Interferons and other cytokines, genetics and beyond in COVID-19 and autoimmunity.

Interferons are the best antiviral agents in vitro against SARS-CoV-2 so far and genetic defects in their signaling cascade or neutralization of alfa-interferons by autoantibodies come with more severe COVID-19. However, there is more, as the SARS-CoV-2 dysregulates not only innate immune mechanisms but also T and B cell repertoires. Most genetic, hematological and immunological studies in COVID-19 are at present phenomenological. However, these and antecedent studies contain the seed grains to resolve many unanswered questions and a whole range of testable hypotheses. What are the links, if existing, between genetics and the occurrence of interferon-neutralizing antibodies? Are NAGGED (neutralizing and generated by gene defect) antibodies involved or not? Is the autoimmune process cause or consequence of virus infection? What are the roles played by cytokine posttranslational modifications, such as proteolysis, glycosylation, citrullination and others? How is systemic autoimmunity linked with type 1 interferons? These questions place cytokines and growth factors at pole positions as keys to unlock basic mechanisms of infection and (auto)immunity. Related to cytokine research, (1) COVID-19 patients develop neutralizing autoantibodies, mainly against alpha interferons and it is not yet established whether this is the consequence or cause of virus replication. (2) The glycosylation of recombinant interferon-beta protects against breaking tolerance and the development of neutralizing antibodies. (3) SARS-CoV-2 induces severe inflammation and release of extracellular proteases leading to remnant epitopes, e.g. of cytokines. (4) In the rare event of homozygous cytokine gene segment deletions, observed neutralizing antibodies may be named NAGGED antibodies. (5) Severe cytolysis releases intracellular content into the extracellular milieu and leads to regulated degradation of intracellular proteins and selection of antibody repertoires, similar to those observed in patients with systemic lupus erythematosus. (6) Systematic studies of novel autoimmune diseases on single cytokines will complement the present picture about interferons. (7) Interferon neutralization in COVID-19 constitutes a preamble of more studies about cytokine-regulated proteolysis in the control of autoimmunity. Here we reformulate these seven conjectures into testable questions for future research.

The design and analysis of non-randomized studies: a case study of off-label use of hydroxychloroquine in the COVID-19 pandemic.

Introduction: The COVID-19 pandemic has prompted researchers to conduct non-randomized studies in an effort to find an off-label drug that can effectively combat the virus and its effects. While these studies can expedite the drug approval process, researchers must carefully design and analyze such studies in order to perform rigorous science that is reproducible and credible. This article focuses on several key design and analysis considerations that can improve the scientific rigor of non-randomized studies of off-label drugs. Areas covered: The aim of this article is to provide an overview of best approaches that should be considered for non-randomized studies on off-label drugs. We discuss these approaches in detail and use a non-randomized study by Rivera et al. in Cancer Discovery as an example of methods that have been undertaken for COVID-19. Expert opinion: While non-randomized studies are inherently biased, they may be unavoidable in situations such as the COVID-19 pandemic, where researchers need to find an effective treatment quickly. We believe that a well-formed experimental design, high-quality data collection, and a well-thought-out statistical and data analysis plan are sufficient to produce rigorous and credible results for making an optimal decision.

Cell-based therapies for COVID-19: A living, systematic review.

OBJECTIVE: This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the available evidence on the role of cell-based therapies in the treatment of patients with COVID-19. DATA SOURCES: We conducted searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature, and in a centralized repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. All the searches covered the period until 23 April 2020 (one day before submission). ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We adapted an already published standard protocol for multiple parallel systematic reviews to the specificities of this question. We searched for randomized trials evaluating the effectiveness and safety of cell-based therapies versus placebo or no treatment in patients with COVID-19. Anticipating the lack of randomized trials directly addressing this question, we also searched for trials evaluating other coronavirus infections, such as MERS-CoV and SARS-CoV, and nonrandomized studies in COVID-19. Two reviewers independently screened each study for eligibility. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit this review to a peer-reviewed journal every time the conclusions change or whenever there are substantial updates. RESULTS: We screened 1 043 records, but no study was considered eligible. We identified 61 ongoing studies, including 39 randomized trials evaluating different types of cell-based therapies in COVID-19. CONCLUSIONS: We did not find any studies that met our inclusion criteria, and hence there is no evidence to support or refute the use of cell-based therapies for treating patients with COVID-19. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers in the near future. PROSPERO REGISTRATION NUMBER: CRD42020179711.

