Ticlopidine, an inhibitor of platelet aggregation, is widely used to treat and prevent stroke and other thrombotic events and has been considered more effective than aspirin [1]. Side effects of ticlopidine include hematologic complications [2] and gastrointestinal and liver diseases [3]. We describe a patient who developed dyspnea, peripheral interstitial lung infiltrates, hypoxemia, and transbronchial biopsy alterations consistent with bronchiolitis obliterans-organizing pneumonia that resolved after withdrawal of ticlopidine therapy.

A 76-year-old nonsmoking woman in whom giant-cell (temporal) arteritis was proven by biopsy and who had had a normal chest radiograph was receiving prednisone, 45 mg/d, and ticlopidine, 250 mg twice daily, for persistence of cloudy vision. After 1 month of ticlopidine therapy, increasing dyspnea and a pruritic skin rash developed. No new symptoms of temporal arteritis occurred. Physical examination showed a respiratory rate of 28 breaths/min at rest, normal body temperature, scanty rales over both pulmonary fields, and a diffuse erythematosus maculopapular eruption. Chest radiography showed diffuse interstitial infiltrates predominantly affecting the periphery of both lungs.

Blood cell count, erythrocyte sedimentation rate, titers of antinuclear antibody and antineutrophil cytoplasmic antibodies, levels of rheumatoid factor and serum angiotensin-converting enzyme, and results of routine laboratory tests were normal. A sample of arterial blood taken while the patient was breathing ambient air showed a pH of 7.53, a PaO₂ of 8.11 kPa, and a PaCO₂ of 3.29 kPa. A test of lung function indicated a mild restrictive pattern with diminished CO diffusion (53% of the predicted value). No macroscopic findings were seen on bronchoscopy. Cultures of bronchioalveolar lavage fluid were negative, as were results of cytology of bronchoaspirated mucus and a serologic test for Mycoplasma and Chlamydia species. Ten percent of cells in bronchioalveolar lavage fluid were polymorphonucleotides, 24% were lymphocytes (lymphocytic populations in bronchioalveolar lavage fluid showed a predominance of CD8 cells with a CD4:CD8 ratio of 0.125), and 66% were macrophages without eosinophils. Transbronchial biopsy (Figure 1) showed widening of the alveolar walls with a mixed inflammatory infiltrate (neutrophils and lymphocytes), air spaces deformed by organizing connective tissue plugs, and foamy macrophages.

View larger version (136K): [in this window] [in a new window]   Figure 1. Transesophageal biopsy specimen showing organizing connective tissue plugs within air spaces.

Ticlopidine therapy was withdrawn; prednisone was given in the same schedule and dose. The patient subsequently felt better, and dyspnea and blanching cutaneous lesions improved. Dyspnea disappeared in 3 months, and the interstitial pattern completely resolved in 5 months.

Bronchiolitis obliterans-organizing pneumonia is a clinical pathologic syndrome with a wide spectrum of causes, including idiopathic and secondary causes [4]. The latter are associated with several connective tissue diseases, inhaled substances and fumes, radiation therapy, and hematologic diseases [4]. No ticlopidine-related pulmonary effects have been reported. Increased CD8 lymphocyte counts and the communicated augmented respiratory-burst metabolism in human neutrophils caused by ticlopidine [5] seem to have contributed to the pathogenesis of lung injury in our patient.