RESUMEN
In 2019, the new coronavirus disease (COVID-19), related to the severe acute respiratory syndrome coronavirus (SARS-CoV-2), started spreading around the word, giving rise to the world pandemic we are still facing. Since then, many strategies for the prevention and control of COVID-19 have been studied and implemented. In addition to pharmacological treatments and vaccines, it is mandatory to ensure the cleaning and disinfection of the skin and inanimate surfaces, especially in those contexts where the contagion could spread quickly, such as hospitals and clinical laboratories, schools, transport, and public places in general. Here, we report the efficacy of ZnO nanoparticles (ZnONPs) against SARS-CoV-2. NPs were produced using an ecofriendly method and fully characterized; their antiviral activity was tested in vitro against SARS-CoV-2, showing a decrease in viral load between 70% and 90%, as a function of the material's composition. Application of these nano-antimicrobials as coatings for commonly touched surfaces is envisaged.
Asunto(s)
Antivirales/farmacología , COVID-19/prevención & control , Nanoestructuras/química , SARS-CoV-2/efectos de los fármacos , Óxido de Zinc/farmacología , Antivirales/química , COVID-19/inducido químicamente , COVID-19/epidemiología , Colorimetría , Humanos , Pruebas de Sensibilidad Microbiana/métodos , Microscopía Electrónica de Transmisión , Nanoestructuras/ultraestructura , Pandemias/prevención & control , Espectroscopía de Fotoelectrones , SARS-CoV-2/fisiología , Espectroscopía Infrarroja por Transformada de Fourier , Resultado del Tratamiento , Carga Viral/efectos de los fármacos , Difracción de Rayos X , Óxido de Zinc/químicaRESUMEN
SARS-CoV-2, a novel coronavirus and an etiologic agent for the current global health emergency, causes acute infection of the respiratory tract leading to severe disease and significant mortality. Ever since the start of SARS-CoV-2, also known as the COVID-19 pandemic, countless uncertainties have been revolving around the pathogenesis and epidemiology of the SARS-CoV-2 infection. While air pollution has been shown to be strongly correlated to increased SARS-CoV-2 morbidity and mortality, whether environmental pollutants such as ground-level ozone affects the susceptibility of individuals to SARS-CoV-2 is not yet established. To investigate the impact of ozone inhalation on the expression levels of signatures associated with host susceptibility to SARS-CoV-2, we analyzed lung tissues collected from mice that were sub-chronically exposed to air or 0.8 ppm ozone for three weeks (4 h/night, 5 nights/week), and analyzed the expression of signatures associated with host susceptibility to SARS-CoV-2. SARS-CoV-2 entry into the host cells is dependent on the binding of the virus to the host cellular receptor, angiotensin-converting enzyme (ACE2), and its subsequent proteolytic priming by the host-derived protease, transmembrane protease serine 2 (TMPRSS2). The Ace2 transcripts were significantly elevated in the parenchyma, but not in the extrapulmonary airways and alveolar macrophages, from ozone-exposed mice. The TMPRSS2 protein and Tmprss2 transcripts were significantly elevated in the extrapulmonary airways, parenchyma, and alveolar macrophages from ozone-exposed mice. A significant proportion of additional known SARS-CoV-2 host susceptibility genes were upregulated in alveolar macrophages and parenchyma from ozone-exposed mice. Our data indicate that the unhealthy levels of ozone in the environment may predispose individuals to severe SARS-CoV-2 infection. Given the severity of this pandemic and the challenges associated with direct testing of host-environment interactions in clinical settings, we believe that this ozone exposure-based study informs the scientific community of the potentially detrimental effects of the ambient ozone levels in determining the host susceptibility to SARS-CoV-2.
