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.

Physiology and Pathophysiology of Human Airway Mucus

The mucus clearance system is the dominant mechanical host defense system of the human lung. Mucus is cleared from the lung by cilia and airflow, including both two-phase gas liquid pumping and cough-dependent mechanisms, and mucus transport rates are heavily dependent on mucus concentration. Importantly, mucus transport rates are accurately predicted by the gel-on-brush model of the mucociliary apparatus from the relative osmotic moduli of the mucus and periciliary-glycocalyceal (PCL-G) layers. The fluid available to hydrate mucus is generated by transepithelial fluid transport. Feedback interactions between mucus concentrations and cilia beating, via purinergic signaling, coordinate Na+ absorptive vs Cl- secretory rates to maintain mucus hydration in health. In disease, mucus becomes hyperconcentrated (dehydrated). Multiple mechanisms derange the ion transport pathways that normally hydrate mucus in muco-obstructive lung diseases, e.g., CF, COPD, NCFB, and PCD. A key step in muco-obstructive disease pathogenesis is the osmotic compression of the mucus layer onto the airway surface with the formation of adherent mucus plaques and plugs, particularly in distal airways. Mucus plaques create locally hypoxic conditions and produce airflow obstruction, inflammation, infection, and, ultimately, airway wall damage. Therapies to clear adherent mucus with hydrating and mucolytic agents are rational, and strategies to develop these agents are reviewed.

Impaired Spontaneous Baroreceptor Reflex Sensitivity in Patients With COPD Compared to Healthy Controls: The Role of Lung Hyperinflation

Background and Objectives: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk for cardiovascular disease. This study aimed to investigate the relationship between pulmonary hyperinflation and baroreceptor reflex sensitivity (BRS), a surrogate for cardiovascular risk.Methods: 33 patients with COPD, free from clinical cardiovascular disease, and 12 healthy controls were studied. Participants underwent pulmonary function and non-invasive hemodynamic measurements. BRS was evaluated using the sequence method during resting conditions and mental arithmetic stress testing.Results: Patients with COPD had evidence of airflow obstruction [forced expiratory volume in 1 s predicted (FEV1%) 26.5 (23.3–29.1) vs. 91.5 (82.8–100.8); P < 0.001; geometric means (GM) with 95% confidence interval (CI)] and lung hyperinflation [residual volume/total lung capacity (RV/TLC) 67.7 (64.3–71.3) vs. 41.0 (38.8–44.3); P < 0.001; GM with 95% CI] compared to controls. Spontaneous mean BRS (BRSmean) was significantly lower in COPD, both during rest [5.6 (4.2–6.9) vs. 12.0 (9.1–17.6); P = 0.003; GM with 95% CI] and stress testing [4.4 (3.7–5.3) vs. 9.6 (7.7–12.2); P < 0.001; GM with 95% CI]. Stroke volume (SV) was significantly lower in the patient group [−21.0 ml (−29.4 to −12.6); P < 0.001; difference of the means with 95% CI]. RV/TLC was found to be a predictor of BRS and SV (P < 0.05 for both), independent of resting heart rate.Conclusion: We herewith provide evidence of impaired BRS in patients with COPD. Hyperinflation may influence BRS through alteration of mechanosensitive vagal nerve activity.

Exercise-Induced Bronchoconstriction in Children

Exercise-induced bronchoconstriction (EIB) is a transient airflow obstruction, typically 5–15 min after physical activity. The pathophysiology of EIB is related to the thermal and osmotic changes of the bronchial mucosa, which cause the release of mediators and the development of bronchoconstriction in the airways. EIB in children often causes an important limitation to physical activities and sports. However, by taking appropriate precautions and through adequate pharmacological control of the condition, routine exercise is extremely safe in children. This review aims to raise awareness of EIB by proposing an update, based on the latest studies, on pathological mechanisms, diagnosis, and therapeutic approaches in children.

Severe pediatric asthma with a poor response to omalizumab: a report of three cases and three-dimensional bronchial wall analysis

Omalizumab is used for the treatment of persistent severe allergic asthma in adults and children. However, some patients remain symptomatic even after omalizumab treatment. In bronchial asthma, chronic inflammation of the bronchial wall causes thickening of the airway wall, resulting from irreversible airway remodeling. Progression of airway remodeling causes airflow obstruction, leading to treatment resistance. We report three Japanese children with severe asthma who had a poor response to omalizumab treatment. They had a long period of inadequate management of asthma before initiating omalizumab. Even after omalizumab treatment, their symptoms persisted, and the parameters of spirometry tests did not improve. We hypothesized that omalizumab was less effective in these patients because airway wall remodeling had already progressed. We retrospectively evaluated the bronchial wall thickness using a three-dimensional bronchial wall analysis with chest computed tomography. The bronchial wall thickness was increased in these cases compared with six responders. Progressed airway wall thickness caused by airway remodeling may be associated with a poor response to omalizumab in children with severe asthma.

