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1.
Sci Rep ; 12(1): 4270, 2022 03 11.
Article in English | MEDLINE | ID: covidwho-1740475

ABSTRACT

Inflammatory burden is associated with COVID-19 severity and outcomes. Residual computed tomography (CT) lung abnormalities have been reported after COVID-19. The aim was to evaluate the association between inflammatory burden during COVID-19 and residual lung CT abnormalities collected on follow-up CT scans performed 2-3 and 6-7 months after COVID-19, in severe COVID-19 pneumonia survivors. C-reactive protein (CRP) curves describing inflammatory burden during the clinical course were built, and CRP peaks, velocities of increase, and integrals were calculated. Other putative determinants were age, sex, mechanical ventilation, lowest PaO2/FiO2 ratio, D-dimer peak, and length of hospital stay (LOS). Of the 259 included patients (median age 65 years; 30.5% females), 202 (78%) and 100 (38.6%) had residual, predominantly non-fibrotic, abnormalities at 2-3 and 6-7 months, respectively. In age- and sex-adjusted models, best CRP predictors for residual abnormalities were CRP peak (odds ratio [OR] for one standard deviation [SD] increase = 1.79; 95% confidence interval [CI] = 1.23-2.62) at 2-3 months and CRP integral (OR for one SD increase = 2.24; 95%CI = 1.53-3.28) at 6-7 months. Hence, inflammation is associated with short- and medium-term lung damage in COVID-19. Other severity measures, including mechanical ventilation and LOS, but not D-dimer, were mediators of the relationship between CRP and residual abnormalities.


Subject(s)
COVID-19/pathology , Pneumonia/diagnostic imaging , Aged , C-Reactive Protein/analysis , COVID-19/complications , COVID-19/diagnostic imaging , Female , Humans , Male , Middle Aged , Patient Acuity , Pneumonia/etiology , Pneumonia/pathology , Retrospective Studies , Risk Factors , Time Factors , Tomography, X-Ray Computed
2.
J Immunol ; 208(2): 321-327, 2022 01 15.
Article in English | MEDLINE | ID: covidwho-1708204

ABSTRACT

Previous studies have demonstrated that 8-hydroxydeoxyguanosine (8-OHdG) exerted key roles in various pulmonary diseases, but the evidence for its role in community-acquired pneumonia (CAP) was lacking. The goal of this research was to evaluate the correlations of serum 8-OHdG with the severity and prognosis among patients with CAP through a prospective cohort study. A total of 239 patients with CAP and 239 healthy participants were enrolled. Fasting blood samples were collected. 8-OHdG and inflammatory cytokines were measured by ELISA. On admission, serum 8-OHdG was significantly increased in patients with CAP compared with control subjects. Besides, serum 8-OHdG was incrementally increased in line with CAP severity scores. Pearson correlative analysis found that serum 8-OHdG was correlated with clinical characteristics and inflammatory cytokines in patients with CAP. Linear and logistic regression analysis showed that serum 8-OHdG was positively associated with CAP severity scores. Furthermore, the prognostic outcomes were tracked. Higher serum 8-OHdG on admission increased the risks for intensive care unit admission, mechanical ventilation, vasoactive agent usage, death, and longer hospital stay among patients with CAP. Serum 8-OHdG combination with confusion, respiratory rate, blood pressure, and age ≥65 y or pneumonia severity index had stronger predictive powers for death than single 8-OHdG, CAP severity scores, or several inflammatory cytokines in patients with CAP. These results indicated that serum 8-OHdG is positively associated with the severity and poor prognosis in patients with CAP, demonstrating that 8-OHdG may be involved in the pathophysiology process of CAP.


Subject(s)
8-Hydroxy-2'-Deoxyguanosine/blood , Community-Acquired Infections/pathology , Pneumonia/blood , Pneumonia/mortality , Severity of Illness Index , Aged , Biomarkers/blood , Community-Acquired Infections/blood , Critical Care/statistics & numerical data , Cytokines/blood , Enzyme-Linked Immunosorbent Assay , Female , Humans , Length of Stay/statistics & numerical data , Male , Middle Aged , Oxidative Stress/physiology , Pneumonia/pathology , Prognosis , Prospective Studies , Respiration, Artificial/statistics & numerical data
4.
Nature ; 603(7899): 145-151, 2022 03.
Article in English | MEDLINE | ID: covidwho-1631700

