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1.
medrxiv; 2023.
Препринт в английский | medRxiv | ID: ppzbmed-10.1101.2023.01.23.23284848

Реферат

Background COVID-19 is a complex multisystem disease, frequently associated with kidney injury. Since the beginning of the COVID-19 pandemic, we observed a striking increase in the incidence of acute tubulointerstitial nephritis (aTIN) without or with uveitis (TINUs) among children. This prompted us to examine whether SARS-CoV-2 might be the underlying trigger. Methods We conducted a French nationwide retrospective cohort study. We included all consecutive children diagnosed with aTIN or TINUs of undetermined cause between April-2020 and March-2021. SARS-CoV-2 antibody responses were tested by a luciferase immunoprecipitation system and compared to age-matched controls. Immunohistochemistry, immunofluorescence and molecular microbiology analyses were performed on kidney biopsies. Results Forty-eight children were included with a median age at diagnosis of 14.7 years (9.4-17.6). aTIN and TINUs incidence rates increased 3-fold and 12-fold, respectively, compared to pre-pandemic years. All patients had impaired kidney function with a median eGFR of 31.9 ml/min/1.73m2 at diagnosis. Kidney biopsies showed lesions of acute tubulointerstitial nephritis and 25% of patients had fibrosis. No patient had concomitant acute COVID-19. All 16 children tested had high anti-N IgG titers and one had anti-S IgGs. Next-generation sequencing failed to detect any infectious agents in kidney biopsies. However, SARS-CoV-2 RNA was detected by PCR in two kidney samples supporting a potential direct link between SARS-CoV-2 and aTIN/TINUs. Conclusions We describe a novel form of post-acute COVID-19 syndrome in children, unique in its exclusive kidney and eye involvement, and its distinctive anti-SARS-CoV-2 N+/S- serological profile. Our results support a causal association linking SARS-CoV-2 infection to this newly-reported burst of renal/eye inflammation.


Тема - темы
COVID-19 , Disease , Fibrosis , Kidney Diseases , Nephritis, Interstitial , Carcinoma, Renal Cell , Uveitis
2.
medrxiv; 2023.
Препринт в английский | medRxiv | ID: ppzbmed-10.1101.2023.01.20.23284812

Реферат

People with weak immune systems are more likely to develop severe COVID-19, less likely to be included in vaccine controlled studies but more likely to be under-vaccinated. We review post-marketing studies to examine the immunogenicity, safety and effectiveness of BNT162b2 vaccine in immunocompromised adolescents and young adults (AYA). We searched more than three international databases from 2020 to 30 May 2022 and used the ROBINS-I for bias assessment. Random effect model was used to estimate pooled proportion, log RR, and mean difference. Egger's regression and Begg's rank correlation were used to examine publication bias. 47 full texts were reviewed, and nine were included. Conditions studied were rheumatic diseases, diabetes mellitus, Down syndrome, solid tumours, neurodisability, and cystic fibrosis. Eight studies used cohort designs and one used cross-sectional designs. Europe led most of the investigations. Most studies had unclear risk of bias and none could rule out selection bias, ascertainment bias, or selective outcome reporting. The overall estimated proportion of combined local and systemic reactions after the first BNT162b2 vaccination was 30%[95% CI: 17-42%] and slightly rose to 32% [95% CI: 19-44%] after the second dose. Rheumatic illnesses had the highest rate of AEFI (40%[95% CI: 16-65%]), while cystic fibrosis had the lowest (27%[95% CI: 17%-38%]). Hospitalizations for AEFIs were rare. Healthy controls exhibited higher levels of neutralizing antibodies and measured IgG than immunocompromised AYA, although pooled estimations did not demonstrate a statistically significant difference after primary dose. BNT162b2 is safe and effective in immunocompromised AYA, with no significant difference to healthy controls. However, current evidence is low to moderate due to high RoB. Our research advocates for improving methodology in studies including specific AYA population.


Тема - темы
Cystic Fibrosis , COVID-19 , Fibrosis , Rheumatic Diseases , Neoplasms , Diabetes Mellitus
3.
biorxiv; 2023.
Препринт в английский | bioRxiv | ID: ppzbmed-10.1101.2023.01.05.522853

