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1.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322449

ABSTRACT

Background: ABO blood groups are associated with different risk of viral infections. In vitro studies demonstrated how anti-A and anti-B antibodies neutralized the infectious capacity of SARS-CoV-2. Therefore, here we describe the inflammatory response of COVID-19 patients in the context of the blood group aiming to assess the lower severity status found in group O patients.Methods: Prospective and consecutive study including blood samples from 108 adult patients diagnosed with COVID-19 and admitted to the “Hospital Clínico Universitario” Valladolid, Spain between March 24 and April 11 2020. Patients were divided according to their ABO blood group. Plasma aliquots were analyzed, in duplicate, for the quantification of 45 mediators by MAGPIX system (Luminex). Statistical analysis was performed using the R statistical package version 4.0.2 Findings: We found a lower risk (2.16 times) of mechanical ventilation or death in patients with blood group O [Log Rank: p=0.042, Hazard Ratio: 0.463, CI 95% (0.213-1.004), p=0.050]. Moreover, 15 cytokines were significantly over-expressed (and only one under-expressed) in blood group O. Last, a multivariate model found BDNF, IL-13 and IL-27 as the best cytokines able to differentiate the immune profile based on blood group. Interpretation: Our cohort showed how blood group O was associated with both lower rates of hospital admission and a lower risk of intubation or death. Indeed, these patients produced higher amounts of cytokines in response to SARS-CoV-2, hence mounting an effective immune response which allowed them to control the viral infection and therefore decrease the risk of further complications.Funding Statement: This research was funded by Instituto de Salud Carlos III, grant number COV20/00491.Declaration of Interests: Alvaro Tamayo-Velasco declares no conflict of interest. - María Jesús Peñarrubia-Ponce declares no conflict of interest. - Francisco Javier Álvarez declares no conflict of interest. - Hugo Gonzalo-Benito declares no conflict of interest. - Ignacio de la Fuente declares no conflict of interest. - Sonia Pérez González declares no conflict of interest. - Lucía Rico declares no conflict of interest. - María Teresa Jiménez-García declares no conflict of interest. - Alba Sánchez-Rodríguez declares no conflict of interest. - Milagros Hijas-Villaizan declares no conflict of interest. - Marta Martín Fernández declares no conflict of interest. - Carlos Dueñas declares no conflict of interest. - Esther Gómez-Sánchez declares no conflict of interest. - María Heredia-Rodríguez declares no conflict of interest. - Óscar Gorgojo-Galindo declares no conflict of interest. - Itziar Fernández declares no conflict of interest. - Lourdes del Río declares no conflict of interest. - Irene Carnicero-Frutos declares no conflict of interest. - María Fe Muñoz-Moreno declares no conflict of interest. - Eduardo Tamayo declares no conflict of interest. - David Bernardo declares no conflict of interest. - Pedro Martínez-Paz declares no conflict of interest.Ethics Approval Statement: The study was approved by the Hospital's Clinical Ethics Committee (CEIm) and approval was obtained from all study participants (cod: PI 20-1717).

2.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-322448

ABSTRACT

Background: Pneumonia is the leading cause of hospital admission and mortality in coronavirus disease 2019 (COVID-19), attributed to a cytokine storm. The objective of our study is to characterize this profile to identify the cytokines responsible for lung damage and mortality. Methods: : Plasma samples of 108 prospectively recruited COVID-19 patients were collected between March and April 2020. Patients were divided into four groups according to the severity of respiratory symptoms: 34 mild (no oxygen support), 26 moderate (low oxygen support using nasal cannula), 16 severe (high oxygen support) and 32 critical (mechanical ventilation). A 45-plex Human XL Cytokine Luminex Performance Panel kit was used in duplicate for each plasma sample. Twenty-eight healthy volunteers were used for normalization of the results. Results: Multiple cytokines showed statistically significant differences when comparing mild and critical patients (HGF, PDGFBB, PIGF-1, IL-1α, MCP-1, VEGFA, IL-15 and IL-2). The best multivariable model included HGF, IL-1α, IL-2 and IL-27. 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). Conclusions: : Our study showed that 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. Indeed, HGF and IL-1α were also mortality biomarkers.

