Document GmyJKvb7yeQQO0exZXObDOGer

UNION CARBIDE CORPORATION old rogebury road, danbury, ct dbbi v Corporate Health, Safety end Environmental Affairs Department February 20, 1985 Dr. R.B.K. Tucker 18, Rockridge Road, Parktown, Johannesburg 2193 Republic of S. Africa , Re: Agenda Item 6.1 - 12th Meeting of AIA/MAP: AIA/20/1/2/HAS Asbestos and Simulative Diseases Dear Ron, I have struggled with this item and have produced the attached draft for your consideration. I must confess that I have largely plaguerized the referenced articles (copies of references 1, 2 and 4 are attached hereto) and suppose that, if we decide to publish this, permission would have to be obtained to reproduce the tables and we should indicate our obligation to the referenced authors. I have not sent copies of this draft to anyone else. When you have reviewed the draft, please make any additions, deletions, comments, etc. and forward to AIA for action if you think it would be appropriate. Please let me know what you decide to do. I am not certain about my future as a member of the MAP at the present time and will not know until mid-March whether I will continue to represent the Asbestos Information Association of North America or not. Kind regards to your wife. Sincerely Hilton C. Lewinsohn, MB.BCh., FCCP, MFOM, DIH Assistant Corporate Medical Director HCL:jsh 0111N UCC 010765 THE DIFFERENTIAL DIAGNOSIS OF ASBESTOSIS FROM OTHER FORMS OF INTERSTITIAL LUNG DISEASE DRAFT Introduction The diagnosis of asbestosis can only be made with certainty in the presence of an exposure history. The symptoms of asbestosis are similar to those of other forms of interstitial lung disease and may not be helpful in distinguishing between them. The object of this paper is to focus on the importance of making a distinction between asbestosis in particular and pulmonary fibrosis (interstitial lung disease) in general, since this will affect therapy, medical management, workers compensation and other issues. Definition The term interstitial lung disease is applied to "a heterogeneous group of diseases grouped together because of common clinical, roentgenographic, physiologic and pathologic features. According to Fulmer ^ the most prevalent interstitial diseases are those caused by occupational and environmental inhalants, predominantly due to inorganic dusts. Clinical Features Irrespective of the etiology of the interstitial lung disease, the clinical presentation is virtually the same in all cases. Breathlessness, 0111N UCC 010766 oCj 'i O -2- DRAFT usually first noted on exertion, is the first recognizable symptom in the majority of cases and is invariably present once the disease process has become fairly extensive. The chest x-ray pattern at this stage will be that of a diffuse infiltrative lesion. The pulmonary fibrosis which develops affects the gas exchanging areas of the lung and in some cases a reduction in the carbon monoxide diffusing capacity may be the earliest indication of the disease process. The interstitial lung diseases are characterized by impairment of gas transfer and a restrictive ventilatory defect. The histological appearances in the final stages of the interstitial lung diseases are non-specific and are those of a progressive diffuse chronic pulmonary fibrosis with few, if any, distinguishing diagnostic features. The disease process involves the alveoli and associated connective tissues. VanOrdstrand (2) points out "that there is no occupation in which the worker is immune to nonoccupational diseases". He believes that in some cases the usual routine diagnostic procedures such as work history, chest x-rays and other tests, are not adequate to differentiate occupational from nonoccupational diffuse lung disease. VanOrdstrand feels that there is a place for the use of lung biopsy in such cases. Table I is based on information extracted from Fulmer's^ classification of the Interstitial Lung Diseases combined with information extracted from a similar classification found in Chapter 18 (Interstitial lung disease) in "Color Atlas of Respiratory Diseases" (Edited by D. Geraint James and Peter R. Studdy). (3) The interstitial lung diseases are grouped 0111N UCC 010767 -3- DRAFT according to whether the etiology is known or unknown. According to Fulmer^ one third have a known etiology. Tables 2-6 complement Table I as indicated and are reproduced from James and Studdy's "Color Atlas". VanOrdstrand's approach (2) is to group the radiologic masqueraders of various pneumoconioses in tabular form and Table 7 is in fact his Table 3. Differential Diagnosis Murphy et al. (4) point out that minimal interstitial pulmonary fibrosis caused by the inhalation of asbestos can be difficult to detect. They state that symptomatology is subjective and pulmonary function studies are often nonspecific. X-rays are not able to indicate the etiological factors responsible in the production of diffuse pulmonary fibrotic lesions. Thus, symptoms and signs per se, do not enable asbestosis to be differentiated from other fibrotic lung diseases and it is necessary in each and every case to obtain a detailed medical history and occupational history. There are some features of asbestosis and some details in the medical history which may assist in the differential diagnosis. Fulmer^ discusses the diagnostic approach to patients with interstitial lung disease and emphasizes the need for a systematic approach stating that "A detailed occupational history is mandatory in diagnosing the inorganic dust diseases." Some of the issues which should be covered when taking the medical history include the following few examples: iOr> *;'f L' LJ'. UCC 010768 -4- DRAFT 1. Detailed occupational history - the long latent interval between first exposure to asbestos and development of disease must be recognized and taken into account - contact with household members exposed to asbestos may result in exposure not recognized by the patient - casual workplace exposure may be responsible for the lesions and in some cases living in the neighborhood of a plant may raise suspicions of cause and effect. - farmers' lung and psittacosis may be suggested by a history of exposure to moldy hay or bird droppings respectively - other organic dust exposure possibilities such as use of home humidifiers, vaporizers, saunas - exposure to organic chemicals 2. Detailed drug use history. - Three major groups of drugs are responsible for most drug-induced interstitial diseases. They are listed by Fulmer as the cytotoxic and immunosuppressive agents (bleomycin, nitrosoureas, methotrexate, etc.); the neuroactive and 0111N UCC 010769 vO - 5- DRAFT vasoactive agents (methysergide, Phenytoxin, etc.) and antimicrobial agents (Nitrofurantoin, sulfonamides, etc.). 3. Family history - sarcoidosis - collagen vascular disorders mixed connective tissue disease rheumatoid lung (Skin and eye manifestations of sarcoidosis, collagen-vascular disorders, neurofibromatosis and Wegener's granulomatosis may help in the differential diagnosis). Investigating the patient with an interstitial lung disease may include, in addition to the medical history, interpretation of chest radiographs, and pulmonary function evaluation, special investigations such as serological studies, bronchoalveolar lavage, conjunctival, skin and lymph node biopsy, fiberoptic bronchoscopy and transbronchial biopsy and finally, open lung biopsy may be indicated. In the case of a suspected occupational lung disease, where the diagnosis will determine eligibility for compensation, and where death benefits may be payable to defendants, the opportunity to confirm the clinical diagnosis at autopsy should be vigorously pursued. The chest x-ray is of diagnostic value in only a few types of diffuse interstitial pulmonary fibrosis. Radiographic appearances can be correlated with laboratory data in many instances to yield diagnostic information. According to Fulmer, diffuse interstitial infiltrates with sparing of the 0111N UCC 010770 -6- DRAFT costophrenic angles in a young male is suggestive of histiocytosis-X. In a young black patient in the USA hilar adenopathy with uveitis and skin lesions is thought to be diagnostic of sarcoidosis. Pulmonary function studies are generally not helpful in the differential diagnosis of interstitial disease, including occupational lung diseases. Serological studies are of value in the diagnosis of collagen-vascular disorder and sarcoidosis. Circulating