High blood pressure variability (BPV) is associated with cerebrovascular damage and dementia, but it is unknown whether short-term BPV during hospitalisation is also associated with cerebral white matter (WM) damage. We examined whether BPV, measured in-hospital using continuous monitoring, is associated with WM microstructural integrity in COVID-19 patients.

We included hospitalised COVID-19 patients from the CORONavirus and Ischemic Stroke (CORONIS) study who underwent continuous vital signs monitoring using a wearable device during hospital admission and had an MRI shortly after discharge. Systolic BPV was calculated as Average Real Variability (ARV) and Coefficient of Variation (CV) with 1-, 5- and 20-minute intervals. We used diffusion tensor imaging to assess fractional anisotropy (FA) and peak width of skeletonised mean diffusivity (PSMD) as markers of WM integrity. Associations between BPV and WM integrity were examined with linear regression adjusted for age, mean systolic blood pressure (BP), number of BP measurements and type of respiratory support.

We included 47 COVID-19 patients (mean age: 59.6 years). BP was measured 6306 ± 4343 times per patient (median admission: 11 days (Interquartile Range [IQR] 7.5-15.0). Both higher ARV and CV were associated with lower WM microstructural integrity, reflected by lower FA (ARV: β = -0.40, p = .010; CV: β = -0.33, p = 0.026) and higher PSMD (CV: β = 0.28, p = .038) after adjustment for confounders. Correction for WM hyperintensities did not change these results.

High BPV during hospitalisation is associated with lower WM integrity in COVID-19 patients, although causality needs to be demonstrated. Our findings need validation in hospitalised patients without COVID-19 to examine generalisability.

Inflammation is the body's response to infection, trauma or injury and is activated in a coordinated fashion to ensure the restoration of tissue homeostasis and healthy physiology. This process requires communication between stromal cells resident to the tissue compartment and infiltrating immune cells which is dysregulated in disease. Clinical innovations in patient diagnosis and stratification include measures of inflammatory activation that support the assessment of patient prognosis and response to therapy. We propose that (i) the recent advances in fast, dynamic monitoring of inflammatory markers (e.g., cytokines) and (ii) data-dependent theoretical and computational modeling of inflammatory marker dynamics will enable the quantification of the inflammatory response, identification of optimal, disease-specific biomarkers and the design of personalized interventions to improve patient outcomes - multidisciplinary efforts in which biomedical engineers may potentially contribute. To illustrate these ideas, we describe the actions of cytokines, acute phase proteins and hormones in the inflammatory response and discuss their role in local wounds, COVID-19, cancer, autoimmune diseases, neurodegenerative diseases and aging, with a central focus on cardiac surgery. We also discuss the challenges and opportunities involved in tracking and modulating inflammation in clinical settings.

Experimental and observational studies suggest that circulating micronutrients, including vitamin D (VD), may increase COVID-19 risk and its associated outcomes. Mendelian randomization (MR) studies provide valuable insight into the causal relationship between an exposure and disease outcomes.

The aim was to conduct a systematic review and meta-analysis of causal inference studies that apply MR approaches to assess the role of these micronutrients, particularly VD, in COVID-19 risk, infection severity, and related inflammatory markers.

Searches (up to July 2023) were conducted in 4 databases.

The quality of the studies was evaluated based on the MR-STROBE guidelines. Random-effects meta-analyses were conducted where possible.

There were 28 studies (2 overlapped) including 12 on micronutrients (8 on VD) and COVID-19, 4 on micronutrients (all on VD) and inflammation, and 12 on inflammatory markers and COVID-19. Some of these studies reported significant causal associations between VD or other micronutrients (vitamin C, vitamin B6, iron, zinc, copper, selenium, and magnesium) and COVID-19 outcomes. Associations in terms of causality were also nonsignificant with regard to inflammation-related markers, except for VD levels below 25 nmol/L and C-reactive protein (CRP). Some studies reported causal associations between cytokines, angiotensin-converting enzyme 2 (ACE2), and other inflammatory markers and COVID-19. Pooled MR estimates showed that VD was not significantly associated with COVID-19 outcomes, whereas ACE2 increased COVID-19 risk (MR odds ratio = 1.10; 95% CI: 1.01-1.19) but did not affect hospitalization or severity of the disease. The methodological quality of the studies was high in 13 studies, despite the majority (n = 24) utilizing 2-sample MR and evaluated pleiotropy.

MR studies exhibited diversity in their approaches but do not support a causal link between VD/micronutrients and COVID-19 outcomes. Whether inflammation mediates the VD-COVID-19 relationship remains uncertain, and highlights the need to address this aspect in future MR studies exploring micronutrient associations with COVID-19 outcomes.

PROSPERO registration no. CRD42022328224.

Natural small molecule compounds have become the alternative options for developing antiviral reagent due to their broad-spectrum antiviral properties and low toxicity. Eugenol is a natural volatile phenolic aromatic compound primarily derived from clove oil. The small compound is well-recognized for its local anesthetic, anti-inflammatory, and preservative properties, making it a common choice for oral disinfection and as an adjunctive treatment for periodontitis. Clinical and experimental evidence shows that eugenol exhibits significant inhibitory effects against a variety of pathogenic microorganisms, including bacteria, fungi, and the viruses. In viral infectious diseases, eugenol can directly interact with pathogenic antigens in viral structures to prevent viral invasion. Additionally, it offers anti-inflammatory and antioxidant benefits by inhibiting multiple inflammatory mediators, thereby reducing organ damage. To the best of our knowledge, recent advancements in the antiviral properties of eugenol have not been solely addressed. This review aims to offer a new insight into the antiviral activity of eugenol and its potential mechanisms of action. Based on the literature review, we suggest that the antiviral mechanisms of eugenol are associated with cellular autophagy, and that the nuclear factor kappa-B (NF-κB) signaling pathway is the primary inflammatory pathway regulated by eugenol. These findings highlight the need for further investigation through rigorously designed experimental studies focused on specific viruses.

