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

Caleb P. Skipper, Katherine Huppler Hullsiek, Anna M Stadelman, Darlisha A. Williams, Kenneth Ssebambulidde, Elizabeth Okafor, Lillian Tugume, Edwin Nuwagira, Andrew Akampurira, Abdu K Musubire, Mahsa Abassi, Conrad Muzoora, Joshua Rhein, David R. Boulware, David B Meya

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4 Scopus citations


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.

Original languageEnglish (US)
Article number46
JournalJournal of Fungi
Issue number1
StatePublished - Jan 2023

Bibliographical note

Funding Information:
This research was made possible through support from the National Institutes of Health’s National Center for Advancing Translational Sciences (KL2TR002492 and UL1TR002494); National Institute of Allergy and Infectious Diseases (T32AI055433, U01AI089244, K23AI138851); National Institute of Neurologic Disorders and Stroke (R01NS086312); and the Fogarty International Center (K01TW010268, K43TW010718).

Publisher Copyright:
© 2022 by the authors.


  • AIDS
  • Cryptococcus
  • HIV
  • cryptococcal meningitis

PubMed: MeSH publication types

  • Journal Article


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