immune complexes or antibasement membrane antibody can also be of use if studied in conjunction with lung tissue or lavage cellular analysis. Interest in the latter procedure has grown recently with regard to the diagnosis of intestitial diseases. Thus far it has proved to be of value only in alveolar proteinosis and the pulmonary hemorrhage syndromes. Hemosiderin-laden macrophages (indicative of pulmonary hemorrhage) and the presence of circulating antibasement membrane antibodies are necessary to diagnose Goodpasture's syndrome. Brocho-alveolar lavage promises to develop into a useful diagnostic procedure. Two distinct cellular patterns have been described. Predominant lymphocytosis is suggestive of sarcoidosis, organic dust disease, acute idiopathic pulmonary fibrosis, certain collagen-vascular disorders, and acute histiocytosis-X. A predominant finding of polymorphonuclear leukocytosis may be seen in inorganic dust diseases, idiopathic pulmonary fibrosis. collagen-vascular disorders and advanced sarcoidosis. Further studies are OlllN UCC 010771 ' - k., * c. }' -7- DRAFT required before this procedure becomes useful in the differential diagnosis of interstitial lung diseases. Transbronchial biopsy may be useful in the diagnosis of interstitial lung disease. Some conditions which may be diagnosed by this procedure are listed in Table 8 (Fulmer's Table 4^). Open lung biopsy is hardly ever justified unless the possibility exists that the outcome will affect treatment of a potentially curable condition. The diagnosis of asbestosis is based upon a history of adequate exposure, radiographic evidence consistent with diffuse interstitial pulmonary fibrosis, a restrictive pulmonary function defect and the presence of bilateral basilar crackles in the lungs. Dyspnoea, cough, sputum production and clubbing of the fingers are usually late, non-specific manifestations. The chest radiograph may provide important clues to the asbestos-related etiology of a case of interstitial lung disease. Pleural plaques are fibrotic areas mainly affecting the parietal pleura. They are usually bilateral, smooth or nodular, and discrete. They are most frequently seen on the posterolateral or anterolateral chest walls, run along the rib margins (most commonly the sixth-tenth ribs) and are also found on the domes of the diaphragm. The apices and costo-phrenic angles are usually clear. Calcification may occur as the years go by. They are considered to be a unique radiographic sign presumptive of asbestos etiology.^ Oil IN UCC 010772 C3S6; -8- DRAFT The small irregular opacities seen on a chest x-ray do not have characteristics which differentiate those seen in cases of asbestosis from those seen in a number of other conditions. Some normal adults will exhibit these radiographic patterns as a part of aging, especially in persons who had repeated pulmonary infections (e.g. bronchitis, pneumonitis). There will be an overlap in the frequency distribution of small opacity profusion in normal and pneumoconiotic individuals at the low levels of profusion.^ Caution must be exercised by the interpreter of radiographs showing such low levels of profusion and unless the exposure history is clear-cut, a positive diagnosis may not be possible without further observation and investigation. Higher levels of profusion of small irregular opacities may also pose problems of interpretation in the absence of an adequate occupational exposure history. Scleroderma, lipoid pneumonia, desquamative interstitial pneumonitis and sarcodosis may produce basal irregular patterns similar to those seen in asbestosis.^ The American College of Radiology's Asbestos Working Group's monograph describes many other diagnosis features of value in making a diagnosis of asbestosis and they point out the differences between early and late findings.^ 0111N UCC 010773 K. Recommendations -9- DRAFT 1. Obtain a detailed medical history, including a meticulous exposure history. 2. In the absence of exposure, a diagnosis of asbestosis can only be made when other etiological agents or conditions have been eliminated to a reasonable degree of certainty. 3. Radiographs must be of good quality, serial films should be available and interpretation should be by a radiologist expert in the diagnosis of pneumoconiosis in particular and chest disorders in general. 4. Pulmonary function tests should only be used to confirm the presence of a restrictive syndrome once there are no specific physiological differences between the many varieties of interstitial lung disorders. 5. Other diagnostic tests should be considered and used in all doubtful cases to rule out conditions which can masquerade as asbestosis. 0111N UCC 010774 3 Gx,*} >}r " References: DRAFT 1. Fulmer, Jack D.r The Interstitial Lung Diseases. Chest 1982; 82:172-178. 2. VanOrdstrand, H.S., Pneumoconioses and Their Masqueraders. J. Occup. Med 1977; 19:747-753. 3. Color Atlas of Respiratory Diseases, Chapter 18, pages 161-182 Edited by D. Geraint James and Peter R. Studdy. Published by Year Book Medical Publishers Inc., Chicago. 1982. 4. Murphy, Raymond L.H. et al.. Crackles in the Early Detection of Asbestosis. Am. Rev. Respir Dis. 1984; 129:375-379 5. Asbestos Related Diseases: Clinical, Epidemiologic, Pathologic, and Radiologic Characteristics and Manifestations. Prepared by the Asbestos Working Group (Chairman: Russel H. Morgan). Published by American College of Radiology, 20 North Hacker Drive, Chicago, Illinois 60606 (1982). 6. Morgan, R.H., Donner, M.W., Gayler, B.W., et al.: Decision processes and observer error in the diagnosis of pneumoconiosis by chest roentgenography. Am. J. Roentgenol. 1973; 117:757-764. 0111N UCC 010775 . O'vJ Table 1; Classification of Interstitial Lung Disease* DRAFT Known Etiology Occupational and Environmental Inhalants: Inorganic (see Table 2) Organic (see Table 3) Fumes, gases, vapors, aerosols (see Table 4) Drugs (see Table 5) Poisons Radiation Infectious agents - schistosoma mansoni Pulmonary oedema (cardiac disease) Uremia (metabolic diseases) I | I I I 1 I I 1 I 1 1 I 1 1 I I 1 1 I Unknown Etioloqy Idiopathic pulmonary fibrosis Necrotising angiitis (see Table 6) Collagen disorders - rheumatoid arthritis - progressive systemic sclerosis - Sjogren's syndrome - ankylosing spondylitis Inherited disorders - tuberous sclerosis - neurofibromatosis Miscellaneous - sarcoidosis - pulmonary hemorrhagic syndromes - eosiophilic granuloma - idiopathic hemiosiderosis - amylodosis - veno-occlusive disease - Lymphangioleiomyomatosis *Data compiled from combination of Fulmer's^ Table 1 and James and Studdy's Table on page 161 of "Color Atlas of Respiratory Diseases."^ oiiin UCC 010776 TABLE 2. Causes of occupational Interstitial lung disease. Inorganic dust Industrial hazard Aluminium Asbestos Beryllium 1 Cadmium J Coal Diatomaceous earth Graphite Kaolin Mica Iron oxide (Siderosis) Silica Talc Titanium Grinding Mining Fireproofing Lagging Dock workers Alloys . Electronics Nuclear workers Mining Processing Polishing Welding Mining and manufacturing Drilling, blasting Foundry and glass workers Ceramics and cosmetics Paint UCC 010777 c: 3869 TABLE 3 /Nature and sources of organic dust antigens in extrinsic allergic alveolitis. (Probably IgE mediated obstructive airways disease) Disease Dust exposure Nature of antigen to which precipitin shown Fanners' lung Fog-fever in cattle Bagassosis Mushroom workers' lung Maltworkers' lung Bird fanciers' lung Pituitary snufftakers' lung Wheat weevil disease (Millers' lung) Maple strippers' lung Sequoiosis Suberosis Woodworkers' lung Cheese-washers' lung `New Guinea' lung Smallpox-handlers' lung Paprika splitters' lung Humidifier or forced-air-system lung Coptic lung Poultry handlers' lung Coffee and tea growers' disease Mouldy overheated hay Mouldy hay Mouldy overheated sugar-cane bagasse Mushroom compost dust Mouldy barley or malt Pigeon and budgerigar droppings Wax coating feathers - `pigeon bloom' Powder of porcine and bovine posterior-pituitary extract Infested wheat flour Thermophilic actinomycetes Micropolyspora faeni Thermoactinomyces vulgaris Micropolyspora faeni Mouldy bagasse Thermoactinomyces sacharii Thermophilic actinomycetes (see farmers' lung) Aspergillus fumigatus Aspergillus clavatus Avian serum protein antigens Serum protein and pituitary antigens Sitophilus granarius Maple bark Mouldy redwood sawdust Oak bark, cork dust t Sawdusts of oak, cedar, etc. Moulds on cheese Mouldy