Severe respiratory viral infections can lead to viral sepsis (VS), a life-threatening condition characterized by lung and extrapulmonary organ dysfunction. However, the pathology of VS is not clear. Specifically, it is unknown how the cytokine storm and direct virus infection contribute to the damage of extrapulmonary organs.

In this study, we established survival and lethal mouse models of VS by intranasally administering different doses of PR8/H1N1 influenza virus in C57BL/6J male mice, as well as model of bacterial sepsis (BS) caused by Streptococcus pneumoniae as references. Viraemia and extrapulmonary dissemination and infection of the virus were examined. Single-cell sequencing of the lungs and livers was performed at different days post-infection (dpi) in three groups.

While bacteria can spread and colonize extensively in extrapulmonary organs, causing multiple organ injuries, IAVs mainly replicate and cause damage in pulmonary cells. Live virus can be isolated in the blood and extrapulmonary organs. Disseminating via the bloodstream, IAVs transiently infect the liver and spleen, causing liver dysfunction and spleen atrophy, without affecting kidney function, despite systematically elevated cytokine levels. Compared to BS, a more significant decrease in the proportion of alveolar macrophages, epithelial cells, endothelial cells, and fibroblasts in the lungs, as well as endothelial cells and Kupffer cells in the liver, was observed in VS. This was accompanied by a longer activated PANoptosis pathway and downregulated genes responsible for barrier function and antigen presentation in the epithelial and endothelial cells.

Our study suggests that H1N1 influenza virus disseminates through the bloodstream and infects extrapulmonary organs to varying extents, which may lead to differential cell death, organ dysfunction, and trigger VS.

This research was supported by the National Natural Science Foundation of China (82241056, 82170015, 82030002, 82470007, 824B2001), the National Key R&D Program of China (2023YFC2306300), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2021-I2M-1-048), the Innovation Team and Talents Cultivation Program of National Administration of Traditional Chinese Medicine (ZYYCXTD-D-202208), New Cornerstone Science Foundation, National High Level Hospital Clinical Research Funding (2024-NHLHCRF-LX-01-0101, 2024-NHLHCRF-LX-01-0102), Beijing Research Ward Excellence Program (BRWEP2024W114060103), Noncommunicable Chronic Diseases-National Science and Technology Major Project (2023ZD0506200, 2023ZD0506203) and Special Research Fund for Central Universities, Peking Union Medical College (3332024193).

Acute COVID-19 infection frequently affects the cardiovascular system and causes acute myocardial injury. Epicardial Adipose Tissue (EAT), a visceral adipose tissue surrounding the myocardium and coronary arteries, has unique paracrine and endocrine effects, modulating the heart's inflammatory environment. Systemic inflammation stimulates TNF-α and Interleukin-6 secretion from EAT, contributing to cytokine storms and intensifying systemic responses. We aimed to determine whether EAT amount differs in patients with and without acute COVID-19 infection and myocardial injury.

This study analyzed the CoV-COR registry cohort, conducted at the University Hospital Essen, including patients with symptoms suggestive of COVID-19 infection. The infection was confirmed by PCR. EAT thickness was measured by two-dimensional TTE.

A total of 296 patients (mean age 63.6 ± 17.26 years, 55.4 % male) were included. Patients with confirmed COVID-19 infection were younger, more frequently treated with antihypertensive medication, and had higher BMI and systolic blood pressures. Univariate logistic regression showed no association between EAT and myocardial injury 0.97 (0.74; 1.28, p = 0.82). A trend towards an association was observed between increasing EAT thickness and COVID-19 infection 1.25 (0.99; 1.59, p = 0.060). Adjusting for age and gender strengthened the association, with a 48 % (1.14; 1.93, p = 0.004) increased odds of COVID-19 infection per increase in EAT thickness. Multivariable regression yielded consistent effect sizes 1.47 (1.01; 2.16, p = 0.047).

EAT thickness is associated with the presence of an acute COVID-19 infection but not with a myocardial injury. Further research is needed to assess if systemic viral infection induces dynamic changes in EAT.

SARS-CoV-2 nucleocapsid (N) antigen has been confirmed in the peripheral blood of patients with new coronavirus infection,yet its diagnostic and prognostic significance remains unclear. This study aimed to characterize the dynamics of SARS-CoV-2 N antigenemia in patients with novel coronavirus positivity, and to assess its potential association with clinical severity and plasma biomarker levels.

We analyzed the level of SARS-CoV-2 N antigen, spike receptor-binding domain (S-RBD) IgG, neutralizing antibodies (NAb) and tissue-damage biomarkers was assessed in 180 plasma samples from 51 SARS-CoV-2-positive individuals. Plasma antigen levels were compared with concurrent respiratory nucleic acid amplification test results.

