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Drug-Induced Lung Disease
CRITICAL REVIEW Drug-Induced Lung Disease Michael E. Whitcomb, Maj., MC, USA 0
The clinical and roentgenographic features of the major drug-induced pulmonary reactions are reviewed. In most instances, a correct clinical diagnosis can be made if the physician is knowledgeable of the drugs which have been implicated in the pathogenesis of drug-induced lung reactions and recognizes the characteristic clinical and roentgenographic features present in each case. Discontinuation of the offending drug wiD result in resolution of lung disease in some cases. Administration of steroids may be of added benefit in selected cases. In those instances in which irreversible pathologic changes have already occurred, further deterioration of lung function may be prevented.
In
recent years, drug-induced pulmonary reactions have been reported with increasing frequency. There has been both an increase in the number of drugs reported to cause pulmonary reactions and a greater recognition of the variable clinical manifestations of these reactions. Because of the diverse nature of the drug-induced pulmonary diseases, the correct diagnosis in any individual case will be made only if physicians are knowledgeable of the drugs which have been implicated in the pathogenesis of these reactions and recognize the characteristic clinical and roentgenographic features associated with these drugs. It is the purpose of this paper to review the subject of drug-induced lung disease, with primary emphasis on the clinical presentation and therapeutic response of these entities. This review has been limited to those drug reactions which cause both clinical disease and roentgenographic abnormalities. Because the pathogenesis of most druginduced pulmonary reactions is speculative, discus. sion of pathogenesis is included only when clinical and laboratory studies have supported specific theories. °Chief, Pulmonary Disease Service, Walter Reed General Hospital, Washington, D. C. Reprint requests: Maior Whitcomb, Walter Reed Army Medical Center, Washington, D.C. 20012
418
ANTI-NEOPLASTIC DRUGS
Busulfan
In 1961, Oliner! reported the development of diffuse interstitial pneumonitis and fibrosis in two patients receiving busulfan. Since then, approximately 20 additional cases of busulfan-induced lung disease have been reported." In general, this syndrome occurs only after the patient has been taking the drug for at least one year. Progressive dyspnea, the clinical hallmark of the onset of the disease, is accompanied by the development of diffuse interstitial infiltrates on the chest roentgenogram. Clinical and postmortem studies have demonstrated that the drug does not cause uniform impairment of pulmonary function or consistent pathologic changes in all patients receiving it, but that the development of busulfan-induced lung disease occurs in a sporadic manner. Pathologic examination of the lungs of patients who have developed this syndrome has revealed an interstitial mononuclear cell infiltrate and fibrosis of the interstitial tissues. Atypia of the alveolar lining cells with desquamation of granular pneumocytes into the alveolar spaces is also present." Discontinuation of the drug and the use of steroids has been effective in controlling the progression of the disease in several cases. CHEST, VOL. 63, NO.3, MARCH, 1973
DRUG-INDUCED LUNG DISEASE
AIethotrexate In 1969, Clarysse," reported the development of acute pulmonary disease in seven patients with acute lymphoblastic leukemia in remission, who were receiving intermittent methotrexate as maintenance therapy. Five of the seven patients developed fever, cough, and dyspnea in association with bilateral confluent pulmonary infiltrates. Eosinophilia was noted during the acute illness in five of the seven patients. A total of 14 cases of methotrexate-induced lung disease have now been reported.! The pulmonary reaction has occurred within the first six months of therapy in all patients except one. Acute self limited pulmonary disease has been observed most frequently; however, several cases of chronic interstitial lung disease have also been reported. Although the occurrence of the syndrome was initially reported only in patients with acute lymphoblastic leukemia in remission, more recently the syndrome has been observed in three patients with dermatologic diseases and in one patient with bronchogenic carcinoma. Lung biopsies have been performed in three cases. Noncaseating granuloma and lymphocytic infiltrates consistent with an allergic granulomatous pneumonitis have been observed in two cases, and the pathologic changes of bronchiolitis obliterans were observed in the third case. Recent reports have documented that the syndrome responds dramatically to steroid therapy, with rapid resolution of systemic symptoms and clearing of the roentgenogram within several days. Bleomycin Bleomycin has also been reported to cause interstitial pneumonitis and fibrosis." The clinical syndrome and pathogenesis of the pulmonary lesions have not been well defined. Experimental studies have demonstrated that bleomycin is capable of inducing interstitial pneumonitis in dogs and monkeys and that the pathology of this lesion is similar to that observed in busulfan-induced lung disease." Cyclophosphamide A single case of diffuse lung disease has been reported occurring after cyclophosphamide therapy.8 Fever, cough, and severe dyspnea developed after 22 weeks of parenteral therapy and progressed to death in ten days. Marked proliferation of atypical alveolar lining cells and interstitial lymphocytic infiltration were present at autopsy. ANTIBIOTICS
Nitrofurantoin Nitrofurantoin has been implicated in the pathoCHEST, VOL. 63, NO.3, MARCH, 1973
419 genesis of two different pulmonary reactions. An acute syndrome characterized by the development of fever, cough, and shortness of breath within hours to several days after the institution of therapy has been reported most frequently." Eosinophilia has been detected in approximately one-third of these patients. The chest roentgenogram has most frequently revealed diffuse interstitial or alveolar infiltrates, although localized confluent pulmonary infiltrates and small pleural effusions may aso be seen on occasion. This syndrome usually resolves within days when administration of nitrofurantoin is discontinued. Less frequently reported has been the development of chronic interstitial lung disease during the course of prolonged nitrofurantoin therapy. Most recently, Rosenow'? has reported five patients with progressive dyspnea and chronic interstitial lung disease who had been taking nitrofurantoin for six months to six years prior to the onset of pulmonary symptoms. Pleural effusions and eosinophilia were not present in these patients. Biopsy findings in one case revealed nonspecific interstitial pneumonitis and fibrosis. Definite improvement was observed in these patients when nitrofurantoin therapy was discontinued and steroids were administered.
