{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:55:35Z","timestamp":1787068535065,"version":"build-2736575974"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T00:00:00Z","timestamp":1776124800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJERPH"],"abstract":"<jats:p>Background: The early diagnosis of pulmonary tuberculosis (PTB) remains a global challenge. While serum adenosine deaminase (ADA) has been associated with tuberculosis-related immune activation, its consistency across different regions and laboratory methods remains unclear. This study aims to evaluate group-level differences in serum ADA levels and identify factors influencing these variations. Methods: A systematic search was conducted across PubMed, Embase, and Scopus up to February 2026. A meta-analysis using a random-effects model was performed to calculate the pooled standardized mean difference (SMD), reflecting group-level differences in serum ADA levels between PTB patients and control groups. Results: Thirty-four studies were included. Serum ADA levels were significantly higher in PTB patients compared to healthy controls (SMD = 3.15, 95% CI: [2.51\u20133.79], p &lt; 0.0001) and other respiratory diseases (SMD = 2.06, 95% CI: [1.38\u20132.74], p &lt; 0.0001). Subgroup analyses revealed that geographical region and ADA measurement methods did not significantly account for the observed high heterogeneity (I2 &gt; 95%), indicating that ADA elevation was consistently observed across studies. Conclusions: Serum ADA levels were significantly elevated in patients with PTB, indicating a consistent biological association with disease status. However, given the high heterogeneity and the absence of diagnostic accuracy measures (e.g., sensitivity and specificity), these findings should not be interpreted as evidence of clinical diagnostic performance. Further diagnostic test accuracy studies are required to establish its clinical utility.<\/jats:p>","DOI":"10.3390\/ijerph23040498","type":"journal-article","created":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T12:23:56Z","timestamp":1776169436000},"page":"498","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Association of Serum ADA Levels in Pulmonary Tuberculosis: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"23","author":[{"given":"Jirarat","family":"Songsri","sequence":"first","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"},{"name":"Center of Excellence Research for Melioidosis and Microorganisms (CERMM), Walailak University, Thasala, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-4542-8980","authenticated-orcid":false,"given":"Jongkonnee","family":"Thanasai","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Mahasarakham University, Mahasarakham 44000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4768-7829","authenticated-orcid":false,"given":"Jitbanjong","family":"Tangpong","sequence":"additional","affiliation":[{"name":"School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat 80160, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anchalee","family":"Chittamma","sequence":"additional","affiliation":[{"name":"Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok 10400, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5247-166X","authenticated-orcid":false,"given":"Wiyada Kwanhian","family":"Klangbud","sequence":"additional","affiliation":[{"name":"Medical Technology Program, Faculty of Science, Nakhon Phanom University, Nakhon Phanom 48000, Thailand"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Lyon, S.M., and Rossman, M.D. (2017). Pulmonary Tuberculosis. Microbiol. Spectr., 5.","DOI":"10.1128\/microbiolspec.TNMI7-0032-2016"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3","DOI":"10.4103\/jgid.jgid_112_24","article-title":"Tuberculosis Diagnosis and Management: Recent Advances","volume":"17","author":"Shrivas","year":"2025","journal-title":"J. Glob. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"545","DOI":"10.1016\/j.jinf.2017.02.012","article-title":"Diagnostic test accuracy of adenosine deaminase for tuberculous meningitis: A systematic review and meta-analysis","volume":"74","author":"Pormohammad","year":"2017","journal-title":"J. Infect."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1258\/000456303766477011","article-title":"Diagnostic value of adenosine deaminase in tuberculous pleural effusion: A meta-analysis","volume":"40","author":"Goto","year":"2003","journal-title":"Ann. Clin. Biochem."