ABSTRACT

COVID-19, which is caused by infection with SARS-CoV-2, is characterized by lung pathology and extrapulmonary complications1,2. Type I interferons (IFNs) have an essential role in the pathogenesis of COVID-19 (refs 3-5). Although rapid induction of type I IFNs limits virus propagation, a sustained increase in the levels of type I IFNs in the late phase of the infection is associated with aberrant inflammation and poor clinical outcome5-17. Here we show that the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway, which controls immunity to cytosolic DNA, is a critical driver of aberrant type I IFN responses in COVID-19 (ref. 18). Profiling COVID-19 skin manifestations, we uncover a STING-dependent type I IFN signature that is primarily mediated by macrophages adjacent to areas of endothelial cell damage. Moreover, cGAS-STING activity was detected in lung samples from patients with COVID-19 with prominent tissue destruction, and was associated with type I IFN responses. A lung-on-chip model revealed that, in addition to macrophages, infection with SARS-CoV-2 activates cGAS-STING signalling in endothelial cells through mitochondrial DNA release, which leads to cell death and type I IFN production. In mice, pharmacological inhibition of STING reduces severe lung inflammation induced by SARS-CoV-2 and improves disease outcome. Collectively, our study establishes a mechanistic basis of pathological type I IFN responses in COVID-19 and reveals a principle for the development of host-directed therapeutics.


Subject(s)
COVID-19/immunology , COVID-19/pathology , Interferon Type I/immunology , Membrane Proteins/metabolism , Nucleotidyltransferases/metabolism , SARS-CoV-2/immunology , Animals , COVID-19/metabolism , COVID-19/virology , Cells, Cultured , DNA, Mitochondrial/metabolism , Disease Models, Animal , Disease Progression , Endothelial Cells/pathology , Female , Gene Expression Regulation/immunology , Humans , Immunity, Innate , Lung/immunology , Lung/metabolism , Lung/pathology , Lung/virology , Macrophages/immunology , Membrane Proteins/antagonists & inhibitors , Mice , Mice, Inbred C57BL , Pneumonia/immunology , Pneumonia/metabolism , Pneumonia/pathology , Pneumonia/virology , SARS-CoV-2/pathogenicity , Signal Transduction , Skin/immunology , Skin/metabolism , Skin/pathology
5.
Int J Mol Sci ; 23(3)2022 Jan 19.
Article in English | MEDLINE | ID: covidwho-1625612

ABSTRACT

Repurposing of the anthelminthic drug niclosamide was proposed as an effective treatment for inflammatory airway diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease. Niclosamide may also be effective for the treatment of viral respiratory infections, such as SARS-CoV-2, respiratory syncytial virus, and influenza. While systemic application of niclosamide may lead to unwanted side effects, local administration via aerosol may circumvent these problems, particularly when the drug is encapsulated into small polyethylene glycol (PEG) hydrospheres. In the present study, we examined whether PEG-encapsulated niclosamide inhibits the production of mucus and affects the pro-inflammatory mediator CLCA1 in mouse airways in vivo, while effects on mucociliary clearance were assessed in excised mouse tracheas. The potential of encapsulated niclosamide to inhibit TMEM16A whole-cell Cl- currents and intracellular Ca2+ signalling was assessed in airway epithelial cells in vitro. We achieved encapsulation of niclosamide in PEG-microspheres and PEG-nanospheres (Niclo-spheres). When applied to asthmatic mice via intratracheal instillation, Niclo-spheres strongly attenuated overproduction of mucus, inhibited secretion of the major proinflammatory mediator CLCA1, and improved mucociliary clearance in tracheas ex vivo. These effects were comparable for niclosamide encapsulated in PEG-nanospheres and PEG-microspheres. Niclo-spheres inhibited the Ca2+ activated Cl- channel TMEM16A and attenuated mucus production in CFBE and Calu-3 human airway epithelial cells. Both inhibitory effects were explained by a pronounced inhibition of intracellular Ca2+ signals. The data indicate that poorly dissolvable compounds such as niclosamide can be encapsulated in PEG-microspheres/nanospheres and deposited locally on the airway epithelium as encapsulated drugs, which may be advantageous over systemic application.


Subject(s)
Niclosamide/administration & dosage , Pneumonia/drug therapy , Respiratory System/drug effects , Animals , Asthma/drug therapy , Asthma/metabolism , Asthma/pathology , COVID-19/complications , COVID-19/drug therapy , Cells, Cultured , Disease Models, Animal , Drug Carriers/chemistry , Drug Compounding , Humans , Hydrogels/chemistry , Instillation, Drug , Mice , Microspheres , Mucus/drug effects , Mucus/metabolism , Nanospheres/administration & dosage , Nanospheres/chemistry , Niclosamide/chemistry , Niclosamide/pharmacokinetics , Pneumonia/pathology , Polyethylene Glycols/chemistry , Respiratory Mucosa/drug effects , Respiratory Mucosa/metabolism , Respiratory System/metabolism , SARS-CoV-2/drug effects , SARS-CoV-2/physiology , Trachea
6.
J Ethnopharmacol ; 287: 114965, 2022 Apr 06.
Article in English | MEDLINE | ID: covidwho-1587284

