Drug-Induced Lung Disease Imaging

Drugs that adversely affect the respiratory system present a great challenge to physicians. More than 600 drugs are known to have the potential to cause pulmonary disease. The clinical study group, Groupe d'Etudes de la Pathologie Pulmonaire Iatrogene (GEPPI), maintains an active website listing of drugs that have been associated with pulmonary toxicity, which provides details on the frequency with which toxicities have been associated with individual drugs. ^{[1, 2, 3, 4, 5, 6, 7]}

Although conventional chest radiography is the first choice among imaging options for identifying patients with pulmonary manifestations of drug toxicity, limitations of the pattern approach often necessitate the use of other imaging techniques, in addition to clinical and laboratory assessments. In select cases, high-resolution computed tomography (HRCT) and radionuclide imaging play a role in detecting lung toxicity early, when it is still reversible, or in differentiating drug toxicity from other lung pathology. ^[8]

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

Early recognition is important because drug-induced lung disease can often 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. ^[9]  Likewise, bilateral pleural effusion and extensive pulmonary interstitial prominence suggesting pulmonary fibrosis on CT scan in a patient presenting with dyspnea and dry cough may alert the clinician to pulmonary injury resulting from use of nitrofurantoin for treatment of an uncomplicated urinary tract infection. ^[10]

In these and many other cases, early detection of pulmonary toxicity would allow prompt treatment and could prevent significant pulmonary damage. ^[11]

Although ultrasonography has no direct role in the management of drug-induced lung disease, it is useful in confirming pleural effusions and in assessing pleural intervention.

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Conventional chest radiography is usually an initial investigation for 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, limitations of the pattern approach often necessitate the use of other imaging techniques, in addition to clinical and laboratory evaluation. Many pathologies, such as infection, sarcoidosis, lymphoma, and interstitial pneumonia, 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 occasionally may become reticulonodular. Pneumocystis (jrovecii) pneumonia (PCP) and interstitial leukemic infiltrates can have a similar appearance. 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% of cases, generally 1-3 months after commencement of therapy. 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.

Mesalazine can lead to progressive shortness of breath, generally after 2-3 years of treatment. Chest radiography shows increased bilateral infiltrates, and CT reveals diffuse peribronchial and subpleural consolidations in bilateral lungs. A case report of a 75-year-old female patient with ulcerative colitis shows that early identification of mesalazine-related lung disease followed by discontinuation of this agent and initiation of steroid therapy led to improved clinical symptoms and radiographic images, as well as discharge from hospital, illustrating a favorable outcome with proper management of this life-threatening adverse event. ^[12]

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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 may occur.

Nitrofurantoin lung toxicity may appear at an acute stage or at 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 evident.

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Pulmonary granulomas are composed of macrophages reacting to various drugs, such as methotrexate and nitrofurantoin. Another common form of granulomatous reaction is seen after long-term aspiration of mineral oils, which may lead 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 50% of patients. Aspirin overdose may also cause pulmonary edema.

Amiodarone therapy for heart dysrhythmia leads to lung toxicity in about 1-5% of cases. Lung manifestations are widely variable and include 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. Lung toxicity can be reversible but may be irreversible and sometimes is fatal. Risks must always be considered, and amiodarone should be used only for short periods. ^[16]

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 disease. Ground-glass pulmonary opacification is a nonspecific finding but is 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.

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 exclusion of other causes of lung injury. As this diagnosis is difficult to make, computed tomography is an important diagnostic tool. Recognition of CT manifestations of interstitial lung disease induced by tyrosine kinase inhibitors is key for early recognition and management of this pulmonary toxicity. ^{[17, 18, 19, 20, 21, 22]}

The main value of high-resolution computed tomography (HRCT) can be seen in the depiction of parenchymal abnormalities among symptomatic patients who have normal or questionable findings on chest radiography. ^{[23, 24, 25]}

High-resolution CT 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%. ^[26]  Abnormalities most commonly overlooked on radiography include ground-glass opacities and mild fibrosis.

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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 1 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, acute respiratory distress syndrome (ARDS), or bronchiolitis obliterans organizing pneumonia (BOOP).

Richman et al found diffuse gallium-67 (⁶⁷Ga) localization in both lungs in 2 patients with interstitial pneumonitis associated with bleomycin therapy. ^[27] Clinical symptoms and the results of laboratory evaluation of pulmonary status were correlated with scintigraphic findings in these 2 patients, although 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. ^[28] The patient had been taking multiple medications, including phenytoin. Chest radiography and CT scan revealed no active disease. A ⁶⁷Ga study showed diffuse intense uptake in both lungs. 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 baseline showed marked improvement in the lungs, with concurrent clinical recovery. This case illustrates the usefulness of ⁶⁷Ga imaging for detection of drug-induced pneumonitis and for follow-up of response to therapy.

Brown et al described a case of pulmonary granulomatosis in a user who habitually injected methylphenidate intravenously. ^[29] Symptomatic and objective improvement occurred with corticosteroid therapy. Ga-67 lung scan showed increased accumulation of the radionuclide; a diffusely increased concentration of ⁶⁷Ga was observed in both lungs. Abnormal accumulation of ⁶⁷Ga was reduced, arterial oxygen pressure and diffusing capacity for carbon monoxide were improved, and the infiltrate was reduced on chest radiography 2 months after the start of therapy.

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 (PET) 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 findings of lung toxicity on these images. Ga-67 uptake may occur in other types of granulomatous disease, such as sarcoid, infection, and lymphoma.

