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1.
BMJ Open ; 10(11): e039951, 2020 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-33191263

RESUMO

INTRODUCTION: About 25% of patients with COVID-19 develop acute respiratory distress syndrome (ARDS) associated with a high release of pro-inflammatory cytokines such as interleukin-6 (IL-6). The aim of the SARICOR study is to demonstrate that early administration of sarilumab (an IL-6 receptor inhibitor) in hospitalised patients with COVID-19, pulmonary infiltrates and a high IL-6 or D-dimer serum level could reduce the progression of ARDS requiring high-flow nasal oxygen or mechanical ventilation (non-invasive or invasive). METHODS AND ANALYSIS: Phase II, open-label, randomised, multicentre, controlled clinical trial to study the efficacy and safety of the administration of two doses of sarilumab (200 and 400 mg) plus best available therapy (BAT) in hospitalised adults with COVID-19 presenting cytokine release syndrome. This strategy will be compared with a BAT control group. The efficacy and safety will be monitored up to 28 days postadministration. A total of 120 patients will be recruited (40 patients in each arm). ETHICS AND DISSEMINATION: The clinical trial has been approved by the Research Ethics Committee of the coordinating centre and authorised by the Spanish Agency of Medicines and Medical Products. If the hypothesis is verified, the dissemination of the results could change clinical practice by increasing early administration of sarilumab in adult patients with COVID-19 presenting cytokine release syndrome, thus reducing intensive care unit admissions. TRIAL REGISTRATION NUMBER: NCT04357860.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Adolescente , Adulto , Idoso , Betacoronavirus , Ensaios Clínicos Fase II como Assunto , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Interleucina-6/imunologia , Masculino , Pessoa de Meia-Idade , Estudos Multicêntricos como Assunto , Pandemias , Pneumonia Viral/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/imunologia , Adulto Jovem
2.
J Renin Angiotensin Aldosterone Syst ; 21(4): 1470320320972018, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33169644

RESUMO

In the wake of the COVID-19 pandemic it has become clear that there is a need for therapies that are capable of reducing damage caused to patients from infections. Infections that induce Acute Respiratory Distress Syndrome (ARDS) are especially devastating because lung damage is so critical and difficult to manage. Angiotensin (1-7) [A(1-7)] has already been shown to protect pulmonary health and architecture in various models of disease. There is also evidence that A(1-7) can modulate immune function and protect various organs (lung, kidney, and heart) from oxidative damage and inflammation. Here we focus on making a case for the development of novel therapies that target the protective arm of the Renin Angiotensin System (RAS).


Assuntos
Angiotensina I/uso terapêutico , Betacoronavirus/fisiologia , Infecções por Coronavirus/complicações , Fragmentos de Peptídeos/uso terapêutico , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/virologia , Angiotensina I/fisiologia , Animais , Infecções por Coronavirus/mortalidade , Humanos , Pandemias , Fragmentos de Peptídeos/fisiologia , Peptidil Dipeptidase A/metabolismo , Pneumonia Viral/mortalidade , Sistema Renina-Angiotensina/efeitos dos fármacos , Sistema Renina-Angiotensina/fisiologia
3.
Biochemistry (Mosc) ; 85(7): 833-837, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-33040727

RESUMO

Nrf2 is a key transcription factor responsible for antioxidant defense in many tissues and cells, including alveolar epithelium, endothelium, and macrophages. Furthermore, Nrf2 functions as a transcriptional repressor that inhibits expression of the inflammatory cytokines in macrophages. Critically ill patients with COVID-19 infection often present signs of high oxidative stress and systemic inflammation - the leading causes of mortality. This article suggests rationale for the use of Nrf2 inducers to prevent development of an excessive inflammatory response in COVID-19 patients.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/metabolismo , Citocinas/antagonistas & inibidores , Citocinas/metabolismo , Terapia de Alvo Molecular/métodos , Fator 2 Relacionado a NF-E2/metabolismo , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/metabolismo , Animais , Antioxidantes/farmacologia , Antioxidantes/uso terapêutico , Catequina/análogos & derivados , Catequina/farmacologia , Catequina/uso terapêutico , Infecções por Coronavirus/virologia , Fumarato de Dimetilo/farmacologia , Fumarato de Dimetilo/uso terapêutico , Feminino , Humanos , Imunossupressores/farmacologia , Imunossupressores/uso terapêutico , Inflamação/metabolismo , Isotiocianatos/farmacologia , Isotiocianatos/uso terapêutico , Masculino , Camundongos , Estresse Oxidativo/efeitos dos fármacos , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/metabolismo , Síndrome do Desconforto Respiratório do Adulto/virologia , Resveratrol/farmacologia , Resveratrol/uso terapêutico , Transdução de Sinais/efeitos dos fármacos , Tiossulfatos/farmacologia , Tiossulfatos/uso terapêutico
4.
Front Immunol ; 11: 2167, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33013911