ABSTRACT

ETHNOPHARMACOLOGICAL RELEVANCE: Coronavirus and influenza virus infection seriously threaten human health. Cangma Huadu Granules (CMHD) is an in-hospital preparation composed of eight traditional Chinese medicines (TCM), which has been clinically used against COVID-19 in China and may be a promising candidate for the treatment of influenza. However, the role of its treatment urgently needs to be studied. AIM OF THE STUDY: To evaluate the therapeutic effects of CMHD on pneumonia induced by coronavirus (HCoV-229E) and influenza A virus (H1N1/FM1) in mice and explore its mechanism of anti-infection. MATERIALS AND METHODS: Mice were infected with HCoV-229E or H1N1/FM1 virus through the nasal cavity. CMHD (12.1, 6.05 and 3.03 g/kg/d) or the positive control drugs were administered intragastrically. The lung index and histopathological changes were used to evaluate the therapeutic effect of CMHD. The expression of TNF-α, IL-1ß, IL-6 and IL-4 in Serum and the proportion of CD4+ and CD8+ T lymphocytes in peripheral blood were detected to evaluate the anti-inflammatory and immune regulation effects of CMHD, respectively. Furthermore, the levels of p-NF-κBp65/ NF-κB p65, which was the key targets of the NF-κB pathway was analyzed. RESULTS: In HCoV-229E-induced pneumonia, the lung index was markedly reduced, and lung pathology was improved in mice that treated with CMHD (12.1, 6.05 g/kg/d). Meanwhile, the expression of TNF-α, IL-6 were obviously inhibited, but the expression of IL-4 was significantly increased in CMHD groups. Compared with the model group, CMHD could also markedly upregulate the level of CD4+ and CD8+. Furthermore, CMHD has a markedly effect on inhibit the expression of p-NF-κB p65/NF-κB p65 in the lung. In H1N1-induced pneumonia, the lung index of mice in the CMHD (12.1 g/kg/d) treatment group was lower than that in the model group, and less inflammatory infiltration could be seen in the lung pathological. Moreover, CMHD could also obviously decrease the expression of TNF-α, IL-1ß, IL-6, but significantly increase the expression of IL-4. Except for that, CMHD could also markedly downregulate the level of CD4+ and upregulate the level of CD8+ compared with the model group. In addition, CMHD has a markedly effect on inhibit the expression of p-NF-κB p65/NF-κB p65 in the lung. CONCLUSION: CMHD can significantly combats viral infections caused by HCoV-229E and H1N1, and the mechanism may be related to its multiple functions of anti-inflammatory, immunity regulating and inhibiting NF-κB signal transduction pathway.


Subject(s)
Anti-Inflammatory Agents/pharmacology , Coronavirus Infections/drug therapy , Drugs, Chinese Herbal/pharmacology , Influenza A Virus, H1N1 Subtype/drug effects , Medicine, Chinese Traditional/methods , Orthomyxoviridae Infections/drug therapy , Animals , Anti-Inflammatory Agents/therapeutic use , Coronavirus 229E, Human/drug effects , Cytokines/metabolism , Disease Models, Animal , Drugs, Chinese Herbal/therapeutic use , Female , Immunity/drug effects , Male , Mice, Inbred BALB C , Mice, Inbred ICR , Pneumonia/drug therapy , Pneumonia/pathology , T-Lymphocytes/metabolism , Transcription Factor RelA/metabolism
7.
Front Immunol ; 12: 784028, 2021.
Article in English | MEDLINE | ID: covidwho-1581324

ABSTRACT

Background: Extracellular vesicles (EVs) are mediators of cell-to-cell communication in inflammatory lung diseases. They function as carriers for miRNAs which regulate mRNA transcripts and signaling pathways after uptake into recipient cells. We investigated whether miRNAs associated with circulating EVs regulate immunologic processes in COVID-19. Methods: We prospectively studied 20 symptomatic patients with COVID-19 pneumonia, 20 mechanically ventilated patients with severe COVID-19 (severe acute respiratory corona virus-2 syndrome, ARDS) and 20 healthy controls. EVs were isolated by precipitation, total RNA was extracted, profiled by small RNA sequencing and evaluated by differential gene expression analysis (DGE). Differentially regulated miRNAs between groups were bioinformatically analyzed, mRNA target transcripts identified and signaling networks constructed, thereby comparing COVID-19 pneumonia to the healthy state and pneumonia to severe COVID-19 ARDS. Results: DGE revealed 43 significantly and differentially expressed miRNAs (25 downregulated) in COVID-19 pneumonia when compared to controls, and 20 miRNAs (15 downregulated) in COVID-19 ARDS patients in comparison to those with COVID-19 pneumonia. Network analysis for comparison of COVID-19 pneumonia to healthy controls showed upregulated miR-3168 (log2FC=2.28, padjusted<0.001), among others, targeting interleukin-6 (IL6) (25.1, 15.2 - 88.2 pg/ml in COVID-19 pneumonia) and OR52N2, an olfactory smell receptor in the nasal epithelium. In contrast, miR-3168 was significantly downregulated in COVID-19 ARDS (log2FC=-2.13, padjusted=0.003) and targeted interleukin-8 (CXCL8) in a completely activated network. Toll-like receptor 4 (TLR4) was inhibited in COVID-19 pneumonia by miR-146a-5p and upregulated in ARDS by let-7e-5p. Conclusion: EV-derived miRNAs might have important regulative functions in the pathophysiology of COVID-19: CXCL8 regulates neutrophil recruitment into the lung causing epithelial damage whereas activated TLR4, to which SARS-CoV-2 spike protein binds strongly, increases cell surface ACE2 expression and destroys type II alveolar cells that secrete pulmonary surfactants; both resulting in pulmonary-capillary leakage and ARDS. These miRNAs may serve as biomarkers or as possible therapeutic targets.


