Susceptibilidad del TLR-4 en el desarrollo de shock séptico

Introducción: TLR-4 es un receptor transmembranoso que forma parte de la inmunidad innata. Su función es reconocer patrones moleculares expresados por agentes bacterianos y, seguidamente, estimular una respuesta inflamatoria. Nuestro objetivo es analizar si el polimorfismo TLR-4 rs4986790 se asocia al desarrollo de shock séptico tras una cirugía mayor. Métodos: se realiza un estudio de casos y controles en 467 pacientes sometidos a cirugía cardíaca o abdominal. De ellos, 205 pacientes desarrollaron shock séptico (casos) y 262 pacientes desarrollaron SIRS (Controles). El polimorfismo TLR-4 rs4986790 fue genotipado por MassARRAY. El análisis de asociación se realizó bajo un modelo genético dominante (AG / GG vs. AA). Resultados: el genotipo TLR-4 rs4986790 AG / GG se asocia con una menor probabilidad de shock séptico en el análisis de los pacientes sometidos, únicamente, a cirugía abdominal [odds ratio ajustado (aOR) = 2.6 (IC del 95% = 1,75; 6,289; p = 0,034], pero no en el total de pacientes (p = 0,059) o estratificando a los sometidos a cirugía cardíaca (p=0,617). Existen parámetros preoperatorios como insuficiencia renal crónica, tabaquismo y neoplasia (aOR=2,973; p=0,031); y postoperatorios como Score APACHE-II > 19 y Ácido láctico > 2mmol/l (aOR=3,401; p=0,030), que se asocian con dicha susceptibilidad. Conclusiones: el genotipo TLR-4 rs4986790 AG / GG genera un efecto protector en el desarrollo de shock séptico en pacientes sometidos a cirugía mayor abdominal.Grado en Medicin

Importancia del perfil inflamatorio-molecular en la infección por SARS-COV-2 y su relación con el grupo sanguíneo ABO.

