The ACE rs1799752 Variant Is Associated with COVID-19 Severity but Is Independent of Serum ACE Activity in Hospitalized and Recovered Patients.

This paper assesses the association of the insertion/deletion ACE (angiotensin-converting enzyme) variant (rs1799752 I/D) and the serum ACE activity with the severity of COVID-19 as well as its impact on post-COVID-19, and we compare these associations with those for patients with non-COVID-19 respiratory disorders. We studied 1252 patients with COVID-19, 104 subjects recovered from COVID-19, and 74 patients hospitalized with a respiratory disease different from COVID-19. The rs1799752 ACE variant was assessed using TaqMan® Assays. The serum ACE activity was determined using a colorimetric assay. The DD genotype was related to risk for invasive mechanical ventilation (IMV) requirement as an indicator of COVID-19 severity when compared to the frequencies of II + ID genotypes (p = 0.025, OR = 1.428, 95% CI = 1.046-1.949). In addition, this genotype was significantly higher in COVID-19 and post-COVID-19 groups than in the non-COVID-19 subjects. The serum ACE activity levels were lower in the COVID-19 group (22.30 U/L (13.84-32.23 U/L)), which was followed by the non-COVID-19 (27.94 U/L (20.32-53.36 U/L)) and post-COVID-19 subjects (50.00 U/L (42.16-62.25 U/L)). The DD genotype of the rs1799752 ACE variant was associated with the IMV requirement in patients with COVID-19, and low serum ACE activity levels could be related to patients with severe disease.

Outcome predictors in COVID-19: An analysis of emergent systemic inflammation indices in Mexican population.

Introduction: The systemic viral disease caused by the SARS-CoV-2 called coronavirus disease 2019 (COVID-19) continues to be a public health problem worldwide. Objective: This study is aimed to evaluate the association and predictive value of indices of systemic inflammation with severity and non-survival of COVID-19 in Mexican patients. Materials and Methods: A retrospective study was carried out on 807 subjects with a confirmed diagnosis of COVID-19. Clinical characteristics, acute respiratory distress syndrome (ARDS), severity according to PaO2/FiO2 ratio, invasive mechanical ventilation (IMV), and non-survival outcome were considered to assess the predictive value and the association of 11 systemic inflammatory indices derived from hematological parameters analyzed at the hospital admission of patients. The receiver operating characteristics curve was applied to determine the thresholds for 11 biomarkers, and their prognostic values were assessed via the Kaplan-Meier method. Results: 26% of the studied subjects showed COVID-19 severe (PaO2/FiO2 ratio ≤ 100), 82.4% required IMV, and 39.2% were non-survival. The indices NHL, NLR, RDW, dNLR, and SIRI displayed predictive values for severe COVID-19 and non-survival. NHL, SIRI, and NLR showed predictive value for IMV. The cut-off values for RDW (OR = 1.85, p < 0.001), NHL (OR = 1.67, p = 0.004) and NLR (OR = 1.56, p = 0.012) were mainly associated with severe COVID-19. NHL (OR = 3.07, p < 0.001), AISI (OR = 2.64, p < 0.001) and SIRI (OR = 2.51, p < 0.001) were associated with IMV support, while for non-survival the main indices associated were NHL (OR = 2.65, p < 0.001), NLR (OR = 2.26, p < 0.001), dNLR (OR = 1.92, p < 0.001), SIRI (OR = 1.67, p = 0.002) and SII (OR = 1.50, p = 0.010). The patients with an RDW, PLR, NLR, dNLR, MLR, SII, and NHL above the cut-off had a survival probability of COVID-19 50% lower, with an estimated mean survival time of 40 days. Conclusion: The emergent systemic inflammation indices NHL, NLR, RDW, SII, and SIRI have a predictive power of severe COVID-19, IMV support, and low survival probability during hospitalization by COVID-19 in Mexican patients.

TNFRSF1B and TNF Variants Are Associated With Differences in Levels of Soluble Tumor Necrosis Factor Receptors in Patients With Severe COVID-19.

