Infections, cancer, and trauma can cause life-threatening hyperinflammation. In the present study, using single-cell RNA sequencing of circulating immune cells, we found that the mammalian target of rapamycin (mTOR) pathway plays a critical role in myeloid cell regulation in COVID-19 patients. Previously, we developed an mTOR-inhibiting nanobiologic (mTORi-nanobiologic) that efficiently targets myeloid cells and their progenitors in the bone marrow. In vitro, we demonstrated that mTORi-nanobiologics potently inhibit infection-associated inflammation in human primary immune cells. Next, we investigated the in vivo effect of mTORi-nanobiologics in mouse models of hyperinflammation and acute respiratory distress syndrome. Using 18F-FDG uptake and flow cytometry readouts, we found mTORi-nanobiologic therapy to efficiently reduce hematopoietic organ metabolic activity and inflammation to levels comparable to those of healthy control animals. Together, we show that regulating myelopoiesis with mTORi-nanobiologics is a compelling therapeutic strategy to prevent deleterious organ inflammation in infection-related complications.

The spike protein (SP) is an outward-projecting transmembrane glycoprotein on viral surfaces. SARS-CoV-2 (Severe Acute Respiratory Syndrome Coronavirus 2), responsible for COVID-19 (Coronavirus Disease 2019), uses SP to infect cells that express angiotensin converting enzyme 2 (ACE2) on their membrane. Remarkably, SP has the ability to cross the blood-brain barrier (BBB) into the brain and cause cerebral damage through various pathomechanisms. To combat the COVID-19 pandemic, novel gene-based products have been used worldwide to induce human body cells to produce SP to stimulate the immune system. This artificial SP also has a harmful effect on the human nervous system.

Narrative review.

This narrative review presents the crucial role of SP in neurological complaints after SARS-CoV-2 infection, but also of SP derived from novel gene-based anti-SARS-CoV-2 products (ASP).

Literature searches using broad terms such as "SARS-CoV-2", "spike protein", "COVID-19", "COVID-19 pandemic", "vaccines", "COVID-19 vaccines", "post-vaccination syndrome", "post-COVID-19 vaccination syndrome" and "proteinopathy" were performed using PubMed. Google Scholar was used to search for topic-specific full-text keywords.

The toxic properties of SP presented in this review provide a good explanation for many of the neurological symptoms following SARS-CoV-2 infection and after injection of SP-producing ASP. Both SP entities (from infection and injection) interfere, among others, with ACE2 and act on different cells, tissues and organs. Both SPs are able to cross the BBB and can trigger acute and chronic neurological complaints. Such SP-associated pathologies (spikeopathies) are further neurological proteinopathies with thrombogenic, neurotoxic, neuroinflammatory and neurodegenerative potential for the human nervous system, particularly the central nervous system. The potential neurotoxicity of SP from ASP needs to be critically examined, as ASPs have been administered to millions of people worldwide.

Understanding the mechanisms of interaction between SARS-CoV-2 infection and the immune system is crucial for developing effective treatment strategies against COVID-19. In this paper, a mathematical model is formulated to investigate the interactions among SARS-CoV-2 infection, cellular immunity, and humoral immunity. Clinical data from eight asymptomatic or mild COVID-19 patients in Munich are used to fit the model, and the dynamics of natural killer (NK) cells, cytotoxic T lymphocytes (CTLs), B cells, and antibodies are further explored using the average of the best-fitting parameter values. Subsequently, the impact of NK cells, CTLs, B cells, and antibodies on SARS-CoV-2 infection is numerically investigated. The results indicate that (i) the synergy of NK cells, CTLs, and antibodies leads to a rapid decrease in the viral load during SARS-CoV-2 infection; (ii) antibodies play a crucial role compared to other immune mechanisms, and enhancing B cell stimulation may be more effective in clearing the virus from the lungs; (iii) in terms of cytotoxic effects, CTLs are stronger and more sustained than NK cells. Furthermore, the existence and local stability of the model's equilibria are fully classified, and complex dynamics of the model are further investigated using bifurcation theory, revealing multistability phenomena, including multiple attractors and periodic solutions. These findings suggest potential uncertainty and diversity in SARS-CoV-2 infection outcomes.

The COVID-19 pandemic has greatly enhanced our understanding of CD8+ T cell immunity and their role in natural infection and vaccine-induced protection. Rapid and early SARS-CoV-2-specific CD8+ T cell responses have been associated with efficient viral clearance and mild disease. Virus-specific CD8+ T cell responses can compensate for waning, morbidity-related, and iatrogenic reduction of humoral immunity. After infection or vaccination, SARS-CoV-2-specific memory CD8+ T cells are formed, which mount an efficient recall response in the event of breakthrough infection and help to protect from severe disease. Due to their breadth and ability to target mainly highly conserved epitopes, SARS-CoV-2-specific CD8+ T cells are also able to cross-recognize epitopes of viral variants, thus maintaining immunity even after the emergence of viral evolution. In some cases, however, CD8+ T cells may contribute to the pathogenesis of severe COVID-19. In particular, delayed and uncontrolled, e.g., nonspecific and hyperactivated, cytotoxic CD8+ T cell responses have been linked to poor COVID-19 outcomes. In this minireview, we summarize the tremendous knowledge about CD8+ T cell responses to SARS-CoV-2 infection and COVID-19 vaccination that has been gained over the past 5 years, while also highlighting the critical knowledge gaps that remain.

