Persistent respiratory symptoms and impaired gas exchange are common in patients recovering from COVID-19 pneumonia. The Lung Diffusing Capacity for Carbon Monoxide (DLCO) and Carbon Monoxide Transfer Coefficient (KCO) do not adequately distinguish alveolar membrane dysfunction from vascular abnormalities. This study aimed to characterize persistent diffusion impairment in post-ICU patients with prior SARS-CoV-2 pneumonia and reduced DLCO.

After hospital discharge, patients underwent spirometry, DLCO measurement, and a 6-minute walking test every six months. If DLCO remained impaired at 18-24 months, a combined Lung Diffusing Capacity for Nitric Oxide (DLNO) and DLCO assessment was performed to differentiate alveolar-capillary membrane (DmCO) and pulmonary capillary blood volume (Vc) alterations.

Among 20 patients with persistent DLCO reduction, 3 had an obstructive ventilatory pattern, 6 had restriction, and 12 had low KCO. In restrictive cases, KCO was reduced but remained within normal limits without compensation. The DLNO/DLCO ratio exceeded 113.5% predicted in all patients. DmCO was impaired in 7 patients, while Vc was reduced in 16.

Both DLCO determinants were affected, with vascular impairment predominating. Vc reduction was present in most patients, with mean values below the lower limit of normality, whereas DmCO was less affected and often normal. The elevated DLNO/DLCO ratio suggests that persistent DLCO reduction is primarily driven by prolonged pulmonary capillary circulation dysfunction rather than alveolar membrane alterations, highlighting the vascular component as the primary site of long-term impairment.

Machine learning models have been employed to predict COVID-19 infections and mortality, but many models were built on training and testing sets from different periods. The purpose of this study is to investigate the impact of temporality, i.e., the temporal gap between training and testing sets, on model performances for predicting COVID-19 infections and mortality. Furthermore, this study seeks to understand the causes of the impact of temporality.

This study used a COVID-19 surveillance dataset collected from Brazil in year 2020, 2021 and 2022, and built prediction models for COVID-19 infections and mortality using random forest and logistic regression, with 20 model features. Models were trained and tested based on data from different years and the same year as well, to examine the impact of temporality. To further explain the impact of temporality and its driving factors, Shapley values are employed to quantify individual contributions to model predictions.

For the infection model, we found that the temporal gap had a negative impact on prediction accuracy. On average, the loss in accuracy was 0.0256 for logistic regression and 0.0436 for random forest when there was a temporal gap between the training and testing sets. For the mortality model, the loss in accuracy was 0.0144 for logistic regression and 0.0098 for random forest, which means the impact of temporality was not as strong as in the infection model. Shapley values uncovered the reason behind such differences between the infection and mortality models.

Our study confirmed the negative impact of temporality on model performance for predicting COVID-19 infections, but it did not find such negative impact of temporality for predicting COVID-19 mortality. Shapley value revealed that there was a fixed set of four features that made predominant contributions for the mortality model across data in three years (2020-2022), while for the infection model there was no such fixed set of features across different years.

Trichinella spiralis (Ts) is known to cause cardiac fibrosis, which is a critical precursor to various heart diseases, and its progression is influenced by metabolic changes. However, the metabolic mechanisms remain unclear. Here, we observed that Ts-infected mice exhibited cardiac fibrosis along with elevated succinate levels in the heart using metabolomic analysis. Administration of succinate exacerbated fibrosis during Ts infection, while deficiency in succinate receptor 1 (Sucnr1) alleviated the condition, highlighting the role of the succinate-Sucnr1 axis in fibrosis development. Furthermore, metagenomics sequencing showed that Ts-infected mice had a higher abundance ratio of succinate-producing bacteria to succinate-consuming bacteria in the intestines. Notably, the succinate-producer Bacteroides vulgatus was enriched in Ts group. Oral supplementation with B. vulgatus aggravated Ts-induced cardiac fibrosis. In summary, our findings underscore the succinate-Sucnr1 axis as a critical pathway in helminth-induced cardiac fibrosis and highlight the potential of targeting this axis for therapeutic interventions. This study presents novel insights into the gut-heart axis, revealing innovative strategies for managing cardiovascular complications associated with helminth infections.

Respiratory infectious diseases, particularly those caused by respiratory viruses, have the potential to lead to global pandemics, thereby posing significant threats to public and human health. Historically, the primary treatment for respiratory bacterial infections has been antibiotic therapy, while severe cases of respiratory viral infections have predominantly been managed by controlling inflammatory cytokine storms. Ferroptosis is a novel form of programmed cell death that is distinct from apoptosis and autophagy. In recent years, Recent studies have demonstrated that ferroptosis plays a significant regulatory role in various respiratory infectious diseases, indicating that targeting ferroptosis may represent a novel approach for the treatment of these conditions. This article summarized the toxic mechanisms underlying ferroptosis, its relationship with respiratory infectious diseases, the mechanisms of action, and current treatment strategies. Particular attentions were given to the interplay between ferroptosis and Mycobacterium tuberculosis, Epstein-Barr virus, severe acute respiratory syndrome coronavirus-2, Pseudomonas aeruginosa, dengue virus, influenza virus and herpes simplex virus type1infection. A deeper understanding of the regulatory mechanisms of ferroptosis in respiratory infections will not only advance our knowledge of infection-related pathophysiology but also provide a theoretical foundation for the development of novel therapeutic strategies. Targeting ferroptosis pathways represents a promising therapeutic approach for respiratory infections, with significant clinical and translational implications.

