The increasing age of respiratory syncytial virus-related hospitalisation during COVID-19 pandemic in Lyon was associated with reduced hospitalisation costs.

BACKGROUND: Preventive measures applied during the COVID-19 pandemic have modified the age distribution, the clinical severity and the incidence of Respiratory Syncytial Virus (RSV) hospitalisations during the 2020/21 RSV season. The aim of the present study was to estimate the impact of these aspects on RSV-associated hospitalisations (RSVH) costs stratified by age group between pre-COVID-19 seasons and 2020/21 RSV season. METHODS: We compared the incidence, the median costs, and total RSVH costs from the national health insurance perspective in children < 24 months of age during the COVID-19 period (2020/21 RSV season) with a pre-COVID-19 period (2014/17 RSV seasons). Children were born and hospitalised in the Lyon metropolitan area. RSVH costs were extracted from the French medical information system (Programme de Médicalisation des Systémes d'Information). RESULTS: The RSVH-incidence rate per 1000 infants aged < 3 months decreased significantly from 4.6 (95 % CI [4.1; 5.2]) to 3.1 (95 % CI [2.4; 4.0]), and increased in older infants and children up to 24 months of age during the 2020/21 RSV season. Overall, RSVH costs for RSVH cases aged below 2 years old decreased by €201,770 (31 %) during 2020/21 RSV season compared to the mean pre-COVID-19 costs. CONCLUSIONS: The sharp reduction in costs of RSVH in infants aged < 3 months outweighed the modest increase in costs observed in the 3-24 months age group. Therefore, conferring a temporal protection through passive immunisation to infants aged < 3 months should have a major impact on RSVH costs even if it results in an increase of RSVH in older children infected later in life. Nevertheless, stakeholders should be aware of this potential increase of RSVH in older age groups presenting with a wider range of disease to avoid any bias in estimating the cost-effectiveness of passive immunisation strategies.

Polyclonal expansion of TCR Vbeta 21.3+ CD4+ and CD8+ T cells is a hallmark of Multisystem Inflammatory Syndrome in Children.

Multiple Inflammatory Syndrome in Children (MIS-C) is a delayed and severe complication of SARS-CoV-2 infection that strikes previously healthy children. As MIS-C combines clinical features of Kawasaki disease and Toxic Shock Syndrome (TSS), we aimed to compare the immunological profile of pediatric patients with these different conditions. We analyzed blood cytokine expression, and the T cell repertoire and phenotype in 36 MIS-C cases, which were compared to 16 KD, 58 TSS, and 42 COVID-19 cases. We observed an increase of serum inflammatory cytokines (IL-6, IL-10, IL-18, TNF-α, IFNγ, CD25s, MCP1, IL-1RA) in MIS-C, TSS and KD, contrasting with low expression of HLA-DR in monocytes. We detected a specific expansion of activated T cells expressing the Vß21.3 T cell receptor ß chain variable region in both CD4 and CD8 subsets in 75% of MIS-C patients and not in any patient with TSS, KD, or acute COVID-19; this correlated with the cytokine storm detected. The T cell repertoire returned to baseline within weeks after MIS-C resolution. Vß21.3+ T cells from MIS-C patients expressed high levels of HLA-DR, CD38 and CX3CR1 but had weak responses to SARS-CoV-2 peptides in vitro. Consistently, the T cell expansion was not associated with specific classical HLA alleles. Thus, our data suggested that MIS-C is characterized by a polyclonal Vß21.3 T cell expansion not directed against SARS-CoV-2 antigenic peptides, which is not seen in KD, TSS and acute COVID-19.

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.

Application of a forecasting model to mitigate the consequences of unexpected RSV surge: Experience from the post-COVID-19 2021/22 winter season in a major metropolitan centre, Lyon, France.

