Cryptococcal antigenemia is associated with meningitis or death in HIV-infected adults with CD4 100–200 cells/mm3

Abstract

Background: 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 3 . While cryptococcal meningitis occurs in individuals with CD4 100-200 cells/mm 3 , 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/ mm 3 . Methods: We 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. Results: We enrolled 2383 PLWH, and 1309 participants had serum samples tested by CrAg EIA. The median CD4 was 317 cells/mm 3 (interquartile range: 173-491 cells/mm 3 ). By CD4 count at baseline, there were 209 individuals with a CD4 count of 100-200 cells/mm 3 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) CrAgparticipants 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/mm 3 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). Conclusions: Although 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/mm 3 , systematic CrAg screening may reduce morbidity and mortality in PLWH with CD4 100-200 cells/mm 3 .

Prevalence of cryptococcal meningitis among people living with human immuno-deficiency virus and predictors of mortality in adults on induction therapy in Africa: A systematic review and meta-analysis

“…In this review, over 80% of the studies included reported a CD4 count of less than 50 cells/mm 3 at baseline. Unlike most studies that suggest that the occurrence of CM is common in those with CD4 count less than 200, our study found an even lower CD4 count as a common finding ( 23 , 56 ). This could explain why the majority of our studies had a mortality percentage greater than 30% which was comparable to 44% (short-term mortality) reported by Tenforde et al ( 31 ) and 36.7% by Majumder et al ( 57 ).…”

“…Patients who presented with either a low Glasgow coma scale, altered behavior, or simply altered mental status died or had a longer hospital admission ( 19 – 22 ). Furthermore, a CD4 count between 100 and 200 cells/mm 3 predisposes one with CM to worse symptoms and clinical outcomes ( 23 ). Anemia is a hematological finding that has been reported as a significant contributor to 2 and 10-week mortality if present in the moderate to severe forms at baseline ( 24 ).…”

Predictors of AIDS-related death among adult HIV-infected inpatients in Kisangani, the Democratic Republic of Congo

“…These conditions occur in HIV-infected patients whose CD4 count has collapsed (<100 cells/mm 3 ). Although serum screening for cryptococcal antigens is reserved for an HIV-positive person having a CD4 T cell count of less than 100 cells/mm 3 according to current WHO guidelines [ 25 ], a recent study highlights that a positive cryptococcal antigens result was strongly associated with an increased risk of cryptococcal meningitis or death [ 26 ]. Those authors suggest that raising the threshold for cryptococcal antigens screening to 200 cells/mm 3 could help reduce morbidity and mortality in HIV-infected patients in cryptococcus-endemic regions [ 27 ].…”

“…Implementing a targeted screening of HIV patients with low body mass index, CD4 count < 100 cells, having headaches; and treatment for asymptomatic cryptococcal disease should be considered among inpatients infected by HIV in DRC. Additional data is needed to better define the epidemiology of cryptococcal antigenemia and its predictors in DRC in order to optimize the prevention, diagnosis, and treatment strategies [ 26 ].…”

Cryptococcal Antigen Screening Among Antiretroviral Therapy–Experienced People With HIV With Viral Load Nonsuppression in Rural Uganda

“…[ 7 , 8 ]. However, CrAg positivity appears to predict cryptococcal meningitis and death even at a cutoff of <200 cells/mm 3 among ART-naïve PWH [ 9 ]. The World Health Organization (WHO) recommends CrAg screening among newly diagnosed PWH with a CD4 count <100 cells/mm 3 , and conditionally among those with a CD4 count of 100–200 cells/mm 3 [ 10 ].…”