You are in: eMedicine Specialties > Radiology > CHEST Lung, Drug-Induced DiseaseArticle Last Updated: Jun 4, 2008AUTHOR AND EDITOR INFORMATIONSection 1 of 10
  Author: 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 Ali Nawaz Khan is a member of the following medical societies: American Institute of Ultrasound in Medicine, Radiological Society of North America, Royal College of Physicians, Royal College of Physicians and Surgeons of the United States, Royal College of Radiologists, and Royal College of Surgeons of England Coauthor(s): 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 Editors: Kitt Shaffer, MD, PhD, Director of Undergraduate Medical Education, Associate Professor, Department of Radiology, Cambridge Health Alliance; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; John D Newell, Jr, MD, FACR, FCCP, FASER, Co-Director of Thoracic Imaging, UCDHSC; Director of Lung Imaging Center, Professor of Radiology and Professor of Medicine, Department of Radiology, University of Colorado Health Sciences Center, National Jewish Medical and Research Center; Univ. Colorado Hospital; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Kavita Garg, MD, Professor, Department of Radiology, University of Colorado Health Sciences Center Author and Editor Disclosure Synonyms and related keywords: pulmonary hypersensitivity allergic reactions, asthma, hypersensitivity pneumonitis, eosinophilic pneumonia, drug-induced interstitial fibrosis, drug-induced pulmonary edema, drug-induced alveolar hemorrhage, drug-induced pleural effusions, drug-induced lung vasculitis, mediastinal inflammation, lymphadenopathy, drug-induced respiratory failure, drug-induced granulomatous lung disease, drug-induced systemic lupus erythematosus, interstitial lung disease, ILD INTRODUCTIONSection 2 of 10
  BackgroundThe 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 PathophysiologyOur 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). FrequencyUnited StatesThe 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:
InternationalNo 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
RaceSome ethnic groups are at increased risk for adverse reactions to drugs.
SexCertain drug-induced lung diseases have a sex predilection.
AgeDrug-induced lung disease is prevalent in both adults and children.
Clinical DetailsClassic drug-induced interstitial lung disease
Drug-induced interstitial lung disease with acute respiratory failure
Preferred ExaminationAlthough 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 TechniquesThe 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. DIFFERENTIALSSection 3 of 10
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 RADIOGRAPHSection 4 of 10
FindingsBusulfan toxicity causes drug-induced pulmonary damage after prolonged exposure, usually after 3-4 years of therapy. Approximately 1-10% of patients taking the drug are affected. Conventional radiographic changes include diffuse linear opacities, which may occasionally become reticulonodular. Pneumocystis jiroveci pneumonia (PCP) and interstitial leukemic infiltrates can have similar appearances. The abnormalities in the lung parenchyma may partially or completely resolve after the drug is withdrawn. Bleomycin lung toxicity occurs with doses larger than 300 mg in 3-6% cases, generally 1-3 months after the commencement of therapy (see Images 1-2). Increasing age, conjoint radiation therapy, and high concentrations of oxygen are associated with high rates of lung toxicity. Radiographic changes include subpleural linear and/or nodular opacities at the lung bases. Methotrexate lung toxicity is not dose related and is self-limiting despite continuing therapy. It is often associated with blood eosinophilia.23 Radiographic changes include linear and/or reticulonodular opacities early in the process, followed by acinar filling. On occasion, transient mediastinal lymphadenopathy and pleural effusions occur. Nitrofurantoin lung toxicity may appear in an acute stage or in a chronic stage. An acute presentation is more common than a chronic one and is often associated with fever and eosinophilia. The chronic form manifests as a pulmonary fibrotic process, often with no accompanying eosinophilia. Bilateral basal interstitial opacities are observed (see Image 4). Pulmonary granulomas are composed of macrophages reacting to various drugs, such as methotrexate and nitrofurantoin. A common form of granulomatous reaction is also seen after chronic aspiration of mineral oils, which leads to the formation of chronic basilar, often conglomerate, masses.24 A case of salazosulfapyridine-induced pneumonitis associated with multiple pulmonary nodules and lymphadenopathy has been reported.25 Heroin, propoxyphene, or methadone overdose is often associated with pulmonary edema with widespread airspace consolidation. Aspiration pneumonia may be a complication in more than one half of patients. Aspirin overdose may also cause pulmonary