BACKGROUND: The impact of genetic variants in the expression of tumor necrosis factor-α (TNF-α) and its receptors in coronavirus disease 2019 (COVID-19) severity has not been previously explored. We evaluated the association of TNF (rs1800629 and rs361525), TNFRSF1A (rs767455 and rs1800693), and TNFRSF1B (rs1061622 and rs3397) variants with COVID-19 severity, assessed as invasive mechanical ventilation (IMV) requirement, and the plasma levels of soluble TNF-α, TNFR1, and TNFR2 in patients with severe COVID-19. METHODS: The genetic study included 1353 patients. Taqman assays were used to assess the genetic variants. ELISA was used to determine soluble TNF-α, TNFR1, and TNFR2 in plasma samples from 334 patients. RESULTS: Patients carrying TT (TNFRSF1B rs3397) exhibited lower PaO2/FiO2 levels than those with CT + CC genotypes. Differences in plasma levels of TNFR1 and TNFR2 were observed according to the genotype of TNFRSF1B rs1061622, TNF rs1800629, and rs361525. According to the studied genetic variants, there were no differences in the soluble TNF-α levels. Higher soluble TNFR1 and TNFR2 levels were detected in patients with COVID-19 requiring IMV. CONCLUSIONS: Genetic variants in TNF and TNFRSFB1 influence the plasma levels of soluble TNFR1 and TNFR2, implicated in COVID-19 severity.

Comparison between the persistence of post COVID-19 symptoms on critical patients requiring invasive mechanical ventilation and non-critical patients.

BACKGROUND: During follow-up, patients severely affected by coronavirus disease 2019 (COVID-19) requiring invasive mechanical ventilation (IMV), show symptoms of Post-Intensive Care Syndrome (PICS) such as cognitive impairment, psychological disability, and neuromuscular deconditioning. In COVID-19 pandemic, it is a priority to develop multidisciplinary post-acute care services to address the long-term multisystemic impact of COVID-19. RESEARCH QUESTION: Which are the most relevant multisystemic sequelae in severe post-COVID-19 patients? STUDY DESIGN AND METHODS: Observational chart review study that included adult patients discharged from a referral hospital for respiratory diseases in Mexico after recovering from severe COVID-19 disease from December 23, 2020, to April 24, 2021. Data were collected from 280 of 612 potentially eligible patients to evaluate persistent symptoms and compare sequelae in patients who required intubation, using a standardized questionnaire of symptoms, in addition to findings reported during the face-to-face health assessment. Univariable and multivariate analyses were performed for the association among the requirement of IMV and the long-term persistence of symptoms. RESULTS: 280 patients were included. The median age was 55 (range, 19 to 86) years, and 152 (54.3%) were men. The mean length of hospital stay was 19 (SD, 14.1) days. During hospitalization 168 (60%) participants received IMV. A large proportion of these patients reported fatigue (38.7%), paresthesia (35.1%), dyspnea (32.7%) and headache (28%); meanwhile only 3 (1.8%) of them were asymptomatic. Patients who required intubation were more likely to have neuropsychiatric (67.3% vs 55.4%; OR, 1.79 [95% CI, 1.08 to 2.97]) and musculoskeletal involvement (38.7% vs. 25.9%; OR, 1.92 [95% CI, 1.12 to 3.27]), adjusted for age,sex and hospitalization time. INTERPRETATION: The proportion of patients requiring intubation was 60%, reporting persistent symptoms in 98% of them. Neuropsychiatric and musculoskeletal symptoms were the most predominant symptoms in these patients, with a significant difference. Post-COVID-19 syndrome is a frequent problem in patients who required IVM. Physicians in ICU and in care of COVID-19 patients should be aware of this syndrome in order to avoid more complications.

IFNAR2 relevance in the clinical outcome of individuals with severe COVID-19.

Interferons (IFNs) are a group of cytokines with antiviral, antiproliferative, antiangiogenic, and immunomodulatory activities. Type I IFNs amplify and propagate the antiviral response by interacting with their receptors, IFNAR1 and IFNAR2. In COVID-19, the IFNAR2 (interferon alpha and beta receptor subunit 2) gene has been associated with the severity of the disease, but the soluble receptor (sIFNAR2) levels have not been investigated. We aimed to evaluate the association of IFNAR2 variants (rs2236757, rs1051393, rs3153, rs2834158, and rs2229207) with COVID-19 mortality and to assess if there was a relation between the genetic variants and/or the clinical outcome, with the levels of sIFNAR2 in plasma samples from hospitalized individuals with severe COVID-19. We included 1,202 subjects with severe COVID-19. The genetic variants were determined by employing Taqman® assays. The levels of sIFNAR2 were determined with ELISA in plasma samples from a subgroup of 351 individuals. The rs2236757, rs3153, rs1051393, and rs2834158 variants were associated with mortality risk among patients with severe COVID-19. Higher levels of sIFNAR2 were observed in survivors of COVID-19 compared to the group of non-survivors, which was not related to the studied IFNAR2 genetic variants. IFNAR2, both gene, and soluble protein, are relevant in the clinical outcome of patients hospitalized with severe COVID-19.

COVID-19 Survivor Patients Carrying the Rs35705950 Risk Allele in MUC5B Have Higher Plasma Levels of Mucin 5B.