Cytotoxic drugs

Approximately 10% of patients receiving cytotoxic drugs develop drug-induced lung reactions. ^[30]  Any chemotherapeutic drug can adversely affect the lung, but bleomycin, methotrexate, carmustine, busulfan, and cyclophosphamide are most commonly implicated in lung toxicity. ^{[31, 32, 33, 34, 35, 36, 37, 38]}

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. ^{[39, 40, 41]}

A case report describes a 64-year-old female patient with a medical history of scoliosis, cholecystectomy, and Hodgkin lymphoma who was admitted for dry cough, dyspnea, fever, loss of appetite, and weight loss. Respiratory insufficiency due to bleomycin toxicity was diagnosed. The patient died on the sixth day after transfer to the intensive care unit. Case authors recommend that although bleomycin is an effective chemotherapeutic agent for Hodgkin lymphoma treatment, clinicians should always remember that bleomycin toxicity may lead to fatal complications in patients with comorbid conditions. ^[42]

Multicycle chemotherapy or local radiotherapy for treatment of lymphoma has resulted in adverse events such as drug-induced lung disease. Positron emission tomography/computed tomography (PET/CT) is often used to evaluate the lesion, effects of treatment, and prognosis for patients with this hematologic disease. ^[43]

A case report and literature review of lung toxicity in non-small-cell lung cancer patients receiving 2 different anaplastic lymphoma kinase–tyrosine kinase inhibitors (ALK-TKIs) assessed the clinical significance of this toxicity. Radiologic patterns of pneumonia were reported in 25 patients, and imaging suggestive of interstitial lung disease was noted in 37 patients. Overall, 25 of 105 patients permanently discontinued treatment because of lung toxicity. Lung toxicity is a rare, albeit potentially severe, side effect in non-small-cell lung cancer patients receiving ALK-TKIs, apparently more frequent with brigatinib. Its early recognition and treatment are crucial for best outcomes for this subgroup of patients, whose overall prognosis has been improved by the availability of several targeted agents. ^[44]

High-resolution CT findings in chemotherapeutic drug–induced lung reactions reflect histologic findings. The most consistent findings in chemotherapy-induced (particularly bleomycin-induced) lung reactions 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. ^[45]

Acute respiratory distress syndrome (ARDS) may occur within days after induction of chemotherapy and may cause bilateral and predominantly dependent airspace consolidation. Bronchiiolitis obliterans organizing pneumonia (BOOP) is a less common reaction to chemotherapeutic drugs, particularly bleomycin. ^[45]  This condition commonly results in peribronchial or subpleural areas of consolidation.

Cardiovascular agents

Amiodarone is the most common drug related to cardiovascular pulmonary abnormalities. ^[46]  Lung toxicity affects 1-5% of individuals receiving the drug. The main treatment is discontinuation of the drug. ^[16]

High-resolution CT (HRCT) shows diffuse interstitial thickening or, infrequently, nodular areas of subpleural consolidation (BOOP). On occasion, patients present with 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 is not pathognomonic of amiodarone-induced pulmonary toxicity.

Lung disease may progress initially because of the prolonged half-life and accumulation of amiodarone in adipose tissue. Regarding prognosis, lung toxicity can be reversible, but in some cases it is irreversible and it is sometimes fatal. The risks associated with its use must always be considered. ^[16]

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 reactions. The most common presentation is that of an acute hypersensitivity reaction.

High-resolution CT shows airspace consolidation with a basal predominance and pleural effusions, which is a pattern consistent with noncardiogenic pulmonary edema. ^[47]  Chronic pneumonitis and fibrosis occur infrequently and usually are 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 be seen.

In a case report of an 81-year-old woman with shortness of breath and cough 3 days after initiation of nitrofurantoin, it was determined that nitrofurantoin was the probable cause. Immediate cessation of the medication showed marked clinical improvement and resolution after 10 days. ^[10]

Illicit drugs

Illicit drug abuse is now regarded as the most common cause of drug-related lung toxicity. ^[48]  Pulmonary talcosis is a known complication of intravenous drug abuse. High-resolution CT 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. ^[49]

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. ^[46]

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. High-resolution CT shows changes of interstitial pneumonitis and occasionally centrilobular nodules or a localized nodular airspace consolidation.

Immune checkpoint inhibitors (ICIs)

Immunotherapy given alone or in combination with chemotherapy is standard first-line therapy for patients with advanced non-small-cell lung cancer. Despite significant benefits, immune checkpoint inhibitors (ICIs) can cause toxicities within any organ, termed immune-related adverse events. Pneumonitis is a potentially life-threatening complication of ICIs. Currently, there are no established guidelines for use of ICIs in patients with underlying autoimmune or interstitial lung disease, and few studies have been published. ^[50]

Immunosuppressants

Lung toxicity is a rare but serious adverse effect of sirolimus, a mammalian target of rapamycin inhibitor used as an immunosuppressive agent in solid-organ transplant recipients. ^[51]

One report describes a 67-year-old male patient who 12 years ago underwent living-related renal transplant that was complicated by chronic allograft dysfunction. He presented with fever, cough, and shortness of breath. Chest imaging showed bilateral patchy and ground-glass opacities. Before symptoms of lung toxicity became present, the patient's sirolimus levels were in the range of high normal. Bronchoalveolar lavage ruled out infection, and a transbronchial biopsy was inconclusive. A fluorodeoxyglucose (FDG) PET scan showed high uptake in the area of lung opacities, with a standard uptake value of 4.7. Symptoms improved after the patient was switched from sirolimus to tacrolimus. A thoracic CT scan after 6 weeks showed complete resolution. ^[51]

Pulmonary toxicity should be considered in any patient on sirolimus treatment with respiratory symptoms and opacities on chest imaging. ^[51]