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Objective: Pro-resolving molecules, including the peptide Angiotensin-(1-7) [Ang-(1-7)], have potential adjunctive therapy for infections. Here we evaluate the actions of Ang-(1-7) in betacoronavirus infection in mice., Methods: C57BL/6J mice were infected intranasally with the murine betacoronavirus MHV-3 and K18-hACE2 mice were infected with SARS-CoV-2. Mice were treated with Ang-(1-7) (30 µg/mouse, i.p.) at 24-, 36-, and 48-hours post-infection (hpi) or at 24, 36, 48, 72, and 96 h. For lethality evaluation, one additional dose of Ang-(1-7) was given at 120 hpi. At 3- and 5-days post- infection (dpi) blood cells, inflammatory mediators, viral loads, and lung histopathology were evaluated., Results: Ang-(1-7) rescued lymphopenia in MHV-infected mice, and decreased airways leukocyte infiltration and lung damage at 3- and 5-dpi. The levels of pro-inflammatory cytokines and virus titers in lung and plasma were decreased by Ang-(1-7) during MHV infection. Ang-(1-7) improved lung function and increased survival rates in MHV-infected mice. Notably, Ang-(1-7) treatment during SARS-CoV-2 infection restored blood lymphocytes to baseline, decreased weight loss, virus titters and levels of inflammatory cytokines, resulting in improvement of pulmonary damage, clinical scores and lethality rates., Conclusion: Ang-(1-7) protected mice from lung damage and death during betacoronavirus infections by modulating inflammation, hematological parameters and enhancing viral clearance., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: Highly pathogenic coronaviruses (CoVs), such as severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV), and the most recent SARS-CoV-2 responsible for the COVID-19 pandemic, pose significant threats to human populations over the past two decades. These CoVs have caused a broad spectrum of clinical manifestations ranging from asymptomatic to severe distress syndromes (ARDS), resulting in high morbidity and mortality., Areas Covered: The accelerated advancements in antiviral drug discovery, spurred by the COVID-19 pandemic, have shed new light on the imperative to develop treatments effective against a broad spectrum of CoVs. This perspective discusses strategies and lessons learnt in targeting viral non-structural proteins, structural proteins, drug repurposing, and combinational approaches for the development of antivirals against CoVs., Expert Opinion: Drawing lessons from the pandemic, it becomes evident that the absence of efficient broad-spectrum antiviral drugs increases the vulnerability of public health systems to the potential onslaught by highly pathogenic CoVs. The rapid and sustained spread of novel CoVs can have devastating consequences without effective and specifically targeted treatments. Prioritizing the effective development of broad-spectrum antivirals is imperative for bolstering the resilience of public health systems and mitigating the potential impact of future highly pathogenic CoVs.

Libraries composed of licensed drugs represent a vast repertoire of molecules modulating physiological processes in humans, providing unique opportunities for the discovery of host-targeting antivirals. We screened the Repurposing, Focused Rescue, and Accelerated Medchem (ReFRAME) repurposing library with approximately 12,000 molecules for broad-spectrum coronavirus antivirals and discovered 134 compounds inhibiting an alphacoronavirus and mapping to 58 molecular target categories. Dominant targets included the 5-hydroxytryptamine receptor, the dopamine receptor, and cyclin-dependent kinases. Gene knock-out of the drugs' host targets including cathepsin B and L (CTSB/L; VBY-825), the aryl hydrocarbon receptor (AHR; Phortress), the farnesyl-diphosphate farnesyltransferase 1 (FDFT1; P-3622), and the kelch-like ECH-associated protein 1 (KEAP1; Omaveloxolone), significantly modulated HCoV-229E infection, providing evidence that these compounds inhibited the virus through acting on their respective host targets. Counter-screening of all 134 primary compound candidates with SARS-CoV-2 and validation in primary cells identified Phortress, an AHR activating ligand, P-3622-targeting FDFT1, and Omaveloxolone, which activates the NFE2-like bZIP transcription factor 2 (NFE2L2) by liberating it from its endogenous inhibitor KEAP1, as antiviral candidates for both an Alpha - and a Betacoronavirus . This study provides an overview of HCoV-229E repurposing candidates and reveals novel potentially druggable viral host dependency factors hijacked by diverse coronaviruses., Competing Interests: The authors declare no conflict of interest.

To combat SARS-CoV-2 variants and MERS-CoV, as well as the potential re-emergence of SARS-CoV and spillovers of sarbecoviruses, which pose a significant threat to global public health, vaccines that can confer broad-spectrum protection against betacoronaviruses (β-CoVs) are urgently needed. A mosaic ferritin nanoparticle vaccine is developed that co-displays the spike receptor-binding domains of SARS-CoV, MERS-CoV, and SARS-CoV-2 Wild-type (WT) strain and evaluated its immunogenicity and protective efficacy in mice and nonhuman primates. A low dose of 10 µg administered at a 21-day interval induced a Th1-biased immune response in mice and elicited robust cross-reactive neutralizing antibody responses against a variety of β-CoVs, including a series of SARS-CoV-2 variants. It is also able to effectively protect against challenges of SARS-CoV, MERS-CoV, and SARS-CoV-2 variants in not only young mice but also the more vulnerable mice through induction of long-lived immunity. Together, these results suggest that this mosaic 3-RBD nanoparticle has the potential to be developed as a pan-β-CoV vaccine., (© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.)

Coronaviruses are a group of related RNA viruses that cause respiratory diseases in humans and animals. Understanding the mechanisms of translation regulation during coronaviral infections is critical for developing antiviral therapies and preventing viral spread. Translation of the viral single-stranded RNA genome in the host cell cytoplasm is an essential step in the life cycle of coronaviruses, which affects the cellular mRNA translation landscape in many ways. Here we discuss various viral strategies of translation control, including how members of the Betacoronavirus genus shut down host cell translation and suppress host innate immune functions, as well as the role of the viral non-structural protein 1 (Nsp1) in the process. We also outline the fate of viral RNA, considering stress response mechanisms triggered in infected cells, and describe how unique viral RNA features contribute to programmed ribosomal -1 frameshifting, RNA editing, and translation shutdown evasion., (© 2024. The Author(s).)

Coronaviruses pose a permanent risk of outbreaks, with three highly pathogenic species and strains (SARS-CoV, MERS-CoV, SARS-CoV-2) having emerged in the last twenty years. Limited antiviral therapies are currently available and their efficacy in randomized clinical trials enrolling SARS-CoV-2 patients has not been consistent, highlighting the need for more potent treatments. We previously showed that cobicistat, a clinically approved inhibitor of Cytochrome P450-3A (CYP3A), has direct antiviral activity against early circulating SARS-CoV-2 strains in vitro and in Syrian hamsters. Cobicistat is a derivative of ritonavir, which is co-administered as pharmacoenhancer with the SARS-CoV-2 protease inhibitor nirmatrelvir, to inhibit its metabolization by CPY3A and preserve its antiviral efficacy. Here, we used automated image analysis for a screening and parallel comparison of the anti-coronavirus effects of cobicistat and ritonavir. Our data show that both drugs display antiviral activity at low micromolar concentrations against multiple SARS-CoV-2 variants in vitro, including epidemiologically relevant Omicron subvariants. Despite their close structural similarity, we found that cobicistat is more potent than ritonavir, as shown by significantly lower EC50 values in monotherapy and higher levels of viral suppression when used in combination with nirmatrelvir. Finally, we show that the antiviral activity of both cobicistat and ritonavir is maintained against other human coronaviruses, including HCoV-229E and the highly pathogenic MERS-CoV. Overall, our results demonstrate that cobicistat has more potent anti-coronavirus activity than ritonavir and suggest that dose adjustments could pave the way to the use of both drugs as broad-spectrum antivirals against highly pathogenic human coronaviruses., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Iart Luca Shytaj is inventor of a patent application covering the use of cobicistat for treatment of coronavirus infection., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Importance: The function of betacoronavirus internal protein has been relatively understudied. The earliest report on the internal protein of mouse hepatitis virus suggested that the internal protein is a structural protein without significant functions in virus replication and virulence. However, the internal proteins of s evere a cute r espiratory s yndrome c oronavirus (SARS-CoV), Middle-East respiratory syndrome coronavirus, and SARS-CoV-2 have been shown to evade immune responses. Despite the reported functions of the internal protein in these highly pathogenic human coronaviruses, its role in mediating pathogenesis in experimentally infected animals has not been characterized. Our data indicated that despite the similar genomic location and expression strategy of these internal proteins, their effects on virulence are vastly different and virus specific, highlighting the complexity between host-virus interaction and disease outcome., Competing Interests: N.C.W. consults for HeliXon. The authors have no other competing interests, financial or non-financial.

Lipids perform a series of cellular functions, establishing cell and organelles' boundaries, organizing signaling platforms, and creating compartments where specific reactions occur. Moreover, lipids store energy and act as secondary messengers whose distribution is tightly regulated. Disruption of lipid metabolism is associated with many diseases, including those caused by viruses. In this scenario, lipids can favor virus replication and are not solely used as pathogens' energy source. In contrast, cells can counteract viruses using lipids as weapons. In this review, we discuss the available data on how coronaviruses profit from cellular lipid compartments and why targeting lipid metabolism may be a powerful strategy to fight these cellular parasites. We also provide a formidable collection of data on the pharmacological approaches targeting lipid metabolism to impair and treat coronavirus infection., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Cesar-Silva, Pereira-Dutra, Giannini, Maya-Monteiro and de Almeida.)

