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The proceedings contain 54 papers. The topics discussed include: cytokines in severe childhood asthma;transcriptional gene regulation of interleukin-6 in epithelial cells in viral-induced asthma exacerbation;assessment of the long-term safety and efficacy of dupilumab in children with asthma: LIBERTY ASTHMA EXCURSION;impulse oscillometry bronchodilator response in preschool children;pulmonary function in non-hospitalized adults and children after mild Covid-19;exhaled aerosols in PCR-confirmed SARS-CoV-2-infected children;early respiratory infectious diseases have an influence on the gut microbiome;comparison of three eradication treatment protocols for pseudomonas aeruginosa in children and adolescents with cystic fibrosis;neutrophilic airway inflammation in children with repaired esophageal atresia-tracheoesophageal fistula (EA/TEF);and multiplex immunofluorescence and multispectral imaging as a tool to evaluate host directed therapy.
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Background: bronchiolitis is a common lung infection in young children and infants. Bronchiolitis is almost always caused by a virus. Typically, the peak time for bronchiolitis is during the winter months. During covid pandemic, the incidence of bronchiolitis had drastically decreased but this winter, cases of this airway inflammation increased and were more severe. Objective(s): to study the prevalence of bronchiolitis during the winter season and describe its epidemiology, clinical features and outcome. Method(s): retrospective study in a general pediatric ward from november 2021 till january 2022. Result(s): we collected 207 cases admitted for bronchiolitis, in compraison with 162 cases in 2020. Le The hospitalization peak was in november 2021 (36.7%). The sex ratio was 1.43. The mean age was 88 days, the younger than 3 months represented 69.5% of cases. A viral contat was noted in 84.5% of cases. The bronchiolitis was mild in 20.2% of cases, moderate in 57.9% of cases and severe in 21.7% of cases. RSV was isolated in 25 case, Influenza A in 20 cases, viral co-infection was noted in 14 cases while bacterial co-infection was observed in 25 patients. Oxygenotherapy was indicated in 64.7% of patients with a mean duration of 5.6 days. Twenty-two patients were transferred in ICU with the use of non-invasive ventilation in 14 cases and mecahnical ventilation in 13 cases. The mean hospital stay was about 6.7 days. Conclusion(s): although the decrease of the incidence of bronchiolitis during covid 19 pandemic, an important incerease in incidence and intensity of this airway pathology was noted after the 4th wave, explained by the loss of the collective immunity in the younger infants less than 3 months.
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The novel coronavirus disease 2019 (COVID-19) has given rise to a global pandemic, as well as a multitude of long-term sequelae that continue to perplex physicians around the world, including in the United States. Among the most common and impactful long-haul symptoms experienced by survivors is COVID-19 fatigue. This review will use long COVID-19, post-acute COVID-19 syndrome (PCS), and PostAcute Sequelae of COVID-19 (PASC) as synonymous terms to refer to the chronic symptomatology;chronic fatigue associated with PASC will be referred to as COVID-19 fatigue. While the knowledge and research on the exact pathophysiological mechanisms involved in the disease is still limited, parallels have been drawn between fatigue as a component of long COVID-19 and myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS). Current studies suggest applying principles of pathophysiology, diagnosis, and treatment similar to those for ME/CFS in order to aid in managing chronic fatigue in COVID-19 survivors, particularly in the primary care setting. The osteopathic family physician can use the proposed pharmacologic agents, along with osteopathic manipulative treatment (OMT), as therapeutic modalities that can be tailored to each patient's unique case. Nevertheless, research on proven successful treatments is still scarce. For that reason, it is essential that COVID-19 fatigue is recognized early, especially since its longitudinal impacts may be debilitating for many. This review of the available literature on COVID-19 fatigue aims to help provide quality care and lessen the disease burden experienced by patients.Copyright © 2023 by the American College of Osteopathic Family Physicians. All rights reserved.
