Clinical-epidemiological relation between sars-cov-2 and kawasaki disease: an integrative literature / Relação clínico-epidemiológica entre sars-cov-2 e doença de kawasaki: uma revisão integrativa da literatura

ABSTRACT Objective: To analyze the current scientific literature to document, in an integrative review, the main findings that correlate Kawasaki disease (KD) to COVID-19. Data sources: The search was carried out in June 2020 in the following databases: Biblioteca Virtual em Saúde (BVS), periódico da CAPES and U.S National Library of Medicine (PubMed). The combination of descriptors used was [(COVID-19 OR SARS-CoV-2) AND (Kawasaki disease)], and the inclusion criteria stipulated were studies published from January 2019 to June 2020, without restriction of language or location, and available online in full. News, editorials, comments, and letters, as well as duplicates and articles that did not answer the guiding question were excluded. Data synthesis: A total of 97 articles were identified, of which seven comprised this review. The association of KD to the new coronavirus appears to trigger a severe clinical condition of vasculitis. Different from the usual, in this inflammatory syndrome, patients are older, and prevalence is higher in children from African or Caribbean ancestry; clinical and laboratory manifestations are also atypical, with a predominance of abdominal complaints and exaggerated elevation of inflammatory markers. In addition, there was a greater report of rare complications and greater resistance to the recommended treatment for KD. Conclusions: Pediatric COVID-19 and its potential association to severe KD, still unfamiliar to health professionals, reinforces the importance of testing patients with vasculitis for the new coronavirus and the need to wage high surveillance and preparation of the health system during the current pandemic.

RESUMO Objetivo: Analisar a literatura científica atual a fim de documentar, por meio de revisão integrativa, os principais achados que associam a doença de Kawasaki (DK) à doença do coronavírus (COVID-19). Fonte de dados: A busca ocorreu em junho de 2020, nas bases de dados: Biblioteca Virtual em Saúde (BVS), periódico da Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) e U.S. National Library of Medicine (PubMed). Os descritores utilizados foram [(COVID-19 OR SARS-CoV-2) AND (Kawasaki Disease)], e os critérios de inclusão estipulados compreenderam estudos publicados de janeiro de 2019 a junho de 2020, sem restrição de idioma ou localização e disponíveis online integralmente. Foram excluídos notícias, editoriais, comentários e cartas de apresentação, assim como duplicatas e artigos que não respondiam à pergunta norteadora. Síntese dos dados: Identificaram-se 97 artigos, dos quais sete compuseram esta revisão. A associação da DK com o novo coronavírus parece desencadear um quadro de vasculite grave. Diferentemente do usual, nessa síndrome inflamatória, os pacientes são mais velhos e a descendência prevalente é africana ou caribenha; as manifestações clínicas e laboratoriais também são atípicas, com predomínio de queixas abdominais e elevação exagerada de marcadores inflamatórios. Além disso, houve maior relato de complicações raras e maior resistência ao tratamento preconizado para DK. Conclusões: A COVID-19 pediátrica e sua potencial associação com uma DK grave, ainda pouco conhecida pelos profissionais da saúde, reforçam a importância da testagem de pacientes com vasculite para o novo coronavírus e a necessidade de empreender alta vigilância e preparação do sistema de saúde durante a atual pandemia.

Índices neutrófilo/linfocito, plaqueta/linfocito e inmunidad/inflamación sistémica en pacientes con neumonía por COVID-19 / Neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio and systemic immune-inflammation index in patients with COVID-19-associated pneumonia

Resumen Introducción: Existen índices hematológicos que correlacionan la severidad y predicen la mortalidad, principalmente en estados sépticos y de inflamación. Objetivo: Correlacionar los índices neutrófilo/linfocito (INL), plaqueta/linfocito (IPL) e inmunidad/inflamación sistémica (IIIS) con la severidad de COVID-19. Método: Estudio descriptivo, analítico y retrospectivo de pacientes con neumonía por COVID-19, en quienes se analizaron INL, IPL e IIIS. Resultados: Se incluyeron 100 pacientes, 54 hombres y 46 mujeres, con una media de 49.4 ± 19.3 años. Las medias de INL, IPL e IIIS fueron 10.7 ± 10.9, 290.1 ± 229.2 y 2.6 ± 3.4 × 109, respectivamente. En 54 %, la neumonía fue leve y en 46 %, grave. En cuanto a los desenlaces hospitalarios, 75 % egresó por mejoría y 25 % falleció. Las medias de INL, IPL e IIIS de los pacientes que fallecieron versus las de los pacientes que mejoraron fueron 20.4 ± 16.9 versus 7.5 ± 4.9 (p = 0.001), 417.1 ± 379.7 versus 247.7 ± 127.4 (p = 0.038) y 4.8 ± 6.1 versus 1.9 ± 1.2 × 109 (p = 0.030), respectivamente. Conclusión: Los índices hematológicos en pacientes con neumonía por COVID-19 pueden ser empleados como predictores de severidad y pronóstico.

