AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Background

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

Pathophysiology

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.

CLINICAL

Section 3 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

History

Drug-induced lung disease is usually considered a diagnosis of exclusion (eg, after excluding infectious and other causes). Discontinuance of the offending agent is often followed by spontaneous improvement, whereas failure to appreciate the causal relationship between the drug and the pulmonary disease can lead to irreversible lung injury.

Importantly, drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic, or histologic findings. Unfortunately, certain aspects of drug-induced disease can hinder the recognition of this cause-and-effect relationship. Although many drugs can cause diffuse infiltrative lung disease, very few of the patients who receive such drugs experience this disease. In the case of cytotoxic drug-induced disease, the onset of respiratory symptoms can occur many weeks after the last exposure to the offending agent. Finally, the drugs that cause diffuse infiltrative lung disease are often prescribed for conditions that are themselves associated with an increased risk for the disease.

Thus, clinicians evaluating patients with possible drug-induced pulmonary symptoms must obtain a thorough drug exposure history, maintain a high index of suspicion, and use a systematic diagnostic approach to make the correct and firm diagnosis. Irey⁷  defined the following set of criteria for the diagnosis of drug reactions:

• Correct identification of the drug, its dose, and its duration of administration
• Exclusion of other primary or secondary lung diseases
• Temporal eligibility - Appropriate latent period (exposure to toxicity)
• Recurrence with rechallenge (a practice not commonly performed)
• Singularity of drug (ie, other drugs the patient is taking)
• Remission of symptoms with removal of the drug
• Characteristic pattern of reaction to a specific drug (perhaps previous documentation)
• Quantification of drug levels that confirm abnormal levels (especially for overdoses)
• Degree of certainty of drug reaction (ie, causative, probable, or possible)

Physical

The physical findings of drug-induced lung disease are nonspecific. The patient may have crackles in the case of NCPE, wheezes in the case of bronchospasm, and decreased breath sounds in pleural effusion. Furthermore, bibasilar Velcro crackles may be audible in cases of drug-mediated interstitial lung disease.

Causes

The major clinical syndromes associated with drug-induced lungs disease are discussed below.
 
NCPE/capillary leak syndrome 

A variety of drugs can cause NCPE. It is a less common pattern of drug-induced involvement than pneumonitis and fibrosis. Drugs can cause pulmonary edema by 2 mechanisms. First, some drugs cause injury to the capillary endothelium, leading to leakage of fluid and protein into the interstitium of the lungs. Second, certain drugs depress the central nervous system, resulting in neurogenic pulmonary edema.

The clinical features of acute pulmonary edema (with no evidence for left ventricular dysfunction or overload) manifest as an acute onset of dyspnea with tachypnea, tachycardia, hypoxemia, diffuse crackles upon physical examination, and fluffy infiltrates on the chest radiograph.

Drugs that cause NCPE include heroin, interleukin 2, MTX, cocaine, tocolytic therapy, hydrochlorothiazide, cyclophosphamide, and iodine radiographic contrast agents.⁸

Hypersensitivity reaction

Drug hypersensitivity results from interactions between a pharmacologic agent and the human immune system. These reactions are commonly associated with nitrofurantoin, MTX, beta-blockers, and procarbazine. Drug-mediated hypersensitivity reactions manifest as an acute syndrome consisting of dyspnea, fever, and nonproductive cough. Peripheral eosinophilia may be present, and the chest radiograph shows localized or bilateral alveolar infiltrates.

Bronchiolitis obliterans-organizing pneumonia

Pulmonary vascular disease

Drugs can affect the pulmonary vascular circulation by causing venous thromboembolism, pulmonary hypertension, vasculitis, or pulmonary veno-occlusive disease.

Pulmonary veno-occlusive disease is characterized by chronic congestive changes, mild-to-moderate arterial hypertensive changes, and obstruction of small veins. Oral contraceptives, bleomycin, and carmustine (BCNU) have been reported to cause this rare disorder.

Oral contraceptives⁹ also cause  a 4- to 7-fold increased risk of venous thromboembolism.¹⁰ The mechanism responsible for this effect is not known, but estrogens are well known to increase platelet adhesiveness and decrease venous tone and can cause a procoagulant effect. Other implicated drugs include phenytoin, procainamide, and retinoic acid.

