteroid use Frequent courses ofCoOral corticosteroids (e.g. two or more courses a year) Symptoms suggesting complications or sub-types of asthma e.g. aspirin-exacerbated respiratory disease (p.102); allergic bronchopulmonary aspergillosis Additional reasons for referral in children 6-11 years Doubts about diagnosis of asthma e.g. respiratory symptoms are not responding well to treatment in a child who was born prematurely Symptoms or exacerbations remain uncontrolled despite medium dose ICS (Box 3-6B, p.63) with correct inhaler technique and good adherence Suspected side-effects of treatment (e.g. growth delay) Concerns about the child's welfare or well-being ED: emergency department; ICS: inhaled corticosteroids; ICU: intensive care unit. For indications for referral in children 0-5 years, see p.158. 3. Treating to control symptoms and minimize future risk 87 PART C. GUIDED ASTHMA SELF-MANAGEMENT EDUCATION AND SKILLS TRAINING KEY POINTS With a chronic disease such as asthma, it is important for patients to be provided with education and skills in order to effectively manage their asthma. This is most effectively achieved through a partnership between the patient and their health care providers. The essential components for this include: o Skills training to use inhaler devices effectively o Encouraging adherence with medications, appointments and other advice, within an agreed management strategy o Asthma information o Training in guided self-management, with self-monitoring of symptoms or peak flow; a written asthma action plan to show how to recognize or trained health care worker. and respond to worsening asthma; and regular reviewTbEy a health care provider In developing, customizing and evaluating self-management interventions for differeRnItBcUultures, sociocultural factors should be taken into account.416 DIST SKILLS TRAINING FOR EFFECTIVE USE OF INHALER DEVICES OR Delivery of action, and respiratory medications by inhalation fewer systemic adverse effects than achieves systemic daehlivigehryc.oHnocweneOtvrPaeYrti,ounsiinngthaenainirwhaalyesr,ismaorsekirlal pthidatomnsuestt of be learnt and maintained in order for the medication to be delivered effeTctCively. Poor inhaler technique leads to poor asthma control, increased rNisOk of exacerbations and increased adverse effects.99 Most patients (up to 70-80%) are unable to unable to correctly demonstrate how to use tuhseeinthheailreirnshtahlee-yrDcpOorerrseccrtilbye. .U41n7foMrotusntapteeolyp,lemwanityh health care providers are incorrect technique are unaware that they have a problem. There is no `perfeRctI'AinLhaler - patients can have problems using any inhaler device. Strategies for ensuring effective use of inhaler deAvTicEes are summarized in Box 3-12, p.89.418 These principles apply to (pMDIs), use of a spacer iamllptryopveessodfeinlivhearlyeEraDdnedMv(icfoersI.CFSo)r patients reduces prescribed pressurized metered dose inhalers the potential for local side-effects such as dysphonia Canhdecokrainlgcaannddidcioarsriesc.4ti1n9gWinithhaIlCerSt,etchheInGriiqsHukTeouf scianngdaidsiatasnisdcaardnizaelsdocbheecrekldisutcteadkebsyorinnlsyin2g-3anmdinsuptiettsinagnodulteaafdtesrtousime.proved asthma control in adults420,421 anPdYoRlder children418 (Evidence A). A physical demonstration is essential to improve inhaler technique.422 This is technique falls off with time, eCsaoOsciehsetcikf itnhge health care provider and re-training must has placebo be repeated inhalers and a regularly. This spacer. After is particularly training, inhaler important for patients with poor symptom control or a history of exacerbations. Attaching a pictogram423,424 or a list of inhaler technique steps425 to the inhaler substantially increases the retention of correct technique at follow-up. Pharmacists, nurses and trained lay health workers can provide highly effective inhaler skills training.418,426-428 Some inhaler devices and techniques for their use are illustrated on the GINA website (www.ginasthma.org) and the ADMIT website (www.inhalers4u.org). 88 3. Treating to control symptoms and minimize future risk Box 3-12. Strategies to ensure effective use of inhaler devices CHOOSE Choose the most appropriate inhaler device for the patient before prescribing. Consider the medication options (Box 3-5, p.61), the available devices, patient skills and cost. If different options are available, encourage the patient to participate in the choice. For pMDIs, use of a spacer improves delivery and (with ICS) reduces the potential for side-effects. Ensure that there are no physical barriers, e.g. arthritis, that limit use of the inhaler. Avoid use of multiple different inhaler types where possible, to avoid confusion. CHECK Check inhaler technique at every opportunity. Ask the patient to show you how they use their inhaler (don't just ask if they know hUoTwEto use it). Identify any errors using a device-specific checklist. RIB CORRECT DIST Show the patient how to use the device correctly with a physical demOonRstration, e.g. using a placebo inhaler. Check technique again, paying attention to problematic steps. YoPuhYmalaeyr cnoereredcttolyreafpteeratsethviserparlorceepsesat2s-o3f ttirmaeinsin.4g20. Only consider an alternative device if the patient cannot use thCeOin Re-check inhaler technique frequently. After initial training, eTrrors often recur within 4-6 weeks.429 CONFIRM NO Clinicians should be able to demonstrate correct te-cDhnOique for each of the inhalers they prescribe. Pharmacists and nurses can provide highly eRffIeAcLtive inhaler skills training.426,427 ADHERENCE WITH MEDICATIONS AND OMTHAETRE ADVICE Identifying poor adherence TED Pprooovridaedrh. eTrheenrceeisisindcerfeinaesdinagsatwhearIfeGaniHleusres of of treatment to be the importance taken as agreed upon by the of poor adherence in chronic patient and the health care diseases, and of the potential to develop interventions to imprPovYeRadherence.430 Approximately 50% of adults and children on long-term therapy for asthma fail to take medicaCtOions as directed at least part of the time.168 In clinical practice, poor adherence may be identified by an empathic question that acknowledges the likelihood of incomplete adherence and encourages an open discussion. See Box 3-13, p.90 for examples. Checking the date of the last prescription or the date on the inhaler may assist in identifying poor adherence. In some health systems, pharmacists can assist in identifying poorly adherent patients by monitoring dispensing records. Electronic inhaler monitoring has also been used in clinical practice to identify poor adherence in patients with difficult-to-treat asthma.156,157 In clinical studies, poor adherence may be identified by short adherence behavior questionnaires, or from dispensing records; dose or pill counting; electronic inhaler monitoring;431 and drug assay such as for prednisolone.432 Factors contributing to poor adherence It is important to elicit patients' beliefs and concerns about asthma and asthma medications in order to understand the reasons behind their medication-taking behavior. Factors involved in poor adherence are listed in Box 3-13, p.90. They 3. Treating to control symptoms and minimize future risk 89 include both intentional and unintentional factors. Issues such as ethnicity,433 health literacy,434,435 and numeracy179 are often overlooked. Patients' concerns about side-effects may be either real or perceived.318,436 Interventions that improve adherence in asthma Few adherence interventions have been studied comprehensively in asthma. Some examples of successful interventions are: Shared decision-making for medication/dose choice improved adherence and asthma outcomes.170,173 Electronic inhaler reminders, either proactively or for missed doses, improved adherence437-440 and reduced exacerbations and oral corticosteroid use.437-439 In a difficult inner-city environment, home visits for a comprehensive asthma program by an asthma nurse led to improved adherence and reduced prednisone courses over the following several months.441 Providing adherence information to clinicians did not improve ICS use among patients with asthma unless clinicians chose to view the details of their patients' medication use.442 Irnefaillshewaeltrhe mduaeinoternoavnecrdeuoergleadnitzoaitmiopnr,oavnedauICtoSmaatdehderveoniccee rreeclaotgivneititoonupsruoaglrcaamrew, ibtUhutTmnEeosdsiaffgeeresntcrieggineruerdgewnhten care visits.443 TRIB In one study, directly observed oversight, was associated with controller medication administration more symptom-free days and fewer uartgsecnhDtovIoSisl,itcsotmhabnineudsuwailthcaterele.4m44edicine Improving adherence to controller medications may not necessarily translate tOoRimproved clinical outcomes.445 Further studies are needed of adherence strategies that are feasible for implemCOenPtaYtion in primary care. Box 3-13. Poor medication adherence in asthma NOT Factors contributing to poor adherence H-oDwOto identify poor adherence in clinical practice Medication/regimen factors Difficulties using inhaler device (e.g. arthritis) RIAL Ask an empathic question Acknowledge the likelihood of incomplete adherence and Burdensome regimen (e.g. multiple times peArTdEay) encourage an open non-judgmental discussion. Multiple different inhalers Unintentional poor adherence ED M Examples are: `Many patients don't use their inhaler as prescribed. Misunderstanding about instructIiGonHsT In the last 4 weeks, how many days a week have you been taking it - not at all, 1, 2, 3 or more days a week?'446 Forgetfulness Absence of a daily routine PYR `Do you find it easier to remember your inhaler in the morning or the evening?' Cost CO Check medication usage Intentional poor adherence Check the date of the last controller prescription Perception that treatment is not necessary Check the date and dose counter on the inhaler Denial or anger about asthma or its treatment In some health systems, prescribing and dispensing Inappropriate expectations frequency can be monitored electronically by clinicians Concerns about side-effects (real or perceived) and/or pharmacists Dissatisfaction with health care providers See review articles for more detail.167,447 Stigmatization Cultural or religious issues Cost Examples of successful adherence interventions Shared decision-making for medication/dose choice170,173 Inhaler reminders, either proactively or for missed doses437-439 90 3. Treating to control symptoms and minimize future risk  Prescribing low dose ICS once-daily versus twice-daily448 Home visits for a comprehensive asthma program by an asthma nurse441 ASTHMA INFORMATION While education is relevant to asthma patients of all ages, the information and skills training required by each person may vary, as will their ability or willingness to take responsibility. All individuals will require certain core information and skills but most education must be personalized and provided in a number of steps. For young children, the focus of asthma education will be on the parent/carer, but young children can be taught simple asthma management skills. Adolescents may have unique difficulties regarding adherence, and peer support group education may help in addition to education provided by the health care provider.449 These are complex interventions, and there have been few studies. Regional issues and the adolescent's developmental stage may affect the outcomes of such programs.450 The key features and components of an asthma education program are provided in BoxU3T-1E4. Information alone itmo pmraovinetsaiknnpoowslietidvegebbeuhtavdiooeraslncohtainmgper,oavnedasskthilmlsaaroeurtceoqmuieresd.45fo1 rSeofcfeiacltiavnedmpesdyicchaoTtiloRongIBidcaellivseurpyp.oArtt may also the initial be required consultation, verbal information should be supplemented with written or pictorial452,453 informDaItSion about asthma and its treatment. The GINA website (www.ginasthma.org) contains patient educational Patients and their families should be encouraged to make a note omfaatenryiaqlsuOeaRsstiwonesll as links to several asthma websites. that arise from reading this information or as a result of the consultation, and should be given timOePtYo address these during the next consultation. Asthma education and training, for both adults and children, can TbeCdelivered effectively by a range of health care providers including pharmacists community health workers) can NO and nurses426,427,454,455 (Evidence A). Trained lay deliver discrete areas of respiratory care such as health workers (also known as asthma self-management education. Asthma education by trained lay health workers has bee-nDfOound to improve patient outcomes and healthcare utilization fcinodminpgasresduwggitehsut sthuealnceaered,f4o28r,4a56ddaintidontoalastsuimdiielasrteoRxatIesAnsLet sass nurse-led education applicability in other in primary care457 (Evidence settings and populations. B). These ATE Box 3-14. Asthma information ED M Gthoeiarla: sTtohmpraovinidpeatrhtneeprsehrsiponwwithiththIaGesiHrthThmeaal,ththceairrefapmroilyvidaendrsother carers with suitable information and training to manage YR Content Approach Focus on the develoCpmOePnt of the partnership. Asthma diagnosis Accept that this is a continuing process. Share information. Adapt the approach to the patient's level of health literacy (Box 3-1, p.47). Rationale for treatment, and differences between `relievers' and `controllers' Potential side-effects of medications Prevention of symptoms and flare-ups Fully discuss expectations, fears and concerns. Develop shared goals. How to recognize worsening asthma and what actions to take; how and when to seek medical attention Management of comorbidities 3. Treating to control symptoms and minimize future risk 91 TRAINING IN GUIDED ASTHMA SELF-MANAGEMENT Guided self-management may involve varying degrees of independence, ranging broadly from patient-directed selfmanagement to doctor-directed self-management. With patient-directed self-management patients make changes in accordance with a prior written action plan without needing to first contact their health care provider. With doctordirected self-management, patients still have a written action plan, but refer most major treatment decisions to their physician at the time of a planned or unplanned consultation. The essential components of effective guided asthma self-management education are:171 Self-monitoring of symptoms and/or peak flow A written asthma action plan to show how to recognize and respond to worsening asthma; and Regular review of asthma control, treatment and skills by a health care provider. Self-management education that includes these components dramatically reduces asthma morbidity in both adults171,428,458 (Evidence A) and asthma-related hospitalizations, ecmhieldrrgeenn1c72y,4d58e(pEavrtidmeennctevAis)it.sBaenndefuitnssicnhceludduelerdedduoccttioornoorfcolinnTeicE-tvhiisrditst,omtwisos-ethdirds in work/school days, and program in 20 patients nocturnal prevents wakening.171 It has one hospitalization, been estimated and successful cthoamtpthleetioimnpolef msuecnhtRaaItBipoUrnoogfraamseblyf-m8 apnaatigeenmtsent prevents one emergency department visit.171,459 Less intensive interventions that iDnvISoTlve self-management education but not a written action plan are less effective,460 and RCTs on supported self-management for asthma icnofonrfimrmaetiodnthaalot nitereisduinceefsfeucntOisvceRh.4e51duAlesdyshteeamltahtcicarmeeutase-r,eivmiepwroovfe2s70 acostshtsm(aEcvoidnetrnocle, isA)a.4p5p8licable to a wide range of target groups and cliniCcaOl PseYttings, and does not increase health care Self-monitoring of symptoms and/or peak flow NOT Pneactieesnstsarsyhwouhlednbseytmrapintoemdstostkaeret ptotwraocrkseonf .thPeeiraskyemxpptiroamtosr-y(wDflioOthwo(rPwEiFth)omutoanitdoiarirnyg),maanyd notice and sometimes take action be useful: if Short-term monitoring o Following an exacerbation, to monitor recoRvIeArLy o Following a change in treatment, to heAlTpEin assessing whether the patient has responded o o ITfosyamsspistotminsidaepnpteifaicraetixocneossf iovcec(uEfopDraotMiobnjeacltiovredeovmideesnticcetroigf gdeergsrefoer owfolursnegnfiunngcatisotnhmimapcaoirnmtreonl t) Long-term monitoring o For earlier detection of exaIGceHrTbations, mainly in patients with poor perception of airflow limitation131 o o For For patients patients with who ahahvisePtYodrRifyficouf lst-utod-dceonnstreovl eorreseexvaecreerabsatthiomnas CO For patients carrying out PEF monitoring, use of a laterally compressed PEF chart (showing 2 months on a landscape format page) allows more accurate identification of worsening asthma than other charts.154 One such chart is available for download from www.woolcock.org.au/moreinfo/. There is increasing interest in internet or phone-based monitoring of asthma. Based on existing studies, the main benefit is likely to be for more severe asthma461 (Evidence B). Written asthma action plans Personal written asthma action plans show patients how to make short-term changes to their treatment in response to changes in their symptoms and/or PEF. They also describe how and when to access medical care.462,463 The term `written' action plan includes printed, digital or pictorial plans, i.e. the patient is given a record of the instructions. The benefits of self-management education for asthma morbidity are greater in adults when the action plans include both a step up in ICS and the addition of OCS, and for PEF-based plans, when they are based on personal best rather than percent predicted PEF463 (Evidence A). 92 3. Treating to control symptoms and minimize future risk The efficacy of self-management education is similar regardless of whether patients self-adjust their medications according to an individual written plan or whether the medication adjustments are made by a doctor460 (Evidence A). Thus, patients who are unable to undertake guided self-management can still achieve benefit from a structured program of regular medical review. Examples of written asthma action plan templates, including for adult and pediatric patients with low literacy, can be found on several websites (e.g. Asthma UK, www.asthma.org.uk; Asthma Society of Canada, www.asthma.ca; Family Physician Airways Group of Canada, www.fpagc.com; National Asthma Council Australia, www.nationalasthma.org.au) and in research publications.464,465 Health care providers should become familiar with action plans that are relevant to their local health care system, treatment options, and cultural and literacy context. Details of the specific treatment adjustments that can be recommended for written asthma action plans are described in the next chapter (Box 4-2, p.129). Regular review by a healthcare provider or trained healthcare worker The third component of effective asthma self-management education is regular review bUyTaEhealthcare provider or trained healthcare the following: worker. Follow-up consultations should take place at regular intTerRvIaBls. Regular review should include Ask the patient if they have any questions and concerns. Discuss issues, and provide additional educational messages as neDcIeSssary; if available, refer the patient to someone trained in asthma education. OR Assess asthma control. OPY Review the patient's level of symptom control and Ask about flare-ups to identify contributory factors raisnkdTfwaCchteotrhse(rBthoex 2-2, p.36). patient's response was appropriate (e.g. was an action plan used?). NO Review Assess the patient's symptom comorbidities. or PEF diary, if - DthOey keep one. Assess treatment issues. RIAL WAsastecshsthmeepdaictaietniotnusaedhtheereirnicnehaalnedrA, aTasnEkdacbooruretcatdahnedrernec-cehbeacrkriteercsh(nBiqouxe3i-f1n3e, cpe.9s0sa).ry (Box 3-12 p.89). Ask about adherence with Review the asthma action poltEahnDeraMinndteurvpednattieonitsif(ele.gve. lsomfoaksinthgmcaescsoanttiroonl)o. r treatment have changed.466 A single page prompt to cliniciansIGhaHsTbeen shown to improve the provision of preventive care to children with asthma dwuitrhinsgeoveffriceedvisiseitass.e467aFt roisllokwo-fPuhYpoRbspyittaellea-dhmeaisltshicoanr.e461is unlikely to benefit in mild asthma but may be of benefit in those CO School-based programs for children A systematic review found that school-based studies (most conducted in the US and Canada) that included selfmanagement skills for children aged 5-18 years was associated with a 30% decrease in emergency department visits, and a significant decrease in hospitalizations and in days of reduced activity.468 3. Treating to control symptoms and minimize future risk 93 PART D. MANAGING ASTHMA WITH MULTIMORBIDITY AND IN SPECIFIC POPULATIONS KEY POINTS Multimorbidity is common in patients with chronic diseases such as asthma. It is important to identify and manage multimorbidity, as it contributes to impaired quality of life, increased healthcare utilization, and adverse effects of medications. In addition, comorbidities such as rhinosinusitis, obesity and gastro-esophageal reflux disease may contribute to respiratory symptoms and some contribute to poor asthma control. For patients with dyspnea or wheezing on exertion: o Distinguish between exercise-induced bronchoconstriction (EIB) and symptoms that result from obesity or a lack of fitness or are the result of alternative conditions such as inducible laryngeal obstruction. o Provide advice about preventing and managing EIB. All adolescents and adults with asthma should receive ICS-containing controller medication to reduce their risk of severe exacerbations. It should formoterol for symptom relief. be taken every day or, as an alternative in mild asthmaU,TbEy as-needed ICS- Refer patients with difficult-to-treat or severe asthma to a specialist or severe astThmRIaBservice, after addressing common problems such as incorrect diagnosis, poor adherence (see Section 3E, p.104). incorrect inhaler technique, oDngISoing environmental exposures, and Y OR MANAGING COMORBIDITIES COP Multimorbidity is a common problem in patients with chronic diseasOeTs such as asthma. It is associated with worse quality of life, increased common among healthcare utilization and those with difficult-to-treat increased or severe aadsvthemrsaDe.1Oe01ffNeAccttsivoef treatment. 169 management Multimorbidity is of comorbidities particularly such as rhinosinusitis, obesity and gastro-esophageal reflux respiratory symptom burden and lead to medication dinistIeeAraaLsc-etioisnsim. Spoormtaenct,oamsotrhbeidseitiecosnadlsitoiocnosnmtraibyutaelstoo contribute to poor asthma control.469 TER Obesity MA Clinical features TED Being overweight or obese is a risk faIGctHor for childhood asthma and wheeze, particularly in girls.470 Asthma is more dcoiffmicourlbt itdoitcieosntsruocl hinaosboebssetrpuacttieivnPetYss.Rl3e8e8-p391apTnheisamaanyd be due to a different type of airway inflammation, contributory gastroesophageal reflux disease (GERD), mechanical factors, or other as yet undefined factorCs.OIn addition, lack of fitness and reduction in lung volume due to abdominal fat may contribute to dyspnea. Diagnosis Document body mass index (BMI) for all patients with asthma. Because of other potential contributors to dyspnea and wheeze in obese patients, it is important to confirm the diagnosis of asthma with objective measurement of variable expiratory airflow limitation (Box 1-2, p.23). Asthma is more common in obese than non-obese patients,57 but both overand under-diagnosis of asthma occur in obesity.37,58 Management As for other patients with asthma, ICS are the mainstay of treatment in obese patients (Evidence B), although their response may be reduced.391 Weight reduction should be included in the treatment plan for obese patients with asthma (Evidence B). Increased exercise alone appears to be insufficient (Evidence B).397 Weight loss can improve asthma control, lung function, health status and reduces medication needs in obese patients,393,394 but the studies have generally been small, quality of some studies is poor, and the interventions and results have been variable.392 The most 94 3. Treating to control symptoms and minimize future risk striking results have been observed after bariatric surgery,395,396,471 but even 5-10% weight loss can lead to improved asthma control and quality of life.397 For patients with comorbid obstructive sleep apnea, one study showed a significant reduction in moderate exacerbations with 6 months of continuous positive airway pressure (CPAP) therapy.472 Gastroesophageal reflux disease (GERD) Clinical features GERD can cause symptoms such as heartburn, and epigastric or chest pain, and is also a common cause of dry cough. Symptoms and/or diagnosis of GERD are more common in people with asthma than in the general population,469 but this may be in part due to cough being attributed to asthma; in addition, some asthma medications such as beta2agonists and theophylline cause relaxation of the lower esophageal sphincter. Asymptomatic gastroesophageal reflux is not a likely cause of poorly controlled asthma.469 Diagnosis In patients with confirmed asthma, no value in screening patients with GERD should be considered as a possible cause uncontrolled asthma for GERD (Evidence A). For opIBfaUatieTdnErtys cwoiuthgha;shthomwaevaenrd, there is symptoms suggestive of reflux, an empirical agent, may be considered, as in the general trial of anti-reflux population. If the medication, such symptoms do not aIrSesTsaoRlpvreo,tosnpepcuifmicpininvheisbtiitgoartioornms ostuilcithy as 24-hour pH monitoring or endoscopy may be considered. R D Management PY O Clinical trials of proton showed small benefits pump inhibitors in patients with confirmed for lung function, but no significant benefit afosCrthOomthae,rmaostshtmofawohuotcmomhaeds.a473d,4ia74gInnoasisstoufdGy EofRaDd,ult patients with symptomatic asthma but without symptoms of GNEORTD, treatment with high dose proton pump inhibitors did not red limited uc to e asthma symptoms patients with both sy or exacerbations mptomatic reflux .475 I and nniggeh-nt-DetirOmale, benefits of respiratory proton pump inhibitors in symptoms.476 Other treat asthma a ment opti ppear to b ons includ e e mpoootirlliytycaognetrnotlsle, dlifaesstthymleachsahnogueldsnaontdbfeuntrdeoaptelidcawtiiotRhnI.AaInnLtis-ruemflumxatrhye, rsaypmyputonmlesasticthreeyfluaxlssohhoauvlde be treated, but patients symptomatic reflux with (Evidence A).474 Few data are available for chAilTdEren with asthma symptoms and symptoms of GERD.477,478 Anxiety and depression ED M Clinical features Anxiety symptoms and psychiatricIGdHisoTrders, particularly depressive and anxiety disorders, are more prevalent among people with asthma.479,480 PsPycYhRiatric comorbidity is also associated with worse asthma symptom control and medication iandchreearesnecdea, satnhdmwa-orresleateasdCtheOmxaac-ererblaatteiodnqsuaanlidtyeomf elifreg.e48n1cAynvxisioituss.48a2nPdadneicpraetstascivkes symptoms have been associated may be mistaken for asthma. with Diagnosis Although several tools are available for screening for anxious and depressive symptomatology in primary care, the majority have not been validated in asthma populations. Difficulties in distinguishing anxiety or depression from asthma symptoms may therefore lead to misdiagnosis. It is important to be alert to possible depression and/or anxiety in people with asthma, particularly when there is a previous history of these conditions. Where appropriate, patients should be referred to psychiatrists or evaluated with a disease-specific psychiatric diagnostic tool to identify potential cases of depression and/or anxiety. Management There have been few good quality pharmacological and non-pharmacological treatment trials for anxiety or depression in patients with asthma, and results are inconsistent. A Cochrane review of 15 randomized controlled trials of psychological interventions for adults with asthma included cognitive behavior therapy, psychoeducation, relaxation, and biofeedback.483 Results for anxiety were conflicting, and none of the studies found significant treatment differences for 3. Treating to control symptoms and minimize future risk 95 depression. Drug treatments and cognitive behavior therapy484 have been described as having some potential in patients with asthma; however, current evidence is limited, with a small number of studies and methodological shortcomings. Food allergy and anaphylaxis Clinical features Rarely, food allergy is a trigger for asthma symptoms (<2% of people with asthma). In patients with confirmed foodinduced allergic reactions (anaphylaxis), co-existing asthma is a strong risk factor for more severe and even fatal reactions. Food-induced anaphylaxis often presents as life-threatening asthma.102 An analysis of 63 anaphylaxis-related deaths in the United States noted that almost all had a past history of asthma; peanuts and tree nuts were the foods most commonly responsible.485 A UK study of 48 anaphylaxis-related deaths found that most were regularly treated for asthma, and that in most of these, asthma was poorly controlled.486 Diagnosis In patients with confirmed food allergy, it is important to assess for asthma. Children withIBfoUoTdEallergy have a four-fold increas allergy ed or i likeliho ntolera od of h nce for aving asth specialist ma compared with c allergy assessment. hildren This m wit ay hinoculut dfoeoadpaplrleorpgryia.4tIe8S7TaRlRleefregryptaetsietinngts with such suspected f as skin pric ood k testing and/or blood testing for specific IgE. On occasion, carefully supervised fRooDd challenges may be needed. Management PY O Patients who have a confirmed food available at all times, and be trained allergy how to that use puts them at it. They, and rthisekirfofarmaCnilyaO,pmhyulastxbisemeudsutchaatevde an epinephrine auto-injector in appropriate food avoidance strategies, and in the medical notes, they should be flNagOgTed as being at high risk. It is especially important to ensure that their asthma is well controlled, they have a and anaphylaxis, and are reviewed on a regular basis. writ-teDnOaction plan, understand the difference between asthma Rhinitis, sinusitis and nasal polyps RIAL Clinical features ATE Evidence allergic or cnleoanr-layllseurgpipco, rhtasvaelicnoknbceutrwreenetnrhdiEinsDietiasM,seansdof1t0h-e4u0p%peorf and lower airways.488 Most patients with asthma, either patients with allergic rhinitis have asthma.489 Depending on sensitization and exposure, allergens), or intermittent (e.g. faulrlreerdgIicpGerHhtsTin).i4t9is0 may be seasonal (e.g. ragweed or grass pollen), perennial (e.g. mite Rhinitis is defined as irritation anPdYinRflammation of the mucous membranes of the nose. Allergic rhinitis may be accompanied by ocular sympCtoOms (conjunctivitis). Rhinosinusitis is defined as inflammation of the nose and paranasal sinuses characterized by more than two symptoms including nasal blockage/obstruction and/or nasal discharge (anterior/posterior nasal drip).491 Other symptoms may include facial pain/pressure and/or a reduction or loss of smell. Sinusitis rarely occurs in the absence of rhinitis. Rhinosinusitis is defined as acute when symptoms last <12 weeks with complete resolution, and chronic when symptoms occur on most days for at least 12 weeks without complete resolution. Chronic rhinosinusitis is an inflammatory condition of the paranasal sinuses that encompasses two clinically distinct entities: chronic rhinosinusitis without nasal polyposis and chronic rhinosinusitis with nasal polyposis.492 The heterogeneity of chronic rhinosinusitis may explain the wide variation in prevalence rates in the general population ranging from 1-10% without polyps and 4% with polyps. Chronic rhinosinusitis is associated with more severe asthma, especially in patients with nasal polyps.493 Diagnosis Rhinitis can be classified as either allergic or non-allergic depending on whether allergic sensitization is demonstrated. Variation in symptoms by season or with environmental exposure (e.g. furred pets) suggests allergic rhinitis. Examination of the upper airway should be arranged for patients with severe asthma. 96 3. Treating to control symptoms and minimize future risk Management Evidence-based guidelines (Allergic Rhinitis in Asthma, ARIA)488 recommend intranasal corticosteroids for treatment of allergic rhinitis. In a case-control study, treatment of rhinitis with intranasal corticosteroids was associated with less need for asthma-related hospitalization and emergency department visits,494 but a meta-analysis found improvement in asthma outcomes only in patients not also receiving ICS.495 However, few placebo-controlled studies have systematically evaluated the effect of proper treatment and management of chronic rhinosinusitis on asthma control. A placebo-controlled trial of nasal mometasone in adults and children with chronic rhinosinusitis and poorly controlled asthma showed no benefit for asthma outcomes, suggesting that, while chronic rhinosinusitis can contribute to respiratory symptoms, e.g. chronic cough, its treatment in patients with asthma should be targeted at the symptoms of rhinosinusitis rather than to improve asthma control.496 In patients with nasal polyposis, omalizumab,497 mepolizumab498,499 and dupilumab500,501 improved subjective and objective assessments including nasal symptoms and polyp size, compared with placebo. In patients with chronic dsiunpuisluitmisawbi.t5h00nasal polyposis and comorbid asthma, asthma symptom control and lunIgBfUuTncEtion were also improved with MANAGING ASTHMA IN SPECIFIC POPULATIONS OR SETTINGS ISTR This section includes brief advice about managing asthma in specific populatioDns or settings in which the usual tsreecattimonenotf aCphparpotaecrh1m(pa.y28n)e. ed to be modified. Also refer to the DiagnoPsiYs oOf Rrespiratory symptoms in other settings Low- and middle-income countries Clinical features CO NOT In 2019, 96% of asthma deaths and 84% of disability-ad-juDsOted life years (DALYs) were in LMICs.502 Symptoms of as ex thma posur are simi es such lar as world-wide, smoking an b d ut patient biomass fluaenlgeuxapgoeIsAumLraeyadnidff er, inc and comorbidities idence of chronic may vary depending respiratory infections on environmental from tuberculosis and HIV/AIDS. TER Management MA The fundamental principles and aims oTfEaDsthma treatment are the same in LMICs as in high-income countries, but common barriers to effective long-IGteHrm asthma care include the lack of availability and affordability of inhaled medicines, and prioritization of acute carPeYoRver chronic care by healthcare systems. Recommendations by WHCOOand the International Union Against Tuberculosis and Lung Disease (The Union)503 form the basis of treatments offered in many LMICs.60 The WHO Model List of Essential Medicines504 (Appendix, Chapter 5) includes ICS, combination ICS-formoterol, and bronchodilators. Spacers are included in the WHO list of essential technology but are rarely available due to obstacles to their manufacture or purchase, practical issues of cleaning, and inconvenience for ambulatory use. Effective spacers can be made at no cost from plastic drink bottles.505 Medicines selected as `essential' are not necessarily the most effective or convenient, particularly for patients with more severe disease, and a limited choice does not allow for consideration of patient preferences and likelihood of adherence. However, ICS-containing controllers, when provided for large populations, have achieved impressive reductions in mortality and morbidity,506 including in LMICs. In Brazil, government policy ensuring nationwide easy access to ICS, at no cost to patients, was associated with a 34% reduction in hospitalizations for asthma.164 Prescribing ICS-formoterol as the symptom reliever, with (GINA Steps 3-5) or without (Steps 1-2) maintenance ICS-formoterol, provides the safest and most effective asthma treatment for adolescents and adults163,193, and avoids the behavioral consequences of starting treatment with SABA alone. 3. Treating to control symptoms and minimize future risk 97 Inclusion of essential asthma medicines in formularies and guidelines does not assure sustained and equitable supply to patients. The supply of medicines in many LMICs tends to be sporadic for a wide variety of reasons, sometimes determined by the ability of governments to pay for supplies, issues relating to procurement, poor administration and record keeping, and problems in the supply chain, particularly to remote dispensaries.60 Availability of asthma medicines varies widely between LMICs, with some having only oral bronchodilators (salbutamol and theophylline tablets/solutions) supplemented from time to time with oral corticosteroids. Oral bronchodilators have a slow onset of action and more adverse effects than inhaled SABA, and even occasional courses of OCS are associated with a significant risk of short-term adverse effects such as pneumonia and sepsis,507 and with long-term adverse effects including osteoporosis, cataract and diabetes.309 The largest (52 countries) survey of the accessibility and affordability of inhaled asthma medicines, conducted in 2011, reported that salbutamol was available in only half of public hospitals; ICS was available in fewer than one in five public pharmacies and not at all in 14 countries.508 Obtaining asthma medicines often represents a catastrophic household expense. A recent systematic review of the availability, unavailable cost and uanndafafoffrodradbalebiplitayrtoicf uelsasrleynftoiarlImCSedaicnidnecsomfobr iansatthiomnaICaSnd-LCAOBAP.D509inTLhMisICmseafonuUsnTtdhEatht ethsee to be largely essential cornerstone of treatment that achieves substantial reductions in morbidity and mortaliTtyRisIBout of reach for the great majority of the world's children, adolescents and adults living with asthma. DIS It is not acceptable in 2022 to manage asthma with treatments. The research community must develop aSnAdBeAvsaalunadteoraaplpcrooraticchoessteOdroReisdisgninesdtetoadobovf iparteevbeanrtriiveersICtoSc-caorentianining resource-constrained settings. A World Health Assembly Resolution on OeqPuYitable access to affordable care, including inhaled medicines, for children, valuable step forward - as was raedcoelentslcyeancthsieavneddafdourlttshewsituhpapslythomfOainT,swuChlienrfeovredriathbeeytelisv.e51i0nGthINeAwsotrrlodn, gwlyousludpbpeorats this initiative. O N In the meantime, in general, Track 2 treatment, although Lle-ssDeffective in reducing asthma exacerbations, may be considered treatment. preferable The "other cinosnetrtotilnlegrsowpthioenres"ciunrrFeingtuareva3Ei.la5RbAIiA,littyhoourgahffoprodteanbtiliiatyllycolenssstrcaoinsstlyth, emaaybiblitey to implement Track considerably less 1 ereffseocutirvcee (see.gtt.inLgT(ReA.gs.)uosremoof rae lhoawrmdofusle(eIC.gS. minaMhianAlteTernwanhceeneOvCerSa),SoAr BnoAt iws etallkseunppfoorrtseydmbpytoemvidreelniecfe). eOsfptehceisaellythinreteheotlhoewr- cthoanttraonlleICr Sopwtiaosnsp,rtohveidtehdir,dawt oleualdstbdeurcilnogsTessEytmDtopttohme aptriecfpeerrreioddrse.commendations in Tracks 1 and 2, as it would ensure Adolescents YRIGH Clinical features COP Care of teenagers with asthma should take into account the rapid physical, emotional, cognitive and social changes that occur during adolescence. Asthma control may improve or worsen, although remission of asthma is seen more commonly in males than females.511 Exploratory and risk-taking behaviors such as smoking occur at a higher rate in adolescents with chronic diseases than in healthy adolescents. In a large meta-analysis of adherence with ICS by adolescents and young adults,168 overall adherence was 28%, and slightly higher in those <18 years (36%). However, pharmacy refill data provided lower estimates of adherence than selfreport measures. Predictors of adherence included personality, illness perceptions, and treatment beliefs. Management General principles for managing chronic disease in adolescents have been published by WHO.512 Adolescents and their parent/carers should be encouraged in the transition towards asthma self-management by the adolescent. This may involve the transition from a pediatric to an adult health care facility. During consultations, the adolescent should be seen separately from the parent/carer so that sensitive issues such as smoking, adherence and mental health can be discussed privately, and confidentiality agreed. Information and self-management strategies should be tailored to the 98 3. Treating to control symptoms and minimize future risk patient's stage of psychosocial development and desire for autonomy; adolescents are often focused on short-term rather than long-term outcomes. An empathic approach should be used to identify beliefs and behaviors that may be barriers to optimal treatment; for example, adolescents may be concerned about the impact of treatment on their physical or sexual capabilities. Medication regimens should be tailored to the adolescent's needs and lifestyle, and reviews arranged regularly so that the medication regimen can be adjusted for changing needs. Information about local youth-friendly resources and support services should be provided, where available. In adolescents with mild asthma, adherence as-needed ICS-formoterol reduced risk of severe exacerbations compared with SABA alone, and without the need for daily treatment. Change in height from baseline in younger adolescents was significantly greater with asneeded ICS-formoterol than with daily low-dose ICS plus as-needed SABA.214 Exercise-induced bronchoconstriction (EIB) Clinical features Pbrhoynscichaolcaocntsivtriticytiiosnantypimicpaollrytawnot rssteimnuinlugsaffoterracsethsmsaatiosnymopf teoxmerscfisoer .mHaonwyepvaetrie, nshtso,rwtniethsssyomTf Ebprtoematsh and or wheezing during exercise may also relate to laryngeal obstruction.42,47 obesity or a lack of fitness, or to comorbid or alternative RcoIBnUditions such as inducible Management DIST Regular controller treatment with ICS significantly reduces EIB47 (EvidenceOAR). Training and sufficient warm-up reduce the (Ev incidence idence A), and but severity of EIB47 (Evidenc tolerance to the protective eefAfe).cTtsaokfinSgASBAABsAasn,dLALABOBAPAsYsoracgharinosmt oEnIeBsdpervioerlotopsewxeitrhc ise prevents regular (mor EIB e than once-daily) use (Evidence A).47 However, in a 6-week study in paTtieCnts with mild asthma, low dose budesonide- formoterol, taken as needed for relief of symptoms and beforeNeOxercise, was non-inferior for reducing EIB to regular dpareilsycIrCibSedwaiths-anse-endeeeddIeCdSS-fAoBrmAo.2t1e9rMolotorepsrteuvdeienst eaxraecneer-beadDteOiodn, sbuatntdhicsosnutrgoglessytms pthtoamt psactiaenntussweitthhemsiladmaestmhmedaicwahtioonare prior to exercise, if needed, and do not need pMDIs have been discontinued globally. to beRpIAreLscribed a SABA for pre-exercise use (Evidence B). Chromone Breakthrough EIB often indicates poorly contrAoTlleEd asthma, and stepping up controller treatment (after checking inhaler Atthelcehtneisque and adherence) generallyHreTsEuDltsMin the reduction of exercise-related symptoms. Clinical features YRIG Athletes, particularly those coPmpeting at a high level, have an increased prevalence of various respiratory conditions compared to non-athletesC. OThey experience a higher prevalence of asthma, EIB, allergic or non-allergic rhinitis, chronic cough, inducible laryngeal obstruction, and recurrent respiratory infections. Airway hyperresponsiveness is common in elite athletes, often without reported symptoms. Asthma in elite athletes is commonly characterized by less correlation between symptoms and pulmonary function; higher lung volumes and expiratory flows; less eosinophilic airway inflammation; more difficulty in controlling symptoms; and some improvement in airway dysfunction after cessation of training. Management Preventative measures to avoid high exposure to air pollutants, allergens (if sensitized) and chlorine levels in pools, particularly during training periods, should be discussed with the athlete. They should avoid training in extreme cold or pollution (Evidence C), and the effects of any therapeutic trials of asthma medications should be documented. Adequate anti-inflammatory therapy, especially ICS, is advised; minimization of use of beta2-agonists will help to avoid the development of tolerance.47 Information on treatment of exercise-induced asthma in athletes can be found in a Joint Task Force Report prepared by the European Respiratory Society, the European Academy of Allergy and Clinical Immunology, and GA(2)LEN513 and the World Anti-Doping Agency website (www.wada-ama.org). 3. Treating to control symptoms and minimize future risk 99 Pregnancy Clinical features Asthma control often changes during pregnancy; in approximately one-third of women asthma symptoms worsen, in one-third they improve, and in the remaining one-third they remain unchanged.514 Exacerbations are common in pregnancy, particularly in the second trimester.103 Exacerbations and poor asthma control during pregnancy may be due to mechanical or hormonal changes, or to cessation or reduction of asthma medications due to concerns by the mother and/or the health care provider. Pregnant women appear to be particularly susceptible to the effects of viral respiratory infections,515 including influenza. Exacerbations and poor symptom control are associated with worse outcomes for both the baby (pre-term delivery, low birth weight, increased perinatal mortality) and the mother (pre-eclampsia).103 If asthma is well controlled throughout pregnancy there is little or no increased risk of adverse maternal or fetal complications.49 Management Although there is a general concern about any medication use asthma in pregnancy markedly outweigh any potential risks of uinsupraelgcnoanntrcoyl,lethr eanaddvrealTnieEtavgeersmoefdaiccatitvioenlyst4r9eating (eEvveindewnhceenAt)h.eFirosrathfeistyreinasporeng, nuasnincgy mhaesdincoattiboenesntouanechqiueivveocgaolloydpsroyvmepnt.oUmsceoonftrIoClSa,nbdReptIarBeU-vaegnotneisxtasc,emrboanttieolnuskaisstjuosrtified theophylline is not associated with an increased incidence of fetal abnormalities.51D6 IST 2 IImCSpodrutarinntgly,pIrCegSnraendcuyceis tahesirgisnkifiocfaenxt aricsekrfbaacttioornfsoor feaxsatchemrbaadtiuorninsg103p(rEegvnidaennccyOe49RA,5)1.7,A518s(tEudvyiduesnicneg Aa)d,manindisctreastsivaetiodnataof reported that uncontrolled maternal asthma increased the risk of early-oOnsPeYt asthma in the offspring.519 One study reported that a treatment algorithm in with significantly fewer exacerbations naonnd-bsmetotekrinfegtaplreoguntcaonmt wesomtheOannTbaCansaeldgoornithmmonbtahslyedFeoNnlOy and ACQ was associated on ACQ.520 However, the ACQ-only increased algorithm did not to medium dose, reflect current and ICS could cblienisctaolprpeecdo;m5m8%enDodfaOwtioNonmse, nasinLtAhBeAAwCQas-oinntlryogdruocuepdwoenrlye after ICS had being treated been without ICS by the children of wenodmoefnpirnetghneaFnceyN.OIngarofoulploawn-dupinsctuhdilydraefnteorIfA4w-L6o-myeeanrsr,etcheeivpinregvIaCleSnicnethoef asthma was ACQ group, over 50% lower both in compared with women ainlstoheapclpineiacraeldgrtooubpewphrootedcidtivneotforrecaesitvhemIaCSin.5t2h1eUcshTeiEldoR.f52IC1 S in early pregnancy (before randomization at weeks 12-20) MA On (Ev balanc idence e, given the evidenc A), including due to elaicnkporfeIgCnSaTnoEcrDypaonodr infancy for adverse outcomes from ex adherence,103 and evidence for safety ac of erbations dur usual doses ing pregnanc of ICS and y 49 LABA516 delivery (Evidence (Evidence A), D), aanlodwICpSrioshrioRtyuIGlsdhHnooutldbbeestpolapcpeedd on stepping down in preparation for treatment (however guided) until pregnancy or during pregnancy after (Evidence C). OPY Despite lack of evidence for Cadverse effects of asthma treatment in pregnancy, many women and doctors remain concerned.522 Pregnant patients with asthma should be advised that poorly controlled asthma, and exacerbations, provide a much greater risk to their baby than do current asthma treatments. Educational resources about asthma management during pregnancy may provide additional reassurance.523 During pregnancy, monthly monitoring of asthma is recommended.523 It is feasible for this to be achieved by pharmacist-clinician collaboration, with monthly telephone monitoring of asthma symptom control.524 One observational study found that pregnant women whose asthma was well- controlled without controller therapy and who have no history of previous exacerbations were at low risk for exacerbations during pregnancy.525 However, they should still be closely monitored. For women with severe asthma, evidence on use of biologic therapies during pregnancy is scarce526. A registry study found no evidence of an increased risk of major congenital malformations when mothers received omalizumab during pregnancy. Women should be counselled that the potential risks associated with biologic exposure during pregnancy need to be balanced against the risks for themselves and their children caused by uncontrolled asthma.527 Respiratory infections should be monitored and managed appropriately during pregnancy.515 During acute asthma exacerbations, pregnant women may be less likely to be treated appropriately than non-pregnant patients.103 To avoid 100 3. Treating to control symptoms and minimize future risk fetal hypoxia, it is important to aggressively treat acute exacerbations during pregnancy with SABA, oxygen and early administration of systemic corticosteroids. During labor and delivery, usual controller medications should be taken, with reliever if needed. Acute exacerbations during labor and delivery are uncommon, but bronchoconstriction may be induced by hyperventilation during labor, and should be managed with SABA. Neonatal hypoglycemia may be seen, especially in preterm babies, when high doses of beta-agonists have been given within the last 48 hours prior to delivery. If high doses of SABA have been given during labor and delivery, blood glucose levels should be monitored in the baby (especially if preterm) for the first 24 hours.528 A review of asthma guidelines for the management of asthma during pregnancy highlighted the need for greater clarity in current recommendations and the need for more RCTs among pregnant asthma patients.529 Women - perimenstrual asthma (catamenial asthma) Clinical features In approximately 20% of severe asthma, a higher women, asthma is worse in the premenstrual phase. body mass index, a longer duration of asthma, and a TghreeasteerwIBloikUmeTleiEhnotoedndoftoasbpeiroinldeexra, chearvbeamteodre rmeesnpsirtarutoarlybdleiseedainseg.. TThheeyromleoroef ohfotremnohnaeveledveyslsmaenndosrryhsetae,mpicreimnfelanmstmruaatliosnynredmrDoamIiSneTs,Rsuhnocrletearr.m53e0 nstrual cycles, and longer Management OR In addition to the usual strategies for management of asthma, oral conPtrYaceptives and/or leukotriene receptor antagonists may be helpful530 (Evidence D). Further research is neeCdOed. Occupational asthma NOT Clinical features - DO oInccthuepaotciocnuaplaatisotnhaml as)e.ttOinngc,erhainpitaistieonfttehnapsrbeececodmesethsIAeeLndseitvizeelodptmo eannt oocf causpthamtioan(asleaellepr.g2e8nr,etghaerdleinvgeldoiaf genxposoissuoref ncoencetinssuaerdyetoxpinodsuurcee, spyemrspistotemnst smyamypbtoemesxtarMenmdATeirElryeRvloewrs;ibrelesualitrinflogwexliamcietarbtioantiomnsayberecsoumlte.44increasingly severe, and with Management TED Dweithtaaileddultin-ofonrsmeat atiostnhims aavsahiolaubldlebienIGeaHsvikdeednaceb-obuatstehdeirguwiodreklinheisstoarbyoauntdmoatnhaegr eemxpeonstuorfeosc(cEuvpidaetinocnealAa)s. tThhmeae.4a4rAlyll patients identification and elimination PoYf oRccupational sensitizers and the removal of sensitized patients from any further eoxcpcuopsautrieonaarel eimxppoosrutarenthaasCvpOeebcteseonfsthueccmesasnfaugl,eemspeenct ioaflloycincuinpdautiostnraiallassetthtimngas(.E44vCidoesntc-eeffAe)c.tiAvtetemminpitms itzoarteiodnucoef latex sensitization can be achieved by using non-powdered low-allergen gloves instead of powdered latex gloves.44 Patients with suspected or confirmed occupational asthma should be referred for expert assessment and advice, if this is available, because of the economic and legal implications of the diagnosis (Evidence A). The elderly Clinical features Lung function generally decreases with longer duration of asthma and increasing age, due to stiffness of the chest wall, reduced respiratory muscle function, loss of elastic recoil and airway wall remodeling. Older patients may not report asthma symptoms, and may attribute breathlessness to normal aging or comorbidities such as cardiovascular disease and obesity.531-533 Comorbid arthritis may contribute to reduced exercise capacity and lack of fitness, and make inhaler device use difficult. Asthma costs may be higher amongst older patients, because of higher hospitalization rates and medication costs.532 3. Treating to control symptoms and minimize future risk 101 Management Decisions about management of asthma in older people with asthma need to take into account both the usual goals of symptom control and risk minimization and the impact of comorbidities, concurrent treatments and lack of self- management skills.531,532 Data on efficacy of asthma medications in the elderly are limited because these patients are often excluded from major clinical trials. Side-effects of beta2-agonists such as cardiotoxicity, and corticosteroid side- effects such as skin bruising, osteoporosis, and cataracts, are more common in the elderly than in younger adults.531 Clearance of theophylline is also reduced.531 Elderly patients should be asked about all of the other medications they are taking, including eye-drops, and potential drug interactions should be considered. Factors such as arthritis, muscle weakness, impaired vision and inspiratory flow should be considered when choosing inhaler devices for older patients,532,534 and inhaler technique should be checked at each visit. Older patients may have difficulties with complex medication regimens, and prescribing of multiple inhaler devices should be avoided if possible. Large print versions may be needed for written information such as asthma action plans. Patients with cognitive impairment may require a carer to help them use their asthma medications. For diagnosis and initial management of patients with asthma-COPD overlap, see Chapter 5, p.141. Surgery and asthma UTE TRIB Clinical features DIS There is no ev increased risk ide for nce of increased patients with CO peri-operat PD,535 and ive r this isk for the general may also apply to asthma asthma ppOaotRpieunlatstiownit.h535r Howev educed er, there FEV . T is he an inc i denc e of severe peri-operative bronchospasm in people with asthma is low, buOt iPt Ymay be life threatening.536 1 Management T C For elective surgery, meticulous attention should be paid pre-opeNraOtively to achieving good asthma control, as detailed elsewhere history, or in this chapter, especially for persistent airflow limitation536 