{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T13:00:13Z","timestamp":1792069213425,"version":"4.4.0"},"reference-count":100,"publisher":"Cambridge University Press (CUP)","license":[{"start":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T00:00:00Z","timestamp":1629244800000},"content-version":"unspecified","delay-in-days":229,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Expert Rev. Mol. Med."],"published-print":{"date-parts":[[2021]]},"abstract":"<jats:title>Abstract<\/jats:title>\n\t  <jats:sec id=\"S1462399421000107_sec_a1\">\n\t    <jats:title>Objective<\/jats:title>\n\t    <jats:p>Otitis media (OM) is a common reason for children to be prescribed antibiotics and undergo surgery but a thorough understanding of disease mechanisms is lacking. We evaluate the evidence of a dysregulated immune response in the pathogenesis of OM.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S1462399421000107_sec_a2\" sec-type=\"methods\">\n\t    <jats:title>Methods<\/jats:title>\n\t    <jats:p>A comprehensive systematic review of the literature using search terms [otitis media OR glue ear OR AOM OR OME] OR [middle ear AND (infection OR inflammation)] which were run through Medline and Embase via Ovid, including both human and animal studies. In total, 82 955 studies underwent automated filtering followed by manual screening. One hundred studies were included in the review.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S1462399421000107_sec_a3\" sec-type=\"results\">\n\t    <jats:title>Results<\/jats:title>\n\t    <jats:p>Most studies were based on in vitro or animal work. Abnormalities in pathogen detection pathways, such as Toll-like receptors, have confirmed roles in OM. The aetiology of OM, its chronic subgroups (chronic OM, persistent OM with effusion) and recurrent acute OM is complex; however, inflammatory signalling mechanisms are frequently implicated. Host epithelium likely plays a crucial role, but the characterisation of human middle ear tissue lags behind that of other anatomical subsites.<\/jats:p>\n\t  <\/jats:sec>\n\t  <jats:sec id=\"S1462399421000107_sec_a4\" sec-type=\"conclusions\">\n\t    <jats:title>Conclusions<\/jats:title>\n\t    <jats:p>Translational research for OM presently falls far behind its clinical importance. This has likely hindered the development of new diagnostic and treatment modalities. Further work is urgently required; particularly to disentangle the respective immune pathologies in the clinically observed phenotypes and thereby work towards more personalised treatments.<\/jats:p>\n\t  <\/jats:sec>","DOI":"10.1017\/erm.2021.10","type":"journal-article","created":{"date-parts":[[2021,8,18]],"date-time":"2021-08-18T05:08:12Z","timestamp":1629263292000},"source":"Crossref","is-referenced-by-count":20,"title":["Dysregulation of immune response in otitis media"],"prefix":"10.1017","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7972-7111","authenticated-orcid":false,"given":"Michael W.","family":"Mather","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4896-2324","authenticated-orcid":false,"given":"Benjamin","family":"Talks","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Ward","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colin D.","family":"Bingle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muzlifah","family":"Haniffa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Powell","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"56","published-online":{"date-parts":[[2021,8,18]]},"reference":[{"key":"S1462399421000107_ref32","doi-asserted-by":"publisher","DOI":"10.1136\/adc.82.2.165"},{"key":"S1462399421000107_ref39","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00283.2020"},{"key":"S1462399421000107_ref76","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.24022"},{"key":"S1462399421000107_ref83","doi-asserted-by":"publisher","DOI":"10.1097\/MAO.0000000000002328"},{"key":"S1462399421000107_ref89","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2014.05.009"},{"key":"S1462399421000107_ref26","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2012.06.013"},{"key":"S1462399421000107_ref90","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2017.00909"},{"key":"S1462399421000107_ref2","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/160.1.83"},{"key":"S1462399421000107_ref97","doi-asserted-by":"publisher","DOI":"10.1002\/lary.23795"},{"key":"S1462399421000107_ref65","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2008.5"},{"key":"S1462399421000107_ref72","doi-asserted-by":"publisher","DOI":"10.4161\/tisb.24997"},{"key":"S1462399421000107_ref3","doi-asserted-by":"publisher","DOI":"10.1136\/adc.85.2.91"},{"key":"S1462399421000107_ref5","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01278-12"},{"key":"S1462399421000107_ref48","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2006.01.031"},{"key":"S1462399421000107_ref54","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddt103"},{"key":"S1462399421000107_ref62","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2007.10.005"},{"key":"S1462399421000107_ref28","doi-asserted-by":"publisher","DOI":"10.1016\/S0091-6749(97)70130-1"},{"key":"S1462399421000107_ref98","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2016.07.025"},{"key":"S1462399421000107_ref45","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01012-09"},{"key":"S1462399421000107_ref81","doi-asserted-by":"publisher","DOI":"10.1038\/nri3228"},{"key":"S1462399421000107_ref12","doi-asserted-by":"publisher","DOI":"10.1177\/1753425909103170"},{"key":"S1462399421000107_ref42","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1080\/00016489950181422","article-title":"Cellular