Exacerbation predictive modelling using real-world data from the myCOPD app.

Background: Acute exacerbations of COPD (AECOPD) are episodes of breathlessness, cough and sputum which are associated with the risk of hospitalisation, progressive lung function decline and death. They are often missed or diagnosed late. Accurate timely intervention can improve these poor outcomes. Digital tools can be used to capture symptoms and other clinical data in COPD. This study aims to apply machine learning to the largest available real-world digital dataset to develop AECOPD Prediction tools which could be used to support early intervention and improve clinical outcomes. Objective: To create and validate a machine learning predictive model that forecasts exacerbations of COPD 1-8 days in advance. The model is based on routine patient-entered data from myCOPD self-management app. Method: Adaptations of the AdaBoost algorithm were employed as machine learning approaches. The dataset included 506 patients users between 2017 and 2021. 55,066 app records were available for stable COPD event labels and 1263 records of AECOPD event labels. The data used for training the model included COPD assessment test (CAT) scores, symptom scores, smoking history, and previous exacerbation frequency. All exacerbation records used in the model were confined to the 1-8 days preceding a self-reported exacerbation event. Results: TheEasyEnsemble Classifier resulted in a Sensitivity of 67.0 % and a Specificity of 65 % with a positive predictive value (PPV) of 5.0 % and a negative predictive value (NPV) of 98.9 %. An AdaBoost model with a cost-sensitive decision tree resulted in a a Sensitivity of 35.0 % and a Specificity of 89.0 % with a PPV of 7.08 % and NPV of 98.3 %. Conclusion: This preliminary analysis demonstrates that machine learning approaches to real-world data from a widely deployed digital therapeutic has the potential to predict AECOPD and can be used to confidently exclude the risk of exacerbations of COPD within the next 8 days.

Structural Predictors of Lung Function Decline in Young Smokers with Normal Spirometry.

Rationale: Chronic obstructive pulmonary disease (COPD) due to tobacco smoking commonly presents when extensive lung damage has occurred. Objectives: We hypothesized that structural change would be detected early in the natural history of COPD and would relate to loss of lung function with time. Methods: We recruited 431 current smokers (median age, 39 yr; 16 pack-years smoked) and recorded symptoms using the COPD Assessment Test (CAT), spirometry, and quantitative thoracic computed tomography (QCT) scans at study entry. These scan results were compared with those from 67 never-smoking control subjects. Three hundred sixty-eight participants were followed every six months with measurement of postbronchodilator spirometry for a median of 32 months. The rate of FEV1 decline, adjusted for current smoking status, age, and sex, was related to the initial QCT appearances and symptoms, measured using the CAT. Measurements and Main Results: There were no material differences in demography or subjective CT appearances between the young smokers and control subjects, but 55.7% of the former had CAT scores greater than 10, and 24.2% reported chronic bronchitis. QCT assessments of disease probability-defined functional small airway disease, ground-glass opacification, bronchovascular prominence, and ratio of small blood vessel volume to total pulmonary vessel volume were increased compared with control subjects and were all associated with a faster FEV1 decline, as was a higher CAT score. Conclusions: Radiological abnormalities on CT are already established in young smokers with normal lung function and are associated with FEV1 loss independently of the impact of symptoms. Structural abnormalities are present early in the natural history of COPD and are markers of disease progression. Clinical trial registered with www.clinicaltrials.gov (NCT03480347).

Two Cases of Adrenal Malignancy With Macroscopic Fat.

The presence of macroscopic fat on computed tomography (CT) imaging has been traditionally regarded as an indication that an adrenal lesion is likely to be a benign myelolipoma, for which further investigation is not usually required. Two cases are described where an adrenal lesion was eventually found to be malignant on histology (adrenocortical carcinoma in the first case, undifferentiated sarcoma in the second case), despite the presence of macroscopic fat on CT. In both cases there were other clinical and radiological indicators of potential malignant pathology. These cases add to increasing awareness in the literature that malignant adrenal tumors may rarely contain macroscopic fat, emphasizing a need for clinical vigilance.

