Histoplasmosis in Solid Organ Transplant Recipients

To the Editor—Cuellar-Rodriguez et al [1] present a review of their experience with the diagnosis and management of progressive disseminated histoplasmosis (PDH) in a large cohort of patients who had undergone solid organ transplantation. We comment upon some aspects of the observations and conclusions they have proposed in this important and timely report. In their case definitions of clinical scenarios, the authors include as proven cases of active infection the coexistence of compatible clinical manifestations (undefined) and the histopathologic observation of yeast forms compatible with Histoplasma capsulatum. They report that yeast forms were observed in 9 explanted lung/lymph node specimens and in 4 donor lung specimens. In an additional patient, similar findings were present in the spleen removed during liver transplantation. Symptoms and laboratory examinations compatible with posttransplantation histoplasmosis were not identified in this group, prompting the authors to speculate that this may have resulted from the effectiveness of a standardized posttransplantation regimen of inhaled amphotericin B followed by an 18-month course of itraconazole (for lung transplant recipients) or fluconazole (for liver transplant recipients). This conclusion was based upon their presumption that these patients were at risk for “reactivation” of latent foci of viable H. capsulatum, which had been harbored within granulomas. However, there is no evidence that supports this premise. Convincing evidence to the contrary may be gleaned from an autopsy series [2] in which calcified granulomas were examined and 67% found to contain typical yeast forms. Fungal cultures of the contents of the granulomas were sterile and inoculation into experimental animals failed to cause infection; the investigators concluded that the yeast forms were not viable. In addition, reactivation did not occur in any of the 449 solid organ transplant recipients observed at Indiana University over a 3-year period (1283 patient-years), many of whom had serologic (24%) and radiographic (4%) evidence of old histoplasmosis and for whom antifungal prophylaxis was not used routinely [3]. The authors also speculate regarding the unanticipated presence of yeast-like forms in both explanted and donor organs, particularly in lung transplantation. The presence of asymptomatic granulomas within lung tissue and its adjacent lymph nodes, as well as the spleen, are reflective of the region's endemicity for histoplasmosis [4], an infection which occurs asymptomatically and/or is unrecognized in as many as 95% of affected individuals. In view of this, the opportunistic infections reported in the Cleveland Clinic series might be more likely attributable to environmental exposure [5] than to reactivation of latent foci of infection. Lastly, our experience with the Histoplasma urine antigen assay (Table 1) performed on individuals with culture-proven PDH does not comport with that presented in the Cleveland Clinic series. In the latter, of 13 patients in whom antigen testing was performed, all of whom had H. capsulatum recovered from blood cultures, only 9 (69%) were antigen positive. This contrasts with our Indianapolis experience, in which urine antigen test results were positive for 100% of patients with PDH confirmed by culture and of those with negative culture results and for 92% of patients with PDH in whom cultures were not performed. Histoplasma Antigen Detection in Patients with Progressive Disseminated Histoplasmosis at Indiana University Medical Center NOTE. TNF, tumor necrosis factor. Histoplasma Antigen Detection in Patients with Progressive Disseminated Histoplasmosis at Indiana University Medical Center NOTE. TNF, tumor necrosis factor. Potential conflicts of interest. L.J.W. is an employee of MiraVista Diagnostics, the laboratory that performs the Histoplasma antigen test. C.H. and M.B.K.: no conflicts.