Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis.

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD.

Valaciclovir for Epstein-Barr Virus Suppression in Moderate-to-Severe COPD: A Randomized Double-Blind Placebo-Controlled Trial.

BACKGROUND: Epstein-Barr virus (EBV) frequently is measured at high levels in COPD using sputum quantitative polymerase chain reaction, whereas airway immunohistochemistry analysis has shown EBV detection to be common in severe disease. RESEARCH QUESTION: Is valaciclovir safe and effective for EBV suppression in COPD? STUDY DESIGN AND METHODS: The Epstein-Barr Virus Suppression in COPD (EViSCO) trial was a randomized double-blind placebo-controlled trial conducted at the Mater Hospital Belfast, Northern Ireland. Eligible patients had stable moderate-to-severe COPD and sputum EBV (measured using quantitative polymerase chain reaction) and were assigned randomly (1:1) to valaciclovir (1 g tid) or matching placebo for 8 weeks. The primary efficacy outcome was sputum EBV suppression (defined as ≥ 90% sputum viral load reduction) at week 8. The primary safety outcome was the incidence of serious adverse reactions. Secondary outcome measures were FEV1 and drug tolerability. Exploratory outcomes included changes in quality of life, sputum cell counts, and cytokines. RESULTS: From November 2, 2018, through March 12, 2020, 84 patients were assigned randomly (n = 43 to valaciclovir). Eighty-one patients completed trial follow-up and were included in the intention-to-treat analysis of the primary outcome. A greater number of participants in the valaciclovir group achieved EBV suppression (n = 36 [87.8%] vs n = 17 [42.5%]; P < .001). Valaciclovir was associated with a significant reduction in sputum EBV titer compared with placebo (-90,404 copies/mL [interquartile range, -298,000 to -15,200 copies/mL] vs -3,940 copies/mL [interquartile range, -114,400 to 50,150 copies/mL]; P = .002). A statistically nonsignificant 24-mL numerical FEV1 increase was shown in the valaciclovir group (difference, -44 mL [95% CI, -150 to 62 mL]; P = .41). However, a reduction in sputum white cell count was noted in the valaciclovir group compared with the placebo group (difference, 2.89 [95% CI, 1.5 × 106-7.4 × 106]; P = .003). INTERPRETATION: Valaciclovir is safe and effective for EBV suppression in COPD and may attenuate the sputum inflammatory cell infiltrate. The findings from the current study provide support for a larger trial to evaluate long-term clinical outcomes. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03699904; URL: www. CLINICALTRIALS: gov.

Altered Differentiation and Inflammation Profiles Contribute to Enhanced Innate Responses in Severe COPD Epithelium to Rhinovirus Infection.

Background: Respiratory viral infections are closely associated with COPD exacerbations, hospitalisations, and significant morbidity and mortality. The consequences of the persisting inflammation and differentiation status in virus associated severe disease is not fully understood. The aim of this study was to evaluate barrier function, cellular architecture, the inflammatory response in severe COPD bronchial epithelium to human rhinovirus (HRV) induced pathological changes and innate immune responses. Methods: Well-differentiated primary bronchial epithelial cells (WD-PBECs) derived from severe COPD patients and age-matched healthy controls were cultured in the air-liquid interface (ALI) model. The differentiation phenotype, epithelial barrier integrity, pathological response and cytokine secreting profile of these cultures before and after HRV infection were investigated. Results: WD-PBECs derived from severe COPD patients showed aberrant epithelium differentiation with a decreased proportion of ciliated cells but increased numbers of club cells and goblet cells compared with healthy controls. Tight junction integrity was compromised in both cultures following HRV infection, with heightened disruptions in COPD cultures. HRV induced increased epithelial cell sloughing, apoptosis and mucus hypersecretion in COPD cultures compared with healthy controls. A Th1/Th2 imbalance and a strong interferon and pro-inflammatory cytokine response was also observed in COPD cultures, characterized by increased levels of IFNγ, IFNß, IP-10, IL-10 and decreased TSLP and IL-13 cytokine levels prior to HRV infection. Significantly enhanced basolateral secretion of eotaxin 3, IL-6, IL-8, GM-CSF were also observed in both mock and HRV infected COPD cultures compared with corresponding healthy controls. In response to HRV infection, all cultures displayed elevated levels of IFNλ1 (IL-29), IP-10 and TNFα compared with mock infected cultures. Interestingly, HRV infection dramatically reduced IFNλ levels in COPD cultures compared with healthy subjects. Conclusion: An altered differentiation phenotype and cytokine response as seen in severe COPD WD-PBECs may contribute to increased disease susceptibility and an enhanced inflammatory response to HRV infection.

