Document xzMQDjrQ89eB0gjzZdJV5zynE

136 PostScript Thorax 2002;57:166-188 NOTICE: THIS MATERIAL MAY BE PROTECTED BY CWRIQHT LAW (TITLE 17 U.5- CODfc) LETTERS TO THE EDITOR BMD and airways disease The papers recently published in Thorax by Tiuersfield a aV and Walsh a af alter important information aboul the possible adverse affects of corticosteroids on bone mineral density (BMD). Tattersfield and her colleagues reported no change in BMD with inhaled corticosteroids for mild asthma, while Waish it a! found a dose related Increase in the incidence of fractures In those taking oral corticosteroids. We would like to report our study of BMD in patients with airways disease, which reinforces these findings and highiights men as being particularly at risk. vje prospectively studied 100 consecutive outpatients (44 men) with steroid responsive airways disease. The formulation and cumula tive dose of corticosteroid was recorded in each individual, together with all prescribed prophy laxis for osteoporosis. Bone mineral density was measured in the non-dnminam forearm. Vvfe found no relationship between inhaled corticosteroid dose and BMD. Mean BMD was significantly reduced in those on oral as opposed to inhaled steroid s- In men the mean 1 scores for those on inhaled and oral cortico steroids were 0,1 and -0,6, respectively (p=0.07), while women had mean Z scores of 0.5 and -0.3 for Inhaled and oral cortico steroids, respectively (p=0,0J6). Our patient numbers were insufficient to confirm a dose jesponse. The surprising result was that men were more likely to meet the WHO criteria for osteoporosis than women (25% v 12.5%). This result is explained at least in part by the use of prophylaxis which was prescribed to 21 women but to only two men. Of those on regular oral steroids, only 5,5% of men received prophylaxis compared with 62.5% of women. Similar results have been reported in other chronic dis eases, with a greater reduction in BMD being reported in men with cystic fibrosis.1 Unfortunately it appears to have been assumed that men are protected from osteo porosis by virtue of their gender When chronic disease is treated with oral cortico steroids, both men and women are equally at risk of osteoporosis and all should be consid ered for prophylaxis. C Elmer, P Bortholemew, A Lopworth, P Turner, C Kelly Department of Medicine, Queen Elizobelh Hospital, Gateshead NE9 65K, UK References . 1 TartarsfiekJ AE, Town Gl, Jobnell O, efof. Bone mineral density in subjects with mild asthma randomised to treatment with inhaled corticosteroids or noneorticosteroid treatment for two years, thorax 2001,56:272-8 2 Wobh U. Wong CA, Obarne J, elol. Adverse effect at oral corticotleraid& in relation to dose irt patients with lung disease. Thorax 2001;56:279-34. 3 Conway SP, Morton AM, Oldroyd 6, et al. Osteoporosis and osteopenia in adults and adolescents in cystic fibrosis; prevalence and associated factors, ihorax 2MO;55:798B04. AHR in asthma Peat el al' have contributed a helpful review to the debate on techniques for measuring II you hove burning desire to respond to a popar published in Thorax, why not moke use of our "rapid response' option? log on to our website lwww.thoroxjnl.com), find the paper that interests you, and send your response via email by clicking on the "eLeHers' option In the box at the top right hand comer. Providing it isn't libellous or obscene, it will be posted within seven days. You can retrieve it by clicking on "read elstters' on our homepage. The editors will decide os before whether to also publish it In a future paper issue. asthma in population studies. However, they' have endorsed airway hyperresponsiveness (AHR) while neatly sidestepping the issue of what test they are discussing. Inhaled provo cation tests used in epidemiological work have included histamine, methacholine, hypertonic saline, cold air, and adenosine. Exercise provocation tests have also been used. Peat ei a! have previously shown that exercise and histamine challenges may define different groups of children,' and we have shown that longer term repeatability of a Tree running exercise provocation test is poor within a childhood population.1 In adults quite considerable within subject variability in PD,, to methacholine has been observed during a 1 year period,' and a childhood population study found that methacholine PD,, varied by >4 doubling doses within the course of a year in 33% of the subjects.' We would suggest that more care should be taken to define the precise measure of ahr used before comments can be made about Its sensitivity and specifidly in an epidemiologi cal survey. The medium term temporal varia tion In AHR seen by a number cf researchers is another measure which may mate it difficult to make useful comparisons between populations. fi A Primhok Sheffield Children's Hospital, Western Bank, Sheffield SI 0 2TH, UK C V E Powell Departments of Emergency Medicine and General Paediatrics, Royal Children's Hospital. Poifcville, Victoria 30S2 ond University ol Melbourne, Victoria, Australia References 1 Peal J, Toeile B, Morks G, el al. Continuing the debate about measuring asthma in population studies. Thorax 2001 ;56:406-l 1. 