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1.
Cell Transplant ; 30: 9636897211054481, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34757857

RESUMO

Biological and cellular interleukin-6 (IL-6)-related therapies have been used to treat severe COVID-19 pneumonia with hyperinflammatory syndrome and acute respiratory failure, which prompted further exploration of the role of IL-6 in human umbilical cord mesenchymal stem cell (hUCMSC) therapy. Peripheral blood mononuclear cells (PBMCs) were responders cocultured with hUCMSCs or exogenous IL-6. A PBMC suppression assay was used to analyze the anti-inflammatory effects via MTT assay. The IL-6 concentration in the supernatant was measured using ELISA. The correlation between the anti-inflammatory effect of hUCMSCs and IL-6 levels and the relevant roles of IL-6 and IL-6 mRNA expression was analyzed using the MetaCore functional network constructed from gene microarray data. The location of IL-6 and IL-6 receptor (IL-6R) expression was further evaluated. We reported that hUCMSCs did not initially exert any inhibitory effect on PHA-stimulated proliferation; however, a potent inhibitory effect on PHA-stimulated proliferation was observed, and the IL-6 concentration reached approximately 1000 ng/mL after 72 hours. Exogenous 1000 ng/mL IL-6 inhibited PHA-stimulated inflammation but less so than hUCMSCs. The inhibitory effects of hUCMSCs on PHA-stimulated PBMCs disappeared after adding an IL-6 neutralizing antibody or pretreatment with tocilizumab (TCZ), an IL-6R antagonist. hUCMSCs exert excellent anti-inflammatory effects by inducing higher IL-6 levels, which is different from TCZ. High concentration of IL-6 cytokine secretion plays an important role in the anti-inflammatory effect of hUCMSC therapy. Initial hUCMSC therapy, followed by TCZ, seems to optimize the therapeutic potential to treat COVID-19-related acute respiratory distress syndrome (ARDS).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/complicações , Interleucina-6/biossíntese , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Síndrome do Desconforto Respiratório/terapia , SARS-CoV-2 , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Neutralizantes/imunologia , Células Cultivadas , Técnicas de Cocultura , Terapia Combinada , DNA Complementar/genética , Regulação da Expressão Gênica/efeitos dos fármacos , Humanos , Inflamação , Interleucina-6/genética , Interleucina-6/farmacologia , Leucócitos Mononucleares/citologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Fito-Hemaglutininas/farmacologia , RNA Mensageiro/biossíntese , RNA Mensageiro/genética , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/biossíntese , Receptores de Interleucina-6/genética , Síndrome do Desconforto Respiratório/tratamento farmacológico , Síndrome do Desconforto Respiratório/etiologia , Cordão Umbilical/citologia
2.
Sci Rep ; 11(1): 21522, 2021 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-34728658

RESUMO

There is controversy whether IL-6 (receptor) antagonists are beneficial in treating COVID-19 patients. We therefore update our systematic review to answer the following research questions: (1) Do patients hospitalized for COVID-19 treated with IL-6 (receptor) antagonists have lower mortality compared to standard of care? (2) Do patients hospitalized for COVID-19 treated with IL-6 (receptor) antagonists have more side effects compared to standard of care? The following databases were search up to December 1st 2020: PubMed, PMC PubMed Central, MEDLINE, WHO COVID-19 Database, Embase, Web-of-Science, COCHRANE LIBRARY, Emcare and Academic Search Premier. In order to pool the risk ratio (RR) and risk difference of individual studies we used random effects meta-analysis. The search strategy retrieved 2975 unique titles of which 71 studies (9 RCTs and 62 observational) studies comprising 29,495 patients were included. Mortality (RR 0.75) and mechanical ventilation (RR 0.78) were lower and the risk of neutropenia (RR 7.3), impaired liver function (RR 1.67) and secondary infections (RR 1.26) were higher for patients treated with IL-6 (receptor) antagonists compared to patients not treated with treated with IL-6 (receptor) antagonists. Our results showed that IL-6 (receptor) antagonists are effective in reducing mortality in COVID-19 patients, while the risk of side effects was higher. The baseline risk of mortality was an important effect modifier: IL-6 (receptor) antagonists were effective when the baseline mortality risk was high (e.g. ICU setting), while they could be harmful when the baseline mortality risk was low.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/imunologia , COVID-19/mortalidade , COVID-19/virologia , Humanos , Razão de Chances , Respiração Artificial , SARS-CoV-2/isolamento & purificação , Taxa de Sobrevida
3.
Eur J Med Res ; 26(1): 117, 2021 Oct 02.
Artigo em Inglês | MEDLINE | ID: mdl-34600589

