eMedicine Specialties > Radiology > Chest

Lung, Drug-Induced Disease

Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR, LRCP, Chairman of Medical Imaging, Professor of Radiology, NGHA, King Fahad National Guard Hospital, King Abdulaziz Medical City, Riyadh, Saudi Arabia
Klaus L Irion, MD, PhD, Consulting Staff, The Cardiothoracic Centre Liverpool NHS Trust, The Royal Liverpool University Hospital, UK; Chitra P Nagarajaiah, MBBS, MRCP, Acute Medicine Specialist Registrar, City Hospital of Birmingham, UK
Contributor Information and Disclosures

Updated: Jun 4, 2008

Introduction

Background

The number of drugs that adversely affect the respiratory system continues to increase, and their effects pose a great challenge to all physicians. A review in 1972 identified only 19 drugs with the potential to cause pulmonary disease; now, more than 350 (and counting) have been identified. Awareness of drug-induced pulmonary disease is increasing. The sole purpose of one clinical study group, the Groupe d'Etudes de la Pathologie Pulmonaire Iatrogene (GEPPI), is to provide information regarding individual cases, to collect and update literature on drug-induced lung disease, to publish updated lists of offending compounds, and to provide warnings when adverse effects of drugs are recognized.^{1, 2, 3, 4, 5, 6, 7, 8, 9, 10}

Related Medscape topics:
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Specialty Site Pulmonary Medicine
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CME/CE Highlights of the American Academy of Allergy, Asthma & Immunology 2008 Annual Meeting
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Pathophysiology

Our understanding of the mechanisms of drug-associated injury of the lung is limited compared to our knowledge of diseases in other tissues (eg, liver), and no specific markers are known to differentiate drug-associated interstitial lung disease from other pathological processes. In addition, many drugs are used at the same time or in close sequence — a practice that makes the assignment of toxicity to a specific agent difficult.

Drugs cause lung injury as a result of direct pharmacologic action, persistence or metabolism in the tissue, or the production of a reactive metabolite. The result of this injury ranges from cellular dysfunction to apoptosis and alteration of repair mechanisms essential for replacing critical tissue elements and for function. Chemotherapeutic drugs and novel agents, such as those targeting the epidermal growth factor receptor (EGFR), appear to affect both normal and neoplastic cells. However, unlike chemotherapy, which has systemic actions that are directly the result of biotransformation or cell injury, treatment with EGFR-targeting agents is more likely to exert a pharmacologic effect focused on the epithelia.

In many cases, drug-induced lung disease is dose related, particularly with regard to cytotoxic agents, such bleomycin, busulphan, and carmustine. Other factors, such as increased patient age, decreased renal function, radiation therapy, oxygen therapy, and other associated cytotoxic drug therapy, may enhance the toxic effects.^{11, 12}

Risk factors for the development of adverse pulmonary reactions, as well as biologic markers of incipient toxicity, must be prospectively identified. By aiding the identification of more than 1000 proteins or peptides in blood samples, the field of proteomics will hopefully allow scientists to identify candidate markers.

The most common histopathologic patterns of drug-associated lung injury are pulmonary edema; diffuse alveolar damage; nonspecific interstitial pneumonia (NSIP); cryptogenic organizing pneumonia (COP), which was previously known as bronchiolitis obliterans organizing pneumonia (BOOP); eosinophilic pneumonia; and pulmonary hemorrhage.^{13, 14} Pulmonary hemorrhage is most commonly a complication of anticoagulant therapy or drug-induced thrombocytopenia. In rare cases, penicillamine causes a pulmonary renal syndrome similar to Goodpasture syndrome. Pulmonary hemorrhage has also been reported with nitrofurantoin, quinidine, and oxyphenbutazone.^{15, 16}

Causes

In addition to drugs, other potential causes of respiratory disease are biomolecules (eg, interferons, immunoglobulins, anti-thymocyte globulin), stem-cell modulators (eg, all-trans retinoic acid, granulocyte colony-stimulating factor [G-CSF]), transfusions of blood or blood products, stem-cell transplantation, herbs, and dietary supplements (eg, ephedra, comfrey, germander, aristolochic acid, shrub leaves containing Sauropus androgynus). Some can cause severe or irreversible disease.

