Drug-Induced Pulmonary Toxicity

Updated: Dec 31, 2015
  • Author: Ryland P Byrd, Jr, MD; Chief Editor: Zab Mosenifar, MD, FACP, FCCP  more...
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Practice Essentials

Drug-induced pulmonary toxicity is a diagnosis of exclusion. Other disease processes must be ruled out before establishing the diagnosis of a drug-induced pulmonary toxicity. These diseases include respiratory infections; occupational, recreational, and environmental exposures; specific respiratory disorders; and systemic diseases. Drug-induced pulmonary toxicity can be suspected if the patient has been exposed to the drug, develops new signs and symptoms, and has a remittence of these symptoms once the drug is withheld. The best evidence for drug-induced pulmonary toxicity is to rechallenge the patient, but this is potentially hazardous and rarely done in human subjects.

Adverse drug reactions can involve the pulmonary parenchyma, the pleura, the airways, the pulmonary vascular system, the mediastinum, and the neuromuscular system that provides for respiration. These reactions can manifest acutely, subacutely, or chronically. More than 600 prescribed medications have been reported to cause drug-induced pulmonary toxicity. In addition, illicit drugs are well-known to result in pulmonary toxicities. See the image below.

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

Signs and symptoms

Drug-induced lung diseases have no pathognomonic clinical, laboratory, physical, radiographic, or histologic findings. Drug-induced lung disease is usually considered a diagnosis of exclusion (eg, after eliminating infectious and other causes).

Irey [1] 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)

The physical findings of drug-induced lung disease are nonspecific. The patient may have crackles in the case of noncardiac pulmonary edema (NCPE), wheezes in the case of bronchospasm, and decreased breath sounds in pleural effusion.

See Clinical Presentation for more detail.


The diagnosis of drug-mediated pulmonary toxicity is usually established based on clinical findings. In general, laboratory analyses are not helpful in establishing the diagnosis of drug-induced pulmonary toxicity. Chest radiographs are typically obtained. However, high-resolution computed tomography (CT) scanning is more sensitive than chest radiography for defining the radiographic abnormalities. [2]

The radiologic patterns observed in drug-induced pulmonary toxicity are highly variable and depend on the type of adverse reaction the patient is experiencing. Since most of the drug-induced pulmonary toxicities involve the parenchyma, interstitial infiltrates may be demonstrated on radiographs. Pleural fluid may be the only finding. However, the radiograph may be normal or minimally abnormal if the airways or pulmonary vasculature is being affected.

On pulmonary function tests (PFTs), toxicity from most drugs results in a restrictive lung disease pattern, with decreases in the total lung capacity (TLC). The ratio of forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) may be normal or increased. The diffusion capacity of the lung (DLCO) is typically decreased. This measure of lung function often is the first to be diminished.

If the drug-induced pulmonary toxicity causes airway obstruction, then the FEV1/FVC ratio is reduced. The FEV1 will be reduced. The residual volume to total lung capacity (RV/TLC) ratio may be increased.

Bronchoscopy with transbronchial biopsy is typically unrewarding in establishing the diagnosis of drug-induced pulmonary toxicity. Transbronchial biopsy, however, may aid in the diagnosis of pulmonary involvement by other diseases such as sarcoidosis, metastatic cancer, or lymphoma. Bronchoalveolar lavage (BAL) can contribute to the expected clinicopathologic pattern of a given drug-induced lung disease such as identifying eosinophils in a drug-induced eosinophilic pneumonia. BAL also is helpful in the differential diagnosis, primarily by excluding an infective etiology to the pulmonary infiltrates.

Similarly, video-assisted thoracoscopic and open lung biopsies are not typically useful in establishing the diagnosis of drug-induced pulmonary toxicities. These invasive procedures, however, may lead to the diagnosis of other diseases.

See Workup for more detail.


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 often remit 24-48 hours after the drug has been discontinued. Chronic syndromes may take a month or months to resolve.

General supportive measures include the following:

  • Smoking cessation

  • Control of other chronic underlying lung disease

  • Prompt treatment of concomitant respiratory infections

Anecdotal reports indicate that glucocorticoid therapy has been associated with rapid improvement in gas exchange and reversal of radiographic abnormalities in some drug-induced pulmonary toxicities.

See Treatment and Medication for more detail.



