Complement system activation: bridging physiology, pathophysiology, and therapy.

The complement system is a set of over 50 proteins that constitutes an essential part of the innate immune system. Complement system activation involves an organized proteolytic cascade. Overactivation of complement system activation is the main pathogenic mechanism of several diseases and contributes to the manifestations of many other conditions. This review describes the normal complement system and the role for complement dysregulation in critical illnesses, notably sepsis and acute respiratory distress syndrome. Complement activation is involved in the immune system response to pathogens but, when excessive, can contribute to tissue damage, runaway inflammation, and capillary leakage syndrome. Complement overactivation may play a key role in severe forms of coronavirus disease 2019 (COVID-19). Two diseases whose manifestations are mainly caused by complement overactivation, namely, atypical hemolytic and uremic syndrome (aHUS) and myasthenia gravis, are discussed. A diagnostic algorithm for aHUS is provided. Early complement-inhibiting therapy has been proven effective. When renal transplantation is required, complement-inhibiting drugs can be used prophylactically to prevent aHUS recurrence. Similarly, acetylcholine-receptor autoantibody-positive generalized myasthenia gravis involves complement system overactivation and responds to complement inhibition. The two main complement inhibitors used in to date routine are eculizumab and ravulizumab. The main adverse event is Neisseria infection, which is rare and preventable, but can be fatal. The complement system is crucial to health but, when overactivated, can cause or contribute to disease. Effective complement inhibitors are now available, although additional data are required to determine optimal regimens. Further research is also needed to better understand the complement system, develop advanced diagnostic tools, and identify markers that allow the personalization of treatment strategies.

Effect of methylprednisolone in reducing severe COVID-19 and mortality in high-risk patients: A retrospective study.

Introduction: The treatment of COVID-19 patients, especially high-risk patients, remains a large challenge. Glucocorticoids have been accepted as effective medicines for severe COVID-19. However, the glucocorticoid usage guidelines do not cover all the indications for high-risk patients. Objective: To identify more effective treatments for high-risk patients with COVID-19, this retrospective study analyzed routine epidemiological, clinical, and laboratory data from 33 high-risk patients with COVID-19 in Beijing Gobroad Boren Hospital, Beijing, China, most of whom responded well to treatment. Methods: Severe acute respiratory syndrome coronavirus-2 infection was confirmed via real-time reverse transcriptase polymerase chain reaction assays. Outcome measures such as duration of mechanical ventilation, intensive care unit length of stay, and 28-day mortality were analyzed. Patients were divided into two groups: mild to moderate COVID-19 (n = 26) and severe COVID-19 (n = 7). Chest computed tomography images were used to guide methylprednisolone administration or withdrawal. Results: Upon intensive care unit admission, 12.1% of patients were mechanically ventilated with an average partial pressure of oxygen/fraction of inspired oxygen(PaO2/FiO2) ratio of 279 ± 146. No coinfections with other endemic viruses were observed. The duration of mechanical ventilation was 16 days (interquartile range: 8-28); the intensive care unit length of stay was 11 (interquartile range: 2-33) days; and the 28-day total mortality was 3.0%. Conclusion: Multivariate regression analysis revealed that low-dose, timely methylprednisolone administration was associated with a lower severe COVID-19 rate and mortality in high-risk patients. For high-risk patients, once there are ground-glass opacities (GGO) in the computed tomography image, continuous and low-dose methylprednisolone administration promotes inflammation remission and protects them from severe COVID-19 or mortality.

Identifying the plasma metabolome responsible for mediating immune cell action in severe COVID-19: a Mendelian randomization investigation.