Asunto(s)
COVID-19/metabolismo , Macrófagos Alveolares/metabolismo , Ozono/toxicidad , SARS-CoV-2/metabolismo , Serina Endopeptidasas/metabolismo , Regulación hacia Arriba/efectos de los fármacos , Animales , COVID-19/inducido químicamente , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/metabolismo , RatonesRESUMEN
Hospitalized patients with COVID-19 infection frequently have coagulopathy resembling disseminated intravascular coagulation (DIC). An elevation of D-dimer level is associated with a poor prognosis; however, the role of other fibrin degradation products, such as soluble fibrin monomers (SFMC), is not known. The objective of the study was to investigate the frequency and prognostic role of elevated SFMC in patients with COVID-19. In this retrospective cohort study, patients hospitalized between April 1, 2020 and December 14, 2020 at Mayo Clinic with COVID-19 infection who underwent DIC panel testing were identified. Results of laboratory tests and outcomes (thrombosis and death) within 40 days of testing were obtained via medical record review. Of 108 patients, D-dimer was elevated in 82 (75.9%) patients. Of those with elevated D-dimer, SFMC was elevated in 19/82 (23%) patients. There were 16 thrombotic events and 16 deaths during the 40-day follow-up. The incidence of overt-DIC was 4.6%. In univariate analysis, D-dimer ≥5 x highest upper limit normal (ULN) and elevated SFMC were each associated with higher 40-day mortality. However, when used in combination with D-dimer ≥5 x highest ULN, an elevated SFMC provided no further mortality predictive value. Compared to 75.9% of patients with elevated D-dimers, of those tested, only 23% had elevated SFMC. These results support the hypothesis that elevated D-dimer in COVID-19 infection is a direct consequence of endothelial damage and not overt-DIC.
Asunto(s)
COVID-19/sangre , Coagulación Intravascular Diseminada/sangre , Productos de Degradación de Fibrina-Fibrinógeno/metabolismo , SARS-CoV-2/metabolismo , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/inducido químicamente , COVID-19/complicaciones , Coagulación Intravascular Diseminada/etiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios RetrospectivosAsunto(s)
Antirreumáticos/efectos adversos , Artritis/tratamiento farmacológico , Productos Biológicos/efectos adversos , COVID-19/inducido químicamente , Abatacept/efectos adversos , Administración Intravenosa , Anciano , Anticuerpos Monoclonales Humanizados/efectos adversos , Linfocitos B , Productos Biológicos/administración & dosificación , Productos Biológicos/uso terapéutico , Femenino , Hospitalización , Humanos , Infliximab/efectos adversos , Masculino , Persona de Mediana Edad , Gravedad del Paciente , Factores de Riesgo , Rituximab/efectos adversos , SARS-CoV-2RESUMEN
OBJECTIVE: Environmental pollution is a leading global challenge affecting weather conditions and causing severe environmental, social, and public health problems. This study explores the impact of ambient air pollutants, particular matter (PM), PM2.5 and PM10 on morbidity and mortality of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) globally. MATERIALS AND METHODS: In this study, initially 492 research articles were identified through seven search engines containing Web of Science, Medline, PubMed, EMBASE, Scopus, WHO COVID-19 literature, and Ovid databases by consuming keywords "Environmental pollution, Ambient air pollutants, particulate matter, PM2.5, PM10, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), and COVID-19 pandemic". Finally, 26 original research publications were included for the analysis, and the remaining were excluded. These studies were originated from the United States of America (9), China (5), Italy (3), India (1), worldwide (1), and one study each from England, Spain, Canada, Saudi Arabia, Singapore, Japan, and Iran. RESULTS: The analysis based on a worldwide dataset assembled the information from the global literature from December 2019 to September 30, 2021. The assessment for the various regions to a global extent was based on air pollutants and COVID-19 cases and deaths. Twenty- six studies met the selection criteria representing almost all over the world. Based on the synthesis of scientific studies, it was identified that PM2.5 and PM10 are associated with 15.08%, 11.44 increased COVID-19 cases, and 9.26% and 0.75% COVID-19 deaths, respectively. CONCLUSIONS: The evidence indicates that PM2.5 and PM10 can affect COVID-19 epidemiology in various geographical regions. The findings established an association and a possible causal link between increasing ambient air pollutants, particulate matter PM2.5 and PM10 with increased incidence and mortality of COVID-19. The global health authorities must take strict preventive measures to minimize air pollution and combat such challenging and threatening COVID-19 pandemic globally.
