Endemic Fungal Infections in Solid Organ Transplantation

Abstract

The endemic mycoses, histoplasmosis, blastomycosis and coccidioidomycosis, are fungal diseases prevalent in specific geographic regions. The environment is the main source for exposure to these fungi, with the respiratory tract serving as the primary portal of entry into the human body. Although the epidemiologic and clinical features of each infection are unique, some characteristics are shared. Symptomatic disease occurs in both the immunocompetent and immunocompromised host with the severity of infection correlating with underlying immune status. Cell mediated immunity plays an important role in the susceptibility to and control of these infections. Recently reports of endemic fungal infections occurring in organ transplant recipients have been increasing (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,2Freifeld A Iwen PC Lesiak BL Gilroy RK Stevens RB Kalil AC Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center.Transpl Infect Dis. 2005; 7: 109-115Crossref PubMed Scopus (0) Google Scholar). In addition, increased recognition of donor-derived fungal infections in recipients prompted the recent development of guidelines discussing the unique characteristics, evaluation and approach to their management (3Singh N Huprikar S Burdette SD Morris MI Blair JE Wheat LJ the American Society of Transplantation, Infectious Diseases Community of Practice, Donor-Derived Fungal Infection Working GroupDonor-Derived Fungal Infections in Organ Transplant Recipients: Guidelines of the American Society of Transplantation, Infectious Diseases Community of Practice(†).Am J Transplant. 2012; 12: 2414-2428Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). Although the true incidence of these infections among this population is unknown, estimates suggest it is <5% (4Pappas P Alexander B Marr K Invasive fungal infections (IFIs) in hematopoietic stem cell (HSCTs) and organ transplant recipients (OTRs): Overview of the TRANSNET database [abstract 671].in: Programs and abstracts of the 42nd Annual Meeting of the Infectious Diseases Society of America (Boston) Alexandria. Infectious Diseases Society of America., VA2004: 174Google Scholar, 5Singh N Fungal infections in the recipients of solid organ transplantation.Infect Dis Clin North Am. 2003; 17: 113-134Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar, 6Pappas P Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar). The focal geographic distribution of the endemic fungi and indolent symptoms of infection frequently lead to diagnostic delays and contribute to increased morbidity and mortality (5Singh N Fungal infections in the recipients of solid organ transplantation.Infect Dis Clin North Am. 2003; 17: 113-134Abstract Full Text Full Text PDF PubMed Scopus (167) Google Scholar,7Dworkin M Duckro AN Proia L Semel JD Huhn G The epidemiology of blastomycosis in Illinois and factors associated with death.Clin Infect Dis. 2005; 41: e107-e111Crossref PubMed Google Scholar). Knowledge of the epidemiology, pathogenesis, clinical manifestations, diagnostic methodologies and therapy will enable clinicians to more effectively identify and manage transplant recipients with endemic mycoses. Blastomycosis refers to disease caused by the fungus, Blastomyces dermatitidis, which occurs more often in persons living in the midwestern, southeastern and south central United States, particularly along the Ohio-Mississippi River Valley (8Sarosi G Davies SF Blastomycosis: State of the art.Am Rev Respir Dis. 1979; 120: 911-938PubMed Google Scholar). B. dermatitidis is also found in the soil of northern New York and Canadian provinces that border the Great Lakes and St. Lawrence Seaway. Recent studies have shown an increase in the incidence of blastomycosis in some of these endemic regions (6Pappas P Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar,9Carlos W Rose AS Wheat LJ et al.Blastomycosis in Indiana: Digging up more cases.Chest. 2010; 138: 1377-1382Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar,10Fanella S Skinner S Trepman E Embil JM Blastomycosis in children and adolescents: A 30-year experience from Manitoba.Med Mycol. 