RESUMO

The inflammatory response to and the subsequent development of Adult Respiratory Distress Syndrome (ARDS) is considered to underpin COVID-19 pathogenesis. With a developing world catastrophe, we need to examine our known therapeutic stocks, to assess suitability for prevention and/or treatment of this pro-inflammatory virus. Analyzing commonly available and inexpensive immunomodulatory and anti-inflammatory medications to assess their possible effectiveness in improving the host response to COVID-19, this paper recommends the following: (1) optimize current health-cease (reduce) smoking, ensure adequate hypertension and diabetes control, continue exercising; (2) start on an HMG CoA reductase inhibitor "statin" for its immunomodulatory and anti-inflammatory properties, which may reduce the mortality associated with ARDS; and (3) consider using Diclofenac (or other COX-2 inhibition medications) for its anti-inflammatory and virus toxicity properties. For purposes of effectiveness, this needs to be in the early course of the disease (post infection and/or symptom presentation) and given in a high dose. The downsides to these recommended interventions are considered manageable at this stage of the pandemic.


Assuntos
Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Corticosteroides/uso terapêutico , Animais , Anti-Inflamatórios não Esteroides/efeitos adversos , Anti-Inflamatórios não Esteroides/uso terapêutico , Antivirais/efeitos adversos , Antivirais/uso terapêutico , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Inibidores de Ciclo-Oxigenase 2/efeitos adversos , Diclofenaco/efeitos adversos , Diclofenaco/uso terapêutico , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Humanos , Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Pandemias/prevenção & controle , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/prevenção & controle , Síndrome do Desconforto Respiratório do Adulto/virologia , Internalização do Vírus/efeitos dos fármacos
5.
Rev Bras Ter Intensiva ; 32(3): 354-362, 2020.
Artigo em Português, Inglês | MEDLINE | ID: mdl-33053024

RESUMO

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


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Adulto , Infecções por Coronavirus/fisiopatologia , Humanos , Unidades de Terapia Intensiva , Escores de Disfunção Orgânica , Pandemias , Pneumonia Viral/fisiopatologia , Estudos Prospectivos , Respiração Artificial , Síndrome do Desconforto Respiratório do Adulto/virologia , Fatores de Tempo
6.
BMC Infect Dis ; 20(1): 794, 2020 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-33109122

RESUMO

BACKGROUND: Pulmonary hemorrhage is an important complication of leptospirosis. Once acute respiratory distress syndrome (ARDS) occurs as a secondary condition, treatment is extremely difficult and the mortality rate is very high. CASE PRESENTATION: The patient was a 49-year-old. He was admitted to the hospital because he had experienced a fever and cough for 4 days. Hemorrhage, respiratory failure, ARDS and other symptoms appeared soon after admission. Due to severe pulmonary hemorrhage secondary to ARDS, mechanical ventilation was performed through tracheal intubation. During intubation, the patient suffered cardiac arrest, and the patient's condition worsened. He was confirmed to have leptospirosis through second-generation sequencing of the alveolar lavage fluid. Finally, we successfully treated the patient with penicillin as an anti-infective medication and venous-venous extracorporeal membrane oxygenation (v-vECMO). To the best of our knowledge, this report is the first to describe the successful application of ECMO in mainland China. CONCLUSIONS: Leptospirosis can induce serious but transient ARDS with a better prognosis than other causes of ARDS. Our patient was successfully treated with V-vECMO.


