Impact of COVID-19 pandemic on the PREDIMED-Plus randomized clinical trial: Effects on the interventions, participants follow-up, and adiposity.

Background: The COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity. Methods: We assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown. Results: During the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants' follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60-0.91]) and after (0.72 cm [95% CI: 0.56-0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: -0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: -0.30 to -0.04]). Conclusion: Mitigating strategies to enforce the intervention and patient's follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity. Clinical trial registration: https://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870.

Impact of COVID-19 pandemic on the PREDIMED-Plus randomized clinical trial: Effects on the interventions, participants follow-up, and adiposity

Background The COVID-19 pandemic has affected the implementation of most ongoing clinical trials worldwide including the PREDIMED-Plus study. The PREDIMED-Plus is an ongoing, multicenter, controlled intervention trial, aimed at weight-loss and cardiovascular disease prevention, in which participants were randomized (1:1 ratio) to an intervention group (energy-reduced Mediterranean diet, promotion of physical activity, and behavioral support) or to a control group (Mediterranean diet with usual care advice). When the pandemic began, the trial was in the midst of the planned intervention. The objective of this report was to examine the effects of the pandemic on the delivery of the intervention and to describe the strategies established to mitigate the possible adverse effects of the pandemic lockdown on data collection and adiposity. Methods We assessed the integrity of the PREDIMED-Plus trial during 5 identified periods of the COVID-19 pandemic determined according to restrictions dictated by the Spanish government authorities. A standardized questionnaire was delivered to each of the 23 PREDIMED-Plus recruiting centers to collected data regarding the trial integrity. The effect of the restrictions on intervention components (diet, physical activity) was evaluated with data obtained in the three identified lockdown phases: pre lockdown, lockdown proper, and post lockdown. Results During the lockdown (March/2020-June/2021), 4,612 participants (48% women, mean age 65y) attended pre-specified yearly follow-up visits to receive lifestyle recommendations and obtain adiposity measures. The overall mean (SD) of the proportions reported by each center showed that 40.4% (25.4) participants had in-person visits, 39.8% (18.2) participants were contacted by telephone and 35% (26.3) by electronic means. Participants' follow-up and data collection rates increased across lockdown periods (from ≈10% at onset to ≈80% at the end). Compared to pre-lockdown, waist circumference increased during (0.75 cm [95% CI: 0.60–0.91]) and after (0.72 cm [95% CI: 0.56–0.89]) lockdown. Body weight did not change during lockdown (0.01 kg [95% CI: –0.10 to 0.13) and decreased after lockdown (-0.17 kg [95% CI: –0.30 to –0.04]). Conclusion Mitigating strategies to enforce the intervention and patient's follow-up during lockdown have been successful in preserving the integrity of the trial and ensuring its continuation, with minor effects on adiposity. Clinical trial registration https://doi.org/10.1186/ISRCTN89898870, identifier ISRCTN89898870.

An Interplay between Oxidative Stress (Lactate Dehydrogenase) and Inflammation (Anisocytosis) Mediates COVID-19 Severity Defined by Routine Clinical Markers.

Viral infections activate the innate immune response and the secretion of inflammatory cytokines. They also alter oxidative stress markers, which potentially can have an involvement in the pathogenesis of the disease. The aim of this research was to study the role of the oxidative stress process assessed through lactate dehydrogenase (LDH) on the severity of COVID-19 measured by oxygen saturation (SaO2) and the putative interaction with inflammation. The investigation enrolled 1808 patients (mean age of 68 and 60% male) with COVID-19 from the HM Hospitals database. To explore interactions, a regression model and mediation analyses were performed. The patients with lower SaO2 presented lymphopenia and higher values of neutrophils-to-lymphocytes ratio and on the anisocytosis coefficient. The regression model showed an interaction between LDH and anisocytosis, suggesting that high levels of LDH (>544 U/L) and an anisocytosis coefficient higher than 10% can impact SaO2 in COVID-19 patients. Moreover, analysis revealed that LDH mediated 41% (p value = 0.001) of the effect of anisocytosis on SaO2 in this cohort. This investigation revealed that the oxidative stress marker LDH and the interaction with anisocytosis have an important role in the severity of COVID-19 infection and should be considered for the management and treatment of the oxidative phenomena concerning this within a precision medicine strategy.

Longwise Cluster Analysis for the Prediction of COVID-19 Severity within 72 h of Admission: COVID-DATA-SAVE-LIFES Cohort.

The use of routine laboratory biomarkers plays a key role in decision making in the clinical practice of COVID-19, allowing the development of clinical screening tools for personalized treatments. This study performed a short-term longitudinal cluster from patients with COVID-19 based on biochemical measurements for the first 72 h after hospitalization. Clinical and biochemical variables from 1039 confirmed COVID-19 patients framed on the "COVID Data Save Lives" were grouped in 24-h blocks to perform a longitudinal k-means clustering algorithm to the trajectories. The final solution of the three clusters showed a strong association with different clinical severity outcomes (OR for death: Cluster A reference, Cluster B 12.83 CI: 6.11-30.54, and Cluster C 14.29 CI: 6.66-34.43; OR for ventilation: Cluster-B 2.22 CI: 1.64-3.01, and Cluster-C 1.71 CI: 1.08-2.76), improving the AUC of the models in terms of age, sex, oxygen concentration, and the Charlson Comorbidities Index (0.810 vs. 0.871 with p < 0.001 and 0.749 vs. 0.807 with p < 0.001, respectively). Patient diagnoses and prognoses remarkably diverged between the three clusters obtained, evidencing that data-driven technologies devised for the screening, analysis, prediction, and tracking of patients play a key role in the application of individualized management of the COVID-19 pandemics.

