COVID-19 Disease Severity Research Articles

Complex changes in serum protein levels in COVID-19 convalescents

The COVID-19 pandemic, triggered by severe acute respiratory syndrome coronavirus 2, has affected millions of people worldwide. Much research has been dedicated to our understanding of COVID-19 disease heterogeneity and severity, but less is known about recovery associated changes. To address this gap in knowledge, we quantified the proteome from serum samples from 29 COVID-19 convalescents and 29 age-, race-, and sex-matched healthy controls. Samples were acquired within the first months of the pandemic. Many proteins from pathways known to change during acute COVID-19 illness, such as from the complement cascade, coagulation system, inflammation and adaptive immune system, had returned to levels seen in healthy controls. In comparison, we identified 22 and 15 proteins with significantly elevated and lowered levels, respectively, amongst COVID-19 convalescents compared to healthy controls. Some of the changes were similar to those observed for the acute phase of the disease, i.e. elevated levels of proteins from hemolysis, the adaptive immune systems, and inflammation. In contrast, some alterations opposed those in the acute phase, e.g. elevated levels of CETP and APOA1 which function in lipid/cholesterol metabolism, and decreased levels of proteins from the complement cascade (e.g. C1R, C1S, and VWF), the coagulation system (e.g. THBS1 and VWF), and the regulation of the actin cytoskeleton (e.g. PFN1 and CFL1) amongst COVID-19 convalescents. We speculate that some of these shifts might originate from a transient decrease in platelet counts upon recovery from the disease. Finally, we observed race-specific changes, e.g. with respect to immunoglobulins and proteins related to cholesterol metabolism.

Cholesterol and COVID-19-therapeutic opportunities at the host/virus interface during cell entry.

The rapid development of vaccines to combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections has been critical to reduce the severity of COVID-19. However, the continuous emergence of new SARS-CoV-2 subtypes highlights the need to develop additional approaches that oppose viral infections. Targeting host factors that support virus entry, replication, and propagation provide opportunities to lower SARS-CoV-2 infection rates and improve COVID-19 outcome. This includes cellular cholesterol, which is critical for viral spike proteins to capture the host machinery for SARS-CoV-2 cell entry. Once endocytosed, exit of SARS-CoV-2 from the late endosomal/lysosomal compartment occurs in a cholesterol-sensitive manner. In addition, effective release of new viral particles also requires cholesterol. Hence, cholesterol-lowering statins, proprotein convertase subtilisin/kexin type 9 antibodies, and ezetimibe have revealed potential to protect against COVID-19. In addition, pharmacological inhibition of cholesterol exiting late endosomes/lysosomes identified drug candidates, including antifungals, to block SARS-CoV-2 infection. This review describes the multiple roles of cholesterol at the cell surface and endolysosomes for SARS-CoV-2 entry and the potential of drugs targeting cholesterol homeostasis to reduce SARS-CoV-2 infectivity and COVID-19 disease severity.

Comparing COVID-19 severity in patients hospitalized for community-associated Delta, BA.1 and BA.4/5 variant infection.

Despite decreasing COVID-19 disease severity during the Omicron waves, a proportion of patients still require hospitalization and intensive care. To compare demographic characteristics, comorbidities, vaccination status, and previous infections in patients hospitalized for community-associated COVID-19 (CAC) in predominantly Delta, Omicron BA.1 and BA.4/5 SARS-CoV-2 waves. Data were extracted from three national databases-the National COVID-19 Database, National Vaccination Registry and National Registry of Hospitalizations. Among the hospitalized CAC patients analyzed in this study, 5,512 were infected with Delta, 1,120 with Omicron BA.1, and 1,143 with the Omicron BA.4/5 variant. The age and sex structure changed from Delta to BA.4/5, with the proportion of women (9.5% increase), children and adolescents (10.4% increase), and octa- and nonagenarians increasing significantly (24.5% increase). Significantly more patients had comorbidities (measured by the Charlson Comorbidity Index), 30.3% in Delta and 43% in BA.4/5 period. The need for non-invasive ventilatory support (NiVS), ICU admission, mechanical ventilation (MV), and in-hospital mortality (IHM) decreased from Delta to Omicron BA.4/5 period for 12.6, 13.5, 11.5, and 6.3%, respectively. Multivariate analysis revealed significantly lower odds for ICU admission (OR 0.68, CI 0.54-0.84, p < 0.001) and IHM (OR 0.74, CI 0.58-0.93, p = 0.011) during the Delta period in patients who had been fully vaccinated or boosted with a COVID-19 vaccine within the previous 6 months. In the BA.1 variant period, patients who had less than 6 months elapsed between the last vaccine dose and SARS-CoV-2 positivity had lower odds for MV (OR 0.38, CI 0.18-0.72, p = 0.005) and IHM (OR 0.56, CI 0.37- 0.83, p = 0.005), but not for NIVS or ICU admission. The likelihood of developing severe CAC in hospitalized patients was higher in those with the Delta and Omicron BA.1 variant compared to BA.4/5.