More than 600 drugs are known to cause pulmonary toxicity. This number will undoubtedly continue to increase as new therapeutic agents and illicit drugs are developed. Because the medications that cause respiratory diseases are used by a variety of healthcare providers, including generalists, specialists, and subspecialists, virtually no area of medicine is free from encounters of patients experiencing adverse drug reactions.

To minimize the potential morbidity and mortality from drug-induced respiratory diseases, health care providers should be familiar with the possible adverse effects of the medications they prescribe. Recognition of drug-induced lung disease is difficult because the clinical, radiological, and histological findings are nonspecific. Instead, 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. Fortunately, a list of drugs that are reported to cause pulmonary toxicity is available on the continually updated Web site PNEUMOTOX online .



Medications can elicit a wide variety of thoracic tissue effects and responses. The adverse reactions can involve the pulmonary parenchyma, the pleura, the airways, the pulmonary vascular system, the mediastinum, and neuromuscular system. The clinical and histopathological entities reported as drug-induced pulmonary toxicities are listed below.

Adverse reactions involving the pulmonary parenchyma are as follows:

  • Interstitial pneumonitides - Usual interstitial pneumonitis, nonspecific interstitial pneumonitis, desquamative interstitial pneumonitis, giant cell interstitial pneumonitis, lymphocytic interstitial pneumonitis, respiratory bronchiolitis with interstitial pneumonitis

  • Noncardiac pulmonary edema (NCPE)

  • Cardiac pulmonary edema (from myocardial toxicities)

  • Pulmonary infiltrates and eosinophilia (PIE)

  • Eosinophilic pneumonia

  • Hypersensitivity pneumonitis

  • Cryptogenic organizing pneumonia (COP)

  • Diffuse alveolar damage (DAD)

  • Pulmonary hemorrhage

  • Granulomatous pneumonitis

  • Lipoid pneumonia

  • Pulmonary alveolar proteinosis

  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

  • Pulmonary fibrosis

  • Pulmonary nodule or nodules

Adverse reactions involving the pleura are as follows:

  • Pleural effusion

  • Drug-induced lupus with pleural effusion

  • Eosinophilic pleural effusion

  • Pleural thickening or fibrosis

  • Ovarian hyperstimulation syndrome

  • Pneumothorax

Adverse reactions involving the airways are as follows:

  • Bronchospasm, bronchoconstriction, asthma

  • Bronchiolitis obliterans

  • Cough

  • Dysphonia or hoarseness

  • Calcification of cartilaginous rings

  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

  • Cryptogenic organizing pneumonia

Adverse reactions involving the pulmonary vasculature are as follows:

  • Pulmonary hypertension

  • Pulmonary thromboembolic disease

  • Pulmonary veno-occlusive disease

  • Pulmonary hemorrhage

  • Pulmonary vasculitis

  • Eosinophilic granulomatosis with polyangiitis (Churg-Strauss syndrome)

  • Diffuse alveolar hemorrhage

  • Hemoptysis

  • Pulmonary hematoma

Adverse reactions involving the mediastinum are as follows:

  • Pseudosarcoidosis

  • Mediastinal lymphadenopathy

  • Lymphoproliferative disease

  • Mediastinal lipomatosis

Adverse reactions involving neuromuscular dysfunction are as follows:

  • Respiratory muscle weakness or paralysis

  • Respiratory muscle rigidity

  • Central respiratory depression, apnea

  • Noncardiac pulmonary edema

These reactions can manifest acutely, subacutely, or chronically. Moreover, in some drug-induced pulmonary toxicities, there is involvement of the parenchyma and the airways or the parenchyma and the pulmonary vasculature.

Mechanisms of pulmonary injury

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

  • Oxidant injury

  • Pulmonary vascular damage

  • Deposition of phospholipids within cells

  • Immune system–mediated injury

  • Central nervous system (CNS) depression

  • Direct toxic effect

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, antineoplastic drugs may disturb oxidant/antioxidant system homeostasis, 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 interstitial 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 as follows:

  • Naloxone

  • Heroin

  • Interleukin 2

  • All-trans -retinoic acid

  • Contrast media

  • Intrathecal methotrexate (MTX)

  • 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 from 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 for these selected drugs are as follows:

  • Advanced age

  • Cumulative dose

  • Simultaneous oxygen therapy

  • Combination therapy

  • Radiation therapy

  • Occupational factors

  • Underlying lung disease

  • Genetic factors

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.

