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.].

Saliva for molecular detection of SARS-CoV-2 in pre-school and school-age children.

SARS-CoV-2 diagnosis is a cornerstone for the management of coronavirus disease 2019 (COVID-19). Numerous studies have assessed saliva performance over nasopharyngeal sampling (NPS), but data in young children are still rare. We explored saliva performance for SARS-CoV-2 detection by RT-PCR according to the time interval from initial symptoms or patient serological status. We collected 509 NPS and saliva paired samples at initial diagnosis from 166 children under 12 years of age (including 57 children under 6), 106 between 12 and 17, and 237 adults. In children under 12, overall detection rate for SARS-CoV-2 was comparable in saliva and NPS, with an overall agreement of 89.8%. Saliva sensitivity was significantly lower than that of NPS (77.1% compared to 95.8%) in pre-school and school-age children but regained 96% when considering seronegative children only. This pattern was also observed to a lesser degree in adolescents but not in adults. Sensitivity of saliva was independent of symptoms, in contrary to NPS, whose sensitivity decreased significantly in asymptomatic subjects. Performance of saliva is excellent in children under 12 at early stages of infection. This reinforces saliva as a collection method for early and unbiased SARS-CoV-2 detection and a less invasive alternative for young children.

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.

Reassessing the Performance of the "Step-By-Step" Approach to Febrile Infants 90 Days of Age and Younger in the Context of the COVID-19 Pandemic: A Multicentric Retrospective Study.

BACKGROUND: Infants with COVID-19 can often present with fever without source, which is a challenging situation in infants <90 days old. The "step-by-step" algorithm has been proposed to identify children at high risk of bacterial infection. In the context of the COVID-19 pandemic, we aimed to reassess the diagnostic performance of this algorithm. METHODS: We performed a multicentric retrospective study in 3 French pediatric emergency departments between 2018 and 2020. We applied the "step-by-step" algorithm to 4 clinical entities: COVID-19, febrile urinary tract infections (FUTI), invasive bacterial infection (IBI), and enterovirus infections. The main outcome was the proportion of infants classified at high risk (ill-appearing, ≤21 days old, with leukocyturia or procalcitonin level ≥0.5 ng/mL). RESULTS: Among the 199 infants included, 40 had isolated COVID-19, 25 had IBI, 60 had FUTI, and 74 had enterovirus infection. All but 1 infant with bacterial infection were classified at high risk (96% for IBI and 100% for FUTI) as well as 95% with enterovirus and 82% with COVID-19. Infants with COVID-19 were classified at high risk because an ill-appearance (72%), an age ≤21 days (27%), or leukocyturia (19%). All these infants had procalcitonin values <0.5 ng/mL and only 1 had C-reactive protein level >20 mg/L. CONCLUSIONS: The "step-by-step" algorithm remains effective to identify infants with bacterial infection but misclassifies most infants with COVID-19 as at high risk of bacterial infection leading to unnecessary cares. An updated algorithm based adding viral testing may be needed to discriminate fever related to isolated COVID-19 in infants <90 days old.

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.

A monocyte/dendritic cell molecular signature of SARS-CoV-2-related multisystem inflammatory syndrome in children with severe myocarditis.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children is generally milder than in adults, but a proportion of cases result in hyperinflammatory conditions often including myocarditis. METHODS: To better understand these cases, we applied a multiparametric approach to the study of blood cells of 56 children hospitalized with suspicion of SARS-CoV-2 infection. Plasma cytokine and chemokine levels and blood cellular composition were measured, alongside gene expression at the bulk and single-cell levels. FINDINGS: The most severe forms of multisystem inflammatory syndrome in children (MIS-C) related to SARS-CoV-2 that resulted in myocarditis were characterized by elevated levels of pro-angiogenesis cytokines and several chemokines. Single-cell transcriptomics analyses identified a unique monocyte/dendritic cell gene signature that correlated with the occurrence of severe myocarditis characterized by sustained nuclear factor κB (NF-κB) activity and tumor necrosis factor alpha (TNF-α) signaling and associated with decreased gene expression of NF-κB inhibitors. We also found a weak response to type I and type II interferons, hyperinflammation, and response to oxidative stress related to increased HIF-1α and Vascular endothelial growth factor (VEGF) signaling. CONCLUSIONS: These results provide potential for a better understanding of disease pathophysiology. FUNDING: Agence National de la Recherche (Institut Hospitalo-Universitaire Imagine, grant ANR-10-IAHU-01; Recherche Hospitalo-Universitaire, grant ANR-18-RHUS-0010; Laboratoire d'Excellence ''Milieu Intérieur," grant ANR-10-LABX-69-01; ANR-flash Covid19 "AIROCovid" and "CoVarImm"), Institut National de la Santé et de la Recherche Médicale (INSERM), and the "URGENCE COVID-19" fundraising campaign of Institut Pasteur.