Abstract Introduction: There are hematological parameters that correlate severity and predict mortality mainly in septic and inflammatory states. Objective: To correlate the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII) with COVID-19 severity. Method: Descriptive, analytical, retrospective study of patients with COVID-19 pneumonia, in which NLR, PLR and SII were analyzed. Results: One-hundred patients were included, 54 men and 46 women, with a mean age of 49.4 ± 19.3 years. NLR, PLR and SII means were 10.7 ± 10.9, 290.1 ± 229.2, and 2.6 ± 3.4 × 109, respectively. In 54 %, pneumonia was mild, and in 46 %, severe. Regarding hospital outcomes, 75 % were discharged due to improvement and 25 % died. NLR, PLR and SII means of the patients who died versus the patients who improved were 20.4 ± 16.9 versus 7.5 ± 4.9 (p = 0.001), 417.1 ± 379.7 versus 247.7 ± 127.4 (p = 0.038) and 4.8 ± 6.1 versus 1.9 ± 1.2 × 109 (p = 0.030), respectively. Conclusion: Hematological parameters can be used in patients with COVID-19-associated pneumonia as predictors of severity and prognosis.

Pronóstico de pacientes hospitalizados por COVID-19 en un centro terciario en Chile: estudio de cohorte / Prognosis of patients with COVID-19 admitted to a tertiary center in Chile: a cohort study

Introducción Desde el comienzo de la pandemia de COVID-19, se han desarrollado diversas investigaciones sobre el pronóstico de pacientes con SARS-CoV-2 asociado a factores como edad, condiciones biodemográficas, comorbilidades, factores sociales, parámetros clínicos, hematológicos, marcadores inflamatorios, de coagulación, bioquímicos y gasométricos, entre otros. Hasta ahora, existen escasos estudios que hayan abordado el tema en América Latina, por lo que es de interés conocer el comportamiento de la enfermedad en la región. Objetivo Evaluar el curso del COVID-19 en pacientes ingresados en un centro terciario en Chile y analizar factores predictores, medidos en el período cercano a la admisión, que se asocien al pronóstico vital y al uso de ventilación mecánica invasiva. Métodos Estudio de cohorte retrospectivo realizado en Clínica Indisa de Santiago, Chile. Participaron todos los pacientes de 15 años o más hospitalizados entre el 11 de marzo y el 25 de julio de 2020. Se analizó la letalidad hospitalaria, la complejidad de los casos y se aplicaron modelos de regresión logística para identificar predictores de las variables de resultado definidas. Resultados La muestra estuvo constituida por 785 sujetos. La edad media fue 59 años, 59% fueron hombres y 61,3% tenía comorbilidades. El 45% requirió cuidados intensivos y 24% ventilación mecánica invasiva. La letalidad hospitalaria global fue de 18,7%. En pacientes de unidad de cuidados intensivos fue 32,1% y en quienes recibieron ventilación mecánica invasiva 59,4%. Los factores de riesgo independientes de morir incluyeron la edad (Odds ratio 1,09; intervalo de confianza 95%: 1,07 a 1,12), diabetes (1,68; 1,06 a 2,67), enfermedad pulmonar crónica (2,80; 1,48 a 5,28) y mayores niveles de proteína C reactiva, creatinina y ferritina. No se demostró asociación con el sexo, pertenencia al seguro público de salud, antecedente de cardiopatía, obesidad, ni dímero D. Similares factores fueron predictores de ventilación mecánica invasiva. Conclusiones El pronóstico y factores predictores en esta cohorte de pacientes hospitalizados en Chile por COVID-19 fueron comparables en su mayoría a los reportados en estudios similares de países de mayores ingresos. El sexo masculino no fue un factor de mal pronóstico en este grupo de pacientes.

Introduction Since the beginning of the COVID-19 pandemic, extensive research has been done on the prognosis of patients with SARS-CoV-2 associated with age, biodemographic conditions, comorbidities, social factors, clinical parameters, inflammatory blood markers, coagulation, biochemical and blood gas parameters, among others. Few studies have addressed this problem in Latin America, so it is of interest to know how the disease plays out in this region. Objective The purpose of our study is to evaluate the course of COVID-19 in patients admitted to a tertiary center in Chile and to assess factors measured close to hospital admission that may be associated with death and the need for invasive mechanical ventilation. Methods We did a retrospective cohort study at Indisa Clinic in Santiago, Chile. We included all patients aged 15 years and older hospitalized between March 11 and July 25, 2020. Hospital mortality and severity of the cases were analyzed, and logistic regression models were applied to identify predictors of outcome variables. Results The sample included 785 subjects. The mean age was 59 years, 59% were men, and 61.3% had comorbidities. Forty five per cent required intensive care, and 24% invasive mechanical ventilation. The overall hospital fatality rate was 18.7%. In intensive care patients, the case fatality was 32.1%, and in those who received invasive mechanical ventilation, it was 59.4%. Independent risk factors for death included age (odds ratio 1.09; 95% confidence interval: 1.07 to 1.12), diabetes (1.68; 1.06 to 2.67), chronic lung disease (2.80; 1.48 to 5.28), increased C-reactive protein, creatinine, and ferritin. No association with sex, public health insurance, history of heart disease, oxygen saturation upon admission, or D-dimer was found. Similar factors were predictors of invasive mechanical ventilation. Discussion The prognosis and predictive factors in this cohort of patients hospitalized in Chile for COVID-19 were comparable to those reported in similar studies from higher-income countries. Male sex was not associated with a poor prognosis in this group of patients.