thatch dust Smallpox scabs Mouldy paprika pods Fungal spores in air-conditioning ducts and in home humidifiers Cloth wrappings of mummies Poultry feathers and products Green coffee bean Tea fluff Cryptostroma (Coniosporium) corticale Aureobasidium (Putlularia) - pullulans - graphium Mouldy oak bark P. frequentans Sawdust extracts Penicillium casei Extracts of thatch Mucor stolonifer T. candidus T. vulgaris Naegleria gruberi Turkey and chicken proteins UCC 010778 as*5 TABLE 4 Fumes causing interstitial lung disease. Exposure Vapour inhaled Swimming pools Chlorine gas Ore-smelting Sulphur dioxide Nose drops Oil Vineyard spray Bordeaux mixture of copper sulphate and lime Insecticides Pyrethrum UCC 010779 TABLE 5 Causes of drug-induced chronic interstitial lung disease. Busulphan Bleomycin Diphenylhydantoin Gold salts Chlorambucil Nitrofurantoin Cyclophosphamide Paraquat Methotrexate Penicillin Nitrosoureas Procarbazine Vincristine Pentolinium Sulphonamides UCC 010780 1: TABLE 6 Causes of necrotisiiig angiitis. Polyarteritis nodosa - Classical - HBsAg associated in 20 per cent Churg-Strauss eosinophilic granulomatosis Wegener's granulomatosis (see page 155) Systemic lupus erythematosus (see page 145) Behcet's syndrome (see page 146) Henoch-Schonlein purpura Arteritis - Hypersensitivity angiitis - Giant-cell temporal - Takayasu's pulseless aortic - Retinal vasculitis - Rheumatoid arthritis (see page 143) - Rheumatic fever UCC 010781 03893 Table 7: Radiologic Masqueraders of Asbestosis* DRAFT Sarcoidosis Scleroderma Rheumatoid Lung Adult Respiratory distress Syndrome Pse udolymphoma Idiopathic Pulmonary Hemosiderosis Alveolar Proteinosis Thesaurosis Drug Infiltrates Goodpasture's Syndrome Bronchiectasis Universalis Hamman-rich Syndrome Pneumocystis Carinii Chemical Pneumonias Amyloidosis Histiocytosis Parenchymal Hodgkins Disease Pulmonary Edema Inclusion Body Pneumonia Cholesterol Pneumonitis *This is Table 3 in VanOxstrand's publication previously referred to in the text. (reference number 2). 0111N UCC 010782 03SS4 TABLE 8 - INTERSTITIAL LUNG DISEASES THAT CAN BE DIAGNOSED BY TRANSBRONCHIAL BIOPSY.* DRAFT Sarcoidosis Organic dust diseases (hypersensitivity pneumonitides) Histiocytosis-X Pulmonary hemorrhage syndromes Inorganic dust diseases Eosinophilic pneumonias Drug-induced interstitial diseases Lymphangioleiomyomatosis Infectious agents *This list includes diseases in which diagnostic tissue can be obtained, as well as those in which tissue is suggestive put the diagnosis must be made by clinical and laboratory correlation. 0111N UCC 010783 { ' '* *' rL o6Jd 1 ... i. t__ I "f today's practice ot cardiopulmonary medicine The Interstitial Lung Diseases* Jack D. Fulmer, M.D., F.C.C.P. T^he interstitial lung diseases are a heterogenous group of diseases grouped together because of common clinical, roentgenographic, physiologic, and pathologic features.1'* Most patients present with insidious breathlessness and have a diffuse infiltra tive pattern on chest roentgenogram (Fig 1A). Not uncommonly, an isolated reduction in carbon mon oxide diffusing capacity (Deo) on routine pulmo nary function testing is the first indication of un derlying interstitial disease. The pathology of these diseases is characterized by an inflammatory cellu lar infiltration and an apparent increase in connec tive tissue of alveolar septae; in some, there are inflammatory cells within alveolar airspaces (Fig IB). Many of die interstitial diseases also have disease of airways, pulmonary vasculature, and sometimes pleural disease.13 4 From the Veterans Administration Medical Center, and the Pulmonary Division, Department of Medicine, Univer sity of Alabama in Birmingham. Reprint requests: Dr. Fulmer, Department of Medicine, Pulmonary Division, University of Alabama in Birmingham, Birmingham 35294 This review will deal mainly with chronic, pro gressive, interstitial diseases. A classification and recent advances in the pathogenesis and pathophysi ology of the diseases will be discussed. Finally, an approach to the diagnosis and management of these diseases will be presented. Classification One approach to the classification of these dis eases is to group them according to whether the etiology is known or unknown (Table 1 ).1-* Approx imately one third of these diseases have known etiology; the remaining must be classified by clini cal-pathologic features. The most prevalent interstitial diseases are those caused by occupational and environmental in halants. Of these, the inorganic dust diseases pre dominate. The organic dust diseases (hypersensi tivity pneumonitides) are caused by inhalation of foreign proteins or complex polysaccharides to which the person has been previously sensitized. Fir.tTRE 1. 30-year-old woman with idiopathic pulmonary' fibrosis. (A), Chest roentgenogram. Diffuse reticular pattern. (B), Open lung biopsy specimen showing interstitial and intra-alveolar inflammatory process (alveolitis) and connective tissue derangement. Cuboidal cells replace normal alveolar epithelium. (H&E, original magnification X 600). The Interstitial Lung Otieite* /Jack D. Fulmer) UCC 010784 Table 1--Classification of the Interttitial Lung Diieuei Known Etiology Unknown Etiology Occupational and environmental inhalants Inorganic dusts Organic dusts Gases, fumes, vapors, aerosols Drugs Poisons Radiation Infectious agents Cardiac disease Metabolic diseases Idiopathic pulmonary fibrosis Interstitial diseases associated with collagen-vascular disorders Sarcoidosis Histiocytosis-X Vasculitides Pulmonary hemorrhage syndromes Lymphocytic infiltrative disorders Inherited disorders Ankylosing spondylitis Eosinophilic pneumonias ' Lymphangioh iomyomatosis Nearly 30 clinical organic dust diseases have been defined by either antigen (eg, aspergillosis) or spe cific environmental exposure (eg, farmer's lung).1-3 Most antigens are fungal spores, although bacterial and animal proteins have been described; recently synthetic organic compounds have been impli cated.3 The remaining interstitial diseases of known etiology are caused by drugs, poisons, radiation, in fectious agents, and cardiac or metabolic diseases. Sarcoidosis is the most prevalent interstitial lung disease of unknown etiology- and is estimated to be 20/100,000 persons worldwide.4 Idiopathic pulmo nary- fibrosis (cryptogenic fibrosing alveolitis) is also common, but no data are available on the prevalence of this disease. The interstitial diseases associated with the collagen-vascular disorders are s vide spectrum. Clinically significant chronic in terstitial disease is most common in mixed-connec tive tissue disease, rheumatoid arthritis, and pro gressive systemic sclerosis. In contrast, interstitial disease is rare in polymyositis, systemic lupus ery thematous, and Sjogren's syndrome. The pulmonary vasculitides are an important group of interstitial diseases;6 there is, however, no acceptable classification. One approach, is to group those vasculitides in which lung is always involved (Table 2). Of those, Wegener's granulomatosis, the Churg-Strauss syndrome, overlap vasculitis, and lymphomatoid granulomatosis are the major dis eases. Lymphocytic angiitis and granulomatosis is often grouped with lymphomatoid granulomatosis; some believe, however, that it is a separate disease. An additional group of pulmonary vasculitides are those in which the primary- pathology is a vascu litis, and lung may be involved (Table 2). In many of these, pathologic documentation of a pulmonary vasculitis may not exist and is only- inferred by the association with the cutaneous vasculitis. Included in this group are the Henoch-Schonlein syndrome and disseminated leukocytolastic vasculitis. Classic polyarteritis nodosa rarely involves lung. Often classified with the vasculitides, Goodpasture's syn drome, and idiopathic pulmonary hemosiderosis are the major hemorrhage syndromes. One of the most difficult groups of interstitial diseases are the lymphocytic infiltrative lung dis orders. Some of these disorders are associated with defined clinical syndromes, such as Sjogren's syn drome and Waldenstrom's macroglobulinemia; others cannot be classified, and many (10 to 15 per cent) may progress to a lymphoid malignancy. The remaining interstitial diseases of unknown etiology are uncommon; some, such as lymphangioleiomyomatosis, are quite rare. Pathogenesis Regardless of etiology-, current data suggest that the majority of the interstitial diseases have a com mon pathogenesis.1,3 Initially, there is some type of injury to lung cells. Many of the known agents (poisons) are directly toxic to alveolar or capillary endothelial cells. Other agents (inorganic dust) in jure lung through the generation of toxic radicals by inflammatory cells. The organic dusts and some drugs injure lung through immune mechanisms. Similarly, many of the interstitial diseases of un known etiology are associated with alterations in the immune system. For example, immune com plexes have been described in idiopathic pulmonaryfibrosis, the collagen-vascular disorders, histiocytosis-X, and some of the pulmonary- vasculitides.