Malnutrition, Sarcopenia, and Malnutrition-Sarcopenia Syndrome in Older Adults with COPD

Purpose: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death in the world population. In addition to airflow obstruction, COPD is associated with multiple systemic manifestations, including impaired nutritional status or malnutrition and changes in body composition (low muscle mass, LMM). Poor nutritional status and sarcopenia in subjects with COPD leads to a worse prognosis and increases health-related costs. Data from previous studies indicate that 30–60% of subjects with COPD are malnourished, 20–40% have low muscle mass, and 15–21.6% have sarcopenia. This study aimed to assess the prevalence of malnutrition, sarcopenia, and malnutrition-sarcopenia syndrome in elderly subjects with COPD and investigate the relationship between COPD severity and these conditions.Patients and methods: A cross-sectional study involving 124 patients with stable COPD, aged ≥60, participating in a stationary pulmonary rehabilitation program. Nutritional status was assessed following the Global Leadership Initiative on Malnutrition (GLIM) criteria and sarcopenia with the European Working Group on Sarcopenia in Older People 2 (EWGSOP2) criteria. The results of pulmonary function tests and exercise capacity were obtained from the hospital database. Results: 22.6% of participants had malnutrition according to the GLIM criteria. Subjects with malnutrition had lower gait speed (p = 0.0112) and worse results of the Six Minute Walk Test. Sixteen participants (12.9%) had sarcopenia; 12 subjects with sarcopenia had concomitant malnutrition. The prevalence of severe and very severe obstruction (GOLD3/GOLD4) was 91.7%. It was significantly higher in patients with malnutrition-sarcopenia syndrome. Conclusions: Malnutrition was found in nearly one out of four subjects with COPD, while sarcopenia was one out of seven patients. About 10% of our study sample had malnutrition-sarcopenia syndrome. The prevalence of severe and very severe obstruction was significantly higher in patients with malnutrition-sarcopenia syndrome.

Regulatory Peptides in Asthma

Numerous regulatory peptides play a critical role in the pathogenesis of airway inflammation, airflow obstruction and hyperresponsiveness, which are hallmarks of asthma. Some of them exacerbate asthma symptoms, such as neuropeptide Y and tachykinins, while others have ameliorating properties, such as nociception, neurotensin or β-defensin 2. Interacting with peptide receptors located in the lungs or on immune cells opens up new therapeutic possibilities for the treatment of asthma, especially when it is resistant to available therapies. This article provides a concise review of the most important and current findings regarding the involvement of regulatory peptides in asthma pathology.

Cardiovascular Risk in Patients with COPD: Cardiovascular Comorbidities in Patients with COPD Increase CAT and mMRC Dyspnea Scores

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is associated with a number of different comorbidities. Cardiovascular diseases (CVD) are the most frequent comorbidities in COPD. The economic burden associated with cardiovascular comorbidity (CVC) in this population of patients is considerable. The COPD patients are related to the increased systemic inflammation, reduced capacity for physical activity, and airflow obstruction. AIM: The aim of our investigation was to evaluate the dyspnea as a disabling symptom in COPD patients with cardiovascular comorbidity (CVC) especially heart failure. The main aim of this study is to evaluate its intensity in patients with COPD in stages II according to GOLD. METHODS: The investigation was conducted from December 2019 to January 2020, on pulmonology and allergology clinic and cardiology clinic of medical faculty in Skopje. We investigated 65 outpatients with COPD, 44 with different type of CVD, Group I, and 21 without CVD, Group II. All patients were with partial chronic respiratory failure (In type 1 respiratory failure hypoxemic). Patients, according GOLD initiative, were in COPD stadium II, 70% < forced expiratory volume in 1 s (FEV1)>50%. Heart condition was diagnosed on the basis of clinical examination, electrocardiography, and echocardiography of the heart. Included patients with CVD were with ejection fraction (EF) <65%. Dyspnea was measured with modified MRC (mMRC) dyspnea scale. RESULTS: The forced vital capacity and forced expiratory volume in 1 s were statically significantly higher in Group II with CVD. Dyspnea measured with Modified Medical Research Council (MRC) dyspnea scale showed statistically significantly higher values in Group I COPD patients with CVC (2.9 ± 1.4) versus Group II without CVC (1.7 ± 1.4), (p < 0.05). The perception of the higher dyspnea in Group I was associated with increased COPD assessment test-scores, in Group I: Group I (19.8 ± 9.1) versus Group II: (9.8 ± 9.1), (p < 0.001). The number of exacerbations and what is more important the number of severe exacerbation leading to hospitalizations was statistically higher in patients of Group I with CVC than in Group II without CVC (3.0 ± 1.1 vs. 1.0 ± 2.1), (p < 0.001) and the number of hospitalizations (1.0 ± 1.1 vs. 0.3 ± 2.1) (p < 0.001). CONCLUSION: We can conclude that patients with COPD who have CVC have an increased risk of high symptoms, which mean poor quality of life and increased morbidity.