To explore the potential impact of the coronavirus disease 2019 (COVID-19) pandemic on the epidemiology of small-cell lung cancer (SCLC).

SCLC patients were collected from the Surveillance, Epidemiology, and End-Results (SEER) database (diagnosed between 2018 and 2021) and grouped according to the timing of the COVID-19 pandemic. Intergroup comparisons and survival analyses were performed on clinicopathologic characteristics and survival data to explore the differences in morbidity characteristics and survival in SCLC patients before and after the pandemic.

SCLC Patients diagnosed in the post-COVID-19 pandemic tended to have earlier tumor stage, receive chemotherapy (OR 1.14, 95% CI 1.02-1.27, P-value = 0.02) rather than radiotherapy (OR 0.89, 95% CI 0.84-0.96, P-value < 0.01), and have increased time to treatment delay. Balancing follow-up time and constructing improved survival curves, patients with SCLC diagnosed after the pandemic tended to have a worse prognosis.

Differences in some clinicopathologic factors and treatment choices, or the pandemic itself, may result in a tendency for patients with SCLC diagnosed after the pandemic to have a worse prognosis, alerting clinicians to the need to focus on the management and treatment of this population.

This study investigated new incident clinical disorders in patients with COVID-19-related hyperinflammatory syndrome (cHIS) 3.5 years post infection. We analyzed 14,335 patients hospitalized with COVID-19 from March-2020 to July-2023. cHIS was defined based on a point system that included elevated body temperature, macrophage activation, hematological dysfunction, coagulopathy, and hepatic enzyme. Outcomes were newly diagnosed disorders of hypertension, diabetes, cardiovascular diseases, chronic kidney disease (CKD), chronic obstructive pulmonary disease (COPD), and asthma post COVID-19. Cumulative incidences and hazard ratios were computed. Compared to non-cHIS patients, cHIS patients were older, fewer female, more Blacks, higher prevalence of pre-existing comorbidities. Patients with cHIS had higher risk of developing cardiovascular disease (HR = 1.24 [1.04,1.47] p < 0.05), CKD (1.24 [1.01, 1.53] p < 0.05), and obesity (1.61 [1.31,1.98], p < 0.001) but not hypertension, diabetes, COPD, and asthma. Cumulative incidence analysis showed that patients ≥ 50 years old showed markedly higher new incidences of individual new disorders compared to patients < 50 years old. COVID-19 related hyperinflammatory syndrome confers a significantly higher risk for developing new common clinical disorders. Identifying risks for developing new clinical disorders in patients with COVID-19 related hyperinflammatory syndrome may encourage diligent follow-up of high-risk individuals.

Dysregulated neutrophil recruitment drives many pulmonary diseases, but most preclinical screening methods are unsuited to evaluate pulmonary neutrophilia, limiting progress toward therapeutics. Namely, high-throughput therapeutic assays typically exclude critical neutrophilic pathophysiology, including blood-to-lung recruitment, dysfunctional activation, and resulting impacts on the air-blood barrier. To meet the conflicting demands of physiological complexity and high throughput, we developed an assay of 96-well leukocyte recruitment in an air-blood barrier array (L-ABBA-96) that enables in vivo-like neutrophil recruitment compatible with downstream phenotyping by automated flow cytometry. We modeled acute respiratory distress syndrome (ARDS) with neutrophil recruitment to 20 ng/mL epithelial-side interleukin 8 and found a dose-dependent reduction in recruitment with physiologic doses of baricitinib, a JAK1/2 inhibitor recently Food and Drug Administration-approved for severe Coronavirus Disease 2019 ARDS. Additionally, neutrophil recruitment to patient-derived cystic fibrosis sputum supernatant induced disease-mimetic recruitment and activation of healthy donor neutrophils and upregulated endothelial e-selectin. Compared to 24-well assays, the L-ABBA-96 reduces required patient sample volumes by 25 times per well and quadruples throughput per plate. Compared to microfluidic assays, the L-ABBA-96 recruits two orders of magnitude more neutrophils per well, enabling downstream flow cytometry and other standard biochemical assays. This novel pairing of high-throughput in vitro modeling of organ-level lung function with parallel high-throughput leukocyte phenotyping substantially advances opportunities for pathophysiological studies, personalized medicine, and drug testing applications.

Measles, hepatitis C, and COVID-19 are significant human diseases caused by RNA viruses. While vaccines exist to prevent infections, there are a small number of currently available therapeutic agents that can effectively treat these diseases after infection occurs. This study explores a new therapeutic strategy using a small molecule designated polyprenyl immunostimulant (PI) to increase innate immune responses and combat viral infections. Using a multi-disciplinary approach, this study quantifies the effects of PI in mice and THP-1 cells using flow cytometry to identify immune phenotypic markers and mass spectroscopy to monitor the metabolomic profiles of immune cells perturbed by PI treatment. The metabolomic studies identified that sphinganine and ceramide, which are precursors of sphingosine-1-phosphate (S1P), were the common metabolites upregulated in THP-1 and mice blood. Sphingosine-1-phosphate can mediate the trafficking of T cells, whereas ceramide can signal the activation and proliferation of T cells, thereby modulating the mammalian host's immunity. To demonstrate proof-of-principle, a case study was conducted to examine the benefit of administering PI to improve the outcomes of a feline co-infected with two distinct RNA viruses-feline leukemia virus and feline infectious peritonitis virus. Both viruses produce deadly symptoms that closely resemble RNA viruses that infect humans. The results identify quantifiable cellular and metabolic markers arising from PI treatment that can be used to establish a platform measuring the efficacy of PI in modulating the innate immune system.

