Pharmacometric in silico studies used to facilitate a national dose standardisation process in neonatology - application to amikacin.

BACKGROUND AND AIMS: Pharmacometric in silico approaches are frequently applied to guide decisions concerning dosage regimes during the development of new medicines. We aimed to demonstrate how such pharmacometric modelling and simulation can provide a scientific rationale for optimising drug doses in the context of the Swiss national dose standardisation project in paediatrics using amikacin as a case study. METHODS: Amikacin neonatal dosage is stratified by post-menstrual age (PMA) and post-natal age (PNA) in Switzerland and many other countries. Clinical concerns have been raised for the subpopulation of neonates with a post-menstrual age of 30-35 weeks and a post-natal age of 0-14 days ("subpopulation of clinical concern"), as potentially oto-/nephrotoxic trough concentrations (Ctrough >5 mg/l) were observed with a once-daily dose of 15 mg/kg. We applied a two-compartmental population pharmacokinetic model (amikacin clearance depending on birth weight and post-natal age) to real-world demographic data from 1563 neonates receiving anti-infectives (median birth weight 2.3 kg, median post-natal age six days) and performed pharmacometric dose-exposure simulations to identify extended dosing intervals that would ensure non-toxic Ctrough (Ctrough <5 mg/l) dosages in most neonates. RESULTS: In the subpopulation of clinical concern, Ctrough <5 mg/l was predicted in 59% versus 79-99% of cases in all other subpopulations following the current recommendations. Elevated Ctrough values were associated with a post-natal age of less than seven days. Simulations showed that extending the dosing interval to ≥36 h in the subpopulation of clinical concern increased the frequency of a desirable Ctrough below 5 mg/l to >80%. CONCLUSION: Pharmacometric in silico studies using high-quality real-world demographic data can provide a scientific rationale for national paediatric dose optimisation. This may increase clinical acceptance of fine-tuned standardised dosing recommendations and support their implementation, including in vulnerable subpopulations.

Vaccine Immunity in Children After Hematologic Cancer Treatment: A Retrospective Single-center Study.

BACKGROUND: Children lose their vaccine-induced protection and are particularly vulnerable to vaccine-preventable diseases after chemotherapy. However, revaccination guidelines are heterogeneous, and there is often a lack of revaccination post-treatment. AIMS: We conducted a retrospective study of children with hematologic cancer to evaluate vaccine immunity before and after the end of treatment and to determine whether the current institutional revaccination program based on vaccine serology results was followed and effective. MATERIALS AND METHODS: Data of all children treated by chemotherapy between April 2015 and July 2021 were extracted from hospital medical records for analysis. Serum antibody levels and time of vaccination were evaluated for diphtheria, tetanus, Streptococcus pneumoniae , Haemophilus influenzae type b (Hib), measles, varicella, and hepatitis B. RESULTS: We included 31 patients (median age, 9 years). At cancer diagnosis, 90% of children were protected against tetanus, diphtheria, and measles; 65% to 67% were protected against pneumococcus and varicella; and 25% against hepatitis B. At the end of chemotherapy, 67% to 71% of patients were protected against tetanus, varicella, and measles; 40% remained protected against hepatitis B; and 27% to 33% against pneumococcus and diphtheria. Patients were revaccinated at various times after the end of treatment but not systematically. During the first-year post-treatment, 20% to 25% of children remained unprotected against pneumococcus, measles, and hepatitis B, one third against diphtheria, but all were protected against tetanus and varicella. CONCLUSIONS: An effective individualized vaccination program post-cancer based on serology results should be accompanied by an appropriate serology tracking method and follow-up to assess if booster doses are necessary. Our study supports vaccinating all children with a dose of the 13-valent pneumococcal conjugate at cancer diagnosis and at 3 months post-treatment with the combined diphtheria-tetanus-acellular pertussis/poliomyelitis vaccine/hepatitis B virus plus or minus Hib and 13-valent pneumococcal conjugate and meningococcal vaccine, including measles/mumps/rubella-varicella zoster virus vaccine if good immune reconstitution is present.

Organ Dysfunction in Children With Blood Culture-Proven Sepsis: Comparative Performance of Four Scores in a National Cohort Study.