BACKGROUND: Genetic susceptibility to infectious diseases is partly due to the variation in the human genome, and COVID-19 is not the exception. This study aimed to identify whether risk alleles of known genes linked with emphysema (SERPINA1) and pulmonary fibrosis (MUC5B) are associated with severe COVID-19, and whether plasma mucin 5B differs according to patients' outcomes. MATERIALS AND METHODS: We included 1258 Mexican subjects diagnosed with COVID-19. We genotyped rs2892474 and rs17580 of the SERPINA1 gene and rs35705950 of MUC5B. Based on the rs35705950 genotypes, mucin 5B plasma protein levels were quantified. RESULTS: Homozygous for the risk alleles of the three polymorphisms were found in less than 5% of the study population, but no statistically significant difference in the genotype or allele association analysis. At the protein level, non-survivors carrying one or two copies of the risk allele rs35705950 in MUC5B (GT + TT) had lower levels of mucin 5B compared to the survivors (0.0 vs. 0.17 ng/mL, p = 0.0013). CONCLUSION: The polymorphisms rs28929474 and rs17580 of SERPINA1 and rs35705950 of MUC5B are not associated with the risk of severe COVID-19 in the Mexican population. COVID-19 survivor patients bearing one or two copies of the rs35705950 risk allele have higher plasma levels of mucin 5B.

SERPINE1 rs6092 Variant Is Related to Plasma Coagulation Proteins in Patients with Severe COVID-19 from a Tertiary Care Hospital.

An impaired coagulation process has been described in patients with severe or critical coronavirus disease (COVID-19). Nevertheless, the implication of coagulation-related genes has not been explored. We aimed to evaluate the impact of F5 rs6025 and SERPINE1 rs6092 on invasive mechanical ventilation (IMV) requirement and the levels of coagulation proteins among patients with severe COVID-19. Four-hundred fifty-five patients with severe COVID-19 were genotyped using TaqMan assays. Coagulation-related proteins (P-Selectin, D-dimer, P-selectin glycoprotein ligand-1, tissue plasminogen activator [tPA], plasminogen activator inhibitor-1, and Factor IX) were assessed by cytometric bead arrays in one- and two-time determinations. Accordingly, SERPINE1 rs6092, P-Selectin (GG 385 pg/mL vs. AG+AA 632 pg/mL, p = 0.0037), and tPA (GG 1858 pg/mL vs. AG+AA 2546 pg/mL, p = 0.0284) levels were different. Patients carrying the CT F5-rs6025 genotype exhibited lower levels of factor IX (CC 17,136 pg/mL vs. CT 10,247 pg/mL, p = 0.0355). Coagulation proteins were also different among IMV patients than non-IMV. PSGL-1 levels were significantly increased in the late stage of COVID-19 (>10 days). The frequencies of F5 rs6025 and SERPINE1 rs6092 variants were not different among IMV and non-IMV. The SERPINE1 rs6092 variant is related to the impaired coagulation process in patients with COVID-19 severe.

Circulating Levels of PD-L1, TIM-3 and MMP-7 Are Promising Biomarkers to Differentiate COVID-19 Patients That Require Invasive Mechanical Ventilation.

BACKGROUND: COVID-19 is an infectious disease caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Many COVID-19 patients require invasive mechanical ventilation (IMV) while others, even with acute respiratory failure, do not (NIMV). Therefore, we aimed to evaluate serum levels of MMP-7 and molecules related to exhausted T-cells as potential biomarkers to differentiate between IMV and NIMV patients. METHODS: 105 patients diagnosed with COVID-19 and confirmed by RT-PCR for SARS-CoV-2 were divided into two groups according to the requirement for IMV. Serum levels of sPD-L1, sPD-L2, sTIM-3, sGal-9 and sMMP-7 were quantified by ELISA and correlated with clinical data. Twelve patients were followed up after eight months to compare the levels of the biomarkers between acute disease and post-COVID-19. RESULTS: IMV patients experienced a lower PaO2/FiO2 (p < 0.0001) and a longer hospital stay (p < 0.0001), and exhibited higher levels of sPD-L1 (p < 0.05), sTIM-3 (p < 0.01) and sMMP-7 (p < 0.0001) when compared with NIMV patients. According to a ROC analysis, sMMP-7 had the highest sensitivity (78%) and specificity (76%) with a cut point of 4.5 ng/mL, followed by sTIM-3 and sPD-L1. Eight months post-COVID-19, IMV patients displayed a significant decrease in the initially high levels of sPD-L1, sTIM-3 and sGal-9, while sPD-L2 was increased, and sMMP-7 was unchanged. CONCLUSION: Circulating levels of sPD-L1, sTIM-3 and sMMP-7 are potential biomarkers of disease severity to distinguish patients requiring IMV. MMP-7 could also be a marker for the persistence of lung lesions post-COVID-19.