Understanding the relationships between proteins and specific disease phenotypes contributes to the early detection of diseases and advances the development of personalized medicine. The acquisition of a large amount of proteomics data has facilitated this process. To improve discovery efficiency and reduce the time and financial costs associated with biological experiments, various computational methods have yielded promising results. However, the lack of rich and reliable protein-related information still presents challenges in this process.

In this paper, we propose an ensemble prediction model, named HPOseq, which predicts human protein-phenotype relationships based only on sequence information. HPOseq establishes two base models to achieve objectives. One directly extracts internal information from amino acid sequences as protein features to predict the associated phenotypes. The other builds a protein-protein network based on sequence similarity, extracting information between proteins for phenotype prediction. Ultimately, an ensemble module is employed to integrate the predictions from both base models, resulting in the final prediction.

The results of 5-fold cross-validation reveal that HPOseq outperforms seven baseline methods for predicting protein-phenotype relationships. Moreover, we conduct case studies from the points of phenotype annotation and protein analysis to verify the practical significance of HPOseq.

Critically ill patients in COVID-19 to the intensive care unit (ICU) may develop multiple organ dysfunction syndrome, with some requiring extracorporeal organ support. This study aimed to assess the effects of combined CytoSorb hemoperfusion (HP) and continuous renal replacement therapy (CRRT) on the improvement of the multiorgan failure of patients with COVID-19.

Fifty-six patients hospitalized in the ICU with a confirmed diagnosis of COVID-19 were included in this quasi-experimental study. All the patients had acute respiratory distress syndrome (ARDS). They were treated with 1-4 sessions of HP therapy.

Serum Interleukin-6 (IL6), C-reactive protein (CRP), d-dimer, procalcitonin (PCT), Neutrophil gelatinase-associated lipocalin (NGAL), ferritin, and bilirubin levels were decreased, while the concentration of albumin was significantly increased after HP/CRRT (p < 0.05). No significant differences were observed in O2 saturation (Sao2) and creatinine levels.

Combined HP and CRRT hold promise as a potential intervention for severe COVID-19 cases with multiple organ dysfunction, leading to improved clinical outcomes.

The Coronavirus disease (COVID-19) has impacted pregnant women significantly, with increased mortality and morbidity. The implications of this virus are linked to extracellular vesicles (EVs) and maternal inflammation due to the cytokine storm. Hence, this study aims to investigate the impact of COVID-19 on the pro-inflammatory cytokine profile in both plasma and EVs of South African pregnant women.

Plasma samples were obtained from pregnant women in the third trimester, from which EVs were extracted using the Invitrogen Total Exosome Isolation Kit. These plasma-derived EVs were characterised using transmission electron microscopy and nanoparticle tracking analysis (NTA).

COVID-19 infection in pregnancy did not significantly affect the average particle size and concentration of isolated EVs. The levels of IFN gamma, IL-6, MIP-1 alpha and TNF alpha were analysed in the plasma and circulating EVs through a multiplex assay. Compared to the control group, a significant increase in IL-6, IFN-γ, TNF-α and MIP-1α levels were observed in both plasma and EVs content of COVID-19 pregnancies.

These findings suggest that COVID-19 infection impacts the pro-inflammatory cytokine profile in the plasma and EVs of South African pregnant women.

Severe acute respiratory syndrome coronavirus 2 can cause acute respiratory distress syndrome, requiring prolonged invasive mechanical ventilation. However, patients with coronavirus disease 2019 (COVID-19) undergoing invasive mechanical ventilation experience barotrauma. We assessed whether limiting the maximum positive end-expiratory pressure (PEEP) may prevent barotrauma more effectively than using PEEP/fraction of inspired oxygen (FiO2) in patients with COVID-19 undergoing invasive mechanical ventilation.

We retrospectively included patients who met the diagnostic criteria at our center; they were divided into an ordinary PEEP group (PEEP/higher FiO2 table) and a limited PEEP group (maximum PEEP of <10 cmH2O) during intensive care unit admission. We evaluated the maximum ventilator variables for mechanical ventilation and limited PEEP to inhibit barotrauma as the primary outcome.

Patients in the ordinary PEEP group (n = 34) were significantly older and had higher body mass indexes than those in the limited PEEP group (n = 27). The maximum PEEP and maximum peak inspiratory pressure were significantly higher in the ordinary PEEP group than in the limited PEEP group. The ordinary PEEP group had a significantly higher incidence of barotrauma than the limited PEEP group.

Limiting the maximum PEEP to <10 cmH2O may prevent barotrauma in patients with COVID-19 undergoing invasive mechanical ventilation.

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.

ObjectiveTo evaluate the efficacy and adverse events of immunomodulators in the treatment of severe coronavirus disease 2019 (COVID-19).MethodsA literature search for the meta-analysis was performed using PubMed, The Cochrane Library, Embase, Wanfang Data, CNKI, and Web of Science to identify randomized controlled trials assessing the outcomes of patients treated with corticosteroids alone and/or interleukin-6 receptor antagonists for COVID-19. The risk of bias was assessed using the Cochrane method. The protocol was registered with PROSPERO (registry number: CRD42022356904).ResultsCompared with patients receiving standard of care, patients treated with corticosteroids alone had an increased risk of 14-day in-hospital death, whereas those treated with interleukin-6 receptor antagonists alone or in combination with corticosteroids had a lower risk of 14-day in-hospital death. Corticosteroid therapy alone was associated with increased risk of several adverse events, including intensive care unit admission and non-invasive ventilation, whereas interleukin-6 receptor antagonists alone or in combination with corticosteroids were not linked to adverse effects.ConclusionsThe findings supported the safety and efficacy of interleukin-6 receptor antagonists, either alone or together with corticosteroids, in patients with severe COVID-19; evidence supporting the efficacy and safety of corticosteroids monotherapy is lacking.

