, Volume 69, Issue 11, pp 1403–1415 | Cite as

Endemic Fungal Infections in Patients Receiving Tumour Necrosis Factor-α Inhibitor Therapy

Therapy in Practice


Tumour necrosis factor (TNF)-α inhibitors are widely used agents in the treatment of a variety of inflammatory and granulomatous diseases. It has long been appreciated that these agents confer an increased risk of tuberculosis; however, more recently it has been recognized that patients being treated with TNFα inhibitors are also at significant risk for infection with the endemic fungi, in particular Histoplasma capsulatum, and when infected, to develop severe disseminated infection. Patients often present in an atypical manner and the symptoms of the fungal infection can be mistaken for those of the underlying disease. Thus, delay in diagnosis and treatment is common, and mortality has been high. In an attempt to increase awareness of this problem, the US FDA issued a ‘black box’ warning for clinicians in September 2008 to alert providers of the risks of endemic fungal infections in patients treated with TNFα inhibitors. The management of patients who develop endemic fungal infection while receiving TNFα inhibitor therapy should include discontinuation of the TNFα inhibitor and early use of antifungal agents including polyenes and/or azoles according to the Infectious Diseases Society of America guidelines for treatment of these infections in immunocompromised hosts.



No sources of funding were used in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review.


  1. 1.
    Roach DR, Bean AG, Demangel C, et al. TNF regulates chemokine induction essential for cell recruitment, granuloma formation, and clearance of mycobacterial infection. J Immunol 2002; 168: 4620–7PubMedGoogle Scholar
  2. 2.
    Flynn JL, Goldstein MM, Chan J, et al. Tumor necrosis factor-alpha is required in the protective immune response against Mycobacterium tuberculosis in mice. Immunity 1995; 2: 561–72PubMedCrossRefGoogle Scholar
  3. 3.
    Kindler V, Sappino AP, Grau GE, et al. The inducing role of tumor necrosis factor in the development of bactericidal granulomas during BCG infection. Cell 1989; 56: 731–40PubMedCrossRefGoogle Scholar
  4. 4.
    Maini R, St Clair EW, Breedveld F, et al. Infliximab (chimeric anti-tumour necrosis factor-alpha monoclonal antibody) vs placebo in rheumatoid arthritis patients receiving concomitant methotrexate: a randomized phase III trial. Lancet 1999; 354: 1932–9PubMedCrossRefGoogle Scholar
  5. 5.
    Moreland LW, Schiff MH, Baumgartner SW, et al. Etanercept therapy in rheumatoid arthritis: a randomized, controlled trial. Ann Intern Med 1999; 130: 478–86PubMedGoogle Scholar
  6. 6.
    Doran MF, Crowson CS, Pond GR, et al. Frequency of infection in patients with rheumatoid arthritis compared with controls: a population based study. Arthritis Rheum 2002; 46: 2287–93PubMedCrossRefGoogle Scholar
  7. 7.
    Infliximab (Remicade) prescribing information. Malvern (PA): Centocor, 2006Google Scholar
  8. 8.
    Sullivan TP, Welsh E, Kerdel FA, et al. Infliximab for hidradenitis suppurativa. Br J Dermatol 2003; 149: 51046–9CrossRefGoogle Scholar
  9. 9.
    Graves JE, Nunley K, Heffernan MP. Off-label uses of biologics in dermatology: rituximab, omalizumab, infliximab, etanercept, adalimumab, efalizumab, and alefacept. J Am Acad Dermatol 2007; 56: e55–7PubMedCrossRefGoogle Scholar
  10. 10.
    Etanercept (Enbrel) prescribing information. Thousand Oaks (CA): Amgen, 2006Google Scholar
  11. 11.
    Adalimumab (Humira) prescribing information. Chicago (IL): Abbott Laboratories, 2005Google Scholar