Antibiotics, AIiscellaneous Penicillin, 11 para-aminosalicylic acid l 2 and the sulfonamides'" have all been reported to cause acute drug-induced lung disease. The syndrome is identical with each drug and is characterized by the presence of fever, cough, and shortness of breath associated with pulmonary infiltrates and eosinophilia. This acute syndrome usually resolves rapidly when the therapy is discontinued. Recurrent migratory pulmonary infiltrates characteristic of Loeffler's syndrome have also been reported. In one patient who was receiving sulfadimethoxine, recurrent migratory infiltrates were present over a sixweek period and resolved rapidly with steroid administration. A lung biopsy in this patient revealed an eosinophilic and histocytic infiltrate. ANTIHYPERTENSION DRUGS
Drug-induced pulmonary disease caused by antihypertensive agents is primarily of historical interest, since the drugs which have been implicated are now infrequently used. In 1953, Morrison" reported the development of interstitial lung disease in three hypertensive patients who were being treated with hexamethonium. The patients had been receiving the drug seven, nine, and 15 months, respectively, prior to the onset of the disease.
420
MICHAEL E. WHITCOMB
Despite the fact that their hypertension was improved on therapy prior to the onset of lung disease, the development of the interstitial fibrosis was thought to be the result of organization of alveolar transudates, caused by recurrent episodes of left ventricular failure. In the same year, Morrow l 5 confirmed this association when he reported five deaths attributed to progressive interstitial pneumonitis among 258 patients who were treated with a combination of hydralazine and hexamethonium. In 1957, Perry!" attempted to elucidate the mechanism of the development of interstitial fibrosis in patients receiving hexamethonium. He compared the postmortem pathologic changes in the lungs of patients with malignant hypertension who had been treated with hexamethonium to the pathologic changes observed in the lungs of hypertensive patients who had not been treated and the lungs of patients who died with mitral stenosis. The pulmonary changes were most marked in the hypertensive patients treated with hexamethonium. He concluded that recurrent episodes of left ventricular failure were not responsible for these pathologic findings, since similar changes should have been prominent in those patients who died with mitral stenosis. Subsequently, similar cases of interstitial pneumonitis and fibrosis were reported in hypertensive patients who had not been treated with hexamethonium, but who had received pentolinium or mecamylamine. 17 The pathogenesis of the lung disease associated with antihypertensive therapy is unresolved, but the results of Perry's study make it unlikely that recurrent episodes of pulmonary edema can explain the pathologic changes. DRUG ABUSE
There are two major pulmonary reactions associated with drug abuse. The most frequently recognized is the syndrome of acute pulmonary edema induced by heroin." Patients with this syndrome usually present in either marked respiratory distress or in coma. The chest roentgenogram characteristically reveals pulmonary edema, with a normal sized heart. Although this syndrome usually occurs after intravenous administration of heroin, it has been reported to follow nasal inhalation. A similar syndrome of acute pulmonary edema has also been recognized after oral administration of methadone. 19 Less frequently recognized is the syndrome of angiothrombotic pulmonary hypertension." Patients with this syndrome present with a gradual onset of dyspnea on exertion, associated with the . development of progressive interstitial fibrosis on
the chest roentgenogram. Occasionally, localized pulmonary infiltrates may be observed. In the presence of progressive disease, pulmonary hypertension becomes evident, and the patients eventually become disabled and die. The pathogenesis of this syndrome has been well defined. Embolization to the pulmonary vessels of the inert filler material used in the preparation of capsules of tablets occurs when these preparations are administered by vein. Pathologic examination reveals starch or talc granulomas associated with arteriolar thromboses and interstitial fibrosis. Triplelenamine has been the drug most frequently implicated in this syndrome, but prolonged intravenous administration of any drug contaminated by an inert substance could be predicted to cause similar pathologic changes. LIPID PNEUMONIA
Aspiration of lipid-containing medications is probably the most frequent cause of drug-induced pulmonary infiltrates." These patients generally have nonspecific symptoms of cough or mild shortness of breath, unaccompanied by any systemic complaints. The chest roentgenogram characteristically reveals bilateral basilar infiltrates, which may have a stippled or confluent appearance. Unilateral infiltrates or localized nodular lesions simulating a malignancy may also occur. The diagnosis can be suspected when there is a history of chronic use of oil-containing medications, such as nose drops or mineral laxatives, and can be substantiated by the observation of many lipidcontaining macrophages in sputum examined under controlled conditions. Treatment consists of discontinuation of the use of the lipid containing medication. Steroids may be useful if there is diffuse pulmonary involvement associated with significant symptomatology." ANTICOAGULANTS