2011; 49: 627-632PubMed Google Scholar). The majority of reported cases of blastomycosis after organ transplantation have occurred in patients residing in endemic areas (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). Historically blastomycosis has been a disease that affects immunocompetent hosts, predominantly men with outdoor occupations or recreational activities involving soil exposure, although many individuals have no apparent source for infection (8Sarosi G Davies SF Blastomycosis: State of the art.Am Rev Respir Dis. 1979; 120: 911-938PubMed Google Scholar,12Crampton T Light RB Berg GM et al.Epidemiology and clinical spectrum of blastomycosis diagnosed at Manitoba hospitals.Clin Infect Dis. 2002; 34: 1310-1316Crossref PubMed Scopus (112) Google Scholar). In the immunocompromised host, it may be associated with severe pneumonia or disseminated infection, particularly in patients with diabetes, HIV or those receiving chronic corticosteroids or cytotoxic chemotherapy (13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar). Unlike coccidioidomycosis or histoplasmosis, blastomycosis has been described infrequently as an opportunistic pathogen after solid organ transplantation (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,6Pappas P Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). In one review, the cumulative incidence posttransplant was only 0.14% during a 16-year period (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). Reports of blastomycosis after renal, cardiac, hepatic and lung transplantation have been published with disease onset ranging from 1 week to 20 years posttransplant (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,6Pappas P Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar,14Serody J Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: Report of a case and review.Clin Infect Dis. 1993; 16: 54-58Crossref PubMed Google Scholar). Blastomycosis in this population may result from primary infection, reactivation of latent disease or conversion of subclinical infection to symptomatic disease after organ transplantation (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). To date, there are no reports of donor transmission of B. dermatitidis. Infection with B. dermatitidis results from inhalation of fungal spores into pulmonary alveoli. Cell-mediated immunity limits progression of B. dermatitidis infection in the lungs. If impaired, pneumonia or extrapulmonary dissemination may develop. As such, the majority of transplant recipients who develop blastomycosis are concurrently taking two or more immunosuppressive agents (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar,14Serody J Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: Report of a case and review.Clin Infect Dis. 1993; 16: 54-58Crossref PubMed Google Scholar). Cytomegalovirus (CMV) infection can also impair cellular immune defenses and, although its exact role is unclear, in one study one-third of patients with posttransplant blastomycosis were co-infected with CMV (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). There are no data to suggest that acute rejection increases the risk for blastomycosis (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). Though less common, blastomycosis arising from primary cutaneous inoculation is also described (15Gray N Baddour LM Cutaneous inoculation blastomycosis.Clin Infect Dis. 2002; 34 (E44–E9)Crossref Google Scholar). Pneumonia with or without extra-pulmonary dissemination is the most common presentation of blastomycosis in solid organ transplant recipients (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,6Pappas P Alexander BD Andes DR et al.Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET).Clin Infect Dis. 2010; 50: 1101-1111Crossref PubMed Scopus (1035) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar,14Serody J Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: Report of a case and review.Clin Infect Dis. 1993; 16: 54-58Crossref PubMed Google Scholar). Although the time from transplantation to development of blastomycosis is variable, the median time ranges from 1 to 2 years posttransplant (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). Median time from symptom onset to diagnosis is 14 days (range 3–90 days; Ref.11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). Though nearly all transplant associated blastomycosis infections involve the lungs, the spectrum of pulmonary infection ranges from subclinical disease to acute or chronic pneumonia (11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,16Bradsher RJ Pulmonary