In severe COVID-19 patients, excessive inflammation can lead to multiorgan dysfunction. Current anti-inflammatory treatments like glucocorticoids partially improve the outcomes, while immune systems are compromised. We have identified that SARS-CoV-2-infected obese mice were a good model of the cytokine storm seen in COVID-19. Here, we revealed that iguratimod (IGU), an approved agent for rheumatoid arthritis, improved survival by attenuating inflammation with minimal immune suppression. In this study, C57BL/6 mice were fed a high-fat diet (HFD) or a normal-fat diet (NFD) for ten weeks before being infected with a mouse-adapted SARS-CoV-2. IGU significantly improved survival rates and reduced lung inflammation in HFD-fed mice, with minimal impact on interferon-induced genes and viral load. Meanwhile, dexamethasone (DEX) did not improve survival, while it suppressed various immune reactions with different mechanisms to IGU. Interestingly, IGU-treated mice had fewer SARS-CoV-2 positive cells in the lung, although viral replication was comparable to the control mice. Neither IGU nor DEX inhibited the SARS-CoV-2 infection in Vero-E6 cells, unlike the antiviral agent, remdesivir. Of note, IGU was effective prophylactically and therapeutically in HFD mice, and showed beneficial effects in NFD-fed mice with a lethal dose exposure of SARS-CoV-2. We demonstrated that IGU could be a promising treatment for severe COVID-19, especially in obese patients, by fine-tuning inflammation without compromising antiviral immunity. This study supports the possibility of drug repositioning for IGU COVID-19 beyond autoimmune diseases.

Proinflammatory cytokines have been associated with poor prognosis in community-acquired and COVID-19 pneumonia. There is a paucity of reports on the cytokine release syndrome, also called cytokine storm in the Mexican population with pneumonia and COVID-19; therefore, our objective was to compare proinflammatory cytokine levels in Mexican patients without COVID-19 (non-COVID-19) and those with moderate, severe, and critical COVID-19 pneumonia.

This study included 30 patients with non-COVID-19 pneumonia and 57 with COVID-19 pneumonia. Disease diagnosis and severity were determined using the radiographic pulmonary edema assessment (RALE) score. Quantification of IL-6, IL-10, and TNF-α was performed using multiplex immunoassays. A receiver operating characteristic curve was constructed to classify subjects with elevated cytokine levels. Logistic regression was used to find associations between elevated cytokine levels and the presence of COVID-19 pneumonia.

The severity classification of patients with COVID-19 pneumonia was as follows: moderate (n = 20), severe (n = 19), and critical (n = 18). The proinflammatory cytokines IL-6 and IL-10 were significantly increased in COVID-19 patients compared to non-COVID-19 patients (p < 0.005), while TNF-α levels were lower in critically ill patients with COVID-19 pneumonia. High levels of IL-6 and IL-10, adjusted for age, sex, the presence of comorbidities, and the neutrophil-to-lymphocyte ratio (NLR), showed an elevated risk (OR IL-6 = 4.02; OR IL-10 = 9.36) of presenting pneumonia and COVID-19 compared to pneumonia without COVID-19 in patients. Likewise, 61% of COVID-19 patients with elevated proinflammatory cytokines (IL-6 and IL-10) had a fatal outcome.

Elevated levels of both IL-6 and IL-10 are a differential risk factor for developing COVID-19 pneumonia. These elevated levels were more frequently observed in Mexican COVID-19 pneumonia patients who died at the onset of the COVID-19 pandemic. It is important that they are monitored from initial diagnosis as they may be markers of a fatal outcome in severe and critical COVID-19 patients.

As new SARS-CoV-2 variants emerge and as treatment of COVID-19 ARDS remains exclusively supportive, there is an unmet need to better characterize its different phenotypes to tailor personalized treatments. Clinical, biological, spirometric and CT data hardly allow deciphering of Heavy (H), Intermediate (I) and Light (L) phenotypes of COVID-19 ARDS and the implementation of tailored specific strategies (prone positioning, PEEP settings, recruitment maneuvers). We hypothesized that the ratio of two pivotal COVID-19 biomarkers (interleukin 6 [IL-6] and Krebs von den Lungen 6 [KL-6], related to inflammation and pneumocyte repair, respectively) would provide a biologic insight into the disease timeline allowing 1) to differentiate H, I and L phenotypes, 2) to predict outcome and 3) to reflect some of CT findings.

This was a retrospective analysis of prospectively acquired data (COVID HUS cohort). Inclusion concerned any patient with severe COVID-19 pneumonia admitted to two intensive care units between March 1st and May 1st, 2020, in a high-density cluster of the first epidemic wave (Strasbourg University Hospital, France). Demographic, clinical, biological (standard, IL-6 [new generation ELISA], KL-6 [CLEIA technique]), spirometric (driving pressure, respiratory system compliance) and CT data were collected longitudinally. CT analysis included semi-automatic and automatic lung measurements and allowed segmentation of lung volumes into 4 (poorly aerated, non-aerated, overinflated and normally aerated) and 3 (ground-glass, restricted normally aerated, and overinflated) zones, respectively. The primary outcome was to challenge the IL-6/KL-6 ratio capacity to decipher the three COVID-19 ARDS phenotypes (H, I and L) defined on clinical, spirometric and radiologic grounds. Secondary outcomes were the analysis of the prognostic value of the IL-6/KL-6 ratio and its correlates with CT-acquired data. Multivariate analysis was based on principal component analysis. One hundred and forty-eight ventilated COVID-19 ICU patients from the COVID HUS cohort were assessed for eligibility and 77 were included in the full analysis. Most were male, all were under invasive mechanical ventilation and vasopressor therapy and displayed high severity scores (SAPSII: 48 [42-56]; SOFA: 8 [7-10]). The L, I and H COVID ARDS phenotypes were identified in 11, 15 and 48 patients, respectively. In three patients, the phenotype could not be defined precisely. Thirty patients (39%) died in the ICU and the number of ventilator-free days was 2 [0-2] days. The IL-6/KL-6 ratio was not significantly different between the L, I and H phenotypes and evolved according to similar patterns over time. Surviving and deceased patients displayed an inverse kinetic of KL-6. IL-6 and the IL-6/KL-6 ratio were linearly associated with ground-glass volume on semi-automatic and automatic CT lung measurements.

