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1.
BMC Infect Dis ; 20(1): 964, 2020 Dec 22.
Artículo en Inglés | MEDLINE | ID: mdl-33353546

RESUMEN

BACKGROUND: Due to the lack of proven therapies, we evaluated the effects of early administration of tocilizumab for COVID-19. By inhibition of the IL-6 receptor, tocilizumab may help to mitigate the hyperinflammatory response associated with progressive respiratory failure from SARS-CoV-2. METHODS: A retrospective, observational study was conducted on hospitalized adults who received intravenous tocilizumab for COVID-19 between March 23, 2020 and April 10, 2020. RESULTS: Most patients were male (66.7%), Hispanic (63.3%) or Black (23.3%), with a median age of 54 years. Tocilizumab was administered at a median of 8 days (range 1-21) after initial symptoms and 2 days (range 0-12) after hospital admission. Within 30 days from receiving tocilizumab, 36 patients (60.0%) demonstrated clinical improvement, 9 (15.0%) died, 33 (55.0%) were discharged alive, and 18 (30.0%) remained hospitalized. Successful extubation occurred in 13 out of 29 patients (44.8%). Infectious complications occurred in 16 patients (26.7%) at a median of 10.5 days. After tocilizumab was administered, there was a slight increase in PaO2/FiO2 and an initial reduction in CRP, but this effect was not sustained beyond day 10. CONCLUSIONS: Majority of patients demonstrated clinical improvement and were successfully discharged alive from the hospital after receiving tocilizumab. We observed a rebound effect with CRP, which may suggest the need for higher or subsequent doses to adequately manage cytokine storm. Based on our findings, we believe that tocilizumab may have a role in the early treatment of COVID-19, however larger randomized controlled studies are needed to confirm this.


Asunto(s)
Anticuerpos Monoclonales Humanizados/uso terapéutico , Receptores de Interleucina-6/antagonistas & inhibidores , Insuficiencia Respiratoria/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/farmacología , Estudios de Cohortes , Femenino , Hospitalización , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Respiratoria/virología , Estudios Retrospectivos , Resultado del Tratamiento
2.
Pan Afr Med J ; 35(Suppl 2): 130, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33193945

RESUMEN

The COVID-19 pandemic has strained health care systems beyond capacity resulting in many people not having access to life-sustaining measures even in well-resourced countries. Palliative and end-of-life care are therefore essential to alleviate suffering and ensure a continuum of care for patients unlikely to survive. This is challenging in sub-Saharan Africa where lack of trained teams on basic palliative care and reduced access to opioids limit implementation of palliative and end-of-life care. At the same time, health care providers have to cope with local cultural conceptions of death and absence of advance care directives.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/terapia , Cuidados Paliativos/organización & administración , Pandemias , Neumonía Viral/terapia , Cuidado Terminal/organización & administración , Directivas Anticipadas , África del Sur del Sahara/epidemiología , Analgésicos Opioides/provisión & distribución , Analgésicos Opioides/uso terapéutico , Actitud Frente a la Muerte , Barreras de Comunicación , Continuidad de la Atención al Paciente , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/psicología , Cultura , Accesibilidad a los Servicios de Salud , Humanos , Cuidados Paliativos/psicología , Neumonía Viral/epidemiología , Neumonía Viral/psicología , Relaciones Profesional-Paciente , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/mortalidad , Estigma Social , Cuidado Terminal/psicología
3.
Trials ; 21(1): 934, 2020 Nov 19.
Artículo en Inglés | MEDLINE | ID: mdl-33213529