blastomycosis.Semin Respir Crit Care Med. 2008; 29: 174-181Crossref PubMed Scopus (0) Google Scholar). Acute pulmonary blastomycosis is a flu-like illness which develops 30–45 days after initial infection. Typical symptoms include fever, chills, arthralgias and productive cough with an accompanying alveolar or lobar infiltrate on chest radiography. In solid organ transplant recipients the most common presenting symptoms are fever and cough (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). These symptoms are not specific for blastomycosis and, not uncommonly, patients may be misdiagnosed with bacterial pneumonia. Radiographic findings in transplant patients include lobar or interstitial infiltrates, a reticulonodular pattern with mediastinal adenopathy or lung cavities (14Serody J Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: Report of a case and review.Clin Infect Dis. 1993; 16: 54-58Crossref PubMed Google Scholar). A subset of individuals with pulmonary blastomycosis develop fulminant multi-lobar pneumonia and rapid progression to the adult respiratory distress syndrome (ARDS) and respiratory failure (17Meyer K McManus EJ Maki DG Overwhelming pulmonary blastomycosis associated with the adult respiratory distress syndrome.N Engl J Med. 1993; 329: 1231-1236Crossref PubMed Google Scholar). In patients who underwent solid organ transplantation, diffuse bilateral pneumonia was the most common radiographic finding; 78% developed respiratory failure and ARDS complicated 67% of cases. The majority of patients that developed ARDS died (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). Chronic pulmonary blastomycosis may follow acute infection with more prolonged symptoms such as fever, night sweats, anorexia, weight loss, productive cough, pleurisy and occasional hemoptysis. Chest radiography or a computed tomography (CT) scan may show a mass-like infiltrate or cavitary pneumonia mimicking tuberculosis or malignancy (8Sarosi G Davies SF Blastomycosis: State of the art.Am Rev Respir Dis. 1979; 120: 911-938PubMed Google Scholar). Although blastomycosis usually remains localized to the lungs, 25–40% of those infected will develop extra-pulmonary dissemination manifested by cutaneous, osteo-articular, genitourinary or central nervous system (CNS) disease (8Sarosi G Davies SF Blastomycosis: State of the art.Am Rev Respir Dis. 1979; 120: 911-938PubMed Google Scholar). In solid organ transplant patients, disseminated disease was observed in 36–50%, with skin being the most common site of involvement outside the lungs (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar,14Serody J Mill MR Detterbeck FC Harris DT Cohen MS Blastomycosis in transplant recipients: Report of a case and review.Clin Infect Dis. 1993; 16: 54-58Crossref PubMed Google Scholar). CNS blastomycosis is rare in the setting of organ transplantation; though has been reported (11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,13Pappas P Threlkeld MG Bedsole GD Cleveland KO Gelfand MS Dismukes WE Blastomycosis in immunocompromised patients.Medicine (Baltimore). 1993; 72: 311-325Crossref PubMed Google Scholar). Fungemia is rare. A presumptive diagnosis of blastomycosis is made by identifying the organism in sputum, bronchoalveolar lavage (BAL) fluid or tissue specimens; growth in culture confirms the diagnosis (16Bradsher RJ Pulmonary blastomycosis.Semin Respir Crit Care Med. 2008; 29: 174-181Crossref PubMed Scopus (0) Google Scholar). In one study of solid organ transplant patients, culture of sputum or BAL fluid was 100% sensitive for diagnosing pulmonary blastomycosis (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar). Alternatively other sites of involvement, such as skin, bone, synovial fluid, brain tissue or cerebrospinal fluid (CSF) may be sampled for histopathologic examination and culture. Gastric lavage cultures may also be a useful diagnostic technique, particularly in pediatric patients, as it may avert the need for more invasive diagnostic techniques (18Fanella S Walkty A Bridger N et al.Gastric lavage for the diagnosis of pulmonary blastomycosis in pediatric patients.Pediatr Infect Dis J. 2010; 29: 1146-1148Crossref PubMed Scopus (5) Google Scholar). The characteristic fungal forms seen on direct examination are large (8–15 μm), broad-based budding yeast. A potassium hydroxide (KOH) wet mount or special fungal stains, may enhance visualization of B. dermatitidis in body fluids or tissue. Micro-abscesses and noncaseating granulomas are often observed on histopathology since the initial inflammatory response to B. dermatitidis is both neutrophilic and cell-mediated. A second generation assay for detection of Blastomyces antigen in urine, blood and BAL fluid is available and can often lead to more rapid diagnosis than culture (19Durkin 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: 4873-4875Crossref PubMed Scopus (167) Google Scholar, 20Connolly P Hage CA Bariola JR et al.Blastomyces dermatitidis antigen detection by quantitative enzyme immunoassay.Clin Vaccine Immunol. 