Dataset Information

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

ABSTRACT:

Background

In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks.

Methods

We pooled individual-level CSF data from 3 sequential cryptococcal meningitis clinical trials conducted during 2010-2017. All 738 subjects received amphotericin?+?fluconazole induction therapy and had serial quantitative CSF cultures. The log10-transformed colony-forming units (CFUs) per mL CSF were analyzed by general linear regression versus day of culture over the first 10 days.

Results

Mortality through 18 weeks was 37% for EFA > = 0.60 (n?=?170), 36% for 0.40-0.59 (n?=?182), 39% for 0.30-0.39 (n?=?112), 35% for 0.20-0.29 (n?=?87), and 50% for those with EFA? = 0.20, was 1.60 (95% confidence interval, 1.25, 2.04; P?=?.002). The lowest EFA group had lower median CD4 T-cell counts (P?ConclusionsEFA is associated with all-cause mortality in cryptococcal meningitis. An EFA threshold of > = 0.20 log10 CFU/mL/day was associated with similar 18-week mortality (37%) compared to 50% mortality with EFA?

SUBMITTER: Pullen MF

PROVIDER: S-EPMC7755087 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

Pullen Matthew F MF Hullsiek Katherine Huppler KH Rhein Joshua J Musubire Abdu K AK Tugume Lillian L Nuwagira Edwin E Abassi Mahsa M Ssebambulidde Kenneth K Mpoza Edward E Kiggundu Ruben R Akampurira Andrew A Nabeta Henry W HW Schutz Charlotte C Evans Emily E EE Rajasingham Radha R Skipper Caleb P CP Pastick Katelyn A KA Williams Darlisha A DA Morawski Bozena M BM Bangdiwala Ananta S AS Meintjes Graeme G Muzoora Conrad C Meya David B DB Boulware David R DR

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 20201001 7

<h4>Background</h4>In cryptococcal meningitis phase 2 clinical trials, early fungicidal activity (EFA) of Cryptococcus clearance from cerebrospinal fluid (CSF) is used as a surrogate endpoint for all-cause mortality. The Food and Drug Administration allows for using surrogate endpoints for accelerated regulatory approval, but EFA as a surrogate endpoint requires further validation. We examined the relationship between rate of CSF Cryptococcus clearance (EFA) and mortality through 18 weeks.<h4>Me ...[more]

PMID: 31912875

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Project description:BACKGROUND:Individuals with cryptococcal antigenemia are at high risk of developing cryptococcal meningitis if untreated. The progression and timing from asymptomatic infection to cryptococcal meningitis is unclear. We describe a subpopulation of individuals with neurologic symptomatic cryptococcal antigenemia but negative cerebral spinal fluid (CSF) studies. METHODS:We evaluated 1201 human immunodeficiency virus-seropositive individuals hospitalized with suspected meningitis in Kampala and Mbarara, Uganda. Baseline characteristics and clinical outcomes of participants with neurologic-symptomatic cryptococcal antigenemia and negative CSF cryptococcal antigen (CrAg) were compared to participants with confirmed CSF CrAg+ cryptococcal meningitis. Additional CSF testing included microscopy, fungal culture, bacterial culture, tuberculosis culture, multiplex FilmArray polymerase chain reaction (PCR; Biofire), and Xpert MTB/Rif. RESULTS:We found 56% (671/1201) of participants had confirmed CSF CrAg+ cryptococcal meningitis and 4% (54/1201) had neurologic symptomatic cryptococcal antigenemia with negative CSF CrAg. Of those with negative CSF CrAg, 9% (5/54) had Cryptococcus isolated on CSF culture (n = 3) or PCR (n = 2) and 11% (6/54) had confirmed tuberculous meningitis. CSF CrAg-negative patients had lower proportions with CSF pleocytosis (16% vs 26% with ?5 white cells/?L) and CSF opening pressure >200 mmH2O (16% vs 71%) compared with CSF CrAg-positive patients. No cases of bacterial or viral meningitis were detected by CSF PCR or culture. In-hospital mortality was similar between symptomatic cryptococcal antigenemia (32%) and cryptococcal meningitis (31%; P = .91). CONCLUSIONS:Cryptococcal antigenemia with meningitis symptoms was the third most common meningitis etiology. We postulate this is early cryptococcal meningoencephalitis. Fluconazole monotherapy was suboptimal despite Cryptococcus-negative CSF. Further studies are warranted to understand the clinical course and optimal management of this distinct entity. CLINICAL TRIALS REGISTRATION:NCT01802385.

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-?, 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-1? (MIP-1?). 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:BACKGROUND:(1?3)-?-d-Glucan (BDG) is a helpful diagnostic marker for many invasive fungal infections. However, BDG is not thought to be useful in diagnosing cryptococcosis. We evaluated the utility of BDG as an adjunct diagnostic tool for patients infected with human immunodeficiency virus (HIV) and presenting with suspected cryptococcal meningitis. METHODS:The Fungitell assay was used to measure BDG concentrations in cerebrospinal fluid (CSF) (n = 177) and serum (n = 109) of HIV-infected Ugandans and South Africans with suspected meningitis. Correlations between BDG concentrations and quantitative CSF cryptococcal cultures, CSF cryptococcal antigen (CRAG) titers, and 18 different CSF cytokine concentrations were assessed using non-parametric tests. Mixed models evaluated longitudinal changes in CSF BDG concentrations. Survival analyses were used to evaluate BDG's relationship with mortality. RESULTS:The Fungitell BDG assay provided 89% sensitivity and 85% specificity in CSF for cryptococcal meningitis. Serum sensitivity was suboptimal (79%). Cerebrospinal fluid BDG concentrations at diagnosis were median (interquartile range) 343 (200-597) pg/mL in cryptococcal patients and 37 (23-46) pg/mL in patients without cryptococcosis. Sensitivity in CSF improved to 98% (53 of 54) when initial fungal burdens were ?10 000 colony-forming units/mL. (1?3)-?-d-Glucan normalized rapidly after initiating antifungal therapy. Baseline BDG concentrations correlated with CSF fungal burden (rho = 0.820; P < .001), CSF CRAG lateral flow assay titers (rho = 0.780, P < .001), and monocyte chemotactic protein-1 levels in CSF (P = .047). In patients with cryptococcal meningitis, BDG ?500 pg/mL at diagnosis was associated with increased 10-week mortality. CONCLUSIONS:(1?3)-?-d-Glucan is detectable in the CSF of HIV-infected patients with Cryptococcus, and it may provide useful prognostic information. Sensitivity is less than CRAG; however, BDG normalizes rapidly, unlike CRAG, making BDG potentially useful in diagnosing recurrent episodes.

Dataset Information

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

Background

Methods

Results

Publications

Cerebrospinal Fluid Early Fungicidal Activity as a Surrogate Endpoint for Cryptococcal Meningitis Survival in Clinical Trials.

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