Deciphering Respiratory-Virus-Associated Interferon Signaling in COPD Airway Epithelium.

COPD is a chronic lung disorder characterized by a progressive and irreversible airflow obstruction, and persistent pulmonary inflammation. It has become a global epidemic affecting 10% of the population, and is the third leading cause of death worldwide. Respiratory viruses are a primary cause of COPD exacerbations, often leading to secondary bacterial infections in the lower respiratory tract. COPD patients are more susceptible to viral infections and associated severe disease, leading to accelerated lung function deterioration, hospitalization, and an increased risk of mortality. The airway epithelium plays an essential role in maintaining immune homeostasis, and orchestrates the innate and adaptive responses of the lung against inhaled and pathogen insults. A healthy airway epithelium acts as the first line of host defense by maintaining barrier integrity and the mucociliary escalator, secreting an array of inflammatory mediators, and initiating an antiviral state through the interferon (IFN) response. The airway epithelium is a major site of viral infection, and the interaction between respiratory viruses and airway epithelial cells activates host defense mechanisms, resulting in rapid virus clearance. As such, the production of IFNs and the activation of IFN signaling cascades directly contributes to host defense against viral infections and subsequent innate and adaptive immunity. However, the COPD airway epithelium exhibits an altered antiviral response, leading to enhanced susceptibility to severe disease and impaired IFN signaling. Despite decades of research, there is no effective antiviral therapy for COPD patients. Herein, we review current insights into understanding the mechanisms of viral evasion and host IFN antiviral defense signaling impairment in COPD airway epithelium. Understanding how antiviral mechanisms operate in COPD exacerbations will facilitate the discovery of potential therapeutic interventions to reduce COPD hospitalization and disease severity.

The Impact of Aging in Acute Respiratory Distress Syndrome: A Clinical and Mechanistic Overview.

Acute respiratory distress syndrome (ARDS) is associated with increased morbidity and mortality in the elderly population (≥65 years of age). Additionally, age is widely reported as a risk factor for the development of ARDS. However, the underlying pathophysiological mechanisms behind the increased risk of developing, and increased severity of, ARDS in the elderly population are not fully understood. This is compounded by the significant heterogeneity observed in patients with ARDS. With an aging population worldwide, a better understanding of these mechanisms could facilitate the development of therapies to improve outcomes in this population. In this review, the current clinical evidence of age as a risk factor and prognostic indicator in ARDS and the potential underlying mechanisms that may contribute to these factors are outlined. In addition, research on age-dependent treatment options and biomarkers, as well as future prospects for targeting these underlying mechanisms, are discussed.

Airway Inflammation and Host Responses in the Era of CFTR Modulators.

The arrival of cystic fibrosis transmembrane conductance regulator (CFTR) modulators as a new class of treatment for cystic fibrosis (CF) in 2012 represented a pivotal advance in disease management, as these small molecules directly target the upstream underlying protein defect. Further advancements in the development and scope of these genotype-specific therapies have been transformative for an increasing number of people with CF (PWCF). Despite clear improvements in CFTR function and clinical endpoints such as lung function, body mass index (BMI), and frequency of pulmonary exacerbations, current evidence suggests that CFTR modulators do not prevent continued decline in lung function, halt disease progression, or ameliorate pathogenic organisms in those with established lung disease. Furthermore, it remains unknown whether their restorative effects extend to dysfunctional CFTR expressed in phagocytes and other immune cells, which could modulate airway inflammation. In this review, we explore the effects of CFTR modulators on airway inflammation, infection, and their influence on the impaired pulmonary host defences associated with CF lung disease. We also consider the role of inflammation-directed therapies in light of the widespread clinical use of CFTR modulators and identify key areas for future research.

Mechanisms of Virus-Induced Airway Immunity Dysfunction in the Pathogenesis of COPD Disease, Progression, and Exacerbation.

Chronic obstructive pulmonary disease (COPD) is the integrated form of chronic obstructive bronchitis and pulmonary emphysema, characterized by persistent small airway inflammation and progressive irreversible airflow limitation. COPD is characterized by acute pulmonary exacerbations and associated accelerated lung function decline, hospitalization, readmission and an increased risk of mortality, leading to huge social-economic burdens. Recent evidence suggests ~50% of COPD acute exacerbations are connected with a range of respiratory viral infections. Nevertheless, respiratory viral infections have been linked to the severity and frequency of exacerbations and virus-induced secondary bacterial infections often result in a synergistic decline of lung function and longer hospitalization. Here, we review current advances in understanding the cellular and molecular mechanisms underlying the pathogenesis of COPD and the increased susceptibility to virus-induced exacerbations and associated immune dysfunction in patients with COPD. The multiple immune regulators and inflammatory signaling pathways known to be involved in host-virus responses are discussed. As respiratory viruses primarily target airway epithelial cells, virus-induced inflammatory responses in airway epithelium are of particular focus. Targeting virus-induced inflammatory pathways in airway epithelial cells such as Toll like receptors (TLRs), interferons, inflammasomes, or direct blockade of virus entry and replication may represent attractive future therapeutic targets with improved efficacy. Elucidation of the cellular and molecular mechanisms of virus infections in COPD pathogenesis will undoubtedly facilitate the development of these potential novel therapies that may attenuate the relentless progression of this heterogeneous and complex disease and reduce morbidity and mortality.

Airway epithelial cell apoptosis and inflammation in COPD, smokers and nonsmokers.

We hypothesised that primary bronchial epithelial cells (PBECs) from subjects with chronic obstructive pulmonary disease (COPD) respond differently to Pseudomonas aeruginosa lipopolysaccharide (LPS) after cigarette smoke extract (CSE) exposure than PBECs obtained from smokers without airflow obstruction and nonsmokers. PBECs from 16 COPD subjects, 10 smokers without airflow obstruction and nine nonsmokers were cultured at air-liquid interface. Cultures were incubated with CSE prior to stimulation with P. aeruginosa LPS. Interleukin (IL)-6 and IL-8 were measured by ELISA and Toll-like receptor (TLR)-4 expression by fluorescence-activated cell sorter. Activation of nuclear factor (NF)-κB was determined by Western blotting and ELISA, and MAPK and caspase-3 activity by Western blotting. Apoptosis was evaluated using Annexin-V staining and the terminal transferase-mediated dUTP nick end-labelling methods. Constitutive release of IL-8 and IL-6 was greatest from the COPD cultures. However, CSE pretreatment followed by P. aeruginosa LPS stimulation reduced IL-8 release from COPD PBECs, but increased it from cells of smokers without airflow obstruction and nonsmokers. TLR-4 expression, MAPK and NF-κB activation in COPD cultures were reduced after CSE treatment, but not in the smokers without airflow obstruction or nonsmoker groups, which was associated with increased apoptosis. CSE attenuates inflammatory responses to LPS in cells from people with COPD but not those from nonsmoking individuals and those who smoke without airflow obstruction.