OBJECTIVES: Previous studies applying Sepsis-3 criteria to children were based on retrospective analyses of PICU cohorts. We aimed to compare organ dysfunction criteria in children with blood culture-proven sepsis, including emergency department, PICU, and ward patients, and to assess relevance of organ dysfunctions for mortality prediction. DESIGN: We have carried out a nonprespecified, secondary analysis of a prospective dataset collected from September 2011 to December 2015. SETTING: Emergency departments, wards, and PICUs in 10 tertiary children's hospitals in Switzerland. PATIENTS: Children younger than 17 years old with blood culture-proven sepsis. We excluded preterm infants and term infants younger than 7 days old. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We compared the 2005 International Pediatric Sepsis Consensus Conference (IPSCC), Pediatric Logistic Organ Dysfunction-2 (PELOD-2), pediatric Sequential Organ Failure Assessment (pSOFA), and Pediatric Organ Dysfunction Information Update Mandate (PODIUM) scores, measured at blood culture sampling, to predict 30-day mortality. We analyzed 877 sepsis episodes in 807 children, with a 30-day mortality of 4.3%. Percentage with organ dysfunction ranged from 32.7% (IPSCC) to 55.3% (pSOFA). In adjusted analyses, the accuracy for identification of 30-day mortality was area under the curve (AUC) 0.87 (95% CI, 0.82-0.92) for IPSCC, 0.83 (0.76-0.89) for PELOD-2, 0.85 (0.78-0.92) for pSOFA, and 0.85 (0.78-0.91) for PODIUM. When restricting scores to neurologic, respiratory, and cardiovascular dysfunction, the adjusted AUC was 0.89 (0.84-0.94) for IPSCC, 0.85 (0.79-0.91) for PELOD-2, 0.87 (0.81-0.93) for pSOFA, and 0.88 (0.83-0.93) for PODIUM. CONCLUSIONS: IPSCC, PELOD-2, pSOFA, and PODIUM performed similarly to predict 30-day mortality. Simplified scores restricted to neurologic, respiratory, and cardiovascular dysfunction yielded comparable performance.

Congenital syphilis in Switzerland: a marker of inequality? A mini-review.

Syphilis remains a global public health problem, with growing incidence in most regions of the world, particularly among women of childbearing age. This alarming trend has led to an increase in cases of congenital syphilis, resulting in devastating consequences. While the implementation of measures by the World Health Organization (WHO) and various governments has contributed to a decline in the global incidence of congenital syphilis, many countries are facing an escalating crisis, as incidence continues to rise. This mini-review aims to provide an overview of the current state of this disease in different parts of the world, focusing on the most affected populations and highlighting congenital syphilis as a marker of vulnerability. It also focuses on Switzerland, a country with a robust economy, to identify shortcomings in the healthcare system that contribute to the persistence of congenital syphilis, even though the infection is easily detectable and treatable. In conclusion, this mini-review highlights the persistent risk of congenital syphilis worldwide, regardless of country prevalence or economic status, and underscores the need for sustained efforts to reach underserved women, emphasizing the vital role of comprehensive training for healthcare professionals.

Evaluation of Pupillometry for CYP2D6 Phenotyping in Children Treated with Tramadol.

Following the contraindication of codeine use in children, increasing use of tramadol has been observed in pain management protocols. However, tramadol's pharmacokinetics (PK) and pharmacodynamics are influenced by cytochrome P450 (CYP)2D6 activity, similarly to codeine. Previous studies in adults have demonstrated a correlation between pupillary response and tramadol PK. Our objective was to evaluate pupillometry as a phenotyping method to assess CYP2D6 activity in children treated with tramadol. We included 41 children (mean age 11 years) receiving a first dose of tramadol (2 mg/kg) in the emergency room (ER) as part of their routine care. CYP2D6 phenotyping and genotyping were performed. The concentrations of tramadol and its active metabolite, M1, were measured, and static and dynamic pupillometry was conducted using a handheld pupillometer at the time of tramadol administration and during the ER stay. Pupillometric measurements were obtained for 37 children. Tramadol affected pupillary parameters, with a decrease in pupil diameter in 83.8% of children (p = 0.002) (mean decrease 14.1 ± 16.7%) and a decrease in reflex amplitude constriction in 78.4% (p = 0.011) (mean decrease 17.7 ± 34.5%) at T150 compared to T0. We were unable to identify a correlation between pupillometry measurements and CYP2D6 activity. Likely confounding factors include light intensity, pain, and stress, making the procedure less feasible in paediatric emergency settings.