Mesenchymal stromal cells to fight SARS-CoV-2: Taking advantage of a pleiotropic therapy.

The devastating global impact of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has prompted scientists to develop novel strategies to fight Coronavirus Disease of 2019 (COVID-19), including the examination of pre-existing treatments for other viral infections in COVID-19 patients. This review provides a reasoned discussion of the possible use of Mesenchymal Stromal Cells (MSC) or their products as a treatment in SARS-CoV-2-infected patients. The main benefits and concerns of using this cellular therapy, guided by preclinical and clinical data obtained from similar pathologies will be reviewed. MSC represent a highly immunomodulatory cell population and their use may be safe according to clinical studies developed in other pathologies. Notably, four clinical trials and four case reports that have already been performed in COVID-19 patients obtained promising results. The clinical application of MSC in COVID-19 is very preliminary and further investigational studies are required to determine the efficacy of the MSC therapy. Nevertheless, these preliminary studies were important to understand the therapeutic potential of MSC in COVID-19. Based on these encouraging results, the United States Food and Drug Administration (FDA) authorized the compassionate use of MSC, but only in patients with Acute Respiratory Distress Syndrome (ARDS) and a poor prognosis. In fact, patients with severe SARS-CoV-2 can present infection and tissue damage in different organs, such as lung, heart, liver, kidney, gut and brain, affecting their function. MSC may have pleiotropic activities in COVID-19, with the capacity to fight inflammation and repair lesions in several organs.

Different Innate and Adaptive Immune Responses to SARS-CoV-2 Infection of Asymptomatic, Mild, and Severe Cases.

SARS-CoV-2 is a novel coronavirus, not encountered before by humans. The wide spectrum of clinical expression of SARS-CoV-2 illness suggests that individual immune responses to SARS-CoV-2 play a crucial role in determining the clinical course after first infection. Immunological studies have focused on patients with moderate to severe disease, demonstrating excessive inflammation in tissues and organ damage. In order to understand the basis of the protective immune response in COVID-19, we performed a longitudinal follow-up, flow-cytometric and serological analysis of innate and adaptive immunity in 64 adults with a spectrum of clinical presentations: 28 healthy SARS-CoV-2-negative contacts of COVID-19 cases; 20 asymptomatic SARS-CoV-2-infected cases; eight patients with Mild COVID-19 disease and eight cases of Severe COVID-19 disease. Our data show that high frequency of NK cells and early and transient increase of specific IgA, IgM and, to a lower extent, IgG are associated with asymptomatic SARS-CoV-2 infection. By contrast, monocyte expansion and high and persistent levels of IgA and IgG, produced relatively late in the course of the infection, characterize severe disease. Modest increase of monocytes and different kinetics of antibodies are detected in mild COVID-19. The importance of innate NK cells and the short-lived antibody response of asymptomatic individuals and patients with mild disease suggest that only severe COVID-19 may result in protective memory established by the adaptive immune response.

Cell-based therapies for COVID-19: A living, systematic review.