Afectación respiratoria por coronavirus (COVID-19) / Respiratory involvement by coronavirus (COVID-19)

In December 2019, an epidemic of cases with unexplained lower respiratory infections detected in Wuhan, China was first reported to the WHO China Office. The respiratory picture presents in various ways, from asymptomatic or paucisymptomatic forms, to clinical conditions characterized by respiratory failure that require mechanical ventilation and support in the ICU, with multi-organ and systemic manifestations in terms of sepsis, septic shock and multiple organ dysfunction syndromes. The etiological agent was identified as a virus belonging to the coronavirus family (CoV) with a high contagion capacity that determined its rapid spread, triggering a pandemic with high morbidity and mortality. This review attempts to address the basics of this disease.

Justificativa e delineamento do estudo Tocilizumabe em pacientes com COVID-19 moderado a grave: estudo aberto, multicêntrico, randomizado, controlado (TOCIBRAS) / Rationale and design of the Tocilizumab in patients with moderate to severe COVID-19: an open-label multicentre randomized controlled trial (TOCIBRAS)

RESUMO Introdução: Os marcadores pró-inflamatórios desempenham papel importante na severidade de pacientes com COVID-19. Assim, terapêuticas anti-inflamatórias são agentes interessantes para potencialmente combater a cascata inflamatória descontrolada em tais pacientes. Delineamos um ensaio para testar tocilizumabe em comparação com o tratamento padrão, tendo como objetivo melhorar os desfechos por meio da inibição da interleucina 6, um importante mediador inflamatório na COVID-19. Métodos e análises: Este será um estudo aberto multicêntrico, randomizado e controlado, que comparará os desfechos de pacientes tratados com tocilizumabe mais tratamento padrão com o tratamento padrão isoladamente em pacientes com COVID-19 moderada a grave. Como critérios de inclusão, serão exigidos dois dos quatro critérios a seguir: dosagens de dímero D acima de 1.000ng/mL, proteína C-reativa acima de 5mg/dL, ferritina acima de 300mg/dL e desidrogenase lática acima do limite superior do normal. O objetivo primário será comparar a condição clínica no dia 15, conforme avaliação por meio de escala ordinal de 7 pontos aplicada nos estudos de COVID-19 em todo o mundo. O desfecho primário será avaliado por regressão logística ordinal assumindo razões de propensão proporcionais ajustadas pelas variáveis de estratificação (idade e sexo). Ética e disseminação: O TOCIBRAS foi aprovado pelos comitês de ética locais e central (nacional) do Brasil em conformidade com as atuais diretrizes e orientações nacionais e internacionais. Cada centro participante obteve aprovação do estudo por parte de seu comitê de ética em pesquisa, antes de iniciar as inscrições no protocolo. Os dados derivados deste ensaio serão publicados independentemente de seus resultados. Se tiver sua efetividade comprovada, esta estratégia terapêutica poderá aliviar as consequências da resposta inflamatória na COVID-19 e melhorar os resultados clínicos.

ABSTRACT Introduction: Pro-inflammatory markers play a significant role in the disease severity of patients with COVID-19. Thus, anti-inflammatory therapies are attractive agents for potentially combating the uncontrolled inflammatory cascade in these patients. We designed a trial testing tocilizumab versus standard of care intending to improve the outcomes by inhibiting interleukin-6, an important inflammatory mediator in COVID-19. Methods and analysis: This open-label multicentre randomized controlled trial will compare clinical outcomes of tocilizumab plus standard of care versus standard of care alone in patients with moderate to severe COVID-19. Two of the following four criteria are required for protocol enrolment: D-dimer > 1,000ng/mL; C reactive protein > 5mg/dL, ferritin > 300mg/dL, and lactate dehydrogenase > upper limit of normal. The primary objective will be to compare the clinical status on day 15, as measured by a 7-point ordinal scale applied in COVID-19 trials worldwide. The primary endpoint will be assessed by an ordinal logistic regression assuming proportional odds ratios adjusted for stratification variables (age and sex). Ethics and dissemination: The TOCIBRAS protocol was approved by local and central (national) ethical committees in Brazil following current national and international guidelines/directives. Each participating center had the study protocol approved by their institutional review boards before initiating protocol enrolment. The data derived from this trial will be published regardless of the results. If proven active, this strategy could alleviate the consequences of the inflammatory response in COVID-19 patients and improve their clinical outcomes.

Síndrome do desconforto respiratório agudo associada à COVID-19 tratada com DEXametasona (CoDEX): delineamento e justificativa de um estudo randomizado / COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial

RESUMO Objetivo: A infecção causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) disseminou-se por todo o mundo e foi categorizada como pandemia. As manifestações mais comuns da infecção pelo SARS-CoV-2 (doença pelo coronavírus 2019 - COVID-19) se referem a uma pneumonia viral com graus variáveis de comprometimento respiratório e até 40% dos pacientes hospitalizados, que podem desenvolver uma síndrome do desconforto respiratório agudo. Diferentes ensaios clínicos avaliaram o papel dos corticosteroides na síndrome do desconforto respiratório agudo não relacionada com COVID-19, obtendo resultados conflitantes. Delineamos o presente estudo para avaliar a eficácia da administração endovenosa precoce de dexametasona no número de dias vivo e sem ventilação mecânica nos 28 dias após a randomização, em pacientes adultos com quadro moderado ou grave de síndrome do desconforto respiratório agudo causada por COVID-19 provável ou confirmada. Métodos: Este é um ensaio pragmático, prospectivo, randomizado, estratificado, multicêntrico, aberto e controlado que incluirá 350 pacientes com quadro inicial (menos de 48 horas antes da randomização) de síndrome do desconforto respiratório agudo moderada ou grave, definida segundo os critérios de Berlim, causada por COVID-19. Os pacientes elegíveis serão alocados de forma aleatória para tratamento padrão mais dexametasona (Grupo Intervenção) ou tratamento padrão sem dexametasona (Grupo Controle). Os pacientes no Grupo Intervenção receberão dexametasona 20mg por via endovenosa uma vez ao dia, por 5 dias, e, a seguir, dexametasona por via endovenosa 10mg ao dia por mais 5 dias, ou até receber alta da unidade de terapia intensiva, o que ocorrer antes. O desfecho primário será o número de dias livres de ventilação mecânica nos 28 dias após a randomização, definido como o número de dias vivo e livres de ventilação mecânica invasiva. Os desfechos secundários serão a taxa de mortalidade por todas as causas no dia 28, a condição clínica no dia 15 avaliada com utilização de uma escala ordinal de seis níveis, a duração da ventilação mecânica desde a randomização até o dia 28, a avaliação com o Sequential Organ Failure Assessment Score após 48 horas, 72 horas e 7 dias, e o número de dias fora da unidade de terapia intensiva nos 28 dias após a randomização.

Abstract Objective: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV-2 infection (coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop acute respiratory distress syndrome. Several clinical trials evaluated the role of corticosteroids in non-COVID-19 acute respiratory distress syndrome with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe acute respiratory distress syndrome due to confirmed or probable COVID-19. Methods: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48 hours before randomization) moderate or severe acute respiratory distress syndrome, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (Intervention Group) or standard treatment without dexamethasone (Control Group). Patients in the intervention group will receive dexamethasone 20mg intravenous once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until intensive care unit discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment Score evaluation at 48 hours, 72 hours and 7 days and intensive care unit -free days within 28.

Características y resultados de los pacientes infectados con nCoV19 con requerimiento de ventilación mecánica invasiva en la Argentina / Characteristics and outcomes of patients infected with nCoV19 requiring invasive mechanical ventilation in Argentina

RESUMEN Objetivo: El coronavirus ha emergido este año como causa de neumonía viral. Una de las principales características es su rápida transmisión y su potencial severidad. El objetivo de este estudio de serie de casos es describir las características clínicas de los pacientes con confirmación de enfermedad por coronavirus (COVID-19) admitidos en diferentes unidades de cuidados intensivos de la Argentina con requerimiento de ventilación mecánica. Métodos: Estudio de serie de casos, descriptivo-prospectivo, multicéntrico realizado entre el 01 de abril y el 08 de mayo de 2020. Se incluyeron los datos de los pacientes mayores a 18 años, que ingresaron a la unidad de cuidados intensivos con requerimiento de ventilación mecánica por falla respiratoria aguda con diagnóstico positivo de COVID-19 Resultados: Se registraron las variables de 47 pacientes de 31 unidades cuidados intensivos, 78.7% hombres de una mediana de edad de 61 años, con un SAPS II de 43, un índice de Charlson de 3. El modo ventilatorio inicial fue volume control - continuous mandatory ventilation con volumen corriente menor a 8mL/kg en el 100% de los casos, con una mediana de presión positiva al final de la espiración de 10,5cmH2O. A la fecha de cierre del estudio, 29 pacientes fallecieron, 8 alcanzaron el alta, y 10 pacientes continúan internados al cierre del estudio. El SAPS II fue mayor entre los fallecidos (p = 0.046). El índice de Charlson se asoció con mayor mortalidad (OR = 2,27 IC95% 1,13 - 4,55; p = 0,02). Conclusión: Los pacientes con COVID-19 y ventilación mecánica de esta serie presentan variables clínicas similares a las descriptas a la fecha en otros reportes internacionales. Nuestros hallazgos proporcionan datos que permitirían de alguna manera predecir los resultados.

Abstract Objective: A novel coronavirus emerged this year as a cause of viral pneumonia. The main characteristics of the virus are rapid transmission, high contagion capacity and potential severity. The objective of this case series study is to describe the clinical characteristics of patients with confirmed coronavirus disease (COVID-19) admitted to different intensive care units in Argentina for mechanical ventilation. Methods: A descriptive, prospective, multicenter case series study was conducted between April 1 and May 8, 2020. Data from patients older than 18 years who were admitted to the intensive care unit for mechanical ventilation for acute respiratory failure with a positive diagnosis of COVID-19 were included. Results: The variables for 47 patients from 31 intensive care units were recorded: 78.7% were men (median age of 61 years), with a SAPS II score of 43 and a Charlson index score of 3. The initial ventilatory mode was volume control - continuous mandatory ventilation with a tidal volume less than 8mL/kg in 100% of cases, with a median positive end-expiratory pressure of 10.5cmH2O. At the end of the study, 29 patients died, 8 were discharged, and 10 remained hospitalized. The SAPS II score was higher among patients who died (p = 0.046). Charlson comorbidity index was associated with higher mortality (OR = 2.27, 95% CI 1.13 - 4.55, p = 0.02). Conclusion: Patients with COVID-19 and on mechanical ventilation in this series presented clinical variables similar to those described to date in other international reports. Our findings provide data that may predict outcomes.