RESUMO

BACKGROUND: Interleukin-6 receptor antagonists (IL-6RAs) and steroids are emerging immunomodulatory therapies for severe and critical coronavirus disease (COVID-19). In this preliminary report, we aim to describe the epidemiology, clinical characteristics, and outcomes of adult critically ill COVID-19 patients, requiring invasive mechanical ventilation (iMV), and receiving IL-6RA and steroids therapy over the last 11 months. MATERIALS AND METHODS: International, multicenter, cohort study derived from Viral Infection and Respiratory Illness University Study registry and conducted through Discovery Network, Society of Critical Care Medicine. Data were collected between March 01, 2020, and January 10, 2021. RESULTS: Of 860 patients who met eligibility criteria, 589 received steroids, 170 IL-6RAs, and 101 combinations. Patients who received IL-6RAs were younger (median age of 57.5 years vs. 61.1 and 61.8 years in the steroids and combination groups, respectively). The median C-reactive protein level was > 75 mg/L, indicating a hyperinflammatory phenotype. The median daily steroid dose was 7.5 mg dexamethasone or equivalent (interquartile range: 6-14 mg); 80.8% and 19.2% received low-dose and high-dose steroids, respectively. Of the patients who received IL-6RAs, the majority received one dose of tocilizumab and sarilumab (dose range of 600-800 mg for tocilizumab and 200-400 mg for sarilumab). Regarding the timing of administration, we observed that steroid and IL-6RA administration on day 0 of ICU admission was only 55.6% and 39.5%, respectively. By day 28, when compared with steroid use alone, IL-6RA use was associated with an adjusted incidence rate ratio (aIRR) of 1.12 (95% confidence interval [CI] 0.88, 1.4) for ventilator-free days, while combination therapy was associated with an aIRR of 0.83 (95% CI 0.6, 1.14). IL-6RA use was associated with an adjusted odds ratio (aOR) of 0.68 (95% CI 0.44, 1.07) for the 28-day mortality rate, while combination therapy was associated with an aOR of 1.07 (95% CI 0.67, 1.70). Liver dysfunction was higher in IL-6RA group (p = 0.04), while the bacteremia rate did not differ among groups. CONCLUSIONS: Discordance was observed between the registry utilization patterns (i.e., timing of steroids and IL-6RA administration) and new evidence from the recent randomized controlled trials and guideline recommendations. These data will help us to identify areas of improvement in prescribing patterns and enhance our understanding of IL-6RA safety with different steroid regimens. Further studies are needed to evaluate the drivers of hospital-level variation and their impact on clinical outcomes. Trial registration ClinicalTrials.gov: NCT04486521. Registered on July 2020.


Assuntos
Corticosteroides/uso terapêutico , COVID-19/complicações , Receptores de Interleucina-6/antagonistas & inibidores , Sistema de Registros/estatística & dados numéricos , Respiração Artificial/métodos , Insuficiência Respiratória/mortalidade , SARS-CoV-2/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estado Terminal , Feminino , Seguimentos , Humanos , Agências Internacionais , Masculino , Pessoa de Meia-Idade , Prognóstico , Insuficiência Respiratória/epidemiologia , Insuficiência Respiratória/terapia , Insuficiência Respiratória/virologia , Taxa de Sobrevida , Adulto Jovem
4.
Anticancer Res ; 41(10): 4907-4916, 2021 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-34593438

RESUMO

BACKGROUND: Interleukin-6 receptor antibody (IL6R) inhibits colony formation and invasion by colorectal carcinoma (CRC) in vitro. We examined the effect of IL6R antibody on tumor growth of CRC xenografts in vivo. MATERIALS AND METHODS: SW480 cells inoculated subcutaneously into NU/NU mice were treated with anti-IL6R and tumor histology and growth-related signaling were subsequently estimated by hematoxylin and eosin and immunohistochemical staining. RESULTS: Tumor growth was inhibited by anti-IL6R treatment at dosages of both 0.1 and 1.0 mg/kg. Tumor cells had invaded into surrounding tissues in untreated mice, while there was no invasion of tumors in the IL6R antibody-treated mice. The expression of Ki-67, signal transducer and activator of transcription protein 3 (STAT3) and phosphor-extracellular signal-regulated kinase 1 and 2 (ERK1/2) were suppressed in anti-IL6R-treated tumors. CONCLUSION: IL6R antibody inhibited tumor growth and invasiveness in vivo by suppressing the expression of Ki-67, STAT3 and phosphor-ERK1/2. The results imply that the anti-IL6R may be a promising targeted drug for CRC.


