Suppression von IgE gegen Tetanus- und Diphtherie-Toxoid bei Kindern nach ganzzellulärer (aber nicht azellulärer) Bordetella pertussis-Impfung

Hintergrund: Vorangegangene Studien haben gezeigt, dass die zelluläre Bordetella Pertussis-Impfung die IgE-Antwort gegen Impfantigene herunterreguliert. Unbekannt ist, ob hinsichtlich der IgE-Antwort auf kovakzinierte Impfantigene azelluläre Pertussis-Impfstoffe anders als die ganzzellulären Impfstoffe agieren. Es ist anzunehmen, dass die Zellwandbestandteile des zellulären Impfstoffs die IgE-Antwort gegen Impfantigene beeinflussen. In der vorliegenden Arbeit wurde die humorale Immunantwort gegen kovakzinierte Diphtherie- und Tetanus-Antigene bei zellulär und azellulär geimpften Kindern untersucht. Methoden: Aus einer prospektiven Pertussis-Impfstudie aus Schweden standen Seren von 265 Kindern, die im Alter von 2, 4 und 6 Monaten mit einem der folgenden 4 Impfstoffe immunisiert wurden, zur Verfügung: Diphtherie (D)- und Tetanus-Toxoid (T)-Impfstoff (DT, N=68), ganzzellulärer Pertussis-Impfstoff (DTPw, N=68), 2-Komponenten (DTPa2, N=64)- oder 5-Komponenten-azellulärer Pertussis-Impfstoff (DTPa5, N=65). In diesen Seren wurden IgE, IgG4 und IgG gegen Diphtherie- und Tetanus-Toxoid mit dem Radio-Allergo-Sorbent-Test (RAST) im Alter von 2, 7 und 12 Monaten bestimmt. Ergebnisse: Einen Monat nach Grundimmunisierung (7. Lebensmonat) wurden D-IgE in 50,0% (DT), 55,7% (DTPa2) und 60,3% (DTPa5) der Blutproben nachgewiesen; in der DTPw geimpften Gruppe in nur 9,7% (P<0,001). Analog dazu wurden D-IgG4 in 88,1% (DT), 82,3% (DTPa2) und 93,4% (DTPa5) der Blutproben nachgewiesen; jedoch deutlich seltener in der DTPw geimpften Gruppe (42,2%, P<0,001). Sechs Monate nach Grundimmunisierung (12. Lebensmonat) konnte D-IgE in 75,8% (DT), 67,2% (DTPa2) und 79,0% (DTPa5), aber in nur 25,0% der DTPw geimpften gefunden werden (P<0,001). Vergleichbare Trends fanden sich für T-IgE und T-IgG4. Im Gegensatz dazu waren die Unterschiede zwischen den verschiedenen Impfgruppen in Bezug auf D-IgG und T-IgG weniger ausgeprägt. Schlussfolgerung: Die vorliegende Arbeit zeigt, dass der ganzzelluläre Bordetella Pertussis-Impfstoff, nicht aber der azelluläre Impfstoff, die IgE-Antwort gegen kovakzinierte Impfantigene bei Kindern herrunterreguliert, vermutlich ausgelöst durch Zellwandbestandteile von Bordetella pertussis. Ob und unter welchen Umständen mit dieser Strategie auch die IgE-Produktion gegen relevante Umweltallergene bei Kindern mit erhöhtem Risiko für allergische Erkrankungen inhibiert werden kann, muss im Rahmen weiterer Untersuchungen evaluiert werden.Background: It has previously been shown that the IgE response to vaccine antigens is down-regulated by covaccination with cellular Bordetella pertussis vaccine. The presence of bacterial cell wall components in the cellular vaccine is likely to have an impact on the IgE response. In this study we compared humoral immune responses to diphtheria toxoid (D) and tetanus toxoid (T) in relation to covaccinated cellular or acellular Bordetella pertussis vaccine. Methods: Sera of 265 children from a Swedish pertussis vaccine trial vaccinated with D and T (DT, N=68), cellular (DTPw, N=68), a 2 or 5 component acellular Bordetella pertussis vaccine (DTPa2, N=64; DTPa5, N=65) at 2, 4, and 6 months of age, were analyzed for IgE, IgG4, and IgG to D and T at 2, 7, and 12 months of age (RAST). Results: One month after vaccination (7 months of age), D-IgE was detected in 50.0% (DT), 55.7% (DTPa2) and 60.3% (DTPa5) of the serum samples, but significantly less frequently in sera of DTPw vaccinated children (9.7%, P<0.001). Similarly, D-IgG4 was detected in 88.1% (DT), 82.3% (DTPa2) and 93.4% (DTPa5) of the sera, but significantly less frequently in DTPw samples (42.2%, P<0.001). Six months after vaccination (12 months of age), D-IgE was detected in 75.8% (DT), 67.2% (DTPa2) and 79.0% (DTPa5) of the samples, but only in 25.0% of DTPw vaccinated (P<0.001). These findings were mirrored by those for T-IgE and T-IgG4. In contrast, much weaker differences were found between vaccine groups with regard to D-IgG and T-IgG. Conclusion: In summary, cellular (but not acellular) Bordetella pertussis vaccine down-regulates IgE to covaccinated antigens in infants, presumably by cell wall components. The possibility to down-regulate IgE responses in children by safe vaccination of bacterial compounds should be further investigated