INTRODUCTION The emergence of SARS-CoV-2 in China in December 2019 along with its worldwide spread, has generated a need for knowledge about this new viral infection. In our country, official national data as of March 25, 2020 recorded 47,610 diagnosed cases with 3,434 deaths, assuming a mortality rate of 7.21%. Initial studies associated dysregulation of the immune response with cytokine hypersecretion, marked lymphopenia, prothrombotic status and endothelitis. The mechanism of viral replication was also beginning to be detailed, with ACE2 appearing to be, as in SARS-CoV, the host cell receptor employed by the virus. In addition, at that time the ABO blood group began to be related to susceptibility and severity of infection. Blood group A associates intrinsic prothrombotic and inflammatory characteristics, aspects superimposable to the clinical presentation of the new SARS-CoV-2 infection. On the other hand, the polyspecificity of natural antibodies to various antigens in humans is widely known. However, while a relationship between the ABO system and novel SARS-CoV-2 seemed reasonable, the lack of knowledge and the need for specific studies on this interaction were necessary. To this end, new investigations were required that included a larger sample size, the analysis of several evolutionary moments in the course of hospital admission, and the analysis of a broad set of biomarkers related to the immune response. OBJECTIVE To study the inflammatory-molecular response of SARS-CoV-2 infection in order to identify diagnostic and prognostic biomarkers and to evaluate the involvement of ABO blood group in the modulation of this inflammatory response, susceptibility and severity of this infection. METHODOLOGY Prospective and consecutive study of 108 COVID-19 patients admitted to the Hospital Clínico Universitario de Valladolid (Spain) who were recruited between March 24 and April 11, 2020. In addition, 28 healthy controls were also included. Using Luminex technology, plasma from controls and each patient was analyzed in duplicate at admission and 6 days after hospital stay to quantify 45 soluble mediators (45-plex Human XL Cytokine Luminex Performance Panel (R&D) kit). ABO blood typing was performed on a fully automated analyzer (Erytra® Automated System for Blood Typing) using DG Gel® cards. The study was approved by the Hospital's Clinical Ethics Committee (cod: PI 20-1717). Both the statistical package IBM SPSS Statistics Software (SPSS) version 25 and the statistical package R version 4.0.2 (R Core Team; Foundation for Statistical Computing, Vienna, Austria) were used for statistical analyses. RESULTS - Article 1: Patients with COVID-19 showed different levels in multiple cytokines compared to control patients. IP-10 accurately identified patients requiring hospital admission [AUC: 0.962; 95%CI (0.933-0.992); p<0.001]. Results were validated in an independent cohort by multivariate analysis [OR: 25.573; 95%CI (8.127-80.469); p<0.001] and AUROC [AUC: 0.900; 95%CI (0.846-0.954); p<0.001]. In addition, plasma IP-10 levels above 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. - Article 2: High HGF levels were associated with critically ill patients [OR: 3.51; 95%CI (1.95-6.33); p<0.001]. In addition, elevated IL-1&#945; [OR: 1.36; 95%CI (1.07-1.73; p=0.01] and low IL-27 levels [OR: 0.58; 95%CI (0.39-0.85); p<0.005] significantly increased the risk of termination in the severe group. This model was especially sensitive in predicting the critically ill patient [AUC: 0.794; specificity: 69.74%; sensitivity: 81.25%). Elevation of HGF and IL-1&#945; was also significant in survival analysis (p=0.033 and p=0.011, respectively). - Article 3: Blood group A patients had a higher Charlson comorbidity index (p=0.037), higher rate of lymphopenia (p=0.039) and thrombopenia (p=0.014), as well as higher hospital mortality (p=0.044). Blood group A was an independent factor associated with Charlson index [B: 0.582, 95%CI (0.02-1.14), p=0.041]. - Article 4: The cornerstone of the ABO system involved in susceptibility and severity to SARS-CoV-2 infection is its natural anti-A and anti-B antibodies. They are able to interfere with the binding between the S protein of the virus and ACE2 (host cell receptor), which confers protection to patients with natural antibodies (blood group O). Natural antibody titers and IgG isotype may also be determinants of susceptibility. In addition, the elderly population is associated with a worse evolution given the decrease in antibodies and the positive regulation of ACE2 expression during senescence. - Article 5: Blood group O had a 2-fold lower risk of requiring mechanical ventilation or death at 28 days (log rank: p=0.042). At admission, all statistically significant cytokine levels, except HGF, were higher in blood group O patients, while at 6 days of admission they showed a significant decrease, between 20% and 40%. In contrast, the A/B/AB group showed a maintenance of cytokine levels over time. HGF showed a significant association with the risk of intubation or mortality in non-O blood group [OR: 4.229, 95%CI (2.064-8.665), p<0.001] and was also the only biomarker of poor prognosis in O blood group patients [OR: 8.852, 95%CI (1.540-50.878), p=0.015]. At hospital admission, higher cytokine levels in blood group O were associated with a better prognosis. CONCLUSIONS In SARS-CoV-2 infection, the study of the inflammatory-molecular profile together with the involvement of ABO blood group has identified diagnostic markers (IP-10), prognostic markers (HGF, IL-1&#945; and IL-27) and delved into the role played by ABO system antibodies in the modulation of the immune response (blood group O associates higher cytokine elevation that condition a better prognosis). The main conclusions derived from the different research works carried out have been the following: 1. IP-10 was identified as a robust marker in the early detection of SARS-CoV-2 infection in hospitalized patients. 2. Elevated levels of HGF and IL-1, along with decreased IL-27 were strongly associated with disease severity and were excellent predictors of poor prognosis. In fact, IL-1 and HGF were also biomarkers of mortality. 3. In the setting of SARS-CoV-2 infection, blood group A was associated with a higher Charlson comorbidity index as well as higher hospital-level mortality. 4. Blood group O was associated with lower hospital admission rates and lower risk of intubation or mortality. 5. Natural anti-A and B antibodies of the ABO system interfere by hindering the binding between SARS-CoV-2 protein S and host cell ACE2, conferring lower susceptibility and severity to patients of blood group O. 6. The better prognosis in blood group O was associated with significantly higher levels of all cytokines analyzed at admission (except HGF) with a consequent decrease at 6 days of hospital stay, not evidenced in other blood groups. 7. The plasma concentration of antibodies, the relevance of the IgG isotype in blood group O and the positive regulation of ACE2 expression together with the decrease of immunoglobulins in senescence, are other determinants in the severity of infection.INTRODUCCIÓN La aparición del SARS-CoV-2 en China en diciembre de 2019 junto con su expansión mundial, ha generado una necesidad de conocimiento acerca de esta nueva infección viral. En nuestro país, los datos nacionales oficiales a 25 de marzo de 2020 registraban 47.610 casos diagnosticados con 3.434 fallecidos, suponiendo una tasa de mortalidad del 7,21%. Estudios iniciales asociaron una disregulación de la respuesta inmunitaria con hipersecreción de citoquinas, una linfopenia marcada, un estatus protrombótico y una endotelitis. Se empezaba a detallar también el mecanismo de replicación viral, pareciendo ser la ACE2, al igual que en el SARS-CoV, el receptor de la célula huésped empleado por el virus. Además, en ese momento el grupo sanguíneo ABO comenzó a relacionarse con la susceptibilidad y severidad a la infección. El grupo sanguíneo A asocia unas características intrínsecas protrombóticas e inflamatorias, aspectos superponibles a la presentación clínica de la nueva infección por SARS-CoV-2. Por otro lado, la poliespecificidad de los anticuerpos naturales a antígenos diversos en el ser humano es ampliamente conocida. Sin embargo, pareciendo razonable una relación entre el sistema ABO y el nuevo SARS-CoV-2, el desconocimiento y necesidad de estudios específicos sobre esta interacción eran necesarios. Para ello, se requerían nuevas investigaciones que incluyesen un mayor tamaño muestral, el análisis de varios momentos evolutivos en el transcurso del ingreso hospitalario y el análisis de un amplio conjunto de biomarcadores relacionados con la respuesta inmunitaria. OBJETIVO Estudiar la respuesta inflamatoria-molecular de la infección por SARS-CoV-2 para identificar biomarcadores diagnósticos, pronósticos y evaluar la implicación del grupo sanguíneo ABO en la modulación de esta respuesta inflamatoria, la susceptibilidad y la gravedad de esta infección. METODOLOGÍA Estudio prospectivo y consecutivo de 108 pacientes COVID-19 ingresados en el Hospital Clínico Universitario de Valladolid (España) que fueron reclutados entre el 24 de marzo y el 11 de abril de 2020. Además, también se incluyeron 28 controles sanos. Mediante tecnología Luminex se analizó, por duplicado, el plasma de los controles y cada paciente al ingreso y a los 6 días de estancia hospitalaria para cuantificar 45 mediadores solubles (kit 45-plex Human XL Cytokine Luminex Performance Panel (R&D)). La determinación del grupo sanguíneo ABO se realizó en un analizador completamente automatizado (Erytra® Automated System for Blood Typing) usando tarjetas DG Gel®. El estudio fue aprobado por el Comité de Ética Clínica del Hospital (cod: PI 20-1717). Para los análisis estadísticos se emplearon tanto el paquete estadístico Software IBM SPSS Statistics (SPSS) versión 25 como el paquete estadístico R versión 4.0.2 (R Core Team; Foundation for Statistical Computing, Viena, Austria). RESULTADOS - Artículo 1: Los pacientes con COVID-19 mostraron diferentes niveles en múltiples citoquinas en comparación con los pacientes control. La