Telomere Shortening and Its Association with Cell Dysfunction in Lung Diseases.

Telomeres are localized at the end of chromosomes to provide genome stability; however, the telomere length tends to be shortened with each cell division inducing a progressive telomere shortening (TS). In addition to age, other factors, such as exposure to pollutants, diet, stress, and disruptions in the shelterin protein complex or genes associated with telomerase induce TS. This phenomenon favors cellular senescence and genotoxic stress, which increases the risk of the development and progression of lung diseases such as idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, SARS-CoV-2 infection, and lung cancer. In an infectious environment, immune cells that exhibit TS are associated with severe lymphopenia and death, whereas in a noninfectious context, naïve T cells that exhibit TS are related to cancer progression and enhanced inflammatory processes. In this review, we discuss how TS modifies the function of the immune system cells, making them inefficient in maintaining homeostasis in the lung. Finally, we discuss the advances in drug and gene therapy for lung diseases where TS could be used as a target for future treatments.

Angiotensin-Converting Enzyme 2 (ACE2) in the Context of Respiratory Diseases and Its Importance in Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection.

Angiotensin-Converting Enzyme 2 (ACE2) is an 805 amino acid protein encoded by the ACE2 gene expressed in various human cells, especially in those located in the epithelia. The primary function of ACE2 is to produce angiotensin (1-7) from angiotensin II (Ang II). The current research has described the importance of ACE2 and Ang (1-7) in alternative routes of the renin-angiotensin system (RAS) that promote the downregulation of fibrosis, inflammation, and oxidative stress processes in a great variety of diseases, such as hypertension, acute lung injury, liver cirrhosis, and kidney abnormalities. Investigations into the recent outbreak of the new severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have revealed the importance of ACE2 during infection and its role in recognizing viral binding proteins through interactions with specific amino acids of this enzyme. Additionally, the ACE2 expression in several organs has allowed us to understand the clinical picture related to the infection caused by SARS-CoV-2. This review aims to provide context for the functions and importance of ACE2 with regards to SARS-CoV-2 in the general clinical aspect and its impact on other diseases, especially respiratory diseases.

Severe COVID-19 Patients Show an Increase in Soluble TNFR1 and ADAM17, with a Relationship to Mortality.

Overproduction of inflammatory cytokines is a keystone event in COVID-19 pathogenesis; TNF and its receptors (TNFR1 and TNFR2) are critical pro-inflammatory molecules. ADAM17 releases the soluble (sol) forms of TNF, TNFR1, and TNFR2. This study evaluated TNF, TNFRs, and ADAM17 at the protein, transcriptional, and gene levels in COVID-19 patients with different levels of disease severity. In total, 102 patients were divided into mild, moderate, and severe condition groups. A group of healthy donors (HD; n = 25) was included. Our data showed that solTNFR1 and solTNFR2 were elevated among the COVID-19 patients (p < 0.0001), without increasing the transcriptional level. Only solTNFR1 was higher in the severe group as compared to the mildly ill (p < 0.01), and the level was higher in COVID-19 patients who died than those that survived (p < 0.0001). The solTNFR1 level had a discrete negative correlation with C-reactive protein (p = 0.006, Rho = -0.33). The solADAM17 level was higher in severe as compared to mild disease conditions (p < 0.01), as well as in COVID-19 patients who died as compared to those that survived (p < 0.001). Additionally, a potential association between polymorphism TNFRSF1A:rs767455 and a severe degree of disease was suggested. These data suggest that solTNFR1 and solADAM17 are increased in severe conditions. solTNFR1 should be considered a potential target in the development of new therapeutic options.

SARS-CoV-2 infection: Understanding the immune system abnormalities to get an adequate diagnosis.

COVID-19 is the current pandemic caused by the novel coronavirus, SARS-CoV-2, that emerged from China at the end of December 2019. The scientific community is making extraordinary efforts to understand the virus structure and the pathophysiology and immunological processes activated in the host, in order to identify biomarkers, diagnostic tools, treatments, and vaccines to decrease COVID-19 incidence and mortality. Various abnormalities have been noted during SARS-CoV-2 infection both in lymphoid and myeloid cells. Such abnormalities may disturb the immune system function and cause a massive inflammatory response that impairs tissue function. This review discusses the close relationship between the immune system abnormalities and the broad spectrum of clinical manifestations, including fibrosis, in the context of COVID-19 disease. Moreover, we described the current strategies for COVID-19 diagnosis, and we provide a summary of the most useful clinical laboratory parameters to identify severe COVID-19 patients.