University of Liverpool



Reduction in hospitalisations for acute gastroenteritis-associated childhood seizures since introduction of rotavirus vaccination: a time-series and change point analysis of hospital admissions in England.Daniel Hungerford (d.hungerford@liverpool.ac.uk)1,2,3,4, Neil French (french@liverpool.ac.uk)1,5, Miren Iturriza-G?mara (miren@liverpool.ac.uk)1,3, Jonathan M Read (jonathan.read@lancaster.ac.uk)3,4,6, Nigel A Cunliffe (nigelc@liverpool.ac.uk)1,7,Roberto Vivancos (roberto.vivancos@.uk)2,3,4The Centre for Global Vaccine Research, Institute of Infection and Global Health, University of Liverpool, members of Liverpool Health Partners, L69 7BE, Liverpool, UKField Services, Public Health England, L3 1DS, Liverpool, UKNIHR Health Protection Research Unit in Gastrointestinal Infections, L69 3GL, Liverpool, UKNIHR Health Protection Research Unit in Emerging and Zoonotic Infections, L69 3GL, Liverpool, UKRoyal Liverpool and Broadgreen University Hospitals NHS Trust, members of Liverpool Health Partners, L7 8XP, Liverpool, UKCentre for Health Informatics, Computing and Statistics, Lancaster Medical School, Faculty of Health and Medicine, Lancaster University, Lancaster, LA1 4YG, UKAlder Hey Children’s NHS Foundation Trust, members of Liverpool Health Partners, L12 2AP, Liverpool, UKCorrespondence to: Dr Daniel Hungerford, The Centre for Global Vaccine Research, Institute of Infection and Global Health, Ronald Ross Building, 8 West Derby Street, University of Liverpool, L69 7BE, Liverpool, UK; Email: d.hungerford@liverpool.ac.uk. Tel: 0151 795 9609Word count: 2354ABSTRACT Introduction: The incidence of severe childhood diarrhoea has fallen substantially following the introduction of rotavirus vaccine in the UK in July 2013. Since children with rotavirus infection may experience febrile and afebrile seizures, we evaluated the impact of rotavirus vaccination on seizure hospitalisations in children in England.Methods: Using data from Hospital Episode Statistics, we employed interrupted time-series analyses to assess changes in monthly hospital admissions for seizures among children aged <5 years from July 2000 to June 2017. Outcome measures comprised all seizures and febrile seizures, with and without a co-diagnosis of acute gastroenteritis (AGE). Models were adjusted for pneumococcal conjugate vaccine (PCV) introduction. Change-point analysis was used to independently identify step-changes in the time-series. Results: Among hospitalised children aged <5 years, the incidence of any seizures and febrile seizures with AGE, decreased post-vaccine introduction by 23% (95% Confidence interval [95% CI]: 11-33%) and 31% (95% CI: 19-41%), respectively. For febrile seizures with AGE, a single change-point was identified in July 2013 (95% CI: Jun 2013-Dec 2013). Reductions in seizure incidence were higher during the rotavirus-season (49%, 95% CI: 37-58%), compared to out-of-season (13%, 95% CI: -4-28%), and showed no relation to PCV introduction. There were small reductions in any seizures with any co-diagnosis (4%, 95% CI: 0-8%) and in febrile seizures with any co-diagnosis (10%, 95% CI: 2-16%). Conclusions: Rotavirus vaccination has reduced hospitalisations for seizures associated with AGE in England, providing additional evidence of population level impact of rotavirus vaccination on seizure incidence in high-income countries.Keywords: rotavirus; vaccination; gastroenteritis; paediatric; diarrhoea; seizures, pneumococcal, epidemiology, time-series; change-pointWhat is already known on this subject?In addition to symptoms of diarrhoea and vomiting, rotavirus infection may be accompanied by febrile and non-febrile seizures. Studies have reported a significant reduction in the individual risk of seizure hospitalisation following rotavirus vaccination in children <5 years of age.However, population level impact of rotavirus vaccination on hospitalised seizure incidence has not been conclusively demonstrated.What this study adds?We demonstrate that the incidence of gastroenteritis-associated hospital seizures in England has fallen since rotavirus vaccine introduction. Two independent analytical approaches provide confidence that the observed reduction in seizure hospitalisations is attributable to rotavirus vaccination.Our study provides further, strong evidence that rotavirus vaccination results in health benefit beyond prevention of gastroenteritis. BACKGROUND Prior to introduction of rotavirus vaccines into childhood immunisation programmes, rotavirus infection was the most common cause of severe gastroenteritis in children under 5 years, resulting in 40% of diarrhoea hospitalisations globally. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"h6aHveWK","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":1767,"uris":[""],"uri":[""],"itemData":{"id":1767,"type":"article-journal","title":"Global networks of rotavirus gastroenteritis, 2001-2008","container-title":"Weekly Epidemiological Record","page":"421-428","volume":"83","issue":"47","journalAbbreviation":"Wkly Epidemiol Rec","author":[{"family":"World Health Organization","given":""}],"issued":{"date-parts":[["2008",11,21]]}},"locator":"2001–2008"}],"schema":""} [1] In England, the human rotavirus vaccine Rotarix was introduced into its childhood immunisation schedule in July 2013, to be administered as two doses at 2 and 3 months of age. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vsoC7LJh","properties":{"formattedCitation":"[2]","plainCitation":"[2]","noteIndex":0},"citationItems":[{"id":14,"uris":[""],"uri":[""],"itemData":{"id":14,"type":"article-journal","title":"Rotavirus vaccine: a welcome addition to the immunisation schedule in the UK","container-title":"BMJ (Clinical research ed.)","page":"f2347","volume":"346","source":"PubMed","ISSN":"1756-1833","note":"PMID: 23587749","shortTitle":"Rotavirus vaccine","journalAbbreviation":"BMJ","language":"eng","author":[{"family":"Iturriza-Gómara","given":"Miren"},{"family":"Cunliffe","given":"Nigel"}],"issued":{"date-parts":[["2013"]]}}}],"schema":""} [2] Vaccine uptake increased rapidly, reaching over 91% for one dose by February 2014 and 94.6% by July 2016. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Eh0994y9","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":2172,"uris":[""],"uri":[""],"itemData":{"id":2172,"type":"article-journal","title":"National rotavirus immunisation programme: preliminary data for England, February 2016 to July 2016","container-title":"Health Protection Report: weekly report","collection-title":"Health Protection Report","page":"1-6","volume":"10","issue":"32","language":"English","author":[{"family":"Public Health England","given":""}],"issued":{"date-parts":[["2016",9,23]]}}}],"schema":""} [3] Since introduction, there have been large reductions in laboratory detections and hospitalisations for rotavirus gastroenteritis (RVGE), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"a10s8rt66ac","properties":{"unsorted":true,"formattedCitation":"[4\\uc0\\u8211{}6]","plainCitation":"[4–6]","noteIndex":0},"citationItems":[{"id":15,"uris":[""],"uri":[""],"itemData":{"id":15,"type":"article-journal","title":"Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales","container-title":"Journal of Infectious Diseases","page":"jiv398","source":"jid.","abstract":"Background. The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction.\nMethods. We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE–associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013–2014 rotavirus season to the rate during the prevaccination era.\nResults. In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16–.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65–.84) in all-cause AGE–associated hospitalizations in 2013–2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE–associated hospital admissions were averted in 2013–2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014–2015 season.\nConclusions. The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries.","DOI":"10.1093/infdis/jiv398","ISSN":"0022-1899, 1537-6613","note":"PMID: 26232438","journalAbbreviation":"J Infect Dis.","language":"en","author":[{"family":"Atchison","given":"Christina J."},{"family":"Stowe","given":"Julia"},{"family":"Andrews","given":"Nick"},{"family":"Collins","given":"Sarah"},{"family":"Allen","given":"David J."},{"family":"Nawaz","given":"Sameena"},{"family":"Brown","given":"David"},{"family":"Ramsay","given":"Mary E."},{"family":"Ladhani","given":"Shamez N."}],"issued":{"date-parts":[["2015",7,30]]}}},{"id":2168,"uris":[""],"uri":[""],"itemData":{"id":2168,"type":"article-journal","title":"Assessing the impacts of the first year of rotavirus vaccination in the United Kingdom","container-title":"Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin","page":"30077","volume":"20","issue":"48","source":"PubMed","abstract":"The United Kingdom (UK) added rotavirus (RV) vaccine (Rotarix GlaxoSmithKline) to the national vaccine schedule in July 2013. During the 2012-2014 rotavirus seasons, children presenting to the Bristol Royal Hospital for Children Emergency Department with gastroenteritis symptoms had stool virology analysis (real-time PCR) and clinical outcome recorded. Nosocomial cases were identified as patients with non-gastroenteritis diagnosis testing positive for rotavirus > 48h after admission. In comparison to average pre-vaccine seasons, in the first year after vaccine introduction there were 48% fewer attendances diagnosed with gastroenteritis, 53% reduction in gastroenteritis admissions and a total saving of 330 bed-days occupancy. There was an overall reduction in number of rotavirus-positive stool samples with 94% reduction in children aged under one year and a 65% reduction in those too old to have been vaccinated. In the first year after the introduction of universal vaccination against rotavirus we observed a profound reduction in gastroenteritis presentations and admissions with a substantial possible herd effect seen in older children. Extrapolating these findings to the UK population we estimate secondary healthcare savings in the first year of ca ?7.5 (€10.5) million. Ongoing surveillance will be required to determine the long-term impact of the RV immunisation programme.","DOI":"10.2807/1560-7917.ES.2015.20.48.30077","ISSN":"1560-7917","note":"PMID: 26675375","journalAbbreviation":"Euro Surveill.","language":"eng","author":[{"family":"Marlow","given":"Robin"},{"family":"Muir","given":"Peter"},{"family":"Vipond","given":"Barry"},{"family":"Lyttle","given":"Mark"},{"family":"Trotter","given":"Caroline"},{"family":"Finn","given":"Adam"}],"issued":{"date-parts":[["2015"]]}}},{"id":2071,"uris":[""],"uri":[""],"itemData":{"id":2071,"type":"article-journal","title":"Early impact of rotavirus vaccination in a large paediatric hospital in the UK","container-title":"The Journal of Hospital Infection","page":"117-120","volume":"93","issue":"2","source":"PubMed","abstract":"The impact of routine rotavirus vaccination on community-acquired (CA) and healthcare-associated (HA) rotavirus gastroenteritis (RVGE) at a large paediatric hospital, UK, was investigated over a 13-year period. A total of 1644 hospitalized children aged 0-15 years tested positive for rotavirus between July 2002 and June 2015. Interrupted time-series analysis demonstrated that, post vaccine introduction (July 2013 to June 2015), CA- and HA-RVGE hospitalizations were 83% [95% confidence interval (CI): 72-90%) and 83% (95% CI: 66-92%] lower than expected, respectively. Rotavirus vaccination has rapidly reduced the hospital rotavirus disease burden among both CA- and HA-RVGE cases.","DOI":"10.1016/j.jhin.2015.12.010","ISSN":"1532-2939","note":"PMID: 26876744","journalAbbreviation":"J. Hosp. Infect.","language":"eng","author":[{"family":"Hungerford","given":"D."},{"family":"Read","given":"J. M."},{"family":"Cooke","given":"R. P. D."},{"family":"Vivancos","given":"R."},{"family":"Iturriza-Gómara","given":"M."},{"family":"Allen","given":"D. J."},{"family":"French","given":"N."},{"family":"Cunliffe","given":"N."}],"issued":{"date-parts":[["2016",6]]}}}],"schema":""} [4–6] as well as significant reductions in less specific clinical outcomes such as hospitalisations for all-cause gastroenteritis (AGE). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"KEcVfVaP","properties":{"formattedCitation":"[4,5,7]","plainCitation":"[4,5,7]","noteIndex":0},"citationItems":[{"id":2168,"uris":[""],"uri":[""],"itemData":{"id":2168,"type":"article-journal","title":"Assessing the impacts of the first year of rotavirus vaccination in the United Kingdom","container-title":"Euro Surveillance: Bulletin Europeen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin","page":"30077","volume":"20","issue":"48","source":"PubMed","abstract":"The United Kingdom (UK) added rotavirus (RV) vaccine (Rotarix GlaxoSmithKline) to the national vaccine schedule in July 2013. During the 2012-2014 rotavirus seasons, children presenting to the Bristol Royal Hospital for Children Emergency Department with gastroenteritis symptoms had stool virology analysis (real-time PCR) and clinical outcome recorded. Nosocomial cases were identified as patients with non-gastroenteritis diagnosis testing positive for rotavirus > 48h after admission. In comparison to average pre-vaccine seasons, in the first year after vaccine introduction there were 48% fewer attendances diagnosed with gastroenteritis, 53% reduction in gastroenteritis admissions and a total saving of 330 bed-days occupancy. There was an overall reduction in number of rotavirus-positive stool samples with 94% reduction in children aged under one year and a 65% reduction in those too old to have been vaccinated. In the first year after the introduction of universal vaccination against rotavirus we observed a profound reduction in gastroenteritis presentations and admissions with a substantial possible herd effect seen in older children. Extrapolating these findings to the UK population we estimate secondary healthcare savings in the first year of ca ?7.5 (€10.5) million. Ongoing surveillance will be required to determine the long-term impact of the RV immunisation programme.","DOI":"10.2807/1560-7917.ES.2015.20.48.30077","ISSN":"1560-7917","note":"PMID: 26675375","journalAbbreviation":"Euro Surveill.","language":"eng","author":[{"family":"Marlow","given":"Robin"},{"family":"Muir","given":"Peter"},{"family":"Vipond","given":"Barry"},{"family":"Lyttle","given":"Mark"},{"family":"Trotter","given":"Caroline"},{"family":"Finn","given":"Adam"}],"issued":{"date-parts":[["2015"]]}}},{"id":15,"uris":[""],"uri":[""],"itemData":{"id":15,"type":"article-journal","title":"Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales","container-title":"Journal of Infectious Diseases","page":"jiv398","source":"jid.","abstract":"Background. The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction.\nMethods. We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE–associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013–2014 rotavirus season to the rate during the prevaccination era.\nResults. In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16–.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65–.84) in all-cause AGE–associated hospitalizations in 2013–2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE–associated hospital admissions were averted in 2013–2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014–2015 season.\nConclusions. The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries.","DOI":"10.1093/infdis/jiv398","ISSN":"0022-1899, 1537-6613","note":"PMID: 26232438","journalAbbreviation":"J Infect Dis.","language":"en","author":[{"family":"Atchison","given":"Christina J."},{"family":"Stowe","given":"Julia"},{"family":"Andrews","given":"Nick"},{"family":"Collins","given":"Sarah"},{"family":"Allen","given":"David J."},{"family":"Nawaz","given":"Sameena"},{"family":"Brown","given":"David"},{"family":"Ramsay","given":"Mary E."},{"family":"Ladhani","given":"Shamez N."}],"issued":{"date-parts":[["2015",7,30]]}}},{"id":4522,"uris":[""],"uri":[""],"itemData":{"id":4522,"type":"article-journal","title":"Rotavirus vaccine impact and socioeconomic deprivation: an interrupted time-series analysis of gastrointestinal disease outcomes across primary and secondary care in the UK","container-title":"BMC medicine","page":"10","volume":"16","issue":"1","source":"PubMed","abstract":"BACKGROUND: Rotavirus causes severe gastroenteritis in infants and young children worldwide. The UK introduced the monovalent rotavirus vaccine (Rotarix?) in July 2013. Vaccination is free of charge to parents, with two doses delivered at 8 and 12?weeks of age. We evaluated vaccine impact across a health system in relation to socioeconomic deprivation.\nMETHODS: We used interrupted time-series analyses to assess changes in monthly health-care attendances in Merseyside, UK, for all ages, from July 2013 to June 2016, compared to predicted counterfactual attendances without vaccination spanning 3-11 years pre-vaccine. Outcome measures included laboratory-confirmed rotavirus gastroenteritis (RVGE) hospitalisations, acute gastroenteritis (AGE) hospitalisations, emergency department (ED) attendances for gastrointestinal conditions and consultations for infectious gastroenteritis at community walk-in centres (WIC) and general practices (GP). All analyses were stratified by age. Hospitalisations were additionally stratified by vaccine uptake and small-area-level socioeconomic deprivation.\nRESULTS: The uptake of the first and second doses of rotavirus vaccine was 91.4% (29,108/31,836) and 86.7% (27,594/31,836), respectively. Among children aged <?5?years, the incidence of gastrointestinal disease decreased across all outcomes post-vaccine introduction: 80% (95% confidence interval [CI] 70-87%; p?<?0.001) for RVGE hospitalisation, 44% (95% CI 35-53%; p?<?0.001) for AGE hospitalisations, 23% (95% CI 11-33%; p?<?0.001) for ED, 32% (95% CI 7-50%; p?=?0.02) for WIC and 13% (95% CI -3-26%; p?=?0.10) for GP. The impact was greatest during the rotavirus season and for vaccine-eligible age groups. In adults aged 65+ years, AGE hospitalisations fell by 25% (95% CI 19-30%; p?<?0.001). The pre-vaccine risk of AGE hospitalisation was highest in the most socioeconomically deprived communities (adjusted incident rate ratio 1.57; 95% CI 1.51-1.64; p?<?0.001), as was the risk for non-vaccination (adjusted risk ratio 1.54; 95% CI 1.34-1.75; p?<?0.001). The rate of AGE hospitalisations averted per 1,000 first doses of vaccine was higher among infants in the most deprived communities compared to the least deprived in 2014/15 (28; 95% CI 25-31 vs. 15; 95% CI 12-17) and in 2015/16 (26; 95% CI 23-30 vs. 13; 95% CI 11-16).\nCONCLUSIONS: Following the introduction of rotavirus vaccination, incidence of gastrointestinal disease reduced across the health-care system. Vaccine impact was greatest among the most deprived populations, despite lower vaccine uptake. Prioritising vaccine uptake in socioeconomically deprived communities should give the greatest health benefit in terms of population disease burden.","DOI":"10.1186/s12916-017-0989-z","ISSN":"1741-7015","note":"PMID: 29375036","shortTitle":"Rotavirus vaccine impact and socioeconomic deprivation","journalAbbreviation":"BMC Med","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Vivancos","given":"Roberto"},{"family":"Read","given":"Jonathan M."},{"family":"Iturriza-G?mara","given":"Miren"},{"family":"French","given":"Neil"},{"family":"Cunliffe","given":"Nigel A."}],"issued":{"date-parts":[["2018",1,29]]}}}],"schema":""} [4,5,7] In addition to the commonly associated symptoms of diarrhoea and vomiting, rotavirus infection is also associated with childhood seizures. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"Wf3XdvXF","properties":{"formattedCitation":"[8]","plainCitation":"[8]","noteIndex":0},"citationItems":[{"id":4842,"uris":[""],"uri":[""],"itemData":{"id":4842,"type":"article-journal","title":"Rotavirus gastroenteritis and seizures in young children","container-title":"Pediatric Neurology","page":"404-408","volume":"42","issue":"6","source":"PubMed","abstract":"In this retrospective cohort study, a clinical and administrative database of children hospitalized at Primary Children's Medical Center, Salt Lake City, Utah, between January 1, 2002, and December 31, 2006, was used to identify those with laboratory-confirmed rotavirus infections and at least one seizure. In all, 59 children were identified, 34 of whom (58%) had no other potential medical explanation for their seizures. Of these 34 children, 23 (68%) were afebrile at seizure onset and 11 were febrile. Electroencephalography was performed for 21 of the 34 children (62%); all findings were normal, except for a child with slowing related to cerebral edema. Twenty-six of the 34 children (76%) had neuroimaging studies; all findings were normal, except for the child with cerebral edema and a child with an incidental arachnoid cyst. Twenty of the 34 children (59%) had a lumbar puncture; again, all findings were normal. All 34 children recovered uneventfully, including the 6 children who spent at least 1 day in an intensive care unit. Follow-up data on 27 of these children identified 2 children (7%) who required chronic anticonvulsant therapy. The results indicate that seizures associated with rotavirus infection are a relatively benign neurologic condition in young children. With few exceptions, neurodiagnostic studies do not influence management or outcome.","DOI":"10.1016/j.pediatrneurol.2010.03.002","ISSN":"1873-5150","note":"PMID: 20472191","journalAbbreviation":"Pediatr. Neurol.","language":"eng","author":[{"family":"Lloyd","given":"Michael B."},{"family":"Lloyd","given":"Jenifer C."},{"family":"Gesteland","given":"Per H."},{"family":"Bale","given":"James F."}],"issued":{"date-parts":[["2010",6]]}}}],"schema":""} [8] A large multi-centre study in Canada showed that prior to rotavirus vaccine introduction, 7% of children hospitalised with laboratory confirmed rotavirus infection suffered seizures. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"i8DSUPO5","properties":{"formattedCitation":"[9]","plainCitation":"[9]","noteIndex":0},"citationItems":[{"id":2351,"uris":[""],"uri":[""],"itemData":{"id":2351,"type":"article-journal","title":"Substantial Morbidity for Hospitalized Children With Community-Acquired Rotavirus Infections: 2005–2007 IMPACT Surveillance in Canadian Hospitals","container-title":"The Pediatric Infectious Disease Journal","page":"879-882","volume":"29","issue":"9","source":"CrossRef","DOI":"10.1097/INF.0b013e3181e20c94","ISSN":"0891-3668","shortTitle":"Substantial Morbidity for Hospitalized Children With Community-Acquired Rotavirus Infections","language":"en","author":[{"family":"Le Saux","given":"Nicole"},{"family":"Bettinger","given":"Julie A."},{"family":"Halperin","given":"Scott A."},{"family":"Vaudry","given":"Wendy"},{"family":"Scheifele","given":"David W."}],"issued":{"date-parts":[["2010",9]]}}}],"schema":""} [9] Several studies from different countries have assessed the impact and effectiveness of rotavirus vaccine introduction on seizures with conflicting findings. In two independent studies in the United States, risk of seizure emergency department [ED] attendance and admission was shown to be reduced by 21% and 24% respectively in those who were vaccinated. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"YZuYMeVI","properties":{"formattedCitation":"[10,11]","plainCitation":"[10,11]","noteIndex":0},"citationItems":[{"id":2354,"uris":[""],"uri":[""],"itemData":{"id":2354,"type":"article-journal","title":"Protective Association Between Rotavirus Vaccination and Childhood Seizures in the Year Following Vaccination in US Children","container-title":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","page":"173-177","volume":"58","issue":"2","source":"PubMed Central","abstract":"Background\nRotavirus illness has been linked to childhood seizures. We investigated whether a protective association exists between receipt of rotavirus vaccine and being hospitalized or visiting the emergency department for seizures in the year after vaccination.\n\nMethods\nWe retrospectively analyzed a cohort of children born after 28 February 2006 (when rotavirus vaccine was licensed in the United States) and enrolled in the Vaccine Safety Datalink (VSD) through November 2009. Seizure rates from 4 to 55 weeks following last rotavirus vaccination were compared by vaccine exposure status (fully vaccinated and unvaccinated). A time-to-event analysis using a Cox proportional hazards model was performed, accounting for time-varying covariates. We calculated the relative incidence of seizure compared by vaccine exposure status during the postexposure interval.\n\nResults\nOur cohort contained VSD data on 250 601 infants, including 186 502 children fully vaccinated (74.4%) and 64 099 (25.6%) not vaccinated with rotavirus vaccine. Rates of seizures were associated with rotavirus vaccination status. After adjusting for covariates (VSD site, age at last dose, sex, and calendar month of the index date), a statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73–.91) and all seizures (RR = 0.79; 95% CI, .71–.88).\n\nConclusions\nA full course of rotavirus vaccination was statistically associated with an 18%–21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This reduction in childhood seizures complements the well-documented vaccine-related benefit of preventing US diarrhea hospitalizations.","DOI":"10.1093/cid/cit671","ISSN":"1058-4838","note":"PMID: 24265355\nPMCID: PMC4618560","journalAbbreviation":"Clin Infect Dis","author":[{"family":"Payne","given":"Daniel C."},{"family":"Baggs","given":"James"},{"family":"Zerr","given":"Danielle M."},{"family":"Klein","given":"Nicola P."},{"family":"Yih","given":"Katherine"},{"family":"Glanz","given":"Jason"},{"family":"Curns","given":"Aaron T."},{"family":"Weintraub","given":"Eric"},{"family":"Parashar","given":"Umesh D."}],"issued":{"date-parts":[["2014",1]]}},"label":"page"},{"id":4836,"uris":[""],"uri":[""],"itemData":{"id":4836,"type":"article-journal","title":"Rotavirus Vaccination Is Associated With Reduced Seizure Hospitalization Risk Among Commercially Insured US Children","container-title":"Clinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America","page":"1614-1616","volume":"67","issue":"10","source":"PubMed","abstract":"Rotavirus commonly causes diarrhea but can also cause seizures. Analysis of insurance claims for 1773295 US children with 2950 recorded seizures found that, compared to rotavirus-unvaccinated children, seizure hospitalization risk was reduced by 24% (95% confidence interval [CI], 13%-33%) and 14% (95% CI, 0%-26%) among fully and partially rotavirus-vaccinated children, respectively.","DOI":"10.1093/cid/ciy424","ISSN":"1537-6591","note":"PMID: 29788180","journalAbbreviation":"Clin. Infect. Dis.","language":"eng","author":[{"family":"Burke","given":"Rachel M."},{"family":"Tate","given":"Jacqueline E."},{"family":"Dahl","given":"Rebecca Moritz"},{"family":"Aliabadi","given":"Negar"},{"family":"Parashar","given":"Umesh D."}],"issued":{"date-parts":[["2018",10,30]]}},"label":"page"}],"schema":""} [10,11] In Australia, rotavirus vaccination was 35-38% effective at reducing febrile seizure ED attendances and admission in children under 2 years. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"k625qigV","properties":{"formattedCitation":"[12]","plainCitation":"[12]","noteIndex":0},"citationItems":[{"id":2352,"uris":[""],"uri":[""],"itemData":{"id":2352,"type":"article-journal","title":"Febrile Seizures in the Era of Rotavirus Vaccine","container-title":"Journal of the Pediatric Infectious Diseases Society","page":"206-209","volume":"5","issue":"2","source":"academic.","DOI":"10.1093/jpids/piu097","ISSN":"2048-7193","journalAbbreviation":"J Pediatric Infect Dis Soc","author":[{"family":"Sheridan","given":"Sarah L."},{"family":"Ware","given":"Robert S."},{"family":"Grimwood","given":"Keith"},{"family":"Lambert","given":"Stephen B."}],"issued":{"date-parts":[["2016",6,1]]}}}],"schema":""} [12] However, population level studies have found less convincing impact of rotavirus vaccination on seizure incidence. Analysis of a large US health database showed seizure hospital admission rates to be 1-8% lower since rotavirus vaccine introduction, and a study from Spain showed a reduction of 16-34%. