Drug-Induced Lung Disease

REVIEW

METIN ÖZKAN, MD RAED A. DWEIK, MD MUZAFFAR AHMAD, MD Department of Pulmonary and Critical Department of Pulmonary and Critical Department of Pulmonary and Critical Care Medicine, Cleveland Clinic Care Medicine, Cleveland Clinic Care Medicine, Chairman, Division of Medicine, Cleveland Clinic

Drug-induced lung disease

■ ABSTRACT WARENESS OF drug-induced pulmonary A disease is increasing: a review published Drug-induced lung disease is a major source of iatrogenic in 1972 identified only 19 drugs as having the injury. We review the various drugs known to induce injury potential to cause pulmonary disease1; now at and the various patterns of injury seen. least 150 agents are recognized,2,3 and the list continues to grow (TABLE 1). ■ KEY POINTS Adverse reactions occur in about 5% of patients receiving any drug, and 0.03% of hos- Different drugs can cause similar pulmonary syndromes and pital deaths are believed to be drug-related.2 presentations. Early diagnosis is important, because stopping the drug usually reverses toxicity, whereas The most common presentations are an abnormality on the unrecognized toxicity can be progressive and chest radiograph and a symptom complex. even fatal. Diagnosis requires being alert and vigilant for adverse pulmonary reactions in the appropriate clinical settings. Early diagnosis is very important and requires the physician A carefully obtained history that includes to be vigilant for problems in the appropriate clinical medications (including those sold over-the- settings. counter) is essential to suspecting a drug- induced reaction. The diagnosis is usually one of exclusion. In this update, we review the patterns of response seen in drug-induced lung disease. Stopping the drug is sufficient therapy for most drug We also review selected drugs because of their toxicities, but corticosteroid administration may also be importance in drug-induced lung disease, clas- needed. sic presentations of toxicity, prevalence of use, or because our understanding of them has recently changed.

■ PATTERNS OF RESPONSE

Drug-induced pulmonary diseases can present in a variety of syndromes (TABLE 2), clinical presentations (TABLE 3), and radiographic patterns (TABLE 4). The most common presentations of drug-induced pulmonary disease are an abnormality on a chest radiograph or a symptom complex.

Hypersensitivity reactions Most of the drugs that cause pulmonary side effects can show their effects as hypersensitivity reactions. Respiratory symptoms consist of dyspnea, cough, and fever. Peripheral eosinophilia,

782 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. T ABLE 1 Selected drugs known to adversely affect the lungs

Anticonvulsant, antipsychotic, antidepressant Chemotherapeutic and immunosuppressive Carbamazepine Bleomycin Chlordiazepoxide Busulfan Fluoxetine Chlorambucil Phenothiazines Cyclophosphamide Phenytoin Cyclosporin A Trazodone Etoposide Tricyclics Hormonal agents Bicalutamide Anti-inflammatory Nilutamide Aspirin Tamoxifen Gold Melphalan Methotrexate Mitomycin-C Penicillamine Nitrosoureas Antimetabolic Procarbazine Azathioprine Vinca alkaloids (with mitomycin) Cytarabine Contrast media and intravenous substances Fludarabine Blood Gemcitabine Ethanolamine oleate 6-Mercaptopurine Ethiodized oil Methotrexate Talc Antimicrobial Illicit drugs Amphotericin B Cocaine Ethambutol Heroin Isoniazid Methadone Minocycline Methylphenidate Nitrofurantoin Narcotic and sedative drugs Para-aminosalicylic acid Streptomycin Miscellaneous agents Sulfasalazine Appetite suppressants (dexfenfluramine, fenfluramine, Sulfonamides phentermine Tetracycline Beta mimetics (terbutaline, ritodrine) Bromocriptine Biologic response modifiers Dantrolene Granulocyte-macrophage colony-stimulating factor L-tryptophan Interferon Methysergide Interleukin-2 Mineral oil Tumor necrosis factor Propylthiouracil Cardiovascular Radiation Amiodarone Silicone Angiotensin-converting enzyme inhibitors Timolol (ophthalmic) Anticoagulants Tocolytic agents Beta-blockers Dipyridamole Flecainide Hydralazine Hydrochlorothiazide Protamine Tocainide