Реферат

Background: As the pandemic evolves, post-acute sequelae of CoV-2 (PACS) including cardiovascular manifestations have emerged as a new health threat. This study aims to study whether the Spike protein plus obesity can exacerbate PACS-related cardiomyopathy. Methods: A Spike protein-pseudotyped (Spp) virus with the proper surface tropism of SARS-CoV-2 was developed for viral entry assay in vitro and administration into high fat diet (HFD)-fed mice. The systemic viral loads and cardiac transcriptomes were analyzed at 2 and 24 hrs, 3, 6, and 24 weeks post introducing (wpi) Spp using RNA-seq or real time RT-PCR. Echocardiography was used to monitor cardiac functions. Results: Low-density lipoprotein cholesterol enhanced viral uptake in endothelial cells, macrophages, and cardiomyocyte-like H9C2 cells. Selective cardiac and adipose viral depositions were observed in HFD mice but not in normal-chow-fed mice. The cardiac transcriptional signatures in HFD mice at 3, 6, and 24 wpi showed systemic suppression of mitochondria respiratory chain genes including ATP synthases and nicotinamide adenine dinucleotide:ubiquinone oxidoreductase gene members, upregulation of stress pathway-related crucial factors such as nuclear factor-erythroid 2-related factor 1 and signal transducer and activator of transcription 5A, and increases in expression of glucose metabolism-associated genes. As compared with the age-matched HFD control mice, cardiac ejection fraction and fractional shortening were significantly decreased, while left ventricular end-systolic diameter and volume were significantly elevated, and cardiac fibrosis was increased in HFD mice at 24 wpi. Conclusion: Our data demonstrated that the Spike protein could induce long-term transcriptional suppression of mitochondria metabolic genes and cause cardiac fibrosis and myocardial contractile impairment, providing mechanistic insights to PACS-related cardiomyopathy.


Тема - темы
Fibrosis , Cardiomyopathies , Severe Acute Respiratory Syndrome , Obesity
4.
EBioMedicine ; 85: 104296, 2022 Nov.
Статья в английский | MEDLINE | ID: covidwho-2158739

Реферат

BACKGROUND: COVID-19 is characterized by a heterogeneous clinical presentation, ranging from mild symptoms to severe courses of disease. 9-20% of hospitalized patients with severe lung disease die from COVID-19 and a substantial number of survivors develop long-COVID. Our objective was to provide comprehensive insights into the pathophysiology of severe COVID-19 and to identify liquid biomarkers for disease severity and therapy response. METHODS: We studied a total of 85 lungs (n = 31 COVID autopsy samples; n = 7 influenza A autopsy samples; n = 18 interstitial lung disease explants; n = 24 healthy controls) using the highest resolution Synchrotron radiation-based hierarchical phase-contrast tomography, scanning electron microscopy of microvascular corrosion casts, immunohistochemistry, matrix-assisted laser desorption ionization mass spectrometry imaging, and analysis of mRNA expression and biological pathways. Plasma samples from all disease groups were used for liquid biomarker determination using ELISA. The anatomic/molecular data were analyzed as a function of patients' hospitalization time. FINDINGS: The observed patchy/mosaic appearance of COVID-19 in conventional lung imaging resulted from microvascular occlusion and secondary lobular ischemia. The length of hospitalization was associated with increased intussusceptive angiogenesis. This was associated with enhanced angiogenic, and fibrotic gene expression demonstrated by molecular profiling and metabolomic analysis. Increased plasma fibrosis markers correlated with their pulmonary tissue transcript levels and predicted disease severity. Plasma analysis confirmed distinct fibrosis biomarkers (TSP2, GDF15, IGFBP7, Pro-C3) that predicted the fatal trajectory in COVID-19. INTERPRETATION: Pulmonary severe COVID-19 is a consequence of secondary lobular microischemia and fibrotic remodelling, resulting in a distinctive form of fibrotic interstitial lung disease that contributes to long-COVID. FUNDING: This project was made possible by a number of funders. The full list can be found within the Declaration of interests / Acknowledgements section at the end of the manuscript.


Тема - темы
COVID-19 , Lung Diseases, Interstitial , Humans , Lung/diagnostic imaging , Lung/pathology , Lung Diseases, Interstitial/pathology , Fibrosis , Biomarkers/analysis , Ischemia/pathology
5.
Minerva Endocrinol (Torino) ; 47(3): 270-278, 2022 Sep.
Статья в английский | MEDLINE | ID: covidwho-2146119

Реферат

BACKGROUND: Despite severe acute respiratory syndrome (SARS)-Coronavirus (CoV-2) primarily targeting the lungs, the heart represents another critical virus target. Thus, the identification of SARS-CoV-2 disease of 2019 (COVID-19)-associated biomarkers would be beneficial to stratify prognosis and the risk of developing cardiac complications. Aldosterone and galectin-3 promote fibrosis and inflammation and are considered a prognostic biomarker of lung and adverse cardiac remodeling. Here, we tested whether galectin-3 and aldosterone levels can predict adverse cardiac outcomes in COVID-19 patients. METHODS: To this aim, we assessed galectin-3 and aldosterone serum levels in 51 patients diagnosed with COVID-19, using a population of 19 healthy subjects as controls. In in-vitro studies, we employed 3T3 fibroblasts to assess the potential roles of aldosterone and galectin-3 in fibroblast activation. RESULTS: Serum galectin-3 levels were more elevated in COVID-19 patients than healthy controls and correlated with COVID-19 severity classification and cardiac troponin-I (cTnI) serum levels. Furthermore, we observed an augmented secretion of aldosterone in COVID-19 patients. This adrenal hormone is a direct stimulator of galectin-3 secretion; therefore, we surmised that this axis could perpetrate fibrosis and adverse remodeling in these subjects. Thus, we stimulated fibroblasts with 10% of serum from COVID-19 patients. This challenge markedly rose the expression of smooth muscle alpha (α)-2 actin (ACTA2), a myofibroblast marker. CONCLUSIONS: Our study suggests that COVID-19 can affect cardiac structure and function by triggering aldosterone and galectin-3 release that may serve as prognostic and therapeutic biomarkers while monitoring the course of cardiac complications in patients suffering from COVID-19.