2 Haby M, Anderson S, Peat J, vt al. An exercise challenge protocol lor epidemiologtcol studies of asthma in children: comparison with histamine challenge- fur RespirJ 1994;7:43-9. 3 Powell C White R. Primhok R. longitudinal study of free running exercise challenge: reproducibility. Aren Dr's Child 1996;74:126-30. 4 Trigg C, TboleyM, D'Souzo M, el al. Factors affecting the long-term variability of branchial responsiveness in an adult general practice population. EvrRespirJ 1994;7:703-9. 5 Clough J, Williams J, Holgate &. Profile of bronchial responsiveness in children with respiratory symptoms, Arch Dis Child 1992;47:574-9. Authors' reply Primhakand Powell make the valid point that, the presence of airway hyperresponsiveness (AHR) is not an absolute attribute. Abnormal AHR represents one end of a continuum of responsiveness. Furthermore, the distribution of that continuum varies according to the nature of the direct or indirect stimulus that is applied. (n our studies, referred to in the review, we have defined abnormal airway responsiveness as a decline of more than 20% in forced expiratory volume in 1 second (FEV,| after inhalation of a cumulative dose of histamine of 3.9 pmol. Using this criterion, the pres ence of AHR is a useful marker of airway abnormality consistent with asthma in epide miological studies' and Is also predictive of the subsequent course of the disease.1 We acknowledge that other criteria for the pres ence of AHR have not been evaluated as extensively in epidemiological studies. How ever, there is evidence that al least some indi rect agonists, such as non-isotonic aerosols and exercise, also have a high level of specifi city but only moderate sensitivity as markers of asthma symptoms.' ` J K Peat, B G Toeile, G B Marks, C M Mollis Institute of Respiratory Medicine, University ol Sydney, Box M77, Missenden Rood P O, Camper-down, NSW 2050, Australia References 1 Toeile BG, Peot JK, Salome CM, et ol. Toward a definition af asthma for epidemiology. Am Rev Rpir Dis 1992;146:633-7. 2 Peat J, Toeile B, Salome C, et al. Predictive nature oi bronchia! responsiveness ond respiratory symptoms in a one year cohort study of Sydney schoolchildren. Evr RespirJ 1993;6:662-9. 3 Smith C, Anderson S. Inhalation provocation tests using nonisotonic aerosols. J Allergy Clin hnmunol 1989;84:781-90. 4 Haby M, Peof j. Mollis C, et ol. Art exercise challenge For epidemiological studies of childhood ashmo: validity and-repeatability Evr RespirJ 1995;8:729-36. One fibre or many; what causes mesothelioma? In a recent case (00/TLQ/I284) in rhe Queen's Bench Division of the High Court in England, a widow sued on behalf of her husband who had died at the age of 60 of mesothelioma. Unusually for such cases, Mr Justice Curtis found for the defendants, and the grounds for his judgement were sufficiently curious to be of general interest and worthy of debate. ]i was not disputed that the deceased had been exposed to substantial quantities of asbestos during two periods of employment, nor that there had been a breach of statutory duty by his employers at that time. Tbc judge ment was based, however, on the expert and agreed opinion of "two most highly qualified medical men". In their joint report and oral evidence, the judge believed these doctors to have staled that mesothelioma is the conse quence of malignant transformation in a sin gle cell, the result of a hit by either one or sev eral fibres. This led the judge to reason that, although a fibre Or fibres inhaled during one www.