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T ABLE 2 adenopathy may be a complication of dilan- tin, cyclosporin, or methotrexate use. Syndromes of drug- Mediastinal lipomatosis may complicate corti- induced pulmonary disease costeroid use.5 An acute pleural effusion in Asthma association with drugs can also been seen as part of a hypersensitivity reaction. Bronchiolitis obliterans organizing pneumonia Hypersensitivity infiltrate Pulmonary vascular disease Interstitial pneumonitis or fibrosis The incidence of pulmonary veno-occlusive Noncardiogenic pulmonary edema disease, characterized by the occlusion of pul- Pleural effusions monary venules with subsequent elevated pul- Pulmonary infiltrates with eosinophilia monary arterial pressures, is increased in patients receiving cytotoxic agents for the Pulmonary vascular disease treatment of malignancy. The diagnosis usually requires an open lung biopsy. Illicit drugs can cause angiitis and hypertension. Alpha- if present, may help indicate the diagnosis. adrenergic nasal sprays have been associated Chest radiographs show localized or bilateral with interstitial fibrosis and obliteration of alveolar infiltrates. pulmonary vessels. Estrogen-containing drugs as well as appetite suppressants have been Noncardiogenic pulmonary edema associated with development of pulmonary The syndrome of noncardiogenic pulmonary hypertension.6 edema manifests as acute respiratory distress occurring over several hours. In most Drug-induced lupus instances this is due to capillary endothelial Drugs may exacerbate underlying lupus, injury, causing increased permeability edema.4 induce lupus in a predisposed patient, or cause Chest roentgenograms show diffuse ill-defined the disease. Patients with drug-induced lupus The lungs are acinar infiltrates and normal heart size. can develop a variety of systemic symptoms, involved in 50% Physical examination demonstrates diffuse including fever, myalgias, rash, arthralgias, crackles, and laboratory examination shows arthritis, and serositis.7 The lungs and pleurae to 75% of cases significant hypoxemia. are involved in 50% to 75% of cases of drug- of drug-induced induced lupus.4 Patterns of response can be Interstitial pneumonitis or fibrosis pleural effusion with or without pleuritic pain, lupus Acute pneumonitis may present in a manner diffuse interstitial pneumonitis, and alveolar similar to noncardiogenic pulmonary edema. infiltrates.4 In the chronic form, manifestations are a Important features seen in drug-induced slowly progressive cough, dyspnea, weight lupus can help differentiate it from sponta- loss, and clubbing. Radiographic findings are neous lupus. The female-to-male ratio is 1:1 in usually reticular infiltrates starting in the sub- drug-induced lupus, but 9:1 in spontaneous pleural region of the lung bases and progress- lupus. Manifestations that are rare in drug- ing to include the entire lung. The prognosis induced lupus include discoid lesions (occur- generally is worse than for drug-induced non- ring in 0% of cases in one series), malar ery- cardiogenic pulmonary edema. thema (2%), renal disease (5%), and central nervous system disease (0%). Complement Pleural and mediastinal disorders and immune complexes are normal in drug- Pleural effusions that resolve spontaneously or induced lupus and elevated in spontaneous with discontinuation of the drug are seen in lupus. In more than 95% of cases of drug- drug-induced systemic lupus erythematosus. induced lupus, antihistone antibodies are pres- Pneumothorax may complicate systemic ent but other autoantibodies are absent, chemotherapy and illicit drug use. including those directed against double- Hemothorax or mediastinal hematoma can be stranded DNA.7 a complication of anticoagulants. Mediastinal It is estimated that more than 90% of