Assuntos
Anticorpos Monoclonais/farmacologia , Neoplasias Colorretais/prevenção & controle , Neovascularização Patológica/prevenção & controle , Receptores de Interleucina-6/antagonistas & inibidores , Animais , Apoptose , Proliferação de Células , Neoplasias Colorretais/imunologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Receptores de Interleucina-6/imunologia , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Inflamm Res ; 70(10-12): 1233-1246, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34586459

RESUMO

OBJECTIVE AND DESIGN: The aim of this double-blind, placebo-controlled, phase III CORONA clinical trial was to evaluate the efficacy and safety of IL-6 receptor inhibitor levilimab (LVL) in subjects with severe COVID-19. SUBJECTS: The study included 217 patients. The eligible were men and non-pregnant women aged 18 years or older, hospitalized for severe COVID-19 pneumonia. TREATMENT: 206 subjects were randomized (1:1) to receive single subcutaneous administration of LVL 324 mg or placebo, both in combination with standard of care (SOC). 204 patients received allocated therapy. After the LVL/placebo administration in case of deterioration of symptoms, the investigator could perform a single open-label LVL 324 mg administration as the rescue therapy. METHODS: The primary efficacy endpoint was the proportion of patients with sustained clinical improvement on the 7-category ordinal scale on Day 14. All efficacy data obtained after rescue therapy administration were considered missing. For primary efficacy analysis, all subjects with missing data were considered non-responders. RESULTS: 63.1% and 42.7% of patients in the LVL and in the placebo groups, respectively, achieved sustained clinical improvement on Day 14 (P = .0017). The frequency of adverse drug reactions was comparable between the groups. CONCLUSION: In patients with radiologically confirmed SARS-CoV-2 pneumonia, requiring or not oxygen therapy (but not ventilation) with no signs of other active infection administration of LVL + SOC results in an increase of sustained clinical improvement rate. TRAIL REGISTRATION: The trial is registered at the US National Institutes of Health (ClinicalTrials.gov; NCT04397562).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/efeitos adversos , Método Duplo-Cego , Determinação de Ponto Final , Feminino , Humanos , Injeções Subcutâneas , Masculino , Pessoa de Meia-Idade , Oxigenoterapia , Respiração Artificial , Resultado do Tratamento , Adulto Jovem
8.
Exp Mol Med ; 53(7): 1116-1123, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-34253862

RESUMO

Interleukin-6 (IL-6) plays a crucial role in host defense against infection and tissue injuries and is a bioindicator of multiple distinct types of cytokine storms. In this review, we present the current understanding of the diverse roles of IL-6, its receptors, and its signaling during acute severe systemic inflammation. IL-6 directly affects vascular endothelial cells, which produce several types of cytokines and chemokines and activate the coagulation cascade. Endothelial cell dysregulation, characterized by abnormal coagulation and vascular leakage, is a common complication in cytokine storms. Emerging evidence indicates that a humanized anti-IL-6 receptor antibody, tocilizumab, can effectively block IL-6 signaling and has beneficial effects in rheumatoid arthritis, juvenile systemic idiopathic arthritis, and Castleman's disease. Recent work has also demonstrated the beneficial effect of tocilizumab in chimeric antigen receptor T-cell therapy-induced cytokine storms as well as coronavirus disease 2019 (COVID-19). Here, we highlight the distinct contributions of IL-6 signaling to the pathogenesis of several types of cytokine storms and discuss potential therapeutic strategies for the management of cytokine storms, including those associated with sepsis and COVID-19.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/prevenção & controle , Interleucina-6/genética , Receptores de Interleucina-6/genética , Anticorpos Monoclonais Humanizados/imunologia , COVID-19/genética , COVID-19/imunologia , COVID-19/patologia , Síndrome da Liberação de Citocina/genética , Síndrome da Liberação de Citocina/imunologia , Citocinas/genética , Citocinas/metabolismo , Endotélio Vascular/imunologia , Humanos , Interleucina-6/antagonistas & inibidores , Interleucina-6/imunologia , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/imunologia , SARS-CoV-2/imunologia , SARS-CoV-2/patogenicidade , Sepse/genética , Sepse/imunologia , Sepse/patologia , Sepse/prevenção & controle
9.
J Investig Med High Impact Case Rep ; 9: 23247096211019557, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34105382

