{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T04:47:09Z","timestamp":1782276429850,"version":"3.54.5"},"reference-count":25,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,6,20]],"date-time":"2026-06-20T00:00:00Z","timestamp":1781913600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: Hypotonic\u2013hyporesponsive episode (HHE) is a recognised adverse event following immunisation (AEFI) in infants, characterised by sudden hypotonia, hyporesponsiveness, and pallor or cyanosis. Although considered benign, its abrupt and often dramatic presentation often leads to acute medical evaluation. Contemporary data on HHE are limited, and awareness among healthcare professionals needs attention. Methods: We conducted a retrospective analysis of all spontaneous reports of HHE submitted to the national pharmacovigilance centre Lareb between 1 January 2012 and 22 July 2025. Cases were included only when meeting Brighton Collaboration (BC) Level 1 criteria, requiring clear documentation of hypotonia, hyporesponsiveness, and pallor or cyanosis in children younger than 24 months. Demographic and clinical characteristics, vaccine combinations, latency, duration, seriousness, and medical care utilisation were described. Results: A total of 294 Level 1 HHE cases were identified. Most episodes followed combinations of hexavalent vaccines with pneumococcal conjugate vaccines. The median age at onset was 9 weeks, with slightly more reports involving boys. The median latency to onset was 5 h (range 4\u20138 h), and the median episode duration was 10 min (range 3\u201330 min), aligning with the historical literature. All children recovered fully, and no long-term sequelae were reported. Although HHE is clinically benign, 27% of cases were classified as serious, primarily due to hospital admission. Among non-serious cases, one third involved medical assessment or emergency services. Healthcare professionals submitted 44% of reports, notably community child health physicians. Conclusions: Contemporary Dutch pharmacovigilance data confirm that the clinical characteristics of HHE remain highly consistent with long-standig evidence. Despite its benign and self-limiting nature, HHE frequently triggers substantial medical care consumption. Improved awareness of the typical presentation, course, and prognosis, supported by the Brighton Collaboration criteria, may help clinicians recognise HHE more readily, reduce unnecessary medical consumption, and provide reassurance to caregivers.<\/jats:p>","DOI":"10.3390\/vaccines14060547","type":"journal-article","created":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:09:17Z","timestamp":1782270557000},"page":"547","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Characteristics of Hypotonic\u2013Hyporesponsive Episodes (HHEs) Following Childhood Vaccination: A 13-Year Analysis of Spontaneous Reports to the Dutch Pharmacovigilance Centre Lareb"],"prefix":"10.3390","volume":"14","author":[{"given":"Sanne","family":"Boetzkes","sequence":"first","affiliation":[{"name":"Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH \u2018s-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3815-9434","authenticated-orcid":false,"given":"Leontine van","family":"Balveren","sequence":"additional","affiliation":[{"name":"Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH \u2018s-Hertogenbosch, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8965-3224","authenticated-orcid":false,"given":"Florence","family":"van Hunsel","sequence":"additional","affiliation":[{"name":"Pharmacovigilance Centre Lareb, Goudsbloemvallei 7, 5237 MH \u2018s-Hertogenbosch, The Netherlands"},{"name":"Department of Pharmacotherapy, -Epidemiology & -Economics, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1007\/s12452-022-00278-7","article-title":"Wegrakingen na vaccinatie: Vasovagale syncope, hypotone-hyporesponsieve episode en breath holding spell","volume":"54","author":"Haaksman","year":"2022","journal-title":"JGZ Tijdschr. Voor Jeugdgezondheidsz."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6152","DOI":"10.1016\/j.vaccine.2018.08.062","article-title":"Recurrence risk of a hypotonic hyporesponsive episode in two Australian specialist immunisation clinics","volume":"36","author":"Crawford","year":"2018","journal-title":"Vaccine"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1080\/21645515.2017.1287642","article-title":"Hypotonic-hyporesponsive episodes after administration of hexavalent DTP-based combination vaccine: A description of 12 cases","volume":"13","author":"Vigo","year":"2017","journal-title":"Hum. Vaccines Immunother."},{"key":"ref_4","first-page":"E13","article-title":"Frequently asked questions on seven rare adverse events following immunization","volume":"58","author":"Zorzoli","year":"2017","journal-title":"J. Prev. Med. Hyg."