Asunto(s)
Contaminantes Atmosféricos/análisis , COVID-19/epidemiología , Material Particulado/análisis , Contaminantes Atmosféricos/toxicidad , COVID-19/inducido químicamente , COVID-19/mortalidad , Salud Global , Humanos , Incidencia , Mortalidad , Material Particulado/toxicidadRESUMEN
In severe acute respiratory distress syndrome (ARDS), extracorporeal membrane oxygenation (ECMO) is a life-prolonging treatment, especially among COVID-19 patients. Evaluation of lung injury progression is challenging with current techniques. Diagnostic imaging or invasive diagnostics are risky given the difficulties of intra-hospital transportation, contraindication of biopsies, and the potential for the spread of infections, such as in COVID-19 patients. We have recently shown that particle flow rate (PFR) from exhaled breath could be a noninvasive, early detection method for ARDS during mechanical ventilation. We hypothesized that PFR could also measure the progress of lung injury during ECMO treatment. Lipopolysaccharide (LPS) was thus used to induce ARDS in pigs under mechanical ventilation. Eight were connected to ECMO, whereas seven animals were not. In addition, six animals received sham treatment with saline. Four human patients with ECMO and ARDS were also monitored. In the pigs, as lung injury ensued, the PFR dramatically increased and a particular spike followed the establishment of ECMO in the LPS-treated animals. PFR remained elevated in all animals with no signs of lung recovery. In the human patients, in the two that recovered, PFR decreased. In the two whose lung function deteriorated while on ECMO, there was increased PFR with no sign of recovery in lung function. The present results indicate that real-time monitoring of PFR may be a new, complementary approach in the clinic for measurement of the extent of lung injury and recovery over time in ECMO patients with ARDS.
Asunto(s)
COVID-19/fisiopatología , Lipopolisacáridos/toxicidad , Lesión Pulmonar/fisiopatología , Pulmón/fisiopatología , Material Particulado/análisis , Síndrome de Dificultad Respiratoria/fisiopatología , Animales , Análisis de los Gases de la Sangre/métodos , COVID-19/inducido químicamente , Oxigenación por Membrana Extracorpórea/métodos , Pulmón/efectos de los fármacos , Lesión Pulmonar/inducido químicamente , Material Particulado/efectos adversos , Respiración Artificial/métodos , Síndrome de Dificultad Respiratoria/inducido químicamente , PorcinosRESUMEN
We explored the potential link between chronic inflammatory arthritis and COVID-19 pathogenic and resolving macrophage pathways and their role in COVID-19 pathogenesis. We found that bronchoalveolar lavage fluid (BALF) macrophage clusters FCN1+ and FCN1+SPP1+ predominant in severe COVID-19 were transcriptionally related to synovial tissue macrophage (STM) clusters CD48hiS100A12+ and CD48+SPP1+ that drive rheumatoid arthritis (RA) synovitis. BALF macrophage cluster FABP4+ predominant in healthy lung was transcriptionally related to STM cluster TREM2+ that governs resolution of synovitis in RA remission. Plasma concentrations of SPP1 and S100A12 (key products of macrophage clusters shared with active RA) were high in severe COVID-19 and predicted the need for Intensive Care Unit transfer, and they remained high in the post-COVID-19 stage. High plasma levels of SPP1 were unique to severe COVID-19 when compared with other causes of severe pneumonia, and IHC localized SPP1+ macrophages in the alveoli of COVID-19 lung. Investigation into SPP1 mechanisms of action revealed that it drives proinflammatory activation of CD14+ monocytes and development of PD-L1+ neutrophils, both hallmarks of severe COVID-19. In summary, COVID-19 pneumonitis appears driven by similar pathogenic myeloid cell pathways as those in RA, and their mediators such as SPP1 might be an upstream activator of the aberrant innate response in severe COVID-19 and predictive of disease trajectory including post-COVID-19 pathology.
