Viral Exacerbations Research Articles

Transcriptome networks identify mechanisms of viral and nonviral asthma exacerbations in children.

Respiratory infections are common precursors to asthma exacerbations in children, but molecular immune responses that determine whether and how an infection causes an exacerbation are poorly understood. By using systems-scale network analysis, we identify repertoires of cellular transcriptional pathways that lead to and underlie distinct patterns of asthma exacerbation. Specifically, in both virus-associated and nonviral exacerbations, we demonstrate a set of core exacerbation modules, among which epithelial-associated SMAD3 signaling is upregulated and lymphocyte response pathways are downregulated early in exacerbation, followed by later upregulation of effector pathways including epidermal growth factor receptor signaling, extracellular matrix production, mucus hypersecretion, and eosinophil activation. We show an additional set of multiple inflammatory cell pathways involved in virus-associated exacerbations, in contrast to squamous cell pathways associated with nonviral exacerbations. Our work introduces an in vivo molecular platform to investigate, in a clinical setting, both the mechanisms of disease pathogenesis and therapeutic targets to modify exacerbations.

Glucocorticoids and Inflammatory Cytokines Synergize to Maintain TLR2 Expression in Airway Epithelial Cells

RationaleGlucocorticoids (GCs) act on the GC receptor (GR; NR3C1) to downregulate expression of numerous inflammatory genes and reduce inflammation. However, some inflammatory genes, including many involved in innate immune responses, are not repressed by GCs. These effects are poorly understood, yet may be relevant in severe asthma, patients who smoke, or during viral and bacterial exacerbations, which all respond poorly to GC therapy. Transcriptional regulation of the toll‐like receptor, TLR2, is examined as an inflammatory gene that escapes GC repression.MethodsPulmonary epithelial (A549 and BEAS‐2B) cells were used to model TLR2 expression induced by inflammatory stimuli and GCs. TLR2 expression was tested by qPCR and western blotting.ResultsIn A549 cells, IL1B, TNF and dexamethasone (Dex) induced TLR2 mRNA and protein. IL1B, or TNF, co‐treated with Dex produced a delayed synergy on TLR2 expression. Analysis of unspliced RNA, a surrogate of transcription rate, suggested that this effect was transcriptional. ChIP‐seq data from BEAS‐2B cells showed 1 h of TNF or/and Dex to recruit RELA or/and GR, respectively, upstream of the TLR2 gene. In A549 cells, ChIP‐PCR confirmed that 1 h of IL1B or/and GC also induced RELA or/and GR binding, respectively, to the TLR2 promoter. Overexpression of a dominant inhibitor of NF‐κB (IκBαΔN) prevented TLR2 expression induced by IL1B or IL1B + Dex. Silencing of GR significantly reduced TLR2 expression induced by IL1B + Dex. In A549 cells, Dex modestly repressed, IL1B‐ or TNF‐induced NF‐κB‐dependent transcription. Likewise, IL1B and TNF modestly reduced 2×GRE‐dependent transcription induced by Dex. Thus, generic effects on each pathway do not explain TLR2 synergy. Rather NF‐κB and GR are both necessary and synergy occurs following recruitment of each factor at 1 h.Since synergistic increases in TLR2 mRNA following IL1B + Dex co‐treatment are delayed (from ~4 h), a role for additional factors is suggested. One early phase gene induced by GCs is DUSP1. This inhibits MAPKs and promotes repression of multiple inflammatory genes. However, in A549 cells, DUSP1 overexpression enhanced IL1B‐induced TLR2 expression. Similarly, the p38 MAPK inhibitor, SB203580, increased IL1B‐induced TLR2 mRNA. Thus, IL1B‐induced p38 activity acts to reduce TLR2 expression. As Dex inhibits IL1B‐activated p38 from ~1 h, a role for DUSP1 is suggested in the synergistic increase in TLR2 expression produced by IL1B + Dex.ConclusionDual mechanisms by which GCs maintain inflammatory cytokine‐induced TLR2 expression in airway epithelial cells are demonstrated: i) GC‐activated GR and NF‐κB are necessary for TLR2 synergy; and ii) GC‐driven inhibition of p38 MAPK increases TLR2 expression. These regulatory events represent key mechanisms by which innate immune, or other, genes are hardwired to avoid, or escape, the repressive effects of GCs.Support or Funding InformationSupported by Canadian Institutes of Health Research (CIHR)This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Apolipoprotein E is a concentration-dependent pulmonary danger signal that activates the NLRP3 inflammasome and IL-1β secretion by bronchoalveolar fluid macrophages from asthmatic subjects