p(EavtiiednetnscweitBh).mFoorrep-saDetviOeenrtes asthma, uncontrolled requiring emergency symptoms, exacerbation surgery, the risks of proceeding wlointhgo-tuetrmfirshtigahchdieovsiengICgSooodr washtohmhaavceornetcroelivsehdouOldCSbefRowIrAemLigohreedthaagnai2nswtetheeksndeuerdinfgorthimempreedviaiotuess6urmgeornyt.hPsasthieonutsldtraekcinegive hydrocortisone peri-operatively as they are at risAk ToEf adrenal crisis in the context of surgery537 (Evidence B). More immaminetadiiantineginrteragu-olaprecraotnivtreoillsesrutehserraeplaytitnhgrotouEgaDhsotMhumt tahempaenrai-goepmereantitvaereperreiovidewiseidmipnodrteatnati.l elsewhere.536 For all patients, Aspirin-exacerbated respiratory diseIGasHeT Clinical features PYR The clinical picture and coursCeOof aspirin-exacerbated respiratory disease (AERD, previously called aspirin-induced asthma) are well established.364 It starts with nasal congestion and anosmia, and progresses to chronic rhinosinusitis with nasal polyps that re-grow rapidly after surgery. Asthma and hypersensitivity to aspirin and non-steroidal anti- inflammatory drugs (NSAIDs) develop subsequently. Following ingestion of aspirin or NSAIDs, an acute asthma attack develops within minutes to 1-2 hours. It is usually accompanied by rhinorrhea, nasal obstruction, conjunctival irritation, and scarlet flush of the head and neck, and may sometimes progress to severe bronchospasm, shock, loss of consciousness, and respiratory arrest.538,539 AERD is more likely to be associated with low lung function and severe asthma,540,541 and with increased need for emergency care.541 The prevalence of AERD is 7% in general adult asthma populations, and 15% in severe asthma.541,542 Diagnosis A history of exacerbation following ingestion of aspirin or other NSAIDs is highly suggestive of AERD. Aspirin challenge (oral, bronchial or nasal) is the gold standard for diagnosis543,544 as there are no reliable in vitro tests, but oral aspirin challenge tests must only be conducted in a specialized center with cardiopulmonary resuscitation capabilities because 102 3. Treating to control symptoms and minimize future risk of the high risk of severe reactions.543,544 Bronchial (inhalational) and nasal challenges with lysine aspirin are safer than oral challenges and may be safely performed in allergy centers.544,545 Management Patients with AERD should avoid aspirin or NSAID-containing products and other medications that inhibit cyclooxygenase-1 (COX-1), but this does not prevent progression of the disease. Where an NSAID is indicated for other medical conditions, a COX-2 inhibitor (e.g. celocoxib or etoricoxib), or paracetamol (acetaminophen), may be considered546,547 with appropriate health care provider supervision and observation for at least 2 hours after administration548 (Evidence B). ICS are the mainstay of asthma therapy in AERD, but OCS are sometimes required; LTRA may also be useful539,548 (Evidence B), but note the 2020 FDA warning about adverse effects with montelukast.241. See Chapter 3E (p.104) for treatment options for patients with severe asthma. An additional option is aspirin desensitization, which may be conducted under specialist care in a clinic or hospital.549 Desensitization to aspirin followed by daily aspirin treatment can significantly improve upper respiratory symptoms and overall quality of life, dsceocrreesa,sbeurtefceuwrrdeoncuebleo-fbnliansdasl ptuodlyiepss,hraevdeuecxeatmheinneedeadsftohrmOaCoSutacnodmseisn.u54s4,s55u0r,5g5e1 rAys, painridn iUdmeTpsEreonvseitnizaastiaolnainsdaassstohcmiaated with a significantly increased risk of adverse effects such as gastritis and gastrointTesRtiInBal bleeding.551 Allergic bronchopulmonary aspergillosis (ABPA) DIS Clinical features OR Awlhleeregzicinbgr,ofnlecehtoinpguplmuolmnaornyarayspoepragciilltoiessisa(nAdBdPeAv)eilsopamceonmtpolfebxrpounlcmhoienOcatParyYsidsi,sseoamseetcimhaersacwteithrizmedalabiysere, pweeaigtehdt episodes loss and of hemoptysis. Some patients expectorate brownish sputum plugs. TABCPA is most commonly found in asthma or cystic fibrosis, due to a hypersensitivity response to Aspergillus fumNigOatus, a common indoor and outdoor mold. Diagnosis - DO Diagnosis of ABPA serum IgE, specific IisgGbatsoeAd.ofunmcoigmatpuoss,irteadciroitloegriaicRainIlAcfelLuadtuinrgesimamndedbilaotoedheyopseirnsoepnhsiiltsiv.5i5ty2 reaction to A. fumigatus, total Sensitization to fungal allergens, without `severe tahsethfumllapwicittuhrfeunogf aAlBsPeAn,siitsizoafttieonn'f.oundATinEasthma, particularly in severe asthma, where it is sometimes called Management ED M Cwuithrreenxtafciresrtb-laintieonthseorar preyqiusirwinitgh loornIaGgl-HcteoTrrmticoOsCteSr.o5i5d2,s55(3eO.gn.e4ompoennt-hlatbaeplesrtiundgyccooumrspea),riwngithitritaracoconnaazozolelearnedseOrCveSdfofourntdhothsaet patients treated with itraconaPzoYlRe had a slightly lower response rate at 6 weeks but similar long-term response rates, with with sseuvbesrtaenatisatlhlymfaewaenrdsAiCdBeOP-eAfffeocutnsdthsaignnwifiicthanOtlCySfe.5w54eAr erxaancdeormbaizteiodnsdowuibthleo-bmlianldizupmlacaebb(oa-nctoi-nIgtrEo)llethdasntupdlaycienbpoa.5t5ie5 nInts ABPA patients with bronchiectasis, regular physiotherapy and daily drainage are recommended. Difficult-to-treat and severe asthma are covered in the next section, Chapter 3 Part E. 3. Treating to control symptoms and minimize future risk 103 PART E. DIFFICULT-TO-TREAT AND SEVERE ASTHMA IN ADULTS AND ADOLESCENTS KEY POINTS What are difficult to treat and severe asthma? Difficult-to-treat asthma is asthma that is uncontrolled despite prescribing of medium or high dose ICS-LABA treatment or that requires high dose ICS-LABA treatment to maintain good symptom control and reduce exacerbations. It does not mean a `difficult patient'. Severe asthma is asthma that is uncontrolled despite adherence with optimized high dose ICS-LABA therapy and treatment of contributory factors, or that worsens when high dose treatment is decreased. Approximately 3-10% of people with asthma have severe asthma. Severe asthma places a large physical, mental, emotional, social and economic burden on patients. It is often associated with multimorbidity. How should these patients be assessed? UTE Afascstoerssstahlal tpmataieynbtsewcoithntdriibffuictiunlgt ttootsreyamtpatsotmhms,aptooocr oqnufairlmitytohfelidfeia,gonroesxisacoefrabsaTtthRiomInBas,. and to identify and manage Refer for expert advice at any stage, or if asthma does not improve in resDpIoSnse to optimizing treatment. For patients with persistent symptoms and/or exacerbations despite OhigRh dose ICS, the clinical or inflammatory phenotype should be assessed, Management of severe asthma as this may guide the selectionOoPfYadd-on treatment. Depending on the inflammatory phenotype and other clinicaTl C features, add-on treatments for severe asthma include LAMA, LTRA, low dose azithromycin (adults), anNdObiologic agents for severe asthma. Low-dose maintenance OCS should be considere-dDoOnly as a last resort if no other options are available, because of Assess the rtheespirosnesreiotuosalonnyga-tdedr-monsitdreea-etmffeecnRttsI,A.sLtop ineffective treatments, and consider other options. Utilize specialist multidisciplinary team cAaTreEfor severe asthma, if available. For patients with severe clinician, and taking into asthma, account tcEhoDenptMinautieentot'sospoticmiaizl eanpdateiemnot tcioanrealinneceodllas.boration with the primary care Invite patients with severe asIGthHmTa to enroll in a registry or clinical trial, if available and relevant, to help fill See evidence gaps. Boxes 3-16A to 3-16D (staPrtYinRg on p.107) for the GINA severe asthma decision tree. CO Although the majority of patients can achieve the goal of well controlled asthma, some patients' asthma will not be well controlled even with optimal therapy. The material that follows is from the GINA Guide for health professionals on Diagnosis and Management of Difficult-to-Treat and Severe Asthma in Adolescent and Adult Patients v4.0, published in April 2022. A stand-alone copy of the Guide can be downloaded or ordered from the GINA website (www.ginasthma.org). Other resources about severe asthma include an online toolkit published by the Australian Centre of Excellence in Severe Asthma (https: //toolkit.severeasthma.org.au). 104 3. Treating to control symptoms and minimize future risk DEFINITIONS: UNCONTROLLED, DIFFICULT-TO-TREAT AND SEVERE ASTHMA Understanding the definitions of difficult-to-treat and severe asthma starts with the concept of uncontrolled asthma. Uncontrolled asthma includes one or both of the following: Poor symptom control (frequent symptoms or reliever use, activity limited by asthma, night waking due to asthma) Frequent exacerbations (2/year) requiring OCS, or serious exacerbations (1/year) requiring hospitalization Difficult-to-treat asthma199 is asthma that is uncontrolled despite prescribing of medium or high dose inhaled corticosteroids (ICS) with a second controller (usually a LABA) or with maintenance OCS, or that requires high dose treatment to maintain good symptom control and reduce the risk of exacerbations.199 It does not mean a `difficult patient'. In many cases, asthma may appear to be difficult-to-treat because of modifiable factors such as incorrect inhaler technique, poor adherence, smoking or comorbidities, or because the diagnosis is incorrect. Severe asthma199 is a subset of difficult-to-treat asthma adherence with maximal optimized high dose ICS-LABA (trBeoaxtm3e-1n5t)a. nItdmmeaannasgaesmthemntaotfhUcaoTt niEstruibnuctoonrytrofallcetdordse, soprittheat worsens when high dose treatment is decreased.199 At sometimes called `severe refractory asthma'199 since it present, therefore, is defined by being `rseelavetivreelTayRsrteIhBfmraac'toisryatroehtriogshpdeocstieveinlahbaelel.dIt is therapy. However, with the advent of biologic therapies, the word `refractory' isDnIoS longer appropriate. Asthma is not classified as severe if it markedly improves when contributoOryRfactors such as inhaler technique and adherence are addressed.199 PY PREVALENCE: HOW MANY PEOPLE HAVE SEVERE ASTHMA? CO T A study in the Netherlands estimated that around 3.7% of astNhmOa patients have severe asthma, based on the number of spyamtiepntotsmpcreosnctrroible(dbyhAigshthdmosaeCIConSt-rLoAl QBuAe, sotriomnneadiiruem) aonrd-hDihgaOhddgoosoedICadSh-LeAreBnAceplaunsdloinnhga-tleerrmteOchCnSiq,uweh(oBhoaxd3-p1o5o)r.556 RIAL Box 3-15. What proportion of adults havMeAdTifEficult-to-treat or severe asthma? TED IGH COPYR 3. Treating to control symptoms and minimize future risk 105 IMPORTANCE: THE IMPACT OF SEVERE ASTHMA The patient perspective Patients with severe asthma experience a heavy burden of symptoms, exacerbations and medication side-effects. Frequent shortness of breath, wheeze, chest tightness and cough interfere with day-to-day living, sleeping, and physical activity, and patients often have frightening or unpredictable exacerbations (also called attacks or severe flare-ups). Medication side-effects are particularly common and problematic with OCS,308 which in the past were a mainstay of treatment for severe asthma. Adverse effects of long-term OCS include obesity, diabetes, osteoporosis, cataracts, hypertension and adrenal suppression; psychological side-effects such as depression and anxiety are particularly concerning for patients.557 Even short- term use of OCS is associated with sleep disturbance, and increased risk of infection, fracture and thromboembolism.507 Strategies to minimize need for OCS are therefore a high priority. Severe asthma often interferes with family, social and working life, limits career choices and vacation options, and aefxfpeectrsieenmceoitsiosnoaldaifnfedremnetnfrtaolmhethaalttho. fPmatoiesnt tpsewopitlhe sweivtheraesathsmtham.5a57often feel alone and mIisBuUnTdEerstood, as their Adolescents with severe asthma ISTR The teenage years are a time of great psychological and physiological developmeDnt which can impact on asthma management. It is vital to ensure that the young person has a good understanOdRing of their condition and treatment and appropriate should help knowledge to enable supported self-management. The support the young person in gaining greater autonomy apnrodcOreesPsspYoonf striabnilsityitiofonr from their pediatric to own health adult care and wellbeing. Severe asthma may improve over 3 years in approximately 30% of mTaCle and female adolescents; the only predictor of asthma becoming non-severe was higher baseline blood eosinopNhOils.558 Studies with longer follow-up time are needed. Healthcare utilization and costs - DO SOeCvSerseidaes-tehfmfeacths.asInvaerUyKhisgthudhye,ahltehaclathrecacroesctsosdtusepteoRr mpIAaeLtdieicnat twioenrse, physician visits, hospitalizations, and the higher than for type 2 diabetes, stroke, or costs of COPD.559 In a Canadian study, severe uncontrolled asthmaATwEas estimated to account for more than 60% of asthma costs.560 Patients with medications, bsuevt earlseoatshtrhomugahalnodsttheeairrnfianmgsiElieaDnsdMalcsaorebeeracr haosicigensi.ficant financial burden, not only for medical care and ASSESSMENT AND MANAGEMENT IOGFHDTIFFICULT-TO-TREAT AND SEVERE ASTHMA The clinical decision tree startingPYonRpage 107, provides brief information about what should be considered in each phase of diagnosis and manaCgOement of difficult-to-treat and severe asthma. The decision tree is divided into three broad areas: Sections 1-4 (green) are for use in primary care and/or specialist care. Sections 5-8 (blue) are mainly relevant to respiratory specialists. Sections 9-10 (brown) are about maintaining ongoing collaborative care between the patient, GP, specialist and other health professionals. Development of the Guide and decision tree included extensive collaboration with experts in human-centered design to enhance the utility of these resources for end-users. This included translating existing high level flowcharts and textbased information to a more detailed visual format, and applying information architecture and diagramming principles. Further information follows the decision tree. 106 3. Treating to control symptoms and minimize future risk Box 3-16A. Decision tree - investigate and manage difficult to treat asthma in adult and adolescent patients GP OR SPECIALIST CARE Investigate and manage difficult-to-treat asthma in adults and adolescents Consider referring to specialist or severe asthma clinic at any stage DIAGNOSIS: "Difficult- to-treat asthma" For adolescents and adults with symptoms and/or exacerbations despite medium or high dose ICS-LABA, or taking maintenance OCS Key 1 Confirm the diagnosis (asthma/differential diagnoses) 2 Look for factors contributing to symptoms, exacerbations and poor quality of life: Incorrect inhaler technique Suboptimal adherence Comorbidities including obesity, GERD, chronic rhinosinusitis, OSA Modifiable risk factors and triggers at home or work, including smoking, environmental exposures, allergen exposure (if sensitized); medications such as beta-blockers and NSAIDs Overuse of SABA relievers Medication side effects Anxiety, depression and social difficulties decision, filters intervention, treatment 3 4 Optimize management, including: IBUTE Asthma education R Optimize treatment (e.g. check and T correct inhaler technique and IS adherence; switch to ICS-formoterol D maintenance and reliever therapy, R if available) O Consider non-pharmacological Y interventions (e.g. smoking P cessation, exercise, weight loss, O mucus clearance, influenza and C COVID-19 vaccination) T Treat comorbidities and O modifiable risk factors N Consider non-biologic add-on DO therapy (e.g. LABA, LAMA, - LM/LTRA, if not used) L Consider trial of high dose ICS- COPYRIGHTED MATERIA LABA, if not used Review response after ~3-6 months Is asthma yes still uncontrolled? no DIAGNOSIS: "Severe asthma" If not done by now, refer to a specialist, if possible Consider stepping down treatment, OCS first (if used) Does asthma become yes uncontrolled when treatment is stepped down? no Restore previous dose Continue optimizing management diagnosis, confirmation 3. Treating to control symptoms and minimize future risk 107 Box 3-16B. Assess and treat severe asthma phenotypes SPECIALIST CARE; SEVERE ASTHMA CLINIC IF AVAILABLE Assess and treat severe asthma phenotypes Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities, non-pharmacologic strategies) 5 Investigate further and provide patient support Investigate for comorbidities/differential diagnoses and treat/refer as appropriate - Consider: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins; CXR and/or HRCT chest; DLCO; DEXA scan - Skin prick testing or specific IgE for relevant allergens, if not already done - Consider screening for adrenal insufficiency in patients taking maintenance OCS or high dose ICS - If blood eosinophils 300/l, look for and treat non-asthma causes, including parasites (e.g. Strongyloides serology, or stool examination) - If hypereosinophilia e.g. 1500/l, consider causes such as EGPA - Other directed testing (e.g. ANCA, CT sinuses, BNP, echocardiogram) based on clinical suspicion Consider need for social/psychological support Involve multidisciplinary team care (if available) Invite patient to enroll in registry (if available) or clinical trial (if appropriate) 6 7 Assess the severe asthma phenotype IBUTE havCeoTuyldpepa2tiaeinrwt ay yes TR inflammation? DIS Type 2 inflammation R no O Blood eosinophils 150/l and/or PY FeNO 20 ppb and/or O Sputum eosinophils 2%, and/or C Asthma is clinically allergenT driven NO (Repeat blood eosinophils and FeNO up to 3x, at least 1-2 O weeks after OCS or on lowest D possible OCS dose) IAL - Note: these are not the criteria for COPYRIGHTED MATER ** add-on biologic therapy (see 8) Consider other treatments Type 2 airway inflammation Consider adherence tests Consider increasing the ICS dose for 3-6 months Consider add-on non-biologic treatment for specific Type 2 clinical phenotypes, e.g. AERD, ABPA, chronic rhinosinusitis, nasal polyposis, atopic dermatitis Is add-on Type 2 biologic yes therapy available/ affordable? no If add-on Type 2-targeted biologic therapy is NOT available/affordable Consider higher dose ICS, if not used Consider other add-on therapy (e.g. LAMA, LM/LTRA, low dose azithromycin) As last resort, consider add-on low dose OCS, but implement strategies to minimize side-effects Stop ineffective add-on therapies No evidence of Type 2 airway inflammation Go to section 10 Review the basics: differential diagnosis, inhaler technique, adherence, comorbidities, side-effects Avoid exposures (tobacco smoke, allergens, irritants) Consider investigations (if available and not done) - Sputum induction - High resolution chest CT - Bronchoscopy for alternative/additional diagnoses Consider trial of add-on treatments (if available and not already tried) - LAMA - Low dose azithromycin - Anti-IL4R if taking maintenance OCS - Anti-TSLP (but insufficient evidence in patients on maintenance OCS) Not currently eligible for T2-targeted biologic therapy - As last resort, consider add-on low dose OCS, but implement strategies to minimize side-effects Consider bronchial thermoplasty (+ registry) Stop ineffective add-on therapies Go to section 10 *Check local eligibility criteria for specific biologic therapies as these may vary from those listed 3. Treating to control symptoms and minimize future risk 108 Box 3-16C. Consider add-on biologic Type 2-targeted treatments SPECIALIST CARE; SEVERE ASTHMA CLINIC IF AVAILABLE Assess and treat severe asthma phenotypes cont'd Continue to optimize management as in section 3 (including inhaler technique, adherence, comorbidities, non-pharmacologic strategies) 8 Consider add-on biologic Type 2-targeted treatments E Eligibility IBUT Consider add-on Type 2R targeted biologic therapy T for patients with IS exacerbations or poor D symptom control on high R dose ICS-LABA, who have O evidence of Type 2 inflammation* PY Consider local payer O eligibility criteria*, C comorbidities and T predictors of response O when choosing between N available therapies O Also consider cost, dosing D frequency, route (SC or IV), - patient preference MATERIAL Which biologic D is appropriate to COPYRIGHTE start first? Anti-IgE (omalizumab) Is the patient eligible for anti-IgE for severe allergic asthma?* Sensitization on skin prick testing or specific IgE Total serum IgE and weight within dosage range Exacerbations in last year no no Anti-IL5 / Anti-IL5R (benralizumab, mepolizumab, reslizumab) Is the patient eligible for anti-IL5 / anti-IL5R for severe eosinophilic asthma?* Exacerbations in last year Blood eosinophils, e.g. 150/l or 300/l no no Anti-IL4R (dupilumab) Is the patient eligible for anti-IL4R for severe eosinophilic/Type 2 asthma?* Exacerbations in last year Blood eosinophils 150 and 1500/l, or FeNO 25 ppb, or taking maintenance OCS no no Anti-TSLP (tezepelumab) Is the patient eligible for anti-TSLP for severe asthma?* Exacerbations in last year Predictors of asthma response What factors may predict good asthma response to anti-IgE? Blood eosinophils 260/l ++ FeNO 20 ppb + Allergen-driven symptoms + Childhood-onset asthma + What factors may predict good asthma response to anti-IL5/5R? Higher blood eosinophils +++ More exacerbations in previous year +++ Adult-onset of asthma ++ Nasal polyposis ++ What factors may predict good asthma response to anti-IL4R? Higher blood eosinophils +++ Higher FeNO +++ What factors may predict good asthma response to anti-TSLP? Higher blood eosinophils +++ Higher FeNO +++ Eligible for none? Return to section 7 Choose one if eligible*; trial for at least 4 months and assess response No evidence of Type 2 airway inflammation *Check local eligibility criteria for specific biologic therapies as these may vary from those listed No evidence of Type 2 airway inflammation. Go to section 10 Extend trial to 6-12 months* unclear Good asthma response?* no yes Good response to T2-targeted therapy STOP add-on Consider switching to a different Type 2-targeted therapy, if eligible* no Little/no response to T2-targeted therapy 3. Treating to control symptoms and minimize future risk 109 Box 3-16D. Monitor and manage severe asthma treatment SPECIALIST AND PRIMARY CARE IN COLLABORATION Monitor / Manage severe asthma treatment Continue to optimize management 9 10 Review response E Asthma: symptom control, exacerbations, lung function UT Type 2 comorbidities e.g. nasal polyposis, atopic dermatitis IB Medications: treatment intensity, side-effects, affordability TR Patient satisfaction DIS If good response to Type 2-targeted therapy OR Re-evaluate the patient every 3-6 months* Y yes For oral treatments: consider decreasing/stopping OCS first (and P check for adrenal insufficiency), then stopping other add-on medication O For inhaled treatments: consider decreasing after 3-6 months; C continue at least moderate dose ICS-LABA OT Re-evaluate need for ongoing biologic therapy N Order of reduction of treatments based on observed benefit, potential O side-effects, cost and patient preference IAL - D If no good response to Type 2-targeted therapy R Stop the biologic therapy E Review the basics: differential diagnosis, inhaler technique, AT adherence, comorbidities, side-effects, emotional support M Consider high resolution chest CT (if not done) ED no Reassess phenotype and treatment options T - Induced sputum (if available) H - Consider add-on low dose azithromycin IG - Consider bronchoscopy for alternative/additional diagnoses YR - As last resort, consider add-on low dose OCS, but implement P strategies to minimize side-effects O - Consider bronchial thermoplasty (+ registry) C Stop ineffective add-on therapies Continue to optimize management as in section 3, including: Inhaler technique Adherence Comorbidity management Non-pharmacologic strategies Patients' social/emotional needs Two-way communication with GP for ongoing care Notes: Do not stop ICS No evidence of Type 2 airway inflammation. Go to section 10 *Check local eligibility criteria for specific biologic therapies as these may vary from those listed 3. Treating to control symptoms and minimize future risk 110 INVESTIGATE AND MANAGE DIFFICULT-TO-TREAT ASTHMA IN ADULTS AND ADOLESCENTS 1. CONFIRM THE DIAGNOSIS (ASTHMA OR DIFFERENTIAL DIAGNOSES) Stages 1-5 can be carried out in primary or specialist care. Difficult-to-treat asthma is defined if the patient has persistent symptoms and/or exacerbations despite prescribing of medium or high dose ICS with another controller such as LABA, or maintenance OCS, or requires high dose ICS-LABA treatment to maintain good symptom control and prevent exacerbations. It does not mean a `difficult patient'. Consider referral to a specialist or severe asthma clinic at any stage, particularly if: There is difficulty confirming the diagnosis of asthma Patient has frequent urgent healthcare utilization Patient needs frequent or maintenance OCS Occupational asthma is suspected Food allergy or anaphylaxis, as this increases the risk of death UTE Symptoms are suggestive of infective or cardiac cause TRIB Symptoms are suggestive of complications such as bronchiectasis DIS Patient has multimorbidity OR Are the symptoms due to asthma? OPY Perform a likely due tcoaarenfualltheirsntaotriyveanddiapghnyossiicsaol recxoammoinrabtidiointy.toInidveesnttiigfyatwehaTecthcCoerrdsinygmtpotocmlinsicaarlestuysppicicailoonf asthma, and age or are more (see Box 1-5, p.27). NO Dyspnea: COPD, obesity, cardiac disease, deco- nDdOitioning C(aolsuoghc:alilneddupcoibslet-nlaarsyanlgderaipl )o, bgsatsrutrcot-ioenso(pahlRsaoIgAceLaallleredflvuoxcdailsceoarsded(yGsEfuRnDct)io, nb,roVnCcDhi)e,cutapspiesr, airway cough syndrome ACE inhibitors Wheeze: obesity, COPD, tracheobronAcThEomalacia, VCD How can the diagnosis of asthma be coEnDfiMrmed? Confirmat not found ion of to be the the cdoiarrgencotsdisiaigsniomIsGpisoH.r5Tt6a1nPt,ebrfeocrmausspeirino 12-50% metry, be of people ass fore and after umed bronc to have severe asthma, hodilator, to assess bas asthma is eline lung function and seek testing is negative o(b2je0c0tivmeLePovrYidRe1n2c%e of variable expiratory airflow increase in FEV1), consider limitation. repeating If initial bronchodilator responsiveness after withholding bronchodilators or when symptomatic, or considerCsOtepping controller treatment up or down before further investigations such as bronchial provocation testing (see Box 1-3, p.26). Check full flow-volume curve to assess for upper airway obstruction. If spirometry is normal or is not available, provide the patient with a peak flow meter and diary for assessing variability; consider bronchial provocation testing if patient is able to withhold bronchodilators (short-acting beta2-agonist (SABA) for at least 6 hours, LABA for up to 2 days depending on duration of action)27. Strategies for confirming the diagnosis of asthma in patients already taking controller treatment are shown in Box 1-3 (p.26). Airflow limitation may be persistent in patients with long-standing asthma, due to remodeling of the airway walls, or limited lung development in childhood. It is important to document lung function when the diagnosis of asthma is first made. Specialist advice should be obtained if the history is suggestive of asthma but the diagnosis cannot be confirmed by spirometry. 3. Treating to control symptoms and minimize future risk 111 2. LOOK FOR FACTORS CONTRIBUTING TO SYMPTOMS AND EXACERBATIONS Systematically consider factors that may be contributing to uncontrolled symptoms or exacerbations, or poor quality of life, and that can be treated. The most important modifiable factors include: Incorrect inhaler technique (seen in up to 80% patients): ask the patient to show you how they use their inhaler; compare with a checklist or video. Suboptimal adherence (up to 75% asthma patients): ask empathically about frequency of use (e.g. `Many patients don't use their inhaler as prescribed. In the last 4 weeks, how many days a week have you been taking it - not at all, 1 day a week, 2, 3 or more?' or, `Do you find it easier to remember your inhaler in the morning or the evening?' (see Box 3-13, p.90). Ask about barriers to medication use, including cost, and concerns about necessity or side-effects. Check dates on inhalers and view dispensing data, if available. Electronic inhaler monitoring, if available, can be helpful in screening for poor adherence. Comorbidities: review history and examination for comorbidities that can contribute to respiratory symptoms, erhxiancoesrinbuastiiotinss, ,inodrupcoibolreqlauarylintygeoaf lliofeb.sTtrhuecstieonin, cGluEdReDa,nCxiOetPyDa,nodbdsetrpurcetisvseiosnle, eopbeaspitnUye,TadE,ebcroonndcihtiioencitnags,isc,hcraorndiciac disease, and kyphosis due to osteoporosis. Investigate according to clinical sTusRpIiBcion. Menovdiriofinambleenrtaisl ktofbaacctcoorseaxpnodsturrieg,goetrhse:rideennvtirifoynfmacetnotrasl tehxapt oinscurreeassaetthhoemriesDkoISor fweoxrakcinecrbluadtiionngsa, lele.grg. esnmso(kifing, sensitized), indoor and outdoor air pollution, molds and noxious chemOicRals, and medications such as beta- blockers or non-steroidal anti-inflammatory prick testing or specific IgE. drugs (NSAIDs). ForOaPllYergens, check for sensitization using skin Regular or over-use of SABAs: this causes beta-receptor TdoCwn-regulation and reduction in response,562 leading in turn to greater use. Overuse may also be habiNtuOal. Dispensing of 3 SABA canisters per year (ocrohroressppitoanlidziantgiotnoinadveepraegnedeunset omf oserevethriatyn,7d1,a13il3ya) nisd-adsDissOopceinasteindgwoifth1in2crceaansisetderrsispkeorfyeemarer(goennecay department month) is visit Aasnsxoiceitayt,eddewpirthesssuibosntaanntidalslyoicnicarleaansdedercisoknooRfmIdAiecLapthro.7b1,9le7 mRiss:ktsheasree higher with nebulized SABA.563 are very common in asthma, particularly in difficult asthma557 and contribute to sympAtTomE s, impaired quality of life, and poor adherence. IMCeSdmicaaytioconnstriidbeu-teefftoecptoso: rsyqsutaelmityicEoDef flfiMfeectasn,dpainrctirceualasrelythweithlikferelihquooedntoofrpcooonrtianduhoeursenOcCeS. L, oocr alol nsgid-ete-ermffehcitgshodf ose ddyrusgphinotneiraacotriothnrsuisnhclmudaiyngocricsIuGkrHowfTiathdrheignhaldsouspeproerspsoiotennwt iItChSuseespoefcPia4l5ly0ifininhhibaitleorrstescuhcnhiqauseitirsapcooonra.zColoen.sider PYR 3. REVIEW AND OPTIMIZE MCAONAGEMENT Review and optimize treatment for asthma, and for comorbidities and risk factors identified in Section 2. For more details, see Chapter 3D, p.94. Provide asthma self-management education, and confirm that patient has (and knows how to use) a personalized written or electronic asthma action plan. Refer to an asthma educator if available. Optimize inhaled controller medications: confirm that the inhaler is suitable for the patient; check and correct inhaler technique with a physical demonstration and teach-back method, check inhaler technique again at each visit.564 Address suboptimal adherence, both intentional and unintentional.445 Switch to ICS-formoterol maintenance and reliever regimen if available, to reduce the risk of exacerbations.193 Consider non-pharmacologic add-on therapy, e.g. smoking cessation, physical exercise, healthy diet, weight loss, mucus clearance strategies, influenza vaccination, breathing exercises, allergen avoidance, if feasible, for patients who are sensitized and exposed. For details see Box 3-9, p.79. 112 3. Treating to control symptoms and minimize future risk  Treat comorbidities and modifiable risk factors identified in Section 2 of the decision tree, where there is evidence for benefit; however, there is no evidence to support routine treatment of asymptomatic GERD (see p.95). Avoid medications that make asthma worse (beta-blockers including eye-drops; aspirin and other NSAIDs in patients with aspirin-exacerbated respiratory disease, p.102). Refer for management of mental health problems if relevant. Consider trial of non-biologic medication added to medium/high dose ICS, e.g. LABA, LAMA, leukotriene modifier if not already tried. Note FDA boxed warning about potential neuropsychiatric effects with leukotriene modifiers. 565 Consider trial of high dose ICS-LABA if not currently used. 4. REVIEW RESPONSE AFTER APPROXIMATELY 3-6 MONTHS Schedule a review visit to assess the response to the above interventions. Timing of the review visit depends on clinical urgency and what changes to treatment have been made. When assessing the response to treatment, specifically review: UTE Symptom control (symptom frequency, SABA reliever use, night waking duTeRtIoBasthma, activity limitation) Exacerbations since previous visit, and how they were managed DIS Medication side-effects Inhaler technique and adherence OR PY Lung function Patient satisfaction and concerns. T CO Is asthma still uncontrolled, despite optimized therapy? NO YES: if asthma is still uncontrolled, the diagnosis of sev-erDeOasthma has been confirmed. If not done by now, refer the patient to a specialist or severe asthma clinic if poRssIAibLle. NO: if asthma is now checking for adrenal iwnseullffcicoinetnrcoylle, dth,ecnonresmidoevrAesTtoEetphpeirngadddo-wonn treatment. Start by decreasing/ceasing OCS therapy, then decrease ICS dose, but do not first stop (if used), ICS. See Box 3-7 (p.75) for how to gradually dowEnD-titMrate treatment intensity. DoYeEsSa: sifthasmthambaecsoymmpetoumncsobnetcroomlleeIGduHwnTchoenntrtorleleadtmoreannt is stepped down? exacerbation occurs when high dose treatment is stepped down, the diagnosis of severe asthmPaYRhas been confirmed. Restore the patient's previous dose to regain good asthma control, and refer to a specialist oCr sOevere asthma clinic if possible, if not done already. NO: if symptoms and exacerbations remain well-controlled despite treatment being stepped down, the patient does not have severe asthma. Continue optimizing management. ASSESS AND TREAT SEVERE ASTHMA PHENOTYPES 5. INVESTIGATE FURTHER AND PROVIDE PATIENT SUPPORT Further assessment and management should be by a specialist, preferably in a multidisciplinary severe asthma clinic if available. The team may include a certified asthma educator and health professionals from fields such as speech pathology, ENT, social work and mental health. What other tests may be considered at the specialist level? Additional investigations may be appropriate for identifying less-common comorbidities and differential diagnoses contributing to symptoms and/or exacerbations. Tests should be based on clinical suspicion, and may include: 3. Treating to control symptoms and minimize future risk 113  Blood tests: CBC, CRP, IgG, IgA, IgM, IgE, fungal precipitins including Aspergillus Allergy testing for clinically relevant allergens: skin prick test or specific IgE, if not already done Other pulmonary investigations: DLCO; CXR or high-resolution chest CT Bone density scan, because of risk of osteoporosis with maintenance or frequent OCS or long-term high dose ICS311 If blood eosinophils 300/L, look for and treat non-asthma causes, including parasites (e.g. Strongyloides serology or stool examination), because parasitic infection may be the cause of the blood eosinophilia, and because OCS or biologic therapy in a patient with untreated parasitic infection could potentially lead to disseminated disease. Strongyloides infection is usually asymptomatic.566 If hypereosinophilia, e.g. blood eosinophils 1500/L, consider causes such as eosinophilic granulomatosis with polyangiitis (EGPA) Consider Other need directed testing, e.g. ANCA, CT sinuses, for social/psychological support BNP, echocardiogram, based on clUinTicEal suspicion Refer patients to support services, where available, to help them deal with the emotioTnaRl,IBsocial and financial burden of asthma and its treatment, including during and after severe exacerbations.557 psychiatric referral, including for patients with anxiety and/or depression. ConDsiIdSer the need for psychological or Involve multidisciplinary team care (if available) OR Multidisciplinary assessment and treatment of patients with severe asthmOaPYincreases the identification of comorbidities, and improves outcomes.567 T C Invite patient to enroll in a registry (if available) or clinical trialN(Oif appropriate) Systematic collection of data will help in understanding the-mDeOchanisms and burden of severe asthma. There is a need froarndproamgimzeadticcocnlintrioclalel dtritarilaslsindseesvigenreedasfothrmreag,uinlactlourdyinpguIrsAptuoLdseiess comparing two or more may not necessarily be active treatments. Participants representative of patients seen in in clinical practice. For example, a registry study founTdEtRhat over 80% of patients with severe asthma would have been excluded from key studies evaluating biologic tMheArapy.291 6 ASSESS THE SEVERE ASTHMA PHENTOETDYPE The next step is to assess the patientI'Gs Hinflammatory phenotype - is it Type 2 high or low? What is Type 2 inflammation? PYR Type 2 inflammation is foundCinOthe majority of people with severe asthma. It is characterized by cytokines such as interleukin (IL)-4, IL-5 and IL-13, which are often produced by the adaptive immune system on recognition of allergens. It may also be activated by viruses, bacteria and irritants that stimulate the innate immune system via production of IL-33, IL-25 and thymic stromal lymphopoietin (TSLP) by epithelial cells. Type 2 inflammation is often characterized by elevated eosinophils or increased FeNO, and may be accompanied by atopy, whereas non-Type 2 inflammation is often characterized by increased neutrophils.568 In many patients with asthma, Type 2 inflammation rapidly improves when ICS are taken regularly and correctly; this is classified as mild or moderate asthma. In severe asthma, Type 2 inflammation may be relatively refractory to high dose ICS. It may respond to OCS but their serious adverse effects308,309 mean that alternative treatments should be sought. In adult patients with uncontrolled asthma despite medium or high dose ICS plus LABA or other controllers, a history of exacerbations in the previous year, higher blood eosinophil counts and higher FeNO levels are associated with a greater risk of severe exacerbations.569 114 3. Treating to control symptoms and minimize future risk Could the patient have refractory or underlying Type 2 inflammation? The possibility of refractory Type 2 inflammation should be considered if any of the following are found while the patient is taking high dose ICS or daily OCS: Blood eosinophils 150/l, and/or FeNO 20 ppb, and/or Sputum eosinophils 2%, and/or Asthma is clinically allergen-driven Patients requiring maintenance OCS may also have underlying Type 2 inflammation. However, biomarkers of Type 2 inflammation (blood eosinophils, sputum eosinophils and FeNO) are often suppressed by OCS. If possible, therefore, these tests should be performed before starting OCS (a short course, or maintenance treatment), or at least 1-2 weeks after a course of OCS, or on the lowest possible OCS dose. The above criteria are levels associated with rseusgpgoenssteedtofosroimnietiabl iaoslosgeiscssm. Tehnet;ythaoresenofot rthbelocorditeeroiasifnoorpehliiglsibailnitdyUFfoTerENTOypaere2-btaarsgeedteodn the lowest biologic therapy, which may differ - see section 8 and local criteria. TRIB Consider least 1-2 repeating blood eosinophils and weeks after a course of OCS, or FeNO up to 3 on the lowest tpimosessib(lee.gO. CwShednosaes)t,hDbmeIaSfowreorassesnusm, binegfoarsethgmiviangisOnConS-,Toyrpaet 2. One study of patients with uncontrolled asthma taking medium-high dose IOCRS-LABA found that 65% had a shift in their blood eosinophil category over 48-56 weeks.570 OPY Why is the inflammatory phenotype assessed on Most RCT evidence about Type 2 targeted hbiigolhogdiocsseisIOCinTSs?Cuch patients. Modifiable ICS treatment problems such as poor adOheNrence and incorrect inhaler technique are common causes of uncontrolled Type 2 inflammation Currently, the high cost of biologic therapies gLen- eDrally precludes their widespread clinical use in patients whose symptoms or exacerbations and Type 2EbRioImAarkers are found to respond to ICS when it is taken correctly. 7.1. CONSIDER OTHER TREATMENTS IF TMHAETRE IS NO EVIDENCE OF TYPE 2 INFLAMMATION If the patient has no evidence of persisTtEenDt Type 2 inflammation (section 6): Review the basics inhaler technique, afodrhfearRcetInoGcrHse,thcaotmmoarbyidbietiecso,nmtreibduictiantgiotno symptoms or exacerbations: side-effects (Section 2). differential diagnosis, Recommend avoidOanPcYe of relevant exposures (tobacco smoke, pollution, allergens if sensitized and there is evidence of beneCfit from withdrawal, irritants, infections). Ask about exposures at home and at work. Consider additional diagnostic investigations (if available and not already done): sputum induction to confirm inflammatory phenotype, high resolution chest CT, bronchoscopy to exclude unusual comorbidities or alternative diagnoses such as tracheobronchomalacia or sub-glottic stenosis; functional laryngoscopy for inducible laryngeal obstruction. Consider a trial of add-on treatment if available and not already tried: - LAMA274 - Low dose azithromycin (adults),295,571 but first check sputum for atypical mycobacteria, check ECG for long QTc (and re-check after a month on treatment), and consider potential for antibiotic resistance. - Anti-IL4R*1 if taking maintenance OCS (see section 8 for more details) 1 Asterisk indicates to check local eligibility and payer criteria for specific biologic therapies, as they may vary from those listed 3. Treating to control symptoms and minimize future risk 115 - Anti-TSLP* (thymic stromal lymphopoietin) (but insufficient evidence in patients taking maintenance OCS; see section 8 for more details) As a last resort, consider add-on low dose OCS, but implement strategies such as alternate-day treatment to minimize side-effects. Consider bronchial thermoplasty, with registry enrollment. However, the evidence for efficacy and long-term safety is limited.129,349 Stop ineffective add-on therapies. Continue to optimize treatment, including inhaler technique, adherence, non-pharmacologic strategies and treating comorbidities (see sections 3 and 10) 7.2 CONSIDER NON-BIOLOGIC OPTIONS IF THERE IS EVIDENCE OF TYPE 2 INFLAMMATION For patients with elevated Type 2 biomarkers despite high dose ICS (see section 5), consider non-biologic options first, given the current high cost of biologic therapy: Assess adherence objectively by monitoring of prescribing or dispensing recordsU, TbElood prednisone levels,572 or electronic inhaler monitoring.431 In one study, suppression of high FeNO afTteRr I5Bdays of directly observed therapy was an indicator of past poor adherence.573 DIS Consider Consider increasing the ICS dose for 3-6 add-on non-biologic treatment months, and review for specific Type 2 acglianiincO.aRl phenotypes (see Chapter 3D, p.94). Fpoosr seibxalymapslpei,rifnordaesspeinrisni-teizxaaticoenrb(pa.t1e0d2r)e.sFpoirraatollreyrgdicisebarosnec(hAoEpRulDmO)oP, ncYaornysiadsepreardgdill-oosnisle(uAkBoPtrAie)n, ecomnsoiddiefireradadn-don OCS anti-fungal agent (p.103). For chronic rhinosinusitis aTndC/or nasal polyposis, consider intensive intranasal corticosteroids; surgical advice may be needed (p.96). FNorOpatients with atopic dermatitis, topical steroidal or non-steroidal therapy may be helpful. - DO 7.3 IS TYPE 2-TARGETED BIOLOGIC THERAPY AVARIILAALBLE AND AFFORDABLE? If NOT: Consider higher dose ICS-LABA, if not uAseTdE Consider other add-on therapy, e.gE. DLAMMA, LM/LTRA, low dose azithromycin if not used As last resort, consider add-oInGlHowT dose OCS, but implement strategies to minimize side-effects SCtoonptininueeffetoctoivpetimadizde-otrnetaPhteYmrReanptie, sincluding inhaler technique, adherence, non-pharmacologic strategies and treating comorbiditiesC(Osee sections 3 and 10) 8 CONSIDER ADD-ON BIOLOGIC TYPE 2-TARGETED TREATMENTS If available and affordable, consider an add-on Type 2 targeted biologic for patients with exacerbations or poor symptom control despite taking at least high dose ICS-LABA, and who have allergic or eosinophilic biomarkers or need maintenance OCS. Where relevant, test for parasitic infection, and treat if present, before commencing treatment (see section 5). An asterisk (*) means to always check local criteria for eligibility and funding, as they may vary from those listed. Consider whether to start first with anti-IgE, anti-IL5/5R, anti-IL4R or anti-TSLP. When choosing between available therapies, consider the following: Does the patient satisfy local payer eligibility criteria? Type 2 comorbidities such as atopic dermatitis, nasal polyposis 116 3. Treating to control symptoms and minimize future risk  Predictors of asthma response (see below) Cost Dosing frequency Delivery route (IV or SC; potential for self-administration) Patient preference Local payer eligibility criteria for biologic therapy may vary substantially. For any biologic therapy, ensure that the manufacturer's and/or regulator's instructions for storage, administration and the duration of monitoring postadministration are followed. Provide the patient with advice about what to do if they experience any adverse effects, including hypersensitivity reactions. GINA suggests that the first dose of asthma biologic therapy should not be given on the same day as a COVID-19 vaccine, so that adverse effects of either can be more easily distinguished. oTnheerbeioisloagnicu.rgent need for head-to-head comparisons of different biologics in IpBaUtiTenEts eligible for more than Add-on anti-IgE for severe allergic asthma ISTR Currently approved:* omalizumab for ages 6 years, given by SC injection eveDry 2-4 weeks, with dose based on weight and serum IgE. May also be indicated for nasal polyposis and chronic spoOntRaneous (idiopathic) urticaria. Self- administration may be an option. Mechanism: binds to Fc part of free IgE, preventing binding of IgE toOFPcYR1 receptors, reducing free IgE and down- regulating receptor expression. T C Eligibility criteria (in addition to criteria for severe asthma) varNy Obetween payers, but usually include: Sensitization to inhaled allergen(s) on skin prick- tDesOting or specific IgE, and Total More serum than a IsgpEecainfieddbnoudmy wbeerigohftewxiathcienrbloaRctaiIoAlnLdsowsiinthginratnhgeel,aastnydear Outcomes: RCTs in severe allergic asthma: 4A4T%Edecrease in severe exacerbations; improved quality of life.297 No dwoituhbsleevbelirnedarlalenrdgoicmaizsethdmcao,ntthroelrleedwtarisalaEsD5o9fM%OCreSd-supctaiorinngineeffxeacct.eIrnbaatimonetraa-taen, aaly4s1is%orfeodbuscetirovnatiinonthael spturodpieosrtiionnpoaftients patients receiving maintenance OICGSH, Tand a significant improvement in symptom control.574 In patients with nasal fpooulynpdonsois,inocmreaaliszeudmraisbkimofpcrooPnvgYeedRnsituabl jmecatilvfoermanadtioonbsje.5c2t7ive outcomes.497 Registry study of omalizumab in pregnancy Potential predictors of gooCdOasthma response to omalizumab: Baseline IgE level does not predict likelihood of response575 In one observational study, a greater decrease in exacerbations was observed (cf. placebo) with blood eosinophils 260/l576,577 or FeNO 20 ppb576 (these criteria representing their median value in that study) but in two large observational studies, exacerbations were reduced with both low or high blood eosinophils578-580 or with both low or high FeNO.580 Childhood-onset asthma Clinical history suggesting allergen-driven symptoms Adverse effects: injection site reactions; anaphylaxis in ~0.2% patients581 Suggested initial trial: at least 4 months *Check local regulatory and payer criteria, as they may differ from those shown 3. Treating to control symptoms and minimize future risk 117 Add-on anti-IL5 or anti-IL5R for severe eosinophilic asthma Currently approved: For ages 12 years: mepolizumab (anti-IL5), 100 mg by SC injection every 4 weeks, or benralizumab (anti-IL5 receptor ), 30 mg by SC injection every 4 weeks for 3 doses then every 8 weeks. For ages 18 years: reslizumab (anti-IL5), 3 mg/kg by IV infusion every 4 weeks. For ages 6-11 years, mepolizumab (anti-IL5), 40 mg by SC injection every 4 weeks. Mepolizumab may also be indicated for eosinophilic granulomatosis with polyangiitis (EGPA), hypereosinophilic syndrome and chronic rhinosinusitis with nasal polyps. Self-administration may be an option. Mechanism: mepolizumab and reslizumab bind circulating IL-5; benralizumab binds to IL-5 receptor alpha subunit leading to apoptosis (cell death) of eosinophils. Eligibility criteria (in addition to criteria for severe asthma): these vary by product and between payers, but usually include: More than a specified number of severe exacerbations in the last year, and Blood eosinophils above locally specified cut-point for patients taking OCS. level (e.g. 150 or 300/l). There is somUeTtimE es a different eosinophil Outcomes: RCTs and anti-IL5R led in to severe asthma patients with exacerbations in the last year, 47-54% reduction in severe exacerbations. Improvements winitqhuvaTalRirtyyIiBnogf eosinophil criteria: anti-IL5 life, lung function and symptom control were significant,297 but less than the clinically important differencDe.ISAll reduced blood eosinophils; almost completely with benralizumab.582 In post hoc analyses, clinical outcomOesRwith mepolizumab or benralizumab were to be similar in patients reduced by ~50% with with OPY and without an allergic phenotype.583,584 In patients mepolizumab585 or benralizumab300 compared with taking OCS, median OCS placebo. Efficacy data for dose was able mepolizumab in children are limited to one very small uncontrolled open improved subjective and objective outcomes and reduced C label study.301 In patients with OT the need for surgery.498,499 nasal polyposis, mepolizumab Potential predictors of good asthma response to anti-IL5 or anOti-INL5R: Higher blood eosinophils (strongly predictive)586 L - D Higher number of severe Adult-onset asthma587 exacerbations in pErRevIAious year (strongly predictive)586 Nasal polyposis584 MAT Maintenance OCS at baseline584TED Low lung function (FEV1 <65I%GHpredicted in one study)588 Adverse effects: injection site rePacYtiRons; anaphylaxis rare; adverse events generally similar between active and placebo Suggested initial trial: at leasCt 4Omonths Add-on anti-IL4R for severe eosinophilic/Type 2 asthma or patients requiring maintenance OCS Currently approved*: For ages 12 years: dupilumab (anti-IL4 receptor ), 200 mg or 300 mg by SC injection every 2 weeks for severe eosinophilic/Type 2 asthma; 300 mg by SC injection every 2 weeks for OCS-dependent severe asthma or if there is concomitant moderate/severe atopic dermatitis. For children 6-11 years with severe eosinophilic/Type 2 asthma, by SC injection, with dose and frequency depending on weight. May also be indicated for treatment of moderateto-severe atopic dermatitis and for chronic rhinosinusitis with nasal polyposis. Self-administration may be an option. Mechanism: binds to interleukin-4 (IL-4) receptor alpha, blocking both IL-4 and IL-13 signaling Eligibility criteria (in addition to criteria for severe asthma): these vary between payers, but usually include: More than a specified number of severe exacerbations in the last year, and Type 2 biomarkers above a specified level (e.g. blood eosinophils 150/l and 1500/l; or FeNO 25 ppb); OR requirement for maintenance OCS *Check local regulatory and payer criteria, as they may differ from those shown 118 3. Treating to control symptoms and minimize future risk Outcomes: RCTs in patients with uncontrolled severe asthma (ACQ-5 1.5) and at least one exacerbation in the last year: anti-IL4R led to 56% reduction in severe exacerbations; improvements in quality of life, symptom control and lung function were significant,297 but less than the clinically important difference. In a post hoc analysis, clinical outcomes were similar in patients with allergic and non-allergic phenotype at baseline.589 In patients with OCS-dependent severe asthma, without minimum requirements for blood eosinophil count or FeNO, treatment with anti-IL4R reduced mean OCS dose by ~30% versus placebo.590 In children 6-11 years with eosinophilic/Type 2 asthma, dupilumab reduced severe exacerbation rate by 41% and increased lung function by 5.2 percentage points; Children taking maintenance OCS were excluded.302 Dupilumab is also indicated for treatment of moderate-severe atopic dermatitis.591 In patients with chronic rhinosinusitis with nasal polyposis, dupilumab reduced the size of nasal polyps, improved nasal symptoms and reduced the need for OCS or sinus surgery.500,592 Potential predictors of good asthma response to dupilumab: Higher blood eosinophils (strongly predictive)303 Higher FeNO (strongly predictive)303 Adverse effects: injection-site reactions; transient blood eosinophilia; rare cases of eosinUoTpEhilic granulomatosis with pboelcyaaunsgeiitoisf l(iEmGitePdAe).vAidnetni-cILe4(RsuischnoptastiuegngtseswteerdefoerxcplautdieendtsfrowmithPbhaasseelinIIeI torirahlsi)s.tIoSriTcRbIlBood eosinophils >1,500 cells/L Suggested initial trial: at least 4 months OR D Add-on anti-TSLP for Currently approved:* severe asthma For ages 12 years: tezepelumab (anti-TSLP), O21P0Ymg by SC injection every 4 weeks Mechanism: tezepelumab binds circulating TSLP, a bronchial eOpiTthCelial cell-derived alarmin implicated in multiple downstream processes involved in asthma pathophysiology. O N Eligibility criteria (in addition to criteria for severe asthLm-a)D:* these vary between payers, but usually include: Severe exacerbations in Anti-TSLP may also be considered tihneplaatsiet nytesawr.EithRnIAo elevated T2 markers (section 7.1) Outcomes:305,593 in RCTs in severe asthmaMpaAtTients with severe exacerbations in the last year anti-TSLP led to 30-70% raelldeurgcitciosntaintusse. vTehreereexwaacserabactlieoanrsc, oarnrdeTlEaimtDiopnrobveetdwqeueanlihtyigohfelrifeb,alsuenlginfeunbclotioodn and symptom eosinophils or control, irrespective of FeNO and better clinical outcomes. In patients taking mainItGenHance OCS, anti-TSLP did not lead to a reduced OCS dose compared with placebo. As yet there is no evidence thPaYt Rtezepelumab also has an impact on extrapulmonary comorbidities. Potential predictors of gooCdOasthma response to anti-TSLP: Higher blood eosinophils (strongly predictive) Higher FeNO levels (strongly predictive) Adverse effects: injection site reactions; anaphylaxis is rare; adverse events generally similar between active and placebo groups Suggested initial trial: at least 4 months Review response to an initial trial of add-on Type 2-targeted therapy At present, there are no well-defined criteria for a good response, but consider exacerbations, symptom control, lung function, side-effects, treatment intensity (including OCS dose), and patient satisfaction If the response is unclear, consider extending the trial to 6-12 months If there is no response, stop the biologic therapy, and consider switching to a trial of a different