In the last decades, the interest in bioactive compounds derived from natural sources including bacteria, fungi, plants, and algae has significantly increased. It is well-known that aquatic or terrestrial organisms can produce, in special conditions, secondary metabolites with a wide range of biological properties, such as anticancer, antioxidant, anti-inflammatory, and antimicrobial activities. In this study, we focused on the extremophilic microalga Galdieria sulphuraria as a possible producer of bioactive compounds with antiviral activity. The algal culture was subjected to organic extraction with acetone. The cytotoxicity effect of the extract was evaluated by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The antiviral activity was assessed through a plaque assay against herpesviruses and coronaviruses as enveloped viruses and poliovirus as a naked one. The monolayer was treated with different concentrations of extract, ranging from 1 µg/mL to 200 µg/mL, and infected with viruses. The algal extract displayed strong antiviral activity at non-toxic concentrations against all tested enveloped viruses, in particular in the virus pre-treatment against HSV-2 and HCoV-229E, with IC 50 values of 1.7 µg/mL and IC 90 of 1.8 µg/mL, respectively. However, no activity against the non-enveloped poliovirus has been detected. The inhibitory effect of the algal extract was confirmed by the quantitative RT-PCR of viral genes. Preliminary chemical profiling of the extract was performed using ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS), revealing the enrichment in primary fatty acid amides (PFAA), such as oleamide, palmitamide, and pheophorbide A. These promising results pave the way for the further purification of the mixture to explore its potential role as an antiviral agent.

Coronaviruses (CoVs) are enveloped and positive-stranded RNA viruses with a large genome (∼ 30kb). CoVs include essential genes, such as the replicase and four genes coding for structural proteins (S, M, N and E), and genes encoding accessory proteins, which are variable in number, sequence and function among different CoVs. Accessory proteins are non-essential for virus replication, but are frequently involved in virus-host interactions associated with virulence. The scientific literature on CoV accessory proteins includes information analyzing the effect of deleting or mutating accessory genes in the context of viral infection, which requires the engineering of CoV genomes using reverse genetics systems. However, a considerable number of publications analyze gene function by overexpressing the protein in the absence of other viral proteins. This ectopic expression provides relevant information, although does not acknowledge the complex interplay of proteins during virus infection. A critical review of the literature may be helpful to interpret apparent discrepancies in the conclusions obtained by different experimental approaches. This review summarizes the current knowledge on human CoV accessory proteins, with an emphasis on their contribution to virus-host interactions and pathogenesis. This knowledge may help the search for antiviral drugs and vaccine development, still needed for some highly pathogenic human CoVs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hurtado-Tamayo, Requena-Platek, Enjuanes, Bello-Perez and Sola.)

Background: Multisystem inflammatory syndrome in children (MIS-C) is a severe disease with an unpredictable course and a substantial risk of cardiogenic shock. Our objectives were to (a) compare MIS-C phenotypes across the COVID-19 pandemic, (b) identify features associated with intensive care need and treatment with biologic agents., Methods: Youth aged 0-18 years, fulfilling the World Health Organization case definition of MIS-C, and admitted to the Alberta Children's Hospital during the first four waves of the COVID-19 pandemic (May 2020-December 2021) were included in this cohort study. Demographic, clinical, biochemical, imaging, and treatment data were captured., Results: Fifty-seven MIS-C patients (median age 6 years, range 0-17) were included. Thirty patients (53%) required intensive care. Patients in the third or fourth wave (indicated as phase 2 of the pandemic) presented with higher peak ferritin (µg/l, median (IQR) = 1134 (409-1806) vs. 370 (249-629), P = 0.001), NT-proBNP (ng/l, median (IQR) = 12,217 (3013-27,161) vs. 3213 (1216-8483), P = 0.02) and D-dimer (mg/l, median (IQR) = 4.81 (2.24-5.37) vs. 2.01 (1.27-3.34), P = 0.004) levels, and higher prevalence of liver enzyme abnormalities (n(%) = 17 (68) vs. 11 (34), P = 0.02), hypoalbuminemia (n(%) = 24 (100) vs. 25 (81), P = 0.03) and thrombocytopenia (n(%) 18 (72) vs. 11 (34), P = 0.007) compared to patients in the first two waves (phase 1). These patients had a higher need of non-invasive/mechanical ventilation (n(%) 4 (16) vs. 0 (0), P = 0.03). Unsupervised clustering analyses classified 47% of the patients in the correct wave and 74% in the correct phase of the pandemic. NT-proBNP was the only significant contributor to the need for intensive care in all applied multivariate regression models. Treatment with biologic agents was significantly associated with peak CRP (mg/l (median, IQR = 240.9 (132.9-319.4) vs. 155.8 (101.0-200.7), P = 0.02) and ferritin levels (µg/l, median (IQR) = 1380 (509-1753) vs. 473 (280-296))., Conclusions: MIS-C patients in a later stage of the pandemic displayed a more severe phenotype, reflecting the impact of distinct SARS-CoV-2 variants. NT-proBNP emerged as the most crucial feature associated with intensive care need, underscoring the importance of monitoring., (© 2023. The Author(s).)

The purpose of this study is to assess the rate, clinical picture, and management of multisystem inflammatory syndrome in children (MIS-C) during the different COVID-19 variants of concern (VOC) domination periods. This was a retrospective analysis of prospectively collected data. The incidence and clinical picture of MIS-C during the original/Alpha (group 1) and Delta/Omicron (Group 2) variant domination periods were compared. Among 108 eligible patients, 74 (68.5%) were hospitalized during the group 1 domination period, and 34 (31.5%) were hospitalized during the group 2 domination period. The median (Me) patient ages were 76 months (interquartile range [IQR] 35-130) and 73 months (IQR 45-118), and 61% and 65% of patients were male, respectively. There was no significant difference in the presence of positive SARS-CoV 2 antibody test results (IgM or IgG) between the groups (84 vs. 90%; p = 0.54).No differences between groups were observed in fever duration prior to admission (Me [IQR]: 5 days [3-6] vs. 5 days [4-6]; p = 0.26) or the presence of mucocutaneous (95 vs. 100%; p = 0.41), circulatory (70.3 vs. 61.8%; p = 0.86), neurological (6.8 vs. 2.9%; p = 0.662), or gastrointestinal symptoms (84 vs. 79%; p = 0.59). Respiratory symptoms were more common in group 2 (70 vs. 91%; p = 0.015). The need for intensive care unit admission was similar in both groups (16.2 vs. 17.6%, p = 1.0). No deaths occurred in the entire cohort. The studied children were characterized by high C-reactive protein and procalcitonin levels, concentrations of ferritin within normal limits, lymphopenia, moderate hypoalbuminemia, and high B-type natriuretic peptide/brain natriuretic peptide (NT-proBNP) concentrations; however, there were no differences between the groups. Intravenous immunoglobulins were administered as a first-line treatment for almost all patients. There was no significant difference in corticosteroid administration between the groups (87% vs. 74%; p = 0.11); however, the summary dose of methylprednisolone was higher in group 2 (Me [IQR]″ 12.6 mg/kg [10.5-17.8] vs. 16.4 mg/kg [13.3-19.5]; p = 0.03). The median length of stay was 11 days [IQR]: [9-14] and 10 days [8-12], respectively (p = 0.065)., Conclusion: The clinical course of MIS-C is similar in subsequent pandemic waves; however, the incidence of MIS-C seems to be decreasing., What Is Known: • The clinical picture of COVID-19 is evolving. Multisystem inflammatory syndrome in children (MIS-C) is a relatively new serious disease connected with SARS-CoV-2 infection, and in subsequent waves of the pandemic, new cases of the disease have been recorded., What Is New: • The clinical picture of MIS-C is not specific, but the course is still severe. • The incidence of MIS-C during the different pandemic waves is decreasing and the diagnosis in the period of lower prevalance is challenging., (© 2023. The Author(s).)

The fusion of viral and cell membranes is one of the basic processes in the life cycles of viruses. A number of enveloped viruses confer fusion of the viral envelope and the cell membrane using surface viral fusion proteins. Their conformational rearrangements lead to the unification of lipid bilayers of cell membranes and viral envelopes and the formation of fusion pores through which the viral genome enters the cytoplasm of the cell. A deep understanding of all the stages of conformational transitions preceding the fusion of viral and cell membranes is necessary for the development of specific inhibitors of viral reproduction. This review systematizes knowledge about the results of molecular modeling aimed at finding and explaining the mechanisms of antiviral activity of entry inhibitors. The first section of this review describes types of viral fusion proteins and is followed by a comparison of the structural features of class I fusion proteins, namely influenza virus hemagglutinin and the S-protein of the human coronavirus.