Introduction: The immune response regulates the severity of COVID-19 (sCOVID-19). This study examined the cause-and-effect relationship between immune cell traits (ICTs) and the risk of severe COVID-19. Additionally, we discovered the potential role of plasma metabolome in modulating this risk. Methods: Employing data from a genome-wide association study (GWAS), we conducted a two-sample Mendelian randomization (MR) assessment of 731 genetic ICTs and sCOVID-19 (5,101 cases, 1,383,241 controls) incidence. The MR analysis was utilized to further quantitate the degree of plasma metabolome-mediated regulation of immune traits in sCOVID-19. Results: The inverse variance weighted method recognized 2 plasma metabolites (PMs) responsible for casual associations between immune cells and sCOVID-19 risk. These included Tridecenedioate (C13:1-DC) which regulated the association between CD27 on IgD- CD38br (OR 0.804, 95% CI 0.699-0.925, p = 0.002) and sCOVID-19 risk (mediated proportion: 18.7%); arginine to citrulline ratio which controlled the relationship of CD39 on monocyte (OR 1.053, 95% CI 1.013-1.094, p = 0.009) with sCOVID-19 risk (mediated proportion: -7.11%). No strong evidence that genetically predicted sCOVID-19 influenced the aforementioned immune traits. Conclusion: In this study, we have successfully identified a cause-and-effect relationship between certain ICTs, PMs, and the likelihood of contracting severe COVID-19. Our findings can potentially improve the accuracy of COVID-19 prognostic evaluation and provide valuable insights into the underlying mechanisms of the disease.

Exploring the Relationship Between Cannabis Use And COVID-19 Outcomes.

Background: Cannabis use is becoming increasingly prevalent worldwide, yet the full spectrum of its effects largely remain unknown. Although cannabis have immunomodulatory properties, there remains a significant gap in our understanding of the potential impact of marijuana use on COVID-19 outcomes. The purpose of this study is to evaluate the effect of chronic cannabis use on severe COVID-19. Materials and Methods: National Inpatient Sample Database was used to sample individuals admitted with the diagnosis of COVID-19. Patients were divided into two groups based on cannabis use. Baseline demographics and comorbidities were collected using ICD-10 codes. Patients with missing data or age under 18 were excluded. Propensity matching using R was performed to match cannabis users to non-cannabis users 1:1 on age, race, gender, and 17 other comorbidities. The primary outcome was severe COVID-19 infection, defined as a composite of acute respiratory failure, intubation, acute respiratory distress syndrome (ARDS), or severe sepsis with multiorgan failure. Results: Out of 322,214 patients included in the study, 2,603 were cannabis users. Cannabis users were younger and had higher prevalence of tobacco use. On initial analysis, cannabis users had significantly lower rates of severe COVID-19 infection, intubation, ARDS, acute respiratory failure, severe sepsis with multiorgan failure, mortality, and shorter length of hospital stay. After 1:1 matching, cannabis use was associated with lower rates of severe COVID-19 infection, intubation, ARDS, acute respiratory failure, severe sepsis with multiorgan failure, mortality, and shorter length of hospital stay. Conclusion: Cannabis users had better outcomes and mortality compared with non-users. The beneficial effect of cannabis use may be attributed to its immunomodulatory effects.

Causal associations between severe COVID-19 and diseases of seven organs: a proteome-wide mendelian randomization study.

The coronavirus disease 2019 (COVID-19) pandemic poses an enormous threat to public health worldwide. Many retrospective studies and case reports to date have shown associations between severe COVID-19 and diseases of multi-organs. However, the research on the causal mechanisms behind this phenomenon is neither extensive nor comprehensive. We conducted a proteome-wide Mendelian randomization (MR) study using summary statistics from a Genome-Wide Association Studies (GWAS) of severe COVID-19 and diseases related to seven organs: lung, spleen, liver, heart, kidney, testis, and thyroid, based on the European ancestry. The primary analytical method used is the radial inverse variance-weighted (radial IVW) method, supplemented with the inverse variance-weighted (IVW), weighted-median (WM), MR-Egger methods. Our findings have confirmed the association between severe COVID-19 and multiple organ-related diseases, such as Hypothyroidism, strict autoimmune (HTCBSA), Thyroid disorders (TD), and Graves' disease (GD). And we have also identified certain proteins that are associated with organ-related diseases, such as Superoxide Dismutase 2 (SOD2) and TEK Receptor Tyrosine Kinase (TEK), which are also considered potential drug targets. Phenotype scanning and sensitivity analyses were implemented to consolidate the results for Mendelian randomization. This study provides a compelling foundation for investigating COVID-19 caused diseases in future studies.

