Inhibition of bradykinin in SARS-CoV-2 infection: a randomised, double-blind trial of icatibant compared with placebo (ICASARS).

SARS-CoV-2 binds to ACE2 receptors and enters cells. The symptoms are cough, breathlessness, loss of taste/smell and X-ray evidence of infiltrates on chest imaging initially caused by oedema, and subsequently by a lymphocytic pneumonitis. Coagulopathy, thrombosis and hypotension occur. Worse disease occurs with age, obesity, ischaemic heart disease, hypertension and diabetes.These features may be due to abnormal activation of the contact system. This triggers coagulation and the kallikrein-kinin system, leading to accumulation of bradykinin and its derivatives, which act on receptors B1R and B2R. Receptor activation causes cough, hypotension, oedema and release of the cytokine interleukin-6 (IL-6) which recruits lymphocytes. These effects are core features seen in early SARS CoV-2 infection. METHODS AND ANALYSIS: In this study, hypoxic patients with COVID-19 with symptom onset ≤7 days will be randomised to either a bradykinin inhibitor (icatibant) or placebo. Patients and investigators will be blinded. The primary outcome will be blood oxygenation, measured by arterial blood sampling. The secondary outcome will be cardiovascular status. Retinal imaging will be performed to assess vessel size. Blood samples will be taken for measurement of inflammatory analyses including IL-6. As a separate substudy, we will also take comparator blood inflammatory samples from a COVID-19-negative cohort. ETHICS AND DISSEMINATION: The study has received the following approvals: West Midlands-Edgbaston Research Ethics Committee. Medicines and Healthcare products Regulatory Agency has issued a clinical trial authorisation. Belfast Health and Social Care Trust is the study sponsor. Results will be made available to participants upon request and findings will be presented and published. TRIAL REGISTRATION NUMBER: NCT05407597.

Pulmonary Sequelae of COVID-19: Focus on Interstitial Lung Disease.

As the world transitions from the acute phase of the COVID-19 pandemic, a novel concern has arisen-interstitial lung disease (ILD) as a consequence of SARS-CoV-2 infection. This review discusses what we have learned about its epidemiology, radiological, and pulmonary function findings, risk factors, and possible management strategies. Notably, the prevailing radiological pattern observed is organising pneumonia, with ground-glass opacities and reticulation frequently reported. Longitudinal studies reveal a complex trajectory, with some demonstrating improvement in lung function and radiographic abnormalities over time, whereas others show more static fibrotic changes. Age, disease severity, and male sex are emerging as risk factors for residual lung abnormalities. The intricate relationship between post-COVID ILD and idiopathic pulmonary fibrosis (IPF) genetics underscores the need for further research and elucidation of shared pathways. As this new disease entity unfolds, continued research is vital to guide clinical decision making and improve outcomes for patients with post-COVID ILD.

Vascular risk factors for COVID-19 ARDS: endothelium, contact-kinin system.

SARS-CoV-2 binds to ACE2 receptors, expressed within the lungs. Risk factors for hospitalization include hypertension, diabetes, ischaemic heart disease and obesity-conditions linked by the presence of endothelial pathology. Viral infection in this setting causes increased conversion of circulating Factor XII to its active form (FXIIa). This is the first step in the contact-kinin pathway, leading to synchronous activation of the intrinsic coagulation cascade and the plasma Kallikrein-Kinin system, resulting in clotting and inflammatory lung disease. Temporal trends are evident from blood results of hospitalized patients. In the first week of symptoms the activated partial thromboplastin time (APTT) is prolonged. This can occur when clotting factors are consumed as part of the contact (intrinsic) pathway. Platelet counts initially fall, reflecting their consumption in coagulation. Lymphopenia occurs after approximately 1 week, reflecting the emergence of a lymphocytic pneumonitis [COVID-19 acute respiratory distress syndrome (ARDS)]. Intrinsic coagulation also induces the contact-kinin pathway of inflammation. A major product of this pathway, bradykinin causes oedema with ground glass opacities (GGO) on imaging in early COVID-19. Bradykinin also causes release of the pleiotrophic cytokine IL-6, which causes lymphocyte recruitment. Thromobosis and lymphocytic pneumonitis are hallmark features of COVID-19 ARDS. In this review we examine the literature with particular reference to the contact-kinin pathway. Measurements of platelets, lymphocytes and APTT should be undertaken in severe infections to stratify for risk of developing ARDS.

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.

Clinicoradiological outcomes after radical radiotherapy for lung cancer in patients with interstitial lung disease.