2012; 19: 53-56Crossref PubMed Scopus (66) Google Scholar, 21Hage C Davis TE Egan L 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: 43-47Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). In patients with blastomycosis, sensitivity of this assay is over 90%. Specificity is 99% in individuals with nonfungal infections and healthy subjects, however, cross-reactivity occurs in 96% of patients with histoplasmosis (19Durkin 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: 4873-4875Crossref PubMed Scopus (167) Google Scholar, 20Connolly P Hage CA Bariola JR et al.Blastomyces dermatitidis antigen detection by quantitative enzyme immunoassay.Clin Vaccine Immunol. 2012; 19: 53-56Crossref PubMed Scopus (66) Google Scholar, 21Hage C Davis TE Egan L 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: 43-47Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar). The utility of this test has not been well established in solid organ transplant recipients. Limited data suggest sera from patients with proven blastomycosis tests negative for (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar, 2Freifeld A Iwen PC Lesiak BL Gilroy RK Stevens RB Kalil AC Histoplasmosis in solid organ transplant recipients at a large Midwestern university transplant center.Transpl Infect Dis. 2005; 7: 109-115Crossref PubMed Scopus (0) Google Scholar, 3Singh N Huprikar S Burdette SD Morris MI Blair JE Wheat LJ the American Society of Transplantation, Infectious Diseases Community of Practice, Donor-Derived Fungal Infection Working GroupDonor-Derived Fungal Infections in Organ Transplant Recipients: Guidelines of the American Society of Transplantation, Infectious Diseases Community of Practice(†).Am J Transplant. 2012; 12: 2414-2428Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar)-β-d-glucan (Fungitell®; Ref. 22Girouard G Lachance C Pelletier R Observations on (1–3)-beta-D-glucan detection as a diagnostic tool in endemic mycosis caused by Histoplasma or Blastomyces.J Med Microbiol. 2007; 56: 1001-1002Crossref PubMed Scopus (28) Google Scholar). Currently available serologic tests lack sensitivity and are not useful for diagnosis of blastomycosis. The management of blastomycosis in solid organ transplant recipients follows published guidelines (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar). All immunocompromised individuals require treatment and since these patients are more likely to present with severe pulmonary or disseminated infection, amphotericin B is recommended as first line therapy (III). A lipid formulation, such as liposomal amphotericin B or amphotericin B lipid complex, is preferred because of the reduced potential for nephrotoxicity (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar). Amphotericin B is administered for the first 1–2 weeks until clinical improvement is demonstrated at which time transition to oral itraconazole may be acceptable (III) (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar). Liposomal amphotericin B is recommended for infection involving the CNS but more prolonged therapy is given, generally 4–6 weeks, before transitioning to azole therapy (III) (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar). In some patients with mild pulmonary infection, oral itraconazole may be given as initial therapy but close clinical monitoring is warranted (III). Cortico-steroids may be considered as adjunctive therapy in severe blastomycosis-induced ARDS (24Plamondon M Lamontagne F Allard C Pépin J Corticosteroids as adjunctive therapy in severe blastomycosis-induced acute respiratory distress syndrome in an immunosuppressed patient.Clin Infect Dis. 2010; 51: e1-e3Crossref PubMed Scopus (0) Google Scholar). Fluconazole appears to be less effective for blastomycosis (II-1) and should only be used as second line therapy or in high doses for prolonged treatment of CNS infection (III) (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar,25Pappas P Bradsher RW Chapman SW et al.Treatment of blastomycosis with fluconazole: A pilot study. The National Institute of Allergy and Infectious Diseases Mycoses Study Group.Clin Infect Dis. 1995; 20: 267-271Crossref PubMed Google Scholar). Oral voriconazole has good CNS penetration and excellent in vitro activity against B. dermatitidis, thus another option for prolonged therapy of CNS blastomycosis (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar,26Li R Ciblak MA Nordoff N Pasarell L Warnock DW McGinnis MR In vitro activities of voriconazole, itraconazole, and amphotericin B against Blastomyces dermatitidis, Coccidioides immitis, and Histoplasma capsulatum.Antimicrob Agents Chemother. 2000; 44: 1734-1736Crossref PubMed Scopus (163) Google Scholar, 27Espinel-Ingroff A Comparison of In vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts.J Clin Microbiol. 1998; 36: 2950-2956Crossref PubMed Google Scholar, 28Nakai T Uno J Ikeda F Tawara S Nishimura K Miyaji M In vitro antifungal activity of Micafungin (FK463) against dimorphic fungi: Comparison of yeast-like and mycelial forms.Antimicrob Agents Chemother. 2003; 47: 1376-1381Crossref PubMed Scopus (0) Google Scholar). Voriconazole and fluconazole are preferred over itraconazole for CNS infection, given the limited CNS penetration (<1%) and in vitro susceptibilities of itraconazole. Data are lacking for posaconazole use in CNS infection. Echinocandins have intermediate to poor in vitro activity against B. dermatitidis and should not be prescribed (27Espinel-Ingroff A Comparison of In vitro activities of the new triazole SCH56592 and the echinocandins MK-0991 (L-743,872) and LY303366 against opportunistic filamentous and dimorphic fungi and yeasts.J Clin Microbiol. 1998; 36: 2950-2956Crossref PubMed Google Scholar,28Nakai T Uno J Ikeda F Tawara S Nishimura K Miyaji M In vitro antifungal activity of Micafungin (FK463) against dimorphic fungi: Comparison of yeast-like and mycelial forms.Antimicrob Agents Chemother. 2003; 47: 1376-1381Crossref PubMed Scopus (0) Google Scholar). The duration of treatment is generally 12 months with resolution of symptoms and signs of infection (III). Consideration may be given to more prolonged treatment courses for organ transplant recipients, although conclusive data are lacking (III) (23Chapman S Dismukes WE Proia LA et al.Infectious Diseases Society of AmericaClinical practice guidelines for the management of blastomycosis: 2008 update by the Infectious Diseases Society of America.Clin Infect Dis. 2008; 46: 1801-1812Crossref PubMed Scopus (434) Google Scholar). As the Blastomyces antigen assay is quantitative, serial measurements can be used to follow treatment response over time both for adult and pediatric patients (11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar,29Mongkolrattanothai K Peev M Wheat LJ Marcinak J Urine antigen detection of blastomycosis in pediatric patients.Pediatr Infect Dis J. 2006; 25: 1076-1078Crossref PubMed Scopus (0) Google Scholar). However, using the antigen assay to guide treatment duration, is not well established. In a recent series of 8 transplant associated blastomycosis cases, median time to urine antigen negativity was 22 months (range 10–48 months; Ref. 11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). Data suggest that relapse of blastomycosis is uncommon after therapy and evidence of cure (1Gauthier GM Safdar N Klein BS Andes DR Blastomycosis in solid organ transplant recipients.Transpl Infect Dis. 2007; 9: 310-317Crossref PubMed Scopus (97) Google Scholar,11Grim S Proia L Miller R et al.A multicenter study of histoplasmosis and blastomycosis after solid organ transplantation.Transpl Infect Dis. 2012; 14: 17-23Crossref PubMed Scopus (0) Google Scholar). There is no sensitive or specific serologic assay available to diagnose previous exposure to Blastomyces or active disease. Careful screening for active infection, including symptom assessment and chest radiography, should be a part of the pretransplant evaluation of patients who live in Blastomyces endemic areas. There have been no trials of targeted antifungal prophylaxis for prevention of blastomycosis in organ transplant recipients who reside in endemic regions