Patients with Ct values below 30 showed significantly different serum antigen levels compared to those with Ct values above 30 (p < 0.01). However, no significant positive correlation was found between respiratory viral load and serum antigen levels. Further analysis revealed that patients with pneumonia had markedly higher serum antigen levels than those without (p < 0.0001). Additionally, serum amyloid A (SAA) and ferritin (Fe) levels were significantly elevated in the antigenemia-positive group compared to the negative group, while procalcitonin (PCT) and interleukin-6 (IL-6) levels showed no significant differences. Notably, the positivity rate of N antigen in peripheral blood peaked at 47.1% (95% CI: 37.8%-56.7%) during the first week of infection and then gradually decreased over time. Moreover, patients with severe COVID-19 exhibited significantly higher serum antigen levels than those with mild or moderate disease (p < 0.0001). Serum levels of SARS-CoV-2 S-RBD IgG and neutralizing antibodies (NAb) were also significantly higher in antigenemia-negative patients than in antigenemia-positive patients (p < 0.0001).

Our findings highlight the multifaceted role of antigenemia in SARS-CoV-2 and suggest its potential as a biomarker for disease monitoring and risk stratification.

The emergence of new SARS-CoV-2 variants with a higher contagious capability and faster transmissible speed has imposed an incessant menace on global health and the economy. The SARS-CoV-2 infection might reoccur and last much longer than expected. Thence, there is a high possibility that COVID-19 can cause long-term health problems. This condition needs to be investigated thoroughly, especially the post-COVID-19 complications. Respiratory tract disorders are common and typical complications after recovery. Until now, there has been a lack of data on specialized therapeutic medicine for post-COVID-19 complications. The clinical efficacy of NRICM101 has been demonstrated in hospitalized COVID-19 patients. This herbal medicine may also be a promising therapy for post-COVID-19 complications, thanks to its phytochemical constituents. The potential pharmacological mechanisms of NRICM101 in treating post-COVID-19 respiratory complications were investigated using network pharmacology combined with molecular docking, and the results revealed that NRICM101 may exert a beneficial effect through the three primary pathways: PI3K/AKT, HIF-1, and TNF signaling pathways. Flavonoids (especially quercetin) have a predominant role and synergize with other active compounds to produce therapeutic effectiveness. Most of the main active compounds exist in three chief herbal ingredients, including Liquorice root (Glycyrrhiza glabra), Scutellaria root (Scutellaria baicalensis), and Mulberry leaf (Morus alba). To our knowledge, this is the first study of the NRICM101 effect on post-COVID-19 respiratory complications. Our findings may provide a better understanding of the potential mechanisms of NRICM101 in treating SARS-CoV-2 infection and regulating the immunoinflammatory response to improve post-COVID-19 respiratory complications.

Background/Objectives: Genetic variants in cytokine genes such as IL1B, IL6, and TNF may influence inflammatory responses to SARS-CoV-2 and affect disease severity. This study investigates the role of these variants in relation to COVID-19 outcomes, including hospitalization, ICU admission, and mortality. Methods: A total of 500 unvaccinated individuals from southern Brazil diagnosed with COVID-19 via RT-PCR were analyzed. DNA was extracted from nasopharyngeal swabs and genotyped for functional variants selected based on evidence of regulatory function and prior associations with inflammatory outcomes-IL1B (rs4848306, rs1143623, rs16944, rs1143627), IL6 (rs1800795, rs2069832, rs2069840, rs2069845), and TNF (rs1799964, rs1800630, rs1799724, rs1800629, rs361525). Multivariate logistic regression analysis, adjusted for sex and age, was employed to assess the association between these genetic variants and severe clinical outcomes. Results: The results indicated that the IL1B rs16944-AG (OR: 1.98 [95% CI: 1.22-3.23], p = 0.006) and TNF rs1799964-CT (OR: 1.97 [95% CI: 1.22-3.22], p = 0.006) genotypes were associated with the need for hospitalization, while TNF rs1800630-AA (OR: 2.37 [95% CI: 1.08-5.33], p = 0.034) was associated with ICU admission. Additionally, the CC genotype of TNF rs1799964 was associated with a higher risk of mortality (OR: 3.73 [95% CI: 1.21-14.37], p = 0.034). Conclusions: Genetic variants-specifically IL1B rs16944 and rs1143627, and TNF rs1799964 and rs1800630-were associated with COVID-19 severity and should be further investigated in larger studies to evaluate their potential as predictive markers of severe outcomes in COVID-19.

Background: Patients with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) may exhibit altered immune responses to infections such as SARS-CoV-2. This study aimed to characterize the cytokine profiles associated with prior SARS-CoV-2 infection and to identify immune markers related to the persistence of the humoral response in pwMS. Methods: A total of 90 pwMS were recruited before the introduction of COVID-19 vaccination in Spain; 46 were seropositive-defined by the presence of IgG, IgM, or IgA antibodies against SARS-CoV-2-and 44 were seronegative. We compared baseline cytokine levels between groups and followed seropositive individuals for six months to assess IgG antibody persistence. Results: Seropositive patients showed significantly lower baseline levels of IL-10, IL-23, and IFN-α compared to seronegative individuals. Notably, elevated IL-18 at baseline was associated with persistent IgG seropositivity at six months. Conclusions: These findings suggest a distinct cytokine profile in SARS-CoV-2-exposed pwMS and highlight IL-18 as a potential marker of sustained humoral response. This study provides insight into host-virus immune dynamics in MS patients and may help guide future strategies for infection monitoring and immune evaluation in this population.