House dust mite (HDM)-challenged Apoe-/- mice display enhanced airway hyperreactivity and mucous cell metaplasia. We sought to characterize the pathways that induce apolipoprotein E (APOE) expression by bronchoalveolar lavage fluid (BALF) macrophages from asthmatic subjects and identify how APOE regulates IL-1β secretion. Macrophages were isolated from asthmatic BALF and derived from THP-1cells and human monocytes. HDM-derived cysteine and serine proteases induced APOE secretion from BALF macrophages through protease-activated receptor 2. APOE at concentrations of less than 2.5nmol/L, which are similar to levels found in epithelial lining fluid from healthy adults, did not induce IL-1β release from BALF macrophages. In contrast, APOE at concentrations of 25nmol/L or greater induced nucleotide-binding oligomerization domain, leucine-rich repeat-containing protein (NLRP) 3 and pro-IL-1β expression by BALF macrophages, as well as the caspase-1-mediated generation of mature IL-1β secreted from cells. HDM acted synergistically with APOE to both prime and activate the NLRP3 inflammasome. In a murine model of neutrophilic airway inflammation induced by HDM and polyinosinic-polycytidylic acid, APOE reached a concentration of 32nmol/L in epithelial lining fluid, with associated increases in BALF IL-1β levels. APOE-dependent NLRP3 inflammasome activation in macrophages was primarily mediated through a potassium efflux-dependent mechanism. APOE can function as an endogenous, concentration-dependent pulmonary danger signal that primes and activates the NLPR3 inflammasome in BALF macrophages from asthmatic subjects to secrete IL-1β. This might represent a mechanism through which APOE amplifies pulmonary inflammatory responses when concentrations in the lung are increased to greater than normal levels, which can occur during viral exacerbations of HDM-induced asthma characterized by neutrophilic airway inflammation.

Progression of Cystic Fibrosis Lung Disease from Childhood to Adulthood: Neutrophils, Neutrophil Extracellular Trap (NET) Formation, and NET Degradation.

Genetic defects in cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene cause CF. Infants with CFTR mutations show a peribronchial neutrophil infiltration prior to the establishment of infection in their lung. The inflammatory response progressively increases in children that include both upper and lower airways. Infectious and inflammatory response leads to an increase in mucus viscosity and mucus plugging of small and medium-size bronchioles. Eventually, neutrophils chronically infiltrate the airways with biofilm or chronic bacterial infection. Perpetual infection and airway inflammation destroy the lungs, which leads to increased morbidity and eventual mortality in most of the patients with CF. Studies have now established that neutrophil cytotoxins, extracellular DNA, and neutrophil extracellular traps (NETs) are associated with increased mucus clogging and lung injury in CF. In addition to opportunistic pathogens, various aspects of the CF airway milieux (e.g., airway pH, salt concentration, and neutrophil phenotypes) influence the NETotic capacity of neutrophils. CF airway milieu may promote the survival of neutrophils and eventual pro-inflammatory aberrant NETosis, rather than the anti-inflammatory apoptotic death in these cells. Degrading NETs helps to manage CF airway disease; since DNAse treatment release cytotoxins from the NETs, further improvements are needed to degrade NETs with maximal positive effects. Neutrophil-T cell interactions may be important in regulating viral infection-mediated pulmonary exacerbations in patients with bacterial infections. Therefore, clarifying the role of neutrophils and NETs in CF lung disease and identifying therapies that preserve the positive effects of neutrophils, while reducing the detrimental effects of NETs and cytotoxic components, are essential in achieving innovative therapeutic advances.

Pathobiological mechanisms underlying metabolic syndrome (MetS) in chronic obstructive pulmonary disease (COPD): clinical significance and therapeutic strategies.