784 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. T ABLE 3 Drugs causing common clinical presentations of pulmonary toxicity Asthma Interstitial pneumonia or fibrosis Pleural effusion Aspirin Amphotericin B Amiodarone Beta-blockers Bleomycin Anticoagulants Cocaine Busulfan Bleomycin Dipyridamole Carbamazepine Bromocriptine Hydrocortisone Chlorambucil Busulfan Interleukin-2 Cocaine Granulocyte-macrophage colony- Methylphenidate Cyclophosphamide stimulating factor (GM-CSF) Nitrofurantoin Diphenylhydantoin Interleukin-2 Protamine Flecainide Methotrexate Sulfasalazine Heroin Methysergide Timolol Melphalan Mitomycin-C Vinca alkaloids (with mitomycin) Methadone Nitrofurantoin Methotrexate Para-aminosalicylic acid Bronchiolitis obliterans organizing Methylphenidate Procarbazine pneumonia Methysergide Radiation Amiodarone Mineral oil Tocolytic agents Bleomycin Nitrofurantoin Cocaine Nitrosoureas Pulmonary infiltrate Cyclophosphamide Procarbazine with eosinophilia Methotrexate Silicone Amiodarone Mitomycin-C Tocainide Amphotericin B Penicillamine Vinca alkaloids (with mitomycin) Bleomycin Radiation Carbamazepine Sulfasalazine Noncardiac pulmonary edema Diphenylhydantoin Tetracycline, minocycline Beta mimetics (terbutaline, ritodrine) Ethambutol Chlordiazepoxide Etoposide Drug-induced systemic Cocaine GM-CSF lupus erythematosus Cytarabine Isoniazid Diltiazem Ethiodized oil Methotrexate Diphenylhydantoin Gemcitabine Minocycline Hydralazine Heroin Mitomycin-C Hydrochlorothiazide Hydrochlorothiazide Nitrofurantoin Isoniazid Methadone Para-aminosalicylic acid Minocycline Mitomycin-C Procarbazine Para-aminosalicylic acid Phenothiazines Radiation Penicillamine Protamine Sulfasalazine Procainamide Sulfasalazine Sulfonamides Propylthiouracil Tocolytic agents Tetracycline Streptomycin Tricyclics Trazodone Sulfonamides Tumor necrosis factor Vinca alkaloids (with mitomycin) Pulmonary vascular disease Hypersensitivity infiltrate Appetite suppressants (dexfenflu- Azathioprine plus 6-mercaptopurine Parenchymal hemorrhage ramine, fenfluramine, phentermine) Busulfan Anticoagulants Busulfan Fluoxetine Azathioprine plus 6-mercaptopurine Cocaine Radiation Cocaine Heroin Mineral oil Methadone Nitrofurantoin Methylphenidate Radiation Nitrosoureas Radiation

CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 785 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. cases of drug-induced lupus are caused by T ABLE 4 diphenylhydantoin, hydralazine, isoniazid, or procainamide. Radiographic patterns of drug-induced lung disease Drug-induced bronchospasm Focal alveolar opacities Evidence of increased airway resistance is seen Amiodarone in normal persons and patients with asympto- Nitrofurantoin matic asthma who use propranolol and other Aminosalicylic acid beta-adrenergic antagonists.8 These agents Penicillin should be avoided in all patients with known Sulfonamides obstructive lung disease whenever possible. Mineral oil aspiration The same findings have been shown to occur Diffuse alveolar opacities in asthmatic patients receiving timolol eye- Pulmonary edema drops for glaucoma. Cocaine Aspirin produces bronchospasm in about Cytosine arabinoside 4% of asthmatic patients,4 and similar symp- Heroin toms are seen with other nonsteroidal anti- Interleukin-2 inflammatory agents. In asthmatic persons Morphine with nasal polyps, the incidence may be as OKT3 high as 75%.9 Aspirin-induced bronchospasm Ritodrine Salicylates generally becomes apparent in the third to Terbutaline fourth decade of life and is more common in Tricyclics women. Interestingly some inhalational prepara- Pulmonary hemorrhage tions used in the treatment of bronchospasm Anticoagulants (eg, albuterol) can induce cough or bron- Cocaine Penicillamine chospasm because of materials other than the Quinidine bronchodilator agent in the preparation. Bronchospasm Diffuse interstitial opacities due to aspirin ■ EFFECTS OF CARDIOVASCULAR DRUGS Methotrexate Nitrofurantoin generally Amiodarone Procarbazine Carmustine becomes Amiodarone is a classic example of a cardio- Bleomycin vascular drug that causes pulmonary toxici- Busulfan apparent in the ty. It is widely used to suppress ventricular Cyclophosphamide 3rd to 4th and supraventricular tachyarrhythmias. Methotrexate Amiodarone can cause different patterns of Mitomycin-C decade of life pulmonary toxicity, including chronic inter- Amiodarone stitial pneumonitis, bronchiolitis obliterans, Gold salts acute respiratory distress syndrome (ARDS), Oxygen and solitary lung mass.10 Furthermore, fol- Tocainide lowing ventilation with high oxygen con- Pulmonary nodules centration, patients receiving amiodarone Amiodarone may develop an ARDS-like syndrome. Bleomycin Suspected mechanisms of amiodarone lung Cyclosporine toxicity include immunologic disorders, Mineral oil aspiration direct toxicity to the lung cells, and effects of free radicals. When interstitial pneumonitis occurs, it is usually in patients receiving more than 400 ductive cough, dyspnea, weight loss, and dif- mg/day. Chronic interstitial pneumonitis is fuse interstitial and patchy alveolar infiltrates characterized by insidious onset of nonpro- on the chest radiograph.

