Distinct emphysema subtypes defined by quantitative CT analysis are associated with specific pulmonary matrix metalloproteinases

BACKGROUND: Emphysema is characterised by distinct pathological sub-types, but little is known about the divergent underlying aetiology. Matrix-metalloproteinases (MMPs) are proteolytic enzymes that can degrade the extracellular matrix and have been identified as potentially important in the development of emphysema. However, the relationship between MMPs and emphysema sub-type is unknown. We investigated the role of MMPs and their inhibitors in the development of emphysema sub-types by quantifying levels and determining relationships with these sub-types in mild-moderate COPD patients and ex/current smokers with preserved lung function.METHODS: Twenty-four mild-moderate COPD and 8 ex/current smokers with preserved lung function underwent high resolution CT and distinct emphysema sub-types were quantified using novel local histogram-based assessment of lung density. We analysed levels of MMPs and tissue inhibitors of MMPs (TIMPs) in bronchoalveolar lavage (BAL) and assessed their relationship with these emphysema sub-types.RESULTS: The most prevalent emphysema subtypes in COPD subjects were mild and moderate centrilobular (CLE) emphysema, while only small amounts of severe centrilobular emphysema, paraseptal emphysema (PSE) and panlobular emphysema (PLE) were present. MMP-3, and -10 associated with all emphysema sub-types other than mild CLE, while MMP-7 and -8 had associations with moderate and severe CLE and PSE. MMP-9 also had associations with moderate CLE and paraseptal emphysema. Mild CLE occurred in substantial quantities irrespective of whether airflow obstruction was present and did not show any associations with MMPs.CONCLUSION: Multiple MMPs are directly associated with emphysema sub-types identified by CT imaging, apart from mild CLE. This suggests that MMPs play a significant role in the tissue destruction seen in the more severe sub-types of emphysema, whereas early emphysematous change may be driven by a different mechanism.TRIAL REGISTRATION: Trial registration number NCT01701869

Specialist Respiratory Outreach : a case-finding initiative for identifying undiagnosed COPD in primary care

Acknowledgments This report is independent research funded by the National Institute for Health Research Wessex ARC. The views expressed in this publication are those of the author(s) and not necessarily those of the National Institute for Health Research or the Department of Health and Social Care. We are very grateful to Optimum Patient care and their team for their help and support with the data extraction and application of the case-finding risk score. We would also like to thank: The participants, Mark Stafford-Watson (PPI) in memorial, Colin Newell, Dr Fiona McKenna, Dr Andy Powell, Dr Helen Myers, Dr Stuart McKinnes, Dr Mark Williams, Dr Louisa Egbe, Dr Richard Baxter, Dr Sarah A’Court, Dr Elisabeth Willows, Dr Gareth Morris, Dr Ford, Dr Kate Lippiett, Wessex Clinical Research Network, West Hampshire CCG and Southampton City CCGPeer reviewedPublisher PD

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century

Digital healthcare in COPD management: a narrative review on the advantages, pitfalls, and need for further research

Chronic obstructive pulmonary disease (COPD) remains a leading cause of morbidity and mortality despite current treatment strategies which focus on smoking cessation, pulmonary rehabilitation, and symptomatic relief. A focus of COPD care is to encourage self-management, particularly during COVID-19, where much face-to-face care has been reduced or ceased. Digital health solutions may offer affordable and scalable solutions to support COPD patient education and self-management, such solutions could improve clinical outcomes and expand service reach for limited additional cost. However, optimal ways to deliver digital medicine are still in development, and there are a number of important considerations for clinicians, commissioners, and patients to ensure successful implementation of digitally augmented care. In this narrative review, we discuss advantages, pitfalls, and future prospects of digital healthcare, which offer a variety of tools including self-management plans, education videos, inhaler training videos, feedback to patients and healthcare professionals (HCPs), exacerbation monitoring, and pulmonary rehabilitation. We discuss the key issues with sustaining patient and HCP engagement and limiting attrition of use, interoperability with devices, integration into healthcare systems, and ensuring inclusivity and accessibility. We explore the essential areas of research beyond determining safety and efficacy to understand the acceptability of digital healthcare solutions to patients, clinicians, and healthcare systems, and hence ways to improve this and sustain engagement. Finally, we explore the regulatory challenges to ensure quality and engagement and effective integration into current healthcare systems and care pathways, while maintaining patients' autonomy and privacy. Understanding and addressing these issues and successful incorporation of an acceptable, simple, scalable, affordable, and future-proof digital solution into healthcare systems could help remodel global chronic disease management and fractured healthcare systems to provide best patient care and optimisation of healthcare resources to meet the global burden and unmet clinical need of COPD.</p

Defining a role for exercise training in the management of asthma

The prevalence of asthma remains high worldwide, with increasing awareness of the morbidity and mortality from asthma in low income countries. In the UK, despite the development of biological treatments, many patients remain sub optimally controlled, and mortality rates have been static for decades. Therefore, new approaches are needed to treat asthma that are scalable at minimal cost. Exercise immunology is an expanding field, and there is growing Whilst exercise is encouraged in current treatment guidelines, there are no specific recommendations as to the intensity, frequency or duration of exercise exposures. Despite national and international guidance to increase exercise, patients with asthma are less likely to engage in physical activity. This review explores the disease modifying benefit of exercise in asthma We also review the domains in which exercise exerts positive clinical effects in asthma, including the effects of exercise on symptom scores, quality of life, psychosocial health, and in the obese asthma phenotype. Finally, we review the barriers to exercise in asthma, given the benefits it confers. A better understanding of the mechanisms through which exercise exerts its positive effects in asthma may help more accurate prescription of exercise training programmes as part of broader asthma management, with the potential of identification of new drug targets

