{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T15:59:35Z","timestamp":1791388775376,"version":"4.3.3"},"reference-count":114,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T00:00:00Z","timestamp":1769472000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"crossref","award":["2R15HL143545-02"],"award-info":[{"award-number":["2R15HL143545-02"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Pediatric tuberculosis (TB) remains a critically underrecognized contributor to global childhood morbidity and mortality, with the highest burden concentrated in low-resource settings. Although children comprise a minority of overall TB cases, mortality is disproportionately high, particularly among those under five years of age, driven largely by delayed diagnosis, inadequate linkage to care, and limited access to effective treatment. The continued rise of pediatric multidrug-resistant TB (MDR-TB), especially in regions with low sociodemographic development, further highlights persistent gaps in current control strategies. This review synthesizes key aspects of pediatric TB pathogenesis and host immune responses that predispose young children to rapid disease progression and severe outcomes, including immune immaturity and paucibacillary infection. We summarize pulmonary and extrapulmonary disease manifestations and identify populations at heightened risk, including children with HIV, malnutrition, type 1 diabetes mellitus, and congenital or treatment-related immunosuppression. Ongoing challenges in diagnosis and treatment are discussed, including limitations of existing microbiologic and immunologic tests, specimen collection constraints, regimen toxicity, and barriers to adherence. Prevention remains central to reducing pediatric TB mortality. We highlight the sustained importance of bacille Calmette\u2013Gu\u00e9rin (BCG) vaccination in preventing severe disease and death, the context-dependent variability in vaccine effectiveness, and the structural and socioeconomic determinants of vaccine coverage. We conclude that integrating equitable vaccine delivery, scalable preventive therapy, and child-adapted diagnostic strategies is essential to meaningfully reduce the global pediatric TB burden.<\/jats:p>","DOI":"10.3390\/vaccines14020119","type":"journal-article","created":{"date-parts":[[2026,1,27]],"date-time":"2026-01-27T09:21:40Z","timestamp":1769505700000},"page":"119","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["Pediatric Tuberculosis: Unraveling Immunity, Clinical Complexities, and Resource-Driven Disparities in the Pursuit of Prevention"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4025-7412","authenticated-orcid":false,"given":"Daniel","family":"Mashiach","sequence":"first","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin","family":"Shon","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raquel","family":"Mashiach","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Ayzenberg","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Osnat","family":"Barazani","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Aabedi","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2586-1160","authenticated-orcid":false,"given":"Vishwanath","family":"Venketaraman","sequence":"additional","affiliation":[{"name":"College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA 91766, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,1,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Hershkovitz, I., Donoghue, H.D., Minnikin, D.E., Besra, G.S., Lee, O.Y.C., Gernaey, A.M., Galili, E., Eshed, V., Greenblatt, C.L., and Lemma, E. (2008). Detection and Molecular Characterization of 9000-Year-Old Mycobacterium tuberculosis from a Neolithic Settlement in the Eastern Mediterranean. PLoS ONE, 3.","DOI":"10.1371\/journal.pone.0003426"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"305","DOI":"10.1086\/321886","article-title":"Mycobacterium tuberculosis complex DNA from an extinct bison dated 17,000 years before the present","volume":"33","author":"Rothschild","year":"2001","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1136\/thx.37.4.246","article-title":"Robert Koch: Centenary of the discovery of the tubercle bacillus, 1882","volume":"37","author":"Sakula","year":"1982","journal-title":"Thorax"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/j.cll.2014.02.005","article-title":"Molecular diagnosis of tuberculosis and drug resistance","volume":"34","author":"Lin","year":"2014","journal-title":"Clin. Lab. Med."