Severe acute respiratory syndrome coronavirus-2-related and imputable deaths in children: results from the French pediatric national registry.

BACKGROUND: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is responsible for an important mortality rate worldwide. We aimed to evaluate the actual imputability of SARS-CoV-2 on the mortality rate associated with SARS-CoV-2-related illnesses in the pediatric intensive care unit (PICU). Secondary objectives were to identify risk factors for death. METHODS: This national multicenter comparative study comprised all patients under 18 years old with positive SARS-CoV-2 polymerase chain reactions (PCRs) [acute corona virus disease 2019 (COVID-19) or incidental SARS-CoV-2 infection] and/or pediatric inflammatory multisystem syndrome (PIMS) recorded in the French PICU registry (PICURe) between September 1, 2021, and August 31, 2022. Included patients were classified and compared according to their living status at the end of their PICU stay. Deceased patients were evaluated by four experts in the field of pediatric infectiology and/or pediatric intensive care. The imputability of SARS-CoV-2 as the cause of death was classified into four categories: certain, very probable, possible, or unlikely, and was defined by any of the first three categories. RESULTS: There were 948 patients included of which 43 died (4.5%). From this, 26 deaths (67%) could be attributed to SARS-CoV-2 infection, with an overall mortality rate of 2.8%. The imputability of death to SARS-CoV-2 was considered certain in only one case (0.1%). Deceased patients suffered more often from comorbidities, especially heart disease, neurological disorders, hematological disease, cancer, and obesity. None of the deceased patients were admitted for pediatric inflammatory multisystem syndrome (PIMS). Mortality risk factors were male gender, cardiac comorbidities, cancer, and acute respiratory distress syndrome. CONCLUSIONS: SARS-CoV-2 mortality in the French pediatric population was low. Even though the imputability of SARS-CoV-2 on mortality was considered in almost two-thirds of cases, this imputability was considered certain in only one case.

Age-Specific Resurgence in Invasive Pneumococcal Disease Incidence in the COVID-19 Pandemic Era and Its Association With Respiratory Virus and Pneumococcal Carriage Dynamics: A Time-Series Analysis.

Using multiple national surveillance systems, we found an increase in the incidence of invasive pneumococcal disease during after the relaxation of non-pharmaceutical interventions against COVID-19, which strongly varied by age. Age groups with higher incidence of respiratory syncytial virus and influenza also experienced higher increase in invasive pneumococcal disease incidence, with no change in pneumococcal carriage.

Unique Changes in the Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Unravel the Role of Respiratory Pathogens: A Time Series Analysis.

BACKGROUND: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). Although respiratory pathogens are frequently detected in children with ACS, their respective role in triggering the disease is still unclear. We hypothesized that the incidence of ACS followed the unprecedented population-level changes in respiratory pathogen dynamics after COVID-19-related nonpharmaceutical interventions (NPIs). RESEARCH QUESTION: What is the respective role of respiratory pathogens in ACS epidemiology? STUDY DESIGN AND METHODS: This study was an interrupted time series analysis of patient records from a national hospital-based surveillance system. All children aged < 18 years with SCD hospitalized for ACS in France between January 2015 and May 2022 were included. The monthly incidence of ACS per 1,000 children with SCD over time was analyzed by using a quasi-Poisson regression model. The circulation of 12 respiratory pathogens in the general pediatric population over the same period was included in the model to assess the fraction of ACS potentially attributable to each respiratory pathogen. RESULTS: Among the 55,941 hospitalizations of children with SCD, 2,306 episodes of ACS were included (median [interquartile range] age, 9 [5-13] years). A significant decrease was observed in ACS incidence after NPI implementation in March 2020 (-29.5%; 95% CI, -46.8 to -12.2; P = .001) and a significant increase after lifting of the NPIs in April 2021 (24.4%; 95% CI, 7.2 to 41.6; P = .007). Using population-level incidence of several respiratory pathogens, Streptococcus pneumoniae accounted for 30.9% (95% CI, 4.9 to 56.9; P = .02) of ACS incidence over the study period and influenza 6.8% (95% CI, 2.3 to 11.3; P = .004); other respiratory pathogens had only a minor role. INTERPRETATION: NPIs were associated with significant changes in ACS incidence concomitantly with major changes in the circulation of several respiratory pathogens in the general population. This unique epidemiologic situation allowed determination of the contribution of these respiratory pathogens, in particular S pneumoniae and influenza, to the burden of childhood ACS, highlighting the potential benefit of vaccine prevention in this vulnerable population.