The COVID-19 pandemic, caused by SARS-CoV-2, posed a tremendous challenge to healthcare systems globally. Severe COVID-19 infection was reported to be associated with altered immunometabolism and cytokine storms, contributing to poor clinical outcomes and in many cases resulting in mortality. Despite promising preclinical results, many drugs have failed to show efficacy in clinical trials, highlighting the need for novel approaches to combat the virus and its severe manifestations. Mitochondria, crucial for aerobic respiration, play a pivotal role in modulating immunometabolism and neuronal function, making their compromised capability as central pathological mechanism contributing to the development of neurological complications in COVID-19. Dysregulated mitochondrial dynamics can lead to uncontrolled immune responses, underscoring the importance of mitochondrial regulation in shaping clinical outcomes. Aging further accelerates mitochondrial dysfunction, compounding immune dysregulation and neurodegeneration, making older adults particularly vulnerable to severe COVID-19 and its neurological sequelae. COVID-19 infection impairs mitochondrial oxidative phosphorylation, contributing to the long-term neurological complications associated with the disease. Additionally, recent reports also suggest that up to 30% of COVID-19 patients experience lingering neurological issues, thereby highlighting the critical need for further research into mitochondrial pathways to mitigate long-tern neurological consequences of Covid-19. This review examines the role of mitochondrial dysfunction in COVID-19-induced neurological complications, its connection to aging, and potential biomarkers for clinical diagnostics. It also discusses therapeutic strategies aimed at maintaining mitochondrial integrity to improve COVID-19 outcomes.

Inflammatory lung diseases (ILDs) represent a global public health crisis characterized by escalating prevalence, significant morbidity, and substantial mortality. In response to the complex immunopathogenic mechanisms driving these conditions, novel pharmacological strategies targeting resolution pathways have emerged throughout the discovery of specialized pro-resolving lipid mediator (SPM; resolvins, maresins, and protectins) dysregulation across the ILD spectra, positioning these endogenous molecules as promising therapeutic candidates for modulating maladaptive inflammation and promoting tissue repair. Over the past decade, this paradigm has catalyzed extensive translational research into SPM-based interventions as precision therapeutics for respiratory inflammation. In asthma, they reduce mucus hypersecretion, bronchial hyperreactivity, and airway inflammation, with prenatal SPM exposure potentially lowering offspring disease risk. In COPD, SPMs attenuate amyloid A-driven inflammation, normalizing cytokine/chemokine imbalances and oxidative stress and mitigating COVID-19-associated cytokine storm, enhancing survival. This review synthesizes SPMs' pharmacotherapeutic mechanisms in ILDs and evaluates current preclinical and clinical evidence.

Although much is known about the pathophysiology of severe COVID-19, there are still areas that remain to be determined. It is well established that the pivotal molecular event is a hyperinflammatory response also referred to as a cytokine storm. The aim of this retrospective cohort study was to determine miRNAs which might be predictive for the admission to the intensive care unit (ICU). We analyzed blood samples from 210 COVID-19 patients and the control group consisted of 80 healthy individuals. Results revealed the miRNA expression pattern has the potential to predict the severity of COVID-19, reflecting the clinical symptoms of the infection, such as the need for oxygen therapy and concomitant pneumonia. In particular, low expression of miRNAs miR106a-5p, miR17-5p, miR181a-5p, miR191-5p, miR20a-5p and miR451a, especially in the initial phase of the disease, is associated with an unfavorable clinical course of SARS-CoV-2 infection (admission to the ICU).

SARS-CoV-2, the virus causing COVID-19, poses significant health threats due to its high transmissibility and potential for severe respiratory complications. T cells, central to adaptive immunity, also interact with innate immunity, playing a pivotal role in coordinating defenses and eliminating infected cells. Single-cell RNA sequencing (scRNA-seq) has provided more subtle heterogeneity, rare subpopulations, or new subpopulations that are at the district differentiation stage or with specific function. Thus, elucidating how T cell heterogeneity impacts COVID-19 disease severity remains a critical question requiring comprehensive analysis. This review revealed the heterogeneity of the host T cells, including conventional T cells (CD8+, CD4+ T cells) and unconventional T cells, including natural killer T (NKT) cells, mucosal-associated invariant T (MAIT) and gamma-delta T (γδT) cells in COVID-19 patients with different clinical manifestations. Severe COVID-19 had marked lymphopenia, excessive activation, elevated exhaustion and reduced functional diversity of T cells. Pathogenic contributions arise from dysregulated cytotoxic T cells, Treg cells and unconventional T cells collectively driving systemic hyperinflammation and tissue injury. Current therapeutic strategies targeting T cells-such as enhancing virus-specific T cell responses, reverting T-cell exhaustion and alleviating inflammation-exhibit inconsistent efficacy, underscoring the need for combinatorial approaches. This review highlights how scRNA-seq deciphers T cell heterogeneity and dysfunction in COVID-19. By targeting T cell exhaustion, inflammation, and subset-specific deficits, these insights pave the way for therapies and vaccines.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), remains a global public health threat with considerable economic consequences. The nonstructural protein 16 (nsp16), in complex with nsp10, facilitates the final viral mRNA capping step through its 2'-O-methylase activity, helping the virus to evade host immunity and prevent mRNA degradation. However, nsp16 regulation by host factors remains poorly understood. While various E3 ubiquitin ligases interact with SARS-CoV-2 proteins, their roles in targeting nsp16 for degradation remain unclear. In this study, we demonstrate that nsp16 undergoes ubiquitination and proteasomal degradation mediated by the host E3 ligases UBR5 and MARCHF7. UBR5 induces K48-linked ubiquitination, whereas MARCHF7 promotes K27-linked ubiquitination, independently suppressing SARS-CoV-2 replication in cell cultures and in mice. Notably, UBR5 and MARCHF7 also degrade nsp16 variants from different viral strains, exhibiting broad-spectrum antiviral activity. Our findings reveal novel antiviral mechanisms of the ubiquitin-proteasome system (UPS) and highlight their potential therapeutic targets against COVID-19.

