269K.S. Lee et al., Radiology Illustrated: Chest Radiology, Radiology Illustrated,DOI 10.1007/978-3-642-37096-0_27, © Springer-Verlag Berlin Heidelberg 2014

Drug-induced lung injury is seen as a wide variety of histo-logic reaction patterns and thus as diverse CT fi ndings. The most common are interstitial pneumonia and fi brosis (either usual interstitial pneumonia [UIP] or nonspecifi c interstitial pneumonia [NSIP]), eosinophilic pneumonia (including DRESS syndrome; drug reaction with eosinophilia and sys-temic symptoms), cryptogenic organizing pneumonia (COP), diffuse alveolar damage (DAD), and hypersensitivity pneu-monia [ 1 , 2 ]. Other reactions such as granulomatous pneu-monitis, vasculitis, alveolar proteinosis, obliterative bronchiolitis, and veno-occlusive disease are uncommon [ 2 ]. None of these histologic patterns is specifi c 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) fi ndings 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 pneumoni-tis is nonspecifi c interstitial pneumonia (NSIP) [ 1 , 2 ] (Fig. 27.1 ). This is characterized histologically by homoge-neous alveolar wall thickening by fi brous tissue and mono-nuclear infl ammatory cells. The reaction is seen most commonly in association with methotrexate, amiodarone, or carmustine toxicity (Table 27.1 ). The corresponding thin- section CT (TSCT) fi ndings usually consist of patchy or dif-fuse areas of ground-glass opacity (GGO) (Fig. 27.1 ). With progression, there may be evidence of fi brosis, including reticulation, traction bronchiectasis, and honeycombing. The abnormalities show typically lower lung zone predominance. In some patients, the fi brosis is patchy in distribution and predominantly peribronchovascular; fi brotic NSIP pattern, commonly in patients receiving nitrofurantoin [ 3 ].

The second most common histologic form of drug- induced interstitial pneumonitis is usual interstitial pneu-monia (UIP) (Fig. 27.2 ). This is characterized histologically

by a heterogeneous pattern of chronic infl ammation and fi brosis, with foci of dense and loose (fi broblastic) connec-tive tissue being present in the same lobule. Progression of the interstitial disease leads to obliteration of alveolar air-spaces by mature fi brous tissue associated with dilatation of residual transitional airways (honeycombing). This pat-tern 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 fi ndings on TSCT are those of fi brosis with or without associated areas of consolidation. The fi bro-sis is characterized by the presence of irregular reticular opacities, honeycombing, architectural distortion, and trac-tion bronchiectasis (Fig. 27.2 ). On TSCT, the abnormalities are usually bilateral and symmetric, with predominant lower lung zone involvement. A peripheral and subpleural distribu-tion of abnormalities is common [ 1 , 4 ].

Eosinophilic Pneumonia

Eosinophilic pneumonia is characterized histologically by the accumulation of eosinophils in the alveolar airspaces and infi ltration of the adjacent interstitial space by eosino-phils 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-infl am-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, infl am-mation of internal organs, lymphadenopathy, and character-istic hematologic abnormalities such as eosinophilia, thrombocytopenia, and atypical lymphocytes [ 5 ].

Drug-Induced Lung Disease 27

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

Cryptogenic Organizing Pneumonia

Cryptogenic organizing pneumonia (COP) is characterized by parenchymal interstitial infi ltration by mononuclear infl ammatory cells and obliteration of the lumens of respira-tory bronchioles, alveolar ducts, and (usually to a lesser extent) alveoli by fi broblastic tissue. The reaction has been reported most frequently in association with methotrexate, cyclophosphamide, gold, nitrofurantoin, amiodarone, bleo-mycin, and busulfan. On thin-section CT, the areas of con-solidation often have a predominantly peripheral or peribronchovascular distribution [ 2 , 8 ] (Fig. 27.4 ).

a

b

c

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

CT patterns Associated drugs

Interstitial pneumonia and fi brosis (UIP or NSIP)

Methotrexate, amiodarone, carmustine, nitrofurantoin, bleomycin, busulfan, cyclophosphamide, doxorubicin, gold, penicillamine, gefi tinib, sorafenib