Subject(s)
Biomarkers/blood , COVID-19/immunology , Extracellular Vesicles/immunology , MicroRNAs/immunology , Aged , Aged, 80 and over , COVID-19/pathology , Disease Progression , Female , Humans , Male , Middle Aged , Pneumonia/immunology , Pneumonia/pathology , SARS-CoV-2 , Signal Transduction/immunology
8.
J Med Virol ; 94(4): 1289-1291, 2022 Apr.
Article in English | MEDLINE | ID: covidwho-1589037

ABSTRACT

In December 2019, a new type of virus, coronavirus disease 2019 broke out globally and caused great harm. The virus mutates rapidly, and more research reports are urgently needed to increase our understanding of the disease. We found the reversed halo sign (RHS) occurred in the imaging manifestations of severe acute respiratory syndrome coronavirus 2 delta variant of concern pneumonia. In the absence of pathology, the mechanism is unknown. Therefore, we reported two cases of RHS and tried to speculate the pathological mechanism through multiple computed tomography follow-up comparisons to judge the prognosis of the disease.


Subject(s)
COVID-19/diagnostic imaging , SARS-CoV-2/pathogenicity , COVID-19/pathology , COVID-19/virology , Female , Follow-Up Studies , Humans , Male , Middle Aged , Pneumonia/diagnostic imaging , Pneumonia/pathology , Pneumonia/virology , Prognosis , SARS-CoV-2/isolation & purification , Tomography, X-Ray Computed
9.
Med Clin (Barc) ; 157(3): 99-105, 2021 08 13.
Article in English, Spanish | MEDLINE | ID: covidwho-1575444

ABSTRACT

OBJECTIVES: Compare the accuracy of PSI, CURB-65, MuLBSTA and COVID-GRAM prognostic scores to predict mortality, the need for invasive mechanical ventilation in patients with pneumonia caused by SARS-CoV-2 and assess the coexistence of bacterial respiratory tract infection during admission. METHODS: Retrospective observational study that included hospitalized adults with pneumonia caused by SARS-CoV-2 from 15/03 to 15/05/2020. We excluded immunocompromised patients, nursing home residents and those admitted in the previous 14 days for another reasons. Analysis of ROC curves was performed, calculating the area under the curve for the different scales, as well as sensitivity, specificity and predictive values. RESULTS: A total of 208 patients were enrolled, aged 63±17 years, 57,7% were men; 38 patients were admitted to ICU (23,5%), of these patients 33 required invasive mechanical ventilation (86,8%), with an overall mortality of 12,5%. Area under the ROC curves for mortality of the scores were: PSI 0,82 (95% CI: 0,73-0,91), CURB-65 0,82 (0,73-0,91), MuLBSTA 0,72 (0,62-0,81) and COVID-GRAM 0,86 (0,70-1). Area under the curve for needing invasive mechanical ventilation was: PSI 0,73 (95% CI: 0,64-0,82), CURB-65 0,66 (0,55-0,77), MuLBSTA 0,78 (0,69-0,86) and COVID-GRAM 0,76 (0,67-0,85), respectively. Patients with bacterial co-infections of the respiratory tract were 20 (9,6%), the most frequent strains being Pseudomonas aeruginosa and Klebsiella pneumoniae. CONCLUSIONS: In our study, the COVID-GRAM score was the most accurate to identify patients with higher mortality with pneumonia caused by SARS-CoV-2; however, none of these scores accurately predicts the need for invasive mechanical ventilation with ICU admission. The 10% of patients admitted presented bacterial respiratory co-infection.


