{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,17]],"date-time":"2026-06-17T03:01:19Z","timestamp":1781665279887,"version":"3.54.5"},"reference-count":33,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T00:00:00Z","timestamp":1737331200000},"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. Immunol."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>Tuberculous meningitis (TBM) is a non-purulent inflammatory condition affecting the meninges and spinal membranes, caused by Mycobacterium tuberculosis (MTB) infection. This study seeks to explore the impact of varying INH dosages and NAT2 gene polymorphisms on TBM treatment, contributing new insights to improve clinical management and patient prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Patients with TBM hospitalized between July 2020 and December 2022 were categorized into two groups based on INH dosage: the standard-dose group (300 mg\/day) and the high-dose group (600 mg\/day). General and baseline data were collected, and NAT2 genotypes were identified using real-time fluorescent PCR with melting curve analysis. The clinical characteristics and outcomes of patients with TBM under varying INH dosages were analyzed.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>This study enrolled 119 patients with TBM, including 32 (26.9%) in the standard-dose group and 87 (73.1%) in the high-dose group. The NAT2 genotypes were distributed as follows: 34 (28.6%) fast acetylators (FA), 73 (61.3%) intermediate acetylators (IA), and 12 (10.1%) slow acetylators (SA). By month 12, 25 patients (21.0%) experienced disability or death, with 22 cases (18.5%) occurring by the end of the 3rd month. Disability and mortality rates differed significantly between the standard-dose and high-dose groups for IA-type TBM patients (P = 0.014). Univariate analysis showed significant differences between groups in baseline focal neurological impairment and disability or mortality by the 3rd and 12th months. Multivariate logistic regression identified INH dosage, cranial nerve palsy, age, and headache as key prognostic factors for TBM.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>High-dose INH treatment was associated with a reduced incidence of disability or death compared to the standard-dose regimen, indicating better efficacy and prognosis. In patients with IA-type TBM, the high-dose group showed a significantly lower rate of disability or mortality, suggesting that higher INH dosages may reduce the risk of adverse outcomes.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2024.1535447","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T07:21:34Z","timestamp":1737357694000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":5,"title":["The role of isoniazid dosage and NAT2 gene polymorphism in the treatment of tuberculous meningitis"],"prefix":"10.3389","volume":"15","author":[{"given":"Yi","family":"Jian","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuhang","family":"Bao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fashuang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mei","family":"Zhu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.7860\/JCDR\/2015\/11456.5454","article-title":"Prospective analysis of 55 cases of tuberculosis meningitis (TBM) in North India","volume":"9","author":"Kaur","year":"2015","journal-title":"J Clin Diagn Res"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1186\/1756-0500-5-49","article-title":"Diagnostic features of tuberculous meningitis: A cross-sectional study","volume":"5","author":"Pasco","year":"2012","journal-title":"BMC Res Notes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.3390\/jcm9092962","article-title":"Analysis of tuberculosis meningitis pathogenesis, diagnosis, and treatment","volume":"9","author":"Arshad","year":"2020","journal-title":"J Clin Med"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2022.2164348","article-title":"The rare manifestations in tuberculous meningoencephalitis: A review of available literature","volume":"55","author":"He","year":"2023","journal-title":"Ann Med"},{"key":"B5","doi-asserted-by":"publisher","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":"B6","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.pharmtox.37.1.269","article-title":"Molecular mechanisms of genetic polymorphisms of drug metabolism","volume":"37","author":"Meyer","year":"1997","journal-title":"Annu Rev Pharmacol Toxicol"},{"key":"B7","first-page":"29","article-title":"Molecular genetics and epidemiology of the NAT1 and NAT2 acetylation polymorphisms","volume":"9","author":"Hein","year":"2000","journal-title":"Cancer Epidemiol Biomarkers Prev"},{"key":"B8","doi-asserted-by":"publisher","first-page":"196","DOI":"10.1007\/s00204-004-0622-8","article-title":"Re-investigation of the concordance of human NAT2 phenotypes and genotypes","volume":"79","author":"Bolt","year":"2005","journal-title":"Arch Toxicol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.4103\/0971-5916.187106","article-title":"N-acetyltransferase 2 (NAT2) gene polymorphism as a predisposing factor for phenytoin intoxication in tuberculous meningitis or tuberculoma patients having seizures - A pilot study","volume":"143","author":"Adole","year":"2016","journal-title":"Indian J Med Res"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.2147\/DDDT.S87131","article-title":"A proposal for an individualized pharmacogenetic-guided isoniazid dosage regimen for patients with tuberculosis","volume":"9","author":"Jung","year":"2015","journal-title":"Drug Des Devel Ther"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1080\/17512433.2023.2196401","article-title":"Parametric population pharmacokinetics of isoniazid: A systematic review","volume":"16","author":"Li","year":"2023","journal-title":"Expert Rev Clin Pharmacol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1111\/cts.13614","article-title":"Application of a physiologically based pharmacokinetic model to predict isoniazid disposition during pregnancy","volume":"16","author":"Amaeze","year":"2023","journal-title":"Clin Transl Sci"},{"key":"B13","doi-asserted-by":"publisher","first-page":"289","DOI":"10.2217\/pgs.13.2","article-title":"NAT2 sequence polymorphisms and acetylation profiles