Appetite suppressants (eg, amphetamines, fenfluramine) are associated with an increased risk of pulmonary hypertension. Clinicians should remain vigilant because most over-the-counter appetite suppressants contain fenfluramine and dexfenfluramine. Prescription medications such as aminorex, beta-blockers, and mitomycin C have been reported to cause pulmonary hypertension.

Pulmonary vasculitis is caused by several drugs, including nitrofurantoin, sulfonamides, penicillins, phenytoin, and propylthiouracil. This disorder is likely a form of hypersensitivity pneumonitis.

Drug-induced pulmonary hemorrhage is a rare drug-related complication. Patients usually present with hemoptysis, dyspnea, and hypoxemia. Diffuse alveolar hemorrhage is characterized by bilateral infiltrates in the context of anemia of recent onset and hypoxemia. Several anticoagulants and cytosine arabinoside can produce diffuse alveolar hemorrhage.¹¹ Penicillamine,  amiodarone, cocaine, hydralazine, mitomycin C, nitrofurantoin, abciximab, MTX, carbamazepine, and moxalactam disodium are recognized as inciting agents. Treatment is withdrawal of the offending drug and control of the bleeding. The diagnosis is confirmed by bronchoalveolar lavage (BAL), which shows increased blood staining in sequential aliquots.

Interstitial pneumonitis
 
Interstitial pneumonitis is inflammation of the lung interstitium, such as alveolar septa. It is the most common manifestation of drug-induced lung disease. A wide array of drugs can cause interstitial pneumonitis. Some of the agents implicated are azathioprine, bleomycin, chlorambucil, MTX, phenytoin, statins, amiodarone, and sulfasalazine.¹²

Time to onset is from a few days to years into treatment and is unpredictable. The onset of the disease may be progressive over a few weeks, with isolated fever followed by the insidious development of respiratory symptoms, or the onset may be abrupt, especially in patients with MTX lung. Signs and symptoms include increasing dyspnea, dry cough, high fevers, and, sometimes, a rash. The spectrum of severity ranges from mild symptoms and ill-defined pulmonary opacities to extensive consolidation and respiratory failure.
 
Bronchospasm

Aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) can induce bronchospasm. In rare cases, this reaction can lead to death in aspirin-sensitive persons with asthma. Of adult persons with asthma, 8-20% experience bronchospasm following the ingestion of aspirin and other NSAIDs. Asthma and aspirin sensitivity may develop in the months following initial exposure to aspirin or NSAIDs. The acute asthmatic reaction occurs within 20 minutes to 3 hours after ingestion of aspirin or an NSAID.

Patients initially present with an acute episode of vague malaise, sneezing, nasal obstruction, rhinorrhea, and, often, a productive cough. These symptoms resolve in a few weeks but may be followed by persistent rhinitis and the development of nasal polyps. Spirometry typically shows a variable obstructive ventilatory defect.

Bronchospasm has been reported with the use of inhaled pentamidine, amphotericin B, amiodarone, angiotensin-converting enzyme (ACE) inhibitors, dipyridamole, nitrofurantoin, beta-blockers, and penicillamine.

Pleural involvement

Pleural effusions can develop in patients undergoing treatment with MTX, nitrofurantoin, amiodarone, procarbazine, carmustine, and cyclophosphamide. Pleural effusions can also occur in drug-induced lupus. Medications that cause pleural effusions in this setting include hydralazine, procainamide, phenytoin, nitrofurantoin, and ACE inhibitors. Positive serum testing for antinuclear and histone antibodies aids in the diagnosis of this disorder.

Bilateral pleural thickening is a distinctive form of late cyclophosphamide toxicity. Pneumothorax can complicate late stages of drug-induced pulmonary changes and has been reported in association with bleomycin, carmustine, and retinoic acid.

Mediastinal involvement
 
Phenytoin, bleomycin, and carbamazepine can induce enlargement of hilar and mediastinal lymph nodes. In addition, a pseudosarcoidosis syndrome can develop with interferon alfa and beta.

Mediastinal lipomatosis is the accumulation of excess unencapsulated fat within the mediastinum. It may be seen in patients with Cushing disease or those treated with steroid therapy. The usual appearance on the chest radiograph is a smooth widening of the anterior and superior mediastinum without any deformity of the trachea. The fat pads in the costophrenic angles are also often enlarged. The diagnosis is made based on chest CT scanning findings. The treatment is cessation of steroid therapy.

Selected important cytotoxic, cardiovascular, anti-inflammatory, antimicrobial, illicit, and miscellaneous drugs that cause pulmonary toxicity are discussed below.