Quantification of cytokine is indispensable to elucidate the mechanism of immune regulation at the molecular level, thereby contributing to the diagnosis and treatment of several diseases. Here, we aimed to determine the effect of detection method and storage conditions of specimens on the quantification of cytokine levels.

We used four vacuum blood collection tubes containing EDTA, heparin, clot activator, gel and compared the changes in the expression levels of 14 cytokines in serum and plasma samples at different temperatures and durations of storage using AimPlex flow cytometry-based immunoassay. In addition, we analyzed the changes in cytokine sensitivity and its clinical relevance after re-establishing cutoff values compared to those set by the manufacturer.

The cytokine levels were higher in the plasma of healthy individuals than in their serum. Reliable values for most cytokines were obtained in gel-serum samples, centrifuged within 4 h of collection, and stored at -20 °C for up to 24 h. We measured cytokine levels in 1064 healthy controls using tubes containing separation gel to recalculate their cutoff values and observed changes in cytokine positivity in patients. IL-6 positivity increased from approximately 90% to 95% in patients with sepsis and severe pneumonia. Similarly, IL-8 increased from 48.7% and 41.7% to 79.5% and 63.9% in patients with sepsis and severe pneumonia.

Cytokines are more stable in gel-serum than in plasma or clot activator-serum, and they should be quantified within 4 h or within 24 h if the sample is centrifuged and stored at -20 °C.

The 2019 coronavirus illness (COVID 2019) first manifests as a newly identified pneumonia and may quickly escalate to acute respiratory distress syndrome, which has caused a global pandemic. Except for individualized supportive care, no curative therapy has been steadfastly advised for COVID-19 up until this point. T cells and virus-specific T lymphocytes are required to guard against viral infection, particularly COVID-19. Delayed immunological reconstitution (IR) and cytokine storm (CS) continue to be significant barriers to COVID-19 cure. While severe COVID-19 patients who survived the disease had considerable lymphopenia and increased neutrophils, especially in the elderly, their T cell numbers gradually recovered. Exhausted T lymphocytes and elevated levels of pro-inflammatory cytokines, including IL6, IL10, IL2, and IL17, are observed in peripheral blood and the lungs. It implies that while convalescent plasma, IL-6 blocking, mesenchymal stem cells, and corticosteroids might decrease CS, Thymosin α1 and adaptive COVID-19-specific T cells could enhance IR. There is an urgent need for more clinical research in this area throughout the world to open the door to COVID-19 treatment in the future.

Mounting evidence indicates that individuals with chronic obstructive pulmonary disease (COPD) face a heightened risk of severe outcomes upon contracting coronavirus disease 2019 (COVID-19). Current medications for COVID-19 often carry side effects, necessitating alternative therapies with improved tolerance. This review explores the biological mechanisms rendering COPD patients more susceptible to severe COVID-19 and investigates the potential of omega-3 polyunsaturated fatty acids (n-3 PUFAs) in mitigating the severity of COVID-19 in COPD patients.

Current evidence indicates that COPD patients are at an increased risk of severe COVID-19 due to factors including compromised pulmonary function, dysregulated inflammation, weakened immune response, increased oxidative stress, elevated expression of angiotensin-converting enzyme (ACE2) receptors in the lungs, and genetic predispositions. Remarkably, n-3 PUFAs exhibit the potential in ameliorating the clinical outcomes of COPD patients with COVID-19 by modulating inflammation, reinforcing the body's antioxidant defenses, reducing viral entry and replication, and enhancing immunity. N-3 PUFAs hold potential for improving COVID-19 outcomes in patients with COPD. However, there has been limited investigation into the therapeutic effects of n-3 PUFAs in enhancing clinical outcomes for COPD patients. Rigorous clinical studies are essential to evaluate the impact of n-3 PUFAs on COPD patients with concurrent COVID-19 infection.

The molecular mechanisms regulating coronavirus pathogenesis are complex, including virus-host interactions associated with replication and innate immune control. However, some genetic and epigenetic conditions associated with comorbidities increase the risk of hospitalization and can prove fatal in infected patients. This systematic review will provide insight into host genetic and epigenetic factors that interfere with COVID-19 expression in light of available evidence.

This study conducted a systematic review to examine the genetic and epigenetic susceptibility to COVID-19 using a comprehensive approach. Through systematic searches and applying relevant keywords across prominent online databases, including Scopus, PubMed, Web of Science, and Science Direct, we compiled all pertinent papers and reports published in English between December 2019 and June 2023.

The findings reveal that the host's HLA genotype plays a substantial role in determining how viral protein antigens are showcased and the subsequent immune system reaction to these antigens. Within females, genes responsible for immune system regulation are found on the X chromosome, resulting in reduced viral load and inflammation levels when contrasted with males. Possessing blood group A may contribute to an increased susceptibility to contracting COVID-19 as well as a heightened risk of mortality associated with the disease. The capacity of SARS-CoV-2 involves inhibiting the antiviral interferon (IFN) reactions, resulting in uncontrolled viral multiplication.