An uncommon complication of anticoagulant therapy is spontaneous intrapulmonary hemorrhage." Hemoptysis may be the only clinical manifestation of this complication, or evidence of bleeding in other parts of the body may be present. The chest roentgenogram reveals variable pulmonary infiltrates, the appearance of which is dependent on the degree of intrapulmonary hemorrhage. Hemorrhage into the pleural space has also been reported in patients receiving anticoagulants." Roentgenographic evidence of a large pleural effusion associated with a fall in the hematocrit is highly suggestive of this complication of anticoagu-
CHEST, VOL. 63, NO.3, MARCH, 1973
DRUG-INDUCED LUNG DISEASE
lant therapy. Demonstration of a true hemothorax by thoracentesis confirms the diagnosis. This complication has only been reported in patients receiving anticoagulants following pulmonary embolization. It seems likely that the pathogenesis of this complication is hemorrhage from the necrotic infarcted lung tissue and not spontaneous hemor-' rhage from the pleura. MISCELLANEOUS
Hydrochlorothiazide .Two cases of noncardiac pulmonary edema have been reported following ingestion of hydrochlorothiazide." In both cases, acute dyspnea began within 45 minutes after the ingestion of one 5O-mg tablet. The chest roentgenogram revealed a diffuse alveolar filling pattern, typical of pulmonary edema. Neither patient had cardiac disease or evidence of fluid retention prior to taking the drug, making the appearance of pulmonary edema on a previously existent organic basis unlikely. Chlorpropamide A single case of chlorpropamide-induced pulmonary infiltration with peripheral eosinophilia has been reported." The case was of particular significance because two weeks after resolution of this syndrome the patient was treated with sulfamethoxazole for a urinary tract infection and the syndrome recurred. It seems likely that this represented a cross reaction between chlorpropamide and sulfamethoxazole. It should be recalled that the sulfonamides, thiazide diuretics and sulfonoureas are pharmacologically related compounds and cross reactions to these drugs may be expected to occur in a sensitive patient. Diphenlyhydantoin Lymphadenopathy is a common accompaniment of the generalized drug reaction caused by diphenlyhydantoin. Enlargement of the hilar and mediastinal lymph nodes may be evident on the chest roentgenogram during this reaction.F A single case has been reported in which bilateral confluent pulmonary infiltrates occurred five days after the institution of diphenlyhydantoin therapy, and resolved when the drug was discontinued. At one time, diphenlyhydantoin was also implicated in the pathogenesis of diffuse interstitial fibrosis." A later prospective study failed to substantiate this observation and no subsequent reports of interstitial lung disease attributed to diphenlyhydantoin have appeared." CHEST, VOL. 63, NO.3, MARCH, 1973
421 Pituitary Snuff Inhalation of pituitary snuff has been well documented to cause pulmonary disease." The characteristic features of this disease are progressive dyspnea, diffuse confluent pulmonary infiltrates and eosinophilia. An immune mechanism has been clearly defined in the pathogenesis of this reaction. Specific precipitating antibodies to hormone components of pituitary tissue can be demonstrated in the sera of symptomatic patients, and pathologic examination has revealed findings consistent with allergic alveolitis. Although several patients have been reported to develop chronic interstitial fibrosis, resolution of the lung disease generally occurs if the drug is discontinued early in the course of the disease. M ethysergide
The development of pleural disease during the course of chronic methysergide therapy has been reported by several authors. 31•32 Patients who develop this complication have generally been taking the drug for several years before the onset of symptoms, but the reaction has been reported to occur after only six months of treatment. Patients may present with the onset of acute pleuritic pain accompanied by a pleural friction rub or with a more chronic syndrome, characterized by dyspnea and roentgenographic evidence of marked pleural fibrosis. The pleural involvement may be unilateral or bilateral, and effusion may occur at any stage. An unusual feature of the reaction is the propensity for the formation of localized pleural masses, which simulate a malignant process on the chest roentgenogram. These masses consist of fibrous tissue, chronic inflammatory cells and loculated fluid. The symptoms may improve and partial clearing of the pleural fibrosis may occur after the drug is discontinued. Lupus Syndrome A prominent manifestation of the drug-induced lupus syndrome is pleural Involvement.P Symptoms of acute pleuritis are common, and pleural effusions and fibrosis have been reported. Occasionally, patients may develop the onset of pleural disease before any other manifestations of the lupus syndrome becomes apparent. Although the LE cell preparation may be negative, antinuclear antibody will be detected in the serum of essentially all patients. Although pulmonary changes and other manifestations of this syndrome may persist, complete resolution occurs in most cases when administration of the offending drug is discontinued.
