Ongoing Living Update of COVID-19 Therapeutic Options: Summary of Evidence. Rapid Review, 4 May 2022

Background: The urgent need for evidence on measures to respond to the COVID-19 pandemic had led to a rapid escalation in numbers of studies testing potential therapeutic options. The vast amount of data generated by these studies must be interpreted quickly so that physicians have the information to make optimal treatment decisions and manufacturers can scale-up production and bolster supply chains. Moreover, obtaining a quick answer to the question of whether or not a particular intervention is effective can help investigators involved in the many ongoing clinical trials to change focus and pivot to more promising alternatives. It is crucial for healthcare workers to have access to the most up-to-date research evidence to inform their treatment decisions. To address this evidence gap, we compiled the following database of evidence on potential therapeutic options for COVID-19. We hope this information will help investigators, policy makers, and prescribers navigate the flood of relevant data to ensure that management of COVID19, at both individual and population levels, is based on the best available knowledge. We will endeavor to continually update this resource as more research is released into the public space. Summary of evidence: Tables 1 and 2, which divide the total group of identified studies into randomized (Table 1) and non-randomized (Table 2) designs, indicate the primary outcome measures used for each investigation and the level of certainty. Table 3 summarizes the status of evidence for the 193 potential therapeutic options for COVID-19 for which studies were identified through our systematic review.

Características clínicas y evolución de los síntomas en pacientes con covid-19 / Clinical characteristics and evolution of symptoms in patients with COVID-19

RESUMEN Introducción: muchos casos de covid-19 son asintomáticos al ingresar. El desarrollo de síntomas pudiera tener relación con la terapéutica empleada. Objetivo: caracterizar clínicamente los pacientes infectados con SARS-CoV-2 y la evolución de los síntomas en relación con el ingreso, en el Hospital Militar Docente Dr. Mario Muñoz Monroy, de Matanzas. Materiales y métodos: estudio retrospectivo de las historias clínicas de pacientes ingresados confirmados con SARS-CoV-2 hasta el 26 de junio de 2020. Se estudiaron 145 pacientes, divididos en dos grupos: sintomáticos y asintomáticos al ingresar. Se recabaron datos demográficos, antecedentes patológicos personales, síntomas y evolución, parámetros humorales, tratamiento, estadía hospitalaria y complicaciones. Se utilizaron las pruebas de Chi cuadrado y de U de Mann-Whitney, según el tipo de variable. Resultados: la mayoría de los pacientes ingresó sintomático. Solo hasta 19 años predominaron los asintomáticos. Los hipertensos, diabéticos y con insuficiencia renal tuvieron mayor proporción de sintomáticos al momento del ingreso. Un pequeño grupo (n= 38) nunca desarrollo síntomas. En los sintomáticos predominaron tos, malestar general, fiebre, dolor faríngeo, congestión nasal, anosmia y falta de aire. Posterior al ingreso prevalecieron diarreas, dispepsia y vómitos. Los sintomáticos tuvieron mayores valores de enzimas hepáticas, más infección respiratoria baja y distress respiratorio, así como estadía hospitalaria extensa, ingreso en cuidados intensivos y fallecidos. Conclusiones: más de la mitad de los pacientes ingresaron con predominio de síntomas generales y respiratorios. Después del ingreso predominó la sintomatología digestiva, posiblemente relacionada con la terapéutica empleada. Los pacientes sintomáticos al ingresar, tuvieron peores parámetros humorales, más complicaciones y estadía hospitalaria más prolongada (AU).

ABSTRACT Introduction: many cases of covid-19 are asymptomatic when admitted to the hospital. The development of symptoms may be related to the therapies used. Objective: to characterize clinically the patients infected with SARS-CoV-2 and the evolution of symptoms in relation to admission, in the Military Hospital Dr. Mario Muñoz Monroy, of Matanzas. Materials and methods: retrospective study of clinical records of SARS-CoV-2-confirmed patients admitted up to June 26, 2020. 145 patients were studied, divided into two groups: symptomatic and asymptomatic ones at admission. Demographic data, personal pathological history, symptoms and evolution, humoral parameters, treatment, hospital stay and complications were collected. The Chi square and Mann-Whire U tests were used, depending on the type of variable. Results: most patients were symptomatic at admission. Asymptomatic ones predominated only up to 19 years. Hypertensive, diabetic and renal impaired patients had a higher proportion of symptoms at admission. A small group (n = 38) never developed symptoms. Cough, general discomfort, fever, pharyngeal pain, nasal congestion, anosmia and shortness of breath were the predominated symptoms. Diarrhea, dyspepsia and vomiting prevailed after admission. The symptomatic patients showed higher liver enzyme values, more low respiratory infection and respiratory distress, and also had more extended hospital stay, admission to intensive care and deceases. Conclusions: more than half of the patients were admitted with predominance of general and respiratory symptoms. After admission, digestive symptoms predominated, possibly related to the therapies used. Symptomatic patients on admission had worse humoral parameters, more complications and longer hospital stay (AU).