Chronic obstructive pulmonary disease (COPD) is a major incurable global health burden and is currently the 4th largest cause of death in the world. Importantly, much of the disease burden and health care utilisation in COPD is associated with the management of its comorbidities (e.g. skeletal muscle wasting, ischemic heart disease, cognitive dysfunction) and infective viral and bacterial acute exacerbations (AECOPD). Current pharmacological treatments for COPD are relatively ineffective and the development of effective therapies has been severely hampered by the lack of understanding of the mechanisms and mediators underlying COPD. Since comorbidities have a tremendous impact on the prognosis and severity of COPD, the 2015 American Thoracic Society/European Respiratory Society (ATS/ERS) Research Statement on COPD urgently called for studies to elucidate the pathobiological mechanisms linking COPD to its comorbidities. It is now emerging that up to 50% of COPD patients have metabolic syndrome (MetS) as a comorbidity. It is currently not clear whether metabolic syndrome is an independent co-existing condition or a direct consequence of the progressive lung pathology in COPD patients. As MetS has important clinical implications on COPD outcomes, identification of disease mechanisms linking COPD to MetS is the key to effective therapy. In this comprehensive review, we discuss the potential mechanisms linking MetS to COPD and hence plausible therapeutic strategies to treat this debilitating comorbidity of COPD.

Genes and Pathways Regulating Decline in Lung Function and Airway Remodeling in Asthma.

Asthma is a common disorder of the airways characterized by airway inflammation and by decline in lung function and airway remodeling in a subset of asthmatics. Airway remodeling is characterized by structural changes which include airway smooth muscle hypertrophy/hyperplasia, subepithelial fibrosis due to thickening of the reticular basement membrane, mucus metaplasia of the epithelium, and angiogenesis. Epidemiologic studies suggest that both genetic and environmental factors may contribute to decline in lung function and airway remodeling in a subset of asthmatics. Environmental factors include respiratory viral infection-triggered asthma exacerbations, and tobacco smoke. There is also evidence that several asthma candidate genes may contribute to decline in lung function, including ADAM33, PLAUR, VEGF, IL13, CHI3L1, TSLP, GSDMB, TGFB1, POSTN, ESR1 and ARG2. In addition, mediators or cytokines, including cysteinyl leukotrienes, matrix metallopeptidase-9, interleukin-33 and eosinophil expression of transforming growth factor-β, may contribute to airway remodeling in asthma. Although increased airway smooth muscle is associated with reduced lung function (i.e. forced expiratory volume in 1 second) in asthma, there have been few long-term studies to determine how individual pathologic features of airway remodeling contribute to decline in lung function in asthma. Clinical studies with inhibitors of individual gene products, cytokines or mediators are needed in asthmatic patients to identify their individual role in decline in lung function and/or airway remodeling.

Resolving Viral-Induced Secondary Bacterial Infection in COPD: A Concise Review

Chronic obstructive pulmonary disease (COPD) is a leading cause of disability and death world-wide, where chronic inflammation accelerates lung function decline. Pathological inflammation is worsened by chronic bacterial lung infections and susceptibility to recurrent acute exacerbations of COPD (AECOPD), typically caused by viral and/or bacterial respiratory pathogens. Despite ongoing efforts to reduce AECOPD rates with inhaled corticosteroids, COPD patients remain at heightened risk of developing serious lung infections/AECOPD, frequently leading to hospitalization and infection-dependent delirium. Here, we review emerging mechanisms into why COPD patients are susceptible to chronic bacterial infections and highlight dysregulated inflammation and production of reactive oxygen species (ROS) as central causes. This underlying chronic infection leaves COPD patients particularly vulnerable to acute viral infections, which further destabilize host immunity to bacteria. The pathogeneses of bacterial and viral exacerbations are significant as clinical symptoms are more severe and there is a marked increase in neutrophilic inflammation and tissue damage. AECOPD triggered by a bacterial and viral co-infection increases circulating levels of the systemic inflammatory marker, serum amyloid A (SAA). SAA is a functional agonist for formyl peptide receptor 2 (FPR2/ALX), where it promotes chemotaxis and survival of neutrophils. Excessive levels of SAA can antagonize the protective actions of FPR2/ALX that involve engagement of specialized pro-resolving mediators, such as resolvin-D1. We propose that the anti-microbial and anti-inflammatory actions of specialized pro-resolving mediators, such as resolvin-D1 should be harnessed for the treatment of AECOPD that are complicated by the co-pathogenesis of viruses and bacteria.