422
MICHAEL E. WHITCOMB
Roentgenographic evidence of 'pleural disease or symptoms of acute pleuritis may occur in patients taking any of the drugs which have been associated with the drug-induced lupus syndrome and should alert the physician to the possibility of the development of this syndrome. The drugs which have been implicated in the induction of a lupus syndrome are listed. Drug. Implicared in Induction 0/ Lupua Syndrome procainamide hydralazine isoniazid sulfonamides diphenylhydantoin mephenytoin trimethadione
ethosuximide penicillin phenylbutazone tetracycline streptomycin p-aminosalicylic acid griseofulvin REFERENCES
1 Oliner H, Schwartz R, Rubio F, et al: Interstitial pulmonary fibrosis following busulphan therapy. Am J Med 31: 134-139, 1961 2 Bums W A, McFarland W, Mathews MJ: Busulphan induced pulmonary disease. Am Rev Resp Dis 101:408-413, 1970 3 Littler WA, Kay JM, Hasleton PS, et al: Busulphan lung. Thorax 24:639-655,1969 4 Clarysse AM, Cathey WJ, Cartwright GE, et al: Pulmonary disease complicating intermittent therapy with methotrexate. JAMA 209:1861-1864, 1969 5 Whitcomb ME, Schwarz MI, Tormey DC: Methotrexate pneumonitis: case report and review of the literature. Thorax (in press) 6 Ichikawa T, Nakano I, Hirokawa I: Bleomycin treatment of the tumors of penis and scrotum. J Urol 102:699-707, 1969 7 Fleischman RW, Baker jr, Thompson CR, et al: Bleomycin induced interstitial pneumonia in dogs. Thorax 26:675682,1971 8 Rodin AE, Haggard ME, Travis LB: Lung changes and chemotherapeutic agents in childhood. Am J Dis Child 120:337-340, 1970 9 Hailey FJ, Glascock HW, Hewitt WF: Pleuropneumonic reactions to nitrofurantoin. N Engl J Med 281:1087-1090, 1969 10 Rosenow EC, DeRemee RA, Dines DA: Chronic nitrofurantoin pulmonary reaction. N Engl J Med 279: 12581262, 1968 11 Reichlin S, Loveless MH, Kane EG: Loeffler's syndrome following penicillin therapy. Ann Intern Med 38:113-120, 1953 12 Wold DE, Zahn DW: Allergic (Loeffler's) pneumonitis
13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33
occurring during antituberculous chemotherapy. Am Rev Resp Dis 74:445-453, 1956 Fiegenberg DS, Weiss H, Kirshman H: Migratory pneumonia with eosinophilia. Arch Intern Med 120:85-89, 1967 Morrison B: Parenteral hexamethonium in hypertension. Br Med J 1:1291-1299, 1953 Morrow JD, Schroeder HA, Perry HM: Studies on the control of hypertension by hyphex. Circulation 8:829-839, 195\3 Perry H, O'Neal RM, Thomas W A: Pulmonary disease following chronic chemical ganglionic blockade. Am J Med 22:37-50,1957 Rokseth R, Storstein 0: Pulmonary complications during mecamylamine therapy. Acta Med Scand 167:23-27, 1960 Steinberg AD, Karliner JS: The clinical spectrum of heroin pulmonary edema. Arch Intern Med 122:122-127, 1968 Frand UI, Shim CS, Williams MH: Methadone-induced pulmonary edema. Ann Intern Med 76:975-979, 1972 Szwed JJ: Pulmonary angiothrombosis caused by "Blue Velvet" addiction. Ann Intern Med 73:771-774, 1970 Miller A, Bader RA, Bader ME, et al: Mineral oil pneumonia. Ann Intern Med 57:627-634,1962 Ayvazian FL, Stewart DS, Merkel CG, et al: Diffuse lipoid pneumonitis successfully treated with prednisone. Am J Med 43:930-934, 1967 Reussi C, Schiavi JE, Altman R, et al: Unusual complications in the course of anticoagulant therapy. Am J Med 46:460-463, 1969 Macon WL, Morton JH, Adams JT: Significant complications of anticoagulant therapy. Surgery 68:571-582, 1970 Steinberg AD: Pulmonary edema following ingestion of hydrochlorthiazide. JAMA 204:825-827, 1968 Bell RJM: Pulmonary infiltration with eosinophils caused by chlorpropamide. Lancet 1: 1249-1250, 1964 Heitzman ER: Lymphadenopathy related to anticonvulsant therapy. Radiology 89:311-312, 1967 Moore MT: Pulmonary changes in hydantoin therapy. JAMA 171:1328-1333, 1959 Livingston S, Whitehouse D, Pauli LL: Study of the effects of diphenylhydantoin sodium on the lungs. N Engl J Med 264:648-651, 1961 Harper LO, Burrell RG, Lapp NL, et al: Allergic alveolitis due to pituitary snuff. Ann Intern Med 73:581-584, 1970 Graham JR: Cardiac and pulmonary fibrosis during methysergide therapy for headache. Am J Med Sc 254:112,1967 Hindle W, Posner E, Sweetnam MT, et al: Pleural effusion and fibrosis during treatment with methysergide. Br Med J 1:605-606, 1970 Byrd RB, Schanzer B: Pulmonary sequelae in procaine amide induced lupus syndrome. Chest 55:170-172, 1969
CHEST, VOL. 63, NO.3, MARCH, 1973
The clinical and roentgenographic features of the major drug-induced pulmonary reactions are reviewed. In most instances, a correct clinical diagnosis can be made if the physician is knowledgeable of the drugs which have been implicated in the pathogenesis of drug-induced lung reactions and recognizes the characteristic clinical and roentgenographic features present in each case. Discontinuation of the offending drug wiD result in resolution of lung disease in some cases. Administration of steroids may be of added benefit in selected cases. In those instances in which irreversible pathologic changes have already occurred, further deterioration of lung function may be prevented.
