Disseminated Histoplasmosis in Persons with HIV/AIDS, Southern Brazil, 2010–2019

We evaluated disseminated histoplasmosis (DH) in HIV patients over 10 years in southern Brazil. The incidence was 12 cases/1,000 hospitalizations (2010–2019); the mortality rate was 35%. Tuberculosis frequently obscured the diagnosis of DH. We emphasize the need in our region to suspect and investigate DH using more sensitive methods.

Most patients were men; mean age was 41 (range 21-61) years (Table 1). Except for 3, all had co-infections diagnosed concomitantly ( Table 2). The use of antiretroviral therapy at time of DH diagnosis was irregular or nonexistent in 90% (n = 28) of patients. Only 4 had >200 cells/mm 3 of CD4+ lymphocytes (mean 109 cells/mm 3 ; range 7-752 cells/mm 3 ). In 6 (19%), DH was the AIDS-defining illness. A total of 3 persons had DH associated with a systemic inflammatory response syndrome.
DH was diagnosed through classical mycologic exams in 14 (45%) patients, serologic tests in 9 (29%) patients, and urinary antigen assay in 4 (13%) patients. Four (13%) patients had >2 positive results by different methods (Figure). The diagnosis of histoplasmosis occurred after a mean of 10 (range 1-28) days from the beginning of hospitalization. This timing probably represents an underestimated delay,  because several patients reported symptoms that could have led to a diagnostic workup before the illness progressed to a point at which hospitalization was required. The treatment of choice for 81% of patients was intravenous amphotericin deoxycholate (0.7-1 mg/ kg/d, to a maximum 50 mg/d) for 14 days, followed by oral itraconazole (200 mg every 8 h for 3 days, then 200 mg every 12 h) for 12 months. A total of 5 (16%) patients were treated only with itraconazole (4 with early diagnosis of DH and 1 with renal dysfunction). Twelve months after the DH diagnosis, 35% of the patients had died (Table 1); 1 died before laboratory confirmation, and 4 died within an average of 25 (range 0-62) days after diagnosis of DH. Three patients died after 5-6 months while being treated with itraconazole, and 3 had recurrence of the disease after 6, 7, or 12 months because of antifungal interruption, which resulted in death (Table 1).

DH causes severe clinical manifestations in PLHIV
that can lead to death (10). Improved knowledge of the local epidemiology of DH and education of reference services for PLHIV are essential to reduce underdiagnosis and contribute to patient survival (11), especially in Rio Grande, a harbor city with the highest rate of HIV/AIDS among cities in Brazil with >100,000 inhabitants (7).
DH was the AIDS-defining illness in 21% of the patients in this study. Other co-infections (12,13) were noted. Respiratory signs, splenomegaly, and cutaneous lesions were more commonly described in our patients than in other studies, possibly because late diagnosis led to more severe extent of the disease (12,13). The high rate of neurologic impairment in our patients can be attributed to their co-infections; in 69% (9/13) of patients, this impairment was ascribed to neurotoxoplasmosis or herpetic encephalitis. In addition, neurologic signs were detected in 5 other patients without an ascribed neuropathogenic condition, meriting additional investigations.
Many of our patients were exhaustively investigated for TB, and 26% were empirically treated for TB despite negative results from the highly sensitive GeneXpert MTB/RIF assay (Cepheid). The long investigations for TB delayed the confirmation of the DH diagnosis despite descriptions of the concurrence of these 2 diseases (14). TB is a major opportunistic disease in PLHIV (15), evidenced by 29% of our DH patients with concomitant TB. Thus, the investigation of both diseases must occur simultaneously (12), and DH must be investigated in PLHIV with CD4+ lymphocytes <200 cells/mm 3 (11).
Tests to detect Histoplasma antibodies have poor sensitivity (30%-70%) in immunocompromised patients (1). Diagnostic methods with high rates of sensitivity and specificity are vital in areas where histoplasmosis is endemic and could improve the likelihood of early diagnosis and favorable outcomes for patients (1,12). An improvement in the investigation of DH in PLHIV with respiratory symptoms occurred in the UH-FURG-Ebserh in 2017, through a collaboration in a multicenter study (12). Subsequently, the results contributed to the acquisition of the urinary antigen assay by UH-FURG-Ebserh. In the last 3 years of our study, the urinary antigen test was the only method able to detect 25% (4/15) of our patients with DH. The detection of urinary antigens is the standard for DH diagnosis in immunosuppressed patients (11).
The mortality rate in our series (35%) was similar to the rate described in a systematic review from Brazil histoplasmosis cases (33%) (10). Therefore, the underdiagnosis of DH in PLHIV is a national problem in Brazil that must be urgently changed. In our hospital, DH was responsible for high rates of illness in PL-HIV, up to 24 cases/1,000 hospitalizations, and high mortality rates (35%). In addition, we emphasize that 29% of patients were co-infected with TB, a disease with symptoms overlapping with histoplasmosis. Simultaneous investigation for the 2 diseases in all PL-HIV patients living in areas in which histoplasmosis is endemic is mandatory.