There is a notable absence of research into the gender-related predisposition to infection, necessitating a thorough examination. According to the available literature, a significant portion of individuals affected by the ailment or displaying severe ramifications already had suppressed immune systems, categorizing them as a group with elevated risk.

Macrophages are the primary innate immune cells encountered by the invading coronaviruses, and their abilities to initiate inflammatory reactions, to maintain the immunity homeostasis by differential polarization, to train the innate immune system by epigenic modification have been reported in laboratory animal research.

In the current in vitro research, murine macrophage RAW 264.7 cell were infected by mouse hepatitis virus, a coronavirus existed in mouse. At 3-, 6-, 12-, 24-, and 48-h post infection (hpi.), the attached cells were washed with PBS and harvested in Trizol reagent. Then The harvest is subjected to transcriptome sequencing.

The transcriptome analysis showed the immediate (3 hpi.) up regulation of DEGs related to inflammation, like Il1b and Il6. DEGs related to M2 differential polarization, like Irf4 showed up regulation at 24 hpi., the late term after viral infection. In addition, DEGs related to metabolism and histone modification, like Ezh2 were detected, which might correlate with the trained immunity of macrophages.

The current in vitro viral infection study showed the key innated immunity character of macrophages, which suggested the replacement value of viral infection cells model, to reduce the animal usage in preclinical research.

Glomerulonephritis (GN) is an important cause of renal inflammation resulting from kidney-targeted adaptive and innate immune responses and consequent glomerular damage. Given the lack of autoantibodies, immune complexes, or the infiltrating immune cells in some forms of GN, for example, focal segmental glomerulosclerosis and minimal change disease, along with paraneoplastic syndrome and a special form of renal involvement in some viral infections, the likeliest causative scenario would be secreted factors, mainly cytokine(s). Since cytokines can modulate the inflammatory mechanisms, severity, and clinical outcomes of GN, it is rational to consider the umbrella term of cytokine GN as a new outlook to reclassify a group of previously known GN. We focus here, particularly, on cytokines that have the central "canonical effect" in the development of GN.

Bruton's Tyrosine Kinase (BTK), an important element for the production of several inflammatory cytokines, may play a role in the pathogenesis of COVID-19. This study aimed to assess BTK gene expression levels in COVID-19 cases based on disease severity and outcome.

In this study, 33 hospitalized patients with COVID-19 were recruited and divided into two groups based on the severity of the disease: "mild to moderate" and "severe to critical". A blood sample was taken from each patient, peripheral blood mononuclear cells (PBMCs) were extracted, and BTK gene expression was measured. The level of BTK gene expression was compared based on the demographic data, laboratory results, and the severity and outcome of the disease.

Among the 33 patients, 22 (66.7%) were male, with nearly half having at least one underlying condition. The severity groups comprised 12 patients in the "mild to moderate" category and 21 in the "severe to critical" category, with eight (24.2%) experiencing fatal outcomes. Age, weight, and BMI showed no significant associations with BTK expression. BTK expression was notably lower in "severe to critical" and ICU-admitted cases, as well as in individuals with low O2 saturation. However, no significant difference in BTK expression was observed between cured and deceased patients (p = 0.117).

BTK gene expression in PBMCs exhibited an inverse correlation with COVID- 19 severity. However, no difference was found between BTK expression and disease outcome.

Clinical monitoring of pulmonary edema due to vascular hyperpermeability in acute respiratory distress syndrome (ARDS) poses significant clinical challenges. Presently, no biological or radiological markers are available for quantifying pulmonary edema. Our aim was to phenotype pulmonary edema and pulmonary vascular permeability in patients with coronavirus disease 2019 (COVID-19) ARDS. Transpulmonary thermodilution measurements were conducted in 65 patients with COVID-19 ARDS on the day of intubation to determine the extravascular lung water index (EVLWi) and pulmonary vascular permeability index (PVPi). In parallel, ventilatory parameters, clinical outcomes, the volume of lung opacity measured by chest computed tomography (CT), radiographic assessment of lung edema (RALE) score by chest radiography, and plasma proteomics (358 unique proteins) were compared between tertiles based on the EVLWi and PVPi. Regression models were used to associate EVLWi and PVPi with plasma, radiological, and clinical parameters. Computational pathway analysis was performed on significant plasma proteins in the regression models. Patients with the highest EVLWi values at intubation exhibited poorer oxygenation parameters and more days on the ventilator. Extravascular lung water strongly correlated with the total volume of opacity observed on CT (r = 0.72, P < 0.001), whereas the PVPi had weaker associations with clinical and radiological parameters. Extravascular lung water did not correlate with the RALE score (r = 0.15, P = 0.33). Plasma protein concentrations demonstrated a stronger correlation with PVPi than with EVLWi. The highest tertile of PVPi was associated with proteins linked to the acute phase response (cytokine and chemokine signaling) and extracellular matrix turnover. In the clinical setting of COVID-19 ARDS, pulmonary edema (EVLWi) can be accurately quantified through chest CT and parallels deterioration in ventilatory parameters and clinical outcomes. Vascular permeability (PVPi) is strongly reflected by inflammatory plasma proteins.NEW & NOTEWORTHY This study is unique in that it phenotypes pulmonary edema in COVID-19 ARDS using various clinical parameters and biomarkers. First, there is a noteworthy tipping point in the amount of pulmonary edema at which ventilatory and clinical parameters deteriorate. Second, chest CT gives a good approximation of the amount of pulmonary edema. Finally, pulmonary vascular permeability is strongly reflected by inflammatory plasma proteins.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a major concern due to its astonishing prevalence and high fatality rate, especially among elderly people. Patients suffering from COVID-19 may exhibit immunosuppression in the initial stage of infection, while a cytokine storm can occur when the disease progresses to a severe stage. This inopportune immune rhythm not only makes patients more susceptible to the virus but also leads to numerous complications resulting from the excessive production of inflammatory factors. A20, which is widely accepted as a pivotal regulator of inflammation, has been shown to be implicated in the processes of antiviral responses and immunosuppression. Thus, A20 may participate in regulating the pathological processes of COVID-19.