The Role of Early Hemoadsorption in Severe COVID-19 Treatment: A Pilot Randomized Controlled Trial.

INTRODUCTION: Hemoadsorption, an extracorporeal apheresis technique, is reportedly used in severe COVID-19 patients. However, limited evidence from randomized clinical trials supports this practice. METHODS: In this single-center study, severe COVID-19 patients requiring ICU admission were randomly assigned (1:1) to receive HA-330 hemoadsorption in combination with standard treatment or standard therapy alone. Both groups received tocilizumab intravenously if their clinical conditions worsened within 24-48 h. The primary outcome was mortality from any cause within 28 days after randomization. Secondary outcomes included mechanical ventilator-free days, daily C-reactive protein levels, oxygenation (defined by PaO2/FiO2 ratio), daily sequential organ failure assessment score, and severity score of lung infiltration on chest X-rays (CXR RALE score). RESULTS: A total of 28 patients underwent randomization, with 14 (50%) receiving HA-330 hemoadsorption. Only 9 out of 14 patients (64.3%) in the control group experienced clinical worsening and were subsequently administered intravenous tocilizumab. At 28 days, the mortality rate was significantly lower in the intervention group (28.57% vs. 78.57%, p = 0.021), with a hazard ratio of death of 0.26 (95% CI = 0.08-0.81; p = 0.021). All of secondary outcomes were comparable in both groups. CONCLUSION: Based on our pilot randomized trial, the early application of HA-330 hemoadsorption in patients with severe COVID-19 may establish a favorable outcome in term of mortality. These data provide the initial proof of concept for conducting a large-scale study in the future.

Pathway-Based Mendelian Randomization for Pre-Infection IL-6 Levels Highlights Its Role in Coronavirus Disease.

OBJECTIVES: Interleukin 6 (IL-6) levels at hospital admission have been suggested for disease prognosis, and IL-6 antagonists have been suggested for the treatment of patients with severe COVID-19. However, less is known about the relationship between pre-COVID-19 IL-6 levels and the risk of severe COVID-19. To fill in this gap, here we extensively investigated the association of genetically instrumented IL-6 pathway components with the risk of severe COVID-19. METHODS: We used a two-sample Mendelian randomization study design and retrieved genetic instruments for blood biomarkers of IL-6 activation, including IL-6, soluble IL-6 receptor, IL-6 signal transducer, and CRP, from respective large available GWASs. To establish associations of these instruments with COVID-19 outcomes, we used data from the Host Genetics Initiative and GenOMICC studies. RESULTS: Our analyses revealed inverse associations of genetically instrumented levels of IL-6 and its soluble receptor with the risk of developing severe disease (OR = 0.60 and 0.94, respectively). They also demonstrated a positive association of severe disease with the soluble signal transducer level (OR = 1.13). Only IL-6 associations with severe COVID-19 outcomes reached the significance threshold corrected for multiple testing (p < 0.003; with COVID-19 hospitalization and critical illness). CONCLUSIONS: These potential causal relationships for pre-COVID-19 IL-6 levels with the risk of developing severe symptoms provide opportunities for further evaluation of these factors as prognostic/preventive markers of severe COVID-19. Further studies will need to clarify whether the higher risk for a severe disease course with lower baseline IL-6 levels may also extend to other infectious diseases.

Genomic Landscape of Susceptibility to Severe COVID-19 in the Slovenian Population.