Interaction of ACEI antihypertensive agent's administration with the inflammatory status at admission concerning COVID-19 clinical stay outcomes.

Interactions between anti-hypertensive agents (ACEI), comorbidities, inflammation, and stress status may impact hospital stay duration in COVID-19 patients. This retrospective study analyzed epidemiological data, comorbidities, metabolic/inflammatory markers, and clinical information from 165 SARS-CoV-2 positive patients. In a multiple linear regression model, an IL-6 higher than 100 mg/L, glucose at admission (baseline levels at the hospital entry), and the interaction between ACEI administration and LDH predicted the days of hospital admission (P < 0.001). In conclusion, hypertensive patients suffering more severe inflammatory condition assessed by LDH levels clinically benefited more and reduced the hospital stay when prescribed ACEI agents than those with lower systemic baseline inflammation at admission.

Proinflammatory and Hepatic Features Related to Morbidity and Fatal Outcomes in COVID-19 Patients.

OBJECTIVE: to screen putative associations between liver markers and proinflammatory-related features concerning infectious morbidity and fatal outcomes in COVID-19 patients. METHODS: a total of 2094 COVID-19 positive patients from the COVID-DATA-SAFE-LIFES cohort (HM hospitals consortium) were classified according to median values of hepatic, inflammatory, and clinical indicators. Logistic regression models were fitted and ROC cures were generated to explain disease severity and mortality. RESULTS: intensive care unit (ICU) assistance plus death outcomes were associated with liver dysfunction, hyperinflammation, respiratory insufficiency, and higher associated comorbidities. Four models including age, sex, neutrophils, D-dimer, oxygen saturation lower than 92%, C-reactive protein (CRP), Charlson Comorbidity Index (CCI), FIB-4 and interactions with CRP, neutrophils, and CCI explained ICU plus death variance in more than 28%. The predictive values of ROC curves were: FIB-4 (0.7339), AST/ALT ratio (0.7107), CRP (0.7003), CCI index (0.6778), neutrophils (0.6772), and platelets (0.5618) concerning ICU plus death outcomes. CONCLUSIONS: the results of this research revealed that liver and proinflammatory features are important determinants of COVID-19 morbidity and fatal outcomes, which could improve the current understanding of the COVID-19 physiopathology as well as to facilitate the clinical management and therapy decision-making of this disease under a personalized medicine scope.

[Evolution of patients infected with SARS-CoV-2 according to previous metabolic status]. / Evolución de la infección por SARS-CoV-2 en función del estado metabólico previo del paciente.

INTRODUCTION: Introduction: coronavirus disease 2019 (COVID-19) encompasses a wide spectrum of symptoms, including respiratory, gastrointestinal, hematological, and dermatological manifestations. The virus interaction with cells located in the respiratory tract causes the release of inflammatory mediators, whose involvement could be exacerbated by co-existing obesity, diabetes, and cardiovascular events. Objectives: the objective of this research was to analyze the clinically metabolic status in patients who have suffered COVID-19 disease in order to predict the outcome. Methods: this research is a retrospective study based on a cohort of 165 consecutively admitted patients with criteria for COVID-19 pneumonia according to WHO guidelines at the Hospital Universitario Puerta de Hierro between March and April 2020. Recorded variables included demographic and epidemiological data plus diagnoses as well as morbid complications during hospitalization. The Biochemistry Unit Laboratory carried out laboratory analyses according to validated operational procedures. The statistical tests included univariate and multivariate models adjusted for baseline characteristics and clinically relevant features. Results: the most frequent comorbidity in our cohort was arterial hypertension (44.0 %), followed by dyslipidemia (32.1 %), obesity (30.9 %), and diabetes mellitus (20.0 %). The association between admission to the intensive care unit (ICU) with body mass index (BMI) in a multivariate model was statistically significant, evidencing that obese subjects (BMI ≥ 30 kg/m2) have a 19 % higher risk of requiring ICU care. The univariate model revealed a statistically significant association between obesity and ICU admission and length of hospital stay (p < 0.05). The relationship between baseline blood glucose and in-hospital mortality was also statistically significant (p = 0.03), as well as with total cholesterol and ICU admission (p = 0.007). Conclusions: obesity is related to a longer time of hospitalization and a higher rate of admissions to the ICU. Low total cholesterol levels and abnormal baseline blood glucose were risk factors for ICU requirement and in-hospital mortality. Patient categorization based on obesity could be valuable in the development of a precision medicine model within the COVID-19 pandemic.