Тема - темы
COVID-19 , Galectin 3 , Actins , Aldosterone , Biomarkers , COVID-19/complications , Fibrosis , Humans , SARS-CoV-2 , Troponin I
6.
Front Immunol ; 13: 1028613, 2022.
Статья в английский | MEDLINE | ID: covidwho-2142034

Реферат

SARS-CoV-2 infection causes a variety of physiological responses in the lung, and understanding how the expression of SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), and its proteolytic activator, transmembrane serine protease 2 (TMPRSS2), are affected in patients with underlying disease such as interstitial pneumonia will be important in considering COVID-19 progression. We examined the expression of ACE2 and TMPRSS2 in an induced usual interstitial pneumonia (iUIP) mouse model and patients with IPF as well as the changes in whole-lung ACE2 and TMPRSS2 expression under physiological conditions caused by viral infection. Histopathological and biochemical characteristics were analyzed using human specimens from patients with IPF and precision-cut lung slices (PCLS) from iUIP mouse model showing UIP with honeycombing and severe fibrosis after non-specific interstitial pneumonia. ACE2 expression decreased with acute lung inflammation and increased in the abnormal lung epithelium of the iUIP mouse model. ACE2 is also expressed in metaplastic epithelial cells. Poly(I:C), interferons, and cytokines associated with fibrosis decreased ACE2 expression in PCLS in the iUIP model. Hypoxia also decreases ACE2 via HIF1α in PCLS. Antifibrotic agent, nintedanib attenuates ACE2 expression in invasive epithelial cells. Patients with IPF are at a higher risk of SARS-CoV-2 infection due to the high expression of ACE2. However, ACE2 and TMPRSS2 expression is decreased by immune intermediaries, including interferons and cytokines that are associated with viral infection and upon administration of antifibrotic agents, suggesting that most of the viral infection-induced pathophysiological responses aid the development of resistance against SARS-CoV-2 infection.


Тема - темы
COVID-19 , Idiopathic Pulmonary Fibrosis , Lung Diseases , Humans , Mice , Animals , Angiotensin-Converting Enzyme 2/genetics , Peptidyl-Dipeptidase A/metabolism , SARS-CoV-2 , Lung/pathology , Lung Diseases/pathology , Idiopathic Pulmonary Fibrosis/pathology , Cytokines , Interferons , Fibrosis
7.
biorxiv; 2022.
Препринт в английский | bioRxiv | ID: ppzbmed-10.1101.2022.12.15.520561

Реферат

The global high prevalence of COVID-19 is a major challenge for health professionals and patients. SARS-CoV-2 virus mutate predominantly in the spike proteins, whilst the other key viral components remain stable. Previous studies have shown that the human oral cavity can potentially act as reservoir of the SARS-CoV-2 virus and COVID-19 is likely to be connected with poor periodontal health. However, the consequence of SARS-CoV-2 viral infection on human oral health has not been systematically examined. In this research, we aimed to study the pathogenicity of SARS-CoV-2 viral components on human periodontal health. We found that human periodontal tissues, particularly the fibroblasts highly expressed ACE2 and TMPRSS2. Exposure to SARS-CoV-2, especially by the viral envelope and membrane proteins induced fibrotic pathogenic phenotypes, including periodontal fibroblast hyperproliferation, concomitant with increased apoptosis and senescence. The fibrotic degeneration was mediated by a down-regulation of mitochondrial {beta}-oxidation. Fatty acid beta-oxidation inhibitor, etomoxir treatment could mirror the same pathological consequence on the fibroblasts, similar to SARS-CoV-2 infection. Our results therefore provide novel mechanistic insights into how SARS-CoV-2 infection can affect human periodontal health at the cell and molecular level.


Тема - темы
Nerve Degeneration , COVID-19 , Fibrosis , Severe Acute Respiratory Syndrome
8.
medrxiv; 2022.
Препринт в английский | medRxiv | ID: ppzbmed-10.1101.2022.11.29.22282913

