Drug-Induced Pulmonary Toxicity Workup

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

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

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

The clinical and radiological manifestations of pulmonary drug toxicity generally reflect the underlying histopathologic processes. High-resolution CT scanning is more sensitive than chest radiography for defining the radiographic abnormalities. Similar to histopathology, the radiologic patterns can be divided into categories, as described below.

Diffuse alveolar damage

Chest radiographs show bilateral heterogeneous or homogeneous parenchymal consolidation, usually most marked in the dependent lung regions. Fibrosis typically develops within 1 week but, initially, may not be evident on chest radiographs.

High-resolution CT scanning in early DAD typically shows scattered or diffuse areas of ground-glass opacity and intralobular septal thickening; Kerley lines are typically absent.

Interstitial pneumonitis

Both usual interstitial pneumonia and NSIP have been associated with drug injury. The clinical radiographic manifestations are often identical to those of idiopathic pulmonary fibrosis. Radiographic studies indicate bilateral, usually symmetrical, interstitial or alveolar opacities. The infiltrates may localize in the lung bases or midlung zones or may be diffuse. The radiographic density can be discrete haze, ground-glass, or dense bilateral consolidation with air bronchograms and volume loss.

Early high-resolution CT scans may show only scattered or diffuse areas of ground-glass opacity. Later, findings of fibrosis (traction bronchiectasis, honeycombing) predominate in a basal distribution.

Bronchiolitis obliterans-organizing pneumonia

In BOOP, chest radiographs demonstrate bilateral scattered heterogeneous and homogeneous opacities. These areas are typically peripheral in distribution and are equally distributed between the upper and lower lobes. Nodular organizing pneumonia is typically seen in patients exposed to bleomycin, in the form of round-shaped foci that localize mainly in lung bases; however, they may abut the pleura and simulate metastatic nodules.

CT scanning often shows associated poorly defined nodular areas of consolidation, centrilobular nodules, branching linear opacities, and bronchial dilatation. See the image below.

Pulmonary edema

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

Eosinophilic pneumonia

Imaging studies show the pulmonary infiltrates are typically alveolar and symmetrical and occasionally display the classic pattern of a "photographic negative" of pulmonary edema. However, in drug-induced eosinophilic pneumonia, a reverse pulmonary edema pattern is uncommon. CT scanning can be useful for demonstrating the peripheral nature of the pulmonary opacities.

Pulmonary hemorrhage

Drug-related diffuse pulmonary hemorrhage is uncommon. Typical causes are anticoagulants, cyclophosphamide, and penicillamine. Chest radiographs typically reveal bilateral heterogeneous and homogenous opacities. High-resolution CT scanning usually shows bilateral, scattered, or diffuse areas of ground-glass opacity. Pleural effusion is typically absent.

Granulomatous pneumonitis

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

Pulmonary function tests

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

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

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

Flexible bronchoscopy

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

Lung biopsy

Open lung biopsy or video-assisted thoracoscopic lung biopsy may be necessary in selected cases.

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 can, however, contribute to the expected clinicopathologic pattern of a given drug-induced lung disease. BAL also is helpful in 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 for specific drugs are as follows:

• Amiodarone

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

  • Positive for lymphocytes
  • Negative for neutrophils, macrophages, eosinophils, and birefringent particles
• Bleomycin

  • Positive for neutrophils
  • Possibly positive for lymphocytes and eosinophils
  • Negative for macrophages and birefringent particles
• Talc

  • Positive for birefringent particles
  • Negative for neutrophils, macrophages, lymphocytes, and eosinophils

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

Diffuse alveolar damage

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

The main histopathologic features are hyaline membrane formation and fibrin deposits lining the alveolar border, dysplasia of type 2 cells, free alveolar fibrin, cells and debris in alveolar spaces, and various stages of interstitial edema, inflammation, and organization.^[55] Some of the implicated drugs include amiodarone, cyclophosphamide, bleomycin, carbamazepine, etoposide, cocaine, heroin, MTX, and mitomycin C. See the image below.

Nonspecific interstitial pneumonia

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

Bronchiolitis obliterans-organizing pneumonia

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

Eosinophilic pneumonia

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

Pulmonary hemorrhage and vasculitis

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

Granulomatous pneumonitis

Some drugs are capable of producing a granulomatous inflammation without necrosis. These agents can induce a granulomatous pneumonitis with or without the bronchiolitis and interstitial inflammation seen in hypersensitivity pneumonitis.^[56] Examples are cocaine, cromolyn sodium, fluoxetine hydrochloride, MTX, nitrofurantoin, procarbazine, and pentazocine. See the image below.