Respiratory viral infections are a major global public health concern, and current antiviral therapies still have limitations. In recent years, research has revealed significant similarities between the immune systems of the gut and lungs, which interact through the complex physiological network known as the "gut-lung axis." As one of the largest immune organs, the gut, along with the lungs, forms an inter-organ immune network, with strong parallels in innate immune mechanisms, such as the activation of pattern recognition receptors (PRRs). Furthermore, the gut microbiota influences antiviral immune responses in the lungs through mechanisms such as systemic transport of gut microbiota-derived metabolites, immune cell migration, and cytokine regulation. Studies have shown that gut dysbiosis can exacerbate the severity of respiratory infections and may impact the efficacy of antiviral therapies. This review discusses the synergistic role of the gut-lung axis in antiviral immunity against respiratory viruses and explores potential strategies for modulating the gut microbiota to mitigate respiratory viral infections. Future research should focus on the immune mechanisms of the gut-lung axis to drive the development of novel clinical treatment strategies.

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.

We aimed to study transcriptional and phenotypic changes in circulating immune cells associated with increased risk of mortality in COVID-19, resolution of pulmonary fibrosis in post-COVID-19-interstitial lung disease (ILD), and persistence of idiopathic pulmonary fibrosis (IPF). Whole blood and peripheral blood mononuclear cells (PBMCs) were obtained from 227 subjects with COVID-19, post-COVID-19 interstitial lung disease (ILD), IPF, and controls. We measured a 50-gene signature (nCounter, Nanostring) previously found to be predictive of IPF and COVID-19 mortality along with plasma levels of several biomarkers by Luminex. In addition, we performed single-cell RNA sequencing (scRNA-seq) in PBMCs (10x Genomics) to determine the cellular source of the 50-gene signature. We identified the presence of three genomic risk profiles in COVID-19 based on the 50-gene signature associated with low-, intermediate-, or high-risk of mortality and with significant differences in proinflammatory and profibrotic cytokines. Patients with COVID-19 in the high-risk group had increased expression of seven genes in CD14+HLA-DRlowCD163+ monocytic-myeloid-derived suppressive cells (7Gene-M-MDSCs) and decreased expression of 43 genes in CD4 and CD8 T cell subsets. The loss of 7Gene-M-MDSCs and increased expression of these 43 genes in T cells was seen in survivors with post-COVID-19-ILD. On the contrary, patients with IPF had low expression of the 43 genes in CD4 and CD8 T cells. Collectively, we showed that a 50-gene, high-risk profile, predictive of IPF and COVID-19 mortality is characterized by a genomic imbalance in monocyte and T-cell subsets. This imbalance reverses in survivors with post-COVID-19-ILD highlighting genomic differences between post-COVID-19-ILD and IPF.NEW & NOTEWORTHY Changes in the 50-gene signature, reflective of increase in CD14+HLA-DRlowCD163+ monocytes and decrease in CD4 and CD8 T cells, are associated with increased mortality in COVID-19. A reversal of this pattern can be seen in post-COVID-19-ILD, whereas its persistence can be seen in IPF. Modulating the imbalance between HLA-DRlow monocytes and T cell subsets should be investigated as a potential strategy to treat pulmonary fibrosis associated with severe COVID-19 and progressive IPF.

Pulmonary fibrosis (PF) is a chronic, progressive and irreversible interstitial lung disease characterized by unremitting pulmonary myofibroblasts activation, extracellular matrix (ECM) deposition and inflammatory recruitment. PF has no curable medication yet. In this study we investigated the molecular pathogenesis and potential therapeutic targets of PF and discovered drug lead compounds for PF therapy. A murine PF model was established in mice by intratracheal instillation of bleomycin (BLM, 5 mg/kg). We showed that the protein level of pulmonary protein phosphatase magnesium-dependent 1A (PPM1A, also known as PP2Cα) was significantly downregulated in PF patients and BLM-induced PF mice. We demonstrated that TRIM47 promoted ubiquitination and decreased PPM1A protein in PF progression. By screening the lab in-house compound library, we discovered otilonium bromide (OB, clinically used for treating irritable bowel syndrome) as a PPM1A enzymatic activator with an EC50 value of 4.23 μM. Treatment with OB (2.5, 5 mg·kg-1·d-1, i.p., for 20 days) significantly ameliorated PF-like pathology in mice. We constructed PF mice with PPM1A-specific knockdown in the lung tissues, and determined that by targeting PPM1A, OB treatment suppressed ECM deposition through TGF-β/SMAD3 pathway in fibroblasts, repressed inflammatory responses through NF-κB/NLRP3 pathway in alveolar epithelial cells, and blunted the crosstalk between inflammation in alveolar epithelial cells and ECM deposition in fibroblasts. Together, our results demonstrate that pulmonary PPM1A activation is a promising therapeutic strategy for PF and highlighted the potential of OB in the treatment of the disease.

