■HIV相关隐球菌性脑膜炎(CM)患者的生存率仍然很低,尤其是在女性中,尽管目前最佳使用抗真菌药物。隐球菌传播到中枢神经系统[大脑,脊髓,和脑脊液(CSF)]引起细胞因子的局部产生,趋化因子,和其他生物标志物。然而,据报道,没有一致的诊断或预后神经免疫特征来支持死亡风险或确定改善治疗和生存的机制.我们假设,CSF中不同的神经免疫特征将区分幸存者与因抗真菌治疗而死亡的人以及可能受益于定制治疗的人。
■我们考虑了基线临床特征,脑脊液隐球菌真菌负荷,和CSF神经免疫特征,在419名同意的成年人中,按“性别”(168名女性和251名男性按出生时的生物性别定义)在18周存活。
■18周生存率女性明显低于男性{47%vs.59%,分别;风险比(HR)=1.4[95%置信区间(CI),1.0至1.9;p=0.023]}。无监督主成分分析(PCA)显示出不同性别的神经免疫特征,生存,和内特异性存活。总的来说,女性的程序性死亡配体1,白细胞介素(IL)(IL-11RA/IL-1F30和IL-15(IL-15)水平低于男性(均p<0.028).与死亡患者相比,女性幸存者的CCL11和CXCL10趋化因子水平显着升高(均p=0.001),以及增加的T辅助1,调节,和T辅助17细胞因子(所有p<0.041)。相比之下,与死亡男性相比,男性幸存者表达的IL-15和IL-8水平较低(p<0.044)。
■两种性别的幸存者表现出免疫调节IL-10水平的显着增加。总之,CM患者生存率较低的患者伴随着明显不同的性别特异性神经免疫特征.这些女性和男性体内特异性生存相关的神经免疫特征为干预措施提供了潜在的目标,以促进治疗以改善与HIV相关的CM患者的低生存率。
Survival among people with HIV-associated cryptococcal meningitis (CM) remains low, particularly among women, despite the currently optimal use of antifungal drugs. Cryptococcus dissemination into the central nervous system [brain, spinal cord, and cerebrospinal fluid (CSF)] elicits the local production of cytokines, chemokines, and other biomarkers. However, no consistent diagnostic or prognostic neuroimmune signature is reported to underpin the risk of death or to identify mechanisms to improve treatment and survival. We hypothesized that distinct neuroimmune signatures in the CSF would distinguish survivors from people who died on antifungal treatment and who may benefit from tailored therapy.
We considered baseline clinical features, CSF cryptococcal fungal burden, and CSF neuroimmune signatures with survival at 18 weeks among 419 consenting adults by \"gender\" (168 women and 251 men by biological sex defined at birth).
Survival at 18 weeks was significantly lower among women than among men {47% vs. 59%, respectively; hazard ratio (HR) = 1.4 [95% confidence interval (CI), 1.0 to 1.9; p = 0.023]}. Unsupervised principal component analysis (PCA) demonstrated divergent neuroimmune signatures by gender, survival, and intragender-specific survival. Overall, women had lower levels of programmed death ligand 1, Interleukin (IL) (IL-11RA/IL-1F30, and IL-15 (IL-15) than men (all p < 0.028). Female survivors compared with those who died expressed significant elevations in levels of CCL11 and CXCL10 chemokines (both p = 0.001), as well as increased T helper 1, regulatory, and T helper 17 cytokines (all p < 0.041). In contrast, male survivors expressed lower levels of IL-15 and IL-8 compared with men who died (p < 0.044).
Survivors of both genders demonstrated a significant increase in the levels of immune regulatory IL-10. In conclusion, the lower survival among women with CM was accompanied by distinct differential gender-specific neuroimmune signatures. These female and male intragender-specific survival-associated neuroimmune signatures provide potential targets for interventions to advance therapy to improve the low survival among people with HIV-associated CM.