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 with high-dose (>1500 mg/m2bis -chloroethylnitrosourea (BCNU) therapy varies from 20-50%.

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 pneumocytes. 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).

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 can result in the production of oxidant radicals that lead to pulmonary damage. Radiation therapy in combination with chemotherapy may be synergistic. [3]

Occupational exposure to pulmonary toxins can increase the risk of drug-related adverse effects. Asbestos exposure may potentiate the noxious respiratory effects of ergot drugs and bleomycin. [4, 5]

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.



Drug-induced lung disease can be categorized in terms of major clinical syndromes, as follows:

  • NCPE/capillary leak syndrome

  • Hypersensitivity reaction

  • Cryptogenic pulmonary edema (COP)

  • Pulmonary vascular disease

  • Interstitial pneumonitis

  • Bronchospasm

  • Pleural involvement

  • Mediastinal involvement

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 CNS, resulting in neurogenic pulmonary edema.

Clinically, acute NCPE (ie, acute pulmonary edema with no evidence for left ventricular dysfunction or overload) manifests as an acute onset of dyspnea with tachypnea, tachycardia, hypoxemia, and diffuse crackles upon physical examination. Fluffy infiltrates are present on the chest radiograph.

Drugs that cause NCPE include the following [6] :

  • Heroin

  • Interleukin 2

  • MTX

  • Cocaine

  • Tocolytic agents

  • Hydrochlorothiazide

  • Cyclophosphamide

  • Iodinated radiographic contrast agents

Hypersensitivity reaction

Drug hypersensitivity results from interactions between a pharmacologic agent and the patient’s 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.


COP (previously referred to as bronchiolitis obliterans-organizing pneumonia or BOOP) is a distinctive pattern of lung response to a few drugs. Histology reveals interstitial inflammation superimposed on the dominant background of alveolar and ductal fibrosis. Drugs that can cause COP include the following:

  • Acebutolol

  • Amiodarone

  • Amphotericin B

  • Bleomycin

  • Carbamazepine

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 pulmonary veins. Oral contraceptives, bleomycin, and carmustine (BCNU) have been reported to cause this rare disorder.

Oral contraceptives [7] also cause a 4- to 7-fold increased risk of venous thromboembolism. [8] 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. The anorectic agent aminorex was removed from the market for that reason. Clinicians should remain vigilant because most over-the-counter appetite suppressants contain fenfluramine and dexfenfluramine. Prescription medications such as beta-blockers and mitomycin C have also 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. [9] Penicillamine, amiodarone, cocaine, hydralazine, mitomycin C, nitrofurantoin, abciximab, MTX, carbamazepine, and moxalactam disodium are recognized as inciting agents.

The diagnosis is confirmed by bronchoalveolar lavage (BAL), which shows increased blood staining in sequential aliquots. Treatment is withdrawal of the offending drug and control of the bleeding.

Interstitial pneumonitis

Interstitial pneumonitis (ie, inflammation of the lung interstitium, such as alveolar septa) 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. [10, 11]

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 cases caused by MTX. 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.


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 adults 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 the drug.

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 also been reported with the use of the following agents:

  • Inhaled pentamidine

  • Amphotericin B

  • Amiodarone

  • Angiotensin-converting enzyme (ACE) inhibitors

  • Dipyridamole

  • Nitrofurantoin

  • Beta-blockers

  • Penicillamine

Because HIV infection is now better controlled and patients are treated for many years, further study of antiretroviral therapy (ARVT) and lung function will determine whether bronchospasm reverses after cessation of ARVT. In one study of pulmonary function abnormalities in patients with HIV receiving ARVT, univariate analysis demonstrated that ARVT is a risk factor for airway obstruction unresponsive to bronchodilator treatment, with an odds ratio of 4.71. [12]

Pleural involvement

Pleural effusions can develop in patients undergoing treatment with MTX, nitrofurantoin, amiodarone, procarbazine, carmustine, or 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. Some medications cause eosinophilic pleural effusions.

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 corticosteroid 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 computed tomography (CT) scanning findings. The treatment is cessation of steroid therapy.