Cytotoxic drugs

Symptoms may develop as soon as 1 month after treatment or up to more than 10 years after treatment.²⁵ Patients presenting with BCNU-induced pulmonary toxicity typically have nonproductive cough and dyspnea associated with reticular nodular interstitial infiltrates on their chest radiographs.²⁶ PFT results demonstrate reduced forced vital capacity (FVC), total lung capacity (TLC), and DLCO values. The reduced DLCO value can occur in patients with normal chest radiographs.

• Major criteria
• • Hypersensitivity pneumonitis based on histopathology, without evidence of pathogenic organisms
  • Radiologic evidence of pulmonary interstitial or alveolar infiltrates
  • Blood cultures (if febrile) and initial sputum cultures (if sputum is produced) that are negative for pathogenic organisms
• Minor criteria  
• • Nonproductive cough
  • Shortness of breath for less than 8 weeks
  • Oxygen saturation less than or equal 90% on room air at the time of initial evaluation
  • DLCO less than or equal to 70% of predicted for age
  • Leukocyte count less than or equal 15,000 cells/µL

Cardiovascular drugs

Amiodarone

Bronchoscopy with BAL and biopsy helps exclude infection and typically reveals the presence of foamy macrophages with lamellar inclusions (visualized by electron microscopy). These changes within macrophages are indicative of exposure to amiodarone but do not prove that the drug is the cause of the pulmonary process. Similar changes are seen in asymptomatic persons who are receiving the drug.

Amiodarone pulmonary toxicity is a diagnosis of exclusion. Increased lung attenuation on CT scans, increased gallium uptake, and abnormal PFT results are helpful in the diagnosis but are nonspecific. The combination of high-attenuation abnormalities within the lungs, liver, or spleen is characteristic of amiodarone toxicity. A positive gallium scan result is seen in almost all patients with amiodarone pneumonitis and can help differentiate it from pulmonary embolism and congestive heart failure.

Withdrawal of the drug is the cornerstone of treatment for amiodarone-induced lung disease. Glucocorticoids seem to be useful in more severe or persistent cases. Because of its long elimination half-life (approximately 45 d), pulmonary toxicity may initially progress despite drug discontinuation and may recur upon steroid withdrawal. Radiographic resolution generally occurs over 2 months.

Patients taking amiodarone can develop postoperative ARDS, which begins 18-72 hours after surgery.³⁷ A high fraction of inspired oxygen given during the operation and the postoperative period has been postulated to contribute to this complication.^{38, 39}

ACE inhibitors

Naloxone
 
Naloxone is primarily used to reverse respiratory depression induced by heroin. Several case reports describe acute NCPE related to naloxone, although the mechanism remains unknown.

Heroin 

Heroin can cause acute NCPE, which can occur with the first intravenous use of the drug. The exact mechanism of heroin-induced NCPE is unknown, but a postulated mechanism is the direct toxic effect of heroin on the alveolar capillary membrane, which leads to increased permeability, and effects on the central nervous system. This, in turn, leads to a hypoxic effect on the alveolar capillary membrane, resulting in increased capillary permeability.

Other complications of heroin use are septic emboli from infected thrombophlebitis or endocarditis and aspiration pneumonia. In persons with long-term heroin abuse, bronchiectasis and narcotizing bronchitis can be observed because of repeated aspiration pneumonia. Treatment is supportive. Naloxone can be used to reverse respiratory depression.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Other Problems to Be Considered

Diffuse lung diseases
Respiratory failure secondary to hypoxia
Congestive heart failure
Occupational lung diseases (see Asbestosis, Berylliosis, Chemical Worker's Lung, Coal Worker's Pneumoconiosis, Farmer's Lung, Silicosis, Silo Filler's Disease, and Tobacco Worker's Lung)

WORKUP

Section 5 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Lab Studies

The diagnosis of drug-mediated pulmonary toxicity is usually made based on clinical findings. In general, laboratory analyses do not help in establishing the diagnosis.

The CBC count may show increased eosinophils in cases of drug-induced pulmonary eosinophilia. However, the absence of peripheral eosinophilia does not exclude a diagnosis of drug-induced eosinophilic pneumonia.

Patients with drug-induced lupus can test positive for antinuclear antibody and positive for antihistone antibody. Anti–double-stranded DNA test results are negative and complement values are normal.