Seasonal coronaviruses have been circulating widely in the human population for many years. With increasing age, humans are more likely to have been exposed to these viruses and to have developed immunity against them. It has been hypothesized that this immunity to seasonal coronaviruses may provide partial protection against infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and it has also been shown that coronavirus disease 2019 (COVID-19) vaccination induces a back-boosting effects against the spike proteins of seasonal betacoronaviruses. In this study, we tested if immunity to the seasonal coronavirus spikes from OC43, HKU1, 229E, or NL63 would confer protection against SARS-CoV-2 challenge in a mouse model, and whether pre-existing immunity against these spikes would weaken the protection afforded by mRNA COVID-19 vaccination. We found that mice vaccinated with the seasonal coronavirus spike proteins had no increased protection compared to the negative controls. While a negligible back-boosting effect against betacoronavirus spike proteins was observed after SARS-CoV-2 infection, there was no negative original antigenic sin-like effect on the immune response and protection induced by SARS-CoV-2 mRNA vaccination in animals with pre-existing immunity to seasonal coronavirus spike proteins. IMPORTANCE The impact that immunity against seasonal coronaviruses has on both susceptibility to SARS-CoV-2 infection as well as on COVID-19 vaccination is unclear. This study provides insights into both questions in a mouse model of SARS-CoV-2.

Objectives: We aim to describe the early and upto 16 months follow-up of post-coronavirus disease (COVID), multi-system inflammatory syndrome in children (MIS-C), with special reference to cardiac involvement., Study Design: This cohort non-interventional descriptive study included patients <18 years admitted between May, 2020 and April, 2021. Based on underlying similarities, children were classified as post-COVID MIS-C with overlapping Kawasaki Disease, MIS-C with no overlapping Kawasaki Disease, and MIS-C with shock. Post-discharge, patients were followed at 1, 3, 6, 12, and 16 months., Results: Forty-one patients predominantly males (73%), at median age of 7 years (range 0.2-16 years) fulfilled the World Health Organisation criteria for MIS-C. Cardiac involvement was seen in 15 (36.5%); impaired left ventricle (LV) function in 5 (12.2%), coronary artery involvement in 10 (24.4%), pericardial effusion in 6 (14.6%) patients, and no arrhythmias. There were two hospital deaths (4.9%), both in MIS-C shock subgroup (2/10, 20%). At 1 month, there was persistent LV dysfunction in 2/5, coronary artery abnormalities in 7/10, and pericardial effusion resolved completely in all patients. By 6 months, LV function returned to normal in all but coronary abnormalities persisted in two patients. At last follow-up (median 9.8 months, interquartile range 2-16 months), in 36/38 (94.7%) patients, coronary artery dilatation was persistent in 2 (20%) patients., Conclusions: Children with MIS-C have a good early outcome, though MIS-C with shock can be life-threatening subgroup in a resource-constrained country setting. On midterm follow-up, there is normalisation of LV function in all and recovery of coronary abnormalities in 80% of patients.

Four endemic human coronaviruses (HCoV), HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43, are closely related to SARS-CoV-2. These coronaviruses are known to infect humans living in temperate areas, including children under 5 years old; however, the seroprevalence of four HCoVs among children in tropical areas, including the Philippines, remains unclear. This study aimed to assess the prevalence of antibodies against four HCoVs and to determine the reactivity and neutralization of these antibodies against SARS-CoV-2 among children in the Philippines. A total of 315 serum samples collected from 2015 to 2018, before the emergence of SARS-CoV-2, in Biliran island, Philippines, were tested for the presence of antibodies against four HCoVs and SARS-CoV-2 using recombinant spike ectodomain proteins by IgG-enzyme-linked immunosorbent assay (ELISA). Reactivity to and neutralization of SARS-CoV-2 were also investigated. The seroprevalence of the four HCoVs was 63.8% for HCoV-229E, 71.4% for HCoV-NL63, 76.5% for HCoV-HKU1, and 83.5% for HCoV-OC43 by ELISA. Age group analysis indicated that seropositivity to all HCoVs reached 80% by 2-3 years of age. While 69/315 (21.9%) of the samples showed reactive to SARS-CoV-2, almost no neutralization against SARS-CoV-2 was detected using neutralization assay. Reactivity of antibodies against SARS-CoV-2 spike protein obtained by ELISA may not correlate with neutralization capability., (© 2023. The Author(s).)

Little is known about the risk of multisystem inflammatory syndrome in children (MIS-C) with different severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants. In southeast England, MIS-C rates per confirmed SARS-CoV-2 infections in children aged 0-16 years were 56% lower (rate ratio [RR], 0.34 [95% confidence interval {CI}, .23-.50]) during prevaccine Delta, 66% lower (RR, 0.44 [95% CI, .28-.69]) during postvaccine Delta, and 95% lower (RR, 0.05 [95% CI, .02-.10]) during the Omicron period., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Information on the impact of the different variants in children in Latin America is scarce. The objective of this study was to describe epidemiologic and clinical features of COVID-19 infection in children under 18 years of age in Argentina, comparing the periods before and after the circulation of new variants., Methods: Observational, cross-sectional, multicentric, analytical study. All patients under 18 years of age with confirmed SARS-CoV-2 infection admitted at 22 healthcare centers were included. Two study periods were established: Period 1 (EW10-2020 to EW12-2021) for the Wuhan strain; Period 2 (EW13 to EW35 2021) for Alpha, Gamma, Delta and Lambda variants., Findings: A total of 6330 confirmed cases were included. Period 1: 3575 (56.5%), period 2: 2755 (43.5%). During period 2, a lower number of asymptomatic cases was observed, while general, respiratory and neurologic signs and symptoms increased in all age groups. Oxygen therapy requirement was higher during the first period (36.7% vs 19.1%; P < 0.001). No significant differences were observed in the rates of severe or critical cases (6.3% vs 5,4%; P = 0.102), intensive care admission (2.1% vs 2%; P < 0.656) or case fatality (0.3% vs 0.5 %; P < 0.229). MIS-C cases occurred more frequently during the first period (1.9% vs 1.1%; P = 0.009)., Interpretation: The clinical spectrum of COVID-19 in Argentina has evolved. With the emergence of new variants, although the number of asymptomatic cases declined, numbers of severe and critical cases, as well as case fatality rates in children, remained unchanged., Competing Interests: There are no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Background: We hypothesised that the clinical characteristics of hospitalised children and young people (CYP) with SARS-CoV-2 in the UK second wave (W2) would differ from the first wave (W1) due to the alpha variant (B.1.1.7), school reopening and relaxation of shielding., Methods: Prospective multicentre observational cohort study of patients <19 years hospitalised in the UK with SARS-CoV-2 between 17/01/20 and 31/01/21. Clinical characteristics were compared between W1 and W2 (W1 = 17/01/20-31/07/20,W2 = 01/08/20-31/01/21)., Results: 2044 CYP < 19 years from 187 hospitals. 427/2044 (20.6%) with asymptomatic/incidental SARS-CoV-2 were excluded from main analysis. 16.0% (248/1548) of symptomatic CYP were admitted to critical care and 0.8% (12/1504) died. 5.6% (91/1617) of symptomatic CYP had Multisystem Inflammatory Syndrome in Children (MIS-C). After excluding CYP with MIS-C, patients in W2 had lower Paediatric Early Warning Scores (PEWS, composite vital sign score), lower antibiotic use and less respiratory and cardiovascular support than W1. The proportion of CYP admitted to critical care was unchanged. 58.0% (938/1617) of symptomatic CYP had no reported comorbidity. Patients without co-morbidities were younger (42.4%, 398/938, <1 year), had lower PEWS, shorter length of stay and less respiratory support., Conclusions: We found no evidence of increased disease severity in W2 vs W1. A large proportion of hospitalised CYP had no comorbidity., Impact: No evidence of increased severity of COVID-19 admissions amongst children and young people (CYP) in the second vs first wave in the UK, despite changes in variant, relaxation of shielding and return to face-to-face schooling. CYP with no comorbidities made up a significant proportion of those admitted. However, they had shorter length of stays and lower treatment requirements than CYP with comorbidities once those with MIS-C were excluded. At least 20% of CYP admitted in this cohort had asymptomatic/incidental SARS-CoV-2 infection. This paper was presented to SAGE to inform CYP vaccination policy in the UK., (© 2022. The Author(s).)