Background: The emergence of COVID-19 triggered the massive implementation of non-pharmaceutical interventions (NPI) which impacted the circulation of respiratory syncytial virus (RSV) during the 2020/2021 season. Methods: A time-series susceptible-infected-recovered (TSIR) model was used early September 2021 to forecast the implications of this disruption on the future 2021/2022 RSV epidemic in Lyon urban population. Results: When compared to observed hospital-confirmed cases, the model successfully captured the early start, peak timing, and end of the 2021/2022 RSV epidemic. These simulations, added to other streams of surveillance data, shared and discussed among the local field experts were of great value to mitigate the consequences of this atypical RSV outbreak on our hospital paediatric department. Conclusions: TSIR model, fitted to local hospital data covering large urban areas, can produce plausible post-COVID-19 RSV simulations. Collaborations between modellers and hospital management (who are both model users and data providers) should be encouraged in order to validate the use of dynamical models to timely allocate hospital resources to the future RSV epidemics.

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.].

Identifying the Target Population for Primary Respiratory Syncytial Virus Two-Step Prevention in Infants: Normative Outcome of Hospitalisation Assessment for Newborns (NOHAN).

BACKGROUND: Respiratory syncytial virus (RSV) is the leading cause of acute respiratory infection- related hospitalisations in infants (RSVh). Most of these infants are younger than 6 months old with no known risk factors. An efficient RSVh prevention program should address both mothers and infants, relying on Non-Pharmaceutical (NPI) and Pharmaceutical Interventions (PI). This study aimed at identifying the target population for these two interventions. METHODS: Laboratory-confirmed RSV-infected infants hospitalised during the first 6 months of life were enrolled from the Hospices Civils de Lyon birth cohort (2014 to 2018). Clinical variables related to pregnancy and birth (sex, month of birth, birth weight, gestational age, parity) were used for descriptive epidemiology, multivariate logistic regression, and predictive score development. RESULTS: Overall, 616 cases of RSVh in 45,648 infants were identified. Being born before the epidemic season, prematurity, and multiparity were independent predictors of RSVh. Infants born in January or June to August with prematurity and multiparity, and those born in September or December with only one other risk factor (prematurity or multiparity) were identified as moderate-risk, identifying the mothers as candidates for a first-level NPI prevention program. Infants born in September or December with prematurity and multiparity, and those born in October or November were identified as high-risk, identifying the mothers and infants as candidates for a second-level (NPI and PI) intervention. CONCLUSIONS: It is possible to determine predictors of RSVh at birth, allowing early enrollment of the target population in a two-level RSV prevention intervention.

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.

Impact of the French National Lockdown on Admissions to 14 Pediatric Intensive Care Units During the 2020 COVID-19 Pandemic-A Retrospective Multicenter Study.

Background: After the COVID-19 pandemic reached France in January 2020, a national lockdown including school closures was officially imposed from March 17, 2020, to May 10, 2020. Pediatric intensive care units (PICUs) admit critically ill infants, children and teenagers with severe acute conditions, in particular infectious and traumatic diseases. We hypothesized that PICU admissions would be considerably modified by the lockdown. Aims: The objectives of the study were to describe the type of admissions to French PICUs and to compare the occupation of PICU beds according to local epidemic conditions during the French national lockdown period, compared with the same period the previous year. Methods: We conducted a retrospective multicenter study in 14 French PICUs. All children aged from 7 days to 18 years admitted to one of the 14 participating PICUs over two 3-month period (March 1, 2020, to May 31, 2020 and March 1, 2019, to May 31, 2019) were included. Analysis was based on data extracted from the medicalized information systems program (a national database used in all French hospitals, into which all admissions and their diagnoses are coded for the purpose of calculating hospital funding). Each main diagnosis was reclassified in 13 categories, corresponding to normal PICU admissions. Results: We analyzed a total of 3,040 admissions, 1,323 during the 2020 study period and 1,717 during the same period in 2019. Total admissions decreased by 23% [incidence rate ratio (IRR) 0.77, 95% CI 0.71-0.83, p < 0.001], in particular for viral respiratory infections (-36%, IRR 0.64, 95% CI 0.44-0.94, p = 0.001). Admissions for almost all other diagnostic categories decreased, except intoxications and diabetes which increased, while admissions for cardiac and hemodynamic disorders were stable. Patient age and the sex ratio did not differ between the two periods. Median length of stay in the PICU was longer in 2020 [4 (IQR 2-9) vs. 3 (IQR 1-8) days, p = 0.002] in 2019. Mortality remained stable. Conclusions: In this large national study, we showed a decrease in the number of PICU admissions. The most severe patients were still admitted to intensive care and overall mortality remained stable.