Assuntos
Oxigenação por Membrana Extracorpórea , Hemorragia/etiologia , Hemorragia/cirurgia , Leptospira/genética , Leptospirose/complicações , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/cirurgia , Antibacterianos/uso terapêutico , Líquido da Lavagem Broncoalveolar/microbiologia , China , Humanos , Leptospira/isolamento & purificação , Leptospirose/tratamento farmacológico , Leptospirose/microbiologia , Masculino , Pessoa de Meia-Idade , Penicilinas/uso terapêutico , Prognóstico , Respiração Artificial/efeitos adversos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/cirurgia , Resultado do Tratamento
7.
Front Immunol ; 11: 588724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33117402

RESUMO

SARS-CoV-2 infection is a new threat to global public health in the 21st century (2020), which has now rapidly spread around the globe causing severe pneumonia often linked to Acute Respiratory Distress Syndrome (ARDS) and hyperinflammatory syndrome. SARS-CoV-2 is highly contagious through saliva droplets. The structural analysis suggests that the virus enters human cells through the ligation of the spike protein to angiotensin-converting enzyme 2 (ACE2). The progression of Covid-19 has been divided into three main stages: stage I-viral response, stage II-pulmonary phase, and stage III-hyperinflammation phase. Once the patients enter stage III, it will likely need ventilation and it becomes difficult to manage. Thus, it will be of paramount importance to find therapies to prevent or slow down the progression of the disease toward stage III. The key event leading to hyperinflammation seems to be the activation of Th-17 immunity response and Cytokine storm. B2-adrenergic receptors (B2ARs) are expressed on airways and on all the immune cells such as macrophages, dendritic cells, B and T lymphocytes. Blocking (B2AR) has been proven, also in clinical settings, to reduce Th-17 response and negatively modulate inflammatory cytokines including IL-6 while increasing IFNγ. Non-selective beta-blockers are currently used to treat several diseases and have been proven to reduce stress-induced inflammation and reduce anxiety. For these reasons, we speculate that targeting B2AR in the early phase of Covid-19 might be beneficial to prevent hyperinflammation.


Assuntos
Antagonistas de Receptores Adrenérgicos beta 2/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/patologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/patologia , Receptores Adrenérgicos beta 2/efeitos dos fármacos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Betacoronavirus/efeitos dos fármacos , Síndrome da Liberação de Citocina/patologia , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/patologia , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pandemias , Síndrome do Desconforto Respiratório do Adulto/patologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Células Th17/imunologia
8.
BMC Infect Dis ; 20(1): 658, 2020 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-32912165

RESUMO

BACKGROUND: Stenotrophomonas maltophilia-induced pulmonary haemorrhage is considered a fatal infection among haematological patients. The outcome can be explained by the patients' immunity status and late diagnosis and treatment. CASE PRESENTATION: We present the rare case of successful outcome in a 61-year-old female who developed alveolar haemorrhage and acute respiratory distress syndrome 8 days after a chemotherapy session for her acute lymphoblastic leukaemia, in the context of secondary bone marrow aplasia. Stenotrophomonas maltophilia was isolated in sputum culture. The patient benefitted from early empirical treatment with colistin followed by trimethoprim/sulfamethoxazole, according to the antibiogram. Despite a severe initial clinical presentation in need of mechanical ventilation, neuromuscular blocking agents infusion, and ventilation in prone position, the patient had a favourable outcome and was discharged from intensive care after 26 days. CONCLUSIONS: Stenotrophomonas maltophilia severe pneumonia complicated with pulmonary haemorrhage is not always fatal in haematological patients. Empirical treatment of multidrug-resistant Stenotrophomonas maltophilia in an immunocompromised haematological patient presenting with hemoptysis should be taken into consideration.


Assuntos
Antibacterianos/uso terapêutico , Colistina/uso terapêutico , Infecções por Bactérias Gram-Negativas/tratamento farmacológico , Hemorragia/tratamento farmacológico , Pneumonia Bacteriana/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Stenotrophomonas maltophilia/isolamento & purificação , Combinação Trimetoprima e Sulfametoxazol/uso terapêutico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/complicações , Feminino , Infecções por Bactérias Gram-Negativas/etiologia , Hemorragia/etiologia , Humanos , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Pneumonia Bacteriana/etiologia , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Alvéolos Pulmonares/patologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Síndrome do Desconforto Respiratório do Adulto/microbiologia , Escarro/microbiologia , Resultado do Tratamento
9.
Front Immunol ; 11: 1942, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983123