Determining the genetic contribution of susceptibility to severe SARS-CoV-2 infection outcomes is important for public health measures and individualized treatment. Through intense research on this topic, several hundred genes have been implicated as possibly contributing to the severe infection phenotype(s); however, the findings are complex and appear to be population-dependent. We aimed to determine the contribution of human rare genetic variants associated with a severe outcome of SARS-CoV-2 infections and their burden in the Slovenian population. A panel of 517 genes associated with severe SARS-CoV-2 infection were obtained by combining an extensive review of the literature, target genes identified by the COVID-19 Host Genetic Initiative, and the curated Research COVID-19 associated genes from PanelApp, England Genomics. Whole genome sequencing was performed using PCR-free WGS on DNA from 60 patients hospitalized due to severe COVID-19 disease, and the identified rare genomic variants were analyzed and classified according to the ACMG criteria. Background prevalence in the general Slovenian population was determined by comparison with sequencing data from 8025 individuals included in the Slovenian genomic database (SGDB). Results show that several rare pathogenic/likely pathogenic genomic variants in genes CFTR, MASP2, MEFV, TNFRSF13B, and RNASEL likely contribute to the severe infection outcomes in our patient cohort. These results represent an insight into the Slovenian genomic diversity associated with a severe COVID-19 outcome.

A Machine Learning-Based Web Tool for the Severity Prediction of COVID-19.

Predictive tools provide a unique opportunity to explain the observed differences in outcome between patients of the COVID-19 pandemic. The aim of this study was to associate individual demographic and clinical characteristics with disease severity in COVID-19 patients and to highlight the importance of machine learning (ML) in disease prognosis. The study enrolled 344 unvaccinated patients with confirmed SARS-CoV-2 infection. Data collected by integrating questionnaires and medical records were imported into various classification machine learning algorithms, and the algorithm and the hyperparameters with the greatest predictive ability were selected for use in a disease outcome prediction web tool. Of 111 independent features, age, sex, hypertension, obesity, and cancer comorbidity were found to be associated with severe COVID-19. Our prognostic tool can contribute to a successful therapeutic approach via personalized treatment. Although at the present time vaccination is not considered mandatory, this algorithm could encourage vulnerable groups to be vaccinated.

Chest CT Findings at Six Months Following COVID-19 ARDS - Correlation With the mMRC Dyspnea Scale and Pulmonary Function Tests.

Background: Many survivors of severe COVID-19 pneumonia experience lingering respiratory issues. There is limited research on follow-up chest imaging findings in patients with COVID-19 ARDS, particularly in relation to their mMRC dyspnea scores and pulmonary function tests (PFTs). This study addresses this gap by investigating the clinical characteristics, mMRC dyspnea scores, PFTs, and chest CT findings of COVID-19 ARDS patients at the 6 months post-recovery. By analyzing these variables together, we aim to gain a better understanding of the long-term health consequences of COVID-19 ARDS. Methods: This prospective observational study included 56 subjects with COVID-19 ARDS with dyspnea at the six-month follow-up visits. These patients were evaluated by chest CT, mMRC dyspnea scale, and PFT. The CT severity score was calculated individually for each of the four major imaging findings - ground glass opacities (GGOs), parenchymal/atelectatic bands, reticulations/septal thickening, and consolidation - using a modified CT severity scoring system. Statistics were carried out to find any association between individual CT chest findings and the mMRC dyspnea scale and forced vital capacity (FVC). p values < 0.05 were considered statistically significant. Results: Our study population had a mean age of 55.86 ± 9.60 years, with 44 (78.6%) being men. Grades 1, 2, 3, and 4 on the mMRC dyspnea scale were seen in 57.1%, 30.4%, 10.7%, and 1.8% of patients respectively. Common CT findings observed were GGOs (94.6%), reticulations/septal thickening (96.4%), parenchymal/atelectatic bands (92.8%), and consolidation (14.3%). The mean modified CT severity scores for GGOs, reticulations/septal thickening, parenchymal/atelectatic bands, and consolidation were 10.32 ± 5.51 (range: 0-21), 7.66 ± 4.33 (range: 0-19), 4.77 ± 3.03 (range: 0-14) and 0.29 ± 0.91 (range 0-5) respectively. Reticulations/septal thickening (p = 0.0129) and parenchymal/atelectatic bands (p = 0.0453) were associated with an increased mMRC dyspnea scale. Parenchymal/atelectatic bands were also associated with abnormal FVC (<80%) (p = 0.0233). Conclusion: Six-month follow-up chest CTs of COVID-19 ARDS survivors with persistent respiratory problems showed a statistically significant relationship between increased mMRC dyspnea score and imaging patterns of reticulations/septal thickening and parenchymal/atelectatic bands; while parenchymal/atelectatic bands also showed a statistically significant correlation with reduced FVC.