Drug classes

Selected drugs that are important causes of pulmonary toxicity fall into the following classes:

  • Cytotoxic

  • Cardiovascular

  • Anti-inflammatory

  • Antimicrobial

  • Illicit

  • Miscellaneous

Cytotoxic drugs


The rate of bleomycin-induced pulmonary toxicity is approximately 10% (varies from 2-40%). Bleomycin is very useful in the treatment of head and neck carcinomas, germ cell tumors, and lymphoma.

Risk factors for lung toxicity include the following:

  • Old age

  • Cumulative dose greater than 450 total units (10% mortality if >550 total U)

  • Concomitant or prior radiation therapy (lung injury may not be confined to the radiation port)

  • Exposure to a high supplemental fraction of inspired oxygen (> 0.25-0.3), [13] which can lead to the development of ARDS 18-36 hours after exposure

  • Combination therapy with cyclophosphamide or granulocyte-colony stimulating factor

  • Renal failure [14]

A wide variety of adverse reactions to bleomycin have been reported, including chronic interstitial fibrosis, hypersensitivity-type disease, and COP. Clinically, bleomycin toxicity manifests acutely or subacutely with dyspnea and chest pain. [15] Pneumonitis with pulmonary fibrosis [16] can develop 6-8 weeks after the onset of treatment. [17] Crackles may be present upon auscultation of the chest; their presence precedes radiographic changes.

Chest radiographs may show reticulation, ground-glass opacity, and, sometimes, consolidation with a predominant subpleural and lower lobe predominance. [18, 19] Often, generalized loss of lung volume occurs. [20] Lung toxicity can cause multiple pulmonary nodules, [21] which may mimic metastatic disease [22] but have the histologic characteristic of COP.

PFT results typically reveal a restrictive ventilatory defect and reduced diffusion capacity of the lungs for carbon monoxide (DLCO) that predates the onset of overt toxicity by weeks. The BAL cytologic pattern is neutrophilic. [23] Tissue eosinophilia is uncommon but has been reported in patients with bleomycin-induced lung toxicity. [24]

Management includes withdrawal of the drug. Corticosteroids are generally administered to all patients with clinically significant toxicity and then are slowly tapered according to the patient’s clinical response. Clinical improvement typically occurs within weeks, but the condition may take 2 years to completely resolve. The overall mortality rate varies from 10-83%.

Mitomycin C

The rate of pulmonary mitomycin C toxicity is approximately 3-12%. This drug is used in the treatment of breast, gastrointestinal, gynecologic, and lung carcinomas. Pulmonary disorders that have been described with mitomycin C toxicity include the following:

  • Acute pneumonitis

  • Hemolytic-uremic–like syndrome with acute lung injury

  • Chronic pneumonitis with the insidious development of diffuse parenchymal lung disease

  • Exudative pleural exudative effusions

A fraction of inspired oxygen value greater than 50% increases the risk for pulmonary mitomycin C toxicity. Coadministration with vinca alkaloids (eg, vinblastine, vincristine) can cause bronchospasm and hypoxia.

Symptoms of pulmonary mitomycin C toxicity typically appear after the third or fourth course of chemotherapy. Chest radiographs may reveal a reticular pattern and opacities. These pulmonary opacities may clear, or they may persist in patients who progress to the development of chronic interstitial lung disease.

Approximately two thirds of the patients develop chronic respiratory symptoms that respond to corticosteroids. The mortality rate is high, up to 50%.

Nitrosourea (BCNU, carmustine)

The rate of pulmonary toxicity with nitrosourea is 20-30%, with a mortality rate of 90%. BCNU readily crosses the blood-brain barrier and is often used in patients with CNS malignancies. BCNU causes pulmonary toxicity more often than any other nitrosourea.

BCNU may have synergy with other drugs (eg, cyclophosphamide) and radiation therapy in producing pulmonary toxicity. In addition, the following factors increase the risk of toxicity:

  • Younger age

  • Preexisting lung disease

  • Smoking habit

  • Dose greater than 525 mg/m2 (50% affected at dose >1500 mg/m2)

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 include reduced forced vital capacity (FVC), total lung capacity (TLC), and DLCO values. The reduced DLCO value can occur in patients with normal chest radiographs.

Treatment of BCNU-induced pulmonary toxicity is with corticosteroids. [27] Patients presenting early with acute pulmonary toxicity due to BCNU are more responsive to corticosteroid therapy and have a better prognosis. In contrast, late toxicity is characterized by pulmonary fibrosis and a poor therapeutic response. A long-term complication with BCNU toxicity is the development of upper lobe fibrosis.