In our population of severe ventilated COVID ARDS patients, the IL-6/KL-6 ratio was not clue to differentiate the H, I and L phenotypes and tailor a personalized ventilatory approach. There was an interesting correlation between IL-6/KL-6 ratio and ground-glass volume as determined by automated lung CT analysis. Such correlation deserves more in-depth pathophysiological study, at best gathered from a prospective cohort with a larger sample size and histological analysis.

COVID HUS Trial registration number: NCT04405726.

Inflammation is a pathogenic driver of many diseases, including atherosclerosis and rheumatoid arthritis. Hyperinflammation can be seen as any inflammatory response that is deleterious to the host, regardless of cause. In medicine, hyperinflammation is defined as severe, deleterious, and fluctuating systemic or local inflammation with presence of a cytokine storm. It has been associated with rare autoinflammatory disorders. However, advances in omics technologies, including genomics, proteomics, and metabolomics, have revealed it to be more common, occurring in sepsis and severe coronavirus disease 2019. With a focus on proteomics, this review highlights the key role of omics in this shift. Through an exploration of research, we present how omics technologies have contributed to improved diagnostics, prognostics, and targeted therapeutics in the field of hyperinflammation. We also discuss the integration of advanced technologies, multiomics approaches, and artificial intelligence in analyzing complex datasets to develop targeted therapies, and we address their potential for revolutionizing the clinical aspects of hyperinflammation. We emphasize personalized medicine approaches for effective treatments and outline challenges, including the need for standardized methodologies, robust bioinformatics tools, and ethical considerations regarding data privacy. This review aims to provide a comprehensive overview of the molecular mechanisms underpinning hyperinflammation and underscores the potential of omics technologies in enabling successful clinical management.

This meta-analysis aimed to determine the efficacy of melatonin on mortality in patients with severe-to-critical illness COVID-19.

A systematic search was made of PubMed, Embase, Cochrane Library, and clinicaltrials.gov, without language restrictions. Randomized Controlled Trials (RCTs) on the treatment of severe-to-critical COVID-19 with melatonin, compared with placebo or blank, were reviewed. Studies were pooled to Odds Ratios (ORs), with 95 % Confidence Intervals (95 % CIs).

Three RCTs (enrolling 451 participants) met the inclusion criteria. Melatonin showed a significant effect on in-hospital mortality (OR = 0.19, 95 % CI 0.05 to 0.74; p = 0.02).

Melatonin significantly reduced in-hospital mortality in patients with severe-to-critical COVID-19. Melatonin should be considered for severe-to-critical COVID-19 patients.

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.

Pediatric sepsis remains the main cause of morbidity and mortality among children. Interleukin (IL)-6 is usually produced after infection, and elevated IL-6 levels may cause multisystemic damage. This study aimed to evaluate the effect of tocilizumab, an IL-6 receptor antibody, on children with septic shock.

We conducted a retrospective cohort study of children diagnosed with septic shock and admitted to the pediatric intensive care unit (PICU) between 2018 and 2024. Tocilizumab was administered within 24 h to patients with high IL-6 levels who developed refractory septic shock. Outcomes, including 28-day mortality, morbidity, length of PICU stay, and shock duration, were analyzed between septic children with different etiologies and differed treatments.

Fifty-four children with refractory septic shock were included. Patients treated with tocilizumab (n = 21) showed improved outcomes compared to those without tocilizumab (n = 33), including shorter PICU stays and lower mortality rates (14.2% vs. 54.5%, p = 0.03). Subgroup analysis revealed that in the non-hematologic group, tocilizumab-treated patients had a 0% mortality rate compared to 50% in untreated patients (p = 0.006). In the hematologic group, tocilizumab-treated patients exhibited a 27.2% mortality rate compared to 61.5% in untreated patients (p = 0.09). Trends in IL-6 levels (D1 to D7) were significantly higher in non-survivors compared to survivors and in patients with hematological malignancies compared to those without. No adverse events, including secondary infections or long-term liver impairment, were observed.

Tocilizumab appears to mitigate systemic inflammation and improve outcomes in children with refractory septic shock and elevated IL-6 levels. Further prospective studies are warranted to confirm these findings and establish treatment guidelines.

The COVID-19 pandemic has underscored the importance of understanding the interplay between the cardiovascular and immune systems during viral infections. SARS-CoV-2 enters human cells via the ACE-2 enzyme, initiating a cascade of immune responses. This study presents a coupled mathematical model that integrates the cardiovascular system (CVS) and immune system (IS), capturing their complex interactions during infection. The CVS model, based on ordinary differential equations, describes heart dynamics and pulmonary and systemic circulation, while the IS model simulates immune responses to SARS-CoV-2, including immune cell interactions and cytokine production. A coupling strategy transfers information from the IS to the CVS at specific intervals, enabling the exploration of immune-driven cardiovascular effects. Numerical simulations examined how these interactions influence infection severity and recovery. The coupled model accurately replicated the evolution of cardiac function in survivors and non-survivors of COVID-19. Survivors exhibited a left ventricular ejection fraction (LVEF) reduction of up to 25% while remaining within normal limits, whereas non-survivors showed a severe 4-fold decline, indicative of myocardial dysfunction. Similarly, the right ventricular ejection fraction (RV EF) decreased by approximately 50% in survivors but underwent a drastic 5-fold reduction in non-survivors. These findings highlight the model's capacity to distinguish differential cardiac dysfunction across clinical outcomes and its potential to enhance our understanding of COVID-19 pathophysiology.