Efficacy of therapeutic-dose heparin for severe COVID-19 patients at COVID-19 Emergency Hospital Jakarta.

INTRODUCTION: Arterial and venous thrombotic events in COVID-19 cause significant morbidity and mortality. For optimal thromboprophylaxis treatment for hospitalized patients, especially those with severe COVID-19 symptoms, it is still unclear whether to use full- or therapeutic-dose versus prophylactic-dose anticoagulation therapy. The study aim was to evaluate the efficacy and safety of unfractionated heparin (UFH) for thromboprophylaxis in severe degree of COVID-19. METHODOLOGY: In this cross-sectional study, the medical records of 160 COVID-19 patients at the COVID-19 Emergency Hospital Wisma Atlet, Jakarta, from March to August 2021, were collected. The predetermined inclusion criteria for patients were severe COVID-19 infection; age > 18 years; positive D-dimer level > 400 ng/mL; high-flow nasal cannula (HFNC) oxygenation; IMPROVE bleeding risk score < 7; and willingness to participate in the study. The primary outcome was activated partial thromboplastin time (APTT) target achievement, oxygenation changed to nasal cannula or ended with room air, mortality rate, and the principal safety criterion was presence of bleeding. RESULTS: Of 160 subjects, 63.8% were male and 45.6% were aged 45-59 years old. Obesity was the most common comorbidity at 45.6% Among all subjects, 9.4% experienced bleeding, with hematuria being the most frequent type at 66.7%. All subjects released HFNC, and no deaths were reported. CONCLUSIONS: It can be concluded that administration of therapeutic doses of heparin in patients with severe COVID-19 had a low risk of bleeding and no patients were reported to have died. However, further investigation is needed to determine the long-term effects of therapeutic doses of anticoagulants.

Independent Risk Factors and Mortality Implications of De Novo Central Nervous System Involvement in Patients Hospitalized with Severe COVID-19: A Retrospective Cohort Study.

Background/Objectives: Central nervous system (CNS) involvement is a complication of COVID-19, adding to disease burden. The aim of this study is to identify the risk factors independently associated with CNS involvement in a cohort of patients hospitalized with severe forms of COVID-19 and the risk factors associated with all causes of in-hospital mortality and assess the impact of CNS involvement on in-hospital mortality of the severe COVID-19 patients. Methods: We performed a retrospective observational cohort study including adult patients with severe or critical forms of COVID-19 with and without new-onset CNS manifestations between March 2020 and December 2022. Results: We included 162 patients, 50 of which presented with CNS involvement. Independent risk factors for CNS involvement were female sex (p = 0.04, OR 3.67, 95%CI 1.05-12.85), diabetes mellitus (p = 0.008, OR 5.08, 95%CI 1.519-17.04)), lymphocyte count (0.04, OR 0.23, 95%CI 0.05-0.97), platelets count (p = 0.001, OR 0.98, 95%CI 0.98-0.99) CRP value (p = 0.04, OR 1.007, 95%CI 1.000-1.015), and CK value (p = 0.004, OR 1.003, 95%CI 1.001-1.005). Obesity was a protective factor (p < 0.001, OR 0.57, 95%CI 0.016-0.20). New-onset CNS manifestations (p = 0.002, OR 14.48, 95%CI 2.58-81.23) were independent risk factors for in-hospital mortality. In-hospital mortality was higher in the new-onset CNS involvement group compared to patients without neurological involvement, 44% versus 7.1% (p < 0.001). Conclusions: CNS involvement in severe COVID-19 patients contributes to all causes of in-hospital mortality. There are several risk factors associated with new-onset CNS manifestations and preventing and controlling them could have an important impact on patients' outcome.

Recovery from Severe COVID-19 Is an Independent Predictor of Electrocardiographic Abnormal P-Wave Axis.