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be relied upon exclusively to make the diag- Amiodarone-induced enhancement nosis. on computed tomography Because amiodarone contains about 37% iodine by weight, computed tomography (CT) of the lung (without contrast) may be helpful in diagnosis. Infiltrates caused by amiodarone toxicity may enhance even though contrast was not given (FIGURE 1).2 This enhancement, however, is not pathognomonic for amiodarone toxicity either. A bronchoscopy with bronchoalveolar lavage may be helpful in excluding infection. Histologically, an accumulation of foamy macrophages in the alveolar spaces, type II cell hyperplasia, and fibrosis are seen in amiodarone toxicity. These changes, however, are also seen in patients receiving amiodarone without toxicity and cannot be used solely to make the diagnosis. FIGURE 1. A computed tomographic scan without Primary treatment is to stop amiodarone. contrast in a patient receiving amiodarone reveals Corticosteroid therapy, beginning with pred- infiltrates in both lung bases (arrows), due to the iodine content in amiodarone. This enhancement, however, is nisone 40 to 60 mg/day and tapering over 2 to 10 not pathognomonic for amiodarone toxicity. 6 months, can be life-saving in severe cases. Angiotensin-converting enzyme (ACE) inhibitors Organizing pneumonia is characterized by In 3% to 20% of patients, ACE inhibitors Cough develops nonproductive cough, pleuritic chest pain, induce a dry, persistent, and often nocturnal in 3% to 20% of fever, dyspnea, and patchy, alveolar opacities cough that may require stopping therapy. The on chest radiographs (TABLE 4). It is seen in cough usually begins several months after patients taking approximately 25% of cases of amiodarone starting the drug but may begin as early as the ACE inhibitors pulmonary toxicity. first dose or as late as 1 year.2 It usually dimin- Diagnosis. Amiodarone toxicity (like ishes significantly within 3 days and disap- most other drug toxicity) is a diagnosis of pears entirely within 10 days of stopping the exclusion. The clinical presentation can be drug. similar to pneumonia, congestive heart failure The pathogenesis of ACE inhibitor- or pulmonary embolism. induced cough is unclear, but kinins and sub- Several tests may be helpful. It is impor- stance P are suspected to play a role. Because tant to emphasize, however, that none of these both kinins and substance P are metabolized tests is specific or pathognomonic for amio- by angiotensin-converting enzyme (FIGURE 2), darone toxicity and cannot be relied on solely their levels are increased by converting to make the diagnosis. These tests are used pri- enzyme inhibition,11 leading to bronchial irri- marily to exclude other causes of the patient’s tation and cough. Another possible explana- presentation rather than to confirm amio- tion for cough is activation of the arachidonic darone toxicity. acid pathway with ACE inhibition. By this A positive gallium scan is seen in almost mechanism, elevated levels of thromboxane all patients with amiodarone pneumonitis and may potentiate bronchoconstriction. In a can help differentiate it from pulmonary study using picotamide,12 which inhibits embolism and congestive heart failure. A pos- thromboxane synthase and antagonizes the itive gallium scan, however, can also reflect thromboxane receptor, cough resolved in pneumonia or other diseases causing infection eight of nine patients who suffered from or inflammation in the lungs, and thus cannot enalapril-induced cough.