RESUMEN

OBJECTIVES: Zilucoplan (complement C5 inhibitor) has profound effects on inhibiting acute lung injury post COVID-19, and can promote lung repair mechanisms that lead to improvement in lung oxygenation parameters. The purpose of this study is to investigate the efficacy and safety of Zilucoplan in improving oxygenation and short- and long-term outcome of COVID-19 patients with acute hypoxic respiratory failure. TRIAL DESIGN: This is a phase 2 academic, prospective, 2:1 randomized, open-label, multi-center interventional study. PARTICIPANTS: Adult patients (≥18y old) will be recruited at specialized COVID-19 units and ICUs at 9 Belgian hospitals. The main eligibility criteria are as follows: 1) Inclusion criteria: a. Recent (≥6 days and ≤16 days) SARS-CoV-2 infection. b. Chest CT scan showing bilateral infiltrates within the last 2 days prior to randomisation. c. Acute hypoxia (defined as PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen). d. Signs of cytokine release syndrome characterized by either high serum ferritin, or high D-dimers, or high LDH or deep lymphopenia or a combination of those. 2) Exclusion criteria: e. Mechanical ventilation for more than 24 hours prior to randomisation. f. Active bacterial or fungal infection. g. History of meningococcal disease (due to the known high predisposition to invasive, often recurrent meningococcal infections of individuals deficient in components of the alternative and terminal complement pathways). INTERVENTION AND COMPARATOR: Patients in the experimental arm will receive daily 32,4 mg Zilucoplan subcutaneously and a daily IV infusion of 2g of the antibiotic ceftriaxone for 14 days (or until hospital discharge, whichever comes first) in addition to standard of care. These patients will receive additional prophylactic antibiotics until 14 days after the last Zilucoplan dose: hospitalized patients will receive a daily IV infusion of 2g of ceftriaxone, discharged patients will switch to daily 500 mg of oral ciprofloxacin. The control group will receive standard of care and a daily IV infusion of 2g of ceftriaxone for 1 week (or until hospital discharge, whichever comes first), to control for the effects of antibiotics on the clinical course of COVID-19. MAIN OUTCOMES: The primary endpoint is the improvement of oxygenation as measured by mean and/or median change from pre-treatment (day 1) to post-treatment (day 6 and 15 or at discharge, whichever comes first) in PaO2/FiO2 ratio, P(A-a)O2 gradient and a/A PO2 ratio. (PAO2= Partial alveolar pressure of oxygen, PaO2=partial arterial pressure of oxygen, FiO2=Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 2:1 ratio (Zilucoplan: control). Randomization will be done using an Interactive Web Response System (REDCap). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 81 patients will be enrolled: 54 patients will be randomized to the experimental arm and 27 patients to the control arm. TRIAL STATUS: ZILU-COV protocol Version 4.0 (June 10 2020). Participant recruitment started on June 23 2020 and is ongoing. Given the uncertainty of the pandemic, it is difficult to predict the anticipated end date. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on May 11th, 2020 (ClinicalTrials.gov Identifier: NCT04382755 ) and on EudraCT (Identifier: 2020-002130-33 ). 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.


Asunto(s)
Complemento C5/antagonistas & inhibidores , Infecciones por Coronavirus/complicaciones , Hipoxia/tratamiento farmacológico , Neumonía Viral/complicaciones , Insuficiencia Respiratoria/tratamiento farmacológico , Enfermedad Aguda , Adulto , Antibacterianos/administración & dosificación , Antibacterianos/uso terapéutico , Bélgica/epidemiología , Betacoronavirus/aislamiento & purificación , Estudios de Casos y Controles , Ceftriaxona/administración & dosificación , Ceftriaxona/uso terapéutico , Infecciones por Coronavirus/epidemiología , Infecciones por Coronavirus/fisiopatología , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/sangre , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Quimioterapia Combinada , Humanos , Infusiones Intravenosas , Inyecciones Subcutáneas , Oxígeno/sangre , Pandemias , Neumonía Viral/epidemiología , Neumonía Viral/fisiopatología , Neumonía Viral/virología , Estudios Prospectivos , Seguridad , Resultado del Tratamiento
4.
Value Health ; 23(11): 1409-1422, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-33127010

RESUMEN

OBJECTIVE: To review published economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses. METHODS: We conducted a systematic review to identify economic evaluations of antiviral treatment for pandemics and outbreaks of respiratory illnesses, including coronavirus disease 2019 (COVID-19). We searched Medline (EBSCOhost), EMBASE (Ovid), EconLit (Ovid), National Health Service Economic Evaluation Database (Ovid), and Health Technology Assessment (Ovid). The search was last rerun on July 5, 2020. Citation tracking and reference checking were used. Only full economic evaluations published as peer-reviewed articles in the last 10 years were included. Studies were quality assessed using the National Institute for Health and Care Excellence economic evaluation checklist. RESULTS: Overall, 782 records were identified, of which 14 studies met the inclusion criteria. The studies were mostly conducted in high-income countries. All were model-based. Seven (50%) were cost-utility analyses, 4 (28.6%) were cost-effectiveness analyses, 2 (14.3%) were cost-consequences analyses, and 1 (7.1%) was a cost-benefit analysis. Strategies including antiviral treatment were found to be either cost-saving or cost-effective, at the study-specific willingness-to-pay thresholds. Empirical treatment was more cost-effective than test-guided treatment for young adults but less so for older adults. CONCLUSIONS: Antiviral treatment for managing pandemics and outbreaks of respiratory illnesses that have very high case fatality rate, similar to COVID-19 pandemic, are likely to be cost-effective either as a standalone intervention or part of a multifaceted strategy. Investing in the development of such curative treatments and promptly evaluating their cost-effectiveness, relative to other strategies in use at the time of their introduction should be the focus going forward to inform resource allocation decisions particularly in low- and middle-income countries.


