Pneumocystis carinii jiroveci pneumonia following infliximab infusion for Crohn disease: emphasis on prophylaxis.

To the Editor: Pneumocystis carinii pneumonia (PCP) is known to be associated with immunodeficiency states such as AIDS, malignancies and chemotherapy. Lately the occurrence of PCP has increased as the indications for use of immunosuppressive/immunomodulator therapies have broadened. (1,2) PCP following infliximab therapy for Crohn disease, although still uncommon, is increasing in occurrence. Although recommendations for prophylaxis for PCP are well known in HIV patients, there are no guidelines for prophylaxis in non-HIV patients. There has been mention of considering prophylaxis in patients who are receiving immunosuppressive medications or who have an underlying acquired or inherited immunodeficiency. (3) In this letter, we describe a case of PCP following the second dose of infliximab infusion in a woman with Crohn disease.

A 36-year-old white female with a history of Crohn disease presented to the emergency room with complaints of fever and shortness of breath for one day. She was diagnosed with Crohn disease 12 years previously after a partial small bowel resection. Her last Crohn exacerbation was 7 years before presentation. Her most recent treatment regimen included 6-mercaptopurine, Pentasa and prednisone. Two months before presentation, she required hospitalization for partial small bowel obstruction, at which time infliximab was started after a negative PPD skin test. At the time of her follow-up, she had received a total of two infusions of infliximab, the second infusion being 3 weeks prior.

On initial examination, temperature was 99.9[degrees]F, pulse 120, respiratory rate 24 and oxygen saturation 88% on room air. Her physical examination revealed mild tenderness to palpation in the right upper quadrant of her abdomen without any guarding or rigidity. On laboratory examination, WBCs were 4000/[micro]L with 32% bands, potassium 2.8 mEq/L, albumin 2.9 g/dL, AST 62 U/L, ALT 134 U/L, alkaline phosphatase 267 U/L and lactate dehydrogenase 935 U/L. Her chest x-ray showed bilateral infiltrates without evidence of pleural effusion. CT scan of the abdomen did not reveal any abscess, fistula or obstruction. She was empirically started on IV Levaquin and Flagyl. Later during the first day of admission, she developed a fever of 103[degrees]F and her respiratory status deteriorated, requiring endotracheal intubation. Her arterial blood gas analysis showed pH 7.52, pC[O.sub.2] 31, pa[O.sub.2] 56. Subsequently, vancomycin was added for broad antimicrobial coverage. With no significant improvement in clinical status despite IV antibiotics, a bronchoscopy was performed and a bronchoalveolar lavage (BAL) was obtained. BAL demonstrated PCP on silver stain. IV Bactrim and Solu-Medrol were started. The patient had a slow recovery and was extubated on Day 6, with subsequent chest x-ray showing clearing of the lung infiltrates. She was discharged home on prednisone and oral Bactrim 2 tablets four times a day for 2 weeks. On clinical follow-up, she was doing well on Bactrim once a day and a weaning dose of steroids. Later on, the patient did receive another dose of infliximab as an outpatient while she was on Bactrim for secondary prophylaxis for PCP, without further complications.

Infliximab is used worldwide in the treatment of Crohn disease, rheumatoid arthritis, ankylosing spondylitis and psoriatic arthritis. More recently, infliximab has also been approved for patients with moderate to severe ulcerative colitis who have failed other therapies. PCP following infliximab is increasingly recognized due to a larger number of patients receiving immunosuppressive medications or who have altered immune systems. (4) Infliximab has been shown to decrease CD4 lymphocytes and induce apoptosis of activated T-lymphocytes in the lamina propria, which makes the patient susceptible to PCP infection. In our case, infliximab was the main etiology for causing PCP, given the onset of the disease following treatment.

In our review of medical literature, eight cases of PCP following infliximab in patients with inflammatory bowel disease and five cases in patients with rheumatoid arthritis have been identified. Concomitant immunosuppressive therapy was present in all these cases. The average duration from start of infliximab to diagnosis of PCP was one month, and the average number of doses of infliximab was two. (5) PCP remains a serious cause of morbidity and mortality in immunocompromised patients. The survival rates of PCP in HIV patients have improved steadily to 90%, but survival rates of PCP among non-HIV patients is 40 to 70%. (4) As the spectrum of indications for anti-TNF[alpha] therapy broadens, one should bear in mind the possibility of serious opportunistic infections. PCP should be considered high in the differential diagnosis in patients on infliximab, along with other immunosuppressants when presenting with respiratory symptoms. This can lead to early diagnosis and treatment. Another consideration will be the use of primary or secondary prophylaxis for PCP in such patients, which may improve outcome with decreased morbidity and mortality.

Kanan Sharma, MD

Pallavi Rao, MD

Padmini Krishnamurthy, MD

Syed Ahsan Ali, MD

Gregory Beck, MD

Wright State University School of Medicine

Miami Valley Hospital, Medical Surgical

Health Center

Dayton VA Medical Center

Dayton, OH

References

1. Varthalitis I, Aoun M, Daneau D, et al. Pneumocystis carinii pneumonia in patients with cancer: an increasing incidence. Cancer 1993;71:481-485.

2. Mansharamani NG, Garland R, Delaney D, et al. Management and outcome patterns for adult Pneumocystis carinii pneumonia, 1985 to 1995: comparison of HIV-associated cases to other immunocompromised states. Chest 2000;118:704-711.

3. Thomas CF Jr, Limper AH. Pneumocystis pneumonia. N Engl J Med 2004;350:2487-2498.

4. Sepkowitz KA. Opportunistic infections in patients with and patients without acquired immunodeficiency syndrome. Clin Infect Dis 2002;34:1098-107. [Erratum, Clin Infect Dis 2002:34:1293].

5. Food and Drug Administration. Safety update on TNF[alpha] antagonist: Infliximab and etanercept. Food and Drug Administration, Center for Biologics Evaluation and Research, Arthritis Advisory Committee Meeting, August 17, 2001.