Limits...
Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.

Jarvis JN, Meintjes G, Bicanic T, Buffa V, Hogan L, Mo S, Tomlinson G, Kropf P, Noursadeghi M, Harrison TS - PLoS Pathog. (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Botswana-UPenn Partnership, Gaborone, Botswana; Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome.Associations between baseline PC1 and PC2 scores and 2-week mortality and IRIS. The points represent the mean values, with standard errors denoted by the error bars. The adjusted p value are shown, derived from (in the case of mortality) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for mortality, baseline fungal burden and altered mental status; and (in the case of IRIS) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for IRIS, baseline fungal burden and CSF white cell count.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4390200&req=5

ppat.1004754.g004: Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome.Associations between baseline PC1 and PC2 scores and 2-week mortality and IRIS. The points represent the mean values, with standard errors denoted by the error bars. The adjusted p value are shown, derived from (in the case of mortality) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for mortality, baseline fungal burden and altered mental status; and (in the case of IRIS) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for IRIS, baseline fungal burden and CSF white cell count.

Mentions: Fungal burden was negatively correlated with PC1 and PC2 indicating that patients with high fungal burdens tended to have pauci-inflammatory CSF cytokine profiles with high MCP-1 and MIP-1α chemokine expression, while lower fungal burdens were associated with more robust CSF inflammatory responses and lower chemokine levels. Importantly PC1 scores showed a positive correlation with more rapid clearance of cryptococci from the CSF (an association that remained significant after adjustment for treatment group), consistent with the hypothesis that robust pro-inflammatory responses contribute to fungal clearance. Also in keeping with this observation, PC1 scores were lower in patients who had died within 2 weeks compared to those who survived (Fig 4). This association was significant following adjustment for treatment group, CD4 count, and the key predictors of mortality, baseline fungal burden and altered mental status (p = 0.01). There were no significant associations between PC2 and mortality (Fig 4).


Cerebrospinal fluid cytokine profiles predict risk of early mortality and immune reconstitution inflammatory syndrome in HIV-associated cryptococcal meningitis.

Jarvis JN, Meintjes G, Bicanic T, Buffa V, Hogan L, Mo S, Tomlinson G, Kropf P, Noursadeghi M, Harrison TS - PLoS Pathog. (2015)

Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome.Associations between baseline PC1 and PC2 scores and 2-week mortality and IRIS. The points represent the mean values, with standard errors denoted by the error bars. The adjusted p value are shown, derived from (in the case of mortality) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for mortality, baseline fungal burden and altered mental status; and (in the case of IRIS) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for IRIS, baseline fungal burden and CSF white cell count.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4390200&req=5

ppat.1004754.g004: Associations between baseline cerebrospinal fluid immune response profiles and clinical outcome.Associations between baseline PC1 and PC2 scores and 2-week mortality and IRIS. The points represent the mean values, with standard errors denoted by the error bars. The adjusted p value are shown, derived from (in the case of mortality) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for mortality, baseline fungal burden and altered mental status; and (in the case of IRIS) a linear regression model adjusting for treatment group, CD4+-cell count, and the previously described risk factors for IRIS, baseline fungal burden and CSF white cell count.
Mentions: Fungal burden was negatively correlated with PC1 and PC2 indicating that patients with high fungal burdens tended to have pauci-inflammatory CSF cytokine profiles with high MCP-1 and MIP-1α chemokine expression, while lower fungal burdens were associated with more robust CSF inflammatory responses and lower chemokine levels. Importantly PC1 scores showed a positive correlation with more rapid clearance of cryptococci from the CSF (an association that remained significant after adjustment for treatment group), consistent with the hypothesis that robust pro-inflammatory responses contribute to fungal clearance. Also in keeping with this observation, PC1 scores were lower in patients who had died within 2 weeks compared to those who survived (Fig 4). This association was significant following adjustment for treatment group, CD4 count, and the key predictors of mortality, baseline fungal burden and altered mental status (p = 0.01). There were no significant associations between PC2 and mortality (Fig 4).

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Research, Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom; Botswana-UPenn Partnership, Gaborone, Botswana; Division of Infectious Diseases, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America; Desmond Tutu HIV Centre, Institute of Infectious Disease and Molecular Medicine, University of Cape Town, South Africa.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus