Unlocking the potential of broadly reactive coronavirus monoclonal antibodies (mAbs) and their derivatives offers a transformative therapeutic avenue against severe COVID-19, especially crucial for safeguarding high-risk populations. Novel mAb-based immunotherapies may help address the reduced efficacy of current vaccines and neutralizing mAbs caused by the emergence of variants of concern (VOCs). Using phage display technology, we discovered a pan-SARS-CoV-2 mAb (C10) that targets a conserved region within the receptor-binding domain (RBD) of the virus. Noteworthy, C10 demonstrates exceptional efficacy in recognizing all assessed VOCs, including recent Omicron variants. While C10 lacks direct neutralization capacity, it efficiently binds to infected lung epithelial cells and induces their lysis via natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC). Building upon this pan-SARS-CoV-2 mAb, we engineered C10-based, Chimeric Antigen Receptor (CAR)-T cells endowed with efficient killing capacity against SARS-CoV-2-infected lung epithelial cells. Notably, NK and CAR-T-cell mediated killing of lung infected cells effectively reduces viral titers. These findings highlight the potential of non-neutralizing mAbs in providing immune protection against emerging infectious diseases. Our work reveals a pan-SARS-CoV-2 mAb effective in targeting infected cells and demonstrates the proof-of-concept for the potential application of CAR-T cell therapy in combating SARS-CoV-2 infections. Furthermore, it holds promise for the development of innovative antibody-based and cell-based therapeutic strategies against severe COVID-19 by expanding the array of therapeutic options available for high-risk populations.Trial registration: ClinicalTrials.gov identifier: NCT04093596.

& STATEMENT OF IMPACTSARS-COV-2 infection can result in acute and long-lasting cognitive complaints, causing ongoing impairments in daily life which poses a challenge to society. Consequently, the evaluation and characterization of cognitive complaints, specifically in the domain of executive functions (EFs) affecting daily life, is imperative in formulating an effective neuropsychological response.In total 442 participants aged 18-65+ years from the Netherlands, Germany, Mexico, and Spain were included in an online questionnaire. Among others, the questionnaire consisted of demographics, the Behavior Rating Inventory of Executive Functioning for Adults (BRIEF-A), measures of subjective disease progression severity and experienced subjective impairment in daily activities. To assess whether daily life activities are affected by EF impairments, the main BRIEF-A composite score (GEC) was analyzed. To determine whether disease-related COVID-19 factors predict EFs complaints in daily life, a stepwise regression analysis was performed with i) experienced disease severity, ii) time since disease, and iii) health risk factor as predictors.The study revealed noteworthy differences in the occurrence of EFs problems in daily life between both groups, as indicated by the GEC, which exhibited a medium effect size even 6 months post-COVID-19 diagnosis even in mild disease progression. The scores of the BRIEF-A subscales follow a domain-specific profile, and includes clinically relevant impairments in: Working memory, Plan/Organize, Task Monitor, Shift, which are affected by the experienced severity of the disease. This cognitive profile has important implications for targeted cognitive training in rehabilitation and has the potential for an applicability to other viruses as well.

The role of serum ferritin, an acute-phase inflammatory marker, in predicting mortality in patients with severe fever with thrombocytopenia syndrome (SFTS) is not fully understood. This study aimed to investigate the association between serum ferritin levels and inpatient mortality in patients with SFTS. We conducted a retrospective analysis using data from patients diagnosed with SFTS at the Second Affiliated Hospital of Anhui Medical University between May 2017 and September 2024. The association between serum ferritin levels and in-hospital mortality in patients with SFTS was assessed using Cox regression models and restricted cubic spline (RCS) analysis. The receiver operating characteristic (ROC) curve was used to determine the optimal serum ferritin cut-off value for predicting mortality risk. Kaplan-Meier survival curves were compared for survival rates, and propensity score matching with linear trend testing was applied to ensure robustness. This study included 390 patients with SFTS, of whom 312 survived and 78 did not, yielding an in-hospital mortality rate of 20.0%. Cox regression and RCS analyses demonstrated a significant linear association between higher serum ferritin levels and increased in-hospital mortality in patients with SFTS, indicating that the predicted mortality of patients with SFTS increased with elevated serum ferritin levels beyond a certain threshold. ROC analysis revealed an area under the curve of 0.830, with an optimal serum ferritin cut-off of 3.975 (lg, ng/ml), sensitivity of 0.731, and specificity of 0.830. Clinically, serum ferritin levels above 4 (lg ng/ml), were associated with a substantial increase in mortality risk. Sensitivity analysis supported the robustness of these results. Serum ferritin levels are linearly associated with mortality risk in patients with SFTS, with mortality significantly increasing when serum ferritin levels exceed 10,000 ng/ml. Serum ferritin level may serve as a valuable prognostic biomarker for mortality risk in patients with SFTS.

Severe COVID-19 presents with a distinct immunological profile, characterized by elevated neutrophil and reduced lymphocyte counts, seen commonly in fungal and bacterial infections. This study demonstrates that patients hospitalized with COVID-19 show evidence of neutrophil degranulation and have increased expression of neutrophil surface lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), a marker of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Both early LOX-1 and programmed death-ligand 1 (PD-L1) expression on neutrophils were associated with development of severe disease. To determine whether tissue damage or inflammation is required to induce PMN-MDSCs or whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) directly activates neutrophils to become PMN-MDSCs, we incubated healthy human neutrophils with SARS-CoV-2. SARS-CoV-2 rapidly induced LOX-1 surface expression in healthy neutrophils independent of productive infection. LOX-1 induction was dependent on granule exocytosis and promoted up-regulation of reactive oxygen species, CD63, and PD-L1, enabling LOX-1+ neutrophils to suppress autologous T cell proliferation in vitro. These results support a role for PMN-MDSCs in mediating severe COVID-19, and inhibition of PD-L1 represents a potential therapeutic strategy for enhancing the immune response in acute SARS-CoV-2 infection.

Our study aims to investigate the levels of serum cytokines in children with community-acquired pneumonia (CAP) caused by different respiratory pathogens, and evaluate the predictive value of cytokines levels for severe pneumonia.

A retrospective study was conducted on the clinical data of children hospitalized with CAP. According to the pathogens, patients were divided into the M. pneumoniae group, Adenovirus group, respiratory syncytial virus group, H.influenzae group, and S.pneumoniae group.

