Avanços no entendimento da patogenia da covid-19: uma revisão / Advances in understanding covid-19 pathogenesis: a review / Avances en la comprensión de la patogenia de la covid-19: una revisión

Introdução: O SARS-CoV-2, causador da pandemia por Doença por Coronavirus 2019 (COVID-19) gerou desafios à saúde pública, principalmente pelo conhecimento escasso de sua patogênese, e de estratégias terapêuticas e preventivas eficazes. Diversas lacunas de conhecimento sobre a doença envolvem a contribuição de fatores de risco, as doenças concomitantes, os fatores genéticos e imunogenéticos, no direcionamento da resposta imune, bem como a hiperinflamação, a imunidade antiviral e os alelos dos antígenos leucocitários humanos (HLAs) dos pacientes, que estão relacionados ao desfecho da doença. Objetivo: Esta revisão integrativa objetivou aprofundar os conhecimentos sobre os mecanismos de imunidade relacionada aos fatores de risco, da hiperinflamação e da tempestade de citocinas decorrente da infecção por SARS-CoV-2, bem como os avanços de associação dos HLAs nos agravos da doença. Metodologia: A revisão integrativa foi realizada utilizando os descritores nas bases de dados PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, Portal periódicos CAPES e Open Journal System, sem limites de janela cronológica. Resultados: Os efeitos da pandemia e os esforços na busca do conhecimento sobre a patogênese da COVID-19 resultaram em avanço no combate da doença. Conseguiu-se relacionar fatores de risco como obesidade, hipertensão, diabetes, doenças renais crônicas, idade, gênero, e outras condições predisponentes ao agravo da doença. Sob o aspecto da patogênese, também houveram progressos no entendimento dos mecanismos celulares e humorais em resposta à doença, bem como conseguiu vincular a resposta da hiperinflamação e o perfil dos HLAs dos pacientes à evolução da doença ao óbito ou à convalescência. Conclusão: Os esforços científicos conjuntos e os avanços na compreensão dos mecanismos da doença conseguiram estabelecer estratégias de combate a COVID-19, resultando no fim da pandemia, porém ainda há avanços que devem ser alcançados para o combate das sequelas dos pacientes convalescentes e para minimização da COVID longa e seus prejuízos.

Introduction: SARS-CoV-2, which causes the Coronavirus Disease 2019 (COVID-19) pandemic, has generated challenges to public health, mainly due to the limited knowledge of its pathogenesis and effective therapeutic and preventive strategies. Several gaps in knowledge about the disease involve the contribution of risk factors, concomitant diseases, genetic and immunogenetic factors, in directing the immune response, as well as hyperinflammation, antiviral immunity and human leukocyte antigen (HLAs) alleles of patients, which are related to the outcome of the disease. Aim: This integrative review aimed to deepen knowledge about the mechanisms of immunity related to risk factors, hyperinflammation and the cytokine storm resulting from SARS-CoV-2 infection, as well as advances in the association of HLAs in diseases. Methodology: The integrative review was carried out using the descriptors in the databases PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, CAPES periodical portal and Open Journal System, without chronological window limits. Results: The effects of the pandemic and efforts to seek knowledge about the pathogenesis of COVID-19 resulted in progress in combating the disease. It was possible to relate risk factors such as obesity, hypertension, diabetes, chronic kidney disease, age, gender, and other conditions predisposing to the worsening of the disease. From the aspect of pathogenesis, progress has also been made in understanding the cellular and humoral mechanisms in response to the disease, as well as linking the hyperinflammation response and the patients' HLA profile to the progression of the disease to death or convalescence. Conclusion: Joint scientific efforts and advances in understanding the mechanisms of the disease managed to establish strategies to combat COVID-19, resulting in the end of the pandemic, but there are still advances that must be achieved to combat the sequelae of convalescent patients and to minimize of long COVID and its losses.