Asunto(s)
Artritis Reumatoide/inmunología , COVID-19/inmunología , Monocitos/inmunología , Neutrófilos/inmunología , Osteopontina/inmunología , Artritis Reumatoide/metabolismo , Antígeno B7-H1/inmunología , Líquido del Lavado Bronquioalveolar/inmunología , Antígeno CD48/inmunología , COVID-19/inducido químicamente , COVID-19/metabolismo , Proteínas de Unión a Ácidos Grasos/inmunología , Humanos , Lectinas/inmunología , Receptores de Lipopolisacáridos/inmunología , Receptores de Lipopolisacáridos/metabolismo , Pulmón/diagnóstico por imagen , Pulmón/inmunología , Pulmón/metabolismo , Pulmón/patología , Macrófagos/inmunología , Macrófagos/metabolismo , Glicoproteínas de Membrana/inmunología , Monocitos/metabolismo , Neutrófilos/metabolismo , Osteopontina/sangre , Proteínas Tirosina Quinasas Receptoras/metabolismo , Receptores Inmunológicos/inmunología , Proteína S100A12/inmunología , Proteína S100A12/metabolismo , Membrana Sinovial/inmunología , Tomografía Computarizada por Rayos X , FicolinasRESUMEN
The global outbreak of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), as of 8 May 2021, has surpassed 150 700 000 infections and 3 279 000 deaths worldwide. Evidence indicates that SARS-CoV-2 RNA can be detected on particulate matter (PM), and COVID-19 cases are correlated with levels of air pollutants. However, the mechanisms of PM involvement in the spread of SARS-CoV-2 remain poorly understood. Here, we found that PM exposure increased the expression level of angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) in several epithelial cells and increased the adsorption of the SARS-CoV-2 spike protein. Instillation of PM in a hACE2 mouse model significantly increased the expression of ACE2 and Tmprss2 and viral replication in the lungs. Furthermore, PM exacerbated the pulmonary lesions caused by SARS-CoV-2 infection in the hACE2 mice. In conclusion, our study demonstrated that PM is an epidemiological factor of COVID-19, emphasizing the necessity of wearing anti-PM masks to cope with this global pandemic.
Asunto(s)
Enzima Convertidora de Angiotensina 2/metabolismo , COVID-19/inducido químicamente , COVID-19/inmunología , Material Particulado/efectos adversos , SARS-CoV-2 , Adsorción/efectos de los fármacos , Animales , Susceptibilidad a Enfermedades/inducido químicamente , Susceptibilidad a Enfermedades/inmunología , Células Epiteliales/metabolismo , Ratones , Ratones Endogámicos , Material Particulado/química , ARN Viral/análisis , SARS-CoV-2/genética , Serina Endopeptidasas/metabolismo , Glicoproteína de la Espiga del Coronavirus/metabolismo , Internalización del Virus/efectos de los fármacosRESUMEN
BACKGROUND: The objective of this study was to investigate the relation of severe COVID-19 to prior drug prescribing. METHODS: Severe cases were defined by entry to critical care or fatal outcome. For this matched case-control study (REACT-SCOT), all 4251 cases of severe COVID-19 in Scotland since the start of the epidemic were matched for age, sex and primary care practice to 36,738 controls from the population register. Records were linked to hospital discharges since June 2015 and dispensed prescriptions issued in primary care during the last 240 days. RESULTS: Severe COVID-19 was strongly associated with the number of non-cardiovascular drug classes dispensed. This association was strongest in those not resident in a care home, in whom the rate ratio (95% CI) associated with dispensing of 12 or more drug classes versus none was 10.8 (8.8, 13.3), and in those without any of the conditions designated as conferring increased risk of COVID-19. Of 17 drug classes postulated at the start of the epidemic to be "medications compromising COVID", all were associated with increased risk of severe COVID-19 and these associations were present in those without any of the designated risk conditions. The fraction of cases in the population attributable to exposure to these drug classes was 38%. The largest effect was for antipsychotic agents: rate ratio 4.18 (3.42, 5.11). Other drug classes with large effects included proton pump inhibitors (rate ratio 2.20 (1.72, 2.83) for = 2 defined daily doses/day), opioids (3.66 (2.68, 5.01) for = 50 mg morphine equivalent/day) and gabapentinoids. These associations persisted after adjusting for covariates and were stronger with recent than with non-recent exposure. CONCLUSIONS: Severe COVID-19 is associated with polypharmacy and with drugs that cause sedation, respiratory depression, or dyskinesia; have anticholinergic effects; or affect the gastrointestinal system. These associations are not easily explained by co-morbidity. Measures to reduce the burden of mortality and morbidity from COVID-19 should include reinforcing existing guidance on reducing overprescribing of these drug classes and limiting inappropriate polypharmacy. REGISTRATION: ENCEPP number EUPAS35558.