Correlation of ACR TI-RADS and Patient Outcomes in a Real-World Cohort Presenting for Thyroid Ultrasonography.

Context: The American College of Radiology Thyroid Image Reporting and Data System (ACR TI-RADS) was developed to predict malignancy risk in thyroid nodules using ultrasound features. TI-RADS was derived from a database of patients already selected for fine-needle aspiration (FNA), raising uncertainty about applicability to unselected patients. Objective: We aimed to assess the effect of ACR TI-RADS reporting in unselected patients presenting for thyroid ultrasound in a real-world setting. Methods: Records for all patients presenting for thyroid ultrasonography in Canterbury, New Zealand, were reviewed across two 18-month periods, prior to and after implementation of TI-RADS reporting. Patient outcomes were compared between the 2 periods. Malignancy rates were calculated for nodules 10 mm or larger with a definitive FNA or histology result. Results: A total of 1210 nodules were identified in 582 patients prior to implementation of TI-RADS; 1253 nodules were identified in 625 patients after implementation of TI-RADS. TI-RADS category was associated with malignancy rate (0% in TR1 and TR2, 3% in TR3, 5% in TR4, 12% in TR5; P = .02); however, 63% of nodules were graded TR3 or TR4, for which malignancy rate did not meaningfully differ from baseline risk. After implementation of TI-RADS there was a small reduction in the proportion of patients proceeding to FNA (49% vs 60%; P < .01) or surgery (14% vs 18%; P < .05), with no difference in cancer diagnoses (3% vs 4%, not significant). Conclusion: TI-RADS category is associated with malignancy rate and may alter clinical decision-making in a minority of patients; however, it is nondiscriminatory in the majority of nodules. In this study of unselected patients, nodules classified as TR5 and thus considered "highly suspicious" for cancer had only a modest risk of malignancy.

Multiomics links global surfactant dysregulation with airflow obstruction and emphysema in COPD.

Rationale: Pulmonary surfactant is vital for lung homeostasis as it reduces surface tension to prevent alveolar collapse and provides essential immune-regulatory and antipathogenic functions. Previous studies demonstrated dysregulation of some individual surfactant components in COPD. We investigated relationships between COPD disease measures and dysregulation of surfactant components to gain new insights into potential disease mechanisms. Methods: Bronchoalveolar lavage proteome and lipidome were characterised in ex-smoking mild/moderate COPD subjects (n=26) and healthy ex-smoking (n=20) and never-smoking (n=16) controls using mass spectrometry. Serum surfactant protein analysis was performed. Results: Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, surfactant protein (SP)-B, SP-A and SP-D concentrations were lower in COPD versus controls (log2 fold change (log2FC) -2.0, -2.2, -1.5, -0.5, -0.7 and -0.5 (adjusted p<0.02), respectively) and correlated with lung function. Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D, napsin A and CD44 inversely correlated with computed tomography small airways disease measures (expiratory to inspiratory mean lung density) (r= -0.56, r= -0.58, r= -0.45, r= -0.36, r= -0.44, r= -0.37, r= -0.40 and r= -0.39 (adjusted p<0.05)). Total phosphatidylcholine, phosphatidylglycerol, phosphatidylinositol, SP-A, SP-B, SP-D and NAPSA inversely correlated with emphysema (% low-attenuation areas): r= -0.55, r= -0.61, r= -0.48, r= -0.51, r= -0.41, r= -0.31 and r= -0.34, respectively (adjusted p<0.05). Neutrophil elastase, known to degrade SP-A and SP-D, was elevated in COPD versus controls (log2FC 0.40, adjusted p=0.0390), and inversely correlated with SP-A and SP-D. Serum SP-D was increased in COPD versus healthy ex-smoking volunteers, and predicted COPD status (area under the curve 0.85). Conclusions: Using a multiomics approach, we demonstrate, for the first time, global surfactant dysregulation in COPD that was associated with emphysema, giving new insights into potential mechanisms underlying the cause or consequence of disease.

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.

Antiviral Responses of Tissue-resident CD49a+ Lung Natural Killer Cells Are Dysregulated in Chronic Obstructive Pulmonary Disease.

