Variants rs3804099 and rs3804100 in the TLR2 Gene Induce Different Profiles of TLR-2 Expression and Cytokines in Response to Spike of SARS-CoV-2.

The present study aimed to identify in patients with severe COVID-19 and acute respiratory distress syndrome (ARDS) the association between rs3804099 and rs3804100 (TLR2) and evaluate the expression of TLR-2 on the cell surface of innate and adaptive cells of patients' carriers of C allele in at least one genetic variant. We genotyped 1018 patients with COVID-19 and ARDS. According to genotype, a subgroup of 12 patients was selected to stimulate peripheral blood mononuclear cells (PBMCs) with spike and LPS + spike. We evaluated soluble molecules in cell culture supernatants. The C allele in TLR2 (rs3804099, rs3804100) is not associated with a risk of severe COVID-19; however, the presence of the C allele (rs3804099 or rs3804100) affects the TLR-2 ability to respond to a spike of SARS-CoV-2 correctly. The reference group (genotype TT) downregulated the frequency of non-switched TLR-2+ B cells in response to spike stimulus; however, the allele's C carriers group is unable to induce this regulation, but they produce high levels of IL-10, IL-6, and TNF-α by an independent pathway of TLR-2. Findings showed that TT genotypes (rs3804099 and rs3804100) affect the non-switched TLR-2+ B cell distribution. Genotype TT (rs3804099 and rs3804100) affects the TLR-2's ability to respond to a spike of SARS-CoV-2. However, the C allele had increased IL-10, IL-6, and TNF-α by stimulation with spike and LPS.

The BCG vaccine and SARS-CoV-2: Could there be a beneficial relationship?

The COVID-19 disease continues to cause complications and deaths worldwide. Identifying effective immune protection strategies remains crucial to address this ongoing challenge. The Bacillus Calmette-Guérin (BCG) vaccine, developed initially to prevent pulmonary tuberculosis, has gained relevance due to its ability to induce cross-protection against other pathogens of the airways. This review summarizes research on the immunological protection provided by BCG, along with its primary clinical and therapeutic uses. It also explores the immunological features of COVID-19, the mechanisms implicated in host cell death, and its association with chronic pulmonary illnesses such as tuberculosis, which has led to complications in diagnosis and management. While vaccines against COVID-19 have been administered globally, uncertainty still exists about its effectiveness. Additionally, it is uncertain whether the utilization of BCG can regulate the immune response to pathogens such as SARS-CoV-2.

Comparison of IL-6, IL-10, and TNFα levels between PLWHIV with and without Kaposi Sarcoma and healthy controls.

INTRODUCTION: Kaposi sarcoma (KS) is an angioproliferative disease caused by human herpesvirus 8 (HHV-8) and is mediated by cytokines in an immunodeficient environment. This study aimed to compare IL-6, IL-10, and TNFα levels among AIDS patients with disseminated KS (DKS), treatment naïve patients living with HIV (PLWHIV) without DKS, and healthy controls. Secondary outcomes were to compare cytokines levels in patients with DKS and unfavorable outcomes, as well as an analysis of the behavior of cytokines over time. METHODS: This cohort study was performed at two centers in Mexico City. Three groups were included. Group 1: HIV+ treatment naïve with DKS, Group 2: HIV+ treatment naïve without KS, and Group 3: HIV negative, healthy controls. Plasmatic IL-6, IL-10, and TNFα levels were measured at baseline and over time in Groups 1 and 2. RESULTS: Seventy-six patients were included: 39 (52%) in Group 1, 17 (22%) in Group 2, and 20 (26%) in Group 3. The median baseline IL-6, IL-10, and TNFα levels were significantly higher in group 1. In group 1, baseline IL-6 was higher in patients who died than in survivors (14.4 vs 5.8 pg/mL p=0.048). Patients with severe immune reconstitution inflammatory syndrome due to KS (S-IRIS-KS) had higher IL-6 values than those without it (14.4 vs 5.8 pg/mL p=0.004). In the repeated-measures model in group 1, IL-10 levels were higher in patients who died (p<0.001) and developed IRIS-KS (p=0.01). CONCLUSIONS: IL-6, IL-10, and TNF α levels were markedly higher in patients with DKS. IL-6 and IL-10 levels were higher in patients with unfavorable outcomes.