The rate of cyclophosphamide-induced pulmonary toxicity is generally less than 1%. Cyclophosphamide is an alkylating agent used in the treatment of various forms of leukemias and lymphomas and as a conditioning agent prior to bone marrow or stem cell transplantation.

Risk factors for cyclophosphamide lung toxicity include concomitant radiation therapy, use of other cytotoxic agents known to be associated with lung toxicity (eg, bleomycin), and exposure to high oxygen concentrations.

The 2 distinct clinical patterns of pulmonary toxicity associated with cyclophosphamide are (1) an acute pneumonitis that occurs early in the course of treatment and (2) a chronic, progressive, fibrotic process that may occur after prolonged therapy. If diagnosed early, the acute form of cyclophosphamide pulmonary toxicity is largely reversible upon removal of the drug and institution of corticosteroid therapy.

Chronic cyclophosphamide pneumonitis takes the form of progressive pulmonary fibrosis with respiratory failure and, sometimes, digital clubbing. Chronic cyclophosphamide pneumonitis is typically irreversible, even with drug withdrawal and the institution of corticosteroid therapy. [28]

Bilateral reticular or nodular diffuse opacities are the hallmark of both early- and late-onset pulmonary toxicity. In the case of early-onset pneumonitis, chest CT scans reveal ground-glass opacities predominantly in the periphery of the upper lungs. The radiographic opacities of late-onset pneumonitis have a more fibrotic appearance on CT scans, involving mostly mid and upper lung regions. Pneumothorax may develop late in the course of the disease. PFTs typically display a restrictive pattern with a reduced DLCO.

It is important to rule out infection, particularly Pneumocystis jiroveci pneumonia, when evaluating a patient for cyclophosphamide-induced pulmonary toxicity, as both conditions may be present in these patients. In general, treatment of cyclophosphamide-induced pulmonary toxicity is largely supportive, but lung transplantation may be considered.


The rate of busulfan lung toxicity is approximately 5%. Busulfan is an alkylating agent used to treat myeloproliferative disorders. Currently, this drug is almost exclusively administered as part of preparative regimens prior to stem cell transplantation.

Risk factors for toxicity are synergistic pulmonary damage when exposed to oxygen, radiation, or other cytotoxic chemotherapeutic drugs. The time of onset of busulfan lung toxicity ranges from a few months to 10 years. Common clinical manifestations are cough, progressive dyspnea with exertion, fever, weight loss, and brownish pigmentation of the skin.

Chest radiographs may be normal or may reveal bibasilar reticular opacities. Busulfan toxicity can cause a radiological pattern similar to that of alveolar proteinosis. [29] PFT results show a restrictive ventilatory defect and a reduced DLCO.

Treatment is withdrawal of the drug and corticosteroid therapy. Anecdotal reports describe responses to corticosteroids, but no controlled studies are available. The prognosis, in general, is poor, with a mortality rate from 50-80%.


The incidence of MTX pulmonary toxicity varies from 0.3-12%. MTX is an antifolate that is part of several antineoplastic chemotherapy regimens.

Risk factors for MTX-induced lung toxicity include the following:

  • Age older than 60 years

  • Rheumatoid pleuropulmonary involvement

  • Previous use of disease-modifying antirheumatic drugs

  • Hypoalbuminemia (either before or during therapy)

  • Diabetes mellitus

  • Daily rather than weekly drug administration

  • Preexisting lung disease

  • Abnormal PFT results prior to therapy

  • Decreased elimination of MTX (eg, renal failure)

Symptoms usually develop within weeks of the onset of treatment and include fever, dyspnea, persistent nonproductive cough, and/or rash. Patients may also have fatigue and weight loss. Then, typically, the disease accelerates, producing a brisk development of infiltrative lung disease, resulting in respiratory failure. Severe hypoxemia is consistently present. Mild peripheral eosinophilia is present in 40% of patients.

Nonspecific interstitial pneumonia (NSIP) is the most common manifestation of MTX-induced lung disease. Other histopathologic patterns include BOOP, NCPE, and non-Hodgkin (B-cell) lymphoma. Interestingly the non-Hodgkin lymphoma usually regresses after cessation of MTX therapy.

Chest radiographs reveal ill-defined reticular opacities, ground-glass opacity, or consolidation. [30] A basal prominence is typical. High-resolution CT scanning may demonstrate ground-glass changes as prominent abnormalities.

