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1.
Arq. Asma, Alerg. Imunol ; 6(1): 84-90, jan.mar.2022. ilus
Article in English, Portuguese | LILACS | ID: biblio-1400109

ABSTRACT

O SARS-CoV-2 é causador da doença infecciosa COVID-19. A infecção estimula o sistema imunológico a produzir citocinas próinflamatórias. A principal citocina envolvida é a IL-6, e está ligada à gravidade da doença. Devido à associação dos altos níveis de IL-6 com a mortalidade na COVID-19, investiga-se sobre o uso de tocilizumabe (TCZ), um anticorpo monoclonal humanizado antirreceptor de IL-6 humana. O objetivo desta revisão sistemática é avaliar a eficácia do uso do TCZ em pacientes com COVID-19 grave. As buscas foram feitas através das bases de dados Science Direct e PubMed em setembro de 2021. Foram incluídos os ensaios clínicos randomizados com pacientes em um único estágio de COVID-19, casos graves e sem restrição de idade, os quais receberam o TCZ como medicação de intervenção combinado a tratamentos protocolados por cada hospital e associado a corticosteroides. A análise desses estudos demonstrou resultados significantes sobre o uso de TCZ em casos severos de COVID-19. O uso de TCZ associado a glicocorticoides levou a uma redução no índice de mortalidade e de submissão a ventilações mecânicas e a uma melhora expressiva em relação à escala "WHO-endorsed 7-point ordinal scale". Entretanto, não houve melhora relevante quanto ao uso do TCZ de maneira isolada.


SARS-CoV-2 causes the COVID-19 infectious disease that affects the respiratory tract. From the beginning of the infection, the immune system starts to produce pro-inflammatory cytokines and chemokines. The main cytokine involved is IL-6 and is linked to the severity and prognosis of the disease, as it provokes a storm of cytokines and severe inflammatory responses. Due to the association of high levels of IL-6 with severity and mortality in COVID-19, the use of Tocilizumab (TCZ), a humanized anti-human IL-6 receptor monoclonal antibody, which binds to IL receptors, is being investigated. -6 and blocks intracellular signaling reducing cytokine storm and hyperinflammatory state. The aim of this review is to assess the effectiveness of using TCZ in the treatment of patients with severe COVID-19. Searches were performed using the Science Direct and PubMed databases in May 2021. Randomized clinical trials with patients in a single stage of COVID­19, severe cases and without age restriction, who received TCZ as medication for treatment, were included. Intervention was combined with treatments protocoled by each hospital and associated with corticosteroids. The analysis of these studies showed significant results regarding the use of TCZ in severe cases of COVID-19. The use of TCZ associated with glucocorticoids led to a reduction in the rate of mortality and compliance with mechanical ventilation and a significant improvement in relation to the "WHO-endorsed 7-point ordinal scale". However, there was no evidence of relevant improvement when using TCZ alone.


Subject(s)
Humans , Antibodies, Monoclonal, Humanized , SARS-CoV-2 , COVID-19 , Patients , Respiration, Artificial , Therapeutics , Cytokines , Interleukin-6 , Adrenal Cortex Hormones , Receptors, Interleukin-6 , PubMed , Cytokine Release Syndrome , Immune System
2.
Journal of Integrative Medicine ; (12): 274-280, 2022.
Article in English | WPRIM | ID: wpr-929222

ABSTRACT

OBJECTIVE@#Acute lung injury (ALI) is a serious respiratory dysfunction caused by pathogen or physical invasion. The strong induced inflammation often causes death. Tanshinone IIA (Tan-IIA) is the major constituent of Salvia miltiorrhiza Bunge and has been shown to display anti-inflammatory effects. The aim of the current study was to investigate the effects of Tan-IIA on ALI.@*METHODS@#A murine model of lipopolysaccharide (LPS)-induced ALI was used. The lungs and serum samples of mice were extracted at 3 days after treatment. ALI-induced inflammatory damages were confirmed from cytokine detections and histomorphology observations. Effects of Tan-IIA were investigated using in vivo and in vitro ALI models. Tan-IIA mechanisms were investigated by performing Western blot and flow cytometry experiments. A wound-healing assay was performed to confirm the Tan-IIA function.@*RESULTS@#The cytokine storm induced by LPS treatment was detected at 3 days after LPS treatment, and alveolar epithelial damage and lymphocyte aggregation were observed. Tan-IIA treatment attenuated the LPS-induced inflammation and reduced the levels of inflammatory cytokines released not only by inhibiting neutrophils, but also by macrophage. Moreover, we found that macrophage activation and polarization after LPS treatment were abrogated after applying the Tan-IIA treatment. An in vitro assay also confirmed that including the Tan-IIA supplement increased the relative amount of the M2 subtype and decreased that of M1. Rebalanced macrophages and Tan-IIA inhibited activations of the nuclear factor-κB and hypoxia-inducible factor pathways. Including Tan-IIA and macrophages also improved alveolar epithelial repair by regulating macrophage polarization.@*CONCLUSION@#This study found that while an LPS-induced cytokine storm exacerbated ALI, including Tan-IIA could prevent ALI-induced inflammation and improve the alveolar epithelial repair, and do so by regulating macrophage polarization.