Реферат

Background: A significant proportion of patients experience prolonged pulmonary, cardiocirculatory or neuropsychiatric symptoms after Coronavirus disease 2019 (COVID-19), termed post-acute sequelae of COVID (PASC). Lung manifestations of PASC include cough, dyspnea on exertion and persistent radiologic abnormalities and have been linked to viral persistence, ongoing inflammation and immune dysregulation. So far, there is limited data on lung histopathology and tissue-based immune cell subtyping in PASC. Methods: 51 unvaccinated patients (median age, 40 years; 43% female) with a median of 17 weeks (range, 2-55 weeks) after mild SARS-CoV-2 infection (without hospitalization) underwent full clinical evaluation including high-resolution computed tomography (HR-CT) and transbronchial biopsy. We used RT-PCR/FISH and immunohistochemistry (nucleocapsid/spike/CD3/CD4/CD8) for residual SARS-CoV-2 detection and T lymphocyte subtyping, respectively. We assessed interstitial fibrosis and macrophage profiles by transmission electron microscopy (TEM) and immunofluorescence multiplex staining, while cytokine profiling in broncho-alveolar lavage (BAL) fluid was performed by legendplex immunoassay. Results: Dyspnea on exertion was the leading symptom of pulmonary PASC in our cohort. In 16% and 42.9% of patients, FEV1 and MEF50 were [≤]80% and 35.3% showed low attenuation volume (LAV) in >5% of lung area, in line with airflow obstruction. There was a significant correlation between oxygen pulse and time since COVID (p=0.009). Histopathologically, PASC manifested as organizing pneumonia (OP), fibrinous alveolitis and increased CD4+ T cell infiltrate predominantly around airways (bronchiolitis), while the residual virus components were detectable in only a single PASC patient (2%). T cell infiltrates around small airways were inversely correlated with time since COVID, however, this trend failed to reach statistical significance. We identified discrete interstitial fibrosis and a pro-fibrotic macrophage subtype (CD68/CD163/S100A9) as well as significantly elevated interleukin 1{beta} in BAL fluid from PASC patients (p=0.01), but H-scores for fibrotic macrophage population did not correlate with severity of clinical symptoms or T cell infiltration. Interpretation: We show decreased FEV1/MEF50 and increased LAV in line with obstructive lung disease due to CD4+ T cell-predominant bronchiolitis as well as evidence of pro-fibrotic signaling in a subset of unvaccinated PASC patients. Since our results point towards self-limiting inflammation of small airways without detectable viral reservoirs, it remains unclear whether pulmonary symptoms in PASC are SARS-CoV-2-specific or represent a general response to viral infection. Still, evidence of pro-fibrotic signaling should warrant clincal follow-up and further research into possible long-time fibrotic remodeling in PASC patients.


Тема - темы
Pneumonia , Mental Disorders , COVID-19 , Fibrosis , Adenocarcinoma, Bronchiolo-Alveolar , Lung Diseases, Obstructive , Dyspnea , Bronchiolitis , Virus Diseases , Pulmonary Fibrosis , Inflammation
9.
Ann Med ; 54(1): 3189-3200, 2022 12.
Статья в английский | MEDLINE | ID: covidwho-2106905

Реферат

INTRODUCTION: In order to identify therapeutic targets in Coronavirus disease 2019 (COVID-19), it is important to identify molecules involved in the biological responses that are modulated in COVID-19. Lysophosphatidic acids (LPAs) are involved in the pulmonary inflammation and fibrosis are one of the candidate molecules. The aim of this study was to evaluate the association between the serum levels of autotaxin (ATX), which are enzymes involved in the synthesis of lysophosphatidic acids. MATERIAL AND METHODS: We enrolled 134 subjects with COVID-19 and 58 normal healthy subjects for the study. We measured serum ATX levels longitudinally in COVID-19 patients and investigated the time course and the association with severity and clinical parameters. RESULTS: The serum ATX levels were reduced in all patients with COVID-19, irrespective of the disease severity, and were negatively associated with the serum CRP, D-dimer, and anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibody levels. DISCUSSION: Considering the biological properties of LPAs in the pulmonary inflammation and fibrosis, modulation of ATX might be compensatory biological responses to suppress immunological overreaction especially in the lung, which is an important underlying mechanism for the mortality of the disease. CONCLUSIONS: COVID-19 patients showed a decrease in the serum levels of ATX, irrespective of the disease severity. Key MessagesAutotaxin (ATX) is an enzyme involved in the synthesis of lysophosphatidic acid (LPA), which has been reported to be involved in pulmonary inflammation and fibrosis. Patients with COVID-19 show decrease in the serum levels of ATX. Modulation of ATX might be compensatory biological responses to suppress immunological overreaction.


Тема - темы
COVID-19 , Phosphoric Diester Hydrolases , Humans , COVID-19/blood , Fibrosis , Lung , Lysophospholipids , Phosphoric Diester Hydrolases/blood , SARS-CoV-2
10.
medrxiv; 2022.
Препринт в английский | medRxiv | ID: ppzbmed-10.1101.2022.11.28.22282811

Реферат

SARS-CoV-2 infection can manifest as a wide range of respiratory and systemic symptoms well after the acute phase of infection in over 50% of patients. Key questions remain on the long-term effects of infection on tissue pathology in recovered COVID-19 patients. To address these questions we performed multiplexed imaging of post-mortem lung tissue from 12 individuals who died post-acute COVID-19 (PC) and compare them to lung tissue from patients who died during the acute phase of COVID-19, or patients who died with idiopathic pulmonary fibrosis (IPF), and otherwise healthy lung tissue. We find evidence of viral presence in the lung up to 359 days after the acute phase of disease, including in patients with negative nasopharyngeal swab tests. The lung of PC patients are characterized by the accumulation of senescent alveolar type 2 cells, fibrosis with hypervascularization of peribronchial areas and alveolar septa, as the most pronounced pathophysiological features. At the cellular level, lung disease of PC patients, while distinct, shares pathological features with the chronic pulmonary disease of IPF. which may help rationalize interventions for PC patients. Altogether, this study provides an important foundation for the understanding of the long-term effects of SARS-CoV-2 pulmonary infection at the microanatomical, cellular, and molecular level.


