Imaging in Drug-Induced Lung Disease

Updated: Jul 07, 2016
  • Author: Ali Nawaz Khan, MBBS, FRCS, FRCP, FRCR; Chief Editor: Eugene C Lin, MD  more...
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Overview

Overview

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]

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. [11]

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.

Early recognition of drug-induced lung disease is important because it can be reversed if appropriate therapy is instituted soon after the onset of symptoms. Lack of response to empiric antibiotic treatment and an imaging pattern of organizing pneumonia should raise suspicion of everolimus-induced pneumonitis in patients undergoing therapy with this drug. [12]

See the images below.

A 48-year-old man was given a chemotherapeutic reg A 48-year-old man was given a chemotherapeutic regimen containing bleomycin to treat metastatic testicular cancer. This chest radiograph was obtained at the start of therapy (see also Image 2 in Multimedia). Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.

 

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Radiography

Conventional chest radiography is usually an initial investigation in patients with pulmonary and/or cardiac symptoms and may be the only imaging required. Although 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.

Busulfan 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 the images below). 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.

A 48-year-old man was given a chemotherapeutic reg A 48-year-old man was given a chemotherapeutic regimen containing bleomycin to treat metastatic testicular cancer. This chest radiograph was obtained at the start of therapy (see also Image 2 in Multimedia). Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
The patient shown in the previous image became sho The patient shown in the previous image became short of breath after 5 cycles of chemotherapy. This chest radiograph was obtained before he was hospitalized. It shows scattered reticular opacities. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.

Methotrexate lung toxicity is not dose related and is self-limiting despite continuing therapy. It is often associated with blood eosinophilia. [13] 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 the image below).

Nitrofurantoin lung. Scattered areas of reticular Nitrofurantoin lung. Scattered areas of reticular opacities, consistent with fibrosis, are apparent. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.

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. [14]

A case of salazosulfapyridine-induced pneumonitis associated with multiple pulmonary nodules and lymphadenopathy has been reported. [15]

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.

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Computed Tomography

The 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 the images below.) [16, 17, 18, 19, 20, 21, 22, 23]

Amiodarone lung. CT image shows nearly diffuse gro Amiodarone lung. CT image shows nearly diffuse ground-glass opacities and reticulation. Subsegmental consolidation in the lower lobes is also noted. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows changes associated with biopsy-proved alveolar proteinosis. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
High-resolution CT (HRCT) shows rapid changes asso High-resolution CT (HRCT) shows rapid changes associated with the use of amiodarone over a 3-month period. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
High-resolution CT (HRCT) shows rapid changes asso High-resolution CT (HRCT) shows rapid changes associated with the use of amiodarone over a 3-month period. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows changes associated with chronic eosinophilic pneumonia. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows collagen vascular-related interstitial lung disease. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows changes associated with hemosiderosis. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows changes associated with hypersensitivity pneumonitis. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.
Differential diagnosis of drug-related lung diseas Differential diagnosis of drug-related lung disease. High-resolution CT (HRCT) shows change associated with mixed disease of the connective tissue. Courtesy of Sat Sharma, MD, FRCPC, FACP, FCCP, DABSM.

Cytotoxic drugs

Approximately 10% of patients receiving cytotoxic drugs develop drug-induced lung reactions. [24] Any chemotherapeutic drug can adversely affect the lung, but the drugs most commonly implicated in lung toxicity are bleomycin, methotrexate, carmustine, busulfan, and cyclophosphamide. [25, 26, 27, 28, 29, 30, 31, 32]

Interstitial pneumonitis and fibrosis, hypersensitivity reaction, acute respiratory distress syndrome (ARDS), and cryptogenic organizing pneumonia (COP) or bronchiolitis obliterans organizing pneumonia (BOOP) are the most common types of lung reaction related to chemotherapy. [33, 34, 35]

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. [36]

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. [36] 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. [37]

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, which is a pattern consistent with noncardiogenic pulmonary edema. [38] 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. [39] 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. [40]

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. [37]

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 confidence

The 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%. [41] Abnormalities most commonly overlooked on radiography include ground-glass opacities and mild fibrosis.

False positives/negatives

Findings 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.

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Ultrasonography

Although 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.

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Nuclear Imaging

Richman et al found diffuse gallium-67 (67 Ga) localization in both lungs in 2 patients with interstitial pneumonitis associated with bleomycin therapy. [42] 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. [43] The patient had been taking multiple medications, including phenytoin. A chest radiograph and CT scan revealed no active disease. A67 Ga 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-up67 Ga study obtained 25 days after the baseline study demonstrated marked improvement in the lungs, with concurrent clinical recovery. This case illustrates the usefulness of67 Ga 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. [44] Symptomatic and objective improvement occurred with corticosteroid therapy.67 Ga lung scans showed increased accumulation of the radionuclide; a diffusely increased concentration of67 Ga was observed in both lungs. The abnormal accumulation of67 Ga 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 confidence

Limited 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. 67Ga uptake may occur in other types of granulomatous disease, such as sarcoids, infections, and lymphomas.

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