Socioeconomic conditions and children's mental health and quality of life during the COVID-19 pandemic: An intersectional analysis.

Background: Children and adolescents are highly vulnerable to the impact of sustained stressors during developmentally sensitive times. We investigated how demographic characteristics intersect with socioeconomic dimensions to shape the social patterning of quality of life and mental health in children and adolescents, two years into the COVID-19 pandemic. Methods: We used data from the prospective SEROCoV-KIDS cohort study of children and adolescents living in Geneva (Switzerland, 2022). We conducted an intersectional Multilevel Analysis of Individual Heterogeneity and Discriminatory Accuracy by nesting participants within 48 social strata defined by intersecting sex, age, immigrant background, parental education and financial hardship in Bayesian multilevel logistic models for poor health-related quality of life (HRQoL, measured with PedsQL) and mental health difficulties (measured with the Strengths and Difficulties Questionnaire). Results: Among participants aged 2-17 years, 240/2096 (11.5%, 95%CI 10.1-12.9) had poor HRQoL and 105/2135 (4.9%, 95%CI 4.0-5.9) had mental health difficulties. The predicted proportion of poor HRQoL ranged from 3.4% for 6-11 years old Swiss girls with highly educated parents and no financial hardship to 34.6% for 12-17 years old non-Swiss girls with highly educated parents and financial hardship. Intersectional strata involving adolescents and financial hardship showed substantially worse HRQoL than their counterparts. Between-stratum variations in the predicted frequency of mental health difficulties were limited (range 4.4%-6.5%). Conclusions: We found considerable differences in adverse outcomes across social strata. Our results suggest that, post-pandemic, interventions to address social inequities in HRQoL should focus on specific intersectional strata involving adolescents and families experiencing financial hardship, while those aiming to improve mental health should target all children and adolescents.

Sensitivity of ICD coding for sepsis in children-a population-based study.

Background: International Classification of Diseases 10th edition (ICD-10) is widely used to describe the burden of disease. Aim: To describe how well ICD-10 coding captures sepsis in children admitted to the hospital with blood culture-proven bacterial or fungal infection and systemic inflammatory response syndrome. Methods: Secondary analysis of a population-based, multicenter, prospective cohort study on children with blood culture-proven sepsis of nine tertiary pediatric hospitals in Switzerland. We compared the agreement of validated study data on sepsis criteria with ICD-10 coding abstraction obtained at the participating hospitals. Results: We analyzed 998 hospital admissions of children with blood culture-proven sepsis. The sensitivity of ICD-10 coding abstraction was 60% (95%-CI 57-63) for sepsis; 35% (95%-CI 31-39) for sepsis with organ dysfunction, using an explicit abstraction strategy; and 65% (95%-CI 61-69) using an implicit abstraction strategy. For septic shock, the sensitivity of ICD-10 coding abstraction was 43% (95%-CI 37-50). Agreement of ICD-10 coding abstraction with validated study data varied by the underlying infection type and disease severity (p < 0.05). The estimated national incidence of sepsis, inferred from ICD-10 coding abstraction, was 12.5 per 100,000 children (95%-CI 11.7-13.5) and 21.0 per 100,000 children (95%-CI 19.8-22.2) using validated study data. Conclusions: In this population-based study, we found a poor representation of sepsis and sepsis with organ dysfunction by ICD-10 coding abstraction in children with blood culture-proven sepsis when compared against a prospective validated research dataset. Sepsis estimates in children based on ICD-10 coding may thus severely underestimate the true prevalence of the disease. Supplementary Information: The online version contains supplementary material available at 10.1007/s44253-023-00006-1.

Factors associated with nonadherence to the American Academy of Pediatrics 2014 bronchiolitis guidelines: A retrospective study.

