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.

Voriconazole plus flucytosine is not superior to amphotericin B deoxycholate plus flucytosine as an induction regimen for cryptococcal meningitis treatment

“…(2) The relationship between sterile CSF culture and mortality is still controversial. Although rapid clearance of CSF Cryptococcus is associated with a high survival rate, some studies also indicated that high sterile culture rate was not associated with a low survival rate of patients 33,34 and was even associated with high mortality 35 . Notably, AIDS patients had a trend of high 90‐day mortality compared with CM patients without predisposing disease and non‐AIDS patients with other predisposing disease although no statistical significance was found (log‐rank p = .174).…”

Diagnosis of invasive respiratory mycoses in the immunocompromised host

“…Host damage may occur as a result of tissue invasion due to inadequate defences, or due to a poorly regulated and overly exuberant response (Fig. 2) [11 ▪ ,12]. Patients susceptible to IFRI often have broad immunological deficits, such as severe combined immunodeficiency [13].…”

“…The immunocompromised host may also exhibit damaging excess inflammation. HIV-associated immune dysregulation is implicated in acute respiratory distress syndrome in Pneumocystis jirovecii pneumonia (PCP) and also likely contributes to mortality in cryptococcal meningitis [12].…”

The prognostic factors for cryptococcal meningitis in non‐human immunodeficiency virus patients: An observational study using nationwide database

“…The prognosis of CM remains poor, with a mortality rate of approximately 20% within 3 months of infection, even after standard therapies for the condition have been established 2–4 . In developing countries with limited medical resources, the mortality rate of CM has been reported to be 40%–70% 5–8 …”

“…[2][3][4] In developing countries with limited medical resources, the mortality rate of CM has been reported to be 40%-70%. [5][6][7][8] In general, patients with cryptococcosis are categorized into three groups according to their background and host immune status: patients with HIV, post-organ transplant patients and other patients. 9 Patient background and immune status largely differ between these groups, [10][11][12][13] and several reports have shown that CM in HIV patients has a better prognosis at 3 months than CM in non-HIV patients.…”