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.

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.

Interleukin 40 (IL-40) is a novel cytokine that has been associated with B lymphocytes, particularly IgA-secreting cells in gut mucosa. Considering mucosal association of IL-40, we aimed to determine serum IL-40 levels in patients with Covid-19. We compared IL-40 concentrations in healthy people to both patients with mild symptoms of SARS-CoV-2 infection and pneumonia. IL-40 was measured by ELISA. Serum IgA levels were tested by nephelometry. For the first time, we demonstrated that SARS-CoV-2 infection increased serum IL-40 levels significantly. The elevation of IL-40 in serum was related to severity of the infection. Therefore, IL-40 concentrations were quite higher in patients with symptoms of pneumonia. Our findings indicated that IgA and NETosis biomarkers were related with IL-40 increase. Based on these findings, we speculated that IL-40 would be associated with immune activities in the mucosa of the lungs of SARS-CoV-2-infected patients. This association may be linked to a mechanism that has a control on IgA and NETosis.

This study aimed to compare the results of the Dysphonia Severity Index (DSI) and Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) between patients hospitalized with COVID-19 and healthy subjects, as well as to investigate the correlation between DSI and CAPE-V.

Cross-sectional survey.

Eighty subjects, 40 COVID-19 patients (with a mean age of 41.2± 5.41) and 40 healthy subjects (with a mean age of 44.50± 3.50) participated in this study. Assessments included the DSI for aerodynamic-acoustic measurement and the Persian version of Consensus Auditory-Perceptual Evaluation of Voice (CAPE-V) for evaluating auditory-perceptual voice quality. Data were analyzed by means of the independent t-test and Pearson correlation at the 5% significance level.

The results showed COVID-19 patients got significantly lower score in DSI compared to healthy subjects (P < 0.05). Moreover, the patients with COVID-19 had higher scores in all categories of voice production (severity, roughness, loudness, pitch, strain and breathiness) than the healthy group (P < 0.05). Comparing the result of the two voice assessments in each group revealed that there was a greater negative significant correlation in the diseased group (r p: -0.68, P: 0.001) than in the healthy group (r p: -0.37,P: 0.049).

Hospitalized COVID-19 patients experience deviations in the voice quality and acoustic-aerodynamic features of their voice. Also, the results of this study showed the patient group had higher perceptual dysphonia and lower voice quality compared to the healthy group. Further studies are recommended to determine the relationship between objective and subjective voice evaluation in patients with COVID-19 after recovery.

Novel therapeutic approaches are needed to treat respiratory infections due to the rising antimicrobial resistance and the lack of effective antiviral therapies. A promising avenue to overcome treatment failure is to develop strategies that target the host immune response rather than the pathogen itself. Granulocyte-macrophage colony-stimulating factor (GM-CSF) plays a critical role in controlling homeostasis in lungs, alveolar macrophages being the most sensitive cells to GM-CSF signaling. In this review, we discuss the importance of GM-CSF secretion for lung homeostasis and its alteration during respiratory infections. We also present the pre-clinical evidence and clinical investigations evaluating GM-CSF-based treatments (administration or inhibition) as a therapeutic strategy for treating respiratory infections, highlighting both supporting and contradictory findings.

The World Health Organization has declared that COVID-19 no longer constitutes a "public health emergency of international concern," yet the long-term impact of SARS-CoV-2 infection on bone health continues to pose new challenges for global public health. In recent years, numerous animal model and clinical studies have revealed that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can lead to secondary osteoporosis. The mechanisms involved are related to the virus's direct effects on bone tissue, dysregulation of the body's inflammatory response, hypoxia, noncoding RNA imbalance, and metabolic abnormalities. Although these studies have unveiled the connection between SARS-CoV-2 infection and osteoporosis, current research is not comprehensive and in depth. Future studies are needed to evaluate the long-term effects of SARS-CoV-2 on bone density and metabolism, elucidate the specific mechanisms of pathogenesis, and explore potential interventions. This review aims to collate existing research literature on SARS-CoV-2 infection-induced secondary osteoporosis, summarize the underlying mechanisms, and provide direction for future research.

