Sterile Cerebrospinal Fluid Culture at Cryptococcal Meningitis Diagnosis Is Associated with High Mortality

Abstract

Cryptococcus is the leading cause of AIDS-related meningitis in sub-Saharan Africa. The clinical implications of a sterile cerebrospinal fluid (CSF) culture among individuals diagnosed with cryptococcal meningitis using CSF cryptococcal antigen (CrAg) are unclear. We prospectively enrolled 765 HIV-positive Ugandans with first-episode cryptococcal meningitis from November 2010 to May 2017. All persons were treated with amphotericin-based induction therapy. We grouped participants by tertile of baseline CSF quantitative Cryptococcus culture burden and compared clinical characteristics, CSF immune profiles, and 18-week mortality. We found 55 (7%) CSF CrAg-positive participants with sterile CSF cultures. Compared to the non-sterile groups, participants with sterile CSF cultures had higher CD4 counts, lower CSF opening pressures, and were more frequently receiving ART. By 18 weeks, 47% [26/55] died in the sterile culture group versus 35% [83/235] in the low culture tertile, 46% [107/234] in the middle tertile, and 56% [135/241] in the high tertile (p < 0.001). The sterile group had higher levels of CSF interferon-gamma (IFN-γ), IFN-α, interleukin (IL)-6, IL-17, G-CSF, GM-CSF, and chemokine CXCL2 compared with non-sterile groups. Despite persons with sterile CSF cultures having higher CD4 counts, lower CSF opening pressures, and CSF cytokine profiles associated with better Cryptococcus control (e.g., IFN-γ predominant), mortality was similar to those with higher fungal burdens. This unexpected finding challenges the traditional paradigm that increasing CSF fungal burdens are associated with increased mortality but is consistent with a damage-response framework model.

Keywords: AIDS; Cryptococcus; HIV; cryptococcal meningitis.

Figure 1

Kaplan–Meier Curve of 18-week Survival by CSF Fungal Burden Tertile in Cryptococcal Meningitis. Figure 1 demonstrates cumulative survival probability by Kaplan–Meier curve with Log Rank testing. At 18 weeks, the high tertile group has the poorest survival with 56% [135/241] dead, followed by the sterile culture group with 47% [26/55] dead, the middle tertile group with 46% [107/234] dead, and the low tertile group with 35% [83/235] dead. Log Rank p-value is calculated across all groups. CSF quantitative culture tertiles: Low Tertile = 1–14,700 CFU/mL; Middle Tertile = 14,701–206,000 CFU/mL; High Tertile > 206,000 CFU/mL.

Figure 2

Simplified Damage-Response Parabolic Framework Model of Cryptococcal Meningitis Disease. Figure 2 demonstrates a hypothesized damage-response model for HIV-associated cryptococcal disease. The model proposes that clinical disease can occur by either of two mechanisms: (1) Uncontrolled fungal dissemination characterized by suboptimal IFN-γ predominated Type 1 helper (Th₁) response with increasing CSF quantitative culture burden, or (2) Excessive damaging host immune response characterized by exaggerated IFN-γ predominated Th₁ host response with persons presenting with sterile CSF cultures. The host is most likely protected by a moderate, balanced immune response. (Figure is originally adapted from Pirofski and Casadevall concept, and further modified from our prior publication [29]).