},{"key":"ref_5","unstructured":"World Health Organization (2025). Global Tuberculosis Report 2025, World Health Organization."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e898","DOI":"10.1016\/S2214-109X(17)30289-9","article-title":"The global burden of tuberculosis mortality in children: A mathematical modelling study","volume":"5","author":"Dodd","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"901","DOI":"10.1038\/s41390-025-03917-1","article-title":"Global burden of multidrug-resistant tuberculosis in children and adolescents","volume":"98","author":"Zhong","year":"2025","journal-title":"Pediatr. Res."},{"key":"ref_8","unstructured":"GBD Tuberculosis Collaborators (2018). The global burden of tuberculosis: Results from the Global Burden of Disease Study 2015. Lancet Infect. Dis., 18, 261\u2013284."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1186\/s40249-021-00803-w","article-title":"Trends in burden of multidrug-resistant tuberculosis in countries, regions, and worldwide from 1990 to 2017: Results from the Global Burden of Disease study","volume":"10","author":"Ou","year":"2021","journal-title":"Infect. Dis. Poverty"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"604","DOI":"10.1164\/rccm.200308-1101OC","article-title":"Cough-generated aerosols of Mycobacterium tuberculosis: A new method to study infectiousness","volume":"169","author":"Fennelly","year":"2004","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S369","DOI":"10.1093\/clinids\/11.Supplement_2.S369","article-title":"Immune mechanisms in the pathogenesis of pulmonary tuberculosis","volume":"11","author":"Dannenberg","year":"1989","journal-title":"Rev. Infect. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"814943","DOI":"10.1155\/2011\/814943","article-title":"Pathogenesis, immunology, and diagnosis of latent Mycobacterium tuberculosis infection","volume":"2011","author":"Ahmad","year":"2011","journal-title":"Clin. Dev. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1016\/S1473-3099(18)30157-9","article-title":"Tuberculosis susceptibility and protection in children","volume":"19","author":"Roy","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_14","first-page":"278","article-title":"The clinical epidemiology of childhood pulmonary tuberculosis: A critical review of literature from the pre-chemotherapy era","volume":"8","author":"Marais","year":"2004","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_15","first-page":"781320","article-title":"Immune vulnerability of infants to tuberculosis","volume":"2013","author":"Persson","year":"2013","journal-title":"Clin. Dev. Immunol."},{"key":"ref_16","first-page":"20","article-title":"Diagnosis of tuberculosis in children","volume":"196\u2013197","author":"Anane","year":"1992","journal-title":"Child. Trop."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1016\/j.pcl.2017.03.010","article-title":"Tuberculosis in children","volume":"64","author":"Thomas","year":"2017","journal-title":"Pediatr. Clin. N. Am."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jinf.2004.02.010","article-title":"Tuberculous meningitis and miliary tuberculosis: The Rich focus revisited","volume":"50","author":"Donald","year":"2005","journal-title":"J. Infect."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1306","DOI":"10.1007\/s00247-008-1028-1","article-title":"Magnetic resonance imaging of miliary tuberculosis of the central nervous system in children with tuberculous meningitis","volume":"38","author":"Andronikou","year":"2008","journal-title":"Pediatr. Radiol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1016\/S1473-3099(14)70852-7","article-title":"Treatment outcomes of childhood tuberculous meningitis: A systematic review and meta-analysis","volume":"14","author":"Chiang","year":"2014","journal-title":"Lancet Infect. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bang, N.D., Caws, M., Truc, T.T., Duong, T.N., Dung, N.H., Ha, D.T., Thwaites, G.E., Heemskerk, D., Tarning, J., and Merson, L. (2016). Clinical presentations, diagnosis, mortality and prognostic markers of tuberculous meningitis in Vietnamese children: A prospective descriptive study. BMC Infect. Dis., 16.","DOI":"10.1186\/s12879-016-1923-2"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Marx, G.E., and Chan, E.D. (2011). Tuberculous meningitis: Diagnosis and treatment overview. Tuberc. Res. Treat.","DOI":"10.1155\/2011\/798764"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"S184","DOI":"10.1086\/651490","article-title":"Pediatric tuberculosis: Global overview and challenges","volume":"50","author":"Swaminathan","year":"2010","journal-title":"Clin. Infect. Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"178","DOI":"10.12688\/wellcomeopenres.15516.1","article-title":"Neurocognitive and Functional Impairment in Adult and Paediatric Tuberculous Meningitis","volume":"4","author":"Davis","year":"2019","journal-title":"Wellcome Open Res."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1164\/rccm.202208-1543OC","article-title":"The long-term impact of early-life tuberculosis disease on child health: A prospective birth cohort study","volume":"207","author":"Martinez","year":"2023","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1136\/thorax-2022-219085","article-title":"Reduced Lung Function and Health-Related Quality of Life after Treatment for Pulmonary Tuberculosis in Gambian Children: A Cross-Sectional Comparative Study","volume":"78","author":"Nkereuwem","year":"2023","journal-title":"Thorax"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"102406","DOI":"10.1016\/j.eclinm.2023.102406","article-title":"Impaired lung function in adolescents with pulmonary tuberculosis during treatment and following treatment completion","volume":"67","author":"Jongen","year":"2024","journal-title":"EClinicalMedicine"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"7","DOI":"10.5588\/ijtld.17.0354","article-title":"Preclinical tools for the evaluation of tuberculosis treatment regimens for children","volume":"22","author":"Tucker","year":"2018","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1016\/S1473-3099(08)70182-8","article-title":"Paediatric Tuberculosis","volume":"8","author":"Newton","year":"2008","journal-title":"Lancet Infect. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1111\/cei.13565","article-title":"Immunological Basis of Early Clearance of Mycobacterium tuberculosis Infection: The Role of Natural Killer Cells","volume":"204","author":"Abebe","year":"2021","journal-title":"Clin. Exp. Immunol."},{"key":"ref_31","first-page":"658","article-title":"Tuberculosis Immunology in Children: Diagnostic and Therapeutic Challenges and Opportunities","volume":"8","author":"Lewinsohn","year":"2004","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Whittaker, E., Nicol, M., Zar, H.J., and Kampmann, B. (2017). Regulatory T Cells and Pro-Inflammatory Responses Predominate in Children with Tuberculosis. Front. Immunol., 8.","DOI":"10.3389\/fimmu.2017.00448"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Stringari, L.L., Covre, L.P., da Silva, F.D.C., de Oliveira, V.L., Campana, M.C., Hadad, D.J., Palaci, M., Salgame, P., Dietze, R., and Gomes, D.C.O. (2021). Increase of CD4+CD25highFoxP3+ Cells Impairs In Vitro Human Microbicidal Activity against Mycobacterium tuberculosis during Latent and Acute Pulmonary Tuberculosis. PLoS Negl. Trop. Dis., 15.","DOI":"10.1371\/journal.pntd.0009605"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e36779","DOI":"10.1016\/j.heliyon.2024.e36779","article-title":"Comparative Analysis of Pediatric Pulmonary and Extrapulmonary Tuberculosis: A Single-Center Retrospective Cohort Study in Syria","volume":"10","author":"Hamdar","year":"2024","journal-title":"Heliyon"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"e147","DOI":"10.1093\/cid\/ciw376","article-title":"Official American Thoracic Society\/Centers for Disease Control and Prevention\/Infectious Diseases Society of America Clinical Practice Guidelines: Treatment of Drug-Susceptible Tuberculosis","volume":"63","author":"Nahid","year":"2016","journal-title":"Clin. Infect. Dis."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1097\/01.inf.0000199259.04970.d1","article-title":"Tuberculous Lymphadenitis as a Cause of Persistent Cervical Lymphadenopathy in Children from a Tuberculosis-Endemic Area","volume":"25","author":"Marais","year":"2006","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.ijid.2022.09.030","article-title":"Clinicoepidemiologic Considerations in the Diagnosis of Tuberculous Lymphadenitis: Evidence from a High Burden Country","volume":"124","author":"Assefa","year":"2022","journal-title":"Int. J. Infect. Dis."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"999","DOI":"10.1016\/S1474-4422(13)70168-6","article-title":"Tuberculous Meningitis: More Questions, Still Too Few Answers","volume":"12","author":"Thwaites","year":"2013","journal-title":"Lancet Neurol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"117","DOI":"10.4103\/ijmr.IJMR_786_17","article-title":"Tuberculous Meningitis in Children: Clinical Management & Outcome","volume":"150","author":"Daniel","year":"2019","journal-title":"Indian J. Med. Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"832","DOI":"10.1097\/00006454-199111000-00008","article-title":"Miliary Tuberculosis in Children: A Review of 94 Cases","volume":"10","author":"Hussey","year":"1991","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_41","first-page":"703","article-title":"Challenges in the Diagnosis & Treatment of Miliary Tuberculosis","volume":"135","author":"Sharma","year":"2012","journal-title":"Indian J. Med. Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/S2352-4642(21)00311-4","article-title":"Global, regional, and national causes of under-5 mortality in 2000\u201319: An updated systematic analysis with implications for the Sustainable Development Goals","volume":"6","author":"Perin","year":"2022","journal-title":"Lancet Child Adolesc. Health"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"US Department of Health and Human Services (2013). Guideline: The Prevention and Treatment of Opportunistic Infections in HIV-Exposed and HIV-Infected Children. Pediatrics, 132, e1464.","DOI":"10.1542\/peds.2013-2512"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"506","DOI":"10.1097\/QAI.0000000000003591","article-title":"High incidence of tuberculosis in young children living with HIV in the Western Cape, South Africa","volume":"98","author":"Anderson","year":"2025","journal-title":"J. Acquir. Immune Defic. Syndr."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"303","DOI":"10.5588\/ijtld.19.0237","article-title":"Tuberculosis in a Spanish Cohort of Children Living with HIV: The CHOTIS Study","volume":"24","author":"Sainz","year":"2020","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e2021054663","DOI":"10.1542\/peds.2021-054663","article-title":"Committee on Infectious Diseases. Tuberculosis Infection in Children and Adolescents: Testing and Treatment","volume":"148","author":"Nolt","year":"2021","journal-title":"Pediatrics"},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Powell, L., Denoeud-Ndam, L., Herrera, N., Masaba, R., Tchounga, B., Siamba, S., Ouma, M., Petnga, S.J., Machekano, R., and Pamen, B. (2023). HIV Matters When Diagnosing TB in Young Children: An Ancillary Analysis in Children Enrolled in the INPUT Stepped Wedge Cluster Randomized Study. BMC Infect. Dis., 23.","DOI":"10.1186\/s12879-023-08216-w"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1016\/S1473-3099(09)70282-8","article-title":"Tuberculosis and Diabetes Mellitus: Convergence of Two Epidemics","volume":"9","author":"Dooley","year":"2009","journal-title":"Lancet Infect. Dis."},{"key":"ref_49","first-page":"868","article-title":"High Prevalence of Mycobacterium tuberculosis Infection and Disease in Children and Adolescents with Type 1 Diabetes Mellitus","volume":"13","author":"Webb","year":"2009","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Majaliwa, E.S., Muze, K., Godfrey, E., Byashalira, K., Mmbaga, B.T., Ramaiya, K., and Mfinanga, S.G. (2023). Latent Tuberculosis in Children and Youth with Type 1 Diabetes Mellitus in Dar es Salaam, Tanzania: A Cross-Section Survey. BMC Infect. Dis., 23.","DOI":"10.1186\/s12879-023-08753-4"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e96","DOI":"10.1097\/MD.0000000000000096","article-title":"Increased risk of tuberculosis in patients with type 1 diabetes mellitus: Results from a population-based cohort study in Taiwan","volume":"93","author":"Shen","year":"2014","journal-title":"Medicine"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s10096-017-3145-y","article-title":"Patients with Type 1 Diabetes Mellitus Have Impaired IL-1\u03b2 Production in Response to Mycobacterium tuberculosis","volume":"37","author":"Lachmandas","year":"2017","journal-title":"Eur. J. Clin. Microbiol. Infect. Dis."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1093\/cid\/ciae158","article-title":"Tuberculosis Disease in Immunocompromised Children and Adolescents: A Pediatric Tuberculosis Network European Trials Group Multicenter Case-Control Study","volume":"79","author":"Tebruegge","year":"2024","journal-title":"Clin. Infect. Dis."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1111\/imr.12272","article-title":"Inherited and Acquired Immunodeficiencies Underlying Tuberculosis in Childhood","volume":"264","author":"Bustamante","year":"2015","journal-title":"Immunol. Rev."