Rationale: Tissue-resident natural killer (trNK) cells have been identified in numerous organs, but little is known about their functional contribution to respiratory immunity, in particular during chronic lung diseases such as chronic obstructive pulmonary disease (COPD). Objectives: To investigate the phenotype and antiviral responses of trNK cells in murine cigarette smoke-induced experimental COPD and in human lung parenchyma from COPD donors. Methods: Mice were exposed to cigarette smoke for 12 weeks to induce COPD-like lung disease. Lung trNK cell phenotypes and function were analyzed by flow cytometry in both murine and human disease with and without challenge with influenza A virus. Measurements and Main Results: In the mouse lung, CD49a+CD49b+EOMES+ and CD49a+CD49b-EOMESlo NK cell populations had a distinct phenotype compared with CD49a- circulating NK cells. CD49a+ NK cells were more extensively altered earlier in disease onset than circulating NK cells, and increased proportions of CD49a+ NK cells correlated with worsening disease in both murine and human COPD. Furthermore, the presence of lung disease delayed both circulating and trNK cell functional responses to influenza infection. CD49a+ NK cells markedly increased their NKG2D, CD103, and CD69 expression in experimental COPD after influenza infection, and human CD49a+ NK cells were hyperactive to ex vivo influenza infection in COPD donors. Conclusions: Collectively, these results demonstrate that trNK cell function is altered in cigarette smoke-induced disease and suggests that smoke exposure may aberrantly prime trNK cell responsiveness to viral infection. This may contribute to excess inflammation during viral exacerbations of COPD.

Synthetic Heparan Sulfate Mimetic Pixatimod (PG545) Potently Inhibits SARS-CoV-2 by Disrupting the Spike-ACE2 Interaction.

Heparan sulfate (HS) is a cell surface polysaccharide recently identified as a coreceptor with the ACE2 protein for the S1 spike protein on SARS-CoV-2 virus, providing a tractable new therapeutic target. Clinically used heparins demonstrate an inhibitory activity but have an anticoagulant activity and are supply-limited, necessitating alternative solutions. Here, we show that synthetic HS mimetic pixatimod (PG545), a cancer drug candidate, binds and destabilizes the SARS-CoV-2 spike protein receptor binding domain and directly inhibits its binding to ACE2, consistent with molecular modeling identification of multiple molecular contacts and overlapping pixatimod and ACE2 binding sites. Assays with multiple clinical isolates of SARS-CoV-2 virus show that pixatimod potently inhibits the infection of monkey Vero E6 cells and physiologically relevant human bronchial epithelial cells at safe therapeutic concentrations. Pixatimod also retained broad potency against variants of concern (VOC) including B.1.1.7 (Alpha), B.1.351 (Beta), B.1.617.2 (Delta), and B.1.1.529 (Omicron). Furthermore, in a K18-hACE2 mouse model, pixatimod significantly reduced SARS-CoV-2 viral titers in the upper respiratory tract and virus-induced weight loss. This demonstration of potent anti-SARS-CoV-2 activity tolerant to emerging mutations establishes proof-of-concept for targeting the HS-Spike protein-ACE2 axis with synthetic HS mimetics and provides a strong rationale for clinical investigation of pixatimod as a potential multimodal therapeutic for COVID-19.

Understanding the Needs and Priorities of People Living with Persistent Pain and Long-Term Musculoskeletal Conditions during the COVID-19 Pandemic-A Public Involvement Project.