The nature of the effector and memory T cell response in the lungs following acute SARS-CoV-2 infections remains largely unknown. To define the pulmonary T-cell response to COVID-19, we compared effector and memory T-cell responses to SARS-CoV-2 and influenza A virus (IAV) in mice. Both viruses elicited potent effector T cell responses in lungs, but memory T cells showed exaggerated contraction in SARS-CoV-2-infected mice. Specifically, unlike the T-bet/EOMES-driven effector transcription program in IAV lungs, SARS-CoV-2-specific CD8 T cells embarked on a STAT-3-centric transcriptional program, a defining characteristic of a pro-fibro-inflammatory program: limited cytotoxicity, diminished expression of tissue-protective inhibitory receptors (PD-1, LAG-3, and TIGIT), and augmented mucosal imprinting (CD103). Circulating CD45RO+HLA-DR+ CD8 T cells in hospitalized COVID-19 patients expressed elevated levels of STAT-3 and low levels of TIGIT. IL-6 blockade experiments implicated IL-6 in STAT-3 induction and downregulation of PD-1 expression on SARS-CoV-2-specific primary effector CD8 T cells. Memory CD8 T cells specific to a single epitope, induced by mucosal vaccination, differentiated into cytotoxic effectors and expressed high levels of CD103, effectively reducing viral burden in lungs following a breakthrough SARS-CoV-2 infection. Our findings have implications for developing targeted immunotherapies to mitigate immunopathology and promote protective T cell immunity to SARS-CoV-2.

Regulatory T cells (Tregs) play a crucial role in maintaining immune tolerance by suppressing immune responses against pathogens. The fluctuation of Treg proportions in COVID-19 remains a topic of debate, and the mechanisms triggering Treg activation in COVID-19 are still unclear. Understanding these issues is essential for better managing immune responses in COVID-19 patients.

We collected a cohort of COVID-19 patients with varying disease severity and stage to explore the transcriptomic and functional traits of Tregs in these individuals. Using transcriptomic analysis, we evaluated the proportion and functionality of different Treg subsets, specifically HLA_DR+ Tregs, across different stages of COVID-19 patients.

Our analysis revealed that the proportion of CCR7 + Tregs decreased as the disease advanced, while the cell proportion of HLA_DR+ regs escalated with the severity of the disease. Moreover, the transcription actor CARHSP1 exhibited apositive correlation with the proportion of HLA_DR+ Tregs. Notably, the heightened suppressive function of HLA_DR+ Tregs in severe COVID-19 patients, with interactions between PF4 and CXCR3, contributed to the homeostasis of HLA_DR+ Tregs in severe COVID-19 patients. Furthermore, we observed that Tregs in COVID-19 patients exhibited weakened TCR clonotype expansion, and the suppression of HLA_DR+ Tregs with expanded TCR clonotypes in severe COVID-19 cases did not show a significant increase compared to asymptomatic and mild COVID-19 groups. The findings indicate that Tregs may be activated through the bystander effect, as evidenced by the analysis of TCR clonotype characteristics.

Our research delineates the diversity of dynamic alterations in Tregs and sheds light on potential mechanisms underlying Treg activation, providing a theoretical foundation and offering treatment strategies for managing COVID-19 patients.

The SARS-CoV-2 virus (termed COVID-19) was responsible for over 34 million global deaths. Although the COVID-19 pandemic has subsided, infection by emerging mutant variants of SARS-CoV-2 poses a continuing threat to public health. COVID-19 infection has been associated with the development of cytokine storm syndrome, hypercoagulability, immunological dysregulation and direct viral invasion of organs, and the long-term consequences for the health of COVID-19 survivors are currently unknown. Our research focuses on the possible mutagenic aspects of infection by COVID-19 and measures their harmful effects on DNA composition. DNA damage was investigated, using the comet assay method, during two periods: in the epidemic peak of COVID-19 and during the post-COVID-19 period, both in patients infected with COVID-19 and in those with influenza. During the epidemic peak, the levels of DNA damage ranged from the highest to the lowest levels in the following groups, respectively: intubated-ICU, non-intubated-ICU, non-ICU, and influenza, with a discernible increase in DNA damage in ICU-treated patients. The levels of DNA damage in the post-COVID-19 period were significantly lower compared to those in the epidemic peak period but there was still a discernible increase in DNA damage in the ICU group. Our results indicate that levels of DNA damage may be an effective indicator in prognostic decision-making and may therefore help to reduce mortality. Given that DNA damage and impaired repair processes can contribute to chronic diseases like diabetes, cancer, and neurodegenerative conditions, it will be crucial to investigate potential similar effects in patients with COVID-19.

