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CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec002\">\n<jats:title>Methods<\/jats:title>\n<jats:p>We enrolled 401 adults with HIV-associated cryptococcal meningitis in Uganda who received amphotericin and fluconazole induction therapy. We assessed the association of CSF leukocytes, chemokine, and cytokine responses with 18-week survival.<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec003\">\n<jats:title>Results<\/jats:title>\n<jats:p>Participants with CSF leukocytes \u226550\/microliter had a higher probability of 18-week survival compared with those with \u226450 cells\/microliter (68% (52\/77 vs. 52% (151\/292); Hazard Ratio = 1.63, 95% confidence interval 1.14\u20132.23; p = 0.008). Survival was also associated with higher expression of T helper (Th)-1, Th17 cytokines, and immune regulatory elements. CSF levels of Programmed Death-1 Ligand, CXCL10, and Interleukin (IL)-2 independently predicted survival. In multivariate analysis, CSF leukocytes were inversely associated with CSF fungal burden and positively associated with CSF protein and immune parameters (interferon-gamma (IFN-\u03b3), IL-17A, tumor necrosis factor alpha (TNF)-\u03b1, and circulating CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> T cells).<\/jats:p>\n<\/jats:sec>\n<jats:sec id=\"sec004\">\n<jats:title>Conclusion<\/jats:title>\n<jats:p>18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-\u03b3, IL-2 and TNF-\u03b1 cytokines), T helper 17 (IL-17A cytokine) and CXCR3<jats:sup>+<\/jats:sup> T cell (CXCL10 chemokine) responses. These results highlight the interdependent contribution of soluble and cellular immune responses in predicting survival and may support potential pathways for adjunctive immune therapy in HIV-associated cryptococcal meningitis.<\/jats:p>\n<\/jats:sec>","DOI":"10.1371\/journal.pntd.0012873","type":"journal-article","created":{"date-parts":[[2025,2,10]],"date-time":"2025-02-10T18:37:24Z","timestamp":1739212644000},"page":"e0012873","update-policy":"https:\/\/doi.org\/10.1371\/journal.pntd.corrections_policy","source":"Crossref","is-referenced-by-count":6,"title":["Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis"],"prefix":"10.1371","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9292-8687","authenticated-orcid":true,"given":"Samuel","family":"Okurut","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David R.","family":"Boulware","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari C.","family":"Manabe","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lillian","family":"Tugume","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caleb P.","family":"Skipper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth","family":"Ssebambulidde","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua","family":"Rhein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdu K.","family":"Musubire","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew","family":"Akampurira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C.","family":"Okafor","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph O.","family":"Olobo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edward N.","family":"Janoff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David B.","family":"Meya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"for ASTRO Trial Team","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2025,2,10]]},"reference":[{"key":"pntd.0012873.ref001","doi-asserted-by":"crossref","first-page":"1004","DOI":"10.1056\/NEJMoa1710922","article-title":"Antifungal combinations for treatment of cryptococcal meningitis in Africa.","volume":"378","author":"SF Molloy","year":"2018","journal-title":"New England Journal of Medicine"},{"key":"pntd.0012873.ref002","doi-asserted-by":"crossref","first-page":"1683","DOI":"10.1093\/cid\/ciz485","article-title":"Cryptococcal-related Mortality Despite Fluconazole Preemptive Treatment in a Cryptococcal Antigen Screen-and-Treat Program","volume":"70","author":"RM Wake","year":"2020","journal-title":"Clin Infect Dis"},{"key":"pntd.0012873.ref003","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1016\/S1473-3099(17)30243-8","article-title":"Global burden of disease of HIV-associated cryptococcal meningitis: an updated analysis","volume":"17","author":"R Rajasingham","year":"2017","journal-title":"Lancet Infect Dis"},{"key":"pntd.0012873.ref004","doi-asserted-by":"crossref","first-page":"4922","DOI":"10.1128\/IAI.73.8.4922-4933.2005","article-title":"Cryptococcus neoformans \u03b1 strains preferentially disseminate to the central nervous system during coinfection","volume":"73","author":"K Nielsen","year":"2005","journal-title":"Infect Immun"},{"key":"pntd.0012873.ref005","first-page":"8","article-title":"Trojan horse transit contributes to blood-brain barrier crossing of a eukaryotic pathogen","author":"FH Santiago-Tirado","year":"2017","journal-title":"mBio"},{"key":"pntd.0012873.ref006","doi-asserted-by":"crossref","first-page":"840","DOI":"10.1111\/myc.13122","article-title":"Landmark clinical observations and immunopathogenesis pathways linked to HIV and Cryptococcus fatal central nervous system co\u2010infection.","volume":"63","author":"S Okurut","year":"2020","journal-title":"Mycoses"},{"key":"pntd.0012873.ref007","doi-asserted-by":"crossref","first-page":"e00779","DOI":"10.1128\/IAI.00779-19","article-title":"B cell Compartmentalization in Blood and Cerebrospinal Fluid of HIV-Infected Ugandans with Cryptococcal Meningitis. 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