BACKGROUND: Critiques of public involvement (PI) are associated with failing to be inclusive of under-represented groups, and this leads to research that fails to include a diversity of perspectives. AIM: The aim of this PI project was to understand the experiences and priorities of people from three seldom-heard groups whose musculoskeletal pain may have been exacerbated or treatment delayed due to COVID-19. Engaging representatives to report diverse experiences was important, given the goal of developing further research into personalised and integrated care and addressing population health concerns about access and self-management for people with musculoskeletal pain. METHODS: The project was approved via Sheffield Hallam University Ethics but was exempt from further HRA approval. A literature review was conducted, followed by informal individual and group discussions involving professionals and people with lived experience of (a) fibromyalgia pain, (b) those waiting for elective surgery and (c) experts associated with the care home sector. Findings from the literature review were combined with the insights from the public involvement. Resulting narratives were developed to highlight the challenges associated with persistent pain and informed the creation of consensus statements on the priorities for service improvement and future research. The consensus statements were shared and refined with input from an expert steering group. RESULTS: The narratives describe pain as a uniformly difficult experience to share with professionals; it is described as exhausting, frustrating and socially limiting. Pain leads to exclusion from routine daily activities and often resigns people to feeling and being unwell. In all cases, there are concerns about accessing and improving services and critical issues associated with optimising physical activity, functional wellbeing and managing polypharmacy. Exercise and/or mobilisation are important and commonly used self-management strategies, but opportunity and advice about safe methods are variable. Services should focus on personalised care, including self-management support and medication management, so that people's views and needs are heard and validated by health professionals. CONCLUSIONS: More research is needed to explore the most effective pain management strategies, and public involvement is important to shape the most relevant research questions. Health and care systems evaluation is also needed to address the scale of the population health need. The pandemic appears to have highlighted pre-existing shortcomings in holistic pain management.

Biomarkers to guide the use of antibiotics for acute exacerbations of COPD (AECOPD): a systematic review and meta-analysis.

BACKGROUND: Antibiotics are frequently prescribed for acute exacerbations of COPD (AECOPD) even though most do not have a bacterial aetiology. Biomarkers may help clinicians target antibiotic use by identifying AECOPD caused by bacterial pathogens. We aimed to summarise current evidence on the diagnostic accuracy of biomarkers for detecting bacterial versus non-bacterial AECOPD. METHODS: We searched Embase and Medline using a search strategy including terms for COPD, biomarkers and bacterial infection. Data regarding diagnostic accuracy for each biomarker in predicting bacterial cause of exacerbation were extracted and summarised. We used to QUADAS-2 tool to assess risk of bias. RESULTS: Of 509 papers identified, 39 papers evaluating 61 biomarkers were eligible for inclusion. Moderate quality evidence was found for associations between serum C-reactive protein (CRP), serum procalcitonin (PCT), sputum interleukin (IL)-8 and sputum tumour necrosis factor alpha (TNF-α), and the presence of bacterial pathogens in the sputum of patients with AECOPD. Having bacterial pathogens was associated with a mean difference (higher) CRP and PCT of 29.44 mg/L and 0.76 ng/mL respectively. There was inconsistent or weak evidence for associations between bacterial AECOPD and higher levels of sputum IL-1ß, IL-6, myeloperoxidase (MPO) and neutrophil elastase (NE). We did not find any consistent evidence of diagnostic value for other biomarkers. CONCLUSIONS: There is moderate evidence from heterogeneous studies that serum CRP and PCT are of value in differentiating bacterial from non-bacterial AECOPD, and little evidence for other biomarkers. Further high-quality research on the role of biomarkers in identifying bacterial exacerbations is needed.

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.

Clinician Perspectives on How to Hold Earlier Discussions About Palliative and End-of-Life Care With Chronic Obstructive Pulmonary Disease Patients: A Qualitative Study.

Chronic obstructive pulmonary disease is associated with progressive symptoms and increased treatment burden, especially at the end of life. However, most patients do not receive palliative care until late in their lives or discuss their end-of-life preferences with clinicians. This study explored clinicians' perspectives on the timing and nature of palliative care discussions. Qualitative interviews were conducted with 7 physicians and 7 nurses working in primary and secondary care settings. Data were analyzed using a thematic analysis. Participants advocated for early, gradual, and informed palliative and future care discussions, because these discussions were thought to be less traumatic and better accepted by patients. Despite this, patient- and clinician-related barriers severely affected clinicians' ability to start discussions at earlier stages. Participants felt many patients were not ready for these discussions and feared damaging hope if the subject was broached. Therefore, clinicians delayed discussions until patients approached the end of life. Stand-alone conversations about and near the end of life were described as current practice; however, clinicians believed these discussions reduced patients' hope and were potentially upsetting. Instead, individualized early, regular, and gradual discussions about immediate and long-term care plans were thought to be less negative and be better accepted.