The mechanisms by which severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes severe lung inflammation and mortality remain unclear. While the role of alveolar macrophages in COVID-19 is known, data on pulmonary intravascular macrophages (PIMs) is lacking. PIMs are key inflammatory cells present in species like cattle and pigs. Though constitutively absent in humans and rodents, their recruitment in rodents triggers exaggerated inflammation. We investigated the recruitment of PIMs and other immune cells, using immunofluorescence, hematoxylin and eosin (H&E) staining, and immunogold labeling in a hamster model of SARS-CoV-2 infection. Syrian golden hamsters were divided into 6 groups: uninfected control, unvaccinated-infected at 2-, 5-, and 14-days post infection (dpi) and vaccinated-infected at 5- and 14-dpi. Lung tissues were analyzed for neutrophils (myeloperoxidase), monocytes/macrophages (CCR2, CX3CR1), macrophages (IBA-1), and T cells (CD3). Septal macrophages increased at 2-, 5-, and 14-dpi in infected animals vs. control. CX3CR1 + cells decreased at 14-dpi in unvaccinated animals, but CX3CR1/CCR2 double positive cells were higher at 5-dpi, indicating a pro-inflammatory macrophage phenotype. PIMs were confirmed by transmission electron microscopy. These are the first data showing recruitment of pro-inflammatory PIMs in SARS-CoV-2 infected lungs.

The coronavirus disease 2019 (COVID-19) pandemic has resulted in high mortality among hospitalized patients; thus, identifying mortality markers in treating these patients is essential. To evaluate the association between viral load and serum biomarkers with mortality among hospitalized patients with COVID-19.

A retrospective cohort study was conducted among 198 inpatient records from a tertiary hospital in Mexico City between January and April 2021. The association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral load and serum biomarkers with death due to COVID-19 was assessed using Cox regression models.

The median age was 54.9 years, and 61.6% were males. The mortality rate was 43.4%. After adjusting for potential confounders, patients with higher viral load [adjusted hazard ratio (aHR) = 1.56; 95% confidence interval (95% CI) = 1.01, 2.42; P value = 0.041]; and higher concentrations of BUN (aHR = 4.87;95% CI = 2.70, 8.79; P value = 0.001), creatinine (aHR = 1.60;95% CI = 1.01, 2.54; P value = 0.043), osmolality (aHR = 4.37;95% CI = 2.34, 8.14; P value = 0.001), and glucose (aHR = 2.41;95% CI = 1.40, 4.18; P value = 0.001) were more likely to have a fatal prognosis. Conversely, mortality risk was lower among patients with high concentrations of lymphocytes (aHR = 0.47;95% CI = 0.30, 0.72; P value = 0.001).

SARS-CoV-2 viral load and serum biomarkers such as BUN, creatinine, glucose, osmolarity, and lymphocytes could help physicians identify individuals who require closer monitoring.

This study investigated the consistency of the FIB-4, APRI, and GPR indices in assessing significant liver fibrosis and cirrhosis in patients with Coronavirus Disease 2019(COVID-19) who also suffer from various liver diseases, providing references for the clinical selection and application for non-invasive assessment methods.

The study evaluated 744 COVID-19 patients with coexisting liver diseases: 508 cases with non-alcoholic fatty liver disease (NAFLD), 158 cases with chronic hepatitis B (CHB), and 78 cases with a combination of both ailments. FIB-4, APRI, and GPR were employed to assess significant liver fibrosis and cirrhosis. Concordance among the methods was determined using Kappa analysis, and receiver operating characteristic (ROC) curves helped identify the optimal cutoff values for each index.

For COVID-19 patients with NAFLD, Kappa values for significant liver fibrosis were 0.81, 0.90, 0.80, and 0.79, and for cirrhosis, they were 0.88, 0.97,0.88, and 0.88, respectively (all p < 0.05). Among those with CHB, Kappa values were 0.81, 0.81, 0.83, and 0.75 for fibrosis, and0.87, 0.91, 0.88, and 0.92 for cirrhosis (all p < 0.05). In patients with coexisting liver diseases, the values were 0.87, 0.86, 0.86, and 0.78 for fibrosis, and 0.67, 0.69, 0.54, and 0.81for cirrhosis (all p < 0.05). Linear trend analysis revealed significant relationships between FIB-4 values, APRI values, GPR values, and the severity of COVID-19 (χ2 trend: 15.205,35.114, and 13.973, respectively, all p < 0.001), between FIB-4 values and APRI values and the coronavirus negative conversion time (all p < 0.05) in COVID-19 with NAFLD, and between FIB-4 values and GPR values and the coronavirus negative conversion time in patients with COVID-19 with CHB(all p < 0.05).

Using the current cutoff values, the non-invasive assessments demonstrated almost perfect consistency in evaluating significant liver fibrosis and cirrhosis in COVID-19 patients with liver diseases, though FIB-4 and GPR showed moderate consistency in cirrhosis evaluation in patients with coexisting liver conditions. Moreover, it also indicated that increased liver fibrosis correlates with more severe COVID-19 and prolonged coronavirus negative conversion time.

COVID-19 manifestations range from asymptomatic to severe, and are influenced by host genetic factors. This study examined the association between vitamin D receptor (VDR) polymorphisms (TaqI and FokI) and transmembrane serine protease 2 (TMPRSS2) gene polymorphisms (rs12329760) and COVID-19 severity.

242 COVID-19 patients underwent genotyping using PCR-RFLP. Statistical analysis were conducted using SPSS v.21 and SHesis software, and validated by Sanger sequencing. The association of the VDR TaqI, FokI, and TMPRSS2 rs12329760 polymorphisms with COVID-19 severity was investigated. Computational analysis of TMPRSS2 was used to determine the pathogenicity and structural effects of these SNPs. For VDR TaqI, the 'TC' genotype showed higher prevalence in severe cases (50.5%) compared to mild cases (41.4%); however, no statistically significant association was observed [OR: 1.545 (0.893-2.675), p > 0.05]. Similar patterns were noted for the 'CC' genotype and 'C' allele, without statistical significance. For VDR FokI, the 'Ff' genotype showed higher prevalence in severe cases (25.8%) compared to mild cases (20.0%) [OR: 0.766 (0.199-2.951), p = 0.69], with no significant association. In haplotype analysis, elevated frequencies of 'Tf' and 'ft' haplotypes were observed in severe cases, but without statistical significance. For TMPRSS2 rs12329760, the 'CT' genotype showed a marginally higher prevalence in severe cases (50.5%) than in mild cases (49.7%) [OR: 0.805 (0.276-2.345), p > 0.05], without significant association. Computational analysis indicated that the variant does not demonstrate pathogenic effects but may influence protein stability.