IP-10 identificó con precisión a pacientes que requirieron ingreso hospitalario [AUC: 0,962; IC95% (0,933&#8211;0,992); p<0,001]. Los resultados fueron validados en una cohorte independiente mediante análisis multivariante [OR: 25.573; 95%CI (8.127&#8211;80.469); p<0.001] y AUROC [AUC: 0.900; 95%CI (0.846&#8211;0.954); p<0.001]. Además, niveles plasmáticos de IP-10 superiores a 173,35 pg/mL identificaron el COVID-19 con mayor sensibilidad (86,20%) que la primera PCR de SARS-CoV-2. - Artículo 2: Altos niveles de HGF se asociaron con pacientes críticos [OR: 3,51; IC95% (1,95&#8211;6,33); p<0,001]. Además, la elevación de la IL-1&#945; [OR: 1,36; IC95% (1,07&#8211;1,73; p=0,01] y niveles bajos de IL-27 [OR: 0,58; IC95% (0,39&#8211;0,85); p<0,005] aumentaron considerablemente el riesgo de terminar en el grupo severo. Este modelo fue especialmente sensible para predecir al paciente crítico [AUC: 0,794; especificidad: 69,74%; sensibilidad: 81,25%). La elevación de la HGF y la IL-1&#945; también resultó significativa en el análisis de supervivencia (p=0,033 y p=0,011, respectivamente). - Artículo 3: Los pacientes del grupo sanguíneo A tuvieron un mayor índice de comorbilidad de Charlson (p=0,037), mayor tasa de linfopenia (p=0,039) y trombopenia (p=0,014), así como mayor mortalidad hospitalaria (p=0,044). El grupo sanguíneo A fue un factor independiente asociado con el índice de Charlson [B: 0,582, IC95% (0,02&#8211;1,14), p=0,041]. - Artículo 4: La piedra angular del sistema ABO involucrada en la susceptibilidad y gravedad a la infección por SARS-CoV-2 son sus anticuerpos naturales anti-A y anti-B. Son capaces de interferir en la unión entre la proteína S del virus y la ACE2 (receptor de la célula huésped), lo que confiere protección a los pacientes con anticuerpos naturales (grupo sanguíneo O). Los títulos de anticuerpos naturales y el isotipo IgG pueden ser también determinantes en la susceptibilidad. Además, la población anciana está asociada a una peor evolución dado el descenso de anticuerpos y la regulación positiva de la expresión de ACE2 durante la senescencia. - Artículo 5: El grupo sanguíneo O presentó un riesgo dos veces inferior de requerir ventilación mecánica o fallecer a los 28 días (log rank: p=0,042). Al ingreso, todos los niveles de citoquinas estadísticamente significativos, excepto HGF, fueron más altos en los pacientes del grupo sanguíneo O, mientras que, a los 6 días de ingreso mostraron un descenso significativo, entre 20% y 40%. Por el contrario, el grupo A/B/AB presentó un mantenimiento de los niveles de citoquinas a lo largo del tiempo. HGF mostró una asociación significativa con el riesgo de intubación o mortalidad en el grupo sanguíneo no-O [OR: 4,229, IC95% (2,064&#8211;8,665), p<0,001] y también fue el único biomarcador de mal pronóstico en pacientes del grupo sanguíneo O [OR: 8,852, IC95% (1,540&#8211;50,878), p=0,015]. Al ingreso hospitalario, los mayores niveles de citoquinas en el grupo sanguíneo O asociaron un mejor pronóstico. CONCLUSIONES En la infección por SARS-CoV-2, el estudio del perfil inflamatorio-molecular junto con la implicación del grupo sanguíneo ABO ha identificado marcadores diagnósticos (IP-10), pronósticos (HGF, IL-1&#945; e IL-27) y ahondado en el papel que juegan los anticuerpos del sistema ABO en la modulación de la respuesta inmune (grupo sanguíneo O asocia mayor elevación de citoquinas que condicionan un mejor pronóstico). Las principales conclusiones derivadas de los diferentes trabajos de investigación realizados han sido las siguientes: 1. Se identificó la IP-10 como un marcador robusto en la detección precoz de la infección por SARS-CoV-2 en pacientes hospitalizados. 2. Elevados niveles de HGF e IL-1, junto con el descenso de la IL-27 estaban fuertemente asociados con la gravedad de la enfermedad y fueron excelentes predictores de mal pronóstico. De hecho, IL-1 y HGF eran también biomarcadores de mortalidad. 3. En el contexto de una infección por SARS-CoV-2, el grupo sanguíneo A se asoció con un mayor índice de comorbilidad de Charlson así como con una mayor mortalidad a nivel hospitalario. 4. El grupo sanguíneo O asoció menores tasas de ingreso hospitalario y menor riesgo de intubación o mortalidad. 5. Los anticuerpos naturales anti-A y B del sistema ABO interfieren dificultando la unión entre la proteína S del SARS-CoV-2 y la ACE2 de la célula huésped, confiriendo una menor susceptibilidad y gravedad a los pacientes de grupo sanguíneo O. 6. El mejor pronóstico en el grupo sanguíneo O se asoció con niveles significativamente mayores de todas las citoquinas analizadas al ingreso (excepto la HGF) con un consiguiente descenso a los 6 días de estancia hospitalaria, no evidenciado en otros grupos sanguíneos. 7. La concentración plasmática de los anticuerpos, la relevancia del isotipo IgG en el grupo sanguíneo O y la regulación positiva de la expresión de la ACE2 junto con el descenso de las inmunoglobulinas en la senescencia, son otros determinantes en la severidad de la infección. &#8195;Escuela de DoctoradoDoctorado en Investigación en Ciencias de la Salu

