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3.
Clin Immunol ; 219: 108555, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32771488

RESUMO

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19.


Assuntos
Lesão Renal Aguda/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Betacoronavirus/patogenicidade , Inativadores do Complemento/uso terapêutico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Síndrome Respiratória Aguda Grave/imunologia , Lesão Renal Aguda/complicações , Lesão Renal Aguda/tratamento farmacológico , Lesão Renal Aguda/virologia , Adulto , Betacoronavirus/imunologia , Biomarcadores/metabolismo , Ativação do Complemento/efeitos dos fármacos , Complemento C4b/antagonistas & inibidores , Complemento C5/antagonistas & inibidores , Complexo de Ataque à Membrana do Sistema Complemento/antagonistas & inibidores , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Feminino , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Humanos , Imunidade Humoral/efeitos dos fármacos , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/imunologia , Pessoa de Meia-Idade , Neutrófilos/imunologia , Neutrófilos/patologia , Pandemias , Fragmentos de Peptídeos/antagonistas & inibidores , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Síndrome Respiratória Aguda Grave/complicações , Síndrome Respiratória Aguda Grave/tratamento farmacológico , Síndrome Respiratória Aguda Grave/virologia
4.
Appl Microbiol Biotechnol ; 104(18): 7777-7785, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32780290

RESUMO

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a novel ß-coronavirus, is the main pathogenic agent of the rapidly spreading pneumonia called coronavirus disease 2019 (COVID-19). SARS-CoV-2 infects much more people, especially the elder population, around the world than other coronavirus, such as SARS-CoV and MERS-CoV, which is challenging current global public health system. Beyond the pathogenesis of SARS-CoV-2, microbial coinfection plays an important role in the occurrence and development of SARS-CoV-2 infection by raising the difficulties of diagnosis, treatment, prognosis of COVID-19, and even increasing the disease symptom and mortality. We summarize the coinfection of virus, bacteria and fungi with SARS-CoV-2, their effects on COVID-19, the reasons of coinfection, and the diagnosis to emphasize the importance of microbial coinfection in COVID-19. KEY POINTS: • Microbial coinfection is a nonnegligible factor in COVID-19. • Microbial coinfection exacerbates the processes of the occurrence, development and prognosis of COVID-19, and the difficulties of clinical diagnosis and treatment. • Different virus, bacteria, and fungi contributed to the coinfection with SARS-CoV-2.


Assuntos
Infecções Bacterianas/epidemiologia , Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/epidemiologia , Linfopenia/epidemiologia , Micoses/epidemiologia , Pandemias , Pneumonia Viral/epidemiologia , Viroses/epidemiologia , Antibacterianos/uso terapêutico , Antivirais/uso terapêutico , Infecções Bacterianas/tratamento farmacológico , Infecções Bacterianas/microbiologia , Infecções Bacterianas/virologia , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Coinfecção , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/microbiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/biossíntese , Progressão da Doença , Interações Hospedeiro-Patógeno/imunologia , Humanos , Imunidade Inata/efeitos dos fármacos , Linfócitos/microbiologia , Linfócitos/virologia , Linfopenia/tratamento farmacológico , Linfopenia/microbiologia , Linfopenia/virologia , Micoses/tratamento farmacológico , Micoses/microbiologia , Micoses/virologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Viroses/tratamento farmacológico , Viroses/microbiologia , Viroses/virologia
5.
Adv Biol Regul ; 77: 100735, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32773098

RESUMO

The novel Corona virus infection (Covid-19) first identified in China in December 2019 has rapidly progressed in pandemic leading to significant mortality and unprecedented challenge for healthcare systems. Although the clinical spectrum of Covid-19 is variable, acute respiratory failure and systemic coagulopathy are common in severe Covid-19 patients. Lung is an important target of the SARS-CoV-2 virus causing eventually acute respiratory distress syndrome associated to a thromboinflammatory state. The cytokinic storm, thromboinflammation and pulmonary tropism are the bedrock of tissue lesions responsible for acute respiratory failure and for prolonged infection that may lead to multiple organ failure and death. The thrombogenicity of this infectious disease is illustrated by the high frequency of thromboembolic events observed even in Covid-19 patients treated with anticoagulation. Increased D-Dimers, a biomarker reflecting activation of hemostasis and fibrinolysis, and low platelet count (thrombocytopenia) are associated with higher mortality in Covid-19 patients. In this review, we will summarize our current knowledge on the thromboembolic manifestations, the disturbed hemostatic parameters, and the thromboinflammatory conditions associated to Covid-19 and we will discuss the modalities of anticoagulant treatment or other potential antithrombotic options.