The latest guideline from the American Academy of Pediatrics for the management of bronchiolitis has helped reduce unnecessary interventions and costs. However, data on patients still receiving interventions are missing. In patients with acute bronchiolitis whose management was assessed and compared with current achievable benchmarks of care, we aimed to identify factors associated with nonadherence to guideline recommendations. In this single-centre retrospective study the management of bronchiolitis pre-guideline (Period 1: 2010 to 2012) was compared with two periods post-guideline (Period 2: 2015 to 2016, early post-guideline; and Period 3: 2017 to 2018, late post-guideline) in otherwise healthy infants aged less than 1 year presenting at the Children's University Hospitals of Geneva (Switzerland). Post-guideline, bronchodilators were more frequently administered to older (>6 months; OR 25.8, 95%CI 12.6-52.6), and atopic (OR 3.5, 95%CI 1.5-7.5) children with wheezing (OR 5.4, 95%CI 3.3-8.7). Oral corticosteroids were prescribed more frequently to older (>6 months; OR 5.2, 95%CI 1.4-18.7) infants with wheezing (OR 4.9, 95% CI 1.3-17.8). Antibiotics and chest X-ray were more frequently prescribed to children admitted to the intensive care unit (antibiotics: OR 4.2, 95%CI 1.3-13.5; chest X-ray: OR 19.4, 95%CI 7.4-50.6). Latest prescription rates were all below the achievable benchmarks of care. In summary, following the latest American Academy of Pediatrics guideline, older, atopic children with wheezing and infants admitted to the intensive care unit were more likely to receive nonevidence-based interventions during an episode of bronchiolitis. These patient profiles are generally excluded from bronchiolitis trials, and therefore not specifically covered by the current guideline. Further research should focus on the benefit of bronchiolitis interventions in these particular populations.

Impact of the COVID-19 pandemic on children and adolescents: determinants and association with quality of life and mental health-a cross-sectional study.

BACKGROUND: The medium-term impact of the COVID-19 pandemic on the wellbeing of children and adolescents remains unclear. More than 2 years into the pandemic, we aimed to quantify the frequency and determinants of having been severely impacted by the COVID-19 pandemic and estimate its impact on health-related quality of life (HRQoL) and mental health. METHODS: Data was drawn from a population-based cohort of children and adolescents, recruited between December 2021 and June 2022, in Geneva, Switzerland. The Coronavirus impact scale was used to assess the multidimensional impact of the pandemic on children through parent's report. A score higher than one standard deviation above the mean was deemed a severe impact. Parents additionally reported about their offspring HRQoL and mental health with validated scales. Determinants of having been severely impacted were assessed with logistic models, as were the associations between having experienced a severe impact and poor HRQoL or mental health. RESULTS: Out of 2101 participants aged 2-17, 12.7% had experienced a severe pandemic impact. Having a lasting health condition, a pandemic-related worsening of lifestyle habits or an unfavorable family environment were associated with having been severely impacted by the pandemic, while a previous anti-SARS-CoV-2 infection was not. Participants who had experienced a severe pandemic impact were more likely to present poor HRQoL (aOR = 3.1; 95% CI 2.3-4.4) and poor mental health (aOR = 3.9; 95% CI 2.5-6.2). CONCLUSION: The COVID-19 pandemic may have persistent consequences on the wellbeing of children and adolescents, especially among those with health and family vulnerabilities.

First nosocomial infections in children supported by veno-arterial extracorporeal membrane oxygenation (VA-ECMO).