3.
Sci Rep ; 12(1): 1650, 2022 01 31.
Article in English | MEDLINE | ID: covidwho-1661981

ABSTRACT

SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) is the coronavirus strain causing the respiratory pandemic COVID-19 (coronavirus disease 2019). To understand the pathobiology of SARS-CoV-2 in humans it is necessary to unravel the metabolic changes that are produced in the individuals once the infection has taken place. The goal of this work is to provide new information about the altered biomolecule profile and with that the altered biological pathways of patients in different clinical situations due to SARS-CoV-2 infection. This is done via metabolomics using HPLC-QTOF-MS analysis of plasma samples at COVID-diagnose from a total of 145 adult patients, divided into different clinical stages based on their subsequent clinical outcome (25 negative controls (non-COVID); 28 positive patients with asymptomatic disease not requiring hospitalization; 27 positive patients with mild disease defined by a total time in hospital lower than 10 days; 36 positive patients with severe disease defined by a total time in hospital over 20 days and/or admission at the ICU; and 29 positive patients with fatal outcome or deceased). Moreover, follow up samples between 2 and 3 months after hospital discharge were also obtained from the hospitalized patients with mild prognosis. The final goal of this work is to provide biomarkers that can help to better understand how the COVID-19 illness evolves and to predict how a patient could progress based on the metabolites profile of plasma obtained at an early stage of the infection. In the present work, several metabolites were found as potential biomarkers to distinguish between the end-stage and the early-stage (or non-COVID) disease groups. These metabolites are mainly involved in the metabolism of carnitines, ketone bodies, fatty acids, lysophosphatidylcholines/phosphatidylcholines, tryptophan, bile acids and purines, but also omeprazole. In addition, the levels of several of these metabolites decreased to "normal" values at hospital discharge, suggesting some of them as early prognosis biomarkers in COVID-19 at diagnose.


Subject(s)
Asymptomatic Infections/epidemiology , COVID-19/blood , COVID-19/diagnosis , Metabolome , Metabolomics/methods , Pandemics , SARS-CoV-2/genetics , Severity of Illness Index , Adult , Aged , Aged, 80 and over , Biomarkers/blood , COVID-19/epidemiology , COVID-19/physiopathology , Case-Control Studies , Cohort Studies , Female , Follow-Up Studies , Humans , Male , Middle Aged , Patient Admission , Polymerase Chain Reaction/methods , Spain/epidemiology
4.
Eur J Immunol ; 51(12): 2708-3145, 2021 12.
Article in English | MEDLINE | ID: covidwho-1568038

ABSTRACT

The third edition of Flow Cytometry Guidelines provides the key aspects to consider when performing flow cytometry experiments and includes comprehensive sections describing phenotypes and functional assays of all major human and murine immune cell subsets. Notably, the Guidelines contain helpful tables highlighting phenotypes and key differences between human and murine cells. Another useful feature of this edition is the flow cytometry analysis of clinical samples with examples of flow cytometry applications in the context of autoimmune diseases, cancers as well as acute and chronic infectious diseases. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid. All sections are written and peer-reviewed by leading flow cytometry experts and immunologists, making this edition an essential and state-of-the-art handbook for basic and clinical researchers.


Subject(s)
Autoimmune Diseases/immunology , Flow Cytometry , Infections/immunology , Neoplasms/immunology , Animals , Chronic Disease , Humans , Mice , Practice Guidelines as Topic
5.
EuropePMC; 2021.
Preprint in English | EuropePMC | ID: ppcovidwho-294214

ABSTRACT

SARS-CoV-2 causes a severe inflammatory syndrome (COVID-19) leading, in many cases, to bilateral pneumonia, severe dyspnea and in ∼5% of these, death. DNA methylation is known to play an important role in the regulation of the immune processes behind COVID-19 progression, however it has not been studied in depth, yet. In this study, we aim to evaluate the implication of DNA methylation in COVID-19 progression by means of a genome-wide DNA methylation analysis combined with DNA genotyping. The results reveal the existence of epigenomic regulation of functional pathways associated with COVID-19 progression and mediated by genetic loci. We found an environmental trait-related signature that discriminates mild from severe cases, and regulates IL-6 expression via the transcription factor CEBP. The analyses suggest that an interaction between environmental contribution, genetics and epigenetics might be playing a role in triggering the cytokine storm described in the most severe cases.