Asunto(s)
Antivirales/economía , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/epidemiología , Análisis Costo-Beneficio , Brotes de Enfermedades , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/epidemiología , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/epidemiología , Betacoronavirus/efectos de los fármacos , Humanos , Evaluación de la Tecnología Biomédica
5.
J Clin Pharmacol ; 60(11): 1411-1415, 2020 11.
Artículo en Inglés | MEDLINE | ID: mdl-32885463

RESUMEN

The pathophysiology of respiratory failure associated with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) remains under investigation. One hypothesis is that progressive endothelial damage from the virus leads to microvascular thrombosis. It is uncertain if empiric therapeutic anticoagulation provides benefit over standard deep vein thrombosis (DVT) prophylaxis in critically ill patients with SARS-CoV-2. A retrospective cohort study was performed to evaluate adult patients admitted to the intensive care unit at 3 hospitals with polymerase chain reaction-confirmed SARS-CoV-2-associated respiratory failure requiring invasive mechanical ventilation. A Kaplan-Meier survival analysis was used to compare patients who were initiated on therapeutic anticoagulation prior to the time of intubation and those receiving standard DVT prophylaxis doses. The primary outcome was the difference in the 28-day mortality of patients between the 2 groups. Twenty-eight-day mortality did not differ between groups, occurring in 26.1% of patients who received therapeutic anticoagulation and 29.5% of those who received a prophylactic dose only (hazard ratio, 0.52; P = .055). There was no difference in 28-day mortality between groups in patients who were admitted with a serum D-dimer ≥ 2 µg/mL (hazard ratio, 0.67; P = .41). Empiric therapeutic anticoagulation in patients who require invasive mechanical ventilation for confirmed SARS-CoV-2 infection does not improve 28-day mortality compared with standard DVT prophylaxis, even among those with elevated D-dimer levels.


Asunto(s)
Anticoagulantes/uso terapéutico , Infecciones por Coronavirus/complicaciones , Infecciones por Coronavirus/mortalidad , Enfermedad Crítica/mortalidad , Neumonía Viral/complicaciones , Neumonía Viral/mortalidad , Insuficiencia Respiratoria/etiología , Insuficiencia Respiratoria/mortalidad , Anciano , Anticoagulantes/efectos adversos , Estudios de Cohortes , Infecciones por Coronavirus/tratamiento farmacológico , Femenino , Productos de Degradación de Fibrina-Fibrinógeno/análisis , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/tratamiento farmacológico , Respiración Artificial , Insuficiencia Respiratoria/tratamiento farmacológico , Estudios Retrospectivos , Análisis de Supervivencia
6.
Pediatrics ; 146(4)2020 10.
Artículo en Inglés | MEDLINE | ID: mdl-32943536

RESUMEN

OBJECTIVES: To evaluate the survival and neurodevelopmental impairment (NDI) in extremely low birth weight (ELBW) infants at 18 to 26 months with early hypoxemic respiratory failure (HRF). We also assessed whether African American infants with early HRF had improved outcomes after exposure to inhaled nitric oxide (iNO). METHODS: ELBW infants ≤1000 g and gestational age ≤26 weeks with maximal oxygen ≥60% on either day 1 or day 3 were labeled as "early HRF" and born between 2007 and 2015 in the Neonatal Research Network were included. Using a propensity score regression model, we analyzed outcomes and effects of exposure to iNO overall and separately by race. RESULTS: Among 7639 ELBW infants born ≤26 weeks, 22.7% had early HRF. Early HRF was associated with a mortality of 51.3%. The incidence of moderate-severe NDI among survivors was 41.2% at 18 to 26 months. Mortality among infants treated with iNO was 59.4%. Female sex (adjusted odds ratio [aOR]: 2.4, 95% confidence interval [CI]: 1.8-3.3), birth weight ≥720 g (aOR: 2.3, 95% CI: 1.7-3.1) and complete course of antenatal steroids (aOR: 1.6, 95% CI: 1.1-2.2) were associated with intact survival. African American infants had a similar incidence of early HRF (21.7% vs 23.3%) but lower exposure to iNO (16.4% vs 21.6%). Among infants with HRF exposed to iNO, intact survival (no death or NDI) was not significantly different between African American and other races (aOR: 1.5, 95% CI: 0.6-3.6). CONCLUSIONS: Early HRF in infants ≤26 weeks' gestation is associated with high mortality and NDI at 18 to 26 months. Use of iNO did not decrease mortality or NDI. Outcomes following iNO exposure were not different in African American infants.


