The incidence of histoplasmosis and cryptococcal antigenemia among patients attending a large HIV clinic in Trinidad

Publication summary

Invasive infections caused by the fungi Histoplasma capsulatum and Cryptococcus neoformans present a significant and life-threatening risk to people living with HIV, and both pathogens have been deemed highly important by the World Health Organization (WHO). Fungal screening is essential for preventing severe diseases, such as disseminated histoplasmosis and cryptococcal meningitis, in people living with HIV who have low CD4+ cell counts and/or are not on antiretroviral therapy. The gold standard for screening and diagnosis involves culture or histopathology for Histoplasma species and culture of cerebrospinal fluid (CSF) for Cryptococcus species. Both culture and histopathology have low sensitivity for identifying Histoplasma, and culture takes several weeks to produce a result and requires a Biosafety Level 3 laboratory. CSF culture to identify Cryptococcus species can take several weeks and requires trained laboratory staff. This study evaluated the use of antigen assays to screen for Histoplasma capsulatum and Cryptococcus neoformans in 280 people living with HIV who had CD4+ counts of less than 350 cells per cubic millimeter (mm³) from November 2021 to June 2022 at an HIV clinic in Trinidad.

Who this is for

• Clinicians and microbiologists working with people living with HIV
• Policymakers addressing diagnostic test access low-resource settings

Key findings

HIV and fungal infections in Trinidad

There are about 11,000 people living with HIV in Trinidad, and about 65% of them are estimated to be on antiretroviral therapy. H capsulatum, which is often isolated from soil and bat droppings, is endemic in Trinidad, as it is in much of the Americas and the Caribbean. C neoformans, the most common cause of meningitis in people living with HIV, may be present in soil and bird droppings. 

As part of this study, the Medical Research Foundation, a clinic in Trinidad that serves more than 5,000 people living with HIV, screened 280 patients living with HIV who had CD4+ counts of less than 350 cells per cubic millimeter (mm³) and were newly diagnosed with HIV, hospitalized with signs and symptoms of HIV/AIDS, had stopped receiving HIV care for more than 90 days, and/or were failing antiretroviral treatment from November 2021 to June 2022. All patients were screened for H capsulatum (on urine) and C neoformans (on sera) with both an antigen enzyme immunoassay (EIA) and an antigen lateral flow assay (LFA). 

Histoplasma incidence

Among urine isolates from 280 people:

• 16 patients had both a positive EIA and LFA, 12 of whom had signs and symptoms of disseminated histoplasmosis. All 16 patients received itraconazole therapy for 12 months.
• 16 patients had a positive LFA and a negative EIA. None of these patients had signs or symptoms of disseminated histoplasmosis, did not receive antifungal treatment, and were well as of December 2022.
• Six patients had a positive EIA and a negative LFA, two of whom had signs and symptoms of disseminated histoplasmosis. All six patients received itraconazole therapy for 12 months.
• The incidence of disseminated histoplasmosis was deemed to be 18 cases (the 16 patients with both a positive EIA and LFA and the two symptomatic patients with a positive EIA and a negative LFA). The median CD4+ count among people with probable disseminated histoplasmosis was 31 cells/mm³.
• Among the 18 patients with probable disseminated histoplasmosis, 11 patients were asymptomatic and continuing itraconazole therapy as of the time of the article’s publication, three patients had not started therapy, and four patients died.
• The Histoplasma antigen EIA had a sensitivity of 100%, a specificity of 98.5%, a positive predictive value of 81.8%, and a negative predictive value of 100%.
• The Histoplasma antigen LFA had a sensitivity of 88.9%, a specificity of 93.9%, a positive predictive value of 50%, and a negative predictive value of 99.2%.

Cryptococcus incidence

Among sera collected from 280 people:

• Six patients had both a positive EIA and LFA, and one patient had a positive EFA and a negative LFA. The incidence of cryptococcal antigenemia was deemed to be seven cases, and the median CD4+ count among cases was 69 cells/mm³.
• Two patients with cryptococcal antigenemia were diagnosed with cryptococcal meningitis, both of whom died.
• The five patients who survived did not have neurological symptoms, and they received 800 milligrams of fluconazole daily for 2 weeks, followed by a reduced dose, and were well as of the time of the article’s publication.

Rapid diagnostic capacity in Trinidad

Antigen detection tests for pathogenic fungi may ensure that people living with HIV receive rapid and necessary care for life-threatening illnesses, and antigen tests may be particularly helpful in resource-limited settings that lack laboratory facilities and trained personnel to carry out culture and histopathology. The authors note that, in Trinidad, results from the EIA may not have been available as quickly as they could have been, as the test could only be done every two weeks once enough isolates were on the plate to reduce reagent waste.

The Histoplasma and Cryptococcus LFAs can return results quickly, be provided at the point of care, and require minimal training to administer and interpret, making them a suitable screening tool in settings that lack enzyme-linked immunosorbent assay (ELISA) equipment. Given the lower sensitivity of the LFA, however, the authors caution that confirmation of results in asymptomatic patients should be done with an EIA, when possible.