Stratifying Disease Severity in Pediatric COVID-19: A Correlative Study of Serum Biomarkers and Lung Ultrasound-A Retrospective Observational Dual-Center Study.

The COVID-19 pandemic, caused by SARS-CoV-2, has manifested distinct impacts on infants and children. This study delves into the intricate connection between lung ultrasound (LUS) findings and serum biomarkers in neonates and infants with COVID-19. Exploring factors contributing to the mild symptoms in this demographic, including immune responses and pre-existing immunity, the study spans 3 years and 9 months, involving 42 patients. Respiratory and gastrointestinal symptoms predominate, and LUS emerges as a vital, non-irradiating tool for evaluating pulmonary abnormalities. Serum biomarkers like CRP, procalcitonin, and cytokines provide key insights into the pathophysiology. Correlations reveal nuanced links between LUS score and clinical parameters, unveiling associations with hospitalization duration (rho = 0.49), oxygen saturation (rho = -0.88), and inflammatory markers, like ferritin (rho = 0.62), LDH (rho = 0.73), and D-dimer (rho = 0.73) with significance level (p < 0.05). The absence of large consolidations in LUS suggests unique pulmonary characteristics. The novelty of these findings lies in the comprehensive integration of LUS with serum biomarkers to assess and monitor the severity of lung involvement in neonates and infants affected by SARS-CoV-2. This approach offers valuable insights into disease severity, biomarker levels, the duration of hospitalization, and oxygen saturation, providing a multifaceted understanding of COVID-19's impact on this vulnerable population.

Comparison of DASH diet score and total antioxidant capacity of diet on serum levels of TMPRSS-2, inflammatory biomarkers, and disease severity in COVID-19 patients: A case-control study.

There is evidence that healthy diets improve the immune system and lessen the severity of infectious diseases such as COVID-19. We have investigated whether the dietary total antioxidant capacity (TAC) and dietary approach to stop hypertension (DASH) score could be associated with the occurrence and clinical outcomes of COVID-19. This case-control study included 120 adults who were admitted to the hospital. Dietary TAC and DASH diet scores were determined by a 138-item semi-quantitative food frequency questionnaire (FFQ). Inflammation-related markers including C-reactive protein (CRP) and transmembrane protease serine 2 (TMPRSS-2) differential were measured. Also, using chest radiology criteria, the severity of the disease was evaluated. The mean CRP values in the lowest and highest tertiles of either dietary TAC or DASH diet scores were 9.44 ± 11.26 and 3.52 ± 4.83 mg/dL (p = .003) or 9.04 ± 11.23 and 4.40 ± 6.23 mg/dL (p = .013), respectively. Individuals with higher dietary TAC were at a lower risk of COVID-19 (OR: 0.06, p < ·0001). Individuals with greater DASH diet scores were also at decreased odds of COVID-19 (OR: 0.12, p < ·0001). No significant associations were found between dietary TAC and DASH diet scores with severity of COVID-19 disease, CRP, or TMPRSS-2 (p > 0.05). The study found that adherence to a diet with higher dietary TAC and DASH diet scores may be protective against COVID-19 and improve outcomes of the disease. More research is needed to corroborate these findings.