The M. pneumoniae group was higher than RSV group in the level of serum pro-inflammatory cytokines include IL-2, IL-6, IL-17 A, and IFN-γ. But M. pneumoniae group was higher than Adenovirus group only in IL-6. M. pneumoniae group was higher than H. influenzae group and S. pneumoniae group in IL-17 A, IFN-γ. as primary anti-inflammatory cytokine, IL-10 was lower in the M. pneumoniae group compared with Adenovirus and RSV groups. IL-6 was higher in S. pneumoniae group than RSV group. IFN-γ was lower in H. influenzae group than Adenovirus group and RSV group. IL-10 was higher in RSV group than H. influenzae group. IL-6 was higher in Adenovirus group than RSV group. In M. pneumoniae group and H. influenzae group, the levels of IL-6, IL-10, and IFN-γ were significantly higher in the severe pneumonia subgroup compared with the non-severe pneumonia subgroup (P < 0.05).

Compared with other groups, M. pneumoniae group was higher in the level of serum proinflammatory cytokines. Additionally, the levels of IL-6, IL-10, and IFN-γ can be used as predictors of severe pneumonia caused by M. pneumoniae and H. influenzae.

Immune-mediated protection generated to COVID-19 mRNA vaccines is associated with anti-Spike (S) protein neutralizing antibodies. However, humoral immunity is compromised in B cell depleting (BCD) therapies, used to treat autoimmune diseases such as Multiple Sclerosis (MS). To study the effect of BCD on the durability and protective efficacy of vaccine-induced immunity, we evaluated S-reactive antibodies and T cell responses 1-70 weeks post-vaccination in MS cohorts treated with BCD compared to non-BCD therapies from four centers. BCD-treated participants had significantly reduced antibody levels and enhanced frequencies of S-reactive CD4+ and CD8+ memory T cells to COVID-19 vaccination compared to the non-BCD group, with some variations among different BCD formulations. T cell memory responses persisted up to 14 months post-vaccination in both BCD and non-BCD cohorts, who experienced similar clinical protection from COVID-19. Together, our results establish a critical role for T cell-mediated immunity in anti-viral protection independent of humoral immunity.

COVID-19 progression and recovery involve complex gene expression changes and immune dysregulation, but their dynamic alterations remain poorly understood. Current clinical indicators lack precision in distinguishing severe cases, highlighting the need for molecular biomarkers and diagnostic tools.

Three transcriptomic datasets were analyzed: 1) COVID-19 progression from Healthy, Moderate, Severe, to ICU patients; 2) recovery stages (1, 3, and 6 months) compared to Healthy controls; and 3) COVID-19 ICU versus non-ICU patients. Differential expression analysis, immune cell infiltration estimation, machine learning (LASSO regression and random forest), and functional enrichment were used to identify key genes and molecular mechanisms.

Gene expression analysis revealed dynamic changes during COVID-19 progression. Adaptive immune cells (e.g., B cells and T cells) decreased, while innate immune cells (e.g., monocytes and neutrophils) increased, particularly in ICU patients. Recovery analysis showed significantly reduced adaptive immune cells at 1 month, with partial recovery by 3 and 6 months. Machine learning identified CCR5, CYSLTR1, and KLRG1 as diagnostic biomarkers for distinguishing ICU from non-ICU patients, with AUC values of 0.916, 0.885, and 0.899, respectively.

This study identified CCR5, CYSLTR1, and KLRG1 as efficient diagnostic biomarkers for severe COVID-19 using machine learning and revealed immune regulatory features across COVID-19 progression and recovery.

The Prognostic Nutritional Index (PNI), an integrative measure of body's immune and nutritional status, has demonstrated its prognostic value across a range of diseases. However, its role in critically ill patients with Chronic Obstructive Pulmonary Disease (COPD) remains unclear. This study investigates the association between PNI levels and clinical outcomes in critically ill COPD patients, with a focus on identifying its role as a potential predictor of mortality.

A retrospective analysis of 1,250 critically ill COPD patients from the MIMIC-IV (v2.2) database was conducted. Patients were grouped by PNI tertiles. Primary and secondary outcomes were 28-day and 90-day mortality, respectively. Associations were evaluated using restricted cubic splines, Cox proportional hazards regression analysis, and Kaplan‒Meier survival curves. The predictive performance of PNI was assessed via receiver operating characteristic (ROC) curves analysis, and a nomogram integrating Boruta-selected features was developed to enhance clinical utility.

The final cohort comprised 1,250 critically ill COPD patients, with observed mortality rates of 25.3% and 33.2% at 28 and 90 days, respectively. Higher PNI levels were associated with reduced risk of both 28-day and 90-day mortality [28-day HR: 0.95 (95% CI: 0.93-0.97), P < 0.001; 90-day HR: 0.94 (95% CI: 0.93-0.96), P < 0.001]. Restricted cubic spline analysis confirmed this trend. Furthermore, ROC analysis demonstrated the utility of PNI as a predictor for 28-day mortality (AUC: 0.61). Boruta-selected features reinforced the importance of PNI, and the constructed nomogram exhibited excellent predictive accuracy (AUC: 0.712).

Higher PNI is linked to reduced mortality risk in critically ill COPD patients, indicating its potential as a prognostic marker.

Elevated serum lactate dehydrogenase (LDH) levels have been associated with poor prognosis in various diseases. This study investigates the relationship between serum LDH levels and 90-day mortality in patients with connective tissue disease (CTD) receiving glucocorticoids and hospitalized with pneumonia. A total of 298 CTD patients were included in this study. The cohort was divided into three groups based on serum LDH levels (Group 1: < 246 U/L, 0% mortality; Group 2: 246-407 U/L, 26% mortality; Group 3: ≥ 407 U/L, 48% mortality). Clinical and laboratory data were analyzed to evaluate the association between LDH levels and 90-day mortality using Kaplan-Meier survival curves, Cox regression models, and subgroup analyses. Elevated LDH levels were significantly associated with increased mortality. The Kaplan-Meier survival analysis demonstrated that patients in Group 3 (highest LDH levels) had the highest 90-day mortality rate, while those in Group 1 (lowest LDH levels) had the lowest (p < 0.0001). Multivariate Cox regression analysis revealed that every 100 U/L increase in LDH was associated with a higher risk of mortality (HR 1.07, 95% CI 1.01-1.13, p = 0.02). Patients in Group 3 showed a significantly increased risk of mortality (HR 2.29, 95% CI 1.06-4.96, p = 0.036). The subgroup analyses demonstrated stable results across different clinical subgroups. Elevated serum LDH levels, particularly in Group 3, are independently associated with increased 90-day mortality in CTD patients receiving glucocorticoids and hospitalized with pneumonia. LDH may serve as an important prognostic marker for these patients.