immune response of adenoidal and tonsillar lymphocytes to the P6 outer membrane protein of non-typeable Haemophilus influenzae and its relation to otitis media","volume":"119","author":"Kodama","year":"1999","journal-title":"Acta Oto-Laryngologica"},{"key":"S1462399421000107_ref68","doi-asserted-by":"publisher","DOI":"10.1038\/s41390-018-0060-6"},{"key":"S1462399421000107_ref20","doi-asserted-by":"publisher","DOI":"10.1111\/j.1462-5822.2010.01546.x"},{"key":"S1462399421000107_ref9","doi-asserted-by":"publisher","DOI":"10.1128\/iai.36.1.289-296.1982"},{"key":"S1462399421000107_ref86","doi-asserted-by":"publisher","DOI":"10.1038\/nrc.2017.118"},{"key":"S1462399421000107_ref100","unstructured":"100. Cochrane. Chronic Otitis Media Cochrane Scoping Review. Available at https:\/\/ent.cochrane.org\/sites\/ent.cochrane.org\/files\/public\/uploads\/com_scoping_document_january_2017.pdf."},{"key":"S1462399421000107_ref15","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00204-09"},{"key":"S1462399421000107_ref73","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2013.03.004"},{"key":"S1462399421000107_ref17","doi-asserted-by":"publisher","DOI":"10.1086\/593213"},{"key":"S1462399421000107_ref33","doi-asserted-by":"publisher","DOI":"10.1097\/01.mlg.0000240170.48584.73"},{"key":"S1462399421000107_ref22","doi-asserted-by":"publisher","DOI":"10.1139\/m80-093"},{"key":"S1462399421000107_ref37","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2007.094870"},{"key":"S1462399421000107_ref1","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.63"},{"key":"S1462399421000107_ref58","first-page":"94","article-title":"Absence of CCL3 compromises resolution of experimental otitis media and impairs host defense of the middle ear","volume":"63","author":"Nuyen","year":"2015","journal-title":"Journal of Investigative Medicine"},{"key":"S1462399421000107_ref78","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-38369-7"},{"key":"S1462399421000107_ref84","doi-asserted-by":"publisher","DOI":"10.1002\/dvdy.24541"},{"key":"S1462399421000107_ref82","doi-asserted-by":"publisher","DOI":"10.1016\/j.heares.2019.01.023"},{"key":"S1462399421000107_ref47","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-005-0361-8"},{"key":"S1462399421000107_ref64","article-title":"Risk factors for chronic and recurrent otitis media-a meta-analysis","volume":"9","author":"Zhang","year":"2014","journal-title":"PLoS ONE"},{"key":"S1462399421000107_ref67","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijid.2014.10.015"},{"key":"S1462399421000107_ref70","doi-asserted-by":"publisher","DOI":"10.1038\/nature12807"},{"key":"S1462399421000107_ref10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2014.00461"},{"key":"S1462399421000107_ref43","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-3038.2007.00682.x"},{"key":"S1462399421000107_ref75","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0152865"},{"key":"S1462399421000107_ref77","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2016.03.008"},{"key":"S1462399421000107_ref74","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01104-13"},{"key":"S1462399421000107_ref44","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2020.03.017"},{"key":"S1462399421000107_ref50","doi-asserted-by":"publisher","DOI":"10.1097\/INF.0b013e3182611d6b"},{"key":"S1462399421000107_ref57","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901167"},{"key":"S1462399421000107_ref85","doi-asserted-by":"publisher","DOI":"10.1136\/thoraxjnl-2012-201761"},{"key":"S1462399421000107_ref13","first-page":"2149","article-title":"Role of interleukin-10 and transforming growth factor beta 1 in otitis media with effusion","volume":"122","author":"Zhao","year":"2009","journal-title":"Chinese Medical Journal"},{"key":"S1462399421000107_ref29","doi-asserted-by":"publisher","DOI":"10.1177\/1753425919872266"},{"key":"S1462399421000107_ref56","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.0020149"},{"key":"S1462399421000107_ref19","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0b013e3181fd8ec3"},{"key":"S1462399421000107_ref34","doi-asserted-by":"publisher","DOI":"10.2500\/ajra.2016.30.4393"},{"key":"S1462399421000107_ref99","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1901299"},{"key":"S1462399421000107_ref79","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1002336"},{"key":"S1462399421000107_ref88","doi-asserted-by":"publisher","DOI":"10.1159\/000057786"},{"key":"S1462399421000107_ref92","first-page":"1627","article-title":"Expressions of MUC5AC and TNF-alpha in middle ear mucosa, and influence of anti-TNF-alpha McAb treatment on rat model of acute otitis media with effusion","volume":"18","author":"Liu","year":"2019","journal-title":"Tropical Journal