Potential risk factors for medication non-adherence in patients with chronic obstructive pulmonary disease (COPD).

AIMS: To investigate the effect of a range of demographic and psychosocial variables on medication adherence in chronic obstructive pulmonary disease (COPD) patients managed in a secondary care setting. METHODS: A total of 173 patients with a confirmed diagnosis of COPD, recruited from an outpatient clinic in Northern Ireland, participated in the study. Data collection was carried out via face-to-face interviews and through review of patients' medical charts. Social and demographic variables, co-morbidity, self-reported drug adherence (Morisky scale), Hospital Anxiety and Depression (HAD) scale, COPD knowledge, Health Belief Model (HBM) and self-efficacy scales were determined for each patient. RESULTS: Participants were aged 67 ± 9.7 (mean ± SD) years, 56 % female and took a mean (SD) of 8.2 ± 3.4 drugs. Low adherence with medications was present in 29.5 % of the patients. Demographic variables (gender, age, marital status, living arrangements and occupation) were not associated with adherence. A range of clinical and psychosocial variables, on the other hand, were found to be associated with medication adherence, i.e. beliefs regarding medication effectiveness, severity of COPD, smoking status, presence of co-morbid illness, depressed mood, self-efficacy, perceived susceptibility and perceived barriers within the HBM (p < 0.05). Logistic regression analysis showed that perceived ineffectiveness of medication, presence of co-morbid illness, depressed mood and perceived barriers were independently associated with medication non-adherence in the study (P < 0.05). CONCLUSIONS: Adherence in COPD patients is influenced more by patients' perception of their health and medication effectiveness, the presence of depressed mood and co-morbid illness than by demographic factors or disease severity.

Cost-utility analysis of a pharmacy-led self-management programme for patients with COPD.

OBJECTIVE: To undertake a cost-utility analysis (CUA) of a pharmacy-led self-management programme for Chronic Obstructive Pulmonary Disease (COPD). SETTING: A single outpatient COPD clinic at the Mater Hospital, Belfast, Northern Ireland between. METHOD: CUA alongside a randomised control trial. The economic analysis used data from 127 COPD patients aged over 45 years, with an FEV1 of 30-80% of the predicted normal value. Participants received either a pharmacy-led education and self-management programme, or usual care. One year costs were estimated from the perspective of the National Health Service and Personal Social Services and quality-adjusted life years (QALYs) were calculated based on responses to the EQ-5D at baseline, 6 and 12 months. MAIN OUTCOME MEASURE: Cost per QALY gained. RESULTS: The mean differences in costs and effects between the self-management and education programme and usual care were -£671.59 (95 CI%: -£1,584.73 to -£68.14) and 0.065 (95% CI; 0.000-0.128). Thus the intervention was the dominant strategy as it was both less costly and more effective than usual care. The probability of the intervention being cost-effective was 95% at a threshold of £20,000/QALY gained. Sensitivity analyses indicated that conclusions were robust to variations in most of the key parameters. CONCLUSION: The self-management and education programme was found to be highly cost-effective compared to usual care. Further research is required to establish what aspects of self-management and education programmes have the greatest impact on cost-effectiveness.

Clinical pharmacy-led disease and medicine management programme for patients with COPD.