This narrative literature review summarizes recent evidence on the mechanisms of A20 in regulating the pathological processes of COVID-19. We also downloaded single-cell RNA-seq data sets from healthy individuals and patients with varying severities of COVID-19 from the NCBI GEO database to further dissect A20's regulatory mechanisms of these intricate cytokine pathways that are closely associated with SARS-CoV-2 infection.

A20 might be one of the most critical anti-infectious and anti-inflammatory factors involved in the pathogenesis of COVID-19. It effectively suppresses the immune damage and inflammatory storm caused by viral infection.

Understanding the relationship between A20-regulated signaling pathways and pathological processes of COVID-19 can provide insight into potential targets for intervention. Precise regulation of A20 to induce antiviral activity and an anti-inflammatory response could mediate the pathogenesis of COVID-19 and could become an effective treatment.

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.

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.

SARS-CoV-2 infection is associated with increased cardiovascular (CV) morbidity and mortality, manifesting as increased adverse outcomes in the first 30 days, extending to 12 months. This study aimed to investigate trends in sudden unexpected deaths between 2018 and 2022, with a focus on CV deaths.

A retrospective analysis was performed on autopsy reports (n=9,330) obtained from New South Wales Coroners Court, Australia, specifically targeting cases of unexplained deaths that occurred between 2018 and 2022. Statistical analysis was conducted using chi-square tests and a post hoc analysis with Bonferroni correction, as well as analysis of variance with multiple comparisons.

There were 349 (18.3%) CV deaths in 2018, 346 (18.0%) in 2019, 338 (17.5%) in 2020, 395 (21.9%) in 2021, and (23.4%) 413 in 2022 (p=0.0002). Among CV deaths, the number of deaths from sudden arrhythmic death syndrome were 25 (7.2%) in 2018, 26 (7.5%) in 2019, 18 (5.3%) in 2020, 52 (13.2%) in 2021, and 80 (19.4%) in 2022 (p=0.0001). Atherosclerosis was the most common cause of death among all CV categories; there were 196 (56.2%) atherosclerosis deaths in 2018, 207 (59.8%) in 2019, 192 (56.8%) in 2020, 221 (56.0%) in 2021, and 197 (47.7%) in 2022 (p=0.43). The average age of death from sudden arrhythmic death syndrome (42.8±19.1 years) across 2018-2022 was younger than atherosclerosis (56.2±12.4 years) and total groups (53.1±15.1 years) (p<0.001). Males comprised 76% of all CV deaths from 2018 to 2022 (p<0.0001).

Compared with pre-pandemic data, a noteworthy increase in CV deaths was observed in occurrence with the escalation in COVID-19 cases in Australia. This may be attributed to direct or indirect factors, such as lifestyle modifications, disrupted access to routine cardiac care, or COVID-19 infection-triggered CV deaths.

Hyponatremia is the most frequent electrolyte alteration among hospitalized patients and it has been reported in 20-40% of patients with SARS-CoV-2 (COVID-19) infection. Multiple causes of hyponatremia have been hypothesized in these patients. The syndrome of inappropriate antidiuresis (SIAD) has been considered one of the main reasons leading to hyponatremia in this condition. SIAD can be secondary to cytokines release, in particular IL-6. Positive pressure ventilation can be another cause of hyponatremia due to SIAD. Other possible etiologies of hyponatremia in COVID-19 patients can be related to secondary hypocortisolism, nausea, vomiting, heart and kidney damage. Similar to many other clinical conditions, there is strong evidence that hyponatremia is associated with a worse prognosis also in patients with COVID-19 infection. In particular, hyponatremia has been identified as an independent risk of ICU transfer, need of non-invasive ventilation and death. Hyponatremia in COVID-19 patients is in principle acute and symptomatic and should be treated as such, according to the published guidelines. Therefore, patients should be initially treated with i.v. hypertonic saline (3% NaCl) infusion and serum [Na+] should be frequently monitored, in order to remain within a safe rate of correction. There is evidence showing that serum [Na+] correction is associated with a better outcome in different pathologies, including COVID-19 infection.

Sepsis represents a significant global health and hygiene challenge. Excessive activation of macrophages in sepsis can result in certain patients displaying characteristics akin to those observed in Macrophage Activation Syndrome (MAS). MAS represents a grave immune system disorder characterized by persistent and severe inflammation within the body. In the context of sepsis, MAS presents atypically, leading some researchers to refer to it as Macrophage Activation-Like Syndrome (MALS). However, there are currently no effective treatment measures for this situation. The purpose of this article is to explore potential treatment methods for sepsis-associated MALS.

The objective of this review is to synthesize the specific pathophysiological mechanisms and treatment strategies of MAS to investigate potential therapeutic approaches for sepsis-associated MALS.

We searched major databases (including PubMed, Web of Science, and Google Scholar etc.) for literature encompassing macrophage activation syndrome and sepsis up to Mar 2024 and combined with studies found in the reference lists of the included studies.