Subject(s)
Abietanes , Acute Lung Injury/drug therapy , Animals , Cytokine Release Syndrome , Cytokines , Inflammation/drug therapy , Lipopolysaccharides/toxicity , Macrophage Activation , Macrophages , Mice , Triacetoneamine-N-Oxyl/pharmacology
3.
NOVA publ. cient ; 19(37): 11-24, jul.-dic. 2021. tab, graf
Article in Spanish | LILACS | ID: biblio-1360608

ABSTRACT

Resumen Una de las herramientas más novedosas en inmunoterapias adoptivas contra leucemias y tumores malignos es el uso del receptor de antígeno quimérico "CAR". El receptor CAR ha sido ampliamente utilizada en células T (células CAR-T) potenciando su eficacia en el reconocimiento y eliminación de tumores, obteniéndose a la fecha terapias basadas en esta tecnología. No obstante, las células CAR-T llegan a repercutir negativamente en la salud del paciente, presentando el síndrome neurológico de efecto inmune asociado a células (ICANS) y el síndrome de lanzamiento de citocinas (SLC). Como consecuencia, el paciente necesita ser hospitalizado durante la terapia. Además, el coste de manufactura y terapia es elevado, siendo una tecnología limitada a un sector muy bajo de la población. En este trabajo, mencionamos el empleo de una terapia emergente de células asesinas naturales (NK) con el receptor CAR (CAR-NK), que cuentan con muchas ventajas por encima de las células CAR-T. Las células CAR-NK conservan su capacidad citotóxica en contra de tumores gracias a su acción dependiente de receptores activadores e inhibidores, por lo que el receptor CAR, solo estimula sus habilidades y persistencia. Sumado a esto, el coste de una terapia de células CAR-NK podría resultar redituable debido a la capacidad de las células CAR-NK de eliminar múltiples células tumorales sin generar daño colateral en el paciente. Aquí analizamos las características de los múltiples receptores CAR y los fenotipos de células NK que han sido utilizados durante múltiples ensayos (NK-92, células NK de sangre cordal y periférica, y células NK iPSC).


Abstract One of the novel and effective devices against leukemia and solid tumors in adoptive immunotherapies is the use of the chimeric antigen receptor "CAR". CAR technology has been widely used in T-cells (CAR-T cells) empowering its efficacy on the identification and elimination of tumor cells, getting today certain drugs based on this technology. Nevertheless, CAR-T cells can have a negative impact on patient health, causing in many cases immune effector cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS). As a consequence, the patient will have to be hospitalized for the duration of therapy. Moreover, the cost of manufacture and therapy is quite expensive, limiting its use to a low range of people. On the other hand, we analyze the advantages of Natural Killer cells with the CAR receptor (CAR-NK), which have many plusses over CAR-T cells. CAR-NK cells retain their cytotoxic abilities against tumor cells due their activator/ inhibitor receptors balance. Thus, the CAR receptor technology just increases their skills and persistence. Furthermore, CAR-NK therapy could be more profitable since CAR-NK can eliminate multiple tumor cells without generating collateral damage on patient health. Here, we discuss the characteristics of the multiples CAR receptors in general and the NK types cells that have been used in trials demonstrating their viable emerging therapy (NK-92, cord and peripheral blood NK cells, and iPSC-derived NK cells).


Subject(s)
Humans , Leukemia , Therapeutics , Immunotherapy, Adoptive , Cytokine Release Syndrome
4.
Bol. latinoam. Caribe plantas med. aromát ; 20(5): 463-481, sept. 2021. ilus, tab
Article in English | LILACS | ID: biblio-1368606

ABSTRACT

Resveratrol is a phenolic phytoconstituent found in many plants. This molecule has always caught the attention of scientists because of biological potentials such as inhibition of inflammation, oxidative stress and platelet aggregation as well as to prevent/protect against cardiovascular and neurodegenerative disease/disorders. Literature search have been conducted over resveratrol in covid-19 and asthma studies published in Pubmed and Google Scholars until 30 September 2020. The criteria used in the literature review were determined and were reviewed works on resveratrol including 368 articles and 47 articles on covid-19 and asthma, respectively. As a result of meta-analysis, TNF-α values of the studies showed a significant difference (heterogeneity) of I2=68.39% from each other in total (Cohran Q:6.33, p<0.0423). This study shows that resveratrol would have a potential to reduce ARDS symptoms, by suppressing the cytokine storm and severe inflammation caused by SARS-CoV-2, and by showing strong activity against various types of DNA/RNA viruses.


