Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis.
<h4>Introduction</h4>Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.<h4>Methods</h4>We...
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2025-02-01
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| Series: | PLoS Neglected Tropical Diseases |
| Online Access: | https://doi.org/10.1371/journal.pntd.0012873 |
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| author | Samuel Okurut David R Boulware Yukari C Manabe Lillian Tugume Caleb P Skipper Kenneth Ssebambulidde Joshua Rhein Abdu K Musubire Andrew Akampurira Elizabeth C Okafor Joseph O Olobo Edward N Janoff David B Meya for ASTRO Trial Team |
| author_facet | Samuel Okurut David R Boulware Yukari C Manabe Lillian Tugume Caleb P Skipper Kenneth Ssebambulidde Joshua Rhein Abdu K Musubire Andrew Akampurira Elizabeth C Okafor Joseph O Olobo Edward N Janoff David B Meya for ASTRO Trial Team |
| author_sort | Samuel Okurut |
| collection | DOAJ |
| description | <h4>Introduction</h4>Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.<h4>Methods</h4>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.<h4>Results</h4>Participants with CSF leukocytes ≥50/microliter had a higher probability of 18-week survival compared with those with ≤50 cells/microliter (68% (52/77 vs. 52% (151/292); Hazard Ratio = 1.63, 95% confidence interval 1.14-2.23; 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-γ), IL-17A, tumor necrosis factor alpha (TNF)-α, and circulating CD4+ and CD8+ T cells).<h4>Conclusion</h4>18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ 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. |
| format | Article |
| id | doaj-art-e99e68538b724d7fbf83a3c7cfffd334 |
| institution | OA Journals |
| issn | 1935-2727 1935-2735 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Public Library of Science (PLoS) |
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| series | PLoS Neglected Tropical Diseases |
| spelling | doaj-art-e99e68538b724d7fbf83a3c7cfffd3342025-08-20T02:28:18ZengPublic Library of Science (PLoS)PLoS Neglected Tropical Diseases1935-27271935-27352025-02-01192e001287310.1371/journal.pntd.0012873Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis.Samuel OkurutDavid R BoulwareYukari C ManabeLillian TugumeCaleb P SkipperKenneth SsebambuliddeJoshua RheinAbdu K MusubireAndrew AkampuriraElizabeth C OkaforJoseph O OloboEdward N JanoffDavid B Meyafor ASTRO Trial Team<h4>Introduction</h4>Cryptococcal meningitis remains a prominent cause of death in persons with advanced HIV disease. CSF leukocyte infiltration predicts survival at 18 weeks; however, how CSF immune response relates to CSF leukocyte infiltration is unknown.<h4>Methods</h4>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.<h4>Results</h4>Participants with CSF leukocytes ≥50/microliter had a higher probability of 18-week survival compared with those with ≤50 cells/microliter (68% (52/77 vs. 52% (151/292); Hazard Ratio = 1.63, 95% confidence interval 1.14-2.23; 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-γ), IL-17A, tumor necrosis factor alpha (TNF)-α, and circulating CD4+ and CD8+ T cells).<h4>Conclusion</h4>18-week survival after diagnosis of cryptococcal meningitis was associated with higher CSF leukocytes at baseline with greater T helper 1 (IFN-γ, IL-2 and TNF-α cytokines), T helper 17 (IL-17A cytokine) and CXCR3+ 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.https://doi.org/10.1371/journal.pntd.0012873 |
| spellingShingle | Samuel Okurut David R Boulware Yukari C Manabe Lillian Tugume Caleb P Skipper Kenneth Ssebambulidde Joshua Rhein Abdu K Musubire Andrew Akampurira Elizabeth C Okafor Joseph O Olobo Edward N Janoff David B Meya for ASTRO Trial Team Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. PLoS Neglected Tropical Diseases |
| title | Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. |
| title_full | Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. |
| title_fullStr | Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. |
| title_full_unstemmed | Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. |
| title_short | Impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with HIV-associated cryptococcal meningitis. |
| title_sort | impact of cerebrospinal fluid leukocyte infiltration and activated neuroimmune mediators on survival with hiv associated cryptococcal meningitis |
| url | https://doi.org/10.1371/journal.pntd.0012873 |
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