CORRELATION OF SPECIFIC NK CELL RECEPTOR LIGANDS WITH COPD SEVERITY

SESSION TITLE: Biomarkers in Obstructive Lung Disease SESSION TYPE: Original Investigations PRESENTED ON: 10/10/2018 07:30 AM - 08:30 AM PURPOSE: COPD is the third-leading cause of death in the United States, with few proven disease modifying therapies. Recent studies have focused on the role of immune function in the role of COPD progression after viral exacerbations. Studies of murine COPD models and of COPD patients have shown chronic cigarette smoking primes NK cell activation. The B7 family is a group of cellular receptors that provide both stimulatory and inhibitory signals to NK cells. We looked at B7H3, a direct inhibitor of NK function, and B7H6, a direct activator of NK function, and their soluble ligand levels in never smoking controls and patients with varying degrees of COPD. METHODS: Serum samples were obtained from the COPD VA Cohort. ELISAs for B7H6 (N=73) and B7H3 (N=38) were performed on samples including control patients, former and current smokers, and varying severities of COPD (based on GOLD classification). ELISAs performed according to manufacturer protocol. Results were analyzed with 5-parameter logarithmic regression. RESULTS: We measured the serum levels of B7H3 and B7H6 and evaluated based on correlation with control, current smokers, former smokers, and varying stages of COPD (GOLD I/II based on FEV1 >50% and GOLD III/IV based on FEV1 <50%). We found that there was an inverse relationship between B7H6 levels and COPD severity. Compared with controls and smokers, COPD patients had significantly decreased B7H6 levels as disease severity progressed (p=0.041). We also found that there was a significant decrease in B7H6 between mild-moderate COPD and severe COPD (p=0.032). Our studies found that there was no statistical relationship when comparing B7H3 levels in control, smokers, and COPD patients (p=0.16). CONCLUSIONS: Our study showed that soluble level of B7H3 ligand was not correlated with COPD severity, but that soluble level of B7H6 was inversely correlated with disease progression. This finding fits with our expected theory of NK cell function and COPD progression. As disease progresses and viral exacerbations occur, the body is unable to fight these infections as activating soluble ligands have decreased. A follow-up study using Immunohistochemistry to look at tissue expression of B7H6 may give more insight into why this receptor ligand decreases with disease. CLINICAL IMPLICATIONS: Ultimately the level of B7H6 soluble ligand may be useful as a clinical tool in patients with COPD exacerbations as it may aid in differentiating between viral illnesses and inflammatory exacerbations. Those with viral infections may actually benefit from withholding steroids, as their NK cells respond appropriately to the infection. DISCLOSURES: No relevant relationships by Michael Borchers, source=Web Response No relevant relationships by Jeff Miller, source=Web Response no disclosure on file for Andrew Osterburg

Interferon-\u03b2 deficiency at asthma exacerbation promotes MLKL mediated necroptosis

Defective production of antiviral interferon (IFN)-β is thought to contribute to rhinovirus-induced asthma exacerbations. These exacerbations are associated with elevated lung levels of lactate dehydrogenase (LDH), indicating occurrence of cell necrosis. We thus hypothesized that reduced lung IFN-β could contribute to necrotic cell death in a model of asthma exacerbations. Wild-type and IFN-β−/− mice were given saline or house dust mite (HDM) intranasally for 3 weeks to induce inflammation. Double-stranded RNA (dsRNA) was then given for additional 3 days to induce exacerbation. HDM induced an eosinophilic inflammation, which was not associated with increased expression of cleaved caspase-3, cleaved PARP or elevated bronchoalveolar lavage fluid (BALF) LDH levels in wild-type. However, exacerbation evoked by HDM + dsRNA challenges increased BALF levels of LDH, apoptotic markers and the necroptotic markers receptor-interacting protein (RIP)-3 and phosphorylation of mixed linage kinase domain-like protein (pMLKL), compared to HDM + saline. Absence of IFN-β at exacerbation further increased BALF LDH and protein expression of pMLKL compared to wild-type. We demonstrate that cell death markers are increased at viral stimulus-induced exacerbation in mouse lungs, and that absence of IFN-β augments markers of necroptotic cell death at exacerbation. Our data thus suggest a novel role of deficient IFN-β production at viral-induced exacerbation.