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In December 2019, the novel coronavirus strain SARS-CoV-2 caused an outbreak that quickly spread worldwide and led to the COVID-19 pandemic. COVID-19, the severe infectious disease caused by SARS-CoV-2, often presents with symptoms including fever, cough, and mental confusion and can cause the acute respiratory inflammatory disorder. Additionally, viral infection with SARS-CoV-2 is associated with mental health, neuronal degeneration, and psychiatric complications. With infection by the virus, cytokines are released by immune cells, causing acute systemic inflammation affecting the lungs. Lung damage can occur, resulting in hypoxia, brain damage, and mental health dysfunction. In addition, a cascade of inflammatory cytokines, including IL-1, IL-6, and TNF, are released, a phenomenon termed the "cytokine storm" that causes serious pathological damage to tissues and organs and mental health. This exaggerated production of cytokines leads to lymphopenia and disrupts the balance of Treg and Th17 cells, weakening the immune system. The elderly population is particularly at risk for damage associated with the "cytokine storm", which can affect neurological functions or result in death. Copyright © by BIOLIFE.
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Background: There is a growing interest in airway inflammation and mental health. Recent genetic and epidemiological evidence supports an association between PTSD and asthma however, contributory immune mediators/mechanisms are unclear. Recent work from our group employs mouse aeroallergen, house dust mite (HDM) models to examine the role of severe asthma linked inflammatory T helper cells, Th17 and interleukin 17 (IL-17A) in regulating PTSD-relevant behaviors. Methods: A combination of behavioral, immunological, transgenic and transcriptomic approaches were used. 1) BALBc-C5a receptor treatment that shifts Th2 mild asthma phenotype to Th17/IL17a expansion and robust airway inflammation;2) IL-17a receptor knockout mice and 3) RNAseq transcriptomics of cortical and blood brain barrier compromised area, subfornical organ (SFO) tissue was performed. Fear conditioning and extinction was assessed as a PTSD-relevant behavior. Results: Induction of Th17/IL-17 in the BALBc/anti-C5aR1 treated mice resulted in compromised fear extinction and increased fear reinstatement. Absence of IL-17 signaling in IL17Ra deficient mice attenuated HDM effects on fear extinction. Preliminary evidence suggests a potential of the SFO in translating HDM effects to the medial prefrontal cortex, an area regulating fear extinction. Transcriptomic analyses revealed modulation of immune T cell-targeted signaling pathways within the SFO in mice with Th17A expansion. Conclusion: Overall, our work provides novel insights on mechanisms by which mediators of severe airway inflammation, Th17/IL17A regulate fear memory of relevance to PTSD. Beyond asthma-PTSD, our findings have relevant implications for other pulmonary (e.g. COVID-19) and autoimmune inflammatory conditions and mental health.
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RATIONALE: Airway inflammation plays a role in airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), chronic bronchitis, and COVID-19 that affect millions of people worldwide. Previously, we showed that acute (24-h) exposure to the pro-inflammatory cytokine tumor necrosis factor α (TNFα) triggers an endoplasmic reticulum (ER) stress response in human airway smooth muscle (hASM) cells. In hASM cells, TNFα selectively activates the inositol requiring enzyme 1α (IRE1α) ER stress pathway with downstream splicing of X-box binding protein 1 (XBP1s), which transcriptionally activates expression of target genes that include proteins mediating phosphorylation of dynamin-related protein 1 (pDRP1) at the Ser616 (S616) residue. Increased pDRP1 at S616 is associated with mitochondrial fission (fragmentation);however, DRP1 is also phosphorylated at Ser637 (S637) residue, and the balance between phosphorylation at S616 and S637 regulates the translocation of DRP1 from cytosol to mitochondria and subsequent fragmentation of mitochondria. In the present study, we hypothesized that TNFα induces ER stress leading to XBP1s mediated increase in the expression of specific kinases that phosphorylate DRP1 at S616 and promote mitochondrial fragmentation. METHODS: hASM cells, dissociated from bronchial tissue obtained from patients with no history of respiratory diseases, were exposed to TNFα (20 ng/ ml for 6-h). As an inhibitor of fragmentation, cells were treated with Mdivi1 (50 μM for 6-h), GTPase inhibitor of DRP1. The expression and phosphorylation status of IRE1α, DRP1, XBP1, cyclin dependent kinases (CDK1, CDK5) and cyclin B1 were quantified by Western blot and immunohistochemistry. Mitochondrial morphology was assessed by 3D confocal microscopy using MitoTracker. XBP1-targets were confirmed by chromatin immunoprecipitation (ChIP) and quantitative PCR. RESULTS: Bioinformatics analysis predicted putative binding sites of XBP1 in the promoter region of CDK1, CDK5 and cyclin B1 genes that are reported to phosphorylate DRP1 at S616. Consistent with our previous findings, we found that TNFα increases IRE1α phosphorylation and XBP1 splicing. The TNFα induced increase in XBP1s transcriptionally activated expression of CDK1, CDK5 and cyclin B1 and leads to subsequent phosphorylation of DRP1 at S616 with no change in S637 phosphorylation. As a result, TNFα mediated increase in the ratio of S616/ S637 phosphorylation, which promoted translocation of DRP1 from cytosol to mitochondria and mitochondrial fragmentation. We also showed that Mdivi1 mediated inhibition of DRP1-GTPase activity ameliorated phosphorylation at S616 residue and significantly reduced mitochondrial fragmentation. CONCLUSIONS: The present study elucidates the mechanism underlying TNFα induced ER stress and mitochondrial fragmentation.
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Rationale We have previously reported blocking the IL-25 receptor (IL-17RB) prevented viral increased allergic airways inflammation and this was associated with reduced lung viral load. To investigate IL-25 regulation of airway anti-viral immunity we hypothesised that IL-25 directly inhibits airway epithelial cell (AEC) type I/III interferon expression and antibody blockade of IL-25 in vivo boosts lung interferon expression and reduces lung viral load in parallel with reduced type 2 airway inflammation. Methods In vitro Immunofluorescence was used to visualise epithelial IL-25 and IL- 17RB proteins in endobronchial biopsies from patients with asthma and healthy subjects and in AEC differentiated at ALI. AEC from n = 14 donors with asthma were differentiated at the air-liquid interface (ALI) and infected with RV-A1, MOI=0.1. A subset of AECs was treated with anti-IL-25 mAb (LNR125) before infecting with RV-A1 or human coronavirus 229E. Differentiated AEC from healthy donors were treated with recombinant IL-25 protein and infected with RV-A1. Nanostring immune transcriptomic data expressed as digital mRNA counts for exact copy number or was expressed as log2 fold change ratio against -log10 Bejamini-Yekutieli-corrected p-values. In vivo 6- 8-week-old, BALB/c mice sensitised and intranasally challenged daily for 3 days with ovalbumin to induced allergic airways disease. A single subcutaneous injection of 250 μg LNR125 was administered during ovalbumin challenge. Mice were then infected i.n. with RV-A1, 6 hours after final allergen challenge. On day 1 and day 7 post-infection, BAL were collected, lung lobe tissue was collected for viral RNA and cytokine expression. Results IL-25 and IL-17RB were constitutively expressed at the apical surface of airway epithelium in biopsies and AEC cultures. RV infection increased IL-25 expression by AEC from asthmatic donors. LNR125 treatment reduced IL-25 mRNA and significantly increased RV induced IFN-β a and IFN-λ protein expression and this was confirmed by Nanostring transcriptomic analyses which also identified down-regulated type-2 immune genes CCL26 (eotaxin 3) and IL1RL1(IL-33 receptor). LN125 treatment also increased IFN-λ expression by 229E-infected differentiated AECs. IL-25 treatment increased viral load associated with 50% reduced expression of IFN-β and CXCL10 and 75% reduced IFN-λ. Allergen challenged, RV-infected mice treated with LNR125 had significantly increased BAL IFN-β protein and 60% reduction in lung viral load associated with reduced IL-25, IL-4, IL-5 and IL-13 BAL proteins compared to controls. Conclusion IL-25-induced inflammation combined with suppression of AEC anti-viral immunity identify IL-25 as a central mediator of viral asthma exacerbations and therefore a target for mAb-based treatment.