PFTs in patients who can tolerate the procedure reveal restrictive ventilatory defects with a low diffusing capacity. Hypoxemia may be present on arterial blood gas (ABG) analysis. BAL may be helpful for excluding an infectious etiology such as P jiroveci pneumonia [31] and in supporting the diagnosis of MTX pneumonitis. Lymphocytic predominance with an increase in the number of helper T lymphocytes and the helper/suppressor T-cell ratio is observed in the BAL fluid of patients with MTX pneumonitis. [32, 33]

The diagnosis of MTX-induced lung toxicity must be made on the basis of the clinical setting, clinical manifestations, radiographic abnormalities, and BAL results. Occasionally, lung histopathology is necessary.

The diagnostic criteria proposed by Searles and McKendry for MTX-induced toxicity consist of major and minor criteria. [34] Major criteria are as follows:

  • 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 are as follows:

  • 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

  • Leukocyte count less than or equal 15,000 cells/µL

Definitive diagnosis of MTX pneumonitis can be made if the patient has 1 or 2 major criteria in conjunction with 3 of the 5 minor criteria.

The management of MTX pneumonitis includes drug discontinuation. If symptoms and radiographic findings persist despite discontinuation of the drug, corticosteroid therapy is recommended. However, no prospective, randomized, placebo-controlled trials have been performed to support the use of corticosteroids in MTX pulmonary toxicity.

Pulmonary abnormalities from MTX, in contrast to those from many other cytotoxic agents, are often reversible; 85% of affected patients fully recover. Fibrosis of the lungs after MTX pneumonitis is unusual. The overall mortality rate is 15%. Death is caused by rapidly progressive respiratory failure.

Cardiovascular drugs


The incidence of amiodarone-induced lung disease is approximately 5-7%. Amiodarone is an antiarrhythmic agent used in the treatment of many types of tachyarrhythmia.

Although no definitive correlation exists between the development of drug toxicity and the duration of therapy or the total accumulative dose, the risk for amiodarone-induced lung disease may be increased if the daily maintenance dose is greater than 400 mg and the patient is elderly or if the duration of therapy exceeds 2 months. Recognized risk factors include preexisting lung disease and a history of thoracic or nonthoracic surgery or pulmonary angiography.

Patients who have developed amiodarone-induced lung toxicity usually present with nonspecific symptoms such as cough, dyspnea, fever, and weight loss. These symptoms may be mistaken for, or obscured by, symptoms of overt cardiac failure in a patient who is critically ill.

Radiologically, amiodarone toxicity can manifest as a focal lesion or diffuse interstitial abnormality. Less commonly, ill-defined nodules or masses that occasionally cavitate can be present. [35, 36]

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 and 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. Sato et al reported successful treatment of one case with polymyxin beta-immobilized fiber column direct hemoperfusion. [37]

Patients taking amiodarone can develop postoperative ARDS, which begins 18-72 hours after surgery. [38] A high fraction of inspired oxygen given during the operation and the postoperative period has been postulated to contribute to this complication. [39, 40]

ACE inhibitors

Up to 20% of patients develop a dry cough after taking ACE inhibitors. The exact mechanism of ACE inhibitor cough is unknown, but it is thought to be linked to the accumulation of substances normally metabolized by ACE. These substances include bradykinin or tachykinins (with the consequent stimulation of vagal afferent nerve fibers) and substance P. [41, 42, 43, 44, 45]

Resolution of ACE inhibitor–induced cough usually occurs within 1-4 days but may take weeks to months. Patients can be switched to an angiotensin receptor blocker, which rarely induces cough. Sulindac has been reported to be of benefit in the management of ACE inhibitor–induced cough. Studies have also suggested that intermediate doses of aspirin (500 mg/d), but not low doses (100 mg/d), can suppress ACE inhibitor cough. [46, 47, 48]

Although ACE inhibitors are generally safe in most patients with obstructive airways disease, case reports suggest that in a subpopulation of patients, these agents can increase bronchial reactivity, asthma symptoms, or exacerbations.

Another symptom of ACE therapy is angioneurotic edema (0.68% of patients). [49] It manifests as swelling of the tongue, lips, and mucous membranes within hours or weeks after initiating treatment and can rapidly evolve into respiratory distress. This complication can be treated with a subcutaneous injection of epinephrine every 15-20 minutes, diphenhydramine, and steroid therapy.