Asunto(s)
COVID-19/diagnóstico , COVID-19/epidemiología , Cuidados Críticos/tendencias , Polifarmacia , Psicotrópicos/efectos adversos , Índice de Severidad de la Enfermedad , Anciano , Anciano de 80 o más Años , COVID-19/inducido químicamente , Estudios de Casos y Controles , Comorbilidad , Relación Dosis-Respuesta a Droga , Prescripciones de Medicamentos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Psicotrópicos/uso terapéutico , Escocia/epidemiologíaRESUMEN
AIMS: The relationship between metformin therapy and the risk of coronavirus disease (COVID-19) has not been reported among patients with type 2 diabetes mellitus (DM). We aimed to investigate whether metformin therapy was associated with the incidence of COVID-19 among type 2 DM patients in South Korea. METHODS: The National Health Insurance Service-COVID-19 cohort database, comprising COVID-19 patients from 1 January 2020 to 4 June 2020, was used for this study. Among them, adult patients with type 2 DM were included in this study. Metformin users were defined as those who had been prescribed continuous oral metformin for over a period of ≥ 90 days, and the control group was defined as all other patients. RESULTS: Overall, 27,493 patients with type 2 DM (7204, metformin user group; 20,289, control group) were included. After propensity score matching, 11,892 patients (5946 patients in each group) were included in the final analysis. In the logistic regression analysis, the odds of metformin users developing COVID-19 was 30% lower than that of the control group [odds ratio (OR): 0.70, 95% confidence interval (CI): 0.61-0.80; P < 0.001]. However, in the multivariate model, metformin use was not associated with hospital mortality when compared with that of the control group (OR: 1.26, 95% CI: 0.81-1.95; P = 0.301). CONCLUSIONS: Metformin therapy might have potential benefits for the prevention of COVID-19 among patients with type 2 DM in South Korea. However, it did not affect the hospital mortality of type 2 DM patients diagnosed with COVID-19.
Asunto(s)
COVID-19/epidemiología , Bases de Datos Factuales/tendencias , Diabetes Mellitus Tipo 2/epidemiología , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Programas Nacionales de Salud/tendencias , Adulto , Anciano , COVID-19/inducido químicamente , COVID-19/prevención & control , Estudios de Cohortes , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Mortalidad Hospitalaria/tendencias , Humanos , Hipoglucemiantes/efectos adversos , Masculino , Metformina/efectos adversos , Persona de Mediana Edad , República de Corea/epidemiología , Factores de RiesgoRESUMEN
BACKGROUND: Hydroxychloroquine (HCQ) and azithromycin (AZT) have been proposed for COVID-19 treatment. Data available in the literature reported a potential increased risk of fatal arrhythmias under these therapies. The aim of this study was to assess the effects of these drugs on QT interval and outcome in a COVID-19 population. METHOD: A total of 112 consecutive COVID-19 patients were included in this analysis and were divided in 3 groups according to the receiving therapeutic regimens: 19 (17%) patients in Group 1 (no treatment), 40 (36%) in Group 2 (HCQ only), 53 (47%) in Group 3 (HCQ/AZT). RESULTS: A prolonged QTc interval was found in 61% of patients treated with HCQ alone or in combination with AZT, but only 4 (4%) patients showed a QTc > 500 ms. HCQ/AZT combination determined a greater increase of QTc duration compared to the other two strategies (Group 3 452 ± 26.4 vs Group 2 436.3 ± 28.4 vs Group 1 424.4 ± 24.3 ms, respectively; p < 0.001). Multivariate analysis demonstrated that HCQ/AZT combination (OR 9.02, p = 0.001) and older age (OR 1.04, p = 0.031) were independent predictors of QTc prolongation. The risk increased with age (incremental utility analysis p = 0.02). Twenty patients (18%) died, and no cardiac arrest neither arrhythmic fatalities were documented. CONCLUSIONS: The HCQ/AZT combination therapy causes a significantly increase of QT interval compared to HCQ alone. Older patients under such regimen are at higher risk of experiencing QT prolongation. The use of such drugs may be considered as safe relating to arrhythmic risk in the treatment of COVID-19 patients as no arrhythmic fatalities occurred.