RESUMO

Severe cases of COVID-19 present with serious lung inflammation, acute respiratory distress syndrome and multiorgan damage. SARS-CoV-2 infection is associated with high cytokine levels, including interleukin-6 and certain subsets of immune cells, in particular, NK, distinguished according to the cell surface density of CD56. Cytokine levels are inversely correlated with lymphocyte count, therefore cytokine release syndrome may be an impediment to the adaptive immune response against SARS-CoV-2 infection. Canakinumab, a monoclonal antibody targeting IL-1ß is under investigation for the treatment of severe SAR-CoV-2 infection. An 85 year old male presenting in our hospital with COVID-19, whose condition was complicated by acute respiratory distress syndrome and cardiac and renal failure (with oliguria) after 25 days of hospitalization, was intubated and received canakinumab for compassionate use. On the next day, diuresis recovered and conditions improved: high IL-6 levels and NK cells expressing CD56 bright (associated with cytokine relase) were significantly reduced giving rise to NK CD56 dim . Patient died on day 58 with pulmonary bacterial superinfection and persistent SARS-CoV-2 positivity. In conclusion, canakinumab rescued a high risk, very elderly patient, from multiorgan damage complicating COVID-19. It may represent an useful treatment in severe cases.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Antígeno CD56/metabolismo , Infecções por Coronavirus/virologia , Evolução Fatal , Humanos , Interleucina-1beta/antagonistas & inibidores , Interleucina-6/sangue , Células Matadoras Naturais/imunologia , Masculino , Pandemias , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Índice de Gravidade de Doença
10.
Front Immunol ; 11: 2132, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32983172

RESUMO

In December 2019, a novel coronavirus, COVID-19, was discovered to be the causal agent of a severe respiratory infection named SARS-CoV-2, and it has since been recognized worldwide as a pandemic. There are still numerous doubts concerning its pathogenesis and particularly the underlying causes of the various clinical courses, ranging from severe manifestations to asymptomatic forms, including acute respiratory distress syndrome. The major factor responsible for acute respiratory distress syndrome is the so-called "cytokine storm," which is an aberrant response from the host immune system that induces an exaggerated release of proinflammatory cytokines/chemokines. In this review, we will discuss the role of cytokine storm in COVID-19 and potential treatments with which counteract this aberrant response, which may be valuable in the clinical translation.


Assuntos
Betacoronavirus/imunologia , Quimiocinas/sangue , Quimiocinas/imunologia , Infecções por Coronavirus/imunologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Animais , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Glucocorticoides/uso terapêutico , Humanos , Hidroxicloroquina/uso terapêutico , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Pandemias , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Receptores de Interleucina-6/antagonistas & inibidores , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico
11.
JAMA ; 324(13): 1307-1316, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-32876695

RESUMO

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). Main Outcomes and Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions and Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.


Assuntos
Anti-Inflamatórios/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Administração Intravenosa , Idoso , Anti-Inflamatórios/efeitos adversos , Betacoronavirus , Brasil , Infecções Relacionadas a Cateter/epidemiologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/terapia , Dexametasona/efeitos adversos , Término Precoce de Ensaios Clínicos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/mortalidade , Pneumonia Viral/terapia , Síndrome do Desconforto Respiratório do Adulto/etiologia
12.
Clin Immunol ; 220: 108598, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32961333

RESUMO

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for countering the detrimental consequences of SARS-CoV-2 infection. Whether blockade of terminal complement effectors (C5, C5a, or C5aR1) may elicit similar outcomes to upstream intervention at the level of C3 remains debated. Here we compare the efficacy of the C5-targeting monoclonal antibody eculizumab with that of the compstatin-based C3-targeted drug candidate AMY-101 in small independent cohorts of severe COVID-19 patients. Our exploratory study indicates that therapeutic complement inhibition abrogates COVID-19 hyper-inflammation. Both C3 and C5 inhibitors elicit a robust anti-inflammatory response, reflected by a steep decline in C-reactive protein and IL-6 levels, marked lung function improvement, and resolution of SARS-CoV-2-associated acute respiratory distress syndrome (ARDS). C3 inhibition afforded broader therapeutic control in COVID-19 patients by attenuating both C3a and sC5b-9 generation and preventing FB consumption. This broader inhibitory profile was associated with a more robust decline of neutrophil counts, attenuated neutrophil extracellular trap (NET) release, faster serum LDH decline, and more prominent lymphocyte recovery. These early clinical results offer important insights into the differential mechanistic basis and underlying biology of C3 and C5 inhibition in COVID-19 and point to a broader pathogenic involvement of C3-mediated pathways in thromboinflammation. They also support the evaluation of these complement-targeting agents as COVID-19 therapeutics in large prospective trials.