Assuntos
Anticoagulantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/complicações , Coagulação Intravascular Disseminada/complicações , Pneumonia Viral/complicações , Embolia Pulmonar/complicações , Insuficiência Respiratória/complicações , Doença Aguda , Biomarcadores/sangue , Plaquetas/efeitos dos fármacos , Plaquetas/patologia , Plaquetas/virologia , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/diagnóstico , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/diagnóstico , Coagulação Intravascular Disseminada/tratamento farmacológico , Coagulação Intravascular Disseminada/virologia , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Heparina/uso terapêutico , Interações Hospedeiro-Patógeno , Humanos , Pulmão/irrigação sanguínea , Pulmão/efeitos dos fármacos , Pulmão/patologia , Pulmão/virologia , Pandemias , Pneumonia Viral/diagnóstico , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/virologia , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamento farmacológico , Embolia Pulmonar/virologia , Insuficiência Respiratória/diagnóstico , Insuficiência Respiratória/tratamento farmacológico , Insuficiência Respiratória/virologia , Análise de Sobrevida
6.
mSphere ; 5(4)2020 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-32817460

RESUMO

Many coronavirus disease 2019 (COVID-19) patients demonstrate lethal respiratory complications caused by cytokine release syndrome (CRS). Multiple cytokines have been implicated in CRS, but levels of tumor necrosis factor superfamily 14 (TNFSF14) (LIGHT) have not been previously measured in this setting. In this study, we observed significantly elevated serum LIGHT levels in hospitalized COVID-19 patients compared to healthy age- and gender-matched control patients. The assay detected bioavailable LIGHT unbound to the inhibitor Decoy receptor-3 (DcR3). Bioavailable LIGHT levels were elevated in patients both on and off ventilatory support, with a trend toward higher levels in patients requiring mechanical ventilation. In hospitalized patients over the age of 60, who exhibited a mortality rate of 82%, LIGHT levels were significantly higher (P = 0.0209) in those who died than in survivors. As previously reported, interleukin 6 (IL-6) levels were also elevated in these patients, with significantly (P = 0.0076) higher levels observed in patients who died than in survivors, paralleling the LIGHT levels. Although attempts to block IL-6 binding to its receptor have shown limited success in COVID-19 CRS, neutralization of LIGHT may prove to be more effective owing to its more central role in regulating antiviral immune responses. The findings presented here demonstrate that LIGHT is a cytokine which may play an important role in COVID-19 patients presenting with acute respiratory distress syndrome (ARDS) and CRS and suggest that LIGHT neutralization may be beneficial to COVID-19 patients.


Assuntos
Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/virologia , Pneumonia Viral/imunologia , Síndrome do Desconforto Respiratório do Adulto/imunologia , Síndrome do Desconforto Respiratório do Adulto/virologia , Membro 14 da Superfamília de Ligantes de Fatores de Necrose Tumoral/sangue , Adulto , Fatores Etários , Idoso , Anticorpos Monoclonais/uso terapêutico , Betacoronavirus , Ensaios Clínicos como Assunto , Infecções por Coronavirus/complicações , Hospitalização/estatística & dados numéricos , Humanos , Interleucina-6/imunologia , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Respiração Artificial/estatística & dados numéricos
7.
Blood ; 136(7): 914, 2020 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-32790856
8.
J Transl Med ; 18(1): 297, 2020 08 03.
Artigo em Inglês | MEDLINE | ID: mdl-32746922

RESUMO

BACKGROUND: The severe acute respiratory syndrome virus SARS-CoV-2, a close relative of the SARS-CoV virus, is the cause of the recent COVID-19 pandemic affecting, to date, over 14 million individuals across the globe and demonstrating relatively high rates of infection and mortality. A third virus, the H5N1, responsible for avian influenza, has caused infection with some clinical similarities to those in COVID-19 infections. Cytokines, small proteins that modulate immune responses, have been directly implicated in some of the severe responses seen in COVID-19 patients, e.g. cytokine storms. Understanding the immune processes related to COVID-19, and other similar infections, could help identify diagnostic markers and therapeutic targets. METHODS: Here we examine data of cytokine, immune cell types, and disease associations captured from biomedical literature associated with COVID-19, Coronavirus in general, SARS, and H5N1 influenza, with the objective of identifying potentially useful relationships and areas for future research. RESULTS: Cytokine and cell-type associations captured from Medical Subject Heading (MeSH) terms linked to thousands of PubMed records, has identified differing patterns of associations between the four corpuses of publications (COVID-19, Coronavirus, SARS, or H5N1 influenza). Clustering of cytokine-disease co-occurrences in the context of Coronavirus has identified compelling clusters of co-morbidities and symptoms, some of which already known to be linked to COVID-19. Finally, network analysis identified sub-networks of cytokines and immune cell types associated with different manifestations, co-morbidities and symptoms of Coronavirus, SARS, and H5N1. CONCLUSION: Systematic review of research in medicine is essential to facilitate evidence-based choices about health interventions. In a fast moving pandemic the approach taken here will identify trends and enable rapid comparison to the literature of related diseases.


