{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T02:25:16Z","timestamp":1793413516505,"version":"4.5.0"},"reference-count":49,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,11,25]],"date-time":"2021-11-25T00:00:00Z","timestamp":1637798400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001807","name":"Funda\u00e7\u00e3o de Amparo \u00e0 Pesquisa do Estado de S\u00e3o Paulo","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001807","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Background and Aims<\/jats:title><jats:p>Congenital heart diseases (CHDs) are diagnosed in approximately 9 in 1,000 newborns, and early cardiac corrective surgery often requires partial or complete thymectomy. As the long-term effect of early thymectomy on the subsequent development of the immune system in humans has not been completely elucidated, the present study aimed to evaluate the effects of thymus removal on the functional capacity of the immune system after different periods.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A systematic review of the literature was performed using MEDLINE, EMBASE, LILACS and Scopus. The inclusion criteria were original studies that analyzed any component of the immune system in patients with CHD who had undergone thymectomy during cardiac surgery in the first years of life. The results were evaluated for the quality of evidence.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Twenty-three studies were selected and showed that patients who underwent a thymectomy in the first years of life tended to exhibit important alterations in the T cell compartment, such as fewer total T cells, CD4+, CD8+, na\u00efve and CD31+ T cells, lower TRECs, decreased diversity of the TCR repertoire and higher peripheral proliferation (increased Ki-67 expression) than controls. However, the numbers of memory T cells and Treg cells differed across the selected studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Early thymectomy, either partial or complete, may be associated with a reduction in many T cell subpopulations and TCR diversity, and these alterations may persist during long-term follow-up. Alternative solutions should be studied, either in the operative technique with partial preservation of the thymus or through the autograft of fragments of the gland.<\/jats:p><\/jats:sec><jats:sec><jats:title>Systematic Review Registration<\/jats:title><jats:p>Prospero [157188].<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2021.774780","type":"journal-article","created":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T02:33:45Z","timestamp":1638326025000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":42,"title":["Early Thymectomy Is Associated With Long-Term Impairment of the Immune System: A Systematic Review"],"prefix":"10.3389","volume":"12","author":[{"given":"Nara Vasconcelos","family":"Cavalcanti","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patr\u00edcia","family":"Palmeira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcelo Biscegli","family":"Jatene","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mayra","family":"de Barros Dorna","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Magda","family":"Carneiro-Sampaio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,11,25]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/s0735-1097(02)01886-7","article-title":"The Incidence of Congenital Heart Disease","volume":"39","author":"Hoffman","year":"2002","journal-title":"J Am Coll Cardiol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2011.08.025","article-title":"Birth Prevalence of Congenital Heart Disease Worldwide: A Systematic Review and Meta-Analysis","volume":"58","author":"van der Linde","year":"2011","journal-title":"J Am Coll Cardiol"},{"key":"B3","article-title":"Immunodeficiency Following Neonatal Thymectomy in Man","volume":"70","author":"Brearley","year":"1987","journal-title":"Clin Exp Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacc.2021.03.012","article-title":"Lifespan Perspective on Congenital Heart Disease Research: JACC State-Of-the-Art Review","volume":"77","author":"Diller","year":"2021","journal-title":"J Am Coll Cardiol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijcard.2015.04.230","article-title":"The Care of Adults With Congenital Heart Disease Across the Globe: Current Assessment and Future Perspective","volume":"195","author":"Webb","year":"2015","journal-title":"Int J Cardiol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"e0180385","DOI":"10.1371\/journal.pone.0180385","article-title":"Autoimmunity and Allergy Control in Adults Submitted to Complete Thymectomy Early in Infancy","volume":"12","author":"Silva","year":"2017","journal-title":"PLoS One"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201746971","article-title":"Human Neonatal Thymectomy Induces Altered B-Cell Responses and Autoreactivity","volume":"47","author":"van den Broek","year":"2017","journal-title":"Eur J Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1098\/rspb.1962.0048","article-title":"Effect of Neonatal Thymectomy on the Immunological Responsiveness of the Mouse","volume":"156","author":"Miller","year":"1962","journal-title":"Proc R Soc B"},{"key":"B9","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1016\/j.jaci.2016.05.014","article-title":"Early Thymectomy Leads to Premature Immunologic Ageing: An 18-Year Follow-Up","volume":"138","author":"Gudmundsdottir","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84997","article-title":"Neonatal Thymectomy Reveals Differentiation and Plasticity Within Human Naive T Cells","volume":"126","author":"van den Broek","year":"2016","journal-title":"J Clin Invest"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 202 statement: an updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.15.2008","article-title":"Meta-Analysis of Observational Studies in Epidemiology: A Proposal for Reporting. Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) Group","volume":"283","author":"Stroup","year":"2000","journal-title":"JAMA"},{"key":"B13","unstructured":"WellsG\n            SheaB\n            O\u2019connellDP\n            PetersonJ\n            WelchV\n            LososM\n          The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomized Studies in Meta-Analyses2013"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1136\/bmj.39489.470347.AD","article-title":"GRADE: An Emerging Consensus on Rating Quality of Evidence and Strength of Recommendations","volume":"336","author":"Guyatt","year":"2008","journal-title":"BMJ"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2006.03139.x","article-title":"Evidence for Extrathymic T Cell Maturation After Thymectomy in Infancy","volume":"145","author":"Torfadottir","year":"2006","journal-title":"Clin Exp Immunol"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2011-03-341396","article-title":"Long-Term Restoration of the Human T-Cell Compartment After Thymectomy During Infancy: A Role for Thymic Regeneration","volume":"118","author":"van Gent","year":"2011","journal-title":"Blood"},{"key":"B17","doi-asserted-by":"publisher","first-page":"1743","DOI":"10.1016\/j.jaci.2017.08.002","article-title":"T-Cell Receptor Sequencing Reveals Decreased Diversity 18 Years After Early Thymectomy","volume":"140","author":"Gudmundsdottir","year":"2017","journal-title":"J Allergy Clin Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-015-1174-9","article-title":"Immunologic Aging in Adults With Congenital Heart Disease: Does Infant Sternotomy Matter","volume":"36","author":"Elder","year":"2015","journal-title":"Pediatr Cardiol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtcvs.2012.12.015","article-title":"Complete But Not Partial Thymectomy in Early Infancy Reduces T Cell Mediated Immune Response: Three-Year Tracing Study After Pediatric Cardiac Surgery","volume":"145","author":"Kurobe","year":"2013","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.2741\/3896","article-title":"Effect of Thymectomy on Cellular Immune Function","volume":"16","author":"Cao","year":"2011","journal-title":"Front Biosci (Landmark Ed)"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2008.03771.x","article-title":"Longitudinal Analysis of Immune Function in the First 3 Years of Life in Thymectomized Neonates During Cardiac Surgery","volume":"154","author":"Mancebo","year":"2008","journal-title":"Clin Exp Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-5223(98)70403-9","article-title":"Neonatal Thymectomy: Does it Affect Immune Function","volume":"115","author":"Wells","year":"1998","journal-title":"J Thorac Cardiovasc Surg"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2008.08.023","article-title":"Thymectomy in Early Childhood: Significant Alterations of the CD4(+)CD45RA(+)CD62L(+) T Cell Compartment in Later Life","volume":"130","author":"Prelog","year":"2009","journal-title":"Clin Immunol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1172\/JCI39269","article-title":"Evidence of Premature Immune Aging in Patients Thymectomized During Early Childhood","volume":"119","author":"Sauce","year":"2009","journal-title":"J Clin Invest"},{"key":"B25","doi-asserted-by":"publisher","first-page":"277","DOI":"10.1016\/j.jaci.2013.08.030","article-title":"Differential Homeostatic Dynamics of Human Regulatory T-Cell Subsets Following Neonatal Thymectomy","volume":"133","author":"Schadenberg","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1203\/01.PDR.0000147735.19342.DE","article-title":"Thymic Function and Impaired Maintenance of Peripheral T Cell Populations in Children With Congenital Heart Disease and Surgical Thymectomy","volume":"57","author":"Halnon","year":"2005","journal-title":"Pediatr Res"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1201235","article-title":"Lymphopenia-Driven Homeostatic Regulation of Naive T Cells in Elderly and Thymectomized Young Adults","volume":"189","author":"Sauce","year":"2012","journal-title":"J Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00020","article-title":"IL-7 Induced Proliferation of Human Naive CD4 T-Cells Relies on Continued Thymic Activity","volume":"8","author":"Silva","year":"2017","journal-title":"Front Immunol"},{"key":"B29","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1186\/s12979-016-0058-z","article-title":"Efforts of the Human Immune System to Maintain the Peripheral CD8+ T Cell Compartment After Childhood Thymectomy","volume":"13","author":"Zlamy","year":"2016","journal-title":"Immun Ageing"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-3083.2008.02203.x","article-title":"Vbeta Usage and T Regulatory Cells in Children Following Partial or Total Thymectomy After Open Heart Surgery in Infancy","volume":"69","author":"Eysteinsdottir","year":"2009","journal-title":"Scand J Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2004.02437","article-title":"The Influence of Partial or Total Thymectomy During Open Heart Surgery in Infants on the Immune Function Later in Life","volume":"136","author":"Eysteinsdottir","year":"2004","journal-title":"Clin Exp Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1006\/clin.1996.0189","article-title":"Phenotypic and Functional Evaluation of Natural Killer Cells in Thymectomized Children","volume":"81","author":"Ramos","year":"1996","journal-title":"Clin Immunol Immunopathol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2003.07.003","article-title":"Pediatric AIDS Clinical Trials Group. Lymphocyte Subsets in Healthy Children From Birth Through 18 Years of Age: The Pediatric AIDS Clinical Trials Group P1009 Study","volume":"112","author":"Shearer","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2011.04.004","article-title":"Thymic Microenvironment Reconstitution After Postnatal Human Thymus Transplantation","volume":"140","author":"Li","year":"2011","journal-title":"Clin Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2015.04.027","article-title":"Development of Immunity in Early Life","author":"Goenka","year":"2015","journal-title":"J Infect"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1111\/sji.12435","article-title":"Healthy Preterm Newborns Show an Increased Frequency of CD4(+) CD25(high) CD127(low) FOXP3(+) Regulatory T Cells With a Naive Phenotype and High Expression of Gut-Homing Receptors","volume":"83","author":"Renn\u00f3","year":"2016","journal-title":"Scand J Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.7512","article-title":"Human Na\u00efve Regulatory T-Cells Feature High Steady State Turnover and Are Maintained by IL-7","volume":"7","author":"Silva","year":"2016","journal-title":"Oncotarget"},{"key":"B38","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1007\/s10875-020-00805-7","article-title":"Inborn Errors of Adaptive Immunity in Down Syndrome","volume":"40","author":"Verstegen","year":"2020","journal-title":"J Clin Immunol"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00447","article-title":"Thymic Epithelium Abnormalities in DiGeorge and Down Syndrome Patients Contribute to Dysregulation in T Cell Development","volume":"10","author":"Marcovecchio","year":"2019","journal-title":"Front Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-019-0180-1","article-title":"Mechanisms Underlying T Cell Ageing","volume":"19","author":"Goronzy","year":"2019","journal-title":"Nat Rev Immunol"},{"key":"B41","doi-asserted-by":"publisher","first-page":"18","DOI":"10.1038\/nm.4241","article-title":"T Memory Stem Cells in Health and Disease","volume":"23","author":"Gattinoni","year":"2017","journal-title":"Nat Med"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1007\/s00281-021-00840-5","article-title":"Dynamics of Thymus Function and T Cell Receptor Repertoire Breadth in Health and Disease","volume":"43","author":"Granadier","year":"2021","journal-title":"Semin Immunopathol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.4.1536","article-title":"T Cell Receptor Gene Deletion Circles Identify Recent Thymic Emigrants in the Peripheral T Cell Pool","volume":"96","author":"Kong","year":"1999","journal-title":"Proc Natl Acad Sci USA"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1002\/eji.200636976","article-title":"Correlation Between Recent Thymic Emigrants and CD31+ (PECAM-1) CD4+ T Cells in Normal Individuals During Aging and in Lymphopenic Children","volume":"37","author":"Junge","year":"2007","journal-title":"Eur J Immunol"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1097-4652(200003)182:3<311::AID-JCP1>3.0.CO;2-9","article-title":"The Ki67 Protein From the Known and the Unknown","volume":"182","author":"Scholzen","year":"2000","journal-title":"J\u00a0Cell Physiol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.174.11.6571","article-title":"The Many Faces of IL-7: From Lymphopoiesis to Peripheral T Cell Maintenance","volume":"174","author":"Fry","year":"2005","journal-title":"J Immunol"},{"key":"B47","doi-asserted-by":"publisher","first-page":"2294","DOI":"10.1016\/j.jaci.2018.01.037","article-title":"Long-Term Clinical Effects of Early Thymectomy: Associations With Autoimmune Diseases, Cancer, Infections, and Atopic Diseases","volume":"141","author":"Gudmundsdottir","year":"2018","journal-title":"J Allergy Clin Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fneur.2021.596859","article-title":"Thymectomy in Juvenile Myasthenia Gravis is Safe Regarding Long Term Immunological Effects","volume":"12","author":"Popperud","year":"2021","journal-title":"Front Neurol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1016\/s0091-6749(99)70431-8","article-title":"Long- Term Immunologic Effects of Thymectomy in Patients With Myasthenia Gravis","volume":"103","author":"Gerli","year":"1999","journal-title":"J Allergy Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.774780\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,1]],"date-time":"2021-12-01T02:33:49Z","timestamp":1638326029000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.774780\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,11,25]]},"references-count":49,"alternative-id":["10.3389\/fimmu.2021.774780"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.774780","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,11,25]]},"article-number":"774780"}}