RESUMO

An outbreak of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus-2, initially in December 2019 at Wuhan, China, subsequently spread around the world. We describe a case series of COVID-19 patients treated at our academic medical center with focus on cytokine storm and potential therapeutic role of tocilizumab. A 59-year-old female admitted for shortness of breath (SOB), productive cough, fever, and nausea in the setting of COVID-19 pneumonia. Oxygen saturation was 81% necessitating supplemental oxygen. She was transferred to intensive care unit (ICU) for worsening hypoxia; intubated and received tocilizumab following which her oxygen requirements improved. A 52-year-old female admitted from an outside hospital with SOB, intubated for worsening hypoxia, in the setting of COVID-19 pneumonia. She received tocilizumab 400 mg intravenous for 2 doses on ICU admission, with clinical improvement. A 56-year-old female hospitalized with worsening SOB, fever, and cough for 8 days saturating 88% on room air in the setting of COVID-19 pneumonia. Worsening hypoxia necessitated high flow nasal cannula. She was transferred to the ICU where she received 2 doses of tocilizumab 400 mg intravenous. She did not require intubation and was transitioned to nasal cannula. A hyperinflammatory syndrome may cause a life-threatening acute respiratory distress syndrome in patients with COVID-19 pneumonia. Tocilizumab is the first marketed interleukin-6 blocking antibody, and through targeting interleukin-6 receptors likely has a role in treating cytokine storm. We noted clinical improvement of patients treated with tocilizumab.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome do Desconforto Respiratório/tratamento farmacológico , COVID-19/diagnóstico por imagem , COVID-19/tratamento farmacológico , Cuidados Críticos , Síndrome da Liberação de Citocina/diagnóstico por imagem , Síndrome da Liberação de Citocina/etiologia , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pessoa de Meia-Idade , Oxigenoterapia , Pennsylvania , Síndrome do Desconforto Respiratório/diagnóstico por imagem , SARS-CoV-2 , Centros de Traumatologia
10.
Radiol Med ; 126(9): 1170-1180, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34089436

RESUMO

PURPOSE: To evaluate CT and laboratory changes in COVID-19 patients treated with tocilizumab, compared to a control group, throughout a combined semiquantitative and texture analysis of images. MATERIALS AND METHODS: From March 11 to April 20, 2020, 57 SARS-CoV-2 positive patients were retrospectively compared: group T (n = 30) receiving tocilizumab and group non-T (n = 27) undergoing only antivirals/antimalarials. Chest-CT and laboratory findings were analyzed before and after treatment. CT evaluation included both semiquantitative scoring and texture analysis of all parenchymal lesions. Survival and recovery analyses were also provided with Kaplan-Meier method. RESULTS: In group T, no significant differences were found for CT score after treatment, while several texture features significantly changed, including mean attenuation (p < 0.0001), skewness (p < 0.0001), entropy (p = 0.0146) and higher-order parameters, suggesting considerable fading of parenchymal lesions. PaO2/FiO2 mean value significantly increased after treatment, from 240 ± 93 to 363 ± 107 (p = 0.0003), with parallel decrease in inflammatory biomarkers (CRP, D-dimer and LDH). In group non-T, CT scoring, texture and laboratory parameters showed significant worsening at follow-up. Findings were clinically associated with opposite trends between two groups, with reduction of severe cases in group T (from 21/30 to 5/30; p < 0.0001) as compared to a significant worsening in group non-T (severe cases increasing from 6/27 to 14/27; p = 0.0473). Probability of discharge was significantly higher in group T (p < 0.0001), as well as survival rate, although not statistically significant. CONCLUSIONS: Our results suggest the potential role of CT texture analysis for assessing response to treatment in COVID-19 pneumonia, using Tocilizumab, as compared to semiquantitative evaluation, providing insight into the intrinsic parenchymal changes.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , COVID-19/tratamento farmacológico , Pulmão/diagnóstico por imagem , Receptores de Interleucina-6/antagonistas & inibidores , Tomografia Computadorizada por Raios X , Adulto , Idoso , Idoso de 80 Anos ou mais , COVID-19/diagnóstico por imagem , COVID-19/mortalidade , Feminino , Humanos , Estimativa de Kaplan-Meier , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
12.
Cells ; 10(5)2021 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-34064515

RESUMO

Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology. SSc causes damage to the skin and various organs including the lungs, heart, and digestive tract, but the extent of the damage varies from patient to patient. The pathology of SSc includes ischemia, inflammation, and fibrosis, but the degree of progression varies from case to case. Many cytokines have been reported to be involved in the pathogenesis of SSc: interleukin-6 is associated with inflammation and transforming growth factor-ß and interleukin-13 are associated with fibrosis. Therapeutic methods to control these cytokines have been proposed; however, which cytokines have a dominant role in SSc might differ depending on the extent of visceral lesions and the stage of disease progression. Therefore, it is necessary to consider the disease state of the patient to be targeted and the type of evaluation method when an anti-cytokine therapy is conducted. Here, we review the pathology of SSc and potential cytokine targets, especially interleukin-6, as well as the use of anti-cytokine therapy for SSc.