Early morbidities following paediatric cardiac surgery: a mixed-methods study

BackgroundOver 5000 paediatric cardiac surgeries are performed in the UK each year and early survival has improved to > 98%.ObjectivesWe aimed to identify the surgical morbidities that present the greatest burden for patients and health services and to develop and pilot routine monitoring and feedback.Design and settingOur multidisciplinary mixed-methods study took place over 52 months across five UK paediatric cardiac surgery centres.ParticipantsThe participants were children aged MethodsWe reviewed existing literature, ran three focus groups and undertook a family online discussion forum moderated by the Children’s Heart Federation. A multidisciplinary group, with patient and carer involvement, then ranked and selected nine key morbidities informed by clinical views on definitions and feasibility of routine monitoring. We validated a new, nurse-administered early warning tool for assessing preoperative and postoperative child development, called the brief developmental assessment, by testing this among 1200 children. We measured morbidity incidence in 3090 consecutive surgical admissions over 21 months and explored risk factors for morbidity. We measured the impact of morbidities on quality of life, clinical burden and costs to the NHS and families over 6 months in 666 children, 340 (51%) of whom had at least one morbidity. We developed and piloted methods suitable for routine monitoring of morbidity by centres and co-developed new patient information about morbidities with parents and user groups.ResultsFamilies and clinicians prioritised overlapping but also different morbidities, leading to a final list of acute neurological event, unplanned reoperation, feeding problems, renal replacement therapy, major adverse events, extracorporeal life support, necrotising enterocolitis, surgical infection and prolonged pleural effusion. The brief developmental assessment was valid in children aged between 4 months and 5 years, but not in the youngest babies or 5- to 17-year-olds. A total of 2415 (78.2%) procedures had no measured morbidity. There was a higher risk of morbidity in neonates, complex congenital heart disease, increased preoperative severity of illness and with prolonged bypass. Patients with any morbidity had a 6-month survival of 81.5% compared with 99.1% with no morbidity. Patients with any morbidity scored 5.2 points lower on their total quality of life score at 6 weeks, but this difference had narrowed by 6 months. Morbidity led to fewer days at home by 6 months and higher costs. Extracorporeal life support patients had the lowest days at home (median: 43 days out of 183 days) and highest costs (£71,051 higher than no morbidity).LimitationsMonitoring of morbidity is more complex than mortality, and hence this requires resources and clinician buy-in.ConclusionsEvaluation of postoperative morbidity provides important information over and above 30-day survival and should become the focus of audit and quality improvement.Future workNational audit of morbidities has been initiated. Further research is needed to understand the implications of feeding problems and renal failure and to evaluate the brief developmental assessment.FundingThis project was funded by the NIHR Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 8, No. 30. See the NIHR Journals Library website for further project information.Katherine L Brown is a member of the Health Technology Assessment (HTA) Clinical Trials Board (2017–21) and a member of the domain expert group of the National Congenital Heart Diseases Audit (2014–19). David L Barron is a member of the National Congenital Heart Disease Audit Steering Committee (2014–18). Monica Lakhanpaul is part of the following boards or panels: HTA Maternal, Neonatal and Child Health (MNCH) Methods Group, HTA MNCH Panel (2012–17) and Psychological and Community Therapies Panel (2012–15). Steve Morris has been a member of the following boards or panels: Health Services and Delivery Research (HSDR) Board Members (2014–18), HSDR Commissioned Board Members, HSDR Evidence Synthesis Sub Board 2016 and the Public Health Research Research Funding Board (2011–17). Thomas Witter was a member of the National Congenital Heart Disease Audit Steering Committee (2014–18). The research reported in this issue of the journal was funded by the HS&DR programme or one of its preceding programmes as project number 12/5005/06

Further investigations of the IgE response to tetanus and diphtheria following covaccination with acellular rather than cellular Bordetella pertussis

Background: It has previously been shown in an uncontrolled study that the IgE response to vaccine antigens is downregulated by co-vaccination with cellular Bordetella pertussis vaccine. Methods: In the present study, we compared in a controlled trial the humoral immune response to diphtheria toxoid (D) and tetanus toxoid (T) in relation to co-vaccinated cellular or acellular B pertussis vaccine. IgE, IgG4, and IgG to D and T were analyzed at 2, 7, and 12 months of age in sera of children vaccinated with D and T (DT, N = 68), cellular (DTPw, N = 68), 2- or 5-component acellular B pertussis vaccine (DTPa2, N = 64; DTPa5, N = 65). Results: One month after vaccination, D-IgE was detected in 10% sera of DTPw-vaccinated children, whereas vaccination in the absence of whole-cell pertussis resulted in 50%-60% IgE positivity. Six months after vaccination, the IgE antibody levels were found to be more persistent than the IgG antibodies. These diphtheria findings were mirrored by those for tetanus. Only minor differences between vaccine groups were found with regard to D-IgG and T-IgG. No immediate-type allergic reactions were observed. Conclusion: Cellular (but not acellular) B pertussis vaccine downregulates IgE to co-vaccinated antigens in infants. We assume that the absence of immediate-type allergic reactions is due to the high levels of IgG antibodies competing with IgE antibodies