Specialty: Pulmonary Medicine
Brigham and Women’s Hospital
15 Francis Street
Boston, MA 02115
The following is a list of recent publications for which this Partners Asthma Center physician has been cited as an author in PubMed databases. Study abstracts have been provided for your convenience.
Epler, G. R. and L. L. Laskaris (2001). "Individualized health care and the pharmaceutical industry." Am J Health Syst Pharm 58(11): 1042.
Epler, G. R. (2001). "Bronchiolitis obliterans organizing pneumonia." Arch Intern Med 161(2): 158-64.
Bronchiolar disorders can be divided into 2 general categories: (1) airway disorders (cellular bronchiolitis and obliterative bronchiolitis) and (2) parenchymal disorders (respiratory bronchiolitis-interstitial lung disease, which occurs in smokers and is treatable with smoking cessation or corticosteroid therapy, and bronchiolitis obliterans organizing pneumonia, an inflammatory lung disease simultaneously involving the terminal bronchioles and alveoli). This article reviews the clinical findings and therapeutic management of bronchiolitis obliterans organizing pneumonia.
Janz, T. G., R. Madan, et al. (2000). "Clinical conference on management dilemmas: progressive infiltrates and respiratory failure." Chest 117(2): 562-72.
Epler, G. R. (1998). "Heterogeneity of bronchiolitis obliterans organizing pneumonia." Curr Opin Pulm Med 4(2): 93-7.
Reports of the characterization and understanding of bronchiolitis obliterans organizing pneumonia (BOOP) have continued at an accelerated rate for several years. The radiographic and high-resolution CT features of BOOP continue to be documented. There have been new insights into the pathogenesis of BOOP. An animal model has been developed. Video-assisted thoracoscopic biopsy has become a standard for confirming the diagnosis. Childhood BOOP has been described in several reports. Idiopathic BOOP continues to be the most common type; however, a variety of clinical settings such as inhalation of mold spores and associated disorders such as renal transplantation continue to be described. This paper provides an update of advances in the pathogenesis, radiographic features, clinical course, and categorization of the heterogeneity of BOOP.
Epler, G. R. (1996). "Bronchiolar disorders with airflow obstruction." Curr Opin Pulm Med 2(2): 134-40.
Bronchiolar lesions continue to be increasingly recognized as a cause of airflow obstruction. Thus, it is important to have a current update of the current clinical, radiographic, and immunologic perspective of these disorders. Diffuse panbronchiolitis has been reported to occur in the United States and Europe, and the anti-inflammatory action of erythromycin appears to be effective in management. Idiopathic bronchiolitis obliterans, post-fume or post-infectious, or connective tissue disorder bronchiolitis obliterans continues to be rare and often has a poor prognosis. Lung transplantation bronchiolitis obliterans continues to be the major complication and cause of mortality in transplant recipients. Risk factors of this form of chronic rejection include more frequent and more severe acute rejection and the coexistence of organizing pneumonia. The recognition of the distinctive differences among the bronchiolar airflow disorders continues to be essential for improved patient care, greater understanding of the pathogenesis, and development of therapeutic advances.
Epler, G. R. (1995). "Bronchiolitis obliterans organizing pneumonia." Semin Respir Infect 10(2): 65-77.
Bronchiolitis obliterans organizing pneumonia (BOOP) is increasingly recognized as an important cause of diffuse infiltrative lung disease. It is a diagnostic consideration in patients with a febrile flu-like illness of a few weeks’ duration and a roentgenogram showing bilateral patchy infiltrates that are not responsive to a typical course of antibiotics. It is defined as granulated tissue plugs within lumens of small airways that extend into alveolar ducts and alveoli. Clinically, a flu-like illness, cough, and crackles are common. Pulmonary function studies of patients show a decreased vital capacity, normal flow rates (except in smokers), and a decreased diffusing capacity. It is generally idiopathic, but it may occur during the resolution of a viral or mycoplasma pneumonia. It is also associated with a variety of systemic illnesses and clinical settings. These include the connective tissue disorders, antineoplastic and other drugs, and immunological disorders, as well as bone marrow and lung transplantation. There are numerous related disorders, including human immunodeficiency virus infection, radiation therapy, thyroiditis, and alcoholic cirrhosis. In idiopathic BOOP, complete resolution occurs in 65% to 85% of patients treated with corticosteroid therapy. This type of therapy is often effective in patients with associated systemic disorders or in other clinical settings, but there may be limited or no response in patients with dermatomyositis, immunosuppression, or interstitial opacities at the lung bases. Respiratory failure leading to death may occur in 5% of patients. It is important to add BOOP to the differential diagnosis of febrile, noninfectious illnesses that are mimics of pneumonia.