Substandard housing and the risk of COVID-19 infection and disease severity: A retrospective cohort study

In this study we examine associations between substandard housing and the risk of COVID-19 infection and severity during the first year of the pandemic by linking individual-level housing and clinical datasets. Residents of Chelsea, Massachusetts who were tested for COVID-19 at any Mass General Brigham testing site and who lived at a property that had received a city housing inspection were included (N = 2873). Chelsea is a densely populated city with a high prevalence of substandard housing. Inspected properties with housing code violations were considered substandard; inspected properties without violations were considered adequate. COVID-19 infection was defined as any positive PCR test, and severe disease defined as hospitalization with COVID-19. We used a propensity score design to match individuals on variables including age, race, sex, and income. In the severity model, we also matched on ten comorbidities. We estimated the risk of COVID-19 infection and severity associated with substandard housing using Cox Proportional Hazards models for lockdown, the first phase of reopening, and the full study period. In our sample, 32% (919/2873) of individuals tested positive for COVID-19 and 5.9% (135/2297) had severe disease. During lockdown, substandard housing was associated with a 48% increased risk of COVID-19 infection (95%CI 1.1–2.0, p = 0.006). Through Phase 1 reopening, substandard housing was associated with a 39% increased infection risk (95%CI 1.1–1.8, p = 0.020). The difference in risk attenuated over the full study period. There was no difference in severe disease risk between the two groups. The increased risk, observed only during lockdown and early reopening – when residents were most exposed to their housing – strengthens claims that substandard housing conveys higher infection risk. The results demonstrate the value of combining cross-sector datasets. Existing city housing data can be leveraged 1) to identify and prioritize high-risk areas for future pandemic response, and 2) for longer-term housing solutions.

Biochemical and Familial Factors Influencing COVID-19 Disease Progression

Introduction:: COVID-19 is a global pandemic that has caused significant mortality. The disease severity varies among individuals, and the factors influencing its course remain unclear. This study aimed to investigate the influence of biochemical parameters and familial data on COVID-19 outcomes. Methods:: A retrospective analysis of 122 COVID-19 patients was conducted. Patients were categorized into two groups: outpatients with mild symptoms and those admitted to the intensive care unit (ICU) and intubated. Demographic data, biochemical levels of vitamin D, vitamin B12, and magnesium, and COVID-19 outcomes of first-, second-, and third-degree relatives were collected. Results:: The ICU group had a higher proportion of males (75%) and older patients (average age: 63.18±12.89 years) than the outpatient group (40% males and an average age of 45.13±13.77 years). Both groups had similar BMI, vitamin D, and vitamin B12 levels. However, magnesium levels were significantly higher in the ICU group (mean 2.25±0.3 mg/dL) than in the outpatient group (mean: 1.98±0.2 mg/dL). A significant familial relationship was identified between COVID-19 outcomes and disease course. Among the ICU patients, 25% had first-degree relatives who died from COVID- 19, compared to only 10% of the outpatient patients. Similarly, second- and third-degree relatives of ICU patients had a higher mortality rate from COVID-19 than relatives of outpatient patients. Conclusion:: Age, gender, and magnesium levels may influence COVID-19 disease severity. Familial ties (genetic relatedness) may also play a role, suggesting potential genetic predisposition. Further research is needed to validate these findings and elucidate the underlying mechanisms

Information bias for case definitions and mortality between and within studies over time undermines our understanding of COVID-19 transmission and disease severity

Information bias for case definitions and mortality between and within studies over time undermines our understanding of COVID-19 transmission and disease severity

Impact of Tuberculosis on Disease Severity and Viral Shedding Duration in COVID-19 Patients.

Accumulating evidence show a potential association between tuberculosis and COVID-19 disease severity. To further clarify the impact of tuberculosis on COVID-19 disease severity and viral shedding duration, a retrospective study was conducted on 223 COVID-19 patients, including 34 with tuberculosis and 189 without tuberculosis. Clinical information and viral load shedding time were collected. A higher percentage of severe/critical COVID-19 diagnosis and deaths was observed in patients with tuberculosis than in those without tuberculosis (8.8% vs. 3.2%, p = 0.142; 2.9% vs. 1.1%, p = 0.393), and COVID-19 patients with tuberculosis had longer viral shedding than those without tuberculosis (median: 15.0 days vs. 11.0 days; p = 0.0001). Having tuberculosis (HR = 2.21, 95% CI 1.37-3.00; p = 0.000), being of elderly age (HR = 1.02, 95% CI 1.01-1.03; p = 0.001) and being diagnosed with severe or critical COVID-19 (HR = 5.63, 95% CI 2.10-15.05; p = 0.001) were independent factors associated with prolonged virus time of SARS-CoV-2. COVID-19 patients with tuberculosis receiving anti-tuberculosis therapy time (ATT) for <2 months had a significantly longer virus shedding duration than those receiving ATT for ≥ 4 months (17.5 vs. 11.5 days, p = 0.012). Our results demonstrated that COVID-19 patients with tuberculosis tend to have more severe disease and a worse prognosis, and tuberculosis prolonged viral shedding, highlighting special attention and/or care required for COVID-19 patients with tuberculosis receiving ATT for <2 months.