Patient-centered discussions about disease progression, symptom, and treatment burden in chronic obstructive pulmonary disease could facilitate the integration of end-of-life discussions in the disease trajectory: patient, clinician, and literature perspectives: a multimethod approach

Background: patients with chronic obstructive pulmonary disease (COPD) seldom discuss preferences for future care/treatments with clinicians. The lack of discussions prevents the delivery of care grounded on patient preferences. Instead, treatments become increasingly burdensome as disease progresses and patients approach the end of life.Objective: identify current and best practice in initiating and conducting conversations about future and palliative care, by integrating data from multiple sources.Design: multiphasic study where the findings of a systematic literature review and qualitative interviews were combined and synthesized using a triangulation protocol.Setting/Participants: thirty-three patients with COPD and 14 clinicians from multiple backgrounds were recruited in the United Kingdom.Results: clinicians' and patients' poor understanding about palliative care and COPD, difficulties in timing and initiating discussions, and service rationing were the main factors for late discussions. Divergent perspectives between patients and clinicians about palliative care discussions often prevented their start. Instead, early and gradual patient-centered discussions on treatment choices, symptom, and treatment burden were recommended by patients, clinicians, and the literature. Earlier patient-centered discussions may reduce their emotional impact and enable patients to participate fully, while enabling clinicians to provide timely and accurate information on illness progression and appropriate self-management techniques.Conclusion: current approaches toward palliative care discussions in COPD do not guarantee that patients' preferences are met. Early and gradual patient-centered discussions may enable patients to fully express their care preferences as they evolve over time, while minimizing the impact of symptom and treatment burden

IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection

BackgroundBacterial respiratory tract infections and exacerbations of chronic lung diseases are commonly caused by nontypeable Haemophilus influenzae (NTHi). Cell-mediated cytotoxicity may be key to controlling infection, but the responses of NTHi-specific T cell populations are not well understood. Mucosal-associated invariant T (MAIT) cells are a recently-discovered, innate-like subset of T cells with cytotoxic function, whose role in lung immunity is unclear. ObjectiveThe aim of this study was to determine the mechanisms behind conventional T and MAIT cell cytotoxic responses to NTHi. MethodsHuman ex vivo lung explants were infected with a clinical strain of NTHi. Monocyte-derived macrophages were also infected with NTHi in vitro and co-cultured with autologous T cells. Cytotoxic responses of T cell subsets were measured by flow cytometry. ResultsWe found significant upregulation of the cytotoxic markers, CD107a and granzyme B, in lung CD4+, CD8+ and MAIT cell populations. We show that MAIT cell cytotoxic responses were upregulated by a combination of both time-dependent antigen presentation and through a novel mechanism by which IL-12 and IL-7 synergistically control granzyme B through upregulation of the IL-12 receptor. ConclusionsOverall our data provide evidence for a cytotoxic role of MAIT cells in the lung and highlight important differences in the control of adaptive and innate-like T cell responses. Understanding these mechanisms may lead to new therapeutic opportunities to modulate the anti-bacterial response and improve clinical outcome. <br/

Dysregulation of anti-viral function of CD8+T cells in the COPD lung: role of the PD1/PDL1 axis

Rationale: COPD patients are susceptible to respiratory viral infections which cause exacerbations. Mechanisms underlying susceptibility are not understood. Effectors of the adaptive immune response; CD8+ T cells which clear viral infections, are present in increased numbers in lungs of COPD patients but fail to protect against infection and may contribute to the immunopathology of the disease. Objectives: CD8+ function and signalling through the Programmed Cell Death (PD-1) exhaustion pathway was investigated as a potential key mechanism of viral exacerbation of the COPD lung. Methods: Tissue from control or COPD patients undergoing lung resection was infected with live influenza virus ex vivo. Viral infection and expression of lung cell markers was analysed using flow cytometry. Measurements and Main Results: The proportion of lung CD8+ T cells expressing PD-1 was greater in COPD(mean=16.2%) than controls(4.4%, p=0.029). Only epithelial cells and macrophages were infected with influenza and there was no difference in the proportion of infected cells between controls and COPD. Infection upregulated T cell PD-1 expression in control and COPD samples. Concurrently, influenza significantly upregulated the marker of cytotoxic degranulation (CD107a) on CD8+ T cells(p=0.03) from controls, but not from COPD patients. Virus-induced expression of the ligand PD-L1 was decreased on COPD macrophages(p=0.04) with a corresponding increase in IFN? release from infected COPD explants compared to controls(p=0.04). Conclusions: This study has established a signal of cytotoxic immune dysfunction and aberrant immune regulation in the COPD lung that may explain both the susceptibility to viral infection and the excessive, inflammation associated with exacerbations

Monitoring wellness in Chronic Obstructive Pulmonary Disease using the myCOPD app

According to the World Health Organisation, Chronic Obstructive Pulmonary Disease (COPD) is the third leading cause of death worldwide. Risks include environmental factors, especially pollution, and behaviours such as smoking. It is persistent and progressive, with an early diagnosis and treatment benefit in controlling the progression of the disease and reduce flare ups, known as exacerbations. Smartphone and desktop apps which allow regular self-reporting are one way that can engage individuals in the self-management of their condition. Potentially, the data from these apps represent a significant source of information to support care. This study looked at self-reported well-being measures along with other indicators from the myCOPD app. In this chapter, we focus primarily on the prediction of exacerbations using these data, while also providing some preliminary insights into app-user behaviours. Our results indicate that it is possible to make some exacerbation predictions from the myCOPD app from relative few data types, but that integrating environmental data sources such as weather and pollution remains problematic. Further, app usage patterns show individual differences in how well-being is reported rather than seasonal effects. The results have led to a significant multi-disciplinary follow-on project to carry the prediction work forward