Epler, G. R. (1992). "Clinical overview of occupational lung disease." Radiol Clin North Am 30(6): 1121-33.
The workplace has been a source of lung injury for centuries, yet awareness of the types of injuries has varied over time. Because of distinctive differences among the occupational lung disorders, a continual update of the clinical findings, dose response data, physiologic characteristics, and radiographic findings is needed. The radiologist plays a key role for the evaluation of miners, foundry or factory workers exposed to mineral dusts, and of workers exposed to the "biologic" dusts, infectious agents, cancer causing agents, and chemicals causing interstitial lung diseases. This overview includes a discussion of classification systems, criteria for diagnosis of occupational lung diseases, the pulmonary clinician’s evaluation, and important aspects of specific disorders and concludes with a discussion of pulmonary disability determination.
Epler, G. R. (1992). "Bronchiolitis obliterans organizing pneumonia: definition and clinical features." Chest 102(1 Suppl): 2S-6S.
There are several bronchiolar diseases with different pathologic and clinical findings. Idiopathic BOOP is a distinct entity consisting of a flu-like illness, late inspiratory crackles, patchy infiltrates roentgenographically, and physiologically decreased vital capacity and diffusing capacity. Response to corticosteroid therapy is good and relapse does not occur if sufficient therapy is given. Bronchiolitis obliterans organizing pneumonia is an appropriate description of this entity. The term is specific because it includes bronchioles and alveoli and excludes disorders involving only alveoli such as organizing pneumonitis or organizing diffuse alveolar damage. The term is general enough to include a sufficient number of patients with a homogenous disorder. Furthermore, the entity can be described to clinicians and pathologists throughout the world in such a fashion that patient care and research can be standardized. Researchers from different centers studying the cause or utilizing treatment protocols are able to discuss a single BOOP entity rather than comparing results of a heterogeneous group of many different types of interstitial lung disorders. This will lead to breakthroughs in discovery of etiologic causes and new effective therapeutic regimens.
Jederlinic, P. J., J. L. Abraham, et al. (1990). "Pulmonary fibrosis in aluminum oxide workers. Investigation of nine workers, with pathologic examination and microanalysis in three of them." Am Rev Respir Dis 142(5): 1179-84.
Epidemiologic surveys have indicated an excess of nonmalignant respiratory disease in workers exposed to aluminum oxide (Al2O3) during abrasives production. However, clinical, roentgenographic, histologic, and microanalytic description of these workers are lacking. This is a report of nine Al2O3-exposed workers with abnormal chest roentgenograms (profusion greater than or equal to 1/0, ILO/UC) from a plant engaged in the production of Al2O3 abrasives from alundum ore. Mean duration of exposure was 25 yr, and time since first exposure was 28 yr. in a subgroup of three, the severity of symptoms, reduction in the forced vital capacity (67% predicted) and diffusing capacity (51% predicted), and progressive roentgenographic changes (profusion greater than or equal to 2/2) prompted open lung biopsy. Lung tissue was analyzed by scanning electron microscopy and electron microprobe analysis. In each of the three biopsies, interstitial fibrosis with honeycombing was seen on routine section. In one biopsy, silica and asbestos fiber counts were at the low end of the range seen with silicosis and asbestosis; however, the absence of asbestos bodies and silicotic nodules suggested that the fibrosis was due to another cause. Metals occurred in amounts several orders of magnitude above background, and the majority was aluminum as Al2O3 and aluminum alloys. The findings in these nine workers suggests a common exposure as the possible cause. The nonspecific pathologic findings, absence of asbestos bodies and silicotic nodules, and the striking number of aluminum-containing particles suggest that Al2O3 is that common exposure. The possibility of "mixed dust" fibrosis should also be considered.