This study revealed no statistically significant association between VDR (TaqI and FokI) and TMPRSS2 (rs12329760) polymorphisms and COVID-19 severity. Large-scale investigations and functional analysis are required to delineate the impact of these genetic variations on COVID-19 susceptibility and severity.

Early antibody therapy can prevent severe SARS-CoV-2 infection (COVID-19). However, the effectiveness of COVID-19 convalescent plasma (CCP) therapy in treating severe COVID-19 remains inconclusive. To test a hypothesis that some CCP units are associated with a coagulopathy hazard in severe disease that offsets its benefits, we tracked 304 CCP units administered to 414 hospitalized COVID-19 patients to assess their association with the onset of unfavorable post-transfusion D-dimer trends. CCP recipients with increasing or persistently elevated D-dimer trajectories after transfusion experienced higher mortality than those whose D-dimer levels were persistently low or decreasing after transfusion. Within the CCP donor-recipient network, recipients with increasing or persistently high D-dimer trajectories were skewed toward association with a minority of CCP units. In in vitro assays, CCP from "higher-risk" units had higher cross-reactivity with the spike protein of human seasonal betacoronavirus OC43. "Higher-risk" CCP units also mediated greater Fcγ receptor IIa signaling against cells expressing SARS-CoV-2 spike compared with "lower-risk" units. This study finds that post-transfusion activation of coagulation pathways during severe COVID-19 is associated with specific CCP antibody profiles and supports a potential mechanism of immune complex-activated coagulopathy.

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia in the general population and the most frequently presented arrhythmia in the intensive care unit. We investigated the effects of AF on the outcomes of critical COVID-19 patients, especially focusing on differences between chronic (CAF) and new-onset AF (NOAF) during critical disease. MATERIAL AND METHODS In this case-control study, we investigated the association of CAF and NOAF as an exposure, with in-hospital mortality as an outcome. We identified 2 patient groups, NOAF and CAF, which were compared with controls (all other hospitalized patients with critical COVID-19 pneumonia). No specific selection or matching was performed. The chi-square test was used for categorical variables; t test and Mann-Whitney U tests were used for continuous variables, depending on distribution. P<0.05 was considered significant. RESULTS In-hospital mortality was significantly higher in the NOAF group, while in the CAF group, it was similar to that of the control group. The NOAF group had significantly higher markers of inflammation and more severe acute respiratory distress syndrome (ARDS), measured with computed tomography. NOAF was strongly associated with in-hospital death, with OR 6.392 (95% CI, 2.758-14.815), P<0.000. In comparison, the CAF group was older and had more cardiovascular comorbidities, with similar markers of inflammation and severity of ARDS as the control group. CONCLUSIONS NOAF in COVID-19 was linked with significant risk of death, being a sign of extreme cardiac, pulmonary, and metabolic instability. NOAF should be considered as an important marker of instability and predictor of poor outcomes among patients with COVID-19.

Several studies suggest that the heterogeneous spread of SARS-CoV-2 pandemics started on December 2019 could be partially upheld by the prevalence of permissive class I HLA alleles in specific populations. Such HLA alleles are in fact unable to shape an efficient anti-viral immune-response in the hosts or sustain an exaggerated inflammatory T cell mediated response responsible for the COVID-19 disease. We previously reported an ecologic correlation between the risk of COVID-19 spreading across Italy and the germinal expression of permissive HLA-C*01 and -B*44 alleles in specific inter and intraregional populations along the first spreading wave.

Considering that SARS-CoV-2 has undergone multiple adaptative mutations since the beginning of pandemics related to a natural immunization and to the worldwide campaign of anti-SARS-CoV-2 vaccination, we have carried out further analyses to evaluate whether the predictive value of class I HLA-allele gene prevalence and COVID-19 incidence has changed with time along the first four pandemics spreading waves in Italy. To this purpose we carried out an ecologic study followed by a case-control study.

| Our data revealed that the direct correlation of HLA-C*01, and HLA-B*44 gene expression and COVID-19 risk was completely lost just after the first pandemics wave in Italy. On the contrary, the expression of HLA-B*49 allele in specific populations emerged as inversely correlated to the risk of COVID-19 and could be considered as a protective factor. The statistical significance of this correlation was progressively enforced in each subsequent spreading wave until February 2022. The following case-control study in the two Regions of Campania and Calabria in Italy confirmed the protective value of HLA-B*49 allele gene expression (OR = 0.289; p = 0.041), although statistical significance is lost after adjustment by logistic regression model. The analysis also detected multiple class I HLA-alleles whose expression was strongly correlated with COVID-19 risk: HLA-B*08 (ORadj = 3.193; p = 0.015); -B*14:01 (ORadj = 3.596; p = 0.018); -B*15:01 (ORadj = 5.124; p = 0.001); -B*35 (ORadj = 2.972; p = 0.002).

Our study not only identifies specific HLA alleles related to COVID-19 risk but also exemplifies a rapid and inexpensive approach that can be used to identify individuals needing prioritization during vaccination campaigns.

Human Endogenous Retroviruses (HERVs), which can be activated by viral infections, have complex roles in gene regulation and immune modulation. However, their contribution to disease progression is not yet fully understood. Dengue fever ranges from mild symptoms to severe cases characterized by plasma leakage and immune dysregulation, providing a relevant context to investigate these interactions.