Animal models of COVID-19 facilitate the development of vaccines and antivirals against SARS-CoV-2. The efficacy of antivirals or vaccines may differ in different animal models with varied degrees of disease. Here, we introduce a mouse model expressing human angiotensin-converting enzyme 2 (ACE2). In this model, ACE2 with the human cytokeratin 18 promoter was knocked into the Hipp11 locus of C57BL/6J mouse by CRISPR - Cas9 (K18-hACE2 KI). Upon intranasal inoculation with high (3 × 105 PFU) or low (2.5 × 102 PFU) dose of SARS-CoV-2 wildtype (WT), Delta, Omicron BA.1, or Omicron BA.2 variants, all mice showed obvious infection symptoms, including weight loss, high viral loads in the lung, and interstitial pneumonia. 100% lethality was observed in K18-hACE2 KI mice infected by variants with a delay of endpoint for Delta and BA.1, and a significantly attenuated pathogenicity was observed for BA.2. The pneumonia of infected mice was accompanied by the infiltration of neutrophils and pulmonary fibrosis in the lung. Compared with K18-hACE2 Tg mice and HFH4-hACE2 Tg mice, K18-hACE2 KI mice are more susceptible to SARS-CoV-2. In the antivirals test, REGN10933 and Remdesivir had limited antiviral efficacies in K18-hACE2 KI mice upon the challenge of SARS-CoV-2 infections, while Nirmatrelvir, monoclonal antibody 4G4, and mRNA vaccines potently protected the mice from death. Our results suggest that the K18-hACE2 KI mouse model is lethal and stable for SARS-CoV-2 infection, and is practicable and stringent to antiviral development.

There have been differential mortality rates from COVID-19 in different parts of the world. It is not clear whether the clinical presentation does also differ, thus the need for this study in a sub-Saharan African setting. The aim of this study was to describe the clinical manifestations and outcomes of patients diagnosed with COVID-19 in selected tertiary hospitals in Tanzania.

This was a retrospective analysis of hospitalised adults confirmed SAR-COV-2 infection in five tertiary-level hospitals in Tanzania. Data collected and analysed included sociodemographic, radiological and clinical characteristics of the patients as well as the outcome of the admission (discharge vs death).

Out of 1387 COVID-19 patients, 52% were males. The median age was 60 years ((IQR)=(19-102)). The most common symptoms were dyspnoea (943,68%), cough (889, 64%), fever (597,43%) and fatigue (570, 41%). In-hospital mortality was (476, 34%). Mortality significantly increased with increasing age, being the most in age >90 years (aHR (95% CI)=4.4 (2.52 to 28.82), p=0.02). Other predictors of mortality were not possessing a health insurance, (aHR (95% CI)=3.7 (1.09 to 14.25), p=0.04); chest pain, (aHR (95% CI)=2.27 (1.36 to 4.13), p=0.03); HIV positivity, (aHR (95% CI)=3.9 (1.46 to 8.15), p=0.03); neutrophilia, (aHR (95% CI)=1.12 (1.01 to 2.65), p=0.03); no use of ivermectin, (aHR (95% CI)=1.21 (1.04 to 1.57), p=0.04) and non-use of steroids, (aHR (95% CI)=1.36 (1.18 to 2.78), p=0.04). The retrospective nature of this study which based on documented patients' records, with a large number of patients left out of the analysis due to missed data, this might in a way affect the results of the present study.

In-hospital mortality was 34%. The independent predictors of mortality were advanced age, HIV infection, no possession of a health insurance, chest pain, neutrophilia and no use of steroids or ivermectin.

Secondary organizing pneumonia (OP) and acute fibrinous and organizing pneumonia (AFOP) are frequently observed in cases of COVID-19 pneumonia. Nevertheless, the identification of risk factors related to OP/AFOP and their impact on patient outcomes remain inadequately elucidated.

This retrospective study aimed to identify risk factors associated with OP/AFOP in patients with COVID-19 pneumonia and to compare clinical outcomes between patients with and without OP/AFOP. The study included hospitalized patients with COVID-19 pneumonia admitted between July 1 and September 30, 2021. Factors associated with OP/AFOP were identified using multivariable regression analysis. Additionally, a multivariable Cox proportional hazard model was used to evaluate the association of OP/AFOP with 90-day mortality.

Among the 666 hospitalized patients with COVID-19 pneumonia, 53 (8%) developed OP/AFOP during their admission. When compared to patients younger than 50 years old, those aged 50-70 and over 70 years old exhibited an increased risk of developing OP/AFOP, with adjusted odds ratios (aOR) of 3.87 (95% CI, 1.24-12.11; P=0.02) and 5.74 (95% CI, 1.80-18.27; P=0.003), respectively. Other factors associated with OP/AFOP included a history of diabetes mellitus (aOR 2.37; 95% CI, 1.27-4.44; P=0.01) and patients with oxygen saturation at admission below 88% (aOR 4.52; 95% CI, 1.22-16.67; P=0.02). Furthermore, the presence of OP/AFOP was correlated with an increased risk of various complications, such as respiratory failure, acute kidney injury, secondary infections, pneumothorax, pneumomediastinum, and pulmonary embolism. Lastly, patients with OP/AFOP exhibited significantly higher 90-day mortality (adjusted hazard ratio 3.40; 95% CI, 1.68-6.92; P=0.001) compared to those without OP/AFOP.

We identified factors associated with an increased risk of OP/AFOP in patients with COVID-19 pneumonia, which included age ≥50 years, a history of DM, and hypoxemia on admission (SpO2 <88%). Furthermore, our study revealed that OP/AFOP was significantly linked to higher 90-day mortality.

