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1.
J Infect ; 85(1): 86-89, 2022 Jul.
Article in English | MEDLINE | ID: covidwho-1814751

ABSTRACT

BACKGROUND: Variations in the ACE2 activity in saliva could explain the striking differences of susceptibility to infection and risk of severe disease. METHODS: We analyze the activity of ACE2 in saliva in different population groups across a wide age range and disease status during April to June 2020, before SARS-CoV-2 vaccine implementation, and we establish differences between infected people and participants considered resistant (highly exposed healthcare workers and children who cohabited with parents with COVID-19 without isolation and remain IgG negative). RESULTS: We included 74 adults, of which 47 (64%) were susceptible and 27 (36%) were resistant, and 79 children, of which 41 (52%) were susceptible and 38 (48%) were resistant. Resistant adults have significantly lower ACE2 activity in saliva than susceptible adults and non-significant higher values than susceptible and resistant children. ACE2 activity is similar in the susceptible and resistant pediatric population (p = 0.527). In contrast, we observe an increase in activity as the disease's severity increases among the adult population (mild disease vs. severe disease, 39 vs. 105 FU, p = 0.039; severe disease vs. resistant, 105 vs. 31 FU, p < 0.001). CONCLUSIONS: using an enzymatic test, we show that ACE2 activity in saliva correlates with the susceptibility to SARS-Cov-2 infection and disease severity. Children and adults with low-susceptibility to SARS-Cov-2 infection showed the lowest ACE2 activity. These findings could inform future strategies to identify at-risk individuals.


Subject(s)
Angiotensin-Converting Enzyme 2 , COVID-19 , SARS-CoV-2 , Adult , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/enzymology , COVID-19 Vaccines , Child , Humans , Saliva/enzymology
2.
Front Immunol ; 13: 836516, 2022.
Article in English | MEDLINE | ID: covidwho-1785343

ABSTRACT

Background: COVID-19 can generate a broad spectrum of severity and symptoms. Many studies analysed the determinants of severity but not among some types of symptoms. More importantly, very few studies analysed patients highly exposed to the virus that nonetheless remain uninfected. Methods: We analysed serum levels of ACE2, Angiotensin II and anti-Spike antibodies in 2 different cohorts at high risk of viral exposure, highly exposed but uninfected subjects, either high risk health care workers or persons cohabiting with infected close relatives and seropositive patients with symptoms. We tested the ability of the sera of these subjects to neutralize lentivirus pseudotyped with the Spike-protein. Results: We found that the serum levels of ACE2 are significantly higher in highly exposed but uninfected subjects. Moreover, sera from this seronegative persons can neutralize SARS-CoV-2 infection in cellular assays more strongly that sera from non-exposed negative controls eventhough they do not have anti-CoV-2 IgG antibodies suggesting that high levels of ACE2 in serum may somewhat protect against an active infection without generating a conventional antibody response. Finally, we show that among patients with symptoms, ACE2 levels were significantly higher in infected patients who developed cutaneous as compared with respiratory symptoms and ACE2 was also higher in those with milder symptoms. Conclusions: These findings suggest that soluble ACE2 could be used as a potential biomarker to predict SARS-CoV-2 infection risk and to discriminate COVID-19 disease subtypes.


Subject(s)
COVID-19 , Angiotensin-Converting Enzyme 2 , Antibodies, Neutralizing , Antibodies, Viral , Humans , SARS-CoV-2 , Spike Glycoprotein, Coronavirus
3.
J Proteome Res ; 21(3): 623-634, 2022 03 04.
Article in English | MEDLINE | ID: covidwho-1671479

ABSTRACT

Despite the scientific and human efforts to understand COVID-19, there are questions still unanswered. Variations in the metabolic reaction to SARS-CoV-2 infection could explain the striking differences in the susceptibility to infection and the risk of severe disease. Here, we used untargeted metabolomics to examine novel metabolic pathways related to SARS-CoV-2 susceptibility and COVID-19 clinical severity using capillary electrophoresis coupled to a time-of-flight mass spectrometer (CE-TOF-MS) in plasma samples. We included 27 patients with confirmed COVID-19 and 29 healthcare workers heavily exposed to SARS-CoV-2 but with low susceptibility to infection ("nonsusceptible"). We found a total of 42 metabolites of SARS-CoV-2 susceptibility or COVID-19 clinical severity. We report the discovery of new plasma biomarkers for COVID-19 that provide mechanistic explanations for the clinical consequences of SARS-CoV-2, including mitochondrial and liver dysfunction as a consequence of hypoxemia (citrulline, citric acid, and 3-aminoisobutyric acid (BAIBA)), energy production and amino acid catabolism (phenylalanine and histidine), and endothelial dysfunction and thrombosis (citrulline, asymmetric dimethylarginine (ADMA), and 2-aminobutyric acid (2-AB)), and we found interconnections between these pathways. In summary, in this first report several metabolic pathways implicated in SARS-CoV-2 susceptibility and COVID-19 clinical progression were found by CE-MS based metabolomics that could be developed as biomarkers of COVID-19.