Background Pulmonary fibrosis (PF) is associated with coronavirus disease 2019 (COVID-19) through the occurrence of acute respiratory distress syndrome (ARDS). The overall sequence results in the elevation of the inflammation profile of infected individuals. The risk of PF onset in COVID-19 patients is not limited to the infection course but extends to post-infection periods. Gamma-inducible protein-10 (GIP-10) is a chemokine; its production and release are induced by interferon-gamma (IFN-γ). Objectives In this study, we aimed to investigate the role of GIP-10, Galectin-3 (Gal-3), and hypoxia inducible factor 1 (HIF-1) in PF-associated COVID-19 and the effectiveness of the Pfizer vaccine against the progression of PF and inflammation through evaluating these three biomarkers and their correlation with a few hematological parameters. Design & methods The study included 120 subjects (34-68 years) from Ibn Al-Nafees Hospital (Baghdad, Iraq). Three groups of 40 subjects were designed for our investigation as control, non-vaccinated COVID-19, and vaccinated COVID-19 patients. The presence of PF was evaluated in each participant. The COVID-19 patients with chronic kidney disease, liver cirrhosis, cancer, and pregnant women were excluded from this study. The GIP-10, Gal-3, and HIF-1 were evaluated in the subjects' serum using Sandwich ELISA technology. Results The results have shown significantly elevated levels of GIP-10, Gal-3, and HIF-1 in vaccinated and non-vaccinated PF-associated COVID-19 patients compared to the control, but the vaccinated patients exhibited significantly (p<0.05) lower levels of GIP-10, Gal-3, and HIF-1 compared to non-vaccinated patients. Moreover, in non-vaccinated PF-associated COVID-19 patients, GIP-10 did not correlate significantly with any parameter, while in vaccinated patients, it was correlated positively with age, WBC, RBC, and ESR. All of GIP-10, Gal-3, and HIF-1 expressed Odds ratios (OR) 1< as risks for PF in COVID-19 patients and can be used excellently to predict PF-associated COVID-19. Conclusions The Pfizer vaccine for COVID-19 has a positive role in managing GIP-10 and, therefore, better controls patients' inflammation profiles.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, has affected hundreds of millions of people globally, resulting in millions of deaths. During this pandemic, children have demonstrated greater resistance than adults, exhibiting lower infection rates, reduced mortality, and milder symptoms. Summarizing the differences in resistance between children and adults during COVID-19 can provide insights into protective mechanisms and potential implications for future treatments. In this review, we focused on summarizing and discussing the mechanisms for better protection of children in COVID-19. These protective mechanisms encompass several factors: the baseline expression of cell surface receptor ACE2 and hydrolase TMPRSS2, the impact of complications on COVID-19, and age-related cytokine profiles. Additionally, differences in local and systemic immune responses between children and adults also contribute significantly, particularly interferon responses, heterologous protection from non-COVID-19 vaccinations, and immune status variations influenced by micronutrient levels. The advantageous protection mechanisms of these children may provide insights into the prevention and treatment of COVID-19. Importantly, while age-related metabolic profiles and differential COVID-19 vaccine responses may contribute to protection in children, current comparative research remains limited and requires further investigation.

Heart failure (HF) is a growing public health concern, with an increasing incidence among younger populations. Traditionally, HF was considered a condition primarily affecting the elderly, but of late, emerging evidence hints at a rapidly rising HF incidence in youth in the past 2 decades. HF in youth has been linked to a complex interaction between emerging risk factors, such as metabolic syndrome, environmental exposures, genetic predispositions, and lifestyle behaviors. This review examines these evolving determinants, including substance abuse, autoimmune diseases, and the long-term cardiovascular effects of coronavirus disease 2019, which disproportionately affect younger individuals. Through a comprehensive analysis, the study highlights the importance of early detection, targeted prevention strategies, and multidisciplinary management approaches to address this alarming trend. Promoting awareness and integrating age-specific interventions could significantly reduce the burden of HF and improve long-term outcomes among younger populations.

Identifying immune markers driving early and effective antibody response in patients with severe coronavirus disease 2019 (COVID-19) is critical due to the threat of future coronavirus pandemics, incomplete global vaccination, and suboptimal booster coverage. Patients with life-threatening severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are characterized by dysregulated thromboinflammation and cytokine storm that could influence the isotype virus-specific antibody response and the subsequent clinical outcome. We investigated the association between COVID-19-related mortality with the dynamics, magnitude, and relative avidity of nucleoprotein (N), spike (S), and receptor-binding domain (RBD)-specific IgM, IgA, and IgG in circulation. We also assessed the relationship between the virus-specific antibody responses and cytokine patterns, as well as systemic and pulmonary thromboinflammation markers. This multicenter study included COVID-19 patients hospitalized early in the pandemic, classified as survivors (n=62) and non-survivors (n=17). We developed indirect enzyme-linked immunosorbent assays (ELISAs) to evaluate each virus-specific isotype using well-characterized outpatient COVID-19 (n=180) and pre-pandemic cohorts (n=111). The pro-inflammatory interleukin (IL)-6 and tumor necrosis factor (TNF)-α, as well as the regulatory IL-10, transforming growth factor (TGF)-β1, and soluble tumor necrosis factor receptor I (sTNFRI) levels were evaluated. The ELISAs performed highly for all virus-specific isotypes, although modest for IgM-N. Non-survivors increased N-specific, but no S-specific, IgM and IgA responses throughout the disease course and, more notably, a delayed class switching to IgG-S and IgG-RBD compared to survivors. No differences were observed in the virus-specific IgG relative avidity. Survivors exhibited an antibody response proportional to the degree of systemic and pulmonary thromboinflammation, whereas non-survivors showed those dissociated because of their uncontrolled severe thromboinflammation. Only the survivors showed a dominant regulatory cytokine pattern in the early phase of infection (<10 days after symptoms onset), which strongly correlated with developing IgG-S and IgG-RBD protective antibodies. We developed easy-to-use immune assays that enable patient monitoring and identify at-risk populations in low- to middle-income regions. Non-survivors displayed an ineffective N-mediated antibody response, marked by an inability to control inflammation and a compromised time-dependent class switching toward S and RBD-specific IgG. The regulatory cytokine axis, including TGF-β1, maybe a critical immune correlate of effective antibody-mediated immunity 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 outcome of the immune response depends on the content and magnitude of inflammatory mediators, the right time to start, and the duration of inflammatory responses. Patients with coronavirus disease 2019 (COVID-19) represent diverse disease severity. Understanding differences in immune responses in individuals with different disease severity levels can help elucidate disease mechanisms. Here, we serially analyzed the cytokine profiles of 809 patients with mild to critical COVID-19. The cytokine profile revealed an overall increase in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 and impaired production of IFN-α and -β. Only an early rise in IL-1Ra, IL-6, and IL-2 levels was linked to worse disease outcomes. On the other hand, long-term rises in IL-1β, IL-1Ra, TNF-α, IL-6, IL-2, IL-8, and IL-18 levels were linked to worse disease outcomes. Principal component analysis identified a component, including IL-1β, TNF-α, IFN-α, and IL-12, that was associated with disease severity. Spearman analysis revealed that the correlation of IL-1β and IFN-α was entirely different between mild and critical patients. Therefore, the ratio of IL-1β to IFN-α seemed to be a suitable criterion for distinguishing critical patients from mild ones. The higher levels of the IL-1β to IFN-α ratio correlated with improved outcomes. These data point to an imbalance of IL-1β/IFNα, contributing to hyperinflammation in COVID-19.