Modelo temporal del comportamiento de pacientes críticos con covid-19 durante su estadía en cuidados intensivos. Lombardía, Italia / Temporal model of the behavior of critically ill patients with COVID-19 during their staying in intensive care. Lombardy, Italy

RESUMEN Introducción: una serie temporal es el producto de la observación de una variable en el tiempo. Es una herramienta matemática que se aplica con frecuencia en la salud. No se han elaborado modelos temporales que predigan el comportamiento de los pacientes durante su ingreso en la Unidad de Cuidados Intensivos. Objetivos: crear una serie temporal que permita predecir el comportamiento, durante su ingreso en la Unidad de Cuidados Intensivos, de pacientes graves producto de la covid-19 en la región de Lombardía, Italia. Materiales y métodos: analítico, longitudinal prospectivo con un grupo de pacientes críticos que ingresaron del 1 de abril al 1 de mayo de 2020, con diagnóstico de covid-19, en el Hospital Mayor de Crema, en la región de Lombardía, Italia. El universo estuvo constituido por 28 pacientes y se trabajó con el total de ellos. Resultados: composición por sexo: 48 % masculino. Media de edad: 83 años. Serie temporal: Modelo 1 que ajusta (Hold) PO2/FiO2 p = 0,251; Modelo 2 (ARIMA) SatO2/FiO2 p = 0,674 (en los dos primeros modelos el resultado se incrementó con los días, siguiendo un comportamiento predecible); Modelo 3 (ARIMA) p = 0,406 (en este caso, el resultado esperado decreció a medida que transcurrió el tiempo). Las funciones obtenidas permiten calcular el valor esperado según el día desde el ingreso. Conclusiones: predecir la evolución del paciente en la Unidad de Cuidados Intensivos permitió detectar tempranamente aquellos con una curva inesperada y dirigir hacia a ellos las terapéuticas más agresivas (AU).

ABSTRACT Introduction: a time series is the product of the observation of a variable in time. It is a mathematical tool frequently applied in health. No temporal models have been developed to predict patients' behavior during their staying in the Intensive Care Unit. Objectives: to create a time series allowing to predict the behavior of seriously-ill patients due to COVID-19, during their staying in the Intensive Care Unit in the region of Lombardy, Italy. Materials and methods: analytic, longitudinal prospective study with a group of critical patients who were admitted from April 1st to May 1st, with COVID-19 diagnosis, to Ospedale Maggiore di Crema, in the Lombardy region, Italy. The universe was formed by 28 patients and all of them were worked on. Results: 48% of patients were male. Average age: 83 years; Time series: Model 1 holding PO2/FiO2 p = 0.251; Model 2 (ARIMA) SatO2/FiO2 p = 0.674 (in the two first models the result increased with the days, following a predictable behavior=; Model 3 (ARIMA) p = 0.406 (in this case the expected result decreased as time passed). The obtained functions allow to calculate the expected value according to the day from the admission. Conclusions: predicting patient's evolution in the Intensive Care Unit allowed early detecting those with unexpected curves and targeting more aggressive therapies toward them (AU).

A influência da resposta dos EUA à COVID-19 no contexto da Saúde Global / The influence of the U.S. response to COVID-19 in Global Health

Resumo A resposta americana à pandemia envolve um proeminente volume de recursos federais, em especial destinados ao desenvolvimento e aquisição de produtos no uso interno, como diagnósticos ou vacinas. As justificativas para esse desembolso se baseiam em mecanismos de investimentos e aspectos históricos. Assim, a construção social do nacionalismo na formação na sociedade americana prejudica o acesso a tecnologias em saúde. A revisão desses aspectos demonstra como os Estados Unidos (EUA) garantiram compra de grande quantitativo de produtos em potencial, inclusive assegurando excessiva produção local. Essa política externa unilateral tem influenciado outros países ou blocos regionais e prejudicado a cooperação e a solidariedade global com impacto na saúde coletiva de diversas nações.

