Scriven James E, Graham Lisa M, Schutz Charlotte, Scriba Thomas J, Wilkinson Katalin A, Wilkinson Robert J, Boulware David R, Urban Britta C, Lalloo David G, Meintjes Graeme
Liverpool School of Tropical Medicine Wellcome Trust Liverpool Glasgow Centre for Global Health Research, Liverpool Clinical Infectious Diseases Research Initiative Department of Medicine, University of Cape Town and Groote Schuur Hospital, South Africa.
Clinical Infectious Diseases Research Initiative.
J Infect Dis. 2016 Jun 1;213(11):1725-34. doi: 10.1093/infdis/jiw007. Epub 2016 Jan 14.
Cryptococcal meningitis remains a significant cause of death among human immunodeficiency virus type 1 (HIV)-infected persons in Africa. We aimed to better understand the pathogenesis and identify immune correlates of mortality, particularly the role of monocyte activation.
A prospective cohort study was conducted in Cape Town, South Africa. Patients with a first episode of cryptococcal meningitis were enrolled, and their immune responses were assessed in unstimulated and stimulated blood specimens, using flow cytometry and cytokine analysis.
Sixty participants were enrolled (median CD4(+) T-cell count, 34 cells/µL). Mortality was 23% (14 of 60 participants) at 14 days and 39% (22 of 57) at 12 weeks. Nonsurvivors were more likely to have an altered consciousness and higher cerebrospinal fluid fungal burden at presentation. Principal component analysis identified an immune signature associated with early mortality, characterized by monocyte deactivation (reduced HLA-DR expression and tumor necrosis factor α response to lipopolysaccharide); increased serum interleukin 6, CXCL10, and interleukin 10 levels; increased neutrophil counts; and decreased T-helper cell type 1 responses. This immune signature remained an independent predictor of early mortality after adjustment for consciousness level and fungal burden and was associated with higher serum titers of cryptococcal glucuronoxylomannan.
Cryptococcal-related mortality is associated with monocyte deactivation and an antiinflammatory blood immune signature, possibly due to Cryptococcus modulation of the host immune response. Validation in other cohorts is required.
在非洲，隐球菌性脑膜炎仍是1型人类免疫缺陷病毒（HIV）感染者死亡的重要原因。我们旨在更好地了解其发病机制，并确定与死亡率相关的免疫因素，尤其是单核细胞活化的作用。
在南非开普敦进行了一项前瞻性队列研究。纳入首次发生隐球菌性脑膜炎的患者，并使用流式细胞术和细胞因子分析，在未刺激和刺激的血液样本中评估其免疫反应。
共纳入60名参与者（CD4(+) T细胞计数中位数为34个/µL）。14天时死亡率为23%（60名参与者中有14名），12周时为39%（57名中有22名）。非幸存者在就诊时更可能有意识改变和脑脊液真菌负荷更高。主成分分析确定了一种与早期死亡率相关的免疫特征，其特征为单核细胞失活（HLA-DR表达降低和对脂多糖的肿瘤坏死因子α反应降低）；血清白细胞介素6、CXCL10和白细胞介素10水平升高；中性粒细胞计数增加；以及1型辅助性T细胞反应降低。在调整意识水平和真菌负荷后，这种免疫特征仍然是早期死亡率的独立预测因素，并且与隐球菌葡糖醛酸木聚糖的血清滴度较高有关。
隐球菌相关死亡率与单核细胞失活和抗炎性血液免疫特征有关，可能是由于隐球菌对宿主免疫反应的调节。需要在其他队列中进行验证。