Mechanical ventilator as a shared resource for the COVID-19 pandemic / El ventilador mecánico como recurso divisible ante la pandemia de COVID-19

Abstract COVID-19, the causative agent of which is a new type of coronavirus called SARS-CoV-2, has caused the most severe pandemic in the last 100 years. The condition is mainly respiratory, and up to 5 % of patients develop critical illness, a situation that has put enormous pressure on the health systems of affected countries. A high demand for care has mainly been observed in intensive care units and critical care resources, which is why the need to redistribute resources in critical medicine emerged, with an emphasis on distributive justice, which establishes the provision of care to the largest number of people and saving the largest number of lives. One principle lies in allocating resources to patients with higher life expectancy. Mechanical ventilator has been assumed to be an indivisible asset; however, simultaneous mechanical ventilation to more than one patient with COVID-19 is technically possible. Ventilator sharing is not without risks, but the principles of beneficence, non-maleficence and justice prevail. According to distributive justice, being a divisible resource, mechanical ventilator can be shared; however, we should ask ourselves if this action is ethically correct.

Resumen COVID-19, cuyo agente causal es un nuevo tipo de coronavirus denominado SARS-CoV-2, ha provocado la pandemia más grave en los últimos 100 años. La afección es principalmente respiratoria y hasta 5 % de los pacientes desarrolla enfermedad crítica, lo cual ha producido una enorme presión sobre los sistemas de salud de los países afectados. Principalmente se ha observado alta demanda de atención en las unidades de cuidados intensivos y de recursos de atención vital. De ahí la necesidad de redistribuir los recursos en medicina crítica, con énfasis en la justicia distributiva, la cual establece atender al mayor número de personas y salvar el mayor número de vidas. Un principio estriba en asignar los recursos a pacientes con mayores expectativas de vida. Se ha dado por hecho que el ventilador mecánico es un bien indivisible; sin embargo, técnicamente es posible la ventilación mecánica simultánea a más de un paciente con COVID-19. La acción de compartir el ventilador no está exenta de riesgos, pero prevalecen los principios de beneficencia, no maleficencia y justicia. Conforme la justicia distributiva, al ser un bien divisible, el ventilador mecánico puede ser compartido, sin embargo, cabe preguntarse si esta acción es éticamente correcta.

The big challenge of SARS-CoV-2 latency: testes as reservoir / El gran desafío de la latencia de SARS-CoV-2: el testículo como reservorio

Abstract In the efforts to explain COVID-19 pathophysiology, studies are being carried out on the correspondence between the expression of SARS-CoV-2 cell receptors and viral sequences. ACE2, CD147 and TMPRSS2 receptors expression could indicate poorly explored potential infection targets. For the genomic analysis of SARS-CoV-2 receptors, using BioGPS information was decided, which is a portal that centralizes genetic annotation resources, in combination with that of The Human Protein Atlas, the largest portal of human transcriptome and proteome data. We also reviewed the most recent articles on the subject. RNA and viral receptor proteins expression was observed in numerous anatomical sites, which partially coincides with the information reported in the literature. High expression in testicular cells markedly stood out, and it would be therefore important ruling out whether this anatomical site is a SARS-CoV-2 reservoir; otherwise, germ cell damage, as it is observed in infections with other RNA viruses, should be determined.

Resumen En el afán por explicar la fisiopatogenia de COVID-19 se están realizando estudios en torno a la correspondencia entre la expresión de receptores celulares de SARS-CoV-2 y las secuencias virales. La expresión de los receptores ACE2, CD147 y TMPRSS2 podría indicar blancos de infección poco explorados. Para el análisis genómico de los receptores de SARS-CoV-2 se optó por utilizar la información del BioGPS, un portal que centraliza los recursos de anotación genética, en combinación con la de The Human Protein Atlas, el portal más grande de datos del transcriptoma y proteoma humanos. También se revisaron los artículos más recientemente respecto al tema. En numerosos sitios anatómicos se observó la expresión de ARN y proteínas de los receptores del virus, que coinciden parcialmente con la información reportada en la literatura. Resaltó la alta expresión en las células de los testículos, por lo que sería importante descartar si este sitio anatómico es un reservorio de SARS-CoV-2; de no ser así, determinar el daño en las células germinales, tal como sucede en infecciones por otros virus ARN.

Recomendaciones de tratamiento para pacientes adultos graves con COVID-19 / Recommendations for the management of critically ill adult patients with COVID-19

Resumen Con excepción de las mujeres embarazadas, el manejo de los pacientes adultos graves con COVID-19 durante la pandemia incluye los procedimientos estándar que se llevan a cabo en cualquier paciente que requiere atención en la unidad de cuidados intensivos, así como la administración limitada de las soluciones cristaloides, la intubación orotraqueal, la ventilación mecánica invasiva ante deterioro clínico del paciente y la relajación muscular en infusión continua solo cuando sea necesaria. No se recomienda la ventilación mecánica no invasiva, la oxigenoterapia de alto flujo debido a la generación de aerosol (asociado con riesgo de propagación del virus entre el personal de salud), la oxigenación por membrana extracorpórea ni el empleo de esteroides. Hasta el momento no hay tratamiento antiviral específico para pacientes con COVID-19 ni resultados de estudios controlados que avalen su uso.

Abstract Except for pregnant women, the management of critically ill patients with COVID-19 during the pandemic includes the standard procedures that are used for any patient that requires to be attended to at the intensive care unit, as well as limited administration of crystalloid solutions, orotracheal intubation, invasive mechanical ventilation in the event of patient clinical deterioration, and muscle relaxants continuous infusion only if necessary. Non-invasive mechanical ventilation and high-flow oxygen therapy are not recommended due to the generation of aerosol (associated with risk of viral spread among health personnel), and neither is extracorporeal membrane oxygenation or the use of steroids. So far, there is no specific antiviral treatment for patients with COVID-19, and neither are there results of controlled trials supporting the use of any.

