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.

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.

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.

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, IFNβ, 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.

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. Is valaciclovir safe and effective for EBV suppression in COPD? 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. 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). 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. ClinicalTrials.gov; No.: NCT03699904; URL: www. gov.

Introduction: Liberal administration of supplemental oxygen (O ₂ ) is ubiquitous across numerous healthcare settings. However, appropriate O ₂ titration targets remain controversial and despite numerous large-scale randomised trials, there is an ongoing lack of consensus regarding optimal oxygenation strategies and the absence of high-quality mechanistic data pertaining to the potential proinflammatory effects of hyperoxia. Methods and analysis: We hypothesise that (1) short-term exposure to hyperoxia will induce mild pulmonary inflammation and cellular injury and that (2) hyperoxia will accentuate pulmonary inflammation and cellular injury in the setting of inhaled lipopolysaccharide challenge. To test our hypotheses, we will conduct a randomised, double-blind, placebo-controlled study of hyperoxia administered via a high-flow nasal O ₂ delivery system (fractional inspired oxygen 1.0, 60 L/min flow rate) compared with synthetic medical air. Blocked randomisation will be undertaken by an independent clinical trials statistician. Healthy non-smoking adult volunteers (<45 years of age), taking no regular medications will be recruited. Bronchoalveolar lavage (BAL) will be performed at 6 hours. The study outcome measures will include BAL markers of inflammation and injury (including but not limited to interleukin (IL)-8, IL-6, tumour necrosis factor alpha), BAL differential cell counts, BAL markers of oxidative stress (superoxide dismutase and glutathione), alveolar epithelial cell injury (SP-D, vWF, RAGE) and markers of systemic inflammation (neutrophils and plasma C-reactive protein). Ethics and dissemination: Dissemination of the research findings will be achieved in the following ways: (1) Our findings will be presented at national and international meetings with open-access abstracts online and (2) in accordance with the open-access policies proposed by the leading research funding bodies we aim to publish the findings in high quality peer-reviewed open-access journals. Trial registration number: NCT05414370 .