Assuntos
Betacoronavirus/patogenicidade , Complemento C3/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Fatores Imunológicos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Estudos de Coortes , Ativação do Complemento/efeitos dos fármacos , Complemento C3/genética , Complemento C3/imunologia , Complemento C5/genética , Complemento C5/imunologia , Infecções por Coronavirus/complicações , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/virologia , Armadilhas Extracelulares/efeitos dos fármacos , Feminino , Expressão Gênica , Humanos , Interleucina-6/metabolismo , Masculino , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/imunologia , Neutrófilos/virologia , Pandemias , Peptídeos Cíclicos/uso terapêutico , Pneumonia Viral/complicações , Pneumonia Viral/imunologia , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/complicações , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Índice de Gravidade de Doença
13.
In Vivo ; 34(5): 3027-3028, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32871847
14.
Int J Mol Sci ; 21(17)2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32872332

RESUMO

Acute Respiratory Distress Syndrome (ARDS) causes up to 40% mortality in humans and is difficult to treat. ARDS is also one of the major triggers of mortality associated with coronavirus-induced disease (COVID-19). We used a mouse model of ARDS induced by Staphylococcal enterotoxin B (SEB), which triggers 100% mortality, to investigate the mechanisms through which Δ9-tetrahydrocannabinol (THC) attenuates ARDS. SEB was used to trigger ARDS in C3H mice. These mice were treated with THC and analyzed for survival, ARDS, cytokine storm, and metabolome. Additionally, cells isolated from the lungs were used to perform single-cell RNA sequencing and transcriptome analysis. A database analysis of human COVID-19 patients was also performed to compare the signaling pathways with SEB-mediated ARDS. The treatment of SEB-mediated ARDS mice with THC led to a 100% survival, decreased lung inflammation, and the suppression of cytokine storm. This was associated with immune cell apoptosis involving the mitochondrial pathway, as suggested by single-cell RNA sequencing. A transcriptomic analysis of immune cells from the lungs revealed an increase in mitochondrial respiratory chain enzymes following THC treatment. In addition, metabolomic analysis revealed elevated serum concentrations of amino acids, lysine, n-acetyl methionine, carnitine, and propionyl L-carnitine in THC-treated mice. THC caused the downregulation of miR-185, which correlated with an increase in the pro-apoptotic gene targets. Interestingly, the gene expression datasets from the bronchoalveolar lavage fluid (BALF) of human COVID-19 patients showed some similarities between cytokine and apoptotic genes with SEB-induced ARDS. Collectively, this study suggests that the activation of cannabinoid receptors may serve as a therapeutic modality to treat ARDS associated with COVID-19.


Assuntos
Apoptose/efeitos dos fármacos , Betacoronavirus/fisiologia , Agonistas de Receptores de Canabinoides/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Citocinas/imunologia , Dronabinol/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Idoso , Animais , Líquido da Lavagem Broncoalveolar/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Enterotoxinas/efeitos adversos , Feminino , Humanos , Pulmão/imunologia , Pulmão/virologia , Masculino , Camundongos , Camundongos Endogâmicos C3H , MicroRNAs/genética , Pessoa de Meia-Idade , Pandemias , Pneumonia/tratamento farmacológico , Pneumonia/virologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Síndrome do Desconforto Respiratório do Adulto/mortalidade , Síndrome do Desconforto Respiratório do Adulto/virologia , Transdução de Sinais/efeitos dos fármacos
15.
Blood Adv ; 4(18): 4358-4361, 2020 09 22.
Artigo em Inglês | MEDLINE | ID: mdl-32926122
17.
Trials ; 21(1): 743, 2020 Aug 26.
Artigo em Inglês | MEDLINE | ID: mdl-32843098