Epler, G. R. (1990). "Screening for lung cancer. Is it worthwhile?" Postgrad Med 87(6): 181-6.
Prevention of lung cancer remains the best method of decreasing lung cancer mortality. Patients who smoke should be urged to quit, and children, teenagers, and young adults must not begin smoking. At high risk are smokers, especially those under 40 years of age who may have smoked two to four packs of cigarettes per day for 20 years; persons who have had a previous lung cancer; patients with bullous emphysema; patients with asbestosis; and patients with evidence of chronic airflow obstruction. Although radiographic screening may detect lung cancer earlier and lead to increased 5-year survival rates, it does not reduce lung cancer mortality rates.
Epler, G. R. (1989). "Silo-filler’s disease: a new perspective." Mayo Clin Proc 64(3): 368-70.
Epler, G. R. (1988). "Bronchiolitis obliterans and airways obstruction associated with graft-versus-host disease." Clin Chest Med 9(4): 551-6.
Bronchiolitis obliterans is a nonspecific pathologic lesion seen after fume inhalation and infections, which is associated with connective tissue disorders and is a complication of organ transplantation. Bronchiolitis obliterans with organizing pneumonia is also associated with the connective tissue disorders but is usually idiopathic and has better prognosis with corticosteroid therapy. Bone marrow-related obliterative bronchiolitis is limited to patients who develop chronic graft-versus-host disease. Symptoms begin with cough in 3 to 6 months and progress to dyspnea and severe airflow obstruction. The roentgenogram is normal or shows hyperinflation. Prognosis is poor and most patients develop disabling irreversible airflow obstruction. Bronchiolitis obliterans is the most important clinical complication in heart-lung transplant recipients. It is not preceded by typical features of chronic graft-versus-host disease, but has the same clinical course of dyspnea, airflow obstruction, and poor response to therapy. Bronchiolitis obliterans in transplant recipients may represent a form of allograft rejection.
Epler, G. R. (1988). "Incidental exposure to asbestos: how real is the risk?" Hosp Pract (Off Ed) 23(1A): 6, 9-10.
McLoud, T. C., G. R. Epler, et al. (1986). "Bronchiolitis obliterans." Radiology 159(1): 1-8.
Gardner, R. M., J. L. Clausen, et al. (1986). "Quality assurance in pulmonary function laboratories." Am Rev Respir Dis 134(3): 625-7.
Epler, G. R., T. C. McLoud, et al. (1986). "Pleural lipoma. Diagnosis by computed tomography." Chest 90(2): 265-8.
Until recently, a definitive diagnosis of lipoma in the thorax could only be established by thoracotomy. We undertook this study to determine if chest CT could provide such an answer. Among 4,000 chest CT scans, six patients were found to have lipoma according to the following selected criteria: CT features of a pleural mass; a lesion showing completely homogeneous density with CT numbers indicating fat, and exclusion of other fatty lesions. In these six patients, the lipoma was an incidental finding, four were men, the mean age was 64.3 years, one-half were obese, and none had chest pains or dyspnea. Lesions varied in size from 2 to 4 cm and occurred along the chest wall. The CT numbers of the masses ranged from -54 to -129. None developed malignancy. In conclusion, we recommend clinical and chest CT follow-up for the asymptomatic patient who fulfills our CT criteria for lipoma. Biopsy or resection is recommended for lesions that are inhomogeneous.
McLoud, T. C., B. O. Woods, et al. (1985). "Diffuse pleural thickening in an asbestos-exposed population: prevalence and causes." AJR Am J Roentgenol 144(1): 9-18.