Repetitive TLR3 activation in the lung induces skeletal muscle adaptations and cachexia

Due to immunosenescence, older adults are particularly susceptible to lung-based viral infections, with increased severity of symptoms in those with underlying chronic lung disease. Repeated respiratory viral infections produce lung maladaptations, accelerating pulmonary dysfunction. Toll like 3 receptor (TLR3) is a membrane protein that senses exogenous double-stranded RNA to activate the innate immune response to a viral infection. Polyinosinic-polycytidylic acid [poly(I:C)] mimics double stranded RNA and has been shown to activate TLR3. Utilizing an established mouse viral exacerbation model produced by repetitive intranasal poly(I:C) administration, we sought to determine whether repetitive poly(I:C) treatment induced negative muscle adaptations (i.e. atrophy, weakness, and loss of function). We determined skeletal muscle morphological properties (e.g. fiber-type, fiber cross-sectional area, muscle wet mass, etc.) from a treated group ((poly(I:C), n = 9) and a sham-treated control group (PBS, n = 9); age approximately 5 months. In a subset (n = 4 for both groups), we determined in vivo physical function (using grip test for strength, rotarod for overall motor function, and treadmill for endurance) and muscle contractile properties with in vitro physiology (in the EDL, soleus and diaphragm). Our findings demonstrate that poly(I:C)-treated mice exhibit both muscle morphological and functional deficits. Changes of note when comparing poly(I:C)-treated mice to PBS-treated controls include reductions in fiber cross-sectional area (−27% gastrocnemius, −25% soleus, −16% diaphragm), contractile dysfunction (soleus peak tetanic force, −26%), muscle mass (gastrocnemius −19%, soleus −23%), physical function (grip test −34%), body mass (−20%), and altered oxidative capacity (140% increase in succinate dehydrogenase activity in the diaphragm, but 66% lower in the gastrocnemius). Our data is supportive of a new model of cachexia/sarcopenia that has potential for future research into the mechanisms underlying muscle wasting.

Longitudinal profiling of the lung microbiome in the AERIS study demonstrates repeatability of bacterial and eosinophilic COPD exacerbations

BackgroundAlterations in the composition of the lung microbiome associated with adverse clinical outcomes, known as dysbiosis, have been implicated with disease severity and exacerbations in COPD.ObjectiveTo characterise longitudinal changes in...

IL-1\u03b2 mediates lung neutrophilia and IL-33 expression in a mouse model of viral-induced asthma exacerbation

BackgroundViral-induced asthma exacerbations, which exhibit both Th1-type neutrophilia and Th2-type inflammation, associate with secretion of Interleukin (IL)-1β. IL-1β induces neutrophilic inflammation. It may also increase Th2-type cytokine expression. We hypothesised that IL-1β is causally involved in both Th1 and Th2 features of asthma exacerbations. This hypothesis is tested in our mouse model of viral stimulus-induced asthma exacerbation.MethodWild-type (WT) and IL-1β deficient (IL-1β−/−) mice received house dust mite (HDM) or saline intranasally during three weeks followed by intranasal dsRNA (PolyI:C molecule known for its rhinovirus infection mimic) for three consecutive days to provoke exacerbation. Bronchoalveolar lavage fluid was analysed for inflammatory cells and total protein. Lung tissues were stained for neutrophilic inflammation and IL-33. Tissue homogenates were analysed for mRNA expression of Muc5ac, CXCL1/KC, TNF-α, CCL5, IL-25, TSLP, IL-33, IL-1β, CCL11 and CCL2 using RT-qPCR.ResultsExpression of IL-1β, neutrophil chemoattractants, CXCL1 and CCL5, the Th2-upstream cytokine IL-33, and Muc5ac were induced at exacerbation in WT mice and were significantly inhibited in IL-1β−/− mice at exacerbation. Effects of HDM alone were not reduced in IL-1β-deficient mice.ConclusionWithout being involved in the baseline HDM-induced allergic asthma, IL-1β signalling was required to induce neutrophil chemotactic factors, IL-33, and Muc5ac expression at viral stimulus-induced exacerbation. We suggest that IL-1β has a role both in neutrophilic and Th2 inflammation at viral-induced asthma exacerbations.