Ventilación mecánica simultánea con un solo ventilador a varios pacientes / Simultaneous mechanical ventilation of several patients with a single ventilator

Resumen Introducción: La ventilación mecánica simultánea a varios pacientes con un solo ventilador podría disminuir el déficit de esos dispositivos para atender a los enfermos con insuficiencia respiratoria aguda por Covid-19. Objetivo: Comunicar los resultados de un ejercicio de ventilación mecánica con un ventilador en un simulador de pulmón, y simultáneamente en dos y cuatro simuladores. Resultados: No se observaron diferencias estadísticamente significativas entre la presión positiva al final de la espiración, presión media de la vía aérea y presión pico programadas, registradas y medidas, excepto al ventilar simultáneamente cuatro simuladores de pulmón. Conclusiones: La ventilación mecánica simultánea debe ser instaurada por personal médico con experiencia en el procedimiento, restringirse a dos pacientes y ser realizada en la unidad de cuidados intensivos.

Abstract Introduction: Simultaneous mechanical ventilation of several patients with a single ventilator might reduce the deficit of these devices for the care of patients with acute respiratory failure due to Covid-19. Objective: To communicate the results of a mechanical ventilation exercise with a ventilator in a lung simulator, and simultaneously in two and four. Results: No statistically significant differences were observed between positive end-expiratory pressure, mean airway pressure, and programmed, recorded and measured peak pressure, except when simultaneously ventilating four lung simulators. Conclusions: Simultaneous mechanical ventilation should be implemented by medical personnel with experience in the procedure, be restricted to two patients and carried out in the intensive care unit.

Eje Renina Angiotensina, Enzima Convertidora de Angiotensina 2 y Coronavirus / Renin Angiotensin Axis, Angiotensin Converting Enzyme 2 and Coronavirus

Resumen: El sistema renina angiotensina aldosterona (SRAA) es el principal regulador del volumen plasmático, manteniendo la homeostasis cardiovascular e hidrosalina. En la vía clásica, la enzima convertidora de angiotensina (ECA) genera Angiotensina II (AngII), de potente efecto inflamatorio y vasoconstrictor. Esta vía clásica es a su vez regulada por la ECA2, que convierte AngII a Ang 1-7, cuyas acciones vaso dilatadoras y antiinflamatorias dan balance a los efectos de AngII. La ECA2 se ha relacionado con la patogenia de infecciones respiratorias como el virus respiratorio sincicial y el síndrome respiratorio agudo grave por coronavirus (SARS-CoV y SARS-CoV-2). Estudios recientes han demostrado que la ECA2 corresponde al principal receptor del SARS-CoV-2, que en conjunto con otros receptores como la serin proteasa TMPRSS2, permiten la fijación, fusión y entrada del virus a la célula huésped. En animales infectados por SARS-CoV se produce una caída de la concentración tisular de ECA2 y Ang 1-7, con la consiguiente sobreexpresión de AngII, y sus efectos vasoconstrictores e inflamatorios. Experimentos con ECA2 recombinante han mostrado un efecto protector frente a la sobreexpresión del SRAA en animales infectados por SARS-CoV, efecto similar al demostrado con el uso de bloquea- dores del receptor de AngII, AT1. La evidencia sobre el rol protector de ECA2 parece respaldar las recomendaciones respecto a no suspender estos medicamentos en la infección SARS-CoV-2. En este artículo presentamos el conocimiento actual sobre el rol del SRAA en la infección por SARS-CoV, a partir de conceptos fisiopatológicos, bases moleculares, y evidencia experimental y clínica.

Abstract: The renin-angiotensin-aldosterone system (RAAS) is the main plasma volume regulator, which maintains cardiovascular and hydrosaline homeostasis. In the classical pathway, the angiotensin converting enzyme (ACE) generates Angiotensin II (AngII), which is powerfully inflammatory and vasoconstrictive. This classical pathway is also regulated by ACE2, which converts AngI to Ang 1-9, and degrades AngII to Ang 1-7, whose vasodilatory and anti-inflammatory functions balance out the effects of AngII. ACE2 has been associated with the pathogenesis of respiratory infections such as RSV and severe acute respiratory syndrome coronavirus (SARS-CoV and SARS-CoV-2). Recent studies have shown that ACE2 corresponds to the main SARS-CoV-2 receptor, which together with other receptors such as the TMPRSS2, allows the virus to attach, fuse, and enter the host cell. These studies have shown that in animals infected with coronavirus there is a drop in tissue concentration of ACE2 and Ang 1-7, leading to overexpression of AngII and its vasoconstrictive and inflammatory effects. Experiments with recombinant ACE2 have shown a protective effect against overexpression of RAAS in coronavirus-infected animals, which is similar to that demonstrated with the use of AnglI receptor blockers (AT1). Evidence on the protective role of ACE2 seems to support the recommendations re garding not discontinuing these drugs in COVID-19 infection. In this article, we present the current knowledge about the role of RAAS in coronavirus infection, based on physiopathological concepts, molecular bases, and experimental and clinical evidence.