Long coronavirus disease (COVID), also known as the post-acute sequelae of coronavirus disease 2019 (COVID-19) (PASC), is a significant concern since the end of the COVID-19 pandemic, as it still manifests in individuals with persistent symptoms and complications beyond the acute phase of infection. Defining this disease is challenging, as it manifests as a spectrum of symptoms varying in severity among individuals who have previously tested positive for COVID-19. Long COVID is more prevalent in hospitalized COVID-19 patients and presents in various ways, ranging from pulmonary to extrapulmonary symptoms. This literature review examines the current body of research on long COVID with a focus on its effects on the cardiovascular, hematological, respiratory, renal, and neurological systems with systematically analyzed, peer-reviewed articles retrieved from the PubMed database. There have been several proposed pathophysiological mechanisms by which severe acute respiratory syndrome coronavirus 2 affects the aforementioned organ systems; however, research on the definite mechanisms is lacking, especially when considering the management of long COVID in the perioperative setting. The impact of post-COVID sequelae necessitates individualized management strategies tailored to each symptomatic profile, particularly in patients with comorbidities. The COVID-19 pandemic affected millions of people and had a profound impact on those who developed PASC, lowering their quality of life and increasing potential surgical risks. However, there is still uncertainty regarding the specific risk factors for long COVID and who is most susceptible to it. Further research is required to fill these gaps and explore potential avenues for preventing PASC.

Efficacy of mesenchymal stem cells (MSCs) for treatment of acute respiratory distress syndrome (ARDS) suggests bioactive bone marrow MSC extracellular vesicles (BM-MSC EVs) may be effective. A patient with severe COVID-19 associated ARDS who was presumed to expire was treated with a BM-MSC EV preparation (14 doses over two months) as a rescue treatment for refractory COVID ARDS. Near complete reversal of lung inflammation and fibrosis (per computed tomography), near complete restoration of mobility, hospital discharge (3 months) with resumption of normal activities of daily living (one year) and return to work occurred. No adverse events occurred despite repeated dosing of investigational product, highlighting safety of this potential therapy for ARDS.

COVID-19 has affected millions worldwide, causing significant morbidity and mortality. While predominantly involving the respiratory tract, SARS-CoV-2 has also caused systemic illnesses involving other sites. Liver injury due to COVID-19 has been variably reported in observational studies. It has been postulated that liver damage may be due to direct damage by the SARS-CoV-2 virus or multifactorial secondary to hepatotoxic therapeutic options, as well as cytokine release syndrome and sepsis-induced multiorgan dysfunction. The approach to a COVID-19 patient with liver injury requires a thorough evaluation of the pattern of hepatocellular injury, along with the presence of underlying chronic liver disease and concurrent medications which may cause drug-induced liver injury. While studies have shown uneventful recovery in the majority of mildly affected patients, severe COVID-19 associated liver injury has been associated with higher mortality, prolonged hospitalization, and greater morbidity in survivors. Furthermore, its impact on long-term outcomes remains to be ascertained as recent studies report an association with metabolic-fatty liver disease. This present review provides insight into the subject by describing the postulated mechanism of liver injury, its impact in the presence of pre-existing liver disease, and its short- and long-term clinical implications.

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.

People living with human immunodeficiency virus (PLWH) are a significant population globally. Research delineating our understanding of coinfections in PLWH is critical to care for those navigating infection with other pathogens. The recent COVID-19 pandemic underscored the urgent need for studying the effects of SARS-CoV-2 infections in therapy-controlled and uncontrolled immunodeficiency viral infections. This study established the utility of a feline model for the in vivo study of coinfections. Domestic cats are naturally infected with SARS-CoV-2 and Feline Immunodeficiency Virus, a lentivirus molecularly and pathogenically similar to HIV. In this study, comparisons are made between FIV-positive and FIV-negative cats inoculated with SARS-CoV-2 (B.1.617.2.) in an experimental setting. Of the FIV+ cats, three received Zidovudine (AZT) therapy in the weeks leading up to SARS-CoV-2 inoculation, and two did not. SARS-CoV-2 viral RNA was quantified, histopathologic comparisons of respiratory tissues were made, and T-cell populations were analyzed for immune phenotype shifts between groups. CD4+ T lymphocyte responses varied, with FIV+-untreated cats having the poorest CD4+ response to SARS-CoV-2 infection. While all cats had significant pulmonary inflammation, key histopathologic features of the disease differed between groups. Additionally, viral genomic analysis was performed, and results were analyzed for the presence of emerging, absent, amplified, or reduced mutations in SARS-CoV-2 viral RNA after passage through the feline model. Positive selection is noted, especially in FIV+ cats untreated with AZT, and mutations with potential relevance were identified; one FIV+-untreated cat had persistent, increasing SARS-CoV-2 RNA in plasma five days post-infection. These findings and others support the utility of the feline model for studying coinfection in people with HIV and highlight the importance of antiretroviral therapy in clearing SARS-CoV-2 coinfections to minimize transmission and emergence of mutations that may have deleterious effects.

Coronavirus disease 2019 (COVID-19), caused by the highly pathogenic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), primarily impacts the respiratory tract and can lead to severe outcomes such as acute respiratory distress syndrome, multiple organ failure, and death. Despite extensive studies on the pathogenicity of SARS-CoV-2, its impact on the hepatobiliary system remains unclear. While liver injury is commonly indicated by reduced albumin and elevated bilirubin and transaminase levels, the exact source of this damage is not fully understood. Proposed mechanisms for injury include direct cytotoxicity, collateral damage from inflammation, drug-induced liver injury, and ischemia/hypoxia. However, evidence often relies on blood tests with liver enzyme abnormalities. In this comprehensive review, we focused solely on the different histopathological manifestations of liver injury in COVID-19 patients, drawing from liver biopsies, complete autopsies, and in vitro liver analyses. We present evidence of the direct impact of SARS-CoV-2 on the liver, substantiated by in vitro observations of viral entry mechanisms and the actual presence of viral particles in liver samples resulting in a variety of cellular changes, including mitochondrial swelling, endoplasmic reticulum dilatation, and hepatocyte apoptosis. Additionally, we describe the diverse liver pathology observed during COVID-19 infection, encompassing necrosis, steatosis, cholestasis, and lobular inflammation. We also discuss the emergence of long-term complications, notably COVID-19-related secondary sclerosing cholangitis. Recognizing the histopathological liver changes occurring during COVID-19 infection is pivotal for improving patient recovery and guiding decision-making.