The clinical manifestations of the cytokine storm (CS) associated with COVID-19 resemble the acute phase of sepsis. Metabolomics may contribute to understanding the specific pathobiology of these two syndromes. The aim of this study was to compare serum metabolomic profiles in CS associated with COVID-19 vs. septic surgery patients. In a retrospective cross-sectional study, serum samples from patients with CS associated with COVID-19, with and without comorbidity, as well as serum samples from patients with surgical sepsis were investigated. Targeted metabolomic analysis was performed on all samples using LC-MS/MS. Analysis revealed that similar alterations in the serum metabolome of patients with COVID-19 and surgical septic patients were associated with amino acid metabolism, nitrogen metabolism, inflammatory status, methionine cycle and glycolysis. The most significant difference was found for serum levels of metabolites of kynurenine synthesis, tricarboxylic acid cycle, gamma-aminobutyric acid and niacinamide. The metabolic pathway of cysteine and methionine metabolism was significantly disturbed in COVID-19 and surgical septic patients. For the first time, the similarities and differences between the serum metabolomic profiles of patients with CS associated with COVID-19 and patients with surgical sepsis were investigated for patients from the Northwest of the Russian Federation.

Coronavirus disease 2019 (COVID-19), caused by infection with the enveloped RNA betacoronavirus, SARS-CoV-2, led to a global pandemic involving over 7 million deaths. Macrophage inflammatory responses impact COVID-19 severity; however, it is unclear whether macrophages are infected by SARS-CoV-2. We sought to identify mechanisms regulating macrophage expression of ACE2, the primary receptor for SARS-CoV-2, and to determine if macrophages are susceptible to productive infection. We developed a humanized ACE2 (hACE2) mouse whereby hACE2 cDNA was cloned into the mouse ACE2 locus under control of the native promoter. We validated the susceptibility of hACE2 mice to SARS-CoV-2 infection relative to wild-type mice and an established K18-hACE2 model of acute fulminating disease. Intranasal exposure to SARS-CoV-2 led to pulmonary consolidations with cellular infiltrate, edema, and hemorrhage, consistent with pneumonia, yet unlike the K18-hACE2 model, hACE2 mice survived and maintained stable weight. Infected hACE2 mice also exhibited a unique plasma chemokine, cytokine, and growth factor inflammatory signature relative to K18-hACE2 mice. Infected hACE2 mice demonstrated evidence of viral replication in infiltrating lung macrophages, and infection of macrophages in vitro revealed a transcriptional profile indicative of altered RNA and ribosomal processing machinery as well as activated cellular antiviral defense. Macrophage IL-1β-driven NF-κB transcription of ACE2 was an important mechanism of dynamic ACE2 upregulation, promoting macrophage susceptibility to infection. Experimental models of COVID-19 that make use of native hACE2 expression will allow for mechanistic insight into factors that can either promote host resilience or increase susceptibility to worsening severity of infection.

Continuous monitoring of acute inflammation can become a very important next step for guiding therapeutic interventions in severely ill patients. This Perspective discusses the current medical need for patients with acute inflammatory diseases and the potential of continuous biosensing technologies. First, we discuss biomarkers that could help to monitor the state of a patient with acute systemic inflammation based on theoretical studies and empirical data. Then, based on the state of the art, we describe sensing strategies that could be applied for the continuous monitoring of acute inflammatory biomarkers, followed by challenges that must be overcome. Nanoswitch-based continuous biosensors enable suitable measurement frequencies but still lack sensitivity, while regeneration risks lower sensor reliability. Developments are still needed in bioreceptors and molecular architectures, regeneration techniques, combined with suitable sampling and sample pretreatment methods, for bringing continuous biosensing of inflammation closer to reality. Furthermore, collaborations between healthcare professionals and scientists, regulatory bodies, and biosensor engineers are needed for a successful translation of sensing technologies from the laboratory to clinical practice.

The COVID-19 pandemic has left an indelible mark globally, presenting numerous challenges to public health. This crisis, while disruptive and impactful, has provided a unique opportunity to gather precious clinical data extensively. In this observational, case-control study, we utilized data collected at the Azienda Sanitaria Universitaria Friuli Centrale, Italy, to comprehensively characterize the immuno-inflammatory features in COVID-19 patients. Specifically, we employed multicolor flow cytometry, cytokine assays, and inflammatory biomarkers to elucidate the interplay between the infectious agent and the host's immune status. We characterized immuno-inflammatory profiles within the first 72 hours of hospital admission, stratified by age, disease severity, and time elapsed since symptom onset. Our findings indicate that patients admitted to the hospital shortly after symptom onset exhibit a distinct pattern compared to those who arrive later, characterized by a more active immune response and heightened cytokine activity, but lower markers of tissue damage. We used univariate and multivariate logistic regression models to identify informative markers for outcome severity. Predictors incorporating the immuno-inflammatory features significantly outperformed standard baselines, identifying up to 59% of patients with positive outcomes while maintaining a false omission rate as low as 4%. Overall, our study sheds light on the immuno-inflammatory aspects observed in COVID-19 patients prior to vaccination, providing insights for guiding the clinical management of first-time infections by a novel virus.

Acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) is associated with high morbidity and mortality in the intensive care unit (ICU) and can cause excessive inflammation. Dexmedetomidine (DEX) is a drug that exerts anti-inflammatory effects. Identifying the anti-inflammatory mechanism of DEX in the context of ALI/ARDS possesses potential significance for the prevention and treatment of ARDS. In this study, DEX was used to treat mouse models of cecal ligation and puncture (CLP) and lipopolysaccharide (LPS)-stimulated cells. Immunofluorescence, western blot analysis, and flow cytometry were used to detect macrophage phenotypic markers in mice, and western blot analysis, real-time qPCR (RT-qPCR), ELISA, and immunofluorescence were used to detect macrophage phenotype markers in RAW264.7 cells. Flow cytometry was used to detect phenotypic markers of bone marrow-derived macrophages (BMDM). Culture medium collected from macrophages was used to cultivate human non-small cell adenocarcinoma epithelial cells (A549) to detect their aquaporins 1 (AQP1) expression and apoptosis status. Western blot analysis was used to detect the activation of the AMP-activated protein kinase (AMPK)/sirtuin 1(SIRT1) signaling pathway both in vivo and in vitro. The regulatory effect of DEX on macrophage phenotype remodeling was detected by knocking down AMPK expression in cells using AMPK shRNA. The results showed that in both in vivo and in vitro experiments, DEX downregulated the expression of M1 markers (tumor necrosis factor-α [TNF-α], nitric oxide synthase [iNOS], and cluster of differentiation [CD]-86) and upregulated the expression of M2 markers (arginase-1 [ARG-1], interleukin [IL]-10, and CD206) in macrophages. The culture medium of macrophages treated with DEX alleviated the edema and apoptosis of A549 cells. DEX activates the AMPK/SIRT1 signaling pathway in macrophages. After AMPK knockdown, the ability of DEX to regulate macrophage phenotype remodeling decreased. Together, this study suggests that DEX regulates macrophage phenotype remodeling by activating the AMPK/SIRT1 pathway, thereby reducing ALI/ARDS.

Toll-like receptors (TLRs) of human are considered as the most critical immunological mediators of inflammatory pathogenesis of COVID-19. These immunoregulatory glycoproteins are located on the surface and/or intracellular compartment act as innate immune sensors. Upon binding with distinct SARS-CoV-2 ligand(s), TLRs signal activation of different transcription factors that induce expression of the proinflammatory mediators that collectively induce 'cytokine storm'. Similarly, TLR activation is also pivotal in conferring protection to infection and invasion as well as upregulating the tissue repair pathways. This dual role of the human TLRs in deciding the fate of SARS-CoV-2 has made these receptor proteins as the critical mediators of immunoprotective and immunopathogenic consequences associated with COVID-19. Herein, pathbreaking discoveries exploring the immunobiological importance of the TLRs in COVID-19 and developing TLR-directed therapeutic intervention have been reviewed by accessing the up-to-date literatures available in the public domain/databases. In accordance with our knowledge in association with the importance of TLRs' role against viruses and identification of viral particles, they have been recognized as suitable candidates with high potential as vaccine adjuvants. In this regard, the agonists of TLR4 and TLR9 have effective potential in vaccine technology while the others need further investigations. This comprehensive review suggests that basal level expression of TLRs can act as friends to keep our body safe from strangers but act as a foe via overexpression. Therefore, selective inhibition of the overexpressed TLRs appears to be a solution to counteract the cytokine storm while TLR-agonists as vaccine adjuvants could lessen the risk of infection in the naïve population.

Background/Objectives: SARS-CoV-2 was responsible for the global pandemic. Approximately 10-15% of patients with COVID-19 developed respiratory failure with adult acute respiratory distress syndrome (ARDS), which required treatment in the Intensive Care Unit (ICU). The cytokine storm observed in severe COVID-19 was frequently handled with steroids. Synergically, tocilizumab, an anti-interleukin-6 receptor monoclonal antibody, gained popularity as a cytokine storm-suppressing agent. However, immunosuppression was proven to increase the predisposition to infections with resistant bacteria. Our study aimed to assess the relationship between positive tests for secondary infections and the survival of patients with severe COVID-19-attributed ARDS treated with immunosuppressive agents. Methods: This study included 342 patients qualified for the ICU and mechanical ventilation (MV). The patients were divided based on the type of immunomodulating therapy and the culture tests results. Results: The results showed the highest survival rate among patients <61 years, favoring the combined treatment (tocilizumab + steroids). Atrial fibrillation (AF) and coronary heart disease (CHD) correlated with a lower survival rate than other comorbidities. Tocilizumab was associated with an increased risk of positive pathogen cultures, which could potentially cause secondary infections; however, the survival rate among these patients was higher. Conclusions: MV and ICU procedures as well as the application of tocilizumab significantly decreased the mortality rate in patients with severe COVID-19-related ARDS. The suppression of cytokine storms played a crucial role in survival. Tocilizumab was found to be both efficient and safe despite the 'side effect' of the increased risk of positive results for secondary infections.

Severe COVID-19 is associated with a generalized inflammatory response leading to peripheral and organ perfusion disorders. Objectives: This study aimed to evaluate the usefulness of peripheral and organ perfusion assessments in the prediction of prognosis and mortality in patients with severe COVID-19. Patients and Methods: In the first 48 h of hospitalization, peripheral perfusion (saturation, Finger Infrared Thermography-FIT; Capillary Refill Time-CRT), and the color Doppler renal cortex perfusion (RCP) were estimated in a group of 102 severe COVID-19 patients. Results: In total, 40 patients experienced deterioration and required intensification of oxygen treatment, and 24 finally died. In comparison with a stable course of the disease, patients with deterioration had initially higher WBC, CRP, AST, LDH, and CRT, but a lower oxygenation ratio and RCP. Deceased patients were older, had higher CRP, LDH, and CRT, but lower hemoglobin, oxygenation ratio, and RCP compared to survivors. In the multivariable regression analysis from perfusion parameters, only RCP and CRT were independently linked with deterioration (OR 0.002, p < 0.001; OR 1.825, p = 0.003, respectively) and death (OR 0.001, p = 0.004; OR 1.910, p = 0.003, respectively). Conclusions: Initial assessment of peripheral and organ perfusion can be helpful in identifying hospitalized severe COVID-19 patients with a higher risk of deterioration and death. Capillary Refill Time and Renal Cortical Perfusion were prognostic markers of deterioration or death. On the other hand, Finger Infrared Thermography and saturation were not statistically significant in predicting patient outcome. An RCP cut-off value below 0.127 and 0.112 [cm/s] and a Capillary Refill Time longer than 3.25 and 4.25 [s] indicate the risk of deterioration or death, respectively.