Type 2-targeted therapy, if available and the patient is eligible;578,594 review response as above *Check local regulatory and payer criteria, as they may differ from those shown 3. Treating to control symptoms and minimize future risk 119 MANAGE AND MONITOR SEVERE ASTHMA TREATMENT 9. REVIEW RESPONSE AND IMPLICATIONS FOR TREATMENT Review response to add-on biologic therapy after 3-4 months, and every 3-6 months for ongoing care, including: Asthma: symptom control, e.g. Asthma Control Test, Asthma Control Questionnaire (ACQ-5); frequency and severity of exacerbations (e.g. were OCS needed), lung function Type 2 comorbidities, e.g. nasal polyposis, atopic dermatitis Medications: treatment intensity, including dose of OCS, side-effects, affordability Patient satisfaction If the patient has had a good response to Type 2 targeted therapy: Re-evaluate the need for each asthma medication every 3-6 months, but do not completely stop inhaled therapy. Base the order of reduction or cessation of factors, medication side-effects, cost, add-on treatments on the and patient satisfaction. observed benefit when theyUwTeEre started, patient risk For oral treatments, consider gradually decreasing or stopping OCS first, because oTf RthIeBir significant adverse effects. Tapering in patients for severe asthma may be supported by internet-based risk of adrenal insufficiency, and provide patient and mGoPnwitoitrhinagdovficseymaDbpoItSoumt thceonnteroeldafnodr FeNO.595 Monitor extra corticosteroid doses during injury, illness or surgery for up to 6 months after cessation of lonOgR-term OCS. Continue to assess for presence of osteoporosis, and review need for preventative strategies inOcPluYding bisphosphonates.311 For inhaled treatments, consider reducing the ICS dose Current consensus advice is to continue at least medium after dose I3C-S6O.mTPoaCntitehnst,sbsuhtoduoldnboet completely stop reminded of the inhaled therapy. importance of continuing their inhaled controller. O N Fwoithr dbriaowloagl iocf ttrheeabtmioelongtisc,schuorureldntncootnbseecnosnussidaedrveicdeuinstitlhaLaftt-,eDgreanteleraalslyt,1f2ormaopnathtisenotf wtriethatamgeonot,darnedspoonnlyseif,aastthrimalaof remains well-controlled on previous well-documented amlleedrgiuicmtrdigogseer.ICTShethreeraarpeEyRf,eaIwAndst(ufdoireaslloefrgciecsassatthiomnao)fthbieorleogisicntohefurartphye,r59e6,x5p97oisnutrheetsoeastudies, symptom control worsened and/or exacerbatioMnsArTecurred for many (but not all) patients after cessation of the biologic. If the patient has NOT had a good respoTnEseDto any Type 2-targeted therapy: Stop the biologic therapy IGH Rdieavgineowsisth/deifbfearseinctsiaflodriafagcntoosrsis,cPoinnYhtRaribleurttinegchtoniqsyume,patodmhesr,eenxcaec,emrboadtiifoianbsleanridskpofaocrtoqrusaalitnydotfrilgifgee(rsseiencSluedcitniogns2m):oking and other environmental exposurCesOat home or work, comorbidities including obesity, medication side-effects or drug interactions, socio-economic and mental health issues. Consider additional investigations (if not already done): high resolution chest CT; induced sputum to confirm inflammatory phenotype, consider bronchoscopy for alternative or additional diagnoses, consider referral if available, including for diagnosis of alternative conditions. Reassess treatment options (if not already done), such as: Add-on low-dose azithromycin295,598 (adults only; first check sputum for atypical mycobacteria and check ECG for long QTc (and re-check after a month on treatment); consider potential for antibiotic resistance) As last resort, consider add-on low-dose maintenance OCS, but implement strategies such as alternate- day therapy and add-on bisphosphonates to minimize side-effects,311 and alert patient to the need for additional corticosteroid therapy during illness or surgery. Consider bronchial thermoplasty (+ registry) 120 3. Treating to control symptoms and minimize future risk Stop ineffective add-on therapies, but do not completely stop ICS 10. CONTINUE COLLABORATIVE OPTIMIZATION OF PATIENT CARE Ongoing management of a patient with severe asthma involves a collaboration between the patient, the GP, specialist(s), and other health professionals, to optimize clinical outcomes and patient satisfaction. Continue to review the patient every 3-6 months including: Clinical asthma measures (symptom control; exacerbations; lung function) Comorbidities The patient's risk factors for exacerbations Treatments (check inhaler technique and adherence; review need for add- on treatments; assess side-effects including of OCS; optimize comorbidity management and non-pharmacologic strategies) The The optimal patient's social and emotional needs frequency and location of review (GP or specialist) will depend on the patieUntT'sEasthma control, risk factors and comorbidities, and their confidence in self-management, and may depend on lToRcaIBl payer requirements and availability of specialist physicians. DIS Communicate regularly about: Outcome of review visits (as above) OR PY Patient concerns Action plan for worsening asthma or other risks T CO Changes to medications (asthma and non-asthma); pNoOtential side-effects Indications and contact details for expeditedArLev-ieDwO ATERI HTED M PYRIG CO 3. Treating to control symptoms and minimize future risk 121 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO SECTION 1. ADULTS, ADOLESCENTS AND CHILDREN 6 YEARS AND OLDER IBUTE ISTR R DChapter 4. COPY O NOT Management of - DO RIAL worsening asthma MATE and exacerbations GHTED PYRI CO KEY POINTS Terminology Exacerbations represent an acute or sub-acute worsening in symptoms and lung function from the patient's usual status, or in some cases, a patient may present for the first time during an exacerbation. The terms `episodes', `attacks' and `acute severe asthma' are also often used, but they have variable meanings. The term `flare-up' is preferable for use in discussions with most patients. Patients who are at increased risk of asthma-related death should be identified, and flagged for more frequent review. Written asthma action plans All patients should be provided with a written (i.e. printed, digital or pictorial) asthma action plan appropriate for their level of asthma control and health literacy, so they know how to recognize and respond to worsening asthma. UTE On the action plan, state and access medical care when and how to change reliever and controller if symptoms fail to respond to treatment. meTdiRcaIBtions, use oral corticosteroids, Advise patients who have a history of rapid deterioration to go to an acutDe IcSare facility or see their doctor immediately their asthma starts to worsen. OR Base the action plan on changes in symptoms Management of exacerbations in a primary care or aocr u(otenlcyainreafdaucltislOi)tyPpeYak expiratory flow (PEF). Assess exacerbation severity from the degree of dyspnea, rTesCpiratory rate, pulse rate, oxygen saturation and lung function, while starting short-acting beta2-agonist (SNAOBA) and oxygen therapy. Infection control procedures should be followed. - DO Arrange immediate care if the patient is transfer drowsy ,tcooannfuasceudt,eocrahraesfaIaAcLsiliitleynift there are signs of severe exacerbation, or chest. During transfer, give inhaled SABA to int and ensive ipratropium bromide, controlled oxygen anTdERsystemic corticosteroids. Start treatment with repeated adminisMtraAtion of SABA (in most patients, by pressurized metered dose inhaler aonf dsysmppatcoemr)s, ,eoaxrlyygienntrosdautucrtaiotinonoTfaoEnrdDallucnogrtifcuonsctteioronidasft,earn1dhcoounrt.roGlilveed flow oxygen if available. Review response ipratropium bromide only for severe exacerbations. Consider to initial treatment. inRtIrGavHenous magnesium sulfate for patients with severe exacerbations not responding Do not routinely requeOsPt aYchest X-ray, and do not routinely prescribe antibiotics for asthma exacerbations. Decide about hospitCalization based on the patient's clinical status, lung function, response to treatment, recent and past history of exacerbations, and ability to manage at home. Discharge management Arrange ongoing treatment before the patient goes home. This should include starting inhaled corticosteroid (ICS)-containing controller treatment or stepping up the dose of existing controller treatment for 2-4 weeks, and reducing reliever medication to as-needed use. Arrange early follow-up after any exacerbation, regardless of where it was managed. At follow-up: o Review the patient's symptom control and risk factors for further exacerbations. o Prescribe ICS-containing controller therapy to reduce the risk of further exacerbations. If already taking controller therapy, continue increased doses for 2-4 weeks. o Provide a written asthma action plan and, where relevant, advice about avoiding exacerbation triggers Check inhaler technique and adherence. For management of asthma exacerbations in children 5 years and younger, see Chapter 6, p.168. 124 4. Management of worsening asthma and exacerbations OVERVIEW Definition of asthma exacerbations Exacerbations of asthma are episodes characterized by a progressive increase in symptoms of shortness of breath, cough, wheezing or chest tightness and progressive decrease in lung function, i.e. they represent a change from the patient's usual status that is sufficient to require a change in treatment.24 Exacerbations may occur in patients with a preexisting diagnosis of asthma or, occasionally, as the first presentation of asthma. What triggers asthma exacerbations? Exacerbations usually occur in response to exposure to an external agent (e.g. viral upper respiratory tract infection, pollen or pollution) and/or poor adherence with controller medication; however, a subset of patients present more acutely and without exposure to known risk factors.599,600 Severe exacerbations can occur in patients with mild or well- cinodnetrpoellneddeanst tohfmthaesirylmevpetol mofss.1y8m,22p4toBmoxc2o-n2tBro(l.p.36) lists factors that increase a patientI'Bs UrisTkEof exacerbations, Common exacerbation triggers include: Viral respiratory infections601 DISTR Allergen exposure Food allergy102 e.g. grass pollen,602 soy bean dust,603 fungal spOorRes Outdoor air pollution108,604 OPY Seasonal changes and/or returning Poor adherence with ICS606 to school in fall (auOtuTmCn)605 Epidemics of severe asthma exacerbations may ocOcuNr suddenly, putting high pressure on local health system rgeraspssonpsoellse.nSourcfhunegpaidlesmpoicrsesh,a60v7eabnedewnitrhepeonrvtLeirdo-niDnmaesnstaolceiaxtpioonsuwriethtospsroinygbtiemaen thunderstorms dust.603 and either rye Identifying patients at risk of asthma-related deEaRthIA In addition to factors known to increase theMrisAkTof asthma exacerbations (Box 2-2, p.36), some features are specifically afascstoocrsiastehdouwldithbeanquinicckrelyasideeinntitfhiaeblreisiknToEthfDeasctlhinmicaa-lrenloatteesd, daenadthth(eBsoexp4a-t1ie).nTtshsehporuelsdebneceenocf oounreagoer dmtooreseoefkthuersgeenritsk medical care early in the course oIfGaHn exacerbation. Box 4-1. Factors that increPaYseRthe risk of asthma-related death CO A history of near-fatal asthma requiring intubation and mechanical ventilation608 Hospitalization608,609 or emergency care visit for asthma in the past year Currently using or having recently stopped using oral corticosteroids (a marker of event severity)608 Not currently using inhaled corticosteroids98,608 Over-use of SABAs, especially use of more than one canister of salbutamol (or equivalent) monthly71,116,610 Poor adherence with ICS-containing medications and/or poor adherence with (or lack of) a written asthma action plan109 A history of psychiatric disease or psychosocial problems109 Food allergy in a patient with asthma486,611 Several comorbidities including pneumonia, diabetes and arrhythmias were independently associated with an increased risk of death after hospitalization for an asthma exacerbation.609 4. Management of worsening asthma and exacerbations 125 Terminology about exacerbations The academic term `exacerbation' is commonly used in scientific and clinical literature, although hospital-based studies more often refer to `acute severe asthma'. However, the term `exacerbation' is not suitable for use in clinical practice, as it is difficult for many patients to pronounce and remember.612,613 The term `flare-up' is simpler, and conveys the sense that asthma is present even when symptoms are absent. The term `attack' is used by many patients and health care providers but with widely varying meanings, and it may not be perceived as including gradual worsening.612,613 In pediatric literature, the term `episode' is commonly used, but understanding of this term by parent/carers is not known. DIAGNOSIS OF EXACERBATIONS Exacerbations represent a change in symptoms and lung function from the patient's usual status.24 The decrease in expiratory airflow can be quantified by lung function measurements such as peak expiratory flow (PEF) or forced expiratory volume in 1 second (FEV1),614 compared with the patient's previous lung function or predicted values. In the acute setting, these measurements are frequency of symptoms may, however, bmeoaremroerlieabsleenisnidtiivceatmoresaosfutrheeosf ethveeroitnysoefttohfeaenxaecxearcbeTarEbtiaontiotnhathnasnymPEpFto.m615s. The A minority of patients perceive airflow limitation poorly and can experience a significantRdIeBcUline in lung function without a change in symptoms.131,144,152 This especially affects patients with a history of more common in males. Regular PEF monitoring may be considered for such npeaatiDre-InfSatstTa. l asthma and also appears to be Severe exacerbations are potentially life threatening and their treatment requiOreRs careful assessment and close monitoring. Patients with severe exacerbations should be depending on the organization of local health services, to advised proceed to to stheeeOntPheYeairrehset afaltchilcitayrtehaptropvroidveidr epsroemmpetlrygeonr,cy access for patients with acute asthma. T C SELF-MANAGEMENT OF EXACERBATIONS WITH A WRITTENNAOSTHMA ACTION PLAN All patients with asthma should be provided with guided se-lf-DmOanagement education as described in Chapter 3 (p.88), including monitoring professional.458 (For of symptoms and/or children 5 years and lyuonugnfguenrc,tisoeRne,IAaCLhwarpittteenr asthma action plan, and regular review by a health 6, p.151). A written (i.e. documented) asthma action plan may be printed, digital, or pictorial, to suit thAeTpEatient's needs and literacy. A sample written asthma action plan template guide/. is included in the GINA toolbox, aEvDailaMble from the GINA website at www.ginasthma.org/gina-implementation- Treatment options for written asthmIaGaHcTtion plans A written asthma action plan helPpsYRpatients to recognize and respond appropriately to worsening asthma. It should icnocrltuicdoesstepreocidifsic(OinsCtSru)citfionnesedfCoerOdth(Beopxa4ti-e2n)t about changes to reliever and controller medications, and when and how to access medical care. how to use oral The criteria for initiating an increase in controller medication will vary from patient to patient. For patients taking maintenance-only ICS-containing treatment, this should generally be increased when there is a clinically important change from the patient's usual level of asthma control, for example, if asthma symptoms are interfering with normal activities, or PEF has fallen by >20% for more than 2 days.463 Inhaled reliever medication (ICS-formoterol or SABA) For patients with mild asthma prescribed as-needed combination low dose ICS-formoterol (see Box 3-5A, p.61), increasing the as-needed doses of ICS-formoterol when asthma worsens reduces the risk of severe exacerbations requiring OCS by two-thirds compared with SABA-only treatment,188 and is non-inferior for progression to severe exacerbation compared with daily ICS plus as-needed SABA.188,189 After a day of even small increased doses of ICSformoterol, the risk of severe exacerbation in the following 3 weeks is reduced compared with the same doses of SABA alone.75 Based on product information, the maximum recommended dose of ICS-formoterol in a single day is a total of 126 4. Management of worsening asthma and exacerbations 48 mcg formoterol for beclometasone-formoterol (36 mcg delivered dose), and 72 mcg formoterol for budesonideformoterol (54 mcg delivered dose). For patients prescribed an inhaled short-acting beta2-agonist (SABA) bronchodilator as their reliever, repeated SABA dosing provides temporary relief until the cause of the worsening symptoms passes or increased controller treatment has had time to take effect. However, use of SABA reliever is less effective in preventing progression to severe exacerbation requiring OCS than use of low dose ICS-formoterol reliever, either with193 or without188,189 daily maintenance controller (see Chapter 3). The need for repeated doses of SABA over more than 1-2 days signals the need to review, and possibly increase, controller treatment if this has not already been done. This is particularly important if there has been a lack of response to increased use of beta2-agonist therapy. Combination low dose ICS (budesonide or beclometasone) with formoterol maintenance and reliever regimen The combin as both the ation of rapidcontroller and onset LABA the reliever (formoterol) and medication is eff low ectiv dos e in e ICS (budesonide improving asthma or sy mbepctoloTmmEceotanstroonl,e19)2ina a single inhal nd it reduces er exacerbations needed SABA requiring reliever ( OCS, and hospitalizations193,250-253 compared with the Evidence A). The recommended maximum total dose osfafmoremRooIBrtehUrioglhienr dose of controller with as24 hours with budesonide- formoterol is 72 mcg (delivered dose 54 mcg) and with beclometasone-formoteDroISl Tis 48 mcg (delivered dose 36 mcg). The benefit of worsening ast this regimen hma.74,317 Thi in prevent s regimen ing exacerbations was also effective appears in reduc itnogbeexdauceeOrtboRaitniotenrsv ention at a in children very aged early stage of 4-11 years,271 (sElovwideern-ocnesBe)t.LTAhBisAa, popr rtohaact hlaschkoeuvldidennoct ebeofaettfefimcapcteydanwdithsaoftehteyrwciothmOabPimnYaatiinotnenICanSc-LeAaBnAd controller therapies reliever regimen. with a Other ICS and ICS-LABA maintenance controller regimens OT C In a systematic review of self-management studies, action OplaNns in which the ICS dose was at least doubled were atrsiaslos,citaetmedpowriathriliymdporuobvelindgatshtehmdoasoeuotcfoICmSeswaansdnroetdeufLcfee-cdtDihvee6a1l6th(EcavrideeuntcileizaAt)io; nh4o6w3 e(Evveird,ethnecedeAl)a.yInbepflaocreebinoc-rceoanstrinoglletdhe ICS that dhoigsheer(mICeSand5o-se7sdmayigsh61t7h,6e18l)pmpraeyvheanvt ewocorsnetrnEibinRugItAeads.thSmoma eprsotgurdeiesssiningatodualtss6e1v9earnedeyxoaucnegrbcahtiioldnr.eInn62a0 have reported randomized controlled trial in primary care with patientsMagAeTd 16 years, those who quadrupled their ICS dose (to average of 2000 mcg/day BDP care randomiz eq ed uivalent) a controlled fter the trial of iar dPuTEltEFaDfnedll were significantly adolescent patien less ts us likely to ing ICS require OCS.621 In an with or without LABA, open-label primar early quadrupling y of ICS dose However, (to average 32 a double-blind 0p0lamcecbgoR/d-IcaGoyHnBtrDoPlleedqsutiuvdayleinnt)c was as hildren sociated with a modest reduction 5-11 years with high adherence in to prescribi low dose ng IC of OCS. S found 622 no edqiffueivreanlecnet)invethrseursatceoonftinseuvinOegrPemYeaxinacteenrbaanctioenloswredqousireintgheOraCpSy.i6f2m3 aintenance ICS was quintupled (to 1600 mcg BDP C Given the shape of the ICS dose-response curve, little benefit may be seen from increasing maintenance ICS when background adherence is high, as in this study. In addition, in several of the above studies (e.g. 617,618,623), a pre- specified level of deterioration in symptoms ( lung function) had to be reached before the extra ICS could be started. These factors may help to explain the greater reduction in severe exacerbations seen with maintenance and reliever therapy with ICS-formoterol, where there is no lag between when symptoms appear and when the doses of both ICS and formoterol are increased through as-needed use of the combination inhaler for symptom relief. In adult patients with an acute deterioration, high dose ICS for 7-14 days (500-1600 mcg BDP-HFA equivalent) had an equivalent benefit to a short course of OCS619 (Evidence A). For adults taking combination ICS-LABA as a maintenance controller medication, the ICS dose may be increased by adding a separate ICS inhaler619,622 (Evidence D). More research is needed to standardize this strategy. 4. Management of worsening asthma and exacerbations 127 Leukotriene receptor antagonists For patients with mild asthma using a leukotriene receptor antagonist (LTRA) as their controller, there are no specific studies about how to manage worsening asthma. Clinician judgment should be used (Evidence D). Oral corticosteroids For most patients, the written asthma action plan should provide instructions for when and how to commence OCS. Typically, a short course of OCS is used (e.g. 40-50 mg/day usually for 5-7 days,619 Evidence B) for patients who: Fail to respond to an increase in reliever and controller medication for 2-3 days Deteriorate rapidly or who have a PEF or FEV1 <60% of their personal best or predicted value Have a history of sudden severe exacerbations. For children 6-11 years, the recommended dose of prednisone is 1-2 mg/kg/day to a maximum of 40 mg/day (Evidence B), usually for 3-5 days. Patients should be advised about common side-effects, including sleep disturbance, increased appetite, reflux, and mood changes.624 Patients should contact their doctor if they start takinUgTOECS (Evidence D). Reviewing response Patients should see their doctor immediately or present to an acute care unit if their asTtRhmIBa continues to deteriorate despite following their written asthma action plan, or if their asthma suddenly worsDeInSs. Follow up after a self-managed exacerbation OR After a self-managed exacerbation, patients should see their primary caOrePhYealth care provider for a semi-urgent review (e.g. within 1-2 weeks, but preferably before ceasing oral corticosteTroCids if prescribed), for assessment of symptom control and additional risk factors for exacerbations (Box 2-2, p.3N6O), and to identify the potential cause of the exacerbation. This visit provides an opportunity for additional asthma edu-cDatOion by a trained asthma educator or trained lay health care worker. RIAL Tcahne gwernitteernallaysbthemreadaucctieodntpolapnresvhioouusldlebveerlsev2i-e4wAewdTeEetoksseaefteifritthmeeetxthaeceprabtaietinotn's(Enveieddesn.cMe aDin),teunnalenscsetchoenhtrisotlolerrytrseuagtgmeesntst ttheacht nthiqeueexaancderabdahtioerneonccceuhrraevdeobneeanbcahcekcgkrEoeDudn,Mda of long-term poorly controlled asthma. step up in treatment may be indicated In this situation, (Box 3-5, p.61). provided inhaler Adult and adolescent patients with mIoGreHtThan 1-2 exacerbations per year despite Step 4-5 therapy should be referred to a specialist center for assessCmOePnYt (Rsee decision tree in Chapter 3E, p.104). 128 4. Management of worsening asthma and exacerbations Box 4-2. Self-management of worsening asthma in adults and adolescents with a written asthma action plan R DISTRIBUTE Medication Short-term change (1-2 weeks) for worsening asthma PY O Increase usual reliever: CO Low dose ICS-formoterol OT Short-acting beta2-agonist N (SABA) Increase frequency of as-needed ICS-formoterol Increase frequency of SABA use For pMDI, add spacer - DO Increase usual controller: IAL Maintenance and reliever R ICS-formoterol Continue maintenance ICS-formoterol and increase reliever ICS-formoterol as needed. ATE Maintenance ICS M with SABA as reliever In adults and adolescents, quadruple ICS dose. In children with high adherence, 5x increase in ICS dose is not effective. ED Maintenance ICS-formoterol Quadruple maintenance ICS-formoterol. T with SABA as reliever IGH Maintenance ICS plus other YR LABA with SABA as P reliever Step up to higher dose formulation of ICS plus other LABA In adults, consider adding a separate ICS inhaler to quadruple ICS dose. CO Add oral corticosteroids (OCS) and contact doctor; review before ceasing OCS (prednisone or prednisolone) Add OCS for severe exacerbations (e.g. PEF or FEV1 <60% personal best or predicted), or patient not responding to treatment over 48 hours. Once started, morning dosing is preferable. Evidence level A A A A B B B D A Adults: prednisolone 40-50 mg/day, usually for 5-7 days. Children 6-11 years: 1-2 mg/kg/day (maximum 40 mg) usually for D 3-5 days. Tapering is not needed if OCS are prescribed for <2 weeks. B BDP: beclometasone dipropionate; FEV1: forced expiratory volume in 1 second; ICS: inhaled corticosteroid; PEF: peak expiratory flow; SABA: short-acting beta2-agonist. Options in each section are listed in order of evidence. * or equivalent dose of prednisone. ICS-formoterol as-needed for relief of symptoms in mild asthma, or as part of maintenance and reliever regimen with low dose budesonide or beclometasone with formoterol. Based on product information, the maximum recommended dose of ICSformoterol in a single day is a total of 48 mcg formoterol for beclometasone-formoterol (36 mcg delivered dose), and 72 mcg formoterol for budesonide-formoterol (54 mcg delivered dose). 4. Management of worsening asthma and exacerbations 129 MANAGEMENT OF ASTHMA EXACERBATIONS IN PRIMARY CARE (ADULTS, ADOLESCENTS, CHLDREN 6-11 YEARS) Assessing exacerbation severity A brief focused history and relevant physical examination should be conducted concurrently with the prompt initiation of therapy, and findings documented in the notes. If the patient shows signs of a severe or life-threatening exacerbation, treatment with SABA, controlled oxygen and systemic corticosteroids should be initiated while arranging for the patient's urgent transfer to an acute care facility where monitoring and expertise are more readily available. Milder exacerbations can usually be treated in a primary care setting, depending on resources and expertise. History The history should include: Timing of onset and cause (if known) of the present exacerbation Severity of asthma symptoms, including any limiting exercise or disturbing sleep Any symptoms of anaphylaxis UTE Any risk factors for asthma-related death (Box 4-1, p.125) TRIB All current reliever and controller medications, recent dose changes, and response to current including therapy. doses and devices DprISescribed, adherence pattern, any Physical examination OR The physical examination should assess: OPY Signs of exacerbation severity (Box 4-3, p.131) and vital signsT(eC.g. level of consciousness, temperature, pulse rate, respiratory rate, blood pressure, ability to complete seNnOtences, use of accessory muscles, wheeze). CSiogmnsploicfaatilntegrnfaactitvoersco(en.dgi.tiaonnaspthhyaltacxoisu,ldpneexupmlaoinnaiac,up-tneDebOurmeaotthhloersasxn)ess (e.g. cardiac failure, inducible laryngeal obstruction, inhaled foreign body or pulmonaryReImAbLolism). Objective measurements Pulse oximetry. Saturation levels <90% in AchTiEldren or adults signal the need for aggressive therapy. PEF in patients older than 5 years (BEoDx 4M-3, p.131) Treating exacerbations in primary caIGreHT The main initial therapies systemic corticosteroids, ainncdlucdoePntYrreoRplleetditifvloewadomxyingeisntrastuiopnploefmsehnotratt-iaocnt.i6n1g4 inhaled bronchodilators, early introduction of The aim is to rapidly relieve airflow obstruction and hypoxemia, address theCuOnderlying inflammatory pathophysiology, and prevent relapse. Infection control procedures should be followed. Inhaled short-acting beta2-agonists Currently, inhaled salbutamol (albuterol) is the usual bronchodilator in acute asthma management. For mild to moderate exacerbations, repeated administration of inhaled SABA (up to 4-10 puffs every 20 minutes for the first hour) is an effective and efficient way to achieve rapid reversal of airflow limitation625 (Evidence A). After the first hour, the dose of SABA required varies from 4-10 puffs every 3-4 hours up to 6-10 puffs every 1-2 hours, or more often. No additional SABA is needed if there is a good response to initial treatment (e.g. PEF >60-80% of predicted or personal best for 3-4 hours). In emergency department studies, the efficacy and safety of formoterol626 and budesonide-formoterol627 was similar to that of salbutamol in management of acute asthma. Delivery of SABA via a pMDI and spacer or a DPI leads to a similar improvement in lung function as delivery via nebulizer625,628 (Evidence A); however, patients with acute severe asthma were not included in these studies. The most cost-effective route of delivery is pMDI and spacer,629 provided the patient can use this device. Because of static charge, some spacers require pre-washing with detergent before use. The manufacturer's advice should be followed. 130 4. Management of worsening asthma and exacerbations Box 4-3. Management of asthma exacerbations in primary care (adults, adolescents, children 6-11 years) IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO O2: oxygen; PEF: peak expiratory flow; SABA: short-acting beta2-agonist (doses are for salbutamol). 4. Management of worsening asthma and exacerbations 131 Controlled oxygen therapy (if available) Oxygen therapy should be titrated against pulse oximetry (if available) to maintain oxygen saturation at 93-95% (94- 98% for children 6-11 years). In hospitalized asthma patients, controlled or titrated oxygen therapy is associated with lower mortality and better outcomes than high concentration (100%) oxygen therapy630-633 (Evidence A). Oxygen should not be withheld if oximetry is not available, but the patient should be monitored for deterioration, somnolence or fatigue because of the risk of hypercapnia and respiratory failure.630-633 If supplemental oxygen is administered, oxygen saturation should be maintained no higher than 96% in adults.634 Systemic corticosteroids OCS should be given promptly, especially if the patient is deteriorating, or had already increased their reliever and controller medications before presenting (Evidence B). The recommended dose of prednisolone for adults is 1 mg/kg/day or equivalent up to a maximum of 50 mg/day, and 1-2 mg/kg/day for children 6-11 years up to a maximum of 40 mg/day). OCS should usually be continued for 5-7 days in adults635,636 and 3-5 days in children637 (Evidence B). Pmaotoiednctshasnhgoeusld.6b24e advised about common side-effects, including sleep disturbance, incrIeBaUseTdEappetite, reflux and Controller medication ISTR Patients already prescribed controller medication should be provided with advice aDbout increasing the dose for the next 2-4 weeks, as summarized in Box on regular ICS-containing therapy, 4-2 (p.129). Patients not as SABA-only treatment currently taking of asthma is no lcooOnnRgterorllreercmomedmiceantdioend.shAonueldxabceecrboamtimonenced requiring medical care indicates that the patient is at increased risk of fuOtuPreYexacerbations (Box 2-2, p.36). Antibiotics (not recommended) T C Evidence does not support routine use of antibiotics in the treatmNeOnt of acute asthma exacerbations unless there is strong evidence of lung infection (e.g. fever and purulent sp-uDtuOm or radiographic evidence of pneumonia).638 Reviewing response RIAL Dpruersinegnttrweiathtmseignnt,spoaftiaensetsvsehreouolrdlibfee-tchloresaetleynminognAeitTxoEarecde,rbaantdiotnre(aBtomxe4n-t3t,itpra.1te3d1)a,cwchoordfianigl to to their response. Patients respond to treatment, or who who cSoAnBtiAnuteretaotmdeetnetrisohroauteldsbheouclldosbeelytrmanosnfietorrreEeddD.imMmediately to an acute care facility. Patients with little or slow response to For many patients, lung function can IbGeHmTonitored after SABA therapy is initiated. Additional treatment should continue uwnhteilthPeErFtoorseFnEdVt1hreeapcahtieesntahpolmatPeeYaoRur torran(isdfeearlltyh)ermetutornasntoactuhteepcaatrieenfta'sciplitrye.vious best. A decision can then be made CO Follow up Discharge medications should include as-needed reliever medication (low dose ICS-formoterol or SABA), a short course of OCS and regular controller treatment. SABA-only treatment is not recommended. Inhaler technique and adherence should be reviewed before discharge. Patients should be advised to use their reliever inhaler only as-needed, rather than routinely. A follow-up appointment should be arranged for about 2-7 days later, depending on the clinical and social context. At the review visit the health care provider should assess whether the flare-up has resolved, and whether OCS can be ceased. They should assess the patient's level of symptom control and risk factors; explore the potential cause of the exacerbation; and review the written asthma action plan (or provide one if the patient does not already have one). Maintenance controller treatment can generally be stepped back to pre-exacerbation levels 2-4 weeks after the exacerbation, unless the exacerbation was preceded by symptoms suggestive of chronically poorly controlled asthma. In this situation, provided inhaler technique and adherence have been checked, a step up in treatment (Box 3-5, p.61) may be indicated. 132 4. Management of worsening asthma and exacerbations MANAGEMENT OF ASTHMA EXACERBATIONS IN THE EMERGENCY DEPARTMENT (ADULTS, ADOLESCENTS, CHILDREN 6-11 YEARS) Severe exacerbations of asthma are life-threatening medical emergencies, which are most safely managed in an acute care setting e.g. emergency department (Box 4-4). Infection control procedures should be followed. Management of asthma in the intensive care unit is beyond the scope of this report and readers are referred to a comprehensive review.639 Assessment History A brief history and physical examination should be conducted concurrently with the prompt initiation of therapy. Include: Time of onset and cause (if known) of the present exacerbation Severity of asthma symptoms, including any limiting exercise or disturbing sleep Any symptoms of anaphylaxis Risk factors for asthma-related death (Box 4-1, p.125) IBUTE Arellcceunrtrdeonst erecliheavnegr easn,dacnodnrteroslpleornmseedtoiccautirornesn,t itnhcelruadpinyg. doses and devicDeIsSpTrRescribed, adherence pattern, any Physical examination The physical examination should assess: OR PY Signs of exacerbation severity (Box 4-4), including vital signsC(Oe.g. level of consciousness, temperature, pulse rCaotem, prelicsaptirinagtofraycrtaotres,(bel.ogo. danparepshsyularexi,sa, bpinliteyutmo ocnoima,paleteteNleOscetTansteisn,cpense,uumseotohfoaracxceosrsponryeummuosmcleeds)iastinum) Signs of alternative obstruction, inhaled cfoornedigitnionbsodthyaotrcpouullmd oenxaprlayinema-cbDuoOtleismbr)e.athlessness (e.g. cardiac failure, inducible laryngeal Objective assessments RIAL Objective assessments are also needed as theApThEysical examination alone may not indicate the severity of the exacerbation.640,641 However, patients, anEdDnoMt their laboratory values, should be the focus of treatment. Measuremen PEF or FEV1 tsohfoluulndgbfeunrecctiooIGrnd:HetTdhisbeisfosrter ongly reco treatment mmended. is initiated, If a possible, and without unduly delaying tr lthough spirometry may not be possible eatment, in children Owtreixtahytgmaecenuntsteahatuassrtahotmicocanu.:CrLtrhOueisndPgsoYhrfRuoanucpldtliaobtneeascuhlooissuelrdelyabmcehomendoit.noriteodre, dpraetfeornaeblhyobuyr paunldseatoixnitmerevtaryls. Tuhnitsil ias celsepaer creiasllpyounsseefutol in children if they are unable to perform PEF. In children, oxygen saturation is normally >95%, and saturation <92% is a predictor of the need for hospitalization642 (Evidence C). Saturation levels <90% in children or adults signal the need for aggressive therapy. Subject to clinical urgency, saturation should be assessed before oxygen is commenced, or 5 minutes after oxygen is removed or when saturation stabilizes. Arterial blood gas measurements are not routinely required:643 They should be considered for patients with PEF or FEV1 <50% predicted,644 or for those who do not respond to initial treatment or are deteriorating. Supplemental controlled oxygen should be continued while blood gases are obtained. During an asthma exacerbation PaCO2 is often below normal (<40 mmHg). Fatigue and somnolence suggest that pCO2 may be increasing and airway intervention may be needed. PaO2<60 mmHg (8 kPa) and normal or increased PaCO2 (especially >45 mmHg, 6 kPa) indicate respiratory failure. Chest X-ray (CXR) is not routinely recommended: In adults, CXR should be considered if a complicating or alternative cardiopulmonary process is suspected (especially in older patients), or for patients who are not responding to treatment where a pneumothorax may be difficult to diagnose clinically.645 Similarly, in children, routine CXR is not recommended unless there are physical signs suggestive of pneumothorax, parenchymal 4. Management of worsening asthma and exacerbations 133 disease or an inhaled foreign body. Features associated with positive CXR findings in children include fever, no family history of asthma, and localized lung examination findings.646 Treatment in acute care settings such as the emergency department The following treatments are usually administered concurrently to achieve rapid improvement.647 Oxygen To achieve arterial oxygen saturation of 93-95% (94-98% for children 6-11 years), oxygen should be administered by nasal cannulae or mask. In severe exacerbations, controlled low flow oxygen therapy using pulse oximetry to maintain saturation at 93-95% is associated with better physiological outcomes than with high concentration (100%) oxygen therapy630-632 (Evidence B). However, oxygen therapy should not be withheld if pulse oximetry is not available (Evidence D). Once the patient has stabilized, consider weaning them off oxygen using oximetry to guide the need for ongoing oxygen therapy. Inhaled short-acting beta2-agonists UTE Inhaled SABA therapy should effective and efficient delivery be administered frequently for is by pMDI with a spacer625,629 patients presenting with (Evidence A). Evidence TiascRlueIBtsesarsotbhumsat .inTsheevmeroesat ncdosnt-ear- fatal asthma. Systematic reviews of intermittent versus continuous SABA in acuteDaIsSthma, which mostly used nebulized SABA, provide conflicting results. Use of nebulizers can disseminate respiratory viral infections.648 Currently, inhaled albuterol is the usual aberoronscohlosOdaiRlnadtopr ointeanctuiatlelyacsothnmtriabumteantoagsepmreeandt.of Similar efficacy and safety have been reported from emergency departmOePnYt studies with formoterol,626 and in one study Cofubrruednetseovnidideen-cfoermdooetesronol.6t2s7uMpoproertstthuedireosutoinf eICuSs-efoormf inottrearvoel ninoeumsNbOeerTgtaeC2n-caygodneipsatsrtimnepnattimenatnsawgiethmseenvtearreeansetehdmead. exacerbations649 (Evidence A). Epinephrine (for anaphylaxis) - DO Intramuscular epinephrine (adrenaline) is indicated inRaIAddLition to standard therapy for acute asthma associated with anaphylaxis and angioedema. It is not routinely iAndTiEcated for other asthma exacerbations. Systemic corticosteroids Systemic corticosteroids speed resolution oEfDexMacerbations and prevent relapse, and in acute care settings should be puotilsizseibdlein, saylsl bteumt tichecomrtiilcdoesstteeroxiadcsesrbhaoIGtuiolHdnTsbeinaaddmuilntsis, taedreodlestocethnetspaantidencthwilditrheinn 6-11 years.650,651 (Evidence 1 hour of presentation.650,652 A). Where Use of systemic corticosteroids is particPuYlaRrly important in the emergency department if: Initial SABA treatmentCfaOils to achieve lasting improvement in symptoms The exacerbation developed while the patient was taking OCS The patient has a history of previous exacerbations requiring OCS. Route of delivery: oral administration is as effective as intravenous. The oral route is preferred because it is quicker, less invasive and less expensive.653,654 For children, a liquid formulation is preferred to tablets. OCS require at least 4 hours to produce a clinical improvement. Intravenous corticosteroids can be administered when patients are too dyspneic to swallow; if the patient is vomiting; or when patients require non-invasive ventilation or intubation. In patients discharged from the emergency department, an intramuscular corticosteroid may be an alternative to a course of OCS for preventing relapse,655 especially if there are concerns about adherence with oral therapy.656 However, current evidence does not demonstrate a benefit of intramuscular over oral corticosteroids.651 (See over for dosage and duration of systemic corticosteroid treatment) 134 4. Management of worsening asthma and exacerbations Box 4-4. Management of asthma exacerbations in acute care facility, e.g. emergency department IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO ICS: inhaled corticosteroids; ICU: intensive care unit; IV: intravenous; O2: oxygen; PEF: peak expiratory flow; FEV1: forced expiratory volume in 1 sec 4. Management of worsening asthma and exacerbations 135 Dosage: daily doses of OCS equivalent to 50 mg prednisolone as a single morning dose, or 200 mg hydrocortisone in divided doses, are typically used for adults. For children, a prednisolone dose of 1-2 mg/kg up to a maximum of 40 mg/day is suggested.657 Duration: 5- and 7-day courses in adults have been found to be as effective as 10- and 14-day courses respectively635,636 (Evidence B), and a 3-5-day course in children is usually considered sufficient for most. A small number of studies examined oral dexamethasone 0.6 mg/kg, given once daily for 1-2 days in children and adults; the relapse rate was similar to that with prednisolone for 3-5 days, with a lower risk of vomiting.658-660 Oral dexamethasone should not be continued beyond 2 days because of concerns about metabolic side-effects. If there is a failure of resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. Evidence from studies in which all patients were taking maintenance ICS after discharge suggests that there is no benefit in tapering the dose of OCS, either in the short term661 or over several weeks662 (Evidence B). Inhaled corticosteroids Within the emergency department: high dose ICS given within the first hour after presentatiUoTnEreduces the need for hospitalization in patients corticosteroids, evidence not receiving systemic corticosteroids652 (Evidence is conflicting in adults.663 In children, administration oAf)I.CWShweTnitRhaIodBrdewdithtooustycsotenmcoicmitant systemic corticosteroids admission and wneitehdinfothresyfisrstet mhoicurcsoortficaotstetenrdoaidnsc6e64to(EthviedeenmceergBe).nOcyvedreaplla,ratmdde-notnmDICiIgSShtarreedwuceell the risk of tolerated; hospital however, cost may be a significant factor, and the agent, dose and duration of treatment withOIRCS in the management of asthma in the emergency department remain unclear. be prescribed, ICS-containing therapy. Patients admitted to hospital forOaPnYasthma exacerbation should continue on, or On discharge home: patients should be prescribed ongoing ICS-coOnTtaCining treatment since the occurrence of a severe exacerbation is a risk factor significantly reduce the risk for future exacerbations of asthma-related death o(Er vhiodsepniDctaeOliBzNa)t(ioBno2x262(-E2v, ipd.e3n6c),eaAn)d. ICS-containing medications SABA-only treatment of asthma is a snyostloenmgaetricrerecvoimewmfeonudneddn. oFosrigsnhifoicrta-tnetrdmiffoeuretcnocmeseswshIuAecnLhI-aCsSrwelearpeseadredequdirtoingsyasdtemmisicsioconr,tsicyomstpetroomidss, and quality of life, after discharge.665 Texhaecreerwbaatsiosnosm, beuetvthideencocen,fidhoenwceevelirm, itthsawt eproestw-didiseTc.h6E6a5Rr(gEevIiCdeSnwceerBe).aCs oesfftemctaivyebaesasyssigtenmificicancot rfaticcotosrteforor ipdastfieonr tms iilndethr e use of high dose ICS, and further studies are rMeqAuired to establish their role.665 Other treatments GHTED Ipratropium bromide For adults and children with modeYraRteI -severe exacerbations, treatment in the emergency department with both SABA P and ipratropium, a short-actinCgOanticholinergic, was associated with fewer hospitalizations (Evidence A for adults666; Evidence B for adolescents/children667) and greater improvement in PEF and FEV1 compared with SABA alone.666-668 (Evidence A, adults/adolescents) For children hospitalized for acute asthma, no benefits were seen from adding ipratropium to SABA, including no reduction in length of stay,667 but the risk of nausea and tremor was reduced.667 Aminophylline and theophylline (not recommended) Intravenous aminophylline and theophylline should not be used in the management of asthma exacerbations, in view of their poor efficacy and safety profile, and the greater effectiveness and relative safety of SABA.669 Nausea and/or vomiting are more common with aminophylline.667,669 The use of intravenous aminophylline is associated with severe and potentially fatal side-effects, particularly in patients already treated with sustained-release theophylline. In adults with severe asthma exacerbations, add-on treatment with aminophylline does not improve outcomes compared with SABA alone.669 Magnesium Intravenous magnesium sulfate is not recommended for routine use in asthma exacerbations; however, when administered as a single 2 g infusion over 20 minutes, it reduces hospital admissions in some patients, including adults 136 4. Management of worsening asthma and exacerbations with FEV1 <25-30% predicted at presentation; adults and children who fail to respond to initial treatment and have persistent hypoxemia; and children whose FEV1 fails to reach 60% predicted after 1 hour of care670-672 (Evidence A). Randomized, controlled trials that excluded patients with more severe asthma showed no benefit with the addition of intravenous or nebulized magnesium compared with placebo in the routine care of asthma exacerbations in adults and adolescents673-675 or children.674,676 (Evidence B). Helium oxygen therapy A systematic review of studies comparing helium-oxygen with air-oxygen suggests there is no role for this intervention in routine care (Evidence B), but it may be considered for patients who do not respond to standard therapy; however, availability, cost and technical issues should be considered.677 Leukotriene receptor antagonists (LTRAs) There is limited evidence to support a role for oral or intravenous LTRAs in acute asthma. Small studies have demonstrated improvement in lung function678,679 but the clinical role and safety of these aTgEents requires more study. ICS-LABA The role combinations of these medications in the emergency department or hospital is unclear. ORnIeBUstudy showed that high dose baunddessaofneitdyep-rfoorfimleottoerSoAl iBnAp,a68t0iebnutst minotrheesetumdeiergseanrceyndeeepdaerdtm. Aennot,thaellrosftwudhyomexraeDmcIeSiniTveeddapdrdeidtionnisoolfosnael,mheatdersoilmtoilaOr CefSficfoarcy hospitalized patients, but was not adequately powered to support a recomOmRendation.681 Antibiotics (not recommended) OPY Evidence does not support the routine use of antibiotics in the treTatCment of acute asthma exacerbations unless there is strong evidence of lung infection (e.g. fever or purulent sputumNOor radiographic evidence of pneumonia).638 Sedatives (must be avoided) - DO Sanexdiaotlyiotinc sahnoduhldypbneostticricdtrlyugasv.oAidneadsdsuorciniagtieoxnabceetrwbReaIeAtionLntsheofuassethomf tahebseecadurusgesoaf nthdearveosidpairbatleoraysdthempraesdseaantht sefhfeacst boef en reported.682,683 ATE Non-invasive ventilation (NIV) The evidence regarding the role of NIV EinDaMsthma is weak. A systematic review identified five studies involving 206 epnadrtoictirpaacnhtesawl iinthtuabcauttioensebuvet roenaesstthIuGmdHyaTitdreeantteifdiedwiftehwNeIrVaodrmpislascioenbso.i6n84thTewNoIsVtugdrioeuspf.oNunoddneoatdhisffewreernecreeipnonrteeeddinfoerither study. Given the small size oPf tYhRe studies, no recommendation is offered. If NIV is tried, the patient should be monitored closely receive (NEIvVid(eEnvcideeDn)c.eItDs)hC.oOuld not be attempted in agitated patients, and patients should not be sedated in order to Reviewing response Clinical status and oxygen saturation should be re-assessed frequently, with further treatment titrated according to the patient's response (Box 4-4, p.135). Lung function should be measured after one hour, i.e. after the first three bronchodilator treatments, and patients who deteriorate despite intensive bronchodilator and corticosteroid treatment should be re-evaluated for transfer to the intensive care unit. 4. Management of worsening asthma and exacerbations 137 Criteria for hospitalization versus discharge from the emergency department From retrospective analyses, clinical status (including the ability to lie flat) and lung function 1 hour after commencement of treatment are more reliable predictors of the need for hospitalization than the patient's status on arrival.685,686 Spirometric criteria proposed for consideration for admission or discharge from the emergency department include:687 If pre-treatment FEV1 or PEF is <25% predicted or personal best, or post-treatment FEV1 or PEF is <40% predicted or personal best, hospitalization is recommended. If post-treatment lung function is 40-60% predicted, discharge may be possible after considering the patient's risk factors (Box 4-1, p.125) and availability of follow-up care. If post-treatment lung function is >60% predicted or personal best, discharge is recommended after considering risk factors and availability of follow-up care. Other factors associated with increased likelihood of need for admission include:688-690 Female sex, older age and non-white race Use of more than eight beta2-agonist puffs in the previous 24 hours UTE Severity of the exacerbation >22 breaths/minute, oxygen (e.g. need saturation for resuscitation <95%, final PEF or rapid medical <50% predicted) interveTnRtioIBn on arrival, respiratory rate Past history of severe exacerbations (e.g. intubations, asthma admissions) DIS Previous unscheduled office and emergency department visits requiringOuRse of OCS. Overall, patients these risk factors should with asthma managed in be considered the acute care by clinicians setting. The wpahteiennmt'saskoOincgPiaYdl ecciricsuiomnsstaonncaedsmsihsosuioldn/adlissochbaergceonfosridered. Discharge planning NOT C aPpripoor itnotmdiesncthwaritgheinfr2o-m7 tdhaeyesm(1e-rg2ednacyysdfeopr acrhtmilderennt )o,rahnodsps-titraDaltOetogiheosmtoe,imaprrraonvgeeamsethnmtsasmhoaunladgbeemmenatdiencfolurdainfgollow-up medications, inhaler skills and written asthma action pRlIaAnL, should be addressed (Box 4-5).315 Follow up after emergency department presentAaTtiEon or hospitalization for asthma Following discharge, the good symptom control is patient should achieved and pbeerEsreoDvniaMelwbeedstblyunthgefiur nhcetaioltnh care provider regularly over subsequent is reached or surpassed. Incentives such weeks until as free transport and telephone reminders imIGprHoTve primary care follow up but have shown no effect on long-term outcomes.315 Patients targeted dfoisrcahnaragsethdmfoalloedwuincgataionPneYpmRroegrgraemnc, yif department presentation or hospitalization for asthma one is available. Patients who were hospitalized may should be especially be particularly receptive to information and CadOvice about their illness. Health care providers should take the opportunity to review: The patient's understanding of the cause of their asthma exacerbation Modifiable risk factors for exacerbations (including, where relevant, smoking) (Box 3-8, p.76) The patient's understanding of the purposes and correct uses of medications, including ICS-containing controller The actions the patient needs to take to respond to worsening symptoms or peak flows. After emergency department presentation, comprehensive intervention programs that include optimal controller management, inhaler technique, and elements of self-management education (self-monitoring, written action plan and regular review171) are cost effective and have shown significant improvement in asthma outcomes315 (Evidence B). Referral for expert advice should be considered for patients who have been hospitalized for asthma, or who repeatedly present to an acute care setting despite having a primary care provider. No recent studies are available, but earlier studies suggest that follow-up by a specialist is associated with fewer subsequent emergency department visits or hospitalizations and better asthma control.315 138 4. Management of worsening asthma and exacerbations Box 4-5. Discharge management after hospital or emergency department care for asthma Medications Inhaled corticosteroids (ICS) Initiate ICS prior to discharge, if not previously prescribed (Box 3-4,A-D, p.55 - p.59). Patients currently prescribed ICS-containing medication should generally have their treatment stepped up for 2-4 weeks (Box 4-2, p.129) and should be reminded about the importance of adherence with daily use. Oral corticosteroids (OCS) To reduce the risk of relapse, prescribe at least a 5-7 day course of OCS for adults (prednisolone or equivalent 40-50 mg/day)665and 3-5 days for children (1-2 mg/kg/day to a maximum of 40 mg/day)691 (Evidence A). Review progress before ceasing OCS. If the OCS is dexamethasone, treatment is only for total 1-2 days,658 but if there is failure of resolution, or relapse of symptoms, consideration should be given to switching to prednisolone. For patients considered at risk of Reliever poor adherence, intramuscular corticosteroids may be considered651 medication - return to as-needed rather than regular use (EvidencUe TBE). Transfer patients back to as-needed rather than regular reliever medication usTeR, IbBased on symptomatic and oabirjweacytivheypimeprrreosvpeomnesnivte. nReesgsualanrduisnecroefaSsAedBAeofsoirneovpehnilic1-in2flwameemkastlieoand, swittohbreedtDauI-cSreecdebprtoonr cdhoowdnil-aretogrurleastipoonn, sinec.6r9e2a,6s93edIf ipratropium bromide was used in the emergency department or hospital, itOmRay be quickly discontinued, as it is unlikely to provide ongoing presentation. benefit. Patients prescribed ICS-formoterol as thOeiPr Yreliever should return to this after an ED Risk factors and triggers that contributed to the exacerbatioTnC NO Identify factors factors that may have contributed to the (Box 3-8, p.76). An exacerbation severe eenxoaucge-hrbDtaoOtiroenqaunirde implement strategies to reduce modifiable risk hospitalization may follow irritant or allergen exposure, viral written asthma raecstipoinraptolaryn.inHfeacntdiownass,hininagd,emquaastkesRlaoIAnndLg-steorcmialt/rpehaytmsiceanlt,dpisrtoabnlceimngs with adherence, and/or lack of a is associated with a reduced risk of acquiring viral respiratory infections, includinAgTiEnfluenza. Self-management skills and written aEsDthMma action plan Review Review itnehchalneiqr uteecwhnitihquPeE(FBomIGxeH3te-Tr12if,ups.e8d9.). Provide soon as a written possible aafsttehrmwaaPrYadcRst.ioPnatpielannts(Bdiosxch4a-2rg, epd.1f2ro9m) otrhreeveimewertgheenpcyatdieenpta'srtemxeisntitnwgitphlaann, either action at discharge or plan and PEF as meter have better ouCtcOomes than patients discharged without these resources.694 Evaluate the patient's response to the exacerbation. If it was inadequate, review the action plan and provide written guidance to assist if asthma worsens again.694,695 Review the patient's use of controller treatment before and during the exacerbation. Was it increased promptly and by how much? Were OCS added and if not, why not? Consider providing a short-course of OCS to be on hand for subsequent exacerbations. Follow up appointment A follow-up appointment within 2-7 days of discharge (1-2 days for children) should be made with the patient's usual health care provider, to ensure that treatment is continued, that asthma symptoms are well controlled, and that the patient's lung function reaches their personal best (if known). ICS: inhaled corticosteroids; OCS: oral corticosteroids; PEF: peak expiratory flow 4. Management of worsening asthma and exacerbations 139 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO IBUTE DISTR Y OR Chapter 5. COP T NO O Diagnosis and initial L - D ERIA treatment of adults with MAT features of asthma, COPD GHTED RI or both COPY (`asthma-COPD overlap') KEY POINTS Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous and overlapping conditions `Asthma' and `COPD' are umbrella labels for heterogeneous conditions characterized by chronic airway and/or lung disease. Asthma and COPD each include several different clinical phenotypes, and are likely to have several different underlying mechanisms, some of which may be common to both asthma and COPD. Symptoms of asthma and COPD may be similar, and the diagnostic criteria overlap. Why are the labels `asthma' and `COPD' still important? There are extremely important differences in evidence-based treatment recommendations for asthma and COPD: treatment with LABA and/or LAMA alone (i.e. without inhaled corticosteroids [ICS]) is recommended as initial treatment in COPD but contraindicated in asthma due to the risk of severe exacerbations and death. Tidheenstiefyriasdkusltapreataielsnotssweehno,infoprastaiefenttys,wshhoouhldavneodt biaegntroesaetesdowf bitohthloansgt-hamctainganbdroCnOcUhPoTDdE,ilmataokrsinagloitniem.portant to In COPD, high dose ICS should not be used because of the risk of pneumonTiaR. IB Many patients have features of both asthma and COPD DIS Distinguishing asthma from COPD may have features of both asthma can and be difficult, COPD. particularly in smoOkRers and older adults, and some patients The terms `asthma-COPD overlap' (ACO) or `asthma+COPD' aOrePsYimple descriptors for patients who have features of both asthma and COPD. T C These terms do not are likely caused by refer to a single disease entity. a range of different underlying mTheecyNhaOinncislumdse. patients with several clinical phenotypes that More research is needed to better define these ph-eDnoOtypes and mechanisms, but in the meantime, safety of pharmacologic treatment is a high priority. RIAL Diagnosis Diagnosis in patients with chronic respirAaTtoEry symptoms involves a stepwise approach, first recognizing that the pchaatierancttiesrilsiktieclyCtOoPhDav, ewcithhrfoenaictuareirsEwDoafyMbsodtihseoar shea,vtihnegnosthyenrdrcoomndiciticoantsegsourcizhaatisonbraosncchhiaercatcatseisri.stic asthma, Lung function testing is esseInGtHiaTl for confirming persistent airflow limitation, but variable airflow obstruction can be detected with serial PpeYaRk flow measurements and/or measurements before and after bronchodilator. Initial treatment for safetyCaOnd clinical efficacy For asthma: ICS are essential either alone or in combination with a long-acting bronchodilator (LABA), to reduce the risk of severe exacerbations and death. Do not treat with LABA and/or long-acting muscarinic antagonist (LAMA) alone without ICS. For patients with features of both asthma and COPD, treat as asthma. ICS-containing therapy is important to reduce the risk of severe exacerbations and death. Do not give LABA and/or LAMA alone without ICS. For COPD: Treat according to current GOLD 2021696 recommendations, i.e. initial treatment with LAMA and/or LABA, with as-needed SABA; add ICS for patients with hospitalizations, 2 exacerbations/year requiring OCS, or blood eosinophils 300/l. All patients should be provided with structured education especially focusing on inhaler technique and adherence as well as being assessed for, and receive appropriate treatment for, other clinical problems, including advice about smoking cessation, immunizations, physical activity, and management of comorbidities. Specialist referral for additional investigations is encouraged, as patients with asthma+COPD often have worse outcomes than those with asthma or COPD alone. 