Imaging Studies

The clinical and radiological manifestations of pulmonary drug toxicity generally reflect the underlying histopathologic processes. High-resolution CT scanning is more sensitive than chest radiography for defining the radiographic abnormalities. Similar to histopathology, the radiologic patterns can be divided into categories, as described below.
 
Diffuse alveolar damage
 
Chest radiographs show bilateral heterogeneous or homogeneous parenchymal consolidation, usually most marked in the dependent lung regions. Fibrosis typically develops within 1 week but, initially, may not be evident on chest radiographs.

High-resolution CT scanning in early DAD typically shows scattered or diffuse areas of ground-glass opacity and intralobular septal thickening; Kerley lines are typically absent. 
 
Interstitial pneumonitis
 
Both usual interstitial pneumonia and NSIP have been associated with drug injury. The clinical radiographic manifestations are often identical to those of idiopathic pulmonary fibrosis. Radiographic studies indicate bilateral, usually symmetrical, interstitial or alveolar opacities. The infiltrates may localize in the lung bases or midlung zones or may be diffuse. The radiographic density can be discrete haze, ground-glass, or dense bilateral consolidation with air bronchograms and volume loss.

Early high-resolution CT scans may show only scattered or diffuse areas of ground-glass opacity. Later, findings of fibrosis (traction bronchiectasis, honeycombing) predominate in a basal distribution.
 
Bronchiolitis obliterans-organizing pneumonia
 
In BOOP, chest radiographs demonstrate bilateral scattered heterogeneous and homogeneous opacities. These areas are typically peripheral in distribution and are equally distributed between the upper and lower lobes. Nodular organizing pneumonia is typically seen in patients exposed to bleomycin, in the form of round-shaped foci that localize mainly in lung bases; however, they may abut the pleura and simulate metastatic nodules.

CT scanning often shows associated poorly defined nodular areas of consolidation, centrilobular nodules, branching linear opacities, and bronchial dilatation. See Media File 1.

Pulmonary edema

On chest radiographs, typical findings of pulmonary edema include interlobular septal thickening (Kerley lines) and pleural effusion. Chest CT scanning may show pleural effusion or ground-glass opacity and, to a lesser extent, consolidation.

Eosinophilic pneumonia

Imaging studies show the pulmonary infiltrates are typically alveolar and symmetrical and occasionally display the classic pattern of a "photographic negative" of pulmonary edema. However, in drug-induced eosinophilic pneumonia, a reverse pulmonary edema pattern is uncommon. CT scanning can be useful for demonstrating the peripheral nature of the pulmonary opacities.
 
Pulmonary hemorrhage
 
Drug-related diffuse pulmonary hemorrhage is uncommon. Typical causes are anticoagulants, cyclophosphamide, and penicillamine. Chest radiographs typically reveal bilateral heterogeneous and homogenous opacities. High-resolution CT scanning usually shows bilateral, scattered, or diffuse areas of ground-glass opacity. Pleural effusion is typically absent.
 
Granulomatous pneumonitis

Granulomatosis has been reported in a few patients after treatment of non-Hodgkin lymphoma with chemotherapeutic agents. It manifests as reticulonodular pulmonary shadows and/or mediastinal lymph node enlargement, with or without involvement of extrathoracic organs. See Media File 2.

Other Tests

Pulmonary function tests

PFTs include spirometry, lung volume determinations, and DLCO. Most drugs cause a restrictive lung disease pattern with decreased TLC, residual volume (RV), functional residual capacity (FVC), and DLCO. The forced expiratory volume in one second (FEV₁) to FVC ratio (FEV₁/FVC ratio) may be normal or increased. However, drugs that cause bronchiolitis obliterans may cause an obstructive ventilatory defect (reduced FEV₁/FVC ratio and FEV₁, increased RV and RV/TLC ratio).

ABG analysis may reveal hypoxemia at rest. Arterial oxygen desaturation may occur with exercise. A 6-minute walk test with oximetry provides a measure of oxygen desaturation with exertion and helps detect disease progression.

A baseline PFT and ABG analysis may be useful in individual patients before initiating therapy with a drug known to cause pulmonary toxicity, particularly in cancer patients. DLCO is the most sensitive test to monitor. Some clinicians recommend discontinuing chemotherapy once the DLCO has decreased to greater than or equal to 50% compared with pretherapy values.