Background: Pilgrims travelling to Saudi Arabia are commonly infected with respiratory viruses. Since the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) emerged in 2012, patients with acute respiratory symptoms returning from an endemic area can be suspected to be infected by this virus., Methods: 98 patients suspected to have MERS-CoV infection from 2014 to 2019 were included in this retrospective cohort study. Upper and lower respiratory tract samples were tested by real-time RT-PCR for the detection of MERS-CoV and other respiratory viruses. Routine microbiological analyses were also performed. Patient data were retrieved from laboratory and hospital databases retrospectively., Results: All patients with suspected MERS-CoV infection travelled before their hospitalization. Most frequent symptoms were cough (94.4%) and fever (69.4%). 98 specimens were tested for MERS-CoV RNA and none of them was positive. Most frequently detected viruses were Enterovirus/Rhinovirus (40/83; 48.2%), Influenzavirus A (34/90; 37.8%) and B (11/90; 12.2%), H-CoV (229E and OC43 10/83; 12% and 7/83; 8.4%, respectively)., Conclusion: From 2014 to 2019, none of 98 patients returning from endemic areas was MERS-CoV infected. However, infections with other respiratory viruses were frequent, especially with Enterovirus/Rhinoviruses and Influenzaviruses., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The cytoskeleton, which includes actin filaments, microtubules, and intermediate filaments, is one of the most important networks in the cell and undertakes many fundamental life activities. Among them, actin filaments are mainly responsible for maintaining cell shape and mediating cell movement, microtubules are in charge of coordinating all cargo transport within the cell, and intermediate filaments are mainly thought to guard against external mechanical pressure. In addition to this, cytoskeleton networks are also found to play an essential role in multiple viral infections. Due to the COVID-19 epidemic, including SARS-CoV-2, SARS-CoV and MERS-CoV, so many variants have caused wide public concern, that any virus infection can potentially bring great harm to human beings and society. Therefore, it is of great importance to study coronavirus infection and develop antiviral drugs and vaccines. In this chapter, we summarize in detail how the cytoskeleton responds and participates in coronavirus infection by analyzing the possibility of the cytoskeleton and its related proteins as antiviral targets, thereby providing ideas for finding more effective treatments., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Background: Immunocompromised patients are at increased risk of SARS-CoV-2 infections. Patients undergoing chimeric antigen receptor (CAR) T-cell therapy for relapsed/refractory B-cell malignancies are uniquely immunosuppressed due to CAR T-mediated B-cell aplasia (BCA). While SARS-CoV-2 mortality rates of 33%-40% are reported in adult CAR T-cell recipients, outcomes in pediatric and young adult CAR T-cell recipients are limited., Methods: We created an international retrospective registry of CAR T recipients aged 0-30 years infected with SARS-CoV-2 within 2 months prior to or any time after CAR T infusion. SARS-CoV-2-associated illness was graded as asymptomatic, mild, moderate, or severe COVID-19, or multisystem inflammatory syndrome in children (MIS-C). To assess for risk factors associated with significant SARS-CoV-2 infections (infections requiring hospital admission for respiratory distress or supplemental oxygen), univariate and multivariable regression analyses were performed., Results: Nine centers contributed 78 infections in 75 patients. Of 70 SARS-CoV-2 infections occurring after CAR T infusion, 13 (18.6%) were classified as asymptomatic, 37 (52.9%) mild, 11 (15.7%) moderate, and 6 (8.6%) severe COVID-19. Three (4.3%) were classified as MIS-C. BCA was not significantly associated with infection severity. Prior to the emergence of the Omicron variant, of 47 infections, 19 (40.4%) resulted in hospital admission and 7 (14.9%) required intensive care, while after the emergence of the Omicron variant, of 23 infections, only 1 (4.3%) required admission and the remaining 22 (95.7%) had asymptomatic or mild COVID-19. Death occurred in 3 of 70 (4.3%); each death involved coinfection or life-threatening condition. In a multivariable model, factors associated with significant SARS-CoV-2 infection included having two or more comorbidities (OR 7.73, CI 1.05 to 74.8, p=0.048) and age ≥18 years (OR 9.51, CI 1.90 to 82.2, p=0.014). In the eight patients infected with SARS-CoV-2 before CAR T, half of these patients had their CAR T infusion delayed by 15-30 days., Conclusions: In a large international cohort of pediatric and young adult CAR-T recipients, SARS-CoV-2 infections resulted in frequent hospital and intensive care unit admissions and were associated with mortality in 4.3%. Patients with two or more comorbidities or aged ≥18 years were more likely to experience significant illness. Suspected Omicron infections were associated with milder disease., Competing Interests: Competing interests: AB: Novartis, Amgen and Medac, speaker’s bureau; Medac, Neovii and Novartis meeting support. SLM: Novartis, advisory boards, study steering committees, clinical trial support; Wugen: advisory board., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Many people who have survived COVID-19 have experienced negative persistent impacts on health. Impacts on health have included persistent respiratory symptoms, decreased quality of life, fatigue, impaired functional capacity, memory deficits, psychological impacts, and difficulties in returning to paid employment. Evidence is yet to be pooled to inform future directions in research and practice, to determine the physical, psychological, social, and spiritual impacts of the illness which extend beyond the acute phase of COVID-19 survivors. This umbrella review (review of systematic reviews) critically synthesized physical (including abnormal laboratory parameters), psychological, social, and spiritual impacts which extended beyond the acute phase of COVID-19 survivors. The search strategy was based on the sample, phenomena of interest, design, evaluation, research model and all publications were double screened independently by four review authors for the eligibility criteria. Data extraction and quality assessment were conducted in parallel independently. Eighteen systematic reviews were included, which represented a total of 493 publications. Sample sizes ranged from n = 15 to n = 44 799 with a total of n = 295 455 participants. There was incomplete reporting of several significant data points including the description of the severe acute respiratory syndrome coronavirus 2 variant, COVID-19 treatments, and key clinical and demographic data. A number of physical, psychological, and social impacts were identified for individuals grappling with post-COVID condition. The long term sequalae of acute COVID-19 and size of the problem is only beginning to emerge. Further investigation is needed to ensure that those affected by post-COVID condition have their informational, spiritual, psychological, social, and physical needs met in the future., (© 2022 The Authors. Journal of Medical Virology published by Wiley Periodicals LLC.)

Outbreaks of coronaviruses (CoVs), especially severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have posed serious threats to humans and animals, which urgently calls for effective broad-spectrum antivirals. RNA-dependent RNA polymerase (RdRp) plays an essential role in viral RNA synthesis and is an ideal pan-coronaviral therapeutic target. Herein, based on cryo-electron microscopy and biochemical approaches, gossypol (GOS) is identified from 881 natural products to directly block SARS-CoV-2 RdRp, thus inhibiting SARS-CoV-2 replication in both cellular and mouse infection models. GOS also acts as a potent inhibitor against the SARS-CoV-2 variant of concern (VOC) and exerts same inhibitory effects toward mutated RdRps of VOCs as the RdRp of the original SARS-CoV-2. Moreover, that the RdRp inhibitor GOS has broad-spectrum anti-coronavirus activity against alphacoronaviruses (porcine epidemic diarrhea virus and swine acute diarrhea syndrome coronavirus), betacoronaviruses (SARS-CoV-2), gammacoronaviruses (avian infectious bronchitis virus), and deltacoronaviruses (porcine deltacoronavirus) is showed. The findings demonstrate that GOS may serve as a promising lead compound for combating the ongoing COVID-19 pandemic and other coronavirus outbreaks., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)

FB2001 is a drug candidate that targets the main protease of SARS-CoV-2 via covalently binding to cysteine 145. In this study, we evaluated the inhibitory activities of FB2001 against several SARS-CoV-2 variants in vitro and in vivo (in mice), and we also evaluated the histopathological analysis and immunostaining of FB2001 on lung and brain which have been rarely reported. The results showed that FB2001 exhibited potent antiviral efficacy against several current SARS-CoV-2 variants in Vero E6 cells, namely, B.1.1.7 (Alpha): EC 50  = 0.39 ± 0.01 μM, EC 90  = 0.75 ± 0.01 μM; B.1.351 (Beta): EC 50  = 0.28 ± 0.11 μM, EC 90  = 0.57 ± 0.21 μM; B.1.617.2 (Delta): EC 50  = 0.27 ± 0.05 μM, EC 90  = 0.81 ± 0.20 μM; B.1.1.529 (Omicron): EC 50  = 0.26 ± 0.06 μM and EC 50  = 0.042 ± 0.007 μM (in the presence of a P-glycoprotein inhibitor). FB2001 remained potent against SARS-CoV-2 replication in the presence of high concentrations of human serum, which indicating that human serum had no significant effect on the in vitro inhibitory activity. Additionally, this inhibitor exhibited an additive effect against SARS-CoV-2 when combined with Remdesivir. Furthermore, FB2001 significantly reduced the SARS-CoV-2 copy numbers and titers in the lungs and brains in vivo, and alleviated the pathological symptoms. In addition, FB2001 could alleviated local bleeding, erythrocyte overflow, edema, and inflammatory cell infiltration in brain tissue, and inhibitors reducing viral titers and improving inflammation in the brain have been rarely reported. A physiologically based pharmacokinetic model was established and verified to predict the FB2001 concentration in human lungs. When FB2001 was administered at 200 mg twice a day for 5 days, the observed C trough ss in plasma and predicted C trough ss of lung total concentration were 0.163 and 2.5 μg/mL, which were approximately 9 and 132-fold higher than the EC 50 of 0.019 μg/mL (0.042 μM) against Omicron variant. Taken together, our study suggests that FB2001 is a promising therapeutic agent in COVID-19 treatment and can be combined with remdesivir to achieve improved clinical outcomes. Owing to its good safety and tolerability in healthy human (NCT05197179 and NCT04766931), FB2001 has been approved for Phase II/III clinical trial (NCT05445934)., Competing Interests: Declaration of competing interest The author(s) declared no potential conflicts of interest with respect to the research., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: COVID-19 poses a global health challenge with more than 325 million cumulative cases and above 5 million cumulative deaths reported till January 17, 2022, by the World Health Organization. Several potential treatments to treat COVID-19 are under clinical trials including antivirals, steroids, immunomodulators, non-specific IVIG, monoclonal antibodies, and passive immunization through convalescent plasma. The need to produce anti-COVID-19 IVIG therapy must be continued, alongside the current treatment modalities, considering the virus is still mutating into variants of concern. In this context, as the present study will exploit pooled diversified convalescent plasma collected from recovered COVID-19 patients, the proposed hyperimmune Anti-COVID-19 intravenous immunoglobulin (C-IVIG) therapy would be able to counter new infectious COVID-19 variants by neutralizing the virus particles. After the successful outcome of the phase I/II clinical trial of C-IVIG, the current study aims to further evaluate the safety and efficacy of single low dose C-IVIG in severe COVID-19 patients for its phase II/III clinical trial., Methods: This is a phase II/III, adaptive, multi-center, single-blinded, randomized controlled superiority trial of SARS-CoV-2 specific polyclonal IVIG (C-IVIG). Patients fulfilling the eligibility criteria will be block-randomized using a sealed envelope system to receive either 0.15 g/Kg C-IVIG with standard of care (SOC) or standard of care alone in 2:1 ratio. The patients will be followed-up for 28 days to assess the primary and secondary outcomes., Discussion: This is a phase II/III clinical trial evaluating safety and efficacy of hyperimmune anti-COVID-19 intravenous immunoglobulin (C-IVIG) in severe COVID-19 patients. This study will provide clinical evidence to use C-IVIG as one of the first-line therapeutic options for severe COVID-19 patients., Trial Registration: Registered at clinicaltrial.gov with NCT number NCT04891172 on May 18, 2021., (© 2022. The Author(s).)