790 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. Why do angiotensin-converting enzyme (ACE) inhibitors cause cough? A possible explanation

Angiotensinogen Kinins Desired effect Adverse effect Renin

Remikiren, enalkiren

Angiotensin I

Angiotensin-converting enzyme (ACE) ACE

ACE inhibitors ACE inhibitors

Angiotensin II

Angiotensin-receptor blockers

Binding to angiotensin receptors Inactive metabolites Increased levels of Vasoconstriction kinins, substance P Bronchial irritation, cough

FIGURE 2. ACE inhibitors have the favorable effect of blocking conversion of angiotensin I to angiotensin II (left), but also lead to accumulation of kinins and substance P (right), which may explain the side effects of bronchial irritation and cough associated with this class of medication. Newer agents (angiotensin II receptor blockers, remikiren, enalkiren) in theory would not be associated with cough.

Stopping the drug is usually enough for sitive to aspirin; this usually appears in the treatment. If the patient has a good antihy- third to fourth decade. Thirty minutes to 2 pertensive response to the ACE inhibitor, an hours after aspirin ingestion, symptoms such angiotensin II receptor antagonist, such as as wheezing, facial flushing, angioedema, and losartan, which blocks only angiotensin II gastrointestinal symptoms begin. receptors and has no effect on kinins or other Aspirin inhibits cyclo-oxygenase I, which mediators, can be considered.13 catalyzes the formation of prostaglandins and thromboxane from arachidonic acid. By ■ EFFECTS OF ANTI-INFLAMMATORY inhibiting this pathway, an alternate pathway AGENTS becomes more active, in which 5-lipo-oxygenase enzyme converts arachidonic acid to the Aspirin potent inflammatory and bronchoconstrictor Aspirin triad is a syndrome characterized by mediators: leukotrienes, LTC4, LTD4, and asthma, nasal polyposis, and drug sensitivity. LTE4 (FIGURE 3). The frequency of the syndrome in asthmatic Traditionally, therapy included avoidance patients is approximately 4%. of aspirin and nonsteroidal anti-inflammatory The first manifestation is vasomotor drugs, and in rare cases, desensitization. With rhinitis with a watery discharge. It is followed the recent availability of leukotriene modi- by the appearance of nasal polyps, and by fiers, both inhibitors of leukotriene synthesis midlife, most patients demonstrate an asth- (such as zileuton) and LTD4 receptor antago- matic response.4 Patients with aspirin- nists (such as zafirlukast and montelukast) induced asthma are usually not previously sen- have become the drugs of choice for treating

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How aspirin and nonsteroidal anti-inflammatory drugs may worsen asthma

Phospholipids

Phospholipase

Phospholipase inhibitors Corticosteroids

Arachidonic acid

Cyclo-oxygenase Lipo-oxygenase

Aspirin Lipo-oxygenase inhibitors Nonsteroidal anti-inflammatory drugs (eg, zileuton)

Thromboxane Prostaglandins Leukotrienes Prostacyclin Receptor-level antagonists (eg, zafirlukast, montelukast)

LTB4 LTC4, LTD4, LTE4 Methotrexate Inflammation Inflammation Bronchospasm complications: Congestion infections, Mucus plugging pneumonitis, FIGURE 3. Aspirin and nonsteroidal anti-inflammatory drugs inhibit cyclo-oxygenase fibrosis, activity, diverting arachidonic acid to the alternate lipo-oxygenase pathway, which converts arachidonic acid to potent bronchoconstrictor mediators: leukotrienes, asthma LTC4, LTD4, and LTE4. Lipo-oxygenase inhibitors and receptor-level antagonists may counteract the effect.

aspirin-induced asthma. This, in a way, repre- methotrexate include opportunistic infec- sents the first specific therapy available for this tions (eg, pneumonid due to Pneumocystis type of asthma. carinii, Aspergillus, Histoplasma, Nocardia, Legionella, or cytomegalovirus), acute inter- Methotrexate stitial pneumonitis, interstitial fibrosis, and Methotrexate is now commonly used in the asthma. In methotrexate pneumonitis, onset treatment of rheumatoid arthritis and other of dyspnea, fever, and cough is usually sub- connective tissue disorders. The anti-inflam- acute. matory dose of methotrexate is much lower Laboratory and radiologic findings than the traditional antineoplastic dose and is include hypoxemia, a restrictive pattern on associated with different side effects. pulmonary function tests, and diffuse bilater- Pulmonary complications seen in al interstitial infiltrates. High-resolution patients who use anti-inflammatory doses of computed tomographic scans of the chest