Vaccine-preventable Pediatric Acute Bacterial Meningitis in France: A Time Series Analysis of a 19-Year Prospective National Surveillance Network.

BACKGROUND: In France, vaccination has been implemented against Hi serotype b (Hib), pneumococcus with pneumococcal conjugate vaccines (PCV), and Neisseria meningitidis serogroup C (MenC). These interventions with different coverage and uptake have disrupted the epidemiology of vaccine-preventable acute bacterial meningitis (ABM). METHODS: We analyzed data from a French prospective surveillance network of ABM in children ≤15 years old enrolled by 259 pediatric wards (estimated national coverage: 61%). From 2001 to 2020, the effect of vaccine implementation was estimated with segmented linear regression. RESULTS: We analyzed 7,186 cases, mainly due to meningococcus (35.0%), pneumococcus (29.8%), and Hi (3.7%). MenC ABM incidence decreased (-0.12%/month, 95% CI: -0.17 to -0.07, P < 0.001) with no change for the overall meningococcal ABM when comparing the pre-MenC vaccination and the post-MenC vaccination trends. Despite a decreasing MenB ABM incidence without a vaccination program (-0.43%/month, 95% CI: -0.53 to -0.34, P < 0.001), 68.3% of meningococcal ABM involved MenB. No change in pneumococcal ABM incidence was observed after the PCV7 recommendation. By contrast, this incidence significantly decreased after the switch to PCV13 (-0.9%/month, 95% CI: -1.6 to -0.2%, P = 0.01). After May 2014, a rebound occurred (0.5%/month, 95% CI: 0.3-0.8%, P < 0.001), with 89.5% of non-PCV13 vaccine serotypes. Hib ABM incidence increased after June 2017. CONCLUSIONS: PCV7 and MenC vaccine introduction in France, with slow vaccine uptake and low coverage, had no to little impact as compared to the switch from PCV7 to PCV13, which occurred when coverage was optimal. Our data suggest that MenB and next-generation PCVs could prevent a large part of the ABM incidence in France.

Early formative objective structured clinical examinations for students in the pre-clinical years of medical education: A non-randomized controlled prospective pilot study.

BACKGROUND: The value of formative objective structured clinical examinations (OSCEs) during the pre-clinical years of medical education remains unclear. We aimed to assess the effectiveness of a formative OSCE program for medical students in their pre-clinical years on subsequent performance in summative OSCE. METHODS: We conducted a non-randomized controlled prospective pilot study that included all medical students from the last year of the pre-clinical cycle of the Université Paris-Cité Medical School, France, in 2021. The intervention group received the formative OSCE program, which consisted of four OSCE sessions, followed by debriefing and feedback, whereas the control group received the standard teaching program. The main objective of this formative OSCE program was to develop skills in taking a structured medical history and communication. All participants took a final summative OSCE. The primary endpoint was the summative OSCE mark in each group. A questionnaire was also administered to the intervention-group students to collect their feedback. A qualitative analysis, using a convenience sample, was conducted by gathering data pertaining to the process through on-site participative observation of the formative OSCE program. RESULTS: Twenty students were included in the intervention group; 776 in the control group. We observed a significant improvement with each successive formative OSCE session in communication skills and in taking a structured medical history (p<0.0001 for both skills). Students from the intervention group performed better in a summative OSCE that assessed the structuring of a medical history (median mark 16/20, IQR [15; 17] versus 14/20, [13; 16], respectively, p = 0.012). Adjusted analyses gave similar results. The students from the intervention group reported a feeling of improved competence and a reduced level of stress at the time of the evaluation, supported by the qualitative data showing the benefits of the formative sessions. CONCLUSION: Our findings suggest that an early formative OSCE program is suitable for the pre-clinical years of medical education and is associated with improved student performance in domains targeted by the program.