-thcxaxjnl.eoin Postscript 1B7 or other period of employment may well have led to the fatal cellular transformation, it was not possible to say which, and he was therefore unable to find either responsible. In coming to his Judgement. Mr Justice Curtis made a distinction between causation and risk factors, in his words "the only relevance of the number of fibres is in connection with the risk of contracting the disease". He was thus dissuaded from being influenced by any evidence that might have shown a relationship between risk of meso thelioma and dose of asbestos, although there is much such evidence from studies both of human lungs and of animals, . I have heard the view expressed before chat one fibre causes mesothelioma. It depends what you mean by "cause". It is in one sense obvious nonsense. VVe all have millions of asbestos fibres in our lungs and the likelihood of us developing mesothelioma depends on how many millions. This means that the disease is dose related. The problem in (his case arose from confusing the disease mesothtiioma with transformation in a Cfll. which may be a factor in the development of the disease. Take the case of the butterfly flapping its wings in the Amazon rain forest. It may be possible for an Ingenious QC to prove that the hurricane that hit the coast of west Africa was caused by thal insect's action, but the other Side would surely point to other risk factors that, taken with the action of the butterfly, contributed significantly to the disaster. Is it really possible to say that the only and necessary cause of mesothelioma is transfor mation in a cell? Are we sure that the milieu in which thal cell lives and divides is not influen tial? Are we sure that inflammation in the tis sue involved is not an important precondition for the development of the disease? Arc we sure that the action of asbestos on other cells does not interfere with the natural defences that would otherwise eliminate the transformed cell? Are we sure Ihat genetic factors and viruses do not also determine whether the transformation occurs or succeeds In overcom ing the body's defences? Or looked ai another way, experimentally, how many rats would have to be used lo produce one mesothelioma after injection of one fibre into the peritoneum? Of course, no one has ever shown that one fibre causes mesothelioma. All thal has been conjec tured is thal the malignant cells that form pan of the tumour may be the genetic offspring of one transformed ceil.' The judge appears in this case to have been persuaded to accept a naive view of causation--that disease has one ultimate cause. Most who have studied the causation of disease would argue thal the likelihood of disease occurring in any individual is influ enced by multiple factors, the outcome of inherited and acquired susceptibility and environmental pretipiianis. In the case of mesothelioma, a very heavily asbestos ex posed individual may have a one in 10 lifetime risk of the disease. Most of us, with very small incidental exposures, have about a one in 1 million annual risk. The risk varies with the length and intensity of exposure, as assessed by the individual's occupational history, we know from animal studies that asbestos fibres do indeed cause mesothelioma, so this evi dence of a dose reiated association strongly suggests that factors other than transforma tion of one cel) ate also, and critically, respon sible for the disease. Among these is likely to be inflammation in the pleura initiated by the presence of many fibres. Such inflammation may not only result in malignant transforma tion of many ceils, but may also inhibit the natural mechanisms whereby such cells arc eliminated. If this is true, and it is certainly more plausible than the one fibre theory, then mesothelioma is caused by the access of large numbers of fibres to the mesotheliai tissue. Since it is a dose reiated disease, it may be argued that all exposures to asbestos before a critical time would be expected to have contributed to the causation of the disease. Thus, attribution of blame should be on the basis of relative intensity and duration of exposure in different trades. The moral of this story is Ihat lawyers are clever people and part of their business is the meaning of words. The word "cause" is one that requires a bit of thought. My Shpner Oxford Dictionary devotes a column to it. A Seaton Department of Environmental and Occupational Medicine, Aberdeen University Medical School, . Forestsrbill, Aberdeen AB25 2ZP, UK; . seatonQobdn .ac.vfc Mesothelioma Vfe write as the three medical witnesses who provided evidence (all in writing, two orally 1 to the Court in the case referred to by Professor Seaton. Essentially we agree with his analysis. The medical evidence presented to the Court made it clear that the risk of mesothelioma increases in relation to the dose of asbestos and that it is not possible lo identify the particular fibre or fibres involved in the genesis