We have synthesized the underlying pathophysiological mechanism of MALS in sepsis, and then summarized the diagnostic criteria and the effects of various treatment modalities utilized in patients with MAS or MALS. In both scenarios, heterogeneous treatment responses resulting from identical treatment approaches were observed. The determination of whether the patient is genuinely experiencing MALS significantly impacts the ultimate outcomes of therapeutic efficacy. In order to tackle this concern, additional clinical trials and research endeavors are imperative.

Introduction The COVID-19 pandemic originated in Wuhan, China, and swiftly spread across all continents. The respiratory system is the most affected in people who acquire sickness as a result of SARS-CoV-2. However, the virus can also affect other systems. The COVID-19 pandemic has become one of the most fatal infectious diseases in the recent past. Patients present with symptoms of fever, cough, tiredness, loss of taste or smell, sore throat, headache, and diarrhea. Objective This study intends to evaluate how COVID-19 has shown its effects on the well-being of the liver by collecting and correlating the data of the liver enzymes and inflammatory markers among hospitalized COVID-19 patients with age- and sex-matched healthy controls.  Materials and methods A retrospective case-control study that included 200 patients diagnosed and hospitalized with COVID-19 was compared with an equal number of age- and sex-matched healthy control groups without COVID-19 at RVM Institute of Medical Sciences and Research Centre (RVMIMS & RC), a tertiary care teaching hospital in Siddipet, Telangana, India. Liver function tests (LFTs) and inflammatory markers were evaluated in both groups.  Results Out of 200 patients, 179 (89.5%) had elevated alanine transaminase (ALT), 191 (95.5%) had elevated aspartate aminotransferase (AST), 33 (16.5%) had elevated alkaline phosphatase (ALP), and 183 (91.5%) showed elevated D-dimer levels. All the patients had elevated interleukin-6 (IL-6) and C-reactive protein (CRP) levels. Conclusion COVID-19 patients have exhibited elevations in liver enzyme panels and inflammatory markers. Further research and follow-up studies may aid in understanding the role of the well-being of the liver in patients affected by COVID-19. Considering the emergence of newer COVID-19 strains, we recommend LFT to patients who test positive for the virus to monitor prognosis and guide treatment protocols through this study.

Inflammation during pregnancy may occur due to various factors. This condition, in which maternal immune system activation occurs, can affect fetal brain development and be related to neurodevelopmental diseases. MIA interacts with the fetus's brain development through maternal antibodies, cytokines, chemokines, and microglial cells. Antibodies are associated with the development of the nervous system by two mechanisms: direct binding to brain inflammatory factors and binding to brain antigens. Cytokines and chemokines have an active presence in inflammatory processes. Additionally, glial cells, defenders of the nervous system, play an essential role in synaptic modulation and neurogenesis. Maternal infections during pregnancy are the most critical factors related to MIA; however, several studies show the relation between these infections and neurodevelopmental diseases. Infection with specific viruses, such as Zika, cytomegalovirus, influenza A, and SARS-CoV-2, has revealed effects on neurodevelopment and the onset of diseases such as schizophrenia and autism. We review the relationship between maternal infections during pregnancy and their impact on neurodevelopmental processes.

Coronavirus disease-19 (COVID-19) is correlated to a severe condition caused by a cytokine storm during which numerous proinflammatory cytokines, including interleukin-6 (IL-6) are released. IL-6 is a critical driver in the COVID-19 inflammatory state, and the inhibition is considered a potential treatment approach to prevent serious complications. Meanwhile, Melaleuca cajuputi is a plant with antibacterial, antiviral, anti-inflammatory, and antioxidant activities. Therefore, this aimed to investigate the anti-inflammatory potential of M. cajuputi in silico. Extraction of leaves was conducted by using 96% ethanol, followed by fractionation to obtain active compounds. Subsequently, LC/MS and GC/MS analyses were performed to obtain active compound profiling. Protein-protein interaction (PPI), as well as molecular docking and dynamic analyses, were performed to examine interaction of active compounds of M. cajuputi with IL-6. The results showed that 30 protein nodes played a significant role in COVID-19 cytokine storm and eight active compounds had interactions with IL-6. Among the active compounds, pinostrobin chalcone had the best delta G interaction with IL-6. In conclusion, M. cajuputi has potential activity as an anti-inflammatory agent against COVID-19.

Dysregulated host cytokine responses to SARS-CoV-2 infection are a primary cause of progression to severe disease, whereas early neutralizing antibody responses are considered protective. However, there are gaps in understanding the early temporal dynamics of these immune responses, and the profile of productive immune responses generated by non-hospitalized people with mild infections in the community.

Here we conducted a prospective cohort study of people with suspected infections/exposures in the US state of North Carolina, before vaccine availability. We recruited participants not only in hospitals/clinics, but also in their homes. With serial sampling, we compared virologic and immunologic factors in 258 community cases versus 114 hospital cases of COVID-19 to define factors associated with severity.

We found that high early neutralizing antibodies were associated with lower nasal viral load, but not protection from hospitalization. Cytokine responses were evaluated in 125 cases, with subsets at first versus second week of illness to assess for time-dependent trajectories. The hospital group demonstrated a higher magnitude of serum IL-6, IL-1R antagonist, IP-10, and MIG; prolonged upregulation of IL-17; and lesser downregulation of GROα, IL-1R antagonist, and MCP1, in comparison to the community group suggesting that these factors may contribute to immunopathology. In the second week of illness, 2-fold increases in IL-6, IL-1R antagonist, and IP-10 were associated with 2.2, 1.8, and 10-fold higher odds of hospitalization respectively, whereas a 2-fold increase in IL-10 was associated with 63% reduction in odds of hospitalization (p<0.05). Moreover, antibody responses at 3-6 months post mild SARS-CoV-2 infections in the community revealed long-lasting antiviral IgM and IgA antibodies as well as a stable set point of neutralizing antibodies that were not waning.