Two types of pleural reaction have been described in association with asbestos exposure: pleural plaques and diffuse pleural thickening. This study was undertaken to determine the prevalence and causes of diffuse thickening in asbestos-exposed persons. Serial chest radiographs in 1373 exposed individuals and 717 controls were interpreted according to the ILO scheme by two B readers. Diffuse pleural thickening was defined as a smooth, noninterrupted pleural density extending over at least one-fourth of the chest wall, with or without costophrenic angle obliteration. Among the exposed group, plaques and diffuse thickening occurred with almost equal frequency, 16.5% and 13.5%, respectively. Of the 185 cases with diffuse thickening, the radiographic appearance was most often due to the residual of a benign asbestos effusion (31.3%) or confluent plaques (25.4%). The most commonly held explanation of diffuse thickening, an extension of pulmonary fibrosis to the visceral and parietal pleura, was actually infrequent (10.2%). Among the group with diffuse thickening without asbestosis, the forced vital capacity and single-breath diffusing capacity were significantly lower than those of comparable normal persons and those with confluent plaques.
Epler, G. R., T. V. Colby, et al. (1985). "Bronchiolitis obliterans organizing pneumonia." N Engl J Med 312(3): 152-8.
In 50 of 94 patients with bronchiolitis obliterans we found no apparent cause or associated disease, and the bronchiolitis obliterans occurred with patchy organizing pneumonia. Histologic characteristics included polypoid masses of granulation tissue in lumens of small airways, alveolar ducts, and some alveoli. The fibrosis was uniform in age, suggesting that all repair had begun at the same time. The distribution was patchy, with preservation of background architecture. Clinically, there was cough or flu-like illness for 4 to 10 weeks, and crackles were heard in the lungs of 68 per cent of the patients. Radiographs showed an unusual pattern of patchy densities with a "ground glass" appearance in 81 per cent. Physiologically, there was restriction in 72 per cent of the patients, and 86 per cent had impaired diffusing capacity. Obstruction was limited to smokers. The mean follow-up period was four years. With corticosteroids, there was complete clinical and physiologic recovery in 65 per cent of the subjects; two died from progressive disease. This disorder differs from bronchiolitis obliterans with irreversible obstruction. It was confused most often with idiopathic pulmonary fibrosis. In view of the benign course and therapeutic response, a histologic distinction is important.
Samet, J. M., R. A. Young, et al. (1984). "Prevalence survey of respiratory abnormalities in New Mexico uranium miners." Health Phys 46(2): 361-70.
To obtain additional data concerning uranium mining and nonmalignant respiratory diseases, we conducted a prevalence survey of 192 long-term New Mexico uranium miners. Survey procedures included spirometry, completion of a respiratory symptoms questionnaire, physical examination and interpretation of available chest x rays. Total duration of underground uranium mining was used as the exposure index. Of the major respiratory symptoms, only the prevalence of dyspnea increased significantly with duration of uranium mining. With linear multiple-regression analysis, small but statistically significant effects of mining were found for two spirometric parameters, the forced expiratory volume in one sec and the maximal midexpiratory flow. By the 1980 International Labor Organization (ILO) U/C classification, 12 of 143 participants with x rays available for interpretation had at least category 1/0 pneumoconiosis. The opacities were predominantly nodular and compatible with silicosis.
Risk, C., G. R. Epler, et al. (1984). "Exercise alveolar-arterial oxygen pressure difference in interstitial lung disease." Chest 85(1): 69-74.
Abnormality of gas exchange is best evaluated by the exercise alveolar-arterial oxygen pressure difference, P(A-a)O2. We studied the P(A-a)O2 in 168 patients with sarcoidosis, desquamative interstitial pneumonia (DIP), usual interstitial pneumonia (UIP), berylliosis, and asbestosis who were seen for clinical and disability consultations. The increase of P(A-a)O2 with exercise was greatest in UIP (mean 16 mm Hg), least in sarcoidosis (mean 1 mm Hg), and intermediate in DIP, berylliosis, and asbestosis (means 9, 9, and 7 mm Hg, respectively). The increase was best predicted by the single breath diffusing capacity (Dsb), and it occurred in patients with sarcoidosis and DIP if the Dsb was less than 50 percent predicted and in patients with the other diseases if the Dsb was less than 70 percent predicted. However, the magnitude of the increase could not be predicted from resting tests, even when multilinear regression equations were used. We conclude that for clinical evaluation of patients with interstitial lung disease, the exercise test with arterial blood gas measurement adds important information if the Dsb is less than 70 percent predicted. For disability evaluation, the invasive exercise study may be helpful when there is a wide discrepancy between clinical findings and resting physiologic studies.
