Drug-Induced Pulmonary Toxicity 

More than 380 medications are known to cause drug-induced respiratory diseases. The number of drugs that cause lung disease will undoubtedly continue to increase as new agents are developed. Because the medications that cause drug-induced respiratory diseases are used by a variety of health care providers, including generalists, specialists, and subspecialists, virtually no area of medicine is free from these adverse reactions. To minimize the potential morbidity and mortality from drug-induced respiratory diseases, all health care providers should be familiar with the possible adverse effects of the medications they prescribe.

Recognition of drug-induced lung disease, however, is difficult because the clinical, radiological, and histological findings are nonspecific. Because no diagnostic studies are available to confirm the presence of a drug-induced lung reaction, health care providers can make a correct diagnosis only if they are aware of the drugs that have been identified to cause pulmonary reactions and their specific manifestations. A list of drugs that cause pulmonary toxicity is available on the continually updated Web site, PNEUMOTOX online .

A Medscape CME course on drug reactions that may be of interest is Drug Insight: Gastrointestinal and Hepatic Adverse Effects of Molecular-Targeted Agents in Cancer Therapy

Medications can elicit a wide variety of thoracic tissue affects and responses. The adverse reactions can involve the pulmonary parenchyma, the pleura, the airways, the pulmonary vascular system, and the mediastinum. These responses include noncardiac pulmonary edema (NCPE), hypersensitivity pneumonitis, bronchiolitis obliterans-organizing pneumonia (BOOP), pulmonary hypertension, interstitial pneumonitis, bronchospasm, pleural effusions, mediastinal lymphadenopathy, diffuse alveolar damage (DAD), eosinophilic pneumonia, pulmonary hemorrhage, and granulomatous pneumonitis. These reactions can manifest acutely, subacutely, or chronically. Very little is known about the metabolism of drugs by the lungs.

Mechanisms of pulmonary injury

Pulmonary toxicity secondary to drugs may be due to a variety of mechanisms, which are as follows:

Oxidant injury

Oxidant-mediated injury plays a significant role in several of the drug-induced pulmonary diseases. Oxidant molecules (eg, oxygen, hydrogen peroxide, hypochlorous acid) that are formed within phagocytic cells such as monocytes, macrophages, and neutrophils may participate in redox reactions resulting in fatty-acid oxidation that lead to membrane instability and perhaps autologous cytotoxicity.

Normally, antioxidant defense mechanisms (ie, superoxide dismutase, glutathione peroxidase, alpha tocopherol) provide the necessary balance to offset the oxidant effects. The classic examples of drug-mediated oxidant injury are chronic reactions to nitrofurantoin and, possibly, many of the chemotherapeutic drug-induced pulmonary injuries.

Nitrofurantoin may produce pulmonary fibrosis by accelerating the generation of oxygen radicals within lung cells, overwhelming the normal antioxidant protective mechanisms; this, in turn, incites an inflammatory and fibrotic reaction.

Similarly, when antineoplastic drugs are administered, a disturbance of oxidant/antioxidant system homeostasis may occur, resulting in pulmonary injury.

Pulmonary vascular damage

Drug-induced pulmonary vascular disease manifests clinically as acute pulmonary edema, diffuse interstitial lung disease, pulmonary vascular occlusion, and pulmonary hypertension or hemorrhage. The proposed mechanisms of lung vascular damage are as follows:

• Increased microvascular hydrostatic pressure
• Increased permeability of the vascular endothelium
• Vascular occlusion by direct activation of inflammatory and immune mechanisms or indirectly by stimulating intravascular coagulation (pulmonary thromboembolism)
• Impaired homeostasis

Deposition of phospholipids within cells

Similar to other amphiphilic compounds, amiodarone can cause an accumulation of phospholipids within lysosomes in the lung cells and other tissues, owing to the inhibition of phospholipase A. Amiodarone has been demonstrated to produce phospholipidosis in alveolar macrophages and in type 2 cells. Ultrastructural studies show myelinoid inclusion bodies in the affected tissue. The process is reversible with discontinuation of the drug.

Immune system–mediated injury

Drugs can act as potential antigens, or haptens, inducing an immune cascade that can lead to immune-mediated lung toxicity. Deposition of antigen-antibody complexes may trigger an inflammatory response, leading to pulmonary edema and intestinal lung disease. Drug-induced systemic lupus erythematosus is an example of immune-mediated lung damage.

Central nervous system depression

The medulla is believed to activate sympathetic components of the autonomic nervous system. An acute neurological crisis, accompanied by a marked increase in intracranial pressure, may stimulate the hypothalamus and the vasomotor centers of the medulla. This, in turn, initiates a massive autonomic discharge, leading to neurogenic pulmonary edema. Acute NCPE can occur after administration of a number of drugs; some examples are naloxone, heroin, interleukin 2, all-trans -retinoic acid, contrast media, intrathecal methotrexate (MTX), and cytarabine.

