{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,1,16]],"date-time":"2026-01-16T13:27:22Z","timestamp":1768570042854,"version":"3.49.0"},"posted":{"date-parts":[[2025,9,27]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":28,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T00:00:00Z","timestamp":1758931200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.medrxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,9,27]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Excessive CNS inflammation is associated with poor outcomes in tuberculous meningitis (TBM). Anti-inflammatory corticosteroid therapy improves survival in HIV-negative TBM, but not in people with HIV. In people with HIV, TBM is fatal in 40-50% of cases. Therefore, we investigated how mortality is associated with the local immune dynamics in people with HIV-associated TBM.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We measured baseline concentrations of immune signaling mediators in cerebrospinal fluid (CSF) of 149 adults with HIV in Uganda, who presented with definite or probable TBM. Participants received both antimycobacterial and corticosteroid therapy.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Non-survivors had more severe TBM disease stage and lower blood CD4 T cells than survivors at baseline. Mortality at 90 days was strongly associated with CSF hypo-inflammation. CSF interferon gamma (IFN-\u03b3) was the cytokine most differentially expressed by survivors (2.2 log\n                    <jats:sub>2<\/jats:sub>\n                    -fold change higher, p=.003), and 90-day mortality was lower with increasing concentrations (Tertile-1=50%, Tertile-2=41%, Tertile-3=18%; p=.006). Even among people who successfully mounted a CSF cellular immune response (&gt;5 white cells\/\u03bcL CSF), those with low CSF IFN-\u03b3 had higher risk of death (Hazard Ratio =3.10 (1.44\u2013 6.68). In contrast, people with intermediate CSF interleukin-13 had lower mortality than extreme (Tertile-1=45%, Tertile-2=22%, Tertile-3=40%; p=.017). Of all sub-groups, those with both peripheral CD4 depletion and low CSF IFN-\u03b3 had the highest mortality (63%).\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In adults with HIV-associated TBM receiving dexamethasone, mortality was strongly associated with CSF hypo-inflammation. Although steroids may be appropriate in those with high inflammation, personalized approaches to immunotherapy are likely necessary to improve outcomes.<\/jats:p>\n                <\/jats:sec>","DOI":"10.1101\/2025.09.24.25336544","type":"posted-content","created":{"date-parts":[[2025,9,28]],"date-time":"2025-09-28T05:50:18Z","timestamp":1759038618000},"source":"Crossref","is-referenced-by-count":0,"title":["CSF Hypo-Inflammation Drives Mortality in HIV-Associated Tuberculous Meningitis"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7078-2533","authenticated-orcid":false,"given":"Anna L.","family":"Wilt","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8854-0321","authenticated-orcid":false,"given":"David B.","family":"Meya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5070-532X","authenticated-orcid":false,"given":"Fiona V.","family":"Cresswell","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abduljewad","family":"Wele","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-8966-944X","authenticated-orcid":false,"given":"Mable","family":"Kabahubya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0291-651X","authenticated-orcid":false,"given":"Enock","family":"Kagimu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jane","family":"Gakuru","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Timothy","family":"Mugabi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-1335-9787","authenticated-orcid":false,"given":"Sarah","family":"Kimuda","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-2254-5994","authenticated-orcid":false,"given":"Suzan","family":"Namombwe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-1444-8389","authenticated-orcid":false,"given":"Asmus","family":"Tukundane","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1495-4596","authenticated-orcid":false,"given":"Elizabeth C.","family":"Okafor","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4747-3687","authenticated-orcid":false,"given":"Biyue","family":"Dai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1118-4194","authenticated-orcid":false,"given":"Nicole","family":"Engen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9431-8938","authenticated-orcid":false,"given":"Nathan C.","family":"Bahr","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4715-0060","authenticated-orcid":false,"given":"David R.","family":"Boulware","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7360-6546","authenticated-orcid":false,"given":"Tyler D.","family":"Bold","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025093006450886000_2025.09.24.25336544v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nrmicro732"},{"key":"2025093006450886000_2025.09.24.25336544v1.2","doi-asserted-by":"publisher","DOI":"10.1002\/JLB.MR0318-102R"},{"issue":"8","key":"2025093006450886000_2025.09.24.25336544v1.3","first-page":"ofaa257","article-title":"Treatment Outcomes in Adult Tuberculous Meningitis: A Systematic Review and Meta-analysis","volume":"7","year":"2020","journal-title":"Open Forum Infect Dis"},{"issue":"12","key":"2025093006450886000_2025.09.24.25336544v1.4","doi-asserted-by":"crossref","first-page":"e0000069","DOI":"10.1371\/journal.pgph.0000069","article-title":"The global burden of tuberculous meningitis in adults: A modelling study","volume":"1","year":"2021","journal-title":"PLOS Glob Public Health"},{"key":"2025093006450886000_2025.09.24.25336544v1.5","doi-asserted-by":"crossref","unstructured":"Lefran\u00e7ais E , Hudrisier D , Neyrolles O , Behar SM , Ernst JD . 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