Breuer, R. and G. R. Epler (1984). "Treatment of occupational lung diseases." Compr Ther 10(5): 18-26.
Epler, G. R. and T. V. Colby (1983). "The spectrum of bronchiolitis obliterans." Chest 83(2): 161-2.
McLoud, T. C., G. R. Epler, et al. (1982). "A radiographic classification for sarcoidosis: physiologic correlation." Invest Radiol 17(2): 129-38.
The chest roentgenogram is frequently used to judge severity and course of sarcoidosis. The only widely used method for staging, suggested by Siltzbach, does not provide for such judgments. Therefore, we devised a scheme for objective description of type and quantity of opacities based on the ILO/UC Classification for the Pneumoconioses. We added a "reticulonodular" category (x y z) to the present "rounded (p q r) and "linear-irregular" (s t u) categories. We retained the 11 point scale for profusion (severity) and added notations to describe ground glass (alveolar) patterns, size of nodes, and hilar retractions. Among 211 patients, x y z (35%) and p q r (33%) opacities predominated while s t u opacities (19%) were unusual. Radiographic severity correlated best with vital capacity (rs = -0.49) and the diffusing capacity (rs = -0.32). With the Siltzbach classification these correlations were not as good (rs = -0.27 and -0.19). Siltzbach Stage III (fibrosis) was a distinct group with poor function and frequent airway obstruction. There was no correlation between radiographic appearance and pathologic severity because the latter grading, on a scale from 0 to 10, never exceeded 3. Sequential studies in 64 patients showed that, when individuals are used as their own controls, overall profusion correlated highly with physiologic changes over time.
Epler, G. R. (1982). "Byssinosis: defining cause and disability." Ann Intern Med 97(5): 772-4.
Epler, G. R., T. C. McLoud, et al. (1982). "Prevalence and incidence of benign asbestos pleural effusion in a working population." Jama 247(5): 617-22.
Benign asbestos effusion was defined by (1) exposure to asbestos, (2) confirmation by roentgenograms or thoracenteses, (3) no other disease related to pleural effusion, and (4) no malignant tumor within three years. There were 34 benign effusions among 1,135 exposed workers compared with no otherwise unexplained effusions among 717 control subjects. Prevalence was dose related with 7.0%, 3.7%, and 0.2% effusions with severe (III), indirect (II), and peripheral (I) exposure, respectively. The latency period was shorter than for other asbestos-related disorders. Benign effusion was the most common asbestos-related abnormality during the first 20 years after exposure. Incidence studies showed 9.2 effusions per 1,000 person-years for level III exposure, 3.9 for level II, and 0.7 for level I. Most effusions were small; 28.6% recurred, and 66% were asymptomatic. There was one mesothelioma six years after effusion. Asbestos exposure should be carefully searched for in patients with "idiopathic" pleural effusion.
Petusevsky, M. L., L. D. Lyons, et al. (1980). "Calibration of time derivatives of forced vital capacity by explosive decompression." Am Rev Respir Dis 121(2): 343-50.
A simple, portable, inexpensive device is described that simulates expiratory flow curves for calibration of spirometers. A 4-L metal cylinder filled with copper mesh is fitted with a precision manometer. The pressure is increased to twice atmospheric and released by explosive decompression through 4 easily interchangeable resistors. The ratio of forced expiratory volume in one second to forced vital capacity ranged from 0.80 to 0.25, thus encompassing the range from normal to severe obstruction. Accuracy was defined by 25 measurements of forced vital capacity that differed by no more than 0.5% from the actual cylinder volume. Repeatability was reflected by a standard deviation of at most 0.04 L/s for one-second forced expiratory volume, mid-expiratory flow, and instantaneous flows at 50 and 25% of the forced vital capacity. Peak flow was less reproducible. Calibrations of a water spirometer at increased altitude and at temperatures from 4 degrees to 37 degrees C revealed no significant changes in volume or flow rates. Standard values have remained unchanged for 2.5 yr. Three volume spirometers and 2 primary flow devices were tested extensively.
