Diagnosis of Midwestern Endemic Mycoses

Abstract

Histoplasmosis and blastomycosis are the two most common midwestern endemic mycoses. A history of exposure to the geographic areas in which these organisms occur is central to raising suspicion for an endemic fungal infection. For infection with these organisms, the diagnosis is definitively established by recovery of the organism in tissue or body fluids, which may take weeks. A rapid diagnosis can be made by finding the distinctive yeasts in tissues or body fluids. Antigen testing allows a presumptive diagnosis of these endemic fungal infections while awaiting culture results, but cross-reactivity between assays for Histoplasma and Blastomyces is routinely seen. Antibody tests provide supportive evidence for infection with either of these endemic mycoses but are less useful in immunosuppressed patients.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. 1.

    Chapman SW, Lin AC, Hendricks KA, Nolan RL, Currier MM, Morris KR, et al. Endemic blastomycosis in Mississippi: epidemiological and clinical studies. Semin Respir Infect. 1997;12:219–28.

    CAS  PubMed  Google Scholar 

  2. 2.

    Saccente M, Woods GL. Clinical and laboratory update on blastomycosis. Clin Microbiol Rev. 2010;23:367–81.

    Article  PubMed  PubMed Central  Google Scholar 

  3. 3.

    De Groote MA, Bjerke R, Smith H, Rhodes LV. Expanding epidemiology of blastomycosis: clinical features and investigation of 2 cases in Colorado. Clin Infect Dis. 2000;30:582–4.

    Article  PubMed  Google Scholar 

  4. 4.

    Smith JA, Kauffman CA. Blastomycosis. Proc Am Thorac Soc. 2010;7:173–80.

    Article  PubMed  Google Scholar 

  5. 5.

    Crampton TL, Light RB, Berg GM, Meyers MP, Schroeder GC, Hershfield ES, et al. Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals. Clin Infect Dis. 2002;34:1310–6.

    Article  PubMed  Google Scholar 

  6. 6.

    Carlos WG, Rose AS, Wheat LJ, Norris S, Sarosi GA, Knox KS, et al. Blastomycosis in Indiana: digging up more cases. Chest. 2010;138:1377–82.

    Article  PubMed  Google Scholar 

  7. 7.

    Anderson JL, Dieckman JL, Reed KD, Meese JK. Canine blastomycosis in Wisconsin: a survey of small-animal veterinary practices. Med Mycol. 2014;52:774–9.

    Article  PubMed  Google Scholar 

  8. 8.

    Gray NA, Baddour LM. Cutaneous inoculation blastomycosis. Clin Infect Dis. 2002;34:e44–9.

    Article  PubMed  Google Scholar 

  9. 9.

    Smith JA, Riddell J, Kauffman CA. Cutaneous manifestations of endemic mycoses. Curr Infect Dis Rep. 2013;15:440–9.

    Article  PubMed  Google Scholar 

  10. 10.

    Martynowicz MA, Prakash UB. Pulmonary blastomycosis: an appraisal of diagnostic techniques. Chest. 2002;121:768–73.

    Article  PubMed  Google Scholar 

  11. 11.

    Durkin M, Witt J, LeMonte A, Wheat B, Connolly P. Antigen assay with the potential to aid in diagnosis of blastomycosis. J Clin Microbiol. 2004;42:4873–5.

    Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Connolly P, Hage CA, Bariola JR, Bensadoun E, Rodgers M, Bradsher RW, et al. Blastomyces dermatitidis antigen detection by quantitative enzyme immunoassay. Clin Vacc Immunol. 2012;19:53–6.

    CAS  Article  Google Scholar 

  13. 13.

    Bariola JR, Perry P, Pappas PG, Proia L, Shealey W, Wright PW, et al. Blastomycosis of the central nervous system: a multicenter review of diagnosis and treatment in the modern era. Clin Infect Dis. 2010;50:797–804.

    Article  PubMed  Google Scholar 

  14. 14.