Chronic IL-33 expression predisposes to virus-induced asthma exacerbations by increasing type 2 inflammation and dampening antiviral immunity

Rhinovirus infection triggers acute asthma exacerbations. IL-33 is an instructive cytokine of type 2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic patients. We sought to determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and invitro human primary airway epithelial cells (AECs). Mice were exposed to pneumonia virus of mice and cockroach extract in early and later life and then challenged with rhinovirus to model disease onset, progression, and chronicity. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic patients and healthy subjects and treated with anti-IL-33 after rhinovirus infection. Anti-IL-33 decreased type 2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high, and rhinovirus challenge exacerbated the type 2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity, and anti-IL-33, but not dexamethasone, promoted antiviral interferon expression and decreased viral load. Rhinovirus replication was higher and IFN-λ levels were lower in AECs from asthmatic patients compared with those from healthy subjects. Anti-IL-33 decreased rhinovirus replication and increased IFN-λ levels at the gene and protein levels. Anti-IL-33 or dexamethasone suppressed the magnitude of type 2 inflammation during a rhinovirus-induced acute exacerbation; however, only anti-IL-33 boosted antiviral immunity and decreased viral replication. The latter phenotype was replicated in rhinovirus-infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defense.

Detection of rhinovirus-associated asthma exacerbations using reverse transcriptase-polymerase chain reaction in Egyptian children

Background: Acute exacerbations of asthma are the leading cause of emergency department visits in pediatric patients. The development of sensitive diagnostic polymerase chain reaction (PCR) based techniques permitted demonstration of an already clinically suspected association between common viral respiratory infections and asthma exacerbations. Respiratory viruses have been identified in 80–85% of exacerbations in school-aged children, with human rhinoviruses (HRVs) being the most frequently detected. A recently identified HRV genotype, HRV-C, is circulating worldwide and is an important cause of febrile wheeze and asthmatic exacerbations in children requiring hospitalization. Objectives: This study aimed to detect HRV- induced asthma exacerbations (including the new HRV-C genotype) among a group of Egyptian children. Methods: This cross-sectional study was conducted on 31 asthmatic children in exacerbations in the period from September 2014 till October 2015. Patients were recruited from the emergency department and chest clinic, Children's hospital, Ain Shams University. Sputum (for children ≥7years) and nasopharyngeal aspirates (for infants and children<7years) were collected for one-step, real-time pan Rhinovirus reverse transcription polymerase chain reaction (RT-PCR) assay. One step RT-PCR was done to detect Rhinovirus C among positive cases. Results: This study included 31 asthmatic children in exacerbations. They were 15 males (48.4%) and 16 females (51.6%). Their ages ranged from 7 months to 12 years with a mean and SD of (4.47 ± 3.15) years. Eight (25.8%) of the studied patients showed positive Rhinovirus RT-PCR test and 4 (50%) of the HRV positive patients were of the Rhinovirus C genotype (12.9% of the total population). HRV positive patients showed higher percentage of positive family history of bronchial asthma (p=0.002), higher mean values of respiratory rate (p=0.001) and temperature (p=0.001), but lower mean value of oxygen saturation (p =0.011). There were statistically significant differences regarding the exacerbation severity (p=0.024) and outcome (p=0.048) between HRV positive and negative patients. Conclusion: HRVs are important triggers of asthma exacerbations among Egyptian children. The newly described HRV-C genotype accounts for a significant proportion of HRV- associated asthma exacerbations. Further studies on a larger scale are needed for HRV-C and other possibly undiscovered HRV genotypes. Keywords: Rhinovirus, Rhinovirus C genotype, asthma exacerbation, real time RT-PCR

Impact of Respiratory Virus Infections in Exacerbation of Acute and Chronic Rhinosinusitis.