The reduction of lung capillary blood volume (Vc) had been identified as the microvascular injury mostly underlying the respiratory Long-COVID syndrome following post-COVID-19 pneumonia. The same kind of injury have been recently also found in several individuals after milder paucisymptomatic SARS-CoV-2 infections. Though current guidelines strongly recommend vac-cination, studies aimed to investigate the in vivo protection of anti-SARS-CoV-2 vaccines on lung microvascular targets still are missing to our best knowledge.

to assess the protection of mRNA vaccines from the reduction of lung capillary blood volume (Vc) caused by pauci-symptomatic SARS.CoV-2 infections in vaccinated compared to unvaccinated individuals.

Non-smoking individuals with recent paucisymptomatic SARS-CoV-2 infection were divided into vaccinated and unvaccinated groups. Lung function parameters, including single-breath diffusing capacity and microvascular blood volume, were compared between groups.

fifty vaccinated and twenty-five unvaccinated well-matched individuals were studied. Differently than usual lung function parameters, only the single-breath simultaneous assessment of sDLCO, sDLNO/sDLCO ratio and Vc allowed to identify the occurrence of the lung microvascular injury with high sensitivity and specificity (p<0.001).

mRNA vaccines proved to exert a high protection from the loss of lung capillary blood volume (Vc) induced by SARS.CoV-2 paucisymptomatic infections (p<0.001). The availability of this non-invasive investigational model should be regarded as a very helpful tool for assessing and comparing in vivo the protective effect of mRNA vaccines on the human microvascular structures of the deep lung.

The high risk of SARS-CoV-2 infection and reinfection and the occurrence of post-acute pulmonary sequelae have highlighted the importance of understanding the mechanism underlying lung repair after injury. To address this concern, comparative and systematic analyses of SARS-CoV-2 infection in COVID-19 patients and animals were conducted. In the lungs of nine patients who died of COVID-19 and one recovered from COVID-19 but died of unrelated disease in early 2020, damage-related transient progenitor (DATP) cells expressing CK8 marker proliferated significantly. These CK8+ DATP cells were derived from bronchial CK5+ basal cells. However, they showed different cell fate toward differentiation into type I alveolar cells in the deceased and convalescent patients, respectively. By using a self-limiting hamster infection model mimicking the dynamic process of lung injury remodeling in mild COVID-19 patients, the accumulation and regression of CK8+ cell marker were found to be closely associated with the disease course. Finally, we examined the autopsied lungs of two patients who died of infection by the recent Omicron variant and found that they only exhibited mild pathological injury with no CK8+ cell proliferation. These results indicate a clear pulmonary cell remodeling route and suggest that CK8+ DATP cells play a primary role in mediating alveolar remodeling, highlighting their potential applications as diagnostic markers and therapeutic targets.

The pathology of severe COVID-19 lung injury is predominantly diffuse alveolar damage, with other reported patterns including acute fibrinous organizing pneumonia, organizing pneumonia, and bronchiolitis. Lung injury was caused by primary viral injury, exaggerated immune responses, and superinfection with bacteria and fungi. Although fatality rates have decreased from the early phases of the pandemic, persistent pulmonary dysfunction occurs and its pathogenesis remains to be fully elucidated.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is a highly contagious and dangerous virus that caused the global COVID-19 pandemic in early 2020. It primarily affects the respiratory system, leading to severe illness and high rates of mortality worldwide. The virus enters the body by binding to a receptor called ACE2, which is present in specific cells of the lungs known as type 2 alveolar epithelial cells. Numerous studies have investigated the consequences of SARS-CoV-2 infection, revealing various impacts on the body. This review provides an overview of SARS-CoV-2, including its structure and how it infects cells. It also examines the different variants of concern, such as Alpha, Beta, Gamma, Delta, and the more recent Omicron variant, discussing their characteristics and the level of damage they cause. The usage of drugs to treat COVID-19 is another aspect that has been covered and compares the effectiveness and use of antiviral drugs in the treatment and its potential benefits in COVID-19 treatment. Furthermore, this review explores the consequences and abnormalities associated with SARS-CoV-2 infection, including its impact on various organs and systems in the body. And also discussing the different COVID-19 vaccines available and their effectiveness in preventing infection and reducing the severity of illness. The current review ensures the recent update of the COVID research with expert's knowledge, collection of numerous data from reliable sources and methodologies as well as update of findings based on reviews. This review also provided clear contextual explanations to aid the interpretation and application of the results. The main motto and limitation of this manuscript are to address the computational methods of drug discovery against the rapidly evolving SARS-CoV-2 virus, which has been discussed. Additionally, current computational approaches which are cost effective and can able to predict the therapeutic agents for the treatment against the virus have also been discussed.