We describe 2116 multisystem inflammatory syndrome in children (MIS-C) cases reported to the Centers for Disease Control and Prevention during Delta and Omicron circulation from July 2021 through January 2022. Half of MIS-C patients were aged 5-11 years, 52% received intensive care unit-level care, and 1.1% died. Only 3.0% of eligible patients were fully vaccinated prior to MIS-C onset., Competing Interests: Potential conflicts of interest. M. E. O. reports payment made to the institution where they have clinical responsibilities from the National Institutes of Health (MUSIC Study) outside of the submitted work. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (Published by Oxford University Press on behalf of Infectious Diseases Society of America 2022.)

Importance: Persistence of COVID-19 symptoms beyond 2 months, or long COVID, is increasingly recognized as a common sequela of acute infection., Objectives: To estimate the prevalence of and sociodemographic factors associated with long COVID and to identify whether the predominant variant at the time of infection and prior vaccination status are associated with differential risk., Design, Setting, and Participants: This cross-sectional study comprised 8 waves of a nonprobability internet survey conducted between February 5, 2021, and July 6, 2022, among individuals aged 18 years or older, inclusive of all 50 states and the District of Columbia., Main Outcomes and Measures: Long COVID, defined as reporting continued COVID-19 symptoms beyond 2 months after the initial month of symptoms, among individuals with self-reported positive results of a polymerase chain reaction test or antigen test., Results: The 16 091 survey respondents reporting test-confirmed COVID-19 illness at least 2 months prior had a mean age of 40.5 (15.2) years; 10 075 (62.6%) were women, and 6016 (37.4%) were men; 817 (5.1%) were Asian, 1826 (11.3%) were Black, 1546 (9.6%) were Hispanic, and 11 425 (71.0%) were White. From this cohort, 2359 individuals (14.7%) reported continued COVID-19 symptoms more than 2 months after acute illness. Reweighted to reflect national sociodemographic distributions, these individuals represented 13.9% of those who had tested positive for COVID-19, or 1.7% of US adults. In logistic regression models, older age per decade above 40 years (adjusted odds ratio [OR], 1.15; 95% CI, 1.12-1.19) and female gender (adjusted OR, 1.91; 95% CI, 1.73-2.13) were associated with greater risk of persistence of long COVID; individuals with a graduate education vs high school or less (adjusted OR, 0.67; 95% CI, 0.56-0.79) and urban vs rural residence (adjusted OR, 0.74; 95% CI, 0.64-0.86) were less likely to report persistence of long COVID. Compared with ancestral COVID-19, infection during periods when the Epsilon variant (OR, 0.81; 95% CI, 0.69-0.95) or the Omicron variant (OR, 0.77; 95% CI, 0.64-0.92) predominated in the US was associated with diminished likelihood of long COVID. Completion of the primary vaccine series prior to acute illness was associated with diminished risk for long COVID (OR, 0.72; 95% CI, 0.60-0.86)., Conclusions and Relevance: This study suggests that long COVID is prevalent and associated with female gender and older age, while risk may be diminished by completion of primary vaccination series prior to infection.

To date, a total of seven human coronaviruses (HCoVs) have been identified, all of which are important respiratory pathogens. Recently, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), has led to a global pandemic causing millions of infections and deaths. Here, we summarize the discovery and fundamental virology of HCoVs, discuss their zoonotic transmission and highlight the weak species barrier of SARS-CoV-2. We also discuss the possible origins of SARS-CoV-2 variants of concern identified to date and discuss the experimental challenges in characterizing mutations of interest and propose methods to circumvent them. As the COVID-19 treatment and prevention landscape rapidly evolves, we summarize current therapeutics and vaccines, and their implications on SARS-CoV-2 variants. Finally, we explore how interspecies transmission of SARS-CoV-2 may drive the emergence of novel strains, how disease severity may evolve and how COVID-19 will likely continue to burden healthcare systems globally., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Coronavirus nonstructural protein 3 (nsp3) is a multi-functional protein, playing a critical role in viral replication and in regulating host antiviral innate immunity. In this study, we demonstrate that nsp3 from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and avian coronavirus infectious bronchitis virus (IBV) directly interacts with melanoma differentiation-associated gene 5 (MDA5), rendering an inhibitory effect on the MDA5-mediated type I interferon (IFN) response. By the co-expression of MDA5 with wild-type and truncated nsp3 constructs, at least three interacting regions mapped to the papain-like protease (PLpro) domain and two other domains located at the N- and C-terminal regions were identified in SARS-CoV-2 nsp3. Furthermore, by introducing point mutations to the catalytic triad, the deubiquitylation activity of the PLpro domain from both SARS-CoV-2 and IBV nsp3 was shown to be responsible for the suppression of the MDA5-mediated type I IFN response. It was also demonstrated that both MDA5 and nsp3 were able to interact with ubiquitin and ubiquitinated proteins, contributing to the interaction between the two proteins. This study confirms the antagonistic role of nsp3 in the MDA5-mediated type I IFN signaling, highlighting the complex interaction between a multi-functional viral protein and the innate immune response.

Purpose: Metabolic disorders have been identified as major risk factors for severe acute courses of COVID-19. With decreasing numbers of infections in many countries, the long COVID syndrome (LCS) represents the next major challenge in pandemic management, warranting the precise definition of risk factors for LCS development., Methods: We identified 50,402 COVID-19 patients in the Disease Analyzer database (IQVIA) featuring data from 1056 general practices in Germany. Multivariate logistic regression analysis was used to identify risk factors for the development of LCS., Results: Of the 50,402 COVID-19 patients included into this analysis, 1,708 (3.4%) were diagnosed with LCS. In a multivariate regression analysis, we identified lipid metabolism disorders (OR 1.46, 95% CI 1.28-1.65, p < 0.001) and obesity (OR 1.25, 95% CI 1.08-1.44, p = 0.003) as strong risk factors for the development of LCS. Besides these metabolic factors, patients' age between 46 and 60 years (compared to age ≤ 30, (OR 1.81 95% CI 1.54-2.13, p < 0.001), female sex (OR 1.33, 95% CI 1.20-1.47, p < 0.001) as well as pre-existing asthma (OR 1.67, 95% CI 1.39-2.00, p < 0.001) and depression (OR 1.27, 95% CI 1.09-1.47, p = < 0.002) in women, and cancer (OR 1.4, 95% CI 1.09-1.95, p = < 0.012) in men were associated with an increased likelihood of developing LCS., Conclusion: Lipid metabolism disorders and obesity represent age-independent risk factors for the development of LCS, suggesting that metabolic alterations determine the risk for unfavorable disease courses along all phases of COVID-19., (© 2022. The Author(s).)

The efforts of the scientific world directed to identifying new antiviral drugs and therapies effective against SARS-CoV-2 continue. New oral antivirals against SARS-CoV-2 such as paxlovid have recently authorized. Evidence shows that these antivirals have good efficacy in reducing the risk of hospitalization in COVID-19 positive patients. Remdesivir is an authorized antiviral for the treatment of SARS-CoV-2 infection. To date, there are still few data in the literature on the safety profile and the risk of generating antiviral-resistant SARS-CoV-2 drug variants. In this manuscript we describe the evidence in the literature on the monotherapy use of paxlovid and monotherapy use of remdesivir, and the scientific hypothesis of using nirmatrelvir and remdesivir in association with the aim of increasing treatment efficacy, reducing the risk of adverse reactions and generating antiviral drug-resistant variants., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Objectives: To describe the severity and clinical spectrum of coronavirus disease 2019 (COVID-19) in children during the 2021 New South Wales outbreak of the Delta variant of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Design, Setting: Prospective cohort study in three metropolitan Sydney local health districts, 1 June - 31 October 2021., Participants: Children under 16 years of age with positive SARS-CoV-2 nucleic acid test results admitted to hospital or managed by the Sydney Children's Hospital Network (SCHN) virtual care team., Main Outcome Measures: Age-specific SARS-CoV-2 infection frequency, overall and separately for SCHN virtual and hospital patients; rates of medical and social reason admissions, intensive care admissions, and paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 per 100 SARS-CoV-2 infections; demographic and clinical factors that influenced likelihood of hospital admission., Results: A total of 17 474 SARS-CoV-2 infections in children under 16 were recorded in NSW, of whom 11 985 (68.6%) received SCHN-coordinated care, including 459 admitted to SCHN hospitals: 165 for medical reasons (1.38 [95% CI, 1.17-1.59] per 100 infections), including 15 admitted to intensive care, and 294 (under 18 years of age) for social reasons (2.45 [95% CI, 2.18-2.73] per 100 infections). In an analysis that included all children admitted to hospital and a random sample of those managed by the virtual team, having another medical condition (adjusted odds ratio [aOR], 7.42; 95% CI, 3.08-19.3) was associated with increased likelihood of medical admission; in univariate analyses, non-asthmatic chronic respiratory disease was associated with greater (OR, 9.21; 95% CI, 1.61-174) and asthma/viral induced wheeze with lower likelihood of admission (OR, 0.38; 95% CI, 0.18-0.78). The likelihood of admission for medical reasons declined from infancy to 5-11 years, but rose again for those aged 12-15 years. Sex and Indigenous status did not influence the likelihood of admission., Conclusion: Most SARS-CoV-2 infections (Delta variant) in children were asymptomatic or associated with mild disease. Hospitalisation was relatively infrequent, and most common for infants, adolescents, and children with other medical conditions. More children were hospitalised for social than for medical reasons., (© 2022 The Authors. Medical Journal of Australia published by John Wiley & Sons Australia, Ltd on behalf of AMPCo Pty Ltd.)

SARS-CoV-2 infection has become a global health problem specially exacerbated with the continuous appearance of new variants. Healthcare workers (HCW) have been one of the most affected sectors. Children have also been affected, and although infection generally presents as a mild disease, some have developed the Pediatric Inflammatory Multisystem Syndrome Temporally Associated with SARS-CoV-2 (PIMS-TS). We recruited 190 adults (HCW and cohabitants, April to June 2020) and 57 children (April 2020 to September 2021), of whom 12 developed PIMS-TS, in a hospital-based study in Spain. Using an in-house Luminex assay previously validated, antibody levels were measured against different spike and nucleocapsid SARS-CoV-2 proteins, including the receptor-binding domain (RBD) of the Alpha, Beta, Gamma, and Delta variants of concern (VoC). Seropositivity rates obtained from children and adults, respectively, were: 49.1% and 11% for IgG, 45.6% and 5.8% for IgA, and 35.1% and 7.3% for IgM. Higher antibody levels were detected in children who developed PIMS-TS compared to those who did not. Using the COVID-19 IgM/IgA ELISA (Vircell, S.L.) kit, widely implemented in Spanish hospitals, a high number of false positives and lower seroprevalences compared with the Luminex estimates were found, indicating a significantly lower specificity and sensitivity. Comparison of antibody levels against RBD-Wuhan versus RBD-VoCs indicated that the strongest positive correlations for all three isotypes were with RBD-Alpha, while the lowest correlations were with RBD-Delta for IgG, RBD-Gamma for IgM, and RBD-Beta for IgA. This study highlights the differences in antibody levels between groups with different demographic and clinical characteristics, as well as reporting the IgG, IgM, and IgA response to RBD VoC circulating at the study period.

Within the past 2 decades, three highly pathogenic human coronaviruses have emerged, namely, severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The health threats and economic burden posed by these tremendously severe coronaviruses have paved the way for research on their etiology, pathogenesis, and treatment. Compared to SARS-CoV and SARS-CoV-2, MERS-CoV genome encoded fewer accessory proteins, among which the ORF4b protein had anti-immunity ability in both the cytoplasm and nucleus. Our work for the first time revealed that ORF4b protein was unstable in the host cells and could be degraded by the ubiquitin proteasome system. After extensive screenings, it was found that UBR5 (ubiquitin protein ligase E3 component N-recognin 5), a member of the HECT E3 ubiquitin ligases, specifically regulated the ubiquitination and degradation of ORF4b. Similar to ORF4b, UBR5 can also translocate into the nucleus through its nuclear localization signal, enabling it to regulate ORF4b stability in both the cytoplasm and nucleus. Through further experiments, lysine 36 was identified as the ubiquitination site on the ORF4b protein, and this residue was highly conserved in various MERS-CoV strains isolated from different regions. When UBR5 was knocked down, the ability of ORF4b to suppress innate immunity was enhanced and MERS-CoV replication was stronger. As an anti-MERS-CoV host protein, UBR5 targets and degrades ORF4b protein through the ubiquitin proteasome system, thereby attenuating the anti-immunity ability of ORF4b and ultimately inhibiting MERS-CoV immune escape, which is a novel antagonistic mechanism of the host against MERS-CoV infection. IMPORTANCE ORF4b was an accessory protein unique to MERS-CoV and was not present in SARS-CoV and SARS-CoV-2 which can also cause severe respiratory disease. Moreover, ORF4b inhibited the production of antiviral cytokines in both the cytoplasm and the nucleus, which was likely to be associated with the high lethality of MERS-CoV. However, whether the host proteins regulate the function of ORF4b is unknown. Our study first determined that UBR5, a host E3 ligase, was a potential host anti-MERS-CoV protein that could reduce the protein level of ORF4b and diminish its anti-immunity ability by inducing ubiquitination and degradation. Based on the discovery of ORF4b-UBR5, a critical molecular target, further increasing the degradation of ORF4b caused by UBR5 could provide a new strategy for the clinical development of drugs for MERS-CoV.

To provide a comparative meta-analysis and systematic review of the risk and clinical outcomes of coronavirus 2019 (COVID-19) infection between fully vaccinated and unvaccinated groups. Eighteen studies of COVID-19 infections in fully vaccinated ("breakthrough infections") and unvaccinated individuals were reviewed from Medline/PubMed, Scopus, Embase, and Web of Science databases. The meta-analysis examined the summary effects and between-study heterogeneity regarding differences in the risk of infection, hospitalization, treatments, and mortality between vaccinated and unvaccinated individuals. he overall risk of infection was lower for the fully vaccinated compared to that of the unvaccinated (relative risk [RR] 0.20, 95% confidence interval [CI]: 0.19-0.21), especially for variants other than Delta (Delta: RR 0.29, 95% CI: 0.13-0.65; other variants: RR 0.06, 95% CI: 0.04-0.08). The risk of asymptomatic infection was not statistically significantly different between fully vaccinated and unvaccinated (RR 0.56, 95% CI: 0.27-1.19). There were neither statistically significant differences in risk of hospitalization (RR 1.06, 95% CI: 0.38-2.93), invasive mechanical ventilation (RR 1.65, 95% CI: 0.90-3.06), or mortality (RR 1.19, 95% CI: 0.79-1.78). Conversely, the risk of supplemental oxygen during hospitalization was significantly higher for the unvaccinated (RR 1.40, 95% CI: 1.08-1.82). Unvaccinated people were more vulnerable to COVID-19 infection than fully vaccinated for all variants. Once infected, there were no statistically significant differences in the risk of hospitalization, invasive mechanical ventilation, or mortality. Still, unvaccinated showed an increased need for oxygen supplementation. Further prospective analysis, including patients' risk factors, COVID-19 variants, and the utilized treatment strategies, would be warranted., (© 2022 Wiley Periodicals LLC.)

Highly pathogenic coronaviruses, including severe acute respiratory syndrome coronavirus 2 (refs.  1,2 ) (SARS-CoV-2), Middle East respiratory syndrome coronavirus 3 (MERS-CoV) and SARS-CoV-1 (ref.  4 ), vary in their transmissibility and pathogenicity. However, infection by all three viruses results in substantial apoptosis in cell culture 5-7 and in patient tissues 8-10 , suggesting a potential link between apoptosis and pathogenesis of coronaviruses. Here we show that caspase-6, a cysteine-aspartic protease of the apoptosis cascade, serves as an important host factor for efficient coronavirus replication. We demonstrate that caspase-6 cleaves coronavirus nucleocapsid proteins, generating fragments that serve as interferon antagonists, thus facilitating virus replication. Inhibition of caspase-6 substantially attenuates lung pathology and body weight loss in golden Syrian hamsters infected with SARS-CoV-2 and improves the survival of mice expressing human DPP4 that are infected with mouse-adapted MERS-CoV. Our study reveals how coronaviruses exploit a component of the host apoptosis cascade to facilitate virus replication., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Coronavirus disease 2019 (COVID-19) can lead to an illness characterized by persistent symptoms which affect various organs and systems, known as long-COVID. This study aimed to assess the prevalence and clinical characteristics of long-COVID in children with immunodeficiency, in comparison to those without. A self-constructed questionnaire was created, which included questions regarding the child's general health, the course of their COVID-19, their symptoms of long-COVID and its impact on their daily functioning, the diagnosis of multisystem inflammatory syndrome (MIS-C), and vaccination status. The questionnaire was completed by parents of 147 children - 70 children with a diagnosis of immunodeficiency (47.6%) and 77 who were immunocompetent (52.4%). Immunocompetent children were more significantly affected by long-COVID than those immunocompromised. Its prevalence in the first 12-week post-infection was 60.0% and 35.7% in these groups, respectively. Beyond this period, these percentages had dropped to 34.6% and 11.43%, respectively. Children who were immunocompetent reported more often symptoms of fatigue, reduced exercise tolerance, and difficulty concentrating. Meanwhile, there was a slight increase in complaints of gastrointestinal symptoms in immunocompromised patients. The risk of developing long-COVID increased with age and COVID-19 severity in both groups. Furthermore, the daily activities of immunocompetent children were limited more frequently (41.8%) than for those who were immunocompromised (25%)., Conclusions: Although immunocompromised children experienced long-COVID, its prevalence and impact on daily functioning were significantly lower than among immunocompetent children. However, as the pathomechanisms of long-COVID are not yet fully understood, it is not currently possible to fully explain these findings., What Is Known: • Long COVID is characterized by persistent symptoms following COVID-19, which can affect various tissues and organs, as well as mental health. • Due to the similar course of COVID-19 - mainly mild or asymptomatic - among children with and without immunodeficiency, the question arises, over whether the prevalence and severity of long-COVID is also similar in both groups., What Is New: • Immunocompromised children also suffer from long-COVID, but the prevalence is significantly lower than in the immunocompetent group of children. • The potential causes of less frequent and milder long-COVID in this group may be the milder course of COVID-19 and the state of reduced immunity protecting against neuroinflammation., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Treatment of the coronavirus disease (COVID-19) is still challenging due to the lack of evidence-based treatment protocols and continuously changing epidemiological situations and vaccinations. Remdesivir (RDV) is among the few antiviral medications with confirmed efficacy for specific patient groups. However, real-world data on long-term outcomes for a short treatment course are scarce., Methods: This retrospective observational cohort study included real-life data collected during the second and third wave of the COVID-19 pandemic in Hungary (September 1, 2020-April 30, 2021) from inpatients at a University Center (n = 947). Participants consisted of two propensity score-matched cohorts (370/370 cases): Group RDV including patients receiving RDV and supplementary oxygen and Group standard of care (SOC) as control. The primary outcome was the effect of 5-day RDV treatment on 30- and 60-day all-cause mortality. Multivariate analyses were performed to assess the effect of RDV by different covariates., Results: Group RDV included significantly more patients from the alpha variant wave, with greater frequency of comorbidities diabetes and anemia, and larger degree of parenchymal involvement. All-cause mortality at 30- and 60-day were significantly lower in Group RDV compared to Group SOC. Significant risk reduction of 60-day all-cause mortality was observed for RDV treatment in men and patients with COPD or multiple comorbidities., Conclusions: Hospitalized COVID-19 patients with 5-day RDV treatment had significantly lower 30- and 60-day all-cause mortality, despite their more severe clinical condition. Men and patients with multiple comorbidities, including COPD, profited the most from RDV treatment in the long term. Due to the ongoing COVID-19 pandemic, effective treatment regimens are needed for hospitalized patients., Competing Interests: Disclosure of interest: The authors completed the ICMJE Disclosure of Interest Form (available upon request from the corresponding author) and declare the following activities and relationships: Veronika Müller received consultancy fees from Gilead and Eli Lilly, and was the principle investigator in a study from Richter., (Copyright © 2022 by the Journal of Global Health. All rights reserved.)

Background: Convalescent plasma containing high levels of SARS-CoV-2 antibodies has been studied as a possible treatment for COVID-19. Better understanding of predictors of high antibody levels is needed for improving supply of high-quality therapeutic plasma., Aims: We have evaluated demographic and clinical factors associated with the probability of a convalescent plasma donor having high SARS-CoV-2 IgG antibody levels., Methods: A total of 29,585 convalescent plasma donors employed during the first and second waves of the COVID-19 pandemic in England were included in this study. All had been tested for SARS-CoV-2 IgG antibodies by EUROimmun ELISA. A multivariable logistic regression model was used to quantify the association of the demographic and clinical factors with high (EUROimmun S/Co>6.0) SARS-CoV-2 IgG antibody level., Results: Most of the donors were male (23,024; 78%), with white ethnic background (24,598;83%) and had not been tested for SARS-CoV-2 (15,266; 52%).Overall, less than 20% of convalescent plasma donors with confirmed or suspected SARS-CoV-2 infection harboured high SARS-CoV-2 antibody levels (n = 4,978). We found that older male donors who had been hospitalised with COVID-19 were most likely to harbour high levels of antibodies. White donors were less likely to have high SARS-CoV-2 antibody levels than donors with Asian orblack ethnic backgrounds residing in affluent areas likely reflecting ethnic inequality previously associated with SARS-CoV-2 infection., Discussion: In a time of great uncertainty, and predicted new waves associated with newly emerging SARS-CoV-2 variants, these results will help us to target future convalescent plasma collections., (© 2022 British Blood Transfusion Society.)

Objectives: To compare the clinical, laboratory, and hemodynamic parameters during hospitalization for patients with multisystem inflammatory syndrome in children (MIS-C), across the Original/Alpha and the Delta variants of severe acute respiratory syndrome coronavirus 2 infection., Design: Retrospective cohort study., Setting: Single-center quaternary children's hospital., Patients: Children with MIS-C admitted from May 2020 to February 2021(Original and Alpha variant cohort) and August 2021 to November 2021 (Delta variant cohort)., Measurements and Main Results: Continuous vital sign measurements, laboratory results, medications data, and hospital outcomes from all subjects were evaluated. Of the 134 patients (102 with Original/Alpha and 32 with Delta), median age was 9 years, 75 (56%) were male, and 61 (46%) were Hispanics. The cohort with Original/Alpha variant had more males (61% vs 41%; p = 0.036) and more respiratory/musculoskeletal symptoms on presentation compared with the Delta variant ( p < 0.05). More patients in the Original/Alpha variant cohort received mechanical ventilation (16 vs 0; p = 0.009). Median hospital length of stay (LOS) was 7 days, and ICU LOS was 3 days for the entire cohort. ICU LOS was shorter in cohort with the Delta variant compared with the Original/Alpha variant (4 vs 2 d; p = 0.001). Only one patient had cardiac arrest, two needed extracorporeal membrane oxygenation, and two needed left ventricular assist device (Impella, Danvers, MA), all in the Original/Alpha variant cohort; no mortality occurred in the entire cohort. MIS-C cohort associated with the Delta variant had lower INR, prothrombin time, WBCs, sodium, phosphorus, and potassium median values ( p < 0.05) during hospitalization compared with the Original/Alpha variants. Hemodynamic assessment showed significant tachycardia in the Original/Alpha variants cohort compared with the Delta variant cohort ( p < 0.05)., Interventions: None., Conclusions: Patients with MIS-C associated with the Delta variants had lower severity during hospitalization compared with the Original/Alpha variant. Analysis of distinct trends in clinical and laboratory parameters with future variants of concerns will allow for potential modification of treatment protocol., Competing Interests: Dr. Jain’s institution received funding from the National Institute for Child Health and Human Development (1R61HD105593). Drs. Jain, Annapragada, Muscal, Vogel, and Rusin received support for article research from the National Institutes of Health (NIH). Dr. Annapragada’s institution received funding from the NIH (R61HD105593); he received funding from Alzeca and Sensulin; he disclosed that he is the inventor on numerous patents that are either licensed to or assigned to his employer, past employers, or other entities. Drs. Muscal and Vogel disclosed the off-label product use of Anakinra. Dr. Vogel’s institution received funding from the NIH; she disclosed the off-label product use of IV immunoglobulin for multisystem inflammatory syndrome in children. Dr. Rusin received funding from Medical Informatics Corp; he disclosed that he is the cofounder and Chief Technology Officer of Medical Informatics, and he disclosed that his wife is the cofounder and Chief Executive Officer of Medical Informatics. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.)

The pandemic caused by severe acute respiratory Coronavirus-2 (SARS-CoV-2) has been ongoing for over two years, and treatment for COVID-19, other than monoclonal antibodies, is urgently required. Accordingly, we have investigated the inhibitors of SARS-CoV-2 protein targets by high-throughput virtual screening using a marine natural products database. Considering the calculated molecular properties and availability of the compounds, (+)-usnic acid was selected as a suitable hit. In the in vitro antiviral assay of (+)-usnic acid by the immunofluorescence method, IC 50 was 7.99 μM, which is similar to that of remdesivir used as a positive control. The generalized Born and surface area continuum solvation (MM/GBSA) method was performed to find the potent target of (+)-usnic acid, and the Mpro protein showed the most prominent value, -52.05 kcal/mol, among other SARS-CoV-2 protein targets. Thereafter, RMSD and protein-ligand interactions were profiled using molecular dynamics (MD) simulations. Sodium usnate (NaU) improved in vitro assay results with an IC 50 of 5.33 μM and a selectivity index (SI) of 9.38. Additionally, when (+)-usnic acid was assayed against SARS-CoV-2 variants, it showed enhanced efficacy toward beta variants with an IC 50 of 2.92 μM and SI of 11.1. We report the in vitro anti-SARS-CoV-2 efficacy of (+)-usnic acid in this study and propose that it has the potential to be developed as a COVID-19 treatment if its in vivo efficacy has been confirmed., (© 2022. The Author(s).)