Direct toxic effect

Chemotherapeutic drugs can cause a direct toxic reaction. The acute pulmonary toxicity of bleomycin has been attributed to DNA strand scission with resulting chromosomal injury. Animal studies confirm that more chronic bleomycin injury occurs predominantly in the lungs, which have very low levels of bleomycin hydrolase activity. Type 1 epithelial cells are more vulnerable to bleomycin toxicity. This direct cellular damage can lead to bleomycin-induced pulmonary fibrosis (also called fibrosing alveolitis), which usually develops subacutely from 1-6 months after bleomycin treatment but may occur acutely or more than 6 months following the administration of bleomycin.

Risk factors

The likelihood of developing adverse pulmonary effects secondary to drugs remains largely unpredictable and idiosyncratic. A limiting dose has only been identified for a few drugs. Only for a limited number of drugs (ie, amiodarone, bleomycin) is monitoring of patients who receive the drug advisable, but even this is debatable. Some of the known risk factors are as follows:

• Age: Advanced age has been shown to be a risk factor for the development of drug-induced pulmonary disease. Bleomycin can cause significant lung toxicity in patients older than 70 years.
• Cumulative dose: Cytotoxic agents generally exhibit increasing toxicity with increasing dose. This is believed to be a result of drug accumulation in the lungs themselves. The rate of pulmonary toxicity occurring secondary to high-dose (>1500 mg/m²) bis -chloroethylnitrosourea (BCNU) therapy varies from 20-50%.
• Oxygen therapy: Exposure to high concentrations of oxygen may contribute to or aggravate acute respiratory distress syndrome. A high fraction of inspired oxygen generates free oxidant radicals, which can damage endothelial and type 1 epithelial cells. Importantly, be aware of possible drug synergisms, such as a combination of a high fraction of oxygen with bleomycin or amiodarone, which can cause adult respiratory distress syndrome (ARDS).
• Combination therapy: The role of drugs taken concomitantly may be important. Hazardous associations have been reported with the coadministration of cisplatin and bleomycin, which can increase the risk of bleomycin-induced interstitial lung disease. The combination of vinblastine and mitomycin increases the risk of asthma.
• Radiation: It can result in the production of oxidant radicals that lead to pulmonary damage. Radiation therapy in combination with chemotherapy may be synergistic.^[1]
• Occupational factors: Asbestos exposure may potentiate the noxious respiratory effects of ergot drugs and bleomycin.^{[2, 3]}
• Underlying lung disease: In general, patients with preexisting lung disease are at an increased risk for drug toxicity. For example, rheumatoid pneumonitis may increase the relative risk of developing respiratory disease from disease-modifying drugs.

Frequency

United States

Estimating the exact frequency of drug-induced lung diseases is difficult because of the lack of recognition by clinicians, nonspecific diagnostic test results, and because this is a diagnosis of exclusion.

More than 2 million cases of adverse drug reactions occur annually in the United States, including 100,000 deaths. In the United States, an estimated 0.3% of hospital deaths are drug related.^[4] As many as 10% of patients who receive chemotherapeutic agents develop an adverse drug reaction in their lungs.^[5] These figures, however, probably underestimate the true frequency of the problem.

International

Exact frequency of drug-induced pulmonary toxicity is unknown. Several studies suggest that drug-induced pulmonary toxicity is underdiagnosed worldwide.

Mortality/Morbidity

Failure to recognize a drug-mediated lung disease can lead to significant morbidity and mortality. The following are some examples of drug-associated mortality:

• Death attributable to amiodarone pneumonitis occurs in 10% of cases.
• The overall rate of bleomycin pulmonary toxicity is 10%; cases are fatal in 1-2%.
• Cyclophosphamide-induced pulmonary fibrosis has a mortality rate approaching 50%.
• Approximately 7% of patients with MTX-induced hypersensitivity reactions develop chronic fibrosis and 8% die of progressive respiratory failure.
• Cytosine arabinoside, an antimetabolite used to treat acute leukemia, causes NCPE in 13-20% of patients. The mortality rate varies from 2-50%.
• The incidence of symptomatic busulfan-induced pulmonary fibrosis is approximately 4-5%, with mortality rates ranging from 50-80%.
• BCNU, or carmustine, causes pulmonary fibrosis with a mortality rate of nearly 90%.

Race

Bortezomib is a proteosome inhibitor with good clinical activity in persons with multiple myeloma. It can lead to severe pneumonitis in African American patients.^[6] Additionally, some diseases are more common in certain ethnic groups. For example, sarcoidosis is more common in African American persons. The incidence of drug-induced pulmonary toxicity is high in African American patients taking medications to treat sarcoidosis (ie, MTX toxicity in sarcoid patients).

Sex

The person’s sex alone is not an independent risk factor for the development of drug-induced lung disease. However, certain diseases are more common in females, and they will have more adverse effects compared with males. Similarly, amiodarone lung toxicity is more common in males, but this may be related to the fact that amiodarone is used more often in males, rather than a sex-specific predilection.

Age

In general, both extremes of age (ie, childhood and old age) are associated with an increased risk of drug toxicity. In the case of bleomycin, advanced age is one of the major factors responsible for the development of lung fibrosis.

DAD is the most common manifestation of cyclophosphamide-induced lung disease. Toxicity occurs from 2 weeks to 13 years (mean, 3.5 y) after cyclophosphamide administration. Furthermore, a period of months to perhaps years, as is noted with busulfan use, may elapse before the untoward drug reaction is evident.