In
recent years, drug-induced pulmonary reactions have been reported with increasing frequency. There has been both an increase in the number of drugs reported to cause pulmonary reactions and a greater recognition of the variable clinical manifestations of these reactions. Because of the diverse nature of the drug-induced pulmonary diseases, the correct diagnosis in any individual case will be made only if physicians are knowledgeable of the drugs which have been implicated in the pathogenesis of these reactions and recognize the characteristic clinical and roentgenographic features associated with these drugs. It is the purpose of this paper to review the subject of drug-induced lung disease, with primary emphasis on the clinical presentation and therapeutic response of these entities. This review has been limited to those drug reactions which cause both clinical disease and roentgenographic abnormalities. Because the pathogenesis of most druginduced pulmonary reactions is speculative, discus. sion of pathogenesis is included only when clinical and laboratory studies have supported specific theories. °Chief, Pulmonary Disease Service, Walter Reed General Hospital, Washington, D. C. Reprint requests: Maior Whitcomb, Walter Reed Army Medical Center, Washington, D.C. 20012
418
ANTI-NEOPLASTIC DRUGS
Busulfan
In 1961, Oliner! reported the development of diffuse interstitial pneumonitis and fibrosis in two patients receiving busulfan. Since then, approximately 20 additional cases of busulfan-induced lung disease have been reported." In general, this syndrome occurs only after the patient has been taking the drug for at least one year. Progressive dyspnea, the clinical hallmark of the onset of the disease, is accompanied by the development of diffuse interstitial infiltrates on the chest roentgenogram. Clinical and postmortem studies have demonstrated that the drug does not cause uniform impairment of pulmonary function or consistent pathologic changes in all patients receiving it, but that the development of busulfan-induced lung disease occurs in a sporadic manner. Pathologic examination of the lungs of patients who have developed this syndrome has revealed an interstitial mononuclear cell infiltrate and fibrosis of the interstitial tissues. Atypia of the alveolar lining cells with desquamation of granular pneumocytes into the alveolar spaces is also present." Discontinuation of the drug and the use of steroids has been effective in controlling the progression of the disease in several cases. CHEST, VOL. 63, NO.3, MARCH, 1973
DRUG-INDUCED LUNG DISEASE
AIethotrexate In 1969, Clarysse," reported the development of acute pulmonary disease in seven patients with acute lymphoblastic leukemia in remission, who were receiving intermittent methotrexate as maintenance therapy. Five of the seven patients developed fever, cough, and dyspnea in association with bilateral confluent pulmonary infiltrates. Eosinophilia was noted during the acute illness in five of the seven patients. A total of 14 cases of methotrexate-induced lung disease have now been reported.! The pulmonary reaction has occurred within the first six months of therapy in all patients except one. Acute self limited pulmonary disease has been observed most frequently; however, several cases of chronic interstitial lung disease have also been reported. Although the occurrence of the syndrome was initially reported only in patients with acute lymphoblastic leukemia in remission, more recently the syndrome has been observed in three patients with dermatologic diseases and in one patient with bronchogenic carcinoma. Lung biopsies have been performed in three cases. Noncaseating granuloma and lymphocytic infiltrates consistent with an allergic granulomatous pneumonitis have been observed in two cases, and the pathologic changes of bronchiolitis obliterans were observed in the third case. Recent reports have documented that the syndrome responds dramatically to steroid therapy, with rapid resolution of systemic symptoms and clearing of the roentgenogram within several days. Bleomycin Bleomycin has also been reported to cause interstitial pneumonitis and fibrosis." The clinical syndrome and pathogenesis of the pulmonary lesions have not been well defined. Experimental studies have demonstrated that bleomycin is capable of inducing interstitial pneumonitis in dogs and monkeys and that the pathology of this lesion is similar to that observed in busulfan-induced lung disease." Cyclophosphamide A single case of diffuse lung disease has been reported occurring after cyclophosphamide therapy.8 Fever, cough, and severe dyspnea developed after 22 weeks of parenteral therapy and progressed to death in ten days. Marked proliferation of atypical alveolar lining cells and interstitial lymphocytic infiltration were present at autopsy. ANTIBIOTICS
Nitrofurantoin Nitrofurantoin has been implicated in the pathoCHEST, VOL. 63, NO.3, MARCH, 1973
419 genesis of two different pulmonary reactions. An acute syndrome characterized by the development of fever, cough, and shortness of breath within hours to several days after the institution of therapy has been reported most frequently." Eosinophilia has been detected in approximately one-third of these patients. The chest roentgenogram has most frequently revealed diffuse interstitial or alveolar infiltrates, although localized confluent pulmonary infiltrates and small pleural effusions may aso be seen on occasion. This syndrome usually resolves within days when administration of nitrofurantoin is discontinued. Less frequently reported has been the development of chronic interstitial lung disease during the course of prolonged nitrofurantoin therapy. Most recently, Rosenow'? has reported five patients with progressive dyspnea and chronic interstitial lung disease who had been taking nitrofurantoin for six months to six years prior to the onset of pulmonary symptoms. Pleural effusions and eosinophilia were not present in these patients. Biopsy findings in one case revealed nonspecific interstitial pneumonitis and fibrosis. Definite improvement was observed in these patients when nitrofurantoin therapy was discontinued and steroids were administered.