142 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap OBJECTIVES The objectives of this section of the GINA report are: o To assist primary care clinicians to identify typical asthma and typical COPD and to recognize when patients have features of both. This is particularly relevant in older patients (40 years or above) o To provide advice about safe and effective initial treatment o To provide guidance on indications for referral for specialist assessment. BACKGROUND TO DIAGNOSING ASTHMA AND/OR COPD IN ADULT PATIENTS Why are the labels `asthma' and `COPD' still important? Asthma and COPD are heterogeneous conditions characterized by airway obstruction. Each of these `umbrella' labels includes several different patterns of clinical features (phenotypes) that may overlap. Each may also include different inflammatory COPD.697 patterns and different underlying mechanisms, some of which may be comUmToEn to both asthma and Temhephmyossetmeaasinilyorldeecor gsmnizoekderpshaerneoctylepaerslyodfisatsinthgmuiashaanbdleC. ORPeDguslautcohryasstuadlleiersgiocfapshtTahrmRmIaBaicnocthheilrdarpeyn/iynoausntghmadaualtnsdaCndOPD are largely restricted to patients with very clearly defined asthma or COPD. HoDwIeSver, in the community, the features of asthma and COPD may overlap, especially in older adults. OR There are extremely important differences in treatment with long-acting bronchodilators alone t(ri.eea.twmitehnoturteIcCoSm) mis eOrenPcdYoamtimonesndfoedr asthma and COPD. In particular, for initial treatment in COPD698 but is contraindicated in asthma due to the risk of severe exacerbationsTaCnd death. 130,235,699,700 Several studies have also shown that patients with diagnoses of both asthma and COPDNOare at increased risk of hospitalization or death if they are treated with LABA compared with ICS-LABA.701-703 Challenges in clinical diagnosis of asthma and COPD- DO Although asthma is characterized by variable expiRraItAoLry airflow limitation, at least initially (Box 1-2, p.23), and COPD is cph.1a4ra4c).teTrhizisedmbeyanpsertshiasttecnlitnaicirafllofewaltiumreitsataiorne,6aA9l8sTotEhiemdpeofrintaitniot nins of asthma and COPD making a diagnosis. are not mutually exclusive (Box 5-1, In children and young adults with chronEicDorMrecurrent respiratory symptoms, the differential diagnosis is different from tlahraytningeoaldl eobr satdruuclttsio. nO)nhcaevienfbeecetinoueIGsxcHdliuTsdeeads,etahendmnoosntpliuklemlyocnharroynciconadiriwtioanysd(ies.ega.sceoningcehniiltdarlehneaanrtddyisoeuansge,aidnudlutsciibsle asthma. PYR HDoiswtinegveuris, hininagdtuhletssewfitrhomaChpOiasttioernytsofwloitnhgC-sOtaPnDdiinsgparosbthlemmaa,7t0ic4,,70e5sppeercsiaisltlyenift tahierfyloawrelimsmitaotkioenrsmoaryhabveefoouthnedr70ri6s-7k10factors for COPD.711-714 On the other hand, patients with COPD may show evidence of reversible airflow obstruction when a rapid- acting bronchodilator is administered, a feature more strongly associated with asthma. In medical records, such patients often are assigned both diagnoses.56,715 In keeping with common usage of the term "overlap" in other contexts, e.g. for the association between COPD with sleep disorders, and in overlap syndromes of collagen vascular disease, the descriptive term `asthma-COPD overlap' is often used. Another common descriptor is `asthma+COPD'. However, to date there are no generally agreed more specific terms or defining features for patients with this combination of diagnoses. `Asthma-COPD overlap' is a descriptor for patients often seen in clinical practice, who comprise a heterogeneous group. It does not mean a single disease entity. 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 143 Prevalence and morbidity of asthma-COPD overlap In epidemiological studies, reported prevalence rates for asthma-COPD overlap have ranged between 9% and 55% of those with either diagnosis, with variation by gender and age;709,716-718 the wide range reflects the different criteria that have been used by different investigators. Concurrent doctor-diagnosed asthma and COPD has been reported in between 15 and 32% of patients with one or other diagnosis.715,719,720 There is broad agreement that patients with features of both asthma and COPD have a greater burden of symptoms,721 experience frequent exacerbations,56,707,721 have poor quality of life,56,716,721 a more rapid decline in lung function,721 higher mortality,707,715 and greater use of healthcare resources56,722 compared with patients with asthma or COPD alone. ASSESSMENT AND MANAGEMENT OF PATIENTS WITH CHRONIC RESPIRATORY SYMPTOMS Box 5-1. Current definitions of asthma and COPD, and clinical description of asthma-COPD overlap Asthma UTE Asthma is a heterogeneous disease, usually characterized by chronic airway inflammaTtiRonIB. It is defined by the history of respiratory symptoms such as wheeze, shortness of breath, chest tightness and coDuISgh that vary over time and in intensity, together with variable expiratory airflow limitation. [GINA 2021] OR COPD OPY Chronic obstructive pulmonary disease (COPD) is a common, prevenTtaCble and treatable disease that is characterized by pbeyrssiigsnteifnictarenst peixraptoosruyresytmo pntooxmiosuasnpdaartiircflleoswolirmgiatasteiosnatnhdatinisfludeunecNteodOabirywhaoysatnfadc/otorraslvinecolluadrinagbnaobrnmoarmlitiaelsluunsgually caused development. [GOLD 2021]696 - DO Asthma-COPD overlap, also called asthma+COPD RIAL `Asthma-COPD overlap' and `asthma +COPD' areATteErms used to collectively describe patients who have persistent airflow This is nlimotitaatdioenfintoitgioenthoefrawsitihngclleindicisael afesaetuerEnetDsitytMh, abtuat raedceosncsriisptteivnet with both asthma and COPD. term for clinical use that includes several different clinical phenotypes reflecting differentIGunHdTerlying mechanisms. 1: History and clinical assessmePnYtRto establish the following: The nature and patternCoOf respiratory symptoms (variable and/or persistent) History of asthma diagnosis; childhood and/or current Exposure history: smoking and/or other exposures to risk factors for COPD The features that are most helpful in identifying and distinguishing asthma from COPD, and the features that should prompt a patient to be treated as asthma to reduce the risk of severe exacerbations and death, are shown in Box 5-2. Caution: Consider alternative diagnoses: Other airways diseases, such as bronchiectasis and chronic bronchitis, and other forms of lung disease such as interstitial lung disease may present with some of the above features. The approach to diagnosis provided here does not replace the need for a full assessment of patients presenting with respiratory symptoms, to first exclude non-respiratory diagnoses such as heart failure.16 Physical examination may provide supportive information. 144 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap Box 5-2. Approach to initial treatment in patients with asthma and/or COPD IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO GOLD: Global Initiative for Obstructive Lung Disease; ICS: inhaled corticosteroid; LABA: long-acting 2-agonist; LAMA: long-acting muscarinic antagonist 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 145 2: Lung function testing is essential to confirm the following: The presence of persistent expiratory airflow limitation Variable expiratory airflow limitation Spirometry is preferably performed at the initial assessment. In cases of clinical urgency it may be delayed to a subsequent visit, but confirmation of diagnosis may be more difficult once patients are started on ICS-containing therapy (see Box 1-3, p.26). Early confirmation (or exclusion) of the presence of persistent expiratory airflow limitation may avoid needless trials of therapy, or delays in initiating other investigations. Spirometry can confirm both persistent airflow limitation and reversibility (Box 5-2, p.145, Box 5-3, p.146). Measurement of peak expiratory flow (PEF), if performed repeatedly on the same meter over a period of 1-2 weeks, may help to confirm reversible airflow limitation and the diagnosis of asthma by demonstrating excessive variability (Box 1-2, p.23). However, PEF is not as reliable as spirometry, and a normal PEF does not rule out either asthma or COPD. Box 5-3. Spirometric measures in asthma and COPD UTE TRIB Spirometric variable Asthma COPD DIS Asthma+COPD Normal FEV1/FVC pre- or post BD Compatible with asthma Not compatible wOiRth COPD Not compatible Reduced post-BD FEV1/FVC Indicates airflow limitation Required fOorPdYiagnosis of Required for diagnosis of (< lower limit of normal, or <0.7 (GOLD)) but may improve spontaneously or on treatment CONPODT C O asthma+COPD Post-BD FEV1 80% predicted Casotmhmpaati(bgloeowditahsdthiamganosisLo-f DCompatible with mild persistent airflow limitation if Compatible with mild persistent airflow limitation control or interval symptoms) betEwReIeAn post-BD FEV1/FVC is reduced if post-BD FEV1/FVC is reduced Post-BD FEV1 <80% predicted Casotmhmpaat.ibRleiskwiftahcMtdoAiarTgfonrosis of An indicator of severity of airflow limitation and risk of As for COPD and asthma asthma exTacEeDrbations future events (e.g. mortality and COPD exacerbations) Gt Hsome time in course Common and more likely Common and more likely Post-BD increase in FEV1 >12% and 200 mL from baseline (reversible airflow UofsauYsaRtlhIama, but may not be when FEV1 is low prPesent when well-controlled when FEV1 is low limitation). COor on controller therapy Post-BD increase in FEV1 High probability of asthma Unusual in COPD Compatible with >12% and 400 mL from asthma+COPD baseline (marked reversibility) BD: bronchodilator; FEV1: forced expiratory volume in 1 second; FVC: forced vital capacity; GOLD: Global Initiative for Obstructive Lung Disease. 146 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 3: Selecting initial treatment (See Box 5-2, p.145) For asthma Commence treatment as described in Chapter 3 (Box 3-4,A-D, p.55 - p.59). Pharmacotherapy is based on ICS to reduce the risk of severe exacerbations and death and to improve symptom control, with add-on treatment as required, e.g. add-on LABA and/or LAMA. As-needed low dose ICS-formoterol may be used as the reliever, on its own in mild asthma or in addition to maintenance ICS-formoterol in patients with moderate-severe asthma prescribed maintenance and reliever therapy (see Box 3-5A, p.61). Inhaled therapy should be optimized to minimize the need for oral corticosteroids (OCS). For COPD Commence treatment as in the current GOLD strategy report.696 Pharmacotherapy starts with symptomatic treatment with long-acting bronchodilators (LABA and/or LAMA). ICS may be added as per GOLD for patients with hmoosnpoittahleizraatpioynws,itho2uetxLaAcBerAbaatniodn/osr/yLeAaMr rAe.qIunihrianlgedOtChSer,aoprybslohooduledobseinooppthimilsize3d0t0o/reLd, ubcuet TitshEenonteuesdedfoar lOonCeSa. sIn patients with features of COPD, high dose ICS should be avoided because of the risk of RIBU pneumonia.723,724 For patients with features of asthma and COPD DIST Start treatment as ICS play a pivotal rfoolreaisnthpmreave(Bntoinxg3m-4o,Arb-Did,itpy.a5n5d-epv.e5n9)duenattihl fiunrtphaetrieinnvtseswOtiigtRhatuionncsonhtarovlelebdeaesnthpmerafosrymmepdt.oms, for whom even seemingly `mild' symptoms (compared to those of moderate or OsePvYere COPD) might indicate significant risk of a life-threatening Box 3-6, p.63), attack.725 For patients depending on level of swyimthpatosmthsmaan+dCrOisPkDo,fIaCdSvesTrhsoeCueldffebcetsu,siendcliunditiinagllypinneaumloownoiar. medium dose (see NO Patients with and/or LAMA features or diagnosis of both asthma and to provide adequate symptom control. C- ODOPD will usually also require add-on treatment with LABA Patients with any case-control study ifneactoumremsuonfityasptahtmienatsshwoituhldnenwoRltyIAbdLeiatgrneoasteedd with LABA and/or LAMA alone, COPD found that those who also without ICS. A had a diagnosis large of asthma had a lower risk of COPD hospitalizatAioTnEs and death if treated with combination ICS-LABA than with LABA alo as ne.701 In another lar having asthma with gCeOrPetDrohsapdeclotivweeErlomDngoMirtbuiddiintya l population and hospita cohort s lizations tudy of if they patients received aged 66 years, ICS treatment; a those recorded similar benefit was seen in those with COPD pluIsGcHoTncurrent asthma.703 All patients with Provide advice, cahs rdoensiccriabierfdlPoinYwRthliemGitaINtiAonand GOLD reports, about: Treatment of modifiCaOble risk factors including advice about smoking cessation Treatment of comorbidities Non-pharmacological strategies including physical activity, and, for COPD or asthma-COPD overlap, pulmonary rehabilitation and vaccinations Appropriate self-management strategies Regular follow-up In a majority of patients, the initial management of asthma and COPD can be satisfactorily carried out at primary care level. However, both the GINA and GOLD strategy reports recommend referral for further diagnostic procedures at relevant points in patient management (see below). This may be particularly important for patients with features of both asthma and COPD, given that this is associated with worse outcomes and greater health care utilization. 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 147 4: Referral for specialized investigations (if necessary) Referral for expert advice and further diagnostic evaluation is advised in the following contexts: Patients with persistent symptoms and/or exacerbations despite treatment. Diagnostic uncertainty, especially if an alternative diagnosis (e.g. bronchiectasis, post-tuberculous scarring, bronchiolitis, pulmonary fibrosis, pulmonary hypertension, cardiovascular diseases and other causes of respiratory symptoms) needs to be investigated. Patients with suspected asthma or COPD in whom atypical or additional symptoms or signs (e.g. haemoptysis, significant weight loss, night sweats, fever, signs of bronchiectasis or other structural lung disease) suggest an additional pulmonary diagnosis. This should prompt early referral, without waiting for a trial of treatment for asthma or COPD. When chronic airways disease is suspected but syndromic features of both asthma and COPD are few. Patients with comorbidities that may interfere with the assessment and management of their airways disease. Referral may also be appropriate COPD overlap, as outlined in the for issues GINA and arising GOLD during ongoing management strategy reports. of aUstThEma, COPD or asthma- Box 5-4 (p.148) summarizes specialized investigations that are sometimes used to disTtRinIgBuish asthma and COPD. DIS Box 5-4. Specialized investigations sometimes used in distinguishing aOstRhma and COPD Lung function tests Asthma OPY T C COPD DLCO Normal (or slightly elevated) NO Often reduced Arterial blood gases Normal between exacerba-tiDonOs May be chronically abnormal between exacerbations in more severe forms of COPD Airway hyperresponsiveness Not useful on RitsIAoLwn in distinguishing asthma from COPD, but higher levels (AHR) ATE of AHR favor asthma Imaging High resolution CT Scan Usually noErmDaMl but air trapping and Low attenuation areas denoting either air trapping increIaGsHeTd bronchial wall thickness or emphysematous change can be quantitated; PmYaRy be observed. bronchial wall thickening and features of pulmonary hypertension may be seen. Inflammatory biomarkers CO A positive test for atopy (specific IgE and/or skin prick test to aeroallergens) Increases probability of allergic asthma; not essential for diagnosis of asthma Conforms to background prevalence; does not rule out COPD FeNO A high level (>50 ppb) in nonsmokers is moderately associated with eosinophilic airway inflammation. Usually normal Low in current smokers Blood eosinophilia Supports diagnosis of eosinophilic May be present in COPD including during airway inflammation exacerbations Sputum inflammatory cell analysis Role in differential diagnosis is not established in large populations. DLCO: diffusing capacity of the lungs for carbon monoxide; FeNO: fractional concentration of exhaled nitric oxide; IgE: immunoglobulin E 148 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap FUTURE RESEARCH There is an urgent need for more research on this topic, in order to guide better recognition and safe and effective treatment. Patients who do not have `classical' features of asthma or of COPD, or who have features of both, have generally been excluded from randomized controlled trials of most therapeutic interventions for airways disease, and from many mechanistic studies. Future research should include study of clinical and physiological characteristics, biomarkers, outcomes and underlying mechanisms, among broad populations of patients with respiratory symptoms or with chronic airflow limitation. In the meantime, the present chapter provides interim advice about diagnosis and initial treatment, for the perspective of clinicians, particularly those in primary care and nonpulmonary specialties. Further research is needed to inform evidence-based definitions and a more detailed classification of patients who present overlapping features of asthma and COPD, and to encourage the development of specific interventions for clinical use. IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO 5. Diagnosis and initial treatment of asthma, COPD and asthma-COPD overlap 149 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO SECTION 2. CHILDREN 5 YEARS AND YOUNGER IBUTE DISTR Y OR Chapter 6. COP NOT - DO Diagnosis and AL management of asthma ATERI HTED M in children 5 years and younger PYRIG CO PART A. DIAGNOSIS KEY POINTS Recurrent wheezing occurs in a large proportion of children 5 years and younger, typically with viral upper respiratory tract infections. Deciding when this is the initial presentation of asthma is difficult. Previous classifications of wheezing phenotypes (episodic wheeze and multiple-trigger wheeze; or transient wheeze, persistent wheeze and late-onset wheeze) do not appear to identify stable phenotypes, and their clinical usefulness is uncertain. However, emerging research suggest that more clinically relevant phenotypes will be described and phenotype-directed therapy possible. A diagnosis of asthma in young children with a history of wheezing is more likely if they have: o Wheezing or coughing that occurs with exercise, laughing or crying, or in the absence of an apparent respiratory infection o A history relatives of other allergic disease (eczema or allergic rhinitis), allergen sensitizatioUnToEr asthma in first-degree o Clinical improvement during 2-3 months of controller treatment, and worseninTgRaIBfter cessation. ASTHMA AND WHEEZING IN YOUNG CHILDREN DIS Asthma is the most common chronic disease of childhood and the leading cauOsRe of childhood morbidity from chronic disease as measured early childhood; in up by school absences, to half of people with eamsthermgae,nscyymdpetpoamrtsmceonmt vmiseitnsOcaePndYdurhionsgpcithailldizhaotioodn.s7.27726OAnsstehtmoaf aosftthenmbaeisgins in earlier in males than females.728-730 T C No intervention has yet been shown to prevent the developmentNofOasthma or modify its long-term natural course. Atopy ipsaprtriecuselanrtlyinmthueltipmleajeoarirtlyy-oliffechsieldnrseintizwaittihonass)thismoanwe hoof tahreemo-voeDsrtO3imypeoarrtsanotldri,saknfadcatollersrgfeonr -thspeedceifvicelsoepnmseitinztaotifoans(tahnmda.731 RIAL Viral-induced wheezing Recurrent wheezing occurs in a large proportionAoTf cEhildren aged 5 years or younger. It is typically associated with upper respiratory tract infections (URTI), which ocEcDurMin this age group around 6-8 times per year.732 Some viral infections (respiratory syncytial age group is a highly virus heter oagnednrehoinuosvIciGrouHnsd)Tiatiroena, sasnodcniaotteadllwwithhereezciunrgreinndt iwcahteeeszaestthhrmouag. hAoulat rcgheildphroopoodr.tiWonhoefewzihnegeizninthgis wepitihsoadreessipniryaotournygincfheicldtiroenn iiss tvruiralPyllYyaRninidsuoclaetdedwehveethnet rotrhreepcrheilsdehnatss aasrtehcmurareonrtncolitn. iTchael prerefosreen, tdaeticoindionfgcwhhildehnowodheaeszthinmga may be difficult.730,733 In childCreOn aged under 1 year, bronchiolitis may present with wheeze. It is usually accompanied by other chest signs such as crackles on auscultation. Wheezing phenotypes In the past, two main classifications of wheezing (called `wheezing phenotypes') were proposed: Symptom-based classification:734 this was based on whether the child had only episodic wheeze (wheezing during discrete time periods, often in association with URTI, with symptoms absent between episodes) or multiple-trigger wheeze (episodic wheezing with symptoms also occurring between these episodes, e.g. during sleep or with triggers such as activity, laughing, or crying). Time trend-based classification: this system was initially based on retrospective analysis of data from a cohort study.730 It included transient wheeze (symptoms began and ended before the age of 3 years); persistent wheeze (symptoms began before the age of 3 years and continued beyond the age of 6 years), and late-onset wheeze (symptoms began after the age of 3 years). These general patterns have been confirmed in subsequent studies using unsupervised statistical approaches.735,736 152 6. Diagnosis and management of asthma in children 5 years and younger However, prospective allocation of individual children to these phenotypes has been challenging in `real-life' clinical situations, and the clinical usefulness of these, and other, classification and asthma prediction systems remain a subject of active investigation. For example, one study conducted in a research setting with high medication adherence found that daily ICS treatment reduced exacerbations in pre-school children characterized as `sensitization with indoor pet exposure' or `multiple sensitization with eczema', but not among those characterized as `minimal sensitization' or `sensitization with tobacco smoke exposure'.737 CLINICAL DIAGNOSIS OF ASTHMA It may be challenging to make a confident diagnosis of asthma in children 5 years and younger, because episodic respiratory symptoms such as wheezing and cough are also common in children without asthma, particularly in those 0- 2 years old,738,739 and it is not possible to routinely assess airflow limitation or bronchodilator responsiveness in this age group. A probability-based approach, based on the pattern of symptoms during and between viral respiratory infections,740 may be helpful for discussion with parents/carers (Box 6-1 & 2). This allows individual decisions to be made aebithoeurt owvheert-hoerr utondgeivre-traeatrtimaleonft.controller treatment. It is important to make decisions fIoBrUeTacEh child individually, to avoid Box 6-1. Probability of asthma diagnosis in children 5 years and younger DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO Symptoms suggestive of asthma in children 5 years and younger As shown in Box 6-1 and Box 6-2/2A an asthma diagnosis in children 5 years and younger can often be based on: Symptom patterns (recurrent episodes of wheeze, cough, breathlessness (typically manifested by activity limitation), and nocturnal symptoms or awakenings) Presence of risk factors for development of asthma, such as family history of atopy, allergic sensitization, allergy or asthma, or a personal history of food allergy or atopic dermatitis Therapeutic response to controller treatment. Exclusion of alternate diagnoses. 6. Diagnosis and Management of asthma in children 5 years and younger 153 Box 6-1 is a schematic figure showing the estimated probability of an asthma diagnosis741,742 in children aged 5 years or younger who have viral-induced cough, wheeze or heavy breathing, based on the pattern of symptoms. Many young children wheeze with viral infections and deciding when a child should be given controller treatment may be difficult. The frequency and severity of wheezing episodes and the temporal pattern of symptoms (only with viral colds or also in response to other triggers) should be taken into account. Any controller treatment should be viewed as a treatment trial, with follow up scheduled after 2-3 months to review the response. Review is also important since the pattern of symptoms tends to change over time in a large proportion of children. A diagnosis of asthma in young children is therefore based largely on recurrent symptom patterns combined with a careful clinical assessment of family history and physical findings with careful consideration of the differential diagnostic possibilities. A positive family history of allergic disorders, or the presence of atopy or allergic sensitization provide additional predictive support, as early allergic sensitization increases the likelihood that a wheezing child will develop persistent asthma.731 UTE Box 6-2. Features suggesting a diagnosis of asthma in children 5 years and youTnRgIBer Cough Feature Recurrent or persCishteanrat cntoenr-ipsrtoicdsucstuiDvgeIgSceosutignhgthaastthmmaay be worse at night or accompanied by wheezing anOdRbreathing difficulties Cough occurring with smoke, particularly in ethxeeraOcbisPseeY,nlcaeugohf ianng,acprpyainrgenotrreexsppoirsautorerytointfoebctaiocnco T C Wheezing lRaeucguhrinregn,tcwryhinegezoinr Nge,xOipnocsluudreintgodtoubriancgcsolesempookrewoirthatirrigpgoellurstiosnuch as activity, Difficult or heavy breathing or Occurring wit-hDeOxercise, laughing, or crying shortness of breath RIAL Reduced activity tNiroeAtsrTueEannrliienrg,dpulrainyginwg aolrksla(uwgahnintsg at to the same intensity be carried) as other children; Past or family history EDOMther allergic disease (atopic dermatitis or allergic rhinitis, food allergy). Therapeutic trial with low dose ICS IGHT Asthma in first-degree relative(s) Clinical improvement during 2-3 months of controller treatment and COPYR (Box 6-5, p.165), and as-needed SABA worsening when treatment is stopped ort-acting beta -agonist ICS: inhaled corticosteroid; SABA: sh 2 154 6. Diagnosis and management of asthma in children 5 years and younger Box 6-2A. Questions that can be used to elicit features suggestive of asthma Does your child have wheezing? Wheezing is a high-pitched noise which comes from the chest and not the throat. Use of a video questionnaire,743 or asking a parent to record an episode on a smartphone if available can help to confirm the presence of wheeze and differentiate from upper airway abnormalities. Does your child wake up at night because of coughing, wheezing, or `difficult breathing', `heavy breathing', or `breathlessness? Does your child have to stop running, or play less hard, because of coughing, wheezing or `difficult breathing', `heavy breathing', or `shortness of breath'? Does your child cough, wheeze or get `difficult breathing', `heavy breathing', or `shortness of breath' when laughing, crying, playing with animals, or when exposed to strong smells or smoke? Has your child ever had eczema, or been diagnosed with allergy to foods? Hpraosblaenmyso?ne in your family had asthma, hay fever, food allergy, eczema, or anIByUoTthEer disease with breathing Wheeze ISTR Wheeze is the most common and specific symptom associated with asthma inDchildren 5 years and younger. Wheezing occurs in several different patterns, but a wheeze that occurs recurrently, dOuRring sleep, or with triggers such as activity, alanuygnhoinisgy, obrrecarythiningg, iassco`wnhseisetezinntgw'.7it4h4 aSdoimagencouslitsuroefsadstohmnoat.hCalvineicaiCawnOocProdYnffoirrmwahtieoenzies. important, as parents may describe Wheezing may be interpreted differently Who observes it (e.g. parent/carer based on: versus the health caNreOpTrovider) The environmental involve the lung) context (e.g. high income coun-tDrieOs versus areas with a high prevalence of parasites that dTihaegncousltiusraalncdotnreteaxttm(een.gt.otfhreersepliarativtoeryimtrpaocrttRadniIsAceeLasoef sceinrtagiennseyrmal)p.toms can differ between cultures, as can the Cough ATE Cough due to asthma is generally non-pErDodMuctive, recurrent and/or persistent, and is usually accompanied by wheezing ecopuisgohde(wshaenndtbhreecahthilidngisdaifsfilceuelpti)eosI.rGAaHllcTeorguigchrhthinaittioscmcuarysbweitahsesxoecricaitseed, wlaiuthghcoinuggohrincrtyhinega,binsethneceabosf eanscthemoaf.aAn naopcptaurrennatl respiratory associated iwniftehctciooun,ghsuinpgp.oPrtrsPolYaonRdgiaegdncoosuisgohfinasinthfamnac.yT, haendcocmoumgohnwcitohldouatncdolodthseyrmrpetsopmirsa,toarryeilalnsessosceiasteadrewaitlhsolater parent-reported physicianC-dOiagnosed asthma, independent of infant wheeze. Characteristics of cough in infancy may be early markers of asthma susceptibility, particularly among children with maternal asthma.745 Breathlessness Parents may also use terms such as `difficult breathing', `heavy breathing', or `shortness of breath'. Breathlessness that occurs during exercise and is recurrent increases the likelihood of the diagnosis of asthma. In infants and toddlers, crying and laughing are equivalent to exercise in older children. Activity and social behavior Physical activity is an important trigger of asthma symptoms in young children. Young children with poorly controlled asthma often abstain from strenuous play or exercise to avoid symptoms, but many parents are unaware of such changes in their children's lifestyle. Engaging in play is important for a child's normal social and physical development. For this reason, careful review of the child's daily activities, including their willingness to walk and play, is important when assessing a potential asthma diagnosis in a young child. Parents may report irritability, tiredness and mood changes in their child as the main problems when asthma is not well controlled. 6. Diagnosis and Management of asthma in children 5 years and younger 155 TESTS TO ASSIST IN DIAGNOSIS While no tests specifically and definitively diagnose asthma with certainty, in children 5 years and younger, the following are useful adjuncts. Therapeutic trial A trial of treatment for at least 2-3 months with as-needed short-acting beta2-agonist (SABA) and regular low dose inhaled corticosteroids (ICS) may provide some guidance about the diagnosis of asthma (Evidence D). Response should be evaluated by symptom control (daytime and night-time), and the frequency of wheezing episodes and exacerbations. Marked clinical improvement during treatment, and deterioration when treatment is stopped, support a diagnosis of asthma. Due to the variable nature of asthma in young children, a therapeutic trial may need to be repeated in order to be certain of the diagnosis. Tests for allergic sensitization TE Sensitization sensitization to allergens is present in can the be assessed using majority of children weiitthhearsstkhimn aproicnkcetetshtienygaorreaollveergr e3ny-esapRrescIBiofiUfcaimgem; uhonwogelvoebru,lainbEse. nAclleerogfic sensitization predictor for to common aeroallergens development of persistent does not rule asthma.746 out a diagnosis of asthma. ADlleISrgTic sensitization is the best Chest X-ray OR Radiographs are rarely indicated; however, if there is doubt about the diOagPnYosis of asthma in a wheezing or coughing child, a plain chest X-ray may help to exclude structural abnormalitieTs C(e.g. congenital lobar emphysema, vascular ring) cbheraopnpicroinpfreiactteio,ndsespuecnhdiansgtounbethrceucloosnisd,itaionninbheainlegdcofonrseiidgenrebdo.dOy, NorOother diagnoses. Other imaging investigations may Lung function testing IAL - D tDeusetintgo,tbhreoinncahbiaililtyproofvmocoasttiocnhitledsretinng5, yaenadrsotahnedr pyhoTyuEsnRigoelorgtiocapletrefostrsmdroepnrootdhuacvibelea emxapjiorartroorlyeminatnheeudvieargsn, olusnisgofuf nacsttihomn a at this age. However, by 5 years of age, many MchAildren are capable of performing reproducible spirometry if coached by an experienced technician and with visuaTl iEnDcentives. Exhaled nitric oxide IGH aMgeeasguroreump eanntdocfufrrarecntitolynarel mcoanincsePnpYtrrRiamtiaornilyofaerxehsaelaerdchnittoriocl.oFxiedNeO(FceaNnOb)eismneoatswuirdeedlyinavyaoiulanbglechfoildr rmenoswt icthhitldidraelnbirneaththising, and normal reference valuesChOave been published for children aged 1-5 years.747 In pre-school children with recurrent coughing and wheezing, an elevated FeNO recorded 4 weeks from any URTI predicted physician-diagnosed asthma at school age,748 and increased the odds for wheezing, asthma and ICS use by school age, independent of clinical history and presence of specific IgE.749 Risk profiles A number of risk profile tools aimed at identifying which wheezing children aged 5 years and younger are at high risk of developing persistent asthma symptoms have been evaluated for use in clinical practice. However, these tools have shown limited performance for clinical practice. Only three prediction tools have been externally validated (Asthma Predictive Index750 from Tucson, USA, PIAMA index675 from the Netherlands, and Leicester tool751 from the UK), and a systematic review has shown that these tools have poor predictive accuracy, with variation in sensitivity and positive predictive value.752 Larger predictive studies using more advanced statistical methods, and with objective measurements for asthma diagnosis, are probably needed to propose a practical tool in clinical care to predict persistent asthma in recurrent wheezers in infancy and pre-school age. The role of these tools is to help identify children at greater risk of 156 6. Diagnosis and management of asthma in children 5 years and younger developing persistent asthma symptoms, not as criteria for the diagnosis of asthma in young children. Each tool demonstrates different performance characteristics with varying criteria used to identify risk.753 DIFFERENTIAL DIAGNOSIS A definite diagnosis of asthma in this young age group is challenging but has important clinical consequences. It is particularly important in this age group to consider and exclude alternative causes that can lead to symptoms of wheeze, cough, and breathlessness before confirming an asthma diagnosis (Box 6-3).738 Box 6-3. Common differential diagnoses of asthma in children 5 years and younger Condition Typical features Recurrent viral respiratory Mainly cough, runny congested nose for <10 days; no symptoms between infections tract infections UTE Gastroesophageal reflux Cough feeds; when feeding; poor response recurrent chest infections; to asthma medications vomTiRtsIBeasily especially after large Foreign body aspiration Episode of abrupt, severe cough and/or stridor dDuIrSing eating or play; recurrent chest infections and cough; focal lung signs OR Persistent bacterial Persistent wet cough; poor response tOo PasYthma medications bronchitis T C Tracheomalacia Noisy breathing when crying orNeOating, or during upper airway infections (noisy inspiration irfeetrxatcratitohno;rasycmicpotroemxspoirfattei-onDnpOirfeisnetrnatthsoinrcaecibc)ir;thh;arpsohocr oreusgpho; ninsseptioraatosrtyhmoraemxpeidraictoartiyons Tuberculosis Persistent noisy resRpIiAraLtions and cough; fever unresponsive to normal antibiotics; econnlatragcet dwliythmspohAmTneoEodnees;wphooorharesstpuobnesrceutloosbirsonchodilators or inhaled corticosteroids; Congenital heart disease Cardiac mEDurmMur; cyanosis when eating; failure to thrive; tachycardia; tachypnea or Cystic fibrosis YCh(mReopauIGalgathHbomsTsotearpgrtatiinolygn;)sp;holoooorrtslryeeasgfprteeoranssbyeirtbthou; larkesycthsumtroreaonlsmt cehdeicsattiinofnesctions; failure to thrive Primary ciliary dyskinesiaCOPCough and recurrent chest infections; neonatal respiratory distress, chronic ear infections and persistent nasal discharge from birth; poor response to asthma medications; situs inversus occurs in about 50% of children with this condition Vascular ring Persistently noisy breathing; poor response to asthma medications Bronchopulmonary dysplasia Infant born prematurely; very low birth weight; needed prolonged mechanical ventilation or supplemental oxygen; difficulty with breathing present from birth Immune deficiency Recurrent fever and infections (including non-respiratory); failure to thrive 6. Diagnosis and Management of asthma in children 5 years and younger 157 Key indications for referral of a child 5 years or younger for further diagnostic investigations or therapeutic decisions Any of the following features suggest an alternative diagnosis and indicate the need for further investigations: Failure to thrive Neonatal or very early onset of symptoms (especially if associated with failure to thrive) Vomiting associated with respiratory symptoms Continuous wheezing Failure to respond to asthma medications (inhaled ICS, oral steroids or SABA) No association of symptoms with typical triggers, such as viral URTI Focal lung or cardiovascular signs, or finger clubbing Hypoxemia outside context of viral illness. IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO 158 6. Diagnosis and management of asthma in children 5 years and younger PART B. ASSESSMENT AND MANAGEMENT KEY POINTS The goals of asthma management in young children are similar to those in older patients: o To achieve good control of symptoms and maintain normal activity levels o To minimize the risk of asthma flare-ups, impaired lung development and medication side-effects. Wheezing episodes in young children should be treated initially with inhaled short-acting beta2-agonists (SABA), regardless of whether the diagnosis of asthma has been made. However, for initial episodes of wheeze in children <1 year in the setting of infectious bronchiolitis, SABAs are generally ineffective. A trial of controller therapy should be given if the symptom pattern suggests asthma, alternative diagnoses have been excluded and respiratory symptoms are uncontrolled and/or wheezing episodes are frequent or severe. Response to treatment should be reviewed before deciding whether to continue it. If the response is absent or incomplete, reconsider alternative diagnoses. The choice of inhaler device should be based on the child's age and capability. TUhTeEpreferred device is a pressurized metered dose inhaler and spacer, with face mask for <3 yearsTaRndIBmouthpiece for most children aged 3-5 years. Children should demonstrate good technique. be switched from a face mask to mouDthIpSiece as soon as they are able to Review the need for asthma treatment frequently, as asthma-like sOymRptoms remit in many young children. GOALS OF ASTHMA MANAGEMENT OPY As with other age groups, the goals of asthma management in yoTunCg children are: To achieve good control of symptoms and maintain norNmOal activity levels To minimize future risk; that is to reduce the risk o-fDflaOre-ups, maintain lung function and lung development as close Maintaining tnoonrmoraml aacl taivsitpyolsesviebllse,isapnadrmticiunliamrilzyeimmRpeoIdAritLcaanttioinn side-effects. young children because engaging in play is important for their normal social and physical developmentA. ITt Eis important to also elicit the goals of the parent/carer, as these may differ from The goals conventional medical goals. of asthma management are aEcDhieMved through a partnership between the parent/carer and the health professional team, with a cycle of:IGHT AAsdsjuesststr(edaiatmgneonstis(m, seydmiPcpaYttoRiomnsc,onnotrno-lp, hriasrkmfaacctoolorsg,icinahl aslterar tteegcihensi,qauned, atrdehaetmreenncteo, fpmaroednitfiparbeleferriesnkcfea)ctors) Review response inCcOluding medication effectiveness and side-effects. This is carried out in combination with: Education of parent/carer, and child (depending on the child's age) Skills training for effective use of inhaler devices and encouragement of good adherence Monitoring of symptoms by parent/carer A written personalized asthma action plan. ASSESSMENT OF ASTHMA What does `asthma control' mean? Asthma control means the extent to which the manifestations of asthma are controlled, with or without treatment.24,65 It has two components (Box 6-4, p.160): the child's asthma status over the previous four weeks (current symptom control), and how asthma may affect them in the future (future risk). In young children, as in older patients, both symptom control and future risk should be monitored (Evidence D). The rationale for this is described on p.38. 6. Diagnosis and management of asthma in children 5 years and younger 159 Assessing asthma symptom control Defining satisfactory symptom control in children 5 years and younger depends on information derived from family members and carers, who may be unaware either of how often the child has experienced asthma symptoms, or that their respiratory symptoms represent uncontrolled asthma. Few objective measures to assess symptom control have been validated for children <4 years. The Childhood Asthma Control Test can be used for children aged 4-11 years.88 The Test for Respiratory and Asthma Control in Kids (TRACK) is a validated questionnaire for caregiver completion for preschool aged children with symptoms consistent with asthma; it includes both symptom control and courses of systemic corticosteroids in the previous year.92 Box 6-4 shows a working schema for assessing asthma control in children 5 years, based on current expert opinion. It incorporates assessment of symptoms; the child's level of activity and their need for reliever/rescue treatment; and assessment of risk factors for adverse outcomes (Evidence D). Box 6-4. GINA assessment of asthma control in children 5 years and younger UTE A. Symptom control LWeevlelTl RofIBasthmPaarstlyymptom control In the past 4 weeks, has the child had: conDtrIoSlled controlled Uncontrolled Daytime asthma symptoms for more than a few minutes, more than once a week? Yes No OR Any activity limitation due to asthma? (Runs/plays less Yes NoOPY None 1-2 3-4 SABthAanreolitehveerrcmhielddriecna,tiotirnenseeeadseildy*dmuroinreg twhaanlkso/npclaeyainwg?e)ek?YesOTNCo of these of these of these Any night waking or night coughing due to asthma? YOesN No B. Future risk for poor asthma outcomes L - D Risk factors for asthma exacerbations within thEeRnIeAxt few months Uncontrolled asthma symptoms MAT One The sotramrt oorfethseevcehriled'esxuascuearbl a`fltaiorens-u(pTE'EDsDeaatsteonnd(aenscpee,chiaolslypiitfaaliuztautmionn/,faolrl)course of OCS) in previous year Epextpso, smuorelds):,teosbpaecccioalslymionkceo;minbRdinoIGaotrHioonr outdoor air pollution; with viral infection754 indoor allergens (e.g. house dust mite, cockroach, MPoaojorrapdshyecrheonlcoegiwcaitlhocrosnotOcroiPoll-Yeercmoneodmiciactiporno,boler minscoforrreccht iilndhoarlefar mteiclyhnique Outdoor pollution (NO2 Cand particles)108 Risk factors for persistent airflow limitation Severe asthma with several hospitalizations History of bronchiolitis Risk factors for medication side-effects Systemic: Frequent courses of OCS, high dose and/or potent ICS Local: moderate/high dose or potent ICS; incorrect inhaler technique; failure to protect skin or eyes when using ICS by nebulizer or spacer with face mask ICS: inhaled corticosteroids; OCS: oral corticosteroids; SABA: short-acting beta2-agonist; * Excludes reliever taken before exercise Before stepping up treatment, ensure that the child's symptoms are due to asthma, and that the child has good inhaler technique and good adherence to existing treatment. 160 6. Diagnosis and management of asthma in children 5 years and younger Assessing future risk of adverse outcomes The relationship between symptom control and future risk of adverse outcomes, such as exacerbations (Box 6-4, p.160), has not been sufficiently studied in young children. Although exacerbations may occur in children after months of apparently good symptom control, the risk is greater if current symptom control is poor. Preschool children at high risk of asthma (based on modified API) who were treated with daily low dose ICS experienced fewer days with asthma symptoms and a reduced risk of exacerbations than those receiving placebo.755 The future risk of harm due to excessive doses of inhaled or systemic corticosteroids must also be avoided. This can be minimized by ensuring that the prescribed treatment is appropriate and reduced to the lowest dose that maintains satisfactory symptom control and minimizes exacerbations. The child's height should be measured and recorded at least yearly, as growth velocity may be lower in the first 1-2 years of ICS treatment,127 and poorly controlled asthma can affect growth.126 The minimum effective dose of ICS to maintain good asthma control should be used. If decreased growth velocity is seen, other factors should be considered, including poorly controlled asthma, frequent use of oral corticosteroids, and poor nutrition, and referral should be considered. TE If ICS is delivered through a face-mask shortly after inhalation in order to avoid or nebulizer, the skin on the nose and local side-effects such as steroid rash (arreodudneRdnItiBnhUge mouth should and atrophy). be cleaned MEDICATIONS FOR SYMPTOM CONTROL AND RISK REDUCTION DIST Choosing medications for children 5 years and younger OR Good control of asthma can be achieved in the overwhelming majoritOy PoYf young children with a pharmacological intervention strategy.756 This should be developed in a partnershiTp bCetween the family/carer and the health care provider. oAtshewritkheoyldceormcphoilnderenntsainncdluaddeuletsd,umcaetdioicna,tsioknilslsctoraminpirnisgefoornilnyhNoanOleercdoemvipcoenseanntdofaadshtehrmenacme,annoang-epmhaernmt aincoyloougnicgacl hildren; strategies including environmental control where approp-riDatOe, regular monitoring, and clinical review (see later sections in this chapter). When recommending treatment for a young child,RbIoAthL general and individual questions apply (Box 3-3, p.50). What is the `preferred' medication optioAnTaEt each treatment step to control asthma symptoms and minimize future oribsks?erTvahteiosneadledcaistaio. nSstaurdeiebsassuegdgEoenDstdMtahtaat fcoornesfifdicearcayti,oenffoefcftaivcetonressssuacnhdassaafellteyrgfriocmsecnlisniitcizaal ttiroianlsa,nadn/odropneripheral blood count may However, further hsetulpditeosbaerteItGenrHeiTdeedentdifytowahsiscehscshtihldereanppalriecamboilirtey likely to have a short-term response of these findings in a wider range of to ICS.757 settings, particularly in areas whPeYreRblood eosinophilia may reflect helminth infection rather than asthma or atopy. HoowRdeosepsotnhsiseptaorptiCcreuOvlaiorucshitlrdeadtimffeernftrom other children with asthma, in terms of: o Parental preference (goals, beliefs and concerns about medications) o Practical issues (cost, inhaler technique and adherence)? The following treatment recommendations for children of 5 years of age or younger are based on the available evidence and on expert opinion. Although the evidence is expanding it is still rather limited as most clinical trials in this age group have not characterized participants with respect to their symptom pattern, and different studies have used different outcomes and different definitions of exacerbations. A stepwise treatment approach is recommended (Box 6-5, p.165), based on symptom patterns, risk of exacerbations and side-effects, and response to initial treatment. Generally, treatment includes the daily, long-term use of controller medications to keep asthma well-controlled, and reliever medications for as-needed symptom relief. The choice of inhaler device is also an important consideration (Box 6-7, p.167). 6. Diagnosis and management of asthma in children 5 years and younger 161 Which children should be prescribed regular controller treatment? Intermittent or episodic wheezing of any severity may represent an isolated viral-induced wheezing episode, an episode of seasonal or allergen-induced asthma, or unrecognized uncontrolled asthma. The initial treatment of wheezing is identical for all of these - a SABA every 4-6 hours as needed until symptoms disappear, usually within 1 to 7 days. Further treatment of the acute wheezing episodes themselves is described below (see Acute asthma exacerbations in children 5 years and younger, p.168). However, uncertainty surrounds the addition of other drugs in these children, especially when the nature of the episode is unclear. In general, the following principles apply. If the history and symptom pattern suggest a diagnosis of asthma (Box 6-2, p.154; Box 6-2A, p.155) and respiratory symptoms are uncontrolled (Box 6-4, p.160) and/or wheezing episodes are frequent (e.g. three or more episodes in a season), regular controller treatment should be initiated (Step 2, Box 6-5, p.165) and the response evaluated (Evidence D). Regular controller treatment may also be indicated in a child with less frequent, but more severe episodes of viral- induced wheeze (Evidence D). If the diagnosis frequently, e.g. of asthma more than is in doubt, and inhaled every 6-8 weeks, a trial SoAf rBeAguthlaerracopnytororllceorutrrseeastmoef natnstihboioutliTdcsEbneeceodntsoidbeererdeptoeactoendfirm whether the symptoms at this stage. are due to asthma (Evidence D). Referral for specialist opRinIiBoUn should also be considered It is important to discuss the decision to prescribe controller treatment and the choDicIeSTof treatment with the child's parents or carers. They should be aware of both maintaining normal activity levels for their child's tnhoermrealal tpivheysbiceanleafintsdasnodciraisl kdsOevoRef ltohpemtreenatt.mAeltnhtosu, gahndeftfheectismopfoIrCtaSncoen of growth velocity are seen in pre-pubertal children in the first 1-2 years of OtrePaYtment, this is not progressive or cumulative, and the one study controlled asthma itthsaetlfeaxdavmeirnseedlyloanffge-ctetsrmadouulttchoemigehst.1s2h6oFwoerdmaodreiffedTreetCanicl eseoef only 0.7% Appendix in adult height.127,758 Chapter 5B. Poorly NO Treatment steps to control asthma symptoms and minim-izDeOfuture risk for children 5 years and younger Asthma achieve treatment in young children good symptom control and follows a minimize fsutteuprewirsiRsekIaAopLfperxoaaccehrb(Baotixon6s-5a)n, dwimthemdiecadticioantiosnidea-dejuffsetcetds.uTphoerndeoewdnfotor controller treatment should be provided in Appendix Chapter re-assessed 5, Part C. regulAarTlyE. More details about asthma medications for children 0-5 years are Before considering a step-up of controllerEtDreMatment fIof lsloywmipntgombecfoornetraonl yisspteoporuapnidn/otrreeaxtmaIcGeenHrtbTiasticoonnsspideerrseisdt. despite 3 months of adequate controller therapy, check the Confirm that the symptomPs YarRe due to asthma rather than a concomitant or alternative condition (Box 6-3, p.105). Refer for expert assessCmOent if the diagnosis is in doubt. Check and correct inhaler technique. Confirm good adherence with the prescribed dose. Consider trial of one of the other treatment options for that step, as many children may respond to one of the options. Enquire about risk factors such as allergen or tobacco smoke exposure (Box 6-4, p.160). 