Environmental factors are associated to hospital outcomes in COVID-19 patients during lockdown and post-lockdown in 2020: A nationwide study

Producción CientíficaThis study analyzed, at a postcode detailed level, the relation-ship between short-term exposure to environmental factors and hospital ad-missions, in-hospital mortality, ICU admission, and ICU mortality due to COVID-19 during the lockdown and post-lockdown 2020 period in Spain. Short-term exposure to air pollutants impacts COVID-19 out-comes during the lockdown, especially PM2.5, PM10, NO2, and SO2. These pollutants are associated with hospital admission, hospital mortality and ICU admission, while ICU mortality is mainly associated with PM2.5 and PM10. Our findings reveal the importance of monitoring air pollutants in respiratory infectious diseases.Ministerio de Ciencia e Innovación y Unión Europea – Next Generation EU (CB21/13/00044 y CB21/13/ 00051)Instituto Carlos III - FEDER. Río Hortega grant (CM20/00138

Nosocomial Vs. Community-Acquired Infective Endocarditis in Spain: Location, Trends, Clinical Presentation, Etiology, and Survival in the 21st Century

Major changes have occurred in the epidemiology and etiology of infective endocarditis (IE). Nevertheless, the differences between nosocomial infective endocarditis (NIE) and community-acquired infective endocarditis (CIE) have not been addressed in a population-based study. We conducted a retrospective, nationwide, temporal trend study from 1997 to 2014 analyzing the epidemiology, clinical, geographical, meteorological characteristics of patients diagnosed with IE in Spain, to distinguish NIE from CIE. Among 25,952 patients with IE (62.2 ± 18·6 years; 65.9% men), 45.9% had NIE. The incidence of IE increased from 2.83 to 3.73 due to the NIE incidence increment with a decline in CIE. Patients with NIE were older (63.8 years vs. 60.8 years, p < 0·001), presented a higher Charlson index (1.22 vs. 1.03, p < 0.001), a greater history of implanted cardiac devices (8.7% vs. 4.6%, p < 0.001), and higher mortality (31.5% vs. 21.7%, p < 0.001). The most frequent microorganism for both NIE and CIE was Staphylococcus (p < 0.001), and the North reported a higher incidence (p < 0.001). Risk factors of mortality for NIE were age, Charlson index, hemodialysis, shock, heart failure, and stroke. Risk factors for CIE included female sex, renal disease, and cardiac-device carriers. The etiology of IE shifted from community origins to mostly nosocomial-associated infections. Higher morbidity, mortality, and poorer outcomes are associated with NIE.This research received no external funding. The authors thank Consejería de Educación, Junta de Castilla y León, Spain (reference: VA161G18), for covering the publication charges of this article.S

Predictive modeling of poor outcome in severe COVID-19: A single-center observational study based on clinical, cytokine and laboratory profiles

Producción CientíficaPneumonia is the main cause of hospital admission in COVID-19 patients. We aimed to perform an extensive characterization of clinical, laboratory, and cytokine profiles in order to identify poor outcomes in COVID-19 patients. Methods: A prospective and consecutive study involving 108 COVID-19 patients was conducted between March and April 2020 at Hospital Clínico Universitario de Valladolid (Spain). Plasma samples from each patient were collected after emergency room admission. Forty-five serum cytokines were measured in duplicate, and clinical data were analyzed using SPPS version 25.0. Results: A multivariate predictive model showed high hepatocyte growth factor (HGF) plasma levels as the only cytokine related to intubation or death risk at hospital admission (OR = 7.38, 95%CI—(1.28–42.4), p = 0.025). There were no comorbidities included in the model except for the ABO blood group, in which the O blood group was associated with a 14-fold lower risk of a poor outcome. Other clinical variables were also included in the predictive model. The predictive model was internally validated by the receiver operating characteristic (ROC) curve with an area under the curve (AUC) of 0.94, a sensitivity of 91.7% and a specificity of 95%. The use of a bootstrapping method confirmed these results. Conclusions: A simple, robust, and quick predictive model, based on the ABO blood group, four common laboratory values, and one specific cytokine (HGF), could be used in order to predict poor outcomes in COVID-19 patients.Instituto de Salud Carlos III - ( Proyecto COV20/00491)Consejeria de Educación de Castilla y León - (Proyecto VA256P20)Junta de Castilla y León y Fondo Europeo de Desarrollo Regional (FEDER) - (Proyecto EDU/1100/2017

HGF, IL-1α, and IL-27 are robust biomarkers in early severity stratification of COVID-19 patients

© 2021 by the authors.Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.This work was supported by the Carlos III Health Institute (Grant COV20/00491)

HGF, IL-1α, and IL-27 Are Robust Biomarkers in Early Severity Stratification of COVID-19 Patients