Assuntos
Citocinas/metabolismo , Escleroderma Sistêmico/metabolismo , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Citocinas/antagonistas & inibidores , Desenvolvimento de Medicamentos , Humanos , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/metabolismo , Escleroderma Sistêmico/tratamento farmacológico , Escleroderma Sistêmico/patologia
13.
J Med Invest ; 68(1.2): 192-195, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33994470

RESUMO

This report presents a case of a 74-year-old man who showed dramatic therapeutic response to treatment of coronavirus infectious disease-19 (COVID-19) pneumonia. He reported four-day history of sustained fever and acute progressive dyspnea. He developed severe respiratory failure, underwent urgent endotracheal intubation and showed marked elevation of inflammatory and coagulation markers such as c-reactive protein (CRP), ferritin, lactate dehydrogenase (LDH) and D-dimer. Chest computed tomography (CT) demonstrated diffuse consolidation and ground glass opacity (GGO). We diagnosed critical COVID-19 pneumonia with detailed sick contact history and naso-pharyngeal swab of a reverse-transcriptase-polymerase-chain reaction (RT-PCR) assay testing. He received anti-viral drug, anti-interleukin (IL-6) receptor antagonist and intravenous methylprednisolone. After commencing combined intensive therapy, he showed dramatic improvement of clinical condition, serum biomarkers and radiological findings. Early diagnosis and rapid critical care management may provide meaningful clinical benefit even if severe case. J. Med. Invest. 68 : 192-195, February, 2021.


Assuntos
COVID-19/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , SARS-CoV-2 , Idoso , Amidas/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antivirais/administração & dosagem , COVID-19/diagnóstico por imagem , Estado Terminal , Quimioterapia Combinada , Glucocorticoides/administração & dosagem , Humanos , Pulmão/diagnóstico por imagem , Masculino , Metilprednisolona/administração & dosagem , Pneumonia Viral/diagnóstico por imagem , Pirazinas/administração & dosagem , Receptores de Interleucina-6/antagonistas & inibidores , Tomografia Computadorizada por Raios X , Resultado do Tratamento
14.
Lung ; 199(3): 239-248, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-34050796

RESUMO

BACKGROUND: To date, only dexamethasone has been shown to reduce mortality in coronavirus disease-19 (COVID-19) patients. Tocilizumab has been recently added to the treatment guidelines for hospitalized COVID-19 patients, but data remain conflicting. STUDY DESIGN AND METHODS: Electronic databases such as MEDLINE, EMBASE, and Cochrane central were searched from March 1, 2020, until March 10, 2021, for randomized controlled trials evaluating the efficacy of tocilizumab in hospitalized COVID-19 patients. The outcomes assessed were all-cause mortality, mechanical ventilation, and time to discharge. RESULTS: Nine studies (with 6490 patients) were included in the analysis. In total, 3358 patients received tocilizumab, and 3132 received standard care/placebo. Pooled analysis showed a significantly decreased risk of all-cause mortality (RR 0.89, 95% CI 0.80-0.98, p = 0.02) and progression to mechanical ventilation (RR 0.80, 95% CI 0.71-0.89, p < 0.0001) in the tocilizumab arm compared to standard therapy or placebo. In addition, there was a trend towards improved median time to hospital discharge (RR 1.28, 95% CI 1.12-1.45, p = 0.0002). CONCLUSIONS: Tocilizumab therapy improves outcomes of mortality and need for mechanical ventilation, in hospitalized patients with COVID-19 infection compared with standard therapy or placebo. Our findings suggest the efficacy of tocilizumab therapy in hospitalized COVID-19 patients and strengthen the concept that tocilizumab is a promising therapeutic intervention to improve mortality and morbidity in COVID-19 patients.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , COVID-19 , Receptores de Interleucina-6/antagonistas & inibidores , COVID-19/tratamento farmacológico , COVID-19/imunologia , COVID-19/mortalidade , Humanos , Fatores Imunológicos/farmacologia , Avaliação de Resultados em Cuidados de Saúde , SARS-CoV-2
15.
Lancet Respir Med ; 9(6): 655-664, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33930329

RESUMO

The pleiotropic cytokine interleukin-6 (IL-6) has been implicated in the pathogenesis of COVID-19, but uncertainty remains about the potential benefits and harms of targeting IL-6 signalling in patients with the disease. The efficacy and safety of tocilizumab and sarilumab, which block the binding of IL-6 to its receptor, have been tested in adults with COVID-19-related acute respiratory illness in randomised trials, with important differences in trial design, characteristics of included patients, use of co-interventions, and outcome measurement scales. In this Series paper, we review the clinical and methodological heterogeneity of studies of IL-6 receptor antagonists, and consider how this heterogeneity might have influenced reported treatment effects. Timing from clinical presentation to treatment, severity of illness, and concomitant use of corticosteroids are among the factors that might have contributed to apparently inconsistent results. With an understanding of the sources of variability in these trials, available evidence could be applied to guide clinical decision making and to inform the enrichment of future studies.