    Hage CA, Davis TE, Egan L, Parker M, Fuller D, Demonte AM, et al. Diagnosis of pulmonary histoplasmosis and blastomycosis by detection of antigen in bronchoalveolar lavage fluid using an improved second-generation enzyme-linked immunoassay. Respir Med. 2007;101:43–7.

    Article  PubMed  Google Scholar 

  15. 15.

    Hage CA, Knox KS, Davis TE, Wheat LJ. Antigen detection in bronchoalveolar lavage fluid for diagnosis of fungal pneumonia. Curr Opin Pulm Med. 2011;17:167–71.

    CAS  Article  PubMed  Google Scholar 

  16. 16.

    Bariola JR, Hage CA, Durkin M, Bensadoun E, Gubbins PO, Wheat LJ, et al. Detection of Blastomyces dermatitidis antigen in patients with newly diagnosed blastomycosis. Diagn Microbiol Infect Dis. 2011;69:187–91.

    CAS  Article  PubMed  Google Scholar 

  17. 17.•

    Frost HM, Novicki TJ. Blastomyces antigen detection for diagnosis and management of blastomycosis. J Clin Microbiol. 2015;53:3660–2. Report on the effectiveness of the Blastomyces EIA assay for detecting B. dermatitidis antigen. Sensitivity was lower than previously reported. The authors report that the EIA test in urine can be followed to assess response to therapy.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    Van Der Veer J, Lewis RJ, Emtiazjoo AM, Allen SD, Wheat J, Hage CA. Cross-reactivity in the Platelia™ Aspergillus enzyme immunoassay caused by blastomycosis. Med Mycol. 2012;50:396–8.

    Article  Google Scholar 

  19. 19.

    Cummmings JR, Jamison GR, Boudreaux JW, Howles MJ, Walsh TJ, Hayden RT. Cross-reactivity of non-Aspergillus fungal species in the Aspergillus galactomannan enzyme immunoassay. Diagn Microbiol Infect Dis. 2007;59:113–5.

    Article  Google Scholar 

  20. 20.

    Soufleris AJ, Klein BS, Courtney BT, Proctor MA, Jones JM. Utility of anti-WI-1 serological testing in the diagnosis of blastomycosis in Wisconsin residents. Clin Infect Dis. 1994;19:87–91.

    CAS  Article  PubMed  Google Scholar 

  21. 21.

    Klein BS, Jones JM. Isolation, purification, and radiolabeling of a novel 120-kD surface protein on Blastomyces dermatitidis yeasts to detect antibody in infected patients. J Clin Invest. 1990;85:152–61.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  22. 22.•

    Richer SM, Smedema ML, Durkin MM, Brandhorst TT, Hage CA, Connolly PA, et al. Development of a highly sensitive and specific blastomycosis antibody enzyme immunoassay using Blastomyces dermatitidis surface protein BAD-1. Clin Vacc Immunol. 2014;21:143–6. Report of a recently developed antibody assay that might prove to be more specific for blastomycosis than prior assays.

    Article  Google Scholar 

  23. 23.

    Babady NE, Buckwalter SP, Hall L, Le Febre KM, Binnicker MJ, Wengenack NL. Detection of Blastomyces dermatitidis and Histoplasma capsulatum from culture isolates and clinical specimens by use of real-time PCR. J Clin Microbiol. 2011;49:3204–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Sidamonidze K, Peck MK, Perez M, Baumgardner D, Smith G, Chaturvedi V, et al. Real-time PCR assay for identification of Blastomyces dermatitidis in culture and in tissue. J Clin Microbiol. 2012;50:1783–6.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Bialek R, Cirera AC, Herrmann T, Aepinus C, Shearn-Bochsler VI, Legendre AM. Nested PCR assays for detection of Blastomyces dermatitidis in paraffin-embedded canine tissue. J Clin Microbiol. 2003;41:205–8.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  26. 26.

    Cano M, Hajjeh RA. The epidemiology of histoplasmosis: a review. Semin Respir Infect. 2001;16:109–18.

    CAS  Article  PubMed  Google Scholar 

  27. 27.