Producción CientíficaPneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19). We aimed to identify the cytokines responsible for lung damage and mortality. We prospectively recruited 108 COVID-19 patients between March and April 2020 and divided them into four groups according to the severity of respiratory symptoms. Twenty-eight healthy volunteers were used for normalization of the results. Multiple cytokines showed statistically significant differences between mild and critical patients. High HGF levels were associated with the critical group (OR = 3.51; p < 0.001; 95%CI = 1.95–6.33). Moreover, high IL-1α (OR = 1.36; p = 0.01; 95%CI = 1.07–1.73) and low IL-27 (OR = 0.58; p < 0.005; 95%CI = 0.39–0.85) greatly increased the risk of ending up in the severe group. This model was especially sensitive in order to predict critical status (AUC = 0.794; specificity = 69.74%; sensitivity = 81.25%). Furthermore, high levels of HGF and IL-1α showed significant results in the survival analysis (p = 0.033 and p = 0.011, respectively). HGF, IL-1α, and IL 27 at hospital admission were strongly associated with severe/critical COVID-19 patients and therefore are excellent predictors of bad prognosis. HGF and IL-1α were also mortality biomarkers.Instituto de Salud Carlos III (grant COV20/00491

Evaluation of cytokines as robust diagnostic biomarkers for COVID-19 detection

Producción CientíficaAntigen tests or polymerase chain reaction (PCR) amplification are currently COVID-19 diagnostic tools. However, developing complementary diagnosis tools is mandatory. Thus, we performed a plasma cytokine array in COVID-19 patients to identify novel diagnostic biomarkers. A discovery–validation study in two independent prospective cohorts was performed. The discovery cohort included 136 COVID-19 and non-COVID-19 patients recruited consecutively from 24 March to 11 April 2020. Forty-five cytokines’ quantification by the MAGPIX system (Luminex Corp., Austin, TX, USA) was performed in plasma samples. The validation cohort included 117 patients recruited consecutively from 15 to 25 April 2020 for validating results by ELISA. COVID-19 patients showed different levels of multiple cytokines compared to non-COVID-19 patients. A single chemokine, IP-10, accurately identified COVID-19 patients who required hospital admission (AUC: 0.962; 95%CI (0.933–0.992); p < 0.001)). The results were validated in an independent cohort by multivariable analysis (OR: 25.573; 95%CI (8.127–80.469); p < 0.001) and AUROC (AUC: 0.900; 95%CI (0.846–0.954); p < 0.001). Moreover, showing IP-10 plasma levels over 173.35 pg/mL identified COVID-19 with higher sensitivity (86.20%) than the first SARS-CoV-2 PCR. Our discover–validation study identified IP-10 as a robust biomarker in clinical practice for COVID-19 diagnosis at hospital. Therefore, IP-10 could be used as a complementary tool in clinical practice, especially in emergency departments.Instituto de Salud Carlos III (grant COV20/00491)Consejo Superior de Investigaciones científicas (grant CSIC-COV19-016/202020E155)Junta de Castilla y León (project COVID 07.04.467B04.74011.0)IBGM excellence programme (grant CLU-2029-02

Can the Cytokine Profile According to ABO Blood Groups Be Related to Worse Outcome in COVID-19 Patients? Yes, They Can

Producción CientíficaSevere status of coronavirus disease 2019 (COVID-19) is extremely associated to cytokine release. Moreover, it has been suggested that blood group is also associated with the prevalence and severity of this disease. However, the relationship between the cytokine profile and blood group remains unclear in COVID-19 patients. In this sense, we prospectively recruited 108 COVID-19 patients between March and April 2020 and divided according to ABO blood group. For the analysis of 45 cytokines, plasma samples were collected in the time of admission to hospital ward or intensive care unit and at the sixth day after hospital admission. The results show that there was a risk of more than two times lower of mechanical ventilation or death in patients with blood group O (log rank: p = 0.042). At first time, all statistically significant cytokine levels, except from hepatocyte growth factor, were higher in O blood group patients meanwhile the second time showed a significant drop, between 20% and 40%. In contrast, A/B/AB group presented a maintenance of cytokine levels during time. Hepatocyte growth factor showed a significant association with intubation or mortality risk in non-O blood group patients (OR: 4.229, 95% CI (2.064–8.665), p < 0.001) and also was the only one bad prognosis biomarker in O blood group patients (OR: 8.852, 95% CI (1.540–50.878), p = 0.015). Therefore, higher cytokine levels in O blood group are associated with a better outcome than A/B/AB group in COVID-19 patients.Instituto de Salud Carlos III (grant COV20/00491)Junta de Castilla y León (grant 18IGOF

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality