title: Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept.
abstract: OBJECTIVE
  Two tumor necrosis factor alpha (TNFalpha) antagonists were recently licensed in the US. Infliximab was licensed in 1998 for the treatment of Crohn's disease (CD), and since 1999, it has been licensed in combination with methotrexate for treatment of rheumatoid arthritis (RA). Etanercept was licensed in 1998 for treatment of RA and, more recently, for juvenile RA and psoriatic arthritis. Because of potential immunosuppression related to use of anti-TNFalpha agents, we sought to identify postlicensure cases of opportunistic infection, including histoplasmosis, in patients treated with these products.
  
  
  METHODS
  The US Food and Drug Administration's (FDA) passive surveillance database for monitoring postlicensure adverse events was reviewed to identify all reports received through July 2001 of histoplasmosis in patients treated with either infliximab or etanercept.
  
  
  RESULTS
  Ten cases of Histoplasma capsulatum (HC) infection were reported: 9 associated with infliximab and 1 associated with etanercept. In patients treated with infliximab, manifestations of histoplasmosis occurred within 1 week to 6 months after the first dose and typically included fever, malaise, cough, dyspnea, and interstitial pneumonitis. Of the 10 patients with histoplasmosis, 9 required treatment in an intensive care unit, and 1 died. All patients had received concomitant immunosuppressive medications in addition to infliximab or etanercept, and all resided in HC-endemic regions.
  
  
  CONCLUSIONS
  Postlicensure surveillance suggests that acute life-threatening histoplasmosis may complicate immunotherapy with TNFalpha antagonists, particularly infliximab. Histoplasmosis should be considered early in the evaluation of patients who reside in HC-endemic areas in whom infectious complications develop during treatment with infliximab or etanercept.
authors.affiliation: Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448, USA.
authors.forename: Jong-Hoon
authors.initials: JH
authors.lastname: Lee
authors.forename: Nancy R
authors.initials: NR
authors.lastname: Slifman
authors.forename: Sharon K
authors.initials: SK
authors.lastname: Gershon
authors.forename: Evelyne T
authors.initials: ET
authors.lastname: Edwards
authors.forename: William D
authors.initials: WD
authors.lastname: Schwieterman
authors.forename: Jeffrey N
authors.initials: JN
authors.lastname: Siegel
authors.forename: Robert P
authors.initials: RP
authors.lastname: Wise
authors.forename: S Lori
authors.initials: SL
authors.lastname: Brown
authors.forename: John N
authors.initials: JN
authors.lastname: Udall
authors.forename: M Miles
authors.initials: MM
authors.lastname: Braun
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D018501:Antirheumatic Agents / Q000009:adverse effects*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000382:microbiology; D002648:Child; D000068800:Etanercept; D005260:Female; D006658:Histoplasma; D006660:Histoplasmosis / Q000150:complications*; D006801:Humans; D007074:Immunoglobulin G / Q000009:adverse effects*; D000069285:Infliximab; D008297:Male; D008875:Middle Aged; D011358:Product Surveillance, Postmarketing; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors; D014481:United States
chemical_list: D000911:Antibodies, Monoclonal; D018501:Antirheumatic Agents; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab; D000068800:Etanercept