Patient groups

The prediction of drug-induced lung disease is an unresolved issue. Explanations for the unequal risks among patients include idiosyncratic reactions; previous respiratory reactions to the drug, a congener, or unrelated compounds; underlying disease for which a drug is being given (eg, rheumatoid arthritis and ulcerative colitis may increase the relative risk of respiratory disease due to disease-modifying drugs); occupational factors (eg, exposure to asbestos potentiates the noxious respiratory effects of ergot drugs); activation of detoxification pathways, which differ among individuals; concurrent chemotherapy, irradiation, or high concentrations of oxygen; and comorbidities (eg, renal failure).

Frequency

United States

The exact frequency of drug-induced lung disease is difficult to determine, and any estimate is probably an underestimate because no effective screening tool is available.

One of the best resources is Pneumotox Online. This site grades evidence that a given drug is responsible for a specific lung disease. There are 4 categories of evidence: evidence based on 1-5 isolated case reports; evidence based on approximately 10 cases; evidence based on 20-100 cases; and evidence based on more than 100 cases.

Incidences of pulmonary toxicity for different drugs are as follows:

• Amiodarone causing pleuropulmonary toxicity — 6%
• Vinca alkaloid (mitomycin–vinca alkaloid combination therapy) causing acute respiratory distress syndrome (ARDS) — 3-6%
• Transfusion-related acute lung injury (TRALI) — 1 in 5000 transfusions or 1 in 2000 patients who undergo transfusion
• Aspirin-induced asthma — 10-20%
• Vinorelbine (vinca alkaloid) causing bronchospasm — 5%
• Angiotensin-converting enzyme inhibitor (ACE-I) causing cough — 10%^{17, 18}
• Sodium morrhuate (esophageal sclerosant) causing pleural effusions — 40-50%
• Absolute alcohol (esophageal sclerosant) causing pleural effusions — 19%
• Methysergide causing pleuropulmonary complications — Less than 1%
• Bromocriptine causing pleural thickening and effusions — 6%
• Bleomycin causing pleuropulmonary reactions — 6-10%
• Methotrexate-induced pleuropulmonary disease — 3-4%
• Nitrofurantoin causing acute pleuropulmonary effects — 5-25%
• Interleukin 2 causing pleuropulmonary abnormalities — 75%
• Hydralazine-induced lupus causing pleuropulmonary disease — 30% (isolated parenchymal disease in <5%)

International

No data suggest that the international frequency of drug-induced lung disease is different from that in the United States. Some differences may occur in parts of the world where the availability of certain drugs is limited.

Mortality/Morbidity

• Diffuse alveolar hemorrhage occurring as a complication of a cytotoxic drug reaction has a mortality rate of 50-100%.
• Transfusion-related acute lung injury has a mortality rate of 5-10%.

Race

Some ethnic groups are at increased risk for adverse reactions to drugs.

• When gefitinib is used in cases of advanced non–small-cell lung cancer (NSCLC), the incidence of interstitial lung disease is higher in Japanese populations (1.9%) than in the rest of the world (0.3%).
• ACE-Is and cough have been reported in Thai patients.¹⁹
• Angioedema and cough have been reported in Nigerian patients receiving ACE-Is.¹⁷

Sex

Certain drug-induced lung diseases have a sex predilection.

• Aspirin-induced asthma is more common in women than in men.
• Cough associated with the use of ACE-Is is more common in women than in men.

Age

Drug-induced lung disease is prevalent in both adults and children.

• Chemotherapy, radiotherapy, or their combination in early childhood (eg, for brain tumors or lymphoma) may lead to a pattern of progressive pulmonary fibrosis.
• Cytotoxic drug-induced pulmonary disease has been reported in infants and children.²⁰
• Active lung fibrosis occurring as long as 17 years after chemotherapy has been reported with carmustine therapy (1,3-bis (2-chloroethyl)-1-nitrosourea [BCNU]) in childhood.²¹