Assuntos
Betacoronavirus , Infecções por Coronavirus/imunologia , Pneumopatias/imunologia , Pneumonia Viral/imunologia , Publicações , Análise por Conglomerados , Comorbidade , Síndrome da Liberação de Citocina/virologia , Citocinas/imunologia , Células-Tronco Hematopoéticas/citologia , Humanos , Sistema Imunitário , Virus da Influenza A Subtipo H5N1 , Influenza Humana/imunologia , Pandemias , PubMed , Síndrome Respiratória Aguda Grave/imunologia
9.
BMC Med ; 18(1): 214, 2020 07 15.
Artigo em Inglês | MEDLINE | ID: mdl-32664932

RESUMO

BACKGROUND: COVID-19, a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), commonly presents as fever, cough, dyspnea, and myalgia or fatigue. Although the majority of patients with COVID-19 have mild symptoms, some are more prone to serious outcomes, including pneumonia, acute respiratory distress syndrome (ARDS), and even death. Hemophagocytic lymphohistiocytosis (HLH) is a severe, life-threatening inflammatory syndrome associated with intense cytokine release (also known as a "cytokine storm"). Similar to COVID-19, HLH is characterized by aggressive course leading to multi-organ failure. MAIN TEXT: The purpose of this review article is to draw attention to the possibility of the complication of HLH in patients with the severe course of COVID-19. Indeed, some of the clinical characteristics observed in the more severe cases of COVID-19 are reminiscent of secondary HLH (which can be triggered by infections, malignancies, rheumatological diseases, or autoimmune/immunodeficiency conditions). The pathogenesis of SARS-CoV-2 infection also suggests that HLH or a similar hyperinflammatory syndrome is the cause of the severe course of the infection. CONCLUSION: The pathogenesis and clinical symptoms of severe COVID-19 indicate that an increased inflammatory response corresponding to HLH is occurring. Therefore, patients with severe COVID-19 should be screened for hyperinflammation using standard laboratory tests to identify those for whom immunosuppressive therapy may improve outcomes.


Assuntos
Infecções por Coronavirus/complicações , Síndrome da Liberação de Citocina/virologia , Linfo-Histiocitose Hemofagocítica/virologia , Pneumonia Viral/complicações , Betacoronavirus , Infecções por Coronavirus/terapia , Humanos , Linfo-Histiocitose Hemofagocítica/diagnóstico , Linfo-Histiocitose Hemofagocítica/terapia , Pandemias , Pneumonia Viral/terapia
10.
Clin Immunol ; 219: 108544, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32707089

RESUMO

Glucose 6-phosphate dehydrogenase (G6PD) deficiency facilitates human coronavirus infection due to glutathione depletion. G6PD deficiency may especially predispose to hemolysis upon coronavirus disease-2019 (COVID-19) infection when employing pro-oxidant therapy. However, glutathione depletion is reversible by N-acetylcysteine (NAC) administration. We describe a severe case of COVID-19 infection in a G6PD-deficient patient treated with hydroxychloroquine who benefited from intravenous (IV) NAC beyond reversal of hemolysis. NAC blocked hemolysis and elevation of liver enzymes, C-reactive protein (CRP), and ferritin and allowed removal from respirator and veno-venous extracorporeal membrane oxygenator and full recovery of the G6PD-deficient patient. NAC was also administered to 9 additional respirator-dependent COVID-19-infected patients without G6PD deficiency. NAC elicited clinical improvement and markedly reduced CRP in all patients and ferritin in 9/10 patients. NAC mechanism of action may involve the blockade of viral infection and the ensuing cytokine storm that warrant follow-up confirmatory studies in the setting of controlled clinical trials.