Post-COVID-19 lung disease (PCLD) is a significant concern following the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. PCLD encompasses persistent debilitating respiratory symptoms and radiological changes beyond the acute disease phase. It highlights the ongoing search to identify and manage lingering diseases. This prospective study utilizes F18-Fludeoxyglucose (FDG) PET/CT to identify residual inflammatory lung lesions in PCLD. Treatment response was assessed after anti-inflammatory and antifibrotic therapies.

Thirty patients post-severe COVID-19 pneumonia enrolled. They underwent baseline 18F-FDG PET/CT scans to unveil residual lung inflammation lesions on FDG and CT. They received antifibrotic (Pirfenidone) and anti-inflammatory (Methylprednisolone) drugs for 6-12 weeks. They were followed up for clinical, biochemical, and imaging treatment responses.

Baseline 18F-FDG PET/CT revealed ongoing lung inflammation in all PCLD (mean SUVmax: 3.8 ± 2.3 and number of segments: 8±3 ). The mean CT severity score was 17.7 ± 3.4 with moderate (n = 16) or severe (n = 14) disease involvement. Mild, moderate, and severe 18F-FDG PET/CT categories were noted in the 8, 14, and 8 patients, respectively. Following treatment, a PET scan showed a significant decrease in disease extent (segments) and severity (FDG uptake) and an improvement in disease grading on imaging (97% of patients). In PET concordance, there was a significant clinical and radiological improvement with a fall in inflammatory markers (p < 0.005). Serum Ferritin and total leukocyte counts were significantly associated with PCLD severity on 18F-FDG PET/CT(p < 0.05).

This prospective study identifies and quantifies ongoing significant residual lung inflammation in PCLD on 18F-FDG PET/CT. Anti-inflammatory and antifibrotic drug therapy led to clinical and radiological improvement. 18F-FDG PET/CT as a non-invasive biomarker helped manage and follow up PCLD patients.

Not applicable.

Background: Elderly patients infected with SARS-CoV-2 are at higher risk of developing cytokine storm and severe outcomes; however, specific immunological and proteomic biomarkers for early prediction remain unclear in this vulnerable group. Methods: We enrolled 182 elderly COVID-19 patients from the Chinese PLA General Hospital between November 2022 and April 2023, categorizing them based on progression to respiratory failure requiring mechanical ventilation (defined as severe progression). Olink proteomic analysis was performed on admission serum from 40 propensity score-matched samples, with differentially expressed proteins (DEPs) validated by cytometric bead array (CBA) in 178 patients. To predict severe progression, a model was developed using a 70% training set and validated on a 30% validation set. LASSO regression screened features followed by logistic regression and receiver operating characteristic (ROC) analysis to optimize the model by incrementally incorporating features ranked by random forest importance. Results: Elderly patients progressing to severe COVID-19 exhibited early immune dysregulation, including neutrophilia, lymphopenia, monocytopenia, elevated procalcitonin (PCT), C-reactive protein (CRP), interleukin-6 (IL-6), neutrophil-to-lymphocyte ratio (NLR), and systemic immune-inflammation index (SII), as well as coagulation dysfunction and multi-organ injury. Proteomics identified a set of biomarkers, including tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and revealed disruptions in signaling pathways, including the mTOR and VEGF signaling pathways. The optimal predictive model, which incorporated PCT, IL-6, monocyte percentage, lymphocyte count, and TRAIL, achieved an area under curve (AUC) of 0.870 (0.729-1.000) during validation. TRAIL levels negatively correlated with fibrinogen (p < 0.05). Conclusions: Elderly COVID-19 patients with severe progression demonstrate early immune dysregulation, hyperinflammation, coagulation dysfunction, and multi-organ injury. The model we proposed effectively predicts disease progression in elderly COVID-19 patients, providing potential biomarkers for early clinical risk stratification in this vulnerable population.

Vaccines have been proven to be one of the safest and most effective ways to prevent and combat diseases. However, the main focus has been on the evaluation of the potency of effector mechanisms and the lack of adverse effects of vaccine candidates. Recently, the importance of induced regulatory mechanisms of the immune system after vaccination has come to light. With the increase in our knowledge about these regulatory mechanisms including the regulatory T cells (Tregs), we have come to understand the significance of this arm of the immune system in controlling immunopathology and/or diminishing the effectiveness of vaccines, especially viral vaccines. Tregs play a dual role during infectious diseases by limiting immune-mediated pathology and also contributing to chronic pathogen persistence by decreasing effector immunity and clearance of infection. Tregs may also affect immune responses after vaccination primarily by inhibiting antigen presenting cell function such as cytokine secretion and co-stimulatory molecule expression as well as effector T (Teff) and B cell function. In this article, we review the current knowledge on the induction of Tregs after several life-threatening virus infections and their available vaccines to bring them to the spotlight and emphasise that studying viral-induced antigen-specific Tregs will help us improve the effectiveness and decrease the immunopathology or side effects of viral vaccines. Trial Registration: ClinicalTrials.gov identifier: NCT04357444.

Coronavirus disease identified in 2019 (COVID-19), caused by severe acute respiratory syndrome-coronavirus-2, had a global impact on human health and the economy. The aim of this study was to quantify cytokines, chemokines, and acute phase proteins in the plasma of patients with COVID-19 to elucidate potential biomarkers to inform prognostic and treatment decisions. Clustering analysis using the K-prototypes method identified underlying biological patterns in patients with COVID-19. The penalized multinomial logistic regression analysis identified two comorbidities (hypertension, congestive heart failure) and thirteen analytes as potential risk factors for COVID-19 progression with 88.2% accuracy. Based on a patient's age, high concentrations of interleukin (IL)-6, monocyte chemoattractant protein-1, and pentraxin 3 were important biomarkers for lethal COVID-19. Decreased concentrations of interferon gamma-induced protein-10, IL-10, and soluble tumor necrosis factor receptor I were found to be associated with mild COVID-19, while increasing concentrations of these analytes could be used to predict COVID-19 severity.