Comparison of Initial Thoracic CT Images of COVID-19 Patients with Non-Variant, Alpha, Delta, and Omicron Variants: A Retrospective Study

Background:: CT findings and Ground glass opacity (GGO) volumes may differ between SARS CoV-2 non-variant, alpha, delta, and omicron variants. Objective:: To compare the thoracic CT findings, GGO volumes, and GGOs’ lung uptake rates among patients with COVID-19 variants. Methods:: Thoracic CT images of 83 patients with non-variant, 78 patients with alpha variant, 93 patients with delta variant, and 73 patients with omicron variant having positive Real-Time Polymerase Chain Reaction test results were analyzed retrospectively. GGO volumes and lung volumes were calculated by using the Cavalieri Principle. Differences in CT findings, ground-glass opacity volumes, and lung involvement rates between non-variant and variant groups were evaluated. Results:: There were significant differences found in the incidence of GGOs (p &lt; 0.001), air bronchogram (p = 0.007), reticulation (p = 0.002) and subpleural lines, and linear opacities (p = 0.034) between non-variant and variant groups. GGO uptake rates (ground glass opacity volumes × 100 ÷ lung volume) were 8.88% in the non-variant, 4.83% in the alpha variant, 3.50% in the delta variant, and 2.02% in the omicron variant. In estimating variant groups, it was determined that the increase in the rate of GGOs in the right lung increased the probability of having an omicron variant, whereas the presence of nodules decreased it. The possibility of the delta variant increased with an increase in the rate of ground glass opacities in the left lung. Conclusion:: Thoracic CT findings solely can be helpful in distinguishing COVID-19 variants. Decreased frequency of uptake rates of GGOs suggested that the severity of COVID-19 disease was gradually decreasing.

Associations of length of stay with frailty status and COVID-19 disease severity among older adults at a community treatment facility in Singapore

Associations of length of stay with frailty status and COVID-19 disease severity among older adults at a community treatment facility in Singapore

Genetic characteristics involved in COVID-19 severity. The CARGENCORS case-control study and meta-analysis.

Pre-existing coronary artery disease (CAD), and thrombotic, inflammatory, or virus infectivity response phenomena have been associated with COVID-19 disease severity. However, the association of candidate single nucleotide variants (SNVs) related to mechanisms of COVID-19 complications has been seldom analysed. Our aim was to test and validate the effect of candidate SNVs on COVID-19 severity. CARGENCORS (CARdiovascular GENetic risk score for Risk Stratification of patients positive for SARS-CoV-2 [COVID-19] virus) is an age- and sex-matched case-control study with 818 COVID-19 cases hospitalized with hypoxemia, and 1636 controls with COVID-19 treated at home. The association between severity and SNVs related to CAD (n = 32), inflammation (n = 19), thrombosis (n = 14), virus infectivity (n = 11), and two published to be related to COVID-19 severity was tested with adjusted logistic regression models. Two external independent cohorts were used for meta-analysis (SCOURGE and UK Biobank). After adjustment for potential confounders, 14 new SNVs were associated with COVID-19 severity in the CARGENCORS Study. These SNVs were related to CAD (n = 10), thrombosis (n = 2), and inflammation (n = 2). We also confirmed eight SNVs previously related to severe COVID-19 and virus infectivity. The meta-analysis showed five SNVs associated with severe COVID-19 in adjusted analyses (rs11385942, rs1561198, rs6632704, rs6629110, and rs12329760). We identified 14 novel SNVs and confirmed eight previously related to COVID-19 severity in the CARGENCORS data. In the meta-analysis, five SNVs were significantly associated to COVID-19 severity, one of them previously related to CAD.

Exploring the Relationship of Comorbidities, Smoking Status, HRCT Findings With COVID-19 Disease Severity and Outcomes.