Epler, G. R., F. A. Saber, et al. (1980). "Determination of severe impairment (disability) in interstitial lung disease." Am Rev Respir Dis 121(4): 647-59.
Physicians trained primarily to recognize and treat disease are being asked more frequently to quantify impairment of health. Criteria for defining impairment due to chronic obstructive pulmonary diseases are widely accepted, but it has been difficult to establish guidelines for interstitial diseases. To develop and validate criteria, we selected 2,420 patients with airflow obstruction; 821 had interstitial disease, and 938 were employees of asbestos industries. We found that clinical and roentgenographic criteria were inappropriate for defining impairment. The forced vital capacity and single-breath diffusing capacity, each expressed as a percentage of the predicted value, were selected for analysis. Sensitivity studies using response to standard exercise as an independent criterion suggested that the limits reflecting severe impairment were a forced vital capacity 50% of predicted and a single-breath diffusing capacity 40% of predicted. Applying these criteria, 35.6% of patients with interstitial pneumonia, 12.1% with sarcoidosis, and 13.6% with pneumoconioses, but only 1.1% of the workers exposed to asbestos were severely impaired. In more than one half of patients the single-breath diffusing capacity was the only test that indicated severe impairment.
Epler, G. R., M. X. Fitz Gerald, et al. (1980). "Asbestos-related disease from household exposure." Respiration 39(4): 229-40.
The importance of nonoccupational asbestos exposure has been emphasized recently. To illustrate this problem, we report 4 persons with asbestos-related disease from household exposure. There were 2 wives of asbestos workers, who cleaned their husbands’ work clothes. One developed a mesothelioma and the other plaques, calcification, benign asbestos pleural effusion and subpleural parenchymal fibrosis. 2 men were exposed as children while playing in a cellar room which was also used for their father’s muffler repair business. At ages 27 and 33, they had pleural and diaphragmatic calcifications.
Samet, J. M., G. R. Epler, et al. (1979). "Absence of synergism between exposure to asbestos and cigarette smoking in asbestosis." Am Rev Respir Dis 120(1): 75-82.
To assess both independent and synergistic effects of exposure to asbestos and cigarette smoking on the development of asbestosis, survey data from 4 groups of workers exposed to asbestos were analyzed with multivariate statistical models. Survey methods were standardized and included for the 383 subjects a respiratory symptoms questionnaire, occupational history, physical examination, pulmonary function testing, and a chest radiograph. Exposure to asbestos and cigarette smoking were assessed by questionnaire. Synergism between the 2 exposures was not present for previously identified manifestations of asbestosis including bilateral fine crackles, clubbing, dyspnea, radiographic abnormality, decreased forced vital capacity, and decreased single-breath diffusing capacity of the lung for CO. However, additive, independent effects of these 2 exposures were present for each of these parameters.
Epler, G. R., G. L. Snider, et al. (1979). "Bronchiolitis and bronchitis in connective tissue disease. A possible relationship to the use of penicillamine." Jama 242(6): 528-32.
Rapid onset of severe and irreversbile airflow obstruction developed in two women. One had eosinophilic fasciitis and the other had rheumatoid arthritis. Both were treated with penicillamine. In the first patient, aged 42 years, dyspnea developed after six months of therapy. Her roentgenogram showed hyperinflation. Forced vital capacity expired in one second (FEV1/FVC%) decreased from 75% to 40%, and the residual volume increased by 1 L. In the second patient, aged 54 years, cough and dyspnea developed after ten months of therapy. The FEV1/FVC% was 56%, the FEV1 was 0.9 L, and the roentgenogram was normal. Lung biopsy specimens demonstrated severe and widespread bronchiolitis. An association between obliterative bronchiolitis and rheumatoid arthritis has been reported. Penicillamine may impair healing of bronchiolitis in such patients.