Presentation

Classic drug-induced interstitial lung disease

• Hypersensitivity pneumonitis
  • Typical drugs — Methotrexate, chrysotherapy, cyclophosphamide, nitrofurantoin, antidepressants.
  • Characteristic features — Sensitization, lymphocytic bronchoalveolar lavage (BAL) fluid. BAL may support a certain clinical/pathological pattern in drug-induced interstitial lung disease, which is helpful for excluding other diseases, such as malignancies with pulmonary metastasis, heart disease with pulmonary congestion, or infections.
  • Diagnostic tests — Histopathology, BAL.
  • Outcome — Favorable; recovery usually occurs with use of steroids or on dechallenge.
• Mild eosinophilic pneumonitis
  • Typical drugs — Methotrexate, sulfasalazine, minocycline, para-aminosalicylic acid, nitrofurantoin, nonsteroidal anti-inflammatory drugs (NSAIDs).
  • Characteristic features — Eosinophilic BAL fluid, skin rash, fever, negative for pulmonary edema on radiography.
  • Diagnostic test — BAL.
  • Outcome — Favorable; recovery usually occurs with use of steroids or on dechallenge.
• Amiodarone pneumonitis
  • Typical drug — Amiodarone
  • Characteristic features — Dyspnea, chest pain, cough, mild fever, asymmetrical and nonsegmental opacities on radiographs
  • Diagnostic test — Radiography
  • Outcome — Favorable
• Pulmonary fibrosis
  • Typical drugs — Amiodarone, chemotherapy
  • Characteristic features — Fibrotic nonspecific interstitial pneumonia
  • Diagnostic test — Radiography
  • Outcome — Poor
• Desquamative interstitial pneumonia
  • Typical drugs — Methotrexate, interferons, etanercept-D2E7
  • Characteristic features — Alveolar accumulation of macrophages, mosaic pattern on radiographs
  • Diagnostic test — Radiography
  • Outcome — Favorable

Drug-induced interstitial lung disease with acute respiratory failure

• Methotrexate lung
  • Typical drugs — Methotrexate, chrysotherapy (gold therapy).
  • Characteristic features — Lymphocytic BAL fluid, history of infiltrative lung disease, high temperature.
  • Diagnostic tests — BAL, biopsy.
  • Outcome — Favorable; recovery usually occurs with use of steroids or on dechallenge.
• Acute eosinophilic pneumonitis
  • Typical drug — Minocycline
  • Characteristic features — Eosinophilic BAL fluid, fever, skin rash
  • Diagnostic test — BAL
  • Outcome — Favorable on cessation of minocycline
• Chemotherapy lung with diffuse alveolar damage
  • Typical drugs — Bleomycin, busulphan, carmustine, mitomycin
  • Characteristic features — Diffuse alveolar damage
  • Diagnostic tests — Radiography, high-resolution CT scanning
  • Outcome — Death in 50-60% of patients
• Pulmonary edema
  • Typical drugs — Cytosine arabinoside (Ara-C), beta2-receptor agonists, blood, blood products, narcotics, diuretics
  • Characteristic features — Permeability leakage in alveoli, bilateral consolidation on radiography
  • Diagnostic test — BAL (water in BAL fluid)
  • Outcome — Favorable
• Alveolar hemorrhage
  • Typical drugs — Oral anticoagulants, fibrinolytic agents, platelet glycoprotein inhibitors
  • Characteristic features — Bland hemorrhage or capillaritis, diffuse ground-glass appearance on radiographs
  • Diagnostic test — BAL
  • Outcome — Favorable

Preferred Examination

Although conventional chest radiography is the first choice in imaging options in evaluating patients for pulmonary manifestations of drug toxicity, the limitations of the pattern approach often necessitate the use of other imaging techniques in addition to clinical and laboratory evaluation. In select cases, high-resolution computed tomography (HRCT) and radionuclide imaging have a role in detecting lung toxicity early, when it is still reversible, or in differentiating drug toxicity from other lung pathology.²²

Limitations of Techniques

The major problem with all imaging is that drug-related lung toxicity has a nonspecific appearance, and similar patterns have been described with many interstitial lung diseases. Lung toxicity resulting from various drugs can induce similar changes. In patients taking drug combinations, the imaging findings alone may not reveal the culprit.

Differential Diagnoses

References

• Acute Pulmonary Embolism (Helical CT)
• Acute Respiratory Distress Syndrome
• Alveolar Proteinosis
• Asbestos-Related Disease
• Asbestosis
• Aspergillosis, Thoracic
• Aspiration Pneumonia
• Bronchiolitis Obliterans Organizing Pneumonia
• Lung, Metastases
• Lung, Nontuberculous Mycobacterial Infections
• Pulmonary Edema, Noncardiogenic
• Pulmonary Hypertension
• Pulmonary Interstitial Emphysema
• Radiation Pneumonitis