Post-COVID syndrome has unveiled intricate connections between inflammation, depressive psychopathology, and cognitive impairment. This study investigates these relationships in 101 COVID-19 survivors, focusing on sex-specific variations. Utilizing path modelling techniques, we analyzed the interplay of a one-month 48-biomarker inflammatory panel, with three-months of depressive symptoms and cognitive performance. The findings indicate that cognitive impairment is influenced by both inflammation and depression in the overall cohort. However, prominent sex-specific differences emerged. In females, a lingering imbalance between pro- and anti-inflammatory responses-likely reflecting the long-lasting immune alterations triggered by COVID-19-significantly affects cognitive functioning and shows a marginal, though not statistically significant, association with depressive symptoms. This suggests that a mixed inflammatory profile may contribute to these outcomes. Conversely, in males, inflammation was inversely associated with depression severity, with protective effects from regulatory mediators (IL-2, IL-4, IL-6, IL-15, LIF, TNF-α, β-NGF) against depression. In males, cognitive impairment appeared to be driven mainly by depressive symptoms, with minimal influence from inflammatory markers. These results highlight distinct sex-specific pathways in immune and inflammatory responses post-COVID-19, potentially shaped by endocrine mechanisms. The findings suggest that persistent inflammation may foster long-term neuropsychiatric sequelae, possibly through its effects on the brain, and underscore the need for sex-tailored therapeutic strategies to address the lasting impact of COVID-19.

Macrophages are pivotal immune cells involved in maintaining immune homeostasis and defending against pathogens. They exhibit significant plasticity and heterogeneity, enabling polarization into pro-inflammatory M1 or anti-inflammatory M2 phenotypes in response to distinct microenvironmental cues. The process of macrophage polarization is tightly regulated by complex signaling pathways and transcriptional networks. This review explores the factors influencing macrophage polarization, the associated signaling pathways, and their roles in the pathogenesis of lung diseases, including fibrosis, cancer, and chronic inflammatory conditions. By summarizing recent advances, we aim to provide insights into the immunoregulatory functions of macrophages and their therapeutic potential. Based on our review, it is believed that targeting macrophage polarization emerges as a promising approach for developing effective treatments for lung diseases, balancing inflammation and repair while mitigating disease progression.

Pneumonia virus of mice (PVM) infection is a reference animal model for human respiratory syncytial virus (hRSV), a leading cause of lower respiratory tract disease in children under 5 years of age and in the elderly. This longitudinal study employed necropsy to examine macroscopic lesions, histological slides to assess microscopic lesions, and qRT-PCR to measure lung viral load and cytokine expression in PVM-infected mice from three different genetic backgrounds, spanning from day 1 to day 6 post-infection. Our analysis reveals a strong correlation between viral load and microscopic lesions across the 129/Sv, BALB/c, and SJL/J mouse lines, indicating that PVM pathogenicity is partially driven by the virus itself. Additionally, a significant correlation between cytokine levels and lesion severity was observed in 129/Sv and BALB/c mice, suggesting an important role of cytokines in disease progression. This study emphasizes the interplay between viral load and cytokine-driven tissue damage, with genetic background significantly influencing disease outcomes.

Coronavirus 2019 (COVID-19) is an infectious disease caused by a novel coronavirus, SARS-CoV-2. Acute kidney injury (AKI) affects approximately 20-40% of patients with COVID-19 admitted to the intensive care unit (ICU), and it is a complication that has been linked to increased morbidity and mortality. Neutrophil gelatinase-associated lipocalin (NGAL) is a biomarker of acute kidney injury.

Articles were searched from databases such as PubMed, Google Scholar, and Cochrane Library till June 2023. Pooled sensitivity, specificity, area under the curve (AUC), diagnostic odds ratio (DOR), and summery receiver operating curve (SROC) were calculated with 95% confidence interval. I2 statistics and Chi-square test were used to look for the heterogeneity in between studies. Meta-regression was conducted to look for the source of heterogeneity and GRADE analysis was performed to look for the certainty of evidence.