Rhinosinusitis (RS) is a symptomatic disease classification of many causes and is a major economic burden worldwide. It is widely accepted that RS is further classified into acute (ARS) and chronic (CRS) rhinosinusitis based on the duration of the symptoms, and that viral infection plays a large role in initiating or potentiating the disease. In this review, we examine the role of respiratory virus infection in the exacerbation of ARS and CRS. We explore the epidemiology of viral exacerbation of ARS and CRS and highlight key viruses that may cause exacerbation. We also review the current understanding of viral infections in the upper airway to further explain the putative underlying mechanisms of inflammatory events in ARS and CRS exacerbation. Advances in accurate diagnosis of the etiologic respiratory viruses of ARS and CRS symptoms which can lead to better disease management are also surveyed. In addition to the current treatments which provide symptomatic relief, we also explore the potential of harnessing existing antiviral strategies to prevent ARS and CRS exacerbation, especially with improved viral diagnostic tools to guide accurate prescription of antivirals against causative respiratory viruses.

Azithromycin augments rhinovirus-induced IFNβ via cytosolic MDA5 in experimental models of asthma exacerbation.

Deficient production of anti-viral interferons (IFNs) may be involved in causing viral-induced asthma exacerbations. Hence, drugs inducing lung IFN production would be warranted. Azithromycin may reduce asthma exacerbations but its modus operandi is unknown. Here, we investigated if azithromycin induces IFNβ expression in vitro in rhinovirus-infected bronchial epithelial cells from asthmatic donors and in vivo in our allergic inflammation-based mouse model of viral stimulus-induced asthma exacerbations. Azithromycin dose-dependently augmented viral-induced IFNβ expression in asthmatic, but not in healthy bronchial epithelial cells. The effect negatively correlated with viral load. Knockdown of MDA5 and RIG-I by siRNA showed involvement of MDA5 but not RIG-I in azithromycin's IFN-inducing effects in vitro. In vivo azithromycin induced IFNβ protein, restoring a reduced lung IFN response exclusively in allergic exacerbating mice. This was associated with induction of interferon-stimulated genes and MDA5, but not RIG-I. We suggest that clinically relevant concentrations of azithromycin produce MDA5-dependent, anti-viral, IFN-inducing effects in bronchial epithelium distinctly from asthmatic donors. Similarly, azithromycin induced MDA5-associated IFN in virally stimulated lungs in vivo exclusively in allergic mice. Effects of azithromycin and MDA5-active drugs on viral-induced exacerbations deserve further research.

The Role of Human Parainfluenza Virus Infections in the Immunopathology of the Respiratory Tract.

Viral infections are leading causes of both upper and lower airway acute illness in all age groups of healthy persons, and have also been implicated in the acute exacerbations of chronic respiratory disorders like asthma and COPD. Human rhinovirus, respiratory syncytial virus, influenza virus and coronavirus have been considered as the most important respiratory pathogens and relatively little attention has been paid to the role of parainfluenza viruses (hPIVs). Human parainfluenza viruses are single-stranded RNA viruses belonging to the paramyxovirus family that may evoke lower respiratory infections in infants, children and immunocompromised individuals. Among non-immune compromised adults, hPIV infection typically causes mild disease manifested as upper respiratory tract symptoms and is infrequently associated with severe croup or pneumonia. Moreover, hPIV infection may be associated with viral exacerbations of chronic airway diseases, asthma or COPD or chronic rhinosinusitis. In this review, we summarized the basic epidemiology and immunology of hPIVs and addressed the more recent data implicating the role of parainfluenza viruses in the exacerbation of chronic airway disorders.

ANALYTICAL ASSESSMENT OF OUT-PATIENT TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS

Objective: to carry out the analytical assessment of outpatient management of patients with rheumatoid arthritis in real clinical practice and study the structure of comorbid pathology. Material and methods. The medical records of 88 patients have been analyzed at 6 outpatient clinics of Gomel. The Charlson comorbidity index was applied for the quantitative assessment of the comorbid status. Results. The most common provoking factors of the development of rheumatoid arthritis were acute respiratory viral infections and exacerbation of chronic diseases; and the background disease was thyroid pathology. The most frequent complications of rheumatoid arthritis were osteoarthritis, anemia of chronic inflammation, osteoporosis, coronary heart disease. Comorbid pathology occured in 97.7 % of the patients with rheumatoid arthritis. Conclusion. At present, the problems of management of patients with rheumatoid arthritis are late diagnostics; discrepancy of real treatment to the modern recommendations of EULAR; insufficient use of disease-modifying antirheumatic drugs; absence of individual approach aimed at early detection of comorbid pathology and its adequate treatment.

