COVID-19 in children: what did we learn from the first wave?

A pandemic caused by the novel coronavirus, severe acute respiratory syndrome - coronavirus 2 (SARS-CoV-2), has caused high rates of mortality, predominantly in adults. Children are significantly less affected by SARS-CoV-2 with far lower rates of recorded infections in children compared to adults, milder symptoms in the majority of children and very low mortality rates. A suspected late manifestation of the disease, paediatric inflammatory multisystem syndrome - temporally associated with SARS-CoV-2 (PIMS-TS), has been seen in small numbers of children and has a more severe disease course than acute SARS-CoV-2. The pandemic has meant that children around the world have been kept off school, isolated from their extended family and friends and asked to stay inside. The UK has been declared as being in an economic recession and unemployment rates are increasing. These indirect effects of SARS-CoV-2 are likely to have a significant impact on many children for years to come. Consolidating the knowledge that has accumulated during the first wave of this pandemic is essential for recognising the clinical signs, symptoms and effective treatment strategies for children; identifying children who may be at increased risk of severe SARS-CoV-2 infection; planning the safe delivery of healthcare and non-health related services that are important for childrens' wellbeing; and engaging in, and developing, research to address the things that are not yet known. This article summarises the evidence that has emerged from the early phase of the pandemic and offers an overview for those looking after children or planning services.

Implementation of a centralized pharmacovigilance system in academic pan-European clinical trials: Experience from EU-Response and conect4children consortia.

Setting-up a high quality, compliant and efficient pharmacovigilance (PV) system in multi-country clinical trials can be more challenging for academic sponsors than for companies. To ensure the safety of all participants in academic studies and that the PV system fulfils all regulations, we set up a centralized PV system that allows sponsors to delegate work on PV. This initiative was put in practice by our Inserm-ANRS MIE PV department in two distinct multinational European consortia with 19 participating countries: conect4children (c4c) for paediatrics research and EU-Response for Covid-19 platform trials. The centralized PV system consists of some key procedures to harmonize the complex safety processes, creation of a local safety officer (LSO) network and centralization of all safety activities. The key procedures described the safety management plan for each trial and how tasks were shared and delegated between all stakeholders. Processing of serious adverse events (SAEs) in a unique database guaranteed the full control of the safety data and continuous evaluation of the risk-benefit ratio. The LSO network participated in efficient regulatory compliance across multiple countries. In total, there were 1312 SAEs in EU-Response and 83 SAEs in c4c in the four trials. We present here the lessons learnt from our experience in four clinical trials. We managed heterogeneous European local requirements and implemented efficient communication with all trial teams. Our approach builds capacity for PV that can be used by multiple academic sponsors.

Cost Utility Of Vaccination Against COVID-19 In Brazil

IntroductionThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), is a single-strand ribonucleic acid virus that was first identified in January 2020 in patients with viral pneumonia in Wuhan, China. The virus has since spread rapidly around the world, leading the World Health Organization to declare it a pandemic on 11 March 2020. In Brazil there have been 21.8 million cases of SARS-CoV-2 infection and 608,500 deaths. The objective of this study was to evaluate the cost utility of the Oxford, CoronaVac, and Janssen vaccines from the perspective of the Brazilian public health system.MethodsThree microsimulation models were constructed using individual data. The simulations contained seven transition states related to the natural history of COVID-19. The model with a daily cycle had a time horizon of one year and used data from 289 days of the pandemic. The analysis considered direct medical costs from the Brazilian health system perspective. Outpatient, hospital, and mortality databases were used for the model inputs and patient data were stratified by age. Effective vaccines reduced the likelihood of patients becoming ill. Information on the quality of life of patients receiving treatment in the outpatient or hospital setting and disease sequelae were extracted from the published literature. The main outcome of the analysis was quality-adjusted life-years (QALYs).ResultsThe vaccines had incremental cost-utility ratios ranging from USD 4,121 (Oxford) to USD 3,160 per QALY (CoronaVac). The older the population, the lower the incremental cost-utility ratio. Given a willingness-to-pay threshold of BRL 3,129 per QALY, all the vaccines were considered cost effective in the probabilistic sensitivity analysis. The incremental cost-effectiveness ratio stratified by age ranged from USD 6,327 per QALY in patients older than 75 years (Janssen) to USD 20,993 per QALY in patients younger than 59 years (CoronaVac).ConclusionsThe results of this analysis, stratified by patient age, can help in the preparation of a vaccination prioritization plan.