of a particular mesothelioma. From an epidemio logical standpoint it is therefore appropriate to regard all sources of significant exposure as having contributed to causation of the disease, in the same way that all cigarettes smoked would be considered to have contributed to causation of a lung cancer. Mr Justice Curtis, however, accepted the invitation of Leading Counsel for one of the defendants to adopt a strictly mechanistic approach to causation. He decided that, be cause the claimant Could not show whether the fibre or fibres actually involved in the genesis of the tumour were derived from either or both of two sources ol exposure, causation could not be established against either of two defendants. More recently, a different view has been taken in a similar case by Mr Justice Mitring (Queen's Bench Division C200i0111) He con sidered thar there was "no substantia) differ ence between saying that what the defendant did materially increased ihe risk of injury to the claimant and saying thal what the defendant did made a material contribution to his Injury", It would be "wholly artificial to require a claimant to prove which fibre or fibres, inhaled in whose employment In precisely what circumstances, caused or set off or contributed to the process by which one or more mesotheliai cells become malignant''. He concluded that breach of duty on the pan of both defendants caused the mesothelioma. Both cases are soon to be considered by the Court of Appeal and the outcome wil] determine whether the many mesothelioma victims who happen to have derived their asbestos exposure from more than one source are to be left without Tedress. R Rudd Medical Oncology Deportment, St Bartholomew's Hospital, London EC1A ?B1. UK; R.M.Rudd@qmiil.Oc.uk J Moore-Gillon Respiratory Medicine Deportment, St Bartholomew's Hospital, louden EC1A 7BE, UK M MuerS Respiratory Unit, The General Infirmary at Leeds, Leeds IS! 3EX, UK; amando.jonei61eedsth.nhs.uk Statement on malignant mesothelioma in the UK We would like to provide the following additional material to Appendix J "Sources of information and help available for patients and carers" which appeared on pages 263-4 of the BTS statement on malignant mesothe lioma in the UK published recently In Thorax.' The following Asbestos Support Groups are the major practical sources of information in the UK for people with asbestos related diseases. Most provide a drop in and tele phone service, giving confidential free advice and support to patients and families. They also have particular expertise in the field of industrial injury benefits and government and civil compensation claims. Although most of the groups are in the north of England, telephone queries from any part of Great Brit ain are acceptable to them. Manchester (id: 0161 953 4037) Sheffield (tel: 0114 282 3212 or 01709 513 587) Liverpool (tel:0151 236 1895) Bradford (lei: 01274 393 949) Vvtest Tories (lei: 0113 243 9979) Cheshire (tel: 01928 576641) Nottingham (tel: 0115 927 5108) In Scotland: Clydeside Aclion on Asbestos (Lei: 0141 552 8852) Clydebank Asbestos Group fie): 0141 95J 1008) Other important sources uf help and Infor mation are: The Macmillan Mesothelioma information line (lei: 0113 206 6466; email: mavisro@ulth.northy.nhs.uk) and the Occu pational and Environmental Diseases Associ ation (OEDA), both of which were mentioned in the original statement. . M Robinson Mesothelioma Information Service, Cookridge Hospital, Leeds LSI6 608, UK; mavisra@ullh.oerthy.nhs.uk J Wiggins Department pf General Medicine, Wexhom Pork Hospital, Slough, Berkshire SL2 4HL, UK Reference ' 1 British Thoracic Society Standards of Care Committee. Statement on malignant mesothelioma in the United Kingdom, Thgrox 2001;56:250-65. Asymptomatic pulmonary involvement in RA Dawson el aV found HRCT evidence of fibros ing alveolitis (FA) in 19% of 150 outpatients with rheumatoid arthritis (RA). The presence of FA did not relate to previously described predisposing factors such as male sex, nodular and/or extra-articular disease, disease dura tion and severity. Moreover, the authors did not find any relation with respiratory symp toms such as dyspnoea or cough, chest radio graphic appearance of FA, or restrictive pattern at pulmonary function iesLs.The only features significantly associated with FA on the HRCT scan were the presence of bibasal Crackles and the reduction in carbon monox ide transfer factor (Tloo). These findings are more difficult to explain, especially consider ing that FA was defined as an HRCT pattern www.thoroxjid.com