Asunto(s)
Azitromicina/administración & dosificación , Azitromicina/efectos adversos , COVID-19/inducido químicamente , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/efectos adversos , Síndrome de QT Prolongado/tratamiento farmacológico , Anciano , Anciano de 80 o más Años , Antibacterianos/administración & dosificación , Antibacterianos/efectos adversos , Antimaláricos/administración & dosificación , Antimaláricos/efectos adversos , COVID-19/diagnóstico , COVID-19/fisiopatología , Quimioterapia Combinada , Electrocardiografía/efectos de los fármacos , Electrocardiografía/tendencias , Femenino , Estudios de Seguimiento , Humanos , Síndrome de QT Prolongado/diagnóstico , Masculino , Persona de Mediana Edad , Seguridad del Paciente , Estudios RetrospectivosRESUMEN
BACKGROUND: The effect of immunosuppressive treatment for immune-mediated diseases on risk of the novel coronavirus disease 2019 (COVID-19) has not been established. We aimed to define the effect of targeted biologic and immunomodulator therapy on risk of COVID-19 in a multi-institutional cohort of patients with inflammatory bowel disease (IBD). METHODS: We identified patients 18 years and older who received care for IBD at Partners Healthcare between January 2019 and April 2020. The primary outcome was development of COVID-19 defined as a positive polymerase chain reaction test for severe acute respiratory syndrome coronavirus 2. Multivariable regression models were used to examine the effect of immunosuppression on risk of COVID-19 and its outcomes. RESULTS: In a cohort of 5302 IBD patients, 39 (0.7%) developed COVID-19. There was no difference in age, sex, or race between IBD patients with and without COVID-19. The rate of COVID-19 was similar between patients treated with immunosuppression (0.8%) compared with those who were not (0.64%; P = 0.55). After adjusting for age, sex, race, and comorbidities, use of immunosuppressive therapy was not associated with an increased risk of COVID-19 (odds ratio, 1.73; 95% confidence interval, 0.82-3.63). The presence of obesity was associated with a higher risk of COVID-19 (odds ratio, 8.29; 95% confidence interval, 3.72-18.47). There were 7 hospitalizations, 3 intensive care unit stays, and 1 death. Older age and obesity but not immunosuppressive treatment were associated with severe COVID-19 infection. CONCLUSIONS: The use of systemic immunosuppression was not associated with an increased risk of COVID-19 in a multi-institutional cohort of patients with IBD.