Inflammation and physical dysfunction: responses to moderate intensity exercise in chronic kidney disease.

BACKGROUND: People with chronic kidney disease (CKD) experience skeletal muscle wasting, reduced levels of physical function and performance, and chronic systemic inflammation. While it is known that a relationship exists between inflammation and muscle wasting, the association between inflammation and physical function or performance in CKD has not been well studied. Exercise has anti-inflammatory effects, but little is known regarding the effect of moderate intensity exercise. This study aimed to (i) compare systemic and intramuscular inflammation between CKD stage G3b-5 and non-CKD controls; (ii) establish whether a relationship exists between physical performance, exercise capacity and inflammation in CKD; (iii) determine changes in systemic and intramuscular inflammation following 12 weeks of exercise; and (iv) investigate whether improving inflammatory status via training contributes to improvements in physical performance and muscle mass. METHODS: This is a secondary analysis of previously collected data. CKD patients stages G3b-5 (n = 84, n = 43 males) and non-CKD controls (n = 26, n = 17 males) underwent tests of physical performance, exercise capacity, muscle strength and muscle size. In addition, a subgroup of CKD participants underwent 12 weeks of exercise training, randomized to aerobic (AE, n = 21) or combined (CE, n = 20) training. Plasma and intramuscular inflammation and myostatin were measured at rest and following exercise. RESULTS: Tumour necrosis factor-α was negatively associated with lower $^{^{^{.}}}{\rm V}$O2Peak (P = 0.01), Rectus femoris-cross sectional area (P = 0.002) and incremental shuttle walk test performance (P < 0.001). Interleukin-6 was negatively associated with sit-to-stand 60 performances (P = 0.006) and hand grip strength (P = 0.001). Unaccustomed exercise created an intramuscular inflammatory response that was attenuated following 12 weeks of training. Exercise training did not reduce systemic inflammation, but AE training did significantly reduce mature myostatin levels (P = 0.02). Changes in inflammation were not associated with changes in physical performance. CONCLUSIONS: Systemic inflammation may contribute to reduced physical function in CKD. Twelve weeks of exercise training was unable to reduce the level of chronic systemic inflammation in these patients, but did reduce plasma myostatin concentrations. Further research is required to further investigate this.

Pulmonary EV miRNA profiles identify disease and distinct inflammatory endotypes in COPD.

Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous condition without effective disease modifying therapies. Identification of novel inflammatory endotype markers such as extracellular vesicles (EVs), which are important intercellular messengers carrying microRNA (miRNA), may enable earlier diagnosis and disease stratification for a targeted treatment approach. Our aim was to identify differentially expressed EV miRNA in the lungs of COPD patients compared with healthy ex-smokers and determine whether they can help define inflammatory COPD endotypes. Methods: EV miRNA were isolated and sequenced from ex-smoking COPD patients and healthy ex-smoker bronchoalveolar lavage fluid. Results were validated with RT-qPCR and compared to differential inflammatory cell counts. Results: Expression analysis identified five upregulated miRNA in COPD (miR-223-3p, miR-2110, miR-182-5p, miR-200b-5p and miR-625-3p) and three downregulated miRNA (miR-138-5p, miR-338-3p and miR-204-5p), all with a log2 fold change of >1/-1, FDR < 0.05. These miRNAs correlated with disease defining characteristics such as FEF 25-75% (a small airways disease measure) and DLCO% (a surrogate measure of emphysema). Receiver operator curve analysis demonstrated miR-2110, miR-223-3p, and miR-182-5p showed excellent combinatory predictive ability (AUC 0.91, p < 0.0001) in differentiating between health and mild COPD. Furthermore, miR-223-3p and miR-338-3p correlated with airway eosinophilia and were able to distinguish "pure eosinophilic" COPD from other airway inflammatory subtypes (AUC 0.94 and 0.85, respectively). Discussion: This is the first study to identify differentially expressed miRNA in COPD bronchoalveolar lavage fluid EVs. These findings suggest specific lung derived EV miRNA are a strong predictor of disease presence even in mild COPD. Furthermore, specific miRNA correlated with inflammatory cell numbers in COPD, and may have a role in defining inflammatory endotypes for future treatment stratification.