AIM: Abnormal P-wave axis (aPwa) have been correlated with an increased risk of supraventricular arrhythmias. The aim of this study was to analyze whether infection with COVID-19 may cause a predisposition for supraventricular arrhythmia in the long term, following recovery. MATERIALS AND METHODS: In this study, a total of 252 subjects with a confirmed history of COVID-19 (recovered COVID-19) and 251 healthy subjects without a history of COVID-19 were included. The recovered COVID-19 group was divided into three subgroups designated as mild, moderate, and severe according to the severity score of their chest CT. The aPwa data were obtained using 12-lead electrocardiography (ECG) and compared between the healthy subjects and the recovered COVID-19 subgroups. RESULTS: This study showed that in the recovered severe COVID-19 subgroup the prevalence of aPwa was significantly increased compared to the controls and the other COVID-19 subgroups. No correlation could be detected in Spearman's Rho correlation between the existence of aPwa and the number of positive PCR tests for COVID-19 and the time elapsed after infection with COVID-19. The binary logistic regression analysis showed that recovery from severe COVID-19, the severity score of the chest CT in the recovered from COVID-19 subjects, and the existence of hypertension (HT) were all independent predictors of aPwa (hazard ratio: 3.542, 95% confidence interval: 1.398-8.969, p: 0.01; hazard ratio: 0.896, 95% confidence interval: 0.840-0.955, p < 0.001; hazard ratio: 2.710, 95% confidence interval: 1.079-6.804, p: 0.03, respectively). CONCLUSIONS: Individuals who have recovered from severe COVID-19 have shown an increased prevalence of aPwa. The existence of aPwa was not associated with the number of positive PCR tests for COVID-19 or the time elapsed after infection with COVID-19. Therefore, recovery from severe COVID-19 is an independent predictor of electrocardiographic abnormal P-wave axis.

Anti-Xa activity below range is related to thrombosis in patients with severe COVID-19.

OBJECTIVE: We aimed to anlayse the relationship between anti-Xa activity below range and thomboembolic events. DESIGN: Single center prospective observational longitudinal cohort study (February-November 2021). SETTING: Patients admitted to the ICU of a University Hospital. PARTICIPANTS: Patients with severe COVID-19 pneumoniae. INTERVENTIONS: Enoxaparin was used for prophylactic and therapeutic anticoagulation. Enoxaparin dosing and dose adjustment were based on anti-Xa activity according to the hospital protocol. MAIN VARIABLES OF INTEREST: Target: thomboembolic events. PREDICTORS: demographics, pharmacotherapy, anti-Xa measurements, clinical data, and laboratory results. Logistic regression was used to identify independent risk factors for thomboembolic events. RESULTS: Data were available for 896 serum anti-Xa measurements from 228 subjects. Overall, 71.9% were male, with a median age of 62. Most patients needed invasive mechanical ventilation (87.7%) and mortality was 24.1%. A total of 28.9% new thomboembolic events were diagnosed. There were 27.1% anti-Xa measesurements below range. When multivariable logistic regression analysis was performed anti-Xa activity below range (RR, 4.2; p = 0.000), C-reactive protein (25 mg/L increase) (RR, 1.14; p = 0.005) and D-dimer (1000 ng/L increase) (RR, 1.06; p = 0.002) were the independent factors related to new thomboembolic events in patients with severe COVID-19. CONCLUSIONS: Anti-Xa activity below range, C-reactive protein and D-dimer were the independent factors related to thomboembolic events in patients with severe COVID-19. Purposely designed clinical trials should be carried out to confirm the benefit of an anti-Xa monitoring.

Communication between alveolar macrophages and fibroblasts via the TNFSF12-TNFRSF12A pathway promotes pulmonary fibrosis in severe COVID-19 patients.