    Kauffman CA. Histoplasmosis: a clinical and laboratory update. Clin Microbiol Rev. 2007;20:115–32.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  28. 28.

    Kauffman CA, Freifeld AG, Andes DR, Baddley JW, Herwaldt L, Walker RC, et al. Endemic fungal infections in solid organ and hematopoietic cell transplant recipients enrolled in the Transplant-Associated Infection Surveillance Network (TRANSNET). Transpl Infect Dis. 2014;16:213–24.

    CAS  Article  PubMed  Google Scholar 

  29. 29.

    Limaye AP, Connolly PA, Sagar M, Fritsche TR, Cookson BT, Wheat LJ, et al. Transmission of Histoplasma capsulatum by organ transplantation. N Engl J Med. 2000;343:1163–6.

    CAS  Article  PubMed  Google Scholar 

  30. 30.

    Cuellar-Rodriquez J, Avery RK, Lard M, Budev M, Gordon SM, Shrestha NK, et al. Histoplasmosis in solid organ transplant recipients: 10 years of experience at a large transplant center in an endemic area. Clin Infect Dis. 2009;49:710–6.

    Article  Google Scholar 

  31. 31.•

    Benedict K, Thompson GR, Deresinski S, Chiller T. Mycotic infections acquired outside areas of known endemicity, United States. Emerg Infect Dis. 2015;21:1935–41. Interesting review of cases of endemic mycoses reported in patients and animals living outside the areas endemic for these fungi.

    Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Connolly PA, Durkin MM, LeMonte AM, Hackett E, Wheat LJ. Detection of Histoplasma antigen by a quantitative immunoassay. Clin Vacc Immunol. 2007;14:1587–91.

    CAS  Article  Google Scholar 

  33. 33.

    Hage CA, Ribes JA, Wengenack NL, Baddour LM, Assi M, McKinsey DS, et al. A multicenter evaluation of tests for diagnosis of histoplasmosis. Clin Infect Dis. 2011;53:448–54.

    Article  Google Scholar 

  34. 34.

    Wheat LJ. Approach to the diagnosis of the endemic mycoses. Clin Chest Med. 2009;30:379–90.

    Article  PubMed  Google Scholar 

  35. 35.

    Hage CA, Davis TE, Fuller D, Egan L, Witt JR, Wheat LJ, et al. Diagnosis of histoplasmosis by antigen detection in BAL fluid. Chest. 2010;137:623–8.

    CAS  Article  PubMed  Google Scholar 

  36. 36.

    Wheat LJ, Musial CE, Jenny-Avital E. Diagnosis and management of central nervous system histoplasmosis. Clin Infect Dis. 2005;40:844–52.

    CAS  Article  PubMed  Google Scholar 

  37. 37.

    Swartzentruber S, LeMonte A, Witt J, Fuller D, Davis T, Hage C, et al. Improved detection of Histoplasma antigenemia following dissociation of immune complexes. Clin Vacc Immunol. 2009;16:320–2.

    CAS  Article  Google Scholar 

  38. 38.

    Swartzentruber S, Rhodes L, Kurkjian K, Zahn M, Brandt ME, Connolly P, et al. Diagnosis of acute pulmonary histoplasmosis by antigen detection. Clin Infect Dis. 2009;49:1878–82.

    CAS  Article  PubMed  Google Scholar 

  39. 39.

    Scheel CM, Samayoa B, Herrera A, Lindsley MD, Benjamin L, Reed Y, et al. Development and evaluation of an enzyme-linked immunosorbent assay to detect Histoplasma capsulatum antigenuria in immunocompromised patients. Clin Vacc Immunol. 2009;16:852–8.

    CAS  Article  Google Scholar 

  40. 40.

    Cloud JL, Bauman SK, Neary BP, et al. Performance characteristics of a polyclonal enzyme immunoassay for the quantitation of Histoplasma antigen in human urine samples. Am J Clin Pathol. 2007;128:18–22.

    CAS  Article  PubMed  Google Scholar 

  41. 41.