Evidence Around the Impact of Pulmonary Rehabilitation and Exercise on Redox Status in COPD: A Systematic Review.

Introduction: Oxidative stress is increasingly recognized as a significant factor in the pathogenesis of chronic obstructive pulmonary disease (COPD). Pulmonary rehabilitation, a major component of which is prescribed exercise, is essential in COPD care. Regular exercise has been proposed to increase antioxidant defenses and overall enhance the ability of the body to counteract oxidative stress. However, the mechanisms through which it improves COPD outcomes remain unclear. Objectives: We aimed to appraise the current evidence around the impact of pulmonary rehabilitation on redox status, compared with other exercise interventions, to gain an understanding of optimal exercise interventions to modify this pathophysiological mechanism. Methods: We performed a systematic review through searching CENTRAL, MEDLINE, PubMed, Scopus, and Web of Science. Results were independently reviewed and relevant studies were selected by two independent assessors. Studies were assessed by two independent people using the modified RoB 2 tool and discrepancies were resolved through discussion. Results: We identified 1,710 records and 1,117 records after duplicate removal. Six studies were included in the final analysis. The evidence available was low quality and four studies had high risk of bias and two studies had unclear risk of bias. Studies were small (15-56 participants); only two included details of randomization and patient cohorts were of varying ages and poorly described. Differences in smoking status and previous exercise levels, which are known to impact redox status, were not well documented. Studies were not standardized and used different exercise doses and measured different outcomes. One study reported lower malondialdehyde levels, a marker of lipid peroxidation, after pulmonary rehabilitation, compared with control. However, one study saw no difference following whole-body vibration training and another study showed higher malondialdehyde levels following supervised modified arm swing exercise compared with control. Conclusion: Understanding the impact of exercise on oxidative stress in COPD could lead to tailored exercise programs and modification of pathological mechanisms. However, we identify a lack of high-quality evidence to determine this. Larger, standardized, and high quality randomized controlled trials (RCTs) are essential, which use carefully clinically characterized and controlled cohorts to determine the relative impact of different exercise interventions on redox status to guide COPD management. We propose an idealized RCT design, which could be used to try and meet this need.

The Role of Extracellular Vesicles as a Shared Disease Mechanism Contributing to Multimorbidity in Patients With COPD.

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide. Individuals with COPD typically experience a progressive, debilitating decline in lung function as well as systemic manifestations of the disease. Multimorbidity, is common in COPD patients and increases the risk of hospitalisation and mortality. Central to the genesis of multimorbidity in COPD patients is a self-perpetuating, abnormal immune and inflammatory response driven by factors including ageing, pollutant inhalation (including smoking) and infection. As many patients with COPD have multiple concurrent chronic conditions, which require an integrative management approach, there is a need to greater understand the shared disease mechanisms contributing to multimorbidity. The intercellular transfer of extracellular vesicles (EVs) has recently been proposed as an important method of local and distal cell-to-cell communication mediating both homeostatic and pathological conditions. EVs have been identified in many biological fluids and provide a stable capsule for the transfer of cargo including proteins, lipids and nucleic acids. Of these cargo, microRNAs (miRNAs), which are short 17-24 nucleotide non-coding RNA molecules, have been amongst the most extensively studied. There is evidence to support that miRNA are selectively packaged into EVs and can regulate recipient cell gene expression including major pathways involved in inflammation, apoptosis and fibrosis. Furthermore changes in EV cargo including miRNA have been reported in many chronic diseases and in response to risk factors including respiratory infections, noxious stimuli and ageing. In this review, we discuss the potential of EVs and EV-associated miRNA to modulate shared pathological processes in chronic diseases. Further delineating these may lead to the identification of novel biomarkers and therapeutic targets for patients with COPD and multimorbidities.