Tuberculosis (TB), a leading cause of death from infectious diseases, faced considerable challenges during the coronavirus disease 2019 (COVID-19) pandemic. This review examines the impact of pandemic-related disruptions, including the diversion of healthcare resources, reduced access to TB diagnostics and treatment, and declining BCG vaccination rates, on TB trends. The aim is to forecast the post-COVID-19 TB burden, identify risk factors that exacerbate transmission, and propose strategies to prevent a global resurgence.

This narrative review incorporates epidemiological data, modeling research, and reports from the World Health Organization and national health systems. It examines TB trends before and after COVID-19, the outcomes of coinfection, and the pandemic's impact on immunology, socioeconomic factors, and health systems. The review also compares trends in India and South Africa-two countries facing significant challenges-to those observed during the COVID-19 pandemic.

COVID-19 disruptions in healthcare led to an 18% decrease in TB notifications in 2020, resulting in delayed diagnoses, increased household transmission, and higher mortality. Immune dysregulation, including T-cell depletion and cytokine storms, contributed to a 12.3% mortality rate in COVID-19-TB coinfections. Models predict a 5%-15% rise in TB incidence and an additional 1.4 million deaths by 2025. Individuals with HIV, diabetes, and malnutrition were particularly vulnerable. Factors such as overcrowding, air pollution, and reduced Bacillus Calmette-Guérin (BCG) coverage in endemic regions have further heightened susceptibility to TB.

COVID-19 has undone years of progress in TB control, highlighting the need for a unified health strategy. Early diagnosis, treatment of latent TB, and BCG catch-up initiatives are crucial. Strengthening health systems, addressing socioeconomic factors such as poverty and hunger, and utilizing pandemic advancements like telemedicine and vaccine research will be key to preventing a resurgence of TB. Continued financial support and international cooperation are essential to eliminating TB by 2030.

Sphingosine-1-phosphate receptor 1 (S1P1) ligands effectively reduce immunopathological damage in viral pneumonia models. Specifically, S1P1 ligands inhibit cytokine storm and help preserve lung endothelial barrier integrity. We recently showed that the S1P receptor ligand ozanimod can be safely administered to hospitalized patients with coronavirus disease 2019 (COVID-19) exhibiting severe symptoms of viral pneumonia, with potential clinical benefits. Here, we extend on this study and investigate the impact of ozanimod on key features of the immune response in patients with severe COVID-19. We quantified circulating cytokine levels, peripheral immune cell numbers, proportions and activation status; we also monitored the quality of the humoral response by assessing anti-severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) antibodies. Our findings reveal that patients receiving ozanimod during acute SARS-CoV-2 infection exhibit significantly reduced numbers of circulating monocytes compared with those receiving standard care. Correspondingly, in the ozanimod-treated group, circulating levels of C-C motif ligand 2 (CCL2) were decreased. While treatment with ozanimod negatively impacted the humoral response to COVID-19 in unvaccinated patients, it did not impair the development of a robust anti-SARS-CoV-2 antibody response in vaccinated patients. These findings suggest that ozanimod influences key immune mechanisms during the acute phase of SARS-CoV-2 infection.

Background: Various studies have shown that the incidence of BSI is greater in COVID-19 patients hospitalized in the intensive care unit (ICU). Aims: Our study aimed to determine the risk factors for BSI, mortality rates, and factors affecting mortality in adult COVID-19 patients hospitalized in the ICU. Methods: All COVID-19 patients who met the study criteria and stayed in intensive care for more than 2 days at a tertiary university hospital during the two-year pandemic period were included in the study. Logistic regression analysis was used to determine the risk factors for BSI and mortality. Results: We found that respiratory rate (RR) ≥ 30 breaths per minute at the time of admission [OR: 2.342 (95% CI: 1.12-4.897)] and antibiotic use in the month before admission ICU [OR: 3.137 (95% CI: 1.321-7.451)] were independent risk factors for BSI in COVID-19 patients. Subanalysis was also performed according to the doses of immunomodulators such as anakinra, tocilizumab, and corticosteroids, and it was found that they had no effect on the BSI (P > .05). The predominant causative pathogens were K. pneumoniae, A. baumannii and enterococci. The multidrug resistant rate among bacteria was 78%. Although their comorbidities and disease severity at the time of ICU admission were similar, patients with BSIs had a higher mortality rate (58.1 to 81.9%, P = .000). The SAPS-2 score at ICU admission [OR: 3.095 (95% CI: 1.969-4.865)] and mechanical ventilation requirement throughout the ICU admission [OR: 9.314 (95% CI: 3.878-22.37)] were found to be independent risk factors for mortality by multivariate analysis. BSI was not found to be a risk factor for mortality (> .05). Conclusions: Antibiotic use in patients with severe COVID-19 significantly increases the risk of BSI; unnecessary antibiotic use should be avoided.

IntroductionCOVID-19, caused by the SARS-CoV-2 virus, has resulted in a global public health crisis with a wide spectrum of clinical manifestations, ranging from asymptomatic infections to severe pneumonia. This study explores the association between various biomarkers and COVID-19 progression, aiming to identify early indicators of disease severity and enhance patient management.Materials and MethodsThe study included 750 confirmed COVID-19 patients categorized into four groups based on disease severity. Patients were recruited at the General Hospital in Tešanj, Bosnia and Herzegovina. All biochemical, hematological and coagulation parameters were analyzed using standard IFCC protocols.ResultsThe study identified significant differences in biochemical, hematological, and coagulation biomarkers across varying COVID-19 severities. Key markers such as C-reactive protein (CRP), D-dimer, lymphocyte count, erythrocyte sedimentation rate (ESR), and platelet count were analyzed. Elevated CRP and D-dimer were strongly linked to severe cases, while decreased lymphocyte count, elevated ESR, and platelet abnormalities were also associated with increased disease severity.ConclusionsOur study highlights the vital role of specific biochemical, hematological and coagulation parameters in predicting COVID-19 severity. Integrating these findings into clinical practice could enhance timely risk stratification, early intervention, and improved outcomes for affected individuals.