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0TB9rm1E","properties":{"formattedCitation":"[13,14]","plainCitation":"[13,14]","noteIndex":0},"citationItems":[{"id":2353,"uris":[""],"uri":[""],"itemData":{"id":2353,"type":"article-journal","title":"Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures:","container-title":"The Pediatric Infectious Disease Journal","page":"769-773","volume":"34","issue":"7","source":"CrossRef","DOI":"10.1097/INF.0000000000000723","ISSN":"0891-3668","shortTitle":"Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures","language":"en","author":[{"family":"Pardo-Seco","given":"Jacobo"},{"family":"Cebey-López","given":"Miriam"},{"family":"Martinón-Torres","given":"Nazareth"},{"family":"Salas","given":"Antonio"},{"family":"Gómez-Rial","given":"José"},{"family":"Rodriguez-Tenreiro","given":"Carmen"},{"family":"Martinón-Sánchez","given":"José María"},{"family":"Martinón-Torres","given":"Federico"}],"issued":{"date-parts":[["2015",7]]}},"label":"page"},{"id":4840,"uris":[""],"uri":[""],"itemData":{"id":4840,"type":"article-journal","title":"Trends in Rate of Seizure-Associated Hospitalizations Among Children <5 Years Old Before and After Rotavirus Vaccine Introduction in the United Sates, 2000-2013","container-title":"The Journal of Infectious Diseases","page":"581-588","volume":"217","issue":"4","source":"PubMed","abstract":"Background: Rotavirus is a common cause of acute gastroenteritis and has also been associated with generalized tonic-clonic afebrile seizures. Since rotavirus vaccine introduction, hospitalizations for treatment of acute gastroenteritis have decreased. We assess whether there has been an associated decrease in seizure-associated hospitalizations.\nMethods: We used discharge codes to abstract data on seizure hospitalizations among children <5 years old from the State Inpatient Databases of the Healthcare Cost and Utilization Project. We compared seizure hospitalization rates before and after vaccine introduction, using Poisson regression, stratifying by age and by month and year of admission. We performed a time-series analysis with negative binomial models, constructed using prevaccine data from 2000 to 2006 and controlling for admission month and year.\nResults: We examined 962899 seizure hospitalizations among children <5 years old during 2000-2013. Seizure rates after vaccine introduction were lower than those before vaccine introduction by 1%-8%, and rate ratios decreased over time. Time-series analyses demonstrated a decrease in the number of seizure-coded hospitalizations in 2012 and 2013, with notable decreases in children 12-17 months and 18-23 months.\nConclusions: Our analysis provides evidence for a decrease in seizure hospitalizations following rotavirus vaccine introduction in the United States, with the greatest impact in age groups with a high rotavirus-associated disease burden and during rotavirus infection season.","DOI":"10.1093/infdis/jix589","ISSN":"1537-6613","note":"PMID: 29325147","journalAbbreviation":"J. Infect. Dis.","language":"eng","author":[{"family":"Pringle","given":"Kimberly D."},{"family":"Burke","given":"Rachel M."},{"family":"Steiner","given":"Claudia A."},{"family":"Parashar","given":"Umesh D."},{"family":"Tate","given":"Jacqueline E."}],"issued":{"date-parts":[["2018",1,30]]}},"label":"page"}],"schema":""} [13,14] However, recent studies from the UK, Portugal and Spain showed no measurable impact of rotavirus vaccination on seizure hospitalisations ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"NayqzHoA","properties":{"formattedCitation":"[15\\uc0\\u8211{}17]","plainCitation":"[15–17]","noteIndex":0},"citationItems":[{"id":4834,"uris":[""],"uri":[""],"itemData":{"id":4834,"type":"article-journal","title":"Lack of impact of rotavirus vaccination on childhood seizure hospitalizations in England - An interrupted time series analysis","container-title":"Vaccine","page":"4589-4592","volume":"36","issue":"31","source":"PubMed","abstract":"Observational studies have linked a reduction in childhood seizures (CS) to the introduction of rotavirus vaccination (RV). England is opportunely placed to explore this due to well-defined introduction, high uptake of RV and centralised Hospital Episodes Statistics recording all admissions. We investigated the association between seizures and vaccine use through interrupted time-series analysis of all CS admissions in children <3?years old (ICD-10 codes; G40?-G41?, R56.0?) during 2007-2017. We did not detect a statistically significant association between the introduction of RV and admission with febrile (p?=?0.84), afebrile (p?=?0.83) or all CS (p?=?0.93), even when limited to peak rotavirus seasonality (March). This is the first ecological study in a country that exclusively uses the monovalent vaccine. Although a negative finding, we would argue that if an effect cannot be detected at this population level then it is unlikely to be clinically or economically significant but generates hypotheses of potential non-specific effects.","DOI":"10.1016/j.vaccine.2018.06.029","ISSN":"1873-2518","note":"PMID: 29937243","journalAbbreviation":"Vaccine","language":"eng","author":[{"family":"Biggart","given":"Rachael"},{"family":"Finn","given":"Adam"},{"family":"Marlow","given":"Robin"}],"issued":{"date-parts":[["2018"]],"season":"25"}},"label":"page"},{"id":4838,"uris":[""],"uri":[""],"itemData":{"id":4838,"type":"article-journal","title":"Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5?years old in Spain","container-title":"Human Vaccines & Immunotherapeutics","page":"1534-1538","volume":"14","issue":"6","source":"PubMed","abstract":"INTRODUCTION: Up to date the impact of rotavirus (RV) vaccines on seizures has been poorly evaluated, with some studies but not all, showing different degrees of protection.\nOBJECTIVES: To assess the impact of RV vaccines on convulsions-related hospitalizations among children under 5?years of age residing in the Region of Valencia, Spain.\nMETHODS: A population-based, ecological study using the hospital discharge record (MBDS), the population-based administrative database (SIP) and the vaccine register (SIV), among Valencia Region's children <5?years old, during 2003 - 2015. Impact of vaccination on seizures-related hospitalization rates (780.3* ICD-9-MC code) was estimated by a multivariate Bayesian mixed Poisson regression model.\nRESULTS: Since RV vaccines licensure in 2007, its coverage rate increased up to around 42%. When the impact of vaccination against seizures was controlled for potential confounders in the multivariate analysis, there was a non-statistically significant protective effect.\nCONCLUSIONS: We could not find any impact of RV vaccine coverage on seizure-related hospitalizations in children <5 years.","DOI":"10.1080/21645515.2018.1435225","ISSN":"2164-554X","note":"PMID: 29393748\nPMCID: PMC6037443","journalAbbreviation":"Hum Vaccin Immunother","language":"eng","author":[{"family":"Orrico-Sánchez","given":"Alejandro"},{"family":"López-Lacort","given":"Mónica"},{"family":"Mu?oz-Quiles","given":"Cintia"},{"family":"Díez-Domingo","given":"Javier"}],"issued":{"date-parts":[["2018"]],"season":"03"}},"label":"page"},{"id":4832,"uris":[""],"uri":[""],"itemData":{"id":4832,"type":"article-journal","title":"Lack of impact of rotavirus vaccination on childhood seizure hospital attendances in Portugal - An interrupted time series analysis","container-title":"Vaccine","source":"PubMed","DOI":"10.1016/j.vaccine.2018.12.074","ISSN":"1873-2518","note":"PMID: 30661838","journalAbbreviation":"Vaccine","language":"eng","author":[{"family":"Marlow","given":"Robin"},{"family":"Finn","given":"Adam"},{"family":"Rodrigues","given":"Fernanda"}],"issued":{"date-parts":[["2019",1,17]]}},"label":"page"}],"schema":""} [15–17]. Seizures associated with laboratory confirmed rotavirus infection are likely to contribute a very small proportion of all seizures among hospitalised children. Therefore, detection of a population level impact of rotavirus vaccination using all hospitalised seizures as an endpoint will be challenging. We therefore assessed population level impact of rotavirus vaccination on hospitalised seizures in association with AGE in children in England, using interrupted time-series analysis, change-point analysis for multiple seizure related endpoints and further checks for plausible causation by analysing in- and out of-rotavirus season.METHODSData sources and case definitionsAggregated hospital admission records were extracted from Hospital Episode Statistics (HES) accessed through Public Health England (PHE). HES is a records-based system maintained by NHS digital, which contains information on all hospital admissions covering all NHS Trusts in England. Hospital episodes include codes for main diagnoses (primary diagnosis and 19 secondary diagnosis fields), which are assigned on discharge using the International Classification of Diseases, Tenth Revision (ICD-10). Seizures were defined using ICD10 codes in primary or following diagnosis fields as “febrile convulsion” (R56.0), “Other and unspecified convulsion” (R56.8 and R56.9), “Convulsions of newborn” (P90), and “Epilepsy” (G40). We could not include seizure hospitalisations with a co-diagnosis of rotavirus infection as an endpoint due to low numbers and low sensitivity of ICD10-coded rotavirus in England (Heinsbroek E, The impact of rotavirus vaccination on hospital pressures in a large paediatric hospital in the United Kingdom, NCT03271593). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"T27N3Bx5","properties":{"formattedCitation":"[18]","plainCitation":"[18]","noteIndex":0},"citationItems":[{"id":4999,"uris":[""],"uri":[""],"itemData":{"id":4999,"type":"article-journal","title":"Do hospital pressures change following rotavirus vaccine introduction? A retrospective database analysis in a large paediatric hospital in the United Kingdom","container-title":"BMJ Open","volume":"In Press","author":[{"family":"Heinsbroek","given":"Ellen"},{"family":"Hungerford","given":"Dan"},{"family":"Cooke","given":"R. P. D."},{"family":"Chowdhury","given":"M"},{"literal":"J.S Cargill"},{"family":"Bar-Zeev","given":"Naor"},{"family":"French","given":"Neil"},{"family":"Theodorou","given":"Eleni"},{"family":"Standaert","given":"Baudouin"},{"family":"Cunliffe","given":"N.A."}],"issued":{"date-parts":[["2019"]]}}}],"schema":""} [18] Because approximately 45% of AGE hospitalisations prior to rotavirus vaccine introduction were estimated to be associated with rotavirus infection, we used seizures with a co-diagnosis of AGE as our primary measure of vaccine impact on rotavirus associated seizures. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"yY75cj4Z","properties":{"formattedCitation":"[1]","plainCitation":"[1]","noteIndex":0},"citationItems":[{"id":1767,"uris":[""],"uri":[""],"itemData":{"id":1767,"type":"article-journal","title":"Global networks of rotavirus gastroenteritis, 2001-2008","container-title":"Weekly Epidemiological Record","page":"421-428","volume":"83","issue":"47","journalAbbreviation":"Wkly Epidemiol Rec","author":[{"family":"World Health Organization","given":""}],"issued":{"date-parts":[["2008",11,21]]}}}],"schema":""} [1] Study groups (seizure with any co-diagnosis or with AGE)Admission for febrile seizure (ICD10 code: R56.0) with any co-diagnosis Admission for seizure (ICD10 code: R56.0, R56.8, R56.9, P90 or G40) with any co-diagnosisAdmissions for all-cause AGE (ICD10 code: A00-A09, K52.9), ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"LMSngScJ","properties":{"unsorted":true,"formattedCitation":"[7,19]","plainCitation":"[7,19]","noteIndex":0},"citationItems":[{"id":4522,"uris":[""],"uri":[""],"itemData":{"id":4522,"type":"article-journal","title":"Rotavirus vaccine impact and socioeconomic deprivation: an interrupted time-series analysis of gastrointestinal disease outcomes across primary and secondary care in the UK","container-title":"BMC medicine","page":"10","volume":"16","issue":"1","source":"PubMed","abstract":"BACKGROUND: Rotavirus causes severe gastroenteritis in infants and young children worldwide. The UK introduced the monovalent rotavirus vaccine (Rotarix?) in July 2013. Vaccination is free of charge to parents, with two doses delivered at 8 and 12?weeks of age. We evaluated vaccine impact across a health system in relation to socioeconomic deprivation.\nMETHODS: We used interrupted time-series analyses to assess changes in monthly health-care attendances in Merseyside, UK, for all ages, from July 2013 to June 2016, compared to predicted counterfactual attendances without vaccination spanning 3-11 years pre-vaccine. Outcome measures included laboratory-confirmed rotavirus gastroenteritis (RVGE) hospitalisations, acute gastroenteritis (AGE) hospitalisations, emergency department (ED) attendances for gastrointestinal conditions and consultations for infectious gastroenteritis at community walk-in centres (WIC) and general practices (GP). All analyses were stratified by age. Hospitalisations were additionally stratified by vaccine uptake and small-area-level socioeconomic deprivation.\nRESULTS: The uptake of the first and second doses of rotavirus vaccine was 91.4% (29,108/31,836) and 86.7% (27,594/31,836), respectively. Among children aged <?5?years, the incidence of gastrointestinal disease decreased across all outcomes post-vaccine introduction: 80% (95% confidence interval [CI] 70-87%; p?<?0.001) for RVGE hospitalisation, 44% (95% CI 35-53%; p?<?0.001) for AGE hospitalisations, 23% (95% CI 11-33%; p?<?0.001) for ED, 32% (95% CI 7-50%; p?=?0.02) for WIC and 13% (95% CI -3-26%; p?=?0.10) for GP. The impact was greatest during the rotavirus season and for vaccine-eligible age groups. In adults aged 65+ years, AGE hospitalisations fell by 25% (95% CI 19-30%; p?<?0.001). The pre-vaccine risk of AGE hospitalisation was highest in the most socioeconomically deprived communities (adjusted incident rate ratio 1.57; 95% CI 1.51-1.64; p?<?0.001), as was the risk for non-vaccination (adjusted risk ratio 1.54; 95% CI 1.34-1.75; p?<?0.001). The rate of AGE hospitalisations averted per 1,000 first doses of vaccine was higher among infants in the most deprived communities compared to the least deprived in 2014/15 (28; 95% CI 25-31 vs. 15; 95% CI 12-17) and in 2015/16 (26; 95% CI 23-30 vs. 13; 95% CI 11-16).\nCONCLUSIONS: Following the introduction of rotavirus vaccination, incidence of gastrointestinal disease reduced across the health-care system. Vaccine impact was greatest among the most deprived populations, despite lower vaccine uptake. Prioritising vaccine uptake in socioeconomically deprived communities should give the greatest health benefit in terms of population disease burden.","DOI":"10.1186/s12916-017-0989-z","ISSN":"1741-7015","note":"PMID: 29375036","shortTitle":"Rotavirus vaccine impact and socioeconomic deprivation","journalAbbreviation":"BMC Med","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Vivancos","given":"Roberto"},{"family":"Read","given":"Jonathan M."