Subject(s)
COVID-19 , Pneumonia , Aged , COVID-19/pathology , Female , Hospitalization , Humans , Male , Middle Aged , Pneumonia/pathology , Respiration, Artificial , Retrospective Studies , Severity of Illness Index
10.
Int J Mol Sci ; 22(23)2021 Nov 27.
Article in English | MEDLINE | ID: covidwho-1560687

ABSTRACT

Acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) are severe respiratory disorders that are caused by aspiration, sepsis, trauma, and pneumonia. A clinical feature of ALI/ARDS is the acute onset of severe hypoxemia, and the mortality rate, which is estimated at 38-50%, remains high. Although prostaglandins (PGs) are detected in the bronchoalveolar lavage fluid of patients with ALI/ARDS, the role of PGF2α in ALI remains unclear. We aimed to clarify the role of PGF2α/PGF2α receptor (FP) signaling in acid-induced ALI using an FP receptor antagonist, AL8810. Intratracheal injection of hydrochloric acid (HCl) increased neutrophil migration into the lungs, leading to respiratory dysfunction. Pre-administration of AL8810 further increased these features. Moreover, pre-treatment with AL8810 enhanced the HCl-induced expression of pro-inflammatory cytokines and neutrophil migratory factors in the lungs. Administration of HCl decreased the gene expression of lung surfactant proteins, which was further reduced by co-administration of AL8810. Administration of AL8810 also increased lung edema and reduced mRNA expression of epithelial sodium channel in the lungs, indicating that AL8810 reduced fluid clearance. Furthermore, AL8810 also increased lipopolysaccharide-induced expression of adhesion molecules such as intracellular adhesion molecule-1 and E-selectin in human umbilical vein endothelial cells. These results indicate that inhibition of FP receptors by AL8810 exacerbated HCl-induced ALI.


Subject(s)
Acute Lung Injury/metabolism , Lung/drug effects , Pneumonia/metabolism , Receptors, Prostaglandin/antagonists & inhibitors , Respiratory Distress Syndrome/metabolism , Acute Lung Injury/chemically induced , Acute Lung Injury/pathology , Animals , Disease Models, Animal , Female , Hydrochloric Acid/toxicity , Lung/metabolism , Lung/pathology , Mice , Mice, Inbred C57BL , Pneumonia/chemically induced , Pneumonia/immunology , Pneumonia/pathology , Prostaglandins F/metabolism , Respiratory Distress Syndrome/chemically induced , Respiratory Distress Syndrome/pathology
11.
PLoS One ; 16(11): e0259732, 2021.
Article in English | MEDLINE | ID: covidwho-1518359

ABSTRACT

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.


Subject(s)
Acute Lung Injury/complications , Acute Lung Injury/virology , COVID-19/pathology , Extracellular Vesicles/metabolism , Mesenchymal Stem Cells/metabolism , Pneumonia/complications , Pneumonia/virology , Angiotensin-Converting Enzyme 2/metabolism , Animals , Disease Models, Animal , Extracellular Vesicles/ultrastructure , Humans , Immunomodulation , Male , Models, Biological , Pneumonia/pathology , Rats, Sprague-Dawley , SARS-CoV-2/physiology , Signal Transduction , THP-1 Cells
12.
Biomed Res Int ; 2021: 1896762, 2021.
Article in English | MEDLINE | ID: covidwho-1511530

ABSTRACT

The proposed method introduces algorithms for the preprocessing of normal, COVID-19, and pneumonia X-ray lung images which promote the accuracy of classification when compared with raw (unprocessed) X-ray lung images. Preprocessing of an image improves the quality of an image increasing the intersection over union scores in segmentation of lungs from the X-ray images. The authors have implemented an efficient preprocessing and classification technique for respiratory disease detection. In this proposed method, the histogram of oriented gradients (HOG) algorithm, Haar transform (Haar), and local binary pattern (LBP) algorithm were applied on lung X-ray images to extract the best features and segment the left lung and right lung. The segmentation of lungs from the X-ray can improve the accuracy of results in COVID-19 detection algorithms or any machine/deep learning techniques. The segmented lungs are validated over intersection over union scores to compare the algorithms. The preprocessed X-ray image results in better accuracy in classification for all three classes (normal/COVID-19/pneumonia) than unprocessed raw images. VGGNet, AlexNet, Resnet, and the proposed deep neural network were implemented for the classification of respiratory diseases. Among these architectures, the proposed deep neural network outperformed the other models with better classification accuracy.


Subject(s)
COVID-19/pathology , COVID-19/virology , Image Processing, Computer-Assisted/methods , Lung/pathology , Lung/virology , Algorithms , Deep Learning , Expert Systems , Humans , Machine Learning , Pneumonia/pathology , Pneumonia/virology , X-Rays
13.
Eur Rev Med Pharmacol Sci ; 25(19): 5922-5927, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1478933

ABSTRACT

Systemic capillary leak syndrome (SCLS) is a very rare and lethal disease characterized by hemoconcentration and hypoalbuminemia caused by reversible plasma extravasation. The underlying cause for SCLS remains largely unknown and acute treatment has remained mainly supportive. Prophylaxis with intravenous immunoglobulin (IVIG) has been shown to successfully prevent further episodes in affected patients. We reported a case of SCLS in a patient who presented to our hospital with COVID-19 and developed profound shock.