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1111\/j.1440-1843.2009.01690.x","article-title":"Genetic susceptibility in tuberculosis","volume":"15","author":"Yim","year":"2010","journal-title":"Respirology"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e64","DOI":"10.1016\/S1473-3099(17)30623-0","article-title":"Genetics of human susceptibility to active and latent tuberculosis: Present knowledge and future perspectives","volume":"18","author":"Abel","year":"2018","journal-title":"Lancet Infect. Dis."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"173","DOI":"10.1016\/j.humimm.2010.11.002","article-title":"Major histocompatibility complex class III (C2, C4, factor B) and C3 gene variants in patients with pulmonary tuberculosis","volume":"72","author":"Senbagavalli","year":"2011","journal-title":"Hum. Immunol."},{"key":"ref_58","first-page":"2561","article-title":"Tuberculosis Disease in Children and Adolescents on Therapy with Antitumor Necrosis Factor-\u03b1 Agents: A Collaborative, Multicenter Paediatric Tuberculosis Network European Trials Group (ptbnet) Study","volume":"71","author":"Brinkmann","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"54","DOI":"10.1186\/s12969-015-0054-4","article-title":"Tuberculosis in Pediatric Patients Treated with Anti-TNF\u03b1 Drugs: A Cohort Study","volume":"13","year":"2015","journal-title":"Pediatr. Rheumatol."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Li, C., Chen, X., and Zeng, P. (2025). Rheumatic Diseases and Latent Tuberculosis Infection in Children: Diagnostic and Therapeutic Challenges. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1659211"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1175","DOI":"10.1097\/INF.0000000000001270","article-title":"EREMITA Study Group. Pediatric Extrapulmonary Tuberculosis: Clinical Spectrum, Risk Factors and Diagnostic Challenges in a Low Prevalence Region","volume":"35","year":"2016","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1097\/INF.0000000000000847","article-title":"The Role of Clinical Symptoms in the Diagnosis of Intrathoracic Tuberculosis in Young Children","volume":"34","author":"Mulenga","year":"2015","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1016\/j.prrv.2010.09.008","article-title":"New Specimens and Laboratory Diagnostics for Childhood Pulmonary TB: Progress and Prospects","volume":"12","author":"Nicol","year":"2011","journal-title":"Paediatr. Respir. Rev."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1056\/NEJMra1008049","article-title":"Tuberculosis in children","volume":"367","author":"Marais","year":"2012","journal-title":"N. Engl. J. Med."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1007\/s00247-003-1117-0","article-title":"CT Scanning for the Detection of Tuberculous Mediastinal and Hilar Lymphadenopathy in Children","volume":"34","author":"Andronikou","year":"2004","journal-title":"Pediatr. Radiol."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1148\/radiology.182.1.1727316","article-title":"Primary Tuberculosis in Childhood: Radiographic Manifestations","volume":"182","author":"Leung","year":"1992","journal-title":"Radiology"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1258\/ar.2011.100429","article-title":"Evaluation of Pneumonia in Children: Comparison of MRI with Fast Imaging Sequences at 1.5T with Chest Radiographs","volume":"52","author":"Yikilmaz","year":"2011","journal-title":"Acta Radiol."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.2214\/AJR.04.0751","article-title":"Pulmonary Tuberculosis in Infants: Radiographic and CT Findings","volume":"187","author":"Kim","year":"2006","journal-title":"AJR Am. J. Roentgenol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1128\/microbiolspec.TNMI7-0037-2016","article-title":"Tuberculosis in Infants and Children","volume":"5","author":"Lamb","year":"2017","journal-title":"Microbiol. Spectr."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2","DOI":"10.4103\/2229-5178.93479","article-title":"Mantoux Test and Its Interpretation","volume":"3","author":"Nayak","year":"2012","journal-title":"Indian Dermatol. Online J."