BACKGROUND: Severe COVID-19 infection has been associated with the development of pulmonary fibrosis, a condition that significantly affects patient prognosis. Understanding the underlying cellular communication mechanisms contributing to this fibrotic process is crucial. OBJECTIVE: In this study, we aimed to investigate the role of the TNFSF12-TNFRSF12A pathway in mediating communication between alveolar macrophages and fibroblasts, and its implications for the development of pulmonary fibrosis in severe COVID-19 patients. METHODS: We conducted single-cell RNA sequencing (scRNA-seq) analysis using lung tissue samples from severe COVID-19 patients and healthy controls. The data was processed, analyzed, and cell types were annotated. We focused on the communication between alveolar macrophages and fibroblasts and identified key signaling pathways. In vitro experiments were performed to validate our findings, including the impact of TNFRSF12A silencing on fibrosis reversal. RESULTS: Our analysis revealed that in severe COVID-19 patients, alveolar macrophages communicate with fibroblasts primarily through the TNFSF12-TNFRSF12A pathway. This communication pathway promotes fibroblast proliferation and expression of fibrotic factors. Importantly, silencing TNFRSF12A effectively reversed the pro-proliferative and pro-fibrotic effects of alveolar macrophages. CONCLUSION: The TNFSF12-TNFRSF12A pathway plays a central role in alveolar macrophage-fibroblast communication and contributes to pulmonary fibrosis in severe COVID-19 patients. Silencing TNFRSF12A represents a potential therapeutic strategy for mitigating fibrosis in severe COVID-19 lung disease.

The association of non-severe COVID-19 infection and progression to frailty among robust older veterans.

BACKGROUND: Studies have shown that frailty was increased in hospitalized COVID-19 patients. However, it is not clear whether non-severe COVID-19 increases the risk for pre-frailty and frailty development. Our study aimed to determine the risk of developing frailty and pre-frailty in robust veterans who contracted non-severe COVID-19. METHODS: We conducted a retrospective cohort study to assess the association of SARS-CoV-2 infection with the development of pre-frailty and frailty status among robust U.S. veterans using VA COVID-19 Shared Data Resource. We included patients 55 years and older who had at least one SARS-CoV-2 testing between March 15, 2020, and November 30, 2020, had been active patients in the past 12 months, and had a VA frailty index of zero (robust status) at the time of testing. Cox proportional hazard model was used to assess the association between COVID-19 infection and developing frailty or pre-frailty and frailty. We also assessed the association by patients' age groups, sex, and race. FINDINGS: We identified 82070 veterans mean age 68.3 ± 7.8, 74738 (91.1%) male, 53899 (65.7%) white, 7557 (9.2%) with mild COVID-19 infection. Over the follow up period of 36 months, testing positive for COVID-19 was associated with a 66% increase in the hazard of becoming frail (adjusted HR = 1.66, 95%CI: 1.32-2.08), and a 68% increase in the hazard of becoming pre-frail (adjusted HR = 1.68, 95%CI: 1.45-1.94). Among male patients, mild COVID-19 infection was associated with a 54% increase in the hazard of becoming frail (adjusted HR = 1.54, 95% CI: 1.21-1.96), while among female patients there was a 330% increase (adjusted HR = 4.30, 95% CI: 2.13-8.64). CONCLUSIONS AND RELEVANCE: Non-severe COVID-19 infection that occurred in robust older adults increased the risk of developing frailty. Further multi-center prospective cohort studies evaluating the mechanism of action and clinical trials of treatment options for post-COVID frailty are indicated in Veterans to support clinical care.

Effect of subcutaneous vs. intravenous tocilizumab in patients with severe COVID-19: a systematic review.

