{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:30:51Z","timestamp":1786681851944,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>\n                      Purified Protein Derivative (PPD) skin test reactivity reflects cell-mediated immune response to\n                      <jats:italic>Mycobacterium tuberculosis<\/jats:italic>\n                      . Evidence regarding the prognostic association of PPD reactivity in TBM, particularly its variation across age groups, remains limited.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a single-center retrospective cohort study of consecutive non-HIV TBM patients. Firth\u2019s penalized logistic regression was used to estimate the association between PPD status and in-hospital mortality using fixed covariate sets selected on clinical grounds. Entropy balancing was used as a complementary covariate-balancing analysis. Age-related heterogeneity in the PPD\u2013mortality association was evaluated on multiplicative and additive scales and explored using restricted cubic splines (RCS). Discrimination, calibration, and exploratory decision-curve net benefit were summarized using the area under the receiver operating characteristic curve (AUC), optimism-corrected AUC, Brier score, calibration intercept and slope, and decision curve analysis.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Among 1,574 patients, 187 (11.9%) died during hospitalization. In the fixed clinical model, there was no clear evidence that PPD positivity was associated with mortality in the full cohort (OR 1.30, 95% CI 0.74\u20132.19) or among adults (OR 0.68, 95% CI 0.31\u20131.34). Among 211 children, 9 of 25 PPD-positive children and 13 of 186 PPD-negative children died. The age- and diagnostic-category-adjusted pediatric estimate was OR 7.20, 95% CI 2.70\u201318.94; however, it was based on only 22 pediatric deaths and should be considered hypothesis-generating. The multiplicative interaction OR for adults versus children was 0.08 (95% CI 0.02\u20130.28), and the pediatric-minus-adult difference in standardized mortality-probability contrasts was 0.321 (95% CI 0.158\u20130.510). Full-cohort model performance was modest (AUC 0.673; optimism-corrected AUC 0.647; Brier score 0.0994). For the primary pediatric model, the E-value was 4.81 for the point estimate and 2.67 for the lower confidence-limit bound after approximate OR-to-RR conversion.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>We found no clear evidence that PPD positivity was associated with in-hospital mortality in the full cohort. The pediatric association was large but imprecise and depended on nine deaths among PPD-positive children; it should be treated as an exploratory signal rather than an established age-dependent prognostic association. Multicenter studies using standardized PPD procedures, quantitative induration and testing-time data, and detailed baseline severity measures are needed to independently replicate the pediatric association.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fneur.2026.1820517","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:23:18Z","timestamp":1786681398000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["PPD skin test positivity and in-hospital mortality across age groups in non-HIV tuberculous meningitis: a retrospective cohort study"],"prefix":"10.3389","volume":"17","author":[{"given":"Wengao","family":"Zeng","sequence":"first","affiliation":[{"name":"Department of Neurology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangzhi","family":"Xiao","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huashan","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sufen","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jue","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Neurology, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Otolaryngology, The Second Hospital of Changsha (West Branch of Changsha Hospital for Maternal & Child Health Care)","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiong","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, The Affiliated Changsha Central Hospital, Hengyang Medical School, University of South China","place":["Changsha, Hunan, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"e0270201","DOI":"10.1371\/journal.pone.0270201","article-title":"Long term outcomes of patients with tuberculous meningitis: the impact of drug resistance","volume":"17","author":"Evans","year":"2022","journal-title":"PLoS One"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"751133","DOI":"10.3389\/fneur.2022.751133","article-title":"Tuberculous meningitis in children: a forgotten public health emergency","volume":"13","author":"du Preez","year":"2022","journal-title":"Front