Cytokine profiles at admission can be related to outcome in AIDS patients with cryptococcal meningitis

Abstract

Cryptococcal meningitis (CM) remains as common life-threatening AIDS-defining illness mainly in resource-limited settings. Previous reports suggested that baseline cytokine profiles can be associated to fungal burden and clinical outcome. This study aimed to evaluate the baseline cytokine profiles in AIDS patients with CM and its relation with the outcome at weeks 2 and 10. Thirty AIDS patients with CM diagnosed by cerebrospinal fluid (CSF) Cryptococcus neoformans positive culture, India ink stain and cryptococcal antigen test were prospectively evaluated. As controls, 56 HIV-infected patients without CM and 48 non-HIV individuals were included. Baseline CSF and sera levels of IL-2, IL-4, IL-8, IL-10, IL-12p40, IL-17A, INF-γ and TNF-α were measured by ELISA. Of 30 CM patients, 24 (80%) were male, median age of 38.1. The baseline CSF high fungal burden and positive blood culture were associated with a positive CSF culture at week 2 (p = 0.043 and 0.029). Most CSF and sera cytokines presented higher levels in CM patients than control subjects (p < 0.05). CSF levels of IL-8, IL-12p40, IL-17A, TNF-α, INF-γ and sera TNF-α were significantly higher among survivors at weeks 2 and 10 (p < 0.05). Patients with increased intracranial pression exhibited CSF IL-10 high levels and poor outcome at week 10 (p = 0.032). Otherwise, baseline CSF log10 IFN-γ and IL-17A were negatively correlated with fungal burden (r = -0.47 and -0.50; p = 0.0175 and 0.0094, respectively). The mortality rate was 33% (10/30) at week 2 and 57% (17/30) at week 10. The severity of CM and the advanced immunodeficiency at admission were related to a poor outcome in these patients. Otherwise, the predominant Th1 cytokines profile among survivors confirms its pivotal role to infection control and would be a prognostic marker in cryptococcal meningitis.

Fig 1. Baseline cerebrospinal fluid (CSF) and sera cytokines levels (pg/mL) of HIV-positive patients with cryptococcal meningitis (CM⁺ HIV⁺) and control groups: HIV-positive patients (CM^- HIV⁺) and HIV-negative subjects (CM^- HIV^-).

Data are shown as boxes: internal horizontal lines, medians; tops and bottom of boxes, 25th and 75th percentiles, respectively. Upper and lower bars, tenth and 90th percentiles, respectively. Statistical comparisons were made using the Kruskal-Wallis test. The symbols (*p < 0.05; ** p < 0.01; ***p < 0.001) represent the statistical analysis based on comparison of the three groups.

Fig 2. Baseline cerebrospinal fluid (CSF) and sera cytokines levels (pg/mL) in survivors (n = 20) and fatal cases (n = 10) at 2 week.

Data are shown as boxes: internal horizontal lines, medians; tops and bottom of boxes, 25th and 75th percentiles, respectively. Upper and lower bars, tenth and 90th percentiles, respectively. Statistical comparisons were made using the Mann-Whitney U test.

Fig 3. Baseline cerebrospinal fluid (CSF) and sera cytokines levels (pg/mL) in survivors (n = 13) and fatal cases (n = 17) at 10 weeks.

Data are shown as boxes: internal horizontal lines, medians; tops and bottom of boxes, 25th and 75th percentiles, respectively. Upper and lower bars, tenth and 90th percentiles, respectively. Statistical comparisons were made using the Mann-Whitney U test.

Fig 4. Correlation between CSF levels of IFN-γ, IL-17A, IL-4 and CSF CFU at baseline.

Correlation between CSF levels of IL-10 and GXM titer. Pearson’s correlation coefficient.