of Pharmaceutical Research: TJPR"},{"key":"S1462399421000107_ref16","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0132551"},{"key":"S1462399421000107_ref35","first-page":"269","article-title":"The role of IL-8 in different types of otitis media and bacteriological correlation","volume":"6","author":"Elmorsy","year":"2010","journal-title":"The Journal of International Advanced Otology"},{"key":"S1462399421000107_ref40","doi-asserted-by":"publisher","DOI":"10.1016\/j.anai.2018.10.014"},{"key":"S1462399421000107_ref30","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/408169"},{"key":"S1462399421000107_ref18","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2172-10-45"},{"key":"S1462399421000107_ref41","doi-asserted-by":"publisher","DOI":"10.1111\/pai.12658"},{"key":"S1462399421000107_ref8","first-page":"Doc05","article-title":"Evidence and evidence gaps in the treatment of Eustachian tube dysfunction and otitis media","volume":"15","author":"Teschner","year":"2016","journal-title":"GMS Current Topics in Otorhinolaryngology \u2013 Head and Neck Surgery"},{"key":"S1462399421000107_ref21","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3182055237"},{"key":"S1462399421000107_ref6","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2019.04.041"},{"key":"S1462399421000107_ref25","doi-asserted-by":"publisher","DOI":"10.1186\/s13756-019-0533-3"},{"key":"S1462399421000107_ref51","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-0691.2010.03083.x"},{"key":"S1462399421000107_ref55","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddl403"},{"key":"S1462399421000107_ref49","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1993.tb05984.x"},{"key":"S1462399421000107_ref63","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2007.09.005"},{"key":"S1462399421000107_ref52","doi-asserted-by":"publisher","DOI":"10.1542\/peds.2007-0524"},{"key":"S1462399421000107_ref53","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.1994.tb06101.x"},{"key":"S1462399421000107_ref80","doi-asserted-by":"publisher","DOI":"10.1097\/MLG.0b013e31817924a3"},{"key":"S1462399421000107_ref87","doi-asserted-by":"publisher","DOI":"10.3109\/00016487309139710"},{"key":"S1462399421000107_ref91","doi-asserted-by":"publisher","DOI":"10.1002\/lary.23973"},{"key":"S1462399421000107_ref94","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(18)31490-9"},{"key":"S1462399421000107_ref95","doi-asserted-by":"publisher","DOI":"10.1097\/00005537-199608000-00023"},{"key":"S1462399421000107_ref93","doi-asserted-by":"publisher","DOI":"10.1001\/archoto.2009.23"},{"key":"S1462399421000107_ref14","doi-asserted-by":"publisher","DOI":"10.1038\/pr.2016.154"},{"key":"S1462399421000107_ref27","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"S1462399421000107_ref38","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2009.120121"},{"key":"S1462399421000107_ref31","doi-asserted-by":"publisher","DOI":"10.1099\/jmm.0.000155"},{"key":"S1462399421000107_ref66","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2014.05.037"},{"key":"S1462399421000107_ref59","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.00148-17"},{"key":"S1462399421000107_ref61","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2249.1999.00916.x"},{"key":"S1462399421000107_ref96","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijporl.2012.04.017"},{"key":"S1462399421000107_ref24","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00756-10"},{"key":"S1462399421000107_ref7","doi-asserted-by":"publisher","DOI":"10.3389\/fgene.2019.01176"},{"key":"S1462399421000107_ref46","doi-asserted-by":"publisher","DOI":"10.1128\/IAI.01148-08"},{"key":"S1462399421000107_ref4","doi-asserted-by":"publisher","DOI":"10.1038\/sigtrans.2017.23"},{"key":"S1462399421000107_ref36","doi-asserted-by":"publisher","DOI":"10.1136\/thx.2008.104067"},{"key":"S1462399421000107_ref60","first-page":"544","article-title":"Recent advances in otitis media with effusion","volume":"55","author":"Bernstein","year":"1985","journal-title":"Annals of Allergy, Asthma and Immunology"},{"key":"S1462399421000107_ref23","doi-asserted-by":"publisher","DOI":"10.1001\/jama.296.2.202"},{"key":"S1462399421000107_ref69","doi-asserted-by":"publisher","DOI":"10.1203\/PDR.0b013e3181eb2ecc"},{"key":"S1462399421000107_ref71","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201709-1819OC"},{"key":"S1462399421000107_ref11","doi-asserted-by":"publisher","DOI":"10.1177\/1753425910393539"}],"container-title":["Expert Reviews in Molecular Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.cambridge.org\/core\/services\/aop-cambridge-core\/content\/view\/S1462399421000107","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,22]],"date-time":"2022-06-22T08:23:39Z","timestamp":1655886219000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.cambridge.org\/core\/product\/identifier\/S1462399421000107\/type\/journal_article"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021]]},"references-count":100,"alternative-id":["S1462399421000107"],"URL":"https:\/\/doi.org\/10.1017\/erm.2021.10","relation":{},"ISSN":["1462-3994"],"issn-type":[{"value":"1462-3994","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021]]},"article-number":"e10"}}