Beta-blockers can precipitate bronchospasm in patients with asthma or chronic obstructive pulmonary disease (COPD). [50] The benefits of using beta-blockers, like any other drug, must be weighed on a case-by-case basis against the risk of adverse effects.

In patients with stable COPD or asthma, beta-blockers can be started at low doses, with careful monitoring for adverse effects. Because of its cardioselectivity, atenolol is the drug of choice for an individual with obstructive airways disease who needs a beta-adrenergic antagonist.

Esmolol is the drug of choice in critically ill patients with asthma or COPD who require a beta-blocker (unstable angina), owing to its beta1 selectivity and extremely short half-life (9 min).

Importantly, ophthalmic beta-blockers, such as timolol, which are used in the treatment of glaucoma, have produced a number of deaths secondary to exacerbation of COPD and asthma. [51] Betaxolol ophthalmic may be a safer alternative to timolol.

Anti-inflammatory drugs


Aspirin-induced asthma (AIA) occurs in less than 1% of healthy individuals and up to 20% of asthmatic individuals. The pathogenesis of AIA is mediated by the production of potent inflammatory and bronchoconstrictor leukotriene (LT) mediators such as LTC4, LTD4, and LTE4 via activation of the 5-lipoxygenase pathway.

In addition to wheezing, reactions are usually accompanied by nasal and ocular symptoms, including congestion, rhinorrhea, and tearing. Facial flushing, angioedema, and gastrointestinal symptoms can also occur. The Samter triad is asthma, nasal polyps, and aspirin sensitivity. The treatment of AIA is steroid therapy and discontinuation of aspirin and NSAIDs.

Of elderly patients on long-term aspirin therapy, 10-15% develop NCPE. It usually occurs when the serum salicylate level is greater than 40 mg/dL. Treatment is usually supportive, but some patients require hemodialysis. Long-term salicylate ingestion can manifest as pseudoseptic syndrome (fever, tachycardia, elevated white blood cell count, hypotension, ARDS, and altered mental status). Elevated salicylate levels are helpful in diagnosing this condition.


Gold-induced drug toxicity is uncommon, occurring in 1% of patients. Toxicity occurs within 2–6 months after therapy is started and is associated with mucocutaneous lesions in 30% of patients. DAD and NSIP are the most common manifestations of gold-induced lung disease. Importantly, that pleural effusion is not associated with gold toxicity.

Toxicity from gold therapy can affect other organs, as well, such as the skin (dermatitis), the nerves (peripheral neuropathy), and the kidneys (proteinuria).

Treatment of gold toxicity is withdrawal of the drug and, in severe cases, steroid therapy. The prognosis is good. Most patients improve after discontinuation of the gold therapy.


Penicillamine is an anti-inflammatory agent mostly used in the treatment of rheumatoid arthritis. It can cause bronchiolitis obliterans, penicillamine-induced systemic lupus erythematosus, pulmonary-renal syndrome, and pneumonitis. Management includes withdrawal of the drug, supportive therapy, and consideration of a trial of corticosteroids. In general, the prognosis is poor.

Antimicrobial drugs


Nitrofurantoin, an antibacterial agent used primarily for the treatment of urinary tract infections, is one of the most common causes of drug-induced lung disease. Both acute and chronic pulmonary toxicity can occur, but the acute syndrome is much more common.

The mechanism of the acute nitrofurantoin reaction is unknown and is not dose dependent. The acute pleuropulmonary reaction begins 2-10 days after the initial drug exposure and is manifested by dyspnea and cough. Fever is present in most cases. Pleurisy occurs in one third of patients.

The chest radiograph shows a pattern of basilar alveolar or interstitial infiltrates, [52] sometimes accompanied by a pleural effusion. Peripheral blood eosinophilia and elevation in the sedimentation rate are seen in one third and nearly one half of the patients, respectively. The prognosis is good, with most patients recovering in 1-4 days after discontinuation of nitrofurantoin therapy.

Chronic toxicity is far less common than the acute reaction and is not associated with systemic symptoms. Chronic pulmonary toxicity typically manifests clinically as an insidious onset dyspnea and cough. Clinically and radiographically, it is indistinguishable from idiopathic pulmonary fibrosis and typically causes no pleural effusion. PFTs demonstrate a restrictive ventilatory defect. If no improvement is noted within 2-3 months after withdrawal of the drug, corticosteroid therapy is indicated.