*-6 Whether they are pathogenic or an epipheDomenon is not known. As a result of injury to lung cells, there is an in flux of inflammatory and immune-effector cells into alveolar septa resulting in an alveolitis (Fig 2). Unchecked, the alveolitis will become chronic and structural derangement will result.1-3 The final com mon pathway for most interstitial diseases is the end-stage (honeycomb) lung. Importantly, injury-, alveolitis, and repair coexist; fibrosis is a result of Table 2--Pulmonary Vatculitidet Diseases in which lung is always involved Churg-Strauss syndrome Overlap vasculitis Wegener's granulomatosis Lymphomatoid granulomatosis Lymphocytic angiitis and granulomatosis Necrotizing sarcoid granulomatosis Bronchocentric granulomatosis Diseases in which lung may be involved Henoch-Schonlein syndrome Disseminated leukocytoclastic vasculitis Disseminated giant cell arteritis Behcet's syndrome Classic polyarteritis nodosa Takavasu's disease Essential cryoglobulinemia ft CHEST / S2 / 2 / AUGUST, 1982 173 UCC 010785 i Figure 2. Pathogenesis of sarcoidosis. (A), Early sarcoidosis showing interstitial and intraalveolar lymphocytes; rare granulomas were present (H&E, original magnification X 500). Un checked (B), alveolitis becomes chronic, granulomas form, and connective tissue becomes deranged (H&E, original magnification X 130). the inflammatory and reparative process.1 mune-effector cells in the interstitial diseases (Fig The alveolitis of these diseases is being intensive 3).'"4 Considerable data indicate that the major ly investigated. Many of the interstitial diseases (inorganic dust, idiopathic pulmonary fibrosis) have an alveolitis that consists mainly of alveolar mac effector cells in both sarcoidosis and organic dis ease are T-lymphocytes.3-4 Furthermore, T-lymphocyte subtyping has suggested that patients with J ! rophages and polymorphonuclear leukocytes. Other active sarcoidosis have an increased number of interstitial diseases mainly have a lymphocytic al lung helper T-lymphocytes that are likely important I veolitis (sarcoidosis, organic dust). In contrast, the in granuloma formation.6 eosinophil and the macrophage are the major im mune-effector of immune cells in die eosinophilic Pathophysiology pneumonias. Recent use of bronchoalveolar lavage The interstitial diseases are classically included has allowed characterization of inflammatory and im in the restrictive lung disorders; vital capacity (VC) u Ficuke 3. Bronchoalveolar lavage cell preparation in sarcoidosis. (A), Lymphocytic (T cell) alveolitis (Giemsa, original magnification X 500). (B), Lymphocyte-macrophage resetting typical of many granulomatous diseases (Giemsa, original magnification x 1,200). 174 $`^ The Interstitial Lung Disease* (J*ck D. Fulmtr) m UCC 010786 is reduced, and respiratory flow rates are pre served.1'* Additional physiologic features of these diseases are a reduction in lung compliance, re duced Doo, and hypoxemia that worsens on ex ercise. Lung volume alterations in the interstitial dis eases vary; a moderate to severe reduction in VC is characteristic of acute idiopathic pulmonary fi brosis and acute organic dust disease. In contrast, the more common subacute or chronic forms of these diseases may not exhibit a reduction, in VC until the disease is in mid-course. As the disease progresses, however, lung architecture becomes re vised, fibrosis develops, and severe reductions in lung volumes result. Gas exchange abnormalities are one of the earli est physiologic alterations in the interstitial dis eases, particularly Doo.1 Whereas early interstitial lung disease is characterized by normal resting arterial blood gases, ventilation-perfusion defects are amplified by exercise so that the alveolararterial oxygen tension difference (P[A-a]02) widens and arterial oxygen tension (PaO) falls. Advanced interstitial disease is characterized by severe rest ing hypoxemia. Ventilatory capacity, however, is maintained until the disease becomes end-stage when resting or exercise hypercapnia may be present. Whereas standard measures of airway function (rimed spirometry and airways resistance) are typi cally normal, many of the interstitial diseases (eg, idiopathic pulmonary fibrosis) exhibit physiologic and morphologic changes consistent with small air ways disease.1-* Patients with both inorganic and organic dust disease, however, may have major obstructive defects. Reversible airflow obstruction is characteristic of only a few of the interstitial dis eases--the eosinophilic pneumonias, the ChurgStrauss syndrome, and overlap vasculitis.1* Diagnosis A systematic approach to patients with intersti tial disease forms the basis for diagnosis. A detailed occupational history is mandatory in diagnosing the inorganic dust diseases. Whereas silicosis re sults from prolonged exposure, asbestosis can re sult from only a brief exposure. Asbestosis can also result from exposure to contaminated clothing by household members or from living in proximity to a processing plant.1 The diagnosis of organic dust disease can be suggested from an exposure history (eg, farming or breeding pigeons); however, the exposure may not be obvious. A detailed history of the use of home humidifiers, vaporizers, saunas, or exposure to organic chemicals is important. An other important clinical feature of organic dust disease is a history of recurrent pneumonias, par ticularly if correlated with an environmental ex posure.1* A detailed drug use history is also important in evaluation. Virtually any drug should be suspect; however, most drug-induced interstitial diseases result from three major groups (Table 3). The cyto toxic and immunosuppressive agents constitute the major offenders. Whereas bleomycin and the nitro sourea agents are dose-related, methotrexate is not. There may, however, be synergism between some cytotoxic agents (eg, cyclophosphamide and bleo mycin). A family history can be useful in the diagnosis in some of the interstitial diseases; sarcoidosis and many of the collagen-vascular disorders can be familial. Family history is particularly important in mixed-connective tissue disease and rheumatoid lung disease, since lung involvement can antedate other systemic manifestations of the disease. Derma tologic or ocular manifestations of sarcoidosis, die collagen-vascular disorders, neurofibromatosis, and W'egener's granulomatosis can be useful, and at times diagnostic.1-*-5 Table 3--Drug-induced interstitial Lung Diteate* Cytotoxic and immunosuppressive agents Busulfan Bleomycin Cyclophosphamide Chlorambucil Nitrosourea Carmustine Semustine Methotrexate Metomycin Melphalan Procarbazine Mcrcaptopurine Neuroactive and vasoactive agents Methysergide Phenytoin (diphenvlhydantoin) Ganglionic blocking agents (hexamethanoium) 5-Blocking agents (practolol) Carbaraazcpine Antimicrobial agents Nitrofurantoin Sulfonamides Aminosalicylic acid Penicillin Miscellaneous Hydrochlorothiazide Chlorpropamide Sulfapyridine Gold salts Drug-induced SLE (hydralazine) Including only drugs that cause chronic, progressive inter stitial disease. w) C3S93 CHEST / -> ?T. 175 UCC 010787 ' ^1 Only a few of the interstitial diseases have a Two major cellular patterns in bronchoalveolar chest roentgenogram that is considered diagnostic. lavage have emerged, a predominant lymphocyto The roentgenogram of chronic eosinophilic pneu sis and a predominant polymorphonuclear leuko monia showing rapidly progressive, nonsegmental, cytosis. While the presence of lavage lymphocytosis peripheral dense pneumonic infiltrates is considered is suggestive of either sarcoidosis or organic dust to be diagnostic.1 Many roentgenographic patterns disease,2 4 recent data indicate that acute idiopathic are suggestive of certain interstitial diseases when