edema. Amiodarone therapy is associated with alveolar and interstitial infiltrates, peripheral consolidation, and pleural thickening adjacent to the consolidation. The lung consolidation tends to have increased density because of the iodine content. Ground-glass opacity may be observed in drug- or radiation-induced lung disease. Ground-glass opacification is much better defined with high-resolution computed tomography (HRCT) than with radiography. Ground-glass opacity is commonly observed in patients with early diffuse pulmonary infiltrative diseases. Ground-glass pulmonary opacification is a nonspecific finding but nevertheless an important sign of disease. It is also a useful sign of an active and treatable component in some diffuse pulmonary diseases, including drug toxicity. Degree of ConfidenceConventional chest radiography is usually an initial investigation in patients with pulmonary and/or cardiac symptoms and may be the only imaging required. False Positives/NegativesAlthough chest radiography is the first choice among 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. Many pathologies, such as infections, sarcoidosis, lymphoma, and interstitial pneumonias, can mimic drug-induced lung disease. CT SCANSection 5 of 10
FindingsThe diagnosis of drug-induced lung disease is often made on the basis of a history of drug exposure, histologic evidence of lung injury, and the exclusion of other causes of lung injury. The main value of HRCT is in the depiction of parenchymal abnormalities in symptomatic patients who have normal or questionable findings on chest radiography (see Images 3, 5-12).26, 27, 28, 29, 30, 31, 32 Cytotoxic drugs Approximately 10% of patients receiving cytotoxic drugs develop drug-induced lung reactions.33 Any chemotherapeutic drug can adversely affect the lung, but the drugs most commonly implicated in lung toxicity are bleomycin, methotrexate, carmustine, busulfan, and cyclophosphamide.34, 35, 36, 37, 38 Interstitial pneumonitis and fibrosis, hypersensitivity reaction, ARDS, and COP or BOOP are the most common types of lung reaction related to chemotherapy.39, 40, 41 HRCT findings in chemotherapeutic drug-induced lung reactions reflect the histologic findings. The most consistent findings in chemotherapy-induced (particularly bleomycin-induced) lung reaction include interstitial pneumonitis and fibrosis, which result in ground-glass attenuations, focal areas of consolidation, and irregular and linear attenuations that predominantly involve the lower zones of the lungs. Hypersensitivity lung reaction complicating chemotherapy resembles other types of hypersensitivity pneumonitis, which cause ground-glass opacities and poorly defined centrilobular nodules. Bilateral extensive airspace consolidation can also occur, particularly as a reaction to methotrexate.42 ARDS may occur within days after induction of chemotherapy, and it may cause bilateral and predominantly dependent airspace consolidation. BOOP is a less common reaction to chemotherapeutic drugs, particularly bleomycin.42 BOOP commonly results in peribronchial or subpleural areas of consolidation. Cardiovascular agents Amiodarone is the most common drug related to cardiovascular pulmonary abnormalities. It affects as many as 6% of individuals receiving the drug.43 HRCT shows diffuse interstitial thickening or, infrequently, nodular areas of subpleural consolidation (BOOP). On occasion, patients present with the acute onset of dyspnea and fever, which cause areas of dependent consolidation. Amiodarone contains iodine. Therefore, lung parenchymal opacities have increased attenuation (82-174 HU). This finding is suggestive, but it is not pathognomonic of amiodarone-induced pulmonary toxicity. Antibiotics Nitrofurantoin, amphotericin B, sulfonamides, and sulfasalazine are known to cause lung toxicity. Antibiotic-related lung disease includes interstitial pneumonitis and fibrosis, hypersensitivity reaction, ARDS, and BOOP. Nitrofurantoin is responsible for lung toxicity in less than 1% of patients receiving the drug; however, it remains an important cause of adverse drug reaction. The most common presentation is that of an acute hypersensitivity reaction. HRCT shows airspace consolidation with a basal predominance and pleural effusions — a pattern consistent with noncardiogenic pulmonary edema.44 Chronic pneumonitis and fibrosis occur infrequently and are usually related to prolonged therapy over years. Chronic pneumonitis and fibrosis may mimic idiopathic pulmonary fibrosis on HRCT, with bilateral, predominantly basilar reticular opacities. On occasion, a BOOP-like reaction may also be seen. Illicit drugs Illicit drug abuse is now regarded as the most common cause of drug-related lung toxicity.45 Pulmonary talcosis is a known complication of intravenous drug abuse. HRCT shows diffuse micronodularity resulting from a foreign-body granulomatous response. These micronodules may become confluent, forming