Educational Setting and SARS-CoV-2 Transmission Among Children With Multisystem Inflammatory Syndrome: A French National Surveillance System.

Background: Multisystem inflammatory syndrome in children (MIS-C) is the most severe form associated with SARS-CoV-2 infection in children. To reduce the spread of SARS-CoV-2 at the population level, educational setting closure have been implemented in many countries. However, the direct benefit of school closure on the MIS-C burden remains to be explored. We aimed to assess the role of educational settings in SARS-CoV-2 transmission among children with MIS-C. Methods: We conducted a French national prospective surveillance of MIS-C, coordinated by Public Health France, from April 2020 to March 2021. During this period, we included all children with MIS-C fulfilling the WHO definition who were reported to Public Health France. For each child, we traced the source of SARS-CoV-2 transmission. The main outcome was the proportion of children with MIS-C, with educational setting-related SARS-CoV-2 infection, during the period of school opening. Results: We included 142 children fulfilling WHO criteria for MIS-C: 104 (70%) cases occurred during school opening periods. In total, 62/104 children (60%, 95%CI [50; 69]) had been contaminated by a household contact and 5/104 in educational settings (5%, 95%CI [2; 11]). Among children with MIS-C occurring during school closure periods, the proportion of household transmission remained similar (66%, 25/38). Conclusion: Children with MIS-C were mainly infected by SARS-CoV-2 within their family environment, and the educational setting played a marginal role in this transmission. This suggests that mitigating school attendance may not reduce substantially the burden of MIS-C.

Characteristics of the delayed respiratory syncytial virus epidemic, 2020/2021, Rhône Loire, France.

The Rhône-Loire metropolitan areas' 2020/21 respiratory syncytial virus (RSV) epidemic was delayed following the implementation of non-pharmaceutical interventions (NPI), compared with previous seasons. Very severe lower respiratory tract infection incidence among infants ≤ 3 months decreased twofold, the proportion of cases among children aged > 3 months to 5 years increased, and cases among adults > 65 years were markedly reduced. NPI appeared to reduce the RSV burden among at-risk groups, and should be promoted to minimise impact of future RSV outbreaks.

Type-I Interferon assessment in 45 minutes using the FilmArray® PCR platform in SARS-CoV-2 and other viral infections.

Low concentrations of type-I interferon (IFN) in blood seem to be associated with more severe forms of Coronavirus disease 2019 (COVID-19). However, following the type-I interferon response (IR) in early stage disease is a major challenge. We evaluated detection of a molecular interferon signature on a FilmArray® system, which includes PCR assays for four interferon stimulated genes. We analyzed three types of patient populations: (i) children admitted to a pediatric emergency unit for fever and suspected infection, (ii) ICU-admitted patients with severe COVID-19, and (iii) healthcare workers with mild COVID-19. The results were compared to the reference tools, that is, molecular signature assessed with Nanostring® and IFN-α2 quantification by SIMOA® (Single MOlecule Array). A strong correlation was observed between the IR measured by the FilmArray®, Nanostring®, and SIMOA® platforms (r-Spearman 0.996 and 0.838, respectively). The FilmArray® panel could be used in the COVID-19 pandemic to evaluate the IR in 45-min with 2 min hand-on-time at hospitalization and to monitor the IR in future clinical trials.

Association of Intravenous Immunoglobulins Plus Methylprednisolone vs Immunoglobulins Alone With Course of Fever in Multisystem Inflammatory Syndrome in Children.