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Respiratory diseases are common conditions that endanger human health. Their etiology, pathogenesis, and prognosis are complex, and clinical research has been extensive. This paper reviews studies from the PubMed database to assess the progress of traditional Chinese medicine in the treatment of respiratory diseases in 2021, focusing on related animal and cell models of coronavirus disease 2019. Traditional Chinese medicine extracts, such as polysaccharides and emodin, and classic prescriptions, such as Mahuang decoction, respond to the treatment of influenza by reducing viral infections and regulating the body’s immune response. Chinese herbal extracts, such as schizandra B and andrographolide, treat asthma by inhibiting inflammatory response pathway formation, NLRP3 inflammasome formation, oxidative stress, and autophagy. Traditional Chinese medicine extracts such as fucoxanthin, and proprietary Chinese medicines such as the Xihuang pill is used in the treatment of lung cancer, as it regulates the cell cycle, inhibit tumor cell proliferation, and enhance the body’s immune function. Classic formulas such as the kidney tonic lung formula and proprietary Chinese medicine, such as compound grass stone silkworm granules, relieve airway inflammation and improve lung function in chronic obstructive pulmonary disease. Chinese herbal extracts, such as jostilbene and sage phenol, inhibit epithelial cell–mesenchymal transformation and regulate the levels of inflammatory factors to treat idiopathic pulmonary fibrosis to provide a reliable basis for the treatment of respiratory diseases.
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Introduction: The induction of regulatory T cells (Tregs) is indicated as a potential therapeutic strategy in inflammatory lung diseases including, asthma, viral-induced pneumonia, viral-induced acute lung injury (ALI), severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and SARSCoV- 2-induced ALI. We previously identified that components of the bacteria Streptococcus pneumoniae (T + P) are able to increase Tregs to suppress experimental allergic airways disease, however, this mechanism of suppression and therapy has not been examined in ALI. Methods: We established a murine model of ALI using aerosolized LPS (100 μg/ml) in BALB/c mice. ALI was measured by the presence of neutrophils in the airways up to 96 hours post-exposure, and Tregs and dendritic cells were assessed by flow cytometry. To assess the therapeutic of T + P in ALI and the mechanisms involved, the combination was administered prior to LPS exposure in the absence or presence of anti-CD25. Results: Treatment with T + P significantly reduced total airway inflammation and suppressed the neutrophil chemokine C-X-C motif chemokine ligand 1 (Cxcl1) compared to Saline+LPS alone in experimental ALI. The numbers of Tregs were reduced in experimental ALI model and were restored by T + P treatment. Depletion of Tregs with anti- CD25 confirmed that the suppressive effects of T + P on ALI was through the induction of Tregs. Conclusion: Treatment with S. pneumoniae components T + P suppresses neutrophilic inflammation in ALI through immunoregulatory mechanisms that involve Tregs and may be a novel treatment for ALI including in COVID-19.
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The novel β-coronavirus SARS-COV-2 since the end of 2019 has caused considerable morbidity and mortality worldwide. The coronavirus disease 19 (COVID-19) has a wide spectrum of severity;the clinical presentation varies from asymptomatic or paucisymptomatic forms to a severe respiratory infection, frequently with fatal outcome. The inflammatory response, in particular the overproduction of proinflammatory cytokines and overactivation of immune cells (the so-called cytokine storm), determines the disease severity. At present, factors contributing to the development of this excessive inflammatory response are still under investigation, but it is known that some environmental pollutants are cause of chronic systemic and airway inflammation, finally leading to innate immune system hyperactivation, elevated production of proinflammatory cytokines, and thrombosis. In this review we discuss the influence of environmental and occupational pollutants on severity of SARS-COV-2 disease, taking account of the immune response induced by various pollutants.