Reporting guideline for overviews of reviews of healthcare interventions: development of the PRIOR statement.

OBJECTIVE: To develop a reporting guideline for overviews of reviews of healthcare interventions. DESIGN: Development of the preferred reporting items for overviews of reviews (PRIOR) statement. PARTICIPANTS: Core team (seven individuals) led day-to-day operations, and an expert advisory group (three individuals) provided methodological advice. A panel of 100 experts (authors, editors, readers including members of the public or patients) was invited to participate in a modified Delphi exercise. 11 expert panellists (chosen on the basis of expertise, and representing relevant stakeholder groups) were invited to take part in a virtual face-to-face meeting to reach agreement (≥70%) on final checklist items. 21 authors of recently published overviews were invited to pilot test the checklist. SETTING: International consensus. INTERVENTION: Four stage process established by the EQUATOR Network for developing reporting guidelines in health research: project launch (establish a core team and expert advisory group, register intent), evidence reviews (systematic review of published overviews to describe reporting quality, scoping review of methodological guidance and author reported challenges related to undertaking overviews of reviews), modified Delphi exercise (two online Delphi surveys to reach agreement (≥70%) on relevant reporting items followed by a virtual face-to-face meeting), and development of the reporting guideline. RESULTS: From the evidence reviews, we drafted an initial list of 47 potentially relevant reporting items. An international group of 52 experts participated in the first Delphi survey (52% participation rate); agreement was reached for inclusion of 43 (91%) items. 44 experts (85% retention rate) completed the second Delphi survey, which included the four items lacking agreement from the first survey and five new items based on respondent comments. During the second round, agreement was not reached for the inclusion or exclusion of the nine remaining items. 19 individuals (6 core team and 3 expert advisory group members, and 10 expert panellists) attended the virtual face-to-face meeting. Among the nine items discussed, high agreement was reached for the inclusion of three and exclusion of six. Six authors participated in pilot testing, resulting in minor wording changes. The final checklist includes 27 main items (with 19 sub-items) across all stages of an overview of reviews. CONCLUSIONS: PRIOR fills an important gap in reporting guidance for overviews of reviews of healthcare interventions. The checklist, along with rationale and example for each item, provides guidance for authors that will facilitate complete and transparent reporting. This will allow readers to assess the methods used in overviews of reviews of healthcare interventions and understand the trustworthiness and applicability of their findings.

Cost Utility of Vaccination Against COVID-19 in Brazil.

OBJECTIVES: The objective of this study was to evaluate the cost-utility of the Oxford, CoronaVac, and Janssen COVID-19 vaccines from the perspective of the Brazilian public health system. METHODS: A total of 3 microsimulation models were constructed with individual data to evaluate the 3 vaccines. The simulation contains 7 transition states that are related to the natural history of the disease. The model with a daily cycle has a time horizon of 1 year and uses data from 289 days of the pandemic. The analysis was conducted from the perspective of the Brazilian public health system considering direct medical costs. For the model inputs, outpatient and hospital databases were used with information on treated patients stratified by age. Information on mortality was also stratified based on patients' age in the mortality database (SIM). The efficacy of vaccines to reduce the likelihood of patients becoming ill was evaluated independently for each vaccine. Information on the quality of life of patients in outpatient or hospital treatment and the sequelae resulting from the disease were extracted from the literature. The main outcome of the analysis was quality-adjusted life-years (QALYs). RESULTS: The vaccines showed incremental cost-utility ratios ranging from R$-23 161.3/QALY (Oxford) to R$17 757.85/QALY (CoronaVac). The older the population, the lower was the incremental cost-utility ratio. Given a willingness-to-pay threshold of R$17 586/QALY, all the vaccines were considered cost-effective in the probabilistic sensitivity analysis. CONCLUSIONS: The results of the analysis by age group can help in the preparation of a vaccination prioritization plan.

Impact of the COVID-19 Pandemic on Breast Cancer Management in Portugal: A Cross-Sectional Survey-Based Study of Medical Oncologists.

