Medications have long been recognized as having the potential to cause pulmonary injury even when given at therapeutic doses. The precise incidence of drug-induced respiratory disease is difficult to ascertain and potentially is confounded by reporting bias for positive events; the signs and symptoms of lung toxicity are shared by many other pulmonary conditions and diseases. Data on adverse events are supplied to national databases such as the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the Japanese Adverse Event Report (JADER), and these databases can be utilized to determine patterns and incidence of events. However, these databases are limited by data input, and concerns inevitably are raised about the completeness and accuracy of direct submissions from providers and healthcare facilities compared with those from drug manufacturers.1,2 As the categories and varieties of therapeutic drugs continue to increase, clinicians will encounter disease from new culprit drugs in addition to well-established drug reactions. A web-based data repository, Pneumotox V2.2 (www.pneumotox.com), is a useful tool for the clinician, as it provides frequent updates based on the emerging literature on drug-induced respiratory toxicities.
When the clinician-scientist explores the literature on drug-induced lung injury, it is critical to recognize that not all reported associations between medications, over-the-counter supplements or illegal drugs, and respiratory disease imply a definitive causal link between a specific drug and the injury pattern described. The literature needs to be cautiously interpreted before concluding that the reported associations are due to the implicated drug rather than a confluence of clinical conditions. This chapter addresses the principles that characterize drug-induced lung disease and examines some of the more common medications and drug classes that are implicated in pulmonary toxicity. Chemotherapeutic agents are discussed in a separate chapter 64.
GENERAL PRINCIPLES OF DRUG-INDUCED LUNG DISEASE
Drug-related pulmonary injury is a rare event. Reactions typically occur in a small minority of individuals exposed to a given agent. The incidence of drug- and radiation-induced interstitial disease was examined over a 12-year period (1997–2008) in a database of approximately 9 million patients from the United Kingdom, and an incidence of 0.8 per 1,000,000 patients per annum for drug-related interstitial disease was reported. Notably, this cohort was assembled before the utilization of many immunomodulatory and biologic therapies, and more recent data suggest a rate of drug-induced interstitial disease as high as 12.4 cases per million per year.3 These data, however, reflect only a portion of the impact of drug-induced respiratory disease, because not only the interstitium is affected; the alveoli, upper and lower airways, pleura, pulmonary vasculature, muscles of respiration, and the central nervous system governing respiratory control are all susceptible to injury from ingested, inhaled, and parenterally administered agents.
In many cases, lung injury appears to be an idiosyncratic event and is not easily predicted by dose, time from drug initiation, duration of exposure, ...