Asunto(s)
Broncodilatadores/uso terapéutico , Hipoxia/complicaciones , Recien Nacido Extremadamente Prematuro , Trastornos del Neurodesarrollo/epidemiología , Óxido Nítrico Sintasa de Tipo II/uso terapéutico , Insuficiencia Respiratoria/mortalidad , Administración por Inhalación , Afroamericanos , Puntaje de Apgar , Peso al Nacer , Broncodilatadores/administración & dosificación , Femenino , Rotura Prematura de Membranas Fetales , Mortalidad Hospitalaria , Humanos , Hipertensión Pulmonar/tratamiento farmacológico , Incidencia , Lactante , Recien Nacido con Peso al Nacer Extremadamente Bajo , Recién Nacido , Masculino , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/tratamiento farmacológico , Trastornos del Neurodesarrollo/etnología , Óxido Nítrico Sintasa de Tipo II/administración & dosificación , Alta del Paciente , Embarazo , Puntaje de Propensión , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etnología , Insuficiencia Respiratoria/etiología , Factores de Riesgo , Factores Sexuales , Esteroides/uso terapéutico
7.
JAMA ; 324(13): 1298-1306, 2020 10 06.
Artículo en Inglés | MEDLINE | ID: mdl-32876689

RESUMEN

Importance: Coronavirus disease 2019 (COVID-19) is associated with severe lung damage. Corticosteroids are a possible therapeutic option. Objective: To determine the effect of hydrocortisone on treatment failure on day 21 in critically ill patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and acute respiratory failure. Design, Setting, and Participants: Multicenter randomized double-blind sequential trial conducted in France, with interim analyses planned every 50 patients. Patients admitted to the intensive care unit (ICU) for COVID-19-related acute respiratory failure were enrolled from March 7 to June 1, 2020, with last follow-up on June 29, 2020. The study intended to enroll 290 patients but was stopped early following the recommendation of the data and safety monitoring board. Interventions: Patients were randomized to receive low-dose hydrocortisone (n = 76) or placebo (n = 73). Main Outcomes and Measures: The primary outcome, treatment failure on day 21, was defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Prespecified secondary outcomes included the need for tracheal intubation (among patients not intubated at baseline); cumulative incidences (until day 21) of prone position sessions, extracorporeal membrane oxygenation, and inhaled nitric oxide; Pao2:Fio2 ratio measured daily from day 1 to day 7, then on days 14 and 21; and the proportion of patients with secondary infections during their ICU stay. Results: The study was stopped after 149 patients (mean age, 62.2 years; 30.2% women; 81.2% mechanically ventilated) were enrolled. One hundred forty-eight patients (99.3%) completed the study, and there were 69 treatment failure events, including 11 deaths in the hydrocortisone group and 20 deaths in the placebo group. The primary outcome, treatment failure on day 21, occurred in 32 of 76 patients (42.1%) in the hydrocortisone group compared with 37 of 73 (50.7%) in the placebo group (difference of proportions, -8.6% [95.48% CI, -24.9% to 7.7%]; P = .29). Of the 4 prespecified secondary outcomes, none showed a significant difference. No serious adverse events were related to the study treatment. Conclusions and Relevance: In this study of critically ill patients with COVID-19 and acute respiratory failure, low-dose hydrocortisone, compared with placebo, did not significantly reduce treatment failure (defined as death or persistent respiratory support) at day 21. However, the study was stopped early and likely was underpowered to find a statistically and clinically important difference in the primary outcome. Trial Registration: ClinicalTrials.gov Identifier: NCT02517489.