Antimicrobial treatment of lower respiratory tract infections in children.

Lower respiratory tract infections (LRTI) encompass a wide range of clinical syndromes, prominently including bronchiolitis, bronchitis and pneumonia. LRTIs are the second leading cause of antibiotic prescriptions. The vast majority of these infections are due to (or triggered by) viruses and are self-limited diseases. Pneumonia in children is responsible for significant morbidity and mortality worldwide. For clinicians, one of the main difficulties consists in diagnosing pneumonia in febrile children with (or without) cough. The diagnosis is given on the basis of anamnesis, clinical examination and (if necessary) complementary examinations, with chest X-ray or thoracic ultrasound; biological markers are particularly important. Over recent years, since the implementation of PCV13, the bacterial epidemiology of pneumonia and empyema has evolved; involvement in these diseases of pneumococcus has been reduced, and resistance to penicillin has lessened - and remained extremely low. In 2021, according to the National Pneumococcal Reference Center, only 6% of the strains isolated from blood cultures in children are resistant to amoxicillin. The therapeutic choices proposed in this article are in full compliance with the previously published official French recommendations.

Immunomodulatory Therapy for MIS-C.

CONTEXT: Studies comparing initial therapy for multisystem inflammatory syndrome in children (MIS-C) provided conflicting results. OBJECTIVE: To compare outcomes in MIS-C patients treated with intravenous immunoglobulin (IVIG), glucocorticoids, or the combination thereof. DATA SOURCES: Medline, Embase, CENTRAL and WOS, from January 2020 to February 2022. STUDY SELECTION: Randomized or observational comparative studies including MIS-C patients <21 years. DATA EXTRACTION: Two reviewers independently selected studies and obtained individual participant data. The main outcome was cardiovascular dysfunction (CD), defined as left ventricular ejection fraction < 55% or vasopressor requirement ≥ day 2 of initial therapy, analyzed with a propensity score-matched analysis. RESULTS: Of 2635 studies identified, 3 nonrandomized cohorts were included. The meta-analysis included 958 children. IVIG plus glucocorticoids group as compared with IVIG alone had improved CD (odds ratio [OR] 0.62 [0.42-0.91]). Glucocorticoids alone group as compared with IVIG alone did not have improved CD (OR 0.57 [0.31-1.05]). Glucocorticoids alone group as compared with IVIG plus glucocorticoids did not have improved CD (OR 0.67 [0.24-1.86]). Secondary analyses found better outcomes associated with IVIG plus glucocorticoids compared with glucocorticoids alone (fever ≥ day 2, need for secondary therapies) and better outcomes associated with glucocorticoids alone compared with IVIG alone (left ventricular ejection fraction < 55% ≥ day 2). LIMITATIONS: Nonrandomized nature of included studies. CONCLUSIONS: In a meta-analysis of MIS-C patients, IVIG plus glucocorticoids was associated with improved CD compared with IVIG alone. Glucocorticoids alone was not associated with improved CD compared with IVIG alone or IVIG plus glucocorticoids.

Neurological features related to influenza virus in the pediatric population: a 3-year monocentric retrospective study.

