Drug-Induced Lung Disease

Drug-induced lung injury is seen as a wide variety of histologic reaction patterns and thus as diverse CT findings. The most common are interstitial pneumonia and fibrosis (either usual interstitial pneumonia [UIP] or nonspecific interstitial pneumonia [NSIP]), eosinophilic pneumonia (including DRESS syndrome; drug reaction with eosinophilia and systemic symptoms), cryptogenic organizing pneumonia (COP), diffuse alveolar damage (DAD), and hypersensitivity pneumonia [1, 2]. Other reactions such as granulomatous pneumonitis, vasculitis, alveolar proteinosis, obliterative bronchiolitis, and veno-occlusive disease are uncommon [2]. None of these histologic patterns is specific for either drug reaction in general or the reaction to a particular drug. Consequently, the diagnosis of drug-induced lung disease is based on a combination of radiologic, clinical, and histologic (when imperative) findings in a patient who has received a drug known to cause the abnormalities.

Interstitial Pneumonitis and Fibrosis

One of the most common forms of drug-induced pneumonitis is nonspecific interstitial pneumonia (NSIP) [1, 2] (Fig. 27.1). This is characterized histologically by homogeneous alveolar wall thickening by fibrous tissue and mononuclear inflammatory cells. The reaction is seen most commonly in association with methotrexate, amiodarone, or carmustine toxicity (Table 27.1). The corresponding thinsection CT (TSCT) findings usually consist of patchy or diffuse areas of ground-glass opacity (GGO) (Fig. 27.1). With progression, there may be evidence of fibrosis, including reticulation, traction bronchiectasis, and honeycombing. The abnormalities show typically lower lung zone predominance. In some patients, the fibrosis is patchy in distribution and predominantly peribronchovascular; fibrotic NSIP pattern, commonly in patients receiving nitrofurantoin [3].

The second most common histologic form of druginduced interstitial pneumonitis is usual interstitial pneumonia (UIP) (Fig. 27.2). This is characterized histologically

by a heterogeneous pattern of chronic inflammation and fibrosis, with foci of dense and loose (fibroblastic) connective tissue being present in the same lobule. Progression of the interstitial disease leads to obliteration of alveolar airspaces by mature fibrous tissue associated with dilatation of residual transitional airways (honeycombing). This pattern of injury occurs most commonly in association with cytotoxic chemotherapeutic agents such as bleomycin, busulfan, methotrexate, doxorubicin, and carmustine. Noncytotoxic drugs such as nitrofurantoin, amiodarone, gold, and penicillamine also result in this reaction occasionally.

The predominant findings on TSCT are those of fibrosis with or without associated areas of consolidation. The fibrosis is characterized by the presence of irregular reticular opacities, honeycombing, architectural distortion, and traction bronchiectasis (Fig. 27.2). On TSCT, the abnormalities are usually bilateral and symmetric, with predominant lower lung zone involvement. A peripheral and subpleural distribution of abnormalities is common [1, 4].

Eosinophilic Pneumonia

Eosinophilic pneumonia is characterized histologically by the accumulation of eosinophils in the alveolar airspaces and infiltration of the adjacent interstitial space by eosinophils and variable numbers of lymphocytes and plasma cells. Peripheral eosinophilia is present in up to 40 % of patients. As a drug reaction, it is seen most commonly in association with methotrexate, sulfasalazine, para-amino- salicylic acid, nitrofurantoin, and nonsteroidal anti-inflam- matory drugs.

DRESS syndrome, standing for drug reaction (rash) with eosinophilia and systemic symptoms, is caused by exposure to certain medication, which may cause a rash, fever, inflammation of internal organs, lymphadenopathy, and characteristic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytes [5].

TSCT exhibits bilateral airspace consolidation, which tends to involve mainly the peripheral lung regions and the upper lobes [6, 7] (Fig. 27.3).

a

Table 27.1 CT patterns of drug-induced lung disease and drugs causing such patterns of lung abnormality

Note: UIP usual interstitial pneumonia, NSIP nonspecific interstitial pneumonia

Fig. 27.2 Gemcitabine-induced pulmonary fibrosis of usual interstitial pneumonia pattern in a 69-year-old man with pancreas head cancer. (a, b) Lung window images of CT scans (5.0-mm section thickness) obtained at levels of azygos arch (a) and cardiac ventricle (b), respectively, show combined pulmonary emphysema (arrowheads) and fibro-

sis (ground-glass opacity and reticulation) in both lungs. (c, d) Two-month follow-up CT scans obtained at similar levels to (a) and (b), respectively, demonstrate progressive pulmonary fibrosis with new appearance of honeycomb cysts (arrows) and increased extent of reticulation (open arrows)

Diffuse alveolar damage (DAD) is characterized by the presence of alveolar airspace and interstitial edema, hyaline membrane formation, and proliferation of type II pneumocytes. In relation to drug-induced pulmonary disease, it occurs most commonly in association with cytotoxic agents such as bleomycin, aspirin, and narcotics. The corresponding radiologic features are those of adult respiratory distress syndrome (ARDS). TSCT demonstrates extensive bilateral areas of GGO and dependent airspace consolidation [9] (Fig. 27.5).

Hypersensitivity pneumonitis (HP) is a relatively uncommon manifestation of drug-induced lung toxicity. HP is histologically characterized by the presence of cellular bronchiolitis, peribronchiolar noncaseating granulomas, and lymphocytic interstitial pneumonia. On TSCT scans, HP is shown as small, poorly defined centrilobular nodules or widespread areas of GGO. TSCT images obtained at the end of maximal expiration may exhibit lobular areas of decreased attenuation and vascularity, representing air trapping. Conditions of HP may occur after gefitinib or erlotinib treatment [10] (Fig. 27.6).

Fig. 27.3 Methotrexate-associated eosinophilic lung disease in a 50-year-old man with Crohn’s disease. (a, b) Lung window images of CT scans (5.0-mm section thickness) obtained at levels of great vessels (a) and main bronchi (b), respectively, show patchy areas of ground-

glass opacity (arrows) in both lungs. Also note several areas of emphysema in upper lung zones. His peripheral blood eosinophil count was abnormally high and parenchymal opacity disappeared after cessation of methotrexate therapy

Fig. 27.4 Amiodarone-induced interstitial lung disease of cryptogenic organizing pneumonia pattern in a 60-year-old man with arrhythmia. (a) Lung window image of CT scan (5.0-mm section thickness) obtained at level of cardiac ventricle shows patchy areas of consolida-

tion in both lower lobes. (b) Coronal reformatted image (2.5-mm section thickness) demonstrates multifocal areas of consolidation (arrows), distributed mainly along bronchovascular bundles