Coronavirus has caused high-mortality viral pneumonia worldwide. The pathogenesis is characterized by hyperinflammatory reactions resulting from immune homeostasis dysregulation. Verbenalin, an iridoid glucoside derived from Verbena officinalis L., is widely used in Traditional Chinese Medicine (TCM) clinical practice for its antioxidant, anti-inflammatory and antiviral properties.

This study aimed to investigate the pharmacological effects and underlying mechanisms of verbenalin on coronavirus pneumonia both in vivo and in vitro.

A coronavirus pneumonia mouse model and macrophage injury models, including mouse alveolar macrophage cell line (MH-S) cells and primary macrophages, were established to initially confirm the antiviral effects of verbenalin. Time-resolved proteomic were then employed to uncover proteomic changes and identify potential therapeutic targets for coronavirus treatment. Subsequently, flow cytometry and Western blot were employed to investigate verbenalin's effects on NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome pathway. Additionally, the targeting regulation of phosphatase and tensin homolog-induced putative kinase 1 (PINK1) / E3 ubiquitin ligase Parkin (Parkin) pathway by verbenalin was validated through molecular docking, surface plasmon resonance (SPR), immunofluorescent staining, RNA interference (RNAi), and mitophagy inhibition both in vivo and in vitro.

Verbenalin reduced cell injury and inflammation in Human coronavirus 229E (HCoV-229E)-infected macrophages and improved lung inflammation in mice. Proteomics analysis highlighted the roles of nucleotide-binding oligomerization domain (NOD)-like receptor signaling and mitophagy pathways in coronavirus pneumonia. Verbenalin bound strongly to PINK1 and Parkin proteins, increased mitochondrial membrane potential (MMP), decreased mitochondrial reactive oxygen species (mtROS) levels, reduced the opening of mitochondrial permeability transition pore (MPTP), maintained mitochondrial mass, promoted mitophagy flux, upregulated the expression of PINK1, Parkin, and microtubule-associated protein 1A/1B-light chain 3BII (LC3BII). Additionally, verbenalin inhibited the activation of the NLRP3 inflammasome and downregulated the expression of Interleukin-1 beta (IL-1β), cysteine aspartate-specific protease 1 (caspase-1), and gasdermin D (GSDMD) both in vivo and in vitro. Furthermore, treatment with a mitophagy inhibitor and RNAi attenuated the inhibitory effects of verbenalin on NLRP3 activation, confirming the involvement of the PINK1/Parkin/NLRP3 pathway in verbenalin's protective effects.

Verbenalin enhances PINK1/Parkin-mediated mitophagy to suppress NLRP3 activation, thereby promoting immune homeostasis and mitigating HCoV-229E-induced inflammation.

Background: Despite the multiple waves of the COVID-19 pandemic, follow-up strategies for recovered patients remain inconclusive. This study aimed to evaluate chest computed tomography (CT) and pulmonary function test (PFT) abnormalities in convalescents six months after COVID-19 and to compare these findings with those from a representative population cohort. The goal was to support more individualized pulmonary management of post-COVID-19 sequelae. Methods: This study population consisted of 2 groups: I-232 post-COVID-19 patients and II-543 patients from a population cohort. Chest CT was performed during the acute phase of COVID-19 and six months after. The PFTs were conducted six months after COVID-19. Results: There were no significant differences in FEV1, FVC, TLC, and DLCO in the two study groups. A singular GGO in 24 patients (20%), a crazy paving pattern in 1 patient (0.8%), thickening of interlobular septa in 4 patients (3.5%), consolidations in 4 patients (3.5%), traction bronchiectasis in 6 patients (5%), fibrosis in 6 patients (5%), and singular nodular densities in 68 patients (58%) were observed in chest CT 6 months after COVID-19. Most radiological abnormalities were clinically insignificant and did not require further diagnostic evaluation. No significant differences in chest CT and PFT six months after infection were observed between patients differing in the severity of inflammation during the acute disease or SARS-CoV-2 variant. Conclusions: The majority of chest CT abnormalities resolved within six months of recovery, regardless of SARS-CoV-2 variant or initial disease severity. Pulmonary function tests should be prioritized in post-COVID-19 follow-up, as PFT results in convalescents were comparable to those observed in the general population.

The pandemic of Coronavirus Disease 2019 (COVID-19) has a significant impact on older individuals, those with comorbidities, and a bias toward males. Mortality, associated with an exacerbated immune response by proinflammatory cytokines, suggests potential hormonal influences in this scenario. The objective of this research was to analyze the expression of Estrogen Receptor α (ERα), Estrogen Receptor β (ERβ), G Protein-Coupled Estrogen Receptor (GPER), and the Angiotensin-Converting Enzyme 2 (ACE2) receptor, as well as their relationship with the viral load of SARS-CoV-2 and serum cytokine levels in three demographic groups of unvaccinated individuals diagnosed with COVID-19: premenopausal women, postmenopausal women, and men. The presence and expression of ERα, ERβ, and GPER, along with the ACE2 receptor, were analyzed by immunofluorescence assays in cells obtained from nasopharyngeal swabs of individuals with confirmed COVID-19 through RT-qPCR testing. Additionally, serum cytokine levels were evaluated using a chemiluminescent microparticle immunoassay. The results highlighted notable disparities in the expression of ERα and ACE2, as well as a higher expression of IL-8 and MIP-1β in the premenopausal women group compared to postmenopausal women and men. These findings suggest that in premenopausal women with COVID-19, the elevated expression of ERα and ACE2 could play a protective role, strengthening the antiviral immune response. The importance of exploring the complex hormonal and molecular influences in the pathogenesis of COVID-19 is emphasized, underscoring the need for additional research to better understand the factors determining severity and immune response in different demographic groups.