Influenza virus is generally characterized by fever, myalgia, and respiratory symptoms. Neurological entities have already been described, such as acute necrotizing encephalitis (ANE). We aimed to highlight the non-exceptional nature and explore the clinical spectrum and evolution of neurological features related to influenza virus in children. This monocentric observational study included patients under 18 years old, positive for influenza virus, between January 2017 and April 2019 in a pediatric university hospital. Patients were classified into two groups: those with or without a previous significant neurological or metabolic disorder. Two hundred eighty-nine children were identified with influenza infection. Thirty seven had a neurological manifestation: 14 patients who had previous significant neurological or metabolic disorder and 23 patients with no medical history. We identified several clinical patterns: 22 patients had seizures, 7 behavior disorders, 5 disturbances of consciousness, and 3 motor deficits. Four were diagnosed with a known influenza-associated neurological syndrome: 1 ANE, 1 cytotoxic lesion of the corpus callosum, 1 hemiconvulsion-hemiplegia-epilepsia syndrome, and 1 recurrent encephalitis in the context of a RANBP2 mutation. The neurological outcome was favorable in most cases. None of the patients with previous significant disorder retained sequalae or had a recurrence. Two patients had a fatal outcome, and both had a predisposing disorder. CONCLUSION: Various neurological manifestations can be associated with influenza virus. Certain entities led to a poor prognosis, but in most cases, symptoms improved within a few days. The severity of the neurological manifestations correlated with previous neurological or metabolic disorders. WHAT IS KNOWN: • Influenza viruses are well known pathogens with a seasonal epidemic evolution, particularly affecting children. These viruses cause acute fever with respiratory symptoms, associated with myalgia and headaches. Neurological presentation in influenza-virus infection is a well-established possibility as influenza virus is considered to be responsible for 27 to 36% of childhood encephalitis. Some specific and severe entity as acute necrotizing encephalitis, cytotoxic lesion of the corpus callosum, or Hemiconvulsion-hemiplegia-epilepsy syndrome are well described. WHAT IS NEW: • In a French monocentric cohort of 37 children with influenza-related neurologic manifestations, the majority of these manifestations, including seizure, drowsiness, motor deficiency, hallucination… are self limiting and do not lead to after-effects. In rare cases (4/37), they may reveal severe encephalitis requiring rapid and appropriate treatment. Otherwise, comparison of a group of 14 children with underlying neurological or metabolic disorder with a group of 23 children free of any significant disorder show that the severity of the neurological manifestations was largely related to previous neurological or metabolic disorders highlighting the importance of vaccination in this population.

Risk of Admission to the Pediatric Intensive Care Unit for SARS-CoV-2 Delta and Omicron Infections.

BACKGROUND: The severity of SARS-CoV-2-related diseases in children remains unclear. This study aimed to describe the incidence of French pediatric intensive care units (PICUs) admissions with acute COVID-19, incidental positive SARS-CoV-2 test result, and multisystem inflammatory syndrome in children (MIS-C) during the delta and omicron variant periods. METHODS: This study used the French PICU registry to obtain data on all patients admitted to 41 French PICUs diagnosed with acute COVID-19, incidental positive SARS-CoV-2 test result, or MIS-C between August 30, 2021 and April 20, 2022. Data regarding the total number of positive SARS-CoV-2 polymerase chain reaction results according to the type of variants were obtained from the French National Public Health Agency. RESULTS: Of 745 children, 244 (32.8%) were admitted for acute COVID-19, 246 (33.0%) for incidental positive SARS-CoV-2 test results, and 255 (34.2%) for MIS-C. The incidence of each group was higher with delta than with omicron. The incidence rate ratios with the delta variant were 7.47 (95% CI, 4.22-13.26) for acute COVID-19, 4·78 (95% CI, 2.30-9.94) for incidental positive SARS-CoV-2 test results, and 10.46 (95% CI, 5.98-18.31) for MIS-C compared to the omicron variant. The median age was 66 (7.7-126.8) months; 314 (42%) patients had comorbidities. Patients with acute COVID-19 and incidental positive SARS-CoV-2 test results had similar proportions of comorbidities. No patient with MIS-C died, whereas the mortality rates in the acute COVID-19 and incidental positive SARS-CoV-2 test results groups were 6.8% and 3.8%, respectively. CONCLUSIONS: The incidence of acute COVID-19, incidental positive SARS-CoV-2 test results, and MIS-C admitted to the PICU were significantly higher with the delta variant than with the omicron variant.

A high-throughput sequencing approach identifies immunotherapeutic targets for bacterial meningitis in neonates.