Antibiotics, AIiscellaneous Penicillin, 11 para-aminosalicylic acid l 2 and the sulfonamides'" have all been reported to cause acute drug-induced lung disease. The syndrome is identical with each drug and is characterized by the presence of fever, cough, and shortness of breath associated with pulmonary infiltrates and eosinophilia. This acute syndrome usually resolves rapidly when the therapy is discontinued. Recurrent migratory pulmonary infiltrates characteristic of Loeffler's syndrome have also been reported. In one patient who was receiving sulfadimethoxine, recurrent migratory infiltrates were present over a sixweek period and resolved rapidly with steroid administration. A lung biopsy in this patient revealed an eosinophilic and histocytic infiltrate. ANTIHYPERTENSION DRUGS
Drug-induced pulmonary disease caused by antihypertensive agents is primarily of historical interest, since the drugs which have been implicated are now infrequently used. In 1953, Morrison" reported the development of interstitial lung disease in three hypertensive patients who were being treated with hexamethonium. The patients had been receiving the drug seven, nine, and 15 months, respectively, prior to the onset of the disease.
420
MICHAEL E. WHITCOMB
Despite the fact that their hypertension was improved on therapy prior to the onset of lung disease, the development of the interstitial fibrosis was thought to be the result of organization of alveolar transudates, caused by recurrent episodes of left ventricular failure. In the same year, Morrow l 5 confirmed this association when he reported five deaths attributed to progressive interstitial pneumonitis among 258 patients who were treated with a combination of hydralazine and hexamethonium. In 1957, Perry!" attempted to elucidate the mechanism of the development of interstitial fibrosis in patients receiving hexamethonium. He compared the postmortem pathologic changes in the lungs of patients with malignant hypertension who had been treated with hexamethonium to the pathologic changes observed in the lungs of hypertensive patients who had not been treated and the lungs of patients who died with mitral stenosis. The pulmonary changes were most marked in the hypertensive patients treated with hexamethonium. He concluded that recurrent episodes of left ventricular failure were not responsible for these pathologic findings, since similar changes should have been prominent in those patients who died with mitral stenosis. Subsequently, similar cases of interstitial pneumonitis and fibrosis were reported in hypertensive patients who had not been treated with hexamethonium, but who had received pentolinium or mecamylamine. 17 The pathogenesis of the lung disease associated with antihypertensive therapy is unresolved, but the results of Perry's study make it unlikely that recurrent episodes of pulmonary edema can explain the pathologic changes. DRUG ABUSE
There are two major pulmonary reactions associated with drug abuse. The most frequently recognized is the syndrome of acute pulmonary edema induced by heroin." Patients with this syndrome usually present in either marked respiratory distress or in coma. The chest roentgenogram characteristically reveals pulmonary edema, with a normal sized heart. Although this syndrome usually occurs after intravenous administration of heroin, it has been reported to follow nasal inhalation. A similar syndrome of acute pulmonary edema has also been recognized after oral administration of methadone. 19 Less frequently recognized is the syndrome of angiothrombotic pulmonary hypertension." Patients with this syndrome present with a gradual onset of dyspnea on exertion, associated with the . development of progressive interstitial fibrosis on
the chest roentgenogram. Occasionally, localized pulmonary infiltrates may be observed. In the presence of progressive disease, pulmonary hypertension becomes evident, and the patients eventually become disabled and die. The pathogenesis of this syndrome has been well defined. Embolization to the pulmonary vessels of the inert filler material used in the preparation of capsules of tablets occurs when these preparations are administered by vein. Pathologic examination reveals starch or talc granulomas associated with arteriolar thromboses and interstitial fibrosis. Triplelenamine has been the drug most frequently implicated in this syndrome, but prolonged intravenous administration of any drug contaminated by an inert substance could be predicted to cause similar pathologic changes. LIPID PNEUMONIA
Aspiration of lipid-containing medications is probably the most frequent cause of drug-induced pulmonary infiltrates." These patients generally have nonspecific symptoms of cough or mild shortness of breath, unaccompanied by any systemic complaints. The chest roentgenogram characteristically reveals bilateral basilar infiltrates, which may have a stippled or confluent appearance. Unilateral infiltrates or localized nodular lesions simulating a malignancy may also occur. The diagnosis can be suspected when there is a history of chronic use of oil-containing medications, such as nose drops or mineral laxatives, and can be substantiated by the observation of many lipidcontaining macrophages in sputum examined under controlled conditions. Treatment consists of discontinuation of the use of the lipid containing medication. Steroids may be useful if there is diffuse pulmonary involvement associated with significant symptomatology." ANTICOAGULANTS