Abstract The American response to the pandemic involves a prominent volume of federal resources, especially for developing and acquiring products for internal use, such as diagnostics or vaccines. Investment mechanisms and historical aspects justify this expenditure. Thus, the social construction of nationalism in American society hinders access to health technologies. The review of such aspects shows how the United States (U.S.) secured a large number of potential products, ensuring excessive local production. This unilateral foreign policy has influenced other countries or regional blocs and undermined global cooperation and solidarity, affecting the collective health of several nations.

Síndrome inflamatorio multisistémico en niños, relacionado con COVID-19: actualización a propósito de la presentación de 2 pacientes críticos / Multisystem inflammatory syndrome in children related to COVID-19: An update regarding the presentation of two critically ill patients

El síndrome inflamatorio multisistémico en niños asociado con enfermedad por coronavirus 2019 se define por la presencia de fiebre persistente, inflamación y disfunción orgánica, con evidencia de infección pasada o reciente por coronavirus tipo 2 del síndrome respiratorio agudo grave, y exclusión de otra causa microbiana. Acarrea la superposición con otras enfermedades inflamatorias (enfermedad de Kawasaki y síndrome de shock tóxico) y comparte características con entidades que presentan hipercitocinemia (linfohistiocitosis hemofagocítica y síndrome de activación macrofágica). Se diferencia de estas y de la forma aguda grave de enfermedad por coronavirus 2019 en su presentación clínica y parámetros de laboratorio. Su evolución es potencialmente grave y puede presentar falla cardiovascular; la mortalidad es baja (del 2 %).Se realiza una actualización de este síndrome, y se describe la presentación de 2 casos clínicos con disfunción cardiovascular, que requirieron sostén vasoactivo y asistencia ventilatoria invasiva. El laboratorio sérico evidenció parámetros de inflamación. Ambos recibieron tratamiento con gammaglobulina endovenosa y corticoides sistémicos, con evolución favorable

Multisystem inflammatory syndrome in children related to COVID-19 is defined as the presence of persistent fever, inflammation, and organ dysfunction, with evidence of past or recent severe acute respiratory syndrome coronavirus 2 infection, and excluding other microbial causes. It overlaps with other inflammatory diseases (Kawasaki disease and toxic shock syndrome) and shares some features with hypercytokinemia conditions (hemophagocytic lymphohistiocytosis and macrophage activation syndrome). It differs from these and severe acute COVID-19 in its clinical presentation and laboratory parameters. It has a potentially severe course and may occur with cardiovascular failure; mortality is low (2 %).Here we provide an update on this syndrome and describe the presentation of two clinical cases with cardiovascular dysfunction who required vasoactive support and invasive ventilation. Serum lab tests showed inflammation parameters. Both patients were treated with intravenous immunoglobulin and systemic corticosteroids and had a favorable course

Análise espacial das condições de enfrentamento à COVID-19: uma proposta de Índice da Infraestrutura da Saúde do Brasil / Spatial analysis of Brazil's COVID-19 response capacity: a proposal for a Healthcare Infrastructure Index

Resumo Uma das preocupações ligadas à pandemia da COVID-19 se refere à capacidade da estrutura do sistema de saúde suportar a demanda por atendimento e tratamento de pessoas acometidas por esta doença. Diante disso, o objetivo deste estudo consiste em criar e mapear o Índice de Infraestrutura de Saúde (IIS) das Unidades da Federação (UFs) brasileiras, bem como verificar a sua distribuição espacial. Para isso, foi aplicada a metodologia de Análise Fatorial por Componentes Principais. Aplicou-se os testes de Bartlett e Kaiser-Meyer-Olkin para verificação da sua adequabilidade. Em seguida procedeu-se a Análise Exploratória de Dados Espaciais. Os dados foram coletados no DATASUS, COFEN, Ministério da Saúde, Portal de Compras do Governo e Portal da Transparência. Quanto aos resultados, o índice revelou que nove estados do Norte e Nordeste registraram os menores índices e cinco estados do Sudeste e Sul apresentaram os maiores índices. Foi registrado um cluster baixo-baixo nos estados do Amazonas e Pará e um Cluster alto-alto em Minas Gerais, Rio de Janeiro, São Paulo e Paraná.