Asunto(s)
Antiinflamatorios/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Hidrocortisona/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Respiración Artificial , Insuficiencia Respiratoria/terapia , Anciano , Antiinflamatorios/administración & dosificación , Betacoronavirus , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/terapia , Enfermedad Crítica , Método Doble Ciego , Terminación Anticipada de los Ensayos Clínicos , Femenino , Humanos , Hidrocortisona/administración & dosificación , Masculino , Persona de Mediana Edad , Terapia por Inhalación de Oxígeno , Pandemias , Neumonía Viral/mortalidad , Neumonía Viral/terapia , Respiración Artificial/estadística & datos numéricos , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/etiología , Insuficiencia del Tratamiento
8.
Adv Biol Regul ; 77: 100735, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32773098

RESUMEN

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.


Asunto(s)
Anticoagulantes/uso terapéutico , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Síndrome de Liberación de Citoquinas/complicaciones , Coagulación Intravascular Diseminada/complicaciones , Neumonía Viral/complicaciones , Embolia Pulmonar/complicaciones , Insuficiencia Respiratoria/complicaciones , Enfermedad Aguda , Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Plaquetas/patología , Plaquetas/virología , Infecciones por Coronavirus/diagnóstico , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/diagnóstico , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/virología , Coagulación Intravascular Diseminada/diagnóstico , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/virología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Heparina/uso terapéutico , Interacciones Huésped-Patógeno , Humanos , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pandemias , Neumonía Viral/diagnóstico , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/virología , Embolia Pulmonar/diagnóstico , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/virología , Insuficiencia Respiratoria/diagnóstico , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/virología , Análisis de Supervivencia
9.
Adv Biol Regul ; 77: 100744, 2020 08.
Artículo en Inglés | MEDLINE | ID: mdl-32773104
11.
Infection ; 48(5): 767-771, 2020 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-32642806
12.
Proc Natl Acad Sci U S A ; 117(32): 18951-18953, 2020 08 11.
Artículo en Inglés | MEDLINE | ID: mdl-32699149

RESUMEN

Around the tenth day after diagnosis, ∼20% of patients with coronavirus disease 2019 (COVID-19)-associated pneumonia evolve toward severe oxygen dependence (stage 2b) and acute respiratory distress syndrome (stage 3) associated with systemic inflammation often termed a "cytokine storm." Because interleukin-1 (IL-1) blocks the production of IL-6 and other proinflammatory cytokines, we treated COVID-19 patients early in the disease with the IL-1 receptor antagonist, anakinra. We retrospectively compared 22 patients from three different centers in France with stages 2b and 3 COVID-19-associated pneumonia presenting with acute severe respiratory failure and systemic inflammation who received either standard-of-care treatment alone (10 patients) or combined with intravenous anakinra (12 patients). Treatment started at 300 mg⋅d-1 for 5 d, then tapered with lower dosing over 3 d. Both populations were comparable for age, comorbidities, clinical stage, and elevated biomarkers of systemic inflammation. All of the patients treated with anakinra improved clinically (P < 0.01), with no deaths, significant decreases in oxygen requirements (P < 0.05), and more days without invasive mechanical ventilation (P < 0.06), compared with the control group. The effect of anakinra was rapid, as judged by significant decrease of fever and C-reactive protein at day 3. A mean total dose of 1,950 mg was infused with no adverse side effects or bacterial infection. We conclude that early blockade of the IL-1 receptor is therapeutic in acute hyperinflammatory respiratory failure in COVID-19 patients.


Asunto(s)
Antiinflamatorios/uso terapéutico , Infecciones por Coronavirus/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Insuficiencia Respiratoria/tratamiento farmacológico , Anciano , Antiinflamatorios/administración & dosificación , Estudios de Casos y Controles , Infecciones por Coronavirus/complicaciones , Femenino , Humanos , Factores Inmunológicos/administración & dosificación , Inyecciones Intravenosas , Proteína Antagonista del Receptor de Interleucina 1/administración & dosificación , Masculino , Persona de Mediana Edad , Pandemias , Neumonía Viral/complicaciones , Neumonía Viral/etiología , Insuficiencia Respiratoria/etiología
13.
J Mol Cell Cardiol ; 146: 32-40, 2020 09.
Artículo en Inglés | MEDLINE | ID: mdl-32681845