Respuestas rápidas a la pandemia de COVID-19 a través de la ciencia y la colaboración global: el ensayo clínico Solidaridad

RESUMEN La COVID-19 representa una crisis global. La realización rápida de un ensayo clínico con la rigurosidad necesaria para obtener resultados confiables requiere la colaboración de diversos actores que participan en el desarrollo, evaluación y autorización de los ensayos clínicos (EC), como el patrocinador del ensayo, los investigadores, la autoridad regulatoria y el comité de ética (CE). Llevar a cabo estos estudios no solo es científicamente apropiado, sino una obligación ética y moral para ofrecer a las personas infectadas con COVID-19 un tratamiento efectivo. Solidaridad es un megaensayo clínico que reclutará miles de sujetos de investigación con enfermedad moderada a grave, a quienes se les asignará aleatoriamente a uno de los grupos de tratamiento en evaluación incluyendo hidroxicloroquina, lopinavir/ritonavir asociado o no a interferón; o remdesivir en comparación con el manejo estándar. El Perú se ha sumado a la lista de países donde se reproducirá el ensayo, mediante el cual se podrá identificar rápidamente si alguno de estos fármacos ofrece un beneficio real a los pacientes.

ABSTRACT COVID-19 represents a global crisis. Rapidly conducting a clinical trial with the rigor necessary to obtain reliable results requires the collaboration of various participants involved in the development, evaluation and authorization of clinical trials (CT) such as the trial sponsor, researchers, regulatory authority and the ethics committee (EC). Carrying out these studies is not only scientifically appropriate, but an ethical and moral obligation to guarantee our patients effective treatment. SOLIDARITY is a mega clinical trial that recruited thousands of subjects with moderate to severe disease, who were randomly assigned to one of the treatment groups under evaluation, including hydroxychloroquine, lopinavir/ritonavir associated or not with interferon; or remdesivir compared to standard therapy. Peru has joined the list of countries where the trial will be reproduced, through which it will be possible to quickly identify if any of these drugs offers a real benefit to patients.

Caracterización de pacientes con COVID-19 grave atendidos en un hospital de referencia nacional del Perú / Description of patients with severe COVID-19 treated in a national referral hospital in Peru

RESUMEN Con el objetivo de describir las manifestaciones de pacientes con enfermedad por coronavirus 2019 (COVID-19), se evaluaron variables sociodemográficas, antecedentes, manifestaciones clínicas y radiológicas, tratamientos y evolución en pacientes que ingresaron por emergencia, del 6 al 25 de marzo de 2020, al Hospital Nacional Edgardo Rebagliati Martins en Lima. Se registraron 17 pacientes: el 76% eran varones, edad promedio de 53,5 años (rango de 25 a 94); el 23,5% había regresado del extranjero; 41,2% referido de otros establecimientos de salud; 41,2% ingresó a ventilación mecánica; falleció el 29,4% (5 pacientes). Los factores de riesgo detectados fueron adulto mayor, tener hipertensión arterial y obesidad; los principales síntomas, tos, fiebre y disnea; los hallazgos de laboratorio frecuentes, proteína C reactiva elevada y linfopenia; la presentación radiológica predominante, el infiltrado pulmonar intersticial bilateral. Se reporta una primera experiencia en el manejo de pacientes con diagnóstico de la COVID-19 grave en el Perú.

ABSTRACT In order to describe manifestations from patients with coronavirus disease 2019 (COVID-19), sociodemographic variables such as, previous medical history, clinical and radiological manifestations, treatments and evolution of patients were evaluated. This took place from March 6th to 25th, 2020, in the "Edgardo Rebagliati Martins" National Hospital in Lima. Seventeen patients were registered: 76% were male, with an average age of 53.5 years (range 25-94); 23.5% had returned from abroad; 41.2% were referred from other health facilities; 41.2% were admitted to mechanical ventilation; 29.4% (5 patients) died. The risk factors detected were: advanced age, arterial hypertension and obesity. The main symptoms detected were: cough, fever and dyspnea. Frequent laboratory findings were: elevated C-reactive protein and lymphopenia. The predominant radiological presentation was bilateral interstitial lung infiltrate. A first experience in the management of patients diagnosed with severe COVID-19 in Peru is reported.

COVID-19: la pandemia por el nuevo virus SARS-CoV-2

RESUMEN Durante las primeras semanas de 2020 se comenzaron a informar casos de personas con SARS-CoV-2 fuera de China, con un rápido aumento de casos y muertes en todo el mundo. El SARS-CoV-2 es un virus ARN monocatenario positivo, envuelto en una bicapa lipídica derivada de la membrana celular del huésped y constituido por cuatro proteínas estructurales (S, M, E y N), además de una hemaglutinina-esterasa. La unión de la proteína S con el receptor de enzima convertidora de angiotensina 2 (ECA2) permite la entrada del virus a la célula huésped y es una potencial diana terapéutica. El 81% de los enfermos hace cuadro leve; el 14%, grave; y el 5% requiere cuidados intensivos. La fiebre es el síntoma más frecuente, seguido de tos y disnea. La mayoría de los pacientes no presentan leucocitosis pero sí linfopenia, con cultivos de esputo que no muestran otros patógenos. En las biopsias de pulmón de pacientes graves el hallazgo más llamativo es el daño alveolar difuso. Radiológicamente se aprecian patrones de vidrio esmerilado y alveolar, siendo las lesiones de predominio basal, subpleural y posterior, con una distribución periférica multifocal, afectando más el lóbulo inferior derecho. Hay una marcada respuesta inflamatoria, que llega hasta la tormenta de citoquinas, en la que el tratamiento antiinflamatorio con terapia de pulso con metilprednisolona estaría indicado. Aunque no existan estudios en gran escala respecto al uso de cloroquina/hidroxicloroquina, debido a la situación mundial se ha autorizado su uso por su efecto anti SARS-CoV-2 y anti-inflamatorio, el cual puede ser potenciado con el uso de azitromicina.