Fibrosis is a dynamic process characterized by a typical cascade of events as a result of overexpressed repair of connective tissue in response to injury, and manifested by excessive accumulation of extracellular matrix. The development of fibrosis is a determining factor in the pathogenesis, clinical course and prognosis of many diseases, among which interstitial lung diseases occupy a special place. According to a large Russian registry (ClinicalTrials.gov: NCT04492384), in a third of patients with COVID-19, the volume of lung parenchyma involvement exceeds 50% (CT 3-4). The rapid growth in the number of patients who have had a coronavirus infection with lung damage has raised the issues of its long-term consequences to the number of the most relevant in internal medicine of the current time. Often, in the outcome of a coronavirus infection, patients retain clinical and functional changes that are similar to interstitial lung diseases of a different origin, the prognosis of which is determined by the development of interstitial fibrosis and the rate of its progression. This article is an attempt to consider topical issues of fibrogenesis in patients who have undergone a new coronavirus infection through the prism of polar data on immunobiology, clinical course and prognosis.

Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory disease characterized by severe acute infection. In some cases, COVID-19 symptoms may persist for a long term, posing a significant social problem. Long-term COVID-19 symptoms resemble those observed in various autoimmune diseases, such as dermatomyositis and polymyositis. In this report, we present the case of a 55-year-old woman who had been experiencing persistent dyspnea on exertion since contracting COVID-19 a month ago and was subsequently diagnosed with anti-synthetase syndrome (ASS). The patient presented with fever, dyspnea, rash, mechanic's hands, and arthritis. Computed tomography imaging revealed findings indicative of interstitial pneumonia. Immunological test results were positive for anti-EJ antibody, leading to a diagnosis of ASS based on Solomon's established criteria. The patient's condition improved following treatment with prednisolone, tacrolimus, and intravenous cyclophosphamide. Pathological findings of transbronchial biopsy revealed nonspecific interstitial pneumonia with organizing pneumonia, leading to speculation that ASS had developed after COVID-19. Given the scarcity of reports on ASS development post COVID-19, we conducted a literature review and compared our present case to previous ones. This report highlights the importance of considering ASS in the differential diagnosis of patients with long-term COVID-19 symptoms.

During the outbreak of the coronavirus disease 2019 (COVID-19) pandemic, particular interest rose regarding the interaction between metabolic dysfunction-associated fatty liver disease (MAFLD) and the COVID-19 infection. Several studies highlighted the fact that individuals with MAFLD had higher probability of severe acute respiratory syndrome coronavirus 2 infection and more severe adverse clinical outcomes. One of the proposed mechanisms is the inflammatory response pathway, especially the one involving cytokines, such as interleukin 6, which appeared particularly elevated in those patients and was deemed responsible for additional insult to the already damaged liver. This should increase our vigilance in terms of early detection, close follow up and early treatment for individuals with MAFLD and COVID-19 infection. In the direction of early diagnosis, biomarkers such as cytokeratin-18 and scoring systems such as Fibrosis-4 index score are proposed. COVID-19 is a newly described entity, expected to be of concern for the years to come, and MAFLD is a condition with an ever-increasing impact. Delineating the interaction between these two entities should be brought into the focus of research. Reducing morbidity and mortality of patients with COVID-19 and MAFLD should be the ultimate objective, and the optimal way to achieve this is by designing evidence-based prevention and treatment policies.

As a primary target of severe acute respiratory syndrome coronavirus 2, lung exhibits heterogeneous histopathological changes following infection. However, comprehensive insight into their protein basis with spatial resolution remains deficient, which hinders further understanding of coronavirus disease 2019 (COVID-19)-related pulmonary injury. Here, we generate a region-resolved proteomic atlas of hallmark pathological pulmonary structures by integrating histological examination, laser microdissection, and ultrasensitive proteomics. Over 10,000 proteins are quantified across 71 post-mortem specimens. We identify a spectrum of pathway dysregulations in alveolar epithelium, bronchial epithelium, and blood vessels compared with non-COVID-19 controls, providing evidence for transitional-state pneumocyte hyperplasia. Additionally, our data reveal the region-specific enrichment of functional markers in bronchiole mucus plugs, pulmonary fibrosis, airspace inflammation, and alveolar type 2 cells, uncovering their distinctive features. Furthermore, we detect increased protein expression associated with viral entry and inflammatory response across multiple regions, suggesting potential therapeutic targets. Collectively, this study provides a distinct perspective for deciphering COVID-19-caused pulmonary dysfunction by spatial proteomics.

The immunological signatures driving the severity of coronavirus disease 19 (COVID-19) in Ghanaians remain poorly understood. We performed bulk transcriptome sequencing of nasopharyngeal samples from severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-infected Ghanaians with mild and severe COVID-19, as well as healthy controls to characterize immune signatures at the primary SARS-CoV-2 infection site and identify drivers of disease severity. Generally, a heightened antiviral response was observed in SARS-CoV-2-infected Ghanaians compared with uninfected controls. COVID-19 severity was associated with immune suppression, overexpression of proinflammatory cytokines, including CRNN, IL1A, S100A7, and IL23A, and activation of pathways involved in keratinocyte proliferation. SAMD9L was among the differentially regulated interferon-stimulated genes in our mild and severe disease cohorts, suggesting that it may play a critical role in SARS-CoV-2 pathogenesis. By comparing our data with a publicly available dataset from a non-African (Indians) (GSE166530), an elevated expression of antiviral response-related genes was noted in COVID-19-infected Ghanaians. Overall, the study describes immune signatures driving COVID-19 severity in Ghanaians and identifies immune drivers that could serve as potential prognostic markers for future outbreaks or pandemics. It further provides important preliminary evidence suggesting differences in antiviral response at the upper respiratory interface in sub-Saharan Africans (Ghanaians) and non-Africans, which could be contributing to the differences in disease outcomes. Further studies using larger datasets from different populations will expand on these findings.