This study comes up with a comprehensive analysis of differentially expressed HERVs (DE-HERVs), protein-coding genes (DEGs), and regulatory elements such as microRNAs (DE-miRNA) and non-LTR retroviruses (DE-LINEs and DE-SINEs) derived from the transcriptomes of Brazilian dengue patients across different disease stages.

The results show that DE-HERVs are associated with key genes identified in severe dengue cases, including ARG1, SLC15A2, COL3A1, SVEP1, CH25H, CST7, CXCR1, IL18RAP, SORL1, and TACR1, suggesting their role in immune modulation and endothelial permeability. Specifically, the upregulation of CXCR1 and IL18RAP genes in patients who progressed to severe dengue correlates with a complex regulatory network involving down-regulated microRNAs (miRNAs) and non-LTR retroviruses, emphasizing their relevance to inflammation and vascular permeability. MicroRNAs and non-LTR retroviruses were found to regulate these genes differently across dengue stages, with non-LTR elements appearing predominantly in non-severe cases and miRNA expression profiles varying across the comparison groups.

These findings improve our understanding of the molecular mechanisms underlying dengue progression and suggest that HERV-related regulatory networks may influence viral infections. Further research is required to clarify the specific roles of HERVs in dengue pathogenesis.

Insufficiencies of the majority of targeted therapies for the most severe, life-threatening forms of COVID-19 warrant alternative, adjuvant treatment options for enhanced life maintenance that include extracorporeal blood purification and homeostasis support. The goal of the current study is to evaluate the clinical efficacy of hemoadsorption with mesoporous hypercrosslinked polystyrene beads (Efferon CT single-use cartridge) in an expanded cohort of patients with severe and critical COVID-19 resistant to antibody therapies and requiring post-therapy invasive mechanical lung ventilation (MLV) versus parameter-matched control group with no hemoadsorption.

A single-center cohort study (NCT06402279) enrolled patients from October 2020 to February 2022: the Efferon CT group (non-responders to anti-cytokine antibody therapy requiring IMV, hemadsorption, and standard treatment, n = 65) and retrospectively acquired propensity-matched control group (no hemadsorption, standard treatment only, n = 65).

This observational study revealed the capability of Efferon CT hemoadsorption to safely, rapidly, and significantly reduce the need for norepinephrine, increase the oxygenation index, prevent the sepsis-associated AKI, decrease the development of multiorgan failure, and restore the immune system balance by decreasing pro-inflammatory IL-6, ferritin levels, and neutrophil-to-lymphocyte ratio.

The clinical efficiency of hemoadsorption using Efferon CT was confirmed by the resolution of acute respiratory failure in 54% of patients, significantly increasing the number of days without mechanical ventilation and increasing early the index of oxygenation. Most importantly, the hemoadsorption with Efferon CT was safe and resulted in a significant decrease in the mortality of severe COVID-19 patients.

www.clinicaltrials.gov, Identifier NCT06402279.

Background: Hyperbaric Oxygen Therapy (HBOT) is a medical treatment that involves administering 100% oxygen at increased atmospheric pressure to enhance oxygen delivery to tissues. Initially developed for decompression sickness, HBOT has since been utilized for a wide range of medical conditions, including severe infections, non-healing wounds, and, more recently, COVID-19. Objective: This review explores the historical development of HBOT, its principles, its emerging role in the management of and its outcome as treatment in COVID-19, particularly in mitigating inflammation, hypoxemia, and oxidative stress. Methods: A comprehensive review of the literature was conducted, analyzing case reports and case series that examined the effectiveness of HBOT in various clinical scenarios, with a focus on COVID-19. Results: HBOT has been shown to enhance tissue oxygenation, reduce inflammation, and modulate oxidative stress, thereby improving clinical outcomes in patients with severe COVID-19. The therapy's ability to increase dissolved oxygen levels in blood and tissues, independent of hemoglobin, makes it particularly beneficial in conditions like COVID-19, where hypoxemia and inflammation are prominent. Conclusion: HBOT offers a promising adjunctive treatment for severe COVID-19, with the potential to reduce mortality and improve recovery by targeting key pathophysiological processes such as hypoxemia, inflammation, and oxidative stress. Further research is warranted to optimize treatment protocols and confirm long-term benefits.

In the study, it was aimed to determine the experiences of elderly COVID-19 patients hospitalized in intensive care units. The study was conducted based on the phenomenological design, one of the qualitative research methods. In-depth interviews were conducted using a semi-structured interview form with 15 participants, who were determined by the homogeneous and criterion sampling methods, two of the purposive sampling methods. Data were analyzed using Colaizzi's seven-step method. After the interviews, four themes were determined: intensive care experiences, importance of nursing care, intensive care environment and coping mechanisms related to COVID-19 disease, and post-intensive care realizations. In addition, 13 sub-themes were determined. This study provided a better understanding of the psychological experiences of elderly individuals during the disease, who have been hospitalized in intensive care unit and survived COVID-19.

Hydroxychloroquine and Chloroquine (CQ) and Hydroxychloroquine (HCQ) are antimalarial drugs with well-known anti-inflammatory and antiviral effects used to treat various diseases, with few side effects. After COVID-19 emergence, numerous researches from around the world have examined the potential of using CQ or HCQ as potential treatment of COVID-19. However, conflicting outcomes have been found in COVID-19 clinical trials after treatment with CQ or HCQ. This study aims to evaluate research on CQ and HCQ for COVID-19 treatment and prophylaxis control using bibliometric methods.

We analyzed bibliometric data on HCQ and COVID-19 (HCQ-C19) quantitatively and semantically (2020-2023) using the Scopus database VOSviewer, Bibliometrix, and MS Excel.