INTRODUCCIÓN: Introducción: la enfermedad por COVID-19 engloba un amplio espectro de síntomas entre los que destacan los trastornos respiratorios, digestivos, hematológicos y dermatológicos. La interacción del virus con las células ubicadas en el tracto respiratorio provoca la liberación de mediadores inflamatorios cuya producción podría estar relacionada con la obesidad, la diabetes y los eventos cardiovasculares. Objetivos: analizar el estado metabólico al ingreso de los pacientes infectados por SARS-CoV-2 y su capacidad para predecir el desenlace clínico. Métodos: este trabajo consiste en un estudio retrospectivo basado en una cohorte de 165 pacientes ingresados consecutivamente en el Hospital Universitario Puerta de Hierro Majadahonda entre marzo y abril de 2020 con criterios de neumonía COVID-19 según las pautas de la OMS. Las variables registradas incluyeron datos socio-demográficos y epidemiológicos, herramientas diagnósticas y complicaciones durante el ingreso hospitalario. El Servicio de Bioquímica del centro realizó los análisis de laboratorio empleando procedimientos validados. El estudio estadístico incluye modelos univariantes y multivariados, ajustados por las características basales clínicamente relevantes de la población. Resultados: la comorbilidad más frecuente en nuestra población fue la hipertensión arterial (44,0 %), seguida por la dislipemia (32,1 %), la obesidad (30,9 %) y la diabetes mellitus (20,0 %). En el análisis multivariante, la asociación del ingreso en la Unidad de Cuidados Intensivos (UCI) con el índice de masa corporal (IMC) resultó estadísticamente significativa, con un 19 % más de riesgo en aquellos pacientes con IMC ≥ 30 kg/m2. El modelo univariante reveló la asociación estadísticamente significativa de la obesidad y el ingreso en la UCI con la duración de la estancia hospitalaria (p < 0,05). La relación entre glucemia basal y mortalidad intrahospitalaria también resultó estadísticamente significativa (p = 0,03). Los niveles bajos de colesterol total se asociaron a una tasa mayor de ingresos en la UCI (p = 0,007). Conclusiones: la obesidad se asocia a una mayor estancia hospitalaria y necesidad de ingreso en la UCI en los pacientes infectados por el SARS-CoV-2. El descenso en las cifras de colesterol total y una glucemia basal alterada son factores de riesgo del ingreso en la UCI y la mortalidad intrahospitalaria. La categorización en función del grado de obesidad de los pacientes podría ser de utilidad en el desarrollo de un modelo de medicina de precisión en el contexto de la COVID-19.

Inflammatory-Related Clinical and Metabolic Outcomes in COVID-19 Patients.

BACKGROUND: Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-COV-2) infection elicits inflammatory manifestations that relate with a "cytokine storm." OBJECTIVE: The aim of this research was to assess the role of circulating interleukin 6 (IL-6) levels and other inflammatory markers in patients with coronavirus disease 2019 (COVID-19) on metabolic functions and accompanying clinical complications. Patients and Methods. A total of 165 patients diagnosed with COVID-19 pneumonia were examined for medical features and inflammatory markers such as blood IL-6, CRP, ferritin, LDH, neutrophil/lymphocyte index (NLI), D-Dimer, and Red Cell Distribution Width (RDW). Regression analyses concerning electronically collected medical data were adjusted by appropriate factors and confounding variables. Results. Plasma IL-6 determinations evidenced a consistent association with hospital stay days, Intensive Care Unit (ICU) admission, and mortality rates. Similar trends were found for other proinflammatory variables, where ferritin and NLI showed a remarkable value as surrogates. Hyperglycaemia and the Charlson Comorbidity Index Score were positively associated with the inflammatory response induced by the SARS-COV-2 infection. An unhealthy lifestyle such as smoking and alcoholic drinks consumption as well as excessive body adiposity influenced inflammatory-related outcomes in the screened patients. CONCLUSION: IL-6 together with other inflammatory biomarkers accompanied poor clinical and metabolic outcomes in COVID-19-infected patients. IL-6 may result in a suitable proxy to individually categorise patients in order to manage this infectious pandemic.

Exploring Host Genetic Polymorphisms Involved in SARS-CoV Infection Outcomes: Implications for Personalized Medicine in COVID-19.

OBJECTIVE: To systematically explore genetic polymorphisms associated with the clinical outcomes in SARS-CoV infection in humans. METHODS: This comprehensive literature search comprised available English papers published in PubMed/Medline and SCOPUS databases following the PRISMA-P guidelines and PICO/AXIS criteria. RESULTS: Twenty-nine polymorphisms located in 21 genes were identified as associated with SARS-CoV susceptibility/resistance, disease severity, and clinical outcomes predominantly in Asian populations. Thus, genes implicated in key pathophysiological processes such as the mechanisms related to the entry of the virus into the cell and the antiviral immune/inflammatory responses were identified. CONCLUSIONS: Although caution must be taken, the results of this systematic review suggest that multiple genetic polymorphisms are associated with SARS-CoV infection features by affecting virus pathogenesis and host immune response, which could have important applications for the study and understanding of genetics in SARS-CoV-2/COVID-19 and for personalized translational clinical practice depending on the population studied and associated environments.