INTRODUCTION: Cancer care providers have faced many challenges in delivering safe care for patients during the COVID-19 pandemic. This cross-sectional survey-based study investigated the impact of the pandemic on clinical practices of Portuguese medical oncologists caring for patients with breast cancer. METHODS: An anonymous online survey comprising 42 questions gathered information regarding COVID-19 testing, treatment in (neo)adjuvant and metastatic settings, and other aspects of breast cancer management. Practices before and during the pandemic were compared, and potential differences in outcomes according to respondents' regions, case volumes, and practice type were explored. RESULTS: Of 129 respondents, 108 worked in the public health system, giving a representative national picture of the impact of the COVID-19 pandemic on breast cancer management. Seventy-one percent of respondents reported a reduction in visits for new cases of breast cancer, and there was a shift towards increased use of telemedicine. Clinical decision-making was largely unaffected in the most aggressive indications (i.e., triple-negative, HER2-positive, visceral crisis). The use of neoadjuvant therapy increased when access to surgery was difficult, whereas dose-dense regimens decreased, and cyclin-dependent kinase 4/6 inhibitor treatment decreased for less aggressive disease and increased for more aggressive disease. The use of oral formulations and metronomic chemotherapy regimens increased, and clinical trial participation decreased. Some differences by respondents' region and case volume were noted. CONCLUSION: Medical oncologists in Portugal implemented many changes during the COVID-19 pandemic, most of which were logical and reasonable responses to the current healthcare emergency; however, the true impact on patient outcomes remains unknown.

This study was an online survey of Portuguese medical oncologists to determine how they managed patients with breast cancer during the COVID-19 pandemic. Forty-two questions covered topics such as how COVID testing was done, the types of cancer treatments used, and how this compared to before the pandemic. It also examined whether the geographic region, the number of patients each doctor was responsible for (caseload), and the type of medical institution influenced how patients with breast cancer were managed. One hundred and twenty-nine oncologists completed the survey, of whom 108 worked in the public health system, making this survey representative of breast cancer management during the COVID-19 pandemic across Portugal. Most (71%) said there were fewer visits for new cases of breast cancer during lockdown. The use of telemedicine increased, as did the use of pre-surgery hormone therapy or chemotherapy when access to surgery was difficult, and the use of anticancer medications taken orally or metronomically (low doses given frequently over a long time period). Chemotherapy given very frequently (dose-dense) was used less often, and fewer patients participated in clinical trials. Treatment decisions for patients with aggressive breast cancer types (e.g., triple-negative breast cancer) were largely unchanged, except for greater use of cyclin-dependent kinase 4/6 inhibitors­drugs targeting the cell cycle and cell division control. Geographic region and caseload influenced treatment decisions. All of these changes in breast cancer treatment during the COVID-19 pandemic were logical and reasonable for the circumstances, but their long-term impact is not yet known.

An immunodominant NP105-113-B*07:02 cytotoxic T cell response controls viral replication and is associated with less severe COVID-19 disease.

NP105-113-B*07:02-specific CD8+ T cell responses are considered among the most dominant in SARS-CoV-2-infected individuals. We found strong association of this response with mild disease. Analysis of NP105-113-B*07:02-specific T cell clones and single-cell sequencing were performed concurrently, with functional avidity and antiviral efficacy assessed using an in vitro SARS-CoV-2 infection system, and were correlated with T cell receptor usage, transcriptome signature and disease severity (acute n = 77, convalescent n = 52). We demonstrated a beneficial association of NP105-113-B*07:02-specific T cells in COVID-19 disease progression, linked with expansion of T cell precursors, high functional avidity and antiviral effector function. Broad immune memory pools were narrowed postinfection but NP105-113-B*07:02-specific T cells were maintained 6 months after infection with preserved antiviral efficacy to the SARS-CoV-2 Victoria strain, as well as Alpha, Beta, Gamma and Delta variants. Our data show that NP105-113-B*07:02-specific T cell responses associate with mild disease and high antiviral efficacy, pointing to inclusion for future vaccine design.

Early Impact of Severe Acute Respiratory Syndrome Coronavirus 2 on Pediatric Clinical Research: A Pan-European and Canadian Snapshot in Time.