Introducción: El SARS-CoV-2, causante de la pandemia de la Enfermedad del Coronavirus 2019 (COVID-19), ha generado desafíos a la salud pública, principalmente por el limitado conocimiento de su patogénesis y estrategias terapéuticas y preventivas efectivas. Varios vacíos en el conocimiento sobre la enfermedad involucran la contribución de factores de riesgo, enfermedades concomitantes, factores genéticos e inmunogenéticos, en la dirección de la respuesta inmune, así como la hiperinflamación, la inmunidad antiviral y los alelos del antígeno leucocitario humano (HLA) de los pacientes, que están relacionados con el resultado de la enfermedad. Objetivo: Esta revisión integradora tuvo como objetivo profundizar el conocimiento sobre los mecanismos de inmunidad relacionados con los factores de riesgo, la hiperinflamación y la tormenta de citocinas resultante de la infección por SARS-CoV-2, así como los avances en la asociación de los HLA en las complicaciones de la enfermedad. Metodología: La revisión integradora se realizó utilizando los descriptores de las bases de datos PubMed, SCIELO, CINAHL, SCOPUS, Web of Science, MedNar, portal periódico CAPES y Open Journal System, sin límites de ventana cronológica. Resultados: Los efectos de la pandemia y los esfuerzos por buscar conocimiento sobre la patogénesis de la COVID-19 resultaron en avances en el combate de la enfermedad. Se logró relacionar factores de riesgo como obesidad, hipertensión, diabetes, enfermedad renal crónica, edad, sexo y otras condiciones que predisponen al agravamiento de la enfermedad. Desde el punto de vista de la patogénesis, también se ha avanzado en la comprensión de los mecanismos celulares y humorales de respuesta a la enfermedad, así como en la vinculación de la respuesta de hiperinflamación y el perfil HLA de los pacientes con la progresión de la enfermedad hasta la muerte o la convalecencia. Conclusión: Los esfuerzos científicos conjuntos y los avances en la comprensión de los mecanismos de la enfermedad lograron establecer estrategias para combatir el COVID-19, teniendo como resultado el fin de la pandemia, pero aún quedan avances que se deben lograr para combatir las secuelas de los pacientes convalecientes y para Minimizar el COVID prolongado y sus pérdidas.

Highlights of clinical and laboratory parameters among severe COVID-19 patients treated with tocilizumab: a retrospective observational study

ABSTRACT BACKGROUND: Coronavirus disease 2019 (COVID-19) can cause cytokine release syndrome (CRS), which leads to high mortality rates. Tocilizumab suppresses CRS by blocking the signal transduction of interleukin-6 (IL-6). OBJECTIVE: To evaluate the clinical and laboratory parameters associated with mortality among patients receiving tocilizumab treatment. DESIGN AND SETTING: Retrospective observational study conducted in the chest disease departments of two different training and research hospitals in the center of Ankara, Turkey. METHODS: Patients who were hospitalized and treated with tocilizumab in September 2020 were retrospectively analyzed. Their laboratory parameters and clinical characteristics were obtained from the hospital information system database. Comparative analyses were performed between the patients who died and the ones who survived. RESULTS: A total of 58 patients who received tocilizumab treatment were included in this study, among whom 35 (60.3%) died. There was no difference between the mortality and survival groups in terms of white blood cell (WBC), neutrophil, lymphocyte, ferritin or C-reactive protein (CRP) levels detected on admission. WBC, lymphocyte, neutrophil and CRP levels measured on the third and fifth days after tocilizumab administration were found to be significantly lower in the survival group (P < 0.05). In multiple logistic regression analysis, age and oxygen saturation were determined to be independent risk factors for mortality. CONCLUSION: Persistently high WBC, CRP and neutrophil levels and low lymphocyte levels could be considered to be valuable indicators of mortality among COVID-19 patients treated with tocilizumab. Age and low oxygen saturation are independent risk factors for mortality among patients receiving tocilizumab treatment.

El tratamiento con Jusvinza disminuye la hiperinflamación y la hipercoagulación en pacientes críticos con la COVID-19

RESUMEN Introducción: La infección con el SARS-CoV-2 induce un estado protrombótico en los pacientes, atribuible a la combinación de la respuesta hiperinflamatoria y la hipoxia. En Cuba, se usa el fármaco Jusvinza, basado en un péptido inmunomodulador, para el tratamiento de los pacientes con la COVID-19, que presenten signos y síntomas de hiperinflamación. Objetivos: Describir la evolución clínica y las variaciones de biomarcadores asociados con la inflamación y la coagulación, en un grupo de pacientes críticos con la COVID-19, tratados con Jusvinza, en comparación con un grupo de pacientes que no recibieron tratamiento con este péptido. Métodos: Se incluyeron 40 pacientes críticos con la COVID-19; se dividieron en 2 grupos: 20 pacientes tratados con Jusvinza y 20 no fueron tratados con dicho péptido (grupo control). Las características demográficas, comorbilidades, signos vitales, parámetros respiratorios, biomarcadores de la inflamación y de la coagulación se obtuvieron a partir de las historias clínicas de cada paciente. Resultados: El tratamiento con Jusvinza indujo una mejoría clínica en los pacientes, asociada con la disminución de varios biomarcadores de la inflamación y la coagulación. La sobrevida de los pacientes tratados con Jusvinza fue significativamente superior a la sobrevida de los pacientes no tratados con este péptido. Conclusiones: Jusvinza es capaz de controlar la hiperinflamación y la hipercoagulación en pacientes críticos con la COVID-19.