},{"key":"ref_71","first-page":"578","article-title":"Booster Effect of Tuberculin Testing in Healthy 6-Year-Old School Children Vaccinated with Bacillus Calmette-Gu\u00e9rin at Birth in Santiago, Chile","volume":"7","author":"Sepulveda","year":"1988","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"e1763","DOI":"10.1542\/peds.2014-2983","article-title":"Interferon-\u03b3 Release Assays for Diagnosis of Tuberculosis Infection and Disease in Children","volume":"134","author":"Starke","year":"2014","journal-title":"Pediatrics"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/j.jinf.2013.06.011","article-title":"QuantiFERON to Diagnose Infection by Mycobacterium tuberculosis: Performance in Infants and Older Children","volume":"67","author":"Gourgouillon","year":"2013","journal-title":"J. Infect."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Liang, Y., Wang, J., Yang, J., Liu, J., and He, X. (2025). Global Burden and Trend of Tuberculosis in Children and Adolescents (Under 15 Years Old) from 1990 to 2021, with Projections to 2040. Front. Public Health, 13.","DOI":"10.3389\/fpubh.2025.1578658"},{"key":"ref_75","unstructured":"World Health Organization (2025, December 12). Guidance for National Tuberculosis Programmes on the Management of Tuberculosis in Children, Available online: https:\/\/www.ncbi.nlm.nih.gov\/books\/NBK214449\/."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"911","DOI":"10.1056\/NEJMoa2104535","article-title":"Shorter Treatment for Nonsevere Tuberculosis in African and Indian Children","volume":"386","author":"Turkova","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1164\/rccm.202410-2096ST","article-title":"Updates on the Treatment of Drug-Susceptible and Drug-Resistant Tuberculosis: An Official ATS\/CDC\/ERS\/IDSA Clinical Practice Guideline","volume":"211","author":"Saukkonen","year":"2025","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_78","doi-asserted-by":"crossref","unstructured":"Wilkinson, T., Garcia-Prats, A.J., Sachs, T., Paradkar, M., Suryavanshi, N., Kinikar, A., Frias, M.V., Sinanovic, E., Hesseling, A.C., and Seddon, J.A. (2024). Pharmaceutical Cost Dynamics for the Treatment of Rifampicin-Resistant Tuberculosis in Children and Adolescents in South Africa, India, and the Philippines. PLoS ONE, 19.","DOI":"10.1371\/journal.pone.0305930"},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"117185","DOI":"10.1016\/j.diagmicrobio.2025.117185","article-title":"Drug Resistance and Clinical Characteristics of Pediatric and Adolescent Tuberculosis: A Multicenter Retrospective Study in China","volume":"114","author":"Zhou","year":"2026","journal-title":"Diagn. Microbiol. Infect. Dis."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"810","DOI":"10.1056\/NEJMoa2119430","article-title":"Bedaquiline\u2013Pretomanid\u2013Linezolid Regimens for Drug-Resistant Tuberculosis","volume":"387","author":"Conradie","year":"2022","journal-title":"N. Engl. J. Med."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1097\/INF.0000000000001532","article-title":"Serious Adverse Reactions from Anti-Tuberculosis Drugs among 599 Children Hospitalized for Tuberculosis","volume":"36","author":"Li","year":"2017","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/S1665-2681(19)31492-9","article-title":"Hepatic Dysfunction in Children with Tuberculosis on Treatment with Antituberculous Therapy","volume":"11","author":"Mansukhani","year":"2012","journal-title":"Ann. Hepatol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.2147\/PPA.S258292","article-title":"Adherence to Anti-Tuberculosis Treatment among Pediatric Patients at Nekemte Specialized Hospital, Western Ethiopia","volume":"14","author":"Fekadu","year":"2020","journal-title":"Patient Prefer. Adherence"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1097\/INF.0000000000001721","article-title":"Better Completion of Pediatric Latent Tuberculosis Treatment Using 4 Months of Rifampin in a US-Based Tuberculosis Clinic","volume":"37","author":"Gaensbauer","year":"2018","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"2003028","DOI":"10.1183\/13993003.03028-2020","article-title":"Tuberculosis Prevention in Children: A Prospective Community-Based Study in South Africa","volume":"57","author":"Mandalakas","year":"2021","journal-title":"Eur. Respir. J."},{"key":"ref_86","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1016\/S2213-2600(24)00083-3","article-title":"Effectiveness of Preventive Treatment among Different Age Groups and Mycobacterium tuberculosis Infection Status: A Systematic Review and Individual-Participant Data Meta-Analysis of Contact Tracing Studies","volume":"12","author":"Martinez","year":"2024","journal-title":"Lancet Respir. Med."