  12. 12.
    Keystone E, Haraoui B. Adalimumab therapy in rheumatoid arthritis. Rheum Dis Clin North Am 2004; 30: 349–64PubMedCrossRefGoogle Scholar
  13. 13.
    Certolizumab pegol (Cimzia) prescribing information. Smyrna (GA): UCB, 2008Google Scholar
  14. 14.
    Fossati G, Nesbitt A. In vitro complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity by the anti-TNF agents adalimumab, etanercept, infliximab, and certolizumab pegol (CDP870). Am J Gastroenterol 2005; 100: S299CrossRefGoogle Scholar
  15. 15.
    Utz JP, Limper AH, Kalra S, et al. Etanercept for the treatment of stage II and III progressive pulmonary sarcoidosis. Chest 2003; 124: 177–85PubMedCrossRefGoogle Scholar
  16. 16.
    Ehlers S. Tumor necrosis factor and its blockade in granulomatous infections: differential modes of action of infliximab and etanercept? Clin Infect Dis 2005; 41: S199–203PubMedCrossRefGoogle Scholar
  17. 17.
    Wallis RS. Tumour necrosis factor antagonists: structure, function, and tuberculosis risks. Lancet Infect Dis 2008; 8: 601–11PubMedCrossRefGoogle Scholar
  18. 18.
    Keane J, Gershon S, Wise RP, et al. Tuberculosis associated with infliximab, a tumor necrosis factor-alpha-neutralizing agent. N Engl J Med 2001; 345: 1098–104PubMedCrossRefGoogle Scholar
  19. 19.
    Weisman MH. What are the risks of biologic therapy in rheumatoid arthritis? An update on safety. J Rheumatol 2002; 65: 33–8Google Scholar
  20. 20.
    Wallis RS, Broder M, Wong J, et al. Reactivation of latent granulomatous infections by infliximab. Clin Infect Dis 2005; 41: S194–8PubMedCrossRefGoogle Scholar
  21. 21.
    Tsiodras S, Samonis G, Boumpas DT, et al. Fungal infections complicating tumor necrosis factor-α blockade therapy. Mayo Clin Proc 2008; 83: 181–94PubMedGoogle Scholar
  22. 22.
    Tubach F, Salmon-Ceron D, Ravaud P, et al. The RATIO observatory: French registry of opportunistic infections, severe bacterial infections, and lymphomas complicating anti-TNF-alpha therapy. Joint Bone Spine 2005; 72: 456–60PubMedCrossRefGoogle Scholar
  23. 23.
    Listing J, Strangfeld A, Kary S, et al. Infections in patients with rheumatoid arthritis treated with biologic agents. Arthritis Rheum 2005; 52: 3403–12PubMedCrossRefGoogle Scholar
  24. 24.
    Kassiotis G, Kollias G. Uncoupling the proinflammatory from the immunosuppressive properties of tumor necrosis factor (TNF) at the p55 TNF receptor level: implications for pathogenesis and therapy of autoimmune demyelination. J Exp Med 2001; 193: 4327–34CrossRefGoogle Scholar
  25. 25.
    Zou JX, Braun J, Sieper J. Immunological basis for the use of TNF-α blocking agents in ankylosing spondylitis and immunological changes during treatment. Clin Exp Rheumatol 2002; 20 Suppl. 28: E34–7Google Scholar
  26. 26.
    Kauffman CA. Histoplasmosis. Clinical and laboratory update. Clin Microbiol Rev 2007; 20: 115–32CrossRefGoogle Scholar
  27. 27.
    Smith JG, Magee DM, Williams DM, et al. Tumor necrosis factor-alpha plays a role in host defense against Histoplasma capsulatum. J Infect Dis 1990; 162: 1349–53PubMedCrossRefGoogle Scholar
  28. 28.
    Wu-Hsieh BA, Lee G-S, Franco M, et al. Early activation of splenic macrophages by tumor necrosis factor alpha is important in determining the outcome of experimental histoplasmosis in mice. Infect Immun 1992; 60: 4230–8PubMedGoogle Scholar
  29. 29.
    Deepe GS. Modulation of infection with Histoplasma capsulatum by inhibition of tumor necrosis factor-α activity. Clin Infect Dis 2005; 41: S204–7PubMedCrossRefGoogle Scholar