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Zhou, R., Qiu, X., Ying, J., Yue, Y., Ruan, T., and Yu, L. (2022). Diagnostic performance of adenosine deaminase for abdominal tuberculosis: A systematic review and meta-analysis. Front. Public Health, 10.","DOI":"10.3389\/fpubh.2022.938544"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"61","DOI":"10.3329\/bjm.v35i2.70630","article-title":"Diagnostic role of serum adenosine deaminase in smear-negative pulmonary tuberculosis","volume":"35","author":"Ali","year":"2024","journal-title":"Bangladesh J. Med."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Arghir, I.A., Arghir, O.C., Otelea, M.R., Andronache, I.T., and Ion, I. (2025). Adenosine deaminase and systemic immune-inflammatory index\u2014A biomarker duet signature of pulmonary tuberculosis severity. Medicina, 61.","DOI":"10.3390\/medicina61061096"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"603","DOI":"10.1007\/s10654-010-9491-z","article-title":"Critical evaluation of the Newcastle-Ottawa scale for the assessment of the quality of nonrandomized studies in meta-analyses","volume":"25","author":"Stang","year":"2010","journal-title":"Eur. J. Epidemiol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"914","DOI":"10.1136\/bmj.39343.408449.80","article-title":"Uncertainty in heterogeneity estimates in meta-analyses","volume":"335","author":"Ioannidis","year":"2007","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1136\/bmj.315.7109.629","article-title":"Bias in meta-analysis detected by a simple, graphical test","volume":"315","author":"Egger","year":"1997","journal-title":"BMJ"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"133","DOI":"10.4103\/1687-8426.184369","article-title":"Diagnostic utility of serum adenosine deaminase level in the diagnosis of pulmonary tuberculosis","volume":"10","author":"Abdelsadek","year":"2016","journal-title":"Egypt. J. Bronchol."},{"key":"ref_14","first-page":"252","article-title":"Diagnostic value of serum adenosine deaminase level in pulmonary tuberculosis","volume":"18","author":"Afrasiabian","year":"2013","journal-title":"J. Res. Med. Sci. Off. J. Isfahan Univ. Med. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21","DOI":"10.4103\/ejcdt.ejcdt_34_20","article-title":"Usefulness of serum adenosine deaminase for diagnosing pulmonary and extrapulmonary tuberculosis","volume":"70","author":"Ahmed","year":"2021","journal-title":"Egypt. J. Chest Dis. Tuberc."},{"key":"ref_16","first-page":"763","article-title":"Adenosine deaminase activity in serum and pleural effusions of tuberculous and non-tuberculous patients","volume":"43","year":"1997","journal-title":"Biochem. Mol. Biol. Int."},{"key":"ref_17","first-page":"277","article-title":"Akci\u011fer t\u00fcberk\u00fclozunda serum adenozin deaminaz aktivitesi [Serum adenosine deaminase activity in pulmonary tuberculosis]","volume":"51","author":"Uslu","year":"2003","journal-title":"Tuberk. Toraks"},{"key":"ref_18","first-page":"64","article-title":"Diagnosis of pulmonary and extra-pulmonary tuberculosis: Role of adenosine deaminase levels in different body fluids","volume":"17","author":"Almawla","year":"2021","journal-title":"Al-Anbar Med. J."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1016\/j.ejcdt.2014.11.004","article-title":"The diagnostic value of adenosine deaminase activity in pulmonary tuberculosis: Comparison between sputum and serum","volume":"64","author":"Atta","year":"2015","journal-title":"Egypt. J. Chest Dis. Tuberc."},{"key":"ref_20","first-page":"3","article-title":"Study of Serum Adenosine Deaminase (ADA) Level in Diagnosis of Extrapulmonary and Smear Negative Tuberculosis","volume":"4","author":"Badade","year":"2015","journal-title":"Biochemistry"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1002\/(SICI)1098-2825(1999)13:5<209::AID-JCLA3>3.0.CO;2-F","article-title":"The comparison of adenosine deaminase activity values with polymerase chain reaction results in patients with tuberculosis","volume":"13","author":"Canbolat","year":"1999","journal-title":"J. Clin. Lab. Anal."},{"key":"ref_22","first-page":"20","article-title":"The Relationship Between Serum Adenosine Deaminase Levels in Lung Tuberculosis Along with Drug Resistance and the Category of Tuberculosis","volume":"9","author":"Hoca","year":"2008","journal-title":"Thorac. Res. Pract."