6.
J Clin Invest ; 131(23)2021 12 01.
Article in English | MEDLINE | ID: covidwho-1546628

ABSTRACT

BackgroundThere is considerable variability in COVID-19 outcomes among younger adults, and some of this variation may be due to genetic predisposition.MethodsWe combined individual level data from 13,888 COVID-19 patients (n = 7185 hospitalized) from 17 cohorts in 9 countries to assess the association of the major common COVID-19 genetic risk factor (chromosome 3 locus tagged by rs10490770) with mortality, COVID-19-related complications, and laboratory values. We next performed metaanalyses using FinnGen and the Columbia University COVID-19 Biobank.ResultsWe found that rs10490770 risk allele carriers experienced an increased risk of all-cause mortality (HR, 1.4; 95% CI, 1.2-1.7). Risk allele carriers had increased odds of several COVID-19 complications: severe respiratory failure (OR, 2.1; 95% CI, 1.6-2.6), venous thromboembolism (OR, 1.7; 95% CI, 1.2-2.4), and hepatic injury (OR, 1.5; 95% CI, 1.2-2.0). Risk allele carriers age 60 years and younger had higher odds of death or severe respiratory failure (OR, 2.7; 95% CI, 1.8-3.9) compared with those of more than 60 years (OR, 1.5; 95% CI, 1.2-1.8; interaction, P = 0.038). Among individuals 60 years and younger who died or experienced severe respiratory failure, 32.3% were risk-variant carriers compared with 13.9% of those not experiencing these outcomes. This risk variant improved the prediction of death or severe respiratory failure similarly to, or better than, most established clinical risk factors.ConclusionsThe major common COVID-19 genetic risk factor is associated with increased risks of morbidity and mortality, which are more pronounced among individuals 60 years or younger. The effect was similar in magnitude and more common than most established clinical risk factors, suggesting potential implications for future clinical risk management.


Subject(s)
Alleles , COVID-19 , Chromosomes, Human, Pair 3/genetics , Gene Frequency , Genetic Loci , Polymorphism, Genetic , SARS-CoV-2 , Age Factors , Aged , Aged, 80 and over , COVID-19/genetics , COVID-19/mortality , Female , Humans , Male , Middle Aged , Patient Acuity , Risk Factors
7.
Front Immunol ; 12: 726283, 2021.
Article in English | MEDLINE | ID: covidwho-1497074

ABSTRACT

Severe 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.


Subject(s)
COVID-19/immunology , Cytokines/blood , SARS-CoV-2/physiology , ABO Blood-Group System , Aged , Biomarkers , COVID-19/diagnosis , COVID-19/mortality , Disease Progression , Female , Hepatocyte Growth Factor/blood , Hospitalization , Humans , Male , Middle Aged , Prognosis , Prospective Studies , Respiration, Artificial , Severity of Illness Index , Survival Analysis
8.
Sci Adv ; 7(1)2021 01.
Article in English | MEDLINE | ID: covidwho-1388432

ABSTRACT

Using AI, we identified baricitinib as having antiviral and anticytokine efficacy. We now show a 71% (95% CI 0.15 to 0.58) mortality benefit in 83 patients with moderate-severe SARS-CoV-2 pneumonia with few drug-induced adverse events, including a large elderly cohort (median age, 81 years). An additional 48 cases with mild-moderate pneumonia recovered uneventfully. Using organotypic 3D cultures of primary human liver cells, we demonstrate that interferon-α2 increases ACE2 expression and SARS-CoV-2 infectivity in parenchymal cells by greater than fivefold. RNA-seq reveals gene response signatures associated with platelet activation, fully inhibited by baricitinib. Using viral load quantifications and superresolution microscopy, we found that baricitinib exerts activity rapidly through the inhibition of host proteins (numb-associated kinases), uniquely among antivirals. This reveals mechanistic actions of a Janus kinase-1/2 inhibitor targeting viral entry, replication, and the cytokine storm and is associated with beneficial outcomes including in severely ill elderly patients, data that incentivize further randomized controlled trials.


Subject(s)
Antiviral Agents/pharmacology , Azetidines/pharmacology , COVID-19/mortality , Enzyme Inhibitors/pharmacology , Janus Kinases/antagonists & inhibitors , Liver/virology , Purines/pharmacology , Pyrazoles/pharmacology , SARS-CoV-2/pathogenicity , Sulfonamides/pharmacology , Adult , Aged , Aged, 80 and over , COVID-19/drug therapy , COVID-19/metabolism , COVID-19/virology , Cytokine Release Syndrome , Cytokines/metabolism , Drug Evaluation, Preclinical , Female , Gene Expression Profiling , Humans , Interferon alpha-2/metabolism , Italy , Janus Kinases/metabolism , Liver/drug effects , Male , Middle Aged , Patient Safety , Platelet Activation , Proportional Hazards Models , RNA-Seq , Spain , Virus Internalization/drug effects
9.
J Pers Med ; 11(7)2021 Jul 20.
Article in English | MEDLINE | ID: covidwho-1323278

ABSTRACT

Antigen 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.