To investigate the serum IL-6 levels and their rate of change in predicting the mortality of critically ill patients with COVID-19 in Vietnam.

A single-centre, cross-sectional study.

An Intensive Care Centre for the Treatment of Critically Ill Patients with COVID-19 in Ho Chi Minh City, Vietnam.

We included patients aged 18 years or older who were critically ill with COVID-19 and presented to the study centre from 30 July 2021 to 15 October 2021. We excluded patients who did not have serum IL-6 measurements between admission and the end of the first day.

The primary outcome was hospital all-cause mortality.

Of 90 patients, 41.1% were men, the median age was 60.5 years (Q1-Q3: 52.0-71.0), and 76.7% of patients died in the hospital. Elevated IL-6 levels were observed on admission (41.79 pg/mL; Q1-Q3: 20.68-106.27) and on the third day after admission (72.00 pg/mL; Q1-Q3: 26.98-186.50), along with a significant rate of change in IL-6 during that period (839.5%; SD: 2753.2). While admission IL-6 level (areas under the receiver operator characteristic curve (AUROC): 0.610 (95% CI: 0.459 to 0.761); cut-off value ≥15.8 pg/mL) and rate of change in IL-6 on the third day of admission (AUROC: 0.586 (95% CI: 0.420 to 0.751); cut-off value ≥-58.7%) demonstrated poor discriminatory ability in predicting hospital mortality, the third day IL-6 rate of change from admission ≥-58.7% (adjusted OR: 12.812; 95% CI: 2.104 to 78.005) emerged as an independent predictor of hospital mortality.

This study focused on a highly selected cohort of critically ill COVID-19 patients with a high IL-6 level and mortality rate. Despite the poor discriminatory value of admission IL-6 levels, the rate of change in IL-6 proved valuable in predicting mortality. To identify critically ill COVID-19 patients with the highest risk for mortality, monitoring the serial serum IL-6 measurements and observing the rate of change in serum IL-6 levels over time are needed.

Various studies have observed an association between interleukin-6 (IL-6), serum ferritin, d-dimer, and in-hospital mortality in COVID-19 patients. However, multivariate regression analysis was not done in the majority of the studies, Also, the role of interleukin-6 (IL-6), serum ferritin, and d-dimer in hospitalized COVID-19 patients was not adequately studied and reported from our region.

It was a retrospective cohort study in which the serum IL-6, serum ferritin, and d-dimer of 305 hospitalized COVID-19 patients were analyzed, and their association with mortality was determined.

In COVID-19 patients, the levels of IL-6 (P = 0.007), serum ferritin (P = 0.011), and d-dimer (P = 0.004) were significantly elevated in patients with severe SARS-CoV-2 illness (SpO2 < 90 % at admission). IL-6 levels were significantly elevated (186 pg/ml vs. 215 pg/ml, P = 0.003) in non-survivors compared to survivors. However, d-dimer (mg/ml) (P = 0.129) and serum ferritin (mg/ml) (P = 0.051) levels were similar between the two groups. The ROC curve (receiver operating characteristic curve) analysis showed a significant but poor area under the curve (AUC) between elevated IL-6 (>208 pg/ml) and in-hospital mortality (P < 0.008, AUC = 0.61). Kaplan-Meir survival analysis showed poor survival in patients with elevated IL-6 (>208 pg/ml) (Pby log-rank: 0.010) and elevated d-dimer (>1780 mg/ml) (P by log-rank: 0.036). The multivariate cox-regression analysis did not show any association between IL-6, serum ferritin, d-dimer, and in-hospital mortality (P > 0.05). Also, no association was found between serum levels of IL-6, serum ferritin, d-dimer, and the use of a ventilator (P > 0.05) and the severity of SARS-CoV-2 illness (P > 0.05) on multivariate binary logistic regression analysis.

In this study, the serum levels of IL-6, serum ferritin, and d-dimer were not associated with in-hospital mortality in hospitalized COVID-19 patients on multivariate cox-regression analysis, and were the markers of severe SARS-CoV-2 illness.

Several novel high-dimensional biologic measurements are increasingly being applied to biomedical sciences. Acute respiratory distress syndrome (ARDS) is a theoretically fertile ground for such approaches. Not only are these biologic and analytic tools available to better understand ARDS but also arguably, simpler approaches such as respiratory physiology has been vastly underutilized as a means of delivering precision-based care in the field. Here we review the progress made in ARDS toward discovering biologically homogeneous phenotypes, treatment responsive subgroups, the challenges to implement these discoveries at the bedside, and the road ahead that will enable precision medicine in ARDS.

This review explores the neuroinflammatory pathways underlying COVID-19-induced central nervous system (CNS) injury, with a focus on mechanisms of brain damage and strategies for prevention. A comprehensive literature review was conducted to summarize current knowledge on the pathways by which SARS-CoV-2 reaches the brain, the neuroinflammatory responses triggered by viral infection, neurological symptoms and long COVID. Results: We discuss the mechanisms of neuroinflammation in COVID-19, including blood-brain barrier disruption, cytokine storm, microglial activation, and peripheral immune cell infiltration. Additionally, we highlight potential strategies for preventing CNS injury, including pharmacological interventions, immunomodulatory therapies, and lifestyle modifications. Conclusively, Understanding the neuroinflammatory pathways in COVID-19-induced CNS injury is crucial for developing effective prevention and treatment strategies to protect brain health during and after viral infection.