Тема - темы
Lung Diseases , COVID-19 , Fibrosis , Adenocarcinoma, Bronchiolo-Alveolar , Idiopathic Pulmonary Fibrosis , Severe Acute Respiratory Syndrome , Pulmonary Disease, Chronic Obstructive
11.
preprints.org; 2022.
Препринт в английский | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202211.0448.v1

Реферат

Excessive neutrophil influx and activation in lungs during infections, such as manifest during the ongoing SARS CoV-2 pandemic, have brought neutrophil extracellular traps (NETs) and the con-comitant release of granule contents that damage surrounding tissues into sharp focus. Neutro-phil proteases, which are known to participate in NET release, also enable the binding of the viral spike protein to cellular receptors and assist in the spread of infection. Blood and tissue fluids normally also contain liver-derived protease inhibitors that balance the activity of proteases. In-terestingly, neutrophils themselves also express the protease inhibitor alpha-1-antitrypsin (AAT), the product of the SERPINA-1 gene, and store it in neutrophil cytoplasmic granules. The absence of AAT or mutations in the SERPINA-1 gene promote lung remodeling and fibrosis in diseases such as chronic obstructive pulmonary disease (COPD), acute respiratory distress syndrome (ARDS) and increase the risk of allergic responses. Recent observations point to the fact that re-duced activity of AAT presents a major susceptibility factor for severe COVID-19. Here, we focus attention on the mechanism of neutrophil elastase (NE) in NET release and its inhibition by AAT as an additional factor that may determine the severity of COVID-19


Тема - темы
Respiratory Distress Syndrome , COVID-19 , Fibrosis , Drug Hypersensitivity , Pulmonary Disease, Chronic Obstructive
12.
biorxiv; 2022.
Препринт в английский | bioRxiv | ID: ppzbmed-10.1101.2022.11.17.515635

Реферат

A relevant number of coronavirus disease 2019 (COVID-19) survivors suffers from post-acute sequelae of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (PASC). Current evidence suggests a dysregulated alveolar regeneration in COVID-19 as a possible explanation for respiratory PASC symptoms, a phenomenon which deserves further investigation in a suitable animal model. This study investigates morphologic and transcriptomic features of alveolar regeneration in SARS-CoV-2 infected Syrian golden hamsters. We demonstrate that CK8+ alveolar differentiation intermediate (ADI) cells accumulate following SARS-CoV-2-induced diffuse alveolar damage. A subset of ADI cells shows nuclear accumulation of p53 at 6- and 14-days post infection (dpi), indicating a prolonged block in the ADI state. Transcriptome data shows the expression of gene signatures driving ADI cell senescence, epithelial-mesenchymal transition, and angiogenesis. Moreover, we show that multipotent CK14+ airway basal cell progenitors migrate out of terminal bronchioles, aiding alveolar regeneration. At 14 dpi, persistence of ADI cells, peribronchiolar proliferates, M2-type macrophages, and sub-pleural fibrosis is observed, indicating incomplete alveolar restoration. The results demonstrate that the hamster model reliably phenocopies indicators of a dysregulated alveolar regeneration of COVID-19 patients. The study provides a suitable translational model for future research on the pathomechanims of PASC and testing of prophylactic and therapeutical approaches.


Тема - темы
Coronavirus Infections , COVID-19 , Fibrosis , Adenocarcinoma, Bronchiolo-Alveolar , Severe Acute Respiratory Syndrome
13.
biorxiv; 2022.
Препринт в английский | bioRxiv | ID: ppzbmed-10.1101.2022.11.06.515367

Реферат

Patient-specific premorbidity, age, and sex are significant heterogeneous factors that influence the severe manifestation of lung diseases, including COVID-19 fibrosis. The renin-angiotensin system (RAS) plays a prominent role in regulating effects of these factors. Recent evidence suggests that patient-specific alteration of RAS homeostasis with premorbidity and the expression level of angiotensin converting enzyme 2 (ACE2), depending on age and sex, is correlated with lung fibrosis. However, conflicting evidence suggests decreases, increases, or no changes in RAS after SARS-CoV-2 infection. In addition, detailed mechanisms connecting the patient-specific conditions before infection to infection-induced fibrosis are still unknown. Here, a mathematical model is developed to quantify the systemic contribution of heterogeneous factors of RAS in the progression of lung fibrosis. Three submodels are connected - a RAS model, an agent-based COVID-19 in-host immune response model, and a fibrosis model - to investigate the effects of patient-group-specific factors in the systemic alteration of RAS and collagen deposition in the lung. The model results indicate cell death due to inflammatory response as a major contributor to the reduction of ACE and ACE2, whereas there are no significant changes in ACE2 dynamics due to viral-bound internalization of ACE2. Reduction of ACE reduces the homeostasis of RAS including angiotensin II (ANGII), while the decrease in ACE2 increases ANGII and results in severe lung injury and fibrosis. The model explains possible mechanisms for conflicting evidence of RAS alterations in previously published studies. Also, the results show that ACE2 variations with age and sex significantly alter RAS peptides and lead to fibrosis with around 20% additional collagen deposition from systemic RAS with slight variations depending on age and sex. This model may find further applications in patient-specific calibrations of tissue models for acute and chronic lung diseases to develop personalized treatments.


