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Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome.

ABSTRACT: Existing evidence revealed grave prognosis for cryptococcal meningitis (CM), particularly its short-term mortality. However, its long-term survival and prognostic factors remained unknown. This study investigated 3-year mortality and analyzed its predictive factors in patients with CM. This retrospective cohort study with 83 cerebrospinal fluid culture-confirmed CM patients was conducted at China Medical University Hospital from 2003 to 2016. The 3-year mortality rate in patients with CM was 54% (45 deaths among 83 patients). Advanced age, human immunodeficiency virus (HIV) seronegative state, low Glasgow Coma Scale score on admission, decreased hemoglobin and hyperglycemia on diagnosis were associated with 3-year mortality. After multivariate adjustment in the Cox proportional hazard model, only severe hyperglycemia (serum glucose ≥200 mg/dL) on diagnosis could predict 3-year mortality.

SUBMITTER: Tsai ST

PROVIDER: S-EPMC8162582 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome.

Tsai Sheng-Ta ST Lin Fu-Yu FY Chen Pei-Shan PS Chiang Hsiu-Yin HY Kuo Chin-Chi CC

PloS one 20210528 5

Existing evidence revealed grave prognosis for cryptococcal meningitis (CM), particularly its short-term mortality. However, its long-term survival and prognostic factors remained unknown. This study investigated 3-year mortality and analyzed its predictive factors in patients with CM. This retrospective cohort study with 83 cerebrospinal fluid culture-confirmed CM patients was conducted at China Medical University Hospital from 2003 to 2016. The 3-year mortality rate in patients with CM was 54% ...[more]

PMID: 34048463

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Project description:UnlabelledIn sub-Saharan Africa, cryptococcal meningitis (CM) continues to be a predominant cause of AIDS-related mortality. Understanding virulence and improving clinical treatments remain important. To characterize the role of the fungal strain genotype in clinical disease, we analyzed 140 Cryptococcus isolates from 111 Ugandans with AIDS and CM. Isolates consisted of 107 nonredundant Cryptococcus neoformans var. grubii strains and 8 C. neoformans var. grubii/neoformans hybrid strains. Multilocus sequence typing (MLST) was used to characterize genotypes, yielding 15 sequence types and 4 clonal clusters. The largest clonal cluster consisted of 74 isolates. The results of Burst and phylogenetic analysis suggested that the C. neoformans var. grubii strains could be separated into three nonredundant evolutionary groups (Burst group 1 to group 3). Patient mortality was differentially associated with the different evolutionary groups (P = 0.04), with the highest mortality observed among Burst group 1, Burst group 2, and hybrid strains. Compared to Burst group 3 strains, Burst group 1 strains were associated with higher mortality (P = 0.02), exhibited increased capsule shedding (P = 0.02), and elicited a more pronounced Th(2) response during ex vivo cytokine release assays with strain-specific capsule stimulation (P = 0.02). The results of these analyses suggest that cryptococcal strain variation can be an important determinant of human immune responses and mortality.ImportanceCryptococcus neoformans is a common life-threatening human fungal pathogen that is responsible for an estimated 1 million cases of meningitis in HIV-infected patients annually. Virulence factors that are important in human disease have been identified, yet the impacts of the fungal strain genotype on virulence and outcomes of human infection remain poorly understood. Using an analysis of strain variation based on in vitro assays and clinical data from Ugandans living with AIDS and cryptococcal infection, we report that strain genotype predicts the type of immune response and mortality risk. These studies suggest that knowledge of the strain genotype during human infections could be used to predict disease outcomes and lead to improved treatment approaches aimed at targeting the specific combination of pathogen virulence and host response.

Project description:Understanding the host immune response during cryptococcal meningitis (CM) is of critical importance for the development of immunomodulatory therapies. We profiled the cerebrospinal fluid (CSF) immune-response in ninety patients with HIV-associated CM, and examined associations between immune phenotype and clinical outcome. CSF cytokine, chemokine, and macrophage activation marker concentrations were assayed at disease presentation, and associations between these parameters and microbiological and clinical outcomes were examined using principal component analysis (PCA). PCA demonstrated a co-correlated CSF cytokine and chemokine response consisting primarily of Th1, Th2, and Th17-type cytokines. The presence of this CSF cytokine response was associated with evidence of increased macrophage activation, more rapid clearance of Cryptococci from CSF, and survival at 2 weeks. The key components of this protective immune-response were interleukin (IL)-6 and interferon-γ, IL-4, IL-10 and IL-17 levels also made a modest positive contribution to the PC1 score. A second component of co-correlated chemokines was identified by PCA, consisting primarily of monocyte chemotactic protein-1 (MCP-1) and macrophage inflammatory protein-1α (MIP-1α). High CSF chemokine concentrations were associated with low peripheral CD4 cell counts and CSF lymphocyte counts and were predictive of immune reconstitution inflammatory syndrome (IRIS). In conclusion CSF cytokine and chemokine profiles predict risk of early mortality and IRIS in HIV-associated CM. We speculate that the presence of even minimal Cryptococcus-specific Th1-type CD4+ T-cell responses lead to increased recruitment of circulating lymphocytes and monocytes into the central nervous system (CNS), more effective activation of CNS macrophages and microglial cells, and faster organism clearance; while high CNS chemokine levels may predispose to over recruitment or inappropriate recruitment of immune cells to the CNS and IRIS following peripheral immune reconstitution with ART. These results provide a rational basis for future studies of immune modulation in CM, and demonstrate the potential of baseline immune profiling to identify CM patients most at risk of mortality and subsequent IRIS.

Project description:BackgroundCryptococcal meningitis causes high mortality in immunocompromised and immunocompetent patients. The objective of this study was to identify early predictors of clinical outcome, available at the first days of hospitalization, in patients with cryptococcal meningitis in a tertiary center in Brazil.MethodsNinety-six cases of cryptococcal meningitis with clinical, epidemiological and laboratory data, and identification and antifungal susceptibility of the strains were analyzed. Quantitative CSF yeast counts were performed by direct microscopic exam with a Fuchs-Rosenthal cell counting chamber using an institutional protocol. Univariable and multiple analyses using logistic regression were performed to identify predictors, available at the beginning of hospitalization, of in-hospital mortality. Moreover, we performed a secondary analysis for a composite outcome defined by hospital mortality and intensive care unit transfer.ResultsThe species and the antifungal susceptibility were not associated with the outcomes evaluated. The variables significantly associated with the mortality were age (OR = 1.08, 95% CI 1.02-1.15), the cerebrospinal fluid (CSF) yeasts count (OR = 1.65, 95% CI 1.20-2.27), systemic arterial hypertension (OR = 22.63, 95% CI 1.64-312.91) and neurological impairment identified by computed tomography (OR = 41.73, 95% CI 3.10-561.65). At the secondary analysis, CSF yeast count was also associated with the composite outcome, in addition to the culture of Cryptococcus spp. from bloodstream and cerebral toxoplasmosis. The associations were consistent with survival models evaluated.ConclusionsAge and CSF yeast count were independently associated with in-hospital mortality of patients with cryptococcal meningitis but Cryptococcus species identification and antifungal susceptibility were not associated with the outcomes. Quantitative CSF yeast counts used in this study can be evaluated and implemented in other low and middle-income settings.

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Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome.

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Three-year mortality in cryptococcal meningitis: Hyperglycemia predict unfavorable outcome.

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