Neurol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"ofaa257","DOI":"10.1093\/ofid\/ofaa257","article-title":"Treatment outcomes in adult tuberculous meningitis: a systematic review and meta-analysis","volume":"7","author":"Stadelman","year":"2020","journal-title":"Open Forum Infect Dis"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"e59","DOI":"10.1016\/S2214-109X(24)00383-8","article-title":"Global burden of tuberculous meningitis in children aged 0-14 years in 2019: a mathematical modelling study","volume":"13","author":"du Preez","year":"2025","journal-title":"Lancet Glob Health"},{"key":"ref5","volume-title":"WHO Operational Handbook on tuberculosis. Module 5: Management of tuberculosis in children and Adolescents","year":"2022"},{"key":"ref6","volume-title":"StatPearls","author":"Pahal","year":"2025"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"e96","DOI":"10.1016\/S1473-3099(25)00364-0","article-title":"A clinical practice guideline for tuberculous meningitis","volume":"26","author":"Donovan","year":"2026","journal-title":"Lancet Infect Dis"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1186\/s12890-019-0966-8","article-title":"Treatment outcomes of tuberculous meningitis in adults: a systematic review and meta-analysis","volume":"19","author":"Wang","year":"2019","journal-title":"BMC Pulm Med"},{"key":"ref9","first-page":"4487","article-title":"Prognostic factors of tuberculous meningitis: a single-center study","volume":"8","author":"Gu","year":"2015","journal-title":"Int J Clin Exp Med"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"e96","DOI":"10.1016\/S1473-3099(18)30157-9","article-title":"Tuberculosis susceptibility and protection in children","volume":"19","author":"Basu Roy","year":"2019","journal-title":"Lancet Infect Dis"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"20143085","DOI":"10.1098\/rspb.2014.3085","article-title":"Evolution of the immune system in humans from infancy to old age","volume":"282","author":"Simon","year":"2015","journal-title":"Proc Biol Sci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1111\/imm.12454","article-title":"Is the developmentally immature immune response in paediatric sepsis a recapitulation of immune tolerance?","volume":"145","author":"Maddux","year":"2015","journal-title":"Immunology"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"803","DOI":"10.1016\/S1473-3099(10)70138-9","article-title":"Tuberculous meningitis: a uniform case definition for use in clinical research","volume":"10","author":"Marais","year":"2010","journal-title":"Lancet Infect Dis"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"344","DOI":"10.1016\/j.jclinepi.2007.11.008","article-title":"The strengthening the reporting of observational studies in epidemiology (STROBE) statement: guidelines for reporting observational studies","volume":"61","author":"von Elm","year":"2008","journal-title":"J Clin Epidemiol"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1007\/s12098-022-04280-3","article-title":"The new WHO consolidated guidelines for Management of Tuberculosis in children and adolescents: an appraisal","volume":"89","author":"Singhal","year":"2022","journal-title":"Indian J Pediatr"},{"key":"ref16","doi-asserted-by":"publisher","first-page":"700269","DOI":"10.3389\/fneur.2021.700269","article-title":"Progression in neuroimaging of normal pressure hydrocephalus","volume":"12","author":"Yin","year":"2021","journal-title":"Front Neurol"},{"key":"ref17","volume-title":"Diseases of the Brain, Head and Neck, Spine 2020\u20132023: Diagnostic Imaging","author":"Farb","year":"2020"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1007\/s00063-012-0120-3","article-title":"Hyponatremia","volume":"108","author":"Heinrich","year":"2013","journal-title":"Med Klin Intensivmed Notfmed"},{"key":"ref19","first-page":"616","article-title":"Acute stroke diagnosis","volume":"105","author":"Choi","year":"2022","journal-title":"Am Fam Physician"},{"key":"ref20","doi-asserted-by":"publisher","first-page":"617","DOI":"10.1016\/j.anai.2021.08.413","article-title":"Secondary immunodeficiencies: an overview","volume":"127","author":"Tuano","year":"2021","journal-title":"Ann Allergy Asthma Immunol"},{"key":"ref21","first-page":"11","article-title":"Kidney disease: acute kidney injury","volume":"509","author":"Mahowald","year":"2021","journal-title":"FP Essent"},{"key":"ref22","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/biomet\/80.1.27","article-title":"Bias reduction of maximum likelihood estimates","volume":"80","author":"Firth","year":"1993","journal-title":"Biometrika"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"3009","DOI":"10.1007\/s00415-019-09523-6","article-title":"Clinical features, outcomes and prognostic factors of tuberculous