BACKGROUND: Veno-arterial Extracorporeal Membrane Oxygenation (VA-ECMO) is a standard procedure for patient with refractory shock in Pediatric Intensive Care Unit (PICU). There is a paucity of data on the time relationship between VA-ECMO support, nosocomial infection occurrence, and PICU length of stay (LOS). The aim of this study was to determine the characteristics and impact of ECMO-related infections. METHODS: This is a retrospective study from 01/2008 to 12/2014, enrolling children with a VA-ECMO support for > 6 h. We recorded the first PICU infection during the VA-ECMO run, defined as a positive microbiological sample with clinical signs of infection or clinical signs of severe infection without positive sample. RESULTS: During the study period, 41 patients (25/41 male) were included, with a median age of 41.2 months (IQR 12.9-89.9) and a 53% mortality rate. Median time on VA-ECMO was 4.2 d (IQR 2-7.1), median PICU LOS was 14.7 d (IQR 4,7-26,9). Overall, 34% patients developed an infection, with an incidence of 60/1000 VA-ECMO days. Median time to first infection was 4 d (IQR 3-5), with Pseudomonas spp. being the most commonly detected microorganism (42%). Infected sites were ventilator-associated pneumonia (9/14), sternotomy infection (2/14), bloodstream (2/14) and urinary tract infections (1/14). Longer VA-ECMO support (> 5 d) (OR 5.9 (CI 95% 1.4-24.6; p = 0.01) and longer PICU stay (> 14 d) (OR 12 (95% CI 2.2-65.5; p = 0.004) were associated with infection. CONCLUSION: In this single-center study, we underlined the high proportion and early occurrence of infections in patient on VA-ECMO, mostly in the first week. As infection was an early event, it may prolong the duration of VA-ECMO support and PICU LOS. Further research is needed to better understand the impact of infections on VA-ECMO and develop prevention strategies.

Viremia as a predictor of absence of serious bacterial infection in children with fever without source.

Most children with fever without source (FWS) require diagnostic laboratory tests to exclude a serious bacterial infection (SBI), often followed by admission and empirical antibiotics. As febrile children with a viral infection are less likely to have a SBI, identifying patients with systemic viral infection could contribute to exclude SBI. We evaluated whether the presence of virus in the blood could be used as a biomarker to rule out SBI. Children < 3 years old with FWS were prospectively enrolled and had real-time (reverse-transcription) PCR performed on the blood for adenovirus, enterovirus, parechovirus, and HHV6. 20/135 patients had SBI, and in 47/135, at least one virus was detected in the blood. Viremia had a higher sensitivity and negative predictive value (90% and 96%) to rule out SBI compared to CRP (65% and 93%) and PCT (55% and 90%). The odds ratio (OR) for the presence of SBI among non-viremic patients was 5.8 (p = 0.0225), compared to 5.5 for CRP ≥ 40 mg/l (p = 0.0009) and 3.7 for PCT ≥ 0.5 ng/mL (0.0093). This remained significant after adjusting for CRP and PCT (OR 5.6 and 5.9, respectively; p = 0.03 for both). Area under the ROC curve for CRP and PCT were 0.754 and 0.779, respectively, but increased to 0.803 and 0.832, respectively, when combined with viremia. CONCLUSION: The presence of viremia had a better performance than commonly used biomarkers to rule-out SBI and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS. Larger studies should evaluate the role of point-of-care testing of viruses by (revere-transcription) PCR in the plasma in management algorithms of children with FWS. WHAT IS KNOWN: • Most children with FWS have a viral infection, but up to 15% have a SBI; most require laboratory tests, and many admission and empirical antibiotics. • Children with a viral infection are less likely to have a SBI. WHAT IS NEW: • Children with a systemic viral infection are less likely to have an SBI. • Viremia is a better predictor of absence of SBI than commonly used biomarkers and could potentially be used in conjunction with CRP and/or PCT in the evaluation of children with FWS.

Seroprevalence of anti-SARS-CoV-2 antibodies and cross-variant neutralization capacity after the Omicron BA.2 wave in Geneva, Switzerland: a population-based study.