792 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. may demonstrate ground glass infiltrates. Supplemental oxygen use should be mini- Bronchoalveolar lavage demonstrates lym- mized. phocytosis with a variable CD4/CD8 ratio. Transbronchial biopsies may show weakly Mitomycin-C formed granulomas. Mitomycin-C is an antineoplastic alkylating The main challenge to the diagnosis is to agent. Incidence of pulmonary toxicity is exclude infection. This can be done on clin- about 5%. Pulmonary disorders that have ical grounds (absence of fever and leukocyto- been described with mitomycin-C include sis, and sputum culture findings), but usually bronchospasm, acute pneumonitis, hemolytic- requires bronchoalveolar lavage. uremic-like syndrome, acute lung injury, Corticosteroid therapy and withdrawal of chronic interstitial pneumonitis, and pleural methotrexate usually halts pulmonary compli- disease. cations, and the prognosis is usually good.3,4 Pretreatment with corticosteroids may lower the incidence of lung toxicity but does ■ CHEMOTHERAPEUTIC not eliminate the development of lung AND IMMUNOSUPPRESSIVE DRUGS injury.13

Bleomycin Busulfan Bleomycin is deposited in the skin and lungs; Busulfan is an alkylating agent used in myelo- therefore, the most serious side effects are seen proliferative disorders. Symptomatic pul- in the skin (ulceration) and the lungs (inter- monary injury is estimated to occur in fewer stitial fibrosis).4 These two organs are rela- than 5% of patients. tively deficient in the enzyme that inactivates Patients present with cough and progres- bleomycin. Once within its target cells, the sive dyspnea on exertion. Fever and weight drug has the ability to cleave DNA, possibly loss may also occur. The interval between ini- by generating oxygen radicals. This could be tiation of therapy and onset of pulmonary the reason why high-concentration oxygen symptoms may be more than 4 years.14 The administration and radiation therapy augment chest radiograph usually shows a bilateral Bleomycin the toxicity of bleomycin.2 Life-threatening reticular or reticulonodular pattern. toxicity is pneumonitis, which can progress to interstitial pulmonary fibrosis in up to 10% of Cyclophosphamide greater with patients, is the major limitation of bleomycin The incidence of cyclophosphamide-induced higher doses, therapy. pulmonary toxicity is generally less than 1%. Clinical variables that may increase the Patients complain of nonproductive cough, higher FIO2, risk of developing bleomycin lung toxicity dyspnea, fever, and fatigue. Bilateral reticular radiation, other include higher cumulative doses (> 500 or nodular diffuse opacities are seen on the mg/m2), high fractions of inspired oxygen, chest x-ray. Histopathologic findings are non- cytotoxic drugs radiation therapy, and use of other cytotoxic specific. drugs. Symptoms include fever, cough, dyspnea on exertion, and substernal and pleuritic Nitrosourea drugs pain. Nitrosourea drugs include carmustine Radiographic abnormalities usually con- (BCNU), lomustine (CCNU), and semus- sist of bilateral bibasilar, reticular, reticulo- tine (methyl CCNU). Carmustine is the most nodular, or fine nodular opacities, often show- widely used and is associated with high risk of ing a peripheral distribution.2 pulmonary toxicity. Up to 25% of patients The vital capacity and diffusing capacity who receive carmustine develop pulmonary of the lungs for carbon monoxide have been fibrosis within 36 months (early-onset pul- used to monitor patients receiving the drug. monary fibrosis). Lung fibrosis is especially There are no large studies demonstrating the likely with high doses (> 1,500 mg/m2). efficacy of therapy for bleomycin-induced Carmustine may also cause a late-presenting lung injury in humans, but cessation of the form of lung fibrosis (between 8 and 20 years drug and corticosteroids are usually used. after carmustine treatment).15

