Biomarkers of tissue remodelling are elevated in serum of COVID-19 patients who develop interstitial lung disease - an exploratory biomarker study.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is a viral pneumonia that can result in serious respiratory illness. It is associated with extensive systemic inflammation, changes to the lung extracellular matrix, and long-term lung impairment such as interstitial lung disease (ILD). In this study, the aim was to investigate whether tissue remodelling, wound healing, and neutrophil activity is altered in patients with COVID-19 and how these relate to the development of post-COVID ILD. METHOD: Serum samples were collected from 63 patients three months after discharge as part of the Research Evaluation Alongside Clinical Treatment study in COVID-19 (REACT COVID-19), 10 of whom developed ILD, and 16 healthy controls. Samples were quantified using neo-epitope specific biomarkers reflecting tissue stiffness and formation (PC3X, PRO-C3, and PRO-C6), tissue degradation (C1M, C3M, and C6M), wound healing (PRO-FIB and X-FIB), and neutrophil activity (CPa9-HNE and ELP-3). RESULTS: Mean serum levels of PC3X (p < 0.0001), PRO-C3 (p = 0.002), C3M (p = 0.009), PRO-FIB (p < 0.0001), CPa9-HNE (p < 0.0001), and ELP-3 (p < 0.0001) were significantly elevated in patients with COVID-19 compared to healthy controls. Moreover, PC3X (p = 0.023) and PRO-C3 (p = 0.032) were significantly elevated in post-COVID ILD as compared to COVID-19. CONCLUSION: Serological biomarkers reflecting type III collagen remodelling, clot formation, and neutrophil activity were significantly elevated in COVID-19 and type III collagen formation markers were further elevated in post-COVID ILD. The findings suggest an increased type III collagen remodelling in COVID-19 and warrants further investigations to assess the potential of tissue remodelling biomarkers as a tool to identify COVID-19 patients at high risk of developing ILD.

Public health management of pertussis in adults: Practical challenges and future strategies.

A panel of 24 international experts met in July 2022 to discuss challenges associated with pertussis detection, monitoring, and vaccination in adults; conclusions from this meeting are presented. There has been a shift in the epidemiology of pertussis toward older children and adults. This shift has been attributed to the waning of infection- or vaccine-induced immunity, newer detection techniques causing detection bias, and possibly the replacement of whole-cell pertussis with acellular vaccines in high-income countries, which may lead to immunity waning more quickly. The burden of adult pertussis is still likely under-ascertained due to widespread under-recognition by healthcare professionals (HCPs), under-diagnosis, and under-reporting in this age group. Non-standardized testing guidance and varied case definitions have contributed to under-reporting. Key barriers to HCP engagement with the tetanus, diphtheria, and pertussis (Tdap) vaccine include low awareness, lack of time/funding, and lack of motivation due to low prioritization of Tdap.

Cytokine biomarkers of exacerbations in sputum from Chronic Obstructive Pulmonary Disease patients: a prospective cohort study.

BACKGROUND: We determined the relationships between cytokine expression in sputum and clinical data to characterise and understand Chronic Obstructive Pulmonary Disease (COPD) exacerbations in COPD patients. METHODS: We measured 30 cytokines in 936 sputum samples, collected at stable state (ST) and exacerbation (EX) visits from 99 participants in the Acute Exacerbation and Respiratory InfectionS in COPD (AERIS) study (NCT01360398, www.clinicaltrials.gov). We determined their longitudinal expression and examined differential expression based on disease status or exacerbation type. RESULTS: Of the cytokines, 17 were suitable for analysis. As for disease states, in EX sputum samples, IL-17A, TNF-α, IL-1ß, and IL-10 were significantly increased compared to ST sputum samples, but a logistic mixed model could not predict disease state. As for exacerbation types, bacteria-associated exacerbations showed higher expression of IL-17A, TNF-α, IL-1ß, and IL-1α. IL-1α, IL-1ß, and TNF-α were identified as suitable biomarkers for bacteria-associated exacerbation. Bacteria-associated exacerbations also formed a cluster separate from other exacerbation types in principal component analysis. CONCLUSIONS: Measurement of cytokines in sputum from COPD patients could help identify bacteria-associated exacerbations based on increased concentrations of IL-1α, IL-1ß, or TNF-α. This finding may provide a point-of-care assessment to distinguish a bacterial exacerbation of COPD from other exacerbation types.

Smaller biceps femoris aponeurosis size in legs with a history of hamstring strain injury.