Assuntos
Acetilcisteína/uso terapêutico , Antioxidantes/uso terapêutico , Betacoronavirus/patogenicidade , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Deficiência de Glucosefosfato Desidrogenase/tratamento farmacológico , Pneumonia Viral/tratamento farmacológico , Adulto , Antirreumáticos/uso terapêutico , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/complicações , Síndrome da Liberação de Citocina/virologia , Esquema de Medicação , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/metabolismo , Deficiência de Glucosefosfato Desidrogenase/sangue , Deficiência de Glucosefosfato Desidrogenase/complicações , Deficiência de Glucosefosfato Desidrogenase/virologia , Humanos , Hidroxicloroquina/uso terapêutico , Inflamação/prevenção & controle , Masculino , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Resultado do Tratamento
11.
Free Radic Biol Med ; 156: 190-199, 2020 08 20.
Artigo em Inglês | MEDLINE | ID: mdl-32653511

RESUMO

Studies have shown that infection, excessive coagulation, cytokine storm, leukopenia, lymphopenia, hypoxemia and oxidative stress have also been observed in critically ill Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2) patients in addition to the onset symptoms. There are still no approved drugs or vaccines. Dietary supplements could possibly improve the patient's recovery. Omega-3 fatty acids, specifically eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), present an anti-inflammatory effect that could ameliorate some patients need for intensive care unit (ICU) admission. EPA and DHA replace arachidonic acid (ARA) in the phospholipid membranes. When oxidized by enzymes, EPA and DHA contribute to the synthesis of less inflammatory eicosanoids and specialized pro-resolving lipid mediators (SPMs), such as resolvins, maresins and protectins. This reduces inflammation. In contrast, some studies have reported that EPA and DHA can make cell membranes more susceptible to non-enzymatic oxidation mediated by reactive oxygen species, leading to the formation of potentially toxic oxidation products and increasing the oxidative stress. Although the inflammatory resolution improved by EPA and DHA could contribute to the recovery of patients infected with SARS-CoV-2, Omega-3 fatty acids supplementation cannot be recommended before randomized and controlled trials are carried out.


Assuntos
Infecções por Coronavirus/dietoterapia , Síndrome da Liberação de Citocina/dietoterapia , Suplementos Nutricionais , Ácidos Docosa-Hexaenoicos/administração & dosagem , Ácido Eicosapentaenoico/administração & dosagem , Leucopenia/dietoterapia , Pandemias , Pneumonia Viral/dietoterapia , Anti-Inflamatórios não Esteroides/administração & dosagem , Betacoronavirus/patogenicidade , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/epidemiologia , Síndrome da Liberação de Citocina/metabolismo , Síndrome da Liberação de Citocina/virologia , Coagulação Intravascular Disseminada/dietoterapia , Coagulação Intravascular Disseminada/epidemiologia , Coagulação Intravascular Disseminada/metabolismo , Coagulação Intravascular Disseminada/virologia , Humanos , Hipóxia/dietoterapia , Hipóxia/epidemiologia , Hipóxia/metabolismo , Hipóxia/virologia , Leucopenia/epidemiologia , Leucopenia/metabolismo , Leucopenia/virologia , Estresse Oxidativo , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo , Pneumonia Viral/virologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Espécies Reativas de Oxigênio/antagonistas & inibidores , Espécies Reativas de Oxigênio/metabolismo
13.
Int J Dermatol ; 59(9): 1043-1056, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32621284

RESUMO

Recommendations were made recently to limit or stop the use of oral and systemic immunotherapies for skin diseases due to potential risks to the patients during the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) COVID-19 pandemic. Herein, we attempt to identify potentially safe immunotherapies that may be used in the treatment of cutaneous diseases during the current COVID-19 pandemic. We performed a literature review to approximate the risk of SARS-CoV-2 infection, including available data on the roles of relevant cytokines, cell subsets, and their mediators in eliciting an optimal immune response against respiratory viruses in murine gene deletion models and humans with congenital deficiencies were reviewed for viral infections risk and if possible coronaviruses specifically. Furthermore, reported risk of infections of biologic and non-biologic therapeutics for skin diseases from clinical trials and drug data registries were evaluated. Many of the immunotherapies used in dermatology have data to support their safe use during the COVID-19 pandemic including the biologics that target IgE, IL-4/13, TNF-α, IL-17, IL-12, and IL-23. Furthermore, we provide evidence to show that oral immunosuppressive medications such as methotrexate and cyclosporine do not significantly increase the risk to patients. Most biologic and conventional immunotherapies, based on doses and indications in dermatology, do not appear to increase risk of viral susceptibility and are most likely safe for use during the COVID-19 pandemic. The limitation of this study is availability of data on COVID-19.