},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/S0140-6736(19)32045-8","article-title":"Challenges and Controversies in Childhood Tuberculosis","volume":"394","author":"Reuter","year":"2019","journal-title":"Lancet"},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"452","DOI":"10.5588\/ijtld.19.0712","article-title":"Tuberculosis Contact Investigation and Short-Course Preventive Therapy among Young Children in Africa","volume":"24","author":"Schwoebel","year":"2020","journal-title":"Int. J. Tuberc. Lung Dis."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"973","DOI":"10.1016\/S0140-6736(20)30166-5","article-title":"The Risk of Tuberculosis in Children after Close Exposure: A Systematic Review and Individual-Participant Meta-Analysis","volume":"395","author":"Martinez","year":"2020","journal-title":"Lancet"},{"key":"ref_90","doi-asserted-by":"crossref","unstructured":"An, Y., Teo, A.K.J., Huot, C.Y., Tieng, S., Khun, K.E., Pheng, S.H., Leng, C., Deng, S., Song, N., and Nonaka, D. (2023). \u201cThey Do Not Have Symptoms\u2014Why Do They Need to Take Medicines?\u201d Challenges in Tuberculosis Preventive Treatment among Children in Cambodia: A Qualitative Study. BMC Pulm. Med., 23.","DOI":"10.1186\/s12890-023-02379-7"},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"1264","DOI":"10.1111\/j.1365-3156.2012.03053.x","article-title":"Preventive Therapy in Children Exposed to Mycobacterium tuberculosis: Problems and Solutions","volume":"17","author":"Rutherford","year":"2012","journal-title":"Trop. Med. Int. Health"},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1733","DOI":"10.1007\/s00247-023-05606-9","article-title":"Artificial Intelligence in Paediatric Tuberculosis","volume":"53","author":"Naidoo","year":"2023","journal-title":"Pediatr. Radiol."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"e2023063949","DOI":"10.1542\/peds.2023-063949","article-title":"Pediatric Tuberculosis Infection Care Facilitators and Barriers: A Qualitative Study","volume":"153","author":"Adusumelli","year":"2024","journal-title":"Pediatrics"},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"e128","DOI":"10.1016\/S1473-3099(16)30531-X","article-title":"Barriers and Facilitators to the Uptake of Tuberculosis Diagnostic and Treatment Services by Hard-to-Reach Populations in Countries of Low and Medium Tuberculosis Incidence: A Systematic Review of Qualitative Literature","volume":"17","author":"Cremers","year":"2017","journal-title":"Lancet Infect. Dis."},{"key":"ref_95","doi-asserted-by":"crossref","unstructured":"Mindu, C., L\u00f3pez-Varela, E., Alonso-Menendez, Y., Mausse, Y., Augusto, O.J., Gondo, K., M\u00fa\u00f1oz, J., Sacarlal, J., Garc\u00eda-Basteiro, A.L., and Alonso, P.L. (2017). Caretakers\u2019 Perspectives of Paediatric TB and Implications for Care-Seeking Behaviours in Southern Mozambique. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0182213"},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"931","DOI":"10.1016\/j.socscimed.2004.10.026","article-title":"Socio-Cultural Factors Influencing Prevention and Treatment of Tuberculosis in Immigrant and Aboriginal Communities in Canada","volume":"61","author":"Gibson","year":"2005","journal-title":"Soc. Sci. Med."},{"key":"ref_97","first-page":"53","article-title":"History of BCG Vaccine","volume":"8","author":"Luca","year":"2013","journal-title":"Maedica"},{"key":"ref_98","doi-asserted-by":"crossref","unstructured":"Ottenhoff, T.H., and Kaufmann, S.H. (2012). Vaccines against Tuberculosis: Where Are We and Where Do We Need to Go?. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002607"},{"key":"ref_99","doi-asserted-by":"crossref","first-page":"698","DOI":"10.1001\/jama.1994.03510330076038","article-title":"Efficacy of BCG Vaccine in the Prevention of Tuberculosis: Meta-Analysis of the Published Literature","volume":"271","author":"Colditz","year":"1994","journal-title":"JAMA"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"277","DOI":"10.1189\/jlb.0103026","article-title":"TLR2 and TLR4 Serve Distinct Roles in the Host Immune Response against Mycobacterium bovis BCG","volume":"74","author":"Heldwein","year":"2003","journal-title":"J. Leukoc. Biol."