RT info:eu-repo/semantics/doctoralThesis
T1 Importancia del perfil inflamatorio-molecular en la infección por SARS-COV-2 y su relación con el grupo sanguíneo ABO.
A1 Tamayo Velasco, Álvaro
A2 Universidad de Valladolid. Escuela de Doctorado
K1 COVID-19 (Disease)
K1 Hematología
K1 COVID-19
K1 ABO blood group
K1 Grupo sanguíneo ABO
K1 Inflammatory Profile
K1 Perfil Inflamatorio
K1 32 Ciencias Médicas
AB INTRODUCTIONThe 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.OBJECTIVETo 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.CONCLUSIONSIn 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.
YR 2021
FD 2021
LK https://uvadoc.uva.es/handle/10324/59908
UL https://uvadoc.uva.es/handle/10324/59908
LA spa
NO Escuela de Doctorado
DS UVaDOC
RD 22-dic-2024