As the coronavirus disease (COVID-19) pandemic led to a global health crisis, there were limited treatment options and no prophylactic therapies for those exposed to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Convalescent plasma is quick to implement, potentially provides benefits, and has a good safety profile. The therapeutic potential of COVID-19 convalescent plasma (CCP) is likely mediated by antibodies through direct viral neutralization and Fc-dependent functions such as a phagocytosis, complement activation, and antibody-dependent cellular cytotoxicity. In the United States, CCP became one of the most common treatments with more than a half million units transfused despite limited efficacy data. More than a dozen randomized trials now demonstrate that CCP does not provide benefit for those hospitalized with moderate to severe disease. However, similar to other passive antibody therapies, CCP is beneficial for early disease when provided to elderly outpatients within 72 hours after symptom onset. Only high-titer CCP should be transfused. CCP should also be considered for immunosuppressed patients with COVID-19. CCP collected in proximity, by time and location, to the patient may be more beneficial because of SARS-CoV-2 variants. Additional randomized trial data are still accruing and should be incorporated with other trial data to optimize CCP indications., (© 2022 by The American Society of Hematology.)

Pre-existing antibodies that bind endemic human coronaviruses (eHCoVs) can cross-react with SARS-CoV-2, which is the betacoronavirus that causes COVID-19, but whether these responses influence SARS-CoV-2 infection is still under investigation and is particularly understudied in infants. In this study, we measured eHCoV and SARS-CoV-1 IgG antibody titers before and after SARS-CoV-2 seroconversion in a cohort of Kenyan women and their infants. Pre-existing eHCoV antibody binding titers were not consistently associated with SARS-CoV-2 seroconversion in infants or mothers; however, we observed a very modest association between pre-existing HCoV-229E antibody levels and a lack of SARS-CoV-2 seroconversion in the infants. After seroconversion to SARS-CoV-2, antibody binding titers to the endemic betacoronaviruses HCoV-OC43 and HCoV-HKU1, and the highly pathogenic betacoronavirus SARS-CoV-1, but not the endemic alphacoronaviruses HCoV-229E and HCoV-NL63, increased in the mothers. However, eHCoV antibody levels did not increase following SARS-CoV-2 seroconversion in the infants, suggesting the increase seen in the mothers was not simply due to cross-reactivity to naively generated SARS-CoV-2 antibodies. In contrast, the levels of antibodies that could bind SARS-CoV-1 increased after SARS-CoV-2 seroconversion in both the mothers and infants, both of whom were unlikely to have had a prior SARS-CoV-1 infection, supporting prior findings that SARS-CoV-2 responses cross-react with SARS-CoV-1. In summary, we found evidence of increased eHCoV antibody levels following SARS-CoV-2 seroconversion in the mothers but not the infants, suggesting eHCoV responses can be boosted by SARS-CoV-2 infection when a prior memory response has been established, and that pre-existing cross-reactive antibodies are not strongly associated with SARS-CoV-2 infection risk in mothers or infants.

Background: The coronavirus 2019 pandemic placed unprecedented pressures on healthcare services and magnified ethical dilemmas related to how resources should be allocated. These resources include, among others, personal protective equipment, personnel, life-saving equipment, and vaccines. Decision-makers have therefore sought ethical decision-making tools so that resources are distributed both swiftly and equitably. To support the development of such a decision-making tool, a systematic review of the literature on relevant ethical values and principles was undertaken. The aim of this review was to identify ethical values and principles in the literature which relate to the equitable allocation of resources in response to an acute public health threat, such as a pandemic., Methods: A rapid systematic review was conducted using MEDLINE, EMBASE, Google Scholar, LitCOVID and relevant reference lists. The time period of the search was January 2000 to 6th April 2020, and the search was restricted to human studies. January 2000 was selected as a start date as the aim was to capture ethical values and principles within acute public health threat situations. No restrictions were made with regard to language. Ethical values and principles were extracted and examined thematically., Results: A total of 1,618 articles were identified. After screening and application of eligibility criteria, 169 papers were included in the thematic synthesis. The most commonly mentioned ethical values and principles were: Equity, reciprocity, transparency, justice, duty to care, liberty, utility, stewardship, trust and proportionality. In some cases, ethical principles were conflicting, for example, Protection of the Public from Harm and Liberty., Conclusions: Allocation of resources in response to acute public health threats is challenging and must be simultaneously guided by many ethical principles and values. Ethical decision-making strategies and the prioritisation of different principles and values needs to be discussed with the public in order to prepare for future public health threats. An evidence-based tool to guide decision-makers in making difficult decisions is required. The equitable allocation of resources in response to an acute public health threat is challenging, and many ethical principles may be applied simultaneously. An evidence-based tool to support difficult decisions would be helpful to guide decision-makers., (© 2022. The Author(s).)

Molecular imaging techniques such as PET and SPECT have been used to shed light on how coronavirus disease 2019 (COVID-19) affects the human brain. We provide a systematic review that summarizes the current literature according to 5 predominant topics. First, a few case reports have suggested reversible cortical and subcortical metabolic alterations in rare cases with concomitant para- or postinfectious encephalitis. Second, imaging findings in single patients with the first manifestations of parkinsonism in the context of COVID-19 resemble those in neurodegenerative parkinsonism (loss of nigrostriatal integrity), but scarceness of data and a lack of follow-up preclude further etiologic conclusions (e.g., unmasking/hastening of neurodegeneration vs. infectious or parainfectious parkinsonism). Third, several case reports and a few systematic studies have addressed focal symptoms and lesions, most notably hyposmia. The results have been variable, although some studies found regional hypometabolism of regions related to olfaction (e.g., orbitofrontal and mesiotemporal). Fourth, a case series and systematic studies in inpatients with COVID-19-related encephalopathy (acute to subacute stage) consistently found a frontoparietal-dominant neocortical dysfunction (on imaging and clinically) that proved to be grossly reversible in most cases until 6 mo. Fifth, studies on post-COVID-19 syndrome have provided controversial results. In patients with a high level of self-reported complaints (e.g., fatigue, memory impairment, hyposmia, and dyspnea), some authors found extensive areas of limbic and subcortical hypometabolism, whereas others found no metabolic alterations on PET and only minor cognitive impairments (if any) on neuropsychologic assessment. Furthermore, we provide a critical appraisal of studies with regard to frequent methodologic issues and current pathophysiologic concepts. Finally, we devised possible applications of PET and SPECT in the clinical work-up of diagnostic questions related to COVID-19., (© 2022 by the Society of Nuclear Medicine and Molecular Imaging.)

Background: Convalescent plasma (CP) has been widely used to treat COVID-19 and is under study. However, the variability in the current clinical trials has averted its wide use in the current pandemic. We aimed to evaluate the safety and efficacy of CP in severe coronavirus disease 2019 (COVID-19) in the early stages of the disease., Methods: A randomized controlled clinical study was conducted on 101 patients admitted to the hospital with confirmed severe COVID-19. Most participants had less than 14 days from symptoms onset and less than seven days from hospitalization. Fifty patients were assigned to receive CP plus standard therapy (ST), and 51 were assigned to receive ST alone. Participants in the CP arm received two doses of 250 mL each, transfused 24 h apart. All transfused plasma was obtained from "super donors" that fulfilled the following criteria: titers of anti-SARS-CoV-2 S1 IgG ≥ 1:3200 and IgA ≥ 1:800 antibodies. The effect of transfused anti-IFN antibodies and the SARS-CoV-2 variants at the entry of the study on the overall CP efficacy was evaluated. The primary outcomes were the reduction in viral load and the increase in IgG and IgA antibodies at 28 days of follow-up. The per-protocol analysis included 91 patients., Results: An early but transient increase in IgG anti-S1-SARS-CoV-2 antibody levels at day 4 post-transfusion was observed (Estimated difference [ED], - 1.36; 95% CI, - 2.33 to - 0.39; P = 0.04). However, CP was not associated with viral load reduction in any of the points evaluated. Analysis of secondary outcomes revealed that those patients in the CP arm disclosed a shorter time to discharge (ED adjusted for mortality, 3.1 days; 95% CI, 0.20 to 5.94; P = 0.0361) or a reduction of 2 points on the WHO scale when compared with the ST group (HR adjusted for mortality, 1.6; 95% CI, 1.03 to 2.5; P = 0.0376). There were no benefits from CP on the rates of intensive care unit admission (HR, 0.82; 95% CI, 0.35 to 1.9; P = 0.6399), mechanical ventilation (HR, 0.66; 95% CI, 0.25 to 1.7; P = 0.4039), or mortality (HR, 3.2; 95% CI, 0.64 to 16; P = 0.1584). Anti-IFN antibodies and SARS-CoV-2 variants did not influence these results., Conclusion: CP was not associated with viral load reduction, despite the early increase in IgG anti-SARS-CoV-2 antibodies. However, CP is safe and could be a therapeutic option to reduce the hospital length of stay. Trial registration NCT04332835., (© 2022. The Author(s).)