The COVID-19 pandemic, caused by SARS-CoV-2, has significantly affected global health, with severe inflammatory responses leading to tissue damage and persistent symptoms. Macrophage-derived extracellular vesicles (EVs) are involved in the modulation of immune responses, but their involvement in SARS-CoV-2-induced inflammation and senescence remains unclear. Triggering receptors expressed on myeloid cell-1 (TREM-1) are myeloid cell receptors that amplify inflammation, described as a biomarker of the severity and mortality of COVID-19. This study investigated the composition and effects of macrophage-derived EVs stimulated by SARS-CoV-2 (MφV-EVs) on the recipient cell response. Our results, for the first time, show that SARS-CoV-2 stimulation modifies the cargo profile of MφV-EVs, enriching them with TREM-1 and miRNA-155 association, along with MMP-9 and IL-8/CXCL8. These EVs carry senescence-associated secretory phenotype (SASP) components, promote cellular senescence, and compromise antibacterial defenses upon internalization. Our findings provide evidence that MφV-EVs are key drivers of inflammation and immune dysfunction, underscoring their potential as therapeutic targets in COVID-19.

Post-infection sequela of several viruses have been linked with Parkinson's disease (PD). Here, we investigated whether mice infected with SARS-CoV-2 alone or in combination with two putative Parkinsonian toxins, MPTP and paraquat, increased the susceptibility to develop Parkinsonian pathology. We also examined if G2019S LRRK2 mice had any change in sensitivity to SARS-CoV-2 as well as if vaccination against this virus altered any neuropathology. Infection with WA-1/2020 or Omicron B1.1.529 strains sensitized both WT and G2019S LRRK2 mice to the neuropathological effects of a subtoxic exposure to MPTP, but not paraquat. These neuropathologies were rescued in WT mice vaccinated with mRNA- or protein-based SARS-CoV-2 vaccines. However, G2019S LRRK2 mutant mice were only protected with the protein-based vaccine. These results highlight the role of both environmental exposures and familial background on the development of Parkinsonian pathology secondary to viral infection and the benefit of vaccines in reducing these risks.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has highlighted the virus's impact on the central nervous system and its potential to exacerbate neurodegenerative diseases, like Alzheimer disease (AD). Emerging evidence suggests that SARS-CoV-2 infection contributes to chronic neuroinflammation, a key driver in the etiopathogenesis of AD. Shared mechanisms, including blood-brain barrier (BBB) dysfunction, systemic inflammation, and activation of immune pathways, may link SARS-CoV-2 infection to AD onset and/or progression, particularly among vulnerable individuals, such as those of advanced age. This review explores convergent pathways involving the renin-angiotensin-aldosterone system, Wnt/β-catenin signaling, NF-κB activation, and interferon signaling, focusing on their roles in BBB integrity and neuroinflammation. SARS-CoV-2-mediated angiotensin-converting enzyme 2 depletion disrupts renin-angiotensin-aldosterone system homeostasis, favoring proinflammatory signaling that parallels vascular dysfunction in AD. Dysregulation of Wnt/β-catenin signaling exacerbates BBB permeability, whereas NF-κB and interferon pathways contribute to BBB breakdown and propagate central nervous system inflammation via endothelial and immune cell activation. These interactions may amplify prodromal AD pathology and/or initiate AD pathogenesis. By identifying mechanistic overlaps between COVID-19 and AD, this review underlines the need for therapeutic strategies targeting shared pathways of inflammation and BBB dysfunction. Understanding these connections is critical for mitigating the long-term neurologic sequelae of COVID-19 and reducing the burden of AD.

The objective of this clinical trial is to evaluate the efficacy and safety of IL-6 driven personalized treatment strategy with tocilizumab in patients with severe COVID-19 pneumonia.

Randomized, controlled, open-label, single-center trial of a tocilizumab treatment strategy in adult patients hospitalized with severe COVID-19 pneumonia and IL-6 serum levels > 40 pg/mL.

Patients were randomized 1:1 to receive standard of care (SOC) or SOC plus one dose of tocilizumab. The primary outcome was death or need for invasive mechanical ventilation (IMV) within 28 days after randomization. Secondary outcomes included ICU admission, days on IMV and hospital stay. A meta-analysis of clinical trials to evaluate the effect of tocilizumab on mortality and need of IMV in patients with COVID-19 pneumonia was performed.

Sixty-two patients were included: 30 in the SOC arm and 32 in the standard-treatment plus tocilizumab arm. The primary outcome occurred in 12.9% in the tocilizumab arm and 32.3% in the SOC arm(p = 0.068). There was a trend towards fewer days on IMV (7.5 vs 19.5 days, p = 0.073) and a shorter hospital stay (4 vs 8 days, p = 0.134) in the tocilizumab group. No serious adverse events were reported. The meta-analysis revealed a RR for death or IMV of 0.83 (95% CI: 0.77-0.89) in patients receiving tocilizumab, compared to patients receiving SOC.

Tocilizumab could be effective to prevent death or IMV in patients with severe COVID-19 pneumonia and high IL-6 serum levels. Safety profile of tocilizumab does not arise major concern in patients with severe COVID19.

SARS-CoV-2, first identified in December 2019, caused a global pandemic, resulting in over 6.8 million deaths by March 2023. The elderly, or individuals over 65, accounted for the majority of COVID-19 deaths, with 81% of fatalities in the US in 2020 occurring in this group. Beyond mortality, aging populations are also at higher risk of long-term cardiovascular complications and acute respiratory distress syndrome (ARDS). Although these outcomes may be influenced by comorbidities common in the elderly, age has been found to be a standalone risk factor for severe COVID-19 infection. Therefore, investigating age-related factors in COVID-19 outcomes is crucial in protecting this vulnerable group. Of particular interest is the cytokine storm phenomenon, an excessive inflammatory response that contributes to severe COVID-19 symptoms, including ARDS and cardiovascular damage. Elevated levels of multiple cytokines are common in severe cases of COVID-19. We propose that changes that occur to cytokine profiles as we age may contribute to these aberrant inflammatory responses. This review specifically explored the interleukin class cytokines IL-1, IL-6, IL-17, and IL-23 and considered the potential of biologics targeting these cytokines to alleviate severe outcomes in both COVID-19 and aging individuals.