Baseline IL-6 levels have been found to be non-predictive of subsequent outcomes following tocilizumab treatment, highlighting the need for more reliable predictive markers. To address this, a retrospective analysis was conducted on the clinical profiles, diagnostic tests, and follow-up prognoses of 60 patients with severe or critical COVID-19, all of whom were identified as experiencing a cytokine storm and subsequently received tocilizumab treatment. Among the patients, the overall survival rate during follow-up was 80%, with further analysis revealing that advanced age was an independent risk factor for adverse outcomes. Following tocilizumab administration, a statistically significant increase in IL-6 and D-dimer levels was observed, while markers such as C-reactive protein (CRP), procalcitonin (PCT), and fibrinogen demonstrated reductions compared to pre-treatment values. Specifically, IL-6 levels initially surged briefly after tocilizumab intervention before gradually diminishing. To assess the prognostic utility of IL-6, the Receiver Operating Characteristic (ROC) curve was employed, which yielded an area under the curve (AUC) of 0.812, indicating strong predictive capability, with a sensitivity of 100% and a specificity of 53.49%. The optimal cut-off value for IL-6 was identified at 147.79 pg/mL. In conclusion, IL-6 levels tend to rise transiently following tocilizumab therapy, before gradually declining. These post-treatment IL-6 measurements may serve as a valuable biomarker for assessing prognosis in patients undergoing this treatment.

The soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I cell injury associated with outcomes in COVID-19 pneumonia. How plasma sRAGE changes over time and whether it remains associated with long-term clinical outcomes beyond a single measurement in COVID-19 have not been well studied. We studied two cohorts in randomized clinical trials of monoclonal antibody treatment for COVID-19 (bamlanivimab and tixagevimab/cilgavimab). We first studied the association between baseline plasma sRAGE and 90-day clinical outcomes, which had been previously demonstrated in the bamlanivimab cohort, among hospitalized patients with COVID-19 supported with high-flow nasal oxygen (HFNO) or noninvasive ventilation (NIV) in the tixagevimab/cilgavimab study. Next, we investigated the relationship between day 3 sRAGE and 90-day outcomes and how plasma sRAGE changes over the first 3 days of hospitalization in both clinical trial cohorts. We found that plasma sRAGE in the highest quartile in the HFNO/NIV participants in the tixagevimab/cilgavimab trial was associated with a significantly lower rate of 90-day sustained recovery [recovery rate ratio = 0.31, 95% confidence interval (CI) = 0.14-0.71, P = 0.005] and with a significantly higher rate of 90-day mortality (hazard ratio = 2.49, 95% CI = 1.15-5.43, P = 0.021) compared with the lower three quartiles. Day 3 plasma sRAGE in both clinical trial cohorts remained associated with 90-day clinical outcomes. The trajectory of sRAGE was not influenced by treatment assignment. Our results indicate that plasma sRAGE is a valuable prognostic marker in COVID-19 up to 3 days after initial hospital presentation.NEW & NOTEWORTHY The soluble receptor for advanced glycation end-products (sRAGE) is a marker of alveolar type I epithelial cell injury associated with clinical outcomes in acute respiratory distress syndrome and, more recently, in hospitalized subjects with COVID-19. How plasma sRAGE changes over time and whether plasma sRAGE remains associated with long-term clinical outcomes beyond a single baseline measurement in patients with COVID-19 have not been well studied.

To investigate the big data characteristics and trend changes of patients with allergic rhinitis (AR) who sought medical attention at our hospital before (from 2018 to 2019) and after (from 2020 to 2023) COVID-19, and provide reference basis for the treatment of AR. This study used a descriptive epidemiological method to analyze the big data and trend changes of AR patients. A total of 62,196 AR patients were collected, of whom 32,874 were male and 29,322 were female, with an age range of 1-89 years. The monthly change trend of AR patients showed a marked seasonality. The number of AR patients increased year by year. There was no significant difference in the number of patients between different genders. There was a significant difference in the number of patients between different age groups. The number of AR patients increased markedly from 2018 to 2023, and COVID-19 seems to have accelerated this process. There is a clear seasonal pattern. The number of boy patients is significantly higher than that of girl patients, and the change in female hormones may affect the incidence of AR. Therefore, it is necessary to update management measures and formulate relevant policies in response to the changing trend of AR since the COVID-19 epidemic.

Acute lung injury (ALI) is a severe inflammatory syndrome, which was caused by diverse factors. The COVID-19 pandemic has resulted in a higher mortality rate of these conditions. Currently, effective treatments are lacking. Although siRNA nucleotide-based drugs are promising therapeutic approaches, their poor stability and inability to efficiently reach target cells limit their clinical translation. This study identified a peptide from known cell-penetrating peptides that can form an efficient anti-inflammatory complex with TNF-α siRNA, termed SAR6EW/TNF-α siRNA. This complex can effectively transport TNF-α siRNA into the cytoplasm and achieve potent gene silencing in vitro as well as in vivo. By using lactose and triarginine as coexcipients and optimizing the spray-drying process, a powder was produced with micrometer-scale spherical and porous structures, enhancing aerosol release and lung delivery efficiency. The dry powder formulation and process preserve the stability and integrity of the siRNA. When administered intratracheally to ALI model mice, the complex powder demonstrated specific pulmonary gene silencing activity and significantly reduced inflammation symptoms caused by ALI, suggesting a potential strategy for the clinical therapeutic approach of respiratory diseases.