},{"family":"Iturriza-G?mara","given":"Miren"},{"family":"French","given":"Neil"},{"family":"Cunliffe","given":"Nigel A."}],"issued":{"date-parts":[["2018",1,29]]}}},{"id":55,"uris":[""],"uri":[""],"itemData":{"id":55,"type":"article-journal","title":"Ecological assessment of the direct and indirect effects of routine rotavirus vaccination in Merseyside, UK using data from multiple health systems: a study protocol","container-title":"BMJ open","page":"e006161","volume":"4","issue":"11","source":"PubMed","abstract":"INTRODUCTION: Rotavirus is the most common cause of severe gastroenteritis in infants and young children worldwide. Currently 67 countries include rotavirus vaccine in childhood immunisation programmes, but uptake in Western Europe has been slow. In July 2013, rotavirus vaccine was introduced into the UK's routine childhood immunisation programme. Prior to vaccine introduction in the UK, rotavirus was estimated to result in 750,000 diarrhoea episodes and 80,000 general practice (GP) consultations each year, together with 45% and 20% of hospital admissions and emergency department attendances for acute gastroenteritis, in children under 5 years of age. This paper describes a protocol for an ecological study that will assess rotavirus vaccine impact in the UK, to inform rotavirus immunisation policy in the UK and in other Western European countries.\nMETHODS AND ANALYSIS: In Merseyside, UK, we will conduct an ecological study using a 'before and after' approach to examine changes in gastroenteritis and rotavirus incidence following the introduction of rotavirus vaccination. Data will be collected on mortality, hospital admissions, nosocomial infection, emergency department attendances, GP consultations and community health consultations to capture all healthcare providers in the region. We will assess both the direct and indirect effects of the vaccine on the study population. Comparisons of outcome indicator rates will be made in relation to vaccine uptake and socioeconomic status.\nETHICS AND DISSEMINATION: The study has been approved by NHS Research Ethics Committee, South Central-Berkshire REC Reference: 14/SC/1140. Study outputs will be disseminated through scientific conferences and peer-reviewed publications. The study will demonstrate the impact of rotavirus vaccination on the burden of disease from a complete health system perspective. It will identify key areas that require improved data collection tools to maximise the usefulness of this surveillance approach and will provide a template for vaccine evaluations using ecological methods in the UK.","DOI":"10.1136/bmjopen-2014-006161","ISSN":"2044-6055","note":"PMID: 25424995\nPMCID: PMC4248096","shortTitle":"Ecological assessment of the direct and indirect effects of routine rotavirus vaccination in Merseyside, UK using data from multiple health systems","journalAbbreviation":"BMJ Open","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Vivancos","given":"Roberto"},{"family":"French","given":"Neil"},{"family":"Iturriza-Gomara","given":"Miren"},{"family":"Cunliffe","given":"Nigel"}],"issued":{"date-parts":[["2014"]]}}}],"schema":""} [7,19] and with a diagnosis of seizure (ICD10 code: R56.0, R56.8, R56.9, P90, G40)*Admissions for all-cause AGE (ICD10 code: A00-A09, K52.9) and with a diagnosis of febrile seizure (ICD10 code: R56.0)We excluded any AGE admissions with a co-diagnosis of acute respiratory disease and pneumonia (ICD10 codes: J0-J39, J860, J869, H65-H67, G001, A403, B953, M001).In order to support attribution of a change in seizure incidence to rotavirus vaccine, we considered other widespread public health interventions that occurred during the study period. Since acute respiratory infections are associated with the majority of childhood seizures, and Pneumococcal Conjugate Vaccines (PCVs) were introduced into the UK’s childhood immunization schedule, we selected pneumonia-associated conditions as negative control endpoints. The seven valent PCV (PCV7) was introduced in the UK in September 2006; PCV7 was replaced with the 13 valent PCV (PCV13) in April 2010, with doses at 8 and 16 weeks of age and a booster at 12-13 months of age. Negative control groups (seizures with co-diagnosis of pneumonia) ICD10 codes for pneumonia were chosen based on PCV effectiveness and impact studies, local clinical audit and clinical assessment. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"vszsztC3","properties":{"formattedCitation":"[20]","plainCitation":"[20]","noteIndex":0},"citationItems":[{"id":4852,"uris":[""],"uri":[""],"itemData":{"id":4852,"type":"article-journal","title":"Additive impact of pneumococcal conjugate vaccines on pneumonia and empyema hospital admissions in England","container-title":"The Journal of Infection","page":"428-436","volume":"71","issue":"4","source":"PubMed","abstract":"OBJECTIVES: A wider spectrum 13-valent pneumococcal vaccine (PCV13) replaced PCV7 in the child immunization schedule in England from 2010. We assessed the additional impact of PCV13 over PCV7 on all-cause pneumonia and empyema admissions.\nMETHODS: We extracted Hospital Episode Statistics data from 2001 to 2014 on all-cause pneumonia (ICD-10 codes J12-18) and empyema admissions (J86.0, J86.9) for children <16 years in England. Trend analysis and rate ratios (RR) were calculated comparing the Pre-vaccine era to September 2006, the PCV7 era and the PCV13 era from April 2010.\nRESULTS: Annual hospital admissions for pneumonia and empyema were increasing in the Pre-vaccine era peaking in 2005 at 15,733 pneumonia and 382 empyema cases (158.6 and 3.9 per 100,000 children, respectively). These rates fell following PCV7 introduction in 2006 but began to climb soon afterwards until PCV13 was introduced. By 2013, admission rates for pneumonia and empyema were 102.2 and 1.9 per 100,000 children, respectively. We found no added benefit of PCV13 over PCV7 on pneumonia admissions following PCV13 introduction but there was a significant decrease in empyema admissions in children aged <2 years (RR 0.58; 95% CI 0.34-0.99).\nCONCLUSIONS: Additional serotypes covered by PCV13 may be more important in the aetiology of empyema and invasive disease than as a cause of uncomplicated pneumonia.","DOI":"10.1016/j.jinf.2015.06.011","ISSN":"1532-2742","note":"PMID: 26159503","journalAbbreviation":"J. Infect.","language":"eng","author":[{"family":"Saxena","given":"Sonia"},{"family":"Atchison","given":"Christina"},{"family":"Cecil","given":"Elizabeth"},{"family":"Sharland","given":"Mike"},{"family":"Koshy","given":"Elizabeth"},{"family":"Bottle","given":"Alex"}],"issued":{"date-parts":[["2015",10]]}}}],"schema":""} [20] For all negative control groups, admission episodes with a co-diagnosis of AGE were excluded.Admissions for seizure (ICD10 code: R56.0, R56.8, R56.9, P90, G40) with a co-diagnosis of pneumonia (ICD10 code: J12-J18, J860, J869, H65-H67, G001, A403, B953, M001)Admissions febrile seizure (ICD10 code: R56.0) with a co-diagnosis of pneumonia (ICD10 code: J12-J18, J860, J869, H65-H67, G001, A403, B953, M001)Statistical analysesStatistical analyses were conducted in R version 3.5.1 (R Development Core Team, Vienna, Austria).Rotavirus vaccine impact on seizure hospitalisations We examined monthly hospital admissions for all study groups and negative control groups using an interrupted time-series design. Firstly, to predict counterfactual numbers of admissions that would have been expected in the absence of vaccination for the vaccine period, we fitted generalised linear negative binomial models (to account for over-dispersion in the data) to pre-vaccine introduction monthly counts, offset for age-specific population denominator and adjusting for a three-level categorical variable representing PCV7 and PCV13 introduction. We adjusted for seasonal trends and minor lag 1 autocorrelation by including seasonal harmonic terms and secular trends by including a linear term for surveillance year (July to June) as explanatory variables in the models. Secondly, to quantify the percentage reduction in monthly attendances/hospitalisations, we included all data pre- and post-vaccine introduction in a second model with a binary indicator variable denoting the post-vaccine period (1st July 2013 onwards). This second model also included the same terms to adjust for seasonal and secular trends, a three level categorical variable representing PCV7 and PCV13 introduction and allowed the calculation of incidence rate ratios (IRRs). Percentage reduction was calculated as 100 ×(1-IRR). The rotavirus season in the UK occurred consistently between the months of January and May in the pre-vaccine period, with a peak occurring in early to mid-March in most years ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"g6Wd7ObO","properties":{"unsorted":true,"formattedCitation":"[21,22]","plainCitation":"[21,22]","noteIndex":0},"citationItems":[{"id":2121,"uris":[""],"uri":[""],"itemData":{"id":2121,"type":"article-journal","title":"In-season and out-of-season variation of rotavirus genotype distribution and age of infection across 12 European countries before the introduction of routine vaccination, 2007/08 to 2012/13","container-title":"Euro Surveillance: Bulletin Européen Sur Les Maladies Transmissibles = European Communicable Disease Bulletin","volume":"21","issue":"2","source":"PubMed","abstract":"The EuroRotaNet surveillance network has conducted rotavirus genotype surveillance since 2007 in 16 European countries. Using epidemiological and microbiological data from 39,786 genotyped rotavirus-positive specimens collected between September 2007 and August 2013, we assessed genotype distribution and age distribution of rotavirus gastroenteritis (RVGE) cases in and out of peak season in 12 countries which were yet to implement routine rotavirus vaccination. In multinomial multivariate logistic regression, adjusting for year, country and age, the odds of infection caused by genotype-constellation 2 DS-1-like stains (adjusted multinomial odds ratio (aM-OR)?=?1.25; 95% confidence interval (CI): 1.13-1.37; p?<?0.001), mixed or untypable genotypes (aM-OR?=?1.55; 95% CI: 1.40-1.72; p?<?0.001) and less common genotypes (aM-OR?=?2.11; 95% CI:1.78-2.51; p?<?0.001) increased out of season relative to G1P[8]. Age varied significantly between seasons; the proportion of RVGE cases younger than 12 months in the United Kingdom increased from 34% in season to 39% out of season (aM-OR?=?1.66; 95% CI: 1.20-2.30), and the proportion five?years and older increased from 9% in season to 17% out of season (aM-OR?=?2.53; 95% CI: 1.67-3.82). This study provides further understanding of the rotavirus ecology before vaccine introduction, which will help interpret epidemiological changes in countries introducing or expanding rotavirus vaccination programmes.","DOI":"10.2807/1560-7917.ES.2016.21.2.30106","ISSN":"1560-7917","note":"PMID: 26794258","journalAbbreviation":"Euro Surveill.","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Vivancos","given":"Roberto"},{"literal":"EuroRotaNet network members"},{"family":"Read","given":"Jonathan M."},{"family":"Pitzer","given":"Virginia E."},{"family":"Cunliffe","given":"Nigel"},{"family":"French","given":"Neil"},{"family":"Iturriza-Gómara","given":"Miren"}],"issued":{"date-parts":[["2016",1,14]]}}},{"id":4849,"uris":[""],"uri":[""],"itemData":{"id":4849,"type":"article-journal","title":"Impact of rotavirus vaccination on rotavirus genotype distribution and diversity in England, September 2006 to August 2016","container-title":"Eurosurveillance","page":"1700774","volume":"24","issue":"6","source":"","abstract":"Introduction Rotavirus vaccination with the live-attenuated monovalent (a G1P[8] human rotavirus strain) two-dose Rotarix vaccine was introduced in England in July 2013. Since then, there have been significant reductions in rotavirus gastroenteritis incidence. Aim We assessed the vaccine’s impact on rotavirus genotype distribution and diversity 3 years post-vaccine introduction. Methods Epidemiological and microbiological data on genotyped rotavirus-positive samples between September 2006 and August 2016 were supplied by EuroRotaNet and Public Health England. Multinomial multivariable logistic regression adjusting for year, season and age was used to quantify changes in genotype prevalence in the vaccine period. Genotype diversity was measured using the Shannon’s index (H′) and Simpson’s index of diversity (D). Results We analysed genotypes from 8,044 faecal samples. In the pre-vaccine era, G1P[8] was most prevalent, ranging from 39% (411/1,057) to 74% (527/709) per year. In the vaccine era, G1P[8] prevalence declined each season (35%, 231/654; 12%, 154/1,257; 5%, 34/726) and genotype diversity increased significantly in 6–59 months old children (H’ p &lt; 0.001: D p &lt; 0.001). In multinomial analysis, G2P[4] (adjusted multinomial odds ratio (aMOR): 9.51; 95% confidence interval (CI): 7.02–12.90), G3P[8] (aMOR: 2.83; 95% CI: 2.17–3.81), G12P[8] (aMOR: 2.46; 95% CI: 1.62–3.73) and G4P[8] (aMOR: 1.42; 95% CI: 1.02–1.96) significantly increased relative to G1P[8]. Conclusions In the context of reduced rotavirus disease incidence, genotype diversity has increased, with a relative change in the dominant genotype from G1P[8] to G2P[4] after vaccine introduction. These changes will need continued surveillance as the number and age of vaccinated birth cohorts increase in the future.","DOI":"10.2807/1560-7917.ES.2019.24.6.1700774","ISSN":"1560-7917","language":"en","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Allen","given":"David J."},{"family":"Nawaz","given":"Sameena"},{"family":"Collins","given":"Sarah"},{"family":"Ladhani","given":"Shamez"},{"family":"Vivancos","given":"Roberto"},{"family":"Iturriza-Gómara","given":"Miren"}],"issued":{"date-parts":[["2019",2,7]]}}}],"schema":""} [21,22]. We therefore examined the specificity of “seizure / febrile seizure with a co-diagnosis of AGE” group in relation to rotavirus disease by stratifying by events that occurred in-rotavirus season (January to May) and out-of-rotavirus season (June to December). For seasonal analysis, harmonic terms were replaced with a categorical term for month in the models. To examine the impact of rotavirus vaccination by age, we stratified our analyses by age group (<12 months, 12-23 months, and 24-59 months). Change point As an independent measure of potential vaccine impact we used change-point analyses of a time-series ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"gXDt2Xie","properties":{"formattedCitation":"[23\\uc0\\u8211{}26]","plainCitation":"[23–26]","noteIndex":0},"citationItems":[{"id":5097,"uris":[""],"uri":[""],"itemData":{"id":5097,"type":"article-journal","title":"Declines in Human Papillomavirus (HPV)–Associated High-Grade Cervical Lesions After Introduction of HPV Vaccines in Connecticut, United States, 2008–2015","container-title":"Clinical Infectious Diseases","page":"884-889","volume":"65","issue":"6","source":"academic-oup-com.liverpool.idm.","abstract":"Summary. Significant declines in high-grade cervical lesions have occurred among young women since 2008. The age and cohort patterns in declines suggest they a","DOI":"10.1093/cid/cix455","ISSN":"1058-4838","journalAbbreviation":"Clin Infect Dis","language":"en","author":[{"family":"Niccolai","given":"Linda M."