Altogether, eight studies were selected (4 serum/5 urine), out of which one study had both serum and urine NGAL data. The total sample size was 1,067 (349 serum/718 urine). For serum and urine NGAL, the pooled sensitivity was 0.79 (95% CI: 0.72-0.84) and 0.75 (95% CI: 0.68-0.80), pooled specificity was 0.87 (95% CI: 0.81-0.91) and 0.85 (95% CI: 0.77-0.91), DOR was 24 (95% CI: 14-43), and 17 (95% CI: 9-32) and AUC was 0.90 (95% CI: 0.87-0.92) and 0.80 (95% CI: 0.76-0.83), respectively.

Both serum and urine NGAL have favourable pooled sensitivity, specificity, DOR and AUC for the diagnosis of AKI in COVID-19 infection, however, with low certainty of evidence.

Altered immune response and cognitive difficulties have been demonstrated in studies of post-COVID syndrome, including differences in immune status and cognitive functioning in the months following infection. This review aimed to examine immune status and cognitive differences in post-COVID syndrome 12 or more weeks after COVID-19 infection. A further aim of this review was to explore a link between immune response and the cognitive deficits observed in this group.

A systematic review was carried out using PubMed, PsychInfo, EMBASE, and Web of Science electronic databases of observational studies 12+ weeks after COVID-19 infection, with assessment of immune status and cognitive function in post-COVID syndrome samples. This review protocol was recorded on PROSPERO with registration number CRD42022366920.

Following eligibility screening, 11 studies met inclusion criteria and were selected for our review. Six of eight studies that examined between-group differences in specific domains suggested impaired cognition in the post-COVID syndrome population, with the domain of executive function particularly affected. Of 11 studies with immune data, 7 studies reported increased markers of inflammation in the post-COVID syndrome group, when compared with an age- and sex-matched "healthy control" sample, or population norms. Finally, when immune function and cognition are examined together, 6 studies presented results indicating a significant association between elevated immune response and cognitive function in post-COVID syndrome.

This review highlights the frequency of cognitive difficulties months after COVID-19 infection and explores heightened immune response as a predictor of this change. Six studies suggest that immune status is a predictor of cognitive function, examining a marker of immune function and objective cognitive performance at 12 or more weeks following infection. Future studies of cognitive function in post-COVID syndrome are needed to explore this relationship and underlying mechanisms leading to changes in cognitive performance.

Immunomodulators tocilizumab and baricitinib have been used for the treatment of severe COVID-19, however, there are only few published studies comparing their efficacy.

All consecutive non-ICU hospitalized severe COVID-19 patients who received baricitinib or tocilizumab, were included retrospectively. Primary outcomes were mortality or intubation on day 14, time to oxygen therapy weaning and duration of hospitalization. Safety was measured as treatment-related adverse events.

321 hospitalized patients with severe COVID-19 were included (mean age 62.4 years ± 14.7); 241 (75.1%) received baricitinib (mean age 64.2 years ± 15.2) and 80 (24.9%) tocilizumab (mean age 57.3 ± 11.7). Patients who received baricitinib presented significantly lower risk of mortality or intubation on day 14, compared to the tocilizumab group after adjusting for age, sex, vaccination, Charlson comorbidity index, body mass index, remdesivir administration and WHO ordinal scale at enrollment (OR: 0.42, 95% CI: 0.20-0.86). In the augmented inverse-probability weighting regression, the protective role of baricitinib remained statistically significant (OR: 0.76, 95% CI: 0.66-0.88). No difference in secondary bacterial infections was detected, but tocilizumab was associated with significant higher rate of liver injury (Odds Ratio, 95%CI, p < 0.001).

Our study suggests survival and safety are significantly better for baricitinib compared to tocilizumab in severe COVID-19. Clinical randomized trials are needed for confirmation.

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/Objectives: COVID-19 is associated with multiple systemic effects, including cardiovascular complications. However, its interplay with cardiac conduction abnormalities remains underexplored. We compared the clinical profile of COVID-19 patients with pre-existing left bundle branch block (LBBB) or right bundle branch block (RBBB) at hospital admission. Methods: This study included 100 COVID-19 patients with antecedent BBB (50 LBBB, 50 RBBB). Critical cardiometabolic, renal, hematological, and inflammatory markers were measured. Logistic regression was used to identify key predictors differentiating COVID-19 patients with LBBB and RBBB. Spearman's correlations were applied to assess intra-strata associations for these variables. Results: COVID-19 patients with LBBB patients were significantly more likely to display lower systolic blood pressure (p = 0.012) but greater left atrial size (p = 0.008), left ventricular diameter (p = 0.001), and interventricular septal thickness (p = 0.023). Hematological and inflammatory markers differed, with LBBB patients being prone to exhibit higher red cell distribution width (p = 0.005), lymphocyte count (p < 0.001), neutrophil count (p = 0.045), and C-reactive protein (p < 0.001). This group also tended to show lower erythrocyte sedimentation rate (p = 0.013) and glycated hemoglobin (p = 0.045) but higher random glucose (p = 0.014). Absolute lymphocyte count, C-reactive protein, and left ventricular diameter were the most robust predictors distinguishing LBBB from RBBB. Significant associations were found exclusively for LBBB, all of them being weak. These predominantly negative relationships indicated an inflammatory origin, and most of them occurred for lymphocyte count. Conclusions: COVID-19 patients with LBBB and RBBB present distinct clinical profiles at hospital admission. The former group demonstrates a more adverse baseline clinical profile, particularly in terms of cardiac and inflammatory markers. These findings suggest that pre-existing BBB type may influence disease progression, potentially helping in risk stratification for COVID-19 patients.