pulmonary fibrosis, some of the collagen-vascular correlated with laboratory data, however. Diffuse disorders, and acute histiocytosis-X can also exhibit interstitial infiltrates with sparing of the costo- a lymphocytosis {Law DE, Fulmer JD, unpublished phrenic angles in a young male is suggestive of his- observations). Similarly, the inorganic dust diseases, tiocytosis-X. Similarly, hilar adenopathy with uvei idiopathic pulmonary fibrosis, collagen-vascular dis I tis and skin lesions in a young black person is orders, and advanced sarcoidosis may exhibit a considered to be diagnostic of sarcoidosis. polymorphonuclear leukocytosis.28 Clearly, addi As with the chest roentgenogram, pulmonary function is generally of little value in the diagnosis of most interstitial diseases. An exception to this gen eralization is physiologic data consistent with em physema in a young, nulliparous female with inter stitial disease; these data are strongly suggestive of the diagnosis of lymphangioleiomyomatosis. Other laboratory studies may be useful in estab lishing a specific diagnosis. Serologic studies can be specific for the collagen-vascular disorders. Precipitins to specific organic antigens can be useful in diagnosing the organic dust diseases. However, precipitins alone are not diagnostic; the antigens are ubiquitous, and many normal persons have them. Additionally, patients with organic dust dis ease can have false negative tests.1 Once viewed as useful in diagnosing sarcoidosis, serum lysozyme is now known to be nonspecific. In contrast, serum angiotensin converting enzyme can be a valuable aid. Rarely falsely positive {<2 percent) and present in only Gaucher's disease and leprosy, false nega tive values approach 30 percent and are most common in stage 1 and stage 4 sarcoidosis.1'4 7 Cir culating immune complexes or antibasement mem brane antibody can also be useful studies if cor related with lung tissue or lavage cellular analysis. There has been recent interest in bronchoalveolar lavage cellular analysis in the diagnosis of intersti tial diseases.1-4 However, only two diseases can be diagnosed if correlated with clinical or otheT lab oratory data: alveolar proteinosis and the pulmo nary hemorrhage syndromes. In the case of the latter, the finding of hemosiderin-ladened macro phages indicates pulmonary hemorrhage, and cir culating antibasement membrane antibodies are necessary to diagnose Goodpasture's syndrome. Idiopathic pulmonary hemosiderosis cannot be diag nosed by lavage, however. It has been suggested tional studies are needed before lavage cell analy sis can be considered routine in the diagnosis of interstitial diseases. , Additional relatively noninvasive procedures may be useful in diagnosing some of the interstitial dis eases. Conjunctival or skin biopsy in a clinical setting can confirm the diagnosis of sarcoidosis.1 Whereas lymph node biopsy is not recommended to diagnose sarcoidosis, it may be useful in diagnosing some of the lymphocytic infiltrative diseases.1 Skin biopsy may also be useful in diagnosing some vasculitides, the Churg-Strauss syndrome, and disseminated leu- koeytoclastic vasculitis. However, care must be ex ercised, since a cutaneous Ieukocytoclastic vasculitis may be a feature of Wegener's granulomatosis, some of the diffuse infiltrating malignant diseases, and some drug-induced interstitial diseases. Although some of the interstitial diseases of both known and unknown etiology can be diagnosed with reasonable accuracy without lung biopsies, most experts agree that lung biopsy is needed.1 The major reasons are to exclude a more treatable type of interstitial disease (eg, organic dust disease) and to assess the activity of disease. The initial pro cedure of choice is fiberoptic bronchoscopy with transbronchial lung biopsy. Bronchopulmonary lavage performed at the time of bronchoscopy may be useful in diagnosing some infectious or neoplas tic infiltrative diseases. Transbronchial biopsy can establish the diagnosis of many interstitial diseases (Table 4). As with any laboratory tool, clinical cor relation is necessary. Drug-induced disease may pose a problem, but can be diagnosed if there is a search for typical bizarre granular pneumoeytes. An adequate number of biopsies must be performed to exclude malignant disease or infection, how ever, and at least four biopsies are recommended. Transbronchial biopsy showing nonspecific pneu that electron microscopy of the lavage cells can be monitis and fibrosis (usual interstitial pneumonitis) diagnostic of histiocytosis-X. However, these cells is not diagnostic.1011 Areas in proximity to granu have also been described in malignant diseases and lomas, infectious processes, and malignant dis in idiopathic pulmonary fibrosis. eases may have these features. castTM The Intenlitial Lung OiitiMt (Jack D. Fulmer) UCC 010788 I Table 4--Interttitial Lung Disease* that Cm Be Diagnosed by Transbronchial Biopsy Sarcoidosis Organic dust diseases (hypersensitivity pneumonitides) Histiocytosis-X ` Pulmonary hemorrhage syndromes Inorganic dust diseases Eosinophilic pneumonias Drug-induced interstitial diseases . Lymphs ngioleiomyomat os is Infectious agents *This list includes diseases in which diagnostic tissue can be obtained, as well as those in which tissue is suggestive but the diagnosis must be made by clinical and laboratory ' correlation. In the absence of a specific diagnosis by trans bronchial biopsy, open lung biopsy is recommend ed. Open lung biopsy can be performed with mini mum morbidity' and mortality and a very high (>90 percent) diagnostic yield." The latter is maxi mized when the pathologist is aware of the clinical data. An area of average involvement on chest roentgenogram and direct observation should be biopsied. Areas with dense fibrosis will show endstage lung disease. Immediate fixation after hyper inflation will minimize artifacts. Whereas fresh tis sue is necessary for immunofluorescent studies, formalin-fixed tissues generally suffice for the diag nosis of most interstitial diseases. Open lung biopsy will not only establish the diagnosis, hut give the best assessment of the severity of the disease process and the likelihood of response to therapy .1,s Treatment The overall treatment goals for the interstitial diseases are to identify and remove the injurious agent, suppress the inflammatory response to pre vent progression of the disease, and to palliate the complications of the disease.1-3 The mainstay of drug treatment of these diseases is corticosteroids.1-4 Current data indicate that im munosuppressive or cytotoxic agents are useful in the treatment of some diseases (eg, the pulmonary vasculitides).1-5 Although data in experimental models suggest that agents known to alter collagen metabolism (eg, L-proline) may prevent fibrosis, there are no data indicating that these agents are clinically useful. Identifying and removing etiologic agents is im portant in the management of the interstitial dis ease of known etiology.1 Corticosteroid therapy is generally recommended for the acute inorganic dust exposure disease and acute radiation- and drug-induced disease, particularly if there is hy poxemia.1 However, treatment of the chronic vari eties of these diseases remains symptomatic. In con trast, corticosteroids are usually recommended for both acute and chronic organic dust disease. Considerable data support the use of cortico steroids in idiopathic pulmonary fibrosis.1 Patients with early disease with an active alveolitis (eg, increased cellularity) and minimal fibrosis respond best. Clinical and chest roentgenographic correlates of early disease are recent onset of symptoms and a ground glass or acinar pattern. Additionally, young patients respond best to treatment. In con trast, advanced interstitial disease, with minimal alveolitis and advanced fibrosis, does not respond to treatment with corticosteroids. There is no agreement on the dose of corticosteroids or the duration of treatment. Until more sensitive means ' to monitor the disease activity are developed, most experts recommend a regimen of high-dose predni sone (1 mg/kg/day) for four to six weeks, followed by a slow taper to 15 to 20 mg/day for a minimum of six months to one year,13 Immunosuppressive therapy has been recommended as an alternative or an adjunct in the treatment of idiopathic pul monary fibrosis; controlled data, however, do not support this.1 The treatment of pulmonary' sarcoidosis