Abstract One of the concerns linked to the COVID-19 pandemic is the capacity of health systems to respond to the demand for care for people with the disease. The objective of this study was to create a COVID-19 response Healthcare Infrastructure Index (HII), calculate the index for each state in Brazil, and determine its spatial distribution within and across regions. The HII was constructed using principal component factor analysis. The adequacy of the statistical model was tested using the Kaiser-Meyer-Olkin test and Bartlett's test of sphericity. The spatial distribution of the HII was analyzed using exploratory spatial data analysis. The data were obtained from DATASUS, the Federal Nursing Council, Ministry of Health, Government Procurement Portal, and the Transparency Portal. The nine states in the country's North and Northeast regions showed the lowest indices, while the five states from the Southeast and South regions showed the highest indices. Low-low clusters were observed in Amazonas and Pará and high-high clusters were found in Minas Gerais, Rio de Janeiro, São Paulo, and Paraná.

Pediatric patients with COVID-19 admitted to intensive care units in Brazil: a prospective multicenter study / Pacientes pediátricos com COVID-19 admitidos em Unidades de Terapia Intensiva no Brasil: um estudo prospectivo multicêntrico

Abstract Objective: To describe the clinical characteristics of children and adolescents admitted to intensive care with confirmed COVID-19. Method: Prospective, multicenter, observational study, in 19 pediatric intensive care units. Patients aged 1 month to 19 years admitted consecutively (March-May 2020) were included. Demographic, clinical-epidemiological features, treatment, and outcomes were collected. Subgroups were compared according to comorbidities, age < 1 year, and need for invasive mechanical ventilation. A multivariable logistic regression model was used for predictors of severity. Results: Seventy-nine patients were included (ten with multisystemic inflammatory syndrome). Median age 4 years; 54% male (multisystemic inflammatory syndrome, 80%); 41% had comorbidities (multisystemic inflammatory syndrome, 20%). Fever (76%), cough (51%), and tachypnea (50%) were common in both groups. Severe symptoms, gastrointestinal symptoms, and higher inflammatory markers were more frequent in multisystemic inflammatory syndrome. Interstitial lung infiltrates were common in both groups, but pleural effusion was more prevalent in the multisystemic inflammatory syndrome group (43% vs. 14%). Invasive mechanical ventilation was used in 18% (median 7.5 days); antibiotics, oseltamivir, and corticosteroids were used in 76%, 43%, and 23%, respectively, but not hydroxychloroquine. The median pediatric intensive care unit length-of-stay was five days; there were two deaths (3%) in the non- multisystemic inflammatory syndrome group. Patients with comorbidities were older and comorbidities were independently associated with the need for invasive mechanical ventilation (OR 5.5; 95% CI, 1.43-21.12; p = 0.01). Conclusions: In Brazilian pediatric intensive care units, COVID-19 had low mortality, age less than 1 year was not associated with a worse prognosis, and patients with multisystemic inflammatory syndrome had more severe symptoms, higher inflammatory biomarkers, and a greater predominance of males, but only comorbidities and chronic diseases were independent predictors of severity.

Resumo Objetivo: Descrever as características clínicas de crianças e adolescentes internados em unidade de terapia intensiva com COVID-19 confirmada. Método: Estudo prospectivo, multicêntrico, observacional, em 19 unidades de terapia intensiva pediátrica. Foram incluídos pacientes entre um mês e 19 anos, admitidos consecutivamente (março a maio de 2020). As características demográficas, clínico-epidemiológicas, o tratamento e os resultados foram coletados. Os subgrupos foram comparados de acordo com as comorbidades, idade < 1 ano e necessidade de ventilação mecânica invasiva. Um modelo de regressão logística multivariável foi utilizado para preditores de gravidade. Resultados: Setenta e nove pacientes foram incluídos (10 com síndrome inflamatória multi-ssistêmica). Mediana de idade, quatro anos; 54% eram do sexo masculino (síndrome inflamatória multissistêmica, 80%); 41% tinham comorbidades (síndrome inflamatória multissistêmica, 20%). Febre (76%), tosse (51%) e taquipneia (50%) foram comuns nos dois grupos. Sintomas graves egastrointestinais e marcadores inflamatórios mais elevados foram mais frequentes na presença de síndrome inflamatória multissistêmica. Infiltrados intersticiais pulmonares foram comuns em ambos os grupos, mas o derrame pleural foi mais prevalente no grupo com síndrome inflamatória multissistêmica (43% vs. 14%). A ventilação mecânica invasiva foi utilizada em 18% (mediana 7,5 dias); antibióticos, oseltamivir e corticosteroides foram utilizados em 76%, 43% e 23%, respectivamente, mas não a hidroxicloroquina. A mediana do tempo de permanência na unidade de terapia intensiva pediátrica foi de 5 dias; duas mortes ocorreram (3%) no grupo não- síndrome inflamatória multissistêmica. Os pacientes com comorbidades eram mais velhos, e as comorbidades foram independentemente associadas à necessidade de ventilação mecânica invasiva(OR 5,5; IC95%, 1,43-21,12; P 0,01). Conclusões: Nas unidades de terapia intensiva pediátrica brasileiras, a COVID-19 apresentou baixa mortalidade, a idade inferior a um ano não foi associada a um pior prognóstico, os pacientes com síndrome inflamatória multissistêmica apresentaram sintomas mais graves, biomarcadores inflamatórios mais elevados e uma grande predominância no sexo masculino, mas apenas a presença de comorbidades e doenças crônicas foi um preditor independente de gravidade.