Procedures

Flexible bronchoscopy

Flexible bronchoscopy is indicated in selected cases to differentiate drug-induced pulmonary toxicity from other disorders, such as infections and malignancy.

Lung biopsy

• Amiodarone
• • Positive for neutrophils and "foamy" macrophages
  • Possibly positive for lymphocytes
  • Negative for eosinophils and birefringent particles
• Methotrexate
• • Positive for lymphocytes
  • Negative for neutrophils, macrophages, eosinophils, and birefringent particles
• Bleomycin
• • Positive for neutrophils
  • Possibly positive for lymphocytes and eosinophils
  • Negative for macrophages and birefringent particles
• Talc
• • Positive for birefringent particles
  • Negative for neutrophils, macrophages, lymphocytes, and eosinophils

Histologic Findings

Histologic changes for most drug reactions are nonspecific, and the diagnosis rests on correlating clinical, laboratory, and radiologic information. The important histopathologic manifestations of pulmonary drug toxicity include DAD, NSIP, BOOP, eosinophilic pneumonia, obliterative bronchiolitis, pulmonary hemorrhage, pulmonary vasculitis, and granulomatous pneumonitis.

Diffuse alveolar damage

DAD results from necrosis of type 2 pneumocytes and alveolar endothelial cells. Depending on the patient and the time of diagnosis, this condition may be difficult to distinguish clinically from pulmonary edema, diffuse alveolar hemorrhage, accelerated pulmonary fibrosis, or dense interstitial pneumonias.

The main histopathologic features are hyaline membrane formation and fibrin deposits lining the alveolar border, dysplasia of type 2 cells, free alveolar fibrin, cells and debris in alveolar spaces, and various stages of interstitial edema, inflammation, and organization.⁵⁴ Some of the implicated drugs include amiodarone, cyclophosphamide, bleomycin, carbamazepine, etoposide, cocaine, heroin, MTX, and mitomycin C. See Media File 3.
 
Nonspecific interstitial pneumonia

Drug-induced NSIP is a relatively common pulmonary reaction to drugs. The inflammatory process in NSIP is diffuse and uniform, mainly involving the alveolar walls and variably affecting the bronchovascular sheaths and pleura. In drug-induced NSIP, interstitial inflammation is typically more homogeneous and more cellular than that seen in cases of usual interstitial pneumonia. NSIP occurs most commonly as a manifestation of amiodarone, MTX, or carmustine toxicity. Gold salts and chlorambucil toxicity are less common causes of NSIP. See Media File 4.
 
Bronchiolitis obliterans-organizing pneumonia

Histologically, BOOP is characterized by variably dense airspace aggregates of loose fibroblasts in ground substance. The lung architecture is typically preserved, and lymphocytes, plasma cells, and histiocytes are present to a variable degree within the interstitium. Nodular organizing pneumonia is typically seen in patients exposed to bleomycin, in the form of round-shaped foci that localize mainly in lung bases, but may abut the pleura and simulate metastatic nodules. Drugs that can cause BOOP include acebutolol, amiodarone, amphotericin B, bleomycin, and carbamazepine. See Media File 5.

Eosinophilic pneumonia

Drug toxicity is an important cause of acute and chronic eosinophilic pneumonias. Patients also may have blood eosinophilia. Eosinophilic pneumonia is characterized by the accumulation of eosinophils and macrophages in the alveoli. Causative drugs include penicillamine, sulfasalazine, nitrofurantoin, para-aminosalicylic acid, and NSAIDs.
  
Pulmonary hemorrhage and vasculitis

Alveolar hemorrhage and hemoptysis can occur after exposure to certain drugs. Typical agents that can cause diffuse pulmonary hemorrhage include anticoagulants, amiodarone, high-dose cyclophosphamide, mitomycin C, cytarabine, and penicillamine. Penicillamine can cause a pulmonary-renal syndrome similar to Goodpasture syndrome.
 
Granulomatous pneumonitis

Some drugs are capable of producing a granulomatous inflammation without necrosis. These agents can induce a granulomatous pneumonitis with or without the bronchiolitis and interstitial inflammation seen in hypersensitivity pneumonitis.⁵⁵ Examples are cocaine, cromolyn sodium, fluoxetine hydrochloride, MTX, nitrofurantoin, procarbazine, and pentazocine. See Media File 7.