Analyses of 7471 original and conference articles revealed that the total number of publications has continually increased. The country producing the most articles in this field was the United States, followed by Italy, India, and Spain. The top-productive authors on HCQ-C19 are Mussini, C., and Raoult, D. (Italy) with 23 and 21 articles, respectively. The top-impactful organization is IHU Méditerranée Infection, France. A Bibliometrix's network analysis based on the co-occurrence of keywords revealed the following themes HCQ-C19, including "clinical research/practice," "COVID-19," "thrombosis," "HCQ," "epidemiology," and "infectious disease."

In conclusion, the analysis reveals a growing interest in HCQ-C19 research. Prominent contributions come from the United States, Italy, India, and Spain. Key themes include clinical research/practice, COVID-19, thrombosis, HCQ, epidemiology, and infectious disease. Future recommendations include conducting well-designed clinical trials and fostering collaborative interdisciplinary efforts.

COVID-19 encompasses a wide clinical spectrum, from mild influenza-like illness to severe pneumonia and systemic complications. There is emerging literature on hepatobiliary involvement in COVID-19, especially elevation in liver enzymes as surrogate markers of liver injury. Angiotensin-converting enzyme 2 receptors within the hepatobiliary system are a portal of entry for SARS-CoV-2, after which injury may be perpetuated through hypoxia and cytokine storms. This literature review covers studies published before 2024 from databases such as PubMed, Google Scholar, Springer, and BMC Library. The keywords used were "COVID-19", "liver", "SARS-CoV-2", "chronic liver disease", and other relevant terms to ensure a wide scope of investigation. The most common liver enzymes elevated among COVID-19 patients include aspartate transaminase, alanine transaminase, and alkaline phosphatase, all of which are associated with the severity of the disease. Chronic liver disease (CLD) and hepatocellular carcinoma (HCC) patients have worse outcomes with increased ICU admission rates and increased mortality. COVID-19 vaccination in CLD and liver transplant recipients is very often associated with suboptimal antibody responses, adding to the risks. SARS-CoV-2 causes liver involvement through direct viral cytopathic effects, immune-mediated injury, and systemic hypoxia. Individuals with CLD are particularly vulnerable to severe illness.

This study aimed to identify possible early biomarkers of mortality among clinical and biochemical parameters, iron metabolism parameters, and cytokines detected within 24 h from admission in hospitalized COVID-19 patients. We enrolled 80 hospitalized patients (40 survivors and 40 non-survivors) with COVID-19 pneumonia and acute respiratory failure. The median time from the onset of COVID-19 symptoms to hospital admission was lower in non-survivors than survivors (p < 0.05). Respiratory failure, expressed as the ratio of arterial oxygen partial pressure to the fraction of inspired oxygen (P/F), was more severe in non-survivors than survivors (p < 0.0001). Comorbidities were similar in both groups. Among biochemical parameters and cytokines, eGFR and interleukin (IL)-1β were found to be significantly lower (p < 0.05), while LDH, IL-10, and IL-8 were significantly higher in non-survivors than in survivors (p < 0.0005, p < 0.05 and p < 0.005, respectively). Among other parameters, LDH values distribution showed the most significant difference between study groups (p < 0.0001). LASSO feature selection combined with Cox proportional hazards and logistic regression models was applied to identify features distinguishing between survivors and non-survivors. Both approaches highlighted LDH as the strongest predictor, with IL-22 and creatinine emerging in the Cox model, while IL-10, eGFR, and creatinine were influential in the logistic model (AUC = 0.744 for Cox, 0.723 for logistic regression). In a similar manner, we applied linear regression for predicting LDH levels, identifying the P/F ratio as the top predictor, followed by IL-10 and eGFR (NRMSE = 0.128). Collectively, these findings underscore LDH's critical role in mortality prediction, with P/F and IL-10 as key determinants of LDH increases in this Italian COVID-19 cohort.

Background: Coronavirus disease 2019 (COVID-19) has emerged as a global human health threat. While SARS-CoV-2 infection exhibits fever and respiratory symptoms, extrarespiratory manifestations were also reported in many cases. Objectives: This study aimed to determine the prevalence of digestive and hepatic symptoms at the onset of infection and to assess whether digestive symptoms are associated with severe disease progression. Patients and Methods: Prospective study was conducted during the first COVID-19 wave (from April to October 2020). It included consenting Moroccan patients diagnosed with COVID-19 based on PCR test and chest computed tomography. Results: A total of 211 patients participated in the study. The patients mean age was 42.3 years, with a sex ratio (F/M) of 1.7. Digestive symptoms were present in 28% of cases, with the most common being nausea or vomiting (12.8%), diarrhea (11.4%), abdominal pain (5.2%), and anorexia (16.6%). These symptoms were significantly associated with diabetes and hypertension. Patients with digestive symptoms reported a significantly higher frequency of anosmia and headache. Hepatic manifestations were present in 21.3%, and digestive symptoms were significantly associated with higher prevalence of liver function disturbances, particularly cholestasis. Nearly half of the patients with digestive symptoms (49.2%) experienced moderate COVID-19, with a higher percentage observed (61.8%) among those aged 42 years or older. However, this association was not statistically significant. Conclusion: Healthcare professionals need to recognize the range of gastrointestinal and hepatic symptoms to ensure timely diagnosis and effective patient management.

This study investigated post-coronavirus disease 2019 (COVID-19) sequelae among a sample of the Chinese population, and determined the statistical significance of correlations between age, sex, number of COVID-19 vaccinations, number of SARS-CoV-2 infections, development of pneumonia, use of specific drugs (namatevir/ritonavir, azvudine, molnupiravir), chronic underlying diseases, and post-COVID-19 sequelae.