Coronavirus disease 2019 (COVID-19) is a serious illness that can affect multiple organs including the lungs. The COVID-mortality risk is attributed to the quick transmission of the virus, the severity of disease, and preclinical risk factors, such as the presence of comorbidities. High-resolution computed tomography (HRCT) can predict disease severity in COVID-19 patients. This was a retrospective cohort study in which data were obtained from COVID centers at tertiary care hospitals in Azad Jammu and Kashmir. Details of clinical characteristics and HRCT findings along with details of smoking and comorbid history were obtained. Fever at hospital admission, HRCT findings, and having a partner predicted disease severity showed a significant p-value of <0.05. Old age and living in a combined household were associated with severe outcomes (p<0.05). Symptoms of shortness of breath (SOB) on hospital admission could predict the need for ICU admission in COVID-19 patients. HRCT has a good predictive value for disease severity in patients with COVID-19, and old age is a risk factor. Although, limited associations were established in the analysis, in this study hyperlipidemia and hypertension significantly affected the course of disease. Further studies should be done to explore the relationship.

Soluble Endoglin and Syndecan-1 levels predicts the clinical outcome in COVID-19 patients

Endothelial instability is reported to be involved in the pathogenesis of COVID-19. The mechanism that regulates the endothelial dysfunction and disease virulence is not known. Studies on proteins that are released into circulation by activated endothelial cells may provide some means to understand the disease manifestation. The study investigated the circulating levels of two molecules Endoglin (Eng) and Syndecan-1 (SDC-1) that are presumed to be involved in the maintenance of endothelial integrity and their association with hypercoagulation marker in COVID-19 patients. The serum levels of Eng, SDC-1, D-mer were evaluated using ELISA at the time of admission (DOA) and day 7 post-admission among COVID-19 patients (N = 39 with 17 moderate and 22 severe cases). Compared to the time of admission, there was an increase in sEng and sSDC1 levels in all COVID-19 cases on day 7 post admission. The serum levels of sEng and sSDC-1 was significantly (P ≤ 0.001 & P ≤ 0.01 respectively) elevated in severe cases including the four deceased group compared to moderate cases on day 7 post admission. Further, the study molecules showed a strong positive association (P ≤ 0.001) with the hypercoagulation marker D-mer. The results show an early shedding of the endothelial proteins sEng and sSDC-1 into circulation as a host response to the viral infection during the febrile phase of infection. Increased levels of sEng and sSDC-1 along with D-mer could be beneficial in predicting COVID-19 disease severity.

Familial Aggregation and ABO Blood Groups and COVID-19 Severity Among Hospitalized Patients

Abstract Background Planning effective preventive and control measures requires understanding of the variability in the severity of infectious illnesses and factors determining susceptibility. The present study aimed to assess the association between familial susceptibility and ABO blood group with COVID-19 disease severity and adverse outcomes. Methods The present study was a retrospective investigation that was carried out at a tertiary care hospital with a bed capacity of 560 in the state of Kerala, India. A structured questionnaire was used to extract demographic and clinical characteristics from screened records. The study participants were stratified into 2 distinct groups based on the severity of their illness: mild to moderate and severe. Familial aggregation was operationally defined as the occurrence of COVID-19 diagnosis in any first-degree relative. Results A total of 362 hospitalized patients with confirmed COVID-19 infection were included in the analysis. Among them 62 (17.1%) were categorized as severe COVID-19 and 300 (82.9%) were categorized as mild to moderate COVID-19. Binary logistic regression analysis showed that the odds of sever COVID-19 disease was significantly higher among patients with familial aggregation (odds ratio, 2.47; 95% confidence interval, 2.12–2.85) and with non-O blood group (odds ratio, 2.21; 95% confidence interval, 2.01–2.56). Conclusions The findings of our study highlight the significance of familial aggregation and ABO blood group as crucial factors in determining the severity of COVID-19 disease. Comprehending the interrelationship between these variables and the genetic makeup of the host may hold significance in prognosticating the gravity of COVID-19 consequences.

SARS-CoV-2 ORF3a Protein as a Therapeutic Target against COVID-19 and Long-Term Post-Infection Effects.