    Theel ES, Harring JA, Dababneh AS, Rollins LO, Bestrom JE, Jespersen DJ. Re-evaluation of commercial regents for detection of Histoplasma capsulatum antigen in urine. J Clin Microbiol. 2015;53:1198–203.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Zhang C, Lei G-S, Lee CH, Hage CA. Evaluation of two new enzyme immunoassay reagents for diagnosis of histoplasmosis in a cohort of clinically characterized patients. Med Mycol. 2015;53:868–73.

    Article  PubMed  Google Scholar 

  43. 43.

    Wheat J, Wheat H, Connolly P, Kleiman M, Supparatpinyo K, Nelson K, et al. Cross-reactivity in Histoplasma capsulatum variety capsulatum antigen assays of urine samples from patients with endemic mycoses. Clin Infect Dis. 1997;24:1169–71.

    CAS  Article  PubMed  Google Scholar 

  44. 44.

    Hage CA, Kirsch EJ, Stump TE, Kauffman CA, Goldman M, Connolly P, et al. Histoplasma antigen clearance during treatment of histoplasmosis in patients with AIDS determined by a quantitative antigen enzyme immunoassay. Clin Vacc Immunol. 2011;18:661–6.

    CAS  Article  Google Scholar 

  45. 45.

    Wheat LJ, Hackett E, Durkin M, Connolly P, Petraitiene R, Walsh TJ, et al. Histoplasmosis-associated cross-reactivity in the BioRad Platelia Aspergillus enzyme immunoassay. Clin Vacc Immunol. 2007;14:638–40.

    CAS  Article  Google Scholar 

  46. 46.

    Vergidis P, Walker RC, Kaul DR, Kauffman CA, Freifeld AG, Slagle D, et al. Histoplasmosis may be misdiagnosed as aspergillosis due to false-positive Aspergillus galactomannan assay. Transpl Infect Dis. 2012;14:213–7.

    CAS  Article  PubMed  Google Scholar 

  47. 47.•

    Richer SM, Smedema ML, Durkin MM, Herman KM, Hage CA, Fuller D, et al. Improved diagnosis of acute pulmonary histoplasmosis by combining antigen and antibody detection. Clin Infect Dis. 2016;62:896–902. Report of a new antibody assay for histoplasmosis which, when combined with antigen assays in urine and serum, appears to increase the sensitivity of non-culture techniques for the diagnosis of acute pulmonary histoplasmosis.

    Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Koepsell SA, Hinrichs SV, Iwen PC. Applying a real-time PCR assay for Histoplasma capsulatum to clinically relevant formalin-fixed paraffin-embedded human tissue. J Clin Microbiol. 2012;50:3395–7.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  49. 49.

    Bracca A, Tosello ME, Girardini JE, Amigot SL, Gomez C, Serra E. Molecular detection of Histoplasma capsulatum var. capsulatum in human clinical samples. J Clin Microbiol. 2003;41:1753–5.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Rickerts V, Bialek R, Tintelnot K, Jacobi V, Just-Nubling G. Rapid PCR-based diagnosis of disseminated histoplasmosis in an AIDS patient. Eur J Clin Microbiol Infect Dis. 2002;21:821–3.

    CAS  Article  PubMed  Google Scholar 

  51. 51.

    Moncada PA, Budvytiene I, Ho DY, Deresinski SC, Montoya JG, Banaei N. Utility of DNA sequencing for direct identification of invasive fungi from fresh and formalin-fixed specimens. Am J Clin Pathol. 2013;140:203–8.

    Article  PubMed  Google Scholar 

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Correspondence to Marisa H. Miceli.

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Marisa H. Miceli, Caroline G. Castillo, and Carol A. Kauffman declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Advances in Diagnosis of Invasive Fungal Infections

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Miceli, M.H., Castillo, C.G. & Kauffman, C.A. Diagnosis of Midwestern Endemic Mycoses. Curr Fungal Infect Rep 10, 87–95 (2016). https://doi.org/10.1007/s12281-016-0260-7

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Keywords

  • Histoplasmosis
  • Blastomycosis
  • Endemic mycoses
  • Antigen tests
  • Antibody tests
  • Histopathology