Assuntos
Anticorpos Monoclonais Humanizados/farmacologia , COVID-19 , Ensaios Clínicos como Assunto , Receptores de Interleucina-6/antagonistas & inibidores , Anticorpos Monoclonais Humanizados/imunologia , COVID-19/imunologia , COVID-19/terapia , Ensaios Clínicos como Assunto/métodos , Ensaios Clínicos como Assunto/estatística & dados numéricos , Humanos , Seleção de Pacientes , Receptores de Interleucina-6/imunologia , SARS-CoV-2
16.
Expert Rev Clin Immunol ; 17(6): 601-618, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33874829

RESUMO

INTRODUCTION: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a dysregulated hyperinflammatory response. AREAS COVERED: Authors review evidence on IL-6 and IL-6 blockade in coronavirus disease 2019 (COVID-19) and discuss the pathophysiological and prognostic roles of this cytokine and the clinical impact of pharmacological blockade of IL-6 . The material includes original articles and reviews published from March 2020 to March 2021 and searched on PubMed, medRxiv, and bioRxiv. EXPERT OPINION: IL-6 is one of the most prominent pro-inflammatory cytokines. Increased levels are recorded in COVID-19 patients, especially those with severe-to-critical disease. Evidence is accumulating on the relevance of IL-6 as a prognostic marker in COVID-19. Since IL-6 is a druggable target for several inflammatory diseases, pharmacological blockers of the IL-6 signaling pathway were repurposed to blunt the abnormal SARS-CoV-2-induced cytokine release. Data are limited to few randomized controlled trials that reported encouraging, though not conclusive, results, indicating the usefulness of IL-6 blockade early in the course of the disease in patients with hyperinflammation and no or limited organ damage. Further research is warranted to explore the role of IL-6 in different COVID-19 phenotypes and identify subgroups of patients who may mostly benefit from IL-6 pathway inhibition.


Assuntos
Anti-Inflamatórios/uso terapêutico , COVID-19/tratamento farmacológico , Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/antagonistas & inibidores , SARS-CoV-2/patogenicidade , Animais , Anti-Inflamatórios/efeitos adversos , COVID-19/imunologia , COVID-19/virologia , Interações Hospedeiro-Patógeno , Humanos , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , SARS-CoV-2/imunologia , Transdução de Sinais , Resultado do Tratamento
18.
J Am Coll Cardiol ; 77(15): 1845-1855, 2021 04 20.
Artigo em Inglês | MEDLINE | ID: mdl-33858620

RESUMO

BACKGROUND: Prompt myocardial revascularization with percutaneous coronary intervention (PCI) reduces infarct size and improves outcomes in patients with ST-segment elevation myocardial infarction (STEMI). However, as much as 50% of the loss of viable myocardium may be attributed to the reperfusion injury and the associated inflammatory response. OBJECTIVES: This study sought to evaluate the effect of the interleukin-6 receptor inhibitor tocilizumab on myocardial salvage in acute STEMI. METHODS: The ASSAIL-MI trial was a randomized, double-blind, placebo-controlled trial conducted at 3 high-volume PCI centers in Norway. Patients admitted with STEMI within 6 h of symptom onset were eligible. Consenting patients were randomized in a 1:1 fashion to promptly receive a single infusion of 280 mg tocilizumab or placebo. The primary endpoint was the myocardial salvage index as measured by magnetic resonance imaging after 3 to 7 days. RESULTS: We randomized 101 patients to tocilizumab and 98 patients to placebo. The myocardial salvage index was larger in the tocilizumab group than in the placebo group (adjusted between-group difference 5.6 [95% confidence interval: 0.2 to 11.3] percentage points, p = 0.04). Microvascular obstruction was less extensive in the tocilizumab arm, but there was no significant difference in the final infarct size between the tocilizumab arm and the placebo arm (7.2% vs. 9.1% of myocardial volume, p = 0.08). Adverse events were evenly distributed across the treatment groups. CONCLUSIONS: Tocilizumab increased myocardial salvage in patients with acute STEMI. (ASSessing the effect of Anti-IL-6 treatment in Myocardial Infarction [ASSAIL-MI]; NCT03004703).