Our data provide valuable temporal cytokine benchmarks to track the progression of immunopathology in COVID-19 patients and guide improvements in immunotherapies.

Cytokines are known to be a group of growing small proteins that are majorly responsible for the transmission of signals and communication between hematopoietic cells, the cells of the human immune system, and other types of cells. Cytokines play a dominant role in different types of disorders and in perpetuating the inflammation-related disorders. The production of cytokines is a natural process inside the body of a human being against any foreign invasion or due to some pathogenic state to maintain the homeostasis. Cytokines respond in two ways; in some cases, the production and development of cytokines as a therapeutic discovery or intervention will enhance the treatment process and support the reaction given by the body against any pathogenic activity, and in some cases, overproduction of these cytokines responds in the opposite way and behaves as antagonists toward a typical therapeutic drug and its treatment. Overall, 41 articles were reviewed, and it was found that cytokines have proved to be a therapeutic approach among various diseases and can be utilized as a good candidate or a better choice for cancer therapeutics in future development.

Discovered in late 2019, the SARS-CoV-2 coronavirus has caused the largest pandemic of the 21st century, claiming more than seven million lives. In most cases, the COVID-19 disease caused by the SARS-CoV-2 virus is relatively mild and affects only the upper respiratory tract; it most often manifests itself with fever, chills, cough, and sore throat, but also has less-common mild symptoms. In most cases, patients do not require hospitalization, and fully recover. However, in some cases, infection with the SARS-CoV-2 virus leads to the development of a severe form of COVID-19, which is characterized by the development of life-threatening complications affecting not only the lungs, but also other organs and systems. In particular, various forms of thrombotic complications are common among patients with a severe form of COVID-19. The mechanisms for the development of thrombotic complications in COVID-19 remain unclear. Accumulated data indicate that the pathogenesis of severe COVID-19 is based on disruptions in the functioning of various innate immune systems. The key role in the primary response to a viral infection is assigned to two systems. These are the pattern recognition receptors, primarily members of the toll-like receptor (TLR) family, and the complement system. Both systems are the first to engage in the fight against the virus and launch a whole range of mechanisms aimed at its rapid elimination. Normally, their joint activity leads to the destruction of the pathogen and recovery. However, disruptions in the functioning of these innate immune systems in COVID-19 can cause the development of an excessive inflammatory response that is dangerous for the body. In turn, excessive inflammation entails activation of and damage to the vascular endothelium, as well as the development of the hypercoagulable state observed in patients seriously ill with COVID-19. Activation of the endothelium and hypercoagulation lead to the development of thrombosis and, as a result, damage to organs and tissues. Immune-mediated thrombotic complications are termed "immunothrombosis". In this review, we discuss in detail the features of immunothrombosis associated with SARS-CoV-2 infection and its potential underlying mechanisms.

tRNA-derived fragments function as markers in addition to playing the key role of signalling molecules in a number of disorders. It is known that the repertoire of these molecules differs greatly in different cell types and varies depending on the physiological condition. The aim of our research was to compare the pattern of tRF expression in the main blood cell types and to determine how the composition of these molecules changes during COVID-19-induced cytokine storms. Erythrocytes, monocytes, lymphocytes, neutrophils, basophils and eosinophils from control donors and patients with severe COVID-19 were obtained by fluorescence sorting. We extracted RNA from FACS-sorted cells and performed NGS of short RNAs. The composition of tRNA-derived fragments was analysed by applying a semi-custom bioinformatic pipeline. In this study, we assessed the length and type distribution of tRFs and reported the 150 most prevalent tRF sequences across all cell types. Additionally, we demonstrated a significant (p < 0.05, fold change >16) change in the pattern of tRFs in erythrocytes (21 downregulated, 12 upregulated), monocytes (53 downregulated, 38 upregulated) and lymphocytes (49 upregulated) in patients with severe COVID-19. Thus, different blood cell types exhibit a significant variety of tRFs and react to the cytokine storm by dramatically changing their differential expression patterns. We suppose that the observed phenomenon occurs due to the regulation of nucleotide modifications and alterations in activity of various Rnases.

In systemic hyper-inflammation, as in severe COVID-19 disease, there are pronounced disorders of the hematological and lymphatic systems with prognostically relevant hemophagocytosis of the bone marrow. The current work aimed to address the importance of hemophagocytosis in the lymph nodes of patients with severe COVID-19 disease. From 28 patients who died of severe COVID-19 infection, samples of the vertebral bone marrow and lymph nodes from the cervical, hilar, para-aortic, mesenteric and inguinal locations were morphologically and immunohistologically (CD163, CD68, CD61, CD71, CD3, CD20, CD138) examined for the possible presence of hemophagocytosis. In the single-center study at the University Hospital Jena, a total of 191 hemophagocytes were found in the bone marrow and a total of 780 hemophagocytes in the lymph nodes in a standardized area of 21,924 mm2 per tissue sample. With 370 hemophagocytes, hilar lymph nodes were most frequently affected (370/780; 47.44%; 95%-CI: [43.94, 50.95]), followed by cervical lymph nodes (206/780; 26.41%; 95%-CI: [23.41, 29.59]), para-aortic lymph nodes (125/780; 16.03%; 95%-CI: [13.58, 18.73]) and inguinal/mesenteric lymph nodes (79/780; 10.13%; 95%-CI: [8.155, 12.4]). Based on the standard area (21,924 mm2), the difference in the number of hemophagocytes in the bone marrow and in the hilar lymph nodes was statistically significant (p < 0.05), while this did not apply to the lymph nodes from the other locations. In fatal COVID-19 disease, hemophagocytosis is particularly found in the hilar lymph nodes and is therefore a better indicator of the severity of the disease than hemophagocytosis in the bone marrow. The findings provide some evidence for the concept of compartmentalized human host responses to life-threatening infections.