Assuntos
Infecções por Coronavirus/epidemiologia , Síndrome da Liberação de Citocina/imunologia , Fármacos Dermatológicos/efeitos adversos , Suscetibilidade a Doenças/induzido quimicamente , Pneumonia Viral/epidemiologia , Dermatopatias/tratamento farmacológico , Animais , Betacoronavirus/imunologia , Produtos Biológicos/efeitos adversos , Infecções por Coronavirus/complicações , Infecções por Coronavirus/diagnóstico , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/virologia , Dermatologia/métodos , Dermatologia/estatística & dados numéricos , Modelos Animais de Doenças , Suscetibilidade a Doenças/imunologia , Medicina Baseada em Evidências/métodos , Medicina Baseada em Evidências/estatística & dados numéricos , Humanos , Fatores Imunológicos/efeitos adversos , Camundongos , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/diagnóstico , Pneumonia Viral/imunologia , Ensaios Clínicos Controlados Aleatórios como Assunto , Medição de Risco , Índice de Gravidade de Doença , Dermatopatias/imunologia
14.
Pathog Dis ; 78(4)2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32633327

RESUMO

Middle East Respiratory Syndrome (MERS), Severe Acute Respiratory Syndrome (SARS) and Coronavirus Disease 2019 (COVID-19) are caused by three distinct coronaviruses belonging to the same genus. COVID-19 and its two predecessors share many important features in their clinical presentations, and in their propensity for progression to severe disease which is marked by high rates of morbidity and mortality. However, comparison of the three viral illnesses also reveals a number of specific differences in clinical manifestations and complications, which suggest variability in the disease process. This narrative review delineates the pulmonary, cardiac, renal, gastrointestinal, hepatic, neurological and hematologic complications associated with these three respiratory coronaviruses. It further describes the mechanisms of immune hyperactivation-particularly cytokine release syndrome-implicated in the multi-organ system injury seen in severe cases of MERS, SARS and COVID-19.


Assuntos
Infecções por Coronavirus/patologia , Pneumonia Viral/patologia , Síndrome Respiratória Aguda Grave/patologia , Lesão Renal Aguda/virologia , Infecções por Coronavirus/diagnóstico , Síndrome da Liberação de Citocina/virologia , Gastroenteropatias/virologia , Insuficiência Cardíaca/virologia , Humanos , Falência Hepática Aguda/virologia , Doenças do Sistema Nervoso/virologia , Pandemias , Pneumonia Viral/diagnóstico , Insuficiência Respiratória/virologia , Síndrome Respiratória Aguda Grave/diagnóstico
15.
Int J Antimicrob Agents ; 56(3): 106078, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32629115

RESUMO

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is having serious consequences on health and the economy worldwide. All evidence-based treatment strategies need to be considered to combat this new virus. Drugs need to be considered on scientific grounds of efficacy, safety and cost. Chloroquine (CQ) and hydroxychloroquine (HCQ) are old drugs used in the treatment of malaria. Moreover, their antiviral properties have been previously studied, including against coronaviruses, where evidence of efficacy has been found. In the current race against time triggered by the COVID-19 pandemic, the search for new antivirals is very important. However, consideration should be given to old drugs with known anti-coronavirus activity, such as CQ and HCQ. These could be integrated into current treatment strategies while novel treatments are awaited, also in light of the fact that they display an anticoagulant effect that facilitates the activity of low-molecular-weight heparin, aimed at preventing acute respiratory distress syndrome (ARDS)-associated thrombotic events. The safety of CQ and HCQ has been studied for over 50 years, however recently published data raise concerns for cardiac toxicity of CQ/HCQ in patients with COVID-19. This review also re-examines the real information provided by some of the published alarming reports, although concluding that cardiac toxicity should in any case be stringently monitored in patients receiving CQ/HCQ.