Background: More than two years into the COVID-19 pandemic, most of the population has developed anti-SARS-CoV-2 antibodies from infection and/or vaccination. However, public health decision-making is hindered by the lack of up-to-date and precise characterization of the immune landscape in the population. Here, we estimated anti-SARS-CoV-2 antibodies seroprevalence and cross-variant neutralization capacity after Omicron became dominant in Geneva, Switzerland. Methods: We conducted a population-based serosurvey between April 29 and June 9, 2022, recruiting children and adults of all ages from age-stratified random samples of the general population of Geneva, Switzerland. We tested for anti-SARS-CoV-2 antibodies using commercial immunoassays targeting either the spike (S) or nucleocapsid (N) protein, and for antibody neutralization capacity against different SARS-CoV-2 variants using a cell-free Spike trimer-ACE2 binding-based surrogate neutralization assay. We estimated seroprevalence and neutralization capacity using a Bayesian modeling framework accounting for the demographics, vaccination, and infection statuses of the Geneva population. Findings: Among the 2521 individuals included in the analysis, the estimated total antibodies seroprevalence was 93.8% (95% CrI 93.1-94.5), including 72.4% (70.0-74.7) for infection-induced antibodies. Estimates of neutralizing antibodies in a representative subsample (N = 1160) ranged from 79.5% (77.1-81.8) against the Alpha variant to 46.7% (43.0-50.4) against the Omicron BA.4/BA.5 subvariants. Despite having high seroprevalence of infection-induced antibodies (76.7% [69.7-83.0] for ages 0-5 years, 90.5% [86.5-94.1] for ages 6-11 years), children aged <12 years had substantially lower neutralizing activity than older participants, particularly against Omicron subvariants. Overall, vaccination was associated with higher neutralizing activity against pre-Omicron variants. Vaccine booster alongside recent infection was associated with higher neutralizing activity against Omicron subvariants. Interpretation: While most of the Geneva population has developed anti-SARS-CoV-2 antibodies through vaccination and/or infection, less than half has neutralizing activity against the currently circulating Omicron BA.5 subvariant. Hybrid immunity obtained through booster vaccination and infection confers the greatest neutralization capacity, including against Omicron. Funding: General Directorate of Health in Geneva canton, Private Foundation of the Geneva University Hospitals, European Commission ("CoVICIS" grant), and a private foundation advised by CARIGEST SA.

A population-based serological study of post-COVID syndrome prevalence and risk factors in children and adolescents.

Post-COVID syndrome remains poorly studied in children and adolescents. Here, we aimed to investigate the prevalence and risk factors of pediatric post-COVID in a population-based sample, stratifying by serological status. Children from the SEROCoV-KIDS cohort study (State of Geneva, Switzerland), aged 6 months to 17 years, were tested for anti-SARS-CoV-2 N antibodies (December 2021-February 2022) and parents filled in a questionnaire on persistent symptoms in their children (lasting over 12 weeks) compatible with post-COVID. Of 1034 children tested, 570 (55.1%) were seropositive. The sex- and age-adjusted prevalence of persistent symptoms among seropositive children was 9.1% (95%CI: 6.7;11.8) and 5.0% (95%CI: 3.0;7.1) among seronegatives, with an adjusted prevalence difference (ΔaPrev) of 4.1% (95%CI: 1.1;7.3). Stratifying per age group, only adolescents displayed a substantial risk of having post-COVID symptoms (ΔaPrev = 8.3%, 95%CI: 3.5;13.5). Identified risk factors for post-COVID syndrome were older age, having a lower socioeconomic status and suffering from chronic health conditions, especially asthma. Our findings show that a significant proportion of seropositive children, particularly adolescents, experienced persistent COVID symptoms. While there is a need for further investigations, growing evidence of pediatric post-COVID urges early screening and primary care management.

Determinants of adolescents' Health-Related Quality of Life and psychological distress during the COVID-19 pandemic.

BACKGROUND: We examined the determinants of adolescents' Health-Related Quality of Life (HRQoL) and psychological distress (self-reported and parent-reported) during the COVID-19 pandemic, using a random sample of the population of Geneva, Switzerland. METHODS: Data was drawn from participants aged 14-17 years, who participated with their families to a serosurvey conducted in November and December 2020. Adolescents' HRQoL was evaluated using the validated adolescent-reported KIDSCREEN-10 and parent-reported KINDL® scales. Psychological distress was assessed with self-reported sadness and loneliness, and using the KINDL® emotional well-being scale. Using generalized estimating equations, we examined the role of socio-demographic, family and behavioural characteristics in influencing adolescents' mental health status and wellbeing. RESULTS: Among 240 adolescents, 11% had a low HRQoL, 35% reported sadness and 23% reported loneliness. Based on parents' perception, 12% of the adolescents had a low HRQoL and 16% a low emotional well-being. Being a girl (aOR = 3.20; 95%CI: 1.67-6.16), increased time on social media (aOR = 2.07; 95%CI: 1.08-3.97), parents' average to poor mood (aOR = 2.62; 95%CI: 1.10-6.23) and average to poor household financial situation (aOR = 2.31; IC95%: 1.01-6.10) were associated with an increased risk of sadness. Mismatches between adolescents' and their parents' perception of HRQoL were more likely for girls (aOR = 2.88; 95%CI: 1.54-5.41) and in households with lower family well-being (aOR = 0.91; 95%CI: 0.86-0.96). CONCLUSIONS: A meaningful proportion of adolescents experienced low well-being during the second wave of COVID-19, and average well-being was lower than pre-pandemic estimates. Adolescents living in underprivileged or distressed families seemed particularly affected. Monitoring is necessary to evaluate the long-term effects of the pandemic on adolescents.