HLA-G 14-bp variant is associated with exercise-induced oxygen desaturation in the post-COVID-19 condition.

The HLA-G 14-bp indel (rs371194629) variant is associated with IMV requirement in COVID-19 and with exercise-induced desaturation in the post-COVID-19 condition https://bit.ly/3THdx1D.

Persistence of lung structural and functional alterations at one year post-COVID-19 is associated with increased serum PD-L2 levels and altered CD4/CD8 ratio.

BACKGROUND: Persistent respiratory symptoms and lung abnormalities post-COVID-19 are public health problems. This study evaluated biomarkers to stratify high-risk patients to the development or persistence of post-COVID-19 interstitial lung disease. METHODS: One hundred eighteen patients discharged with residual lung abnormalities compatible with interstitial lung disease (COVID-ILD patients) after a severe COVID-19 were followed for 1 year (post-COVID-ILD patients). Physical examination, pulmonary function tests, and chest high-resolution computed tomography (HRCT) were performed. Soluble forms (s) of PD-L1, PD-L2, TIM-3, and GAL-9 were evaluated in serum and cell culture supernatant, as well as T-cells subsets and the transmembrane expression of PD-L1 and PD-L2 on the cell surface. RESULTS: Eighty percent of the post-COVID-ILD patients normalized their lung function at 1-year follow-up, 8% presented COVID-independent ILD, and 12% still showed functional and HRCT alterations. PD-L2 levels were heterogeneous during acute COVID-19 (aCOVID); patients who increased (at least 30%) their sPD-L2 levels at 1 year post-COVID-19 and exhibited altered CD4/CD8 ratio showed persistence of chest tomographic and functional alterations. By contrast, patients who decreased sPD-L2 displayed a complete lung recovery. sPD-L1, sTIM-3, and sGAL-9 increased significantly during aCOVID and decreased in all patients after 1-year follow-up. CONCLUSION: Increased sPD-L2 and an altered CD4/CD8 ratio after 12 months of aCOVID are associated with the persistence of lung lesions, suggesting that they may contribute to lung damage post-COVID-19.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV

ABSTRACT Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoid-proliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

The rs11684747 and rs55790676 SNPs of ADAM17 influence tuberculosis susceptibility and plasma levels of TNF, TNFR1, and TNFR2.

Introduction: The proteolytic activity of A Disintegrin and Metalloproteinase 17 (ADAM17) regulates the release of tumor necrosis factor (TNF) and TNF receptors (TNFRs) from cell surfaces. These molecules play important roles in tuberculosis (TB) shaping innate immune reactions and granuloma formation. Methods: Here, we investigated whether single nucleotide polymorphisms (SNPs) of ADAM17 influence TNF and TNFRs levels in 224 patients with active TB (ATB) and 118 healthy close contacts. Also, we looked for significant associations between SNPs of ADAM17 and ATB status. TNF, TNFR1, and TNFR2 levels were measured in plasma samples by ELISA. Four SNPs of ADAM17 (rs12692386, rs1524668, rs11684747, and rs55790676) were analyzed in DNA isolated from peripheral blood leucocytes. The association between ATB status, genotype, and cytokines was analyzed by multiple regression models. Results: Our results showed a higher frequency of rs11684747 and rs55790676 in close contacts than ATB patients. Coincidentally, heterozygous to these SNPs of ADAM17 showed higher plasma levels of TNF compared to homozygous to their respective ancestral alleles. Strikingly, the levels of TNF and TNFRs distinguished participant groups, with ATB patients displaying lower TNF and higher TNFR1/TNFR2 levels compared to their close contacts. Conclusion: These findings suggest a role for SNPs of ADAM17 in genetic susceptibility to ATB.

The presence of cytotoxic CD4 and exhausted-like CD8+ T-cells is a signature of active tuberculosis.

