Cryptococcal antigenemia is associated with meningitis or death in HIV-infected adults with CD4 100\u2013200 cells/mm3

James Wykowski,Sabina Govere,Connie Celum,Carole L. Wallis,Sean R. Galagan,Paul K. Drain,Mahomed-Yunus Moosa

doi:10.1186/s12879-020-4798-1

Abstract

BackgroundCryptococcal antigen (CrAg) screening with fluconazole prophylaxis has been shown to prevent cryptococcal meningitis and mortality for people living with HIV (PLWH) with CD4 < 100 cells/mm3. While cryptococcal meningitis occurs in individuals with CD4 100–200 cells/mm3, there is limited evidence that CrAg screening predicts cryptococcal meningitis or mortality among this group with moderate immunosuppression. Current IDSA and WHO clinical guidelines recommend restricting CrAg screening to PLWH with CD4 < 100 cells/mm3.MethodsWe conducted a prospective cohort study of PLWH 18+ years who had not initiated ART in South Africa. We followed participants for 14 months to determine onset of cryptococcal meningitis or all-cause mortality. At study completion, we retrospectively tested stored serum samples for CrAg using an enzyme immunoassay (EIA). We calculated CD4-stratified incidence rates of outcomes and used Cox proportional hazards to measure associations between CrAg positivity and outcomes.ResultsWe enrolled 2383 PLWH, and 1309 participants had serum samples tested by CrAg EIA. The median CD4 was 317 cells/mm3 (interquartile range: 173–491 cells/mm3). By CD4 count at baseline, there were 209 individuals with a CD4 count of 100–200 cells/mm3 and available CrAg test results. Of these, four (1.9%) tested positive. Two of four (IR: 58.8 per 100 person-years) CrAg+ participants and 11 of 205 (IR: 5.6 per 100 person-years) CrAg- participants developed cryptococcal meningitis or died for an overall rate of death or cryptococcal meningitis that was 10.0-times higher for those who were CrAg+ (95% confidence interval: 2.2–45.3). Among those with CD4 < 100 cell/mm3 and CrAg EIA test results (N = 179), ten (5.6%) participants tested CrAg+. Among this group, seven of ten (IR: 137.6 per 100 person-years) CrAg+ participants and 26 of 169 (IR: 17.8 per 100 person-years) CrAg- participants developed cryptococcal meningitis or died, for a rate of death or cryptococcal meningitis that was 6.3-times higher for those who were CrAg+ (95% confidence interval: 2.7–14.6).ConclusionsAlthough few PLWH with moderate immunosuppression screened CrAg positive, a positive CrAg test was predictive of increased risk of cryptococcal meningitis or death. Similar to those with a CD4 < 100 cell/mm3, systematic CrAg screening may reduce morbidity and mortality in PLWH with CD4 100–200 cells/mm3.

Highlights

Cryptococcal antigen (CrAg) screening with fluconazole prophylaxis has been shown to prevent cryptococcal meningitis and mortality for people living with Human immunodeficiency virus (HIV) (PLWH) with CD4 < 100 cells/mm3
Conclusions: few people living with HIV (PLWH) with moderate immunosuppression screened CrAg positive, a positive CrAg test was predictive of increased risk of cryptococcal meningitis or death
While PLWH with CD4 < 100 cells/mm3 who are CrAg positive are most likely to have adverse outcomes, our results suggest CrAg screening may be beneficial for PLWH who have CD4 100–200 cells/mm3

Summary

Introduction

Cryptococcal antigen (CrAg) screening with fluconazole prophylaxis has been shown to prevent cryptococcal meningitis and mortality for people living with HIV (PLWH) with CD4 < 100 cells/mm. Current IDSA and WHO clinical guidelines recommend restricting CrAg screening to PLWH with CD4 < 100 cells/ mm. Serum screening for cryptococcal antigen (CrAg) and subsequent prophylaxis for those who screen positive limits the burden of disease by preventing the progression from cryptococcal antigenemia to cryptococcal meningitis or death [1, 3]. Asymptomatic cryptococcal antigenemia is associated with early all-cause mortality in PLWH in sub-Saharan Africa [4]. According to current World Health Organization (WHO) and Infectious Disease Society of America (IDSA) guidelines, screening for CrAg is reserved for PLWH who have a CD4 count less than 100 cells/mm3 [1, 5]. The WHO states that screening may be considered at a higher CD4 threshold of < 200 cells/mm, without specifying the specific circumstances in which to increase the threshold for CrAg screening [1]

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