Тема - темы
Lung Diseases , COVID-19 , Fibrosis , Mastocytosis, Systemic
14.
researchsquare; 2022.
Препринт в английский | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-2245446.v1

Реферат

Background Previous studies reported the Coronavirus disease (COVID-19) has long implications, which involve multiple organs, including the cardiovascular system. This study aims to assess myocardial dysfunction by echocardiograph myocardial longitudinal strain Left ventricular-Global Longitudinal Strain (LV-GLS) and Right Ventricular-Free Wall Strain (RV-FWS) measurements as a marker for myocardial dysfunction and heart fibrosis. Additionally, we aim to identify admission factors that may serve as a predictor of long COVID syndrome.Methods This cross-sectional study assessed echocardiograph global longitudinal strain (GLS) values measurement done three months after initial hospitalization. Multivariate analysis was done to investigate admission factors associated with differences in GLS values.Results 100 subjects with cardiovascular comorbidities and prior COVID-19 infection were enrolled. Echocardiography examination showed lower GLS values in this group compared to the normal population. Demographic and risk factors-matched subjects without a history of COVID-19 (n = 31, Control 1) and healthy subjects (n-31, Control 2) were included as comparisons to validate GLS results. The case group had significantly lower LV-GLS values compared to other groups (p < 0.05, mean ± SD -16.17 ± 3.379, -19.48 ± 1.141, -21.48 ± 1.777 respectively for case, control one, and control two groups). Upon admission, a history of coronary artery disease was found to be associated with decreased LV GLS values in recovered COVID-19 patients with cardiovascular comorbidity.Conclusion LV GLS values significantly decreased in recovered COVID-19 patients with cardiovascular comorbidities. Upon admission, a history of CAD may predict cardiac long COVID-19 syndrome.


Тема - темы
Cardiovascular Diseases , COVID-19 , Fibrosis , Long QT Syndrome , Cardiomyopathies , Sprains and Strains , Coronary Artery Disease
15.
Ann Clin Lab Sci ; 52(5): 781-787, 2022 Sep.
Статья в английский | MEDLINE | ID: covidwho-2072746

Реферат

OBJECTIVE: The prognosis value of fibrosis-4 score (FIB-4) in COVID-19 is controversial. Hence, we conducted a systematic review and meta-analysis to investigate the association between the FIB-4 index and COVID-19 disease progression. METHODS: We performed meta-analysis using the PubMed, Embase, and Cochrane databases. A fixed- or random-effects model was used for evaluating heterogeneity. RESULTS: Thirteen studies were included. The meta-analysis of unadjusted results showed that compared to lower FIB-4 index, patients with higher FIB-4 index had increased odds of mortality (OR=5.1, 95%CI 3.67-7.09; P<0.001), ICU admission (OR=2.32, 95%CI: 1.65-3.25, P<0.00001) and need for mechanical ventilator support (OR=3.51, 95%CI: 2.1-5.85, P<0.001). In addition, the meta-analysis of adjusted results showed patients with higher FIB-4 index was associated with increased risk of mortality (OR=3.01, 95%CI: 2.21-4.09, P<0.001) and need for mechanical ventilator support (OR=3.76, 95%CI: 2.08-6.82, P<0.001) compared to patients with lower FIB-4 index. CONCLUSIONS: This meta-analysis indicated that high FIB-4 index score was associated with the severity and mortality in COVID-19 infected patients.


Тема - темы
COVID-19 , Fibrosis , Humans , Prognosis , Severity of Illness Index
16.
researchsquare; 2022.
Препринт в английский | PREPRINT-RESEARCHSQUARE | ID: ppzbmed-10.21203.rs.3.rs-2239169.v1