El resveratrol es un fitoconstituyente fenólico que se encuentra en muchas plantas. Esta molécula siempre ha llamado la atención de los científicos debido a sus potenciales biológicos como la inhibición de la inflamación, el estrés oxidativo y la agregación plaquetaria, así como para prevenir/proteger contra enfermedades/trastornos cardiovasculares y neurodegenerativos. Se han realizado búsquedas bibliográficas sobre resveratrol en covid-19 y estudios sobre asma publicados en Pubmed y Google Scholars hasta el 30 de septiembre de 2020. Se determinaron los criterios utilizados en la revisión bibliográfica y se revisaron trabajos sobre resveratrol que incluyen 368 artículos y 47 artículos sobre covid-19 y asma, respectivamente. Como resultado del metanálisis, los valores de TNF-α de los estudios mostraron una diferencia significativa (heterogeneidad) de I2=68,39% entre sí en total (Cohran Q: 6,33, p<0,0423). Este estudio muestra que el resveratrol podría reducir los síntomas del ARDS al suprimir la tormenta de citocinas y la inflamación severa causada por el SARS-CoV-2, y al mostrar una fuerte actividad contra varios tipos de virus de ADN/ARN.


Subject(s)
Humans , Asthma/drug therapy , Resveratrol/therapeutic use , COVID-19/drug therapy , Respiratory Distress Syndrome, Newborn/prevention & control , Asthma/complications , Transforming Growth Factor beta , Cytokine Release Syndrome , COVID-19/complications
5.
Rev. cuba. invest. bioméd ; 40(2): e1014, 2021.
Article in Spanish | LILACS, CUMED | ID: biblio-1347464

ABSTRACT

Introducción. La COVID-19 es la enfermedad causada por el virus SARS-CoV-2. Aunque la mayoría de los pacientes presentan síntomas leves o moderados, un 5 por ciento desarrolla un síndrome respiratorio severo. Conocer la dinámica de la respuesta inmune en la infección por SARS-CoV-2 es esencial para el manejo adecuado de los pacientes. Objetivo. Describir los elementos esenciales de la dinámica de la respuesta inmune a la infección por SARS-CoV-2. Métodos: Se realizó una revisión de la literatura actualizada en bases de datos bibliográficas. Se consultaron 40 publicaciones. Se analizó la calidad y fiabilidad de los artículos seleccionados. Análisis e integración de la información: Durante los momentos iniciales de la respuesta inmune al SARS-CoV-2 predominan mecanismos innatos de defensa encaminados a eliminar el virus e impedir el avance de la enfermedad hacia la severidad. Si el sistema inmune no logra erradicar el virus ocurre una desregulación inmune que produce un daño importante por inflamación tisular. La inmunoterapia debe enfocarse en estimular la primera etapa (protectora) y suprimir la segunda. Una respuesta inmune adecuada es vital en el enfrentamiento a las infecciones por coronavirus. Conclusiones. La dinámica de la respuesta antiviral en los infectados por SARS-CoV-2 es uno de los elementos esenciales que condicionan la severidad de la enfermedad. La aparición de la tormenta de citocinas, producto de una desregulación inmune, se ha presentado como causa primaria del síndrome respiratorio severo observado en estos pacientes. Un mayor conocimiento de los mecanismos inmunopatogénicos es imprescindible para el desarrollo de medicamentos con alta eficacia.(AU)


Introduction: COVID-19 is the disease caused by the SARS-CoV-2 virus. Though most patients present mild or moderate symptoms, 5 percent develop severe respiratory syndrome. Awareness of the dynamics of the immune response to SARS-CoV-2 infection is essential for the appropriate management of patients. Objective: Describe the essential elements of the dynamics of the immune response to SARS-CoV-2 infection. Methods: A review was conducted of updated literature contained in bibliographic databases. A total 40 publications were consulted. An analysis was performed of the quality and reliability of the papers selected. Data analysis and integration: In the initial stage of the immune response to SARS-CoV-2 there is a predominance of innate defense mechanisms aimed at eliminating the virus and preventing the progress of the disease toward severity. If the immune system fails to eradicate the virus, immune dysregulation will occur and considerable damage will result from tissue inflammation. Immunotherapy should focus on stimulating the first (protective) stage and delete the second. An appropriate immune response is vital in the combat against coronavirus infections. Conclusions: The dynamics of the antiviral response in SARS-CoV-2 patients are essential elements conditioning the severity of the disease. Occurrence of the cytokine storm resulting from immune dysregulation has been cited as the primary cause of the severe respiratory syndrome developing in these patients. Better knowledge about the immunopathogenic mechanisms involved is indispensable to develop highly efficient drugs(AU)


Subject(s)
Humans , Antiviral Agents , Pharmaceutical Preparations , Coronavirus Infections , Defense Mechanisms , Cytokine Release Syndrome , Immune System
6.
Rev. bras. anal. clin ; 53(2): 180-182, 20210630. ilus
Article in Portuguese | LILACS | ID: biblio-1352922

ABSTRACT

Desde o primeiro caso de COVID-19, ocorrido na China em dezembro de 2019, o espec- tro da doença tem se mostrado muito amplo, incluindo uma miríade de manifestações hematológicas. Relatamos aqui o caso de um paciente com diagnóstico confirmado de COVID-19, o qual apresentou, no sangue periférico, a presença de hemácias apresentan- do projeções citoplasmáticas, semelhantes a uma célula pinçada (pincer cells), também conhecidas como hemácias em forma de cogumelo (mushroom-shaped red blood cells).