OBJECTIVE: To capture the early effects of the coronavirus disease 2019 (COVID-19) pandemic on pediatric clinical research. STUDY DESIGN: Pediatric clinical research networks from 20 countries and 50 of their affiliated research sites completed two surveys over one month from early May to early June 2020. Networks liaised with their affiliated sites and contributed to the interpretation of results through pan-European group discussions. Based on first detection dates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), countries formed 1 early detecting and 1 late detecting cluster. We tested the hypothesis that this clustering influenced clinical research. RESULTS: Research sites were first impacted by the pandemic in mid-March 2020 (March 16 ± 10 days, the same date as lockdown initiation; P = .99). From first impact up until early June, site initiation and feasibility analysis processes were affected for >50% of the sites. Staff were redirected to COVID-19 research for 44% of the sites, and 75.5% of sites were involved in pediatric COVID-19 research (only 6.3% reported COVID-19 cases in their other pediatric trials). Mitigation strategies were used differently between the early and late detecting country clusters and between countries with and without a pediatric COVID-19 research taskforce. Positive effects include the development of teleworking capacities. CONCLUSIONS: Through this collaborative effort from pediatric research networks, we found that pediatric trials were affected and conducted with a range of unequally applied mitigations across countries during the pandemic. The global impact might be greater than captured. In a context where clinical research is increasingly multinational, this report reveals the importance of collaboration between national networks.

The COVID-19 pandemic: An opportunity to rethink and harmonise the frequency of follow-up visits for patients with early stage breast cancer.

PURPOSE: While routine, in-person follow-up of early-stage breast cancer patients (EBC) after completion of initial treatment is common, the COVID-19 pandemic has resulted in unprecedented changes in clinical practice. A systematic review was performed to evaluate the evidence supporting different frequencies of routine follow-up. METHODS: MEDLINE and the Cochrane Collaboration Library were searched from database inception to July 16, 2020 for randomized controlled trials (RCTs) and prospective cohort studies (PCS) evaluating different frequencies of routine follow-up. Citations were assessed by pairs of independent reviewers. Risk of Bias (RoB) was assessed using the Cochrane RoB tool for RCTs and the Newcastle-Ottawa Quality Assessment Scale for Cohort Studies. Findings were summarized narratively. RESULTS: The literature search identified 3316 studies, of which 7 (6 RCTs and 1 PCS) were eligible. Study endpoints included; quality of life (QoL; 5 RCTs and 1 PCS), disease free survival (DFS) (1 RCT), overall survival (OS) (1 RCT) and cost-effectiveness (1 RCT). The results showed reduction in follow-up frequency had no adverse effect on: QoL (6 studies, n = 920), DFS (1 trial, n = 472) or OS (1 trial, n = 472), but improved cost-effectiveness (1 trial, n = 472). Four RCTs specifically examined follow-up on-demand versus scheduled follow-up visits and found no statistically significant differences in QoL (n = 544). CONCLUSION: While no evidence-based guidelines suggest that follow-up of EBC patients improves DFS or OS, routinely scheduled in-person assessment is common. RCT data suggests that reduced frequency of follow-up has no adverse effects.

Erratum to "COVID-19 in children: what did we learn from the first waveË® [Paediatr Child Health 30 (2020) 438-443/1496].

[This corrects the article DOI: 10.1016/j.paed.2020.09.005.].

Pediatric asthma and COVID-19: The known, the unknown, and the controversial.

The novel coronavirus disease-2019 (COVID-19), caused by the pathogen severe acute respiratory syndrome-CoV-2, is causing a global pandemic, with over 26.9 million cases and 880,000 deaths as of September 6, 2020. While there has been speculation and observational research about the impact of COVID-19 on asthma, much remains unknown. The goal of this article is to provide a scoping review on pediatric asthma and COVID-19 and summarize what we do and do not know from the first wave of the pandemic.

Nebulization procedures for children with unknown viral status during the COVID-19 pandemic.

During the Covid19 pandemic there has been much discussion about in-hospital procedures that may generate aerosols. One such procedure, that has led to confusion and concern, is nebulisation of children. In this paper, we discuss the evidence around whether nebulisation procedures generate aerosols, and offer strategies around nebulisation of children with asthma.