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/

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

NTHi-IAV coinfection of macrophages alters infection outcomes and inflammatory responses

Nontypeable Haemophilus influenzae (NTHi) chronically colonises the airway of individuals with chronic respiratory disease, with persistence suggested to be facilitated by invasion of airway macrophages. Previous data supports an interaction between NTHi colonisation and the risk of viruses exacerbating underlying respiratory diseases. As exacerbations are the main cause of morbidity and mortality of respiratory diseases, the drivers of this increased risk need to be identified.The aim of this work was to investigate whether prior NTHi infection compromises the ability of macrophages to respond to a subsequent viral challenge. A monocyte-derived macrophage (MDM)-NTHi intracellular persistence model was adapted to include coinfection with the influenza A virus (IAV). Compared to pathogen-alone controls, NTHi presence significantly increased by 190% (p&lt;0.05), whereas the percentage of IAV-infected MDM significantly decreased (23.9% to 6.8%, p&lt;0.01) during co-infection. This decreased viral infection was associated with NTHi-mediated transcriptomic upregulation of MDM antiviral responses (FDR p&lt;0.05) and IFN-β release (p&lt;0.05) prior to IAV challenge. Coinfected MDM released higher levels of inflammatory mediators (TNF-α, IL-1β, IL-6, IL-8, IL-15, IL-23 and IL-36β, all p&lt;0.05) compared to IAV infection alone.This work demonstrates that although prior NTHi infection primed MDM to better respond to IAV infection, coinfection resulted in increased NTHi load and MDM pro-inflammatory responses. Considering the interactions of colonising airway bacteria and viral infections on host immune responses may better inform on treatment strategies to reduce exacerbations.<br/

Human CD49a+ lung NK cell cytotoxicity in response to Influenza A Virus

Influenza A virus (IAV) is a major global public health burden due to its routine evasion of immunisation strategies. Natural Killer (NK) cells are innate cytotoxic cells with important antiviral activity in the human body, yet the function of these cells in the control of IAV infection is unclear. The aim of this study was to determine the role of lung NK cell cytotoxic responses to IAV. Human lung explants were infected ex vivo with IAV and lung NK cell activation was analysed by flow cytometry. Cytotoxic responses of NK cell subsets against IAV-infected macrophages were measured by flow cytometry and ELISA. Despite reports of hypofunctionality in the pulmonary environment, human lung-associated NK cells responded rapidly to ex vivo IAV infection, with upregulation of surface CD107a 24 h post-infection. The lung NK cell phenotype is similar in maturity and differentiation to NK cells of the peripheral blood but a unique CD56brightCD49a+CD103+CD69+ NK cell population was identified in the lung, indicating NK cell residency within this organ. In response to ex vivo IAV infection a greater proportion of resident CD56brightCD49a+ NK cells expressed surface CD107a compared to CD56brightCD49a- NK cells, suggesting a hyperfunctional NK cell population may be present within human lung tissue and could be the result of innate immunological training. Furthermore NK cells provided significant anti-viral, cytotoxic activity following contact with influenza infected cells, including the production and release of IFN-γ and Granzyme-B resulting in macrophage cell death. These results suggest that a resident, memory NK cell population are present in the human lung and may provide early and important control of viral infection. A greater understanding of this resident mucosal population may provide further insight into the role of these cells in controlling viral infection and generating appropriate adaptive immunity to IAV