Approach Considerations
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 complete blood cell (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.
The clinical and radiologic manifestations of pulmonary drug toxicity generally reflect the underlying histopathologic processes. High-resolution computed tomography (CT) scanning is more sensitive than chest radiography for defining the radiographic abnormalities. [2]
Other studies that may be indicated include the following:
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Pulmonary function tests (PFTs)
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Arterial blood gas (ABG) analyses
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Flexible bronchoscopy
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Open lung biopsy or video-assisted thoracoscopic lung biopsy
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Bronchoalveolar lavage (BAL)
Chest Radiography and Computed Tomography
The radiologic patterns seen in pulmonary drug toxicity can be divided into the following categories:
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Diffuse alveolar damage (DAD)
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Interstitial pneumonitis
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Cryptogenic organizing pneumonia (COP) (bronchiolitis obliterans-organizing pneumonia [BOOP])
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Pulmonary edema
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Eosinophilic pneumonia
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Pulmonary hemorrhage
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Granulomatous pneumonitis
Diffuse alveolar damage
Drugs implicated in DAD include amiodarone, cyclophosphamide, bleomycin, carbamazepine, etoposide, cocaine, heroin, methotrexate (MTX), and mitomycin C. 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.
Chest radiographs show bilateral heterogeneous or homogeneous parenchymal consolidation, usually most marked in the dependent lung regions. Fibrosis typically develops within 1 week, but it may not initially be evident on chest radiographs.
High-resolution computed tomography (CT) scans in patients with early DAD typically show scattered or diffuse areas of ground-glass opacity and intralobular septal thickening. Kerley lines (interlobular septal thickening) are usually absent.
Interstitial pneumonitis
Both usual interstitial pneumonia and nonspecific interstitial pneumonia (NSIP) have been associated with drug injury. The clinical radiographic manifestations are often identical to those of idiopathic pulmonary fibrosis. NSIP occurs most commonly as a manifestation of amiodarone, MTX, or carmustine toxicity. Gold salts and chlorambucil toxicity are less common causes of NSIP.
Radiographic studies indicate bilateral, usually symmetrical, interstitial or alveolar opacities. The infiltrates may localize in the lung bases or mid lung zones or they 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.
COP
In COP (or BOOP), chest radiographs demonstrate bilateral scattered heterogeneous and homogeneous opacities. These areas are typically located in the periphery and are equally distributed between the upper and lower lobes.
Drugs that can cause COP include acebutolol, amiodarone, amphotericin B, bleomycin, and carbamazepine. Nodular organizing pneumonia, which is typically observed in patients exposed to bleomycin, can be seen as round foci that localize mainly in the lung bases; however, they may abut the pleura and simulate metastatic nodules.
CT scanning in COP often shows associated poorly defined nodular areas of consolidation, centrilobular nodules, branching linear opacities, and bronchial dilatation. See the image below.
This image is a standard nonenhanced axial thoracic computed tomography scan. There is left lower lobe consolidation with some loss of volume and an air bronchogram. Transbronchial lung biopsy confirmed the diagnosis of cryptogenic organizing pneumonia (also known as bronchiolitis obliterans-organizing pneumonia [BOOP]).
Pulmonary edema
On chest radiographs, typical findings of pulmonary edema include Kerley lines and pleural effusion. Chest CT scanning may reveal pleural effusion or ground-glass opacity and, to a lesser extent, consolidation.
Eosinophilic pneumonia
Drug toxicity is an important cause of acute and chronic eosinophilic pneumonias. Causative drugs include penicillamine, sulfasalazine, nitrofurantoin, para-aminosalicylic acid, and nonsteroidal anti-inflammatory drugs (NSAIDs). Patients also may have blood eosinophilia.
Eosinophilic pneumonia is characterized by the accumulation of eosinophils and macrophages in the alveoli. Imaging studies show pulmonary infiltrates that 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 causative agents include anticoagulants, amiodarone, high-dose cyclophosphamide, mitomycin C, cytarabine, and penicillamine. Penicillamine can cause a pulmonary-renal syndrome similar to Goodpasture syndrome.
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
On CT scanning, granulomatous pneumonitis manifests as reticulonodular pulmonary shadows, mediastinal lymph node enlargement, or both, with or without involvement of extrathoracic organs. See the image below. Granulomatosis has been reported in a few patients after treatment of non-Hodgkin lymphoma with chemotherapeutic agents, as well as with cocaine, cromolyn sodium, fluoxetine, MTX, nitrofurantoin, procarbazine, and pentazocine.
This image is a computed tomography scan of a patient with sarcoidosis. The pattern of multiple nodules seen here can manifest in patients taking medications that can cause granulomatous reactions.