BACKGROUND: Worldwide, Escherichia coli is the leading cause of neonatal Gram-negative bacterial meningitis, but full understanding of the pathogenesis of this disease is not yet achieved. Moreover, to date, no vaccine is available against bacterial neonatal meningitis. METHODS: Here, we used Transposon Sequencing of saturated banks of mutants (TnSeq) to evaluate E. coli K1 genetic fitness in murine neonatal meningitis. We identified E. coli K1 genes encoding for factors important for systemic dissemination and brain infection, and focused on products with a likely outer-membrane or extra-cellular localization, as these are potential vaccine candidates. We used in vitro and in vivo models to study the efficacy of active and passive immunization. RESULTS: We selected for further study the conserved surface polysaccharide Poly-ß-(1-6)-N-Acetyl Glucosamine (PNAG), as a strong candidate for vaccine development. We found that PNAG was a virulence factor in our animal model. We showed that both passive and active immunization successfully prevented and/or treated meningitis caused by E. coli K1 in neonatal mice. We found an excellent opsonophagocytic killing activity of the antibodies to PNAG and in vitro these antibodies were also able to decrease binding, invasion and crossing of E. coli K1 through two blood brain barrier cell lines. Finally, to reinforce the potential of PNAG as a vaccine candidate in bacterial neonatal meningitis, we demonstrated that Group B Streptococcus, the main cause of neonatal meningitis in developed countries, also produced PNAG and that antibodies to PNAG could protect in vitro and in vivo against this major neonatal pathogen. INTERPRETATION: Altogether, these results indicate the utility of a high-throughput DNA sequencing method to identify potential immunotherapy targets for a pathogen, including in this study a potential broad-spectrum target for prevention of neonatal bacterial infections. FUNDINGS: ANR Seq-N-Vaq, Charles Hood Foundation, Hearst Foundation, and Groupe Pasteur Mutualité.

Respective roles of non-pharmaceutical interventions in bronchiolitis outbreaks: an interrupted time-series analysis based on a multinational surveillance system.

BACKGROUND: Bronchiolitis is a major source of morbimortality among young children worldwide. Non-pharmaceutical interventions (NPIs) implemented to reduce the spread of severe acute respiratory syndrome coronavirus 2 may have had an important impact on bronchiolitis outbreaks, as well as major societal consequences. Discriminating between their respective impacts would help define optimal public health strategies against bronchiolitis. We aimed to assess the respective impact of each NPI on bronchiolitis outbreaks in 14 European countries. METHODS: We conducted a quasi-experimental interrupted time-series analysis based on a multicentre international study. All children diagnosed with bronchiolitis presenting to the paediatric emergency department of one of 27 centres from January 2018 to March 2021 were included. We assessed the association between each NPI and change in the bronchiolitis trend over time by seasonally adjusted multivariable quasi-Poisson regression modelling. RESULTS: In total, 42 916 children were included. We observed an overall cumulative 78% (95% CI -100- -54%; p<0.0001) reduction in bronchiolitis cases following NPI implementation. The decrease varied between countries from -97% (95% CI -100- -47%; p=0.0005) to -36% (95% CI -79-7%; p=0.105). Full lockdown (incidence rate ratio (IRR) 0.21 (95% CI 0.14-0.30); p<0.001), secondary school closure (IRR 0.33 (95% CI 0.20-0.52); p<0.0001), wearing a mask indoors (IRR 0.49 (95% CI 0.25-0.94); p=0.034) and teleworking (IRR 0.55 (95% CI 0.31-0.97); p=0.038) were independently associated with reducing bronchiolitis. CONCLUSIONS: Several NPIs were associated with a reduction of bronchiolitis outbreaks, including full lockdown, school closure, teleworking and facial masking. Some of these public health interventions may be considered to further reduce the global burden of bronchiolitis.

Analysis of COVID-19 Vaccination Status Among Parents of Hospitalized Children Younger Than 5 Years With SARS-CoV-2 Infection During the Delta and Omicron Waves.

This cohort study uses COVID-19 Pediatric Observatory study data to analyze the vaccination status of parents with young children hospitalized for SARS-CoV-2 variants Delta and Omicron.

Correction to "Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study".

[This corrects the article DOI: 10.1016/j.lanepe.2022.100393.].

Incidence of Acute Chest Syndrome in Children With Sickle Cell Disease Following Implementation of the 13-Valent Pneumococcal Conjugate Vaccine in France.