Although severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) responsible for coronavirus disease 2019 (COVID-19) is most well-known for causing pulmonary injury, a significant proportion of patients experience hepatic dysfunction. The mechanism by which SARS-CoV2 causes liver injury is not fully understood. The goal of this study was to describe the hepatic pathology in a large cohort of deceased patients with COVID-19 as compared to a control group of deceased patients without COVID-19.

Consented autopsy cases at two institutions were searched for documentation of COVID-19 as a contributing cause of death. A group of consecutive consented autopsy cases during the same period, negative for SARS-CoV-2 infection, was used as a control group. The autopsy report and electronic medical records were reviewed for relevant clinicopathologic information. H&E-stained liver sections from both groups were examined for pertinent histologic features. Select cases underwent immunohistochemical staining for CD 68 and ACE2 and droplet digital polymerase chain reaction (ddPCR) assay for evaluation of SARS-CoV2 RNA.

48 COVID-19 positive patients (median age 73, M:F 3:1) and 40 COVID-19 negative control patients (median age 67.5, M:F 1.4:1) were included in the study. The COVID-19 positive group was significantly older and had a lower rate of alcoholism and malignancy, but there was no difference in other comorbidities. The COVID-19 positive group was more likely to have received steroids (75.6 % vs. 36.1 %, p < 0.001). Hepatic vascular changes were seen in a minority (10.6 %) of COVID-19 positive cases. When all patients were included, there were no significant histopathologic differences between groups, but when patients with chronic alcoholism were excluded, the COVID-19 positive group was significantly more likely to have steatosis (80.9 % vs. 50.0 %, p = 0.004) and lobular inflammation (45.7 % vs. 20.7 %, p = 0.03). Testing for viral RNA by ddPCR identified 2 of the 18 (11.1 %) COVID-19 positive cases to have SARS-CoV-2 RNA detected within the liver FFPE tissue.

The most significant findings in the liver of COVID-19 positive patients were mild lobular inflammation and steatosis. The high rate of steroid therapy in this population may be a possible source of steatosis. Hepatic vascular alterations were only identified in a minority of patients and did not appear to play a predominant role in COVID-19 mediated hepatic injury. Low incidence of SARS-CoV-2 RNA positivity in liver tissue in our cohort suggests hepatic injury in the setting of COVID-19 may be secondary in nature.

The novel disease produced by SARS-CoV-2 mainly harms the respiratory tract, but it has shown the capacity to affect multiple organs. Epidemiologic evidence supports the relationship between Coronavirus Disease 2019 (COVID-19) and pancreatic and hepatic injury development, identified by alterations in these organ function markers. In this regard, it is important to ascertain how the current prevalence of non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) might affect COVID-19 evolution and complications. Although it is not clear how SARS-CoV-2 affects both the pancreas and the liver, a multiplicity of potential pathophysiological mechanisms seem to be implicated; among them, a direct viral-induced injury to the organ involving liver and pancreas ACE2 expression. Additionally, immune system dysregulation, coagulopathies, and drugs used to treat the disease could be key for developing complications associated with the patient's clinical decline. This review aims to provide an overview of the available epidemiologic evidence regarding developing liver and pancreatic alterations in patients with COVID-19, as well as the possible role that NAFLD/NASH might play in the pathophysiological mechanisms underlying some of the complications associated with COVID-19. This review employed a comprehensive search on PubMed using relevant keywords and filters. From the initial 126 articles, those aligning with the research target were selected and evaluated for their methodologies, findings, and conclusions. It sheds light on the potential pathophysiological mechanisms underlying this relationship. As a result, it emphasises the importance of monitoring pancreatic and hepatic function in individuals affected by COVID-19.

The pandemic of coronavirus disease 2019 (COVID-19) has been the foremost modern global public health challenge. The airway is the primary target in severe acute respiratory distress syndrome coronavirus 2 (SARS-CoV-2) infection, with substantial cell death and lung injury being signature hallmarks of exposure. The viral factors that contribute to cell death and lung injury remain incompletely understood. Thus, this study investigated the role of open reading frame 7b (Orf7b), an accessory protein of the virus, in causing lung injury. In screening viral proteins, we identified Orf7b as one of the major viral factors that mediates lung epithelial cell death. Overexpression of Orf7b leads to apoptosis and ferroptosis in lung epithelial cells, and inhibitors of apoptosis and ferroptosis ablate Orf7b-induced cell death. Orf7b upregulates the transcription regulator, c-Myc, which is integral in the activation of lung cell death pathways. Depletion of c-Myc alleviates both apoptotic and ferroptotic cell deaths and lung injury in mouse models. Our study suggests a major role of Orf7b in the cell death and lung injury attributable to COVID-19 exposure, supporting it as a potential therapeutic target.