162 6. Diagnosis and management of asthma in children 5 years and younger ASTHMA TREATMENT STEPS FOR CHILDREN AGED 5 YEARS AND YOUNGER STEP 1: As-needed inhaled short-acting beta2-agonist (SABA) Preferred option: as-needed inhaled short-acting beta2-agonist (SABA) All children who experience wheezing episodes should be provided with inhaled SABA for relief of symptoms (Evidence D), although it is not effective in all children. See Box 6-7 (p.167) for choice of inhaler device. Use of SABA for the relief of symptoms on average more than twice a week over a one month period indicates the need for a trial of controller medication. Initial episodes of wheeze in children <1 year often occur in the setting of infectious bronchiolitis, and this should be managed according to local bronchiolitis guidelines. SABAs are generally ineffective for bronchiolitis.759 Other options Oral bronchodilator therapy is compared with inhaled SABA not recommended (Evidence D). due to its slower onset of action and hiUghTeEr rate of side-effects For children with intermittent viral-induced wheeze and no interval symptoms, partiTcuRlIaBrly those with underlying atopy (positive mAPI) in whom considered620,760,761 (see MinahnaalegdeSmAeBntAomf wedoircsaetnioinngisasntohtmsaufaficnidenetx,aincteerrbmaittitoennstD,hIpiSg.1h6d8o),sbeuItCbSecmaauysebeof the risk of side- effects, this should only be considered if the physician is confident that theOtrReatment will be used appropriately. STEP 2: Initial controller treatment plus as-needed SABA OPY T C Preferred option: regular daily low dose ICS plus as-neededNOSABA Regular children - DO daily, low dose ICS (Box 6-6, p.166) is recommended 5 years and younger (Evidence A).755,762-764 This initial as the preferred initial treatment treatment should be given for at to control asthma least 3 months to in establish its effectiveness in achieving good asthmRaIAcLontrol. Other options In young children with persistent asthma, reguAlaTrEtreatment with a leukotriene receptor antagonist (LTRA) modestly reduces symptoms and need for oral coErtDicoMsteroids compared with placebo.765 However, for young children with recurrent viralexacerbations induced (Evidenc ewAhe).e76z6inAg,fIuGarHtrheTevrieswyscteomncalutidcerdevtiheawt neither regular nor found that in pre-s intermittent LTRA reduc choolers with asthma or es OCS-r recurrent equir in g wheezing, monothera daily ICS was py.767 Parents mshoorPuelYdeRfbfeecctioveunins impr elled oving symptom control and reducing exacerbations th about the potential adverse effects of montelukast on an regular sleep and LTRA behav ior , and health professionals sChOould consider the benefits and risks of side effects before prescribing; the FDA has required a boxed warning about these problems.241 For pre-school children with asthma characterized by frequent viral-induced wheezing and interval asthma symptoms, as-needed (prn)768 or episodic ICS769 may be considered, but a trial of regular daily low dose ICS should be undertaken first. The effect on exacerbation risk seems similar for regular daily low dose and episodic high dose ICS.764 See also Initial home management of asthma exacerbations, p.169. If good asthma control is not achieved with a given therapy, trials of the alternative Step 2 therapies are recommended prior to moving to Step 3.757 6. Diagnosis and management of asthma in children 5 years and younger 163 STEP 3: Additional controller treatment, plus as-needed SABA and consider specialist referral If 3 months of initial therapy with a low dose ICS fails to control symptoms, or if exacerbations continue to occur, check the following before any step up in treatment is considered. Confirm that the symptoms are due to asthma rather than a concomitant or alternative condition (Box 6-3, p.158). Check and correct inhaler technique. Consider alternative delivery systems if indicated. Confirm good adherence with the prescribed dose. Enquire about risk factors such as allergen or tobacco smoke exposure (Box 6-4, p.160). Preferred option: medium dose ICS (double the `low' daily dose) Doubling the initial low dose of ICS may be the best option (Evidence C). Assess response after 3 months. The child should be referred for expert assessment if symptom control remains poor and/or flare-ups persist, or if side-effects of treatment are observed or suspected. UTE Other options Addition of a LTRA to low dose ICS may be considered, based on data from older chilTdRreInB(Evidence D). The relative cost of different treatment options in some countries may be relevant to controller DchISoices for children. See note above about the FDA warning for montelukast.241 OR Not recommended OPY There are insufficient data about the efficacy short-term (8 week) placebo-controlled study and safety of did not show aICnSy-sLiAgnOBiAfTiciCanncthdiilfdfererenn<c4e years old to recommend their use. A in symptoms between combination fluticasone propionate-salmeterol receiving LABA.770 vs fluticasone propionate aDloOneN; no additional safety signals were noted in the group STEP 4: Continue controller treatment and refer forIeAxLp-ert assessment Preferred option: refer the child for expert adviceTEanRd further investigation (Evidence D). If doubling the initial dose of ICS fails to achievMe Aand maintain good asthma control, carefully reassess inhaler technique and medication adherence as these are cToEmDmon problems in this age group. In addition, reassess and address control of environmental factors where relevaIGntH, and reconsider the asthma diagnosis. Other options PYR The best treatment for this to consider, with specialist apdoCvpOiuclea,tiaorne:has not been established. If the diagnosis of asthma has been confirmed, options Further increase the dose of ICS for a few weeks until the control of the child's asthma improves (Evidence D). Monitor for side-effects. Add LTRA (data based on studies in older children, Evidence D). Benefits, and risks of side effects, should be considered, as described previously.241 Add long acting beta agonist (LABA) in combination with ICS; data based on studies in children 4 years of age Add a low dose of oral corticosteroid (for a few weeks only) until asthma control improves (Evidence D); monitor for side-effects. Add intermittent high dose ICS at onset of respiratory illnesses to the regular daily ICS if exacerbations are the main problem (Evidence D). The need for additional controller treatment should be re-evaluated at each visit and maintained for as short a period as possible, taking into account potential risks and benefits. Treatment goals and their feasibility should be re-considered and discussed with the child's family/carer. 164 6. Diagnosis and management of asthma in children 5 years and younger Box 6-5. Personalized management of asthma in children 5 years and younger IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO ICS: inhaled corticosteroids; LTRA: leukotriene receptor antagonist; SABA: short-acting beta2-agonist Box 6-6. Low daily doses of inhaled corticosteroids for children 5 years and younger This is not a table of equivalence, but instead, suggestions for `low' total daily doses for the ICS treatment recommendations for children aged 5 years and younger in Box 6.5 (p.165), based on available studies and product information. Data on comparative potency are not readily available, particularly for children, and this table does NOT imply potency equivalence. The doses listed here are the lowest approved doses for which safety and effectiveness have been adequately studied in this age group. Low dose ICS provides most of the clinical benefit for most children with asthma. Higher doses are associated with an increased risk of local and systemic side-effects, which must be balanced against potential benefits. Inhaled corticosteroid Low total daily dose (mcg) (age-group with adequate safety and effectiveness data) BDP (pMDI, standard particle, HFA) 100 (ages 5 years and older) BDP (pMDI, extrafine particle, HFA) Budesonide nebulized 55000(a(aggeess51yeyeaaUrsrTaaEnndd older) older) Fluticasone propionate (pMDI, standard particle, HFA) 50 (ages 4TRyeIBars and older) Fluticasone furoate (DPI) Not sufficiently studiDeIdSin children 5 years and younger) Mometasone furoate (pMDI, standard particle, HFA) 10O0R(ages 5 years and older) Ciclesonide (pMDI, extrafine particle, HFA) Not sufficiOenPtYly studied in children 5 years and younger BDP: dose C beclometasone dipropionate; DPI: dry powder inhaler; HFA: hydrofluoroalkane propellant; ICS: inhaled T inhaler (non-chlorofluorocarbon formulations); in children, pMDI should always be used with a spacer corticosteroid; pMDI: pressurized metered NO REVIEWING RESPONSE AND ADJUSTING TREATMENT - DO AThsseecshsimld'esnht eaitgehvt esrhyovuilsditbsehomueldasinucreluddeevaesrtyhmyeaars,yomrpmItAoomLrecooftnetrno.lAasntdhmrisak-lifkaectsoyrms (pBtoomx s6-r4e,mpi.t1i6n0a),saunbdstsaindteia-el fpferocptso.rtion of children of 5 years or younger,771-773 so the needTEfoRr continued controller treatment should be regularly assessed (e.g. every 3-6 months) (Evidence D). If therapy to check whether symptoms have recurred, iasssMttheAeprpaepdy-dmoawynnoereddistocobnetinstueepdp,esdc-huepdourlereainfsotliltouwte-dup(Evvisidite3n-c6e wDe).eks later Marked seasonal variations may be seenTinEDsymptoms and exacerbations in this age-group. For children with seasonal symptoms whose daily long-term conItGroHller treatment is to be discontinued (e.g. 4 weeks after their season ends), the parent/carer medications tshhaotuslhdobueldpbroeviindietidaPtweYditRhtoatrweraittteitn, asthma action and when and plan how detailing specific signs of to contact medical care. worsening asthma, the CO CHOICE OF INHALER DEVICE Inhaled therapy constitutes the cornerstone of asthma treatment in children 5 years and younger. A pressurized metered-dose inhaler (pMDI) with a valved spacer (with or without a face mask, depending on the child's age) is the preferred delivery system774 (Box 6-7, p.167) (Evidence A). This recommendation is based on studies with beta2agonists. The spacer device should have documented efficacy in young children. The dose delivered may vary considerably between spacers, so consider this if changing from one spacer to another. The only possible inhalation technique in young children is tidal breathing. The optimal number of breaths required to empty the spacer depends on the child's tidal volume, and the dead space and volume of the spacer. Generally, 5-10 breaths will be sufficient per actuation. The way a spacer is used can markedly affect the amount of drug delivered: Spacer size may affect the amount of drug available for inhalation in a complex way depending on the drug prescribed and the pMDI used. Young children can use spacers of all sizes, but theoretically a lower volume spacer (<350 mL) is advantageous in very young children. 166 6. Diagnosis and management of asthma in children 5 years and younger  A single pMDI actuation should be delivered at a time, with the inhaler shaken in between. Multiple actuations into the spacer before inhalation may markedly reduce the amount of drug inhaled. Delay between actuating the pMDI into the spacer and inhalation may reduce the amount of drug available. This varies between spacers, but to maximize drug delivery, inhalation should start as soon as possible after actuation. If a health care provider or a carer is giving the medication to the child, they should actuate the pMDI only when the child is ready and the spacer is in the child's mouth. If a face mask is used it must be fitted tightly around the child's mouth and nose, to avoid loss of drug. Ensure that the valve is moving while the child is breathing through the spacer. Static charge may accumulate on some plastic spacers, attracting drug particles and reducing lung delivery. This charge can be reduced by washing the spacer with detergent (without rinsing) and allowing it to air dry, but it may re-accumulate over time. Spacers made of anti-static materials or metals are less subject to this problem. If a patient or health care provider carries a new plastic spacer for emergency use, it should be regularly washed with detergent (e.g. monthly) to reduce static charge. Ncaenbnuolitzbeerst,atuhgehotnelyffevciatibveleuaslteeronfaativsepadceelirvdeeryviscyes.tIefmasneinbcuhlizilderreisn,uasreedrefosredrveelidveforUyrTotEhfeICmSi,niotrsithyooufldchbiledruesnedwhwoith a mouthpiece procedures. to avoid the medication reaching the eyes. If a nebulizer is useTdR, IfBollow local infection control DIS Box 6-7. Choosing an inhaler device for children 5 years and youngeOr R Age Preferred device OPY Alternate device 0-3 years Pressurized metered dose inhaler plus NeTbuClizer with face mask dedicated spacer with face mask NO 4-5 years Pressurized metered dose inhaler plus dedicated spacer with mouthpiece - DO Pressurized metered dose inhaler plus dedicated spacer with face mask or nebulizer with mouthpiece or face mask ASTHMA SELF-MANAGEMENT EDUCATION FORRIACLARERS OF YOUNG CHILDREN Asthma self-management education should bAeTpErovided to family members and carers of wheezy children 5 years and younger when wheeze is suspected to bEeDcMaused by asthma. An educational program should contain: TArbaainsinicgeaxbpolaunt actoiorrneactbionuhtaalaIsGttihoHmnTateacnhdniqthueefactors that influence it AInfworrimtteantioanstohnmtaheacimtiopnoPrpYtalRannc.e of the child's adherence to the prescribed medication regimen Crucial to a successful asCthOma education program are a partnership between patient/carer and health care providers, with a high level of agreement regarding the goals of treatment for the child, and intensive follow-up (Evidence D).25 Written asthma action plans Asthma action plans should be provided for the family/carers of all children with asthma, including those aged 5 years and younger (Evidence D). Action plans, developed through collaboration between an asthma educator, the health care provider and the family, have been shown to be of value in older children,775 although they have not been extensively studied in children of 5 years and younger. A written asthma action plan includes: A description of how the parent or carer can recognize when symptom control is deteriorating The medications to administer When and how to obtain medical care, including telephone numbers of services available for emergencies (e.g. doctors' offices, emergency departments and hospitals, ambulance services and emergency pharmacies). Details of treatments that can be initiated at home are provided in the following section, Part C: Management of worsening asthma and exacerbations in children 5 years and younger, p.168. 6. Diagnosis and management of asthma in children 5 years and younger 167 PART C. MANAGEMENT OF WORSENING ASTHMA AND EXACERBATIONS IN CHILDREN 5 YEARS AND YOUNGER KEY POINTS Symptoms of exacerbation in young children Early symptoms of exacerbations in young children may include increased symptoms; increased coughing, especially at night; lethargy or reduced exercise tolerance; impaired daily activities including feeding; and a poor response to reliever medication. Home management in a written asthma action plan Give a written asthma action plan to parents/carers of young children with asthma so they can recognize an impending severe attack, start treatment, and identify when urgent hospital treatment is required. IPnaitrieanl ttrse/caatmreernstsahtohuoldmseeieskwuirthgeinnht amleeddischaol rcta-arectiifntghebecthai2l-daigsoancisutte(SlyAdBisAt)r,ewssitehdr,elevUiteThwaErgaifcte, rfa1ilshotourreosrpeoanrldietro. Minietidailcbarloantctehnotdioilnatsohrothueldrabpeys, oour gishtwoonrstehneinsga,meespdeacyiaiflliynhinaclehdildSrAeBn A<1isyneeaerdoTefRdaIgmBeo.re often than 3-hourly or for more than 24 hours. DIS There is no compelling evidence to support parent-initiated oral corticOoRsteroids. Management of exacerbations in primary care or acute care facilityOPY Assess severity of the exacerbation while initiating treatment hour) and oxygen (to maintain saturation 94-98%). T Cwith SABA (2-6 puffs every 20 minutes for first Recommend immediate transfer to hospital if there is noNrOesponse to inhaled SABA within 1-2 hours; if the child is unable to speak or drink, has a respiratory-raDtOe >40/minute or is cyanosed, if resources are lacking in Cthoenhsoidmeer ,oorar lifporexdygniesnonsea/tpurreadtionnisoislo<n9e21%-2onmRrIgoA/okLmg/daairy. for children attending an Emergency Department or aadgmeditt3e-d5toyehaorssp, iftoarl,uupptoto5admayasx;imorudmexoAaf Tm2E0etmhags/doanyef0o.r6cmhigld/rkegn/daagyefdor02-2dayyesa.rsIf, tahnedre3i0s mfagilu/draeyofforrecshoilludtrieonn, or relapse of symptoms with dexaEmDethMasone, consideration should be given to switching to prednisolone. ArrangeCehailrdlryefnowllohwo -huapveafetexpr earnieenxIcGaecdHeTarnbaatsiothnma exacerbation are at risk of further exacerbations. Arrange follow-up within 1-2 days of aCnOexPaYcRerbation and again 1-2 months later to plan ongoing asthma management. DIAGNOSIS OF EXACERBATIONS A flare-up or exacerbation of asthma in children 5 years and younger is defined as an acute or sub-acute deterioration in symptom control that is sufficient to cause distress or risk to health, and necessitates a visit to a health care provider or requires treatment with systemic corticosteroids. In pediatric literature, the term `episode' is commonly used, but understanding of this term by parent/carers is not known Early symptoms of an exacerbation may include any of the following: Onset of symptoms of respiratory tract infection An acute or sub-acute increase in wheeze and shortness of breath An increase in coughing, especially while the child is asleep Lethargy or reduced exercise tolerance Impairment of daily activities, including feeding A poor response to reliever medication. 168 6. Diagnosis and management of asthma in children 5 years and younger In a study of children aged 2-5 years, the combination of increased daytime cough, daytime wheeze, and night-time beta2-agonist use was a strong predictor at a group level of an imminent exacerbation (1 day later). This combination predicted around 70% of exacerbations, with a low false positive rate of 14%. In contrast, no individual symptom was predictive of an imminent asthma exacerbation.776 Upper respiratory symptoms frequently precede the onset of an asthma exacerbation, indicating the important role of viral URTI in precipitating exacerbations in many, although not all, children with asthma. In a randomized controlled trial of acetaminophen versus ibuprofen, given for pain or fever in children with mild persistent asthma, there was no evidence of a difference in the subsequent risk of flare-ups or poor symptom control.757 INITIAL HOME MANAGEMENT OF ASTHMA EXACERBATIONS Initial management includes an action plan to enable the child's family members and carers to recognize worsening asthma and initiate treatment, recognize when it is severe, identify when urgent hospital treatment is necessary, and pmreodviidcaetiroencsomanmdednodsaatigoenss afonrdfowllhoewn uapnd(EhvoidwentoceacDc)e.sTshme eadcitcioanl cpalaren. should include sBpUecTiEfic information about Need for urgent medical attention Parents/carers should be advised to seek medical attention immediately if: TRI DIS The child is acutely distressed OR The The child's period osyf mrepliteofmasftearredonsoetsreolifeSvAedBAprboemcpotmlyebsypinrohgarleesdsbivreoOlnycPshYhoodritlaetror A child younger than 1 year requires repeated inhaled SABTACover several hours. Initial treatment at home NO Inhaled SABA via a mask or spacer, and review response- DO The parent/carer should initiate treatment with twoRpIAufLfs of inhaled SABA (200 mcg salbutamol or equivalent), given one puff at a time via a spacer device with or 20-minute intervals, if needed. The child swhitohuAolduTtEbaefoabcseemraveskd (Evidence D). This by the family/carer may and, be repeated if improving, a further two times at maintained in a restful aanbdovreeaaspspulyri;nograotnmtohsepshaemreefodraaynifhmouorrEeoDtrhmaMnor6e.pMufefsdiocfailnahtatelendtioSnAsBhAoualrdebreeqsuoiuregdhtfourrgseynmtlpytoifmanreylioeff twheithfeinatthuerefsirslist t2ed hours, or if the child has not recovIeGrHedTafter 24 hours. Family/carer-initiated corticosteProYiRds Atrelthatomueghntpbryacfatimceidly/icnasreormsCeiOnptahretshoofmtheemwaonrladg,ethmeeenvt iodfeansctehmtoaseuxpapcoertrbthaetioinnistiaintiocnhioldfroernailscworetiacko.s7t7e7-r7o81idP(rOeeCmSp) tive episodic high dose nebulized ICS may reduce exacerbations in children with intermittent viral triggered wheezing.764 However, because of the high potential for side-effects, especially if the treatment is continued inappropriately or is given frequently, family-administered high dose ICS should be considered only where the health care provider is confident that the medications will be used appropriately, and the child is closely monitored for side-effects (see p.172). Leukotriene receptor antagonists In children aged 2-5 years with intermittent viral wheezing, one study found that a short course of an oral LTRA (for 7- 20 days, commenced at the start of an URTI or the first sign of asthma symptoms) reduced symptoms, health care utilization and time off work for the carer.782 In contrast another study found no significant effect with LTRA vs placebo on episode-free days (primary outcome), OCS use, health care utilization, quality of life or hospitalization in children with or without a positive Asthma Predictive Index (API). However, activity limitation and a symptom trouble score were significantly improved, particularly in children with a positive API.783 Parents should be counseled about the FDA warning about risk of adverse effects on sleep and behavior with montelukast.241 6. Diagnosis and management of asthma in children 5 years and younger 169 Box 6-8. Management of acute asthma or wheezing in children 5 years and younger IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO 170 6. Diagnosis and management of asthma in children 5 years and younger PRIMARY CARE OR HOSPITAL MANAGEMENT OF ACUTE ASTHMA EXACERBATIONS IN CHILDREN 5 YEARS OR YOUNGER Assessment of exacerbation severity Conduct a brief history and examination concurrently with the initiation of therapy (Box 6-8, Box 6-9). The presence of any of the features of a severe exacerbation listed in Box 6-9 are an indication of the need for urgent treatment and immediate transfer to hospital (Evidence D). Oxygen saturation from pulse oximetry of <92% on presentation (before oxygen or bronchodilator treatment) is associated with high morbidity and likely need for hospitalization; saturation of 92-95% is also associated with higher risk.642 Agitation, drowsiness and confusion are features of cerebral hypoxemia. A quiet chest on auscultation indicates minimal ventilation, insufficient to produce a wheeze. Several clinical scoring systems such as PRAM (Preschool Respiratory Assessment Measure) and PASS (Pediatric Asthma Severity Score) have been developed for assessing the severity of acute asthma exacerbations in children.784 Box 6-9. Initial assessment of acute asthma exacerbations in children 5 years andUyToEunger Symptoms Mild TRIB Severe* Altered consciousness No ADgIitSated, confused or drowsy Oximetry on presentation (SaO2)** >95% OR <92% Speech Sentences OPY Words Pulse rate <100 beats/minTutCe >180 beats/minute (0-3 years) NO >150 beats/minute (4-5 years) Respiratory rate 4-0D/mOinute >40/minute Central cyanosis RIAL Absent Likely to be present Wheeze intensity ATE Variable Chest may be quiet *Any of these features indicates a severe The normal developmental capability of M asthma exacerbation. **Oximetry before ED the child must be taken into account. treatment with oxygen or bronchodilator. IGHT InCdihcialdtrieonnswfitohrfiematmureedsiaotfeatrsaePnvYsefrReeretxoahceorsbpaittiaoln that fail to resolve within 1-2 hours despite repeated dosing SABA must be referred toChOospital for observation and further treatment (Evidence D). Other indications are with inhaled respiratory arrest or impending arrest; lack of supervision in the home or doctor's office; and recurrence of signs of a severe exacerbation within 48 hours (particularly if treatment with OCS has already been given). In addition, early medical attention should be sought for children with a history of severe life-threatening exacerbations, and those less than 2 years of age as the risk of dehydration and respiratory fatigue is increased (Box 6-10, p.172). Emergency treatment and initial pharmacotherapy Oxygen Treat hypoxemia urgently with oxygen by face mask to achieve and maintain percutaneous oxygen saturation 94-98% (Evidence A). To avoid hypoxemia during changes in treatment, children who are acutely distressed should be treated immediately with oxygen and SABA (2.5 mg of salbutamol or equivalent diluted in 3 mL of sterile normal saline) delivered by an oxygen-driven nebulizer (if available). This treatment should not be delayed, and may be given before the full assessment is completed. Transient hypoxemia due to ventilation/perfusion mismatch may occur during treatment with SABAs. 6. Diagnosis and management of asthma in children 5 years and younger 171 Box 6-10.Indications for immediate transfer to hospital for children 5 years and younger Immediate transfer to hospital is indicated if a child 5 years with asthma has ANY of the following: At initial or subsequent assessment Child is unable to speak or drink Cyanosis Respiratory rate >40 per minute Oxygen saturation <92% when breathing room air Silent chest on auscultation Lack of response to initial bronchodilator treatment Lack of response to 6 puffs of inhaled SABA (2 separate puffs, repeated 3 times) over 1-2 hours Persisting tachypnea* despite three administrations of inhaled SABA, even if the child shows other clinical signs of improvement Social environment that limits delivery of acute treatment, or parent/carer unable to maUnTaEge acute asthma at home During transfer to hospital, continue to give inhaled SABA, oxygen (if available) to maTinRtaIBin saturation 94-98%, and give systemic corticosteroids (see Box 6-8, p.170) DIS R *Normal respiratory rates: <60 breaths/minute in children 0-2 months; <50 breaths/minute in children 2-12 months; Y O <40 breaths/minute in children 1-5 years. Inhaled bronchodilator therapy COP T The initial dose of inhaled SABA may be given by a pMDI with spNaOcer and mask or mouthpiece or an air-driven nebulizer; or, if oxygen saturation is low, by plus spacer is favored as it is more efficient tahnaonxaygneenb-udlirzive-erDnfoOnrebbruolnizcehro(daisladtoersdcerilbiveedrya7b85ov(Eev).idFeonrcme oAs)t, children, pMDI and nebulizers can spread infectious particles. except in acute, severe asthma TwhheeninsitiixalpduoffssesohfoSuAldRBbIAAeLisgitvweon.pWufhfsenofasanlebbuutalizmeorl (100 mcg is used, a per puff) or dose of 2.5 equivalent, mg salbutamol solution is recommended, and infection control pAroTcEedures should be followed. The frequency of dosing depends on the rFeosrpcohnilsdereonbsweitrhvemdoodveerrat1e--2sehvoeurerse(xsaeceebrbeEaloDtwioM)n.s and a poor response to initial SABA, nebulized ipratropium bromide may be added every 20 minutes for 1IGhHouTr only.785 Magnesium sulfate PYR The role of magnesium sulfaCteOis not established for children 5 years and younger, because there are few studies in this age group. Nebulized isotonic magnesium sulfate may be considered as an adjuvant to standard treatment with nebulized salbutamol and ipratropium in the first hour of treatment for children 2 years old with acute severe asthma (e.g. oxygen saturation <92%, Box 6-9, p.171), particularly those with symptoms lasting <6 hours.786 Intravenous magnesium sulfate in a single dose of 40-50 mg/kg (maximum 2 g) by slow infusion (20-60 minutes) has also been used.787 Assessment of response and additional bronchodilator treatment Children with a severe asthma exacerbation must be observed for at least 1 hour after initiation of treatment, at which time further treatment can be planned. If symptoms persist after initial bronchodilator: a further 2-6 puffs of salbutamol (depending on severity) may be given 20 minutes after the first dose and repeated at 20-minute intervals for an hour. Consider adding 1-2 puffs of ipratropium. Failure to respond at 1 hour, or earlier deterioration, should prompt urgent admission to hospital, addition of nebulized ipratropium, and a short-course of oral corticosteroids (Evidence D). 172 6. Diagnosis and management of asthma in children 5 years and younger  If symptoms have improved by 1 hour but recur within 3-4 hours: the child may be given more frequent doses of bronchodilator (2-3 puffs each hour), and oral corticosteroids should be given. The child may need to remain in the emergency department, or, if at home, should be observed by the family/carer and have ready access to emergency care. Children who fail to respond to 10 puffs of inhaled SABA within a 3-4 hour period should be referred immediately to hospital (Evidence D). If symptoms resolve rapidly after initial bronchodilator and do not recur for 1-2 hours: no further treatment may be required. Further SABA may be given every 3-4 hours (up to a total of 10 puffs/24 hours) and, if symptoms persist beyond 1 day, other treatments including inhaled and/or oral corticosteroids are indicated (Evidence D), as outlined below. Box 6-11.Initial emergency department management of asthma exacerbations in children 5 years and younger Therapy Dose and administration TE Supplemental oxygen Delivered by face mask (usually 1 L/minute) to maintain oxygen saturation 94-98% RIBU Short-acting beta2DIST agonist (SABA) 2-6 puffs of salbutamol by spacer, or 2.5 mg of salbutamol by nebulizer, every 20 minutes for first hour*, then reassess severity. If symptoms persist or recur, give an additional 2-3 puffs per hour. Admit to hospital if >10 puffs required in 3-4 hours. Y OR Systemic OP corticosteroids Give initial dose of oral prednisolone (1-2 mg/kg up to a maximum 20 mg for children <2 years old; 30 mg for children 2-5 years) T C OR, intravenous methylprednisolone 1 mg/kg 6-hourly on day 1 NO Additional options in the first hour of treatment TERIAL - DO Ipratropium bromide Consider adding 1-2 puffs of ipratropium bromide by pMDI and spacer For children with moderate-severe exacerbations with a poor response to initial SABA, give nebulized ipratropium bromide 250 mcg every 20 minutes for 1 hour only TED MA Magnesium sulfate Consider nebulized isotonic magnesium sulfate (150 mg) 3 doses in the first hour of treatment for children aged 2 years with severe exacerbation (Box 6-9, p.171) IGH *If inhalation is not possible an intravenous bolus of terbutaline 2 mcg/kg may be given over 5 minutes, followed by continuous infusion of 5 YR mcg/kg/hour788 (Evidence C). The child should be closely monitored, and the dose should be adjusted according to clinical improvement and sideCOP effects. See below for additional and ongoing treatment, including controller therapy. If a nebulizer is used, follow infection control procedures. Additional treatment When treatment in addition to SABA is required for an exacerbation, the options available for children in this age group include ICS; a short course of oral corticosteroid; and/or LTRA (see p.169). However, the clinical benefit of these interventions - particularly on endpoints such as hospitalizations and longer-term outcomes - has not been impressive. Maintain current controller treatment (if prescribed) Children who have been prescribed maintenance therapy with ICS, LTRA or both should continue to take the prescribed dose during and after an exacerbation (Evidence D). Inhaled corticosteroids For children not previously on ICS, an initial dose of ICS twice the low daily dose indicated in Box 6-6 (p.166) may be given and continued for a few weeks or months (Evidence D). Some studies have used high dose ICS (1600 mcg/day, preferably divided into four doses over the day and given for 5-10 days) as this may reduce the need for 6. Diagnosis and management of asthma in children 5 years and younger 173 OCS.620,760,761,789,790 Addition of ICS to standard care (including OCS) does not reduce risk of hospitalization but reduces length of stay and acute asthma scores in children in the emergency department.791 However, the potential for sideeffects with high dose ICS should be taken into account, especially if used repeatedly, and the child should be monitored closely. For those children already on ICS, doubling the dose was not effective in a small study of mild-moderate exacerbations in children aged 6-14 years,792 nor was quintupling the dose in children aged 5-11 years with good adherence. This approach should be reserved mainly for individual cases, and should always involve regular follow up and monitoring of adverse effects (Evidence D). Oral corticosteroids For children with severe exacerbations, a dose of OCS equivalent to prednisolone 1-2 mg/kg/day, with a maximum of 20 mg/day for children under 2 years of age and 30 mg/day for children aged 2-5 years, is currently recommended (Evidence A),793 although several studies have failed to show any benefits when given earlier (e.g. by parents) during periods of worsening wheeze managed in an outpatient setting (Evidence D).777-780,794,795 A meta-analysis demonstrated aberneedfuitciendrirsiskkoof fhhoossppitiatalilzizaatitoionnwwhheenngoivraelncionrttihceosotuetrpoaidtisenwtesreettaindgm.7i9n6isAtecroeudrisnethoef 3e-m5edragyeUsnTcisyEsduefpfiacrietmnteinnt,mbousttncohcildleraern of to this age, and can be stopped confirm they are recovering. without tapering (Evidence D), but the child must be rTeRviIeBwed after discharge (as below) In children discharged from the emergency department, an intramuscular corticosDteIrSoid may be an alternative to a course of OCS for preventing relapse.651 There is insufficient evidence to recoOmRmend intramuscular over oral corticosteroids.651 Regardless of treatment, the severity of the child's symptoms must be cOarPeYfully monitored. The sooner therapy is started in relation to the onset of symptoms, the more likely it is that the impTenCding exacerbation may be clinically attenuated or prevented. NO Discharge and follow up after an exacerbation - DO Before discharge, the without problems). condition of the child should beRsItAaLble (e.g. he/she should be out of bed and able to eat and drink Children who have recently had an asthma exacAerTbEation are at risk of further exacerbations and require follow up. The pauprpproosperiaistetomeaninstuerneacnocme ptrleeatetmreecnotvaenrdy,atdoEheDesrteManbcliesh(EthveidceanuceseDo).f the exacerbation, and, when necessary, to establish Prior to discharge from the emergencIyGdHeTpartment or hospital, family/carers should receive the following advice and information (all are Evidence D).PYR IenxsatrcuecrbtioantioonnsrheocuolgdnbiteCioOindeonf tsifiigends, of recurrence and and strategies for worsening of asthma. The factors that precipitated future avoidance of these factors implemented. the A written, individualized action plan, including details of accessible emergency services Careful review of inhaler technique Further treatment advice explaining that: o SABAs should be used on an as-needed basis, but the daily requirement should be recorded to ensure it is being decreased over time to pre-exacerbation levels. o ICS has been initiated where appropriate (at twice the low initial dose in Box 6-6 (p.166) for the first month after discharge, then adjusted as needed) or continued, for those previously prescribed controller medication. A supply of SABA and, where applicable, the remainder of the course of oral corticosteroid, ICS or LTRA A follow-up appointment within 1-2 days and another within 1-2 months, depending on the clinical, social and practical context of the exacerbation 174 6. Diagnosis and management of asthma in children 5 years and younger SECTION 2. CHILDREN 5 YEARS AND YOUNGER UTE TRIB DCIS hapter 7. Y OR COP OT Primary prevention - DO N of asthma ERIAL MAT GHTED PYRI CO KEY POINTS The development and persistence of asthma are driven by gene-environment interactions. For children, a `window of opportunity' to prevent asthma exists in utero and in early life, but intervention studies are limited. With regard to allergen avoidance strategies aimed at preventing asthma in children: o Strategies directed at a single allergen have not been effective in reducing the incidence of asthma o Multifaceted strategies may be effective, but the essential components have not been identified. Current recommendations for preventing asthma in children, based on high quality evidence or consensus, include: o Avoid exposure to environmental tobacco smoke during pregnancy and the first year of life o Encourage vaginal delivery o Advise breast-feeding for its general health benefits (not necessarily for asthma prevention) o Where possible, avoid use of broad-spectrum antibiotics during the first year of lIiBfeU. TE FACTORS CONTRIBUTING TO THE DEVELOPMENT OF ASTHMA IN CHILDRENISTR Asthma is generally believed to be a heterogeneous disease whose inception andDpersistence is driven by gene- environment interactions. The most important of these interactions may occurOinRearly life and even in utero. There is consensus that a influence asthma `dweivnedloowpmoef notp.pMourtlutinpiltey'eenxviisrotsndmuerinntgalpfraecgtonrasn,cbyoathndbioelOaorgPlyiYcianl life when environmental factors may and sociological, may be important in the development of asthma. Data supporting the role of environmental riTskCfactors for the development of asthma include a focus on: nutrition, allergens (both inhaled and ingested), pollutaNntOs (particularly environmental tobacco smoke), minciclurodbinegs,oacncduppastyiocnhaolsaosctihaml faac, tiosrfso.uAndddiintioAnpapleinnfdoirxmCahtiaopnt-earDb2oO.ut factors contributing to the development of asthma, `SPereimpa.r1y0p1reavnednrteiovnie' wreaferrtisclteosp44refovrensttrinagtetghieesofnosreptroefvRdeIinsAteiLnagseo.cTchuipsactihoanpatlearsftohcmusae. s on primary prevention in children. ATE FNAuCtrTitiOoRnSofAmSSoOthCeIrAaTnEdDbWabITyH INCREAHSTEEDDOMR DECREASED RISK OF ASTHMA IN CHILDREN Maternal diet YRIG For some time, the mother's dietPduring pregnancy has been a focus of concern relating to the development of allergy and asthma in the child. TheCreOis no firm evidence that ingestion of any specific foods during pregnancy increases the risk for asthma. However, a study of a pre-birth cohort observed that maternal intake of foods commonly considered allergenic (peanut and milk) was associated with a decrease in allergy and asthma in the offspring.797 Similar data have been shown in a very large Danish National birth cohort, with an association between ingestion of peanuts, tree nuts and/or fish during pregnancy and a decreased risk of asthma in the offspring.798,799 Epidemiological studies and randomized controlled trials on maternal dietary intake of fish or long-chain polyunsaturated fatty acids during pregnancy showed no consistent effects on the risk of wheeze, asthma or atopy in the child.800-803 Dietary changes during pregnancy are therefore not recommended for prevention of allergies or asthma. Maternal obesity and weight gain during pregnancy Data suggest that maternal obesity and weight gain during pregnancy pose an increased risk for asthma in children. A meta-analysis804 showed that maternal obesity in pregnancy was associated with higher odds of ever asthma or wheeze or current asthma or wheeze; each 1 kg/m2 increase in maternal BMI was associated with a 2% to 3% increase in the odd of childhood asthma. High gestational weight gain was associated with higher odds of ever asthma or wheeze. 176 7. Primary prevention of asthma However, no recommendations can be made at present, as unguided weight loss in pregnancy should not be encouraged. Breastfeeding Despite the existence of many studies reporting a beneficial effect of breastfeeding on asthma prevention, results are conflicting,805 and caution should be taken in advising families that breastfeeding will prevent asthma.806 Breastfeeding decreases wheezing episodes in early life; however, it may not prevent development of persistent asthma (Evidence D). Regardless of its effect on development of asthma, breastfeeding should be encouraged for all of its other positive benefits (Evidence A). Timing of introduction of solids Beginning in the 1990s, many national pediatric agencies and societies recommended delay of introduction of solid food, especially for children at a high risk for developing allergy. However, meta-analyses have found no evidence that this ppreaacntiuctearleledrugcyeins hthigehrirsiskkoifnafallentrsg.i8c07disease (including asthma).807 In the case of peanuBtUs,TeEarly introduction may prevent Dietary supplements for mothers and/or babies Vitamin D TRI DIS Intake of vitamin D may be through diet, dietary supplementation or sunligOhtR. A systematic review of cohort, case control laonwdecrrroissks-osfewcthioeneazlinsgtuidllnieesscsoenscinludcehidldtrheant.8m08aTtehrinsawl daisetnaortycinotnafkiremoefOdvPiintYatmwionrDan, daonmd iozfevditcaomnitnroEll,ewdatrsiaalsssoofcviaitatemdinwiDth supplementation in pregnancy comparing standard dose with higTh Cdose vitamin D, although a significant effect was not rausltehdmoau/rt.e8c09u,8r1r0enWt hwehneethzeeraetsaugltessfr0o-m3tyheeasres.t8w11oTtrhiaelsefwfeecrtewcaoNsmOgbrienaetde,stthaemreowngaswaom25e%n wrehdoumctaioinntaoifnreisdk2o5f(OH)vitamin D levels of at least 30 ng/ml from the time of study entry- tDhrOough delivery, suggesting that sufficient levels of Vitamin D dnuoreinfgfeectasrloyfpvrietagmnainnDcysmupapylebme eimntpaotriotannot ninthdeecdreeRvaesIAlionLpgmriesnktfoorf early life wheezing episodes,811 although in asthma and recurrent wheeze were evident both trials, at the age of 6 years.812 ATE Fish oil and Systematic lroenvgie-wchsaoifncpoohloyrut nstsuadtiuersaatebEdoDuftaMmttyataecrnidasl dietary intake of fish or seafood during pregnancy800,813 and of rando pregn mized c ancy800 oshnotrwoleleddntoriaclosnosnismteaInGtteHernfTfaelcdtsieotanrtyhientraiskke of of fish or long-chained polyunsaturated wheeze, asthma or atopy in the child. fatty One acids study during demons tr at ed decreased wheeze/asthma inPpYrRe-school children at high risk for asthma when mothers were given a high dose fish oil supplement established. in the third triCmOester;814 however `fish oil' is not well defined, and the optimal dosing regimen has not been Probiotics A meta-analysis provided insufficient evidence to recommend probiotics for the prevention of allergic disease (asthma, rhinitis, eczema or food allergy).815 Inhalant allergens Sensitization to indoor, inhaled aero-allergens is generally more important than sensitization to outdoor allergens for the presence of, and/or development of, asthma. While there appears to be a linear relationship between exposure and sensitization to house dust mite,816,817 the relationship for animal allergen appears to be more complex.805 Some studies have found that exposure to pet allergens is associated with increased risk of sensitization to these allergens,818,819 and of asthma and wheezing.820,821 By contrast, other studies have demonstrated a decreased risk of developing allergy with exposure to pets.822,823 A review of over 22,000 school-age children from 11 birth cohorts in Europe found no correlation between pets in the homes early in life and higher or lower prevalence of asthma in children.824 For children at risk of 7. Primary prevention of asthma 177 asthma, dampness, visible mold and mold odor in the home environment are associated with increased risk of developing asthma.825 Overall, there are insufficient data to recommend efforts to either reduce or increase pre-natal or early-life exposure to common sensitizing allergens, including pets, for the prevention of allergies and asthma. Birth cohort studies provide some evidence for consideration. A meta-analysis found that studies of interventions focused on reducing exposure to a single allergen did not significantly affect asthma development, but that multifaceted interventions such as in the Isle of Wight study,826 the Canadian Asthma Primary Prevention Study,827 and the Prevention of Asthma in Children study828 were associated with lower risk of asthma diagnosis in children younger than 5 years.829 Two multifaceted studies that followed children beyond 5 years of age demonstrated a significant protective effect both before and after the age of 5 years.826,830 The Isle of Wight study has shown a continuing positive benefit for early-life intervention through to 18 years of age;831 however, exactly which components of the intervention were important and which specific mechanistic changes were induced remain elusive. Treatment with grass SLIT for 3 years did not reduce the incidence of asthma diagnosis (primary outcome) in a large randomized double-blind placebo-controlled symptoms and asthma medication use were trial in children 5-12 years reduced. At present, SLIT wfoirthchgirladsresn-awlleitrhgigcrarUhsisTnEoaclloenrgjuicncrhtiivniotisc,obnujutnacstitvhimtisa is not recommended for asthma prevention.832 Additional studies are needed. RIB Pollutants DIST Maternal smoking during meta-analysis concluded pregnancy is the most that pre-natal smoking direct route of pre-natal had its strongest effect oennvyiorOounnRmg ecnhtialdlrteonb,awcchoersemasokpeosetx-pnaostaulrme.a83t3erAnal smoking seemed relevant only to asthma development in older children.O83P4 YExposure to outdoor pollutants, such as living near a main road, is associated new pediatric asthma cases (13% of t with incre he global ainsceidderniscke)ofmaasythbmeaOa.T8tt3r5iC,b83u6taAb2le0t1o9 study suggested that up to exposure to traffic-related a 4 ir million pollution (itTiRs AdPiff)i.c8u37ltPtoresneaptaarlaNteOp2,reS-Oa2n, danpdosPt-Mn1a0tael expxpoosusureres.areLas-sDoOciaNted with an increased risk of asthma in childhood,838 but Microbial effects The `hygiene hypothesis', and the more recently coiEnRedIA`microflora hypothesis' and `biodiversity hypothesis',839 suggest T that human interaction with microbiota may beMbeAneficial in preventing asthma. For example, there is a lower risk of oafstnhomna-faarmmoenrsg.8c4h0iTldhreenrirsakisoefdasotnhmfaarmissawTlsiEtohDreexdpuocseudreintochsitladbrelenswahnodsceobnesdurmoopmtiosnhoafvreawhigfahrmlevmelislkothf abnacatemroianl-gdechriivlderden lipopo those lysacchar in homes ide wit heonudtodtooxgisn.o84r1c,8a42tsRS.I8iG2m3HiElaxrplyo, scuhrieldoref nanininhfoamntetso with the 2 dogs mother's or cats are less lik vaginal microflora ely thr to ou be gh allergic vaginal than delivery mvaagyinaalsllyo.8b4e3,8b44enTehfiiscimala; ythreelparteeOvtaPolYednifcfeereonf caessthimn athies higher in children born by cesarean section than those born infant gut microbiota according to their mode of delivery.845 C Respiratory syncytial virus infection is associated with subsequent recurrent wheeze, and preventative treatment of premature infants with monthly injections of the monoclonal antibody, palivizumab, (prescribed for prophylaxis of respiratory syncytial virus) is associated with a reduction in recurrent wheezing in the first year of life.846 However, there is little evidence to suggest that this effect is sustained. Although the risk of parent-reported asthma with infrequent wheeze was reduced at 6 years, there was no impact on doctor-diagnosed asthma or lung function.847 Thus, the long- term effect of palivizumab in the prevention of asthma remains uncertain. Medications and other factors Antibiotic use during pregnancy and in infants and toddlers has been associated with the development of asthma later in life,848 although not all studies have shown this association.849 Intake of the analgesic, paracetamol (acetaminophen), may be associated with asthma in both children and adults,850 although exposure during infancy may be confounded by use of paracetamol for respiratory tract infections.850 Frequent use of paracetamol by pregnant women has been associated with asthma in their children.851 There is no evidence that vaccinations increase the risk of a child developing asthma. 178 7. Primary prevention of asthma Psychosocial factors The social environment to which children are exposed may also contribute to the development and severity of asthma. Maternal distress during pregnancy852 or during the child's early years853 has been associated with an increased risk of the child developing asthma. Obesity A meta-analysis of 18 studies found that being either overweight or obese was a risk factor for childhood asthma and wheeze, particularly in girls.470 In adults, there is evidence suggesting that obesity affects the risk of asthma, but that asthma does not affect the risk of obesity.854,855 ADVICE ABOUT PRIMARY PREVENTION OF ASTHMA Based on the results of cohort and observational studies,856 and a GRADE-based analysis for the Allergic Rhinitis and its Impact on Asthma (ARIA) asthma can be provided with guidelines,805 parents enquiring about the advice summarized in Box 7-1. how to reduce the riUskToEf their children developing Possibly the most important factor is the need to provide a positive, supportive envTirRoInBment for discussion that decreases stress, and which encourages families to make choices with which DthIeSy feel comfortable. OR Box 7-1. Advice about primary prevention of asthma in childrenO5PyYears and younger Padavreicnet:s enquiring about how to reduce the risk of their child dNeOvTeloCping asthma can be provided with the following Children should not be exposed to environmental t-obDaOcco smoke during pregnancy or after birth. Identification and correction pregnancy, may reduce the roisf kVoitaf meainrlyDliifneswufhfIieAceiLeznincgy in women episodes. with asthma who are pregnant, or planning Vaginal delivery should be encouraged whTeErRe possible. Breastfeeding is advised, for reasons oMthAer than prevention of allergy and asthma. The use of broad-spectrum anGtiHbTioEticDs during the first year of life should be discouraged. PYRI CO 7. Primary prevention of asthma 179 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO SECTION 3. TRANSLATION INTO CLINICAL PRACTICE IBUTE DISTR Y OR Chapter 8. COP NOT - DO Implementing asthma AL management strategies ATERI HTED M into health systems PYRIG CO KEY POINTS In order to improve asthma care and patient outcomes, evidence-based recommendations must not only be developed, but also disseminated and implemented at a national and local level, and integrated into clinical practice. Recommendations for implementing asthma care strategies are based on many successful programs worldwide. Implementation requires an evidence-based strategy involving professional groups and stakeholders, and should take into account local cultural and socioeconomic conditions. Cost-effectiveness of implementation programs should be assessed so a decision can be made to pursue or modify them. Local adaptation and implementation of asthma care strategies is aided by the use of tools developed for this purpose. IBUTE INTRODUCTION DISTR Due and to the health exponential increase care professionals in in medical delivering erevsideeanrcceh-pbuabselicdactiaornes.,WprhaecnticaaslthsmyOnatRhceasreesisacreonnseiesdteendt to guide policy makers with evidence-based recommendations, outcomes improve.182,857,858 The Global Strategy for AOsPthYma Management and Prevention is a resource required tdooecnusmuerentthfoerirhfeualflitlmh ecanrt,eapsrowfeesllsaiosntaolsfatcoilietastteabthlisehatchheiemveaTminCegnotaolsf of asthma standards treatment for quality and the asthma actions care. The recent adoption of rigorous methodologies such as GRADE2NfOor the development of clinical practice recommendations, and ADAPTE859 and similar approaches- fDoOr assisting the adaptation of recommendations for local country and regional Adaptation of clinical conditions, has assisted in practice recommendations rteodluocRcianIAlgcLobniadsietiodnospuinsiionngathsethGeRbAaDsiEs for asthma programs method is costly and worldwide. often requires expertise that is including drug availability naontdanvaeiwlabevleidloencaclely, ;ainndAatTdhdEisitiiosnn, oret geualsairlyreavcihsiieovneids.8r6e0qFuuirrethdetro, remain there is abreast of generally developments, very limited high quality evidence developing countries. addressing the manyEdDecMision nodes in comprehensive clinical practice guidelines, particularly in ADAPTING AND IMPLEMENTING ASITGHHMTA CLINICAL PRACTICE GUIDELINES Implementation of asthma manaPgYemRent strategies may be carried out at a national, regional or local level.861 Ideally, implementation should be a mCOultidisciplinary effort involving many stakeholders, and using cost-effective methods of knowledge translation.861-863 Each implementation initiative needs to consider the nature of the local health system and its resources (e.g. human, infrastructure, available treatments) (Box 8-1). Moreover, goals and implementation strategies will need to vary from country to country and within countries, based on economics, culture and the physical and social environment. Priority should be given to high-impact interventions. Specific steps need to be followed before clinical practice recommendations can be embedded into local clinical practice and become the standard of care, particularly in low resource settings. The individual steps are summarized in Box 8-2, and a detailed description of the processes involved in each step can be found in the GINA Appendix Chapter 6, available online at www.ginasthma.org. 182 8. Implementing asthma management strategies in health systems Box 8-1. Approach to implementation of the Global Strategy for Asthma Management and Prevention IBUTE DISTR Y OR COP T NO - DO RIAL Box 8-2. Essential elements required to imApTlEement a health-related strategy S1.tepDseivneliomppalemmueltnidtiinscgipalinnaarsythwmorakisntgEragDtreoMguyp.into a health system 2. Assess the current status of aIGstHhmT a care delivery, care gaps and current needs. 