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1097\/INF.0b013e318162a127","article-title":"The effect of age and dose number on the risk of collapse (hypotonic-hyporesponsive episode) after pertussis vaccination","volume":"27","year":"2008","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"5875","DOI":"10.1016\/j.vaccine.2007.04.061","article-title":"Hypotonic-hyporesponsive episode (HHE) as an adverse event following immunization in early childhood: Case definition and guidelines for data collection, analysis, and presentation","volume":"25","author":"Buettcher","year":"2007","journal-title":"Vaccine"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"7066","DOI":"10.1016\/j.vaccine.2006.07.008","article-title":"Performance of the Brighton collaboration case definition for hypotonic\u2013hyporesponsive episode (HHE) on reported collapse reactions following infant vaccinations in The Netherlands","volume":"24","author":"Bondt","year":"2006","journal-title":"Vaccine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1097\/01.inf.0000183758.15605.68","article-title":"Hypotonic-hyporesponsive episode in a 7-month-old infant after receipt of multiple vaccinations","volume":"24","author":"McPherson","year":"2005","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e52","DOI":"10.1542\/peds.106.4.e52","article-title":"Hypotonic\u2013Hyporesponsive Episodes Reported to the Vaccine Adverse Event Reporting System (VAERS), 1996\u20131998","volume":"106","author":"DuVernoy","year":"2000","journal-title":"Pediatrics"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1001\/archpedi.1997.02170400041007","article-title":"Syncope After Immunization","volume":"151","author":"Braun","year":"1997","journal-title":"Arch. Pediatr. Adolesc. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1097\/INF.0000000000003308","article-title":"Hypotonic-hyporesponsive Episodes After Diphtheria, Tetanus and Acellular Pertussis Vaccination","volume":"40","author":"Hansen","year":"2021","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1097\/INF.0000000000002162","article-title":"Rate of Recurrence of Adverse Events Following Immunization: Results of 19 Years of Surveillance in Quebec, Canada","volume":"38","author":"Zafack","year":"2009","journal-title":"Pediatr. Infect. Dis. J."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e20163707","DOI":"10.1542\/peds.2016-3707","article-title":"Risk of Recurrence of Adverse Events Following Immunization: A Systematic Review","volume":"140","author":"Zafack","year":"2017","journal-title":"Pediatrics"},{"key":"ref_14","unstructured":"Rijksinstituut voor Volksgezondheid en Milieu (2026, April 13). Rijksvaccinatieprogramma. Available online: https:\/\/rijksvaccinatieprogramma.nl\/."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"100556","DOI":"10.1016\/j.jvacx.2024.100556","article-title":"A literature review and evidence-based evaluation of the Dutch national immunisation schedule yield possibilities for improvements","volume":"20","author":"Pluijmaekers","year":"2024","journal-title":"Vaccine X"},{"key":"ref_16","unstructured":"Lareb (2026, April 13). About Lareb. Available online: https:\/\/www.lareb.nl\/en\/pages\/about-lareb."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1016\/S0264-410X(03)00511-5","article-title":"Standardized case definitions of adverse events following immunization (AEFI)","volume":"22","author":"Bonhoeffer","year":"2004","journal-title":"Vaccine"},{"key":"ref_18","first-page":"523","article-title":"Incidence of hypotonic-hyporesponsive episodes associated to the combined DTP\/Hib vaccine used in Brazilian National Immunizations Program","volume":"83","author":"Martins","year":"2007","journal-title":"J. Pediatr."},{"key":"ref_19","unstructured":"Nederlandse Vereniging voor Kindergeneeskunde (2021). Richtlijn Brief Resolved Unexplained Event (BRUE), Nederlandse Vereniging voor Kindergeneeskunde."},{"key":"ref_20","unstructured":"The Council for International Organizations of Medical Sciences (2010). Practical Aspects of Signal Detection in Pharmacovigilance. Report of CIOMS Working Group XIII, The Council for International Organizations of Medical Sciences."},{"key":"ref_21","unstructured":"(2026, April 13). Jaarrapporten Vaccins. Available online: https:\/\/www.lareb.nl\/pages\/jaarrapporten-vaccins\/."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1365","DOI":"10.1111\/bcp.15024","article-title":"Numbers of spontaneous reports: How to use and interpret?","volume":"88","author":"Kant","year":"2022","journal-title":"Br. J. Clin. Pharmacol."},{"key":"ref_23","unstructured":"Rijksinstituut voor Volksgezondheid en Milieu (2025). Vaccinatiegraad Rijksvaccinatieprogramma Nederland\u2014Verslagjaar 2025."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"385","DOI":"10.2165\/00002018-200629050-00003","article-title":"Under-reporting of adverse drug reactions: A systematic review","volume":"29","author":"Hazell","year":"2006","journal-title":"Drug Saf."},{"key":"ref_25","unstructured":"Scholl, J. (2022). Signal Detection in Pharmacovigilance: Time for a New Era?. [Ph.D. Thesis, University of Groningen]."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/6\/547\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T03:57:01Z","timestamp":1782273421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/14\/6\/547"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,20]]},"references-count":25,"journal-issue":{"issue":"6","published-online":{"date-parts":[[2026,6]]}},"alternative-id":["vaccines14060547"],"URL":"https:\/\/doi.org\/10.3390\/vaccines14060547","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,6,20]]}}}