Importance: Acute chest syndrome (ACS) is one of the leading acute severe complications of sickle-cell disease (SCD). Although Streptococcus pneumoniae (S pneumoniae) is highly prevalent in children with SCD, its precise role in ACS is unclear. The efficacy of 13-valent pneumococcal conjugate vaccine (PCV13) implementation on ACS is still unknown. Objective: To assess the association of PCV13 implementation in the general pediatric population with the incidence of ACS in children with SCD. Design, Setting, and Participants: This cohort study used an interrupted time-series analysis of patient records from a national hospital-based French surveillance system. All children younger than 18 years with SCD (based on the International Statistical Classification of Diseases and Related Health Problems, Tenth Revision definition) hospitalized in France between January 2007 and December 2019 were included. Exposures: PCV13 implementation. Main Outcomes and Measures: Monthly incidence of ACS per 1000 children with SCD over time as analyzed by segmented linear regression with autoregressive error; monthly incidence of hospitalization for vaso-occlusive crisis, asthma crisis, and acute pyelonephritis per 1000 children with SCD over the same period as the control outcomes. Results: Among the 107 694 hospitalizations of children with SCD, 4007 episodes of ACS were included (median [IQR] age, 8 [4-12] years; 2228 [55.6%] boys). PCV13 implementation in 2010 was followed by a significant decrease in the incidence of ACS (-0.9% per month; 95% CI, -1.4% to -0.4%; P < .001), with an estimated cumulative change of -41.8% (95% CI, -70.8% to -12.7%) by 2019. Sensitivity analyses yielded the same results, including the incidence of ACS adjusted for that of vaso-occlusive crisis over time. The results were similar among different age groups. By contrast, no change was found for the 3 control outcomes over the study period. Conclusions and Relevance: PCV13 implementation was associated with an important reduction in the incidence of ACS in children with SCD. This vaccine benefit provides new evidence of the key role of S pneumoniae in ACS and should be considered when estimating outcomes associated with current PCVs and the potential benefit of next-generation PCVs in children.

Natural history of Myhre syndrome.

BACKGROUND: Myhre syndrome (MS) is a rare genetic disease characterized by skeletal disorders, facial features and joint limitation, caused by a gain of function mutation in SMAD4 gene. The natural history of MS remains incompletely understood. METHODS: We recruited in a longitudinal retrospective study patients with molecular confirmed MS from the French reference center for rare skeletal dysplasia. We described natural history by chaining data from medical reports, clinical data warehouse, medical imaging and photographies. RESULTS: We included 12 patients. The median age was 22 years old (y/o). Intrauterine and postnatal growth retardation were consistently reported. In preschool age, neurodevelopment disorders were reported in 80% of children. Specifics facial and skeletal features, thickened skin and joint limitation occured mainly in school age children. The adolescence was marked by the occurrence of pulmonary arterial hypertension (PAH) and vascular stenosis. We reported for the first time recurrent strokes from the age of 26 y/o, caused by a moyamoya syndrome in one patient. Two patients died at late adolescence and in their 20 s respectively from PAH crises and mesenteric ischemia. CONCLUSION: Myhre syndrome is a progressive disease with severe multisystemic impairement and life-threathning complication requiring multidisciplinary monitoring.

Association of Nonpharmaceutical Interventions During the COVID-19 Pandemic With Invasive Pneumococcal Disease, Pneumococcal Carriage, and Respiratory Viral Infections Among Children in France.