Importance: Multisystem inflammatory syndrome in children (MIS-C) is the most severe pediatric disease associated with severe acute respiratory syndrome coronavirus 2 infection, potentially life-threatening, but the optimal therapeutic strategy remains unknown. Objective: To compare intravenous immunoglobulins (IVIG) plus methylprednisolone vs IVIG alone as initial therapy in MIS-C. Design, Setting, and Participants: Retrospective cohort study drawn from a national surveillance system with propensity score-matched analysis. All cases with suspected MIS-C were reported to the French National Public Health Agency. Confirmed MIS-C cases fulfilling the World Health Organization definition were included. The study started on April 1, 2020, and follow-up ended on January 6, 2021. Exposures: IVIG and methylprednisolone vs IVIG alone. Main Outcomes and Measures: The primary outcome was persistence of fever 2 days after the introduction of initial therapy or recrudescence of fever within 7 days, which defined treatment failure. Secondary outcomes included a second-line therapy, hemodynamic support, acute left ventricular dysfunction after first-line therapy, and length of stay in the pediatric intensive care unit. The primary analysis involved propensity score matching with a minimum caliper of 0.1. Results: Among 181 children with suspected MIS-C, 111 fulfilled the World Health Organization definition (58 females [52%]; median age, 8.6 years [interquartile range, 4.7 to 12.1]). Five children did not receive either treatment. Overall, 3 of 34 children (9%) in the IVIG and methylprednisolone group and 37 of 72 (51%) in the IVIG alone group did not respond to treatment. Treatment with IVIG and methylprednisolone vs IVIG alone was associated with lower risk of treatment failure (absolute risk difference, -0.28 [95% CI, -0.48 to -0.08]; odds ratio [OR], 0.25 [95% CI, 0.09 to 0.70]; P = .008). IVIG and methylprednisolone therapy vs IVIG alone was also significantly associated with lower risk of use of second-line therapy (absolute risk difference, -0.22 [95% CI, -0.40 to -0.04]; OR, 0.19 [95% CI, 0.06 to 0.61]; P = .004), hemodynamic support (absolute risk difference, -0.17 [95% CI, -0.34 to -0.004]; OR, 0.21 [95% CI, 0.06 to 0.76]), acute left ventricular dysfunction occurring after initial therapy (absolute risk difference, -0.18 [95% CI, -0.35 to -0.01]; OR, 0.20 [95% CI, 0.06 to 0.66]), and duration of stay in the pediatric intensive care unit (median, 4 vs 6 days; difference in days, -2.4 [95% CI, -4.0 to -0.7]). Conclusions and Relevance: Among children with MIS-C, treatment with IVIG and methylprednisolone vs IVIG alone was associated with a more favorable fever course. Study interpretation is limited by the observational design.

Caring for Critically Ill Children With Suspected or Proven Coronavirus Disease 2019 Infection: Recommendations by the Scientific Sections' Collaborative of the European Society of Pediatric and Neonatal Intensive Care.

OBJECTIVES: In children, coronavirus disease 2019 is usually mild but can develop severe hypoxemic failure or a severe multisystem inflammatory syndrome, the latter considered to be a postinfectious syndrome, with cardiac involvement alone or together with a toxic shock like-presentation. Given the novelty of severe acute respiratory syndrome coronavirus 2, the causative agent of the recent coronavirus disease 2019 pandemic, little is known about the pathophysiology and phenotypic expressions of this new infectious disease nor the optimal treatment approach. STUDY SELECTION: From inception to July 10, 2020, repeated PubMed and open Web searches have been done by the scientific section collaborative group members of the European Society of Pediatric and Neonatal Intensive Care. DATA EXTRACTION: There is little in the way of clinical research in children affected by coronavirus disease 2019, apart from descriptive data and epidemiology. DATA SYNTHESIS: Even though basic treatment and organ support considerations seem not to differ much from other critical illness, such as pediatric septic shock and multiple organ failure, seen in PICUs, some specific issues must be considered when caring for children with severe coronavirus disease 2019 disease. CONCLUSIONS: In this clinical guidance article, we review the current clinical knowledge of coronavirus disease 2019 disease in critically ill children and discuss some specific treatment concepts based mainly on expert opinion based on limited experience and the lack of any completed controlled trials in children at this time.