ABSTRACT Introduction: Infection with SARS-CoV-2 induces a prothrombotic state in patients, by the combination of hyperinflammatory response and hypoxia. In Cuba, the drug called Jusvinza, based on an immunomodulatory peptide, is used for the treatment of patients with COVID-19, who present signs and symptoms of hyperinflammation. Objectives: To describe the clinical course and behavior of various biomarkers associated with the inflammation and coagulation, in a group of critically ill patients with COVID-19 treated with Jusvinza, compared to a group of patients who did not receive treatment with this peptide. Methods: 40 critically ill patients with COVID-19 were included. The patients were divided into 2 groups: 20 patients were treated with Jusvinza and 20 were not treated with this peptide (control group). Demographic characteristics, comorbidities, vital signs, respiratory parameters and inflammation and coagulation biomarkers were obtained from the medical records of each patient. Results: Treatment with Jusvinza induced a clinical improvement in the patients, associated with the decrease of several inflammation and coagulation biomarkers. Patients treated with Jusvinza had a significantly higher survival than patients not treated with this peptide. Conclusions: Jusvinza is able to control hyperinflammation and hypercoagulation in critical ill patients with COVID-19.

Péptido inmunomodulador CIGB-258 para el tratamiento de pacientes graves y críticos con la COVID-19 / An immunomodulatory peptide CIGB-258 for the treatment of critical and severe COVID-19 patients

Introducción: El CIGB-258 es un péptido inmunomodulador con propiedades antiinflamatorias. Objetivos: Establecer la frecuencia de dosis y el tiempo de tratamiento con el péptido CIGB-258, para pacientes críticos con COVID-19. Además, definir los criterios de uso y el esquema terapéutico del péptido, para pacientes graves con COVID-19. Métodos: Se incluyeron 9 pacientes críticos y 3 pacientes graves. Las evaluaciones clínicas, radiológicas y de laboratorio se registraron de acuerdo al protocolo establecido. Se obtuvieron muestras de suero antes y después del tratamiento con la CIGB-258, para la determinación de los biomarcadores de la inflamación. Resultados: Se estableció el protocolo de actuación con el péptido CIGB-258, el cual consiste en la administración intravenosa de 1 mg del péptido cada 12 horas a los pacientes críticos. La dosis debe aumentarse a 2 mg cada 12 horas, para los pacientes que no muestren mejoría clínica y radiológica en 24 horas. Después de la extubación, los pacientes deben recibir 1 mg de CIGB-258 al día, durante otros tres días. Los pacientes graves deben recibir 1 mg de CIGB-258 cada 12 horas, hasta que resuelvan su condición clínica. Conclusiones: CIGB-258 mostró un buen perfil de seguridad. El protocolo de actuación establecido contribuyó a que todos los pacientes críticos se recuperaran de la dificultad respiratoria y fueran extubados. Los pacientes graves mejoraron considerablemente. Los niveles de los biomarcadores asociados con hiperinflamación y las citocinas disminuyeron significativamente durante el tratamiento(AU)

Introduction: CIGB-258 is an immunomodulatory peptide with anti-inflammatory properties. Objectives: To establish the therapeutic schedule with CIGB-258 peptide for COVID-19 critically ill patients. In addition, to define the criteria for use and schedule of this peptide for COVID-19 seriously ill patients. Methods: 9 critically ill patients and 3 seriously ill patients were included in this study. Clinical, radiological and laboratory evaluations were recorded according to the established protocol. Serum samples were obtained before and after treatment with CIGB-258, for the determination of the inflammation biomarkers. Results: The therapeutic protocol was established with the CIGB-258 peptide, which consists of intravenous administration of 1 mg of peptide every 12 hours for critically ill patients. The dose should be increased to 2 mg every 12 hours, for patients who do not show clinical and radiological improvement in 24 hours. After extubation, patients should receive 1 mg of CIGB-258 daily, for another three days. Seriously ill patients should receive 1 mg of CIGB-258 every 12 hours, until their clinical condition resolves. Conclusions: CIGB-258 showed an excellent safety profile. The established therapeutic protocol contributed to all critically ill patients recovering from respiratory distress and being extubated. Seriously ill patients improved considerably. The levels of the biomarkers associated with hyperinflammation and cytokines decreased significantly during treatment(AU)

Calcineurin inhibitors revisited: A new paradigm for COVID-19?

Abstract The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can cause mild, moderate or severe disease (COVID-19). In severe disease, there is hyperinflammation causing severe symptoms. Severe COVID-19 is an immunological phenomenon, rather than a direct viral damage disease. Therapies for COVID-19 are all investigational therapies. In case of severe disease, treatment with a calcineurin inhibitor could be promising. In this article we explain the mechanisms of calcineurin inhibitor treatment for COVID-19, based on experiences seen in solid organ transplant recipients who suffered from COVID-19.