Subject(s)
COVID-19/pathology , Capillary Leak Syndrome/pathology , COVID-19/complications , COVID-19/diagnostic imaging , Capillary Leak Syndrome/complications , Capillary Leak Syndrome/diagnostic imaging , Humans , Immunoglobulins, Intravenous/therapeutic use , Male , Middle Aged , Pneumonia/complications , Pneumonia/pathology , Shock/etiology , Shock/pathology , Tomography, X-Ray Computed
14.
PLoS One ; 16(10): e0254985, 2021.
Article in English | MEDLINE | ID: covidwho-1448572

ABSTRACT

BACKGROUND: The goal of this study was to determine if IL-22:Fc would Acute Respiratory Distress Syndrome (ARDS). SUMMARY BACKGROUND DATA: No therapies exist for ARDS and treatment is purely supportive. Interleukin-22 (IL-22) plays an integral component in recovery of the lung from infection. IL-22:Fc is a recombinant protein with a human FC immunoglobulin that increases the half-life of IL-22. STUDY DESIGN: ARDS was induced in C57BL/6 mice with intra-tracheal lipopolysaccharide (LPS) at a dose of 33.3 or 100 ug. In the low-dose LPS group (LDG), IL-22:FC was administered via tail vein injection at 30 minutes (n = 9) and compared to sham (n = 9). In the high-dose LPS group (HDG), IL-22:FC was administered (n = 11) then compared to sham (n = 8). Euthanasia occurred after bronchioalveolar lavage (BAL) on post-injury day 4. RESULTS: In the LDG, IL-22:FC resulted in decreased protein leak (0.15 vs. 0.25 ug/uL, p = 0.02). BAL protein in animals receiving IL-22:Fc in the HDG was not different. For the HDG, animals receiving IL-22:Fc had lower BAL cell counts (539,636 vs 3,147,556 cells/uL, p = 0.02). For the HDG, IL-6 (110.6 vs. 527.1 pg/mL, p = 0.04), TNF-α (5.87 vs. 25.41 pg/mL, p = 0.04), and G-CSF (95.14 vs. 659.6, p = 0.01) levels were lower in the BAL fluid of IL-22:Fc treated animals compared to sham. CONCLUSIONS: IL-22:Fc decreases lung inflammation and lung capillary leak in ARDS. IL-22:Fc may be a novel therapy for ARDS.


Subject(s)
Immunoglobulin Fc Fragments/pharmacology , Interleukins/pharmacology , Lung Injury/drug therapy , Pneumonia/drug therapy , Respiratory Distress Syndrome/drug therapy , Animals , Bronchoalveolar Lavage Fluid/chemistry , Bronchoalveolar Lavage Fluid/cytology , Female , Lipopolysaccharides/toxicity , Lung Injury/pathology , Lymphocyte Count , Lymphocytes/immunology , Macrophages/immunology , Male , Mice , Mice, Inbred C57BL , Neutrophils/immunology , Pneumonia/pathology , Receptors, Interleukin/metabolism , Recombinant Proteins/pharmacology , Respiratory Distress Syndrome/pathology , Respiratory Mucosa/pathology
15.
Dis Markers ; 2021: 6803510, 2021.
Article in English | MEDLINE | ID: covidwho-1443673

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is currently the most significant public health threat worldwide. Patients with severe COVID-19 usually have pneumonia concomitant with local inflammation and sometimes a cytokine storm. Specific components of the SARS-CoV-2 virus trigger lung inflammation, and recruitment of immune cells to the lungs exacerbates this process, although much remains unknown about the pathogenesis of COVID-19. Our study of lung type II pneumocyte cells (A549) demonstrated that ORF7, an open reading frame (ORF) in the genome of SARS-CoV-2, induced the production of CCL2, a chemokine that promotes the chemotaxis of monocytes, and decreased the expression of IL-8, a chemokine that recruits neutrophils. A549 cells also had an increased level of IL-6. The results of our chemotaxis Transwell assay suggested that ORF7 augmented monocyte infiltration and reduced the number of neutrophils. We conclude that the ORF7 of SARS-CoV-2 may have specific effects on the immunological changes in tissues after infection. These results suggest that the functions of other ORFs of SARS-CoV-2 should also be comprehensively examined.