Реферат

BACKGROUND: Early in the pandemic, we established COVID-19 Recovery and Engagement (CORE) Clinics in the Bronx and implemented a detailed evaluation protocol was implemented to assess physical, emotional, and cognitive function, pulmonary function tests, and imaging for COVID-19 survivors. Here we report our findings five months post-acute COIVD-19. METHODS: Main outcomes and measures included pulmonary function tests, imaging tests, and a battery of symptom, physical, emotional, and cognitive assessments 5 months post-acute COVID-19. FINDINGS: Dyspnea, fatigue, decreased exercise tolerance, brain fog, and shortness of breath were the most common symptoms but there were generally no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Many patients had abnormal physical, emotional, and cognitive scores, but most functioned independently; there were no significant differences between hospitalized and non-hospitalized cohorts (p>0.05). Six-minute walk test, lung ultrasound, and diaphragm excursion were abnormal but only in the hospitalized cohort. Pulmonary function tests showed moderately restrictive pulmonary function only in the hospitalized cohort but no obstructive pulmonary function. Newly detected major neurological events, microvascular disease, atrophy, and white-matter changes were rare, but lung opacity and fibrosis-like findings were common after acute COVID-19. INTERPRETATION: Many COVID-19 survivors experienced moderately restrictive pulmonary function, and significant symptoms across the physical, emotional, and cognitive health domains. Newly detected brain imaging abnormalities were rare, but lung imaging abnormalities were common. This study provides insights into post-acute sequelae following SARS-CoV-2 infection in neurological and pulmonary systems which may be used to support at-risk patients, develop effective screening methods and interventions.


Тема - темы
Atrophy , Lung Diseases , COVID-19 , Fibrosis , Microvascular Angina , Dyspnea , Fatigue
17.
medrxiv; 2022.
Препринт в английский | medRxiv | ID: ppzbmed-10.1101.2022.10.30.22281713

Реферат

This article is aim to investigate the safety and immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine booster in patients with chronic liver disease(CLD). A total of 114 patients with CLD who received a SARS-CoV-2 vaccine booster were enrolled in this study. Serum samples were collected from enrolled patients at least 14 days after the booster dose and tested for SARS-CoV-2 neutralizing antibody (novel coronavirus neutralizing antibody, nCoV NTAb) and IgG antibody against SARS-CoV-2 spike binding domain(novel coronavirus spike receptor-binding domain antibodynCoV S-RBD antibody)levels. The positive rates of nCoV NTAb and nCoV S-RBD in patients with CLD were 87.72% and 91.23%, respectively, after the booster injection of coronavirus disease 2019 (COVID-19) vaccine. The booster injection resulted in the production of nCov NTAb in 66.7% of patients and nCov-SRBD antibody in 71.43% of patients with CLD who failed basic immunization. After basic SARS-CoV-2 immunization, the booster SARS-CoV2 vaccine increased the serum conversion rate and the level of nCov NTAb and nCov-SRBD antibodies in patients with CLD (including patients with cirrhosis). The severity of the liver disease is related to the immune response to COVID-19 vaccine.


Тема - темы
Liver Diseases , End Stage Liver Disease , Coronavirus Infections , COVID-19 , Fibrosis
18.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S322, 2022 Oct.
Статья в английский | MEDLINE | ID: covidwho-2062037

Реферат

CONTEXT: Hypereosinophilic syndrome (HES) is characterized by persistent blood eosinophilia, organ damage, and the absence of an underlying cause. Heterogeneous presentations, etiologies, and prognosis are recognized. The landscape of targeted therapies has emphasized the importance of its etiology and pathogenesis. We present a boy with extreme, refractory eosinophilia and end-organ complications. The persistence, severity, and outcome suggested an aggressive myeloid neoplasm. PRESENTATION: A 6-year-old boy presented with fever and respiratory symptoms. A blood count revealed hyperleukocytosis of 200×109/L with 90% eosinophils, normal platelets, and anemia with no hemolysis as well as increased cobalamin levels. Flow cytometry on the blood showed no evidence of hematolymphoid neoplasm. Fluorescent in-situ hybridization on the blood was negative for FIP1L1/PDGFRA, PDGFRB, FGFR1, and CBFB. Renal and liver functions were normal, and no evidence of tumor lysis was present. Parasitic and infectious etiologies were ruled out. Levels of immunoglobulin and complement as well as acute phase reactants were normal. CT scan showed no occult infection or lymphadenopathy. INTERVENTIONS: He was started on glucocorticoids and hydroxyurea as well as imatinib and a trial of antihelmintics. Signs of end-organ damage included 1) CNS hemiparesis, dysarthria, and MRI-documented small-vessel and white matter abnormalities; 2) myocarditis by cardiac ultrasound; and 3) respiratory distress with interstitial infiltrates. Covid PCR test was positive, so he was given Remdesivir, after which PCR became negative. Increased D-dimers led to enoxaparin, intravenous immunoglobulin, and support. Bone marrow evaluation ruled out an abnormal T-cell population and occult acute lymphoblastic leukemia by flow cytometry and immunohistochemistry. Marrow biopsy showed dysmorphic megakaryocytes, so a myeloid neoplasm could not be excluded. Cytogenetics on the marrow showed a normal karyotype, and myeloid-directed next generation sequencing on the blood was negative for mutations. A lung biopsy showed increased eosinophils within vessels and pleural fibrosis but no interstitial fibrosis or vasculitis. Subcutaneous interferon alfa was given 3 times weekly with no response. The 4 drugs were well tolerated. The boy was followed over 9 months, requiring antibiotics, anticoagulation, and oxygen support. Eosinophilia remained high at 40,000-150,000×109/L. The patient expired from respiratory failure. CONCLUSIONS: HES may be life-threatening in the pediatric population. Diagnosis and therapy can be challenging.