RESUMEN

SARS-CoV-2 causes a phenotype of pneumonia with diverse manifestation, which is termed as coronavirus disease 2019 (COVID-19). An impressive high transmission rate allows COVID-19 conferring enormous challenge for clinicians worldwide, and developing to a pandemic level. Combined with a series of complications, a part of COVID-19 patients progress into severe cases, which critically contributes to the risk of fatality. To date, coagulopathy has been found as a prominent feature of COVID-19 and severe coagulation dysfunction may be associated with poor prognosis. Coagulopathy in COVID-19 may predispose patients to hypercoagulability-related disorders including thrombosis and even fatal vascular events. Inflammatory storm, uncontrolled inflammation-mediated endothelial injury and renin angiotensin system (RAS) dysregulation are the potential mechanisms. Ongoing efforts made to develop promising therapies provide several potential strategies for hypercoagulability in COVID-19. In this review, we introduce the clinical features of coagulation and the increased vascular thrombotic risk conferred by coagulopathy according to present reports about COVID-19. The potential underlying mechanisms and emerging therapeutic avenues are discussed, emphasizing an urgent need for effective interventions.


Asunto(s)
Anticoagulantes/uso terapéutico , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Síndrome de Liberación de Citoquinas/complicaciones , Coagulación Intravascular Diseminada/complicaciones , Neumonía Viral/complicaciones , Embolia Pulmonar/complicaciones , Insuficiencia Respiratoria/complicaciones , Enfermedad Aguda , Betacoronavirus/inmunología , Biomarcadores/sangre , Plaquetas/efectos de los fármacos , Plaquetas/patología , Plaquetas/virología , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Síndrome de Liberación de Citoquinas/mortalidad , Síndrome de Liberación de Citoquinas/virología , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/mortalidad , Coagulación Intravascular Diseminada/virología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Heparina/uso terapéutico , Interacciones Huésped-Patógeno/inmunología , Humanos , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pandemias , Tiempo de Tromboplastina Parcial , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/mortalidad , Embolia Pulmonar/virología , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/mortalidad , Insuficiencia Respiratoria/virología , Análisis de Supervivencia
14.
Trials ; 21(1): 491, 2020 Jun 05.
Artículo en Inglés | MEDLINE | ID: mdl-32503663

RESUMEN

OBJECTIVES: The hypothesis of the proposed intervention is that Granulocyte-macrophage colony-stimulating factor (GM-CSF) has profound effects on antiviral immunity, and can provide the stimulus to restore immune homeostasis in the lung with acute lung injury post COVID-19, and can promote lung repair mechanisms, that lead to a 25% improvement in lung oxygenation parameters. Sargramostim is a man-made form of the naturally-occurring protein GM-CSF. TRIAL DESIGN: A phase 4 academic, prospective, 2 arm (1:1 ratio), randomized, open-label, controlled trial. PARTICIPANTS: Patients aged 18-80 years admitted to specialized COVID-19 wards in 5 Belgian hospitals with recent (< 2 weeks prior to randomization) confirmed COVID-19 infection and acute respiratory failure defined as a PaO2/FiO2 below 350 mmHg or SpO2 below 93% on minimal 2 L/min supplemental oxygen. Patients were excluded from the trial in case of (1) known serious allergic reactions to yeast-derived products, (2) lithium carbonate therapy, (3) mechanical ventilation prior to randomization, (4) peripheral white blood cell count above 25.000/µL and/or active myeloid malignancy, (5) high dose systemic steroid therapy (> 20 mg methylprednisolone or equivalent), (6) enrolment in another investigational study, (7) pregnant or breastfeeding or (8) ferritin levels > 2000 µg/mL. INTERVENTION AND COMPARATOR: Inhaled sargramostim 125 µg twice daily for 5 days in addition to standard care. Upon progression of disease requiring mechanical ventilation or to acute respiratory distress syndrome (ARDS) and initiation of mechanical ventilator support within the 5 day period, inhaled sargramostim will be replaced by intravenous sargramostim 125 µg/m2 body surface area once daily until the 5 day period is reached. From day 6 onwards, progressive patients in the active group will have the option to receive an additional 5 days of IV sargramostim, based on the treating physician's assessment. Intervention will be compared to standard of care. Subjects progressing to ARDS and requiring invasive mechanical ventilatory support, from day 6 onwards in the standard of care group will have the option (clinician's decision) to initiate IV sargramostim 125m µg/m2 body surface area once daily for 5 days. MAIN OUTCOMES: The primary endpoint of this intervention is measuring oxygenation after 5 days of inhaled (and intravenous) treatment through assessment of a change in pretreatment and post-treatment ratio of PaO2/FiO2 and through measurement of the P(A-a)O2 gradient (PAO2= Partial alveolar pressure of oxygen, PaO2=Partial arterial pressure of oxygen; FiO2= Fraction of inspired oxygen). RANDOMISATION: Patients will be randomized in a 1:1 ratio. Randomization will be done using REDCap (electronic IWRS system). BLINDING (MASKING): In this open-label trial neither participants, caregivers, nor those assessing the outcomes will be blinded to group assignment. NUMBERS TO BE RANDOMISED (SAMPLE SIZE): A total of 80 patients with confirmed COVID-19 and acute hypoxic respiratory failure will be enrolled, 40 in the active and 40 in the control group. TRIAL STATUS: SARPAC protocol Version 2.0 (April 15 2020). Participant recruitment is ongoing in 5 Belgian Hospitals (i.e. University Hospital Ghent, AZ Sint-Jan Bruges, AZ Delta Roeselare, University Hospital Brussels and ZNA Middelheim Antwerp). Participant recruitment started on March 26th 2020. Given the current decline of the COVID-19 pandemic in Belgium, it is difficult to anticipate the rate of participant recruitment. TRIAL REGISTRATION: The trial was registered on Clinical Trials.gov on March 30th, 2020 (ClinicalTrials.gov Identifier: NCT04326920) - retrospectively registered; https://clinicaltrials.gov/ct2/show/NCT04326920?term=sarpac&recrs=ab&draw=2&rank=1 and on EudraCT on March 24th, 2020 (Identifier: 2020-001254-22). 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.