Subject(s)
COVID-19/metabolism , Chemotaxis , Monocytes/pathology , Neutrophils/pathology , Open Reading Frames/physiology , Pneumonia/pathology , Viral Proteins/metabolism , A549 Cells , Chemokine CCL2/metabolism , Humans , In Vitro Techniques , Monocytes/immunology , Monocytes/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Pneumonia/immunology , Pneumonia/metabolism , SARS-CoV-2/metabolism , Viral Proteins/genetics
16.
Sci Rep ; 11(1): 17885, 2021 09 09.
Article in English | MEDLINE | ID: covidwho-1402124

ABSTRACT

We propose a classification method using the radiomics features of CT chest images to identify patients with coronavirus disease 2019 (COVID-19) and other pneumonias. The chest CT images of two groups of participants (90 COVID-19 patients who were confirmed as positive by nucleic acid test of RT-PCR and 90 other pneumonias patients) were collected, and the two groups of data were manually drawn to outline the region of interest (ROI) of pneumonias. The radiomics method was used to extract textural features and histogram features of the ROI and obtain a radiomics features vector from each sample. Then, we divided the data into two independent radiomic cohorts for training (70 COVID-19 patients and 70 other pneumonias patients), and validation (20 COVID-19 patients and 20 other pneumonias patients) by using support vector machine (SVM). This model used 20 rounds of tenfold cross-validation for training. Finally, single-shot testing of the final model was performed on the independent validation cohort. In the COVID-19 patients, correlation analysis (multiple comparison correction-Bonferroni correction, P < 0.05/7) was also conducted to determine whether the textural and histogram features were correlated with the laboratory test index of blood, i.e., blood oxygen, white blood cell, lymphocytes, neutrophils, C-reactive protein, hypersensitive C-reactive protein, and erythrocyte sedimentation rate. The final model showed good discrimination on the independent validation cohort, with an accuracy of 89.83%, sensitivity of 94.22%, specificity of 85.44%, and AUC of 0.940. This proved that the radiomics features were highly distinguishable, and this SVM model can effectively identify and diagnose patients with COVID-19 and other pneumonias. The correlation analysis results showed that some textural features were positively correlated with WBC, and NE, and also negatively related to SPO2H and NE. Our results showed that radiomic features can classify COVID-19 patients and other pneumonias patients. The SVM model can achieve an excellent diagnosis of COVID-19.


Subject(s)
COVID-19/diagnostic imaging , COVID-19/diagnosis , Pneumonia/diagnostic imaging , Pneumonia/diagnosis , Support Vector Machine , Tomography, X-Ray Computed/methods , Adult , Biomedical Engineering , Blood Sedimentation , C-Reactive Protein/analysis , COVID-19/pathology , Female , Humans , Leukocyte Count , Lung/diagnostic imaging , Male , Middle Aged , Pneumonia/pathology , SARS-CoV-2
17.
Cells ; 10(8)2021 07 29.
Article in English | MEDLINE | ID: covidwho-1339532

ABSTRACT

Neutrophils act as the first line of defense during infection and inflammation. Once activated, they are able to fulfil numerous tasks to fight inflammatory insults while keeping a balanced immune response. Besides well-known functions, such as phagocytosis and degranulation, neutrophils are also able to release "neutrophil extracellular traps" (NETs). In response to most stimuli, the neutrophils release decondensed chromatin in a NADPH oxidase-dependent manner decorated with histones and granule proteins, such as neutrophil elastase, myeloperoxidase, and cathelicidins. Although primarily supposed to prevent microbial dissemination and fight infections, there is increasing evidence that an overwhelming NET response correlates with poor outcome in many diseases. Lung-related diseases especially, such as bacterial pneumonia, cystic fibrosis, chronic obstructive pulmonary disease, aspergillosis, influenza, and COVID-19, are often affected by massive NET formation. Highly vascularized areas as in the lung are susceptible to immunothrombotic events promoted by chromatin fibers. Keeping this fragile equilibrium seems to be the key for an appropriate immune response. Therapies targeting dysregulated NET formation might positively influence many disease progressions. This review highlights recent findings on the pathophysiological influence of NET formation in different bacterial, viral, and non-infectious lung diseases and summarizes medical treatment strategies.


Subject(s)
Extracellular Traps/immunology , Neutrophils/immunology , Pneumonia/immunology , COVID-19/immunology , Disease Progression , Humans , Neutrophils/microbiology , Neutrophils/virology , Pneumonia/microbiology , Pneumonia/pathology , Pneumonia/virology
18.
Biomed Pharmacother ; 141: 111896, 2021 Sep.
Article in English | MEDLINE | ID: covidwho-1300051