Assuntos
Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Cloroquina/uso terapêutico , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Coagulação Intravascular Disseminada/prevenção & controle , Hidroxicloroquina/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/uso terapêutico , Anticoagulantes/uso terapêutico , Autofagia/efeitos dos fármacos , Autofagia/genética , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/imunologia , Infecções por Coronavirus/patologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Coagulação Intravascular Disseminada/virologia , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Fatores Imunológicos/uso terapêutico , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/patologia , Pneumonia Viral/virologia , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
16.
Artigo em Inglês | MEDLINE | ID: mdl-32641296

RESUMO

Coronavirus disease 2019 (COVID-19) leads to inflammatory cytokine release, which can downregulate the expression of metabolizing enzymes. This cascade affects drug concentrations in the plasma. We investigated the association between lopinavir (LPV) and hydroxychloroquine (HCQ) plasma concentrations and the levels of the acute-phase inflammation marker C-reactive protein (CRP). LPV plasma concentrations in 92 patients hospitalized at our institution were prospectively collected. Lopinavir-ritonavir was administered every 12 hours, 800/200 mg on day 1 and 400/100 mg on day 2 until day 5 or 7. HCQ was given at 800 mg, followed by 400 mg after 6, 24, and 48 h. Hematological, liver, kidney, and inflammation laboratory values were analyzed on the day of drug level determination. The median age of study participants was 59 (range, 24 to 85) years, and 71% were male. The median durations from symptom onset to hospitalization and treatment initiation were 7 days (interquartile range [IQR], 4 to 10) and 8 days (IQR, 5 to 10), respectively. The median LPV trough concentration on day 3 of treatment was 26.5 µg/ml (IQR, 18.9 to 31.5). LPV plasma concentrations positively correlated with CRP values (r = 0.37, P < 0.001) and were significantly lower when tocilizumab was preadministered. No correlation was found between HCQ concentrations and CRP values. High LPV plasma concentrations were observed in COVID-19 patients. The ratio of calculated unbound drug fraction to published SARS-CoV-2 50% effective concentrations (EC50) indicated insufficient LPV concentrations in the lung. CRP values significantly correlated with LPV but not HCQ plasma concentrations, implying inhibition of cytochrome P450 3A4 (CYP3A4) metabolism by inflammation.


Assuntos
Antivirais/farmacocinética , Betacoronavirus/efeitos dos fármacos , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Hidroxicloroquina/farmacocinética , Lopinavir/farmacocinética , Pneumonia Viral/tratamento farmacológico , Ritonavir/farmacocinética , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/uso terapêutico , Antivirais/sangue , Antivirais/farmacologia , Betacoronavirus/imunologia , Betacoronavirus/patogenicidade , Biomarcadores/sangue , Proteína C-Reativa/metabolismo , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Esquema de Medicação , Combinação de Medicamentos , Feminino , Hospitais Universitários , Humanos , Hidroxicloroquina/sangue , Hidroxicloroquina/farmacologia , Tempo de Internação/estatística & dados numéricos , Lopinavir/sangue , Lopinavir/farmacologia , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Estudos Retrospectivos , Ritonavir/sangue , Ritonavir/farmacologia , Índice de Gravidade de Doença , Análise de Sobrevida
17.
Int J Antimicrob Agents ; 56(3): 106101, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32687949

RESUMO

The coronavirus infection (COVID-19) has turned into a global catastrophe and there is an intense search for effective drug therapy. Of all the potential therapies, chloroquine and hydroxychloroquine have been the focus of tremendous public attention. Both drugs have been used in the treatment and prophylaxis of malaria. Long-term use of hydroxychloroquine is the cornerstone in the treatment of several auto-immune disorders. There is convincing evidence that hydroxychloroquine has strong in vitro antiviral activity against SARS-CoV-2. A few small uncontrolled trials and several anecdotal reports have shown conflicting results of such drug therapy in COVID-19. However, the results of preliminary large-scale randomized controlled trials have failed to show any survival benefit of such drug therapy in COVID-19. Despite the lack of such evidence, hydroxychloroquine has been used as a desperate attempt for prophylaxis and treatment of COVID-19. The drug has wide-ranging drug interactions and potential cardiotoxicity. Indiscriminate unsupervised use can expose the public to serious adverse drug effects.


Assuntos
Anti-Inflamatórios/administração & dosagem , Antivirais/administração & dosagem , Cloroquina/administração & dosagem , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/prevenção & controle , Hidroxicloroquina/administração & dosagem , Fatores Imunológicos/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Anti-Inflamatórios/efeitos adversos , Antivirais/efeitos adversos , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/imunologia , Cloroquina/efeitos adversos , Ensaios Clínicos como Assunto , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/prevenção & controle , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Esquema de Medicação , Interações Hospedeiro-Patógeno/efeitos dos fármacos , Interações Hospedeiro-Patógeno/genética , Interações Hospedeiro-Patógeno/imunologia , Humanos , Hidroxicloroquina/efeitos adversos , Fatores Imunológicos/efeitos adversos , Pandemias/prevenção & controle , Pneumonia Viral/mortalidade , Pneumonia Viral/prevenção & controle , Pneumonia Viral/virologia , Análise de Sobrevida , Internalização do Vírus/efeitos dos fármacos , Replicação Viral/efeitos dos fármacos
18.
Int J Antimicrob Agents ; 56(3): 106103, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32712333