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Fármacos Cardiovasculares/uso terapêutico , Coração , Receptores de Interleucina-6/antagonistas & inibidores , Infarto do Miocárdio com Supradesnível do Segmento ST/tratamento farmacológico , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Técnicas de Imagem Cardíaca , Fármacos Cardiovasculares/administração & dosagem , Oclusão Coronária/complicações , Oclusão Coronária/diagnóstico por imagem , Oclusão Coronária/patologia , Vasos Coronários , Método Duplo-Cego , Feminino , Coração/diagnóstico por imagem , Coração/efeitos dos fármacos , Humanos , Infusões Intravenosas , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/diagnóstico por imagem , Miocárdio/patologia , Necrose/diagnóstico por imagem , Intervenção Coronária Percutânea , Infarto do Miocárdio com Supradesnível do Segmento ST/diagnóstico por imagem , Infarto do Miocárdio com Supradesnível do Segmento ST/patologia , Infarto do Miocárdio com Supradesnível do Segmento ST/terapia , Tempo para o Tratamento
19.
Lancet Respir Med ; 9(5): 511-521, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33676589

RESUMO

BACKGROUND: Global randomised controlled trials of the anti-IL-6 receptor antibody tocilizumab in patients admitted to hospital with COVID-19 have shown conflicting results but potential decreases in time to discharge and burden on intensive care. Tocilizumab reduced progression to mechanical ventilation and death in a trial population enriched for racial and ethnic minorities. We aimed to investigate whether tocilizumab treatment could prevent COVID-19 progression in the first multicentre randomised controlled trial of tocilizumab done entirely in a lower-middle-income country. METHODS: COVINTOC is an open-label, multicentre, randomised, controlled, phase 3 trial done at 12 public and private hospitals across India. Adults (aged ≥18 years) admitted to hospital with moderate to severe COVID-19 (Indian Ministry of Health grading) confirmed by positive SARS-CoV-2 PCR result were randomly assigned (1:1 block randomisation) to receive tocilizumab 6 mg/kg plus standard care (the tocilizumab group) or standard care alone (the standard care group). The primary endpoint was progression of COVID-19 (from moderate to severe or from severe to death) up to day 14 in the modified intention-to-treat population of all participants who had at least one post-baseline assessment for the primary endpoint. Safety was assessed in all randomly assigned patients. The trial is completed and registered with the Clinical Trials Registry India (CTRI/2020/05/025369). FINDINGS: 180 patients were recruited between May 30, 2020, and Aug 31, 2020, and randomly assigned to the tocilizumab group (n=90) or the standard care group (n=90). One patient randomly assigned to the standard care group inadvertently received tocilizumab at baseline and was included in the tocilizumab group for all analyses. One patient randomly assigned to the standard care group withdrew consent after the baseline visit and did not receive any study medication and was not included in the modified intention-to-treat population but was still included in safety analyses. 75 (82%) of 91 in the tocilizumab group and 68 (76%) of 89 in the standard care group completed 28 days of follow-up. Progression of COVID-19 up to day 14 occurred in eight (9%) of 91 patients in the tocilizumab group and 11 (13%) of 88 in the standard care group (difference -3·71 [95% CI -18·23 to 11·19]; p=0·42). 33 (36%) of 91 patients in the tocilizumab group and 22 (25%) of 89 patients in the standard care group had adverse events; 18 (20%) and 15 (17%) had serious adverse events. The most common adverse event was acute respiratory distress syndrome, reported in seven (8%) patients in each group. Grade 3 adverse events were reported in two (2%) patients in the tocilizumab group and five (6%) patients in the standard care group. There were no grade 4 adverse events. Serious adverse events were reported in 18 (20%) patients in the tocilizumab group and 15 (17%) in the standard care group; 13 (14%) and 15 (17%) patients died during the study. INTERPRETATION: Routine use of tocilizumab in patients admitted to hospital with moderate to severe COVID-19 is not supported. However, post-hoc evidence from this study suggests tocilizumab might still be effective in patients with severe COVID-19 and so should be investigated further in future studies. FUNDING: Medanta Institute of Education and Research, Roche India, Cipla India, and Action COVID-19 India.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Síndrome da Liberação de Citocina , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome do Desconforto Respiratório , SARS-CoV-2/isolamento & purificação , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/complicações , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/terapia , Cuidados Críticos/métodos , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Índia , Masculino , Pessoa de Meia-Idade , Mortalidade , Respiração Artificial/métodos , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento
20.
Lancet Respir Med ; 9(5): 522-532, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33676590