},{"family":"Meek","given":"James I."},{"family":"Brackney","given":"Monica"},{"family":"Hadler","given":"James L."},{"family":"Sosa","given":"Lynn E."},{"family":"Weinberger","given":"Daniel M."}],"issued":{"date-parts":[["2017",9,15]]}},"label":"page"},{"id":5103,"uris":[""],"uri":[""],"itemData":{"id":5103,"type":"article-journal","title":"Association Between Local Pediatric Vaccination Rates and Patterns of Pneumococcal Disease in Adults","container-title":"The Journal of Infectious Diseases","page":"509-515","volume":"213","issue":"4","source":"PubMed Central","abstract":"Background.?Pneumococcal conjugate vaccine (PCV) is now recommended for use in adults in the United States. Because vaccination of children with PCVs protects adults from the targeted serotypes, local variations in PCV uptake among children could influence disease patterns in adults., Methods.?We obtained ZIP code–level data on invasive pneumococcal disease (IPD) from an active population-based surveillance system in Connecticut (study interval, 1998–2009) and ZIP code–level data on immunization with at least 3 or at least 4 doses of 7-valent PCV (PCV7) from the state immunization registry. We fit logistic regression models to estimate the proportion of IPD cases among adults aged >40 years that were caused by PCV7-targeted serotypes. Covariates included ZIP code–level socioeconomic indicators (eg, percentage of the population that was black and income per capita), the percentage of the population that received 3 or 4 doses of PCV7 (mean centered), and a linear spline to control for the average rate of decline across all ZIP codes., Results.?ZIP codes that had a higher proportion of children that did not complete the 4-dose PCV7 series had a higher proportion of adult IPD cases caused by PCV7 serotypes., Conclusions.?Local variations in PCV uptake (and receipt of the booster dose) might influence the effectiveness of PCVs in preventing pneumococcal disease in adults.","DOI":"10.1093/infdis/jiv431","ISSN":"0022-1899","note":"PMID: 26310307\nPMCID: PMC4721904","journalAbbreviation":"J Infect Dis","author":[{"family":"Pingali","given":"Sundia Cassandra"},{"family":"Warren","given":"Joshua L."},{"family":"Mead","given":"Aimee M."},{"family":"Sharova","given":"Nancy"},{"family":"Petit","given":"Susan"},{"family":"Weinberger","given":"Daniel M."}],"issued":{"date-parts":[["2016",2,15]]}},"label":"page"},{"id":5100,"uris":[""],"uri":[""],"itemData":{"id":5100,"type":"article-journal","title":"Adverse events following live-attenuated intranasal influenza vaccination of children with cystic fibrosis: Results from two influenza seasons","container-title":"Vaccine","page":"5019-5026","volume":"35","issue":"37","source":"ScienceDirect","abstract":"Background\nDespite the approved use of live-attenuated intranasal influenza vaccine (LAIV) for seasonal immunization of patients with cystic fibrosis (CF), many questions remain unanswered regarding the timing, duration, and types of adverse events that occur following administration of this vaccine.\nMethods\nIn 2012 and 2013, 264 LAIV doses were administered to 198 patients aged 2–19 with CF. Vaccinees were followed prospectively for 55 days after vaccination (day 0) and information on adverse events was collected. Bayesian change-point analysis was used to identify the risk period following LAIV during which participants had a higher risk of reporting adverse events. Multivariable zero-inflated Poisson regression models were then used to estimate the adjusted incidence rate ratio (aIRR) and 95% credible interval (CrI) of reporting each adverse event in the risk period versus the control period.\nResults\nThere was a higher risk of reporting serious adverse events (SAEs) (aIRR 1.45, 95% CrI (0.29, 5.17)) and solicited symptoms during days 0–6 of follow-up compared to control period days 7–55. However, most SAEs were not causally related to LAIV and the solicited symptom episodes were brief, usually lasting 1–2 days. There was no increased risk of antibiotic prescriptions for respiratory conditions in the risk vs. control periods (aIRR 0.48, 95% CrI (0.23, 0.91)).\nConclusions\nAdverse events were most common 0–6 days after LAIV administration but were generally benign and self-limiting. Pulmonary exacerbations did not increase in frequency.","DOI":"10.1016/j.vaccine.2017.07.068","ISSN":"0264-410X","shortTitle":"Adverse events following live-attenuated intranasal influenza vaccination of children with cystic fibrosis","journalAbbreviation":"Vaccine","author":[{"family":"Boikos","given":"Constantina"},{"family":"Joseph","given":"Lawrence"},{"family":"Scheifele","given":"David"},{"family":"Lands","given":"Larry C."},{"family":"De Serres","given":"Gaston"},{"family":"Papenburg","given":"Jesse"},{"family":"Winters","given":"Nicholas"},{"family":"Chilvers","given":"Mark"},{"family":"Quach","given":"Caroline"}],"issued":{"date-parts":[["2017",9,5]]}},"label":"page"},{"id":4814,"uris":[""],"uri":[""],"itemData":{"id":4814,"type":"article-journal","title":"Bayesian Model Averaging with Change Points to Assess the Impact of Vaccination and Public Health Interventions","container-title":"Epidemiology","page":"889","volume":"28","issue":"6","source":"journals.","abstract":"Background:?Pneumococcal conjugate vaccines (PCVs) prevent invasive pneumococcal disease and pneumonia. However, some low-and middle-income countries have yet to introduce PCV into their immunization programs due, in part, to lack of certainty about the potential impact. Assessing PCV benefits is challenging because specific data on pneumococcal disease are often lacking, and it can be difficult to separate the effects of factors other than the vaccine that could also affect pneumococcal disease rates.\n Methods:?We assess PCV impact by combining Bayesian model averaging with change-point models to estimate the timing and magnitude of vaccine-associated changes, while controlling for seasonality and other covariates. We applied our approach to monthly time series of age-stratified hospitalizations related to pneumococcal infection in children younger 5 years of age in the United States, Brazil, and Chile.\n Results:?Our method accurately detected changes in data in which we knew true and noteworthy changes occurred, i.e., in simulated data and for invasive pneumococcal disease. Moreover, 24 months after the vaccine introduction, we detected reductions of 14%, 9%, and 9% in the United States, Brazil, and Chile, respectively, in all-cause pneumonia (ACP) hospitalizations for age group 0 to <1 years of age.\n Conclusions:?Our approach provides a flexible and sensitive method to detect changes in disease incidence that occur after the introduction of a vaccine or other intervention, while avoiding biases that exist in current approaches to time-trend analyses.","DOI":"10.1097/EDE.0000000000000719","ISSN":"1044-3983","language":"en-US","author":[{"family":"Kürüm","given":"Esra"},{"family":"Warren","given":"Joshua L."},{"family":"Schuck-Paim","given":"Cynthia"},{"family":"Lustig","given":"Roger"},{"family":"Lewnard","given":"Joseph A."},{"family":"Fuentes","given":"Rodrigo"},{"family":"Bruhn","given":"Christian A. W."},{"family":"Taylor","given":"Robert J."},{"family":"Simonsen","given":"Lone"},{"family":"Weinberger","given":"Daniel M."}],"issued":{"date-parts":[["2017",11]]}},"label":"page"}],"schema":""} [23–26]. Unlike in interrupted time-series analysis, an intervention time point is not pre-specified in change-point time series analysis. Therefore, with fewer assumptions, change-point analysis allows the model to identify significant changes in the time-series and the timing of these changes. Using R package strucchange we used linear regression adjusting for seasonal trends and secular trends to estimate change-points through minimising the residual sum of squares. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"EO03dY7C","properties":{"formattedCitation":"[27]","plainCitation":"[27]","noteIndex":0},"citationItems":[{"id":4995,"uris":[""],"uri":[""],"itemData":{"id":4995,"type":"article-journal","title":"strucchange: An R Package for Testing for Structural Change in Linear Regression Models","container-title":"Journal of Statistical Software","page":"1-38","volume":"7","issue":"1","source":"","DOI":"10.18637/jss.v007.i02","ISSN":"1548-7660","shortTitle":"strucchange","language":"en","author":[{"family":"Zeileis","given":"Achim"},{"family":"Leisch","given":"Friedrich"},{"family":"Hornik","given":"Kurt"},{"family":"Kleiber","given":"Christian"}],"issued":{"date-parts":[["2002",1,10]]}}}],"schema":""} [27] RESULTSHospitalised seizure incidencePrior to rotavirus vaccine introduction, there were 538,071 hospital admissions for all seizures and 246,699 admissions for febrile seizures in England between July 2000 to June 2017, at a median yearly rate of 84.7 and 38.8 per 10,000 population, respectively. The three most common co-diagnoses for febrile seizures were J06.9: Acute upper respiratory infection-unspecified, J03.9: Acute tonsillitis-unspecified and B34.9: Viral infection, unspecified (Supplementary Table 1; Figure 1). Acute gastroenteritis was identified as a co-diagnosis in 3.5% (n=18,728) of all seizure hospitalisations and in 3.4% (n=8,334) of febrile seizures. Children aged 24-59 months contributed 44% (n=237,512) of seizure hospitalisations. Children aged 12-23 months contributed 47.5% (n=117,222) of febrile seizure hospitalisations. Prior to rotavirus vaccine introduction, yearly rates of hospital admission for all seizures with any diagnosis were highest in 12-23 month olds (mean: 180.7 per 10,000 population), with a mean rate of 108.6 per 10,000 population in infants <12 months old (Table 1). The rates of hospital admission were highest in 12-23 month olds across all study groups (Table 1).Time-series of hospitalised seizures With any co-diagnosis Peak seasonality of all seizures with any co-diagnosis occurred between November and March each year. There was a year-on-year increasing trend for all seizures prior to rotavirus vaccine introduction. In children 0-4 years of age, the incidence of seizure and febrile seizure hospitalisations reduced by 4% (95% CI: 0-8%; p=0.065) and 10% (95% CI 2-16%; p=0.011), respectively following rotavirus vaccination (Table 1). For all seizures this reduction was greatest in children aged 12-23 months (7%: 95% CI: 2-12%; p=0.005). There was also a reduction in febrile seizures in children age 0-4 years following PCV13 introduction (16% 95% CI: 5-26%; p=0.007). Change-points were not identified for these endpoints. With AGE co-diagnosisPeak seasonality of all seizures with a co-diagnosis of AGE occurred in March. Similar to all seizures with any co-diagnosis, hospitalisations for seizure associated with AGE increased year-on-year prior to rotavirus vaccination (Figure 2). In children 0-4 years of age, the incidence of hospitalised seizures and febrile seizures with a co-diagnosis of AGE decreased post-vaccine introduction by 23% (95% Confidence interval [95% CI]: 11-33%; p<0.001) and 31% (95% CI: 19-41%), respectively. Reductions in seizure hospitalisation incidence were highest in children aged 12-23 months (33%: 95% CI: 20-44%; p<0.001) and lowest in children aged 23-59 months (11%: 95% CI: -4-23%; p=0.136). During the rotavirus-season, seizure reductions (All seizures=43%: 95% CI: 32-52; p<0.001 and febrile seizures=49%, 95% CI: 37-58%) were greater than out of season (All seizures=5%: 95% CI: -10-18; p<0.001 and febrile seizures=13%, 95% CI: -4-28%). There were no observed changes in incidence of seizures with co-diagnosis of AGE following PCV7 and PCV13 introduction. Only a single change-point was identified, for all-seizures with a co-diagnosis of AGE in April 2013 (95% CI: March 2013-August 2013) and for febrile seizures with a co-diagnosis of AGE in July 2013 (95% CI: June 2013-December 2013).Negative control analysisHospitalised seizures with a co-diagnosis of pneumonia-associated conditions showed a seasonal peak between November and March (Supplementary Figure 1). Prior to rotavirus vaccine introduction, pneumonia-associated seizure hospitalisations displayed a downward trend. There was no detectable impact of PCV7, PCV13 or rotavirus vaccine introduction on these endpoints and no change point was identified (Table 1).DISCUSSIONWe have demonstrated that in children under the age of 5 years, substantial decreases occurred in all-cause seizure and febrile seizure-coded hospitalisations with a co-diagnosis of AGE following rotavirus vaccine introduction. Our findings provide compelling evidence that rotavirus vaccination is responsible for these reductions. Firstly, the magnitude of reduction for seizures with a co-diagnosis of AGE is consistent with previously reported reductions for all-cause hospitalised AGE. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"FSlbS0uQ","properties":{"formattedCitation":"[4,7]","plainCitation":"[4,7]","noteIndex":0},"citationItems":[{"id":15,"uris":[""],"uri":[""],"itemData":{"id":15,"type":"article-journal","title":"Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales","container-title":"Journal of Infectious Diseases","page":"jiv398","source":"jid.","abstract":"Background. The oral infant rotavirus vaccine, Rotarix, was introduced in England and Wales in July 2013. We estimated the impact on laboratory-confirmed rotavirus infections and hospitalizations for all-cause acute gastroenteritis (AGE) during the first year after introduction.