Acute respiratory distress syndrome (ARDS) is one of the major problems in COVID-19 that is not well understood. ARDS is usually complicated by co-infections in hospitals. Although ARDS is inherited by Europeans and Africans, this is not clear for those from the Middle East. There are severe limitations in correlations made between COVID-19, ARDS, co-infectome, and patient demographics. We investigated 298 patients for associations of ARDS, coinfections, and patient demographics on COVID-19 patients' outcomes. Of the 149 patients examined for ARDS during COVID-19, 16 had an incidence with a higher case fatality rate (CFR) of 75.0% compared to those without ARDS (27.0%) (p value = 0.0001). The co-infectome association showed a CFR of 31.3% in co-infected patients; meanwhile, only 4.8% of those without co-infections (p value = 0.01) died. The major bacteria were Acinetobacter baumannii and Escherichia coli, either alone or in a mixed infection with Klebsiella pneumoniae. Kaplan-Meier survival analysis of COVID-19 patients with and without ARDS revealed a significant difference in the survival time of patients with ARDS (58.8 +/- 2.7 days) and without ARDS (41.9 +/- 1.8 days) (p value = 0.0002). These findings prove that increased hospital time was risky for co-infectome-induced SDRS later on. This also explained that while empiric therapy and lethal ventilations delayed the mortality in 75% of patients, they potentially did not help those without co-infection or ARDS who stayed for shorter times. In addition, the age of patients (n = 298) was significantly associated with ARDS (72.9 +/- 8.9) compared to those without it (56.2 +/- 15.1) and was irrespective of gender. However, there were no significant differences neither in the age of admitted patients before COVID-19 (58.5 +/- 15.3) and during COVID-19 (57.2 +/- 15.5) nor in the gender and COVID-19 fatality (p value 0.546). Thus, Gram-negative co-infectome potentially induced fatal ARDS, aggravating the COVID-19 outcome. These findings are important for the specific differential diagnosis of patients with and without ARDS and co-infections. Future vertical investigations on mechanisms of Gram-negative-induced ARDS are imperative since hypervirulent strains are rapidly circulating. This study was limited as it was a single-center study confined to Ha'il hospitals; a large-scale investigation in major national hospitals would gain more insights.

Owing to coronavirus disease 2019 (COVID-19), lung damage is seen as an important problem in patients after recovery. In this study, evaluation of respiratory symptoms and lung ultrasonography (LUS) findings of those who have had symptomatic and asymptomatic COVID-19 disease in children was aimed. A total of 81 patients with positive and 18 healthy children with negative COVID-19 antibodies were included to the study. The most common late presentation symptoms were cough (85.2%), shortness of breath (77.8%), and chest pain (60.5%). In LUS, 2 or less B lines, 3 or more B lines, and Z line were seen in 66.7%, 33.3%, and 9.9% of patients, respectively. There was no significant difference between control and patients in terms of these parameters (P > .05). Pleural effusion was detected in 2 patients in the late period. Respiratory system findings may develop in the late period in patients infected with COVID-19. Therefore, patients should be followed closely.

(1) Background: Persistent COVID is characterized by the presence of fatigue, mental fog, and sleep problems, among others. We aimed to study cognitive abilities (attention, executive functions, memory, language) and psychological and emotional factors in a group of participants of the population with persistent COVID-19 and asymptomatic or non-COVID-19-infected patients; (2) Methods: A total of 86 participants aged 18 to 66 years (X = 46.76) took part in the study, with 57 individuals (66.27%) in the experimental group and 29 (33.73%) in the control group. A comprehensive assessment included neuropsychological evaluations, evaluations of anxious and depressive symptomatology, assessments of the impact of fatigue, sleep quality, memory failures in daily life, and the perceived general health status of the participants; (3) Results: significant differences between groups were found in incidental learning within the Key Numbers task (U = 462.5; p = 0.001; p = 0.022) and in the Direct Digit Span (U = 562; p = 0.022), but not in the Inverse Digit Span (U = 632.5; p = 0.105). Differences were also observed in the prospective memory task of the Rivermead Prospective Memory Tasks (from the Rivermead Behavioural Memory Test) in the recall of quotations (U = 610; p = 0.020) as well as in the recall of objects (U = 681.5; p = 0.032). Concerning the task of verbal fluency, significant differences were found for both phonological cues (p- and s-) (t = -2.190; p = 0.031) and semantic cues (animals) (t = -2.277; p = 0.025). In terms of the psychological impact assessment, significant differences were found in the emotional impact across all variables studied (fatigue, quality of sleep, memory lapses, and the perceived general health status), except for quality of life; (4) Conclusions: Our results suggest that the sequelae derived from persistent COVID may have an impact on people's lives, with higher levels of anxiety and depression, worse sleep quality, a greater number of subjective memory complaints, and a greater feeling of fatigue and impact on quality of life. Furthermore, poorer performance was observed in memory and verbal fluency.

Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (COVID-19) pandemic. It is the final outcome of the acute respiratory distress syndrome (ARDS), characterized by an initial exacerbated inflammatory response, metabolic derangement and ultimate tissue scarring. A positive balance of cellular energy may result crucial for the recovery of clinical COVID-19. Hence, we asked if two key pathways involved in cellular energy generation, AMP-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC) signaling and fatty acid oxidation (FAO) could be beneficial. We tested the drugs metformin (AMPK activator) and baicalin (CPT1A activator) in different experimental models mimicking COVID-19 associated inflammation in lung and kidney. We also studied two different cohorts of COVID-19 patients that had been previously treated with metformin. These drugs ameliorated lung damage in an ARDS animal model, while activation of AMPK/ACC signaling increased mitochondrial function and decreased TGF-β-induced fibrosis, apoptosis and inflammation markers in lung epithelial cells. Similar results were observed with two indole derivatives, IND6 and IND8 with AMPK activating capacity. Consistently, a reduced time of hospitalization and need of intensive care was observed in COVID-19 patients previously exposed to metformin. Baicalin also mitigated the activation of pro-inflammatory bone marrow-derived macrophages (BMDMs) and reduced kidney fibrosis in two animal models of kidney injury, another key target of COVID-19. In human epithelial lung and kidney cells, both drugs improved mitochondrial function and prevented TGF-β-induced renal epithelial cell dedifferentiation. Our results support that favoring cellular energy production through enhanced FAO may prove useful in the prevention of COVID-19-induced lung and renal damage.