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Others cillin, and cephalosporins have been associat- Procarbazine causes acute interstitial lung ed with an eosinophilic lung reaction similar to disease with peripheral and pulmonary that seen with sulfasalazine and tetracyclines. eosinophilia and pleural effusions. Griseofulvin, isoniazid, aminosalicylic Melphalan-induced lung toxicity is seen acid, penicillin, streptomycin, sulfonamides, in fewer than 5% of patients receiving mel- and tetracycline are also capable of producing phalan. Interstitial pneumonitis and fibrosis a drug-induced lupus syndrome.19 and pleural effusion are the usual manifestations. ■ APPETITE SUPPRESSANTS AND Paclitaxel is a relatively new antineoplas- PULMONARY HYPERTENSION tic drug which may cause hypersensitivity reactions, characterized by dyspnea, bron- Several reports in recent years suggested an chospasm, and pneumonitis.16 increased risk of pulmonary hypertension with appetite suppressant medications for treat- ■ ANTIMICROBIAL DRUGS ment of obesity.20,21 The association of these drugs with both primary and secondary pul- Nitrofurantoin is the most commonly monary hypertension increases with increased reported antimicrobial drug causing pul- duration of anorexigenic use, especially fenflu- monary toxicity. There are two distinct pre- ramine and primary pulmonary hyperten- sentations: acute, developing hours to days sion.6,21 after initiation of treatment; and chronic and The exact pathogenic events are not insidious, becoming manifest after weeks to known. However, data from patients showed years of continuous therapy. an increase in plasma 5-hydroxytryptamine The acute form is a hypersensitivity reac- (5-HT, serotonin) levels,22 and an increased tion. The most frequently reported symptoms release of 5-HT from platelets.20,22 It appears are fever, dyspnea, irritating cough, and rash. that these agents release 5-HT from storage Chest pain and cyanosis may also occur. sites or inhibit reuptake of 5-HT, or both.2 It Nitrofurantoin Radiographic manifestation consists of a dif- has been shown that 5-HT causes pulmonary toxicity fuse reticular pattern with some basilar pre- vasoconstriction and produces both hyper- dominance. Eosinophilia is the most com- plasia and hypertrophy of isolated cultured can be acute monly reported laboratory finding in the acute pulmonary artery smooth muscle cells.23 or chronic form.17,18 Thus, appetite suppressants which affect the The chronic form represents direct tissue release or uptake of 5-HT may be trigger fac- damage from oxidants. Symptoms are dyspnea, tors that lead to pulmonary hypertension. dry cough, and fatigue. Fever is uncommon in Another possible mechanism is through the chronic form. High-resolution computed nitric oxide.24 tomography may demonstrate a predominant- ly subpleural or peribronchovascular distribu- ■ MISCELLANEOUS DRUGS tion of fibrosis. Sulfasalazine, used in the treatment of Antidepressant and antipsychotic agents inflammatory bowel disease, has been reported and hydrochlorothiazide have been associated to cause interstitial pneumonitis, fibrosis, and with permeability (noncardiogenic) pul- bronchiolitis obliterans organizing pneumo- monary edema.2 nia. The clinical presentation consists of dry Ergotamine and bromocriptine have been cough, progressive dyspnea, and fever, often reported to cause pulmonary fibrosis and associated with skin rash and blood pleural disease.2 eosinophilia 1 to 6 months after initiation of The tocolytic beta-mimetic agents terbu- treatment.4 taline, ritodrine, and isoxsuprine have been Tetracycline and minocycline have been implicated in the development of permeabili- reported to cause lung disease resembling sim- ty pulmonary edema. The incidence of this ple pulmonary eosinophilia.2 Sulfonamides, syndrome is higher in women with twin gesta- para-aminosalicylic acid, ethambutol, ampi- tions. Treatment in almost all cases is discon-

794 CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME 68 • NUMBER 9 SEPTEMBER 2001 Downloaded from www.ccjm.org on September 26, 2021. For personal use only. All other uses require permission. tinuation of tocolytic therapy, diuresis, and actually trigger Churg-Strauss reactions or administration of oxygen.25 whether they unmask a preexisting infiltrative Zafirlukast and related leukotriene eosinophilic disorder as the glucocorticoid antagonists have been associated with certain therapy is withdrawn. manifestations of the Churg-Strauss syndrome Pentamidine, which is the treatment of P in the form of pulmonary infiltrates, car- carinii pneumonia, may cause various pul- diomyopathy, and eosinophilia.26 It is not monary complications including cough, bron- clear, however, whether these medications chospasm, and pneumothorax.27,28

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