\nMethods. We extracted data on laboratory-confirmed rotavirus infections (July 2000 through June 2015) and all-cause AGE–associated hospitalizations (July 2007 through June 2014) for all age groups using national databases (LabBase2 and HES). We determined the ratio of the rate during the 2013–2014 rotavirus season to the rate during the prevaccination era.\nResults. In infants, there was a 77% decline (rate ratio [RR], 0.23; 95% confidence interval [CI], .16–.32) in laboratory-confirmed rotavirus infections and a 26% decline (RR, 0.74; 95% CI, .65–.84) in all-cause AGE–associated hospitalizations in 2013–2014, compared with the prevaccination era. Large reductions were also observed in older children, adults, and older adults. We estimated that 10 884 laboratory-confirmed infections and 50 427 all-cause AGE–associated hospital admissions were averted in 2013–2014. Similar reductions have been observed for laboratory-confirmed rotavirus infections during the 2014–2015 season.\nConclusions. The rapid declines in rotavirus infection and AGE in vaccinated and unvaccinated age groups within 1 year of introducing an infant rotavirus vaccination program are far greater than expected and than previously reported by other countries.","DOI":"10.1093/infdis/jiv398","ISSN":"0022-1899, 1537-6613","note":"PMID: 26232438","journalAbbreviation":"J Infect Dis.","language":"en","author":[{"family":"Atchison","given":"Christina J."},{"family":"Stowe","given":"Julia"},{"family":"Andrews","given":"Nick"},{"family":"Collins","given":"Sarah"},{"family":"Allen","given":"David J."},{"family":"Nawaz","given":"Sameena"},{"family":"Brown","given":"David"},{"family":"Ramsay","given":"Mary E."},{"family":"Ladhani","given":"Shamez N."}],"issued":{"date-parts":[["2015",7,30]]}}},{"id":4522,"uris":[""],"uri":[""],"itemData":{"id":4522,"type":"article-journal","title":"Rotavirus vaccine impact and socioeconomic deprivation: an interrupted time-series analysis of gastrointestinal disease outcomes across primary and secondary care in the UK","container-title":"BMC medicine","page":"10","volume":"16","issue":"1","source":"PubMed","abstract":"BACKGROUND: Rotavirus causes severe gastroenteritis in infants and young children worldwide. The UK introduced the monovalent rotavirus vaccine (Rotarix?) in July 2013. Vaccination is free of charge to parents, with two doses delivered at 8 and 12?weeks of age. We evaluated vaccine impact across a health system in relation to socioeconomic deprivation.\nMETHODS: We used interrupted time-series analyses to assess changes in monthly health-care attendances in Merseyside, UK, for all ages, from July 2013 to June 2016, compared to predicted counterfactual attendances without vaccination spanning 3-11 years pre-vaccine. Outcome measures included laboratory-confirmed rotavirus gastroenteritis (RVGE) hospitalisations, acute gastroenteritis (AGE) hospitalisations, emergency department (ED) attendances for gastrointestinal conditions and consultations for infectious gastroenteritis at community walk-in centres (WIC) and general practices (GP). All analyses were stratified by age. Hospitalisations were additionally stratified by vaccine uptake and small-area-level socioeconomic deprivation.\nRESULTS: The uptake of the first and second doses of rotavirus vaccine was 91.4% (29,108/31,836) and 86.7% (27,594/31,836), respectively. Among children aged <?5?years, the incidence of gastrointestinal disease decreased across all outcomes post-vaccine introduction: 80% (95% confidence interval [CI] 70-87%; p?<?0.001) for RVGE hospitalisation, 44% (95% CI 35-53%; p?<?0.001) for AGE hospitalisations, 23% (95% CI 11-33%; p?<?0.001) for ED, 32% (95% CI 7-50%; p?=?0.02) for WIC and 13% (95% CI -3-26%; p?=?0.10) for GP. The impact was greatest during the rotavirus season and for vaccine-eligible age groups. In adults aged 65+ years, AGE hospitalisations fell by 25% (95% CI 19-30%; p?<?0.001). The pre-vaccine risk of AGE hospitalisation was highest in the most socioeconomically deprived communities (adjusted incident rate ratio 1.57; 95% CI 1.51-1.64; p?<?0.001), as was the risk for non-vaccination (adjusted risk ratio 1.54; 95% CI 1.34-1.75; p?<?0.001). The rate of AGE hospitalisations averted per 1,000 first doses of vaccine was higher among infants in the most deprived communities compared to the least deprived in 2014/15 (28; 95% CI 25-31 vs. 15; 95% CI 12-17) and in 2015/16 (26; 95% CI 23-30 vs. 13; 95% CI 11-16).\nCONCLUSIONS: Following the introduction of rotavirus vaccination, incidence of gastrointestinal disease reduced across the health-care system. Vaccine impact was greatest among the most deprived populations, despite lower vaccine uptake. Prioritising vaccine uptake in socioeconomically deprived communities should give the greatest health benefit in terms of population disease burden.","DOI":"10.1186/s12916-017-0989-z","ISSN":"1741-7015","note":"PMID: 29375036","shortTitle":"Rotavirus vaccine impact and socioeconomic deprivation","journalAbbreviation":"BMC Med","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Vivancos","given":"Roberto"},{"family":"Read","given":"Jonathan M."},{"family":"Iturriza-G?mara","given":"Miren"},{"family":"French","given":"Neil"},{"family":"Cunliffe","given":"Nigel A."}],"issued":{"date-parts":[["2018",1,29]]}}}],"schema":""} [4,7] Secondly, the reduction in seizures with a co-diagnosis of AGE was substantially higher during the rotavirus season compared to out-of-season and was higher in younger, vaccine age-eligible children. Thirdly, no impact of PCV7 and PCV13 was detected for seizures with a co-diagnosis of AGE. Fourthly, change-point analysis identified a break-point at the time of the introduction of rotavirus vaccination in the UK immunisation schedule (July 2013). Lastly, the incidence of pneumonia-associated seizures did not fall following rotavirus vaccine introduction. Our findings are biologically plausible, since rotavirus infection is associated with fever leading to seizures, and rotavirus vaccination is highly (>80%) effective in reducing hospitalised rotavirus gastroenteritis in high-income settings. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"OLAzDT74","properties":{"formattedCitation":"[28]","plainCitation":"[28]","noteIndex":0},"citationItems":[{"id":2336,"uris":[""],"uri":[""],"itemData":{"id":2336,"type":"article-journal","title":"Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies","container-title":"BMC infectious diseases","page":"569","volume":"17","issue":"1","source":"PubMed","abstract":"BACKGROUND: Rotavirus was the leading cause of acute gastroenteritis (AGE) in infants and young children prior to the introduction of routine vaccination. Since 2006 there have been two licensed vaccines available; with successful clinical trials leading the World Health Organization to recommend rotavirus vaccination for all children worldwide. In order to inform immunisation policy we have conducted a systematic review and meta-analysis of observation studies to assess population effectiveness against acute gastroenteritis.\nMETHODS: We systematically searched PubMed, Medline, Web of Science, Cinhal and Academic Search Premier and grey literature sources for studies published between January 2006 and April 2014. Studies were eligible for inclusion if they were observational measuring population effectiveness of rotavirus vaccination against health care attendances for rotavirus gastroenteritis or AGE. To evaluate study quality we use used the Newcastle-Ottawa Scale for non-randomised studies, categorising studies by risk of bias. Publication bias was assessed using funnel plots. If two or more studies reported a measure of vaccine effectiveness (VE), we conducted a random effects meta-analysis. We stratified analyses by World Bank country income level and used study quality in sensitivity analyses.\nRESULTS: We identified 30 studies, 19 were from high-income countries and 11 from middle-income countries. Vaccine effectiveness against hospitalization for laboratory confirmed rotavirus gastroenteritis was highest in high-income countries (89% VE; 95% CI 84-92%) compared to middle-income countries (74% VE; 95% CI 67-80%). Vaccine effectiveness was higher for those receiving the complete vaccine schedule (81% VE; 95% CI 75-86%) compared to partial schedule (62% VE; 95% CI 55-69%). Two studies from high-income countries measured VE against community consultations for AGE with a pooled estimate of 40% (95% CI 13-58%; 2 studies).\nCONCLUSIONS: We found strong evidence to further support the continued use of rotavirus vaccines. Vaccine effectiveness was similar to that reported in clinical trials for both high and middle-income countries. There is limited data from Low income settings at present. There was lower effectiveness against milder disease. Further studies, should continue to report effectiveness against AGE and less-severe rotavirus disease because as evidenced by pre-vaccine introduction studies this is likely to contribute the greatest burden on healthcare resources, particularly in high-income countries.","DOI":"10.1186/s12879-017-2613-4","ISSN":"1471-2334","note":"PMID: 28810833\nPMCID: PMC5556361","shortTitle":"Population effectiveness of the pentavalent and monovalent rotavirus vaccines","journalAbbreviation":"BMC Infect. Dis.","language":"eng","author":[{"family":"Hungerford","given":"Daniel"},{"family":"Smith","given":"Katie"},{"family":"Tucker","given":"Angela"},{"family":"Iturriza-Gómara","given":"Miren"},{"family":"Vivancos","given":"Roberto"},{"family":"McLeonard","given":"Catherine"},{"family":"A Cunliffe","given":"Nigel"},{"family":"French","given":"Neil"}],"issued":{"date-parts":[["2017",8,15]]}}}],"schema":""} [28].We also noted small reductions in all-cause seizures and febrile seizure-coded hospitalisations. Our data support findings from the US, Spain and Australia that reported reductions in all-cause hospital seizures following rotavirus vaccine introduction. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"suwMRCUd","properties":{"formattedCitation":"[10,12\\uc0\\u8211{}14]","plainCitation":"[10,12–14]","noteIndex":0},"citationItems":[{"id":2354,"uris":[""],"uri":[""],"itemData":{"id":2354,"type":"article-journal","title":"Protective Association Between Rotavirus Vaccination and Childhood Seizures in the Year Following Vaccination in US Children","container-title":"Clinical infectious diseases : an official publication of the Infectious Diseases Society of America","page":"173-177","volume":"58","issue":"2","source":"PubMed Central","abstract":"Background\nRotavirus illness has been linked to childhood seizures. We investigated whether a protective association exists between receipt of rotavirus vaccine and being hospitalized or visiting the emergency department for seizures in the year after vaccination.\n\nMethods\nWe retrospectively analyzed a cohort of children born after 28 February 2006 (when rotavirus vaccine was licensed in the United States) and enrolled in the Vaccine Safety Datalink (VSD) through November 2009. Seizure rates from 4 to 55 weeks following last rotavirus vaccination were compared by vaccine exposure status (fully vaccinated and unvaccinated). A time-to-event analysis using a Cox proportional hazards model was performed, accounting for time-varying covariates. We calculated the relative incidence of seizure compared by vaccine exposure status during the postexposure interval.\n\nResults\nOur cohort contained VSD data on 250 601 infants, including 186 502 children fully vaccinated (74.4%) and 64 099 (25.6%) not vaccinated with rotavirus vaccine. Rates of seizures were associated with rotavirus vaccination status. After adjusting for covariates (VSD site, age at last dose, sex, and calendar month of the index date), a statistically significant protective association was observed between a full course of rotavirus vaccination vs no vaccination for both first-ever seizures (risk ratio [RR] = 0.82; 95% confidence interval [CI], .73–.91) and all seizures (RR = 0.79; 95% CI, .71–.88).\n\nConclusions\nA full course of rotavirus vaccination was statistically associated with an 18%–21% reduction in risk of seizure requiring hospitalization or emergency department care in the year following vaccination, compared with unvaccinated children. This reduction in childhood seizures complements the well-documented vaccine-related benefit of preventing US diarrhea hospitalizations.","DOI":"10.1093/cid/cit671","ISSN":"1058-4838","note":"PMID: 24265355\nPMCID: PMC4618560","journalAbbreviation":"Clin Infect Dis","author":[{"family":"Payne","given":"Daniel C."},{"family":"Baggs","given":"James"},{"family":"Zerr","given":"Danielle M."},{"family":"Klein","given":"Nicola P."},{"family":"Yih","given":"Katherine"},{"family":"Glanz","given":"Jason"},{"family":"Curns","given":"Aaron T."},{"family":"Weintraub","given":"Eric"},{"family":"Parashar","given":"Umesh D."}],"issued":{"date-parts":[["2014",1]]}}},{"id":2352,"uris":[""],"uri":[""],"itemData":{"id":2352,"type":"article-journal","title":"Febrile Seizures in the Era of Rotavirus Vaccine","container-title":"Journal of the Pediatric Infectious Diseases Society","page":"206-209","volume":"5","issue":"2","source":"academic.","DOI":"10.1093/jpids/piu097","ISSN":"2048-7193","journalAbbreviation":"J Pediatric Infect Dis Soc","author":[{"family":"Sheridan","given":"Sarah L."},{"family":"Ware","given":"Robert S."},{"family":"Grimwood","given":"Keith"},{"family":"Lambert","given":"Stephen B."}],"issued":{"date-parts":[["2016",6,1]]}}},{"id":2353,"uris":[""],"uri":[""],"itemData":{"id":2353,"type":"article-journal","title":"Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures:","container-title":"The Pediatric Infectious Disease Journal","page":"769-773","volume":"34","issue":"7","source":"CrossRef","DOI":"10.1097/INF.0000000000000723","ISSN":"0891-3668","shortTitle":"Impact of Rotavirus Vaccination on Childhood Hospitalization for Seizures","language":"en","author":[{"family":"Pardo-Seco","given":"Jacobo"},{"family":"Cebey-López","given":"Miriam"},{"family":"Martinón-Torres","given":"Nazareth"},{"family":"Salas","given":"Antonio"},{"family":"Gómez-Rial","given":"José"},{"family":"Rodriguez-Tenreiro","given":"Carmen"},{"family":"Martinón-Sánchez","given":"José María"},{"family":"Martinón-Torres","given":"Federico"}],"issued":{"date-parts":[["2015",7]]}}},{"id":4840,"uris":[""],"uri":[""],"itemData":{"id":4840,"type":"article-journal","title":"Trends in Rate of Seizure-Associated Hospitalizations Among Children <5 Years Old Before and After Rotavirus Vaccine Introduction in the United Sates, 2000-2013","container-title":"The Journal of Infectious Diseases","page":"581-588","volume":"217","issue":"4","source":"PubMed","abstract":"Background: Rotavirus is a common cause of acute gastroenteritis and has also been associated with generalized tonic-clonic afebrile seizures. Since rotavirus vaccine introduction, hospitalizations for treatment of acute gastroenteritis have decreased. We assess whether there has been an associated decrease in seizure-associated hospitalizations.