Sulfasalazine is an antimicrobial drug used for the treatment of inflammatory bowel disease. It can cause eosinophilic pneumonia, desquamative interstitial pneumonitis, NCPE, drug-induced lupus syndrome, and vasculitis, usually after 1-8 months of therapy. More than 50% of patients have peripheral eosinophilia. Management includes removal of the drug, and, if necessary, corticosteroid treatment.

Illicit drugs


Cocaine is one of the most frequently used illicit drugs in the United States. Inhalation of cocaine may result in pneumomediastinum and pneumothorax. [53, 54, 11] Smoking of cocaine is associated with the following effects:

  • Acute exacerbations of asthma

  • Bronchiolitis obliterans

  • Cardiogenic pulmonary edema

  • NCPE

  • Interstitial pneumonitis

  • Pulmonary vascular hypertension

  • Pulmonary hemorrhage

  • Talcosis

  • Thermal injury to the airway

  • Pneumothorax

  • Significant impairment of the diffusing capacity of the lungs


Heroin can cause acute NCPE, which can occur with the first 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. Persons with long-term heroin abuse may experience repeated episodes of aspiration pneumonia, leading to bronchiectasis and narcotizing bronchitis. Treatment is supportive.

Naloxone can be used to reverse respiratory depression. Interestingly, several case reports describe acute NCPE related to naloxone, although the mechanism remains unknown. [55]

Miscellaneous drugs


Talcosis is the development of a foreign body granulomatous reaction and is also termed intravenous drug abuser’s lung. It results from intravenous injection of oral preparations containing particulates of talc. Talc can cause granulomatous pulmonary artery occlusion or granulomatous interstitial fibrosis. Patients present with dyspnea, syncope, or signs of right-sided heart failure.

Chest radiographs may be normal in approximately 50% of cases. Chest radiographs can demonstrate diffuse micronodular densities mimicking alveolar microlithiasis. Talc can also cause nodular lesions in the upper lobes, resembling progressive massive fibrosis or pneumoconiosis.

PFT results may reveal a mixed obstructive and restrictive ventilatory defect with decreased DLCO. Funduscopic examination is helpful by disclosing typical changes of talcosis. Talc emboli can be identified near the macula within the small vessels in 50% of the patients.


Tocolytics (ie, terbutaline, albuterol, ritodrine) are mainly used in the treatment of premature labor. Tocolytics act on the beta-receptors of the vessels and cause peripheral vasodilation. If tocolytics are discontinued abruptly, the vasodilated vessels return to their normal vascular tone; this promotes large increases in intravascular volume, which causes NCPE.

The risk factors for the development of NCPE include the following:

  • Use of corticosteroids

  • Fluid overload

  • Twin gestation

  • Multiparity

  • Anemia

  • Silent cardiac disease

Tocolytic-induced NCPE is treated with diuretics and supportive therapy. Corticosteroids are not helpful.

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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. Several studies suggest that drug-induced pulmonary toxicity is underdiagnosed worldwide.

In the United States, more than 2 million cases of adverse drug reactions occur annually, including 100,000 deaths. An estimated 0.3% of hospital deaths in the US are drug related. [56] As many as 10% of patients who receive chemotherapeutic agents develop an adverse drug reaction in their lungs. [57] These figures, however, probably underestimate the true frequency of the problem.

Racial differences in incidence

Bortezomib, a proteosome inhibitor with good clinical activity in persons with multiple myeloma, can lead to severe pneumonitis in African American patients. [58] Additionally, some diseases are more common in certain ethnic groups. For example, sarcoidosis is more common in African Americans. 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- and age-related differences in incidence

The person’s sex is not an independent risk factor for the development of drug-induced lung disease. However, certain diseases are more common in females, and females 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.

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.



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

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%


Patient Education

Before starting any medication, patients should be educated about the potential adverse effects of the drug. Patients who develop drug toxicity should be advised to avoid the drug in the future.

Drug reactions are a common cause for litigation. Therefore, before starting therapy with any potentially toxic drug, the clinician should explain its risks, benefits, and alternatives to the patient. When drug reactions occur, proper documentation of the type of drug reaction in the medical chart is crucial.