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"607","DOI":"10.1053\/rmed.2001.1273","article-title":"The usefulness of serum adenosine deaminase 2 (ADA2) activity in adults for the diagnosis of pulmonary tuberculosis","volume":"96","author":"Conde","year":"2002","journal-title":"Respir. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"133","DOI":"10.11604\/pamj.2013.15.133.2100","article-title":"Validity of serum adenosine deaminase in diagnosis of tuberculosis","volume":"15","author":"Farazi","year":"2013","journal-title":"Pan Afr. Med. J."},{"key":"ref_25","first-page":"6","article-title":"A comparative study of serum adenosine deaminase enzyme and serum ferroxidase albumin ratio in diagnosis of pulmonary tuberculosis","volume":"4","author":"Gajwani","year":"2012","journal-title":"Int. J. Curr. Res. Rev."},{"key":"ref_26","first-page":"3449","article-title":"Serum levels of adenosine deaminase in patients with tuberculosis and inflammatory lung disease","volume":"26","author":"Gencheva","year":"2020","journal-title":"J. IMAB Annu. Proceeding (Sci. Pap.)"},{"key":"ref_27","first-page":"165","article-title":"The importance of measuring serum adenosine deaminase in tuberculosis","volume":"45","author":"Balkan","year":"2003","journal-title":"Gulhane Med. J."},{"key":"ref_28","first-page":"153","article-title":"Relationship between the activity of serum adenosine deaminase including its isozymes and lymphocyte subpopulation in patients with pulmonary tuberculosis","volume":"72","author":"Ishii","year":"1997","journal-title":"Kekkaku"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"47","DOI":"10.5152\/ttd.2011.11","article-title":"The importance of measuring the serum adenosine deaminase levels in active pulmonary tuberculosis at diagnosis and during the treatment","volume":"12","author":"Izmir","year":"2011","journal-title":"Turk. Toraks Derg."},{"key":"ref_30","first-page":"267","article-title":"A Comparative Study and Evaluation of Serum Adenosine Deaminase Activity in the Diagnosis of Pulmonary Tuberculosis","volume":"14","author":"Jain","year":"2022","journal-title":"Int. J. Pharm. Clin. Res."},{"key":"ref_31","first-page":"Cr476","article-title":"The course of serum adenosine deaminase levels in patients with pulmonary tuberculosis","volume":"12","author":"Kartaloglu","year":"2006","journal-title":"Med. Sci. Monit."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"122","DOI":"10.3904\/kjim.1988.3.2.122","article-title":"C-reactive protein, sialic acid and adenosine deaminase levels in serum and pleural fluid from patients with pleural effusion","volume":"3","author":"Kim","year":"1988","journal-title":"Korean J. Intern. Med."},{"key":"ref_33","first-page":"363","article-title":"Diagnostic utility of adenosine deaminase (ADA) activity in pleural fluid and serum of tuberculous and non-tuberculous respiratory disease patients","volume":"38","author":"Lamsal","year":"2007","journal-title":"Southeast Asian J. Trop. Med. Public Health"},{"key":"ref_34","first-page":"106","article-title":"Evaluation of Serum Adenosine Deaminase (ADA) Values for Detection of Pulmonary and Extra-pulmonary Tuberculosis","volume":"4","author":"Ninghot","year":"2017","journal-title":"Int. J. Clin. Biochem. Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"551","DOI":"10.13005\/bbra\/2068","article-title":"Serum adenosine deaminase: A novel biomarker tool for the diagnosis of tuberculosis","volume":"13","author":"Pandey","year":"2016","journal-title":"Biosci. Biotechnol. Res. Asia"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"299","DOI":"10.1111\/j.0954-6820.1984.tb05011.x","article-title":"Adenosine deaminase in the diagnosis of pleural effusions","volume":"215","author":"Pettersson","year":"1984","journal-title":"Acta Med. Scand."},{"key":"ref_37","first-page":"751","article-title":"Diagnostic significance of adenosine deaminase (ADA) activity in patients of pulmonary tuberculosis with and without pleural effusion","volume":"2","author":"Rajani","year":"2016","journal-title":"Int. J. Appl. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.ijtb.2017.08.001","article-title":"Role of serum adenosine deaminase in pulmonary tuberculosis","volume":"65","author":"Saini","year":"2018","journal-title":"Indian J. Tuberc."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"e21760","DOI":"10.5812\/jjm.21760","article-title":"Diagnostic value of serum adenosine deaminase (ADA) level for pulmonary tuberculosis","volume":"8","author":"Salmanzadeh","year":"2015","journal-title":"Jundishapur J. Microbiol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"77","DOI":"10.34172\/ajcmi.2018.16","article-title":"Diagnostic Value of Serum Adenosine Deaminase Level in Extrapulmonary Tuberculosis","volume":"5","author":"Salmanzadeh","year":"2018","journal-title":"Avicenna J. Clin. Microbiol. Infect."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1007\/s12291-023-01116-5","article-title":"Correlation of serum Adenosine Deaminase levels with microbiological parameters in Pulmonary Tuberculosis","volume":"39","author":"Sarkar","year":"2024","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"126","DOI":"10.4103\/lungindia.lungindia_395_19","article-title":"Changes of serum adenosine deaminase level in new cases of pulmonary tuberculosis before and after intensive phase treatment","volume":"37","author":"Soedarsono","year":"2020","journal-title":"Lung India"},{"key":"ref_43","first-page":"30","article-title":"Study of Adenosine Deaminase Levels in Patients of Pulmonary Tuberculosis with and Without Pleural Effusion","volume":"13","author":"Sonone","year":"2014","journal-title":"IOSR J. Dent. Med. Sci."},{"key":"ref_44","first-page":"189","article-title":"A comparative study and evaluation of serum adenosine deaminase activity in the diagnosis of pulmonary tuberculosis","volume":"21","author":"Rudresh","year":"2010","journal-title":"Biomed. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"242","DOI":"10.18231\/j.ijcbr.2023.042","article-title":"Role of serum adenosine deaminase (ADA) in the diagnosis of tuberculosis & other respiratory diseases","volume":"10","author":"Tadas","year":"2023","journal-title":"Int. J. Clin. Biochem. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1007\/BF02872407","article-title":"Study of adenosine deaminase activity in pulmonary tuberculosis and other common respiratory diseases","volume":"19","author":"Verma","year":"2004","journal-title":"Indian J. Clin. Biochem."},{"key":"ref_47","first-page":"175","article-title":"Serum adenosine deaminase activity in pulmonary tuberculosis","volume":"11","year":"2016","journal-title":"Ann. Thorac. Med."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"43","DOI":"10.3329\/akmmcj.v5i2.21132","article-title":"Adenosine deaminase in diagnosis of tuberculosis: A review","volume":"5","author":"Barua","year":"2014","journal-title":"Anwer Khan Mod. Med. Coll. J."},{"key":"ref_49","first-page":"701","article-title":"Serum adenosine deaminase activity and total antioxidant capacity in pulmonary tuberculosis and non-tuberculosis pulmonary disease","volume":"40","author":"Naderi","year":"2010","journal-title":"Turk. J. Med. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Delemarre, E.M., van Hoorn, L., Bossink, A.W.J., Drylewicz, J., Joosten, S.A., Ottenhoff, T.H.M., Akkerman, O.W., Goletti, D., Petruccioli, E., and Navarra, A. (2021). Serum Biomarker Profile Including CCL1, CXCL10, VEGF, and Adenosine Deaminase Activity Distinguishes Active From Remotely Acquired Latent Tuberculosis. Front. Immunol., 12.","DOI":"10.3389\/fimmu.2021.725447"},{"key":"ref_51","first-page":"86","article-title":"Usefulness of serum adenosine deaminase level in pulmonary tuberculosis","volume":"35","author":"Helali","year":"2011","journal-title":"Chest Heart J."},{"key":"ref_52","first-page":"117","article-title":"Serum adenosine deaminase activity: A novel test for early diagnosis of pulmonary tuberculosis","volume":"15","author":"Irfan","year":"2021","journal-title":"J. Fatima Jinnah Med. Univ."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1053\/rmed.2002.1321","article-title":"The diagnostic value of adenosine deaminase activity in sputum in pulmonary tuberculosis","volume":"96","author":"Dilmac","year":"2002","journal-title":"Respir. Med."}],"container-title":["International Journal of Environmental Research and Public Health"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1660-4601\/23\/4\/498\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,14]],"date-time":"2026-04-14T12:25:49Z","timestamp":1776169549000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1660-4601\/23\/4\/498"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,14]]},"references-count":53,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["ijerph23040498"],"URL":"https:\/\/doi.org\/10.3390\/ijerph23040498","relation":{},"ISSN":["1660-4601"],"issn-type":[{"value":"1660-4601","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,4,14]]}}}