OBJECTIVE: This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the available evidence on the role of cell-based therapies in the treatment of patients with COVID-19. DATA SOURCES: We conducted searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature, and in a centralized repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. All the searches covered the period until 23 April 2020 (one day before submission). ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We adapted an already published standard protocol for multiple parallel systematic reviews to the specificities of this question. We searched for randomized trials evaluating the effectiveness and safety of cell-based therapies versus placebo or no treatment in patients with COVID-19. Anticipating the lack of randomized trials directly addressing this question, we also searched for trials evaluating other coronavirus infections, such as MERS-CoV and SARS-CoV, and nonrandomized studies in COVID-19. Two reviewers independently screened each study for eligibility. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit this review to a peer-reviewed journal every time the conclusions change or whenever there are substantial updates. RESULTS: We screened 1 043 records, but no study was considered eligible. We identified 61 ongoing studies, including 39 randomized trials evaluating different types of cell-based therapies in COVID-19. CONCLUSIONS: We did not find any studies that met our inclusion criteria, and hence there is no evidence to support or refute the use of cell-based therapies for treating patients with COVID-19. A substantial number of ongoing studies should provide valuable evidence to inform researchers and decision-makers in the near future. PROSPERO REGISTRATION NUMBER: CRD42020179711.

Macrolides for the treatment of COVID-19: a living, systematic review. / Macrólidos para el tratamiento de COVID-19: Una revisión sistemática viva.

OBJECTIVE: This living, systematic review aims to provide a timely, rigorous, and continuously updated summary of the evidence available on the role of macrolides for treating patients with COVID-19. DESIGN: A living, systematic review. DATABASE: We conducted searches in the centralized repository L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. Today it is maintained through regular searches in 39 databases. METHODS: We included randomized trials evaluating the effect of macrolides as monotherapy or in combination with other drugs versus placebo or no treatment in patients with COVID-19. Randomized trials evaluating macrolides in infections caused by other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19 were searched in case we found no direct evidence from randomized trials. Two reviewers independently screened each study for eligibility, extracted data, and assessed the risk of bias. Measures included all-cause mortality; the need for invasive mechanical ventilation; extracorporeal membrane oxygenation, length of hospital stay, respiratory failure, serious adverse events, time to SARS-CoV-2 RT-PCR negativity. We applied the GRADE approach to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit it every time the conclusions change or whenever there are substantial updates. RESULTS: The search in the L·OVE platform retrieved 424 references. We considered 260 as potentially eligible and were reviewed in full texts. We included one randomized clinical trial that evaluated the use of azithromycin in combination with hydroxychloroquine compared to hydroxychloroquine alone in hospitalized patients with COVID 19. The estimates for all outcomes evaluated resulted in insufficient power to draw conclusions. The quality of the evidence for the main outcomes was low to very low. CONCLUSIONS: Macrolides in the management of patients with COVID 19 showed no beneficial effects compared to standard of care. The evidence for all outcomes is inconclusive. Larger trials are needed to determine the effects of macrolides on pulmonary and other outcomes in COVID-19 patients. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59.

OBJETIVO: Proporcionar un resumen oportuno, riguroso y continuamente actualizado de la evidencia disponible sobre el papel de los macrólidos para el tratamiento de pacientes con COVID-19. DISEÑO: Revisión sistemática viva. BASE DE DATOS: La búsqueda de evidencia se realizó en el repositorio centralizado L·OVE (Living OVerview of Evidence) COVID-19; una plataforma que mapea las preguntas PICO para identificar la evidencia en la base de datos Epistemonikos. En respuesta a la emergencia de COVID-19, L·OVE se adaptó para ampliar el rango de evidencia que cubre y hoy se mantiene a través de búsquedas regulares en 39 bases de datos. MÉTODOS: Se incluyeron estudios experimentales que evaluaban el efecto de los macrólidos, como monoterapia o en combinación con otros fármacos, versus placebo o ningún tratamiento en pacientes con sospecha o confirmación de COVID-19. Se buscó identificar experimentos clínicos aleatorizados que evaluaran macrólidos en infecciones causadas por otros coronavirus, como MERS-CoV y SARS-CoV. Dos revisores examinaron de forma independiente la elegibilidad de cada estudio, extrajeron los datos y evaluaron el riesgo de sesgo. Se evaluó el efecto de los macrólidos sobre la mortalidad por todas las causas; necesidad de ventilación mecánica invasiva; oxigenación por membrana extracorpórea, duración de la estancia hospitalaria, insuficiencia respiratoria, eventos adversos graves, tiempo hasta la negatividad de la RT-PCR del SARS-CoV-2. La certeza de la evidencia para cada desenlace se evaluó siguiendo la aproximación GRADE. Esta revisión se mantendrá viva y disponible abiertamente durante la pandemia de COVID-19. Se someterán actualizaciones de su publicación cada vez que cambien las conclusiones o cuando haya actualizaciones sustanciales. RESULTADOS: Se identificó un experimento clínico aleatorio que evaluó el uso de azitromicina en combinación con hidroxicloroquina en comparación con el uso de hidroxicloroquina sola, en pacientes hospitalizados por COVID 19. Las estimaciones para todos los resultados evaluados resultaron en un poder estadístico insuficiente para llegar a conclusiones válidas. La calidad de la evidencia para los resultados principales fue baja a muy baja. CONCLUSIONES: El uso de macrólidos en el tratamiento de pacientes con COVID 19 no ha mostrado efectos beneficiosos en comparación con el tratamiento estándar. La evidencia para todos los desenlaces no es concluyente. Se necesitan estudios sobre un mayor número de pacientes con COVID 19, para determinar los efectos del uso de macrólidos sobre los desenlaces relacionados con la enfermedad. SYSTEMATIC REVIEW REGISTRATION: PROSPERO Registration number: CRD42020181032 Protocol preprint DOI: 10.31219/osf.io/rvp59.