RESUMO

BACKGROUND: Elevated proinflammatory cytokines are associated with greater COVID-19 severity. We aimed to assess safety and efficacy of sarilumab, an interleukin-6 receptor inhibitor, in patients with severe (requiring supplemental oxygen by nasal cannula or face mask) or critical (requiring greater supplemental oxygen, mechanical ventilation, or extracorporeal support) COVID-19. METHODS: We did a 60-day, randomised, double-blind, placebo-controlled, multinational phase 3 trial at 45 hospitals in Argentina, Brazil, Canada, Chile, France, Germany, Israel, Italy, Japan, Russia, and Spain. We included adults (≥18 years) admitted to hospital with laboratory-confirmed SARS-CoV-2 infection and pneumonia, who required oxygen supplementation or intensive care. Patients were randomly assigned (2:2:1 with permuted blocks of five) to receive intravenous sarilumab 400 mg, sarilumab 200 mg, or placebo. Patients, care providers, outcome assessors, and investigators remained masked to assigned intervention throughout the course of the study. The primary endpoint was time to clinical improvement of two or more points (seven point scale ranging from 1 [death] to 7 [discharged from hospital]) in the modified intention-to-treat population. The key secondary endpoint was proportion of patients alive at day 29. Safety outcomes included adverse events and laboratory assessments. This study is registered with ClinicalTrials.gov, NCT04327388; EudraCT, 2020-001162-12; and WHO, U1111-1249-6021. FINDINGS: Between March 28 and July 3, 2020, of 431 patients who were screened, 420 patients were randomly assigned and 416 received placebo (n=84 [20%]), sarilumab 200 mg (n=159 [38%]), or sarilumab 400 mg (n=173 [42%]). At day 29, no significant differences were seen in median time to an improvement of two or more points between placebo (12·0 days [95% CI 9·0 to 15·0]) and sarilumab 200 mg (10·0 days [9·0 to 12·0]; hazard ratio [HR] 1·03 [95% CI 0·75 to 1·40]; log-rank p=0·96) or sarilumab 400 mg (10·0 days [9·0 to 13·0]; HR 1·14 [95% CI 0·84 to 1·54]; log-rank p=0·34), or in proportions of patients alive (77 [92%] of 84 patients in the placebo group; 143 [90%] of 159 patients in the sarilumab 200 mg group; difference -1·7 [-9·3 to 5·8]; p=0·63 vs placebo; and 159 [92%] of 173 patients in the sarilumab 400 mg group; difference 0·2 [-6·9 to 7·4]; p=0·85 vs placebo). At day 29, there were numerical, non-significant survival differences between sarilumab 400 mg (88%) and placebo (79%; difference +8·9% [95% CI -7·7 to 25·5]; p=0·25) for patients who had critical disease. No unexpected safety signals were seen. The rates of treatment-emergent adverse events were 65% (55 of 84) in the placebo group, 65% (103 of 159) in the sarilumab 200 mg group, and 70% (121 of 173) in the sarilumab 400 mg group, and of those leading to death 11% (nine of 84) were in the placebo group, 11% (17 of 159) were in the sarilumab 200 mg group, and 10% (18 of 173) were in the sarilumab 400 mg group. INTERPRETATION: This trial did not show efficacy of sarilumab in patients admitted to hospital with COVID-19 and receiving supplemental oxygen. Adequately powered trials of targeted immunomodulatory therapies assessing survival as a primary endpoint are suggested in patients with critical COVID-19. FUNDING: Sanofi and Regeneron Pharmaceuticals.


Assuntos
Anticorpos Monoclonais Humanizados , COVID-19 , Síndrome da Liberação de Citocina , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome do Desconforto Respiratório , SARS-CoV-2/isolamento & purificação , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/efeitos adversos , COVID-19/complicações , COVID-19/imunologia , COVID-19/mortalidade , COVID-19/terapia , Cuidados Críticos/métodos , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/etiologia , Síndrome da Liberação de Citocina/imunologia , Relação Dose-Resposta a Droga , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Fatores Imunológicos/administração & dosagem , Fatores Imunológicos/efeitos adversos , Cooperação Internacional , Masculino , Pessoa de Meia-Idade , Mortalidade , Síndrome do Desconforto Respiratório/diagnóstico , Síndrome do Desconforto Respiratório/etiologia , Índice de Gravidade de Doença , Resultado do Tratamento
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