The Clinical Implications of Aspergillus Fumigatus Sensitization in Difficult-To-Treat Asthma Patients.

BACKGROUND: Fungal sensitivity has been associated with severe asthma outcomes. However, the clinical implication of Aspergillus fumigatus sensitization in difficult-to-treat (or difficult) asthma is unclear. OBJECTIVES: To characterize the clinical implications of A fumigatus sensitization in a large difficult asthma cohort. METHODS: Participants who underwent both skin prick and specific IgE testing to A fumigatus (n = 318) from the longitudinal real-life Wessex AsThma CoHort of difficult asthma, United Kingdom, were characterized by A fumigatus sensitization (either positive skin prick test result or specific IgE) and allergic bronchopulmonary aspergillosis status using clinical/pathophysiological disease measures. RESULTS: A fumigatus sensitization was found in 23.9% (76 of 318) of patients with difficult asthma. Compared with A fumigatus nonsensitized subjects, those with sensitization were significantly more often male (50% vs 31%), older (58 years) with longer asthma duration (33 years), higher maintenance oral corticosteroid (39.7%) and asthma biologic use (27.6%), raised current/maximum log10 total IgE+1 (2.43/2.72 IU/L), worse prebronchodilator airflow obstruction (FEV1 62.2% predicted, FEV1/forced vital capacity 61.2%, forced expiratory flow between 25% and 75% exhalation 30.9% predicted), and frequent radiological bronchiectasis (40%), but had less psychophysiologic comorbidities. Allergic bronchopulmonary aspergillosis diagnosis was associated with higher treatment needs and stronger eosinophilic signals. Factors independently associated with A fumigatus sensitization in difficult asthma included maintenance oral corticosteroid use (odds ratio [OR], 3.34) and maximum log10 total IgE+1 (OR, 4.30), whereas for allergic bronchopulmonary aspergillosis included maintenance oral corticosteroid use (OR, 6.98), maximum log10 total IgE+1 (OR, 4.65), and radiological bronchiectasis (OR, 4.08). CONCLUSIONS: A fumigatus sensitization in difficult asthma identifies a more severe form of airways disease associated with greater morbidity, treatment need, and airways dysfunction/damage, but fewer psychophysiologic comorbidities. Screening of A fumigatus status should be an early element in the comprehensive assessment of patients with difficult asthma.

Dual RNASeq Reveals NTHi-Macrophage Transcriptomic Changes During Intracellular Persistence.

Nontypeable Haemophilus influenzae (NTHi) is a pathobiont which chronically colonises the airway of individuals with chronic respiratory disease and is associated with poor clinical outcomes. It is unclear how NTHi persists in the airway, however accumulating evidence suggests that NTHi can invade and persist within macrophages. To better understand the mechanisms of NTHi persistence within macrophages, we developed an in vitro model of NTHi intracellular persistence using human monocyte-derived macrophages (MDM). Dual RNA Sequencing was used to assess MDM and NTHi transcriptomic regulation occurring simultaneously during NTHi persistence. Analysis of the macrophage response to NTHi identified temporally regulated transcriptomic profiles, with a specific 'core' profile displaying conserved expression of genes across time points. Gene list enrichment analysis identified enrichment of immune responses in the core gene set, with KEGG pathway analysis revealing specific enrichment of intracellular immune response pathways. NTHi persistence was facilitated by modulation of bacterial metabolic, stress response and ribosome pathways. Levels of NTHi genes bioC, mepM and dps were differentially expressed by intracellular NTHi compared to planktonic NTHi, indicating that the transcriptomic adaption was distinct between the two different NTHi lifestyles. Overall, this study provides crucial insights into the transcriptomic adaptations facilitating NTHi persistence within macrophages. Targeting these reported pathways with novel therapeutics to reduce NTHi burden in the airway could be an effective treatment strategy given the current antimicrobial resistance crisis and lack of NTHi vaccines.