\nMethods: We used discharge codes to abstract data on seizure hospitalizations among children <5 years old from the State Inpatient Databases of the Healthcare Cost and Utilization Project. We compared seizure hospitalization rates before and after vaccine introduction, using Poisson regression, stratifying by age and by month and year of admission. We performed a time-series analysis with negative binomial models, constructed using prevaccine data from 2000 to 2006 and controlling for admission month and year.\nResults: We examined 962899 seizure hospitalizations among children <5 years old during 2000-2013. Seizure rates after vaccine introduction were lower than those before vaccine introduction by 1%-8%, and rate ratios decreased over time. Time-series analyses demonstrated a decrease in the number of seizure-coded hospitalizations in 2012 and 2013, with notable decreases in children 12-17 months and 18-23 months.\nConclusions: Our analysis provides evidence for a decrease in seizure hospitalizations following rotavirus vaccine introduction in the United States, with the greatest impact in age groups with a high rotavirus-associated disease burden and during rotavirus infection season.","DOI":"10.1093/infdis/jix589","ISSN":"1537-6613","note":"PMID: 29325147","journalAbbreviation":"J. Infect. Dis.","language":"eng","author":[{"family":"Pringle","given":"Kimberly D."},{"family":"Burke","given":"Rachel M."},{"family":"Steiner","given":"Claudia A."},{"family":"Parashar","given":"Umesh D."},{"family":"Tate","given":"Jacqueline E."}],"issued":{"date-parts":[["2018",1,30]]}}}],"schema":""} [10,12–14] However, subsequent studies conducted in Portugal and Spain failed to document a decline in population level seizure incidence following vaccine introduction; ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"fTebl43R","properties":{"formattedCitation":"[16,17]","plainCitation":"[16,17]","noteIndex":0},"citationItems":[{"id":4838,"uris":[""],"uri":[""],"itemData":{"id":4838,"type":"article-journal","title":"Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5?years old in Spain","container-title":"Human Vaccines & Immunotherapeutics","page":"1534-1538","volume":"14","issue":"6","source":"PubMed","abstract":"INTRODUCTION: Up to date the impact of rotavirus (RV) vaccines on seizures has been poorly evaluated, with some studies but not all, showing different degrees of protection.\nOBJECTIVES: To assess the impact of RV vaccines on convulsions-related hospitalizations among children under 5?years of age residing in the Region of Valencia, Spain.\nMETHODS: A population-based, ecological study using the hospital discharge record (MBDS), the population-based administrative database (SIP) and the vaccine register (SIV), among Valencia Region's children <5?years old, during 2003 - 2015. Impact of vaccination on seizures-related hospitalization rates (780.3* ICD-9-MC code) was estimated by a multivariate Bayesian mixed Poisson regression model.\nRESULTS: Since RV vaccines licensure in 2007, its coverage rate increased up to around 42%. When the impact of vaccination against seizures was controlled for potential confounders in the multivariate analysis, there was a non-statistically significant protective effect.\nCONCLUSIONS: We could not find any impact of RV vaccine coverage on seizure-related hospitalizations in children <5 years.","DOI":"10.1080/21645515.2018.1435225","ISSN":"2164-554X","note":"PMID: 29393748\nPMCID: PMC6037443","journalAbbreviation":"Hum Vaccin Immunother","language":"eng","author":[{"family":"Orrico-Sánchez","given":"Alejandro"},{"family":"López-Lacort","given":"Mónica"},{"family":"Mu?oz-Quiles","given":"Cintia"},{"family":"Díez-Domingo","given":"Javier"}],"issued":{"date-parts":[["2018"]],"season":"03"}}},{"id":4832,"uris":[""],"uri":[""],"itemData":{"id":4832,"type":"article-journal","title":"Lack of impact of rotavirus vaccination on childhood seizure hospital attendances in Portugal - An interrupted time series analysis","container-title":"Vaccine","source":"PubMed","DOI":"10.1016/j.vaccine.2018.12.074","ISSN":"1873-2518","note":"PMID: 30661838","journalAbbreviation":"Vaccine","language":"eng","author":[{"family":"Marlow","given":"Robin"},{"family":"Finn","given":"Adam"},{"family":"Rodrigues","given":"Fernanda"}],"issued":{"date-parts":[["2019",1,17]]}}}],"schema":""} [16,17] this may be explained by low (<50%) vaccine coverage and/or the small contribution of rotavirus to total seizure hospitalisations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"nh9ddd1T","properties":{"formattedCitation":"[29,30]","plainCitation":"[29,30]","noteIndex":0},"citationItems":[{"id":4862,"uris":[""],"uri":[""],"itemData":{"id":4862,"type":"article-journal","title":"Long-term impact of self-financed rotavirus vaccines on rotavirus-associated hospitalizations and costs in the Valencia Region, Spain","container-title":"BMC Infectious Diseases","volume":"17","source":"PubMed Central","abstract":"Background\nRotavirus vaccines are available in Spain from 2007. They are recommended by the Spanish Pediatric Association, but not funded by the National Health System (NHS) and its coverage rate reached 40-50%. The hospitalization rate reduction of rotavirus caused gastroenteritis (RVAGE) directly attributable to vaccination remains unclear due to the large differences described in published studies, ranging from 14 to 44.5% in children <5?years of age, even with similar vaccination coverage. These results could be partly explained by variability in hospitalization policies, different study designs and the timeframe of observation. In addition, the direct economic impact of the reduction of hospitalizations has never been estimated. Therefore, there is a need to analyze the long-term impact of rotavirus vaccines on RVAGE and all cause gastroenteritis (AGE) hospitalizations and the national health system associated costs, minimizing potential confounders or biases.\n\nMethods\nA population-based, ecological study using the hospital discharge registry’s Minimum Basic Data Set (MBDS) and the vaccine register (SIV) was performed, among Valencia Region’s children <5?years old, during 2002 - 2015. RVAGE and AGE hospitalization risk was analyzed by vaccine coverage and adjusted by the total hospitalization rate for all causes to avoid external biases. The impact of AGE-associated health care utilization in prevaccine (2003–2006) versus postvaccine (2008–2014) years was also assessed.\n\nResults\nAfter vaccines licensure, the incidence of RVAGE-associated hospitalizations decreased markedly. A general vaccine coverage-related reduction in RVAGE or AGE-hospitalizations risk was observed in all age groups. Compared with unvaccinated children, RVAGE hospitalization risk decreased by 67% (95% CI: 55-67), 71% (95% CI: 58-81) and 68% (95% CI: 18-92) in children 0, 1 and 4?years of age, respectively, with a vaccination coverage between 40 and 42%. Overall, the hospital related costs were reduced around EUR 6 Mill per 105 children in 7?years.\n\nConclusions\nDespite the low-medium vaccine coverage, the introduction of rotavirus vaccines had a specific coverage-related response impact in the hospitalizations for RVAGE and AGE in children <5?years and their use substantially reduced hospital related costs. The model used reassures that the estimated impact is due to the vaccination and not to other external factors.\n\nElectronic supplementary material\nThe online version of this article (doi:10.1186/s12879-017-2380-2) contains supplementary material, which is available to authorized users.","URL":"","DOI":"10.1186/s12879-017-2380-2","ISSN":"1471-2334","note":"PMID: 28399824\nPMCID: PMC5387249","journalAbbreviation":"BMC Infect Dis","author":[{"family":"Orrico-Sanchez","given":"Alejandro"},{"family":"López-Lacort","given":"Mónica"},{"family":"Pérez-Vilar","given":"Silvia"},{"family":"Díez-Domingo","given":"Javier"}],"issued":{"date-parts":[["2017",4,11]]},"accessed":{"date-parts":[["2019",3,19]]}}},{"id":1766,"uris":[""],"uri":[""],"itemData":{"id":1766,"type":"article-journal","title":"Case Control Study of Rotavirus Vaccine Effectiveness in Portugal during Six Years of Private Market Use","container-title":"The Pediatric Infectious Disease Journal","source":"NCBI PubMed","abstract":"BACKGROUND:: Although recommended by the vaccine committee of the Portuguese Paediatric Society, rotavirus vaccines have not been included in the routine immunisation schedule. They have been available privately since 2006 with estimated coverage reaching approximately 30%. However unlike other European countries using the vaccine, sentinel surveillance has detected fluctuations but no clear trends in the rate of gastrointestinal disease presentations. In this study we set out to establish the real world effectiveness of rotavirus immunisation in this low vaccine coverage setting.\nMETHODS:: We carried out a test negative case control study on a population of children attending a regional paediatric hospital, between 2006 and 2012, with symptoms of acute gastroenteritis and producing a stool sample for routine rotavirus testing. We calculated exposure odds ratio (ratio of odds of antecedent vaccination among cases compared with controls) to derive vaccine effectiveness ((1 -adjusted odds ratio)/100) against both hospital attendance and admission.\nRESULTS:: Vaccine effectiveness against attendance with rotavirus acute gastroenteritis was 83.7% (95% CI 73.9-89.8) and against hospital admission was 96.1% (95% CI 83.8-99.1). No significant difference between the two available vaccines was detected.\nCONCLUSION:: Both rotavirus vaccines offer a high degree of individual protection in this population.","DOI":"10.1097/INF.0000000000000647","ISSN":"1532-0987","note":"PMID: 25551832","journalAbbreviation":"Pediatr. Infect. Dis. J.","language":"ENG","author":[{"family":"Marlow","given":"Robin"},{"family":"Ferreira","given":"Muriel"},{"family":"Cordeiro","given":"Eugénio"},{"family":"Trotter","given":"Caroline"},{"family":"Januário","given":"Luis"},{"family":"Finn","given":"Adam"},{"family":"Rodrigues","given":"Fernanda"}],"issued":{"date-parts":[["2014",12,30]]}},"label":"page"}],"schema":""} [29,30] Furthermore, a study from the UK that also failed to detect a reduction in total hospitalised seizure incidence following rotavirus vaccine introduction, examined shorter pre- and post-vaccination time periods than our study; did not include a co-diagnosis of AGE or adjust for PCV introduction; and employed an annual time-series model which does not account for in-year seasonal variations. ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"0clJTiCg","properties":{"formattedCitation":"[15]","plainCitation":"[15]","noteIndex":0},"citationItems":[{"id":4834,"uris":[""],"uri":[""],"itemData":{"id":4834,"type":"article-journal","title":"Lack of impact of rotavirus vaccination on childhood seizure hospitalizations in England - An interrupted time series analysis","container-title":"Vaccine","page":"4589-4592","volume":"36","issue":"31","source":"PubMed","abstract":"Observational studies have linked a reduction in childhood seizures (CS) to the introduction of rotavirus vaccination (RV). England is opportunely placed to explore this due to well-defined introduction, high uptake of RV and centralised Hospital Episodes Statistics recording all admissions. We investigated the association between seizures and vaccine use through interrupted time-series analysis of all CS admissions in children <3?years old (ICD-10 codes; G40?-G41?, R56.0?) during 2007-2017. We did not detect a statistically significant association between the introduction of RV and admission with febrile (p?=?0.84), afebrile (p?=?0.83) or all CS (p?=?0.93), even when limited to peak rotavirus seasonality (March). This is the first ecological study in a country that exclusively uses the monovalent vaccine. Although a negative finding, we would argue that if an effect cannot be detected at this population level then it is unlikely to be clinically or economically significant but generates hypotheses of potential non-specific effects.","DOI":"10.1016/j.vaccine.2018.06.029","ISSN":"1873-2518","note":"PMID: 29937243","journalAbbreviation":"Vaccine","language":"eng","author":[{"family":"Biggart","given":"Rachael"},{"family":"Finn","given":"Adam"},{"family":"Marlow","given":"Robin"}],"issued":{"date-parts":[["2018"]],"season":"25"}}}],"schema":""} [15] We were unable to use rotavirus infection-related seizures as an endpoint because ICD10 code A08.0 (rotaviral enteritis) is rarely used for laboratory-confirmed rotavirus, and therefore the number of A08-0 coded hospitalisations with a diagnosis of seizure were too few to analyse. As a proxy measure we used seizures with a co-diagnosis of AGE and stratified our analysis by rotavirus season. Our analysis also provides clinicians with a quantified description knowledge of the burden of seizures associated with AGE in the paediatric population in England. Our population based study did not include individual vaccine status; however, the value of using these data in England is limited because of the high level of vaccine coverage (>94% for first dose and 89% for course completion). ADDIN ZOTERO_ITEM CSL_CITATION {"citationID":"D6W8791n","properties":{"formattedCitation":"[3]","plainCitation":"[3]","noteIndex":0},"citationItems":[{"id":2172,"uris":[""],"uri":[""],"itemData":{"id":2172,"type":"article-journal","title":"National rotavirus immunisation programme: preliminary data for England, February 2016 to July 2016","container-title":"Health Protection Report: weekly report","collection-title":"Health Protection Report","page":"1-6","volume":"10","issue":"32","language":"English","author":[{"family":"Public Health England","given":""}],"issued":{"date-parts":[["2016",9,23]]}}}],"schema":""} [3] Also, because our study focused on hospitalisations we were unable to investigate seizure incidence in the community. Finally, while the observed reduction in all-cause seizure