Sexual transmission of SARS-CoV-2 virus and its role in the spread of COVID-19: A living systematic review protocol.

OBJECTIVE: To provide a review of the literature on the presence of SARS-CoV-2 in the sexual fluids of patients with COVID-19 and to observe its possible sexual transmission in a timely, rigorous, and continuously updated manner. DATA SOURCES: We will conduct searches in PubMed/Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), grey literature, and a centralized repository in L·OVE (Living OVerview of Evidence). L·OVE is a platform that maps PICO questions to evidence from the Epistemonikos database. In response to the COVID-19 emergency, L·OVE was adapted to expand the range of evidence it covers and customized to group all COVID-19 evidence in one place. The search will cover the period until the day before submission to a journal. ELIGIBILITY CRITERIA FOR SELECTING STUDIES AND METHODS: We adapted an already published standard protocol for multiple parallel systematic reviews to the specificities of this question. We will include randomized trials evaluating the sexual transmission of the SARS-CoV-2 virus. Randomized trials evaluating the sexual transmission of other coronaviruses, such as MERS-CoV and SARS-CoV, and non-randomized studies in COVID-19 will be searched if no direct evidence from randomized trials is found or if the direct evidence provides a low to a very low level of certainty for critical outcomes. Two reviewers will independently screen each study for eligibility, extract data, and assess the risk of bias. We will perform random-effects meta-analyses and use GRADE to assess the certainty of the evidence for each outcome. A living, web-based version of this review will be openly available during the COVID-19 pandemic. We will resubmit the review if the conclusions change or if there are substantial updates. PROSPERO REGISTRATION: (CRD42020189368).