conglomerate parahilar masses, which tend to have high attenuation because of their talc content. Ground-glass attenuation has also been described. Intravenous methylphenidate abuse may result in talcosis and in severe panlobular emphysema.46 Intravenous heroin and cocaine abuse is a known cause of acute pulmonary edema occurring within a few hours of injection. The effect is presumably related to direct alveolar capillary injury.43 Anti-inflammatory drugs Aspirin is the most common anti-inflammatory drug associated with adverse reactions. An ARDS-type syndrome has been described with salicylate toxicity. Methotrexate is increasingly used as an anti-inflammatory agent to treat many disorders. A low-dose regimen is typically used; nevertheless, pulmonary toxicity has been reported in approximately 4% of patients. Pulmonary reaction to methotrexate is commonly subacute, with a hypersensitivity-like reaction. HRCT shows changes of interstitial pneumonitis and occasionally centrilobular nodules or a localized nodular airspace consolidation. Degree of ConfidenceThe main value of HRCT is in the depiction of parenchymal abnormalities in symptomatic patients who have normal or questionable findings on chest radiography. HRCT is superior to radiography in depicting the presence and distribution of parenchymal abnormalities. One study reported abnormal findings on HRCT in all patients and abnormal findings on radiography in 74%.47 Abnormalities most commonly overlooked on radiography include ground-glass opacities and mild fibrosis. False Positives/NegativesFindings on HRCT associated with drug-induced lung disease can mimic many other pulmonary pathologies, such as infection, pulmonary fibrosis, and disease recurrence. The diagnosis should be suspected in patients receiving one or more drugs known to be potentially damaging to the lung and in those with radiologic findings consistent with interstitial pneumonitis and fibrosis, hypersensitivity reaction, ARDS, or BOOP. ULTRASOUNDSection 6 of 10
FindingsAlthough ultrasonography has no direct role in the management of drug-induced lung disease, it does have a role in the confirmation of pleural effusions and assessment for pleural intervention. NUCLEAR MEDICINESection 7 of 10
FindingsRichman et al found diffuse gallium-67 (67Ga) localization in both lungs in 2 patients with interstitial pneumonitis associated with bleomycin therapy.48 Clinical symptoms and the results of laboratory evaluation of pulmonary status were correlated with scintigraphic findings in these 2 patients, whereas discrepancies between scintigraphic and radiographic findings were observed. Khan et al described a patient receiving a cardiac transplant who presented with a fever of undetermined etiology.49 The patient had been taking multiple medications, including phenytoin. A chest radiograph and CT scan revealed no active disease. A 67Ga study showed diffuse intense uptake in both lungs. A bronchoscopic biopsy confirmed hypersensitivity pneumonitis. Phenytoin was withdrawn, and a corticosteroid was started in therapeutic doses. A follow-up 67Ga study obtained 25 days after the baseline study demonstrated marked improvement in the lungs, with concurrent clinical recovery. This case illustrates the usefulness of 67Ga imaging in the detection of drug-induced pneumonitis and in the follow-up of response to therapy. Brown et al described a case of pulmonary granulomatosis in a user who habitually injected methylphenidate (Ritalin) intravenously.50 Symptomatic and objective improvement occurred with corticosteroid therapy. 67Ga lung scans showed increased accumulation of the radionuclide; a diffusely increased concentration of 67Ga was observed in both lungs. The abnormal accumulation of 67Ga was reduced, the arterial oxygen pressure and the diffusing capacity for carbon monoxide were improved, and the infiltrate was reduced on the chest radiograph 2 months after the start of therapy. Degree of ConfidenceLimited evidence suggests that 67Ga scanning may be useful in evaluating drug-induced pneumonitis and pulmonary granulomatous disease. Although 67Ga scanning and positron-emission tomography scanning are not primary modalities for the diagnosis of lung toxicity, they are commonly used in follow-up imaging of patients with various malignancies; therefore, it is important to recognize the findings of lung toxicity on these images. False Positives/Negatives67Ga uptake may occur in other types of granulomatous disease, such as sarcoids, infections, and lymphomas. INTERVENTIONSection 8 of 10
Transbronchial or percutaneous biopsy is sometimes warranted in the diagnosis of drug-induced lung disease to differentiate it from underlying malignancy and other lung-infiltrating disorders. Medical/Legal Pitfalls
MULTIMEDIASection 9 of 10
REFERENCESSection 10 of 10
Lung, Drug-Induced Disease excerpt Article Last Updated: Jun 4, 2008 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