RESUMO

This systemic review and meta-analysis aimed to assess the efficacy of tocilizumab for the treatment of severe coronavirus disease 2019 (COVID-19). Candidate studies up to 24 May 2020 were identified from PubMed, Cochrane Library, Embase, medRxiv and bioRxiv. Treatment outcomes included mortality, risk of intensive care unit (ICU) admission and the requirement for mechanical ventilation (MV). Seven retrospective studies involving 592 adult patients with severe COVID-19, including 240 in the tocilizumab group and 352 in the control group, were enrolled. All-cause mortality of severe COVID-19 patients among the tocilizumab group was 16.3% (39/240), which was lower than that in the control group (24.1%; 85/352). However, the difference did not reach statistical significance [risk ratio (RR) = 0.62, 95% confidence interval (CI) 0.31-1.22; I2 = 68%]. Additionally, risk of ICU admission was similar between the tocilizumab and control groups (35.1% vs. 15.8%; RR = 1.51, 95% CI 0.33-6.78; I2 = 86%). The requirement for MV was similar between the tocilizumab and control groups (32.4% vs. 28.6%; RR = 0.82, 95% CI 0.14-4.94; I2 = 91%). However, these non-significant differences between the tocilizumab and control groups may have been the result of baseline characteristics of the tocilizumab group, which were more severe than those of the control group. Based on low-quality evidence, there is no conclusive evidence that tocilizumab would provide any additional benefit to patients with severe COVID-19. Therefore, further recommendation of tocilizumab for COVID-19 cases should be halted until high-quality evidence from randomised controlled trials is available.


Assuntos
Anti-Inflamatórios/administração & dosagem , Anticorpos Monoclonais Humanizados/administração & dosagem , Antivirais/administração & dosagem , Infecções por Coronavirus/terapia , Fatores Imunológicos/administração & dosagem , Pneumonia Viral/terapia , Anti-Inflamatórios/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Antivirais/efeitos adversos , Infecções Bacterianas/diagnóstico , Infecções Bacterianas/etiologia , Infecções Bacterianas/imunologia , Infecções Bacterianas/mortalidade , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/crescimento & desenvolvimento , Betacoronavirus/imunologia , Infecções por Coronavirus/imunologia , Infecções por Coronavirus/mortalidade , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/imunologia , Síndrome da Liberação de Citocina/mortalidade , Síndrome da Liberação de Citocina/terapia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Esquema de Medicação , Humanos , Fatores Imunológicos/efeitos adversos , Unidades de Terapia Intensiva , Infecções Oportunistas/diagnóstico , Infecções Oportunistas/etiologia , Infecções Oportunistas/imunologia , Infecções Oportunistas/mortalidade , Pandemias , Pneumonia Viral/imunologia , Pneumonia Viral/mortalidade , Pneumonia Viral/virologia , Respiração Artificial , Estudos Retrospectivos , Índice de Gravidade de Doença , Análise de Sobrevida , Resultado do Tratamento
19.
Virus Res ; 286: 198103, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32717345

RESUMO

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has evolved into a major pandemic called coronavirus disease 2019 (COVID-19) that has created unprecedented global health emergencies, and emerged as a serious threat due to its strong ability for human-to-human transmission. The reports indicate the ability of SARS-CoV-2 to affect almost any organ due to the presence of a receptor known as angiotensin converting enzyme 2 (ACE2) across the body. ACE2 receptor is majorly expressed in the brush border of gut enterocytes along with the ciliated cells and alveolar epithelial type II cells in the lungs. The amino acid transport function of ACE2 has been linked to gut microbial ecology in gastrointestinal (GI) tract, thereby suggesting that COVID-19 may, to some level, be linked to the enteric microbiota. The significant number of COVID-19 patients shows extra-pulmonary symptoms in the GI tract. Many subsequent studies revealed viral RNA of SARS-CoV-2 in fecal samples of COVID-19 patients. This presents a new challenge in the diagnosis and control of COVID-19 infection with a caution for proper sanitation and hygiene. Here, we aim to discuss the immunological co-ordination between gut and lungs that facilitates SARS-CoV-2 to infect and multiply in the inflammatory bowel disease (IBD) and non-IBD patients.