is con troversial. Patients with stage 1 sarcoidosis should not be treated, since more than 90 percent resolve spontaneously.1-4 In contrast, patients with progres sive disease or multiple-organ dysfunction should be treated. Many experts recommend altemate-day corticosteroid therapy in sarcoidosis. There are, however, no concrete data to indicate that cortico steroid treatment is more effective than sympto matic treatment of sarcoidosis. In general, the chronic interstitial diseases asso ciated with the collagen-vascular disorders have a good prognosis.1 Patients with aggressive disease are generally managed in the same manner as pa tients with idiopathic pulmonary fibrosis, although some experts recommend the use of immunosuppres sive therapy on an individual basis. The pulmonary vasculitides represent an impor tant group of patients. Data support the use of corticosteroids and immunosuppressive or cyto toxic agents in these diseases.1* The Churg-Strauss syndrome may respond well to corticosteroids; un responsive cases may respond to cytotoxic agents. Additionally, patients with Henoch-Schonlein syn drome or disseminated leukocytolastie vasculitis respond to corticosteroid treatment. Clearly, cy clophosphamide is the treatment of choice for C3S91 CHEST / *2 / 2 / AUGUST, 1982 177 X V 'X.-- UCC 010789 Wegeners granulomatosis.* Recent data also sup port the use of cyclophosphamide in the treatment of overlap vasculitis. In contrast, the treatment of lymphomatoid granulomatosis is controversial, but most experts recommend early use of cytotoxic agents. ' Plasmapheresis in conjunction with immunosup pressive therapy appears to be emerging as the therapy of choice for pulmonary hemorrhage as sociated with Goodpasture's syndrome and im mune complex disease.1 . Lung biopsy specimen examination is the best estimate of disease activity, but once the decision is made to treat patients, an objective means to monitor response to therapy is needed.1'1 Tradi tionally, the chest roentgenogram and pulmonary function studies have been used to monitor pa tients' conditions. While these studies have enor mous value when used serially, current data in dicate that they are a relatively insensitive means of monitoring the disease.1* 4 Two new tests show promise as monitors of disease activity--bronchoalveolar lavage cellular analysis and nGa lung scanning.14 Several major centers have shown that bronchoalveolar lavage cell analysis accu rately samples the inflammatory cells (alveolitis) as judged by lung biopsy specimen analysis. Addi tionally, a semiquantitative analysis of the uptake of e7Ga in lung has been demonstrated to cor relate well with the degree of alveolitis in lung biopsy specimens.*'4 Both bronchoalveolar lavage cellular analysis and 7Ga lung scanning are being intensively investigated as monitors of interstitial disease. However, further studies are needed be fore they can be recommended for routine man agement. ACKNOWLEDGMENT: The author thanks Ms. Barbara Overton for editorial assistance, Ms. Criss Benefield for technical and library work, and Medical Media Production Services, VA Hospital, Birmingham, Ala, for expert photog raphy. References 1 Fulmer JD, Crystal RG. Interstitial lung diseases. In: Simmons DE, ed. Current pulmonology. Boston: Houghton-Miffhn Publishers, 1979:1-65 2 Weinberger SE, Kelman JA, Elson NA, Young RC, Rey nolds HY, Fulmer JD, et al. Bronchoalveolar lavage in interstitial lung disease. Ann Intern Med 1978; 89:459-66 3 Crystal RG, Gadek JE, Ferrans VJ, Fukner JD, Line BR, Hunninghake GW. Interstitial lung disease: current con cepts of pathogenesis, staging and therapy. Am J Med 1981; 70:54-67 4 Crystal RG, Roberts WC, Hunninghake GW, Gadek JE, Fulmer JD, Line BR. Pulmonary sarcoidosis: a disease characterized and perpetuated by activated lung Tlymphocytes. Ann Intern Med 1981; 94:73-94 5 Fauci AS, Haynes BF, Katz P. The spectrum of vas culitis: clinical, pathologic, immunologic, and therapeutic considerations. Ann Intern Med 1978; 89:660-76 6 Hunninghake GW, Crystal RG. Pulmonary sarcoidosis: a disorder mediated by excess helper T-lymphocyte ac tivity at sites of disease activity. N Engl J Med 1981; 305:429-34 7 Deremee RA, Rohrback MS. Serum angiotensin-convert ing enzyme activity in evaluating the clinical course of sarcoidosis. Arm Intern Med 1980; 92:361-65 8 Roth C, Huchon GJ, Amoux A, Stanislas-Leguern G, Marsac JH, Chretien J. Bronchoalveolar cells in ad vanced pulmonary sarcoidosis. Am Rev Respir Dis 1981; 124:9-12 S Smith LJ. Bronchoalveolar lavage today (editorial). Chest 1981; 80:251-52 10 Wall DP, Gaensler EA, Carrington CB, Hayes JA. Com parison of transhronchial and open biopsies in chronic infiltrative lung diseases. Am Rev Respir Dis 1981; 123: 280-85 11 Gaensler EA, Carrington CB. Open biopsy for chronic diffuse infiltrative lung disease: clinical, noentgenographic, and physiologic correlations in 502 patients. Ann Thorac Surg 1980; 30:411-26 ! 178 r ,r - ^ - <r-> TTiv Intaratltfil Lung Disaas* (Jiek D, Fulmtr) 'J Aw UCC 010790 Pneumoconioses and Their Masqueraders H. S. VanOrdstrand, M.D. It has been traditional that if an adequate occupational history is obtained in workers exposed to harmful dusts, the chest x-ray is the main diagnostic tool. In recent years, however, it has been noted that in most all occupations of these types, there may be marked variation in individual susceptibility to developing a pneumoconiosis without necessarily showing a constant dose relationship. It has also been recognized that there is no oc cupation in which the worker is immune to nonoccupational diseases It is not too infrequent that the usual diagnostic studies will not be sufficient to differentiate between masquerading diseases unrelated to the employment and diseases caused by the known hazards of certain employment. Some patients need more than just the usual work history, routine tests, and chest x-rays to differentiate occupational from nonoccupational diffuse lung disease. In my experience, additional tests, particularly lung biopsv, have found previously unsuspected pneumoconioses in an equal number of workers whose problems have been non occupational and masquerading as a dust disease of the lung. Thus both legal and medical requirements have been met. This article will primarily be one in which the roentgenogram has been the main point of differential diagnosis. A personal classification of pneumoconioses and of hypersensi tivity occupational reactions of the lungs is shown in Table 1. Masqueraders of silicosis as shown by roentgenography are listed in Table 2. An example of such is a man who worked in a glass industry for 30 years He developed a cough and some short ness of breath and a roentgenogram of his chest showed diffuse generalized nodulation which was interpreted as silicosis (Fig 1). A more detailed analysis of this man's work historv with the com pany. however, indicated that he had had a minimal exposure to free crystalline silica. A surgical lung biopsy specimen iFig 2) showed the nodules to be due to hematogenous metastases from a signet ring cell type of carcinoma most compatible with a primary stomach neoplasm. Further roentgenographic studies con firmed the presence of an asymptomatic gastric neoplasm and From the Section on Environmental Health Department o Puiomarv Diseases. The Cleveland Clinic Foundation Cleveland Ohio Presented at the meeting oi The American Occupational Medical Association Boston Massachusetts. April 26. 197?, fttanntad tram JoumJ af OccuMtion*! MMIciM November. 