We examined candidate biomarkers for efficacy outcomes in hospitalized COVID-19 patients who were treated with sirukumab, an IL-6 neutralizing antibody, in a randomized, double-blind, placebo-controlled, phase 2 trial. Between May 2020 and March 2021, 209 patients were randomized (sirukumab, n = 139; placebo, n = 70); 112 had critical COVID-19. Serum biomarkers were evaluated for the pharmacodynamic effect of sirukumab and for their potential prognostic and predictive effect on time to sustained clinical improvement up to Day 28, clinical improvement at Day 28, and mortality at Day 28. The absence of detectable IL-4 increase and smaller increases in CCL13 post-baseline were most significantly associated with better response to sirukumab (versus placebo) treatment for all clinical efficacy outcomes tested, especially in patients with critical COVID-19. These data suggest that patients with critical COVID-19 without detectable sirukumab-induced IL-4 levels are more likely to benefit from sirukumab treatment. ClinicalTrials.gov Identifier: NCT04380961.

Endothelin-1 (ET-1) is a potent vasoconstrictor produced by endothelial cells and cleared from circulating blood mainly in the pulmonary vasculature. In a healthy pulmonary circulation, the rate of local production of ET-1 is less than its rate of clearance. In the present study, we aimed to investigate whether the abnormal pulmonary circulatory handling of ET-1 relates to poor clinical outcomes in patients with coronavirus disease 2019 (COVID-19)-induced acute respiratory distress syndrome (ARDS). To this end, central venous and systemic arterial ET-1 plasma levels were simultaneously measured on Days 1 and 3 following ICU admission in mechanically ventilated COVID-19 patients with ARDS (COVID-19 ARDS, N = 18). Central venous and systemic arterial ET-1 plasma levels were also measured in two distinct SARS-CoV-2-negative mechanically ventilated critically ill patient groups, matched for age, sex, and critical illness severity, with ARDS (non-COVID-19 ARDS, N = 14) or without ARDS (non-COVID-19 non-ARDS, N = 20). Upon ICU admission, COVID-19-induced ARDS patients had higher systemic arterial and central venous ET-1 levels compared to the non-COVID-19 ARDS and non-COVID-19 non-ARDS patients (p < 0.05), yet a normal systemic arterial:central venous (A:V) ET-1 ratio [0.63 (0.49-1.02)], suggesting that pulmonary ET-1 clearance is intact in these patients. On the other hand, the non-COVID-19 ARDS patients demonstrated abnormal ET-1 handling [A:V ET-1 ratio 1.06 (0.93-1.20)], while the non-COVID-19 non-ARDS group showed normal ET-1 handling [0.79 (0.52-1.11)]. On Day 3, the A:V ratio in all three groups was <1. When the COVID-19 ARDS patients were divided based on 28-day ICU mortality, while their systemic arterial and central venous levels did not differ, the A:V ET-1 ratio was statistically significantly higher upon ICU admission in the non-survivors [0.95 (0.78-1.34)] compared to the survivors [0.57 (0.48-0.92), p = 0.027]. Our results highlight the potential importance of ET-1 as both a biomarker and a therapeutic target in critically ill COVID-19 patients. The elevated A:V ET-1 ratio in non-survivors suggests that the early disruption of pulmonary ET-1 handling may be a key marker of poor prognosis.

COVID-19 is characterized by pronounced hypercytokinemia. The cytokine switch, marked by an imbalance between pro-inflammatory and anti-inflammatory cytokines, emerged as a focal point of investigation throughout the COVID-19 pandemic. However, the kinetics and temporal dynamics of cytokine release remain contradictory, making the development of new therapeutics difficult, especially in severe cases. This study collected serum samples from SARS-CoV-2 infected patients at 72 h intervals and monitored them for various cytokines at each timepoint until hospital discharge or death. Cytokine levels were analyzed based on time since symptom onset and patient outcomes. All cytokines studied prospectively were strong predictors of mortality, particularly IL-4 (AUC = 0.98) and IL-1β (AUC = 0.96). First-timepoint evaluations showed elevated cytokine levels in the mortality group (p < 0.001). Interestingly, IFN-γ levels decreased over time in the death group but increased in the survival group. Patients who died exhibited sustained levels of IL-1β and IL-4 and increased IL-6 levels over time. These findings suggest cytokine elevation is crucial in predicting COVID-19 mortality. The dynamic interplay between IFN-γ and IL-4 highlights the balance between Th1/Th2 immune responses and underscores IFN-γ as a powerful indicator of immune dysregulation throughout the infection.

Even though the use of SARS-CoV-2 vaccines during the COVID-19 pandemic showed unprecedented success in a short time, it also exposed a flaw in the current vaccine design strategy to offer broad protection against emerging variants of concern. However, developing broad-spectrum vaccines is still a challenge for immunologists. The development of universal vaccines against emerging pathogens and their variants appears to be a practical solution to mitigate the economic and physical effects of the pandemic on society. Very few reports are available to explain the basic concept of universal vaccine design and development. This review provides an overview of the innate and adaptive immune responses generated against vaccination and essential insight into immune mechanisms helpful in designing universal vaccines targeting influenza viruses and coronaviruses. In addition, the characteristics, safety, and factors affecting the efficacy of universal vaccines have been discussed. Furthermore, several advancements in methods worthy of designing universal vaccines are described, including chimeric immunogens, heterologous prime-boost vaccines, reverse vaccinology, structure-based antigen design, pan-reactive antibody vaccines, conserved neutralizing epitope-based vaccines, mosaic nanoparticle-based vaccines, etc. In addition to the several advantages, significant potential constraints, such as defocusing the immune response and subdominance, are also discussed.