Importance: An association between pneumococcal nasopharyngeal carriage and invasive pneumococcal disease (IPD) has been previously established. However, it is unclear whether the decrease in IPD incidence observed after implementation of nonpharmaceutical interventions (NPIs) during the COVID-19 pandemic was associated with concomitant changes in pneumococcal carriage and respiratory viral infections. Objective: To assess changes in IPD incidence after the implementation of NPIs during the COVID-19 pandemic and examine their temporal association with changes in pneumococcal carriage rate and respiratory viral infections (specifically respiratory syncytial virus [RSV] and influenza cases) among children in France. Design, Setting, and Participants: This cohort study used interrupted time series analysis of data from ambulatory and hospital-based national continuous surveillance systems of pneumococcal carriage, RSV and influenza-related diseases, and IPD between January 1, 2007, and March 31, 2021. Participants included 11 944 children younger than 15 years in France. Exposures: Implementation of NPIs during the COVID-19 pandemic. Main Outcomes and Measures: The estimated fraction of IPD change after implementation of NPIs and the association of this change with concomitant changes in pneumococcal carriage rate and RSV and influenza cases among children younger than 15 years. The estimated fraction of change was analyzed using a quasi-Poisson regression model. Results: During the study period, 5113 children (median [IQR] age, 1.0 [0.6-4.0] years; 2959 boys [57.9%]) had IPD, and 6831 healthy children (median [IQR] age, 1.5 [0.9-3.9] years; 3534 boys [51.7%]) received a swab test. Data on race and ethnicity were not collected. After NPI implementation, IPD incidence decreased by 63% (95% CI, -82% to -43%; P < .001) and was similar for non-13-valent pneumococcal conjugate vaccine serotypes with both high disease potential (-63%; 95% CI, -77% to -48%; P < .001) and low disease potential (-53%; 95% CI, -70% to -35%; P < .001). The overall pneumococcal carriage rate did not significantly change after NPI implementation (-12%; 95% CI, -37% to 12%; P = .32), nor did the carriage rate for non-PCV13 serotypes with high disease potential (-26%; 95% CI, -100% to 52%; P = .50) or low disease potential (-7%; 95% CI, -34% to 20%; P = .61). After NPI implementation, the estimated number of influenza cases decreased by 91% (95% CI, -74% to -97%; P < .001), and the estimated number of RSV cases decreased by 74% (95% CI, -55% to -85%; P < .001). Overall, the decrease in influenza and RSV cases accounted for 53% (95% CI, -28% to -78%; P < .001) and 40% (95% CI, -15% to -65%; P = .002) of the decrease in IPD incidence during the NPI period, respectively. The decrease in IPD incidence was not associated with pneumococcal carriage, with carriage accounting for only 4% (95% CI, -7% to 15%; P = .49) of the decrease. Conclusions and Relevance: In this cohort study of data from multiple national continuous surveillance systems, a decrease in pediatric IPD incidence occurred after the implementation of NPIs in France; this decrease was associated with a decrease in viral infection cases rather than pneumococcal carriage rate. The association between pneumococcal carriage and IPD was potentially modified by changes in the number of RSV and influenza cases, suggesting that interventions targeting respiratory viruses, such as immunoprophylaxis or vaccines for RSV and influenza, may be able to prevent a large proportion of pediatric IPD cases.

Hyper inflammatory syndrome following COVID-19 mRNA vaccine in children: A national post-authorization pharmacovigilance study.

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe clinical entity associated with pediatric SARS-CoV-2 infection with a putative role of the spike protein into the immune system activation. Whether COVID-19 mRNA vaccine can induce this complication in children is unknown. We aimed to assess the risk of hyper-inflammatory syndrome following COVID-19 mRNA vaccine in children. Methods: We conducted a post-authorization national population-based surveillance using the French enhanced pharmacovigilance surveillance system for COVID-19 vaccines. All cases of suspected hyper-inflammatory syndrome following COVID-19 mRNA vaccine in 12-17-year-old children between June 15th, 2021 and January 1st, 2022, were reported. Cases were reviewed according to WHO criteria for MIS-C. The reporting rate of this syndrome was compared to the MIS-C rate per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Findings: Up to January 2022, 8,113,058 COVID-19 mRNA vaccine doses were administered to 4,079,234 12-17-year-old children. Among them, 12 presented a hyper-inflammatory syndrome with multisystemic involvement. Main clinical features included male predominance (10/12, 83%), cardiac involvement (10/12, 83%), digestive symptoms (10/12, 83%), coagulopathy (7/12, 58%), cytolytic hepatitis (6/12, 50%), and shock (5/12, 42%). 4/12 (33%) required intensive care unit transfer, and 3/12 (25%) hemodynamic support. All cases recovered. In eight cases, no evidence of previous SARS-CoV-2 infection was found. The reporting rate was 1.5 (95%CI [0.8; 2.6]) per 1,000,000 doses injected, i.e. 2.9 (95%CI [1.5; 5.1]) per 1,000,000 12-17-year-old vaccinated children. As a comparison, 113 MIS-C (95%CI [95; 135]) occurred per 1,000,000 12-17-year-old children infected by SARS-CoV-2. Interpretation: Very few cases of hyper-inflammatory syndrome with multi-organ involvement occurred following COVID-19 mRNA vaccine in 12-17-year-old children. The low reporting rate of this syndrome, compared to the rate of post-SARS-CoV-2 MIS-C in the same age-group, largely supports the vaccination in a context of an important circulation of SARS-CoV-2. Funding: ESPID Fellowship Award; Grandir-Fonds de Solidarité Pour L'enfance.