1977. Volume 19- No 11 PO 747*753 ^ *r > UCC 010791 '-at"-r*' -- Fig 4. -- Histologic study which showed th pictun of fibrosing interstitial pnoumonitis of tho Hammen-Rich syndrom* inrtood of asboslstit. tern along with reduced clarity of the heart borders so often seen in asbestosis. The man had experienced respiratory symptoms of cough and progressive shortness of breath less .than one year. A biopsv specimen of the lung revealed fibrosing interstitial pneumonitis of the Hamman-Rich syndrome, with no histologic signs of asbestosis IFig 4) Some of the roentgenographic masqueraders of bervlliosis are shown in Table 4. The earliest roentgenographic changes in Fig 5. -- Roentgenogram of a horylliom worhor with 20 years in I bask industry whor* horyilium compounds woro oitroetod from tho on. boryl. The minimal hilar arionopnthy and diffusa ftno sand-lika noduintion in this ro*ntgnogmm h*d bean intorprttad as chronic barylliosis. Diagnostic studies indicated, however, that this was a probfem of sarcoidosis. * a Fig 6. -- Roentgenogram of a bituminous coal mmtr who for most of 20 years had worked at operations at or mar tho faea. The films wan inttrpntad as suggostivs of ample CWP C'3S04 UCC 010792 Tafeio & -- Radiolofic Waaquoradon at Coal wfcor'a PriMMOOIXOM CT*P). KMan TBtradooa *il*y Motmtotc Cmmmo Snoidoois lymphocytic intarstitut Pimooomth DtiquHnMK Mntitol Pimooomtii MwimiOooui DU) to MMnl Suntoh Oudwi fo> Piwmi Milivy Coaximrmn Pidmonny Mmola Miciiititmmu Mmd lipmM ThctanK Pmartert* MmIob SUouiIoiim FI* 12. -- Photograph of i mphim drill lunf biopsy tpacimM which thowod dllfpu lymphocytic lymphoma instoad si diotomocoous earth pnoumoconiotit FI* 11. -- RotntKtAofmn in o vorfcor invohrtd Ni ttM calcinmi proeon of 1. UCC 010793 earth pneumoconioses are shown in Table 8. It is generally believed that this pneumoconiosis results from the heat calcining process with the basic fibrogenic dust being crystobalite. Figure 11 is a roentgenogram of a man who had worked for several years in this occupation: diatomaceous earth pneumoconiosis was sus pected. A needle biopsy (of the trephine drill type), however, showed his diffuse lung involvement to be lymphocytic lymphoma (Fig 12). ' , Roentgenographic masqueraders of the immunologic oc cupational lung disorders are shown in Table 9 Figure 13 shows bilateral lower lung field infiltrates in a farmer who was ex periencing intermittent cough and wheezing which he felt at times might be worse after working in his hay barn. The histologic study, however, as shown in Fig 14, established the diagnosis of tropical eosinophilia instead of farmer's lung (even though he had never been out of his home state of Pennsylvania other than coming to the Cleveland Clinic for diagnostic study). He promptly responded to arsenical therapy as shown in Fig 15. He had no recurrence of his problem. In summary, just as it has been found that certain unusual roent genograms can be due to a specific occupational disease and histologically proven so. in contrast it is also known that there is no occupation which allows a worker to be immune to nonoccupationa! diseases which can mimic roentgenographically the specific fibrogenic dust entity or forms of immunologic oc cupational diseases. This article presents a personal classification of the pneumoconioses and also tables and examples of masqueraders of them. Not too infrequently, the differential diagnostic tool of most importance is the microscope. In these modern times, biopsies can be obtained through various wavs and usually adequatelv to obtain the proper final answer. These biop sies include those obtained through fiberoptic bronchoscopv. the various types of percutaneous needle lung biopsies, and lung biopsy specimens obtained at a minor surgical procedure Medical Responsibilities and Rights It is said that the right to excellent health care, unlike the freedom of speech and other guaran tees derived from the Bill of Rights, is going to make much greater demands on our national re sources and ought not to be considered in the same light. Yet we are determined that there shall be equal access: like other human rights, it cannot be guaranteed to future generations unless de fended and protected against decay by the responsible actions of those now benefited. The process of continuous growth and renewal of biomedical knowledge, as well as the cultivation of professional skills, cannot benefit the next generation without the hetp of the patients ot todav. We have resolved that this burden shall no longer be borne chiefly bv the poor, the ignorant and the wards of the state. If we take an egalitarian view oi the rights of the patient, should we take any other view of fits responsibilities? Nevertheless, in practice these responsibilities are not universally accepted bv patients and their families. Though the maioritv plav their part in good grace some of them make it clear that they consider their involvement an unforeseen indignity. Others simpiv refuse, and one hears, for exam ple: "! don't want to be a guinea pig." "The medical student lor even the intern) can learn on someone else " "I don't think her brother is strong enough to donate blood, and besides he's too busv to come." "If you have doubts about the effectiveness of the new treatment, call me when vou feel more sure." -- From `Sounding Board' bv Thomas P Almv M.D n rhn tnqfond Journal oi Julv 21 19?* UCC 010794 C3SG6 AMERICAN REVIEW OF RESPIRATORY DISEASE, 1984(March); 129(3) ^_375_-379_.______________ Crackles in the Early Detection of Asbestosis'-2 RAYMOND L H. MURPHY, JR, EDWARD A. GAENSLER, STEPHEN K. HOLFORD, ELIZABETH A. DEL BONO, and GARY EPLER CAIC 6332 Code lo 11 30 31 70 76 80 Hitraduction * Minimal interstitial pulmonary fibro sis caused by the inhalation of asbestos can be difficult to detea (1,2). Sympto matology is subjective and pulmonary function studies are often nonspecific Roentgenognphic manifestations of early interstitial disease are often diffi cult to distinguish from normal sha dows (1-3), and observer variability in interpretation of radiographs is also a problem. Discontinuous adventitious hmg sounds (crackles, rales) have been recognized as prominent features of pulmonary asbestosis (4-6) and are thought to be an early finding P-9). Although chest auscultation is regarded as highly subjective, recently developed technology has brought the promise of objective quantification of lung sounds. One such method, called nme-expanded waveform (TEW) analysis, consists of tape recordings of sounds for analysis by a computet. Amplitude is then plotted versus time, with a time axis of 800 mn/f or more, allowing visualiza tion of minute details of pulmonary sounds (10). Because TEW analysis provides documentation of the pres ence of crackles, h can be used to train technicians in auscultation (11). Moni toring of exposed workers by ausculta tion is attractive because it is noninvasive and inexpensive. The purpose of this investigation was to quantify the relationship between the prevalence of crackles assessed by a technician, whose performance had been objective ly validated, to other criteria for asbestosis in exposed workers. *a RiVniPQS The 386 workers included in this study were exposed to asbestos during the manufacture of paper and insulation materials and in a shipyard. Lung sounds were recorded at 4 preselected basilar sues during breathing with the mouth open while the worker was in a sitting position. Workers were asked io breathe slightly more deeply than the usual tidal breathing as in standard clinical prac tice. These sues were the right and left bases m the midscapsuiar line, the right midcla- paeMWe irta m M%. Tha-MWrity (MJ%ie< thoaa atth m abnoimaI arttm ww* oanaoOy afcsaHM. SiwouMtien ay a* aeisntlmy vllpewfl neimiataa oon fca a uaottti anMniaeHi vieular line. and tbe left anterior axillary fine. The number of cackles was estimated ei each auscultation (he using a scale rang ing from 0 (none) to L0 (indicating many), and a weighted cackle score (WCS) was then calculated Scores bom tbe right and left bases posteriorly were doubted sod added to the scares from tbe anterior sites. The rank ing WCS asged bom 0 to 18. Long sounds were recorded at the time of eiiscnltarioa. and selected tape reconiingt were analyzed for frequency content end TEW analysts with and without 800-Hz filtered sound. These were compared with tbe mdepodem observations of a trained techmoaa. For this assessment, worker idcariftcaiiao was masked by me of code numbers. Comparison of tbe WCS was made by 2 observers who interpreted the TEW ana lyses while shnultaaeousty listening to the sounds. Tbe technician's results acre also compared with the pulmonary physician's burning during the surreys. The Kappa wriwif was calculated according to the method of Fleiss (12). Kappe is a numerical method of separating agreement from chance association, and it vena bom 0 (no agreement) to 1J> (complete agreement). For interpretation of tbe intermediate values, we employed the criteria of Landis and Koch (13): t Kappa value of 0.81 to U) indicates almost perfect agreement, 0.61 to 0.80 in dicates substantial agreement, 0.41 to 0.60 indicates moderate agreement, and 0.4 and below indicates slight to poor agreement. Other data were collected using a ques tionnaire on respiratory