meningitis in adults worldwide: systematic review and meta-analysis","volume":"266","author":"Wen","year":"2019","journal-title":"J Neurol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"523","DOI":"10.1093\/cid\/cix849","article-title":"Prognostic models for 9-month mortality in tuberculous meningitis","volume":"66","author":"Thao","year":"2017","journal-title":"Clin Infect Dis"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"656","DOI":"10.1186\/s12879-024-09561-0","article-title":"Analysis of risk factors for long-term mortality in patients with stage II and III tuberculous meningitis","volume":"24","author":"Wang","year":"2024","journal-title":"BMC Infect Dis"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"581","DOI":"10.1038\/nrneurol.2017.120","article-title":"Tuberculous meningitis","volume":"13","author":"Wilkinson","year":"2017","journal-title":"Nat Rev Neurol"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"e61722","DOI":"10.7554\/eLife.61722","article-title":"A Bayesian analysis of the association between leukotriene A4 hydrolase genotype and survival in tuberculous meningitis","volume":"10","author":"Whitworth","year":"2021","journal-title":"eLife"},{"key":"ref28","doi-asserted-by":"publisher","first-page":"3767","DOI":"10.1038\/s41467-019-11783-9","article-title":"Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity","volume":"10","author":"Rohlwink","year":"2019","journal-title":"Nat Commun"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"e01771-20","DOI":"10.1128\/JCM.01771-20","article-title":"Tuberculous meningitis: pathogenesis, immune responses, diagnostic challenges, and the potential of biomarker-based approaches","volume":"59","author":"Manyelo","year":"2021","journal-title":"J Clin Microbiol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"103233","DOI":"10.1016\/j.ebiom.2021.103233","article-title":"Immune profiling of Mycobacterium tuberculosis-specific T cells in recent and remote infection","volume":"64","author":"Mpande","year":"2021","journal-title":"EBioMedicine"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"2477300","DOI":"10.1080\/07853890.2025.2477300","article-title":"Age-related changes in the immune system and challenges for the development of age-specific vaccines","volume":"57","author":"Doherty","year":"2025","journal-title":"Ann Med"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41586-025-09686-5","article-title":"Multi-omic profiling reveals age-related immune dynamics in healthy adults","volume":"648","author":"Gong","year":"2025","journal-title":"Nature"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1093\/infdis\/jiaf181","article-title":"Tuberculous meningitis across the lifespan","volume":"231","author":"Lourens","year":"2025","journal-title":"J Infect Dis"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"1059173","DOI":"10.3389\/fimmu.2022.1059173","article-title":"Immune system modulation in aging: molecular mechanisms and therapeutic targets","volume":"13","author":"Cisneros","year":"2022","journal-title":"Front Immunol"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/s41577-026-01269-3","article-title":"The ageing immune system as a driver of systemic ageing","volume":"26","author":"Jang","year":"2026","journal-title":"Nat Rev Immunol"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"fcaf273","DOI":"10.1093\/braincomms\/fcaf273","article-title":"Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis","volume":"7","author":"Dian","year":"2025","journal-title":"Brain Commun"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"2100167","DOI":"10.1183\/13993003.00167-2021","article-title":"Tests for tuberculosis infection: landscape analysis","volume":"58","author":"Hamada","year":"2021","journal-title":"Eur Respir J"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"49","DOI":"10.1080\/24745332.2022.2036503","article-title":"Chapter 4: diagnosis of tuberculosis infection","volume":"6","author":"Campbell","year":"2022","journal-title":"Can J Respir Crit Care Sleep Med"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1128\/CMR.00034-13","article-title":"Gamma interferon release assays for detection of Mycobacterium tuberculosis infection","volume":"27","author":"Pai","year":"2014","journal-title":"Clin Microbiol Rev"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1820517\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T04:23:20Z","timestamp":1786681400000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2026.1820517\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":39,"alternative-id":["10.3389\/fneur.2026.1820517"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2026.1820517","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]},"article-number":"1820517"}}