The COVID-19 pandemic caused by SARS-CoV-2 has posed unparalleled challenges due to its rapid transmission, ability to mutate, high mortality and morbidity, and enduring health complications. Vaccines have exhibited effectiveness, but their efficacy diminishes over time while new variants continue to emerge. Antiviral medications offer a viable alternative, but their success has been inconsistent. Therefore, there remains an ongoing need to identify innovative antiviral drugs for treating COVID-19 and its post-infection complications. The ORF3a (open reading frame 3a) protein found in SARS-CoV-2, represents a promising target for antiviral treatment due to its multifaceted role in viral pathogenesis, cytokine storms, disease severity, and mortality. ORF3a contributes significantly to viral pathogenesis by facilitating viral assembly and release, essential processes in the viral life cycle, while also suppressing the body's antiviral responses, thus aiding viral replication. ORF3a also has been implicated in triggering excessive inflammation, characterized by NF-κB-mediated cytokine production, ultimately leading to apoptotic cell death and tissue damage in the lungs, kidneys, and the central nervous system. Additionally, ORF3a triggers the activation of the NLRP3 inflammasome, inciting a cytokine storm, which is a major contributor to the severity of the disease and subsequent mortality. As with the spike protein, ORF3a also undergoes mutations, and certain mutant variants correlate with heightened disease severity in COVID-19. These mutations may influence viral replication and host cellular inflammatory responses. While establishing a direct link between ORF3a and mortality is difficult, its involvement in promoting inflammation and exacerbating disease severity likely contributes to higher mortality rates in severe COVID-19 cases. This review offers a comprehensive and detailed exploration of ORF3a's potential as an innovative antiviral drug target. Additionally, we outline potential strategies for discovering and developing ORF3a inhibitor drugs to counteract its harmful effects, alleviate tissue damage, and reduce the severity of COVID-19 and its lingering complications.

The COVID-19 Severity and Its Association with Intestinal Parasite Coinfection and Urine Biochemical Parameters among COVID-19-Confirmed Patients Admitted to Debre Markos University COVID-19 Center, Northwest Ethiopia.

Though most people with COVID-19 disease show asymptomatic to mild illness, a substantial number of patients are at high risk of developing severe disease and adverse outcomes with long COVID-19 and death. Even though some studies showed that previously existing infections with parasites amend the host's body defenses to increase resistance to infection with SARS-CoV-2, there is limited data in Ethiopia. This study is aimed at determining the COVID-19 disease severity and its association with intestinal parasite coinfection and urine biochemical parameters among COVID-19-confirmed patients admitted at Debre Markos University COVID-19 Center, 2021. A prospective cohort study was conducted on 136 RT-qPCR-confirmed COVID-19 patients admitted at Debre Markos University COVID-19 Center from January 1 to March 30, 2021. Sociodemographic and clinical data were collected by using standardized data collection forms. A urine biochemical test was performed using a dry urine dipstick kit and stool examination using direct wet mount microscopic examination and formalin-ether concentration method. The chi-square test, Fisher exact test, and ordinal logistic regression analysis were computed to assess association with outcome variables using Statistical Package for Social Science software (version 24). A total of 136 COVID-19-confirmed patients participated in this study. The median age of the participants was 48 years. The majority (86 (62.5%)) of them were male in sex. Of the 136 cases, 39 (28.7%) had died. Among the 136 patients, 22 (16.2%) were coinfected with intestinal parasites. COVID-19 patients who have intestinal parasite coinfection had lower odds of developing clinically severe COVID-19 compared to noninfected (AOR = 0.37; 95% CI = 0.147-0.944; P = 0.037). The majority (104 (76.5%)) of them have abnormal urine biochemical results. From the abnormal urine biochemical tests observed, the urine blood, glucose, and ketone tests were positive for 54 (39.7%), 36 (26.5%), and 30 (21.1%) patients, respectively. Among the 31 critical COVID-19 patients, 25 (80.6%) showed abnormal urine biochemical parameters. Age and comorbidity were significantly associated with COVID-19 severity (P < 0.05). Patients with old age and comorbidity had an increased risk of developing severe COVID-19 disease. Patients having SARS-CoV-2 and intestinal parasitic coinfections demonstrated mild COVID-19 disease severity. Abnormal urine biochemical results were common among critical COVID-19 patients. Thus, advanced study on the effect of the interaction among intestinal parasites on COVID-19 clinical severity and its mechanisms is essential.