OBJETIVO: Proporcionar una revisión de la literatura sobre la presencia de SARS-CoV-2 en los fluidos sexuales de pacientes con COVID-19 y su posible transmisión sexual de manera oportuna, rigurosa y continuamente actualizada. FUENTES DE DATOS: Realizaremos búsquedas en PubMed / Medline, Embase, Registro Cochrane Central de Ensayos Controlados (CENTRAL), literatura gris y en un repositorio centralizado en L · OVE (Living OVerview of Evidence). L · OVE es una plataforma que mapea las preguntas PICO a la evidencia de la base de datos Epistemonikos. En respuesta a la emergencia de COVID-19, L · OVE se adaptó para ampliar el rango de evidencia que cubre y se personalizó para agrupar todas las pruebas de COVID-19 en un solo lugar. La búsqueda cubrirá el período hasta el día anterior al envío a una revista. CRITERIOS DE ELEGIBILIDAD PARA LA SELECCIÓN DE ESTUDIOS Y MÉTODOS: Adaptamos un protocolo común ya publicado para múltiples revisiones sistemáticas paralelas a las especificidades de esta pregunta. Incluiremos ensayos aleatorios que evalúen la transmisión sexual del virus SARS-CoV-2. Se buscarán ensayos aleatorizados que evalúen la transmisión sexual de otros coronavirus, como MERS-CoV y SARS-CoV, y estudios no aleatorizados en COVID-19 en caso de que no se encuentre evidencia directa de ensayos aleatorizados, o si la evidencia directa proporciona una - o certeza muy baja para resultados críticos. Dos revisores evaluarán de forma independiente la elegibilidad de cada estudio, extraerán datos y evaluarán el riesgo de sesgo. Realizaremos metanálisis de efectos aleatorios y utilizaremos GRADE para evaluar la certeza de la evidencia para cada resultado. Una versión viva basada en la web de esta revisión estará disponible abiertamente durante la pandemia de COVID-19. Lo volveremos a enviar si las conclusiones cambian o hay actualizaciones sustanciales. REGISTRO PROSPERO: (CRD42020189368).

The Management of Cytokine Storm in COVID-19.

Cytokine storm in COVID-19 infection is an excessive immune response to external stimuli where the pathogenesis is complex. The disease progresses rapidly and the mortality is high. Certain evidence shows that the severe deterioration of some patients has been closely related to the strong upregulation of cytokine production in SARS-Co-V2 induced pneumonia with an associated cytokine storm syndrome. Identification of existing approaved therapy with proven safety profile to treat hyperinflammation is critical unmet need in order to reduce COVID-19 associated mortality. To date, no specific therapeutic drugs are available to treat COVID-19 infection. Preliminary studies have shown that immune-modulatory or immune suppressive treatments might be considered as treatment choices for COVID-19, particularly in severe disease. This article review the pathogenesis and treatment strategies of COVID-19 virus-induced inflammatory storm in attempt to provide valuable medication guidance for clinical treatment.

Coronavirus disease 2019 (COVID-19) in domestic animals and wildlife: advances and prospects in the development of animal models for vaccine and therapeutic research.

SARS-CoV-2, which causes coronavirus disease 2019 (COVID-19), is suspected to have been first contracted via animal-human interactions; it has further spread across the world by efficient human-to-human transmission. Recent reports of COVID-19 in companion animals (dogs and cats) and wild carnivores such as tigers have created a dilemma regarding its zoonotic transmission. Although in silico docking studies, sequence-based computational studies, and experimental studies have shown the possibility of SARS-CoV-2 infection and transmission in cats, ferrets, and other domestic/wild animals, the results are not conclusive of infection under natural conditions. Identifying the potential host range of SARS-CoV-2 will not only help prevent the possibility of human-to-animal and animal-to-human transmission but also assist in identifying efficient animal models that can mimic the clinical symptoms, transmission potential, and pathogenesis of the disease. Such an efficient animal model will accelerate the process of development and evaluation of vaccines, immunotherapeutics, and other remedies for SARS-CoV-2.

Antiviral treatment for COVID-19: the evidence supporting remdesivir.

The emergence of the novel beta coronavirus SARS-CoV-2 and the ensuing COVID-19 pandemic has generated a rapidly evolving research landscape in the search for new therapeutic agents. The intravenous antiviral drug remdesivir has in vitro activity against SARS-CoV-2 and now studies have reported its clinical efficacy, demonstrating shorter time to recovery in hospitalised patients with severe COVID-19. Adverse event rates were low and remdesivir has now received conditional marketing authorisation from the European Medicines Agency. An interim clinical commissioning policy is in place in the UK. These studies make remdesivir the first antiviral drug able to alter the natural history of severe COVID-19, and a benchmark for the comparison of new therapies in the future. Ongoing studies are investigating its use in early mild/moderate COVID-19, alternative formulations, and the combination of remdesivir with immunomodulatory agents.