The genetics underlying severe COVID-19: The immune system is complex and involves many genes, including those that encode cytokines known as interferons (IFNs). Individuals that lack specific IFNs can be more susceptible to infectious diseases. Furthermore, the autoantibody system dampens IFN response to prevent damage from pathogen-induced inflammation. Two studies now examine the likelihood that genetics affects the risk of severe coronavirus disease 2019 (COVID-19) through components of this system (see the Perspective by Beck and Aksentijevich). Q. Zhang et al. used a candidate gene approach and identified patients with severe COVID-19 who have mutations in genes involved in the regulation of type I and III IFN immunity. They found enrichment of these genes in patients and conclude that genetics may determine the clinical course of the infection. Bastard et al. identified individuals with high titers of neutralizing autoantibodies against type I IFN-α2 and IFN-ω in about 10% of patients with severe COVID-19 pneumonia. These autoantibodies were not found either in infected people who were asymptomatic or had milder phenotype or in healthy individuals. Together, these studies identify a means by which individuals at highest risk of life-threatening COVID-19 can be identified. Science , this issue p. eabd4570 , p. eabd4585 ; see also p. 404

In late December 2019, the first pneumonia cases of unknown origin were identified in Wuhan, the capital city of Hubei province in central China.¹ The causative pathogen has been identified as a novel enveloped RNA betacoronavirus.² Given the phylogenetic similarity to the previously isolated severe acute respiratory syndrome coronavirus (SARS-CoV), the new virus has been named SARS-CoV-2.³

Immune and inflammatory responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) contribute to disease severity of coronavirus disease 2019 (COVID-19). However, the utility of specific immune-based biomarkers to predict clinical outcome remains elusive. Here, we analyzed levels of 66 soluble biomarkers in 175 Italian patients with COVID-19 ranging from mild/moderate to critical severity and assessed type I IFN–, type II IFN–, and NF-κB–dependent whole-blood transcriptional signatures. A broad inflammatory signature was observed, implicating activation of various immune and nonhematopoietic cell subsets. Discordance between IFN-α2a protein and IFNA2 transcript levels in blood suggests that type I IFNs during COVID-19 may be primarily produced by tissue-resident cells. Multivariable analysis of patients’ first samples revealed 12 biomarkers (CCL2, IL-15, soluble ST2 [sST2], NGAL, sTNFRSF1A, ferritin, IL-6, S100A9, MMP-9, IL-2, sVEGFR1, IL-10) that when increased were independently associated with mortality. Multivariate analyses of longitudinal biomarker trajectories identified 8 of the aforementioned biomarkers (IL-15, IL-2, NGAL, CCL2, MMP-9, sTNFRSF1A, sST2, IL-10) and 2 additional biomarkers (lactoferrin, CXCL9) that were substantially associated with mortality when increased, while IL-1α was associated with mortality when decreased. Among these, sST2, sTNFRSF1A, IL-10, and IL-15 were consistently higher throughout the hospitalization in patients who died versus those who recovered, suggesting that these biomarkers may provide an early warning of eventual disease outcome.

A systematic literature review was conducted up to 15th February 2022 to summarize long COVID evidence and to assess prevalence and clinical presentation in children and adolescents. Articles reporting long COVID prevalence and symptoms based on original data in the paediatric population were included. Case series quality was assessed through the JBI Critical Appraisal Checklist. For observational studies, adherence to STROBE checklist was evaluated. Twenty-two articles were included: 19 observational studies (12 cohort/7 cross-sectional) and 3 case series. Nine studies provided a control group. We found a high variability in terms of prevalence (1.6–70%). The most frequently reported symptoms were fatigue (2–87%), headache (3.5–80%), arthro-myalgias (5.4–66%), chest tightness or pain (1.4–51%), and dyspnoea (2–57.1%). Five studies reported limitations in daily function due to long COVID. Alterations at brain imaging were described in one study, transient electrocardiographic abnormalities were described in a minority of children, while most authors did not evidence long-term pulmonary sequelae. Older age, female sex, and previous long-term pathological conditions were more frequently associated with persistent symptoms.Conclusion: Long COVID evidence in children is limited, heterogeneous, and based on low-quality studies. The lockdown consequences are difficult to distinguish from long COVID symptoms. High-quality studies are required: WHO definition of long COVID should be used, controlled clinical studies should be encouraged, and the impact of new variants on long COVID prevalence should be investigated to ensure an objective analysis of long COVID characteristics in children and a proper allocation of healthcare system resources. What is Known:• Children rarely develop a severe respiratory disease in the acute phase of COVID-19.• A limited number of patients develop a multisystem inflammatory condition that can lead to multiorgan failure and shock. What is New:• Persistent symptoms after SARS-CoV-2 infection are reported in children and limitations in daily function due to long COVID symptoms affect school attendance.• Functional complaints of post-acute COVID are difficult to be distinguished from those due to social restrictions.

The process of obtaining informed consent for clinical trials is tightly regulated; complications arise in circumstances when consent may be waived, or when needed from vulnerable populationshttp://ow.ly/rEMe30j5MVq