SARS-CoV-2 transmission among children and staff in daycare centres during a nationwide lockdown in France: a cross-sectional, multicentre, seroprevalence study.

BACKGROUND: The extent to which very young children contribute to the transmission of SARS-CoV-2 is unclear. We aimed to estimate the seroprevalence of antibodies against SARS-CoV-2 in daycare centres that remained open for key workers' children during a nationwide lockdown in France. METHODS: Children and staff who attended one of 22 daycare centres during a nationwide lockdown in France (between March 15 and May 9, 2020) were included in this cross-sectional, multicentre, seroprevalence study. Hospital staff not occupationally exposed to patients with COVID-19, or to children, were enrolled in a comparator group. The primary outcome was SARS-CoV-2 seroprevalence in children, daycare centre staff, and the comparator group. The presence of antibodies against SARS-CoV-2 in capillary whole blood was measured with a rapid chromatographic immunoassay. We computed raw prevalence as the percentage of individuals with a positive IgG or IgM test, and used Bayesian smoothing to account for imperfect sensitivity and specificity of the assay. This study is registered with ClinicalTrials.gov, NCT04413968. FINDINGS: Between June 4 and July 3, 2020, we enrolled 327 children (mean age 1·9 [SD 0·9] years; range 5 months to 4·4 years), 197 daycare centre staff (mean age 40 [12] years), and 164 adults in the comparator group (42 [12] years). Positive serological tests were observed for 14 children (raw seroprevalence 4·3%; 95% CI 2·6-7·1) and 14 daycare centre staff (7·7%; 4·2-11·6). After accounting for imperfect sensitivity and specificity of the assay, we estimated that 3·7% (95% credible interval [95% CrI] 1·3-6·8) of the children and 6·8% (3·2-11·5) of daycare centre staff had SARS-CoV-2 infection. The comparator group fared similarly to the daycare centre staff; nine participants had a positive serological test (raw seroprevalence 5·5%; 95% CI 2·9-10·1), leading to a seroprevalence of 5·0% (95% CrI 1·6-9·8) after accounting for assay characteristics. An exploratory analysis suggested that seropositive children were more likely than seronegative children to have been exposed to an adult household member with laboratory-confirmed COVID-19 (six [43%] of 14 vs 19 [6%] of 307; relative risk 7·1 [95% CI 2·2-22·4]). INTERPRETATION: According to serological test results, the proportion of young children in our sample with SARS-CoV-2 infection was low. Intrafamily transmission seemed more plausible than transmission within daycare centres. Further epidemiological studies are needed to confirm this exploratory hypothesis. FUNDING: Assistance Publique-Hôpitaux de Paris; Mairie de Paris, Conseil Départemental de Seine Saint Denis. TRANSLATIONS: For the French translation of the abstract see Supplementary Materials section.

Factors Associated With Severe SARS-CoV-2 Infection.

BACKGROUND: Initial reports on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in children suggested that very young age and comorbidities may increase risk of severe evolution, but these findings remained to be confirmed. We aimed to analyze the clinical spectrum of hospitalized pediatric SARS-CoV-2 infection and predictors of severe disease evolution. METHODS: We conducted a French national prospective surveillance of children hospitalized with SARS-CoV-2 infection. We included all children with confirmed SARS-CoV-2 infection in 60 hospitals during February 15 to June 1, 2020. The main outcome was the proportion of children with severe disease, defined by hemodynamic or ventilatory (invasive or not) support requirement. RESULTS: We included 397 hospitalized children with SARS-CoV-2 infection. We identified several clinical patterns, ranging from paucisymptomatic children, admitted for surveillance, to lower respiratory tract infection or multisystem inflammatory syndrome in children. Children <90 days old accounted for 37% of cases (145 of 397), but only 4 (3%) had severe disease. Excluding children with multisystem inflammatory syndrome in children (n = 29) and hospitalized for a diagnosis not related to SARS-CoV-2 (n = 62), 23 of 306 (11%) children had severe disease, including 6 deaths. Factors independently associated with severity were age ≥10 years (odds ratio [OR] = 3.4, 95% confidence interval: 1.1-10.3), hypoxemia (OR = 8.9 [2.6-29.7]), C-reactive protein level ≥80 mg/L (OR = 6.6 [1.4-27.5]). CONCLUSIONS: In contrast with preliminary reports, young age was not an independent factor associated with severe SARS-CoV-2 infection, and children <90 days old were at the lowest risk of severe disease evolution. This may help physicians to better identify risk of severe disease progression in children.