Doctor: Fleur Lorton

Title: Epidemiology of community-onset severe bacterial infections in children

Supervisors: Martin Chalumeau, Elise Launay

Doctoral school: ED 393 Epidemiology and Biomedical Information Sciences, Université de Paris

Date of thesis defense: 11/2020

Jury: Corinne Alberti, Pierre Tattevin, Jean-Claude Desenclos, Jean-Ralph Zahar

Thesis summary:

Severe bacterial infections (SBIs) remain an important cause of morbidity and mortality in children, although some of this morbidity and mortality could theoretically be avoided by vaccination and optimal parental and medical management. The main objective of this doctoral work was to provide new knowledge of the bacterial and clinical epidemiology of community-onset SBI (COSBI) in children and in particular 1) the causative pathogens and their evolution in 10-year intervals; 2) the potential avoidability of deaths and sequelae of COSBI by vaccination; and 3) the quality of care received in the initial management of COSBI in children. The data were derived from a population-based confidential inquiry with independent experts conducted in western France between 2009 and 2014 in a territory accounting for 15% of the French pediatric population. The data were for all children from age 1 month to 16 years hospitalized in a pediatric intensive care unit for COSBI or who died before admission as a result of SBI. First, most probably due to the generalization of meningococcal C and pneumococcal conjugate vaccines, the incidence of COSBI (comparative morbidity figure = 0.47; 95%CI 0.37-0.59) and mortality (comparative mortality figure = 0.27; 95%CI 0.14-0.46) had decreased in France over the last 10 years, except for COSBI with Staphylococcus aureus. However, the youngest children were still exposed to a high risk of SBI, sequelae and death. Contrary to what was observed in neighboring European countries, vaccine-preventable bacteria continued to account for most of the infections. This result reinforces the urgency to improve vaccination coverage for these valences. Second, 25% (95%CI 9-49) of deaths and 25% (95%CI 0-54) of cases of severe sequelae related to COSBI due to Neisseria meningitidis or Streptococcus pneumoniae were theoretically preventable by correct application of the vaccination recommendations in effect at the time of infection. In a context of strong vaccine hesitancy, these results, by accurately identifying the clinical consequences of a vaccine defect, could help improve public opinion about the positive impact of vaccines on children’s health and thus assist physicians in the implementation of the new national vaccine policy. Third, global management of a COSBI in children before admission to resuscitation was considered suboptimal in 34.4% (95%CI 28.6-40.5) of cases. Risk of suboptimal management was increased for children with sequelae (adjusted odds ratio [aOR] = 5.61; 95%CI 1.19-26.36) and reduced for those who died (aOR = 0.16; 95%CI 0.04-0.65) as compared with surviving children without sequelae. This paradoxical association between suboptimal care and decreased risk of death could be explained by insufficient adjustment on the intrinsic severity of SBI related to bacterial virulence and/or genetic susceptibility of the host. Finally, we showed that medical management could probably be optimized by reducing territorial inequalities in access to care and by improving the quality of primary care, particularly in young children. This doctoral work allowed for 1) highlighting the need for national epidemiological surveillance of bacteria responsible for COSBI in order to adapt practices in terms of probabilistic antibiotic therapy and national vaccination policy; 2) evaluating the dire consequences of a missing vaccination and proposing arguments to counter vaccine hesitancy; and 3) identifying priority targets for action to improve COSBI management.

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