3. Select the treatment, material to and adapt tbheePmimYRtpolethmeelnotceadl,caognrteeextoonrmenavinirognomalse,nitd. entify key recommendations for diagnosis and 4. Identify barriers to, aCndOfacilitators of, implementation. 5. Select an implementation framework and its component strategies. 6. Develop a step-by-step implementation plan: Select target populations and evaluable outcomes. Identify local resources to support implementation. Set timelines. Distribute tasks to members. Evaluate outcomes. 7. Continually review progress and results to determine if the strategy requires modification. 8. Implementing asthma management strategies in health systems 183 BARRIERS AND FACILITATORS Many barriers to, and facilitators of, implementation procedures have been described.863-866 Some of the barriers to implementation of evidence-based asthma management relate to the delivery of care, while others relate to patients' attitudes (see Box 8-3, and examples in Appendix Chapter 6, Box 6-1). Cultural and economic barriers can particularly affect the application of recommendations. Box 8-3. Examples of barriers to the implementation of evidence-based recommendations Health care providers Patients Insufficient knowledge of recommendations Low health literacy Lack of agreement with recommendations or Insufficient understanding of asthma and its expectation that they will be effective management TE Resistance to change External barriers (organizational, health policies, LCaucltkuroaflaagnrdeeemcoennot mwiicthbRraeIrcBrioUemrsmendations financial constraints) Peer influence DIST Lack of time and resources Attitudes, belieOfsR, preferences, fears and Medico-legal issues misconceOpPtioYns T C EXAMPLES OF HIGH IMPACT IMPLEMENTATION INTERVENTNIOONS Itdheeahlleya, litnhtesryvsetenmtio.nSstushdioeusldofbteheapmpoliestdeafftetchteivleevmeel oanf sbootfhm-theDedOipcaatlieendtuacnadtiothneshhoewaltthhactairtemparoyvbideedrifafincdu,ltwtoheinredurecelevant, changes in clinical practice. Examples of highly effectRivIeALinterventions are shown in Box 8-4. Box 8-4. Examples of high-impact interventioAnTsEin asthma management Free ICS for patients with a recent hoEspDitaMl admission and/or severe asthma867 Early treatment with ICS, guidedIGsHelTf-management, reduction in exposure to tobacco smoke, improved access to Sasetlhf-minakiendgusctaatmiopn1p8r2omptingPYasRsessment of asthma control and treatment strategies868 Use of individualized wrCittOen asthma action plans as part of self-management education463 An evidence-based care process model for acute and chronic pediatric asthma management, implemented at multiple hospitals869 ICS: inhaled corticosteroids EVALUATION OF THE IMPLEMENTATION PROCESS An important part of the implementation process is to establish a means of evaluating the effectiveness of the program and any improvements in quality of care (see Appendix Chapter 6, Box A6-3). The Cochrane Effective Practice and Organization of Care Group (EPOC) offers suggestions on how to assess the effectiveness of interventions.870 Evaluation involves surveillance of traditional epidemiological parameters, such as morbidity and mortality, as well as specific audits of both process and outcome within different sectors of the health care system. Each country should determine its own minimum sets of data to audit health outcomes. 184 8. Implementing asthma management strategies in health systems HOW CAN GINA HELP WITH IMPLEMENTATION? GINA, through the work of its Dissemination and Implementation Committee, assists in the processes of adaptation and implementation of the recommendations in the Global Strategy for Asthma Management and Prevention report. The GINA report provides an annually updated summary of evidence relevant to asthma diagnosis, management and prevention that may be used in the formulation and adaptation of local guidelines; where evidence is lacking, the GINA report provides approaches for consideration. A web-based implementation `toolkit' will provide a template and guide to local adaptation and implementation of these recommendations, together with materials and advice from successful examples of asthma clinical practice guideline development and implementation in different settings. Educational materials and tools based on the Global Strategy for Asthma Management and Prevention are available in several forms and can be found on the GINA Website (www.ginasthma.org). IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO 8. Implementing asthma management strategies in health systems 185 REFERENCES 1. National Heart Lung and Blood Institute National Asthma Education and Prevention Program, World Health Organization. Global Initiative for Asthma. National Institutes of Health publication no 95-3659. Bethesda: National Institutes of Health; 1995. 2. Schunemann HJ, Jaeschke R, Cook DJ, et al. An official ATS statement: grading the quality of evidence and strength of recommendations in ATS guidelines and recommendations. American Journal of Respiratory & Critical Care Medicine 2006; 174: 605-614. 3. Asher I, Bissell K, Chiang CY, et al. Calling time on asthma deaths in tropical regions-how much longer must people wait for essential medicines? Lancet Respir Med 2019; 7: 13-15. 4. Chiang CY, Ait-Khaled N, Bissell K, et al. Management of asthma in resource-limited settings: role of low-cost corticosteroid/beta-agonist combination inhaler. Int J Tuberc Lung Dis 2015; 19: 129-136. 5. Williamson EJ, Walker AJ, Bhaskaran Nature 2020; 584: 430-436. K, et al. Factors associated with COVID-19-relatedUdTeEath using OpenSAFELY. 6. Liu S, Cao Y, Du T, et al. Prevalence of comorbid asthma and related outcomes in CTORVIBID-19: a systematic review and 7. meta-analysis. Hou H, Xu J, Li J Allergy Clin Immunol Pract 2021; Y, et al. The association of asthma 9: 693-701. with COVID-19 mortality: an DuIpSdated meta-analysis based on adjusted effect estimates. J Allergy Clin Immunol Pract 2021; 9: 3944-3968O.eR3945. 8. Shi T, Pan J, in Scotland: KaantaiktiiroendadliinScVi,deetnatlc.oRhisokrtosftCuOdVy.IDLa-1n9cehtoRspesitpailraMdmedis2s0io2nO2a;Pm1Y0o:n1g9c1h-1il9d8re. n aged 5-17 years with asthma 9. Bloom CI, Drake TM, Docherty AB, et al. Risk of adverse outcomeTs Cin patients with underlying respiratory conditions admitted to hospital with Characterisation Protocol COVID-19: UK. Lancet aRensaptiior nMael,dm2u0l2ti1c:e9n:t6re99pN-r7Oo1s1p.ective cohort study using the ISARIC WHO Clinical 10. Davies GA, Alsallakh MA, Sivakumaran S, et al. Impact o-f DCOOVID-19 lockdown on emergency asthma admissions and 11. deaths: national interrupted time series analyses Virant FS, Randolph C, Nanda A, et al. Pulmonary RpforIorAcSLecodutlraensddaunrdinWg tahleesC. OThVoDr-a1x92p0a2n1d;e7m6:ic8:6a7W-87o3rk.group Report of tInhteeAremsteSrieccatnioAnc.aJdAelmlerygoyfCAlilnleIrmgym, AunstohlmPraa,catnA2dT0IE2m2m. unology (AAAAI) Asthma Diagnosis and Treatment (ADT) 12. 13. Bel EH. Moore WCliCn,icMael pyehresnDoAty,pWesenozfealsSthEm, eat.aCEl.uDIrdrMeOnptiifnicPautilomn Med 2004; of asthma 10: 44-50. phenotypes using cluster analysis in the Severe Asthma Research Program. Am J RIGesHpTir Crit Care Med 2010; 181: 315-323. 14. Wenzel SE. 716-725. Asthma phenotypPeYs:Rthe evolution from clinical to molecular approaches. Nature Medicine 2012; 18: 15. Westerhof GA, Coumou HC, Ode Nijs SB, et al. Clinical predictors of remission and persistence of adult-onset asthma. J Allergy Clin Immunol 2018; 141: 104-109.e103. 16. Levy ML, Fletcher M, Price DB, et al. International Primary Care Respiratory Group (IPCRG) Guidelines: diagnosis of respiratory diseases in primary care. Primary Care Respiratory Journal 2006; 15: 20-34. 17. Quanjer PH, Stanojevic S, Cole TJ, et al. Multi-ethnic reference values for spirometry for the 3-95-yr age range: the global lung function 2012 equations. European Respiratory Journal 2012; 40: 1324-1343. 18. Reddel H, Ware S, Marks G, et al. Differences between asthma exacerbations and poor asthma control [erratum in Lancet 1999;353:758]. Lancet 1999; 353: 364-369. 19. Aaron SD, Vandemheen KL, FitzGerald JM, et al. Reevaluation of diagnosis in adults with physician-diagnosed asthma. JAMA 2017; 317: 269-279. 20. Graham BL, Steenbruggen I, Miller MR, et al. Standardization of spirometry 2019 update. An official American Thoracic Society and European Respiratory Society technical statement. Am J Respir Crit Care Med 2019; 200: e70- e88. 21. Miller MR, Hankinson J, Brusasco V, et al. Standardisation of spirometry. Eur Respir J 2005; 26: 319-338. 186 References 22. Pellegrino R, Viegi G, Brusasco V, et al. Interpretative strategies for lung function tests. Eur Respir J 2005; 26: 948- 968. 23. Tan WC, Vollmer WM, Lamprecht B, et al. Worldwide patterns of bronchodilator responsiveness: results from the Burden of Obstructive Lung Disease study. Thorax 2012; 67: 718-726. 24. Reddel HK, Taylor DR, Bateman ED, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009; 180: 59-99. 25. Brouwer AF, Brand PL. Asthma education and monitoring: what has been shown to work. Paediatr Respir Rev 2008; 9: 193-199. 26. Coates AL, Wanger J, Cockcroft DW, et al. ERS technical standard on bronchial challenge testing: general considerations and performance of methacholine challenge tests. Eur Respir J 2017; 49. 27. Hallstrand TS, Leuppi JD, Joos G, et al. ERS technical standard on bronchial challenge testing: pathophysiology and methodology of indirect airway challenge testing. Eur Respir J 2018; 52. 28. Ramsdale EH, Morris MM, Roberts Immunol 1985; 75: 573-577. RS, et al. Asymptomatic bronchial hyperresponsiUveTnEess in rhinitis. J Allergy Clin 29. van and Haren EH, bronchial Lammers JW, Festen hyperresponsiveness J, et al. The effects of in adult patients with tchyestiinchfaiblerodsciso.rRtiecsopsitrTeMrRoIeiBdd budesonide on lung 1995; 89: 209-214. function 30. Joshi S, Powell T, Watkins WJ, et al. Exercise-induced bronchoconstriction iDnIsSchool-aged children who had chronic lung disease in infancy.[Erratum in J Pediatr. 2013 Jun;162(6):1298]. JoOurRnal of Pediatrics 2013; 162: 813-818.e811. 31. Ramsdale EH, Morris MM, Roberts relationship to airflow obstruction RS, and et al. cold aBirrornecsphoianl srievsepnoensssi.vTeOhnoPersYasxto19m84e;th3a9c:h9o1l2in-e91in8.chronic bronchitis: 32. Ahlstedt S, Murray CS. In vitro diagnosis of allergy: how to intTerCpret IgE antibody results in clinical practice. Primary 33. Care Respiratory Journal Korevaar DA, Westerhof 2006; 15: GA, Wang 228-236. J, et al. Diagnostic accuNrOacy of minimally invasive markers for detection of airway eosinophilia in asthma: a systematic review and met-aD-aOnalysis. The Lancet Respiratory Medicine 2015; 3: 290-300. 34. Fahy JV. 57-65. Type 2 inflammation in asthma--preseRnItAiLn most, absent in many. Nature Reviews Immunology 2015; 15: 35. fAomr ethriecaOnnTlihnoeraancdicOSoffcliineetyM, EeuarsoupreeamneRnetsopAfiTrEaExthoaryleSdoLcoiewtye.rARTeSs/pEirRaStoRreycNomitrmiceOnxdiadteioannsdfoNraSstaalnNditarridciOzexdidPer,o2c0e0d5u.res 36. AHmacecruicriaanAJ,oMurinchalilos fAR, eMspicihraietolsryS,&etCEarilDt.iEcMxahl Calaerde Medicine 2005; 171: 912-930. nitric oxide: a biomarker integrating both lung function and airway inflammation changes. JournalIGofHATllergy & Clinical Immunology 2014; 134: 554-559. 37. MAaerdoincaSlDA,sVsaoncidaetimonheJoenurKnPLa,YlB2Ro0u0l8e;t LP, et al. Overdiagnosis 179: 1121-1131. of asthma in obese and nonobese adults. Canadian 38. Lucas AE, Smeenk FW,CSOmeele IJ, et al. Overtreatment with inhaled corticosteroids and diagnostic problems in primary care patients, an exploratory study. Family practice 2008; 25: 86-91. 39. Marklund B, Tunsater A, Bengtsson C. How often is the diagnosis bronchial asthma correct? Family practice 1999; 16: 112-116. 40. Montnemery P, Hansson L, Lanke J, et al. Accuracy of a first diagnosis of asthma in primary health care. Family practice 2002; 19: 365-368. 41. Gibson PG, Chang AB, Glasgow NJ, et al. CICADA: Cough in Children and Adults: Diagnosis and Assessment. Australian cough guidelines summary statement. Medical Journal of Australia 2010; 192: 265-271. 42. Halvorsen T, Walsted ES, Bucca C, et al. Inducible laryngeal obstruction: an official joint European Respiratory Society and European Laryngological Society statement. Eur Respir J 2017; 50. 43. Desai D, Brightling C. Cough due to asthma, cough-variant asthma and non-asthmatic eosinophilic bronchitis. Otolaryngologic Clinics of North America 2010; 43: 123-130. 44. Baur X, Sigsgaard T, Aasen TB, et al. Guidelines for the management of work-related asthma.[Erratum appears in Eur Respir J. 2012 Jun;39(6):1553]. European Respiratory Journal 2012; 39: 529-545. References 187 45. Henneberger PK, Patel JR, de Groene GJ, et al. Workplace interventions for treatment of occupational asthma. Cochrane Database Syst Rev 2019; 10: CD006308. 46. Levy ML, Nicholson PJ. Occupational asthma case finding: a role for primary care. British Journal of General Practice 2004; 54: 731-733. 47. Parsons JP, Hallstrand TS, Mastronarde JG, et al. An official American Thoracic Society clinical practice guideline: exercise-induced bronchoconstriction. American Journal of Respiratory & Critical Care Medicine 2013; 187: 1016- 1027. 48. Carlsen KH, Anderson SD, Bjermer L, et al. Exercise-induced asthma, respiratory and allergic disorders in elite athletes: epidemiology, mechanisms and diagnosis: part I of the report from the Joint Task Force of the European Respiratory Society (ERS) and the European Academy of Allergy and Clinical Immunology (EAACI) in cooperation with GA2LEN. Allergy 2008; 63: 387-403. 49. Murphy VE, Gibson PG. Asthma in pregnancy. Clinics in chest medicine 2011; 32: 93-110, ix. 50. Adams RJ, Wilson DH, Appleton S, et al. Underdiagnosed asthma in South Australia. Thorax 2003; 58: 846-850. 51. Hsu Clin J, Chen J, Immunol Mirabelli MC. Pract 2018; 6: Asthma morbidity, 236-243.e237. comorbidities, and modifiable factors amUToEng older adults. J Allergy 52. MPaerschhaalnl iMsmBs,,SAcshsweassrmtzsetneti,naRnMd ,MAadnaamgesmL,eenttaol.fADnysOpfnfiecaia.lAAmmeerricicaannJTohuornraacl iocfSRoecsiTeptRiryaIBSttoartyeamnednCt:riUtipcadlaCtearoenMtheedicine 2012; 185: 435-452. DIS 53. Januzzi JL, Jr., Camargo CA, Anwaruddin S, et al. The N-terminal Pro-BNP iOnvRestigation of dyspnea in the emergency 54. department (PRIDE) study. American Journal Global Initiative for Chronic Obstructive Lung oDfisCeaarsdeio(lGoOgyLD20).0G5l;o9b5a:Ol 9SP4tYr8a-t9e5g4y. for Diagnosis, Management and Prevention of COPD. 2022 Report. Fontana, WI, USA: GOLD; 202T2.CAvailable from: https://goldcopd.org/2022-gold- 55. reports-2/. Hanania NA, Celli BR, Donohue JF, et al. Bronchodilator reverNsiObility in COPD. Chest 2011; 140: 1055-1063. 56. Alshabanat A, Zafari Z, Albanyan O, et al. Asthma and CO- DPDOoverlap syndrome (ACOS): a systematic review and 57. mBoeutlaetanLPal.yAssist.hPmLaoSanOdneob2e0s1it5y;.1C0l:inei0ca1l3&60E6x5p.erimRenIAtaLl Allergy 2013; 43: 8-21. 58. mvaonrHbiudilsystoebdeeseA.,RCeassptriroatCoarbyeMzaesdMic,invean20d1e3G; A1e0iTjn7E:G1J3,5e6t-a1l3. 6U4n.derdiagnosis and overdiagnosis of asthma in the 59. Masekela R, Int J Environ Zurba L, Gray D. Dealing Res Public Health 2018; 1w6Ei:thD62aM.ccess to spirometry in Africa: a commentary on challenges and solutions. 60. Mortimer K, Reddel HK, Pitrez PMI,GeHt Tal. Asthma management in low- and middle-income countries: case for 61. cGhloabnagleA. EstuhrmRaesNpeirtwJ 2o0rk2.2T.hePgYloRbal asthma report 2018. Auckland, New Zealand: Global Asthma Network; 2018 [cited 2021 September]. ACvOailable from: http://globalasthmareport.org. 62. Huang WC, Fox GJ, Pham NY, et al. A syndromic approach to assess diagnosis and management of patients presenting with respiratory symptoms to healthcare facilities in Vietnam. ERJ Open Res 2021; 7. 63. Aaron SD, Boulet LP, Reddel HK, et al. Underdiagnosis and overdiagnosis of asthma. Am J Respir Crit Care Med 2018; 198: 1012-1020. 64. World Health Organization. WHO package of essential noncommunicable (PEN) disease interventions for primary health care. Geneva: WHO; 2020. Available from: https://www.who.int/publications/i/item/who-package-of- essential-noncommunicable-(pen)-disease-interventions-for-primary-health-care. 65. Taylor DR, Bateman ED, Boulet LP, et al. A new perspective on concepts of asthma severity and control. Eur Respir J 2008; 32: 545-554. 66. Aroni R, Goeman D, Stewart K, et al. Enhancing validity: what counts as an asthma attack? Journal of Asthma 2004; 41: 729-737. 67. McCoy K, Shade DM, Irvin CG, et al. Predicting episodes of poor asthma control in treated patients with asthma. J Allergy Clin Immunol 2006; 118: 1226-1233. 188 References 68. Meltzer EO, Busse WW, Wenzel SE, et al. Use of the Asthma Control Questionnaire to predict future risk of asthma exacerbation. J Allergy Clin Immunol 2011; 127: 167-172. 69. Schatz M, Zeiger RS, Yang SJ, et al. The relationship of asthma impairment determined by psychometric tools to future asthma exacerbations. Chest 2012; 141: 66-72. 70. Stanford RH, Shah MB, D'Souza AO, et al. Short-acting -agonist use and its ability to predict future asthma-related outcomes. Ann Allergy Asthma Immunol 2012; 109: 403-407. 71. Nwaru BI, Ekstrom M, Hasvold P, et al. Overuse of short-acting beta2-agonists in asthma is associated with increased risk of exacerbation and mortality: a nationwide cohort study of the global SABINA programme. Eur Respir J 2020; 55: 1901872. 72. Tattersfield AE, Postma DS, Barnes PJ, et al. Exacerbations of asthma: a descriptive study of 425 severe exacerbations. The FACET International Study Group. Am J Respir Crit Care Med 1999; 160: 594-599. 73. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respir Med 2007; 101: 2437-2446. 74. oBfushel vRe,rKeuansathPm, PaeetexarsceMrbJ,aetitoanls. Tfohleloewffiencgteopfisbouddeessoonf ihdiegh/forermlieovteerroulsem: aainnteexnpalonrcaetoaUnrTydEarnealileyvseisrothf etwraopyraonndothmeisreisdk, 75. controlled studies with O'Byrne PM, FitzGerald comparisons to standard therapy. JM, Bateman ED, et al. Effect of a sRinegspleirdRaeyso2f0in12cr;e1a3s:eT5dR9aI.Bs-needed budesonide-formoterol use on short-term risk of severe exacerbations in patients with mild asthmDa:ISa post-hoc analysis of the SYGMA 1 study. Lancet Respir Med 2021; 9: 149-158. OR 76. O'Byrne PM, Reddel HK, Eriksson Eur Respir J 2010; 36: 269-276. G, et al. Measuring asthma contOroPlY: a comparison of three classification systems. 77. Thomas M, Kay S, Pike J, et al. The Asthma Control Test (ACT)TasCa predictor of GINA guideline-defined asthma 78. control: analysis of LeMay KS, Armour a multinational cross-sectional CL, Reddel HK. Performance of asubrrvieefy.aNPsOtrhimmaCacroenRtreoslpsicrrJe2e0n0in9g; 18: 41-49. tool in community pharmacy: a cross-sectional and prospective longitudinal analysis-. DPrOimary Care Respiratory Journal 2014; 23: 79-84. 79. Ahmed S, Canadian Ernst P, Tamblyn R, Respiratory Journal 2e0t 0a7l.;V1a4l:id1a0t5io-1n0Ro9fI.ATLhe 30 Second Asthma Test as a measure of asthma control. 80. Pinnock H, Burton C, routine asthma care: Campbell a real-life Sv,aelitdaalt.ioCnlinAsitTcuaEdlyim. PprliimcaCtiaornes of the Respir Royal College of Physicians J 2012; 21: 288-294. three questions in 81. cYoanwtnroBllPe,dWtroiallla.nAPnCn,FRaamnkMMedA,2e0t1a8l;.E1UD6s:eM1o0f0A-1st1h0m. a APGAR Tools in primary care practices: a cluster-randomized 82. Juniper EF, O'Byrne PM, GuyatItGGHHT, et al. Development and validation of a questionnaire to measure asthma 83. cJuonnitpreorl.EEFu,rSRveesnpsisroJn1K9,9M9;Po1Yr4kR:A9C0,2e-t90a7l..Measurement properties and interpretation of three shortened versions of the asthma control quCesOtionnaire. Respir Med 2005; 99: 553-558. 84. Juniper EF, Bousquet J, Abetz L, et al. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006; 100: 616-621. 85. Juniper EF, Bousquet J, Abetz L, et al. Identifying 'well-controlled' and 'not well-controlled' asthma using the Asthma Control Questionnaire. Respiratory Medicine 2006; 100: 616-621. 86. Nathan RA, Sorkness CA, Kosinski M, et al. Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004; 113: 59-65. 87. Schatz M, Kosinski M, Yarlas AS, et al. The minimally important difference of the Asthma Control Test. J Allergy Clin Immunol 2009; 124: 719-723 e711. 88. Liu AH, Zeiger R, Sorkness C, et al. Development and cross-sectional validation of the Childhood Asthma Control Test. J Allergy Clin Immunol 2007; 119: 817-825. 89. Juniper EF, Gruffydd-Jones K, Ward S, et al. Asthma Control Questionnaire in children: validation, measurement properties, interpretation. Eur Respir J 2010; 36: 1410-1416. 90. Nguyen JM, Holbrook JT, Wei CY, et al. Validation and psychometric properties of the Asthma Control Questionnaire among children. Journal of Allergy & Clinical Immunology 2014; 133: 91-97.e91-96. References 189 91. Chipps B, Zeiger RS, Murphy K, et al. Longitudinal validation of the Test for Respiratory and Asthma Control in Kids in pediatric practices. Pediatrics 2011; 127: e737-747. 92. Murphy KR, Zeiger RS, Kosinski M, et al. Test for respiratory and asthma control in kids (TRACK): a caregiver- completed questionnaire for preschool-aged children. J Allergy Clin Immunol 2009; 123: 833-839 e839. 93. Zeiger RS, Mellon M, Chipps B, et al. Test for Respiratory and Asthma Control in Kids (TRACK): clinically meaningful changes in score. J Allergy Clin Immunol 2011; 128: 983-988. 94. Wildfire JJ, Gergen PJ, Sorkness CA, et al. Development and validation of the Composite Asthma Severity Index--an outcome measure for use in children and adolescents. J Allergy Clin Immunol 2012; 129: 694-701. 95. Haselkorn T, Fish JE, Zeiger RS, et al. Consistently very poorly controlled asthma, as defined by the impairment domain of the Expert Panel Report 3 guidelines, increases risk for future severe asthma exacerbations in The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study. Journal of Allergy and Clinical Immunology 2009; 124: 895-902.e891-894. 96. Patel M, Pilcher J, Reddel HK, et al. Metrics of salbutamol use as predictors of future adverse outcomes in asthma. 97. Clinical & Experimental Suissa S, Ernst P, Boivin Allergy 2013; 43: 1144-1151. JF, et al. A cohort analysis of excess mortality in asthma and theUuTsEe of inhaled beta- 98. agonists. Am J Respir Crit Care Med 1994; Ernst P, Spitzer WO, Suissa S, et al. Risk of 149: fatal 604-610. and near-fatal asthma in relation tToRinIBhaled corticosteroid use. JAMA 1992; 268: 3462-3464. DIS 99. Melani AS, Bonavia M, Cilenti V, et al. Inhaler mishandling remains commoOnRin real life and is associated with 100. reduced disease control. Respir Med 2011; 105: 930-938. Fitzpatrick S, Joks R, Silverberg JI. Obesity is associated with increaseOdPaYsthma severity and exacerbations, and increased serum immunoglobulin E in inner-city adults. Clinical &TECxperimental Allergy 2012; 42: 747-759. 101. Denlinger LC, and Frequent Phillips BR, Ramratnam S, et al. Exacerbations. Am J Respir Crit CInafrlaemMmeadt2o0ry17aN;n1dO9C5o: m30o2r-b3id13F.eatures of Patients with Severe Asthma 102. Burks AW, Tang M, Sicherer S, et al. ICON: food allergy.-JoDuOrnal of Allergy & Clinical Immunology 2012; 129: 906- 103. 920. Murphy VE, Clifton VL, Gibson PG. Asthma exacerRbaIAtiLons during pregnancy: incidence and association with adverse 104. pregnancy outcomes. Thorax 2006; Osborne ML, Pedula KL, O'Hollaren M61,:e1t6a9l.-1AA7sT6sEe. ssing future need for acute care in adult asthmatics: the Profile of 105. AChstohJmHa, PRaisikk SSYtu. dAys:soacpiarotisopnebcteitvweeheenalethlEeDcmtraMoinntiecncaignacreetotreguanseizaatnidona-sbtahsmead astmuodny.gChhigehsts2c0h0o7o;l 1st3u2d:e1n1t5s1in-1S1o6u1t.h Korea. PLoS One 2016; 11: e01510IG22H.T 106. Lim H, Kwon HJ, Lim JA, emergency department evtisaitls.PSfYohRroarts-tthemrma:eAffseycsttoefmfianteicpraervtiiecwulaatnedmmaetttae-raonnalcyhsiilsd.rJePnr'esvhMosepditaPluabdlimc iHsseiaolnths and 2016; 49: 205-219. CO 107. Zheng XY, Ding H, Jiang LN, et al. Association between air pollutants and asthma emergency room visits and hospital admissions in time series studies: A systematic review and meta-analysis. PLoS One 2015; 10: e0138146. 108. Mazenq J, Dubus JC, Gaudart J, et al. City housing atmospheric pollutant impact on emergency visit for asthma: A classification and regression tree approach. Respir Med 2017; 132: 1-8. 109. Sturdy PM, Victor CR, Anderson HR, et al. Psychological, social and health behaviour risk factors for deaths certified as asthma: a national case-control study. Thorax 2002; 57: 1034-1039. 110. Fuhlbrigge AL, Kitch BT, Paltiel AD, et al. FEV1 is associated with risk of asthma attacks in a pediatric population. J Allergy Clin Immunol 2001; 107: 61-67. 111. Ulrik CS. Peripheral eosinophil counts as a marker of disease activity in intrinsic and extrinsic asthma. Clin Exp Allergy 1995; 25: 820-827. 112. Pongracic JA, Krouse RZ, Babineau DC, et al. Distinguishing characteristics of difficult-to-control asthma in inner-city children and adolescents. J Allergy Clin Immunol 2016; 138: 1030-1041. 113. Belda J, Giner J, Casan P, et al. Mild exacerbations and eosinophilic inflammation in patients with stable, well- controlled asthma after 1 year of follow-up. Chest 2001; 119: 1011-1017. 190 References 114. Ulrik CS, Frederiksen J. Mortality and markers of risk of asthma death among 1,075 outpatients with asthma. Chest 1995; 108: 10-15. 115. Zeiger RS, Schatz M, Zhang F, et al. Elevated exhaled nitric oxide is a clinical indicator of future uncontrolled asthma in asthmatic patients on inhaled corticosteroids. Journal of Allergy and Clinical Immunology 2011; 128: 412-414. 116. Turner MO, Noertjojo K, Vedal S, et al. Risk factors for near-fatal asthma. A case-control study in hospitalized patients with asthma. Am J Respir Crit Care Med 1998; 157: 1804-1809. 117. Miller MK, Lee JH, Miller DP, et al. Recent asthma exacerbations: a key predictor of future exacerbations. Respir Med 2007; 101: 481-489. 118. Buelo A, McLean S, Julious S, et al. At-risk children with asthma (ARC): a systematic review. Thorax 2018; 73: 813- 824. 119. den Dekker HT, Sonnenschein-van der Voort AMM, de Jongste JC, et al. Early growth characteristics and the risk of reduced lung function and asthma: A meta-analysis of 25,000 children. J Allergy Clin Immunol 2016; 137: 1026-1035. 120. Lange P, Parner J, Vestbo J, et al. A 15-year follow-up study of ventilatory function in adults with asthma. N Engl J 121. Med Ulrik 1998; 339: 1194-1200. CS. Outcome of asthma: longitudinal changes in lung function. Eur Respir J 199U9;T1E3: 904-918. 122. O'Byrne PM, Pedersen S, Crit Care Med 2009; 179: Lamm CJ, 19-24. et al. Severe exacerbations and decline in luTnRgIBfunction in asthma. Am J Respir 123. Raissy HH, Kelly HW, Harkins M, et al. Inhaled corticosteroids in lung diseasDeIsS. Am J Respir Crit Care Med 2013; 187: 798-803. OR 124. Foster JM, Aucott L, van der Werf RH, et al. inhaled corticosteroids in the community: a Hcrigohses-rspeacttiioenntalpaenrcaelyiOvsiesPd.YRseidsepierfMfeectds related to 2006; 100: higher daily 1318-1336. doses of 125. Roland NJ, Bhalla RK, Earis J. The local side effects of inhaled cToCrticosteroids: current understanding and review of 126. the literature. Chest 2004; 126: 213-219. Pedersen S. Do inhaled corticosteroids inhibit growth in chNiOldren? Am J Respir Crit Care Med 2001; 164: 521-535. 127. Loke YK, Blanco P, Thavarajah M, et al. Impact of inh-aDleOd corticosteroids on growth in children with asthma: 128. sWysetcehmslaetricMrEe,vKieewlleaynJdMm, eBtoay-danIOal,yesitsa. Pl.LAocStiOveneRalI2bA0uL1te5r;o1l0o:rep0l1a3c3e4b2o8, .sham acupuncture, or no intervention in 129. asthma. N Engl J Castro M, Rubin AMSe, dLa2v0io1l1e;tt3e6M5:,1e1t9a-1l.2E6f.fAeTcEtiveness and safety of bronchial thermoplasty in the treatment of severe asthma: respiratory and acrmitiuclatlicceanretemr,erdanicdinoEemD2iz0Me1d0,; double-blind, sham-controlled 181: 116-124. clinical trial. American journal of 130. Lazarus SC, Boushey HA, Fahy JIGV,HeTt al. Long-acting beta2-agonist monotherapy vs continued therapy with inhaled 131. cortico Barnes steroids in PJ, Szefler pSJa,tRieendtdsPewYl iHRthK,peetrsails.tSeynmt apstothmmsaa:nadrapnedrcoemptizioend co of ntrolled trial. JAMA airway obstruction 2001; 285: 2583-2593. in asthmatic patients: Clinical implications for use ofCreOliever medications. J Allergy Clin Immunol 2019; 144: 1180-1186. 132. Loymans RJ, Honkoop PJ, Termeer EH, et al. Identifying patients at risk for severe exacerbations of asthma: development and external validation of a multivariable prediction model. Thorax 2016; 71: 838-846. 133. Stanford RH, Shah MB, D'Souza AO, et al. Short-acting -agonist use and its ability to predict future asthma-related outcomes. Annals of Allergy, Asthma & Immunology 2012; 109: 403-407. 134. Agusti A, Bel E, Thomas M, et al. Treatable traits: toward precision medicine of chronic airway diseases. Eur Respir J 2016; 47: 410-419. 135. Kohansal R, Martinez-Camblor P, Agusti A, et al. The natural history of chronic airflow obstruction revisited: an analysis of the Framingham offspring cohort. Am J Respir Crit Care Med 2009; 180: 3-10. 136. McGeachie MJ, Yates KP, Zhou X, et al. Patterns of growth and decline in lung function in persistent childhood asthma. New England Journal of Medicine 2016; 374: 1842-1852. 137. Chalitsios CV, Shaw DE, McKeever TM. Corticosteroids and bone health in people with asthma: A systematic review and meta-analysis. Respir Med 2021; 181: 106374. 138. Kerstjens HA, Brand PL, de Jong PM, et al. Influence of treatment on peak expiratory flow and its relation to airway hyperresponsiveness and symptoms. The Dutch CNSLD Study Group. Thorax 1994; 49: 1109-1115. References 191 139. Brand PL, Duiverman EJ, Waalkens HJ, et al. Peak flow variation in childhood asthma: correlation with symptoms, airways obstruction, and hyperresponsiveness during long-term treatment with inhaled corticosteroids. Dutch CNSLD Study Group. Thorax 1999; 54: 103-107. 140. Bateman ED, Boushey HA, Bousquet J, et al. Can guideline-defined asthma control be achieved? The Gaining Optimal Asthma ControL study. Am J Respir Crit Care Med 2004; 170: 836-844. 141. Jenkins CR, Thien FC, Wheatley JR, et al. Traditional and patient-centred outcomes with three classes of asthma medication. Eur Respir J 2005; 26: 36-44. 142. Li D, German D, Lulla S, et al. Prospective study of hospitalization for asthma. A preliminary risk factor model. Am J Respir Crit Care Med 1995; 151: 647-655. 143. Kitch BT, Paltiel AD, Kuntz KM, et al. A single measure of FEV1 is associated with risk of asthma attacks in long-term follow-up. Chest 2004; 126: 1875-1882. 144. Killian KJ, Watson R, Otis J, et al. Symptom perception during acute bronchoconstriction. Am J Respir Crit Care Med 2000; 162: 490-496. 145. Reddel HK, Jenkins CR, Marks Respir J 2000; 16: 226-235. GB, et al. Optimal asthma control, starting with high doseUsToEf inhaled budesonide. Eur 146. Szefler SJ, Martin RJ, King TS, et al. Significant variability in response to asthma. Journal of Allergy & Clinical Immunology 2002; 109: 410-418. inhaled coTrtRicIoBsteroids for persistent 147. Santanello NC, Zhang J, Seidenberg B, et al. What are minimal important chanDgeISs for asthma measures in a clinical trial? Eur Respir J 1999; 14: 23-27. OR 148. Reddel Thorax HK, Marks GB, Jenkins 2004; 59: 922-924. CR. When can personal best peak flowObPeYdetermined for asthma action plans? 149. Frey U, Brodbeck T, Majumdar A, et al. Risk of severe asthma epiTsoCdes predicted from fluctuation analysis of airway 150. function. Nature 2005; 438: 667-670. Julius SM, Davenport KL, Davenport PW. Perception of intrinsNicOand extrinsic respiratory loads in children with life- threatening asthma. Pediatr Pulmonol 2002; 34: 425-43-3D. O 151. Kikuchi Y, Okabe S, Tamura G, et fatal asthma. N Engl J Med 1994; a3l3. 0C:h1e3m2o9s-e1n3s3i4ti.RviItAyLand perception of dyspnea in patients with a history of near- 152. Magadle R, perception oBfedrayrs-pYnaenaa.yCNh,eWst e2i0n0e2r ;P1. 2T1h:e3r2is9k-A3oT3fE3h.ospitalization and near-fatal and fatal asthma in relation to the 153. Nuijsink children M, Hop WC, Jongste JC, with asthma. Journal of eAtstahl.mPEaeDr2c0eM1p3ti;o5n0o: f56b0ro-5n6c4h.oconstriction: a complementary disease marker in 154. Jansen J, McCaffery KJ, Hayen A, eIGt aHl.TImpact of graphic format on perception of change in biological data: 155. CimhpulnicgaKtiFo,nWs feonrzheleSaElt,hBmroozneiktPoJLYri,Rnegt ianl.cIonntedritniaotnios nsualchERaSs/aAsTtShmguai.dPerliinmeasroynCdareefinRietsiopnir,aetovaryluJaotuiornnaaln2d01tr2e;a2tm1:e9n4t-1o0f 0. severe asthma. Eur RespirCJO2014; 43: 343-373. 156. Sulaiman I, Greene G, MacHale E, et al. A randomised clinical trial of feedback on inhaler adherence and technique in patients with severe uncontrolled asthma. Eur Respir J 2018; 51. 157. Lee J, Tay TR, Radhakrishna N, et al. Nonadherence in the era of severe asthma biologics and thermoplasty. Eur Respir J 2018; 51. 158. National Asthma Education and Prevention Program. Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma-Summary Report 2007. J Allergy Clin Immunol 2007; 120: S94-138. 159. Cloutier MM, Baptist AP, Blake KV, et al. 2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program Coordinating Committee Expert Panel Working Group. J Allergy Clin Immunol 2020; 146: 1217-1270. 160. Dusser D, Montani D, Chanez P, et al. Mild asthma: an expert review on epidemiology, clinical characteristics and treatment recommendations. Allergy 2007; 62: 591-604. 161. Bergstrm SE, Boman G, Eriksson L, et al. Asthma mortality among Swedish children and young adults, a 10-year study. Respir Med 2008; 102: 1335-1341. 192 References 162. Reddel HK, Busse WW, Pedersen S, et al. Should recommendations about starting inhaled corticosteroid treatment for mild asthma be based on symptom frequency: a post-hoc efficacy analysis of the START study. Lancet 2017; 389: 157-166. 163. Crossingham I, Turner S, Ramakrishnan S, et al. Combination fixed-dose beta agonist and steroid inhaler as required for adults or children with mild asthma. Cochrane Database Syst Rev 2021; 5: CD013518. 164. Comaru T, Pitrez PM, Friedrich FO, et al. Free asthma medications reduces hospital admissions in Brazil (Free asthma drugs reduces hospitalizations in Brazil). Respir Med 2016; 121: 21-25. 165. Bousquet J, Mantzouranis E, Cruz AA, et al. Uniform definition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation on Severe Asthma. J Allergy Clin Immunol 2010; 126: 926-938. 166. FitzGerald JM, Barnes PJ, Chipps BE, et al. The burden of exacerbations in mild asthma: a systematic review. ERJ Open Res 2020; 6: 00359-02019. 167. Boulet L-P, Vervloet D, Magar Y, et al. Adherence: the goal to control asthma. Clinics in Chest Medicine 2012; 33: 168. 405-417. Murphy J, McSharry J, Hynes L, et al. Prevalence and predictors of adherence to inhaUlTedE corticosteroids in young 169. aWdiulslotsn(1K5C-,3G0oyueldarMs)Kw, iKthrisahsnthamn JaA: ,aestyaslt.eAmnaOticffirceivaileAwmaenrdicamneTtah-oarnaacliycsSiso.cJieAtsytThWmRoIaBrk2s0h2o0p: 1-23. Report. A framework for addressing multimorbidity in clinical practice guidelines for pulmonary diseDaIsSe, critical Illness, and sleep disorders. Ann Am Thorac Soc 2016; 13: S12-21. OR 170. Taylor YJ, Tapp H, among children. J Shade LE, et al. Impact of shared Asthma 2018; 55: 675-683. decision makiOngPoYn asthma quality of life and asthma control 171. Gibson PG, Powell H, Coughlan J, et al. Self-management eduTcaCtion and regular practitioner review for adults with 172. asthma. Guevara Cochrane Database JP, Wolf FM, Grum Syst CM, eRteavl.2E0f0fe3c:tCsDo0f0e1d1u1c7a.tionNaOl interventions for self management of asthma in children and adolescents: systematic review and me-taD-aOnalysis. BMJ 2003; 326: 1308-1309. 173. Wilson SR, controlled Strub P, asthma. Buist Am J AS, et Respir aClr.itShCaarreedMtreedat2Rm0IA1e0Ln;t decision making 181: 566-577. improves adherence and outcomes in poorly 174. Cabana MD, Slish KK, Evans 2006; 117: 2149-2157. D, et al. ImpacAt ToEf physician asthma care education on patient outcomes. Pediatrics 175. sPealrft-rmidagneaMgeRm, eHniltl.S1R9.9E8nWhaonrclidngAsctahrmEe DafoMMr peeeotipnlge Ewdiuthcaatsiothnmaan:dthDeelrioveleryoof fcoCmarme uWnoicraktiinognG, eroduupca. tEiuorn,RtersapinirinJg20an0d0; 16: 333-348. IGHT 176. 177. MClaargkuNireMP, ,CPaibtcaenaathMlyDC, .NKaPenyYBcR,oemt mal.uTnhiceatciloinnicsikainll-spaantidenhtopwatrotnaecrqshuiipreptahreamdi.gBmM: oJ u2t0c0o2m; 3e2s 5a:ss6o9c7i-a7t0e0d. with physician communication behavCioOr. Clin Pediatr (Phila) 2008; 47: 49-57. 178. Rosas-Salazar C, Apter AJ, Canino G, et al. Health literacy and asthma. Journal of Allergy & Clinical Immunology 2012; 129: 935-942. 179. Rosas-Salazar C, Ramratnam SK, Brehm JM, et al. Parental numeracy and asthma exacerbations in Puerto Rican children. Chest 2013; 144: 92-98. 180. Apter AJ, Wan F, Reisine S, et al. The association of health literacy with adherence and outcomes in moderate- severe asthma. Journal of Allergy & Clinical Immunology 2013; 132: 321-327. 181. Poureslami I, Nimmon L, Doyle-Waters M, et al. Effectiveness of educational interventions on asthma self- management in Punjabi and Chinese asthma patients: a randomized controlled trial. Journal of Asthma 2012; 49: 542-551. 182. Haahtela T, Tuomisto LE, Pietinalho A, et al. A 10 year asthma programme in Finland: major change for the better. Thorax 2006; 61: 663-670. 183. Ait-Khaled N, Enarson DA, Bencharif N, et al. Implementation of asthma guidelines in health centres of several developing countries. Int J Tuberc Lung Dis 2006; 10: 104-109. References 193 184. Plaza V, Cobos A, Ignacio-Garcia JM, et al. [Cost-effectiveness of an intervention based on the Global INitiative for Asthma (GINA) recommendations using a computerized clinical decision support system: a physicians randomized trial]. Medicina clinica 2005; 124: 201-206. 185. Haldar P, Pavord ID, Shaw DE, et al. Cluster analysis and clinical asthma phenotypes. Am J Respir Crit Care Med 2008; 178: 218-224. 186. Gibson PG, Powell H, Ducharme FM. Differential effects of maintenance long-acting beta-agonist and inhaled corticosteroid on asthma control and asthma exacerbations. J Allergy Clin Immunol 2007; 119: 344-350. 187. O'Byrne PM, Naya IP, Kallen A, et al. Increasing doses of inhaled corticosteroids compared to adding long-acting inhaled beta2-agonists in achieving asthma control. Chest 2008; 134: 1192-1199. 188. O'Byrne PM, FitzGerald JM, Bateman ED, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med 2018; 378: 1865-1876. 189. Bateman ED, Reddel HK, O'Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med 2018; 378: 1877-1887. 190. Beasley R, Holliday M, Reddel J Med 2019; 380: 2020-2030. HK, et al. Controlled trial of budesonide-formoterol as neUeTdEed for mild asthma. N Engl 191. Hardy J, Baggott C, Fingleton J, et al. Budesonide-formoterol terbutaline reliever therapy in adults with mild to moderate arsetlhiemvear(tPhReArCapTyICvAeLr)s:TuaRs5mIB2a-wineteekn,aonpceenb-uladbeeslo, nide plus multicentre, superiority, randomised controlled trial. The Lancet 2019; 394: 91D9IS-928. 192. Bateman ED, Reddel HK, Eriksson G, et al. Overall asthma control: the relaOtiRonship between current control and 193. future risk. Journal of Allergy & Clinical Immunology 2010; 125: Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled c6o0r0t-iO6co0Ps8Yt.eroids and long-acting beta-agonists as controller and quick relief therapy with exacerbations and symptTomC control in persistent asthma: A systematic 194. review Petsky and meta-analysis. HL, Li A, Chang AB. JAMA 2018; 319: 1485-1496. Tailored interventions based on spNutOum eosinophils versus clinical symptoms for asthma in children and adults. Cochrane Database Syst Rev 201-7D; 8O: CD005603. 195. AGSibthsomnaPTGR.eUastimngenfrtaAcLtigoonraitlhemxhsatlueddiensit.rCiclinoixciadleatnoRdgIEAuxiLpdeeraimstehnmtaal therapy: design and methodological allergy 2009; 39: 478-490. issues for 196. oDxwideeikleRvAe,lBs o(FgEgNs OPB) ,foErrzculirnuicmalSaCp,pelticaalt.iAonnso. fAfAimcTieaErl iAcaTnS cJoliunricnaallporfaRcteiscpeirgautiodreylianned: inCtreitricparleCtaatrieonMoefdeicxihnaele2d01n1it;r1ic84: 197. 602-615. Petsky HL, Kew KM, Chang AB. Exhaled EnDitrMic oxide levels to guide treatment for children with asthma. Cochrane Database Syst Rev 2016; 11: CD01I1G4H3T9. 198. Petsky HL, Kew KM, Turner Database Syst Rev 2016; 9: CCPD, eY0t1Ra1l4. 4E0x.haled nitric oxide levels to guide treatment for adults with asthma. Cochrane 199. Chung KF, Wenzel SE, BroCzeOk JL, et al. International ERS/ATS Guidelines on Definition, Evaluation and Treatment of Severe Asthma. European Respiratory Journal 2014; 43: 343-373. 200. Heaney LG, Busby J, Hanratty CE, et al. Composite type-2 biomarker strategy versus a symptom-risk-based algorithm to adjust corticosteroid dose in patients with severe asthma: a multicentre, single-blind, parallel group, randomised controlled trial. Lancet Respir Med 2021; 9: 57-68. 201. Roche N, Reddel HK, Agusti A, et al. Integrating real-life studies in the global therapeutic research framework. The Lancet Respiratory Medicine 2013; 1: e29-e30. 202. Chung KF. New treatments for severe treatment-resistant asthma: targeting the right patient. The Lancet Respiratory Medicine 2013; 1: 639-652. 203. Drazen JM. Asthma: the paradox of heterogeneity. Journal of Allergy & Clinical Immunology 2012; 129: 1200-1201. 204. Busse WW, Pedersen S, Pauwels RA, et al. The Inhaled Steroid Treatment As Regular Therapy in Early Asthma (START) study 5-year follow-up: effectiveness of early intervention with budesonide in mild persistent asthma. J Allergy Clin Immunol 2008; 121: 1167-1174. 205. Selroos O, Pietinalho A, Lofroos AB, et al. Effect of early vs late intervention with inhaled corticosteroids in asthma. Chest 1995; 108: 1228-1234. 194 References 206. Selroos O. Effect of disease duration on dose-response of inhaled budesonide in asthma. Respir Med 2008; 102: 1065-1072. 207. Price DB, Buhl R, Chan A, et al. Fractional exhaled nitric oxide as a predictor of response to inhaled corticosteroids in patients with non-specific respiratory symptoms and insignificant bronchodilator reversibility: a randomised controlled trial. Lancet Respir Med 2018; 6: 29-39. 208. Reddel HK, FitzGerald JM, Bateman ED, et al. GINA 2019: a fundamental change in asthma management: Treatment of asthma with short-acting bronchodilators alone is no longer recommended for adults and adolescents. Eur Respir J 2019; 53: 1901046. 209. Hardy J, Baggott C, Fingleton J, et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline reliever therapy in adults with mild to moderate asthma (PRACTICAL): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet 2019; 394: 919-928. 210. Wechsler ME, Szefler SJ, Ortega VE, et al. Step-up therapy in black children and adults with poorly controlled asthma. N Engl J Med 2019; 381: 1227-1239. 211. vKeerrssutjsemnsoHmAeMta,sMonaes-pienrdoacJ,aCtehraoplmoratnwKicRe,-edtaailly. Ofluntciec-adsaoinlye,-ssianlmglee-tienrhoallienrpmaotimenettsawsoiUtnheT-iEninaddaecqauteartoelly-gclyocnotproylrlreodnium 2 12 . asthma El Baou (IRIDIUM): C, Di Santo a randomised, double-blind, controlled phase 3 stefano RL, Alfonso-Cristancho R, et al. Effect of study. inhale L d acnocrTteitRcoRIBsetseprior Med 2020; 8: id particle size 1000-1012. on asthma efficacy and safety outcomes: a systematic literature review and meta-anaDlyIsSis. BMC Pulm Med 2017; 17: 31. 213. Bateman ED, O'Byrne PM, FitzGerald JM, et al. Positioning as-needed bOuRdesonide-formoterol for mild asthma: 214. eRfefdedcteol Hf pKr,eOs'tBuydrynetrPeMatm, FeitnztGienrpalodoJleMd, aentaally.sEisffoicfaScYyGaMndAs1afaentyd o2Of. PaAsYn-nneAemdeTdhbouradceSsoocni2d0e2-f1o;r1m8o: t2e0r0o7l -in20a1d7o.lescents with mild asthma. J Allergy Clin Immunol Pract 2021; 9: 3069-T30C77.e3066. 215. O'Byrne asthma: PthMe,OBPaTrnIMesAPrJa,nRdoodmrigizueedz-tRrioails.iAnmR,JeRteaslp. LiroCwridt oCsaeNreOinMhaelded20b0u1d;e1s6o4n(i8dePtan1d): formoterol in 1392-1397. mild persistent 216. FitzGerald JM, O'Byrne PM, Bateman ED, et al. Safet-yDoOf as-needed budesonide-formoterol in mild asthma: data 217. from the two phase Barnes CB, Ulrik CS. AIIsI tShYmGaMaAnsdtuaddiheesr.eDnrcuegtSoaRifnI2Ah0aL2le1d; 44: 467-478. corticosteroids: current status and future perspectives. Respir 218. Care 2015; Hancox RJ. 60. Concluding remarks: can we exApTlaEin the association of beta-agonists with asthma mortality? A 219. hypothesis. Lazarinis N, JClirngeRnesveAnllLe,rEgkysItmrmmuTn,oEeltD2a0Ml0. 6C;o3m1b: i2n7a9ti-o2n88o.f budesonide/formoterol on demand improves asthma control by reducing exercise-inIdGuHcTed bronchoconstriction. Thorax 2014; 69: 130-136. 220. Papi A, Canonica asthma. N Engl J GW, Med 2M0a0eP7s;Yt3rRe5l6li: P, et al. Rescue 2040-2052. use of beclomethasone and albuterol in a single inhaler for mild 221. Martinez FD, ChinchilliCVOM, Morgan WJ, et al. Use of beclomethasone dipropionate as rescue treatment for children with mild persistent asthma (TREXA): a randomised, double-blind, placebo-controlled trial. Lancet 2011; 377: 650- 657. 222. Calhoun WJ, Ameredes BT, King TS, et al. Comparison of physician-, biomarker-, and symptom-based strategies for adjustment of inhaled corticosteroid therapy in adults with asthma: the BASALT randomized controlled trial. JAMA 2012; 308: 987-997. 223. Sumino K, Bacharier LB, Taylor J, et al. A pragmatic trial of symptom-based inhaled corticosteroid use in African- American children with mild asthma. The journal of allergy and clinical immunology In practice 2019. 224. Pauwels RA, Pedersen S, Busse WW, et al. Early intervention with budesonide in mild persistent asthma: a randomised, double-blind trial. Lancet 2003; 361: 1071-1076. 225. Crompton G. A brief history of inhaled asthma therapy over the last fifty years. Prim Care Respir J 2006; 15: 326- 331. 226. Suissa S, Ernst P, Benayoun S, et al. Low-dose inhaled corticosteroids and the prevention of death from asthma. N Engl J Med 2000; 343: 332-336. References 195 227. Suissa S, Ernst P, Kezouh A. Regular use of inhaled corticosteroids and the long term prevention of hospitalisation for asthma. Thorax 2002; 57: 880-884. 228. Reddel HK, Ampon RD, Sawyer SM, et al. Risks associated with managing asthma without a preventer: urgent healthcare, poor asthma control and over-the-counter reliever use in a cross-sectional population survey. BMJ Open 2017; 7: e016688. 229. Haahtela T, Jarvinen M, Kava T, et al. Comparison of a b2-agonist, terbutaline, with an inhaled corticosteroid, budesonide, in newly detected asthma. New England Journal of Medicine 1991; 325: 388-392. 230. Baan EJ, Hoeve CE, De Ridder M, et al. The ALPACA study: (In)Appropriate LAMA prescribing in asthma: A cohort analysis. Pulm Pharmacol Ther 2021; 71: 102074. 231. Welsh EJ, Cates CJ. Formoterol versus short-acting beta-agonists as relief medication for adults and children with asthma. Cochrane Database Syst Rev 2010: CD008418. 232. Tattersfield AE, Lfdahl CG, Postma DS, et al. Comparison of formoterol and terbutaline for as-needed treatment of asthma: a randomised trial. Lancet 2001; 357: 257-261. 233. Pauwels RA, Sears effectiveness trial. MR, Campbell M, et al. Formoterol as relief medication European Respiratory Journal 2003; 22: 787-794. in asthma: a UwToErldwide safety and 234. aRsatbhemKaFe, AxaticeenrzbaatTio, Mnsa: gayraarnPd,oemt aisle. dEfcfeocnttroofllbeudd,edsoounbidlee-binlincdomstbuidnya.tLioanncweitth20fo0r6m;T3oR6tIe8Br:o7l4f4o-r7r5e3li.ever therapy in 235. Rodrigo GJ, Castro-Rodriguez JA. Safety of long-acting beta agonists for the treDaItSment of asthma: clearing the air. Thorax 2012; 67: 342-349. OR 236. Adams NP, Bestall Database Syst Rev JB, Malouf R, et al. 2005: CD002738. Inhaled beclomethasone versuOsPpYlacebo for chronic asthma. Cochrane 237. Adams NP, Bestall JC, Lasserson TJ, et al. Fluticasone versus placeTbCo for chronic asthma in adults and children. 238. Cochrane Database of Systematic Reviews Tan DJ, Bui DS, Dai X, et al. Does the use of 2in0h0a8l:eCdDc0o0r3ti1c3o5st.eNroOids in asthma benefit lung function in the long-term? A systematic review and meta-analysis. Eur Respir Rev 2-0D2O1; 30. 239. Sumino K, American Bacharier LB, children with Taylor J, et al. mild asthma. J AAlplerraggymCalitniRcIItmArimLaluonfoslyPmrapcttom20-2b0a;se8d: 1in7h6a-1le8d5.ceo1r7ti2c.osteroid use in African- 240. rCehcauurhreanntBaFn,dD/uocrhcahrrmoneicFMas.thAmntai-lienuakdoutlrtisenaenAdaTgceEhniltdsreconm. Cpoacrherdantoe inhaled corticosteroids database of systematic in the management reviews 2012; 5: of 241. CD002314. Food and Drug Administration. FDA reqEuDireMs Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (SinIgGuHlaTir); advises restricting use for allergic rhinitis. FDA; 2020 [cited 2020 04 March 2se0r2io0u].sA-mvaeinlatballe-hferoalmth:-hsitdtpe-se:/Pf/fYewcRwtsw-a.fsdtham.goa-va/nddru-aglsle/drgruy-gd-sruafge.ty-and-availability/fda-requires-boxed-warning-about- 242. Ni Chroinin M, GreenstonCeOI, Lasserson TJ, et al. Addition of inhaled long-acting beta2-agonists to inhaled steroids as first line therapy for persistent asthma in steroid-naive adults and children. Cochrane database of systematic reviews 2009: CD005307. 243. Dahl R, Larsen BB, Venge P. Effect of long-term treatment with inhaled budesonide or theophylline on lung function, airway reactivity and asthma symptoms. Respir Med 2002; 96: 432-438. 244. Rivington RN, Boulet LP, Cote J, et al. Efficacy of Uniphyl, salbutamol, and their combination in asthmatic patients on high-dose inhaled steroids. Am J Respir Crit Care Med 1995; 151: 325-332. 245. American Lung Association Asthma Clinical Research Centers. Clinical trial of low-dose theophylline and montelukast in patients with poorly controlled asthma. American Journal of Respiratory & Critical Care Medicine 2007; 175: 235- 242. 246. Tsiu SJ, Self TH, Burns R. Theophylline toxicity: update. Ann Allergy 1990; 64: 241-257. 247. Guevara JP, Ducharme FM, Keren R, et al. Inhaled corticosteroids versus sodium cromoglycate in children and adults with asthma. Cochrane Database of Systematic Reviews 2006: CD003558. 248. Sridhar AV, McKean M. Nedocromil sodium for chronic asthma in children. Cochrane Database of Systematic Reviews 2006: CD004108. 196 References 249. van der Wouden JC, Uijen JH, Bernsen RM, et al. Inhaled sodium cromoglycate for asthma in children. Cochrane Database of Systematic Reviews 2008: CD002173. 250. Cates CJ, Karner C. Combination formoterol and budesonide as maintenance and reliever therapy versus current best practice (including inhaled steroid maintenance), for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2013; 4: CD007313. 251. Kew KM, Karner C, Mindus SM, et al. Combination formoterol and budesonide as maintenance and reliever therapy versus combination inhaler maintenance for chronic asthma in adults and children. Cochrane Database of Systematic Reviews 2013; 12: CD009019. 252. Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. The Lancet Respiratory Medicine 2013; 1: 23-31. 253. Patel M, Pilcher J, Pritchard A, et al. Efficacy and safety of maintenance and reliever combination budesonide/formoterol inhaler in patients with asthma at risk of severe exacerbations: a randomised controlled trial. The Lancet Respiratory Medicine 2013; 1: 32-42. 254. Bateman ED, maintenance Harrison TW, Quirce and reliever therapy S, et al. Overall for patients on dasiftfhemreantcotrnetarotml aecnhtiesvteepdsw. RitehspbiurdaUteoTsroEynrideese/faorrcmh o2t0e1r1o;l 12: 38. 255. Jorup C, Lythgoe with asthma. Eur D, Bisgaard H. Respir J 2018; Budesonide/formoterol 51. maintenance and relieTveRrIBtherapy in adolescent patients 256. Demoly P, Louis R, Ses-Petersen U, et al. Budesonide/formoterol maintenDanISce and reliever therapy versus conventional best practice. Respir Med 2009; 103: 1623-1632. OR 257. Cates CJ, Schmidt S, Ferrer M, et al. adverse events. Cochrane Database ISnyhsatleRdevst2e0r1o8id; s1w2:itChDa0n0d69w2i2tOh. oPuYt regular salmeterol for asthma: serious 258. Busse WW, Bateman ED, Caplan AL, et al. Combined analysis TofCasthma safety trials of long-acting beta2-agonists. N 259. Engl J Med 2018; 378: 2497-2505. Peters SP, Bleecker ER, Canonica GW, et al. Serious asthmNa Oevents with budesonide plus formoterol vs. budesonide alone. N Engl J Med 2016; 375: 850-860. - DO 260. Stempel alone. N DEnAg,lRJaMpheidou20IH1,6K; r3a7l4K:M18, 2e2t -a1l8. S3e0r.iousRaIAstLhma events with fluticasone plus salmeterol versus fluticasone 261. Woodcock A, Vestbo J, Bakerly clinical practice: an open-label, NpDar,aellteal lg.rEoAfufTepEc,trivaenndeosms iosef dfluctoicnatrsoolnleedfutrrioaal.tLeapnlcuestv2il0a1n7te; r3o9l0o:n22a4st7h-m22a5c5o. ntrol in 262. vSveersdussatceornHti,nJuoinngesuRsu, aBlocsaarneqiunetthNe,AeEstDtahlMm. PaaStiaelfnotr-dreLpuonrgteSdtuoduyt.coRmesepsirwMitehdin2i0ti1a8ti;o1n4o1f: fluticasone 198-206. furoate/vilanterol 263. Virchow JC, Backer V, Kuna P, eIGt aHl.TEfficacy of a house dust mite sublingual allergen immunotherapy tablet in adults 264. with allergic Mosbech H, Dasetchkmelam: aanrnanRPd,YodRme iBzleady clinical trial. JAMA 2016; 315: 1715-1725. F, et al. Standardized quality (SQ) house dust mite sublingual immunotherapy tablet (ALK) reduces inChOaled corticosteroid use while maintaining asthma control: a randomized, double-blind, placebo-controlled trial. J Allergy Clin Immunol 2014; 134: 568-575.e567. 265. Ducharme FM, Ni Chroinin M, Greenstone I, et al. Addition of long-acting beta2-agonists to inhaled steroids versus higher dose inhaled steroids in adults and children with persistent asthma. Cochrane Database of Systematic Reviews 2010: CD005533. 266. Powell H, Gibson PG. Inhaled corticosteroid doses in asthma: an evidence-based approach. Med J Aust 2003; 178: 223-225. 267. Chauhan BF, Ducharme FM. Addition to inhaled corticosteroids of long-acting beta2-agonists versus anti- leukotrienes for chronic asthma. Cochrane Database of Systematic Reviews 2014; 1: CD003137. 268. Evans DJ, Taylor DA, Zetterstrom O, et al. A comparison of low-dose inhaled budesonide plus theophylline and high- dose inhaled budesonide for moderate asthma. N Engl J Med 1997; 337: 1412-1418. 269. Adams NP, Jones PW. The dose-response characteristics of inhaled corticosteroids when used to treat asthma: an overview of Cochrane systematic reviews. Respir Med 2006; 100: 1297-1306. 270. Vaessen-Verberne AA, van den Berg NJ, van Nierop JC, et al. Combination therapy salmeterol/fluticasone versus doubling dose of fluticasone in children with asthma. Am J Respir Crit Care Med 2010; 182: 1221-1227. References 197 271. Bisgaard H, Le Roux P, Bjamer D, et al. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest 2006; 130: 1733-1743. 272. Stempel DA, Szefler SJ, Pedersen S, et al. Safety of adding salmeterol to fluticasone propionate in children with asthma. N Engl J Med 2016; 375: 840-849. 273. Lemanske R, Mauger D, Sorkness C, et al. Step-up therapy for children with uncontrolled asthma receiving inhaled corticosteroids. N Engl J Med 2010; 362: 975-985. 