An uncommon complication of anticoagulant therapy is spontaneous intrapulmonary hemorrhage." Hemoptysis may be the only clinical manifestation of this complication, or evidence of bleeding in other parts of the body may be present. The chest roentgenogram reveals variable pulmonary infiltrates, the appearance of which is dependent on the degree of intrapulmonary hemorrhage. Hemorrhage into the pleural space has also been reported in patients receiving anticoagulants." Roentgenographic evidence of a large pleural effusion associated with a fall in the hematocrit is highly suggestive of this complication of anticoagu-
CHEST, VOL. 63, NO.3, MARCH, 1973
DRUG-INDUCED LUNG DISEASE
lant therapy. Demonstration of a true hemothorax by thoracentesis confirms the diagnosis. This complication has only been reported in patients receiving anticoagulants following pulmonary embolization. It seems likely that the pathogenesis of this complication is hemorrhage from the necrotic infarcted lung tissue and not spontaneous hemor-' rhage from the pleura. MISCELLANEOUS
Hydrochlorothiazide .Two cases of noncardiac pulmonary edema have been reported following ingestion of hydrochlorothiazide." In both cases, acute dyspnea began within 45 minutes after the ingestion of one 5O-mg tablet. The chest roentgenogram revealed a diffuse alveolar filling pattern, typical of pulmonary edema. Neither patient had cardiac disease or evidence of fluid retention prior to taking the drug, making the appearance of pulmonary edema on a previously existent organic basis unlikely. Chlorpropamide A single case of chlorpropamide-induced pulmonary infiltration with peripheral eosinophilia has been reported." The case was of particular significance because two weeks after resolution of this syndrome the patient was treated with sulfamethoxazole for a urinary tract infection and the syndrome recurred. It seems likely that this represented a cross reaction between chlorpropamide and sulfamethoxazole. It should be recalled that the sulfonamides, thiazide diuretics and sulfonoureas are pharmacologically related compounds and cross reactions to these drugs may be expected to occur in a sensitive patient. Diphenlyhydantoin Lymphadenopathy is a common accompaniment of the generalized drug reaction caused by diphenlyhydantoin. Enlargement of the hilar and mediastinal lymph nodes may be evident on the chest roentgenogram during this reaction.F A single case has been reported in which bilateral confluent pulmonary infiltrates occurred five days after the institution of diphenlyhydantoin therapy, and resolved when the drug was discontinued. At one time, diphenlyhydantoin was also implicated in the pathogenesis of diffuse interstitial fibrosis." A later prospective study failed to substantiate this observation and no subsequent reports of interstitial lung disease attributed to diphenlyhydantoin have appeared." CHEST, VOL. 63, NO.3, MARCH, 1973
421 Pituitary Snuff Inhalation of pituitary snuff has been well documented to cause pulmonary disease." The characteristic features of this disease are progressive dyspnea, diffuse confluent pulmonary infiltrates and eosinophilia. An immune mechanism has been clearly defined in the pathogenesis of this reaction. Specific precipitating antibodies to hormone components of pituitary tissue can be demonstrated in the sera of symptomatic patients, and pathologic examination has revealed findings consistent with allergic alveolitis. Although several patients have been reported to develop chronic interstitial fibrosis, resolution of the lung disease generally occurs if the drug is discontinued early in the course of the disease. M ethysergide
The development of pleural disease during the course of chronic methysergide therapy has been reported by several authors. 31•32 Patients who develop this complication have generally been taking the drug for several years before the onset of symptoms, but the reaction has been reported to occur after only six months of treatment. Patients may present with the onset of acute pleuritic pain accompanied by a pleural friction rub or with a more chronic syndrome, characterized by dyspnea and roentgenographic evidence of marked pleural fibrosis. The pleural involvement may be unilateral or bilateral, and effusion may occur at any stage. An unusual feature of the reaction is the propensity for the formation of localized pleural masses, which simulate a malignant process on the chest roentgenogram. These masses consist of fibrous tissue, chronic inflammatory cells and loculated fluid. The symptoms may improve and partial clearing of the pleural fibrosis may occur after the drug is discontinued. Lupus Syndrome A prominent manifestation of the drug-induced lupus syndrome is pleural Involvement.P Symptoms of acute pleuritis are common, and pleural effusions and fibrosis have been reported. Occasionally, patients may develop the onset of pleural disease before any other manifestations of the lupus syndrome becomes apparent. Although the LE cell preparation may be negative, antinuclear antibody will be detected in the serum of essentially all patients. Although pulmonary changes and other manifestations of this syndrome may persist, complete resolution occurs in most cases when administration of the offending drug is discontinued.