Epler, G. R., T. C. McLoud, et al. (1978). "Normal chest roentgenograms in chronic diffuse infiltrative lung disease." N Engl J Med 298(17): 934-9.
We undertook this study to determine the prevalence of normal roentgenograms in chronic diffuse infiltrative lung diseases. Of 458 patients with such disorders histologically confirmed, 44, or 9.6 per cent, had normal pre-biopsy films. In this group with normal x-ray films, desquamative interstitial pneumonia, sarcoidosis and allergic alveolitis were the most frequent diagnoses. Dyspnea was the principal complaint, and fine rales were common. The vital capacity was reduced in 57 per cent, and the single-breath diffusing capacity in 71 per cent. In half, histological changes and functional impairment were moderately severe. Films may be normal in such cases because isolated foci are too small or too few, because diffuse interstitial or intra-alveolar disease may cast no discrete shadows or because the lesions primarily affect airways or blood vessels. Patients with normal chest roentgenograms and normal mechanics of breathing but with impaired gas exchange should have lung biopsy for early diagnosis and therapy.
Epler, G. R., C. B. Carrington, et al. (1978). "Crackles (rales) in the interstitial pulmonary diseases." Chest 73(3): 333-9.
There is renewed interest in the classification and methods of recording adventitious pulmonary sounds. This is a study of the importance of fine crackles (rales) in the diagnosis and estimation of the severity of diffuse infiltrative pulmonary disease. Among 272 cases documented by lung biopsy, bilateral fine crackles were heard in 60 percent of those with interstitial pneumonias and asbestosis but in only 20 percent of those with sarcoidosis and other granulomatoses. These incidences were identical in 335 patients diagnosed clinically. In 322 selected ambulatory patients with chronic obstructive pulmonary disease, fine crackles were recorded in only 10 to 12 percent, while coarse crackles were not uncommon in patients with chronic bronchitis. In workers exposed to asbestos, crackles correlated with exposure. In serial studies of such workers, the occurrence of crackles alone appeared to be a random event, while among those with crackles together with one other of five criteria, almost one-half developed asbestosis within four to six years. Fine crackles correlated with pathologic severity, with radiographic honeycombing, and with physiologic abnormalities.
Epler, G. R. and M. A. Khan (1976). "Letter: Tuberculosis and isoniazid in steroid-treated asthmatic patients." Ann Intern Med 85(1): 129-31.
Black, M., J. R. Mitchell, et al. (1975). "Isoniazid-associated hepatitis in 114 patients." Gastroenterology 69(2): 289-302.
Analysis of the overt hepatic disease that developed in 114 patients while taking isoniazid for chemoprophylaxis of tuberculosis showed it to be mainly hepatocellular. The severity of the hepatic injury was manifested by the 13 fatalities (12.3%) and by the histological demonstration of submassive necrosis in 9 and massive necrosis in 4 patients. The 20 other patients from whom hepatic tissue was available for study included 16 with moderately severe acute hepatocellular injury (4 had a mixed hepatocellular-cholestatic pattern), and 4 with chronic hepatic diseases (1 had cirrhosis). Clinical manifestations of hepatic disease prior to the onset of jaundice included vague digestive complaints in 55% of the group and "viral" disease-like complaints in 35%, some with and some without gastrointestinal symptoms. Jaundice was the presenting complaint in 10% of patients. Fever and rash were reported in very few patients (less than 4%) and eosinophilia of modest degree was noted in approximately 10%. Hepatic injury was recognized during the 1st month of isoniazid administration in 15% and during the 2nd month in an additional 31%. In the remaining 54% of patients, the drug had been administered for periods of 2 to 11 months before hepatic injury was noted. Analyses of variables suggested that hepatic injury which presented after 2 months, especially with bilirubin levels that exceeded 20 mg per 100 ml, was more likely to have a fatal outcome than disease that presented during the first 2 months even with higher bilirubin levels. The case fatality rate was significantly higher in black females than in black males or in whites of either sex. The observations of the present study offer no support for the view that isoniazid-induced hepatic disease results from hypersensitivity to the drug. Other data that support the view that hepatotoxic metabolites of isoniazid may be responsible for the injury are considered.