Older age and comorbidities are associated with adverse outcomes in patients with coronavirus disease 2019 (COVID-19); however, comprehensive identification of mortality risk factors can further guide disease management. We aimed to analyze predictors of in-hospital mortality in hospitalized COVID-19 patients.

This retrospective cohort study included 400 COVID-19 patients admitted between March and December 2020. Demographics, vital signs, medical history, presenting symptoms, laboratory findings, treatments, and outcomes were extracted from the patient's electronic medical records. Patients were stratified into survivor (n = 300) and nonsurvivor (n = 100) groups. Univariate and multivariate logistic regressions were used to analyze associations between variables and mortality.

Nonsurvivors were older (mean age 65 vs 45 years) and had more hypertension (60% vs 33%), diabetes (40% vs 20%), chronic obstructive pulmonary disease (20% vs 5%), and chronic kidney disease (15% vs 3%). Shorter symptom onset to admission (7 vs 4 days), lower oxygen saturation (92% vs 96%), lymphopenia, and elevated inflammatory and coagulation markers were also associated with mortality (all P < 0.001). Mechanical ventilation (60% vs 3%) and therapeutic anticoagulation were more common in nonsurvivors (all P < 0.001). Age over 75 years (adjusted odds ratio 5.2), chronic medical conditions, elevated D-dimer, and mechanical ventilation had the strongest independent associations with mortality (P < 0.001).

Older age, comorbidities such as chronic pulmonary and renal disease, disease severity parameters such as dysregulated inflammatory and coagulation markers, and the need for aggressive interventions predict increased mortality risk in hospitalized COVID-19 patients.

Long COVID affects approximately 5 million people in Africa. This disease is characterized by persistent symptoms or new onset of symptoms after an acute SARS-CoV-2 infection. Specifically, the most common symptoms include a range of cardiovascular problems such as chest pain, orthostatic intolerance, tachycardia, syncope, and uncontrolled hypertension. Importantly, these conditions appear to have endothelial dysfunction as the common denominator, which is often due to impaired nitric oxide (NO) mechanisms. This review discusses the role of mechanisms contributing to endothelial dysfunction in Long COVID, particularly in people living with HIV.

Recent studies have reported that increased inflammation and oxidative stress, frequently observed in Long COVID, may contribute to NO dysfunction, ultimately leading to decreased vascular reactivity. These mechanisms have also been reported in people living with HIV. In regions like Africa, where HIV infection is still a major public health challenge with a prevalence of approximately 26 million people in 2022. Specifically, endothelial dysfunction has been reported as a major mechanism that appears to contribute to cardiovascular diseases and the intersection with Long COVID mechanisms is of particular concern. Further, it is well established that this population is more likely to develop Long COVID following infection with SARS-CoV-2. Therefore, concomitant infection with SARS-CoV-2 may lead to accelerated cardiovascular disease. We outline the details of the worsening health problems caused by Long COVID, which exacerbate pre-existing conditions such as endothelial dysfunction. The overlapping mechanisms of HIV and SARS-CoV-2, particularly the prolonged inflammatory response and chronic hypoxia, may increase susceptibility to Long COVID. Addressing these overlapping health issues is critical as it provides clinical entry points for interventions that could improve and enhance outcomes and quality of life for those affected by both HIV and Long COVID in the region.

Cold atmospheric plasma (CAP) devices generate reactive oxygen and nitrogen species, have antimicrobial and antiviral properties, but also affect the molecular and cellular mechanisms of eukaryotic cells. The aim of this study is to investigate CAP treatment in the upper respiratory tract (URT) to reduce the incidence of ventilator-associated bacterial pneumonia (especially superinfections with multi-resistant pathogens) or viral infections (e.g., COVID-19). For this purpose, the surface-microdischarge-based plasma intensive care (PIC) device was developed by terraplasma medical GmbH. This study analyzes the safety aspects using in vitro assays and molecular characterization of human oral keratinocytes (hOK), human bronchial-tracheal epithelial cells (hBTE), and human lung fibroblasts (hLF). A 5 min CAP treatment with the PIC device at the "throat" and "subglottis" positions in the URT model did not show any significant differences from the untreated control (ctrl.) and the corresponding pressurized air (PA) treatment in terms of cell morphology, viability, apoptosis, DNA damage, and migration. However, pro-inflammatory cytokines (MCP-1, IL-6, and TNFα) were induced in hBTE and hOK cells and profibrotic molecules (collagen-I, FKBP10, and αSMA) in hLF at the mRNA level. The use of CAP in the oropharynx may make an important contribution to the recovery of intensive care patients. The results indicate that a 5 min CAP treatment in the URT with the PIC device does not cause any cell damage. The extent to which immune cell activation is induced and whether it has long-term effects on the organism need to be carefully examined in follow-up studies in vivo.