ABSTRACT During the first weeks of 2020, cases of SARS-CoV-2 began to be reported outside of China, with a rapid increase in cases and deaths worldwide. SARS-CoV-2 is a positive single-stranded RNA virus, encased in a lipid bilayer derived from the host cell membrane and consists of four structural proteins (S, M, E and N), plus a haemagglutinin-sterase. The binding of the S protein to the ECA2 receptor allows the entry of the virus into the host cell and is a potential therapeutic target. 81% of patients develop mild symptoms, 14% have severe symptoms and 5% require intensive care management. Fever is the most frequent symptom, followed by cough and dyspnea. Most patients do not present leukocytosis, but they do present lymphopenia with sputum cultures that do not show other pathogens. In lung biopsies of severe patients, the most noticeable finding is diffuse alveolar damage. Radiologically, ground glass and alveolar patterns are observed; the lesions being predominantly basal, subpleural, and posterior, with a multifocal peripheral distribution, more affecting the right lower lobe. There is a marked inflammatory response, up to the cytokine storm, in which anti-inflammatory treatment with pulse therapy with methylprednisolone would be indicated. Although there are no large-scale studies regarding the use of chloroquine / hydroxychloroquine, due to the global situation, its use has been authorized for its anti-SARS-CoV-2 and anti-inflammatory effect, which can be potentiated with the use of azithromycin.

Infección por el nuevo coronavirus 2019 en niños

RESUMEN La enfermedad del coronavirus 2019 (COVID-19) es poco frecuente en niños y su salud se ve poco comprometida en la mayoría de casos. La presentación clínica más común es tos, fiebre y eritema faríngeo, los casos graves suelen presentarse con taquipnea. El curso de la enfermedad es de una a dos semanas. Los hallazgos de laboratorio son inespecíficos, entre ellos, linfopenia, elevación de la proteína C reactiva y la procalcitonina. En fases iniciales, la radiografía torácica es usualmente normal, y los hallazgos tomográficos más comunes son consolidaciones con signo del halo, vidrio esmerilado y nódulos pequeños, que afectan principalmente las zonas subpleurales. El manejo es sintomático y, en los casos graves, debe estar enfocado a brindar soporte respiratorio. Se recomienda que la manipulación de las secreciones respiratorias sea limitada y que se tengan las mismas precauciones para evitar contaminación que en pacientes adultos.

ABSTRACT COVID-19 is rarely reported in children and they are mildly affected in most cases. The most common clinical presentation of COVID-19 is cough, fever and sore throat; severe cases show tachypnea. The course of the disease is from one to two weeks. Laboratory findings are nonspecific; lymphopenia, elevation of C-reactive protein and procalcitonin have been described. Early chest X-ray is usually normal, and the most common tomographic findings are consolidations with halo, ground-glass opacities and tiny nodules which mainly affects subpleural areas. Management of the disease is supportive; in severe cases, it should be focused on respiratory support. It is recommended to limit the handling of respiratory secretions and to follow the same preventive measures provided to adults.

Otro desafío de la naturaleza: el nuevo coronavirus virología y fisiopatología del SARS-COV-2 / Another challenge of nature: the new coronavirus virology and physiopathology of SARS-CoV-2

The recent outbreak of emerging severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been brought to global attention in the search of knowledge about the virus and its pathogenesis. The immune response is essential to control and eliminate the infection, however, maladjusted immune responses may result in severe disease fisiopathology. Gaining a deeper understanding of the interaction between SARS-CoV-2 and the immune systems of the hosts may help us anticipate the development of persistent pulmonary inflammation and, why not, be the first step to therapeutic success and trying to save more lives. In this review, we provide an update on CoV virology and our vision of pathogenesis understanding it from the stages of infection, without forgetting the cytokine storm resulting from the interaction of the virus with ACE2 receptors widely distributed in the body.

La reciente emergencia de síndrome de distrés respiratorio agudo producido por coronavirus 2 (SARS-CoV-2), enfermedad denominada COVID-19 ha traído la atención mundial a la búsqueda de conocimiento sobre este virus y su patogenia. La respuesta inmune es esencial para controlar y erradicar la infección, sin embargo, las respuestas inmunes descontroladas pueden resultar en la fisiopatología de la enfermedad grave. Lograr una comprensión más profunda de la interacción entre SARS-COV-2 y el sistema inmune de los huéspedes podría ayudar a anticiparnos al desarrollo de una inflamación pulmonar persistente causada por el SARS-CoV-2, y por qué no, ser la puerta de entrada al éxito terapéutico e intentar salvar mayor número de vidas. En esta revisión, proporcionamos una actualización sobre la virología y nuestra visión de la patogenia, entendiéndola desde las fases o etapas de la infección, sin olvidar el estallido de citoquinas resultantes de la interacción del virus con los receptores ACE2 ampliamente distribuidos en el organismo.