Drug-induced diffuse alveolar hemorrhage syndromes and vasculitis Marvin I. Schwarz, MD*, Andrew P. Fontenot, MD Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, 4200 East Ninth Avenue, C272, Denver, CO 80262, USA Diffuse alveolar hemorrhage (DAH) is a clinical- pathologic syndrome that is characterized by the ac- cumulation of red blood cells in the alveolar spaces the accumulation originates from alveolar capil- laries, and, less frequently, from precapillary arterio- les or postcapillary venules [1]. Patients have varying degrees of hemoptysis, cough, and progressive dysp- nea, which may lead to acute respiratory failure. The characteristic laboratory features are a decreasing hematocrit and a hemorrhagic bronchoalveolar la- vage (BAL) that is seen in sequential samples. DAH that appears as a complication of medical therapy is a direct consequence of the drug. This may represent an immune or hypersensitivity reaction to a medication, an injury to the alveolar capillary base- ment membrane, or a coagulation defect that was induced by the medication (Box 1). Histopathology of drug-induced diffuse alveolar hemorrhage Several distinct histopathologies are associated with drug-induced DAH. The first is a small vessel vasculitis of the lung that is known as pulmonary capillaritis. Although pulmonary capillaritis is seen most commonly in the systemic vasculitides and connective tissue diseases, it also occurred after treatment with diphenylhydantoin, propylthioruracil, and all���trans-retinoic acid [2���4]. For all causes of DAH, including systemic vasculitis and the con- nective tissue diseases, pulmonary capillaritis is the most frequent underlying histology. The actual fre- quency in drug-induced DAH is unknown because of the lack of lung tissue that is available for histologic confirmation. The interstitium of the lung is broad- ened and disrupted by infiltrating neutrophils (Fig. 1). The interstitium becomes edematous many of the neutrophils are fragmented as a result of a process known as ������leucocytoclasis,������ which causes nuclear dust to accumulate in the tissue. The capillary walls are destroyed, presumably as a result of the release of elastases and toxic oxygen radicals from the dying neutrophils. This results in edema and fibrinoid necrosis of the alveolar walls (lung interstitium). Because of the destruction of the alveolar capillary basement membranes, red blood cells and neutrophils freely enter the alveolar spaces and produce the histologic appearance of DAH. This same histology is seen in Wegener���s granulomatosis, microscopic polyarteritis, and other systemic vasculitides, such as Henoch-Scho ��nlein purpura, cryoglobulinemia, and primary antiphospholipid syndrome [5���8]. The con- nective tissue diseases, particularly systemic lupus erythematosus (SLE) can produce an identical clini- copathologic picture [9���11]. DAH occurs in 4% of hospitalized patients who have SLE but is a much less frequent event in drug-induced lupus [11]. It is believed, as in the case of drug-induced pulmonary capillaritis, that this represents an autoimmune or hypersensitivity reaction. Pulmonary veno-occlusive disease (PVOD) is a condition that is recognized by fibrous obliteration of pulmonary venules and small pulmonary veins that leads to pulmonary hypertension, signs of left atrial 0272-5231/04/$ ��� see front matter D 2004 Elsevier Inc. All rights reserved. doi:10.1016/S0272-5231(03)00139-4 * Corresponding author. E-mail address: marvin.schwarz@uchsc.edu (M.I. Schwarz). Clin Chest Med 25 (2004) 133���140

hypertension, and sometimes, DAH. Although most often idiopathic, it has been described as a complica- tion of chemotherapy for malignant disease and after preconditioning therapy for bone marrow transplan- tation. Bleomycin and carmustine have the most incriminating data [12���15] however, gemcitabine, mitomycin, and the vinca alkaloids have been impli- cated. Because PVOD has been reported with the collagen vascular disease and AIDS [16���19], it is considered to be an immune or hypersensitivity re- action, as opposed to the direct toxicity that can be caused by chemotherapeutic drugs. There is a single case report of sulfasalazine pulmonary toxicity that resulted in the typical lesions (cavitating nodules) and histology (necrotizing granu- lomatous vasculitis) of Wegener���s granulomatosis in a patient who had ulcerative colitis [20]. This patient was positive for antinuclear cytoplasmic anti- body (c-ANCA) and the lesions cleared following discontinuation of the drug. There have been other reports of Wegener���s-like vasculitis in inflammatory bowel disease, but there was no comment on its association with sulfasalazine [21,22]. An additional pulmonary hypersensitivity reaction, Churg-Strauss syndrome (CSS), was reported after the introduction of leukotriene antagonists as corticosteroid-sparing agents in the treatment of asthma. This is a form of granulomatous vasculitis that is characterized by eosinophilic infiltration and destruction of the walls of small pulmonary arteries. Another probable pulmonary hypersensitivity reaction is the hemolytic uremic syndrome that com- plicates mitomycin treatment [23]. In addition to several systemic complications (see later discussion), these patients develop acute respiratory failure his- tology reveals small vessel intraluminal fibrin clots, DAH, and alveolar edema [24]. Although hypersensitivity reactions to drugs are common, concomitant lung involvement that causes DAH is unusual. Drug hypersensitivity usually ap- pears as a dermatologic leucocytoclastic vasculitis (palpable purpura) following antibiotics (penicillin, sulfanamides, erythromycin), chlorpromazine, and other drugs [25]. Leucocytoclastic vasculitis has similar histologic features to pulmonary capillaritis. Direct lung epithelial toxicity that results from a drug produces the lesion of diffuse alveolar damage (DAD), a similar histology to that of the acute respiratory distress syndrome (ARDS), the acute pneumonitis that complicates connective tissue dis- eases and an idiopathic disease (acute interstitial pneumonia). Early on, the alveolar walls are edema- Box 1. Etiologic classification of drug- induced diffuse alveolar hemorrhage and vasculitis syndromes Hypersensitivity (autoimmune) reaction Propylthiouracil Diphenylhydantoin Penicillin All���trans-retinoic acid Chemotherapeutic agents Sulfasalazine Hydralazine Carbimazole Leukotriene antagonists Mitomycin Direct toxicity Chemotherapeutic agents Amiodarone Bone marrow transplantation Nitrofurantoin Crack cocaine Coagulation defects Thrombolytic agents Anticoagulants Platelet glycoproteins Ib/IIIa inhibitors Platelet aggregation inhibitors Drug-induced thrombocytopenia Dextran 70 Fig. 1. DAH secondary to pulmonary capillaritis. Note the edema and broadening of the alveolar walls which also are infiltrated by neutrophils ( 100). M.I. Schwarz, A.P. Fontenot / Clin Chest Med 25 (2004) 133���140 134