Asunto(s)
Productos Biológicos/efectos adversos , COVID-19/inducido químicamente , Inmunosupresores/efectos adversos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , SARS-CoV-2 , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , COVID-19/epidemiología , COVID-19/virología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/virología , Enfermedad de Crohn/tratamiento farmacológico , Enfermedad de Crohn/virología , Femenino , Humanos , Enfermedades Inflamatorias del Intestino/virología , Masculino , Persona de Mediana Edad , Oportunidad Relativa , Análisis de Regresión , Factores de Riesgo , Adulto JovenRESUMEN
The coronavirus disease (COVID-19) pandemic is a global health priority. Given that cardiovascular diseases (CVD) are the leading cause of morbidity around the world and that several trials have reported severe cardiovascular damage in patients infected with SARS-CoV-2, a substantial number of COVID-19 patients with underlying cardiovascular diseases need to continue their medications in order to improve myocardial contractility and to prevent the onset of major adverse cardiovascular events (MACEs), including heart failure. Some of the current life-saving medications may actually simultaneously expose patients to a higher risk of severe COVID-19. Angiotensin-converting enzyme 2 (ACE2), a key counter regulator of the renin-angiotensin system (RAS), is the main entry gate of SARS-CoV-2 into human host cells and an established drug target to prevent heart failure. In fact, ACE inhibitors, angiotensin II receptor blockers, and mineralocorticoid antagonists may augment ACE2 levels to protect organs from angiotensin II overload. Elevated ACE2 expression on the host cell surface might facilitate viral entrance, at the same time sudden nonadherence to these medications triggers MACEs. Hence, safety issues in the use of RAS inhibitors in COVID-19 patients with cardiac dysfunction remain an unsolved dilemma and need paramount attention. Although ACE2 generally plays an adaptive role in both healthy subjects and patients with systolic and/or diastolic dysfunction, we conducted a literature appraisal on its maladaptive role. Understanding the exact role of ACE2 in COVID-19 patients at risk of heart failure is needed to safely manage RAS inhibitors in frail and non-frail critically ill patients.
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Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , COVID-19/inducido químicamente , COVID-19/epidemiología , Insuficiencia Cardíaca/tratamiento farmacológico , Enzima Convertidora de Angiotensina 2/fisiología , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , Inhibidores de la Enzima Convertidora de Angiotensina/uso terapéutico , Humanos , Sistema Renina-Angiotensina/efectos de los fármacos , Sistema Renina-Angiotensina/fisiología , Medición de RiesgoRESUMEN
Coronavirus disease 2019 (COVID-19) is due to severe acute respiratory syndrome coronavirus (SARS-CoV)-2 which binds and enters the host cells through the angiotensin-converting enzyme (ACE)2. While the potential for benefit with the use of renin-angiotensin-aldosterone system inhibitors (RAASi) and the risks from stopping them is more evident, potential harm by RAΑSi may also be caused by the increase in the activity of the ACE2 receptor, the inefficient counter regulatory axis in the lungs in which the proinflammatory prolyloligopeptidase (POP) is the main enzyme responsible for the conversion of deleterious angiotensin (ANG) II to protective ANG [1-7] and the proinflammatory properties of ACE2(+) cells infected with SARS-CoV-2. Acknowledging the proven RAΑSi benefit in patients with several diseases such as hypertension, heart failure, coronary disease, and diabetic kidney disease in the non-COVID-19 era, it is a reasonable strategy in this period of uncertainty to use these agents judiciously with careful consideration and to avoid the use of RAASi in select patients whenever possible, until definitive evidence becomes available.
Asunto(s)
Inhibidores de la Enzima Convertidora de Angiotensina/efectos adversos , COVID-19/inducido químicamente , Sistema Renina-Angiotensina/efectos de los fármacos , Inhibidores de la Enzima Convertidora de Angiotensina/farmacología , HumanosRESUMEN
Acute lung injury (ALI), a devastating illness induced by systemic inflammation e.g., sepsis or local lung inflammation e.g., COVID-19 mediated severe pneumonia, has an unacceptably high mortality and has no effective therapy. ALI is associated with increased pulmonary microvascular hyperpermeability and alveolar flooding. The small Rho GTPases, RhoA and Rac1 are central regulators of vascular permeability through cytoskeleton rearrangements. RhoA and Rac1 have opposing functional outcome: RhoA induces an endothelial contractile phenotype and barrier disruption, while Rac1 stabilizes endothelial junctions and increases barrier integrity. In ALI, RhoA activity is increased while Rac1 activity is reduced. We have shown that the activation of RhoA in lipopolysaccharide (LPS)-mediated ALI, is dependent, at least in part, on a single nitration event at tyrosine (Y)34. Thus, the purpose of this study was to determine if the inhibition of Rac1 is also dependent on its nitration. Our data show that Rac1 inhibition by LPS is associated with its nitration that mass spectrometry identified as Y32, within the switch I region adjacent to the nucleotide-binding site. Using a molecular modeling approach, we designed a nitration shielding peptide for Rac1, designated NipR2 (nitration inhibitor peptide for the Rho GTPases 2), which attenuated the LPS-induced nitration of Rac1 at Y32, preserves Rac1 activity and attenuates the LPS-mediated disruption of the endothelial barrier in human lung microvascular endothelial cells (HLMVEC). Using a murine model of ALI induced by intratracheal installation of LPS we found that NipR2 successfully prevented Rac1 nitration and Rac1 inhibition, and more importantly attenuated pulmonary inflammation, reduced lung injury and prevented the loss of lung function. Together, our data identify a new post-translational mechanism of Rac1 inhibition through its nitration at Y32. As NipR2 also reduces sepsis induced ALI in the mouse lung, we conclude that Rac1 nitration is a therapeutic target in ALI.