274. Sobieraj DM, Baker WL, Nguyen E, et al. Association of inhaled corticosteroids and long-acting muscarinic antagonists with asthma control in patients with uncontrolled, persistent asthma: a systematic review and meta- analysis. JAMA 2018; 319: 1473-1484. 275. Virchow JC, Kuna P, Paggiaro P, et al. Single inhaler extrafine triple therapy in uncontrolled asthma (TRIMARAN and TRIGGER): two double-blind, parallel-group, randomised, controlled phase 3 trials. Lancet 2019; 394: 1737-1749. 276. Lee LA, Bailes Z, Barnes N, et al. Efficacy and safety of once-daily single-inhaler triple therapy (FF/UMEC/VI) versus FF/VI in patients with inadequately controlled asthma (CAPTAIN): a double-blind, randomised, phase 3A trial. Lancet 277. Respir Med 2021; 9: 69-84. Gessner C, Kornmann O, Maspero J, et al. Fixed-dose combination of indacaterol/glycoUpyTrEronium/mometasone fausrtohamtea:oAncraen-ddaoimlyivseerds,uPshsaaslemIeIItbe,rnool/nfl-uintifcearsioorniteytswtuicdey-d(AaiRlyGpOluNs).tRioetsrpoipriuMmedon2c0e2T-0dR;a1IiBl7y0i:n1p0a6t0ie2n1t.s with uncontrolled 278. Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combinDaItSion long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthmaO. RCochrane Database Syst Rev 2016: 279. Cd011721. Kim LHY, Saleh C, Whalen-Browne A, et al. Triple vs dual inhaler therOapPyYand asthma outcomes in moderate to severe asthma: a systematic review and meta-analysis. JAMA 20T21C; 325: 2466-2479. 280. pCaatsiaelnetTsBw, iAthalsbyemrspRto, mBleateicckaesrthEmR,aeitmapl.rToivoetrsocpliinuimcaRl oeusptcimomateN(sRO)reagdadr-dolnestshoefrabpaysetolininehcahlaerdaccoterrtiisctoicstse. rRoeisdpsiirnMed 2019; 158: 97-109. - DO 281. rMeqaluoirJiLn,gC1a2rt0i0ermAi,cGrohgerzazmosHo, relteasls. oCfobmupdaersisoonnidoefRtfooIAucLor-ntitmroelsm-ai-lddatyo amnoddtewraictee-aa-sdthaymdao. sRiensgprieragtimoreynMs eindsicuibnjee1ct9s95; 282. 89: 537-543. Toogood JH, Baskerville JC, Jennings B, et al. IAnTflEuence of dosing frequency and schedule on the response of chronic 283. asthmatics to the Lofdahl CG, Reiss aerosol TF, Leff steroid, JA, et al. bRuadnedEsooDmniiMsdeed. ,J Allergy Clin Immunol 1982; 70: 288-298. placebo controlled trial of effect of a leukotriene receptor antagonist, montelukast, on taperIiGngHTinhaled corticosteroids in asthmatic patients. BMJ 1999; 319: 87-90. 284. Price DB, Hernandez double dose inhaled bDu, dMeasogynPaidYreRP,inetadalu.lRt apnadtioemntissewditchoansttrhomllead. trial of Thorax montelukast plus inhaled 2003; 58: 211-216. budesonide versus 285. mVaoqdueerraizteo aMstJh, mCaas.aTnhPo,rCaxaCs2Ot0il0lo3;J,5e8t:a2l0. 4Ef-2fe1c0t.of montelukast added to inhaled budesonide on control of mild to 286. Virchow JC, Prasse A, Naya I, et al. Zafirlukast improves asthma control in patients receiving high-dose inhaled corticosteroids. Am J Respir Crit Care Med 2000; 162: 578-585. 287. Tamaoki J, Kondo M, Sakai N, et al. Leukotriene antagonist prevents exacerbation of asthma during reduction of high-dose inhaled corticosteroid. The Tokyo Joshi-Idai Asthma Research Group. Am J Respir Crit Care Med 1997; 155: 1235-1240. 288. Rodrigo GJ, Neffen H. Efficacy and safety of tiotropium in school-age children with moderate-to-severe symptomatic asthma: A systematic review. Pediatr Allergy Immunol 2017; 28: 573-578. 289. Szefler SJ, Vogelberg C, Bernstein JA, et al. Tiotropium Is Efficacious in 6- to 17-Year-Olds with Asthma, Independent of T2 Phenotype. J Allergy Clin Immunol Pract 2019; 7: 2286-2295 e2284. 290. Travers J, Marsh S, Williams M, et al. External validity of randomised controlled trials in asthma: to whom do the results of the trials apply? Thorax 2007; 62: 219-223. 291. Brown T, Jones T, Gove K, et al. Randomised controlled trials in severe asthma: selection by phenotype or stereotype. Eur Respir J 2018; 52. 198 References 292. Broersen LH, Pereira AM, Jorgensen JO, et al. Adrenal insufficiency in corticosteroids use: Systematic review and meta-analysis. J Clin Endocrinol Metab 2015; 100: 2171-2180. 293. Kew KM, Dahri K. Long-acting muscarinic antagonists (LAMA) added to combination long-acting beta2-agonists and inhaled corticosteroids (LABA/ICS) versus LABA/ICS for adults with asthma. Cochrane Database Syst Rev 2016; 1: CD011721. 294. Taylor SL, Leong LEX, Mobegi FM, et al. Long-term azithromycin reduces Haemophilus influenzae and increases antibiotic resistance in severe asthma. Am J Respir Crit Care Med 2019; 200: 309-317. 295. Gibson PG, Yang IA, Upham JW, et al. Effect of azithromycin on asthma exacerbations and quality of life in adults with persistent uncontrolled asthma (AMAZES): a randomised, double-blind, placebo-controlled trial. Lancet 2017; 390: 659-668. 296. Hiles SA, McDonald VM, Guilhermino M, et al. Does maintenance azithromycin reduce asthma exacerbations? An individual participant data meta-analysis. Eur Respir J 2019; 54. 297. Agache I, Rocha C, Beltran J, et al. Efficacy and safety of treatment with biologicals (benralizumab, dupilumab and omalizumab) for severe allergic asthma: A systematic review for the use of biologicals in severe asthma. Allergy 2020; 75: 1043-1057. EAACI GuidelineUsT-Erecommendations on the 298. Haldar P, Brightling CE, Hargadon J Med 2009; 360: 973-984. B, et al. Mepolizumab and exacerbations of rTeRfrIaBctory eosinophilic asthma. N Engl 299. Castro M, Zangrilli J, Wechsler ME, et al. Reslizumab for inadequately contrDoIlSled asthma with elevated blood eosinophil counts: results from two multicentre, parallel, double-blindO, rRandomised, placebo-controlled, phase 3 300. trials. Lancet Respir Med 2015; 3: 355-366. Nair P, Wenzel S, Rabe KF, et al. Oral glucocorticoid-sparing effecOt oPfYbenralizumab in severe asthma. N Engl J Med 2017; 376: 2448-2458. T C 301. aGsutphtmaaAw, IiktehdaanMeo, sGineonpghBi,liectpahle. nLoontygp-tee.rJmAlslaefregtyyCalnindImphmaNrumOnoacl o2d0y1n9a; m14ic4s: of mepolizumab in 1336-1342.e1337. children with severe 302. Bacharier LB, Maspero JF, Katelaris CH, et al. Dupilum- DabOin children with uncontrolled moderate-to-severe asthma. 303. N Engl Castro J Med 2021; M, Corren J, P3a8v5o: r2d23ID0,-2e2t 4a0l..DupilumabReIAffLicacy and safety in moderate-to-severe uncontrolled asthma. The 304. NWeewnzEenlgSl,aCnadsjtorourMna,lCoofrmreendJi,ceintea2l.0D1u8p; i3lu7Am8T:aE2b4e8f6fi-c2a4c9y6a.nd safety in adults with uncontrolled persistent asthma bdleinspditpelaucseeboof-cmonedtrioulmle-dtop-ihviogtha-ldpohsaeEsieDnh2Mableddosceo-rrtaicnogsintegrtoriidasl. plus The a long-acting Lancet 2016; b2agonist: a 388: 31-44. randomised double- 305. Corren J, Parnes JR, Wang L, etIGalH. TTezepelumab in adults with uncontrolled asthma. N Engl J Med 2017; 377: 936- 306. 946. Chupp G, Laviolette M, CoPhYnRL, et al. Long-term outcomes of bronchial thermoplasty in subjects with severe asthma: a comparison of 3-yeaCr fOollow-up results from two prospective multicentre studies. Eur Respir J 2017; 50. 307. Walsh LJ, Wong CA, Oborne J, et al. Adverse effects of oral corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56: 279-284. 308. Lefebvre P, Duh MS, Lafeuille M-H, et al. Acute and chronic systemic corticosteroid-related complications in patients with severe asthma. Journal of Allergy and Clinical Immunology 2015; 136: 1488-1495. 309. Price DB, Trudo F, Voorham J, et al. Adverse outcomes from initiation of systemic corticosteroids for asthma: long- term observational study. J Asthma Allergy 2018; 11: 193-204. 310. Bleecker ER, Menzies-Gow AN, Price DB, et al. Systematic literature review of systemic corticosteroid use for asthma management. Am J Respir Crit Care Med 2020; 201: 276-293. 311. Buckley L, Guyatt G, Fink HA, et al. 2017 American College of Rheumatology guideline for the prevention and treatment of glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2017; 69: 1095-1110. 312. Bateman ED, Bousquet J, Keech ML, et al. The correlation between asthma control and health status: the GOAL study. Eur Respir J 2007; 29: 56-62. 313. Sont JK. How do we monitor asthma control? Allergy 1999; 54 Suppl 49: 68-73. References 199 314. Mintz M, Gilsenan AW, Bui CL, et al. Assessment of asthma control in primary care. Current medical research and opinion 2009; 25: 2523-2531. 315. Schatz M, Rachelefsky G, Krishnan JA. Follow-up after acute asthma episodes: what improves future outcomes? Proceedings of the American Thoracic Society 2009; 6: 386-393. 316. Thomas A, Lemanske RF, Jr., Jackson DJ. Approaches to stepping up and stepping down care in asthmatic patients. Journal of Allergy and Clinical Immunology 2011; 128: 915-924. 317. Bousquet J, Boulet LP, Peters MJ, et al. Budesonide/formoterol for maintenance and relief in uncontrolled asthma vs. high-dose salmeterol/fluticasone. Respiratory Medicine 2007; 101: 2437-2446. 318. Boulet LP. Perception of the role and potential side effects of inhaled corticosteroids among asthmatic patients. Chest 1998; 113: 587-592. 319. Usmani OS, Kemppinen A, Gardener E, et al. A randomized pragmatic trial of changing to and stepping down fluticasone/formoterol in asthma. J Allergy Clin Immunol Pract 2017; 5: 1378-1387.e1375. 320. DiMango E, Rogers L, Reibman J, et al. Risk factors for asthma exacerbation and treatment failure in adults and adolescents 955-961. with well-controlled asthma during continuation and step-down therapy. AUnTnEAm Thorac Soc 2018; 15: 321. Leuppi JD, of inhaled Salome CM, Jenkins CR, et al. Predictive markers of asthma corticosteroids. American journal of respiratory and critical ceaxraecemrbeadticioiTnnRedI2Bu0r0in1g; stepwise dose 163: 406-412. reduction 322. Rogers L, Sugar EA, Blake K, et al. Step-down therapy for asthma well controlleDdISon inhaled corticosteroid and long- acting beta-agonist: A randomized clinical trial. J Allergy Clin Immunol PraOctR2018; 6: 633-643.e631. 323. FitzGerald JM, Boulet LP, Follows RM. dummy comparison of a stable dosing TrheegimCOeNnCoEfPsTaltmriealt:earo1l-/yfleuatric, amOsouPnltYeicpenroteprio, nraantedowmitihzeadn,daodujubsleta-bblliend, double- maintenance dosing regimen of formoterol/budesonide in adultsTwCith persistent asthma. Clinical Therapeutics 324. 2005; 27: 393-406. Bose S, Bime C, Henderson RJ, et al. Biomarkers of Type 2 airwNOay inflammation as predictors of loss of Aathma control during step-down therapy for well-controlled di-seDaOse: the Long-Acting Beta-Agonist Step-Down Study 325. (LASST). Wang K, J Allergy Clin Verbakel JY, OImkemJu,neotlaPl.raUcstin2g02fr0a;c8ti:o3n4a7lR4e-xI3Ah4La8le1d. nitric oxide to guide step-down treatment decisions in 326. pRaatnikenMtsAw, HitahgaasnthJBm,aP:aarksyMstAe,meattaicl. rTehveierwiskanoAdf TainEstdhivmidaueaxlapcaetriebnattiodnataafmteer tsat-oapnpailnygsilso.wEu-droRseespinirhaJ l2e0d2c0o;r5ti5c.osteroids: a systematic review 2013; 131: 724-729. and meta-analysis oEfDraMndomized controlled trials. Journal of Allergy & Clinical Immunology 327. Hagan JB, Samant SA, Volcheck GWIG,HeTt al. The risk of asthma exacerbation after reducing inhaled corticosteroids: a 328. sAyhsmteamdaSt,icKreewviKeMw ,aNnodrmmeatnas-ePalnYl aRRl.ySsitsoopfprinagndloonmgi-zaecdtincognbterotall2e-dagtroinaliss.tsA(lLleArBgAy )2f0o1r4a;d6u9l:ts5w10it-h51a6s.thma well controlled 329. bRyanLkABMAAa, nGdioinnfhraidleddocMorRt,iCcPoOosntegrdoeiedsT.,Ceotcahlr.aSnteepDpaintagbdaoswe nSyfsrtoRmevin2h0a1le5d: Ccodr0t1ic1o3s0t6er.oids with leukotriene inhibitors in asthma: a systematic review and meta-analysis. Allergy Asthma Proc 2015; 36: 200-205. 330. Masoli M, Weatherall M, Holt S, et al. Budesonide once versus twice-daily administration: meta-analysis. Respirology 2004; 9: 528-534. 331. Boulet LP, Drollmann A, Magyar P, et al. Comparative efficacy of once-daily ciclesonide and budesonide in the treatment of persistent asthma. Respiratory Medicine 2006; 100: 785-794. 332. Rice JL, Diette GB, Suarez-Cuervo C, et al. Allergen-specific immunotherapy in the treatment of pediatric asthma: A systematic review. Pediatrics 2018; 141. 333. Lin SY, Erekosima N, Kim JM, et al. Sublingual immunotherapy for the treatment of allergic rhinoconjunctivitis and asthma: a systematic review. JAMA 2013; 309: 1278-1288. 334. Di Bona D, Frisenda F, Albanesi M, et al. Efficacy and safety of allergen immunotherapy in patients with allergy to molds: A systematic review. Clin Exp Allergy 2018; 48: 1391-1401. 335. Abramson MJ, Puy RM, Weiner JM. Injection allergen immunotherapy for asthma. Cochrane Database of Systematic Reviews 2010: CD001186. 200 References 336. Klimek L, Fox GC, Thum-Oltmer S. SCIT with a high-dose house dust mite allergoid is well tolerated: safety data from pooled clinical trials and more than 10 years of daily practice analyzed in different subgroups. Allergo J Int 2018; 27: 131-139. 337. Xu K, Deng Z, Li D, et al. Efficacy of add-on sublingual immunotherapy for adults with asthma: A meta-analysis and systematic review. Ann Allergy Asthma Immunol 2018; 121: 186-194. 338. Calamita Z, Saconato H, Pela AB, et al. Efficacy of sublingual immunotherapy in asthma: systematic review of randomized-clinical trials using the Cochrane Collaboration method. Allergy 2006; 61: 1162-1172. 339. Fortescue R, Kew KM, Leung MST. Sublingual immunotherapy for asthma. Cochrane Database Syst Rev 2020; 9: CD011293. 340. Marogna M, Spadolini I, Massolo A, et al. Long-term comparison of sublingual immunotherapy vs inhaled budesonide in patients with mild persistent asthma due to grass pollen. Annals of Allergy, Asthma, & Immunology 2009; 102: 69-75. 341. Baena-Cagnani CE, Larenas-Linnemann D, Teijeiro A, et al. Will sublingual immunotherapy offer benefit for asthma? 342. Curr Allergy Asthma Rep Burks AW, Calderon MA, 2013. Casale T, et al. Update on allergy immunotherapy: AmericaUnTAEcademy of Allergy, Asthma & Immunology/European Academy of Allergy and Clinical & Clinical Immunology 2013; 131: 1288-1296.e1283. Immunology/PRACTALTL RcoIBnsensus report. Journal of Allergy 343. Dretzke J, Meadows A, Novielli N, et al. Subcutaneous and sublingual immuDnIoStherapy for seasonal allergic rhinitis: a systematic review and indirect comparison. Journal of Allergy & ClinicaOl IRmmunology 2013; 131: 1361-1366. 344. Cates CJ, Rowe BH. Vaccines Reviews 2013; 2: CD000364. for preventing influenza in people wOitPhYasthma. Cochrane Database of Systematic 345. Vasileiou E, Sheikh A, Butler C, et al. Effectiveness of InfluenzaTVCaccines in Asthma: A Systematic Review and Meta- 346. Analysis. Clin Infect Dis 2017; 65: Turner PJ, Fleming L, Saglani S, et 1388-1395. al. Safety of live attenuaNteOd influenza vaccine (LAIV) in children with moderate to severe asthma. J Allergy Clin Immunol 2020; 145: 11-5D7-O1164.e1156. 347. Li L, and Cheng Y, Tu X, meta-analysis. eAtllaelr.gAysAsostchiamtiaonClbinetImwemeunnaRosIltA2hL0m2a0;a1n6d: invasive 94. pneumococcal disease risk: a systematic review 348. Sheikh A, Alves CD002165. B, Dhami S. PneumococcalAvTaEccine for asthma. Cochrane Database of Systematic Reviews 2002: 349. wChitahupdehrusriistRe,nRtuabsitnhAm,aSu(BmTi1n0o+K):,aetfoaElll.DoSwaM-fueptyoafntdhreefefercatnivdeonmesisseodfcbornotnrcohllieadl tthriearlms.oLpalnacsetyt Raeftseprir1M0 yeeda2rs02in1;p9a:ti4e5n7ts- 466. IGHT 350. Cassim Allergy R, Russell 2015; 70: 3M3A9,-3L5o4dP.geYRCJ, et al. The role of circulating 25 hydroxyvitamin D in asthma: a systematic review. 351. Jolliffe DA, GreenbergCL,OHooper RL, et al. Vitamin D supplementation to prevent asthma exacerbations: a systematic review and meta-analysis of individual participant data. Lancet Respir Med 2017; 5: 881-890. 352. Andjar-Espinosa R, Salinero-Gonzlez L, Illn-Gmez F, et al. Effect of vitamin D supplementation on asthma control in patients with vitamin D deficiency: the ACVID randomised clinical trial. Thorax 2021; 76: 126-133. 353. Riverin BD, Maguire JL, Li P. Vitamin D supplementation for childhood asthma: A systematic review and meta- analysis. PLoS One 2015; 10: e0136841. 354. Pojsupap S, Iliriani K, Sampaio TZ, et al. Efficacy of high-dose vitamin D in pediatric asthma: a systematic review and meta-analysis. J Asthma 2015; 52: 382-390. 355. Castro M, King TS, Kunselman SJ, et al. Effect of vitamin D3 on asthma treatment failures in adults with symptomatic asthma and lower vitamin D levels: the VIDA randomized clinical trial. JAMA 2014; 311: 2083-2091. 356. Lazarus SC, Chinchilli VM, Rollings NJ, et al. Smoking affects response to inhaled corticosteroids or leukotriene receptor antagonists in asthma. Am J Respir Crit Care Med 2007; 175: 783-790. 357. Chaudhuri R, Livingston E, McMahon AD, et al. Effects of smoking cessation on lung function and airway inflammation in smokers with asthma. Am J Respir Crit Care Med 2006; 174: 127-133. References 201 358. Rayens MK, Burkhart PV, Zhang M, et al. Reduction in asthma-related emergency department visits after implementation of a smoke-free law. Journal of Allergy and Clinical Immunology 2008; 122: 537-541. 359. Wills TA, Soneji SS, Choi K, et al. E-cigarette use and respiratory disorders: an integrative review of converging evidence from epidemiological and laboratory studies. Eur Respir J 2021; 57. 360. Hansen ESH, Pitzner-Fabricius A, Toennesen LL, et al. Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis. Eur Respir J 2020; 56. 361. Toennesen LL, Meteran H, Hostrup M, et al. Effects of exercise and diet in nonobese asthma patients-a randomized controlled trial. J Allergy Clin Immunol Pract 2018; 6: 803-811. 362. Beggs S, Foong YC, Le HC, et al. Swimming training for asthma in children and adolescents aged 18 years and under. Cochrane Database of Systematic Reviews 2013; 4: CD009607. 363. Kogevinas M, Zock JP, Jarvis D, et al. Exposure to substances in the workplace and new-onset asthma: an international prospective population-based study (ECRHS-II). Lancet 2007; 370: 336-341. 364. Szczeklik A, Nizankowska E, Duplaga M. Natural history of aspirin-induced asthma. AIANE Investigators. European 365. Network on Aspirin-Induced Asthma. Eur Respir J 2000; 16: Covar RA, Macomber BA, Szefler SJ. Medications as asthma 432-436. triggers. Immunol Allergy CUlinTENorth Am 2005; 25: 169- 366. 190. Olenchock BA, Fonarow GG, Pan W, et al. Current use of beta blockers in patientsTwRitIBh reactive airway disease who are hospitalized with acute coronary syndromes. Am J Cardiol 2009; 103: 295-D30IS0. 367. Morales DR, Jackson C, Lipworth BJ, et al. Adverse respiratory effect of acuOtRe beta-blocker exposure in asthma: a 368. systematic review and meta-analysis of randomized Gotzsche PC, Johansen HK. House dust mite control mcoenatsruorlleesdfotrriaalssOt.hCPmhYeas. tC2o0c1h4ra; n1e45d:a7ta7b9a-7s8e6o.f systematic reviews 2008: CD001187. T C 369. Leas BF, D'Anci KE, Apter AJ, et al. Effectiveness of indoor review. J Allergy Clin Immunol 2018; 141: 1854-1869. alleNrgOen reduction in asthma management: A systematic 370. Sheffer AL. Allergen avoidance to reduce asthma-relate-dDmOorbidity. N Engl J Med 2004; 351: 1134-1136. 337721.. RPlaabtittso-MFAill,sCTaArl.sAolnleJrCg,eHneaHvo, iedtaanlc.eAisninthgleetirnetaetrmveenRnttIiAoonLf afosrthcmocakaronadcrhhcinointitsr.oNl rEendgulcJeMs ceodck2r0o0a3c;h3e4x9p: o2s0u7r-e20a8n.d 373. asthma Crocker morbidity in DD, Kinyota children. J S, Dumitru Allergy GG, et aCll.inEfIfmeAcmTtiuEvneonel 2ss01o7f ;h1o4m0e: -5b6a5s-e5d7,0m. ulti-trigger, multicomponent interventions with an journal oefnpvrireovnemnteivnetaml feodciucisnfeor20re1d1u; c4i1nE:gDSa5Ms-t3h2m. a morbidity: a community guide systematic review. American 374. Morgan WJ, Crain EF, Gruchalla RSIG, eHtTal. Results of a home-based environmental intervention among urban 375. cMhuilrdrraeynCwS,itFhoadsetnhmP,aS.uNmEnnegrlPHJ YM, Reetdal2.0P0r4e;ve3n5t1i:n1g0s6e8v-e1r0e8a0s.thma exacerbations in children. A randomized trial of mite-impermeable bedcoCveOrs. Am J Respir Crit Care Med 2017; 196: 150-158. 376. Custovic A, Green R, Taggart SC, et al. Domestic allergens in public places. II: Dog (Can f1) and cockroach (Bla g 2) allergens in dust and mite, cat, dog and cockroach allergens in the air in public buildings. Clin Exp Allergy 1996; 26: 1246-1252. 377. Almqvist C, Larsson PH, Egmar AC, et al. School as a risk environment for children allergic to cats and a site for transfer of cat allergen to homes. J Allergy Clin Immunol 1999; 103: 1012-1017. 378. Shirai T, Matsui T, Suzuki K, et al. Effect of pet removal on pet allergic asthma. Chest 2005; 127: 1565-1571. 379. Wood RA, Chapman MD, Adkinson NF, Jr., et al. The effect of cat removal on allergen content in household-dust samples. J Allergy Clin Immunol 1989; 83: 730-734. 380. Erwin EA, Woodfolk JA, Custis N, et al. Animal danders. Immunology & Allergy Clinics of North America 2003; 23: 469-481. 381. Phipatanakul W, Matsui E, Portnoy J, et al. Environmental assessment and exposure reduction of rodents: a practice parameter. Annals of Allergy, Asthma, & Immunology 2012; 109: 375-387. 202 References 382. Matsui EC, Perzanowski M, Peng RD, et al. Effect of an integrated pest management intervention on asthma symptoms among mouse-sensitized children and adolescents with asthma: A randomized clinical trial. JAMA 2017; 317: 1027-1036. 383. Custovic A, Wijk RG. The effectiveness of measures to change the indoor environment in the treatment of allergic rhinitis and asthma: ARIA update (in collaboration with GA(2)LEN). Allergy 2005; 60: 1112-1115. 384. Eggleston PA, Wood RA, Rand C, et al. Removal of cockroach allergen from inner-city homes. J Allergy Clin Immunol 1999; 104: 842-846. 385. Denning DW, O'Driscoll B R, Hogaboam CM, et al. The link between fungi and severe asthma: a summary of the evidence. Eur Respir J 2006; 27: 615-626. 386. Hirsch T, Hering M, Burkner K, et al. House-dust-mite allergen concentrations (Der f 1) and mold spores in apartment bedrooms before and after installation of insulated windows and central heating systems. Allergy 2000; 55: 79-83. 387. Wood LG, Garg ML, Smart JM, et al. Manipulating antioxidant intake in asthma: a randomized controlled trial. The 388. American Boulet LP, journal of Franssen clinical nutrition 2012; 96: 534-543. E. Influence of obesity on response to fluticasone with or withouUtTsEalmeterol in moderate 389. asthma. Respir Med Lavoie KL, Bacon SL, 2007; 101: Labrecque 2240-2247. M, et al. Higher BMI is associated with worse aTstRhImBa control and quality of life but not asthma severity. Respir Med 2006; 100: 648-657. DIS 390. Saint-Pierre P, Bourdin A, Chanez P, et al. Are overweight asthmatics mOoRre difficult to control? Allergy 2006; 61: 79- 391. 84. Sutherland ER, Goleva E, Strand M, et al. Body mass and glucocorOtiPcoYid response in asthma. Am J Respir Crit Care Med 2008; 178: 682-687. T C 392. Okoniewski W, of Randomized LCuonKtDr,oFlloerdnToriEa.lsW. AeingnhtALmosTshfoorraCchSioldcre2n01a9Nn;dO1A6:d6u1lt3s-w62it5h. Obesity and Asthma. A Systematic Review 393. Adeniyi FB, Young T. Weight loss interventions for ch-rDonOic asthma. Cochrane Database Syst Rev 2012; 7: CD009339. 394. Moreira Practice A, Bonini M, Garcia-Larsen V, et al. Guideline (Part I). Allergy 2013; 68: W42eR5iIg-A4h3Lt9lo. ss interventions in asthma: EAACI Evidence-Based Clinical 395. Boulet LP, Turcotte H, subjects with asthma. Martin J, et Respir Med 2al0.1E2ff;e1cA0t6To:Ef6b5a1r-i6a6tr0ic. surgery on airway response and lung function in obese 396. Dixon AE, Pratley RE, Forgione PM, asthma control, and inflammation. JeEtADallleM.rEgfyfeCcltins of obesity and bariatric surgery on airway Immunol 2011; 128: 508-515 e501-502. hyperresponsiveness, 397. Scott HA, Gibson PG, Garg ML,IGetHaTl. Dietary restriction and exercise improve airway inflammation and clinical 398. oSauntctionmoeTsAi,nCohvaevrewseGigSh, tFraePniYtdaRosbDeAs,eeatsatlh.mBrae:aathrainngdoexmeirzceisdetsrifaolr. Clin Exp Allergy 2013; 43: 36-49. adults with asthma. Cochrane Database Syst Rev 2020; 3: CD001277. CO 399. Slader CA, Reddel HK, Spencer LM, et al. Double blind randomised controlled trial of two different breathing techniques in the management of asthma. Thorax 2006; 61: 651-656. 400. Bruton A, Lee A, Yardley L, et al. Physiotherapy breathing retraining for asthma: a randomised controlled trial. Lancet Respir Med 2018; 6: 19-28. 401. Upham JW, Holt PG. Environment and development of atopy. Curr Opin Allergy Clin Immunol 2005; 5: 167-172. 402. Belanger K, Holford TR, Gent JF, et al. Household levels of nitrogen dioxide and pediatric asthma severity. Epidemiology 2013; 24: 320-330. 403. Howden-Chapman P, Pierse N, Nicholls S, et al. Effects of improved home heating on asthma in community dwelling children: randomised controlled trial. BMJ 2008; 337: a1411. 404. Park HJ, Lee HY, Suh CH, et al. The effect of particulate matter reduction by indoor air filter use on respiratory symptoms and lung function: a systematic review and meta-analysis. Allergy Asthma Immunol Res 2021; 13: 719- 732. 405. Phipatanakul W, Koutrakis P, Coull BA, et al. Effect of school integrated pest management or classroom air filter purifiers on asthma symptoms in students with active asthma: a randomized clinical trial. JAMA 2021; 326: 839-850. References 203 406. Tibosch MM, Verhaak CM, Merkus PJ. Psychological characteristics associated with the onset and course of asthma in children and adolescents: a systematic review of longitudinal effects. Patient education and counseling 2011; 82: 11-19. 407. Rietveld S, van Beest I, Everaerd W. Stress-induced breathlessness in asthma. Psychol Med 1999; 29: 1359-1366. 408. Sandberg S, Paton JY, Ahola S, et al. The role of acute and chronic stress in asthma attacks in children. Lancet 2000; 356: 982-987. 409. Lehrer PM, Isenberg S, Hochron SM. Asthma and emotion: a review. J Asthma 1993; 30: 5-21. 410. Nouwen A, Freeston MH, Labbe R, et al. Psychological factors associated with emergency room visits among asthmatic patients. Behav Modif 1999; 23: 217-233. 411. Hauptman M, Gaffin JM, Petty CR, et al. Proximity to major roadways and asthma symptoms in the School Inner-City Asthma Study. J Allergy Clin Immunol 2020; 145: 119-126 e114. 412. Newson R, Strachan D, Archibald E, et al. Acute asthma epidemics, weather and pollen in England, 1987-1994. Eur Respir J 1998; 11: 694-701. 413. Thien F, Beggs environmental PJ, Csutoros D, triggers, effect et al. The Melbourne epidemic on health services, and patient trhisuknfdaecrtsotrosr.mThaestLhamncaeet vPeUlanTntEe2t0a1ry6:Haenalitnhve2s0t1ig8a;t2io:n of 414. e255-e263. Li Y, Wang W, Wang J, et al. Impact of air pollution control measures and weatherTcRoInBditions on asthma during the 2008 Summer Olympic Games in Beijing. International journal of biometeoroloDgISy 2011; 55: 547-554. 415. Taylor SL, Bush RK, Selner JC, et al. Sensitivity to sulfited foods among sulfOiteR-sensitive subjects with asthma. J 416. Allergy Ahmed Clin Immunol 1988; S, Steed L, Harris K, 81: 1159-1167. et al. Interventions to enhance the adopOtioPnYof asthma self-management behaviour in the South Asian and African American population: a systematic rTevCiew. NPJ Prim Care Respir Med 2018; 28: 5. 417. Fink JB, Rubin BK. Problems with 2005; 50: 1360-1374; discussion inhaler use: 1374-1365. a call for improvNeOd clinician and patient education. Respiratory care 418. Klijn SL, Hiligsmann M, Evers S, et al. Effectiveness and s-uDcOcess factors of educational inhaler technique 419. iNnetewrmveanntiSoPn.sSipnaacsetrhdmeavi&ceCsOfoPrDmpeatteiernetds:daosseysitnehmRalIaeAtriLsc. review. NPJ Prim Care Respir Med 2017; Clin Pharmacokinet 2004; 43: 349-360. 27: 24. 420. cBoamshmetuinIAit,yRpehdadreml aHcKis,tAs.rmJoouurnr aClLo, fetAallle.rIgmyp&roACvTleiEndicaasltIhmmmauonuotlcoogmy e2s0w07it;h1a19s:im15p3le7-in15h3al8e.r technique intervention by 421. pGhiraarumdaVc,isAtsll.aReertspFiAra, tRoorcyhme eNd.iIcninheal2e0r 1te1Ec;Dh1n0Mi5q:u1e8a1n5d-1a8s2t2h.ma: feasability and acceptability of training by 422. van der Palen J, Klein JJ, Kerkhoff IAGHH, Tet al. Evaluation of the long-term effectiveness of three instruction modes for 423. AinlhmaolimnganmieBdAic, iMneosk.hPeamtieenr tEe, PdAulY-cSRaatwioanlhaanNdAc,oeutnasel.lAingno1v9e9l7a;p3p2r:oSa8c7h-9o5f .using educational pharmaceutical pictogram for improving inhaler techCnOiques in patients with asthma. Respir Med 2018; 143: 103-108. 424. Basheti I, Mahboub B, Salameh L, et al. Assessment of novel inhaler technique reminder labels in image format on the correct demonstration of inhaler technique skills in asthma: a single-blinded randomized controlled trial. Pharmaceuticals (Basel) 2021; 14: 150. 425. Basheti IA, Obeidat NM, Reddel HK. Effect of novel inhaler technique reminder labels on the retention of inhaler technique skills in asthma: a single-blind randomized controlled trial. npj Primary Care Respiratory Medicine 2017; 27: 9. 426. Armour CL, Reddel HK, LeMay KS, et al. Feasibility and effectiveness of an evidence-based asthma service in Australian community pharmacies: a pragmatic cluster randomized trial. Journal of Asthma 2013; 50: 302-309. 427. Kuethe MC, Vaessen-Verberne AA, Elbers RG, et al. Nurse versus physician-led care for the management of asthma. Cochrane Database Syst Rev 2013; 2: CD009296. 428. Federman AD, O'Conor R, Mindlis I, et al. Effect of a self-management support intervention on asthma outcomes in older adults: The SAMBA study randomized clinical trial. JAMA Intern Med 2019. 429. Crompton GK, Barnes PJ, Broeders M, et al. The need to improve inhalation technique in Europe: a report from the Aerosol Drug Management Improvement Team. Respir Med 2006; 100: 1479-1494. 204 References 430. Viswanathan M, Golin CE, Jones CD, et al. Interventions to improve adherence to self-administered medications for chronic diseases in the United States: a systematic review. Ann Intern Med 2012; 157: 785-795. 431. Chan AH, Harrison J, Black PN, et al. Using electronic monitoring devices to measure inhaler adherence: a practical guide for clinicians. The Journal of Allergy & Clinical Immunology in Practice 2015; 3: 335-349.e331-335. 432. Cohen JL, Mann DM, Wisnivesky JP, et al. Assessing the validity of self-reported medication adherence among inner- city asthmatic adults: the Medication Adherence Report Scale for Asthma. Ann Allergy Asthma Immunol 2009; 103: 325-331. 433. Poureslami IM, Rootman I, Balka E, et al. A systematic review of asthma and health literacy: a cultural-ethnic perspective in Canada. MedGenMed 2007; 9: 40. 434. Berkman ND, Sheridan SL, Donahue KE, et al. Low health literacy and health outcomes: an updated systematic review. Ann Intern Med 2011; 155: 97-107. 435. Zeni MB. Systematic review of health literacy in Cochrane database studies on paediatric asthma educational interventions: searching beyond rigorous design. Int J Evid Based Health Care 2012; 10: 3-8. 436. Partridge MR, Dal Negro RW, Olivieri D. study. Primary Care Respiratory Journal Understanding patients 2011; 20: 315-323, 317 with asthma and p following 323. COUPTDE: insights from a European 437. cFaorsetepraJtMie,nUtsshweitrhwoasotdhmT,aS.mJoituhrnLa, leot faAl.lIlnerhgaylearnrdemCliinndicearlsImimmpuronvoeloagdyh2e0re1n4c; e13wT4Ri:thI1B2c6o0n-t1ro2l6le8r. treatment in primary 438. Chan AH, Stewart AW, Harrison J, et al. The effect of an electronic monitorDinIgSdevice with audiovisual reminder function on adherence to inhaled corticosteroids and school attendancOeRin children with asthma: a randomised 439. controlled trial. Lancet Respir Med 2015; 3: 210-219. Morton RW, Elphick HE, Rigby AS, et al. STAAR: a randomised conOtrPoYlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomT eCs for children with asthma. Thorax 2017; 72: 347- 440. 354. Foster JM, Usherwood T, Smith L, et al. Inhaler reminders NimOprove adherence with controller treatment in primary care patients with asthma. J Allergy Clin Immunol 20-1D4;O134: 1260-1268. 441. rOatnsduokimMiz,eEdatkriinalM. PNe,dRiaatnrdicsCS2,0e0t9a; l1.2A4d:h1e5r1e3n-c1eR5f2IeA1eL.dback to improve asthma outcomes among inner-city children: a 442. aWdihlleiarmenscLeKi,nPfoetremrasotinonELf,oWr tehlelsirKp,aettieanl.tAs wcAliTuthsEtaesrt-rhamnad.oJmAilzleedrgtyriCallintoImprmovuindoelc2li0n1ic0i;a1n2s6in: h2a2l5e-d23c1o,rt2ic3o1sete2r2o1i-d224. 443. pBeednidaetrriBc Gas,tChvmieatutrseaaPtJm, Genoto:darircahnGdoKEm,DeiztMeadl. Pragmatic trial of health care technologies to improve clinical trial. JAMA Pediatr 2015; 169: 317-323. adherence to 444. Halterman JS, Fagnano M, TajoIGn HRST, et al. Effect of the School-Based Telemedicine Enhanced Asthma Management 445. N(SoBr-mTEaAnMse)llpRro, KgreawmKoMn,aSstPtohYvmoRladmE.oIrnbtiedrivtye:nAtiorannsdtoomimizperdocvleinaicdahletrreianlc. eJAtMo iAnhPaeldeidatsrte2r0o1i8d;s1f7o2r :aest1h7m49a3. 8C.ochrane Database Syst Rev 201C7O; 4: CD012226. 446. Foster JM, Smith L, Bosnic-Anticevich SZ, et al. Identifying patient-specific beliefs and behaviours for conversations about adherence in asthma. Internal Medicine Journal 2012; 42: e136-144. 447. Ulrik CS, Backer V, Soes-Petersen U, et al. The patient's perspective: adherence or non-adherence to asthma controller therapy? Journal of Asthma 2006; 43: 701-704. 448. Price D, Robertson A, Bullen K, et al. Improved adherence with once-daily versus twice-daily dosing of mometasone furoate administered via a dry powder inhaler: a randomized open-label study. BMC Pulmonary Medicine 2010; 10: 1. 449. Kew KM, Carr R, Crossingham I. Lay-led and peer support interventions for adolescents with asthma. Cochrane Database Syst Rev 2017; 4: CD012331. 450. Clark NM, Shah S, Dodge JA, et al. An evaluation of asthma interventions for preteen students. J Sch Health 2010; 80: 80-87. 451. Gibson PG, Powell H, Coughlan J, et al. Limited (information only) patient education programs for adults with asthma. Cochrane Database Syst Rev 2002: CD001005. References 205 452. Houts PS, Bachrach R, Witmer JT, et al. Using pictographs to enhance recall of spoken medical instructions. Patient Educ Couns 1998; 35: 83-88. 453. Meade CD, McKinney WP, Barnas GP. Educating patients with limited literacy skills: the effectiveness of printed and videotaped materials about colon cancer. Am J Public Health 1994; 84: 119-121. 454. Manfrin A, Tinelli M, Thomas T, et al. A cluster randomised control trial to evaluate the effectiveness and cost- effectiveness of the Italian medicines use review (I-MUR) for asthma patients. BMC Health Serv Res 2017; 17: 300. 455. Gao G, Liao Y, Mo L, et al. A randomized controlled trial of a nurse-led education pathway for asthmatic children from outpatient to home. Int J Nurs Pract 2020; 26: e12823. 456. Campbell JD, Brooks M, Hosokawa P, et al. Community health worker home visits for medicaid-enrolled children with asthma: Effects on asthma outcomes and costs. Am J Public Health 2015; 105: 2366-2372. 457. Partridge MR, Caress AL, Brown C, et al. Can lay people deliver asthma self-management education as effectively as primary care based practice nurses? Thorax 2008; 63: 778-783. 458. Pinnock H, Parke HL, Panagioti M, et al. Systematic meta-review of supported self-management for asthma: a 459. healthcare perspective. BMC Med 2017; Boyd M, Lasserson TJ, McKean MC, et al. 15: 64. Interventions for educating children who are aUtTrEisk of asthma-related 460. ePmoweerglleHn,cGy idbespoanrPtmG.eOntpatitotennsdfoarncseel.fC-mocahnraagneemDeanttaebdasuecaotfioSnysftoermaadtuicltsRewviitehwasst2h0Tm0R9aI:.BCCDoc0h0r1a2n9e0D. atabase Syst Rev 2003: CD004107. DIS 461. McLean S, Chandler D, Nurmatov U, et al. Telehealthcare for asthma. CochOrRane Database of Systematic Reviews 462. 2010: CD007717. Fishwick D, D'Souza W, Beasley R. The asthma self-management planOsPyYstem of care: what does it mean, how is it done, does it work, what models are available, what do patientsTwCant and who needs it? Patient Educ Couns 1997; 463. 32: S21-33. Gibson PG, Powell H. Written action plans for asthma: an evidNeOnce-based review of the key components. Thorax 2004; 59: 94-99. - DO 464. Holt S, Masoli M, Beasley R. respiratory journal : journal The use of the of the General Pseralfc-mticRaenIAAagiLrewmaeysntGprolaunps2y0st0e4m; 1o3f: care in 19-27. adult asthma. Primary care 465. Roberts primary NJ, Evans G, Blenkhorn care. Patient Education P, & eCtoauln. sDeelivnegAlo2Tp0Em10e;n8t0o:f1a4n1e-1le4c6t.ronic pictorial asthma action plan and its use in 466. Ring Care N, Malcolm C, Respir J 2007; Wyke S, et al. 16: 271-283. PromoEtDinMg the use of Personal Asthma Action Plans: a systematic review. Prim 467. Halterman JS, Fisher S, Conn KM, IeGt HalT. Improved preventive care for asthma: a randomized trial of clinician 468. pKnroemalpetDin,gHianrpriesdKi,aMtriccDoofnfiaceldsP.VYAMRrc,hetPaeld.iEaftfreActdivoelensecsMs oefds2ch0o0o6;l-1b6a0se: d10s1e8lf--1m0a2n5a.gement interventions for asthma 4am32o-n43g8c.hildren and adoleCsOcents: findings from a Cochrane systematic review and meta-analysis. Thorax 2019; 74: 469. Boulet LP. Influence of comorbid conditions on asthma. European Respiratory Journal 2009; 33: 897-906. 470. Deng X, Ma J, Yuan Y, et al. Association between overweight or obesity and the risk for childhood asthma and wheeze: An updated meta-analysis on 18 articles and 73 252 children. Pediatr Obes 2019; 14: e12532. 471. Upala S, Thavaraputta S, Sanguankeo A. Improvement in pulmonary function in asthmatic patients after bariatric surgery: a systematic review and meta-analysis. Surg Obes Relat Dis 2018. 472. Serrano-Pariente J, Plaza V, Soriano JB, et al. Asthma outcomes improve with continuous positive airway pressure for obstructive sleep apnea. Allergy 2017; 72: 802-812. 473. Chan WW, Chiou E, Obstein KL, et al. The efficacy of proton pump inhibitors for the treatment of asthma in adults: a meta-analysis. Archives of internal medicine 2011; 171: 620-629. 474. Kopsaftis Z, Yap HS, Tin KS, et al. Pharmacological and surgical interventions for the treatment of gastro- oesophageal reflux in adults and children with asthma. Cochrane Database Syst Rev 2021; 5: CD001496. 475. Mastronarde JG, Anthonisen NR, Castro M, et al. Efficacy of esomeprazole for treatment of poorly controlled asthma. N Engl J Med 2009; 360: 1487-1499. 206 References 476. Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006; 173: 1091-1097. 477. Sopo SM, Radzik D, Calvani M. Does treatment with proton pump inhibitors for gastroesophageal reflux disease (GERD) improve asthma symptoms in children with asthma and GERD? A systematic review. J Investig Allergol Clin Immunol 2009; 19: 1-5. 478. Holbrook JT, Wise RA, Gold BD, et al. Lansoprazole for children with poorly controlled asthma: a randomized controlled trial. Journal of the American Medical Association 2012; 307: 373-381. 479. Goodwin RD, Jacobi F, Thefeld W. Mental disorders and asthma in the community. Archives of General Psychiatry 2003; 60: 1125-1130. 480. Ye G, Baldwin DS, Hou R. Anxiety in asthma: a systematic review and meta-analysis. Psychol Med 2021; 51: 11-20. 481. Lavoie KL, Cartier A, Labrecque M, et al. Are psychiatric disorders associated with worse asthma control and quality of life in asthma patients? Respiratory Medicine 2005; 99: 1249-1257. 482. Ahmedani BK, Peterson EL, Wells KE, et al. Examining the relationship between depression and asthma 483. exacerbations in Yorke J, Fleming a prospective SL, Shuldham Cfo. lPlosywc-huoplosgtuicdayl.inPtseyrcvheonstoiomnastficorMaedduilctisnwe i2th01a3s;th7m5:a3U.0CT5oE-c3h1r0a.ne Database of 484. Systematic Reviews 2009. Parry GD, Cooper CL, Moore JM, et al. Cognitive behavioural intervention for aTdRulItBs with anxiety complications of asthma: prospective randomised trial. Respiratory medicine 2012; 106: 802D-I8S10. 485. Bock SA, Munoz-Furlong A, Sampson HA. Further fatalities caused by aOnaRphylactic reactions to food, 2001-2006. 486. Journal of Pumphrey Allergy & Clinical Immunology 2007; 119: 1016-1018. RSH, Gowland MH. Further fatal allergic reactions to foOoPdYin the United Kingdom, 1999-2006. Journal of Allergy & Clinical Immunology 2007; 119: 1018-1019. T C 487. aLisuthAmHa, :JarerasmultilslofrRo,mSitchheerNeartSioHn, aeltHael.aNltahtiaonndalNpurtervitaiolennEcexNaamOndinraitsikonfaScutorvrseyfo2r0f0o5o-d20a0lle6r.gJyouarnndalreolfaAtilolenrsghyip&toClinical Immunology 2010; 126: 798-806.e713. - DO 488. Broek Allergy JL, Bousquet J, Agache I, Clin Immunol 2017; 140: et al. Allergic 950-958. RRhIiAnLitis and its Impact on Asthma (ARIA) guidelines-2016 revision. J 489. Cruz ARIA AA, Popov update, in Tc,oPllaawboarnaktaiornRw, eitthaGl. AC(o2m)LmAENTo.EnAclhlearrgayct2e0r0is7t;ic6s2oSfuupppple8r4a:n1d-4lo1w. er airways in rhinitis and asthma: 490. 1B0ouyseqaursetaJn,dScfuhtuunreemnaenendsH. JJ,ASlalemrgoyliEnCsDlikniMBIm, emtuanl.oAl l2le0r1g2ic; Rhinitis and its Impact 130: 1049-1062. on Asthma (ARIA): achievements in 491. Fokkens WJ, Lund VJ, Mullol J,IeGtHaTl. EPOS 2012: European position paper on rhinosinusitis and nasal polyps 2012. A 492. sTuamn mBKa,rCyhfaonr dortaorRhKin, PoolalrlayPknYgJ,oRelotgails.tIsn.cRidheinnocleogaynd20a1s2so; c5i0a:te1d-1p2r.emorbid diagnoses of patients with chronic rhinosinusitis. JournalCofOAllergy & Clinical Immunology 2013; 131: 1350-1360. 493. Hamilos DL. Chronic rhinosinusitis: epidemiology and medical management. Journal of Allergy & Clinical Immunology 2011; 128: 693-707. 494. Corren J, Manning BE, Thompson SF, et al. Rhinitis therapy and the prevention of hospital care for asthma: a case- control study. J Allergy Clin Immunol 2004; 113: 415-419. 495. Lohia S, Schlosser RJ, Soler ZM. Impact of intranasal corticosteroids on asthma outcomes in allergic rhinitis: a meta- analysis. Allergy 2013; 68: 569-579. 496. Dixon AE, Castro M, Cohen RI, et al. Efficacy of nasal mometasone for the treatment of chronic sinonasal disease in patients with inadequately controlled asthma. J Allergy Clin Immunol 2015; 135: 701-709.e705. 497. Gevaert P, Omachi TA, Corren J, et al. Efficacy and safety of omalizumab in nasal polyposis: 2 randomized phase 3 trials. J Allergy Clin Immunol 2020; 146: 595-605. 498. Gevaert P, Van Bruaene N, Cattaert T, et al. Mepolizumab, a humanized anti-IL-5 mAb, as a treatment option for severe nasal polyposis. Journal of Allergy and Clinical Immunology 2011; 128: 989-995.e988. 499. Bachert C, Sousa AR, Lund VJ, et al. Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial. J Allergy Clin Immunol 2017; 140: 1024-1031.e1014. References 207 500. Bachert C, Han JK, Desrosiers M, et al. Efficacy and safety of dupilumab in patients with severe chronic rhinosinusitis with nasal polyps (LIBERTY NP SINUS-24 and LIBERTY NP SINUS-52): results from two multicentre, randomised, double-blind, placebo-controlled, parallel-group phase 3 trials. Lancet 2019; 394: 1638-1650. 501. Boguniewicz M, Beck LA, Sher L, et al. Dupilumab improves asthma and sinonasal outcomes in adults with moderate to severe atopic dermatitis. J Allergy Clin Immunol Pract 2021; 9: 1212-1223.e1216. 502. Meghji J, Mortimer K, Agusti A, et al. Improving lung health in low-income and middle-income countries: from challenges to solutions. Lancet 2021; 397: 928-940. 503. International Union Against Tuberculosis and Lung Disease. International Union Against Tuberculosis and Lung Disease strategic plan for lung health 2020-2025. International Union Against Tuberculosis and Lung Disease; [cited 2021 October]. Available from: https://theunion.org/our-work/lung-health-ncds/asthma. 504. World Health Organization. WHO Model Lists of Essential Medicines. [web page]: WHO; 2021 [cited 2022 April]. Available from: https://www.who.int/groups/expert-committee-on-selection-and-use-of-essential- medicines/essential-medicines-lists. 505. Zar HJ, Allergy Asmus MJ, Weinberg EG. A 500-ml Immunol 2002; 13: 217-222. plastic bottle: an effective spacer for childrenUwTEith asthma. Pediatr 506. Suissa S, Ernst 107: 937-944. P. Inhaled corticosteroids: impact on asthma morbidity and mortaliTtyR.IJBAllergy Clin Immunol 2001; 507. Waljee AK, Rogers MA, Lin P, et al. Short term use of oral corticosteroids and rDeIlSated harms among adults in the United States: population based cohort study. BMJ 2017; 357: j1415. OR 508. 5B2abloawr Z-Ua,nLdemssiidndgleC-,iMncaocmeeCc, oeut natl.riTehse. Pahvaarilmabaicliotye,coprniocimngicasn2d01a3ff;o3r1dO:aP1b0Yil6it3y-o1f0t8h2r.ee essential asthma medicines in 509. Stolbrink M, Thomson H, Hadfield R, et al. The availability, cost aTndCaffordability of essential medicines for asthma and COPD in low-income and middle-income http://dx.doi.org/10.2139/ssrn.4023200. countries: a sysNteOmatic review. Lancet 2022; Preprint: 510. Organization WH. New WHA Resolution to bring much n- eDeOded boost to diabetes prevention and control efforts. 2W0H2O1-;n2e0w2-1w[huap-dreasteodlu2ti7onM-taoy-b2r0in2g1-;mciutecdh-2n0e2e1deDdeR-cbeIoAmoLsbte-tro].-Adivaabileatbelse-pfrroemve:nhttiotpns-:a/n/wd-wcown.twrohlo-e.ifnfto/rntse.ws/item/27-05- 511. 512. Patton GC, Viner R. Michaud P-A, Suris Pubertal JC, Viner Rtr.aTnhseitiaodnosleinscheenAatlTtwhEi.thLaanccehtro2n0i0c7c;o3n6d9it:i1o1n3:0e-p1i1d3e9m. iology, developmental issues and hhettapl:t/h/wcahrqelipbrdoovcis.wiohno. .2in0t0/7pu[cbitliecdat2io0n1s3/E2ND0o0vM7e/m97b8e9r]2:4A1v5a9il5a7b0le4_freonmg:.pdf. 513. Carlsen KH, Anderson SD, BjermerIGL,HeTt al. Treatment of exercise-induced asthma, respiratory and allergic disorders iSAnollscepiregotyryt2s(E0aR0nS8d); ta6hn3ed: 4rEe9ul2aro-t5ipo0en5aCs.nhOiApPctYaodRdeompyinogf: APlalertrgIIyoafntdheClrienpicoarltImfrommunthoeloJgoyin(EtATAasCkI)FionrccoeoopfeEruartoiopneawnitRheGspAi(r2a)tLoErNy. 514. Gluck JC, Gluck PA. The effect of pregnancy on the course of asthma. Immunology and Allergy Clinics of North America 2006; 26: 63-80. 515. Murphy VE, Powell H, Wark PA, et al. A prospective study of respiratory viral infection in pregnant women with and without asthma. Chest 2013; 144: 420-427. 516. Lim A, Stewart K, Konig K, et al. Systematic review of the safety of regular preventive asthma medications during pregnancy. The Annals of pharmacotherapy 2011; 45: 931-945. 517. Wendel PJ, Ramin SM, Barnett-Hamm C, et al. Asthma treatment in pregnancy: a randomized controlled study. American journal of obstetrics and gynecology 1996; 175: 150-154. 518. Schatz M, Leibman C. Inhaled corticosteroid use and outcomes in pregnancy. Annals of Allergy, Asthma & Immunology 2005; 95: 234-238. 519. Liu X, Agerbo E, Schlunssen V, et al. Maternal asthma severity and control during pregnancy and risk of offspring asthma. J Allergy Clin Immunol 2018; 141: 886-892 e883. 520. Powell H, Murphy VE, Taylor DR, et al. Management of asthma in pregnancy guided by measurement of fraction of exhaled nitric oxide: a double-blind, randomised controlled trial. Lancet 2011; 378: 983-990. 208 References 521. Morten M, Collison A, Murphy VE, et al. Managing Asthma in Pregnancy (MAP) trial: FENO levels and childhood asthma. J Allergy Clin Immunol 2018; 142: 1765-1772.e1764. 522. Lim AS, Stewart K, Abramson MJ, et al. Asthma during pregnancy: the experiences, concerns and views of pregnant women with asthma. Journal of Asthma 2012; 49: 474-479. 523. National Heart Lung and Blood Institute, National Asthma Education and Prevention Program Asthma and Pregnancy Working Group. NAEPP expert panel report. Managing asthma during pregnancy: recommendations for pharmacologic treatment-2004 update. J Allergy Clin Immunol 2005; 115: 34-46. 524. Lim AS, Stewart K, Abramson MJ, et al. Multidisciplinary Approach to Management of Maternal Asthma (MAMMA): a randomized controlled trial. Chest 2014; 145: 1046-1054. 525. Ali Z, Nilas L, Ulrik CS. Determinants of low risk of asthma exacerbation during pregnancy. Clin Exp Allergy 2018; 48: 23-28. 526. Pfaller B, Jos Yepes-Nuez J, Agache I, et al. Biologicals in atopic disease in pregnancy: An EAACI position paper. Allergy 2021; 76: 71-89. 527. Namazy J, Cabana during pregnancy. MD, Scheuerle AE, et al. The J Allergy Clin Immunol 2015; Xolair Pregnancy 135: 407-412. Registry (EXPECT): UthTeEsafety of omalizumab use 528. 529. Nelson-Piercy McLaughlin K, C. Asthma in pregnancy. Thorax 2001; 56: 325-328. Foureur M, Jensen ME, et al. Review and appraisal of guidelinesTfRorIBthe management of asthma during pregnancy. Women Birth 2018; 31: e349-e357. DIS 530. Sanchez-Ramos JL, Pereira-Vega AR, Alvarado-Gomez F, et al. Risk factoOrRs for premenstrual asthma: a systematic 531. rReeveiedwCEa.nAdsmthemtaa-ianntahlyeseisl.dEexrplye:rdtiRagenvoRseisspainrdMmedan2a0g1e7m; 1en1:t.5J7o-u7r2On.aPlYof Allergy & Clinical Immunology 2010; 126: 681-687. T C 532. 533. Gibson PG, McDonald VM, Slavin RG, Haselkorn T, Lee Marks JH, et aGl.BA. Astshtmhmaaininolodledrear daudlutNlst:Oso. bLasenrcveatt2io0n1s0f;r3o7m6:t8h0e3e-p8i1d3e.miology and natural history of asthma: outcomes and treatment regimens (TENO- RD)Ostudy. Annals of Allergy, Asthma, and Immunology 2006; 96: 534. 406-414. Vincken W, Dekhuijzen PR, Barnes P, et al. TheRAIADLMIT series - Issues in inhalation therapy. 4) How to choose inhaler 535. devices for the treatment of Smetana GW, Lawrence VA, COPD. Cornell PJEri.mParerAyoTpCEearraetRiveesppiurlamtoornyaJroyurrinskals2tr0a1t0if;ic1a9t:io1n0-f2o0r .noncardiothoracic surgery: 536. systematic Woods BD, review Sladen fRoNr .thPeerAiompeerriactaivneECcDoollnMesgiedeorfaPtihoynssicfioarntsh. eAnpnaatilesnotf internal medicine 2006; 144: 581-595. with asthma and bronchospasm. British journal of anaesthesia 2009; 103 SuppIlG1H: iT57-65. 537. Wakim JH, Sledge 74: 133-139. KC. AnePstYhRetic implications for patients receiving exogenous corticosteroids. AANA Journal 2006; 538. iSntfelavemnmsoantoDryD.dDruiaggsn. oJ CsAilOsl,eprgreyvCelnintiIomnm, aunndotlr1e9a8tm4;e7n4t:o6f1a7d-6v2e2rs.e reactions to aspirin and nonsteroidal anti- 539. Szczeklik A, Sanak M, Nizankowska-Mogilnicka E, et al. Aspirin intolerance and the cyclooxygenase-leukotriene pathways. Curr Opin Pulm Med 2004; 10: 51-56. 540. Mascia K, Haselkorn T, Deniz YM, et al. Aspirin sensitivity and severity of asthma: evidence for irreversible airway obstruction in patients with severe or difficult-to-treat asthma. Journal of Allergy and Clinical Immunology 2005; 116: 970-975. 541. Morales DR, Guthrie B, Lipworth BJ, et al. NSAID-exacerbated respiratory disease: a meta-analysis evaluating prevalence, mean provocative dose of aspirin and increased asthma morbidity. Allergy 2015; 70: 828-835. 542. Rajan JP, Wineinger NE, Stevenson DD, et al. Prevalence of aspirin-exacerbated respiratory disease among asthmatic patients: A meta-analysis of the literature. Journal of Allergy & Clinical Immunology 2015; 135: 676-681.e671. 543. Nizankowska E, Bestynska-Krypel A, Cmiel A, et al. Oral and bronchial provocation tests with aspirin for diagnosis of aspirin-induced asthma. Eur Respir J 2000; 15: 863-869. 544. Szczeklik A, Stevenson DD. Aspirin-induced asthma: advances in pathogenesis and management. J Allergy Clin Immunol 1999; 104: 5-13. References 209 545. Milewski M, Mastalerz L, Nizankowska E, et al. Nasal provocation test with lysine-aspirin for diagnosis of aspirin- sensitive asthma. J Allergy Clin Immunol 1998; 101: 581-586. 546. El Miedany Y, Youssef S, Ahmed I, et al. Safety of etoricoxib, a specific cyclooxygenase-2 inhibitor, in asthmatic patients with aspirin-exacerbated respiratory disease. Annals of Allergy, Asthma & Immunology 2006; 97: 105-109. 547. Morales DR, Lipworth BJ, Guthrie B, et al. Safety risks for patients with aspirin-exacerbated respiratory disease after acute exposure to selective nonsteroidal anti-inflammatory drugs and COX-2 inhibitors: Meta-analysis of controlled clinical trials. J Allergy Clin Immunol 2014; 134: 40-45. 548. Dahlen SE, Malmstrom K, Nizankowska E, et al. Improvement of aspirin-intolerant asthma by montelukast, a leukotriene antagonist: a randomized, double-blind, placebo-controlled trial. Am J Respir Crit Care Med 2002; 165: 9-14. 549. Pleskow WW, Stevenson DD, Mathison DA, et al. Aspirin desensitization in aspirin-sensitive asthmatic patients: clinical manifestations and characterization of the refractory period. J Allergy Clin Immunol 1982; 69: 11-19. 550. Swierczynska-Krepa M, Sanak M, Bochenek G, et al. Aspirin desensitization in patients with aspirin-induced and 551. aspirin-tolerant Chu DK, Lee DJ, asthma: Lee KM, a double-blind study. J Allergy Clin et al. Benefits and harms of aspirin Immunol 2014; desensitization 1fo3r4a: s8p8i3ri-n8-9eU0xT.aEcerbated respiratory 552. disease: Agarwal aR,sCyshtaekmraabtiacrtrieAvi,eSwhaahndA,meet taal-.aAnllaelrygsiics.bInrotnFcohroupmulAmlloenrgayryRahsinpoelrg2i0ll1o9s;is9: :rTe1Rv4i0IeB9w-1o4f1l9it.erature and proposal of new diagnostic and classification criteria. Clin Exp Allergy 2013; 43: 850-873. DIS 553. Agarwal R, Sehgal IS, Dhooria S, et al. Developments in the diagnosis and tOreRatment of allergic bronchopulmonary 554. aspergillosis. Expert Rev Respir Med Agarwal R, Dhooria S, Singh Sehgal I, 2016; et al. 10: 1317-1334. A Randomized Trial of ItraOcoPnYazole vs Prednisolone in Acute-Stage Allergic Bronchopulmonary Aspergillosis Complicating Asthma. CTheCst 2018; 153: 656-664. 555. bVroosnkcahmoppuAlLm, GonilalmryaansAp,eSrgymilloosniss.KJ,Aeltlearlg. yClCinliincaIml emffuicnaoclyParnadctNim2O0m1u5n; 3o:lo1g9ic2-e1f9fe9c.ts of omalizumab in allergic 556. Hekking PP, Wener RR, Amelink M, et al. The prevalenc-eDoOf severe refractory asthma. Journal of Allergy & Clinical 557. Immunology 2015; 135: 896-902. Foster JM, McDonald VM, Guo M, et al. "I have loRstIAinLevery facet of my life": the hidden burden of severe asthma. 558. European Respiratory Journal 2017; Ross KR, Gupta R, DeBoer MD, et al. 5S0e:ve1r7e00aAs7t6Th5Em. a during childhood and adolescence: A longitudinal study. J 559. Allergy O'Neill Clin Immunol S, Sweeney J, P2a0t2t0e;rs1o4n5:C1C4, 0e-t1a4lE.6DTeh1Me4c9o. st of treating severe refractory asthma in the UK: an economic analysis from the British Thoracic ISGoHciTety Difficult Asthma Registry. Thorax 2015; 70: 376-378. 560. Sadatsafavi Respiratory MJo,uLrynnadl 2L0,1M0a; r1r7a:PC7Y,4Re-8t 0a.l. Direct health care costs associated with asthma in British Columbia. Canadian 561. Hashimoto S, Bel EH. CurrCeOnt treatment of severe asthma. Clinical & Experimental Allergy 2012; 42: 693-705. 562. Hancox RJ, Cowan JO, Flannery EM, et al. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med 2000; 94: 767-771. 563. Paris J, Peterson EL, Wells K, et al. Relationship between recent short-acting beta-agonist use and subsequent asthma exacerbations. Ann Allergy Asthma Immunol 2008; 101: 482-487. 564. Basheti IA, Armour CL, Bosnic-Anticevich SZ, et al. Evaluation of a novel educational strategy, including inhaler- based reminder labels, to improve asthma inhaler technique Patient Education & Counseling 2008; 72: 26-33. 565. U.S. Food and Drug Administration. FDA requires Boxed Warning about serious mental health side effects for asthma and allergy drug montelukast (Singulair); advises restricting use for allergic rhinitis. FDA; 2020 [updated 03/13/2020; cited 2020 04 March 2020]. Available from: https://www.fda.gov/drugs/drug-safety-and- availability/fda-requires-boxed-warning-about-serious-mental-health-side-effects-asthma-and-allergy-drug. 566. Centers for Disease Control and Prevention. Parasites - Stronglyoides. [web page]: U.S. Department of Health & Human Services; 2018 [updated 31 December 2018; cited 2022 April]. Available from: https://www.cdc.gov/parasites/strongyloides/. 