  30. 30.
    Allendoerfer R, Deepe Jr GS. Blockade of endogenous TNF-α exacerbates primary and secondary histoplasmosis by differential mechanisms. J Immunol 1998; 160: 6072–82PubMedGoogle Scholar
  31. 31.
    Allendoerfer R, Deepe Jr GS. Regulation of infection with Histoplasma capsulatum by TNFR1 and -2. J Immunol 2000; 162: 2657–64Google Scholar
  32. 32.
    Nakelchik M, Mangino JE. Reactivation of histoplasmosis after treatment with infliximab [letter]. Am J Med 2002; 112: 78PubMedCrossRefGoogle Scholar
  33. 33.
    Zhang Z, Correa H, Begue RE. Tuberculosis and treatment with infliximab [letter]. N Engl J Med 2002; 346: 624Google Scholar
  34. 34.
    Lee JH, Slifman NR, Gershon SK, et al. Life-threatening histoplasmosis complicating immunotherapy with tumor necrosis factor alpha antagonists infliximab and etanercept. Arthritis Rheum 2002; 46: 10: 2565–70CrossRefGoogle Scholar
  35. 35.
    FDA Alert. Tumor necrosis factor-alpha blockers (TNF blockers), Cimzia (certolizumab pegol), Enbrel (etanercept), Humira (adalimumab), and Remicade (infliximab) [online]. Available from URL: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm124185.htm [Accessed 2009 Jul 2]
  36. 36.
    Wood KL, Hage CA, Knox KS, et al. Histoplasmosis after treatment with anti-tumor necrosis factor alpha therapy. Am J Respir Crit Care Med 2003; 167: 1279–82PubMedCrossRefGoogle Scholar
  37. 37.
    Jain VV, Evans T, Peterson MW. Reactivation histoplasmosis after treatment with anti-tumor necrosis factor α in a patient from a nonendemic area. Respir Med 2006; 100: 1291–3PubMedCrossRefGoogle Scholar
  38. 38.
    Crum NF, Lederman ER, Wallace MR. Infections associated with tumor necrosis factor-α antagonists. Medicine (Baltimore) 2005; 84: 291–302CrossRefGoogle Scholar
  39. 39.
    Wheat LJ. Antigen detection, serology, and molecular diagnosis of invasive mycoses in the immunocompromised host. Transpl Infect Dis 2006; 8: 128–39PubMedCrossRefGoogle Scholar
  40. 40.
    Wheat JL, Freifeld AG, Kleiman MB, et al. Clinical practice guidelines for the management of patients with histoplasmosis: 2007 update by the Infectious Diseases Society of America. Clin Infect Dis 2007; 45: 807–25PubMedCrossRefGoogle Scholar
  41. 41.
    Klein BS, Vergeront JM, DiSalvo AF, et al. Two outbreaks of blastomycosis along rivers in Wisconsin: isolation of Blastomyces dermatitidis from riverbank soil and evidence of its transmission along waterways. Am Rev Respir Dis 1987; 136: 1333–8PubMedCrossRefGoogle Scholar
  42. 42.
    Dworkin MS, Duckro AN, Proia L, et al. The epidemiology of blastomycosis in Illinois and factors associated with death. Clin Infect Dis 2005; 41: e107–11PubMedCrossRefGoogle Scholar
  43. 43.
    Cano MV, Ponce-de-Leon GF, Tippen S, et al. Blastomycosis in Missouri: epidemiology and risk factors for endemic disease. Epidemiol Infect 2003; 131: 907–14PubMedCrossRefGoogle Scholar
  44. 44.
    Crampton TL, Light RB, Berg GM, et al. Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin Infect Dis 2002; 34: 1310–6PubMedCrossRefGoogle Scholar
  45. 45.
    Alvarez G, Burns B, Desjardins M, et al. Blastomycosis in a young African man presenting with a pleural effusion. Can Respir J 2006; 13: 441–4PubMedGoogle Scholar
  46. 46.
    Pappas PG, Pottage JC, Powderly WG, et al. Blastomycosis in patients with acquired immunodeficiency syndrome. Ann Intern Med 1992; 116: 847–53PubMedGoogle Scholar
  47. 47.
    Pappas PG, Threlkeld MG, Bedsole GD, et al. Blastomycosis in immunocompromised patients. Medicine (Baltimore) 1993; 72: 311–25Google Scholar