Chronic infections induce CD4+ T-cells with cytotoxic functions (CD4 CTLs); at present, it is still unknown whether latent tuberculosis (LTB) and active tuberculosis (ATB) induce CD4 CTLs. Plasma and cells from four patient groups-uninfected contact (UC), LTB, and ATB (divided as sensitive [DS-TB]- or resistant [DR-TB]-drug)-were evaluated by flow cytometry, q-PCR, and proteomics. The data showed that ATB patients had an increased frequency of CD4+ T-cells and a decreased frequency of CD8+ T-cells. The latter displays an exhausted-like profile characterized by CD39, CD279, and TIM-3 expression. ATB had a high frequency of CD4 + perforin+ cells, suggesting a CD4 CTL profile. The expression (at the transcriptional level) of granzyme A, granzyme B, granulysin, and perforin, as well as the genes T-bet (Tbx21) and NKG2D (Klrk1), in enriched CD4+ T-cells, confirmed the cytotoxic signature of CD4+ T-cells during ATB (which was stronger in DS-TB than in DR-TB). Moreover, proteomic analysis revealed the presence of HSP70 (in DS-TB) and annexin A5 (in DR-TB), which are molecules that have been associated with favoring the CD4 CTL profile. Finally, we found that lipids from Mycobacterium tuberculosis increased the presence of CD4 CTLs in DR-TB patients. Our data suggest that ATB is characterized by exhausted-like CD8+ T-cells, which, together with a specific microenvironment, favor the presence of CD4 CTLs.

The Immune Response of OAS1, IRF9, and IFI6 Genes in the Pathogenesis of COVID-19.

COVID-19 is characterized by a wide range of clinical manifestations, where aging, underlying diseases, and genetic background are related to worse outcomes. In the present study, the differential expression of seven genes related to immunity, IRF9, CCL5, IFI6, TGFB1, IL1B, OAS1, and TFRC, was analyzed in individuals with COVID-19 diagnoses of different disease severities. Two-step RT-qPCR was performed to determine the relative gene expression in whole-blood samples from 160 individuals. The expression of OAS1 (p < 0.05) and IFI6 (p < 0.05) was higher in moderate hospitalized cases than in severe ones. Increased gene expression of OAS1 (OR = 0.64, CI = 0.52-0.79; p = 0.001), IRF9 (OR = 0.581, CI = 0.43-0.79; p = 0.001), and IFI6 (OR = 0.544, CI = 0.39-0.69; p < 0.001) was associated with a lower risk of requiring IMV. Moreover, TGFB1 (OR = 0.646, CI = 0.50-0.83; p = 0.001), CCL5 (OR = 0.57, CI = 0.39-0.83; p = 0.003), IRF9 (OR = 0.80, CI = 0.653-0.979; p = 0.03), and IFI6 (OR = 0.827, CI = 0.69-0.991; p = 0.039) expression was associated with patient survival. In conclusion, the relevance of OAS1, IRF9, and IFI6 in controlling the viral infection was confirmed.

Immune Deficiency/Dysregulation Associated Lymphoid Proliferations, EBV+ In Persons Living With HIV.

Background: The 5th edition of the World Health Organization Classification of Hematolymphoid Tumors recently defined immune deficiency/dysregulation (IDD)-associated-lymphoid-proliferations in HIV settings, where information is scarce, often gone under or misdiagnosed. Objectives: To describe the clinical picture, histopathology, and outcomes of IDD-associated-lymphoidproliferations Epstein-Barr virus+ (EBV) in people living with HIV without organ transplantation, antiretroviral therapy (ART) treated. Materials and Methods: HIV+ patients diagnosed with IDD-associated-lymphoid-proliferations seen at an academic medical center in Mexico from 2016 to 2019 were included. Immunohistochemical studies, in situ hybridization, and polymerase chain reaction analysis for EBV and LMP1 gene deletions were performed and correlated with clinical data. Results: We included 27 patients, all men who have sex with men, median age 36 years (interquartile range [IQR] 22-54). The median baseline CD4+ T cells were 113/mL (IQR 89-243), the CD4+/CD8+ ratio was 0.15 (IQR: 0.09-0.22), and the HIV viral load was 184,280 copies/mL (IQR: 76,000-515,707). Twenty patients (74.07%) had IDD-associated-lymphoid-proliferations hyperplasia plasma cell type EBV+, 3 (11.1%) had hyperplasia mononucleosis-like type (IM-type), 1 patient (3.70%) had florid follicular hyperplasia, 3 (11.1%) IDD-associated-lymphoid-proliferations polymorphic type, and there were 22 cases (81.4%) of synchronic Kaposi Sarcoma. Two patients were diagnosed with Hodgkin lymphoma following a second positron emission tomography-computed tomography scan-guided biopsy. The median follow-up was 228 weeks (IQR 50-269); 6 patients died (22.2%) of causes unrelated to IDD-associated-lymphoid-proliferations related. Conclusion: IDD-associated-lymphoid-proliferations EBV+ occured in severely immunosuppressed HIV+ patients, a high percentage of whom had concomitant Kaposi sarcoma. The prognosis was good in patients treated only with ART.

Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes.

Association of PADI2 and PADI4 polymorphisms in COVID-19 host severity and non-survival.

Background: Enzymes of the peptidylarginine deiminase family (PADs) play a relevant role in the pathogenesis of COVID-19. However, the association of single nucleotide polymorphisms (SNPs) in their genes with COVID-19 severity and death is unknown. Methodology: We included 1045 patients who were diagnosed with COVID-19 between October 2020 and December 2021. All subjects were genotyped for PADI2 (rs1005753 and rs2235926) and PADI4 (rs11203366, rs11203367, and rs874881) SNPs by TaqMan assays and their associations with disease severity, death, and inflammatory biomarkers were evaluated. Results: 291 patients presented had severe COVID-19 according to PaO2/FiO2, and 393 had a non-survival outcome. Carriers of the rs1005753 G/G genotype in the PADI2 gene presented susceptibility for severe COVID-19, while the heterozygous carriers in rs11203366, rs11203367, and rs874881 of the PADI4 gene showed risk of death. The GTACC haplotype in PADI2-PADI4 was associated with susceptibility to severe COVID-19, while the GCACC haplotype was a protective factor. The GCGTG haplotype was associated with severe COVID-19 but as a protective haplotype for death. Finally, the GTACC haplotype was associated with platelet-to-lymphocyte ratio (PLR), the GCACC haplotype with neutrophil-to-hemoglobin and lymphocyte and the GCGTG haplotype as a protective factor for the elevation of procalcitonin, D-dimer, CRP, LCRP, NHL, SII, NLR, and PLR. Conclusions: Our results suggest that the haplotypic combination of GTACC and some individual genotypes of PADI2 and PADI4 contribute to the subjects' susceptibility for severity and death by COVID-19.

Valganciclovir modulates the tumor necrosis factor axis molecules expression and CD4+ T-cell subsets in disseminated Kaposi Sarcoma patients.

Valganciclovir (VGC) was used in a randomized clinical trial in patients with disseminated Kaposi Sarcoma/human immunodeficiency virus (DKS/HIV) as add-on therapy to evaluate the proinflammatory axis tumor necrosis factor (TNF) and its receptors (TNFRs) in T cells. Two treatment schedules were used: an experimental regime (ER) and a conventional treatment (CT). Mononuclear cells from patients with DKS/HIV were obtained at baseline (W0), 4 (W4), and 12 weeks (W12). Ten DKS/HIV patients received CT (antiretroviral therapy [cART]) and 10 ER (valganciclovir [VGC] initially, plus cART at the fourth week). HIV+ without KS and HIV- patient groups were included as controls. Correlation between T-cell subsets and HHV-8 viral load (VL) and a multivariate linear regression was performed. Data showed that DKS/HIV patients have an increased frequency of CD8+ T cells, which display a high density of CD8 expression. The ER scheme increases naïve and central memory CD4+ T cells at W4 and W12 of follow-up and induces a balanced distribution of activated CD4+ T-cell subsets. Moreover, ER decreases solTNFR2 since W4 and CT decreased the transmembrane forms of TNF axis molecules. Although CT induces a positive correlation between HHV-8 VL and TNFRs, the use of ER positively correlates with TNF and TNFRs levels through follow-up and a moderate correlation with HHV-8 VL and TNF soluble levels. In conclusion, VGC, as an add-on therapy in DKS/HIV patients, gradually modulates the activation of CD4+ T-cell subsets and the TNF/TNFRs axis, suggesting a better regulation of the inflammatory status.