OBJECTIVE: To systematically evaluate the efficacy of subcutaneous tocilizumab in the treatment of patients with severe COVID-19 and provide evidence for the rational use of subcutaneous tocilizumab in patients with severe COVID-19. METHODS: This meta-analysis was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We searched the Cochrane Library, PubMed, Embase, CNKI, SinoMed, and Wanfang Medical Network electronic databases up to 11 January 2023 to identify relevant studies. To obtain the most recent clinical studies of subcutaneous injection of tocilizumab for the treatment of patients with severe COVID-19, we also searched the preprint platforms medRxiv and ChinaXiv. Furthermore, we searched ClinicalTrials.gov for relevant unpublished studies. The studies were screened based on the PICOS principle. The included studies were classified and evaluated for quality based on research type. The RevMan 5.3 software was used to conduct the meta-analysis, and a descriptive analysis was performed to examine relevant outcome indicators. RESULTS: Five observational studies were obtained, involving a total of 498 patients (240 patients in the subcutaneous injection group and 258 patients in the intravenous injection group). All of the studies were of the highest quality. The meta-analysis of the included studies revealed that the mortality rate of patients who received subcutaneous tocilizumab to treat COVID-19 was not significantly higher than that of the intravenous injection group [23.3% (45/193) vs. 18.4% (39/212), RD = 0.06, 95% CI = - 0.01 ~ 0.13, P = 0.11]. Furthermore, there was no significant difference in the proportion of patients requiring mechanical ventilation between the two groups [24.5% (35/143) vs. 22% (35/159), RD = 0.03, 95% CI = - 0.07 ~ 0.12, P = 0.56]. CONCLUSIONS: The meta-analyses do not provide evidence that subcutaneous and intravenous tocilizumab formulations for the treatment of severe COVID-19 infection differ regarding their effectiveness. Considering that the meta-analyses cannot replace an appropriately powered non-inferiority study, subcutaneous formulations still need to be used with caution and only when intravenous formulations are in short supply. At present, there is a lack of randomized controlled trials of subcutaneous injection of tocilizumab for the treatment of severe COVID-19, and more clinical research should be conducted.

Prior COVID-19 Diagnosis, Severe Outcomes, and Long COVID among U.S. Adults, 2022.

Given the increase in COVID-19 emergency department visits and hospitalizations during the winter of 2023-2024, identifying groups that have a high prevalence of COVID-19 cases, severity, and long-term symptoms can help increase efforts toward reducing disparities and prevent severe COVID-19 outcomes. Using data from the 2022 National Health Interview Survey (n = 27,651), we assessed the prevalence of COVID-19 outcomes (prior diagnosis, moderate/severe COVID-19, and long COVID) by sociodemographic characteristics and factors associated with each COVID-19 outcome. Approximately one third of adults reported a prior COVID-19 diagnosis (30.7%), while one half (51.6%) who had COVID-19 reported moderate or severe symptoms, and one fifth (19.7%) who had COVID-19 symptoms reported long COVID. The following were associated with higher odds of moderate/severe COVID-19 and long COVID: havinga high-risk condition (aOR = 1.20, OR = 1.52); having anxiety or depression (OR = 1.46, OR = 1.49); having a disability (OR = 1.41, OR = 1.60); and having a food insecurity (OR = 1.37, OR = 1.50) compared to a lack of these conditions. Having two or more COVID-19 vaccinations was associated with lower odds of a COVID-19 diagnosis (OR = 0.75), moderate/severe COVID-19 (OR = 0.86), and long COVID (OR = 0.82). Improving vaccination coverage and reducing disparities in COVID-19 outcomes could advance health equities and protect against future resurgence of disease.

The TOX-RAGE axis mediates inflammatory activation and lung injury in severe pulmonary infectious diseases.

Thymocyte selection-associated high-mobility group box (TOX) is a transcription factor that is crucial for T cell exhaustion during chronic antigenic stimulation, but its role in inflammation is poorly understood. Here, we report that TOX extracellularly mediates drastic inflammation upon severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by binding to the cell surface receptor for advanced glycation end-products (RAGE). In various diseases, including COVID-19, TOX release was highly detectable in association with disease severity, contributing to lung fibroproliferative acute respiratory distress syndrome (ARDS). Recombinant TOX-induced blood vessel rupture, similar to a clinical signature in patients experiencing a cytokine storm, further exacerbating respiratory function impairment. In contrast, disruption of TOX function by a neutralizing antibody and genetic removal of RAGE diminished TOX-mediated deleterious effects. Altogether, our results suggest an insight into TOX function as an inflammatory mediator and propose the TOX-RAGE axis as a potential target for treating severe patients with pulmonary infection and mitigating lung fibroproliferative ARDS.