  48. 48.
    Pappas PG. Blastomycosis in immunocompromised patients. Semin Respir Infect 1997; 12: 243–51PubMedGoogle Scholar
  49. 49.
    Gauthier GM, Safdar N, Klein BS, et al. Blastomycosis in solid organ transplant recipients. Transpl Infect Dis 2007; 9: 310–7PubMedCrossRefGoogle Scholar
  50. 50.
    Areno JP, Campbell GD, George RB. Diagnosis of blastomycosis. Semin Respir Infect 1997; 12: 252–62PubMedGoogle Scholar
  51. 51.
    Durkin M, Witt J, Lemonte A, et al. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol 2004; 42: 4873–5PubMedCrossRefGoogle Scholar
  52. 52.
    Chapman SW, Dismukes WE, Proia LA, et al. Clinical practice guidelines for the management of blastomycosis. 2008 update by the Infectious Diseases Society of America. Clin Infect Dis 2008; 46: 1801–12Google Scholar
  53. 53.
    Saubolle MA, McKellar PP, Sussland D. Epidemiologic, clinical, and diagnostic aspects of coccidioidomycosis. J Clin Microbiol 2007; 45: 26–30PubMedCrossRefGoogle Scholar
  54. 54.
    Ampel NM, Dols CL, Galgiani JN. Coccidioidomycosis during human immunodeficiency virus infection: results of a prospective study in a coccidioidal endemic area. Am J Med 1993; 94: 235–40PubMedCrossRefGoogle Scholar
  55. 55.
    Blair JE, Logan JL. Coccidioidomycosis in solid organ transplantation. Clin Infect Dis 2001; 33: 536–44CrossRefGoogle Scholar
  56. 56.
    Blair JE, Kusne S, Carey EJ, et al. The prevention of recrudescent coccidioidomycosis after solid organ transplantation. Transplantation 2007; 83: 1182–7PubMedCrossRefGoogle Scholar
  57. 57.
    Slagle DC, Cox RA, Kuruganti U. Induction of tumor necrosis factor-α by spherules of Coccidioides immitis. Infect Immun 1989; 57: 1916–21PubMedGoogle Scholar
  58. 58.
    Ampel NM. In vitro production of TNF-α by adherent human peripheral blood mononuclear cells incubated with killed coccidioidal arthroconidia and spherules. Cell Immunol 1994; 153: 248–55PubMedCrossRefGoogle Scholar
  59. 59.
    Corry DB, Ampel NM, Christian L, et al. Cytokine production by peripheral blood mononuclear cells in human coccidioidomycosis. J Infect Dis 1996; 174: 440–3PubMedCrossRefGoogle Scholar
  60. 60.
    Bergstrom L, Yocum DE, Ampel NM, et al. Increased risk of coccidioidomycosis in patients treated with TNF antagonists. Arthritis Rheum 2004; 50: 1959–66PubMedCrossRefGoogle Scholar
  61. 61.
    Raclette A. Coccidioidomycosis infections in patients on TNFα inhibitors [poster]. American Academy of Dermatology Annual Meeting; 2007 Feb 2–6; Washington, DCGoogle Scholar
  62. 62.
    Dweik M, Baethge BA, Duarte AG. Coccidioidomycosis pneumonia in a nonendemic area associated with infliximab. South Med J 2007; 100: 517–8PubMedCrossRefGoogle Scholar
  63. 63.
    Durkin M, Connoly P, Kuberski T, et al. Diagnosis of coccidioidomycosis with use of the Coccidioides antigen enzyme immunoassay. Clin Infect Dis 2008; 47: e69–73PubMedCrossRefGoogle Scholar
  64. 64.
    Galgiani JN, Ampel NM, Blair JE, et al. Coccidioidomycosis. Clin Infect Dis 2005; 41: 1217–23PubMedCrossRefGoogle Scholar
  65. 65.
    McKinsey DS, Wheat LJ, Cloud GA, et al. Itraconazole prophylaxis for fungal infections in patients with advanced human immunodeficiency virus infection: randomized, placebo-controlled, double-blind study. Clin Infect Dis 1999; 28: 1049–56PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2009

Authors and Affiliations

  1. 1.Division of Infectious DiseasesUniversity of Michigan Medical School, Veterans Affairs Ann Arbor Healthcare SystemAnn ArborUSA

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