MAP3K19 Is Overexpressed in COPD and Is a Central Mediator of Cigarette Smoke-Induced Pulmonary Inflammation and Lower Airway Destruction.

Chronic obstructive pulmonary disease (COPD) is characterized by persistent airflow limitation and lung inflammation resulting in a progressive decline in lung function whose principle cause is cigarette smoke. MAP3K19 is a novel kinase expressed predominantly by alveolar and interstitial macrophages and bronchial epithelial cells in the lung. We found that MAP3K19 mRNA was overexpressed in a limited sampling of lung tissue from COPD patients, and a closer examination found it to be overexpressed in bronchoalveolar macrophages from COPD patients, as well as the bronchial epithelium and inflammatory cells in the lamina propria. We further found MAP3K19 to be induced in various cell lines upon environmental stress, such as cigarette smoke, oxidative and osmotic stress. Exogenous expression of MAP3K19 in cells caused an upregulation of transcriptionally active NF-κB, and secretion of the chemokines CXCL-8, CCL-20 and CCL-7. Inhibition of MAP3K19 activity by siRNA or small molecular weight inhibitors caused a decrease in cigarette smoke-induced inflammation in various murine models, which included a decrease in pulmonary neutrophilia and KC levels. In a chronic cigarette smoke model, inhibition of MAP3K19 significantly attenuated emphysematous changes in airway parenchyma. Finally, in a viral exacerbation model, mice exposed to cigarette smoke and influenza A virus showed a decrease in pulmonary neutrophilia, pro-inflammatory cytokines and viral load upon inhibition of MAP3K19. Collectively, these results suggest that inhibition of MAP3K19 may represent a novel strategy to target COPD that promises to have a potential therapeutic benefit for patients.

A multi-strain Synbiotic may reduce viral respiratory infections in asthmatic children: a randomized controlled trial.

Background and objectiveAsthma is a growing problem worldwide. Acute exacerbations impose considerable morbidity, mortality, and increased cost. Viral respiratory infections are the most common cause (80–85%) of pediatric asthma exacerbations and admissions to the hospital. The aim of this study was to determine the effect of a new synbiotic Lactocare® on viral respiratory infections and asthma exacerbations in asthmatic children.MethodsIn this double blind, placebo-controlled, randomized clinical trial, 72 children with mild persistent asthma, aged between 6 and 12 years, were randomized to receive either Lactocare®, a Synbiotic containing 1 billion CFU/Capsule of Lactobacillus casei, Lactobacillus rhamnosus, Streptococcus thermophilus, Bifidobacterium breve, Lactobacillus acidophilus, Bifidobacterium infantis, Lactobacillus bulgaricus, and Fructooligosacharide (Zist Takhmir, Tehran, Iran) or placebo daily for 60 days. The primary outcome was the number of viral respiratory infections, and secondary outcomes were school absence, salbutamol and prednisolone usage, outpatient visits, and hospital admission for asthma. The outcomes were compared among study groups using the SPSS 11.5 program and the Mann Whitney and Fisher exact tests.ResultsOf the 72 children who were enrolled with mild persistent asthma, 36 were assigned randomly to be treated with synbiotic and 36 with placebo. The number of viral respiratory infections was significantly higher in placebo group than the synbiotic group during the first month of intervention (0.74 ± 0.12 vs. 0.44 ± 0.1, p < 0.007) but not during the second month (0.5 ± 0.8 vs. 0.5 ± 0.8, p < 0.641). Considering the total duration of the study (two months), infection episodes also were significantly lower in the synbiotic group (0.92 ± 0.15 vs. 0.69 ± 0.11, p < 0.046). Salbutamol consumption was significantly lower in the synbiotic group, but there were no significant differences in school absenteeism, oral prednisolone use, outpatient visits, or hospital admissions.ConclusionThis new synbiotic (a mixture of seven probiotic strains plus fructooligosacharide may reduce episodes of viral infection in asthmatic children.Trial registrationThis study is registered in Iranian Registry of Clinical Trials with registration number of IRCT201509234976N3.FundingThis research was supported financially by the Research Council of Mashhad University of Medical Sciences (Grant Number: 911048).