This review provides a broad overview of lessons learned in the five years since COVID-19 was identified. It is a bimodal disease, starting with an initially virus-driven phase, followed by resolution or ensuing inappropriate immune activation causing severe inflammation that is no longer strictly virus dependent. Humoral immunity is beneficial for preventing or attenuating the early stage, without benefit once the later stage begins. Neutralizing antibodies elicited by natural infection or vaccination are short-lived and highly vulnerable to viral sequence variation. By contrast, cellular immunity, particularly the CD8+ T cell arm, has a role in preventing or attenuating severe disease, is far less susceptible to viral variation, and is longer-lived than antibodies. Finally, an ill-defined phenomenon of prolonged symptoms after acute infection, termed "long COVID," is poorly understood but may involve various immunologic defects that are hyperactivating or immunosuppressive. Remaining issues include needing to better understand the immune dysregulation of severe disease to allow more tailored therapeutic interventions, developing antibody strategies that cope with the viral spike sequence variability, prolonging vaccine efficacy, and unraveling the mechanisms of long COVID to design therapeutic approaches.

COVID-19 remains a significant threat to public health globally. Infection in some susceptible individuals causes life-threatening acute lung injury (ALI/ARDS) and/or death. Human surfactant protein A (SP-A) is a C-type lectin expressed in the lung and other mucosal tissues, and it plays a critical role in host defense against various pathogens. The human SP-A genes (SFTPA1 and SFTPA2) are highly polymorphic and comprise several common genetic variants, i.e., SP-A1 (variants 6A2, 6A4) and SP-A2 (variants 1A0, 1A3). Here, we elucidated the differential antiviral and immunoregulatory roles of SP-A variants in response to SARS-CoV-2 infection in vivo.

Six genetically-modified mouse lines, expressing both hACE2 (SARS-CoV-2 receptor) and individual SP-A variants: (hACE2/6A2 (6A2), hACE2/6A4 (6A4), hACE2/1A0 (1A0), and hACE2/1A3 (1A3), one SP-A knockout (hACE2/SP-A KO (KO) and one hACE2/mouse SP-A (K18) mice, were challenged intranasally with 103 PFU SARS-CoV-2 or MEM medium (Sham).

Infected KO and 1A0 mice had more weight loss and mortality compared to other mouse lines. Relative to other infected mouse lines, a more severe ALI was observed in KO, 1A0, and 6A2 mice. Reduced viral titers were generally observed in the lungs of infected SP-A mice relative to KO mice. Transcriptomic analysis revealed an upregulation in genes that play central roles in immune responses such as MyD88, Stat3, IL-18, and Jak2 in the lungs of KO and 1A0 mice. However, Mapk1 was significantly downregulated in 6A2 versus 1A0 mice. Analysis of biological pathways identified those involved in lung host defense and innate immunity, including pathogen-induced cytokine, NOD1/2, and Trem1 signaling pathways. Consistent with the transcriptomic data, levels of cytokines and chemokines such as G-CSF, IL-6, and IL-1β were comparatively higher in the lungs and sera of KO and 1A0 mice with the highest mortality rate. Furthermore, we observed the complexity of COVID-19, such as the difference between lung and systemic immune response to viral infection and of viral load and mortality among SP-A variants in this model.

These findings demonstrate that human SP-A variants differentially modulate SARS-CoV-2-induced lung injury and disease severity by differentially inhibiting viral infectivity and regulating immune-related gene expressions.

Aging affects human immune system functionality, increasing susceptibility to immune-mediated diseases. While gene expression programs accurately reflect immune function, their relationship with biological immune aging and health status remains unclear. Here we developed robust, cell-type-specific aging clocks (sc-ImmuAging) for the myeloid and lymphoid immune cell populations in circulation within peripheral blood mononuclear cells, using single-cell RNA-sequencing data from 1,081 healthy individuals aged from 18 to 97 years. Application of sc-ImmuAging to transcriptome data of patients with COVID-19 revealed notable age acceleration in monocytes, which decreased during recovery. Furthermore, inter-individual variations in immune aging induced by vaccination were identified, with individuals exhibiting elevated baseline interferon response genes showing age rejuvenation in CD8+ T cells after BCG vaccination. sc-ImmuAging provides a powerful tool for decoding immune aging dynamics, offering insights into age-related immune alterations and potential interventions to promote healthy aging.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continues to pose a significant global public health threat, particularly to older adults, pregnant women, and individuals with underlying chronic conditions. Dysregulated immune responses to SARS-CoV-2 infection are believed to contribute to the progression of COVID-19 in severe cases. Previous studies indicates that a deficiency in type I interferon (IFN-I) immunity accounts for approximately 15 %-20 % of patients with severe pneumonia caused by COVID-19, highlighting the potential therapeutic importance of modulating IFN-I signals. Natural products and their derivatives, due to their structural diversity and novel scaffolds, play a crucial role in drug discovery. Some of these natural products targeting IFN-I have demonstrated applications in infectious diseases and inflammatory conditions. However, the immunomodulatory potential of IFN-I in critical COVID-19 pneumonia and the natural compounds regulating the related signal pathway remain not fully understood. In this review, we offer a comprehensive assessment of the association between IFN-I and severe COVID-19, exploring its mechanisms and integrating information on natural compounds effective for IFN-I regulation. Focusing on the primary targets of IFN-I, we also summarize the regulatory mechanisms of natural products, their impact on IFNs, and their therapeutic roles in viral infections. Collectively, by synthesizing these findings, our goal is to provide a valuable reference for future research and to inspire innovative treatment strategies for COVID-19.

Severe pneumonia, frequently accompanied by cytokine storms, stands as a perilous respiratory condition with alarmingly high mortality rates. Tetrastigma hemsleyanum polysaccharide (THP), a pivotal constituent derived from Tetrastigma hemsleyanum Diels et Gilg (TH), has demonstrated efficacy in treating lung inflammation. However, its precise efficacy and underlying mechanisms in the context of severe pneumonia remain elusive. Our research aims to elucidate THP's protective effects in a "two-hit" severe pneumonia model. Our observations indicate that THP administration markedly shields the lungs from injury, reduces pulmonary apoptosis, balances the formation of immune thrombus and alleviates oxidative stress in pneumonia-induced mice. Furthermore, THP significantly decreases the levels of pro-inflammatory cytokines, suggesting its robust anti-inflammatory capabilities. Notably, THP also plays a crucial role in normalizing gut microbiota imbalance, which is vital in the pathogenesis of severe pneumonia. Metabolomic analysis further validates THP's restorative effects on plasma metabolites, indicating its involvement in regulating energy metabolism and immune homeostasis. Mechanistically, THP targets the TLR4/NF-κB signaling pathway, a core mediator of inflammation, thereby dampening the inflammatory cascade. In summary, our findings underscore that THP, through its multifaceted actions targeting inflammation, oxidative stress, immune thrombus formation, gut microbiota regulation, and metabolic modulation, emerges as a promising therapeutic approach for severe pneumonia. This study provides invaluable insights into the potential applications of natural polysaccharides in treating severe pneumonia and highlights the significance of the TLR4/NF-κB pathway in the disease's progression.

