NEW YORK CITY—Patients’ responses to a medication are not all alike. Because identifying the signs of drug complications, as well as susceptible patients, may be essential for limiting potentially deadly damage to the lungs and other organs, a recent workshop provided a primer in such reactions.[1]

“We really have to broaden our horizons … about the different types of adverse pulmonary reactions that can occur from medications,” emphasized Mark S. Dykewicz, MD, Associate Professor of Internal Medicine at St. Louis University School of Medicine. Drug-induced pulmonary complications range from acute bronchospasm and chronic cough to interstitial lung disease, said Dr. Dykewicz.

Aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs), antibiotics, parasympathomimetics, hydrocortisone, and ß-blockers can all trigger immediate bronchospasm. Even ß-blocker eyedrops can yield enough systemic absorption to cause bronchospasm, and “case fatalities have been reported,” Dr. Dykewicz noted.

Up to 20% of patients develop a dry cough after taking angiotensin-converting enzyme (ACE) inhibitors, said Dr. Dykewicz; risk is elevated among blacks, Asians, and women. Because half of affected individuals discontinue taking the medication, their need for an alternative antihypertensive raises the question of whether angiotensin II receptor blockers (ARBs) are similarly problematic. Dr. Dykewicz emphasized, “The vast, vast majority of patients who have problems with ACE-inhibitor cough can get ARBs without a problem.”

Although ACE inhibitors are generally safe in most patients with obstructive airways disease, said Dr. Dykewicz, case reports suggest that in a subpopulation of patients, these agents can increase bronchial reactivity, asthma symptoms, or exacerbations. However, changes in spirometric measurements or asthma symptoms have not been clearly demonstrated in short-term studies.

Citing a controlled, retrospective cohort study,[2] Dr. Dykewicz noted significantly more hyperresponsiveness among ACE-inhibitor recipients: The prevalence of bronchospasm was about 5.5% in those receiving ACE inhibitors but only about 2.3% in a control group. However, among those with a history of bronchospasm, the ACE-inhibitor recipients were no more likely than the controls to experience cough.

The pulmonary infiltrates with eosinophilia (PIE) syndrome is one type of acute infiltrative reaction. Antibiotics (including ß-lactams, nitrofurantoin, sulfonamides, and tetracycline), salicylates, and NSAIDs, as well as antiseizure medications (eg, carbamazepine) and antineoplastics (eg, methotrexate and procarbazine) can produce PIE. This occurs with “a very abrupt onset of cough within about 10 days,” said Dr. Dykewicz. PIE is typically associated with blood eosinophilia and may be accompanied by chest discomfort, headache, rash, or fever.

In patients with PIE syndrome, chest examinations may demonstrate crepitant rales, and chest films show a nodular appearance, sometimes with migratory infiltrates. Pulmonary function tests reveal a restrictive pattern. Tests of lung diffusing capacity for carbon monoxide (DLCO) should be obtained. Said Dr. Dykewicz, “DLCOs will tell the tale, oftentimes”—DLCO is reduced in PIE syndrome. Lung biopsy may reveal “eosinophils, typically in the alveoli and the alveolar walls, and there may be even some perivasculitis present,” he pointed out. “Generally, there is very good resolution of this condition after a couple of weeks” following discontinuation of the problematic drug.

One in 5,000 patients receiving nitrofurantoin develops acute dyspnea, wheezing, cough, fever, chills, and chest pain, with or without eosinophilia; pleural effusion occurs in one third of these cases, said Dr. Dykewicz. Chest films reveal alveolar and/or interstitial patterns of infiltration, greatest at the bases. “It can be confused with infectious pneumonia,” he cautioned: Fever, lowered oxygen tension, and lung infiltrates on chest films may prompt a false diagnosis of community-acquired pneumonia. “There’s very rapid improvement if you stop the drug,” Dr. Dykewicz remarked; immediate re-induction of the syndrome on resumption of the drug suggests an immunologic mechanism.

“You can also develop pulmonary infiltrative reactions without eosinophilia,” Dr. Dykewicz pointed out. Administration of the antiarrhythmic amiodarone is associated with a fairly high incidence (6%) of infiltrates; these cases can be fatal, he stressed. Infiltrative reactions to amiodarone may be accompanied by low-grade fever and nonproductive cough but no eosinophilia; chest films show an interstitial or alveolar process. Computed tomography (CT) can reveal hyperdense regions on the lung in such cases, said Dr. Dykewicz. Additionally, abnormal findings on a gallium scan can distinguish amiodarone-induced pulmonary infiltration from other considerations, such as infection or congestive heart failure. Toxicity generally reverses with drug cessation.

Methotrexate is occasionally employed to reduce corticosteroid use in asthma patients, but, Dr. Dykewicz said, “be aware that it can cause lung problems of its own” within days or after months of use, triggering non-cytotoxic pulmonary reactions with cough, dyspnea, and fever. Chest films reveal diffuse, fine interstitial infiltrate with no tissue eosinophilia, but peripheral eosinophilia and granulomas are possible. Improvement generally occurs within days of discontinuing methotrexate.

“Gold can also cause problems,” said Dr. Dykewicz. Complications of receiving gold usually manifest as exertional dyspnea and arise after months of use.

Bronchiolitis obliterans with organizing pneumonia (BOOP) is a less common finding. Some agents associated with BOOP are amiodarone, codeine, gold, mitomycin-C, bleomycin, cyclophosphamide, methotrexate, penicillamine, and sulfasalazine.

Diagnosis may be tricky, requiring a biopsy: The presence of isolated or patchy air-space opacities on chest films or CT scans “might make you think that there are neoplasms present, or pulmonary infections,” Dr. Dykewicz commented. “It’s important to know that, if you catch it early, [BOOP] responds pretty well to corticosteroids,” he stressed; but, he added, “if you start seeing some fibrosis along with it, patients don’t respond as well.”

Chemotherapy drugs can also be associated with chronic fibrosis, Dr. Dykewicz noted. Potentially fatal lung disease that presents with progressive dyspnea, nonproductive cough, and fever that can mimic opportunistic infection may result from months to years of cytotoxic drug use. The drugs may be “producing reactive oxygen metabolites that are doing the ‘dirty work,’ ” he explained.

A decrease in DLCO may reveal the condition much earlier than would a chest film; therefore, Dr. Dykewicz recommended a full pulmonary function test with DLCO if fibrosis is suspected. Pathologic examination shows abnormalities in type II alveolar lining cells, with hyperchromatic cellular infiltrates, interstitial edema, and fibrosis. Still, “drug cessation and steroids may fail to prevent fatality, because you are dealing with a fibrotic process,” Dr. Dykewicz warned.

Aside from its acute effects, chronic nitrofurantoin administration can induce chronic disease that presents as nonproductive cough and dyspnea without eosinophilia, fever, or pleural effusion. The underlying mechanism may be generation of toxic oxygen radicals. Corticosteroids may be helpful for this disorder.

Contrast media can cause a noncardiac pulmonary edema, noted Dr. Dykewicz. “It’s thought that there’s a complement-induced granulocyte aggregation that’s occurring in the lung capillaries,” he explained. Overdoses of salicylates, methadone, heroin, and propoxyphene are also reported triggers.

—Mimi Zucker, PhD