Objective: Interstitial lung disease (ILD) is relatively common in patients with lung cancer with an incidence of 7.5%. Historically pre-existing ILD was a contraindication to radical radiotherapy owing to increased radiation pneumonitis rates, worsened fibrosis and poorer survival compared with non-ILD cohorts. Herein, the clinical and radiological toxicity outcomes of a contemporaneous cohort are described. Methods: Patients with ILD treated with radical radiotherapy for lung cancer at a regional cancer centre were collected prospectively. Radiotherapy planning, tumour characteristics, and pre- and post-treatment functional and radiological parameters were recorded. Cross-sectional images were independently assessed by two Consultant Thoracic Radiologists. Results: Twenty-seven patients with co-existing ILD received radical radiotherapy from February 2009 to April 2019, with predominance of usual interstitial pneumonia subtype (52%). According to ILD-GAP scores, most patients were Stage I. After radiotherapy, localised (41%) or extensive (41%) progressive interstitial changes were noted for most patients yet dyspnoea scores (n = 15 available) and spirometry (n = 10 available) were stable. One-third of patients with ILD went on to receive long-term oxygen therapy, which was significantly more than the non-ILD cohort. Median survival trended towards being worse compared with non-ILD cases (17.8 vs 24.0 months, p = 0.834). Conclusion: Radiological progression of ILD and reduced survival were observed post-radiotherapy in this small cohort receiving lung cancer radiotherapy, although a matched functional decline was frequently absent. Although there is an excess of early deaths, long-term disease control is achievable. Advances in knowledge: For selected patients with ILD, long-term lung cancer control without severely impacting respiratory function may be possible with radical radiotherapy, albeit with a slightly higher risk of death.

The association of denture wearing with reduced lung function and increased airflow limitation in 58-72 year old men.

OBJECTIVE: To investigate the association between denture wearing and airflow limitation in men in Northern Ireland enrolled in the Prospective Epidemiological Study of Myocardial Infarction (PRIME) study. METHODS: A case-control design was used to study partially dentate men. Cases were men aged 58-72 years who were confirmed as denture wearers. Controls were never denture wearers who were matched by age (± 1 month) and smoking habit to the cases. The men had a periodontal assessment and completed a questionnaire detailing their medical history, dental history and behaviours, social circumstances, demographic background and tobacco use. Physical examination and spirometry measurements of forced expiratory volume in one second (FEV1) and forced vital capacity (FVC) were also undertaken. Spirometry data for edentulous men who wore complete dentures were compared with that recorded for the partially dentate men studied. RESULTS: There were 353 cases who were partially dentate and were confirmed denture wearers. They were matched for age and smoking habit to never denture wearer controls. The cases had an FEV1 that was on average 140 ml lower than the controls, p = 0.0013 and a 4% reduction in percent predicted FEV1, p = 0.0022. Application of the GOLD criteria indicated that 61 (17.3%) of the cases had moderate to severe airflow limitation compared with 33 (9.3%) of controls, p = 0.0051. Fully adjusted multivariable analysis showed that partially dentate men who were denture wearers were significantly more likely (p = 0.01) to have moderate to severe airflow reduction with an adjusted odds ratio (OR) of 2.37 (95% confidence intervals 1.23-4.55). In the 153 edentulous men studied moderate to severe airflow limitation was recorded in 44 (28.4%), which was significantly higher than in the partially dentate denture wearers (p = 0.017), and the men who had never worn a denture (p<0.0001). CONCLUSION: Denture wearing was associated with an increased risk of moderate to severe airflow limitation in the cohort of middle-aged Western European men studied.

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.

Subgingival microbial diversity and respiratory decline: A cross-sectional study.

AIM: To investigate whether there is an association between subgingival microbial diversity and reduced respiratory function. MATERIALS AND METHODS: A group of dentate 58-72-year-old men in Northern Ireland had a comprehensive periodontal examination including subgingival plaque sampling. DNA was extracted from plaque samples and the V1-V3 regions of the 16S rRNA gene were analysed by high-throughput sequencing and a microbial diversity index (MDI) was derived. Spirometry measurements were made using a wedge bellows spirometer. The primary outcome variable of interest was the percentage of predicted forced expiratory volume in 1 s (% predicted FEV1 ). Analysis included multiple linear regression with adjustment for various confounders. RESULTS: Five-hundred and seven men were included in the analysis. The mean age was 63.6 years (SD = 3.1). Of these, 304 (60.0%) men had no or mild periodontitis, 105 (20.7%) had moderate periodontitis and 98 (19.3%) had severe periodontitis. Multiple linear regression analysis showed that a one unit increase in MDI was associated with a 0.71% loss (95% confidence interval: 0.06%-1.35%; p = .03) in % predicted FEV1 after adjustment for all confounders. CONCLUSIONS: In this group of dentate men from Northern Ireland, subgingival microbial diversity was associated with reduced respiratory function.