Since the first case of COVID-19, which occurred in China in December 2019, the spectrum of the disease has been very broad, including a myriad of hematological manifestations. We report here the case of a patient with a confirmed diagnosis of COVID-19, who presented, in peripheral blood, the red blood cells with cytoplasmic projections, similar to a pincer cells, also known as mushroom-shaped red blood cells.


Subject(s)
Humans , Male , Adult , Oxidative Stress , SARS Virus , Erythrocytes , Cytokine Release Syndrome , COVID-19
7.
Rev. chil. infectol ; 38(2): 271-278, abr. 2021. ilus
Article in Spanish | LILACS-Express | LILACS | ID: biblio-1388230

ABSTRACT

INTRODUCCIÓN: La liberación excesiva de citoquinas en COVID-19 grave se asemeja a la linfohistiocitosis hemofagocítica secundaria (sHLH). OBJETIVO: Comparar las características clínicas y de laboratorio entre sHLH y el síndrome de liberación de citoquinas (CRS) en COVID-19. MÉTODOS: Se realizó una revisión de artículos en la base de datos PubMed, a través de las siguientes palabras clave "HLH and COVID", "HScore in COVID". Se incluyeron las publicaciones disponibles hasta el 16 julio 2020. RESULTADOS: Se elaboró un cuadro comparativo basado en los criterios diagnósticos del protocolo HLH 2004, HScore y características del CRS-COVID-19. Se utilizaron 18 variables para la comparación. DISCUSIÓN: El CRS en COVID-19 grave presenta similitud con el CRS del sHLH; sin embargo, no se puede afirmar que se traten de la misma entidad. Los reportes de sHLH en COVID-19 son escasos. HScore es una herramienta que podría orientar el diagnóstico de HLH secundario a COVID-19 de una manera más práctica que los criterios HLH-2004; sin embargo, su aplicación en COVID-19 se encuentra limitada debido a la ausencia de características claves del estado hiperinflamatorio de COVID-19 que sí destacan en HLH. CONCLUSIONES: El CRS-COVID-19 no es sinónimo de sHLH. Aunque esta última entidad podría o no estar presente en COVID-19 grave.


BACKGROUND: Excessive release of cytokines in severe COVID-19 resembles secondary hemophagocytic lymphohistiocytosis (sHLH). AIM: To compare the clinical and laboratory characteristics between sHLH and cytokine release syndrome (CRS) in COVID-19. METHODS: A review of articles in the PubMed database was performed, using the following keywords "HLH and COVID", "HScore in COVID". Articles available until July 16, 2020 were included. RESULTS: A comparative table was prepared based on the diagnostic criteria of the HLH 2004 protocol, HScore and characteristics of the CRS-COVID-19. Eighteen variables are used for comparison. DISCUSSION: The CRS in COVID-19 presented similarity with the CRS of sHLH; however, it cannot be stated that they are the same entity. Case reports of sHLH in COVID-19 are small. HScore is a tool that could guide the diagnosis of sHLH in the context of CRS-COVID-19, in a more practical way than the classic criteria described in HLH-2004; however, its application in COVID-19 is limited due to the absence of key features of the hyperinflammatory state of COVID-19 that are included in HLH. CONCLUSIONS: CRS-COVID-19 is not synonymous with sHLH. Although this last entity may or may not be present in the severe COVID-19.


Subject(s)
Humans , Lymphohistiocytosis, Hemophagocytic/diagnosis , COVID-19 , Cytokine Release Syndrome , SARS-CoV-2
8.
Rev. méd. Minas Gerais ; 31: 31209, 2021.
Article in Portuguese | LILACS | ID: biblio-1292752