Subject(s)
COVID-19 , SARS-CoV-2 , Biomarkers , Humans , Metabolome , Metabolomics/methods
4.
Emerg Microbes Infect ; 10(1): 493-496, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1127287

ABSTRACT

We aim to evaluate the role of single-nucleotide polymorphisms of the angiotensin-converting enzyme 2 in susceptibility to SARS-CoV-2 infection. We included 28 uninfected but highly exposed healthcare workers and 39 hospitalized patients with COVID-19. Thirty-five SNPs were rationally selected. Two variants were associated with increased risk of being susceptible to SARS-CoV-2: the minor A allele in the rs2106806 variant (OR 3.75 [95% CI 1.23-11.43]) and the minor T allele in the rs6629110 variant (OR 3.39 [95% CI 1.09-10.56]). Evaluating the role of genetic variants in susceptibility to SARS-CoV-2 infection could help identify more vulnerable individuals and suggest potential drug targets for COVID-19 patients.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Genetic Predisposition to Disease , Health Personnel , Polymorphism, Single Nucleotide , SARS-CoV-2 , Adult , Aged , Aged, 80 and over , COVID-19/etiology , Female , Humans , Male , Middle Aged
5.
EMBO Mol Med ; 13(3): e13549, 2021 03 05.
Article in English | MEDLINE | ID: covidwho-1038772

ABSTRACT

A correct identification of seropositive individuals for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is of paramount relevance to assess the degree of protection of a human population to present and future outbreaks of the COVID-19 pandemic. We describe here a sensitive and quantitative flow cytometry method using the cytometer-friendly non-adherent Jurkat T-cell line that stably expresses the full-length native spike "S" protein of SARS-CoV-2 and a truncated form of the human EGFR that serves a normalizing role. S protein and huEGFRt coding sequences are separated by a T2A self-cleaving sequence, allowing to accurately quantify the presence of anti-S immunoglobulins by calculating a score based on the ratio of fluorescence intensities obtained by double-staining with the test sera and anti-EGFR. The method allows to detect immune individuals regardless of the result of other serological tests or even repeated PCR monitoring. As examples of its use, we show that as much as 28% of the personnel working at the CBMSO in Madrid is already immune. Additionally, we show that anti-S antibodies with protective neutralizing activity are long-lasting and can be detected in sera 8 months after infection.


Subject(s)
Antibodies, Neutralizing/blood , Antibodies, Viral/blood , COVID-19 Serological Testing/methods , COVID-19/diagnosis , COVID-19/immunology , Flow Cytometry/methods , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Adult , COVID-19/virology , COVID-19 Serological Testing/statistics & numerical data , Enzyme-Linked Immunosorbent Assay , ErbB Receptors/genetics , Female , Flow Cytometry/statistics & numerical data , Hep G2 Cells , Humans , Jurkat Cells , Male , Middle Aged , Neutralization Tests , Pandemics , Polymerase Chain Reaction , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , SARS-CoV-2/genetics , Spike Glycoprotein, Coronavirus/genetics
6.
Clin Microbiol Infect ; 27(2): 238-243, 2021 Feb.
Article in English | MEDLINE | ID: covidwho-871968

ABSTRACT

OBJECTIVES: Tocilizumab has been proposed as a candidate therapy for patients with severe coronavirus disease 2019 (COVID-19), especially among those with higher systemic inflammation. We investigated the association between receipt of tocilizumab and mortality in a large cohort of hospitalized patients. METHODS: In this cohort study of patients hospitalized with COVID-19 in Spain, the primary outcome was time to death and the secondary outcome time to intensive care unit (ICU) admission or death. We used inverse probability weighting to fit marginal structural models adjusted for time-varying covariates to determine the causal relationship between receipt of tocilizumab and outcome. RESULTS: Data from 1229 patients were analysed, with 261 patients (61 deaths) in the tocilizumab group and 969 patients (120 deaths) in the control group. In the adjusted marginal structural models, a significant interaction between receipt of tocilizumab and high C-reactive protein (CRP) levels was detected. Tocilizumab was associated with decreased risk of death (adjusted hazard ratio 0.34, 95% confidence interval 0.16-0.72, p 0.005) and ICU admission or death (adjusted hazard ratio 0.39, 95% confidence interval 0.19-0.80, p 0.011) among patients with baseline CRP >150 mg/L but not among those with CRP ≤150 mg/L. Exploratory subgroup analyses yielded point estimates that were consistent with these findings. CONCLUSIONS: In this large observational study, tocilizumab was associated with a lower risk of death or ICU admission or death in patients with higher CRP levels. While the results of ongoing clinical trials of tocilizumab in patients with COVID-19 will be important to establish its safety and efficacy, our findings have implications for the design of future clinical trials.