422
MICHAEL E. WHITCOMB
Roentgenographic evidence of 'pleural disease or symptoms of acute pleuritis may occur in patients taking any of the drugs which have been associated with the drug-induced lupus syndrome and should alert the physician to the possibility of the development of this syndrome. The drugs which have been implicated in the induction of a lupus syndrome are listed. Drug. Implicared in Induction 0/ Lupua Syndrome procainamide hydralazine isoniazid sulfonamides diphenylhydantoin mephenytoin trimethadione
ethosuximide penicillin phenylbutazone tetracycline streptomycin p-aminosalicylic acid griseofulvin REFERENCES
1 Oliner H, Schwartz R, Rubio F, et al: Interstitial pulmonary fibrosis following busulphan therapy. Am J Med 31: 134-139, 1961 2 Bums W A, McFarland W, Mathews MJ: Busulphan induced pulmonary disease. Am Rev Resp Dis 101:408-413, 1970 3 Littler WA, Kay JM, Hasleton PS, et al: Busulphan lung. Thorax 24:639-655,1969 4 Clarysse AM, Cathey WJ, Cartwright GE, et al: Pulmonary disease complicating intermittent therapy with methotrexate. JAMA 209:1861-1864, 1969 5 Whitcomb ME, Schwarz MI, Tormey DC: Methotrexate pneumonitis: case report and review of the literature. Thorax (in press) 6 Ichikawa T, Nakano I, Hirokawa I: Bleomycin treatment of the tumors of penis and scrotum. J Urol 102:699-707, 1969 7 Fleischman RW, Baker jr, Thompson CR, et al: Bleomycin induced interstitial pneumonia in dogs. Thorax 26:675682,1971 8 Rodin AE, Haggard ME, Travis LB: Lung changes and chemotherapeutic agents in childhood. Am J Dis Child 120:337-340, 1970 9 Hailey FJ, Glascock HW, Hewitt WF: Pleuropneumonic reactions to nitrofurantoin. N Engl J Med 281:1087-1090, 1969 10 Rosenow EC, DeRemee RA, Dines DA: Chronic nitrofurantoin pulmonary reaction. N Engl J Med 279: 12581262, 1968 11 Reichlin S, Loveless MH, Kane EG: Loeffler's syndrome following penicillin therapy. Ann Intern Med 38:113-120, 1953 12 Wold DE, Zahn DW: Allergic (Loeffler's) pneumonitis
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occurring during antituberculous chemotherapy. Am Rev Resp Dis 74:445-453, 1956 Fiegenberg DS, Weiss H, Kirshman H: Migratory pneumonia with eosinophilia. Arch Intern Med 120:85-89, 1967 Morrison B: Parenteral hexamethonium in hypertension. Br Med J 1:1291-1299, 1953 Morrow JD, Schroeder HA, Perry HM: Studies on the control of hypertension by hyphex. Circulation 8:829-839, 195\3 Perry H, O'Neal RM, Thomas W A: Pulmonary disease following chronic chemical ganglionic blockade. Am J Med 22:37-50,1957 Rokseth R, Storstein 0: Pulmonary complications during mecamylamine therapy. Acta Med Scand 167:23-27, 1960 Steinberg AD, Karliner JS: The clinical spectrum of heroin pulmonary edema. Arch Intern Med 122:122-127, 1968 Frand UI, Shim CS, Williams MH: Methadone-induced pulmonary edema. Ann Intern Med 76:975-979, 1972 Szwed JJ: Pulmonary angiothrombosis caused by "Blue Velvet" addiction. Ann Intern Med 73:771-774, 1970 Miller A, Bader RA, Bader ME, et al: Mineral oil pneumonia. Ann Intern Med 57:627-634,1962 Ayvazian FL, Stewart DS, Merkel CG, et al: Diffuse lipoid pneumonitis successfully treated with prednisone. Am J Med 43:930-934, 1967 Reussi C, Schiavi JE, Altman R, et al: Unusual complications in the course of anticoagulant therapy. Am J Med 46:460-463, 1969 Macon WL, Morton JH, Adams JT: Significant complications of anticoagulant therapy. Surgery 68:571-582, 1970 Steinberg AD: Pulmonary edema following ingestion of hydrochlorthiazide. JAMA 204:825-827, 1968 Bell RJM: Pulmonary infiltration with eosinophils caused by chlorpropamide. Lancet 1: 1249-1250, 1964 Heitzman ER: Lymphadenopathy related to anticonvulsant therapy. Radiology 89:311-312, 1967 Moore MT: Pulmonary changes in hydantoin therapy. JAMA 171:1328-1333, 1959 Livingston S, Whitehouse D, Pauli LL: Study of the effects of diphenylhydantoin sodium on the lungs. N Engl J Med 264:648-651, 1961 Harper LO, Burrell RG, Lapp NL, et al: Allergic alveolitis due to pituitary snuff. Ann Intern Med 73:581-584, 1970 Graham JR: Cardiac and pulmonary fibrosis during methysergide therapy for headache. Am J Med Sc 254:112,1967 Hindle W, Posner E, Sweetnam MT, et al: Pleural effusion and fibrosis during treatment with methysergide. Br Med J 1:605-606, 1970 Byrd RB, Schanzer B: Pulmonary sequelae in procaine amide induced lupus syndrome. Chest 55:170-172, 1969
CHEST, VOL. 63, NO.3, MARCH, 1973