ABSTRACT

Introdução: O tratamento da leucemia linfoblástica aguda (LLA) atualmente baseia-se em quimioterapia e/ou transplante de células tronco hematopoiéticas; entretanto, uma nova terapia vem se tornando promissora: a imunoterapia com células T modificadas geneticamente que expressam um receptor de antígeno quimérico (CAR-T) visando antígenos específicos presente em blastos de LLA, gerando resultados promissores em crianças e adultos com doença recidivada e refratária (r/r). Objetivo: Discorrer sobre a LLA e descrever a imunoterapia com CAR-T, como inovação terapêutica no tratamento da LLA de linhagem B. Método: Foi realizada uma revisão bibliográfica por meio de publicações indexadas nas bases de dados Scielo e Pubmed, utilizando os descritores: leucemia linfoblástica aguda de células B; células CAR-T; receptores de antígeno quimérico, recidivados/refratários; imunoterapia. Resultados: As altas taxas de remissão completa (42% até 100%) e parcial (28,5%) da LLA (r/r) tratadas com CAR-T, possibilitam um aumento considerável da sobrevida geral comparado a outros tratamentos convencionais. Efeitos desfavoráveis, tais como síndrome da liberação de citocinas (CRS) (0 até 90%) e neurotoxicidade (NT) (0 até 29%) podem ser vistos, sendo manejáveis, não prejudicando o desfecho do tratamento. Conclusão: A LLA é uma doença grave, de difícil tratamento e prognóstico reservado. A imunoterapia vêm se mostrando promissora à essa enfermidade, principalmente em casos de doença r/r se mostrado uma ferramenta poderosa que permite o foco específico de células malignas por meio de engenharia de células T


Introduction: The treatment of acute lymphoblastic leukemia (ALL) is currently based on chemotherapy and/or hematopoietic stem cell transplantation; however, a new therapy is becoming promising: immunotherapy with genetically modified T cells that express a chimeric antigen receptor (CAR-T) targeting specific antigens present on ALL blasts, reaching promising results in children and adults with relapsed and refractory disease (r/r). Objective: To discuss ALL and describe immunotherapy with CAR-T as a therapeutic innovation in the treatment of B-lineage ALL. Method: A literature review was carried out through publications indexed in the Scielo and Pubmed databases, using the following descriptors: B-cell acute lymphoblastic leukemia; CAR-T cells; chimeric antigen receptors, relapsed/refractory; immunotherapy. Results: The high rates of complete (42% to 100%) and partial remission (28.5%) of ALL (r/r) treated with CAR-T allows a considerable increase in overall survival compared to other conventional treatments. Unfavorable effects such as cytokine release syndrome (CRS) (0 to 90%) and neurotoxicity (NT) (0 to 29%) can be seen, being manageable, not impairing the treatment outcome. Conclusion: ALL is a serious disease, with a difficult treatment and poor prognosis. Immunotherapy has shown benefits for this disease, especially in cases of r/r ALL, showing itself to be a powerful tool that allows the specific focus of malignant cells through T cell engineering.


Subject(s)
Humans , Child , Adult , Leukemia/therapy , Receptors, Chimeric Antigen , Immunotherapy , Neprilysin , Immunotherapy, Adoptive , Hematopoietic Stem Cell Transplantation , Cytokine Release Syndrome
9.
Journal of Experimental Hematology ; (6): 1982-1986, 2021.
Article in Chinese | WPRIM | ID: wpr-922236

ABSTRACT

Chimeric antigen receptor T cell (CAR-T) therapy was awarded as the largest research breakthrough in 2017 by the American Society of Clinical Oncology, at present, it is rapidly becoming the most promising new treatment for hematological malignancies. However, this therapy also produces a new challenge: toxic adverse events such as cytokine release syndrome (CRS) and neurotoxicity, partial of them can bring death to the patients. The incidence and severity of the above toxic events in different multi-center trial reports are also different, which may be attributed to the different in the considerably variable assessment and grading of toxicities between clinical trials and across institutions. The ASTCT published at 2018 advanced the consensus grading for cytokine release syndrome and neurologic toxicity associated with immune effector cells, it was focusing on CRS and neurotoxicity associated with immune effector cells. In order to provide reference for the development of relevant work in this field and the formulation of security strategies in our country, the main content of the consensus was summarized briefly.


Subject(s)
Cell- and Tissue-Based Therapy , Consensus , Cytokine Release Syndrome , Humans , Receptors, Antigen, T-Cell , Receptors, Chimeric Antigen
10.
Journal of Experimental Hematology ; (6): 1203-1208, 2021.
Article in Chinese | WPRIM | ID: wpr-888539

ABSTRACT

OBJECTIVE@#To investigate the relationship between the levels of ferritin, C-reactive protein (CRP), lactate dehydrogenase (LDH) and interleukin-6 (IL-6) in peripheral serum and cytokine release syndrome (CRS) in patients with relapse and/or refractory multiple myeloma (R/R MM) after receiving chimeric antigen receptor T cells (CAR-T) immunotherapy.@*METHODS@#Twenty-eight patients with R/R MM were treated with 1×10@*RESULTS@#Among the 28 patients, 27 cases (96.4%) developed CRS, 24 cases (85.7%) in 1-2 grade CRS and 3 cases (10.7%) in 3-5 grade. The severity grade of CRS of 27 patients was positively correlated with the peak values of ferritin, CRP, LDH, and IL-6 in peripheral blood (r@*CONCLUSION@#After receiving CAR-T cellular immunotherapy, the incidence of CRS in patients with R/R MM is higher, but most of them are in grade 1 or 2. The severity of CRS is positively correlated with the levels of ferritin, CRP, LDH and IL-6 in peripheral blood.