Asunto(s)
Betacoronavirus , Infecciones por Coronavirus/complicaciones , Factor Estimulante de Colonias de Granulocitos y Macrófagos/uso terapéutico , Neumonía Viral/complicaciones , Ensayos Clínicos Controlados Aleatorios como Asunto , Insuficiencia Respiratoria/tratamiento farmacológico , Enfermedad Aguda , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Ensayos Clínicos Fase IV como Asunto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Oxígeno/sangre , Pandemias , Estudios Prospectivos , Proteínas Recombinantes/uso terapéutico , Respiración Artificial , Adulto Joven
16.
Clin Drug Investig ; 40(8): 755-764, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32583295

RESUMEN

BACKGROUND AND OBJECTIVE: Opioid-induced respiratory depression (OIRD) is a potentially fatal complication associated with conventional opioids. Currently, there is a paucity of validated endpoints available to measure respiratory safety. Oliceridine, an investigational intravenous (IV) opioid, is a G-protein selective µ-agonist with limited activity on ß-arrestin2, a signaling pathway associated with adverse events including OIRD. In controlled phase III trials, oliceridine 0.35 mg and 0.5 mg demand doses demonstrated comparable analgesia to morphine 1 mg with favorable improvements in respiratory safety. In this exploratory analysis, we report dosing interruption (DI) and average cumulative duration of DI (CDDI) for both oliceridine and morphine. METHODS: Patients requiring analgesia after bunionectomy or abdominoplasty were randomized to IV demand doses of placebo, oliceridine (0.1 mg, 0.35 mg, or 0.5 mg), or morphine (1 mg), administered via patient-controlled analgesia (PCA), following a loading dose (oliceridine 1.5 mg, morphine 4 mg, volume-matched placebo) with a 6-min lockout interval. Certified nurse anesthetists monitored each patient and withheld study medication according to the patient's respiratory status. For each patient, the duration of all DIs was summed and reported as CDDI. A zero-inflated gamma mixture model was used to compute the mean CDDI for each treatment. RESULTS: Proportion of patients with DI was lower with oliceridine (0.1 mg: 3.2%, 0.35 mg: 13.9%, 0.5 mg: 15.1%) versus morphine (22%). The CDDI was also lower across all demand doses of oliceridine versus morphine. CONCLUSION: Using DI as a surrogate for OIRD indicates improved respiratory safety with oliceridine versus morphine that merits further investigation.