RESUMO

OBJECTIVES: The aim of this study is to explore the effectiveness and safety of high dose dexamethasone treatment for Acute Respiratory Distress Syndrome secondary to SARS-Cov-2 pneumonia. TRIAL DESIGN: Multicentre, randomized clinical trial, controlled, open label, parallel group, to evaluate the effectiveness and safety of high dose dexamethasone in adult patients with confirmed COVID-19, with Acute Respiratory Distress Syndrome. PARTICIPANTS: We will include patients with SARS-Cov-2 pneumonia who develop acute respiratory distress syndrome, in several intensive care units (ICU) in Buenos Aires, Argentina (CEMIC, Clinica Bazterrica, Sanatorio Sagrado Corazon) Inclusion criteria: Men and women, age ≥ 18 years old. Confirmed diagnosis of SARS-CoV-2 infection, by RT-PCR. Diagnosis of Acute Respiratory Distress Syndrome (hypoxemic respiratory failure not explained by cardiac disease + PaO2/FiO2 ratio < 300 with a Positive End-Expiratory Pressure ≥ 5 cm H2O + bilateral pulmonary infiltrates) Length of mechanical ventilation of at least 72 hours Informed consent (next of kin / legal guardian) Exclusion criteria: Pregnant or breast-feeding women. Terminal disease (advanced cancer; under palliative care; cardiovascular, respiratory, or renal disease with a life expectancy less ≤ 1 year). Therapeutic limitation (advance directives or do not resuscitate order) Severe immunosuppression (HIV infection, long-term use of immunosuppressive agents, active cancer). Patients under chronic treatment with glucocorticoids for other diseases (≥ 8 mg prednisone, or equivalent) Participation in another randomized clinical trial. INTERVENTION AND COMPARATOR: Eligible patients will be randomized to receive standard ICU patient care (group 1) or standard ICU patient care plus high dose dexamethasone (group 2). Group 1: dexamethasone up to 6 mg/24 hours for up to 10 days + ventilatory, hemodynamic, nutritional, and antimicrobial support according to international guidelines. Group 2: dexamethasone 16 mg/24 hours for 5 days followed by dexamethasone 8 mg/24 hours for 5 days + ventilatory, hemodynamic, nutritional, and antimicrobial support according to international guidelines. MAIN OUTCOME: The main result is ventilator-free days at 28 days (Days without ventilator support in the first 28 days following randomization). Secondary outcomes are 28-days and 90-days mortality, frequency of nosocomial infections in the first 28 days after randomization, Sequential Organ Failure Assessment (SOFA) score variation and prone position in the first 10-days, viral shedding 28-days after randomization, and delirium and muscle weakness at ICU discharge. RANDOMISATION: Treatment will be assigned according to site stratified randomization by permuted random blocks sequence 1:1 generated with a table in R language concealed in a randomization tool in REDCap (Research Electronic Data CAPture) platform. BLINDING (MASKING): This is an open trial, so no masking of treatment assignment will be used. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): Assuming a 3 days difference in ventilator-free days between treatment groups, with a mean of 9 days, and a standard deviation of 9 days; the necessary sample size would be 284 subjects (142 per group), with a power of 80% and a two-tailed alpha error of 0.05. TRIAL STATUS: The protocol with code 1264, version 3.0 on date: May 13, 2020 is approved by the local Ethics Committee. The trial is in the recruitment phase. Recruitment began May 22, 2020 and is anticipated to be complete by the end of December 2021. TRIAL REGISTRATION: The trial was registered under the title "Dexamethasone for COVID-19 Related ARDS: a Multicenter, Randomized Clinical Trial" with ClinicalTrials number NCT04395105, https://clinicaltrials.gov/ct2/show/NCT04395105 , registered on 20 May 2020. FULL PROTOCOL: The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Dexametasona/administração & dosagem , Glucocorticoides/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Argentina , Betacoronavirus , Infecções por Coronavirus/complicações , Infecção Hospitalar/epidemiologia , Delírio/epidemiologia , Humanos , Mortalidade , Escores de Disfunção Orgânica , Pandemias , Posicionamento do Paciente , Pneumonia Viral/complicações , Decúbito Ventral , Respiração Artificial/estatística & dados numéricos , Síndrome do Desconforto Respiratório do Adulto/etiologia , Eliminação de Partículas Virais
18.
Trials ; 21(1): 717, 2020 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-32799933