Dysregulation of COVID-19 related gene expression in the COPD lung.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of poor outcome from Coronavirus disease (COVID-19). Early data suggest elevated Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) receptor angiotensin converting enzyme 2 (ACE2) expression, but relationships to disease phenotype and downstream regulators of inflammation in the Renin-Angiotensin system (RAS) are unknown. We aimed to determine the relationship between RAS gene expression relevant to SARS-CoV-2 infection in the lung with disease characteristics in COPD, and the regulation of newly identified SARS-CoV-2 receptors and spike-cleaving proteases, important for SARS-CoV-2 infection. METHODS: We quantified gene expression using RNA sequencing of epithelial brushings and bronchial biopsies from 31 COPD and 37 control subjects. RESULTS: ACE2 gene expression (log2-fold change (FC)) was increased in COPD compared to ex-smoking (HV-ES) controls in epithelial brushings (0.25, p = 0.042) and bronchial biopsies (0.23, p = 0.050), and correlated with worse lung function (r = - 0.28, p = 0.0090). ACE2 was further increased in frequent exacerbators compared to infrequent exacerbators (0.51, p = 0.00045) and associated with use of ACE inhibitors (ACEi) (0.50, p = 0.0034), having cardiovascular disease (0.23, p = 0.048) or hypertension (0.34, p = 0.0089), and inhaled corticosteroid use in COPD subjects in bronchial biopsies (0.33, p = 0.049). Angiotensin II receptor type (AGTR)1 and 2 expression was decreased in COPD bronchial biopsies compared to HV-ES controls with log2FC of -0.26 (p = 0.033) and - 0.40, (p = 0.0010), respectively. However, the AGTR1:2 ratio was increased in COPD subjects compared with HV-ES controls, log2FC of 0.57 (p = 0.0051). Basigin, a newly identified potential SARS-CoV-2 receptor was also upregulated in both brushes, log2FC of 0.17 (p = 0.0040), and bronchial biopsies, (log2FC of 0.18 (p = 0.017), in COPD vs HV-ES. Transmembrane protease, serine (TMPRSS)2 was not differentially regulated between control and COPD. However, various other spike-cleaving proteases were, including TMPRSS4 and Cathepsin B, in both epithelial brushes (log2FC of 0.25 (p = 0.0012) and log2FC of 0.56 (p = 5.49E-06), respectively) and bronchial biopsies (log2FC of 0.49 (p = 0.00021) and log2FC of 0.246 (p = 0.028), respectively). CONCLUSION: This study identifies key differences in expression of genes related to susceptibility and aetiology of COVID-19 within the COPD lung. Further studies to understand the impact on clinical course of disease are now required.

Influence of Hypoxia on the Epithelial-Pathogen Interactions in the Lung: Implications for Respiratory Disease.

Under normal physiological conditions, the lung remains an oxygen rich environment. However, prominent regions of hypoxia are a common feature of infected and inflamed tissues and many chronic inflammatory respiratory diseases are associated with mucosal and systemic hypoxia. The airway epithelium represents a key interface with the external environment and is the first line of defense against potentially harmful agents including respiratory pathogens. The protective arsenal of the airway epithelium is provided in the form of physical barriers, and the production of an array of antimicrobial host defense molecules, proinflammatory cytokines and chemokines, in response to activation by receptors. Dysregulation of the airway epithelial innate immune response is associated with a compromised immunity and chronic inflammation of the lung. An increasing body of evidence indicates a distinct role for hypoxia in the dysfunction of the airway epithelium and in the responses of both innate immunity and of respiratory pathogens. Here we review the current evidence around the role of tissue hypoxia in modulating the host-pathogen interaction at the airway epithelium. Furthermore, we highlight the work needed to delineate the role of tissue hypoxia in the pathophysiology of chronic inflammatory lung diseases such as asthma, cystic fibrosis, and chronic obstructive pulmonary disease in addition to novel respiratory diseases such as COVID-19. Elucidating the molecular mechanisms underlying the epithelial-pathogen interactions in the setting of hypoxia will enable better understanding of persistent infections and complex disease processes in chronic inflammatory lung diseases and may aid the identification of novel therapeutic targets and strategies.