AIM: The aim was to investigate the impact of a disease and medicine management programme, focusing on self-management in patients with chronic obstructive pulmonary disease (COPD). METHODS: One hundred and seventy-three patients (mean age 67 years; 54% female) were recruited; 86 patients were randomly assigned to an intervention group and 87 to a usual care (control) group. Intervention patients received education on disease state, medications and breathing techniques. Patients were given booklets and a customized action plan (antibiotic and oral steroid to be initiated promptly by patients for exacerbations). Patients were followed up at 6 and 12 months during a scheduled visit. The St George's Respiratory Questionnaire (SGRQ), COPD Knowledge and Morisky adherence questionnaires were administered to all patients at baseline, 6 and 12 months. Outcome measures included hospital admissions, emergency department (ED) visits, health-related quality of life (HRQoL) and medication adherence. RESULTS: Over the 12-month period in the intervention group, ED visits decreased by 50% (P= 0.02) and hospitalization by approximately 60% (P= 0.01). On the SGRQ, differences reached statistical significance on the symptom (-7.5; P= 0.04) and impact (-7.4; P= 0.03) subscales but not on the physical activity subscale. There was a significant difference between the intervention and usual care groups regarding knowledge scores (75.0 vs. 59.3; P= 0.001) and good adherence to medication (77.8% vs. 60.0%, P= 0.019). There was no significant difference regarding smoking between study groups. CONCLUSIONS: The clinical pharmacy-led management programme can improve adherence, reduce the need for hospital care in patients with COPD and improve aspects of their HRQoL.

Epstein - Barr virus Pneumonitis.

Epstein-Barr virus is an unusual pathogen in the aetiology of alveolitis. We describe a case of Epstein-Barr virus induced pneumonitis and its successful treatment with Aciclovir.

Respiratory viral infection in exacerbations of COPD.

BACKGROUND: Patients with COPD have frequent exacerbations. The role of respiratory viral infection is just emerging. We wished to determine prospectively the incidence of viral infection in exacerbated and stable COPD patients as well as smokers who do not have airways obstruction. METHODS: Stable and exacerbated COPD patients were recruited along with a group of patients who had smoked but who did not have any airways obstruction. Spirometry was performed and sputum specimens were tested for a range of 12 different respiratory viruses using PCR. RESULTS: One hundred and thirty-six patients with exacerbations of COPD, 68 stable COPD patients and 16 non-obstructed smokers were recruited. A respiratory virus was detected in 37% of exacerbations, 12% of stable COPD patients and 12% of non-obstructed smokers, p<0.0005. Rhinovirus was most frequently detected. The symptom of fever was associated with virus detection, p<0.05. Infection with more than one virus was only found in the exacerbated COPD patients. CONCLUSION: Respiratory viral infection is associated with exacerbations of COPD. Rhinovirus was the most common infecting agent identified and in two cases human metapneumovirus was also detected. Dual infections were only seen amongst those patients admitted to hospital with acute exacerbations of COPD. Viruses were more commonly detected in those with more severe airways disease.

Acute and latent adenovirus in COPD.

INTRODUCTION: The COPD airway is infiltrated with CD8+ T cells, which has led to a virus being implicated in its pathogenesis. Some investigators have suggested a role for the persistence of the adenovirus E1A in bronchial epithelial cells. We examined respiratory tract specimens from COPD patients for the presence of E1A DNA and mRNA using real-time PCR. METHODS: Nucleic acid extraction was performed on sputum specimens from patients with COPD. Copy numbers for GAPDH, and adenovirus 5 E1A DNA and mRNA were determined using a quantitative real-time PCR assay. All samples were screened for the adenovirus hexon gene using nested PCR. RESULTS: One hundred and seventy-one patients, 80 male, aged 68.9+/-9.8 years with COPD were recruited. One hundred and thirty-six were seen during an exacerbation when admitted to hospital, 33 of whom were reviewed when clinically stable along with an additional 35 stable COPD patients. Ten patients in the exacerbation group were positive for the adenovirus hexon gene (7%), as were four in the stable group (6%). Only two patients in the exacerbation group were positive for adenovirus 5 E1A. Only one patient in the stable COPD group had detectable E1A DNA/mRNA and also tested positive for the adenovirus hexon gene. CONCLUSION: Adenovirus is detected in similar frequencies in exacerbated and stable COPD patients. Adenovirus E1A DNA is infrequently detected in respiratory secretions from patients with COPD. Our data suggest that the persistence of adenovirus 5 E1A in lung cells of sputum samples in patients with COPD occurs infrequently.