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.

Periodontal status and chronic obstructive pulmonary disease (COPD) exacerbations: a systematic review.

BACKGROUND: A growing body of evidence suggests a role for oral bacteria in lung infections. This systematic review aimed to analyse the association between poor periodontal status and the frequency of chronic obstructive pulmonary disease (COPD) exacerbations. METHODS: PubMed, Embase, Web of Science, CINAHL and Medline were searched for studies published until May 2020, with no language restriction. Studies reporting periodontal condition, or periodontal treatment outcomes, with data on the frequency of exacerbations of COPD, were identified. The primary outcome was the frequency of exacerbations and secondary outcomes included quality of life (QoL) and hospitalisation. Quality and risk of bias assessment were carried out using the Newcastle Ottawa Scale for observational studies, Robins-1 tool for non-randomised intervention studies and Cochrane risk of bias assessment (RoB-2) tool for randomised clinical trials. Studies were assessed for eligibility and quality by two assessors independently. RESULTS: Searches identified 532 records and 8 met the inclusion criteria. Included studies were three clinical trials, one prospective cohort study, one case-control, and three cross-sectional studies. A narrative synthesis was performed. The data from intervention studies showed reduction in the frequency of exacerbations following periodontal treatment. Data from observational studies suggest association of worse plaque scores and fewer teeth with exacerbation, but not pocket depth or clinical attachment loss. Better periodontal health was also associated with reduced frequency of COPD exacerbations, hospitalisations and improved quality of life in COPD patients. Due to the high heterogeneity no meta-analysis was performed. The quality of some of the included studies was low and there was evidence of a high risk of bias. CONCLUSION: The data supports possible association between poor periodontal health, the frequency of exacerbations, hospitalisation and quality of life in COPD patients. The evidence is of moderate to low certainty and is limited by high risk of bias suggesting the need for well-designed and adequately powered randomised controlled trials, to inform future research and clinical practice. The PROSPERO registration number CRD42020180328.

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.

Respiratory viral infection: a potential "missing link" in the pathogenesis of COPD.

Chronic obstructive pulmonary disease (COPD) is currently the third most common cause of global mortality. Acute exacerbations of COPD frequently necessitate hospital admission to enable more intensive therapy, incurring significant healthcare costs. COPD exacerbations are also associated with accelerated lung function decline and increased risk of mortality. Until recently, bacterial pathogens were believed to be responsible for the majority of disease exacerbations. However, with the advent of culture-independent molecular diagnostic techniques it is now estimated that viruses are detected during half of all COPD exacerbations and are associated with poorer clinical outcomes. Human rhinovirus, respiratory syncytial virus and influenza are the most commonly detected viruses during exacerbation. The role of persistent viral infection (adenovirus) has also been postulated as a potential pathogenic mechanism in COPD. Viral pathogens may play an important role in driving COPD progression by acting as triggers for exacerbation and subsequent lung function decline whilst the role of chronic viral infection remains a plausible hypothesis that requires further evaluation. There are currently no effective antiviral strategies for patients with COPD. Herein, we focus on the current understanding of the cellular and molecular mechanisms of respiratory viral infection in COPD.

In patients with resectable non-small-cell lung cancer, is video-assisted thoracoscopic segmentectomy a suitable alternative to thoracotomy and segmentectomy in terms of morbidity and equivalence of resection?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'In patients with resectable non-small-cell lung cancer, is video-assisted thoracoscopic segmentectomy a suitable alternative to thoracotomy and segmentectomy in terms of morbidity and equivalence of resection?' Altogether 232 papers were found as a result of the reported search, of which 7 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Only one study compared the survival rates of video-assisted thoracoscopic surgery (VATS) and open surgery and found no significant difference in overall (P = 0.605) and disease-free (P = 0.996) survival between these groups. The mean length of hospital stay was reported as shorter following VATS when compared with open surgery in all of the studies looking at this outcome. The greatest difference in length of hospital stay reported was 4.8 days (VATS 3.5 days and open 8.3 days). The duration of chest tube placement was also universally reported as shorter in patients having VATS procedures when compared with open procedures. Two studies compared the number of lymph nodes that could be sampled when completing this operation by VATS using an open approach and neither found there to be a significant difference between these numbers. Using the evidence collected, we conclude that anatomical segmentectomy performed by VATS is a safe and effective alternative to conventional techniques in the surgical management of non-small-cell lung cancer. We are aware that the current evidence is limited and existing studies all examine small numbers of patients. Unfortunately, at present there is no blinded randomized control trial comparing these two surgical methods. There is also no study comparing the utility of each method for differing anatomical locations of segments. This should be kept in mind when interpreting the results of the studies presented.