Accelarated immune ageing is associated with COVID-19 disease severity

BackgroundThe striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls.ResultsWe performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3–5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28−ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity (β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document} = 0.174, p = 0.043), with a major influence being disease severity (β\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\beta$$\\end{document} = 0.188, p = 0.01). ConclusionsOur analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK.

To describe the clinical epidemiology of COVID-19 in people of black ethnicity living with HIV in the UK. We investigated the incidence and factors associated with COVID-19 in a previously established and well-characterized cohort of black people with HIV. Primary outcomes were COVID-19 acquisition and severe COVID-19 disease (requiring hospitalization and/or resulting in death). Cumulative incidence was analysed using Nelson-Aalen methods, and associations between demographic, pre-pandemic immune-virological parameters, comorbidity status and (severe) COVID-19 were identified using Cox regression analysis. COVID-19 status was available for 1847 (74%) of 2495 COVID-AFRICA participants (median age 49.6 years; 56% female; median CD4 cell count = 555 cells/μL; 93% HIV RNA <200 copies/mL), 573 (31%) of whom reported at least one episode of COVID-19. The cumulative incidence rates of COVID-19 and severe COVID-19 were 31.0% and 3.4%, respectively. Region of ancestry (East/Southern/Central vs. West Africa), nadir CD4 count and kidney disease were associated with COVID-19 acquisition. Diabetes mellitus [adjusted hazard ratio (aHR) = 2.39, 95% confidence interval (CI): 1.26-4.53] and kidney disease (aHR = 2.53, 95% CI: 1.26-4.53) were associated with an increased risk, and recent CD4 count >500 cells/μL (aHR = 0.49, 95% CI: 0.25-0.93) with a lower risk of severe COVID-19. Region of ancestry was associated with COVID-19 acquisition, and immune and comorbidity statuses were associated with COVID-19 disease severity in people of black ethnicity living with HIV in the UK.

Single-cell RNA sequencing reveals characteristics of myeloid cells in post-acute sequelae of SARS-CoV-2 patients with persistent respiratory symptoms.

Although our understanding of the immunopathology and subsequent risk and severity of COVID-19 disease is evolving, a detailed account of immune responses that contribute to the long-term consequences of pulmonary complications in COVID-19 infection remains unclear. Few studies have detailed the immune and cytokine profiles associated with post-acute sequelae of SARS-CoV-2 infection (PASC) with persistent pulmonary symptoms. The dysregulation of the immune system that drives pulmonary sequelae in COVID-19 survivors and PASC sufferers remains largely unknown. To characterize the immunological features of pulmonary PASC (PPASC), we performed droplet-based single-cell RNA sequencing (scRNA-seq) to study the transcriptomic profiles of peripheral blood mononuclear cells (PBMCs) from a participant naïve to SARS-CoV-2 (Control) (n=1) and infected with SARS-CoV-2 with chronic pulmonary symptoms (PPASC) (n=2). After integrating scRNA-seq data with a naïve participant from a published dataset, 11 distinct cell populations were identified based on the expression of canonical markers. The proportion of myeloid-lineage cells ([MLCs]; CD14+/CD16+monocytes, and dendritic cells) was increased in PPASC (n=2) compared to controls (n=2). MLCs from PPASC displayed up-regulation of genes associated with pulmonary symptoms/fibrosis, while glycolysis metabolism-related genes were downregulated. Similarly, pathway analysis showed that fibrosis-related (VEGF, WNT, and SMAD) and cell death pathways were up-regulated, but immune pathways were down-regulated in PPASC. Further comparison of PPASC with scRNA-seq data with Severe COVID-19 (n=4) data demonstrated enrichment of fibrotic transcriptional signatures. In PPASC, we observed interactive VEGF ligand-receptor pairs among MLCs, and network modules in CD14+ (cluster 4) and CD16+ (Cluster 5) monocytes displayed a significant enrichment for biological pathways linked to adverse COVID-19 outcomes, fibrosis, and angiogenesis. Further analysis revealed a distinct metabolic alteration in MLCs with a down-regulation of glycolysis/gluconeogenesis in PPASC compared to SARS-CoV-2 naïve samples. Analysis of a small scRNA-seq dataset demonstrated alterations in the immune response and cellular landscape in PPASC. The presence of elevated MLC levels and their corresponding gene signatures associated with fibrosis, immune response suppression, and altered metabolic states suggests a potential role in PPASC development.