ABSTRACT

Influenza in humans is often accompanied by gastroenteritis-like symptoms. GeGen QinLian decoction (GQD), a Chinese herb formula, has been widely used to treat infectious diarrhea for centuries and has the effect of restoring intestinal flora. Studies have also reported that GQD were used to treat patients with influenza. However, whether regulating the intestinal flora is one of the ways GQD treats influenza has not been confirmed. In present research, we conducted a systemic pharmacological study, and the results showed that GQD may acts through multiple targets and pathways. In influenza-infected mice, GQD treatment reduced mortality and lung inflammation. Most importantly, the mortality and lung inflammation were also reduced in influenza-infected mice that have undergone fecal microbiota transplantation (FMT) from GQD (FMT-GQD) treated mice. GQD treatment or FMT-GQD treatment restores the intestinal flora, resulting in an increase in Akkermansia_muciniphila, Desulfovibrio_C21_c20 and Lactobacillus_salivarius, and a decrease in Escherichia_coli. FMT-GQD treatment inhibited the NOD/RIP2/NF-κB signaling pathway in the intestine and affected the expression of downstream related inflammatory cytokines in mesenteric lymph nodes (mLNs) and serum. In addition, FMT-GQD treatment showed systemic protection by restraining the inflammatory differentiation of CD4+ T cells. In conclusion, our study shows that GQD can affect systemic immunity, at least in part, through the intestinal flora, thereby protect the mice against influenza virus infectious pneumonia.


Subject(s)
Drugs, Chinese Herbal/therapeutic use , Gastrointestinal Microbiome/drug effects , Orthomyxoviridae , Pneumonia, Viral/drug therapy , Animals , CD4-Positive T-Lymphocytes/drug effects , Cytokines/metabolism , Female , Lymph Nodes/metabolism , Male , Mice , Mice, Inbred C57BL , Mice, Inbred NOD , NF-kappa B/drug effects , Pneumonia/etiology , Pneumonia/pathology , Pneumonia/prevention & control , Pneumonia, Viral/mortality , Receptor-Interacting Protein Serine-Threonine Kinase 2/drug effects , Signal Transduction/drug effects
19.
Cells ; 10(7)2021 07 01.
Article in English | MEDLINE | ID: covidwho-1323124

ABSTRACT

Activation of Transient Receptor Potential (TRP) channels can disrupt endothelial barrier function, as their mediated Ca2+ influx activates the CaM (calmodulin)/MLCK (myosin light chain kinase)-signaling pathway, and thereby rearranges the cytoskeleton, increases endothelial permeability and thus can facilitate activation of inflammatory cells and formation of pulmonary edema. Interestingly, TRP channel subunits can build heterotetramers, whereas heteromeric TRPC1/4, TRPC3/6 and TRPV1/4 are expressed in the lung endothelium and could be targeted as a protective strategy to reduce endothelial permeability in pulmonary inflammation. An update on TRP heteromers and their role in lung inflammation will be provided with this review.


Subject(s)
Pneumonia/metabolism , Protein Multimerization , Transient Receptor Potential Channels/metabolism , Animals , Endothelial Cells/metabolism , Endothelial Cells/pathology , Humans , Ion Channel Gating , Models, Biological , Pneumonia/pathology , Pneumonia/physiopathology
20.
J Immunol Res ; 2021: 6657894, 2021.
Article in English | MEDLINE | ID: covidwho-1314178

ABSTRACT

BACKGROUND: The 2019 novel coronavirus SARS-CoV-2 caused large outbreaks of COVID-19 worldwide. COVID-19 resembles community-acquired pneumonia (CAP). Our aim was to identify lymphocyte subpopulations to distinguish between COVID-19 and CAP. METHODS: We compared the peripheral blood lymphocytes and their subsets in 296 patients with COVID-19 and 130 patients with CAP. Parameters for independent prediction of COVID-19 were calculated by logistic regression. RESULTS: The main lymphocyte subpopulations (CD3+CD4+, CD16+CD56+, and CD4+/CD8+ ratio) and cytokines (TNF-α and IFN-γ) of COVID-19 patients were significantly different from that of CAP patients. CD16+CD56+%, CD4+/CD8+ratio, CD19+, and CD3+CD4+ were identified as predictors of COVID-19 diagnosis by logistic regression. In addition, the CD3+CD4+counts, CD3+CD8+ counts, andTNF-α are independent predictors of disease severity in patients. CONCLUSIONS: Lymphopenia is an important part of SARS-CoV-2 infection, and lymphocyte subsets and cytokines may be useful to predict the severity and clinical outcomes of the disease.


Subject(s)
CD4-CD8 Ratio , COVID-19/blood , Interferon-gamma/blood , Lymphocyte Subsets/cytology , Pneumonia/blood , Tumor Necrosis Factor-alpha/blood , Adult , Aged , COVID-19/immunology , COVID-19/pathology , COVID-19 Testing , Community-Acquired Infections/microbiology , Female , Humans , Lymphocyte Subsets/immunology , Lymphopenia/blood , Lymphopenia/pathology , Male , Middle Aged , Pneumonia/immunology , Pneumonia/pathology , Prognosis , SARS-CoV-2/immunology , Severity of Illness Index
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