Pneumocystis Jiroveci (Carinii) Pneumonia Following Initiation of Infliximab and Azathioprine Therapy in a Patient With Crohn’s Disease Mimouna Seddik, MD,* Hugues Meliez, MD,† David Seguy, MD,* Nathalie Viget, MD,† Antoine Cortot, MD,* and Jean Frederic Colombel, MD*
Abstract: Anti-TNF␣ therapy is an effective treatment of Crohn’s disease. There is an increased risk of infection, including atypical infection associated in 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. Key Words: Crohn’s disease; anti-TNF␣; infliximab; infection; Pneumocystis jiroveci pneumonia; prophylaxis. (Inflamm Bowel Dis 2004;10:436–437)
INTRODUCTION Infliximab, a mouse/human chimeric IgG kappa monoclonal antibody to tumor necrosis factor alpha (TNF-alpha), is indicated for the treatment of patients with moderate to severely active Crohn’s disease and also in the treatment of enterocutaneous fistulizing Crohn’s disease.1 Because of the potential immunosuppressive effects of TNF alpha antagonists, adverse events related to infection are a major concern with use of infliximab. The disease known as Pneumocystis carinii pneumonia (PCP) is a major cause of illness and death in persons with impaired immune systems. In recognition of its genetic and functional distinctness, the organism that causes human PCP is now named Pneumocystis jiroveci.2 We present the case of a young man who developed Pneumocystis jiroveci pneumonia shortly after starting therapy with infliximab.
Received for publication July 11, 2003; accepted November 6, 2003. From the *Department of Gastroenterology, CHRU Lille, rue Michel Polonovsky, Lille, France and the †Department of Infectious and Tropical diseases, Hopital Dron, 135 rue du Pr Coty, Tourcoing, France Reprints: Jean Frederic Colombel, MD, Service des maladies de l’Appareil Digestif – Equipe mixte INSERMU Université de Recherche sur les Maladies inflammatoires Intestinales Hôpital Claude Huriez – Rue Michel Polonovski – 59037 Lille Cedex (France) (e-mail: [email protected]
). Copyright © 2004 by Lippincott Williams & Wilkins
CASE REPORT 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/d (150mg). In August 2002, he received one infusion of infliximab 5 mg/kg IV. He had never smoked or traveled and chest x-ray, HIV serology and white blood cell count before infliximab initiation was 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 (NR 4000–10000), lymphocytes 505 /mm3 (NR 1000–4000), CRP was 107 mg/l (NR 0–5) and hypoxia with a partial pressure of oxygen at 52 mm Hg (NR 80–95). A workup revealed no evidence of active Crohn’s disease, tuberculosis, or infection with Epstein–Barr virus, cytomegalovirus, HIV, or bacteria. Chest x-ray (Fig. 1) showed opacity of the lower right lobe with a bilateral and symmetrical interstitial infiltrates. Thoracic computed tomography displayed bilateral alveolar opacities in the two inferior and the middle lobes (Fig. 2). Bronchoscopy with bronchoalveolar lavage revealed the presence of Pneumocystis jiroveci. Intravenous trimethoprimsulfamethoxazole 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 2003, he had no complaints and nothing abnormal could be found on examination or chest radiographs.
DISCUSSION Given the temporal relationship between infliximab and onset of symptoms, we suspect that anti-TNF␣ therapy was related to Pneumocystis jiroveci infection. To our knowledge, only 1 other case of Pneumocystis jiroveci pneumonia has been fully reported in a 49-year-old man with rheumatoid arthritis following a second infusion of infliximab.3 The manufacturers of infliximab (Schering-Plough/Centocor) have an additional Inflamm Bowel Dis • Volume 10, Number 4, July 2004
Inflamm Bowel Dis • Volume 10, Number 4, July 2004
FIGURE 1. Chest X-ray. Note opacity of the lower right lobe.
9 cases (8 patients with rheumatoid arthritis and 1 patient with Crohn’s disease) on file of Pneumocystis jiroveci pneumonia associated with the use of the agent. Pneumocystis jiroveci induces tumor necrosis factor (TNF)-alpha release by monocytes/macrophages from immunocompetent humans. TNF-alpha activity has been demonstrated in animals with Pneumocystis jiroveci pneumonia and administration of anti TNF-alpha immunoglobulin G to reconstituted SCID mice with Pneumocystis jiroveci pneumonia results in impaired clearance of Pneumocystis jiroveci in the lung. The production of this cytokine in response to the cysts is one of the mechanisms for the control of this parasitic infection.4 By using antiTNF-␣ antibody therapy in Crohn’s disease patients, TNF blockade might interfere with the cell-mediated immune response that is crucial in preventing Pneumocystis related diseases.5 It is worth noting however that in almost all of these cases, including ours, there was concurrent immunosuppression with corticosteroid and/or azathioprine which have also been associated with an increased risk of Pneumocystis 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 Pneumocystis jiroveci pneumonia with trimethoprim–sulfamethoxazole
© 2004 Lippincott Williams & Wilkins
FIGURE 2. Thoracic computed tomography. Bilateral alveolar opacities in the two inferior and the middle lobes can be seen secondary to PCP.
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 antiTNF-␣ antibodies. REFERENCES 1. Sandborn WJ, Hanauer SB. Infliximab in the treatment of Crohn’s disease: A user’s guide for clinicians. Am J Gastroenterol. 2002;97:2962– 2972. 2. Stringer JR, Beard CB, Miller RF, et al. A new name (Pneumocystis jiroveci) for Pneumocystis from humans. Emerg Infect Dis. 2002;8:891– 896. Review. 3. Tai TL, O’Rourke KP, Barry M. Pneumocystis carinii pneumonia following a second infusion of infliximab. Rheumatology. 2002;4:951–952. 4. Chen W, Havell EA, Harmsen AG. Importance of endogenous tumor necrosis factor alpha and gamma interferon in host resistance against Pneumocystis carinii infection. Infect Immun. 1992;60(4):1979–84. 5. Tamburrini E, De Luca A, Ventura G, et al. Pneumocystis carinii stimulates in vitro production of tumor necrosis factor-alpha by human macrophages. Med Microbiol Immunol (Berl). 1991;180(1):15–20.