Subject(s)
Antibodies, Monoclonal, Humanized/therapeutic use , COVID-19/drug therapy , Hospitalization/statistics & numerical data , Aged , Aged, 80 and over , C-Reactive Protein/metabolism , COVID-19/mortality , COVID-19/pathology , Cohort Studies , Female , Hospital Mortality , Humans , Intensive Care Units/statistics & numerical data , Male , Middle Aged , SARS-CoV-2 , Spain/epidemiology , Treatment Outcome
7.
EClinicalMedicine ; 27: 100539, 2020 Oct.
Article in English | MEDLINE | ID: covidwho-753676

ABSTRACT

BACKGROUND: The lack of evidence-based recommendations for therapeutic decisions during the early weeks of the COVID-19 pandemic creates a unique scenario of clinical decision making which is worth to analyze. We aim to identify the drivers of therapeutic aggressiveness during the first weeks of the COVID-19 pandemic. METHODS: This cross-sectional worldwide survey (conducted April 12 to 19, 2020) was aimed at physicians who managed patients diagnosed with COVID-19. Treatment preferences were collected in five different clinical scenarios. We used multilevel mixed-effects ordered logistic regression to identify variables that were associated with the use of more aggressive therapies. FINDINGS: The survey was completed by 852 physicians from 44 different specialties and 29 countries. The heterogeneity of therapeutic decisions increased as the clinical scenario worsened. Factors associated with aggressive therapeutic decisions were higher self-perceived expertise (high vs. null, OR 1.95, 95%CI 1.31-2.89), perceived quality of COVID-19 publications (high vs. null, OR 1.92, 95%CI 1.17-3.16), and female sex (OR 1.17, 95%CI 1.02-1.33). Conversely, Infectious Diseases specialty, Latin American and North American origin, lower confidence in the treatments chosen, and having published articles indexed in PubMed as the first-author were associated with the use of less aggressive therapies. INTERPRETATION: Our study provides insight into the drivers of the decision-making process during a new and extreme health emergency. Different factors including the perceived expertise and quality of publications, gender, geographic origin, medical specialty and implication in medical research influenced this process. The clinical severity attenuated the physician's tolerance for uncertainty. FUNDING: No funding was required.

8.
Clin Immunol ; 219: 108572, 2020 10.
Article in English | MEDLINE | ID: covidwho-713545

ABSTRACT

Human Leukocyte Antigen (HLA) includes a large set of genes with important actions in immune response against viral infection. Numerous studies have revealed the existence of significant associations between certain HLA alleles and the susceptibility and prognosis of different infectious diseases. In this pilot study we analyse the binding affinity between 66 class I HLA alleles and SARS-CoV-2 viral peptides, and its association with the severity of the disease. A total of 45 Spanish patients with mild, moderate and severe SARS-CoV-2 infection were typed for HLA class I; after that, we analysed if an in silico model of HLA I-viral peptide binding affinity and classical HLA supertypes could be correlated to the severity of the disease. Our results suggest that patients with mild disease present Class I HLA molecules with a higher theoretical capacity for binding SARS-Cov-2 peptides and showed greater heterozygosity when comparing them with moderate and severe groups. In this regard, identifying HLA-SARS-CoV-2 peptides binding differences between individuals would help to clarify the heterogeneity of clinical responses to the disease and will also be useful to guide a personalized treatment according to its particular risk.


Subject(s)
Betacoronavirus/pathogenicity , Coronavirus Infections/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions/immunology , Pneumonia, Viral/genetics , Viral Proteins/genetics , Adult , Aged , Alleles , Betacoronavirus/immunology , COVID-19 , Coronavirus Infections/immunology , Coronavirus Infections/pathology , Coronavirus Infections/virology , Disease Progression , Female , Gene Expression , Gene Frequency , Histocompatibility Antigens Class I/classification , Histocompatibility Antigens Class I/immunology , Humans , Immunity, Innate , Male , Middle Aged , Pandemics , Peptides/genetics , Peptides/immunology , Pilot Projects , Pneumonia, Viral/immunology , Pneumonia, Viral/pathology , Pneumonia, Viral/virology , Protein Binding , SARS-CoV-2 , Severity of Illness Index , Spain , Viral Proteins/immunology
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