RESUMO

BACKGROUND: There are no specific generally accepted therapies for the coronavirus disease 2019 (COVID-19). The full spectrum of COVID-19 ranges from asymptomatic disease to mild respiratory tract illness to severe pneumonia, acute respiratory distress syndrome (ARDS), multisystem organ failure, and death. The efficacy of corticosteroids in viral ARDS remains unknown. We postulated that adjunctive treatment of established ARDS caused by COVID-19 with intravenous dexamethasone might change the pulmonary and systemic inflammatory response and thereby reduce morbidity, leading to a decrease in duration of mechanical ventilation and in mortality. METHODS/DESIGN: This is a multicenter, randomized, controlled, parallel, open-label, superiority trial testing dexamethasone in 200 mechanically ventilated adult patients with established moderate-to-severe ARDS caused by confirmed SARS-CoV-2 infection. Established ARDS is defined as maintaining a PaO2/FiO2 ≤ 200 mmHg on PEEP ≥ 10 cmH2O and FiO2 ≥ 0.5 after 12 ± 3 h of routine intensive care. Eligible patients will be randomly assigned to receive either dexamethasone plus standard intensive care or standard intensive care alone. Patients in the dexamethasone group will receive an intravenous dose of 20 mg once daily from day 1 to day 5, followed by 10 mg once daily from day 6 to day 10. The primary outcome is 60-day mortality. The secondary outcome is the number of ventilator-free days, defined as days alive and free from mechanical ventilation at day 28 after randomization. All analyses will be done according to the intention-to-treat principle. DISCUSSION: This study will assess the role of dexamethasone in patients with established moderate-to-severe ARDS caused by SARS-CoV-2. TRIAL REGISTRATION: ClinicalTrials.gov NCT04325061 . Registered on 25 March 2020 as DEXA-COVID19.


Assuntos
Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Dexametasona/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Adulto , Dexametasona/efeitos adversos , Humanos , Avaliação de Resultados em Cuidados de Saúde , Pandemias , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Tamanho da Amostra
19.
Biomolecules ; 10(8)2020 08 11.
Artigo em Inglês | MEDLINE | ID: mdl-32796765

RESUMO

Recently, the stabilization of the endothelium has been explicitly identified as a therapeutic goal in coronavirus disease 2019 (COVID-19). Adrecizumab (HAM8101) is a first-in-class humanized monoclonal anti-Adrenomedullin (anti-ADM) antibody, targeting the sepsis- and inflammation-based vascular and capillary leakage. Within a "treatment on a named-patient basis" approach, Adrecizumab was administered to eight extreme-critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). The patients received a single dose of Adrecizumab, which was administered between 1 and 3 days after the initiation of mechanical ventilation. The SOFA (median 12.5) and SAPS-II (median 39) scores clearly documented the population at highest risk. Moreover, six of the patients suffered from acute renal failure, of whom five needed renal replacement therapy. The length of follow-up ranged between 13 and 27 days. Following the Adrecizumab administration, one patient in the low-dose group died at day 4 due to fulminant pulmonary embolism, while four were in stable condition, and three were discharged from the intensive care unit (ICU). Within 12 days, the SOFA score, as well as the disease severity score (range 0-16, mirroring critical resources in the ICU, with higher scores indicating more severe illness), decreased in five out of the seven surviving patients (in all high-dose patients). The PaO2/FiO2 increased within 12 days, while the inflammatory parameters C-reactive protein, procalcitonin, and interleukin-6 decreased. Importantly, the mortality was lower than expected and calculated by the SOFA score. In conclusion, in this preliminary uncontrolled case series of eight shock patients with life-threatening COVID-19 and ARDS, the administration of Adrecizumab was followed by a favorable outcome. Although the non-controlled design and the small sample size preclude any definitive statement about the potential efficacy of Adrecizumab in critically ill COVID-19 patients, the results of this case series are encouraging.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Infecções por Coronavirus/complicações , Endotélio Vascular/efeitos dos fármacos , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Sepse/tratamento farmacológico , Adulto , Idoso , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/farmacologia , Infecções por Coronavirus/patologia , Estado Terminal , Endotélio Vascular/patologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/patologia , Síndrome do Desconforto Respiratório do Adulto/etiologia , Sepse/etiologia
20.
Mult Scler Relat Disord ; 45: 102437, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32763844

RESUMO

We encourage studies on the effectiveness of multiple sclerosis drugs for the treatment of ARDS in COVID-19 infection. These drugs, through the inhibition of the RhoA/actin-dependent expression of virus receptors in the macrophages and macrophage recruitment to the lungs, have the potential to inhibit cytokine storm of lung macrophages, reduce or eliminate ARDS and improve the outcome of COVID-19 infection.


Assuntos
Infecções por Coronavirus/tratamento farmacológico , Inibidores Enzimáticos/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Síndrome do Desconforto Respiratório do Adulto/tratamento farmacológico , Proteína rhoA de Ligação ao GTP/antagonistas & inibidores , Azetidinas/uso terapêutico , Compostos de Benzil/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/complicações , Cloridrato de Fingolimode/uso terapêutico , Humanos , Esclerose Múltipla/tratamento farmacológico , Pandemias , Pneumonia Viral/complicações , Síndrome do Desconforto Respiratório do Adulto/virologia
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