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

Recomendaciones para el manejo inicial del síndrome inflamatorio multisistémico relacionado temporalmente con COVID-19, en niños y adolescentes / Recommendations for the initial management of multisystem inflammatory syndrome temporally related to COVID-19, in children and adolescents

El síndrome inflamatorio multisistémico en niños y adolescentes temporalmente relacionado con COVID-19 es una presentación clínica de la infección por SARS-CoV-2. Comparte algunas características con la enfermedad de Kawasaki, el shock tóxico, la sepsis, el síndrome de activación macrofágica y la miocarditis. Son escasas las publicaciones que abordan su manejo inicial, que tiene semejanzas con el propuesto para el shock séptico. Esta revisión analiza dicho abordaje basado en las características propias del síndrome inflamatorio multisistémico relacionado con COVID-19, de acuerdo con el paradigma de construcción de una "guía de práctica institucional", y sugiere estrategias de aproximación terapéutica, que incluyen detección temprana, estabilización, referencia, tratamiento específico y análisis de proceso

Multisystem inflammatory syndrome temporally related to COVID-19 in children and adolescents is a clinical presentation of SARS-CoV-2 infection. It shares some features with Kawasaki disease, toxic shock, sepsis, macrophage activation syndrome, and myocarditis. Few publications have addressed its initial management, which is similar to that proposed for septic shock. This review analyzes such approach based on the characteristics typical of multisystem inflammatory syndrome related to COVID-19 in accordance with the paradigm of an "institutional practice guideline" and suggests therapeutic approach strategies, including early detection, stabilization, referral, specific treatment, and process analysis.

Bioética en tiempos de pandemia / Bioethics in times of pandemic

Las estadísticas arrojadas por la pandemia de COVID-19 evidencian que el impacto sobre la población pediátrica no ha tenido la magnitud mostrada en los adultos. Aun así, tanto para los pediatras como para el resto de los integrantes de los equipos de salud, se plantea un dilema entre el mantenimiento de la responsabilidad, el compromiso en la atención de los pacientes afectados y las dudas e incertidumbres surgidas frente a la posibilidad de contraer la enfermedad y de trasmitirla a los seres más cercanos. Desde allí, se estructuran dos cuestiones centrales: ¿existe un límite moral frente a la posibilidad de correr riesgos durante el ejercicio profesional?, ¿qué influencia tiene la dificultad de acceso a mecanismos de protección imprescindibles para disminuir los riesgos que aquel implica? Consideramos que la bioética puede actuar como una herramienta que permita reflexionar sobre estos y otros aspectos a los que la actual pandemia nos enfrenta

It has been demonstrated by statistics that COVID-19 pandemic has not been as aggressive among pediatric population as in adults. Yet, pediatricians and the rest of the health care team face the dilemma of keeping the commitment and responsibilities towards the patients or withstanding the uncertainties arising versus the possibilities of getting infected and spreading it to their beloved ones.There are two main issues: during the professional everyday practice, is there a moral limit when it comes to taking risks? And what is the importance of having difficulty in getting the proper safety equipment in order to decrease the potential risks? Bioethics, as we think, may work as a tool, helping us all to ponder this and the many other bearings we are facing with the current pandemic