SARS-CoV-2 variants of concern in children and adolescents with COVID-19: a systematic review.

OBJECTIVES: Infections by SARS-CoV-2 variants of concern (VOCs) might affect children and adolescents differently than earlier viral lineages. We aimed to address five questions about SARS-CoV-2 VOC infections in children and adolescents: (1) symptoms and severity, (2) risk factors for severe disease, (3) the risk of infection, (4) the risk of transmission and (5) long-term consequences following a VOC infection. DESIGN: Systematic review. DATA SOURCES: The COVID-19 Open Access Project database was searched up to 1 March 2022 and PubMed was searched up to 9 May 2022. ELIGIBILITY CRITERIA: We included observational studies about Alpha, Beta, Gamma, Delta and Omicron VOCs among ≤18-year-olds. We included studies in English, German, French, Greek, Italian, Spanish and Turkish. DATA EXTRACTION AND SYNTHESIS: Two reviewers extracted and verified the data and assessed the risk of bias. We descriptively synthesised the data and assessed the risks of bias at the outcome level. RESULTS: We included 53 articles. Most children with any VOC infection presented with mild disease, with more severe disease being described with the Delta or the Gamma VOC. Diabetes and obesity were reported as risk factors for severe disease during the whole pandemic period. The risk of becoming infected with a SARS-CoV-2 VOC seemed to increase with age, while in daycare settings the risk of onward transmission of VOCs was higher for younger than older children or partially vaccinated adults. Long-term symptoms following an infection with a VOC were described in <5% of children and adolescents. CONCLUSION: Overall patterns of SARS-CoV-2 VOC infections in children and adolescents are similar to those of earlier lineages. Comparisons between different pandemic periods, countries and age groups should be improved with complete reporting of relevant contextual factors, including VOCs, vaccination status of study participants and the risk of exposure of the population to SARS-CoV-2. PROSPERO REGISTRATION NUMBER: CRD42022295207.

The role of children and adolescents in the SARS-CoV-2 pandemic: a rapid review.

BACKGROUND: There has been much discussion about coronavirus disease 2019 (COVID-19) and the virus that causes it, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adolescents, since the pandemic was recognised in early 2020. Understanding their role in this pandemic is important for the development of appropriate prevention measures. OBJECTIVE: To summarise evidence about three aspects of SARS-CoV-2 and COVID-19 in children and adolescents: (1) severity of SARS-CoV-2 presentation, (2) risk of SARS-CoV-2 infection and (3) risk of transmitting SARS-CoV-2.METHODS: We searched PubMed and MedRxiv for studies on SARS-CoV-2 and COVID-19 in children and adolescents from January 2020 to 21 January 2021. The electronic search was supplemented by papers found in a manual search or suggested by experts up to 29 March 2021. We included case reports, cross-sectional studies, cohort studies, narrative reviews or viewpoints, systematic reviews and modelling studies. We synthesised the information descriptively and attempted to report findings separately for: infants and small children (0-5 years) who are mostly pre-school; school children (6-12 years) broadly covering primary school years; and adolescents (13-17 years). RESULTS: Of 2778 screened articles, we included 63 (20 case reports, 18 cross-sectional studies, 8 cohort studies, 6 narrative reviews or viewpoints, 10 systematic reviews and 1 modelling study). Children (≤12 years of age) and adolescents (13-17 years of age) usually present with mild disease, with few requiring intensive care treatment. A minority of children of all ages (<18 years) remains asymptomatic throughout the course of infection. In serological studies, reported symptoms are similar in children with and without SARS-CoV-2 antibodies. Children and adolescents can acquire and transmit SARS-CoV-2. The risks of acquiring and transmitting SARS-CoV-2 seems to increase with age. There was limited information about SARS-CoV-2 variants of concern. Poor reporting of age groups and contextual factors such as levels of community transmission, school closures and other non-pharmaceutical interventions make synthesis of findings across studies difficult. CONCLUSIONS: The clinical presentation and role of children and adolescents in SARS-CoV-2 susceptibility and transmission needs further investigation, particularly with regard to variants of concern. Large, prospective studies that attempt to minimise biases in design, are analysed appropriately and reported comprehensively should be conducted.