Eosinophilic pneumonia

Methotrexate, sulfasalazine, para-aminosalicylic acid (PAS), nitrofurantoin, nonsteroidal anti-infl ammatory drugs (NSAID)

Cryptogenic organizing pneumonia

Methotrexate, cyclophosphamide, carmustine, gold, nitrofurantoin, amiodarone, bleomycin, busulfan, erlotinib, sorafenib

Diffuse alveolar damage

Bleomycin, busulfan, cyclophosphamide, methotrexate, amiodarone, aspirin, narcotics, gefi tinib

Hypersensitivity pneumonia

Nitrofurantoin, gefi tinib, erlotinib

Note : UIP usual interstitial pneumonia, NSIP nonspecifi c interstitial pneumonia

Fig. 27.1 Iressa (gefi tinib)-associated pulmonary fi brosis of nonspe-cifi c interstitial pneumonia pattern of pulmonary fi brosis in a 75-year- old woman with lung adenocarcinoma. ( a ) Lung window image of CT scan (2.5-mm section thickness) obtained at level of right inferior pul-monary vein shows a 59-mm-sized mass in superior segment of right lower lobe and innumerable small cavitating and noncavitating nodules in both lungs (suggestive of pulmonary metastases). Patient received Iressa (gefi tinib) chemotherapy. ( b , c ) Eighteen-month follow-up CT scans obtained at levels of right middle lobar bronchus ( b ) and liver dome ( c ), respectively, demonstrate still visible mass ( arrows in b ) in right lower lobe. Please also note ground-glass opacity, reticulation, traction bronchiectasis ( arrowheads ), and cystic lung changes in both lungs. Subpleural sparing ( open arrows ) and lung fi brosis of deep cen-tral involvement are noticed

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271

Diffuse Alveolar Damage

Diffuse alveolar damage (DAD) is characterized by the presence of alveolar airspace and interstitial edema, hyaline membrane formation, and proliferation of type II pneumo-cytes. In relation to drug-induced pulmonary disease, it occurs most commonly in association with cytotoxic agents such as bleomycin, aspirin, and narcotics. The correspond-ing 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 Pneumonia

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

a b

dc

Fig. 27.2 Gemcitabine-induced pulmonary fi brosis 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 ), respec-tively, show combined pulmonary emphysema ( arrowheads ) and fi bro-

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 fi brosis with new appearance of honeycomb cysts ( arrows ) and increased extent of retic-ulation ( open arrows )

Hypersensitivity Pneumonia

272

a b

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 sec-tion thickness) demonstrates multifocal areas of consolidation ( arrows ), distributed mainly along bronchovascular bundles

a b

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 emphy-sema in upper lung zones. His peripheral blood eosinophil count was abnormally high and parenchymal opacity disappeared after cessation of methotrexate therapy

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273

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a

b

Fig. 27.5 Iressa (gefi tinib)-associated lung disease of acute interstitial pneumonia (diffuse alveolar damage) pattern in a 40-year-old man with lung adenocarcinoma (primary tumor in left lung, lung-to-lung and extrathoracic metastases). ( a , b ) Lung window images of CT scans (5.0-mm section thickness) obtained at levels of aortic arch ( a ) and car-diac ventricle ( b ), respectively, show patchy, extensive, and mixed areas of parenchymal consolidation and ground-glass opacity in both lungs. Also note primary cancer ( open arrows ) and lung-to-lung meta-static nodules ( arrowheads ). Patient took Iressa for 3 months

a

b

Fig. 27.6 Iressa (gefi tinib)-induced hypersensitivity pneumonia in a 53-year-old woman with lung adenocarcinoma and lung-to-lung metas-tases. ( a , b ) Lung window images of CT scans (5.0-mm section thick-ness) obtained at levels of inferior pulmonary veins ( a ) and liver dome ( b ), respectively, show patchy areas of parenchymal ground-glass opac-ity ( arrows ) in both lungs. The lesions disappeared spontaneously with-out any treatment

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