TREATMENT

Section 6 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Medical Care

The treatment of drug-induced lung disease consists of immediately discontinuing the offending drug and appropriately managing the pulmonary symptoms. Acute episodes of drug-induced pulmonary disease usually disappear 24-48 hours after the drug has been discontinued, but chronic syndromes may take longer to resolve.

General supportive measures include the following:

• Smoking cessation
• Control of underlying lung disease
• Prompt treatment of concomitant respiratory infections

Consultations

Consultation with a pulmonologist may be helpful in the management of the drug-induced pulmonary diseases.

MEDICATION

Section 7 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Drug Category: Corticosteroids

Corticosteroids have anti-inflammatory properties and cause profound and varied metabolic effects. Corticosteroids modify the body's immune response to diverse stimuli and minimize activity of inflammatory cells. They are used for disease modulation and symptomatic improvement.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Further Inpatient Care

Complications of drug-induced lung toxicity, such as hypoxia, pulmonary thromboembolic disease, and pneumothorax, may require hospital admission.

Further Outpatient Care

Patients with drug-mediated interstitial lung disease are generally treated in an outpatient setting.

In/Out Patient Meds

Corticosteroid therapy is useful in treating some patients with drug-induced lung toxicity, but results can vary. Generally, most patients require inpatient, as well as outpatient, steroid therapy.

Initially, patients are seen monthly. Subsequently, the patients are seen every 3-6 months. PFTs (especially DLCO), the 6-minute walk test, and chest radiographs are usually needed to monitor the course of the disease.

Transfer

Most patients with drug-induced lung toxicity can be treated in community settings. Transfer to a tertiary care center is indicated when the diagnosis is in doubt or when treatment is ineffective.

Deterrence/Prevention

Drug-induced lung disease can be prevented by careful selection of patients, treatment or stabilization of the underlying lung disease, and recognition of the risk factors.

Complications

Complications of drug-induced pulmonary toxicity are as follows:

• Pulmonary fibrosis
• Respiratory failure requiring mechanical ventilation
• Pulmonary embolism
• Pulmonary hypertension
• Pneumothorax
• Increased incidence of pneumonia

Prognosis

The prognosis is variable and depends on the specific drug and underlying clinical, physiologic, and pathologic severity of the lung disease.

Patient Education

Before starting any medication, patients should be educated about the potential adverse effects of the drug. If patients develop drug toxicity, advise the patient to avoid the drug in the future.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Medical/Legal Pitfalls

When a patient presents with drug toxicity, several important medicolegal aspects should be considered, as follows:

• Drug reactions are a common cause for litigation. Therefore, before starting therapy with any potentially toxic drug, its risks, benefits, and alternatives should be explained to the patient. Proper documentation of the type of drug reaction in the medical chart is crucial.
• Early recognition, a high index of suspicion, and knowledge of the disease pattern may decrease the morbidity and mortality associated with the drug toxicity.

Special Concerns

In cases of severe lung toxicity and irreversible fibrosis, patients may be considered for lung transplantation. According to the registry of the International Society of Heart and Lung Transplantation, 1-, 3-, and 5-year actuarial survival rates after lung transplantation are 70.7%, 54.8%, and 42.6%, respectively.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• INTRODUCTION
• CLINICAL
• DIFFERENTIALS
• WORKUP
• TREATMENT
• MEDICATION
• FOLLOW-UP
• MISCELLANEOUS
• Multimedia
• References

Media file 1:  Standard nonenhanced axial thoracic CT scan shows left lower lobe consolidation with some loss of volume and an air bronchogram. Transbronchial lung biopsy confirmed the diagnosis of bronchiolitis obliterans-organizing pneumonia.
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Media type:  CT

Media file 2:  CT scan of a patient with sarcoidosis illustrating multiple nodules. This pattern can manifest in patients taking medications that can cause granulomatous reactions.
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Media type:  CT

Media file 3:  Histologic section of the lung showing diffuse alveolar damage in a patient with adult respiratory distress syndrome.
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Media type:  Photo

Media file 4:  In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity. Patchy scarring of the lung parenchyma and normal, or nearly normal, alveoli interspersed between fibrotic areas are the hallmarks of this disease. In addition, the lung architecture is completely destroyed.
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Media type:  Image

Media file 5:  Bronchiolitis obliterans-organizing pneumonia (also called proliferative bronchiolitis) is often patchy and peribronchiolar. The proliferation of granulation tissue within small airways and alveolar ducts is excessive and is associated with chronic inflammation of surrounding alveoli.
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