Data from 869 patients, who visited the Emergency Department of Beijing Shijitan Hospital (Beijing, China) between December 7, 2022 to January 31, 2024, were collected. The criteria for admission: Age ≥ 14 years old, and diagnosed with ≥ 1 positive result on nucleic acid or antigen tests. Retrospectively analyzed the main manifestations of sequelae, statistical analysis of the relationship between age; sex; underlying diseases; number of COVID-19 vaccinations received; use of specific antiviral drugs for COVID-19 and prognosis, and statistical analyses, including logistic regression, were performed. Differences with P < 0.05 were considered to be statistically significant. Before entering the model, variables are screened using stepwise regression to ensure that the selected variables are the main ones related to the research question, thereby controlling for confounding factors. SPSS version 27 (IBM Corp. Armonk, NY, USA) was used for statistical analysis. In this study, the duration of sequelae ranged from 2 to 13 months.

This study retrospectively analyzed 869 patients (415 male, 454 female), with an average age of 61.52 ± 23.09 years. There were 401 patients without underlying conditions and 468 patients with one or more underlying conditions. Regarding COVID-19 vaccination status, 320 patients were unvaccinated, while 576 patients received at least one dose of the COVID-19 vaccine. Additionally, 514 patients received antiviral medication, while 355 did not receive antiviral treatment. The primary manifestations of post-COVID-19 included shortness of breath, dizziness and weakness, chronic pneumonia, asthma, and reduced sense of smell. Individuals ≥ 70 years of age were more prone to COVID-19 pneumonia. Patients with underlying disease(s) exhibited statistically higher mortality rates after diagnosis of COVID-19. Vaccination against COVID-19 and the use of specific drugs had a statistically significant effect on mortality and the occurrence of post-COVID-19 sequelae. There was no statistically significant difference in COVID-19 infection rates between males and females, although males were more prone to COVID-19 pneumonia. Young women with COVID-19 often experienced no sequelae, and elderly males exhibited a high mortality rate.

The health benefits of vitamin D are far beyond bone mineral metabolism. Vitamin D has immunomodulator and anti-inflammatory properties and its role in critically ill patients is controversial. The purpose of the study is to understand whether high doses of vitamin D supplementation are beneficial in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pneumonia hospitalized in a polyvalent intensive care unit (ICU) and correlate to all-cause mortality, need for invasive mechanical ventilation, and duration of hospitalization.

A retrospective study was conducted at a single polyvalent ICU, comparing patients supplemented with vitamin D with nonsupplemented patients. Eligible participants were adults with SARS-CoV-2 pneumonia admitted in this unit between April 14, 2020, and October 31, 2020. Demographic and clinical characteristics, comorbidities, and disease-related outcomes were extracted from electronic medical records.

No statistically significant differences were observed between the groups in terms of need for invasive mechanical ventilation or duration of hospitalization. Supplementation with vitamin D was associated with lower all-cause ICU, intrahospital, and total mortality.

High-dose vitamin D supplementation was associated with a reduction of mortality in patients with severe SARS-CoV-2 pneumonia. Randomized clinical trials are needed to confirm these findings and to assess the optimal dosage of supplementation.

Respiratory viruses pose an ongoing threat to human health with excessive cytokine secretion contributing to severe illness and mortality. However, the relationship between cytokine secretion and viral infection remains poorly understood. Here we elucidate the role of CXCL8 as an early response gene to EV-D68 infection. Silencing CXCL8 or its receptors, CXCR1/2, impedes EV-D68 replication in vitro. Upon recognition of CXCL8 by CXCR1/2, the MAPK pathway is activated, facilitating the translocation of nuclear hnRNP-K to the cytoplasm. This translocation increases the recognition of viral RNA by hnRNP-K in the cytoplasm, promoting the function of the 5' untranslated region in the viral genome. Moreover, our investigations also reveal the importance of the CXCL8 signaling pathway in the replication of both influenza virus and rhinovirus. In summary, our findings hint that these viruses exploit the CXCL8/MAPK/hnRNP-K axis to enhance viral replication in respiratory cells in vitro.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) enters host cells via the angiotensin-converting enzyme 2 (ACE2) receptor. Mounting evidence has indicated the presence of hepatic SARS-CoV-2 infection and liver injury in patients with coronavirus disease 2019 (COVID-19). Understanding the mechanisms of hepatic SARS-CoV-2 infection is crucial for addressing COVID-19-related liver pathology and developing targeted therapies. This editorial discusses the significance of ACE2 in hepatic SARS-CoV-2 infection, drawing on the research by Jacobs et al. Their findings indicate that hepatic ACE2 expression, frequency of hepatic SARS-CoV-2 infection, and severity of liver injury are elevated in patients with pre-existing chronic liver diseases. These data suggest that hepatic ACE2 could be a promising therapeutic target for COVID-19.

Background/Objectives: Corona virus disease 2019 (COVID-19) poses a threat to global public health. The early identification of critical cases is crucial to providing timely treatment to patients. Here, we investigated whether the neutrophil levels could predict COVID-19 complications. Methods: We performed a retrospective study of patients with COVID-19, admitted to the Cheikh Khalifa International University Hospital, Casablanca, Morocco. Laboratory test results collected upon admission and during hospitalization were analyzed based on clinical information. Results: Our study revealed that a rise in neutrophil "PNN" levels was associated with respiratory deterioration and intubation. They were positively correlated with the procalcitonin and C-reactive protein levels. Interestingly, PNN (polynuclear neutrophil) levels on day 5 proved to be a better predictor of intubation, acute respiratory distress syndrome (ARDS), and mortality than the initial PNN counts, C-reactive protein, or procalcitonin. Moreover, binary logistic regression with stratified PNN-day 5 data revealed that a PNN level on day 5 > 7.7 (109/L) was an independent risk factor for mortality and ARDS. Finally, the PNN levels on day 5 and proinflammatory cytokine IL-6 were positively correlated. Conclusions: Our data showed that neutrophilia proved to be an excellent predictor of complications and mortality during hospitalization and could be used to improve the management of patients with COVID-19.