history and occu pational exposure, a physical examination including independent observe rr,i,is on lung sounds by 2 or more dies; pf-v '-'ns. dies; roemgenographic readings. <ing to the 1LO scheme, and detailed r>'" try func tion testing (14). Asbestosis in these exposed workers was considered to be present when 3 or 4 of the following otteria were present: (I) radiograph showing irregular opacifica tion of a profusion of 1/2 or more, (?) single-breath diffusing capadty less than BOW predicted. (3) vial capacity less than SOW predicted, and (4) crackles at 2 or more Kotflar StBL Roautts Asbestosis by our criteria was present in only 2JW of the workers and did not occur in workers with less than 11 yr of tstposure. In the 93 workers with over 25 yr of employment, 8.6W were considered to have asbestosis. The pre valence of abnormal findings in each of these criteria is shown in table 1. In general, the prevalence of these criteria increased both with exposure and with age, as is expected in populations wherein age and duration of exposure are closely correlated (figure 1). Pleural abnormalities also showed a similar re lationship to duration of exposure and age (figure 2). Tbe relationship between the tech- (Received tfi onymal form May 26, 1982 and in rrvaed form October 18. 1983) ' Fran the Tufu University School of Medi cine. the Boston University School of Medicine, and the Pulmonary Service. Faulkner Hospital. Boston. Massachusetts. 1 Requests for reprints should be addressed ip Raymond L. H Murphy. )r,, M.D.. Director. Pul monary Service Faulkner Hospital. IlJi Centre Street. Boston MA 02130. ,f' '.M'if til.' -> 8 37 UCC 010795 * CRACKLES IN EARLY DETECTION OF ASBESTOSIS crackles were distributed upwards from the base at the scapular level. The belief that crackles are an early sign is also consistent with many pub* lished reports. Crackles have been re garded as a feature of pulmonary asbestosis for over 50 yr. and even in early reports were considered to be present with minimal disease (17). Clinical features of their nature and distribution on the chest were described in some detail by Smither (9). Mitchell and coworkers (20) found crackles more closely related to duration of exposure to heat-resistant and friction composites than was vital capacity, and they recommended that chest ausculta tion be included as a biologic monitor of the work environment. Reported Tates vary, but about half of the per sons considered to have asbestosis on clinical grounds are reported to have crackles (21-23). These represent selected cases. In order to understand the strength of an association between an exposure and a health effect, it is im portant to know the status of all per sons exposed. If only patients are studied, the effects may appear more striking than if asymptomatic persons are also included. Population-based studies, therefore, allow more precise examination of the frequency of crackles in asbestos-exposed persons. These show prevalences ranging from about 10 to 207. Such prevalences depend on a variety of factors including the method of auscultation, the severity and duration of exposure, the age of population, the prevalence of the diseases causing crackles, etc. Neverthe less, the association between crackles and asbestos exposure is clearly estab lished by: U) high frequency in diag nosed cases, (2) common occurrence in exposed populations, and (3) increased frequency with increased duration of exposure (24, 25). Furthermore, the prevalence in control populations is low (24-27). The correct detection of those in whom the epidemiologic diagnosis of asbestosis was most certain suggests that a trained technician can screen a group of exposed workers to estimate the prevalence of asbestosis. Despite the high true positive rate there are errors in the method. In our study, 5 of the 7 workers with 3 of 4 positive cri teria were missed (false negative). Al though this may represent technician error, it is known that not all those v"' asbestosis have crackles. Indeed, Er* *' and coworkers (7) reported crackle; - TABLE 2 RELATIONSHIP OP AUSCULTATION BY A TECHNICIAN TO NUMBER OP ASBESTOS CRITERIA Number ot Positive Criteria par Worker of 4 Possible Asbestosis Criteria Weighted Crackle Score 0 1 2 3+ Total 0 1 2 3 4 Total 225 34 IS 15 2B9 90 5 3 5 S3 13 . 3 2 5 23 3 '2 0 2 7 0004 4 291 44 20 31 386 377 TABLE 3 TECHNICIAN VALIDATION: COMPARISON OP TECHNICIAN'S WEIGHTED CRACKLE SCORE MADE AT THE INDUSTRIAL SITE TO WAVEFORM INTERPRETATIONS OP THE SAME LUNG SOUNDS* Waveform Interpretations Wtgmd Cracki# ScoreT - - 3 or Mors Less than 3 Total Poettive tor crackles Negative tor crackles Total 6 0 6 28 14 14 16 22 ' Kappa a (LED. W22 m EOT*, t Oman* teoi ooacrmiions. TABU 4 RELATIONSHIP OF ROENTGENOGRAPHIC EVIDENCE OP EMPHYSEMA AND SYMPTOMS OP CHRONIC BRONCHITIS TO ASBESTOSIS AND WEIGHTED CRACKLE SCORE Asbestosis* weighted Crackle Score Yes NO Total Yaa No Total Emphysema? Yea 0 5 9 1 4 S No 11 343 394 28 326 354 Total 11 348 399 29 330 359 Chronic bronchitis* Yea 3 96 99 6 91 59 No 8 319 327 23 304 327 Total 11 375 386 31 395 386 * ksoasioan oaiHiaa a* 3 or * criteria peaitNe. t Empnyetnc Osirnse Dr roemecnegrwluc tiiisna * Chrome btencMia ottinec or American Thoracic Society erttena. TABU 5 RELATIONSHIP OP SMOKING 1HISTORY TO WEIGHTED CRACKLE SCORE* Smoking History (pack-years) Wsightad Crackle Score 0 1.2 34 Total 0-20 21-40 41-60 61 4 Toisi 169 <153.4)t 52 (57.54) 32 (33.93) 17 (25.06) 270 27 (38.64) 20 (14.49) 9 (8.95) 12 16.32) 68 12 (15.91) 6 15.97) 5 (3.52) 5 (2.60) 28 208 78 46 34 366 ` *> * 19.35. p <r 0.005 ' Numotfi 'ft rtttr to tft* ciMei+d wuc lor trial call ... f-f-f ? UCC 010796 - . 1f. 'cftaCxt.ES IN 7.AMLT DETECTION OF AMESTOglS 379 protable that those who develop severe asbestosis have roemgenographic pro gression from UICC grade 0/0 to 3/4 in a relatively orderly fashion. Our re luctance to regard the lesser UICC grades of small opacifications as prima facie evidence of an effect of asbestos is based on the reliability of such evi dence. First, the early diagnosis of in terstitial fibrosis has tong been re garded as one of the most subjective in radiology (2, 3) (other causes for ro entgenologically similar shadows in clude soft tissues, inadequate inspira tion, etc.). Second, it is likely that a variety of other illnesses and exposures produce similar findings (previous pul monary infection, other silicates, drugs, congestive heart failure, etc.). Third, in our studies, lesser grades of opacifica tions in asbestos workers could not be distinguished reliably from shadows seen on roentgenograms of the control sub jects (10, 36). Decreasing the degree of disease required to classify an indi vidual as a positive case in epidemio logic studies frequently leads to an increase in sensitivity. Unfortunately, this also often decreases the specificity or accuracy of the observation (13). The relative "earliness" of pulmonary function abnormalities, roentgeno- graphic findings, and auscultation are all subject to this phenomenon. The re levant issue is which test or set of tests provides reliable monitoring of workers to assure, as far as practicable; their safety. In this regard, a significant advantage of auscultation is its noninvasiveness, as worker acceptance must also be considered. Roentgenograms offered by employers are frequently refused by workers because of the fear of exposure to radiation or personal considerations. The results of these studies indicate that auscultation, by a properly trained and objectively validated technician, can be a useful method for screening industrial populations with exposure to asbestos. Although true positives may be underestimated, the false negative rate is low and the method is inexpen sive. With the use of modern recording and analysis techniques, chest ausculta tion can be verified and permanent records can be made. Further studies of the sensitivity and specificity are war ranted in view of the noninvasive na ture of auscultation. Acknowledgment The writers wish to thank Drs. J. Glassroth, J. O'Brien, M. L. Petusevsky, L. Sicilian, C. P. Wall, and D. Woodford who participated in the industrial surveys, and Drs. R. J. McCunney and B. Raff for their participa tion in observer variability studies. We also thank R. C. Bloom who performed the logis tics regression analysis, 3. C. Berera for tech nical assistance, and L. M. 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