Epidemiological, virological and serological investigation of a SARS-CoV-2 outbreak (Alpha variant) in a primary school: A prospective longitudinal study.

OBJECTIVES: To report a prospective epidemiological, virological and serological investigation of a SARS-CoV-2 outbreak in a primary school. METHODS: As part of a longitudinal, prospective, school-based surveillance study, this investigation involved repeated testing of 73 pupils, 9 teachers, 13 non-teaching staff and 26 household members of participants who tested positive, with rapid antigen tests and/or RT-PCR (Day 0-2 and Day 5-7), serologies on dried capillary blood samples (Day 0-2 and Day 30), contact tracing interviews and SARS-CoV-2 whole genome sequencing. RESULTS: We identified 20 children (aged 4 to 6 years from 4 school classes), 2 teachers and a total of 4 household members who were infected by the Alpha variant during this outbreak. Infection attack rates were between 11.8 and 62.0% among pupils from the 4 school classes, 22.2% among teachers and 0% among non-teaching staff. Secondary attack rate among household members was 15.4%. Symptoms were reported by 63% of infected children, 100% of teachers and 50% of household members. All analysed sequences but one showed 100% identity. Serological tests detected 8 seroconversions unidentified by SARS-CoV-2 virological tests. CONCLUSIONS: This study confirmed child-to-child and child-to-adult SARS-CoV-2 transmission and introduction into households. Effective measures to limit transmission in schools have the potential to reduce the overall community circulation.

Autoantibodies against apolipoprotein A-1 after COVID-19 predict symptoms persistence.

BACKGROUND: SARS-CoV-2 infection triggers different auto-antibodies, including anti-apolipoprotein A-1 IgGs (AAA1), which could be of concern as mediators of persistent symptoms. We determined the kinetics of AAA1 response over after COVID-19 and the impact of AAA1 on the inflammatory response and symptoms persistence. METHODS: All serologies were assessed at one, three, six and twelve months in 193 hospital employees with COVID-19. ROC curve analyses and logistic regression models (LRM) were used to determine the prognostic accuracy of AAA1 and their association with patient-reported COVID-19 symptoms persistence at 12 months. Interferon (IFN)-α and-γ production by AAA1-stimulated human monocyte-derived macrophages (HMDM) was assessed in vitro. RESULTS: AAA1 seropositivity was 93% at one month and declined to 15% at 12 months after COVID-19. Persistent symptoms at 12 months were observed in 45.1% of participants, with a predominance of neurological (28.5%), followed by general (15%) and respiratory symptoms (9.3%). Over time, strength of correlations between AAA1 and anti-SARS-COV2 serologies decreased, but remained significant. From the 3rd month on, AAA1 levels predicted persistent respiratory symptoms (area under the curves 0.72-0.74; p < 0.001), independently of disease severity, age and gender (adjusted odds ratios 4.81-4.94; p = 0.02), while anti-SARS-CoV-2 serologies did not. AAA1 increased IFN-α production by HMDMs (p = 0.03), without affecting the IFN-γ response. CONCLUSION: COVID-19 induces a marked though transient AAA1 response, independently predicting one-year persistence of respiratory symptoms. By increasing IFN-α response, AAA1 may contribute to persistent symptoms. If and how AAA1 levels assessment could be of use for COVID-19 risk stratification remains to be determined.