Тема - темы
COVID-19 , Hypereosinophilic Syndrome , Myeloproliferative Disorders , Acute-Phase Proteins/therapeutic use , Anti-Bacterial Agents/therapeutic use , Anticoagulants/therapeutic use , Child , Enoxaparin/therapeutic use , Fibrosis , Humans , Hydroxyurea/therapeutic use , Hypereosinophilic Syndrome/diagnosis , Hypereosinophilic Syndrome/drug therapy , Imatinib Mesylate/therapeutic use , Immunoglobulins, Intravenous/therapeutic use , Interferon-alpha/therapeutic use , Male , Myeloproliferative Disorders/diagnosis , Oxygen/therapeutic use , Receptor, Platelet-Derived Growth Factor beta/genetics , Receptor, Platelet-Derived Growth Factor beta/therapeutic use , Vitamin B 12
19.
Life Sci ; 309: 121048, 2022 Nov 15.
Статья в английский | MEDLINE | ID: covidwho-2061633

Реферат

Pirfenidone (PFD) is a non-peptide synthetic chemical that inhibits the production of transforming growth factor-beta 1 (TGF-ß1), tumor necrosis factor-alpha (TNF-α), platelet-derived growth factor (PDGF), Interleukin 1 beta (IL-1ß), and collagen 1 (COL1A1), all of which have been linked to the prevention or removal of excessive scar tissue deposition in many organs. PFD has been demonstrated to decrease apoptosis, downregulate angiotensin-converting enzyme (ACE) receptor expression, reduce inflammation through many routes, and alleviate oxidative stress in pneumocytes and other cells while protecting them from COVID-19 invasion and cytokine storm. Based on the mechanism of action of PFD and the known pathophysiology of COVID-19, it was recommended to treat COVID-19 patients. The use of PFD as a treatment for a range of disorders is currently being studied, with an emphasis on outcomes related to reduced inflammation and fibrogenesis. As a result, rather than exploring the molecule's chemical characteristics, this review focuses on innovative PFD efficacy data. Briefly, herein we tried to investigate, discuss, and illustrate the possible mechanisms of actions for PFD to be targeted as a promising anti-inflammatory, anti-fibrotic, anti-oxidant, anti-apoptotic, anti-tumor, and/or anti-SARS-CoV-2 candidate.


Тема - темы
COVID-19 , Transforming Growth Factor beta1 , Humans , Transforming Growth Factor beta1/metabolism , Antioxidants/pharmacology , Antioxidants/therapeutic use , Tumor Necrosis Factor-alpha , Interleukin-1beta , SARS-CoV-2 , COVID-19/drug therapy , Fibrosis , Pyridones/pharmacology , Pyridones/therapeutic use , Collagen Type I/metabolism , Anti-Inflammatory Agents/pharmacology , Anti-Inflammatory Agents/therapeutic use , Platelet-Derived Growth Factor , Inflammation/drug therapy , Transforming Growth Factors , Angiotensins
20.
preprints.org; 2022.
Препринт в английский | PREPRINT-PREPRINTS.ORG | ID: ppzbmed-10.20944.preprints202210.0342.v1

Реферат

A significant number of persons with coronavirus disease 2019 (COVID-19) experience persistent, recurrent, or new symptoms several months after the acute stage of severe acute respiratory syndrome coronavirus 2 (SARS‑CoV‑2) infection. This phenomenon, termed Post-Acute Sequelae of SARS-CoV-2 (PASC) or Long COVID, is associated with high viral titers during acute infection, a persistently hyperactivated immune system, tissue injury by NETosis-induced micro-thrombofibrosis (NETinjury), microbial translocation, complement deposition, fibrotic macrophages, the presence of auto-antibodies, and lymphopenic immune environments. Here, we review the current literature on the immunological imbalances that occur during PASC. Specifically, we focus on data supporting common immunopathogenesis and tissue injury mechanisms shared across this highly heterogenous disorder including NETosis, coagulopathy, and fibrosis. Mechanisms include changes in leukocyte subsets/functions, fibroblast activation, cytokine imbalances, lower cortisol, autoantibodies, co-pathogen reactivation, and residual immune activation driven by persistent viral antigens and/or microbial translocation. Taken together, we develop the premise that SARS-CoV-2 infection results in PASC as a consequence of acute and/or persistent single or multiple organ injury mediated by PASC determinants to include degree of host response (inflammation, NETinjury), residual viral antigen (persistent antigen) and exogenous factors (microbial translocation). Determinants of PASC may be amplified by co-morbidities, age, and sex. Keywords: long COVID, PASC, long haulers, NETosis, T cell, NK cell, DC, neutrophil,


Тема - темы
Coronavirus Infections , Acute Disease , COVID-19 , Fibrosis , Blood Coagulation Disorders , Inflammation
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