Variant rs4986790 of toll-like receptor 4 affects the signaling and induces cell dysfunction in patients with severe COVID-19.

OBJECTIVES: We investigated the expression of toll-like receptor (TLR)-4 on the cell surface of innate and adaptive cells from patients with COVID-19 carrying the rs4986790 GG genotype in the TLR4 gene and the functional profile of these cells. METHODS: We included 1169 hospitalized patients with COVID-19. The rs4986790 in TLR4 was identified by real-time polymerase chain reaction. Peripheral blood mononuclear cells were isolated and cultured to evaluate TLR-4 expression on immune cells. Supernatants recovered culture assays were stored, and we measured cytokines and cytotoxic molecules. RESULTS: We showed that the rs4986790 (GG) was significantly associated (P = 0.0310) with severe COVID-19. Cells of patients with COVID-19 carrying the GG genotype have increased the frequency of monocytes and activated naïve and non-switched B cells positive to TLR-4 when cells are stimulated with lipopolysaccharide and with spike protein of SARS-CoV-2. Also, cells from patients with GG COVID-19 cannot produce pro-inflammatory cytokines after lipopolysaccharide stimulus, but they are high producers of cytotoxic molecules at baseline. CONCLUSIONS: The rs4986790 GG genotype of the TLR4 is associated with the risk of COVID-19 and acute respiratory distress syndrome. Peripheral blood mononuclear cells of patients carrying the rs4986790 (TLR4) GG genotype had a limited delivery of pro-inflammatory cytokines compared to the AA and AG genotypes in which TLR-4 stimulation induces IL-10, IL-6, tumor necrosis factor-α, and Fas ligand production.

Active tuberculosis patients have high systemic IgG levels and B-cell fingerprinting, characterized by a reduced capacity to produce IFN-γ or IL-10 as a response to M.tb antigens.

Introduction: Tuberculosis (TB) is a bacterial infection caused by Mycobacterium tuberculosis (M.tb). B cells are the central mediator of the humoral response; they are responsible for producing antibodies in addition to mediating other functions. The role of the cellular response during the TB spectrum by B cells is still controversial. Methods: In this study, we evaluated the distribution of the circulating B cell subsets in patients with active and latent TB (ATB and LTB, respectively) and how they respond to stimuli of protein or lipid from M.tb. Results: Here, we show that ATB patients show an immune fingerprinting. However, patients with drug-sensitive- (DS-TB) or drug-resistant- (DR-TB) TB have altered frequencies of circulating B cells. DS-TB and DR-TB display a unique profile characterized by high systemic levels of IFN-γ, IL-10, IgG, IgG/IgM ratio, and total B cells. Moreover, B cells from DR-TB are less efficient in producing IL-10, and both DS-TB and DR-TB produce less IFN-γ in response to M.tb antigens. Conclusion: These results provide new insights into the population dynamics of the cellular immune response by B cells against M.tb and suggest a fingerprinting to characterize the B-cell response on DR-TB.

Opportunistic Infections and Immune-Related Adverse Events Associated with Administering Immune Checkpoint Inhibitors: A Narrative Review.

Manipulating the immune system by blocking the immune checkpoint receptors is the basis of immunotherapy, a relevant tool in current clinical oncology. The strategy of blocking the immune checkpoints (Immune Checkpoint Inhibitors, ICI) consists of using monoclonal antibodies to inhibit the interaction between ligand and inhibitory receptors from triggering a complete activation of helper and cytotoxic T cells to fight against tumour cells. Immunotherapy has benefited patients with diverse cancers such as stomach, lung, melanoma, and head and neck squamous cell carcinoma, among others. Unfortunately, a growing number of reports have indicated that the ICI treatment also can show a dark side under specific conditions; some of the adverse effects induced by ICI are immunosuppression, opportunistic infections, and organ-specific alterations. This review discusses some immunologic aspects related to these unwanted effects.

COVID-19 patients with high TNF/IFN-γ levels show hallmarks of PANoptosis, an inflammatory cell death.