incidence with any co-diagnosis following PCV13 introduction suggests some impact of PCV on seizure associated lower respiratory tract infections, further subsequent reductions could be ascribed to rotavirus vaccination.Our study confirms that rotavirus vaccination brings benefits beyond the cardinal symptoms of diarrhoea and vomiting that are associated with rotavirus disease. Quantifying the absolute population impact of rotavirus-associated seizures remains problematic because of non-specific outcome measures and the low relative burden of hospital inpatient rotavirus-associated seizures. Finally, our study highlights the importance of considering the base-line burden of disease when selecting outcome measures, and the value of including multi-faceted analytical approaches to provide confidence in findings from population level impact evaluation.FOOTNOTESAcknowledgements: The authors acknowledge the contribution of Sacha Wyke for writing the original data extraction scripts and for his advice on using HES data.Contributors: NC, MIG, RV, DH and NF conceived of and designed the study. DH and RV acquired the data; DH analysed the data with support from NF, RV and JMR and all authors interpreted the output; DH wrote the first draft of the report; and all authors reviewed the draft and final manuscript.Funding: This study was supported by GlaxoSmithKline Biologicals SA (EPI-Rota-065) through financial support and the University of Liverpool. GlaxoSmithKline Biologicals SA was provided the opportunity to review a preliminary version of this manuscript for factual accuracy, but the authors are solely responsible for final content and interpretation. The authors received no financial support or other form of compensation related to the development of the manuscript. RV receives a salary contribution from the NIHR Health Protection Research Unit in Emerging and Zoonotic Infections. RV and MIG receive salary contributions from the NIHR Health Protection Research Unit in Gastrointestinal Infections. JMR acknowledges support from the Engineering and Physical Sciences Research Council (EP/N014499/1) and the Medical Research Council (MR/S004793/1).Ethics: The data accessed were aggregated and anonymized. Following consultation with the University of Liverpool Ethics Committee, Public Health England guidance and use of the NHS Health Research Authority Research tool “Do I need NHS REC approval” (), seeking of ethical approval deemed unnecessary. Patient consent: “Not applicable”Competing interests: All authors have completed the ICMJE uniform disclosure form at coi_disclosure.pdf and declare: NC, NF, MIG, RV and DH are in receipt of research grant support from GlaxoSmithKline (GSK) Biologicals. Outside of this study MIG and DH are in receipt of research grant support on the topic of rotavirus vaccines from Sanofi Pasteur, and Merck & Co (Kenilworth, New Jersey, USA) after the closure of Sanofi Pasteur-MSD in December 2016. NC has received honoraria for participation in GSK Rotavirus Vaccine DSMB meetings. REFERENCES ADDIN ZOTERO_BIBL {"uncited":[],"omitted":[],"custom":[]} CSL_BIBLIOGRAPHY 1 World Health Organization. Global networks of rotavirus gastroenteritis, 2001-2008. Wkly Epidemiol Rec 2008;83:421–8.2 Iturriza-Gómara M, Cunliffe N. Rotavirus vaccine: a welcome addition to the immunisation schedule in the UK. BMJ 2013;346:f2347.3 Public Health England. National rotavirus immunisation programme: preliminary data for England, February 2016 to July 2016. Health Prot Rep Wkly Rep 2016;10:1–6.4 Atchison CJ, Stowe J, Andrews N, et al. Rapid Declines in Age Group–Specific Rotavirus Infection and Acute Gastroenteritis Among Vaccinated and Unvaccinated Individuals Within 1 Year of Rotavirus Vaccine Introduction in England and Wales. J Infect Dis 2015;:jiv398. doi:10.1093/infdis/jiv3985 Marlow R, Muir P, Vipond B, et al. Assessing the impacts of the first year of rotavirus vaccination in the United Kingdom. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull 2015;20:30077. doi:10.2807/1560-7917.ES.2015.20.48.300776 Hungerford D, Read JM, Cooke RPD, et al. Early impact of rotavirus vaccination in a large paediatric hospital in the UK. 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Lack of impact of rotavirus vaccination on childhood seizure hospitalizations in England - An interrupted time series analysis. Vaccine 2018;36:4589–92. doi:10.1016/j.vaccine.2018.06.02916 Orrico-Sánchez A, López-Lacort M, Mu?oz-Quiles C, et al. Lack of impact of rotavirus vaccines on seizure-related hospitalizations in children under 5?years old in Spain. Hum Vaccines Immunother 2018;14:1534–8. doi:10.1080/21645515.2018.143522517 Marlow R, Finn A, Rodrigues F. Lack of impact of rotavirus vaccination on childhood seizure hospital attendances in Portugal - An interrupted time series analysis. Vaccine Published Online First: 17 January 2019. doi:10.1016/j.vaccine.2018.12.07418 Heinsbroek E, Hungerford D, Cooke RPD, et al. Do hospital pressures change following rotavirus vaccine introduction? A retrospective database analysis in a large paediatric hospital in the United Kingdom. BMJ Open 2019;In Press.19 Hungerford D, Vivancos R, French N, et al. Ecological assessment of the direct and indirect effects of routine rotavirus vaccination in Merseyside, UK using data from multiple health systems: a study protocol. BMJ Open 2014;4:e006161. doi:10.1136/bmjopen-2014-00616120 Saxena S, Atchison C, Cecil E, et al. Additive impact of pneumococcal conjugate vaccines on pneumonia and empyema hospital admissions in England. J Infect 2015;71:428–36. doi:10.1016/j.jinf.2015.06.01121 Hungerford D, Vivancos R, EuroRotaNet network members, et al. In-season and out-of-season variation of rotavirus genotype distribution and age of infection across 12 European countries before the introduction of routine vaccination, 2007/08 to 2012/13. Euro Surveill Bull Eur Sur Mal Transm Eur Commun Dis Bull 2016;21. doi:10.2807/1560-7917.ES.2016.21.2.3010622 Hungerford D, Allen DJ, Nawaz S, et al. Impact of rotavirus vaccination on rotavirus genotype distribution and diversity in England, September 2006 to August 2016. Eurosurveillance 2019;24:1700774. doi:10.2807/1560-7917.ES.2019.24.6.170077423 Niccolai LM, Meek JI, Brackney M, et al. Declines in Human Papillomavirus (HPV)–Associated High-Grade Cervical Lesions After Introduction of HPV Vaccines in Connecticut, United States, 2008–2015. Clin Infect Dis 2017;65:884–9. doi:10.1093/cid/cix45524 Pingali SC, Warren JL, Mead AM, et al. Association Between Local Pediatric Vaccination Rates and Patterns of Pneumococcal Disease in Adults. J Infect Dis 2016;213:509–15. doi:10.1093/infdis/jiv43125 Boikos C, Joseph L, Scheifele D, et al. Adverse events following live-attenuated intranasal influenza vaccination of children with cystic fibrosis: Results from two influenza seasons. Vaccine 2017;35:5019–26. doi:10.1016/j.vaccine.2017.07.06826 Kürüm E, Warren JL, Schuck-Paim C, et al. Bayesian Model Averaging with Change Points to Assess the Impact of Vaccination and Public Health Interventions. Epidemiology 2017;28:889. doi:10.1097/EDE.000000000000071927 Zeileis A, Leisch F, Hornik K, et al. strucchange: An R Package for Testing for Structural Change in Linear Regression Models. J Stat Softw 2002;7:1–38. doi:10.18637/jss.v007.i0228 Hungerford D, Smith K, Tucker A, et al. Population effectiveness of the pentavalent and monovalent rotavirus vaccines: a systematic review and meta-analysis of observational studies. BMC Infect Dis 2017;17:569. doi:10.1186/s12879-017-2613-429 Orrico-Sanchez A, López-Lacort M, Pérez-Vilar S, et al. Long-term impact of self-financed rotavirus vaccines on rotavirus-associated hospitalizations and costs in the Valencia Region, Spain. BMC Infect Dis 2017;17. doi:10.1186/s12879-017-2380-230 Marlow R, Ferreira M, Cordeiro E, et al. Case Control Study of Rotavirus Vaccine Effectiveness in Portugal during Six Years of Private Market Use. Pediatr Infect Dis J Published Online First: 30 December 2014. doi:10.1097/INF.0000000000000647Table 1. Changes in rates of hospital admissions for febrile and all seizure, England Age group (months)Mean yearly rate of hospitalisations and attendances (per 10,000)aPercentage reduction in hospital admissions post-vaccine introduction (95% CI)bPre-rotavirus vaccinationPost-rotavirus vaccination (July 2013-June 2017)ObservedObservedExpectedaPCV 7PCV 13RVAll seizuresHospitals admissions for all seizures with any co-diagnosis?<?12108.6107.8104.9-2 (-8 to 3)1 (-7 to 9)-4 (-8 to 0)?12–23180.7144.8153.15 (-1 to 11)13 (5 to 21)7 (2 to 12)?24-5975.271.875.11 (-7 to 8)4 (-7 to 14)4 (-2 to 9)? 0–59103.293.397.72 (-5 to 7)7 (-1 to 15)4 (0 to 8)Hospitals admissions for all seizures with acute gastroenteritis?<?123.72.63.9-16 (-45 to 7)-12 (-59 to 22)24 (7 to 39)?12–238.55.69.8-13 (-31 to 4)-12 (-41 to 12)33 (20 to 44)?24-592.12.12.6-10 (-28 to 5)-7 (-33 to 15)11 (-4 to 23)0–593.72.94.3-13 (-30 to 2)-9 (-34 to 12)23 (11 to 33)Hospitals admissions for all seizures with pneumonia?<?123.42.82.3-2 (-23 to 16)-9 (-46 to 19)-22 (-44 to -4)?12–239.8778 (-5 to 19)0 (-21 to 18)3 (-8 to 14)?24-593.33.23.4-3 (-17 to 10)-9 (-34 to 12)2 (-11 to 13)? 0–594.63.93.91 (-9 to 11)-5 (-23 to 10)-1 (-10 to 8)Febrile seizuresHospitals admissions for febrile seizures with any co-diagnosis?<?1236.425.82713 (5 to 21)20 (9 to 30)10 (4 to 16)?12–23119.380.386.25 (-3 to 13)16 (5 to 26)8 (2 to 14)?24-5931.622.1244 (-10 to 16)12 (-7 to 27)8 (-2 to 18)0–5950.234.437.65 (-5 to 14)15 (2 to 26)10 (2 to 16)Hospitals admissions for febrile seizures with acute gastroenteritis?<?121.70.91.5-16 (-48 to 8)-6 (-55 to 27)34 (16 to 48)?12–234.72.24.1-29 (-54 to -8)-22 (-59 to 7)33 (19 to 45)?24-590.80.50.7-2 (-28 to 19)15 (-20 to 39)29 (12 to 43)?0–591.80.91.6-21 (-42 to -2)-8 (-38 to 16)31 (19 to 41)Hospitals admissions for febrile seizures with pneumonia?<?121.81.31.1-17 (-50 to 9)-40 (-104 to 3)-27 (-59 to -1)?12–237.54.74.67 (-8 to 19)-1 (-25 to 18)1 (-13 to 13)?24-591.71.21.29 (-10 to 25)6 (-26 to 29)8 (-8 to 22)0–592.91.91.93 (-10 to 15)-3 (-25 to 14)1 (-10 to 11)PCV7: Pneumococcal Conjugate Vaccine 7 valent. PCV13: Pneumococcal Conjugate Vaccine 13 valent. RV: Rotavirus vaccinea Expected in the absence of rotavirus vaccination. b Percentage change is calculated as 1-Incidence rate ratio Figure 1: Median yearly number of seizure and febrile seizure hospital admissions and co-diagnoses, in children <5 years of age in England, by age group between July 2000 and June 2017. Error bars represent the Interquartile rangeFigure 2: Monthly trends in hospitalisations for seizure in four study groups, for children <5 years of age in England, July 2000 to June 2017. Each analysis examines trends, including a comparison of observed incidence (black line) in England with expected incidence (red line) and associated 95% confidence intervals (grey shaded area) in the absence of vaccination. Expected incidence and 95% confidence intervals are based on predictions from regression models fitted to data for the period July 2000 to June 2013 for each outcome measure. The blue hashed line represents the introduction of rotavirus vaccine in the UK in July 2013; the green hashed line represents the introduction of the 7 valent pneumococcal conjugate vaccine (PCV7) in September 2006; and, the yellow hashed line represents the replaced of PCV7 with the 13 valent pneumococcal conjugate vaccine (PCV13) in the UK in April 2010. AGE: acute all-cause gastroenteritisSupplementary MaterialsSupplementary Figure 1: Monthly trends in hospitalisations for validation groups for children <5 years of age in England, July 2000 to June 2017. Each analysis examines trends, including a comparison of observed incidence (black line) in England with expected incidence (red line) and associated 95% confidence intervals (grey shaded area) in the absence of vaccination. Expected incidence and 95% confidence intervals are based on predictions from regression models fitted to data for the period July 2000 to June 2013 for each outcome measure. The blue hashed line represents the introduction of rotavirus vaccine in the UK in July 2013; the green hashed line represents the introduction of the 7 valent pneumococcal conjugate vaccine (PCV7) in September 2006; and, the yellow hashed line represents the replaced of PCV7 with the 13 valent pneumococcal conjugate vaccine (PCV13) in the UK in April 2010. Supplementary Table 1: Number of seizure and febrile seizure hospital admissions and co-diagnoses, in children <5 years of age in England, between July 2000 and June 2017.Co-diagnosisFebrile SeizuresAll-seizures?Yearly Median (IQR)Yearly Median (IQR)0-59 months of ageAcute gastroenteritis534 (471 - 560)1096 (963 - 1255)Pneumonia799 (722 - 928)1370 (1339 - 1441)J06.9: Acute upper respiratory infection-unspecified4169 (3380 - 4620)4925 (4303 - 5441)J03.9: Acute tonsillitis-unspecified 1776 (1493 - 1971)2070 (1673 - 2420)B34.9: Viral infection-unspecified1048 (981 - 1181)1503 (1447 - 1587)Co-diagnosis absent3421 (2586 - 4537)7606 (6465 - 9138)Any co-diagnosis15007 (13241 - 15977)31909 (30878 - 32588)0-11 months of ageAcute gastroenteritis99 (84 - 106)211 (196 - 249)Pneumonia101 (97 - 112)214 (189 - 220)J06.9: Acute upper respiratory infection-unspecified564 (468 - 621)698 (600 - 750)J03.9: Acute tonsillitis-unspecified 166 (144 - 192)190 (154 - 223)B34.9: Viral infection-unspecified167 (152 - 184)232 (222 - 244)Co-diagnosis absent552 (413 - 720.5)1874 (1563.5 - 2085)Any co-diagnosis2242 (1993 - 2312)7100 (6448 - 7208)12-23 months of ageAcute gastroenteritis273 (251 - 294)496 (415 - 584)Pneumonia416 (368 - 503)563 (521 - 615)J06.9: Acute upper respiratory infection-unspecified2114 (1679 - 2427)2379 (2018 - 2686)J03.9: Acute tonsillitis-unspecified 891 (713 - 954)996 (766 - 1080)B34.9: Viral infection-unspecified521 (439 - 577)672 (614 - 678)Co-diagnosis absent1590 (1200 - 2159)2545 (2124 - 3271)Any co-diagnosis7340 (6241 - 7772)10827 (10641 - 11330)24-59 months of ageAcute gastroenteritis149 (126 - 162)407 (352 - 433)Pneumonia285 (256 - 323)622 (587 - 630)J06.9: Acute upper respiratory infection-unspecified1491 (1170 - 1615)1841 (1655 - 2040)J03.9: Acute tonsillitis-unspecified 707 (663 - 836)913 (764 - 1090)B34.9: Viral infection-unspecified378 (339 - 435)642 (598 - 669)Co-diagnosis absent1292 (1013.5 - 1725.75)3244.5 (2830 - 3712)Any co-diagnosis5389 (5007 - 5968)13595 (13359 - 14753)IQR: Interquartile range ................
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