Maximal oxygen uptake (V.O2max) assesses athletic performance; however, its values are inconsistent in post-COVID-19 athletes. This study aimed to analyze the dynamics of V.O2max in post-COVID-19 athletes. Observational studies were identified by screening the PubMed database published up to 17 July 2023. The initial electronic search found 320 studies. Of these, 26 employing the cardiopulmonary exercise test (CPET) to assess aerobic fitness were selected. Of the 2625 pooled athletes, 1464 were infected and considered as the post-COVID-19 group, either asymptomatic or symptomatic, while the remaining 1161, who were uninfected or had V.O2max results prior to infection, were defined as the infection-free group. Age and V.O2max were differently distributed between post-COVID-19 athletes and those without infection (p = 0.03 in both). Persistent symptoms athletes had 8 mL/Kg/min lower V.O2max than those without infection (p = 0.04). In addition, post-infected athletes who underwent CPET after 12 weeks showed a significant reduction of 2.9 mL/Kg/min in V.O2max according to the increase in body mass index (BMI). The pooled analysis showed that aerobic fitness was reduced in athletes post-COVID-19. V.O2max was negatively correlated with BMI in those who underwent CPET at 12 weeks, suggesting that symptoms persist beyond 12 weeks, affecting return-to-play.

This study aimed to compare platelet count, platelet indices, lymphocyte, and systemic inflammation indices between surviving and non-surviving COVID-19 patients, measured at admission and on the eighth day of hospitalization.

A retrospective cohort study was conducted on COVID-19 patients hospitalized at Hasan Sadikin General Hospital, Bandung, from March to December 2020. Patient characteristics and laboratory data were sourced from medical records and the Clinical Pathology Laboratory. Bivariate analysis was performed to determine the comparison of platelet indexes between Surviving and Non-Surviving COVID-19 patients depending on data distribution. Significantly correlated variables in Bivariate analysis were included in the ROC analysis, with the AUC used to identify optimal threshold values for laboratory parameters.

Data from 132 patients were analyzed, with 106 (80.3%) surviving and 32 (19.7%) not surviving. Non-surviving patients had lower platelet count, PLTCT, and lymphocyte levels but higher MPV and PDW compared to survivors. Receiver operating characteristic (ROC) analysis revealed that on day 1, lymphocytes had a higher area under the curve (AUC) than MPV. On day 8, lymphocytes had the highest AUC, followed by platelet count, MPV, PLTCT, and PDW.

Platelet indices, lymphocyte counts, and systemic inflammation index have the potential to distinguish the severity of COVID-19.

We herein summarize currently available and clinically relevant information regarding the human immune responses to SARS-CoV-2 infection and vaccination, in relation to COVID-19 outcomes with a focus on acute respiratory distress syndrome (ARDS) and myocarditis.

Acute pancreatitis (AP) is a major health threat, with a high mortality rate in severe forms. Though alcohol and bile-induced factors are the most common causes, increasing evidence suggests that viral infections such as severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and human immunodeficiency virus (HIV) may also trigger AP development. Our study aims to explore this association in greater detail.

After the PROSPERO registration, we systematically searched PubMed, Embase, Cochrane Library, China Science and Technology Journal Database, China National Knowledge Infrastructure, and Wanfang Data Knowledge Service Platform in February 2023. We included studies with the following PECO framework: Population: AP patients, Exposure/Comparison: with/without virus infection, Outcome: mortality, severity, and complications of AP. Pooled odds ratios (OR) were calculated with 95 % confidence intervals (CIs).

Altogether, 29 cohorts with 2,295,172 patients were identified for the meta-analysis and 858 cases for the qualitative synthesis. Patients with concurrent SARS-CoV-2 infection and AP exhibited heightened odds of in-hospital mortality (OR: 3.15, CI: 2.08-4.76), and necrosis (OR: 1.83, CI: 1.13-2.97). Mild AP was less prevalent in the SARS-CoV-2 group (OR: 0.37, CI: 0.14-0.97) compared to moderately severe and severe AP together. Contrarily, no evidence was found that concomitant HIV infection elevated in-hospital mortality (OR: 1.12, CI: 0.92-1.37) or sepsis occurrence (OR:1.21, CI: 0.41-3.59).

Patients co-diagnosed with AP and SARS-CoV-2 infection require heightened attention due to an increased risk of mortality and complications. No evidence was found that HIV infection elevated the risk of a more severe outcome.

To investigate the infection status and outcomes of biliary atresia (BA) patients during the coronavirus disease 2019 (COVID-19) pandemic in Chinese population.

This retrospective study involved Kasai-postoperative BA patients who had achieved jaundice-free during the SARS-CoV-2 outbreak from December 1, 2022 to February 28, 2023. Children without hepatobiliary diseases hospitalized during the same period were as control group. Data collected included nutritional status, comorbidities, epidemiologic characteristics, fever symptoms (duration, max), respiratory symptoms (cough, runny nose and shortness of breath), and gastrointestinal symptoms (diarrhea and vomiting). All cases infected with SARS-CoV-2 were followed up for 3 months.

A total of 128 BA patients were enrolled, ranged in age from 6 months to 12 years old (median age: 1.8 years). A total of 51 (39.8%) and 49 BA patients (38.3%) were classified as confirmed and suspected COVID-19 cases, respectively. Only two confirmed cases presented with moderate symptoms, while the rest developed asymptomatic or mild cases. Compared to the 115 control groups, the proportion of symptomatic cases in BA was slightly higher (78.1% vs. 67.8%) without significant difference (p = 0.07). Similarly, no differences were found in proportion of fever, respiratory tract symptoms and gastrointestinal symptoms between BA and control groups. However, it is worth noting that 7 BA patients developed symptoms of cholangitis during SARS-CoV-2 infection, who experienced pale stool and elevated bilirubin levels. After hospitalization, six patients achieved jaundice-free survival, but one child finally had to undergo liver transplantation due to hepatic failure.