in Indians","volume":"14","author":"Khan","year":"2013","journal-title":"Pharmacogenomics"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jcma.2014.01.010","article-title":"Recent progress in genetic variation and risk of antituberculosis drug-induced liver injury","volume":"77","author":"Huang","year":"2014","journal-title":"J Chin Med Assoc"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1515\/DMDI.2011.016","article-title":"Gene dose effect of NAT2 variants on the pharmacokinetics of isoniazid and acetylisoniazid in healthy Chinese subjects","volume":"26","author":"Bing","year":"2011","journal-title":"Drug Metabol Drug Interact"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.01736-19","article-title":"Population pharmacokinetic analysis of isoniazid among pulmonary tuberculosis patients from China","volume":"64","author":"Jing","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm\/148.3.650","article-title":"Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis","volume":"148","author":"Ellard","year":"1993","journal-title":"Am Rev Respir Dis"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1016\/j.clinthera.2020.09.009","article-title":"A systematic review and meta-analysis of isoniazid pharmacokinetics in healthy volunteers and patients with tuberculosis","volume":"42","author":"Hong","year":"2020","journal-title":"Clin Ther"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2022.932686","article-title":"Population pharmacokinetics and pharmacodynamics of isoniazid and its metabolite acetylisoniazid in Chinese population","volume":"13","author":"Chen","year":"2022","journal-title":"Front Pharmacol"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1441147","article-title":"Isoniazid-historical development, metabolism associated toxicity and a perspective on its pharmacological improvement","volume":"15","author":"Sankar","year":"2024","journal-title":"Front Pharmacol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.4103\/ijmy.ijmy_106_24","article-title":"Pharmacogenetic study of drugs affecting mycobacterium tuberculosis","volume":"13","author":"Shabani","year":"2024","journal-title":"Int J Mycobacteriol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2024.1332752","article-title":"Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships","volume":"15","author":"Ulanova","year":"2024","journal-title":"Front Pharmacol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.2174\/1381612820666140901215544","article-title":"The case for using higher doses of first line anti-tuberculosis drugs to optimize efficacy","volume":"20","author":"Goutelle","year":"2014","journal-title":"Curr Pharm Des"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1155\/2013\/129723","article-title":"Early therapeutic drug monitoring for isoniazid and rifampin among diabetics with newly diagnosed tuberculosis in Virginia, USA","volume":"2013","author":"Heysell","year":"2013","journal-title":"Tuberc Res Treat"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200208-951OC","article-title":"Low isoniazid concentrations and outcome of tuberculosis treatment with once-weekly isoniazid and rifapentine","volume":"167","author":"Weiner","year":"2003","journal-title":"Am J Respir Crit Care Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1128\/AAC.02376-19","article-title":"N-Acetyltransferase 2 Genotypes among Zulu-Speaking South Africans and Isoniazid and N-Acetyl-Isoniazid Pharmacokinetics during Antituberculosis Treatment","volume":"64","author":"Mthiyane","year":"2020","journal-title":"Antimicrob Agents Chemother"},{"key":"B27","doi-asserted-by":"publisher","first-page":"39","DOI":"10.3346\/jkms.1990.5.1.39","article-title":"Kinetics of isoniazid transfer into cerebrospinal fluid in patients with tuberculous meningitis","volume":"5","author":"Shin","year":"1990","journal-title":"J Korean Med Sci"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1007\/s00228-012-1429-9","article-title":"NAT2 genotype guided regimen reduces isoniazid-induced liver injury and early treatment failure in the 6-month four-drug standard treatment of tuberculosis: A randomized controlled trial for pharmacogenetics-based therapy","volume":"69","author":"Azuma","year":"2013","journal-title":"Eur J Clin Pharmacol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0293708","article-title":"Isoniazid Preventive Therapy during Infancy Does Not Adversely Affect Growth among HIV-Exposed Uninfected Children: Secondary Analysis of Data from a Randomized Controlled Trial","volume":"19","author":"Cherkos","year":"2024","journal-title":"PloS One"},{"key":"B30","doi-asserted-by":"publisher","first-page":"729","DOI":"10.1186\/s12879-024-09511-w","article-title":"Efficacy and tolerability of a 4-month ofloxacin-containing regimen compared to a 6-month regimen in the treatment of patients with superficial lymph node tuberculosis: A randomized trial","volume":"24","author":"Hissar","year":"2024","journal-title":"BMC Infect Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.radcr.2024.01.073","article-title":"Tuberculous meningitis with stroke: A case report of diagnostic dilemma and therapeutic triumph","volume":"19","author":"Katwal","year":"2024","journal-title":"Radiol Case Rep"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.41462","article-title":"Intracranial microhemorrhages in a patient with tubercular meningitis (TBM): A case report","volume":"15","author":"Roy","year":"2023","journal-title":"Cureus"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.7759\/cureus.64332","article-title":"Comprehensive case analysis of tuberculous meningitis in an immunocompetent patient: diagnostic challenges and therapeutic strategies","volume":"16","author":"Sharma","year":"2024","journal-title":"Cureus"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1535447\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T07:21:39Z","timestamp":1737357699000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1535447\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,20]]},"references-count":33,"alternative-id":["10.3389\/fimmu.2024.1535447"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1535447","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,20]]},"article-number":"1535447"}}