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"6883","DOI":"10.1128\/IAI.68.12.6883-6890.2000","article-title":"Maturation of Human Dendritic Cells by Cell Wall Skeleton of Mycobacterium bovis Bacillus Calmette-Gu\u00e9rin: Involvement of Toll-Like Receptors","volume":"68","author":"Tsuji","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"956","DOI":"10.1093\/infdis\/jiu508","article-title":"Heterologous Immunological Effects of Early BCG Vaccination in Low-Birth-Weight Infants in Guinea-Bissau: A Randomized-Controlled Trial","volume":"211","author":"Jensen","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.trivac.2013.11.004","article-title":"Neonatal BCG Vaccination Is Associated with Enhanced T-Helper 1 Immune Responses to Heterologous Infant Vaccines","volume":"3","author":"Libraty","year":"2014","journal-title":"Trials Vaccinol."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"17537","DOI":"10.1073\/pnas.1202870109","article-title":"Bacille Calmette\u2013Gu\u00e9rin Induces NOD2-Dependent Nonspecific Protection from Reinfection via Epigenetic Reprogramming of Monocytes","volume":"109","author":"Kleinnijenhuis","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"e1554","DOI":"10.1093\/cid\/ciaa1235","article-title":"Inoculation Age of Bacillus Calmette-Gu\u00e9rin Tokyo-172 Strain and Vaccine-Related Adverse Reactions in Taiwan Birth Cohort of 2012\u20132017","volume":"73","author":"Huang","year":"2021","journal-title":"Clin. Infect. Dis."},{"key":"ref_106","doi-asserted-by":"crossref","unstructured":"Chen, H., Yang, X., Huang, Y., Jiao, F., Bai, H., Zhu, Y., Cui, P., Jin, H., Guo, Y., and Wang, Y. (2025). Clinical Characteristics and Genetic Features of 35 Cases of Adverse Reactions to Bacillus Calmette\u2013Gu\u00e9rin Vaccine in Children. Front. Cell. Infect. Microbiol., 15.","DOI":"10.3389\/fcimb.2025.1570382"},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"46","DOI":"10.17305\/bjbms.2004.3460","article-title":"Protective Effect of Neonatal BCG Vaccines against Tuberculous Meningitis","volume":"4","year":"2004","journal-title":"Bosn. J. Basic Med. Sci."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"1393","DOI":"10.1016\/S0140-6736(02)08353-8","article-title":"BCG-Induced Increase in Interferon-Gamma Response to Mycobacterial Antigens and Efficacy of BCG Vaccination in Malawi and the UK: Two Randomised Controlled Studies","volume":"359","author":"Black","year":"2002","journal-title":"Lancet"},{"key":"ref_109","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1093\/cid\/cit790","article-title":"Protection by BCG Vaccine against Tuberculosis: A Systematic Review of Randomized Controlled Trials","volume":"58","author":"Mangtani","year":"2014","journal-title":"Clin. Infect. Dis."},{"key":"ref_110","doi-asserted-by":"crossref","unstructured":"Thysen, S.M., Byberg, S., Pedersen, M., Rodrigues, A., Ravn, H., Martins, C., Benn, C.S., Aaby, P., and Fisker, A.B. (2014). BCG Coverage and Barriers to BCG Vaccination in Guinea-Bissau: An Observational Study. BMC Public Health, 14.","DOI":"10.1186\/1471-2458-14-1037"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"e59","DOI":"10.1016\/S1473-3099(22)00500-X","article-title":"Ending tuberculosis in a post-COVID-19 world: A person-centred, equity-oriented approach","volume":"23","author":"Ryckman","year":"2023","journal-title":"Lancet Infect. Dis."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"e585","DOI":"10.1016\/S2214-109X(19)30037-3","article-title":"Assessing Tuberculosis Control Priorities in High-Burden Settings: A Modelling Approach","volume":"7","author":"Vesga","year":"2019","journal-title":"Lancet Glob. Health"},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"e8","DOI":"10.1016\/S2352-3018(20)30299-X","article-title":"Isoniazid Preventive Therapy Plus Antiretroviral Therapy for the Prevention of Tuberculosis: A Systematic Review and Meta-Analysis of Individual Participant Data","volume":"8","author":"Ross","year":"2021","journal-title":"Lancet HIV"},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"1477","DOI":"10.2105\/AJPH.83.10.1477","article-title":"Understanding AIDS: Historical Interpretations and the Limits of Biomedical Individualism","volume":"83","author":"Fee","year":"1993","journal-title":"Am. J. Public Health"}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/2\/119\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,29]],"date-time":"2026-01-29T05:16:39Z","timestamp":1769663799000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/2\/119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,1,27]]},"references-count":114,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2026,2]]}},"alternative-id":["vaccines14020119"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14020119","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,1,27]]}}}