The symptoms and course of COVID-19 in BA patients were similar to those in healthy population. The vast majority of BA patients made a good recovery from COVID-19.

Immune dysregulation and SARS-CoV-2 plasma viremia have been implicated in fatal COVID-19 disease. However, how these two factors interact to shape disease outcomes is unclear.

We carried out viral and immunological phenotyping on a prospective cohort of 280 patients with COVID-19 presenting to acute care hospitals in Boston, Massachusetts and Genoa, Italy between June 1, 2020 and February 8, 2022. Disease severity, mortality, plasma viremia, and immune dysregulation were assessed. A mouse model of lethal H1N1 influenza infection was used to analyze the therapeutic potential of Notch4 and pyroptosis inhibition in disease outcome.

Stratifying patients based on %Notch4+ Treg cells and/or the presence of plasma viremia identified four subgroups with different clinical trajectories and immune phenotypes. Patients with both high %Notch4+ Treg cells and viremia suffered the most disease severity and 90-day mortality compared to the other groups even after adjusting for baseline comorbidities. Increased Notch4 and plasma viremia impacted different arms of the immune response in SARS-CoV-2 infection. Increased Notch4 was associated with decreased Treg cell amphiregulin expression and suppressive function whereas plasma viremia was associated with increased monocyte cell pyroptosis. Combinatorial therapies using Notch4 blockade and pyroptosis inhibition induced stepwise protection against mortality in a mouse model of lethal H1N1 influenza infection.

The clinical trajectory and survival outcome in hospitalized patients with COVID-19 is predicated on two cardinal factors in disease pathogenesis: viremia and Notch4+ Treg cells. Intervention strategies aimed at resetting the immune dysregulation in COVID-19 by antagonizing Notch4 and pyroptosis may be effective in severe cases of viral lung infection.

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.

The immune status of Coronavirus disease 2019 (COVID-19) patients in different stages of infection remains difficult to determine. In this study, we performed high-throughput single-cell mass cytometry on peripheral blood samples from 10 COVID-19 patients and four healthy donors to analyze their immune status at acute and convalescence phases. During the acute stage, the proportion of neutrophils increased significantly while natural killer (NK) cells decreased. In contrast, during the convalescence phase, the proportion of plasma cells decreased from the acute stage of disease onset and was lower than normal. The proportions of B, mast and plasma cell subsets decreased significantly with the process of disease recovery. Further analysis of the subsets of major immune cell types in COVID-19 patients with different clinical presentations in different stages showed that in the acute stages of disease progression, the T helper cell 1 (Th1), IgD+ B and neutrophil subsets increased in COVID-19 patients, especially in symptomatic patients, while the central memory CD4+T cells (CD4 TCM), mucosa-associated invariant T (MAIT) and NK cell subsets decreased significantly, especially in symptomatic patients. Then CD4 TCM and MAIT returned to normal levels at the recovery phase. Dynamic assessment displayed that the immune imbalance at the onset of COVID-19 could be corrected during recovery. Our study provides additional information on the immune status of COVID-19 patients with different clinical manifestations in different stages. These findings may provide new insights into COVID-19 immunotherapy and immune intervention.

Nebulized inhalation administration refers to the dispersion of drugs into small droplets suspended in the gas through a nebulized device, which are deposited in the respiratory tract by inhalation, to achieve the local therapeutic effect of the respiratory tract. Compared with other drug delivery methods, nebulized inhalation has the advantages of fast effect, high local drug concentration, less dosage, convenient application and less systemic adverse reactions, and has become one of the main drug delivery methods for the treatment of respiratory diseases. In this review, we first discuss the characteristics of nebulized inhalation, including its principles and influencing factors. Next, we compare the advantages and disadvantages of different types of nebulizers. Finally, we explore the clinical applications and recent research developments of nebulized inhalation therapy. By delving into these aspects, we aim to gain a deeper understanding of its pivotal role in contemporary medical treatment.

COVID-19-associated acute-respiratory distress syndrome (C-ARDS) results from a direct viral injury associated with host excessive innate immune response mainly affecting the lungs. However, cytokine profile in the lung compartment of C-ARDS patients has not been widely studied, nor compared to non-COVID related ARDS (NC-ARDS).

To evaluate caspase-1 activation, IL-1 signature, and other inflammatory cytokine pathways associated with tissue damage using post-mortem lung tissues, bronchoalveolar lavage fluids (BALF), and serum across the spectrum of COVID-19 severity.

Histological features were described and activated-caspase-1 labeling was performed in 40 post-mortem biopsies. Inflammatory cytokines were quantified in BALF and serum from 19 steroid-treated-C-ARDSand compared to 19 NC-ARDS. Cytokine concentrations were also measured in serum from 128 COVID-19 patients at different severity stages.

Typical "diffuse alveolar damage" in lung biopsies were associated with activated caspase-1 expression and vascular lesions. Soluble Caspase-1p20, IL-1β, IL-1Ra, IL-6 and at lower level IFNγ and CXCL-10, were highly elevated in BALF from steroid-treated-C-ARDS as well as in NC-ARDS. IL-1β appeared concentrated in BALF, whereas circulating IL-6 and IL-1Ra concentrations were comparable to those in BALF and correlated with severity. TNFα, TNFR1 and CXCL8 however, were significantly higher in NC-ARDS compared to C-ARDS, treated by steroid.

In the lungs of C-ARDS, both caspase-1 activation with a predominant IL-1β/IL-6 signature and IFNγ -associated chemokines are elevated despite steroid treatment. These pathways may be specifically targeted in ARDS to improve response to treatment and to limit alveolar and vascular lung damage.