10.
J Am Geriatr Soc ; 69(10): 2752-2758, 2021 10.
Article in English | MEDLINE | ID: covidwho-1301522

ABSTRACT

BACKGROUND: Older adults are at the highest risk of severe disease and death due to COVID-19. Randomized data have shown that baricitinib improves outcomes in these patients, but focused stratified analyses of geriatric cohorts are lacking. Our objective was to analyze the efficacy of baricitinib in older adults with COVID-19 moderate-to-severe pneumonia. METHODS: This is a propensity score [PS]-matched retrospective cohort study. Patients from the COVID-AGE and Alba-Score cohorts, hospitalized for moderate-to-severe COVID-19 pneumonia, were categorized in two age brackets of age <70 years old (86 with baricitinib and 86 PS-matched controls) or ≥70 years old (78 on baricitinib and 78 PS-matched controls). Thirty-day mortality rates were analyzed with Kaplan-Meier and Cox proportional hazard models. RESULTS: Mean age was 79.1 for those ≥70 years and 58.9 for those <70. Exactly 29.6% were female. Treatment with baricitinib resulted in a significant reduction in death from any cause by 48% in patients aged 70 or older, an 18.5% reduction in 30-day absolute mortality risk (n/N: 16/78 [20.5%] baricitinib, 30/78 [38.5%] in PS-matched controls, p < 0.001) and a lower 30-day adjusted fatality rate (HR 0.21; 95% CI 0.09-0.47; p < 0.001). Beneficial effects on mortality were also observed in the age group <70 (8.1% reduction in 30-day absolute mortality risk; HR 0.14; 95% CI 0.03-0.64; p = 0.011). CONCLUSIONS: Baricitinib is associated with an absolute mortality risk reduction of 18.5% in adults older than 70 years hospitalized with COVID-19 pneumonia.


Subject(s)
Azetidines , COVID-19 , Pneumonia, Viral , Purines , Pyrazoles , Sulfonamides , Age Factors , Aged , Aged, 80 and over , Antiviral Agents/administration & dosage , Antiviral Agents/adverse effects , Azetidines/administration & dosage , Azetidines/adverse effects , COVID-19/drug therapy , COVID-19/mortality , COVID-19/physiopathology , Female , Hospital Mortality , Humans , Janus Kinase Inhibitors/administration & dosage , Janus Kinase Inhibitors/adverse effects , Male , Mortality , Outcome and Process Assessment, Health Care , Pneumonia, Viral/diagnosis , Pneumonia, Viral/drug therapy , Purines/administration & dosage , Purines/adverse effects , Pyrazoles/administration & dosage , Pyrazoles/adverse effects , SARS-CoV-2/isolation & purification , Severity of Illness Index , Spain/epidemiology , Sulfonamides/administration & dosage , Sulfonamides/adverse effects
11.
J Clin Med ; 10(9)2021 May 08.
Article in English | MEDLINE | ID: covidwho-1224044

ABSTRACT

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.

12.
Biomedicines ; 9(4)2021 Mar 26.
Article in English | MEDLINE | ID: covidwho-1154285

ABSTRACT

BACKGROUND: Growth arrest-specific factor 6 (GAS6) and the Tyro3, AXL, and MERTK (TAM) receptors counterbalance pro-inflammatory responses. AXL is a candidate receptor for SARS-CoV-2, particularly in the respiratory system, and the GAS6/AXL axis is targeted in current clinical trials against COVID-19. However, GAS6 and TAMs have not been evaluated in COVID-19 patients at emergency admission. METHODS: Plasma GAS6, AXL, and MERTK were analyzed in 132 patients consecutively admitted to the emergency ward during the first peak of COVID-19. RESULTS: GAS6 levels were higher in the SARS-CoV-2-positive patients, increasing progressively with the severity of the disease. Patients with initial GAS6 at the highest quartile had the worst outcome, with a 3-month survival of 65%, compared to a 90% survival for the rest. Soluble AXL exhibited higher plasma concentration in deceased patients, without significant differences in MERTK among SARS-CoV-2-positive groups. GAS6 mRNA was mainly expressed in alveolar cells and AXL in airway macrophages. Remarkably, THP-1 human macrophage differentiation neatly induces AXL, and its inhibition (bemcentinib) reduced cytokine production in human macrophages after LPS challenge. CONCLUSIONS: Plasma GAS6 and AXL levels reflect COVID-19 severity and could be early markers of disease prognosis, supporting a relevant role of the GAS6/AXL system in the immune response in COVID-19.

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