Impact of biological sex on cryptococcal meningitis mortality in Uganda and South Africa

Abstract

The role of biological sex on clinical outcomes and the pathogenesis of AIDS-related opportunistic infections is unknown. We assessed baseline biomarkers and outcomes between 577 men and 400 women in HIV-related cryptococcal meningitis cohorts in Uganda and South Africa from 2010 to 2017. We compared 10-week mortality by sex via Cox proportional hazards models. The 10-week mortality for women was 50% (198/400) and 43% (247/577) for men. Women had higher risk of death in an unadjusted model (Hazard Ratio (HR) = 1.20; 95%CI, 1.00–1.45; P = .05). Women maintained a higher risk when adjusting for quantitative CSF culture, altered mental status, CSF pleocytosis, age, and antiretroviral status (HR = 1.31; 95%CI, 1.07–1.59; P < .01). However, after adjusting for hemoglobin, the risk of death did not differ between women and men (HR = 1.17; 95%CI, 0.94–1.45; P = .17). Moderate to severe anemia (hemoglobin < 8.5 g/dL) was present among 16% (55/355) of women and 10% (55/532) of men (P = .02). Of the 373 participants with CSF biomarkers, men had higher median pro- and anti-inflammatory, monocyte/macrophage differentiation, maturation, and migration, immune exhaustion, and cytotoxicity cytokines than women (P < .05). We identified biological sex as proxy for anemia, a potentially modifiable risk factor for cryptococcal meningitis mortality. Immune response may contribute to the multifaceted underlying mechanisms for the discrepancy in mortality based on sex. Lay Summary We examined the role of biological sex in cryptococcal meningitis mortality in a large cohort. Our findings reveal significant differences in inflammatory markers by biological sex. Women have significantly higher mortality due to cryptococcal meningitis that is attributable to anemia at baseline.

Poor long-term outcomes despite improved hospital survival for patients with cryptococcal meningitis in rural, Northern Uganda

“…Although we previously showed that implementation of this CM-DTP improved diagnosis, treatment, and in-hospital mortality among CM patients, [ 9 ] the current results show that long-term three-year survival remained poor at only 25.6%, suggesting that large numbers of patients die after hospital discharge. There was no difference in mortality between males and females, similar to an earlier study conducted in Uganda [ 28 ]. Even in the interventional CryptoDex trial in Uganda and Asia, a similar trend of sub-optimal long-term survival was observed, with mortality of 60% at 2 years among HIV patients with CM [ 29 , 30 ].…”

Divergent neuroimmune signatures in the cerebrospinal fluid predict differential gender-specific survival among patients with HIV-associated cryptococcal meningitis

“…Two studies done prior to optimized antiretroviral therapy (ART) initiation (delayed for 2 weeks after CM diagnosis based on the COAT Trial ( 9 )) showed no differences in survival by gender ( 26 , 44 ). In contrast, two studies done after initiation of optimized ART with antifungal therapy showed lower survival among women ( 7 , 42 ). To date, no clear immunopathogenic mechanisms have been proposed to explain the divergence in survival by gender despite access to current optimal antifungal treatment and ART.…”

“…In prior studies of CM, men showed increased expression of innate chemokines and cytokines in the CSF associated with increased trafficking of innate lymphoid and myeloid cells compared with women ( 7 ). Of note, no differences were noted in soluble immune factors by survival with CM overall ( 7 ). However, these differences were not evaluated in relation to gender-specific survival.…”

“…Among studies reporting cases of CM by gender (biological sex assigned at birth), the majority of CM was diagnosed among men ( 2 , 7 , 9 , 16 , 26 – 44 ); only four, to date, described survival by gender. Two studies done prior to optimized antiretroviral therapy (ART) initiation (delayed for 2 weeks after CM diagnosis based on the COAT Trial ( 9 )) showed no differences in survival by gender ( 26 , 44 ).…”

“…Indeed, gender-specific differences have been reported in immune responses to vaccines in both humans and animals ( 45 , 46 ), with elevations in cytokine production, endocrine, and metabolic parameters in women compared with that in men. Nevertheless, in CM, the cryptococcal fungal burden, white cell counts, and protein in CSF and CD4 + T-cell numbers in blood were similar by gender ( 7 ). Moreover, the macrophage-mediated host immune evasion mechanism vomocytosis and cryptococcal intracellular proliferation in infected macrophages were similar by gender ( 47 ).…”