Neuroinflammatory Disease following Severe Acute Respiratory Syndrome Coronavirus 2 Infection in Children.

OBJECTIVE: To describe neurologic, radiologic and laboratory features in children with central nervous system (CNS) inflammatory disease complicating severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. STUDY DESIGN: We focused on CNS inflammatory diseases in children referred from 12 hospitals in the Paris area to Necker-Sick Children Reference Centre. RESULTS: We identified 19 children who had a history of SARS-CoV-2 infection and manifest a variety of CNS inflammatory diseases: encephalopathy, cerebellar ataxia, acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, or optic neuritis. All patients had a history of SARS-CoV-2 exposure, and all tested positive for circulating antibodies against SARS-CoV-2. At the onset of the neurologic disease, SARS-CoV-2 PCR results (nasopharyngeal swabs) were positive in 8 children. Cerebrospinal fluid was abnormal in 58% (11/19) and magnetic resonance imaging was abnormal in 74% (14/19). We identified an autoantibody co-trigger in 4 children (myelin-oligodendrocyte and aquaporin 4 antibodies), representing 21% of the cases. No autoantibody was found in the 6 children whose CNS inflammation was accompanied by a multisystem inflammatory syndrome in children. Overall, 89% of patients (17/19) received anti-inflammatory treatment, primarily high-pulse methylprednisolone. All patients had a complete long-term recovery and, to date, no patient with autoantibodies presented with a relapse. CONCLUSIONS: SARS2-CoV-2 represents a new trigger of postinfectious CNS inflammatory diseases in children.

Shift in Clinical Profile of Hospitalized Pneumonia in Children in the Non-pharmaceutical Interventions Period During the COVID-19 Pandemic: A Prospective Multicenter Study.

Non-pharmaceutical interventions (NPIs) against coronavirus disease 2019 were implemented in March 2020. These measures were followed by a major impact on viral and non-viral diseases. We aimed to assess the impact of NPI implementation in France on hospitalized community-acquired pneumonia (hCAP) frequency and the clinical and biological characteristics of the remaining cases in children. We performed a quasi-experimental interrupted time-series analysis. Between June 2014 and December 2020, eight pediatric emergency departments throughout France reported prospectively all cases of hCAP in children from age 1 month to 15 years. We estimated the impact on the monthly number of hCAP using segmented linear regression with autoregressive error model. We included 2,972 hCAP cases; 115 occurred during the NPI implementation period. We observed a sharp decrease in the monthly number of hCAP after NPI implementation [-63.0% (95 confidence interval, -86.8 to -39.2%); p < 0.001]. Children with hCAP were significantly older during than before the NPI period (median age, 3.9 vs. 2.3 years; p < 0.0001), and we observed a higher proportion of low inflammatory marker status (43.5 vs. 33.1%; p = 0.02). Furthermore, we observed a trend with a decrease in the proportion of cases with pleural effusion (5.3% during the NPI period vs. 10.9% before the NPI; p = 0.06). NPI implementation during the COVID-19 (coronavirus disease 2019) pandemic led not only to a strong decrease in the number of hCAP cases but also a modification in the clinical profile of children affected, which may reflect a change in pathogens involved.