Asunto(s)
Lesión Pulmonar Aguda , Barrera Alveolocapilar , COVID-19 , Células Endoteliales , Lipopolisacáridos/toxicidad , Neuropéptidos/metabolismo , SARS-CoV-2/metabolismo , Proteína de Unión al GTP rac1/metabolismo , Lesión Pulmonar Aguda/inducido químicamente , Lesión Pulmonar Aguda/enzimología , Lesión Pulmonar Aguda/patología , Lesión Pulmonar Aguda/virología , Animales , Barrera Alveolocapilar/enzimología , Barrera Alveolocapilar/patología , Barrera Alveolocapilar/virología , COVID-19/inducido químicamente , COVID-19/enzimología , COVID-19/patología , Línea Celular , Células Endoteliales/metabolismo , Células Endoteliales/patología , Células Endoteliales/virología , Humanos , Masculino , Ratones , Neuropéptidos/genética , Proteína de Unión al GTP rac1/genéticaRESUMEN
BACKGROUND: Patients on kidney replacement therapy comprise a vulnerable population and may be at increased risk of death from coronavirus disease 2019 (COVID-19). Currently, only limited data are available on outcomes in this patient population. METHODS: We set up the ERACODA (European Renal Association COVID-19 Database) database, which is specifically designed to prospectively collect detailed data on kidney transplant and dialysis patients with COVID-19. For this analysis, patients were included who presented between 1 February and 1 May 2020 and had complete information available on the primary outcome parameter, 28-day mortality. RESULTS: Of the 1073 patients enrolled, 305 (28%) were kidney transplant and 768 (72%) dialysis patients with a mean age of 60 ± 13 and 67 ± 14 years, respectively. The 28-day probability of death was 21.3% [95% confidence interval (95% CI) 14.3-30.2%] in kidney transplant and 25.0% (95% CI 20.2-30.0%) in dialysis patients. Mortality was primarily associated with advanced age in kidney transplant patients, and with age and frailty in dialysis patients. After adjusting for sex, age and frailty, in-hospital mortality did not significantly differ between transplant and dialysis patients [hazard ratio (HR) 0.81, 95% CI 0.59-1.10, P = 0.18]. In the subset of dialysis patients who were a candidate for transplantation (n = 148), 8 patients died within 28 days, as compared with 7 deaths in 23 patients who underwent a kidney transplantation <1 year before presentation (HR adjusted for sex, age and frailty 0.20, 95% CI 0.07-0.56, P < 0.01). CONCLUSIONS: The 28-day case-fatality rate is high in patients on kidney replacement therapy with COVID-19 and is primarily driven by the risk factors age and frailty. Furthermore, in the first year after kidney transplantation, patients may be at increased risk of COVID-19-related mortality as compared with dialysis patients on the waiting list for transplantation. This information is important in guiding clinical decision-making, and for informing the public and healthcare authorities on the COVID-19-related mortality risk in kidney transplant and dialysis patients.