Background and Objectives: The neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) are novel biomarkers that provide insight into systemic inflammation and how the immune system responds to stress or infection. These ratios have been associated with predicting clinical outcomes in various diseases, including COVID-19. This study aims to evaluate the prognostic value of NLR and PLR in anticipating ICU admission, acute respiratory failure, and disease severity in COVID-19 patients. Materials and Methods: We conducted a retrospective, observational study that included 536 patients diagnosed with COVID-19. We analyzed the NLR and PLR values at admission and correlated them with ICU admission, the onset of acute respiratory failure, and clinical outcomes. Results: Statistical correlations were identified between elevated NLR and PLR values and the development of complications during hospitalization (p = 0.04 and p = 0.00), acute hypoxemic respiratory failure (p = 0.00), and admission to the intensive care unit (ICU) (p = 0.04). No correlations were found between the values of these ratios and mortality (p = 0.46 and p = 0.32) nor with the development of hepatic cytolysis (p = 0.79 and p = 0.87). Conclusions: NLR and PLR are reliable, easily obtainable biomarkers that can aid in the early prediction of ICU admission and disease severity in COVID-19 patients, offering valuable insights for risk stratification and clinical management. Further prospective studies are needed to validate these biomarkers as part of a broader predictive model for critical care in COVID-19.

Background: While the rapid deployment of SARS-CoV-2 vaccines had a significant impact on the ongoing COVID-19 pandemic, rapid viral immune evasion and waning neutralizing antibody titers have degraded vaccine efficacy. Nevertheless, vaccine manufacturers and public health authorities have a number of options at their disposal to maximize the benefits of vaccination. In particular, the effect of booster schedules on vaccine performance bears further study. Methods: To better understand the effect of booster schedules on vaccine performance, we used an agent-based modeling framework and a population pharmacokinetic model to simulate the impact of boosting frequency on the durability of vaccine protection against infection and severe acute disease. Results: Our work suggests that repeated dosing at frequent intervals (three or more times a year) may offset the degradation of vaccine efficacy, preserving the utility of vaccines in managing the ongoing pandemic. Conclusions: Given the practical significance of potential improvements in vaccine utility, clinical research to better understand the effects of repeated vaccination would be highly impactful. These findings are particularly relevant as public health authorities worldwide have reduced the frequency of boosters to once a year or less.

Hypoalbuminemia is commonly observed in patients with severe Coronavirus Disease 2019 (COVID-19) and is independently associated with adverse outcomes. However, the efficacy of albumin administration on the clinical prognosis of these patients remains uncertain.

This multicenter retrospective study enrolled 458 patients with severe COVID-19 in four medical centers from December 1, 2022, to June 1, 2024. Clinical features and laboratory variables were collected through electronic medical records. The cohorts were divided into two groups: albumin administration and non-albumin administration. Propensity score matching (PSM) was used for minimizing confounding effect. Statistical analyses were conducted to assess the relationship between early albumin administration and 28-day mortality.

Four hundred and fifty-eight severe COVID-19 cases were included in the study, of which 167 (36.5%) received early albumin administration, while 291 (63.5%) did not. Among these patients, 140 experienced in-hospital mortality and 318 survived. Compared to survivors, non-survivors exhibited significantly lower serum albumin levels (29.1g/L vs.33.8g/L, p < 0.05). In comparison to patients with admission albumin levels ≥30 g/L, those with albumin levels <30 g/L had a significantly higher in-hospital mortality (48.4% vs 21.1%, p < 0.001). Prior to PSM, the albumin administration group demonstrated significantly higher 28-day and in-hospital cumulative survival rates compared to the non-albumin group (both p < 0.001). However, no significant differences were observed between the two groups following PSM (p = 0.21 and p = 0.41, respectively).

Hypoalbuminemia was correlated with adverse outcomes in severe COVID-19 patients. However, early albumin administration did not reduce 28-day mortality and in-hospital mortality in these patients, and more relative RCTs were required for validation.

The pandemic potential of the Middle East Respiratory Syndrome Coronavirus (MERS-CoV) highlights the critical need for effective vaccines due to its high fatality rate of around 36%. In this review, we identified a variety of immunotherapeutic molecules and diagnostic biomarkers that could be used in MERS vaccine development as human-derived adjuvants. We identified immune molecules that have been incorporated into standard clinical diagnostics such as CXCL10/IP10, CXCL8/IL-8, CCL5/RANTES, IL-6, and the complement proteins Ca3 and Ca5. Utilization of different human monoclonal antibodies in the treatment of MERS-CoV patients demonstrates promising outcomes in combatting MERS-CoV infections in vivo, such as hMS-1, 4C2H, 3B11-N, NBMS10-FC, HR2P-M2, SAB-301, M336, LCA60, REGN3051, REGN3048, MCA1, MERs-4, MERs-27, MERs-gd27, and MERs-gd33. Host-derived adjuvants such as CCL28, CCL27, RANTES, TCA3, and GM-CSF have shown significant improvements in immune responses, underscoring their potential to bolster both systemic and mucosal immunity. In conclusion, we believe that host-derived adjuvants like HBD-2, CD40L, and LL-37 offer significant advantages over synthetic options in vaccine development, underscoring the need for clinical trials to validate their efficacy.

The global impact of SARS-CoV-2 and its associated coronavirus disease (COVID-19) has necessitated urgent characterization of prognostic biomarkers. This study aimed to delineate the epidemiological and clinical predictors of mortality among hospitalized COVID-19 patients.

A retrospective cohort study was conducted on 123 patients with laboratory-confirmed COVID-19 admitted to Huoshenshan Hospital (Wuhan, China) from 1 February 2020 to 30 April 2020. Kaplan-Meier curve and multivariate Cox regression were used to assess the independent factors with survival time. Statistical significance was set at a p-value of <0.05.