CSF Cytokines and Chemokines Involved in Cytotoxic Cell Function and Risk of Acute 14-Day Mortality in Persons with Advanced HIV and Cryptococcal Meningitis

Elizabeth C Okafor; Liliane Mukaremera; Kathy H Hullsiek; Nicole Engen; Lillian Tugume; Kenneth Ssebambulidde; Abdu Musubire; Edwin Nuwagira; Edward Mpoza; Darlisha A Williams; Conrad Muzoora; Joshua Rhein; David B Meya; Kirsten Nielsen; David R Boulware; ASTRO-CM Team

doi:10.1093/infdis/jiae421

CSF Cytokines and Chemokines Involved in Cytotoxic Cell Function and Risk of Acute 14-Day Mortality in Persons with Advanced HIV and Cryptococcal Meningitis

J Infect Dis. 2024 Aug 28:jiae421. doi: 10.1093/infdis/jiae421. Online ahead of print.

Authors

Elizabeth C Okafor¹, Liliane Mukaremera¹, Kathy H Hullsiek², Nicole Engen², Lillian Tugume³, Kenneth Ssebambulidde³, Abdu Musubire^{1

3}, Edwin Nuwagira⁴, Edward Mpoza³, Darlisha A Williams^{1

3}, Conrad Muzoora⁴, Joshua Rhein^{1

3}, David B Meya^{1

3}, Kirsten Nielsen¹, David R Boulware¹; ASTRO-CM Team

Affiliations

¹ University of Minnesota School of Medicine, Minneapolis, Minnesota, USA.
² Division of Biostatistics and Health Data Science, University of Minnesota, Minneapolis, Minnesota, USA.
³ Infectious Diseases Institute, Makerere University, Kampala, Uganda.
⁴ Mbarara University of Science and Technology, Mbarara, Uganda.

PMID: 39207255
DOI: 10.1093/infdis/jiae421

Abstract

Background: Despite availability of HIV treatment globally, cryptococcal meningitis continues to cause considerable morbidity and mortality. The role of the immune response in acute mortality remains unclear.

Methods: To investigate the immune environment in the central nervous system, cerebrospinal fluid (CSF) from 337 Ugandans with advanced HIV and first-episode cryptococcal meningitis was collected at time of hospitalization. Participants were treated with standard of care amphotericin-B and fluconazole. Cytokines and chemokines in the CSF were quantified and compared by 14-day survival, stratification by quartiles, and logistical regression to determine association with acute mortality.

Results: 84 (24.9%) of the participants died by day 14 of hospitalization. Persons who survived to day 14 had higher levels of proinflammatory macrophage inflammatory protein (MIP)-3β and interferon (IFN)-β and cytotoxicity-associated Granzyme-B and inflammatory protein (IP)-10 compared to those who died (P<.05 for each). Logistical regression analysis revealed that per two-fold increase in proinflammatory IL-6, IL-1α, MIP-1β, MIP-3β, and IFN-β and cytotoxicity-associated IL-12, TNF-α, Granzyme-B, and IP-10 CSF concentrations, the risk of acute 14-day mortality decreased. Similar biomarkers were implicated when stratified by quartiles and further identified that lower concentrations of anti-inflammatory IL-10 and IL-13 as associated with 14-day mortality (P<.05 for each).

Conclusion: Proinflammatory and cytotoxicity-associated cytokine and chemokine responses in the CSF decrease the risk of acute 14-day mortality. These data suggest that a cytotoxic immune environment in the CSF could potentially improve acute survival. Further research on cytotoxic cells is crucial to improve understanding of innate and adaptive immune responses in cryptococcal meningitis.

Keywords: Cryptococcus neoformans; Central Nervous System; Cerebrospinal Fluid; Chemokines; Cryptococcal Meningitis; Cytokines; Cytotoxic cells; Cytotoxicity; HIV; Inflammation.

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