Asunto(s)
Dolor Agudo/tratamiento farmacológico , Analgésicos Opioides/efectos adversos , Morfina/efectos adversos , Dolor Postoperatorio/tratamiento farmacológico , Insuficiencia Respiratoria/inducido químicamente , Compuestos de Espiro/efectos adversos , Tiofenos/efectos adversos , Adulto , Analgesia Controlada por el Paciente , Analgésicos Opioides/administración & dosificación , Femenino , Humanos , Incidencia , Masculino , Persona de Mediana Edad , Morfina/administración & dosificación , Manejo del Dolor , Dimensión del Dolor , Insuficiencia Respiratoria/tratamiento farmacológico , Compuestos de Espiro/administración & dosificación , Tiofenos/administración & dosificación
18.
Int J Infect Dis ; 97: 215-218, 2020 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-32422376

RESUMEN

We report the first successful treatment with the IL-1 receptor antagonist anakinra, in association with the most promising and available antiviral therapy, of a severe case of novel coronavirus disease 2019 (COVID-19). We describe the diagnosis, clinical course, and management of the case, including the respiratory failure at presentation, the progression to a scenario characterized by profound inflammatory dysregulation similar to that observed during macrophage activation syndrome, and the clinical improvement after treatment with the IL-1 receptor antagonist anakinra. This case highlights the high tolerability and the interesting immunomodulatory profile of the IL-1 receptor antagonist anakinra in the setting of severe COVID-19 associated with remdesivir therapy. Further studies are needed to confirm the safety and efficacy of this combination strategy in the treatment of this emerging infection.


Asunto(s)
Adenosina Monofosfato/análogos & derivados , Alanina/análogos & derivados , Betacoronavirus , Infecciones por Coronavirus/tratamiento farmacológico , Proteína Antagonista del Receptor de Interleucina 1/uso terapéutico , Neumonía Viral/tratamiento farmacológico , Receptores de Interleucina-1/antagonistas & inhibidores , Insuficiencia Respiratoria/tratamiento farmacológico , Adenosina Monofosfato/uso terapéutico , Alanina/uso terapéutico , Betacoronavirus/efectos de los fármacos , Combinación de Medicamentos , Humanos , Masculino , Persona de Mediana Edad , Pandemias
19.
Acta Haematol ; 143(5): 417-424, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32396903

RESUMEN

Coronavirus disease (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is responsible for the ongoing 2019-2020 pandemic. Venous thromboembolism (VTE), a frequent cardiovascular and/or respiratory complication among hospitalized patients, is one of the known sequelae of the illness. Hospitalized COVID-19 patients are often elderly, immobile, and show signs of coagulopathy. Therefore, it is reasonable to assume a high incidence of VTE among these patients. Presently, the incidence of VTE is estimated at around 25% of patients hospitalized in the intensive care unit for COVID-19 even under anticoagulant treatment at prophylactic doses. In this review, we discuss present knowledge of the topic, the unique challenges of diagnosis and treatment of VTE, as well as some of the potential mechanisms of increased risk for VTE during the illness. Understanding the true impact of VTE on patients with COVID-19 will potentially improve our ability to reach a timely diagnosis and initiate proper treatment, mitigating the risk for this susceptible population during a complicated disease.


Asunto(s)
Anticoagulantes/uso terapéutico , Betacoronavirus/patogenicidad , Infecciones por Coronavirus/complicaciones , Coagulación Intravascular Diseminada/complicaciones , Neumonía Viral/complicaciones , Embolia Pulmonar/complicaciones , Insuficiencia Respiratoria/complicaciones , Tromboembolia Venosa/complicaciones , Enfermedad Aguda , Biomarcadores/sangre , Infecciones por Coronavirus/tratamiento farmacológico , Infecciones por Coronavirus/mortalidad , Infecciones por Coronavirus/virología , Coagulación Intravascular Diseminada/tratamiento farmacológico , Coagulación Intravascular Diseminada/mortalidad , Coagulación Intravascular Diseminada/virología , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , Heparina/uso terapéutico , Humanos , Unidades de Cuidados Intensivos , Pulmón/irrigación sanguínea , Pulmón/efectos de los fármacos , Pulmón/patología , Pulmón/virología , Pandemias , Neumonía Viral/tratamiento farmacológico , Neumonía Viral/mortalidad , Neumonía Viral/virología , Embolia Pulmonar/tratamiento farmacológico , Embolia Pulmonar/mortalidad , Embolia Pulmonar/virología , Insuficiencia Respiratoria/tratamiento farmacológico , Insuficiencia Respiratoria/mortalidad , Insuficiencia Respiratoria/virología , Factores de Riesgo , Análisis de Supervivencia , Troponina/sangre , Tromboembolia Venosa/tratamiento farmacológico , Tromboembolia Venosa/mortalidad , Tromboembolia Venosa/virología
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