The AMP-Related Kinase (AMPK) Induces Ca2+-Independent Dilation of Resistance Arteries by Interfering With Actin Filament Formation.

RATIONALE: Decreasing Ca2+ sensitivity of vascular smooth muscle (VSM) allows for vasodilation without lowering of cytosolic Ca2+. This may be particularly important in states requiring maintained dilation, such as hypoxia. AMP-related kinase (AMPK) is an important cellular energy sensor in VSM. Regulation of Ca2+ sensitivity usually is attributed to myosin light chain phosphatase activity, but findings in non-VSM identified changes in the actin cytoskeleton. The potential role of AMPK in this setting is widely unknown. OBJECTIVE: To assess the influence of AMPK on the actin cytoskeleton in VSM of resistance arteries with regard to potential Ca2+ desensitization of VSM contractile apparatus. METHODS AND RESULTS: AMPK induced a slowly developing dilation at unchanged cytosolic Ca2+ levels in potassium chloride-constricted intact arteries isolated from mouse mesenteric tissue. This dilation was not associated with changes in phosphorylation of myosin light chain or of myosin light chain phosphatase regulatory subunit. Using ultracentrifugation and confocal microscopy, we found that AMPK induced depolymerization of F-actin (filamentous actin). Imaging of arteries from LifeAct mice showed F-actin rarefaction in the midcellular portion of VSM. Immunoblotting revealed that this was associated with activation of the actin severing factor cofilin. Coimmunoprecipitation experiments indicated that AMPK leads to the liberation of cofilin from 14-3-3 protein. CONCLUSIONS: AMPK induces actin depolymerization, which reduces vascular tone and the response to vasoconstrictors. Our findings demonstrate a new role of AMPK in the control of actin cytoskeletal dynamics, potentially allowing for long-term dilation of microvessels without substantial changes in cytosolic Ca2+.

AMPK Dilates Resistance Arteries via Activation of SERCA and BKCa Channels in Smooth Muscle.

The protective effects of 5'-AMP-activated protein kinase (AMPK) on the metabolic syndrome may include direct effects on resistance artery vasomotor function. However, the precise actions of AMPK on microvessels and their potential interaction are largely unknown. Thus, we set to determine the effects of AMPK activation on vascular smooth muscle tone and the underlying mechanisms. Resistance arteries isolated from hamster and mouse exhibited a pronounced endothelium-independent dilation on direct pharmacological AMPK activation by 2 structurally unrelated compounds (PT1 and A769662). The dilation was associated with a decrease of intracellular-free calcium [Ca(2+)]i in vascular smooth muscle cell. AMPK stimulation induced activation of BKCa channels as assessed by patch clamp studies in freshly isolated hamster vascular smooth muscle cell and confirmed by direct proof of membrane hyperpolarization in intact arteries. The BKCa channel blocker iberiotoxin abolished the hyperpolarization but only partially reduced the dilation and did not affect the decrease of [Ca(2+)]i. By contrast, the sarcoplasmic/endoplasmic Ca(2+)-ATPase (SERCA) inhibitor thapsigargin largely reduced these effects, whereas combined inhibition of SERCA and BKCa channels virtually abolished them. AMPK stimulation significantly increased the phosphorylation of the SERCA modulator phospholamban at the regulatory T17 site. Stimulation of smooth muscle AMPK represents a new, potent vasodilator mechanism in resistance vessels. AMPK directly relaxes vascular smooth muscle cell by a decrease of [Ca(2+)]i. This is achieved by calcium sequestration via SERCA activation, as well as activation of BKCa channels. There is in part a mutual compensation of both calcium-lowering mechanisms. However, SERCA activation which involves an AMPK-dependent phosphorylation of phospholamban is the predominant mechanism in resistance vessels.