Subject(s)
Animals , Antigens, CD19 , Cytokine Release Syndrome , Humans , Immunotherapy, Adoptive , Mice , Multiple Myeloma/therapy , Neoplasm Recurrence, Local , Receptors, Chimeric Antigen
11.
Rev. cuba. med. mil ; 49(4): e926, tab, graf
Article in Spanish | LILACS, CUMED | ID: biblio-1156494

ABSTRACT

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)


Subject(s)
Humans , Male , Female , Critical Illness/therapy , Chaperonin 60 , Reference Drugs , Cytokine Release Syndrome/epidemiology , COVID-19/drug therapy
12.
Rev. méd. Maule ; 35(1): 11-17, oct. 2020. ilus
Article in Spanish | LILACS | ID: biblio-1366376

ABSTRACT

In December 2019 a novel coronavirus (SARS-CoV-2) was identified in Wuhan, China, and became rapidly the worst pandemic in 100 years. Coronaviruses are respiratory viruses that can cause diseases ranging from mild to fatal lower respiratory tract infections. In a fraction of the affected patients, coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, can lead to acute respiratory distress syndrome (ARDS) and intensive care unit (ICU) admission, both associated with high mortality. To date, the existing evidence suggests a leading role of the immune system in the pathogenesis of severe COVID-19, including mechanisms associated with hyperinflammation, immune evasion, cytokine release syndrome, depletion of functional T cells, and ineffective humoral immunity. Here we discuss the current evidence regarding these findings.


Subject(s)
Humans , COVID-19/diagnosis , COVID-19/immunology , Respiratory Distress Syndrome, Newborn/physiopathology , C-Reactive Protein/analysis , Cytokines/analysis , Cytokine Release Syndrome , COVID-19/epidemiology , Immunity
13.
Rev. cuba. med. mil ; 49(3): e783, jul.-set. 2020.
Article in Spanish | LILACS, CUMED | ID: biblio-1144491

ABSTRACT

Sin duda alguna la COVID-19 ha suscitado la atención de la población mundial durante el año 2020. La rápida propagación de la enfermedad, así como el número de contagios, complicaciones y muertes, constituyen los principales elementos distintivos de la enfermedad. El proceso inflamatorio, dado por una elevada producción de citocinas proinflamatorias constituye la base de las complicaciones respiratorias. El objetivo de este trabajo es dar a conocer las opciones terapéuticas disponibles para tratar el síndrome de liberación de citoquinas. En este sentido, es importante destacar que fármacos biológicos como el tocilizumab, anakinra y el roxulitinib, así como los glucocorticoides, inmunoglobulinas intravenosas y algunos inmunosupresores como la ciclosporina A, constituyen opciones terapéuticas, con opciones teóricas para combatir el proceso inflamatorio en pacientes graves y que han mostrado resultados alentadores en el transcurso de la crisis sanitaria mundial por la COVID-19.Se concluye que existen opciones terapéuticas para enfrentar la tormenta de citocinas proinflamatorias que caracterizan este síndrome, observado en pacientes graves y críticos con esta enfermedad. Constituye ahora el reto para los científicos y profesionales de la salud, identificar el momento oportuno para las indicaciones terapéuticas y el algoritmo de utilización, en dependencia de las características del cuadro clínico y las condiciones de salud del paciente(AU)


Without doubt, COVID-19 has attracted the attention of the world population during the year 2020. The rapid spread of the disease, as well as the number of infections, complications and deaths, constitute the main distinctive elements of the disease. The inflammatory process, given by a high production of proinflammatory cytokines, forms the basis of respiratory complications. The objective of this work is to publicize the therapeutic options available to treat cytokine release syndrome. In this sense, it is important to highlight that biological drugs such as tocilizumab, anakinra and roxulitinib, as well as glucocorticoids, intravenous immunoglobulins and some immunosuppressants such as cyclosporin A, are therapeutic options, with theoretical options to combat the inflammatory process in seriously ill patients and which have shown encouraging results in the course of the global health crisis caused by COVID-19. It is concluded that there are therapeutic options to face the storm of proinflammatory cytokines that characterize this syndrome, observed in critically ill patients with this disease. It is now a challenge for scientists and health professionals to identify the right time for therapeutic indications and the algorithm of use, depending on the characteristics of the clinical picture and the patient's health conditions(AU)


Subject(s)
Humans , Health Status , Global Health , Immunoglobulins, Intravenous , Coronavirus Infections/drug therapy , Cytokine Release Syndrome
14.
Arq. Asma, Alerg. Imunol ; 4(2): 172-180, abr.jun.2020. ilus
Article in Portuguese | LILACS | ID: biblio-1381903