TNF and IFN-γ trigger cell damage during SARS CoV-2 infection; these cytokines can induce senescence and a cell death process called PANoptosis. This study included 138 vaccine-naïve COVID-19 patients, who were divided into four groups (Gp) according to the plasma level of TNF and IFN-γ (High [Hi] or Normal-Low [No-Low]), Gp 1: TNFHi/IFNγHi; Gp 2: TNFHi/IFNγNo-Low; Gp 3: TNFNo-Low/IFNγHi; and Gp 4: TNFNo-Low/IFNγNo-Low. Thirty-five apoptosis-related proteins and molecules related to cell death and senescence were evaluated. Our results showed that groups did not display differences in age and comorbidities. However, 81% of the Gp 1 patients had severe COVID-19, and 44% died. Notably, the p21/CDKN1A was increased in Gp 2 and Gp 3. Moreover, Gp 1 showed higher TNFR1, MLKL, RIPK1, NLRP3, Caspase 1, and HMGB-1 levels, suggesting elevated TNF and IFN-γ levels simultaneously activate diverse cell death pathways because it is not observed when only one of these cytokines is increased. Thus, high TNF/IFN-γ levels are predominant in severe COVID-19 status, and patients display cell alterations associated with the activation of diverse cell death pathways, including a possible senescent phenotype.

The rs16969968 Tobacco Smoking-Related Single-Nucleotide Variant Is Associated with Clinical Markers in Patients with Severe COVID-19.

Tobacco smoking is the leading risk factor for many respiratory diseases. Several genes are associated with nicotine addiction, such as CHRNA5 and ADAM33. This research aims to evaluate the association of the polymorphisms rs16969968 (CHRNA5) and rs3918396 (ADAM33) in patients who developed severe COVID-19. We included 917 COVID-19 patients hospitalized with critical disease and oxygenation impairment. They were divided into two groups, tobacco-smoking (n = 257) and non-smoker (n = 660) patients. The genotype and allele frequencies of two single nucleotide variants, the rs16969968 (CHRNA5) and rs3918396 (ADAM33), were evaluated. The rs3918396 in ADAM33 does not show a significative association. We analyzed the study population according to the rs16969968 genotype (GA + AA, n = 180, and GG, n = 737). The erythrocyte sedimentation rate (ESR) shows statistical differences; the GA + AA group had higher values than the GG group (p = 0.038, 32 vs. 26 mm/h, respectively). The smoking patients and GA or AA genotype carriers had a high positive correlation (p < 0.001, rho = 0.753) between fibrinogen and C-reactive protein. COVID-19 patients and smokers carriers of one or two copies of the risk allele (rs16969968/A) have high ESR and a positive correlation between fibrinogen and C-reactive protein.

High Expression Levels of miR-21-5p in Younger Hospitalized COVID-19 Patients Are Associated with Mortality and Critical Disease.

In COVID-19, critical disease and invasive mechanical ventilation (IMV) increase the risk of death, mainly in patients over 60 years of age. OBJECTIVES: To find the relationship between miR-21-5p and miR-146a-5p in terms of the severity, IMV, and mortality in hospitalized COVID-19 patients younger than 55 years of age. METHODS: The patients were stratified according to disease severity using the IDSA/WHO criteria for severe and critical COVID-19 and subclassified into critical non-survivors and critical survivors. RESULTS: Ninety-seven severe/critical COVID-19 patients were included; 81.3% of the deceased were male and 18.8% were female. Higher expression miR-21-5p levels were associated as follows: severe vs. critical disease (p = 0.007, FC = 0.498), PaO2/FiO2 index, mild vs. severe (p = 0.027, FC = 0.558), and survivors vs. non-survivors (p = 0.03, FC = 0.463). Moreover, we identified correlations with clinical variables: CRP (rho = -0.54, p < 0.001), D-dimer (rho = -0.47, p < 0.05), related to damage in the kidney (rho = 0.60, p < 0.001), liver (rho = 0.41, p < 0.05), and lung (rho = 0.54, p < 0.001). Finally, miR-21-5p thresholds were calculated according to severity (8.191), IMV (8.191), and mortality (8.237); these values increased the risk of developing a critical disease (OR = 4.19), the need for IMV (OR = 5.63), and death (OR = 6.00). CONCLUSION: Increased expression levels of miR-21-5p are related to worse outcome of COVID-19 in younger hospitalized patients.