Assuntos
Betacoronavirus/patogenicidade , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Disbiose/imunologia , Trato Gastrointestinal/imunologia , Doenças Inflamatórias Intestinais/imunologia , Pulmão/imunologia , Pneumonia Viral/imunologia , Anticorpos Monoclonais/uso terapêutico , Antivirais/uso terapêutico , Betacoronavirus/imunologia , Infecções por Coronavirus/tratamento farmacológico , Infecções por Coronavirus/microbiologia , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Síndrome da Liberação de Citocina/microbiologia , Síndrome da Liberação de Citocina/virologia , Citocinas/antagonistas & inibidores , Citocinas/genética , Citocinas/imunologia , Disbiose/tratamento farmacológico , Disbiose/microbiologia , Disbiose/virologia , Microbioma Gastrointestinal/imunologia , Trato Gastrointestinal/efeitos dos fármacos , Trato Gastrointestinal/microbiologia , Trato Gastrointestinal/virologia , Expressão Gênica , Interações Hospedeiro-Patógeno/imunologia , Humanos , Doenças Inflamatórias Intestinais/tratamento farmacológico , Doenças Inflamatórias Intestinais/microbiologia , Doenças Inflamatórias Intestinais/virologia , Pulmão/efeitos dos fármacos , Pulmão/microbiologia , Pulmão/virologia , Pandemias , Peptidil Dipeptidase A/genética , Peptidil Dipeptidase A/imunologia , Pneumonia Viral/tratamento farmacológico , Pneumonia Viral/microbiologia , Pneumonia Viral/virologia , Receptores Virais/genética , Receptores Virais/imunologia
20.
Ann Rheum Dis ; 79(9): 1143-1151, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32719045

RESUMO

OBJECTIVES: To prospectively investigate in patients with severe COVID-19-associated cytokine storm syndrome (CSS) whether an intensive course of glucocorticoids with or without tocilizumab accelerates clinical improvement, reduces mortality and prevents invasive mechanical ventilation, in comparison with a historic control group of patients who received supportive care only. METHODS: From 1 April 2020, patients with COVID-19-associated CSS, defined as rapid respiratory deterioration plus at least two out of three biomarkers with important elevations (C-reactive protein >100 mg/L; ferritin >900 µg/L; D-dimer >1500 µg/L), received high-dose intravenous methylprednisolone for 5 consecutive days (250 mg on day 1 followed by 80 mg on days 2-5). If the respiratory condition had not improved sufficiently (in 43%), the interleukin-6 receptor blocker tocilizumab (8 mg/kg body weight, single infusion) was added on or after day 2. Control patients with COVID-19-associated CSS (same definition) were retrospectively sampled from the pool of patients (n=350) admitted between 7 March and 31 March, and matched one to one to treated patients on sex and age. The primary outcome was ≥2 stages of improvement on a 7-item WHO-endorsed scale for trials in patients with severe influenza pneumonia, or discharge from the hospital. Secondary outcomes were hospital mortality and mechanical ventilation. RESULTS: At baseline all patients with COVID-19 in the treatment group (n=86) and control group (n=86) had symptoms of CSS and faced acute respiratory failure. Treated patients had 79% higher likelihood on reaching the primary outcome (HR: 1.8; 95% CI 1.2 to 2.7) (7 days earlier), 65% less mortality (HR: 0.35; 95% CI 0.19 to 0.65) and 71% less invasive mechanical ventilation (HR: 0.29; 95% CI 0.14 to 0.65). Treatment effects remained constant in confounding and sensitivity analyses. CONCLUSIONS: A strategy involving a course of high-dose methylprednisolone, followed by tocilizumab if needed, may accelerate respiratory recovery, lower hospital mortality and reduce the likelihood of invasive mechanical ventilation in COVID-19-associated CSS.


Assuntos
Anticorpos Monoclonais Humanizados/administração & dosagem , Betacoronavirus , Infecções por Coronavirus/tratamento farmacológico , Síndrome da Liberação de Citocina/tratamento farmacológico , Glucocorticoides/administração & dosagem , Pneumonia Viral/tratamento farmacológico , Idoso , Proteína C-Reativa/análise , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/virologia , Síndrome da Liberação de Citocina/sangue , Síndrome da Liberação de Citocina/virologia , Citocinas/sangue , Quimioterapia Combinada , Feminino , Ferritinas/sangue , Produtos de Degradação da Fibrina e do Fibrinogênio/análise , Estudo Historicamente Controlado , Humanos , Masculino , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/virologia , Estudos Prospectivos , Padrão de Cuidado , Resultado do Tratamento
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