210 References 567. Clark VL, Gibson PG, Genn G, et al. Multidimensional assessment of severe asthma: A systematic review and meta- analysis. Respirology 2017; 22: 1262-1275. 568. Israel E, Reddel HK. Severe and difficult-to-treat asthma in adults. New England Journal of Medicine 2017; 377: 965- 976. 569. Busse WW, Wenzel SE, Casale TB, et al. Baseline FeNO as a prognostic biomarker for subsequent severe asthma exacerbations in patients with uncontrolled, moderate-to-severe asthma receiving placebo in the LIBERTY ASTHMA QUEST study: a post-hoc analysis. Lancet Respir Med 2021; 9: 1165-1173. 570. Lugogo NL, Kreindler JL, Martin UJ, et al. Blood eosinophil count group shifts and kinetics in severe eosinophilic asthma. Ann Allergy Asthma Immunol 2020; 125: 171-176. 571. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013; 68: 322-329. 572. Gamble J, Stevenson M, McClean E, et al. The prevalence of nonadherence in difficult asthma. American Journal of Respiratory & Critical Care Medicine 2009; 180: 817-822. 573. iMdecnNtiicfhicoaltliDonMo, fSnteovneandshoenreMn,cMe icnGdairfvfiecyulLtPa,setthmal.aT. hAemuetriilcitaynoJfofurarnctailoonfaRl eesxphiarlaetdornyitUarniTcdEoCxriditeicsaul pCparreesMsioendiicnintehe2012; 574. 186: 1102-1108. Bousquet J, Humbert M, Gibson PG, et al. Real-world effectiveness of omalizumTRabIBin severe allergic asthma: a meta- analysis of observational studies. J Allergy Clin Immunol Pract 2021; 9: 270D2-I2S714. 575. Brusselle G, Michils A, Louis R, et al. "Real-life" effectiveness of omalizuOmRab in patients with severe persistent 576. allergic asthma: The Hanania NA, Wenzel PERSIST study. Respir Med S, Rosen K, et al. Exploring 2009; 103: the effects 1o6f 3o3m-O1a6lPi4zYu2m. ab in allergic asthma: an analysis of biomarkers in the EXTRA study. American Journal of RespiratoTryC& Critical Care Medicine 2013; 187: 804-811. 577. Casale TB, Chipps BE, Rosen K, et al. Response to biologics in asthma. Allergy 2018; 73: 490-497. omalizumNaOb using patient enrichment criteria from trials of novel 578. Humbert M, Taille C, Mala L, et al. Omalizumab effec-tDivOeness in patients with severe allergic asthma according to 579. blood Busse eosinophil count: the STELLAIR study. WW. Are peripheral blood eosinophil cEouRurInRAtesLsapigruJid2e0l1in8e; 51. for omalizumab treatment? STELLAIR says no! Eur 580. Respir Casale J 2018; 51: 1800730. TB, Luskin AT, Busse W, et al. OmalAizTuEmab effectiveness by biomarker status in patients with asthma: 581. eNvoirdmenacnesefrlloRm, WPRaOlkSePrESR,OM, ialapnrSoJs,peetcEatDilv.eOMrmeaall-izwuomrladbsftourdays. tJhAmllaerignyaCdluinltsImamnducnhoilldPrreanct. C2o0c1h9r;a7n:e1D56a-t1a6b4asee1o5f1. Systematic Reviews 2014; 1: CDIG0H03T559. 558823.. FLeamrnieerHeAC,,WTailislolnCA, ,LPeoewJKeP,lleYCtR,ael.tIaml.pAancttio-IfL5batsheelrinapeicelsinfiocralaastshthmmaa. CcohcahraracnteeriDstaitcasboansethSeysrteRspeovn2s0e1t7o; m9:eCpDo0li1zu08m3a4b.: a post hoc meta-analyCsiOs of two Phase III trials. Respir Res 2021; 22: 184. 584. FitzGerald JM, Bleecker ER, Menzies-Gow A, et al. Predictors of enhanced response with benralizumab for patients with severe asthma: pooled analysis of the SIROCCO and CALIMA studies. Lancet Respir Med 2018; 6: 51-64. 585. Bel EH, Wenzel SE, Thompson PJ, et al. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl J Med 2014; 371: 1189-1197. 586. Albers FC, Licskai C, Chanez P, et al. Baseline blood eosinophil count as a predictor of treatment response to the licensed dose of mepolizumab in severe eosinophilic asthma. Respir Med 2019; 159: 105806. 587. Brusselle G, Germinaro M, Weiss S, et al. Reslizumab in patients with inadequately controlled late-onset asthma and elevated blood eosinophils. Pulm Pharmacol Ther 2017; 43: 39-45. 588. Bleecker ER, Wechsler ME, FitzGerald JM, et al. Baseline patient factors impact on the clinical efficacy of benralizumab for severe asthma. Eur Respir J 2018; 52. 589. Corren J, Castro M, O'Riordan T, et al. Dupilumab efficacy in patients with uncontrolled, moderate-to-severe allergic asthma. J Allergy Clin Immunol Pract 2020; 8: 516-526. 590. Rabe KF, Nair P, Brusselle G, et al. Efficacy and safety of dupilumab in glucocorticoid-dependent severe asthma. N Engl J Med 2018; 378: 2475-2485. References 211 591. Simpson EL, Akinlade B, Ardeleanu M. Two Phase 3 trials of dupilumab versus placebo in atopic dermatitis. N Engl J Med 2017; 376: 1090-1091. 592. Bachert C, Mannent L, Naclerio RM, et al. Effect of subcutaneous dupilumab on nasal polyp burden in patients with chronic sinusitis and nasal polyposis: A randomized clinical trial. JAMA 2016; 315: 469-479. 593. Menzies-Gow A, Corren J, Bourdin A, et al. Tezepelumab in adults and adolescents with severe, uncontrolled asthma. N Engl J Med 2021; 384: 1800-1809. 594. Chipps BE, Newbold P, Hirsch I, et al. Benralizumab efficacy by atopy status and serum immunoglobulin E for patients with severe, uncontrolled asthma. Ann Allergy Asthma Immunol 2018; 120: 504-511.e504. 595. Hashimoto S, Brinke AT, Roldaan AC, et al. Internet-based tapering of oral corticosteroids in severe asthma: a pragmatic randomised controlled trial. Thorax 2011; 66: 514-520. 596. Haldar P, Brightling CE, Singapuri A, et al. Outcomes after cessation of mepolizumab therapy in severe eosinophilic asthma: a 12-month follow-up analysis. J Allergy Clin Immunol 2014; 133: 921-923. 597. Ledford D, Busse W, Trzaskoma B, et al. A randomized multicenter study evaluating Xolair persistence of response 598. after long-term therapy. J Allergy Clin Immunol 2017; 140: 162-169.e162. Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbUaTtiEons in severe asthma 599. (RAaZmISnAaStTh):VaR,mCulaltrikceSn, tCraemraanrgdoomCAis,eJdr.dMouulbtliece-bnltienrdsptuladcyeboof -ccloinnictraol lfleeadtturrieals. oTfhsourdaxdTe2Rn0I-B1o3n;s6e8t:v3e2r2su-3s2s9lo.wer-onset asthma exacerbations requiring hospitalization. Respir Care 2007; 52: 1013-10D2I0S. 600. Zheng XY, Orellano P, Lin HL, et al. Short-term exposure to ozone, nitrogenOdRioxide, and sulphur dioxide and emergency Environ Int department visits and 2021; 150: 106435. hospital admissions due to asthmaO: PAYsystematic review and meta-analysis. 601. Jackson DJ, Johnston SL. The role of viruses in acute exacerbationTsCof asthma. Journal of Allergy & Clinical 602. Immunology 2010; 125: 1178-1187. Erbas B, Jazayeri M, Lambert KA, et al. Outdoor pollen is a triNggOer of child and adolescent asthma emergency department presentations: A systematic review and me-taD-Oanalysis. Allergy 2018; 73: 1632-1641. 603. Anto Med JM, Sunyer J, Reed CE, 1993; 329: 1760-1763. et al. Preventing asthRmIaAeLpidemics due to soybeans by dust-control measures. N Engl J 604. Orellano P, Quaranta N, Reynoso J, et al. adults: Systematic review and multilevel mEfefetAact-TaoEnfaolyustids.oPoLroaSirOpnoellu2t0io17n;o1n2:aest0h1m74a0e5x0a.cerbations in children and 605. Pike KC, Akhbari M, Kneale Database Syst Rev 2018; 3: DCD, e0t1a2l3.9In3t.eErvDenMtions for autumn exacerbations of asthma in children. Cochrane 606. Williams LK, Peterson EL, Wells K,IeGtHaTl. Quantifying the proportion of severe asthma exacerbations attributable to 607. iAnnhdarleewd cEo,rNtiechomsteerZo,idBenronnaarddPhSeY,rReetnacle..SJtoourmrnyalwoefaAtlhleerrg:yaarnetdroCslipneiccatilvIemamnuanlyosliosgoyf 2d0e1m1a;n1d28fo: r11em85e-r1g1e9n1c.ye1m1e8d2i.cal services during epidemic CthOunderstorm asthma. BMJ 2017; 359: j5636. 608. Alvarez GG, Schulzer M, Jung D, et al. A systematic review of risk factors associated with near-fatal and fatal asthma. Can Respir J 2005; 12: 265-270. 609. Chang YL, Ko HK, Lu MS, et al. Independent risk factors for death in patients admitted for asthma exacerbation in Taiwan. NPJ Prim Care Respir Med 2020; 30: 7. 610. Suissa S, Blais L, Ernst P. Patterns of increasing beta-agonist use and the risk of fatal or near- fatal asthma. Eur Respir J 1994; 7: 1602-1609. 611. Roberts G, Patel N, Levi-Schaffer F, et al. Food allergy as a risk factor for life-threatening asthma in childhood: a case-controlled study. J Allergy Clin Immunol 2003; 112: 168-174. 612. Blaiss MS, Nathan RA, Stoloff SW, et al. Patient and physician asthma deterioration terminology: results from the 2009 Asthma Insight and Management survey. Allergy and Asthma Proceedings 2012; 33: 47-53. 613. Vincent SD, Toelle BG, Aroni RA, et al. "Exasperations" of asthma. A qualitative study of patient language about worsening asthma. Medical Journal of Australia 2006; 184: 451-454. 614. FitzGerald JM, Grunfeld A. Status asthmaticus. In: Lichtenstein LM, Fauci AS, editors. Current therapy in allergy, immunology, and rheumatology. 5th ed. St. Louis, MO: Mosby; 1996. p. p. 63-67. 212 References 615. Chan-Yeung M, Chang JH, Manfreda J, et al. Changes in peak flow, symptom score, and the use of medications during acute exacerbations of asthma. Am J Respir Crit Care Med 1996; 154: 889-893. 616. Kew KM, Quinn M, Quon BS, et al. Increased versus stable doses of inhaled corticosteroids for exacerbations of chronic asthma in adults and children. Cochrane Database Syst Rev 2016: Cd007524. 617. FitzGerald JM, Becker A, Sears MR, et al. Doubling the dose of budesonide versus maintenance treatment in asthma exacerbations. Thorax 2004; 59: 550-556. 618. Harrison TW, Oborne J, Newton S, et al. Doubling the dose of inhaled corticosteroid to prevent asthma exacerbations: randomised controlled trial. Lancet 2004; 363: 271-275. 619. Reddel HK, Barnes DJ. Pharmacological strategies for self-management of asthma exacerbations. Eur Respir J 2006; 28: 182-199. 620. Ducharme FM, Lemire C, Noya FJ, et al. Preemptive use of high-dose fluticasone for virus-induced wheezing in young children. N Engl J Med 2009; 360: 339-353. 621. Oborne J, Mortimer K, Hubbard RB, et al. Quadrupling the dose of inhaled corticosteroid to prevent asthma exacerbations: a randomized, double-blind, respiratory and critical care medicine 2009; placebo-controlled, 180: 598-602. parallel-group clinicUalTtErial. American journal of 622. McKeever T, Mortimer K, Wilson Engl J Med 2018; 378: 902-910. A, et al. Quadrupling inhaled glucocorticoid dToRseIBto abort asthma exacerbations. N 623. Jackson DJ, Bacharier LB, Mauger DT, et al. Quintupling inhaled glucocorticDoiIdSs to prevent childhood asthma exacerbations. N Engl J Med 2018; 378: 891-901. OR 624. Richards 81. RN. Side effects of short-term oral corticosteroids. JournOaPl oYf Cutaneous Medicine & Surgery 2008; 12: 77- 625. Cates CJ, Welsh EJ, Rowe BH. Holding chambers (spacers) verTsuCs nebulisers for beta-agonist treatment of acute 626. asthma. Rodrigo Cochrane G, Neffen HD,aCtaobloadseenocfoSyFs, teetmaal.tFicoRrmevoiteewros l2f0o1r3a.cNuOte asthma in the emergency department: a systematic review with meta-analysis. Ann Allergy Asthma Imm-uDnoOl 2010; 104: 247-252. 627. Balanag VM, treatment of Yunus acute F, Yang PC, et asthma. Pulm al. Efficacy Pharmacol aTRnhdeIArsL2a0fe0t6y; of budesonide/formoterol 19: 139-147. compared with salbutamol in the 628. 629. Selroos O. Dry-powder inhalers Newman KB, Milne S, Hamilton in C, aectuatle. AasActoThmEmpaa.rTishoenraopfeaultbiuctDeerolilvaedrym2in0i1s4te; r5e:d69b-y8m1.etered-dose inhaler and spacer with 121: albuterol by 1036-1041. nebulizer in adultsEpDreMsenting to an urban emergency department with acute asthma. Chest 2002; 630. Chien JW, Ciufo R, Novak R, etIaGl.HUTncontrolled oxygen administration and respiratory failure in acute asthma. Chest 631. 2000; 117: 728-733. Rodrigo GJ, Rodriquez VerPdYeRM, Peregalli V, et al. Effects of short-term 28% and 100% oxygen on PaCO2 and peak expiratory flow rate inCaOcute asthma: a randomized trial. Chest 2003; 124: 1312-1317. 632. Perrin K, Wijesinghe M, Healy B, et al. Randomised controlled trial of high concentration versus titrated oxygen therapy in severe exacerbations of asthma. Thorax 2011; 66: 937-941. 633. Patel B, Khine H, Shah A, et al. Randomized clinical trial of high concentration versus titrated oxygen use in pediatric asthma. Pediatr Pulmonol 2019; 54: 970-976. 634. Siemieniuk RAC, Chu DK, Kim LH, et al. Oxygen therapy for acutely ill medical patients: a clinical practice guideline. Bmj 2018; 363: k4169. 635. Hasegawa T, Ishihara K, Takakura S, et al. Duration of systemic corticosteroids in the treatment of asthma exacerbation; a randomized study. Intern Med 2000; 39: 794-797. 636. Jones AM, Munavvar M, Vail A, et al. Prospective, placebo-controlled trial of 5 vs 10 days of oral prednisolone in acute adult asthma. Respiratory Medicine 2002; 96: 950-954. 637. Chang AB, Clark R, Sloots TP, et al. A 5- versus 3-day course of oral corticosteroids for children with asthma exacerbations who are not hospitalised: a randomised controlled trial. Med J Aust 2008; 189: 306-310. 638. Normansell R, Sayer B, Waterson S, et al. Antibiotics for exacerbations of asthma. Cochrane Database Syst Rev 2018; 6: CD002741. References 213 639. Leatherman J. Mechanical ventilation for severe asthma. Chest 2015; 147: 1671-1680. 640. Shim CS, Williams MH, Jr. Evaluation of the severity of asthma: patients versus physicians. Am J Med 1980; 68: 11- 13. 641. Atta JA, Nunes MP, Fonseca-Guedes CH, et al. Patient and physician evaluation of the severity of acute asthma exacerbations. Braz J Med Biol Res 2004; 37: 1321-1330. 642. Geelhoed GC, Landau LI, Le Souef PN. Evaluation of SaO2 as a predictor of outcome in 280 children presenting with acute asthma. Ann Emerg Med 1994; 23: 1236-1241. 643. Nowak RM, Tomlanovich MC, Sarkar DD, et al. Arterial blood gases and pulmonary function testing in acute bronchial asthma. Predicting patient outcomes. Jama 1983; 249: 2043-2046. 644. Carruthers DM, Harrison BD. Arterial blood gas analysis or oxygen saturation in the assessment of acute asthma? Thorax 1995; 50: 186-188. 645. White CS, Cole RP, Lubetsky HW, et al. Acute asthma. Admission chest radiography in hospitalized adult patients. Chest 1991; 100: 14-16. 646. Roback clinical MG, Dreitlein DA. Chest radiograph in the practice and efficacy. Pediatric Emergency evaluation Care 1998; of first time wheezing 14: 181-184. episUoTdEes: review of current 647. 648. Cates C, FitzGerald JM, O'Byrne PM. Asthma. Clin Evidence Hui DS, Chow BK, Chu LC, et al. Exhaled air and aerosolized 2000; 3: 686-700. droplet dispersion durTinRgIaBpplication of a jet nebulizer. Chest 2009; 135: 648-654. DIS 649. Travers AH, Milan SJ, Jones AP, et al. Addition of intravenous beta(2)-agonOisRts to inhaled beta(2)-agonists for acute 650. asthma. Cochrane Database Syst Rev 2012; 12: CD010179. Rowe BH, Spooner CH, Ducharme FM, et al. Corticosteroids for prevOenPtYing relapse following acute exacerbations of asthma. Cochrane Database of Systematic Reviews 2007: CD000T19C5. 651. dKiirskclhaanrdgeSWfro, mCrothsseEe,mCearmgepnbceylldSe, peat ratlm. IenntrtafmoruasccuultaeravsetrhsmusaN.oCrOaolcchorratniceoDstaetraobiadssetoSyrsetdRuecve 2re0l1a8p;s6e:sCfoDl0lo1w26in2g9. 652. Edmonds ML, Milan SJ, Camargo CA, Jr., et al. Early use-oDf iOnhaled corticosteroids in the emergency department 653. RtraetattomDe,nAtlfoafraocCu,teSiapsstehymJ,ae. tCaolc.hArraenientDraatvaebnaosuesocRfoSIrAytisLctoesmteartoicidRserveiqeuwisre2d01in2s;t1a2tu: Cs Das0t0h2m30at8i.cus? JAMA 1988; 260: 654. 527-529. Harrison BD, Stokes TC, Hart GJ, et al. Need foArTiEntravenous hydrocortisone in addition to oral prednisolone in 655. patients admitted Gries DM, Moffitt DtoR,hPousploitsaEl ,weitthals.eAvesEirneDgaleMstdhomsea without ventilatory failure. Lancet 1986; 1: 181-184. of intramuscularly administered dexamethasone acetate is as effective as oral prednisone to treIaGtHaTsthma exacerbations in young children. J Pediatr 2000; 136: 298-303. 656. aKsritshhmnaa.nAJmA,eRriiecaknerJtoKuArn, aMl coCfPoRyYeJsRVp,ireattoarl.yC&orCtricitoicsatel rCoairdeuMseedaficteinreh2o0sp0i4t;a1l d7i0s:c1h2a8rg1e-1a2m85o.ng high-risk adults with 657. cKoamyapnairSis,oSnhaonfntownoDdCo.sAesdCvoeOfrosreabl sethearvoiiodrsa.lCehfefesctt2s0o0f2t;re1a2t2m: 6e2n4t-f6o2r8a.cute exacerbation of asthma in children: a 658. Keeney GE, Gray MP, Morrison AK, et al. Dexamethasone for acute asthma exacerbations in children: a meta- analysis. Pediatrics 2014; 133: 493-499. 659. Kravitz J, Dominici P, Ufberg J, et al. Two days of dexamethasone versus 5 days of prednisone in the treatment of acute asthma: a randomized controlled trial. Ann Emerg Med 2011; 58: 200-204. 660. Cronin JJ, McCoy S, Kennedy U, et al. A randomized trial of single-dose oral dexamethasone versus multidose prednisolone for acute exacerbations of asthma in children who attend the emergency department. Ann Emerg Med 2016; 67: 593-601.e593. 661. O'Driscoll BR, Kalra S, Wilson M, et al. Double-blind trial of steroid tapering in acute asthma. Lancet 1993; 341: 324- 327. 662. Lederle FA, Pluhar RE, Joseph AM, et al. Tapering of corticosteroid therapy following exacerbation of asthma. A randomized, double-blind, placebo-controlled trial. Arch Intern Med 1987; 147: 2201-2203. 663. Kearns N, Maijers I, Harper J, et al. Inhaled corticosteroids in acute asthma: a systemic review and meta-analysis. J Allergy Clin Immunol Pract 2020; 8: 605-617 e606. 214 References 664. Li CY, Liu Z. Effect of budesonide on hospitalization rates among children with acute asthma attending paediatric emergency department: a systematic review and meta-analysis. World J Pediatr 2021; 17: 152-163. 665. Edmonds ML, Milan SJ, Brenner BE, et al. Inhaled steroids for acute asthma following emergency department discharge. Cochrane Database of Systematic Reviews 2012; 12: CD002316. 666. Kirkland SW, Vandenberghe C, Voaklander B, et al. Combined inhaled beta-agonist and anticholinergic agents for emergency management in adults with asthma. Cochrane Database Syst Rev 2017; 1: CD001284. 667. Craig SS, Dalziel SR, Powell CV, et al. Interventions for escalation of therapy for acute exacerbations of asthma in children: an overview of Cochrane Reviews. Cochrane Database Syst Rev 2020; 8: CD012977. 668. Rodrigo GJ, Castro-Rodriguez JA. Anticholinergics in the treatment of children and adults with acute asthma: a systematic review with meta-analysis. Thorax 2005; 60: 740-746. 669. Nair P, Milan SJ, Rowe BH. Addition of intravenous aminophylline to inhaled beta(2)-agonists in adults with acute asthma. Cochrane Database of Systematic Reviews 2012; 12: CD002742. 670. Rowe BH, Bretzlaff JA, Bourdon C, et al. Magnesium sulfate for treating exacerbations of acute asthma in the 671. emergency department. Cochrane FitzGerald JM. Magnesium sulfate Database Syst is effective for Rev 2000; 2. severe acute asthma treated in theUeTmEergency department. West J 672. Med 2000; 172: 96. Gallegos-Solorzano MC, Perez-Padilla R, Hernandez-Zenteno RJ. Usefulness of TinRhIaBled magnesium sulfate in the coadjuvant management of severe asthma crisis in an emergency departmDenISt. Pulm Pharmacol Ther 2010; 23: 432- 437. OR 673. Goodacre S, Cohen J, severe acute asthma Bradburn M, (3Mg trial): a detoualb.lIen-tbrlainvedn, roaunsdoormniesbedulcisoendOtrmPolaYlegndetsriiualm. LsaunlcpehtaRteesvpeirrsautosrsytaMndedaricdinthee2r0a1p3y; for 1: 293-300. T C 674. Griffiths B, Kew KM. Intravenous department. Cochrane Database mSyasgt nReesviu2m01s6u;lf4a:tCeDfo0r11tr0Ne5aO0t.ing children with acute asthma in the emergency 675. Knightly R, Milan SJ, Hughes R, et al. Inhaled magnes-iuDmOsulfate in the treatment of acute asthma. Cochrane 676. Database Syst Rev 2017; Turker S, Dogru M, Yildiz 11: CD003898. F, et al. The effect of RneIAbLulised magnesium sulphate in the management of childhood 677. moderate asthma exacerbations Rodrigo GJ, Castro-Rodriguez JA. aHsealidojxu-vdarAinvTteEtnrebaettma2e-natg.oAnlliestrsgonleIbmumlizuantioopnaftohrocl h(Mildardern) 2017; 45: 115-120. and adults with acute 678. Rasatmhmsaay:CaFs,yPseteamrsoatnicDr,eMvieildwewnhitahllmS,EeetDat -aMaln. Oalryaslism. AonnntealluskoafsAt lilneragcyu,tAesatshtmhma,a&eIxmacmeurbnaotlioognys:2a01ra4n; d1o1m2:is2e9d-3, 4d.ouble- blind, placebo-controlled trial.ITGhHoTrax 2011; 66: 7-11. 679. Watts K, children. CChoacvharsasneeRDJ.aLtaebuaPksoYetRrSieynsteRreevce2p0t1o2r;a5n:tCaDgo0n0i6s1ts00in. addition to usual care for acute asthma in adults and 680. Balanag VM, Yunus F, CYaOng PC, et al. Efficacy and safety of budesonide/formoterol compared with salbutamol in the treatment of acute asthma. Pulm Pharmacol Ther 2006; 19: 139-147. 681. Peters JI, Shelledy DC, Jones AP, Jr., et al. A randomized, placebo-controlled study to evaluate the role of salmeterol in the in-hospital management of asthma. Chest 2000; 118: 313-320. 682. Joseph KS, Blais L, Ernst P, et al. Increased morbidity and mortality related to asthma among asthmatic patients who use major tranquillisers. BMJ 1996; 312: 79-82. 683. FitzGerald JM, Macklem P. Fatal asthma. Annu Rev Med 1996; 47: 161-168. 684. Lim WJ, Mohammed Akram R, Carson KV, et al. Non-invasive positive pressure ventilation for treatment of respiratory failure due to severe acute exacerbations of asthma. Cochrane Database of Systematic Reviews 2012; 12: CD004360. 685. Kelly A-M, Kerr D, Powell C. Is severity assessment after one hour of treatment better for predicting the need for admission in acute asthma? Respiratory Medicine 2004; 98: 777-781. 686. Wilson MM, Irwin RS, Connolly AE, et al. A prospective evaluation of the 1-hour decision point for admission versus discharge in acute asthma. Journal of Intensive Care Medicine 2003; 18: 275-285. References 215 687. Grunfeld A, FitzGerald J. Discharge considerations for adult asthmatic patients treated in emergency departments. Canadian Respiratory Journal 1996; 3: 322 - 327. 688. Pollack CV, Jr., Pollack ES, Baren JM, et al. A prospective multicenter study of patient factors associated with hospital admission from the emergency department among children with acute asthma. Archives of Pediatrics & Adolescent Medicine 2002; 156: 934-940. 689. Rowe BH, Villa-Roel C, Abu-Laban RB, et al. Admissions to Canadian hospitals for acute asthma: a prospective, multicentre study. Canadian Respiratory Journal 2010; 17: 25-30. 690. Weber EJ, Silverman RA, Callaham ML, et al. A prospective multicenter study of factors associated with hospital admission among adults with acute asthma. American Journal of Medicine 2002; 113: 371-378. 691. Kirkland SW, Vandermeer B, Campbell S, et al. Evaluating the effectiveness of systemic corticosteroids to mitigate relapse in children assessed and treated for acute asthma: A network meta-analysis. J Asthma 2018: 1-12. 692. Hancox RJ, Cowan JO, Flannery EM, et al. Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled beta-agonist treatment. Respir Med 2000; 94: 767-771. 693. Cockcroft DW, McParland CP, Lancet 1993; 342: 833-837. Britto SA, et al. Regular inhaled salbutamol and airway reUspToEnsiveness to allergen. 694. Cowie RL, Revitt exacerbations of SG, Underwood MF, et al. asthma. Chest 1997; 112: The effect of 1534-1538. a peak flow-based action TpRlaInB in the prevention of 695. Ducharme FM, Zemek RL, Chalut D, et al. Written action plan in pediatric emeDrgIeSncy room improves asthma prescribing, adherence, and control. Am J Respir Crit Care Med 2011; 183:O1R95-203. 696. Global Initiative for Chronic Obstructive Lung Disease Prevention of COPD. 2021 Report. Fontana, WI, USA: G(GOOLDLD; )2.0G2l1o.baOl SPtYrategy for Diagnosis, Management and 697. Postma DS, Rabe KF. The Asthma-COPD Overlap Syndrome. N EnTglCJ Med 2015; 373: 1241-1249. 698. PGrloevbeanl tInioitniaotfivCeOfPoDr C2h0r2o0n:icAOvabilsatbrulectfirvoemL:uwngwDwi.sgeoalsdeco(GpOd.LoDr)gN..GOlobal Strategy for Diagnosis, Management and 699. Nelson HS, Weiss ST, Bleecker ER, et al. The Salmeterol-MDuOlticenter Asthma Research Trial: a comparison of usual 700. pharmacotherapy for asthma McMahon AW, Levenson MS, or usual McEvoy pBhWa,rmetaaclo. tARhgeIeAraaLpnyd plus salmeterol. Chest risks of FDA-approved 2006; 129: 15-26. long-acting 2-adrenergic receptor 701. agonists. Gershon APSe,dCiaatmricpsit2e0ll1i M1;A1,2C8r:oex1fo14rd7-R1,1e5t4a.l.ACToEmbination long-acting -agonists and inhaled corticosteroids compared with long-acting 312: 1114-1121. -agonists aEloDneMin older adults with chronic obstructive pulmonary disease. JAMA 2014; 702. Suissa S, Ernst P. Observational stIuGdHieTs of inhaled corticosteroid effectiveness in COPD: Lessons learned. Chest 703. 2018; 154: 257-265. Kendzerska T, Aaron SD, To TP, eYtRal. Effectiveness and safety of inhaled corticosteroids in older individuals with c1h2r6o2n.ic obstructive pulmoCnOary disease and/or asthma. A population study. Ann Am Thorac Soc 2019; 16: 1252- 704. Vonk JM, Jongepier H, Panhuysen CIM, et al. Risk factors associated with the presence of irreversible airflow limitation and reduced transfer coefficient in patients with asthma after 26 years of follow up. Thorax 2003; 58: 322-327. 705. Lange P, Celli B, Agusti A, et al. Lung-function trajectories leading to chronic obstructive pulmonary disease. New England Journal of Medicine 2015; 373: 111-122. 706. Abramson MJ, Schattner RL, Sulaiman ND, et al. Accuracy of asthma and COPD diagnosis in Australian general practice: a mixed methods study. Primary Care Respiratory Journal 2012; 21: 167-173. 707. Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its features and how important is it? Thorax 2009; 64: 728-735. 708. Mannino DM, Gagnon RC, Petty TL, et al. Obstructive lung disease and low lung function in adults in the United States: data from the National Health and Nutrition Examination Survey, 1988-1994. Archives of internal medicine 2000; 160: 1683-1689. 216 References 709. Marsh SE, Travers J, Weatherall M, et al. Proportional classifications of COPD phenotypes. Thorax 2008; 63: 761- 767. 710. Shirtcliffe P, Marsh S, Travers J, et al. Childhood asthma and GOLD-defined chronic obstructive pulmonary disease. Internal medicine journal 2012; 42: 83-88. 711. Guerra S, Sherrill DL, Kurzius-Spencer M, et al. The course of persistent airflow limitation in subjects with and without asthma. Respiratory Medicine 2008; 102: 1473-1482. 712. Silva GE, Sherrill DL, Guerra S, et al. Asthma as a risk factor for COPD in a longitudinal study. Chest 2004; 126: 59-65. 713. van Schayck CP, Levy ML, Chen JC, et al. Coordinated diagnostic approach for adult obstructive lung disease in primary care. Primary Care Respiratory Journal 2004; 13: 218-221. 714. Zeki AA, Schivo M, Chan A, et al. The asthma-COPD overlap syndrome: a common clinical problem in the elderly. Journal of Allergy 2011; 2011: 861926. 715. Kendzerska T, Sadatsafavi M, Aaron SD, et al. Concurrent physician-diagnosed asthma and chronic obstructive pulmonary disease: A population study of prevalence, incidence and mortality. PLoS One 2017; 12: e0173830. 716. Kauppi P, Kupiainen of Asthma 2011; 48: H, Lindqvist 279-285. A, et al. Overlap syndrome of asthma and COPD preUdTicEts low quality of life. Journal 717. Weatherall M, Travers J, Shirtcliffe PM, analysis. European Respiratory Journal et al. 2009; Distinct clinical 34: 812-818. phenotypes of airTwRayIBs disease defined by cluster 718. Inoue H, Nagase T, Morita S, et al. Prevalence and characteristics of asthmaD-ICSOPD overlap syndrome identified by a stepwise approach. Int J Chron Obstruct Pulmon Dis 2017; 12: 1803-18O10R. 719. Uchida A, Sakaue K, Inoue Int 2018; 67: 165-171. H. Epidemiology of asthma-chronic obOstPruYctive pulmonary disease overlap (ACO). Allergol 720. Krishnan JA, Nibber A, Chisholm A, et al. Prevalence and charTacCteristics of Asthma-Chronic Obstructive Pulmonary 721. Disease Overlap in Barrecheguren M, routine Pinto L, Mproimstaarfyavcia-Preouprr-aMctaicnessh.aAdni nSMAm,NeTtOhaol.rIadceSnoticfi2ca0t1io9;n1a6n:d1d14e3fi-n1it1i5o0n. of asthma-COPD overlap: The CanCOLD study. Respirology 2020; 25: 8- 3D6O-849. 722. Andersen H, Lampela P, Nevanlinna A, Respiratory Journal 2013; 7: 342-346. et al. HiRghIAhLospital burden in overlap syndrome of asthma and COPD. Clinical 723. CKeowchKraMn,eSDeantiaubkoasveicohfAS.yIsntheamleadticstReeroviiedws asAn2Td0E1ri4s;k3o:fCpDn0e1u0m1o1n5i.a for chronic obstructive pulmonary disease. 724. Suissa S, Patenaude 68: 1029-1036. V, Lapi F, et al. IEnhDaMled corticosteroids in COPD and the risk of serious pneumonia. Thorax 2013; 725. Louie S, Zeki AA, Schivo M, et aIGl. HThTe asthma-chronic obstructive pulmonary disease overlap syndrome: 726. MphaasromliaMco,tFhaebriaapneDu,tiHcoclotnSPs,iYdeRteraal.tiTohnes.gEloxbpaelrtbruervdieenwooffacsltinhimcaal:pehxaercmutaivcoelsougmy 2m0a1r3y;o6f:t1h9e7G-2IN19A. Dissemination Committee report. AlleCrOgy 2004; 59: 469-478. 727. Simpson CR, Sheikh A. Trends in the epidemiology of asthma in England: a national study of 333,294 patients. Journal of the Royal Society of Medicine 2010; 103: 98-106. 728. Bisgaard H, Szefler S. Prevalence of asthma-like symptoms in young children. Pediatr Pulmonol 2007; 42: 723-728. 729. Kuehni CE, Strippoli MP, Low N, et al. Wheeze and asthma prevalence and related health-service use in white and south Asian pre-schoolchildren in the United Kingdom. Clin Exp Allergy 2007; 37: 1738-1746. 730. Martinez FD, Wright AL, Taussig LM, et al. Asthma and wheezing in the first six years of life. The Group Health Medical Associates. N Engl J Med 1995; 332: 133-138. 731. Sly PD, Boner AL, Bjrksten B, et al. Early identification of atopy in the prediction of persistent asthma in children. Lancet 2008; 372: 1100-1106. 732. Heikkinen T, Jarvinen A. The common cold. Lancet 2003; 361: 51-59. 733. Caudri D, Wijga A, CM AS, et al. Predicting the long-term prognosis of children with symptoms suggestive of asthma at preschool age. Journal of Allergy & Clinical Immunology 2009; 124: 903-910 e901-907. 734. Brand PL, Baraldi E, Bisgaard H, et al. Definition, assessment and treatment of wheezing disorders in preschool children: an evidence-based approach. Eur Respir J 2008; 32: 1096-1110. References 217 735. Belgrave DCM, Simpson A, Semic-Jusufagic A, et al. Joint modeling of parentally reported and physician-confirmed wheeze identifies children with persistent troublesome wheezing. J Allergy Clin Immunol 2013; 132: 575-583.e512. 736. Savenije OE, Kerkhof M, Koppelman GH, et al. Predicting who will have asthma at school age among preschool children. Journal of Allergy & Clinical Immunology 2012; 130: 325-331. 737. Fitzpatrick AM, Bacharier LB, Guilbert TW, et al. Phenotypes of recurrent wheezing in preschool children: identification by latent class analysis and utility in prediction of future exacerbation. J Allergy Clin Immunol Pract 2019; 7: 915-924 e917. 738. Doherty G, Bush A. Diagnosing respiratory problems in young children. The Practitioner 2007; 251: 20, 22-25. 739. Pedersen S. Preschool asthma--not so easy to diagnose. Prim Care Respir J 2007; 16: 4-6. 740. Brand PL, Caudri D, Eber E, et al. Classification and pharmacological treatment of preschool wheezing: changes since 2008. European Respiratory Journal 2014; 43: 1172-1177. 741. Cano Garcinuno A, Mora Gandarillas I, Group SS. Early patterns of wheezing in asthmatic and nonasthmatic children. European Respiratory Journal 2013; 42: 1020-1028. 742. Just J, Saint-Pierre P, Gouvis-Echraghi R, the preschool period. Annals of Allergy, Aesttahlm. Wa,h&eeImzempuhneonlootgyyp2es01in3;y1o1u1n:g2c5h6il-d2r6e1n.eh2aU5v1Te.Edifferent courses during 743. Saglani S, McKenzie SA, Bush A, children with reported wheeze. et al. Arch A video questionnaire identifies Dis Child 2005; 90: 961-964. upper airwaTyRaIbBnormalities in preschool 744. Mellis C. Respiratory noises: how useful are they clinically? Pediatric Clinics ofDNIoSrth America 2009; 56: 1-17, ix. 745. Oren E, Rothers J, Stern DA, et al. Cough during infancy and subsequent chOilRdhood asthma. Clin Exp Allergy 2015; 746. 45: 1439-1446. Azad MB, Chan-Yeung M, Chan ES, et al. Wheezing patterns in early OchPilYdhood and the risk of respiratory and allergic disease in adolescence. JAMA Pediatr 2016; 170: 393-395T. C 747. yVeaanrsDuersiHngeiojdffe-nlinHeHt,idBarol burweearthMinLg,.HPoeedkiasttrraicFP,ueltmaol.nRoelofegrye2n0cN1e4Ov;a4lu9e: s29o1f -e2x9h5a.led nitric oxide in healthy children 1-5 748. Singer F, Luchsinger I, Inci D, et al. Exhaled nitric oxide i-nDsyOmptomatic children at preschool age predicts later 749. asthma. Allergy Caudri D, Wijga 2013; 68: 531-538. AH, Hoekstra MO, et al. PredictionRoIAfLasthma in symptomatic preschool children using exhaled nitric 750. Coaxisdtero, -RRinotdrangdueszpJeAc,ifHicoIlgbEe.rTghCoJr,aWx r2i0g1h0t ;A6L5, :eA8t T0a1El.-A80c7li.nical index to define risk of asthma in young children with 751. recurrent Pescatore wAhMe,eDziongga.rAumCMJ R, eDsupeirmCbrgiteCnaELr,eDeMtMaeld. 2000; 162: 1403-1406. A simple asthma prediction tool for preschool children with wheeze or cough. J Allergy Clin Immunol 2I0G1H4T; 133: 111-118.e111-113. 775523.. ACBoallcelihcrgianyroie2Sr0,1LMB9;.uT4nh9be:li4tr1eD0c,u-4Mr1rei8nCn.etOlllyiPCwY,hReeteazli.nVgaplirdeastciohnooolfcchhilidld-hboeonidgnasothr masathpmreadiincttivhee tmooaklsi:nAg?syAsntnemAlaletircgryeAvisetwhm. Calin Exp Immunol 2015; 115: 463-470. 754. Murray CS, Poletti G, Kebadze T, et al. Study of modifiable risk factors for asthma exacerbations: virus infection and allergen exposure increase the risk of asthma hospital admissions in children. Thorax 2006; 61: 376-382. 755. Guilbert TW, Morgan WJ, Zeiger RS, et al. Long-term inhaled corticosteroids in preschool children at high risk for asthma. New England Journal of Medicine 2006; 354: 1985-1997. 756. Bisgaard H, Allen D, Milanowski J, et al. Twelve-month safety and efficacy of inhaled fluticasone propionate in children aged 1 to 3 years with recurrent wheezing. Pediatrics 2004; 113: e87-94. 757. Fitzpatrick AM, Jackson DJ, Mauger DT, et al. Individualized therapy for persistent asthma in young children. J Allergy Clin Immunol 2016; 138: 1608-1618.e1612. 758. Kelly HW, Sternberg AL, Lescher R, et al. Effect of inhaled glucocorticoids in childhood on adult height. N Engl J Med 2012; 367: 904-912. 759. Gadomski AM, Scribani MB. Bronchodilators for bronchiolitis. Cochrane Database Syst Rev 2014; 6: CD001266. 760. Bisgaard H, Hermansen MN, Loland L, et al. Intermittent inhaled corticosteroids in infants with episodic wheezing. N Engl J Med 2006; 354: 1998-2005. 218 References 761. Wilson NM, Silverman M. Treatment of acute, episodic asthma in preschool children using intermittent high dose inhaled steroids at home. Arch Dis Child 1990; 65: 407-410. 762. Nielsen KG, Bisgaard H. The effect of inhaled budesonide on symptoms, lung function, and cold air and methacholine responsiveness in 2- to 5-year-old asthmatic children. American Journal of Respiratory & Critical Care Medicine 2000; 162: 1500-1506. 763. Szefler SJ, Baker JW, Uryniak T, et al. Comparative study of budesonide inhalation suspension and montelukast in young children with mild persistent asthma. J Allergy Clin Immunol 2007; 120: 1043-1050. 764. Kaiser SV, Huynh T, Bacharier LB, et al. Preventing exacerbations in preschoolers with recurrent wheeze: a meta- analysis. Pediatrics 2016; 137. 765. Knorr B, Franchi LM, Bisgaard H, et al. Montelukast, a leukotriene receptor antagonist, for the treatment of persistent asthma in children aged 2 to 5 years. Pediatrics 2001; 108: E48. 766. Brodlie M, Gupta A, Rodriguez-Martinez CE, et al. Leukotriene receptor antagonists as maintenance and intermittent therapy for episodic viral wheeze in children. Cochrane Database Syst Rev 2015: Cd008202. 767. pCraesstrcoh-oRoolderrsigwueitzhJaAs,tRhomdariogur erez-cMurarretnintewzhCeEe,zDinugc:hAarsmyseteFmMa.tDicarileyviinehwa.lePdedcioarttricPousltmeUoroTniEodls2o0r1m8;o5n3te: l1u6k7a0s-t1f6o7r7. 768. Papi A, Nicolini 64: 1463-1471. G, Baraldi E, et al. Regular vs prn nebulized treatment in wheezTeRpIrBeschool children. Allergy 2009; 769. Zeiger RS, Mauger D, Bacharier LB, et al. Daily or intermittent budesonide iDnIpSreschool children with recurrent wheezing. New England Journal of Medicine 2011; 365: 1990-2001. OR 770. cYhoisldhriheanrayoSu,nTgseurbathkai nT,fIokuerdyaeMar,seotfaal.gTeh. ePeedffiaictarcAyllaenrdgysaImfemtyuonfoflOlu2Pt0iY1ca9s;o3n0e:/1s9a5lm-2e0t3e.rol compared to fluticasone in 771. Piippo-Savolainen E, Remes S, Kannisto S, et al. Asthma and luTnCg function 20 years after wheezing in infancy: results 772. WfroemnnaeprgrroesnpeGc,tHivaenfsoslolonwS-,uEpnsgtsutdroym. AIr,cehtivael.sCohfaPreadctiaetrrisictsiNc&sOaAnddoplersocgennotsMis eodfihcionsepi2t0al0-4tr;e1a5t8e:d1o0b7s0t-r1u0ct7i6ve. bronchitis in children aged less than two years. Acta Paediatric-aD1O992; 81: 40-45. 773. Goksor E, Amark 95: 471-478. M, Alm B, et al. Asthma sympRtoIAmLs in early childhood--what happens then? Acta Paediatrica 2006; 774. Castro-Rodriguez JA, Rodrigo GJ. nebulizer for acute exacerbation Bofetwah-aegeozAninTisgEtsortharsothumghaminectehrileddr-ednousendinehra5leyrewaristhovf aalgvee:dahsoylsdtienmg acthiacmrebveierwvewrsiuths 775. mZeemtae-kanRaLl,yBshiso. gJoaul SrnKa, lDoufcPheadrmiaetriFcMs 2E. 0SDy0s4Mt;e1m4a5t:ic17re2v-1ie7w7.of randomized controlled trials examining written action plans in children: what is the pIlGanH?TArch Pediatr Adolesc Med 2008; 162: 157-163. 776. ASwstehrmnaAISm, TmouzznioClA2,0K0n8o; r1r0PB1Y,:Re6t2a6l-.6P3r0e.dicting an asthma exacerbation in children 2 to 5 years of age. Ann Allergy 777. Brunette MG, Lands L,CTOhibodeau LP. Childhood asthma: prevention of attacks with short-term corticosteroid treatment of upper respiratory tract infection. Pediatrics 1988; 81: 624-629. 778. Fox GF, Marsh MJ, Milner AD. Treatment of recurrent acute wheezing episodes in infancy with oral salbutamol and prednisolone. Eur J Pediatr 1996; 155: 512-516. 779. Grant CC, Duggan AK, DeAngelis C. Independent parental administration of prednisone in acute asthma: a double- blind, placebo-controlled, crossover study. Pediatrics 1995; 96: 224-229. 780. Oommen A, Lambert PC, Grigg J. Efficacy of a short course of parent-initiated oral prednisolone for viral wheeze in children aged 1-5 years: randomised controlled trial. Lancet 2003; 362: 1433-1438. 781. Vuillermin P, South M, Robertson C. Parent-initiated oral corticosteroid therapy for intermittent wheezing illnesses in children. Cochrane Database of Systematic Reviews 2006: CD005311. 782. Robertson CF, Price D, Henry R, et al. Short-course montelukast for intermittent asthma in children: a randomized controlled trial. Am J Respir Crit Care Med 2007; 175: 323-329. 783. Bacharier LB, Phillips BR, Zeiger RS, et al. Episodic use of an inhaled corticosteroid or leukotriene receptor antagonist in preschool children with moderate-to-severe intermittent wheezing. J Allergy Clin Immunol 2008; 122: 1127-1135 e1128. References 219 784. Gouin S, Robidas I, Gravel J, et al. Prospective evaluation of two clinical scores for acute asthma in children 18 months to 7 years of age. Academic Emergency Medicine 2010; 17: 598-603. 785. Pollock M, Sinha IP, Hartling L, et al. Inhaled short-acting bronchodilators for managing emergency childhood asthma: an overview of reviews. Allergy 2017; 72: 183-200. 786. Powell C, Kolamunnage-Dona R, Lowe J, et al. Magnesium sulphate in acute severe asthma in children (MAGNETIC): a randomised, placebo-controlled trial. The Lancet Respiratory Medicine 2013; 1: 301-308. 787. Pruikkonen H, Tapiainen T, Kallio M, et al. Intravenous magnesium sulfate for acute wheezing in young children: a randomised double-blind trial. Eur Respir J 2018; 51. 788. Fuglsang G, Pedersen S, Borgstrom L. Dose-response relationships of intravenously administered terbutaline in children with asthma. Journal of Pediatrics 1989; 114: 315-320. 789. Connett G, Lenney W. Prevention of viral induced asthma attacks using inhaled budesonide. Arch Dis Child 1993; 68: 85-87. 790. Svedmyr J, Nyberg E, Thunqvist P, et al. Prophylactic intermittent treatment with inhaled corticosteroids of asthma 791. exacerbations due to airway infections in toddlers. Acta Paediatr Cai KJ, Su SQ, Wang YG, et al. Dexamethasone versus prednisone 1999; 88: 42-47. or prednisolone for acUuTteE pediatric asthma 792. exacerbations in the Garrett J, Williams S, emergency Wong C, et dael.pTarretamtmenetn: taomf eatcau-taenaaslythsims.aPteicdeiaxtarcEemrbeartgioCnasrewT2iRt0hI2Ba0n. increased dose of inhaled steroid. Archives of Disease in Childhood 1998; 79: 12-17. DIS 793. Rowe BH, Spooner C, Ducharme FM, et al. Early emergency department trOeRatment of acute asthma with systemic 794. corticosteroids. Cochrane Panickar J, Lakhanpaul M, Database of Lambert PC, Seytsatel.mOaratilcpRreevdineiwsoslo2n0e01fo: Cr DpOr0e0Ps2cY1h7o8o.l children with acute virus-induced wheezing. N Engl J Med 2009; 360: 329-338. T C 795. Webb 15-19. MS, Henry RL, Milner AD. Oral corticosteroids for wheeNzOing attacks under 18 months. Arch Dis Child 1986; 61: 796. Castro-Rodriguez JA, Beckhaus AA, Forno E. Efficacy of o- rDaOl corticosteroids in the treatment of acute wheezing 797. eBpuinsyoadveasniinchasSt,hRmifaatsi-cSphrimesacnhoSoL,lePrlsa:tStsy-sMteilmlsaTtAic, reetRvaiIeAl.wLPewainthutm, metialk-,aannadlyswish.ePaetdiinattarkPeudlmuroinngolp2r0e1g6n;a5n1cy: 8is6a8s-8so7c6i.ated 798. with reduced allergy and Maslova E, Granstrom C, asthma Hansen in S, ecthialdl.rPeena. nAJouTutErannadl of Allergy & Clinical Immunology 2014; 133: 1373-1382. tree nut consumption during pregnancy and allergic disease in AchllieldrgreynC-lsihnoImuldmmunootlh2e0rs12d;e1cr3e0a:s7e2t4h-e7i3rE2iDn. taMke? Longitudinal evidence from the Danish National Birth Cohort. J 799. Maslova E, Strom M, Oken E, et alI.GFHisTh intake during pregnancy and the risk of child asthma and allergic rhinitis - 800. lBoensgtitKuPd,iGnaolldevMid,eKnecnenferdoymDt,hPeeYtDaRal.nOismheNgaat-i3onloanl gB-icrthhaiCnoPhUoFrtA. Binrtitaikseh dJouurirnngalporef gNnuatnrictyioann2d0a1l3le;r1g1ic0d: i1s3e1a3se-1o3u2t5c.omes iAnmthJeColifnfsNpuritnrg2:0a1s6y;s1te0m3:Ca1tO2ic8r-e1v4i3e.w and meta-analysis of observational studies and randomized controlled trials. 801. Best KP, Sullivan T, Palmer D, et al. Prenatal fish oil supplementation and allergy: 6-year follow-up of a randomized controlled trial. Pediatrics 2016; 137. 802. Hansen S, Strom M, Maslova E, et al. Fish oil supplementation during pregnancy and allergic respiratory disease in the adult offspring. J Allergy Clin Immunol 2017; 139: 104-111.e104. 803. Best KP, Sullivan TR, Palmer DJ, et al. Prenatal omega-3 LCPUFA and symptoms of allergic disease and sensitization throughout early childhood - a longitudinal analysis of long-term follow-up of a randomized controlled trial. World Allergy Organ J 2018; 11: 10. 804. Forno E, Young OM, Kumar R, et al. Maternal obesity in pregnancy, gestational weight gain, and risk of childhood asthma. Pediatrics 2014; 134: e535-546. 805. Brozek JL, Bousquet J, Baena-Cagnani CE, et al. Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines: 2010 revision. Journal of Allergy & Clinical Immunology 2010; 126: 466-476. 806. Chan-Yeung M, Becker A. Primary prevention of childhood asthma and allergic disorders. Current Opinion in Allergy & Clinical Immunology 2006; 6: 146-151. 220 References 807. Greer FR, Sicherer SH, Burks AW. The effects of early nutritional interventions on the development of atopic disease in infants and children: The role of maternal dietary restriction, breastfeeding, hydrolyzed formulas, and timing of introduction of allergenic complementary foods. Pediatrics 2019; 143. 808. Nurmatov U, Devereux G, Sheikh A. Nutrients and foods for the primary prevention of asthma and allergy: systematic review and meta-analysis. Journal of Allergy & Clinical Immunology 2011; 127: 724-733.e721-730. 809. Chawes BL, Bonnelykke K, Stokholm J, et al. Effect of vitamin D3 supplementation during pregnancy on risk of persistent wheeze in the offspring: a randomized clinical trial. Jama 2016; 315: 353-361. 810. Litonjua AA, Carey VJ, Laranjo N, et al. Effect of Prenatal Supplementation With Vitamin D on Asthma or Recurrent Wheezing in Offspring by Age 3 Years: The VDAART Randomized Clinical Trial. JAMA 2016; 315: 362-370. 811. Wolsk HM, Harshfield BJ, Laranjo N, et al. Vitamin D supplementation in pregnancy, prenatal 25(OH)D levels, race, and subsequent asthma or recurrent wheeze in offspring: Secondary analyses from the Vitamin D Antenatal Asthma Reduction Trial. J Allergy Clin Immunol 2017; 140: 1423-1429.e1425. 812. Litonjua AA, Carey VJ, Laranjo N, et al. Six-year follow-up of a trial of antenatal vitamin D for asthma reduction. N 813. Engl J Med 2020; 382: 525-533. Stratakis N, Roumeliotaki T, Oken E, et al. Fish and seafood consumption during preUgnTaEncy and the risk of asthma and allergic 1465-1477. rhinitis in childhood: a pooled analysis of 18 European and US birthTRcoIBhorts. Int J Epidemiol 2017; 46: 814. Bisgaard H, Stokholm J, Chawes BL, et al. Fish oil-derived fatty acids in pregDnIaSncy and wheeze and asthma in offspring. N Engl J Med 2016; 375: 2530-2539. OR 815. Azad MB, Coneys JG, Kozyrskyj AL, of asthma and wheeze: systematic eret vaile.wPraonbdiomticetsau-papnlaelmyseisn.tBaMtioOJnP2d0Yu1r3i;n3g4p7r:efg6n4a7n1c.y or infancy for the prevention 816. Celedon JC, Milton DK, Ramsey CD, et al. Exposure to dust miTteCallergen and endotoxin in early life and asthma and 817. atopy Lodge iCnJ,chLoildwheoAoJd,.GJouurrrinnaLlCo,feAtlalel.rgHyo&usCelidnuicsatlmImitme suennosliotNigzOyat2i0o0n7i;n1t2o0d:d1le4r4s-1p4re9d. icts current wheeze at age 12 years. Journal of Allergy & Clinical Immunology 2011-;D1O28: 782-788.e789. 818. Custovic A, respiratory SsyimmppstoonmBsMan, dSiamtoppsoyndAur,ientgafli.rsEtffyeeRcatIrAooLffelnifvei:roanrmanednotmalimseadntirpiuall.aLtiaonnceint pregnancy 2001; 358: and early 188-193. life on 819. cPuerrrzeanntowwhskeieMzeSa, tChageew5GyLe,aDrisvjiannaAn,inent earl.-AcCTiatyEt coowhnoerrts.hJoipuirsnaalroisfkAflalectrogyr f&orCtlihneicdael vImelmopumnoelnotgoyf2a0n0t8i-;c1a2t 1Ig:E10b4u7t -not 820. 1052. Melen E, Wickman M, Nordvall SL, eEt Dal.MInfluence of early and current environmental exposure factors on sensitization and outcome of aIsGthHmTa in pre-school children. Allergy 2001; 56: 646-652. 821. rThaiknkitoius:cahemBe,tGa-oannzaalyleszis-B. AaPrllcYeaRrlgayF2J,0E0t8m; 6in3a:n85M7,-8e6t 4a.l. Exposure to furry pets and the risk of asthma and allergic 822. Bufford JD, Gern JE. EaCrlOy exposure to pets: good or bad? Current Allergy & Asthma Reports 2007; 7: 375-382. 823. Ownby DR, Johnson CC, Peterson EL. Exposure to dogs and cats in the first year of life and risk of allergic sensitization at 6 to 7 years of age. JAMA 2002; 288: 963-972. 824. Lodrup Carlsen KC, Roll S, Carlsen KH, et al. Does pet ownership in infancy lead to asthma or allergy at school age? Pooled analysis of individual participant data from 11 European birth cohorts. PloS one 2012; 7: e43214. 825. Quansah R, Jaakkola MS, Hugg TT, et al. Residential dampness and molds and the risk of developing asthma: a systematic review and meta-analysis. PLoS ONE [Electronic Resource] 2012; 7: e47526. 826. Arshad SH, Bateman B, Matthews SM. Primary prevention of asthma and atopy during childhood by allergen avoidance in infancy: a randomised controlled study. Thorax 2003; 58: 489-493. 827. Becker A, Watson W, Ferguson A, et al. The Canadian asthma primary prevention study: outcomes at 2 years of age. Journal of Allergy & Clinical Immunology 2004; 113: 650-656. 828. Schonberger HJAM, Dompeling E, Knottnerus JA, et al. The PREVASC study: the clinical effect of a multifaceted educational intervention to prevent childhood asthma. European Respiratory Journal 2005; 25: 660-670. 829. van Schayck OCP, Maas T, Kaper J, et al. Is there any role for allergen avoidance in the primary prevention of childhood asthma? Journal of Allergy & Clinical Immunology 2007; 119: 1323-1328. References 221 830. Chan-Yeung M, Ferguson A, Watson W, et al. The Canadian Childhood Asthma Primary Prevention Study: outcomes at 7 years of age. Journal of Allergy & Clinical Immunology 2005; 116: 49-55. 831. Scott M, Roberts G, Kurukulaaratchy RJ, et al. Multifaceted allergen avoidance during infancy reduces asthma during childhood with the effect persisting until age 18 years. Thorax 2012; 67: 1046-1051. 832. Valovirta E, Petersen TH, Piotrowska T, et al. Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy. J Allergy Clin Immunol 2018; 141: 529-538.e513. 833. Wongtrakool C, Wang N, Hyde DM, et al. Prenatal nicotine exposure alters lung function and airway geometry through 7 nicotinic receptors. American Journal of Respiratory Cell & Molecular Biology 2012; 46: 695-702. 834. Burke H, Leonardi-Bee J, Hashim A, et al. Prenatal and passive smoke exposure and incidence of asthma and wheeze: systematic review and meta-analysis. Pediatrics 2012; 129: 735-744. 835. Bowatte G, Lodge C, Lowe AJ, et al. The influence of childhood traffic-related air pollution exposure on asthma, allergy and sensitization: a systematic review and a meta-analysis of birth cohort studies. Allergy 2015; 70: 245-256. 836. Khreis H, Kelly C, Tate J, et al. Exposure to traffic-related air pollution and risk of development of childhood asthma: 837. A systematic review and meta-analysis. Achakulwisut P, Brauer M, Hystad P, et Environ Int 2017; 100: 1-31. al. Global, national, and urban burdens of paedUiaTtrEic asthma incidence 838. aHtethriubautZa,bQleintgoCa,mShbaiennytaNnOG2, eptoalllu. tTiohne:imesptiamctatoefspfrreonmatgalloebxaplodsautraesetots.aLirapnocellut tPiolanTnReotnIBHcehailldthho2o0d19w;h3e:eez1in6g6-aen1d78. asthma: A systematic review. Environ Res 2017; 159: 519-530. DIS 839. Haahtela T, Holgate S, Pawankar R, et al. The biodiversity hypothesis and aOllRergic disease: world allergy organization 840. position statement. World Allergy Organization Journal 2013; 6: 3. Riedler J, Braun-Fahrlander C, Eder W, et al. Exposure to farming in eOaPrlYy life and development of asthma and allergy: a cross-sectional survey. Lancet 2001; 358: 1129-1133. T C 841. Braun-Fahrlander C, school-age children. RNieewdleErnJg,laHnedrzJoUu,rentaal lo. fEMnveirdoicnimneen2t0a0l2e;xN3p4Oo7s:u8re69to-8e7n7d. otoxin and its relation to asthma in 842. Karvonen AM, Hyvarinen A, Gehring U, et al. Exposure t-oDmOicrobial agents in house dust and wheezing, atopic dermatitis and atopic sensitization Allergy 2012; 42: 1246-1256. in early childhoRoIAd:La birth cohort study in rural areas. Clinical & Experimental 843. Huang L, Chen Q, Zhao Y, et Journal of Asthma 2015; 52: al. Is elective 16-25. cesAarTeEan section associated with a higher risk of asthma? A meta-analysis. 844. sKuebasgeOqEu,eNntoprmreagnnaJEn,cSietos:cSkySsJt.eLmonatgi-cterermEviDerwisMkasnadnmd ebtean-aenfiatslyassiss.oPcLiaotSedMwedith20c1e8sa; r1e5a:ned1e0l0iv2e4r9y4f.or mother, baby, and 845. Azad MB, Konya T, Maughan H, etIGalH. GTut microbiota of healthy Canadian infants: profiles by mode of delivery and 846. infant diet at Blanken MO, 4RomveornsthMsM. C,MMAoPJleY2n0Ra1a3r; 185: 385-394. JM, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm infants. New England JourCnOal of Medicine 2013; 368: 1791-1799. 847. Scheltema NM, Nibbelke EE, Pouw J, et al. Respiratory syncytial virus prevention and asthma in healthy preterm infants: a randomised controlled trial. Lancet Respir Med 2018; 6: 257-264. 848. Baron R, Taye M, der Vaart IB, et al. The relationship of prenatal antibiotic exposure and infant antibiotic administration with childhood allergies: a systematic review. BMC Pediatr 2020; 20: 312. 849. Celedon JC, Fuhlbrigge A, Rifas-Shiman S, et al. Antibiotic use in the first year of life and asthma in early childhood. Clinical & Experimental Allergy 2004; 34: 1011-1016. 850. Cheelo M, Lodge CJ, Dharmage SC, et al. Paracetamol exposure in pregnancy and early childhood and development of childhood asthma: a systematic review and meta-analysis. Archives of disease in childhood 2015; 100: 81-89. 851. Eyers S, Weatherall M, Jefferies S, et al. Paracetamol in pregnancy and the risk of wheezing in offspring: a systematic review and meta-analysis. Clinical & Experimental Allergy 2011; 41: 482-489. 852. Flanigan C, Sheikh A, DunnGalvin A, et al. Prenatal maternal psychosocial stress and offspring's asthma and allergic disease: A systematic review and meta-analysis. Clin Exp Allergy 2018; 48: 403-414. 853. Kozyrskyj AL, Mai XM, McGrath P, et al. Continued exposure to maternal distress in early life is associated with an increased risk of childhood asthma. Am J Respir Crit Care Med 2008; 177: 142-147. 222 References 854. Xu S, Gilliland FD, Conti DV. Elucidation of causal direction between asthma and obesity: a bi-directional Mendelian randomization study. Int J Epidemiol 2019. 855. Sun YQ, Brumpton BM, Langhammer A, et al. Adiposity and asthma in adults: a bidirectional Mendelian randomisation analysis of The HUNT Study. Thorax 2020; 75: 202-208. 856. Beasley R, Semprini A, Mitchell EA. Risk factors for asthma: is prevention possible? Lancet 2015; 386: 1075-1085. 857. Burgers J, Eccles M. Clinical guidelines as a tool for implementing change in patient care. Oxford: Butterworth- Heinemann; 2005. 858. Woolf SH, Grol R, Hutchinson A, et al. Clinical guidelines: potential benefits, limitations, and harms of clinical guidelines. BMJ 1999; 318: 527-530. 859. ADAPTE Framework. Available from http://www.adapte.org. 2012. 860. Brouwers MC, Kho ME, Browman GP, et al. AGREE II: advancing guideline development, reporting and evaluation in health care. CMAJ 2010; 182: E839-842. 861. Boulet LP, FitzGerald JM, Levy ML, et al. A guide to the translation of the Global Initiative for Asthma (GINA) strategy 862. into improved care. Eur Davis DA, Taylor-Vaisey Respir J 2012; A. Translating 39: 1220-1229. guidelines into practice. A systematic review oUfTtEheoretic concepts, practical 863. HexaprreirsioenncMeBa,nLdergeasreeaFr,cGh reavhidaemncIDe,ienttahle. AaddaoppttiinogncolfincilcianlicparlapcrtaiccetigceuigdueildineelisnteoTs.RloCIcBMalAcJo1n9t9e7xt; 1a5n7d:a4s0s8es-4si1n6g. barriers to their use. CMAJ 2010; 182: E78-84. DIS 864. Partridge MR. Translating research into practice: how are guidelines imOpRlemented? Eur Respir J Suppl 2003; 39: 23s- 865. 29s. Baiardini I, Braido F, Bonini M, et al. Why do doctors and patientsOnPoYt follow guidelines? Curr Opin Allergy Clin Immunol 2009; 9: 228-233. T C 866. Boulet LP, Becker A, Bowie D, et implementation with a focus on aasl.thImmpaleamndenCtOinPgDp. rCaacnticReeNsgOpuiirdJe2lin0e0s6:; a workshop 13 Suppl A: on guidelines 5-47. dissemination and 867. Franco R, Santos AC, do Nascimento HF, et al. Cost-e-ffDeOctiveness analysis of a state funded programme for control 868. of severe asthma. Renzi PM, Ghezzo BMC Public H, Goulet S, Heet aallt.hP2ap00e7r ;st7a:mR82pIA.cLhecklist tool enhances asthma guidelines knowledge and 869. NimkpolyemF,eFnatsastliBo,nSbtoynperiBm,aertyacl.aIrme pprhoyvsiinciganpAseT.dCEiaatnriRceasspthirmJ a20c0ar6e; 13: 193-197. and outcomes across multiple hospitals. Pediatrics 870. 2015; 136: e1602-1610. Cochrane Effective Practice and OrgEanDisMation of Care Group (EPOC). Available at http://epoc.cochrane.org. 2013. YRIGHT COP References 223 IBUTE DISTR Y OR COP T NO AL - DO ATERI HTED M PYRIG CO Visit the GINA website at www.ginasthma.org 2022 Global Initiative for Asthma