Pulmonary Function Tests and Arterial Blood Gas Analysis
Pulmonary function tests (PFTs) include spirometry, lung volume determinations, and diffusing capacity of the lungs for carbon monoxide (DLCO). Most drugs cause a restrictive lung disease pattern with decreases in the following:
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Total lung capacity (TLC)
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Residual volume (RV)
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Functional residual capacity (FVC)
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DLCO
The ratio of forced expiratory volume in 1 second (FEV1) to FVC (FEV1/FVC ratio) may be normal or increased. However, drugs that cause bronchiolitis obliterans or bronchospasm may produce an obstructive ventilatory defect (reduced FEV1/FVC ratio and FEV1, increased RV and RV/TLC ratio).
Arterial blood gases (ABGs) 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 to 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 at least 50% compared with pretherapy values.
Bronchoalveolar Lavage
Bronchoalveolar lavage (BAL) findings are not specific for any drug-induced lung disease, and a definitive diagnosis cannot be made based solely on BAL findings. BAL findings can, however, contribute to the expected clinicopathologic pattern of a given drug-induced lung disease. BAL is also helpful in narrowing the differential diagnosis, primarily in excluding an infective cause or involvement of the lungs by the underlying disease (eg, metastatic cancer, malignant lymphoma).
Appropriate stains, cultures, and molecular techniques for BAL fluid should be performed to exclude opportunistic infections. A low ratio of CD4+ to CD8+ lymphocytes is suggestive of, but not specific for, drug-induced lung disease. BAL can be very helpful in the diagnosis of alveolar hemorrhage, for which the BAL fluid shows increased blood staining in sequential aliquots. High eosinophil counts (>40%) in BAL fluid can be seen in patients with drug-induced pulmonary eosinophilia.
BAL findings in amiodarone toxicity
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Positive for neutrophils and "foamy" macrophages
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Possibly positive for lymphocytes
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Negative for eosinophils and birefringent particles
BAL findings in methotrexate toxicity
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Positive for lymphocytes
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Negative for neutrophils, macrophages, eosinophils, and birefringent particles
BAL findings in bleomycin toxicity
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Positive for neutrophils
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Possibly positive for lymphocytes and eosinophils
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Negative for macrophages and birefringent particles
BAL findings in talc toxicity
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Positive for birefringent particles
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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 the following:
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Diffuse alveolar damage (DAD)
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Nonspecific interstitial pneumonia (NSIP)
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Cryptogenic organizing pneumonia (COP) (bronchiolitis obliterans-organizing pneumonia [BOOP])
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Granulomatous pneumonitis
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Eosinophilic pneumonia
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Obliterative bronchiolitis
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Pulmonary hemorrhage
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Pulmonary vasculitis
DAD
DAD results from necrosis of type 2 pneumocytes and alveolar endothelial cells. The main histopathologic features are as follows [75] :
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Hyaline membrane formation and fibrin deposits lining the alveolar border
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Dysplasia of type 2 cells
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Free alveolar fibrin
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Cells and debris in alveolar spaces
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Various stages of interstitial edema, inflammation, and organization
DAD is the histopathologic equivalent of the adult respiratory distress syndrome (ARDS). See the image below.
This histologic section of the lung shows diffuse alveolar damage in a patient with adult respiratory distress syndrome.
NSIP
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. See the image below.
In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity on histologic examination. 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.
COP
Histologically, COP 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 the lung bases but may abut the pleura and simulate metastatic nodules. See the image below.
Cryptogenic organizing pneumonia (also called bronchiolitis obliterans-organizing pneumonia [BOOP]) 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 the surrounding alveoli.
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. [76] See the image below.
This is a close-up histologic view of a noncaseating granuloma with a giant cell.
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This image is a standard nonenhanced axial thoracic computed tomography scan. There is left lower lobe consolidation with some loss of volume and an air bronchogram. Transbronchial lung biopsy confirmed the diagnosis of cryptogenic organizing pneumonia (also known as bronchiolitis obliterans-organizing pneumonia [BOOP]).
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Cryptogenic organizing pneumonia (also called bronchiolitis obliterans-organizing pneumonia [BOOP]) 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 the surrounding alveoli.
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This image is a computed tomography scan of a patient with sarcoidosis. The pattern of multiple nodules seen here can manifest in patients taking medications that can cause granulomatous reactions.
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This histology image from a lung biopsy specimen was obtained from the patient with sarcoidosis discussed in the previous image (see the computed tomography scan illustrating multiple nodules). Multiple areas of noncaseating granulomas are present. Drugs such as methotrexate, nitrofurantoin, procarbazine, and pentazocine can cause granulomatous lung disease.
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This is a close-up histologic view of a noncaseating granuloma with a giant cell.
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This histologic section of the lung shows diffuse alveolar damage in a patient with adult respiratory distress syndrome.
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In usual interstitial pneumonitis or idiopathic pulmonary fibrosis, subpleural and paraseptal inflammation is present, with an appearance of temporal heterogeneity on histologic examination. 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.