ABSTRACT

Compreender os mecanismos imunopatológicos envolvidos na evolução da COVID-19 é um desafio para a ciência mundial. A observação da existência de formas clínicas diferentes da doença, podendo ocorrer desde manifestações leves até formas graves, demonstra a complexidade da resposta imune desenvolvida frente à infecção pelo SARS-CoV-2. Nesta revisão da literatura, utilizamos as bases de dados PubMed, MEDLINE, LILACS, SciELO a partir de dezembro de 2019, quando surgiram os primeiros casos da doença. A relação entre as diferentes formas clínicas da COVID-19 com o desenvolvimento da resposta imune foi amplamente discutida. As diferenças da evolução da COVID-19 em crianças e idosos foram avaliadas focalizando aspectos da resposta imune que podem conferir prognóstico favorável ou risco de desenvolvimento de formas clínicas graves. Particularidades da infecção pelo SARS-CoV-2 em pacientes com imunossupressão e em portadores de asma foram analisadas. Os mecanismos imunopatológicos envolvidos no desenvolvimento das formas graves da COVID-19 foram abordados com ênfase no fenômeno "tempestade de citocinas".


Understanding the immunopathological mechanisms involved in the evolution of COVID-19 is a challenge for science worldwide. The observed existence of several clinical forms of the disease with mild to severe manifestations demonstrates the complexity of the immune response to SARS-CoV-2 infection. In this literature review, we searched the PubMed, MEDLINE, LILACS, SciELO databases for studies published after December 2019, when the first cases of the disease were described. The relationship between the different clinical forms of COVID-19 and the development of immune response was widely discussed. The differences in the evolution of COVID-19 in children and elderly were evaluated focusing aspects of the immune response that may confer favorable prognosis or risk of developing severe clinical forms. Particularities of SARS-CoV-2 infection in patients with immunosuppression and in asthma patients were analyzed. The immunopathological mechanisms involved in the development of severe forms of COVID-19 were addressed, with emphasis on the cytokine storm phenomenon.


Subject(s)
Humans , SARS-CoV-2 , COVID-19 , Immunity , Patients , Asthma , MEDLINE , Immunosuppression Therapy , PubMed , Cytokine Release Syndrome
16.
Medwave ; 20(7): e7998, 2020.
Article in English, Spanish | LILACS | ID: biblio-1122648

ABSTRACT

El síndrome respiratorio agudo grave coronavirus 2 (SARS-CoV-2) se ha diseminado rápidamente a lo largo del mundo causando una mortalidad significativa en pacientes de alto riesgo con manifestaciones severas. A la fecha, Remdesivir ha sido el único antiviral autorizado por la FDA para uso de emergencia. Una de las posibles complicaciones de esta infección es el desarrollo de tormenta de citoquinas, para la cual no existe un tratamiento óptimo. Presentamos el caso de un varón de 48 años sin antecedentes médicos que acudió al hospital con disnea, tos, fiebre subjetiva y diarrea durante 10 días. La reacción de cadena polimerasa nasofaríngea fue positiva para SARS-CoV-2. Su estado respiratorio empeoró rápidamente hasta el punto de requerir oxígeno suplementario a través cánula nasal de alto flujo con 80% de FiO2. La tomografía computarizada de tórax mostró opacidades confluyentes en vidrio esmerilado en los lóbulos superiores, acompañadas de opacidades irregulares alveolares en los lóbulos inferiores bilateralmente. Se inició terapia con hidroxicloroquina, la cual se cambió a Remdesivir cuando estuvo disponible. Luego se inició metilprednisolona como tratamiento de una posible tormenta de citoquinas. La oxigenación del paciente mejoró significativamente en los días posteriores y fue dado de alta sin requerir oxigeno adicional y saturando 96% en medio ambiente. Nuestro caso ilustra el papel de Remdesivir en el tratamiento de la neumonía grave por COVID-19. También observamos un posible beneficio clínico de los corticoides en tormenta de citoquinas. Se necesitan más estudios para evaluar la eficacia de esta estrategia terapéutica.


Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has rapidly spread throughout the world causing significant mortality in high risk patients with severe manifestations. To date, Remdesivir has been the only antiviral authorized by FDA as therapy for emergency use. One of the potential complications of this infection is cytokine storm, which optimal treatment remains unknown. We present the case of a 48-year-old man with no past medical history who presented to the hospital with dyspnea, cough, subjective fever, and diarrhea for 10 days. Nasopharyngeal PCR was positive for SARS-CoV-2. His respiratory status rapidly worsened to the point of requiring supplemental oxygen by high flow nasal cannula with FiO2 of 80%. Chest computed tomography showed confluent ground glass opacities in upper lobes accompanied by patchy airspace opacities in lower lobes bilaterally. He was started on hydroxychloroquine, which was switched to Remdesivir when it became available. Then, methylprednisolone was initiated for suspected cytokine storm. The patient's oxygenation improved significantly over the following days and he was discharged home with no oxygen supplementation and saturating 96% on room air. Our case illustrates the role of Remdesivir for the treatment of severe COVID-19 pneumonia. We also observed a possible clinical benefit of corticosteroids in the context of suspected cytokine storm. Further studies are needed to evaluate this therapeutic strategy.


Subject(s)
Humans , Male , Middle Aged , Antiviral Agents/therapeutic use , Adenosine Monophosphate/analogs & derivatives , Alanine/analogs & derivatives , COVID-19/drug therapy , Methylprednisolone/therapeutic use , Adenosine Monophosphate/therapeutic use , Alanine/therapeutic use , Pandemics , Cytokine Release Syndrome/etiology , Cytokine Release Syndrome/drug therapy , COVID-19/complications , COVID-19/diagnosis , Glucocorticoids/therapeutic use
17.
Protein & Cell ; (12): 723-739, 2020.
Article in English | WPRIM | ID: wpr-828747

ABSTRACT

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.


Subject(s)
Animals , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Humans , Influenza A virus , Leflunomide , Pharmacology , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus Replication
18.
Protein & Cell ; (12): 740-770, 2020.
Article in English | WPRIM | ID: wpr-828746

ABSTRACT

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Subject(s)
Adult , Aged , Aged, 80 and over , Aging , Genetics , Allergy and Immunology , Betacoronavirus , CD4-Positive T-Lymphocytes , Metabolism , Cell Lineage , Chromatin Assembly and Disassembly , Coronavirus Infections , Allergy and Immunology , Cytokine Release Syndrome , Allergy and Immunology , Cytokines , Genetics , Disease Susceptibility , Flow Cytometry , Methods , Gene Expression Profiling , Gene Expression Regulation, Developmental , Gene Rearrangement , Humans , Immune System , Cell Biology , Allergy and Immunology , Immunocompetence , Genetics , Inflammation , Genetics , Allergy and Immunology , Mass Spectrometry , Methods , Middle Aged , Pandemics , Pneumonia, Viral , Allergy and Immunology , Sequence Analysis, RNA , Single-Cell Analysis , Transcriptome , Young Adult
19.
Protein & Cell ; (12): 723-739, 2020.
Article in English | WPRIM | ID: wpr-828583

ABSTRACT

Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.


Subject(s)
Animals , Antiviral Agents , Pharmacology , Therapeutic Uses , Betacoronavirus , Physiology , Binding Sites , Cell Line , Coronavirus Infections , Drug Therapy , Virology , Crotonates , Pharmacology , Cytokine Release Syndrome , Drug Therapy , Drug Evaluation, Preclinical , Gene Knockout Techniques , Humans , Influenza A virus , Leflunomide , Pharmacology , Mice , Mice, Inbred BALB C , Orthomyxoviridae Infections , Drug Therapy , Oseltamivir , Therapeutic Uses , Oxidoreductases , Metabolism , Pandemics , Pneumonia, Viral , Drug Therapy , Virology , Protein Binding , Pyrimidines , RNA Viruses , Physiology , Structure-Activity Relationship , Toluidines , Pharmacology , Ubiquinone , Metabolism , Virus Replication
20.
Protein & Cell ; (12): 740-770, 2020.
Article in English | WPRIM | ID: wpr-828582

ABSTRACT

Age-associated changes in immune cells have been linked to an increased risk for infection. However, a global and detailed characterization of the changes that human circulating immune cells undergo with age is lacking. Here, we combined scRNA-seq, mass cytometry and scATAC-seq to compare immune cell types in peripheral blood collected from young and old subjects and patients with COVID-19. We found that the immune cell landscape was reprogrammed with age and was characterized by T cell polarization from naive and memory cells to effector, cytotoxic, exhausted and regulatory cells, along with increased late natural killer cells, age-associated B cells, inflammatory monocytes and age-associated dendritic cells. In addition, the expression of genes, which were implicated in coronavirus susceptibility, was upregulated in a cell subtype-specific manner with age. Notably, COVID-19 promoted age-induced immune cell polarization and gene expression related to inflammation and cellular senescence. Therefore, these findings suggest that a dysregulated immune system and increased gene expression associated with SARS-CoV-2 susceptibility may at least partially account for COVID-19 vulnerability in the elderly.


Subject(s)
Adult , Aged , Aged, 80 and over , Aging , Genetics , Allergy and Immunology , Betacoronavirus , CD4-Positive T-Lymphocytes , Metabolism , Cell Lineage , Chromatin Assembly and Disassembly , Coronavirus Infections , Allergy and Immunology , Cytokine Release Syndrome , Allergy and Immunology , Cytokines , Genetics , Disease Susceptibility , Flow Cytometry , Methods , Gene Expression Profiling , Gene Expression Regulation, Developmental , Gene Rearrangement , Humans , Immune System , Cell Biology , Allergy and Immunology , Immunocompetence , Genetics , Inflammation , Genetics , Allergy and Immunology , Mass Spectrometry , Methods , Middle Aged , Pandemics , Pneumonia, Viral , Allergy and Immunology , Sequence Analysis, RNA , Single-Cell Analysis , Transcriptome , Young Adult
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