Pneumocystis jiroveci (carinii) Pneumonia After Initiation of Infliximab and Azathioprine Therapy in a Patient with Crohnʼs Disease

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To the Editor: Anti-tumor necrosis factor α therapy is an effective treatment for Crohn's disease. There is an increased risk of infection, including atypical infection associated with infliximab-treated patients. We report a case of a young man who developed Pneumocystis jiroveci pneumonia shortly after starting therapy with infliximab. Thus, although rare, prophylaxis against Pneumocystis jiroveci pneumonia might be considered when starting a treatment with infliximab, especially in patients receiving concomitant immunosuppressive agents. In September 2002, a 29-year-old man with Crohn's ileitis was admitted to the emergency department with an 8-day history of dyspnea, fever, and asthenia 1 month after the initiation of infliximab. He had been taking corticosteroids since April 2002 but had ongoing active Crohn's disease despite a dose of 60 mg/d of prednisolone. In July 2002, he was placed on azathioprine 2 mg/kg per day (150 mg). In August 2002, he received 1 infusion of intravenous infliximab 5 mg/kg. He had never smoked or traveled, and chest radiographs, HawaiiV serology, and white blood cell count before infliximab initiation were normal. Tuberculin skin testing was also negative before infliximab therapy. Examination revealed pyrexia of 38 °C. The white blood cell count was 3.1 × 103/mm3 (reference range, 4000-10,000/mm3), lymphocyte count was 505/mm3 (reference range, 1000-4000/mm3), C-reactive protein level was 107 mg/L (reference range, 0-5 mg/L), and hypoxia with a partial pressure of oxygen was at 52 mm Hg (reference range, 80-95 mm Hg). A workup revealed no evidence of active Crohn's disease, tuberculosis, or infection with Epstein-Barr virus, cytomegalovirus, HawaiiV, or bacteria. Chest radiographs (Fig. 1) showed opacity of the lower right lobe with bilateral and symmetrical interstitial infiltrates. Thoracic computed tomography displayed bilateral alveolar opacities in the 2 inferior lobes and the middle lobes (Fig. 2). Bronchoscopy with bronchoalveolar lavage revealed the presence of Pneumocystis jiroveci. Intravenous trimethoprim-sulfamethoxazole was given for 2 weeks, followed by oral therapy. Follow-up white blood cell count and chest x-ray showed complete resolution. When last seen, in March 2002, he had no complaints, and nothing abnormal could be found on examination or chest radiographs. Chest radiograph. Note opacity of the lower right lobe. Chest radiograph. Note opacity of the lower right lobe. Thoracic computed tomography. Bilateral alveolar opacities in the 2 inferior lobes and the middle lobes can be seen secondary to PCP. Thoracic computed tomography. Bilateral alveolar opacities in the 2 inferior lobes and the middle lobes can be seen secondary to PCP. Given the temporal relationship between infliximab and onset of symptoms, we suspect that anti-tumor necrosis factor α (TNFα) therapy was related to P. jiroveci infection. To our knowledge, only 1 other case of P. jiroveci pneumonia has been fully reported (in a 49-year-old man with rheumatoid arthritis after a second infusion of infliximab).6 The manufacturers of infliximab (Schering-Plough/Centocor) have an additional 9 cases (8 patients with rheumatoid arthritis and 1 patient with Crohn's disease) on file that had P. jiroveci pneumonia associated with the use of the agent. P. jiroveci induces TNFα release by monocytes/macrophages from immunocompetent humans. TNFα activity has been shown in animals with P. jiroveci pneumonia, and administration of anti-TNFα immunoglobulin G to reconstituted SCID mice with P. jiroveci pneumonia results in impaired clearance of P. jiroveci in the lung. The production of this cytokine in response to the cysts is 1 of the mechanisms for the control of this parasitic infection.7 By using anti-TNFα antibody therapy in patients with Crohn's disease, TNF blockade might interfere with the cell-mediated immune response that is crucial in preventing Pneumocystis-related diseases.8 It is worth noting, however, that in almost all of these cases, including ours, there was concurrent immunosuppression with corticosteroids and/or azathioprine, which have also been associated with an increased risk of P. jiroveci pneumonia. Bronchoalveolar lavage must be rapidly performed in patients with Crohn's disease presenting with fever, pulmonary infiltrates, hypoxemia, and lymphopenia. Thus, although rare, prophylaxis against P. jiroveci pneumonia with trimethoprim-sulfamethoxazole might be considered when starting a treatment with infliximab, especially in patients receiving concomitant immunosuppressive agents including corticosteroids, azathioprine/6-mercaptopurine, methotrexate, and others. Nevertheless, there are not sufficient data to support routine or widespread use unless further Pneumocystis pneumonia associated with the use of infliximab is reported in the future. Finally, practitioners should be aware of the risk when treating patients with anti-TNFα antibodies.

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