Biceps femoris long head (BFLH) aponeurosis size was compared between legs with and without prior hamstring strain injury (HSI) using within-group (injured vs. uninjured legs of previous unilateral HSI athletes) and between-group (previously injured legs of HSI athletes vs. legs of No prior HSI athletes) approaches. Currently healthy competitive male athletes with Prior HSI history (n=23; ≥1 verified BFLH injury; including a sub-group with unilateral HSI history; most recent HSI 1.6 ± 1.2 years ago) and pair-matched athletes with No prior HSI history (n=23) were MRI scanned. Anonymised axial images were manually segmented to quantify BFLH aponeurosis and muscle size. Prior unilateral HSI athletes' BFLH aponeurosis maximum width, aponeurosis area, and aponeurosis:muscle area ratio was 14.0-19.6% smaller in previously injured vs. contralateral uninjured legs (paired t-test, 0.008≤p≤0.044). BFLH aponeurosis maximum width and area were also 9.4-16.5% smaller in previously injured legs (n=28) from prior HSI athletes vs. legs (n=46) of No prior HSI athletes (unpaired t-test, 0.001≤p≤0.044). BFLH aponeurosis size was smaller in legs with Prior HSI vs. those without prior HSI. These findings suggest BFLH aponeurosis size, especially maximum width, could be a potential cause or consequence of HSI, with prospective evidence needed to support or refute these possibilities.

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.

Correction: Proteomic profiling of cereal aphid saliva reveals both ubiquitous and adaptive secreted proteins.

[This corrects the article DOI: 10.1371/journal.pone.0057413.].

Understanding the impact of adult pertussis and current approaches to vaccination: A narrative review and expert panel recommendations.

Pertussis has several notable consequences, causing economic burden, increased strain on healthcare facilities, and reductions in quality of life. Recent years have seen a trend toward an increase in pertussis cases affecting older children and adults. To boost immunity, and protect vulnerable populations, an enduring approach to vaccination has been proposed, but gaps remain in the evidence surrounding adult vaccination that are needed to inform such a policy. Gaps include: the true incidence of pertussis and its complications in adults; regional variations in disease recognition and reporting; and incidence of severe disease, hospitalizations, and deaths in older adults. Better data on the efficacy/effectiveness of pertussis vaccination in adults, duration of protection, and factors leading to poor vaccine uptake are needed. Addressing the critical evidence gaps will help highlight important areas of unmet need and justify the importance of adult pertussis vaccination to healthcare professionals, policymakers, and payers.

Study protocol for a randomised open-label clinical trial examining the safety and efficacy of the Android Artificial Pancreas System (AAPS) with advanced bolus-free features in adults with type 1 diabetes: the 'CLOSE IT' (Closed Loop Open SourcE In Type 1 diabetes) trial.

INTRODUCTION: Multiple automated insulin delivery (AID) systems have become commercially available following randomised controlled trials demonstrating benefits in people with type 1 diabetes (T1D). However, their real-world utility may be undermined by user-associated burdens, including the need to carbohydrate count and deliver manual insulin boluses. There is an important need for a 'fully automated closed loop' (FCL) AID system, without manual mealtime boluses. The (Closed Loop Open SourcE In Type 1 diabetes) trial is a randomised trial comparing an FCL AID system to the same system used as a hybrid closed loop (HCL) in people with T1D, in an outpatient setting over an extended time frame. METHODS AND ANALYSIS: Randomised, open-label, parallel, non-inferiority trial comparing the Android Artificial Pancreas System (AAPS) AID algorithm used as FCL to the same algorithm used as HCL. Seventy-five participants aged 18-70 will be randomised (1:1) to one of two treatment arms for 12 weeks: (a) FCL-participants will be advised not to bolus for meals and (b) HCL-participants will use the AAPS AID algorithm as HCL with announced meals. The primary outcome is the percentage of time in target sensor glucose range (3.9-10.0 mmol/L). Secondary outcomes include other glycaemic metrics, safety, psychosocial factors, platform performance and user dietary factors. Twenty FCL arm participants will participate in a 4-week extension phase comparing glycaemic and dietary outcomes using NovoRapid (insulin aspart) to Fiasp (insulin aspart and niacinamide). ETHICS AND DISSEMINATION: Approvals are by the Alfred Health Ethics Committee (615/22) (Australia) and Health and Disability Ethics Committees (2022 FULL 13832) (New Zealand). Each participant will provide written informed consent. Data protection and confidentiality will be ensured. Study results will be disseminated by publications, conferences and patient advocacy groups. TRIAL REGISTRATION NUMBERS: ACTRN12622001400752 and ACTRN12622001401741.

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).

The utility of rested prolactin sampling in the evaluation of hyperprolactinaemia.

BACKGROUND AND AIMS: Serum prolactin levels may be elevated by venepuncture stress. We investigated the utility of a rested prolactin sample, obtained through an indwelling venous cannula, in preventing the overdiagnosis of hyperprolactinaemia. METHODS: Patients at our institution undergo serial prolactin sampling, usually over 40 min, when investigating hyperprolactinaemia. We retrospectively reviewed all serial prolactin sampling performed during a 3-year period. Patients with possible medication-induced hyperprolactinaemia and macroprolactin interference were excluded. We assessed the effect of venepuncture-associated stress on hyperprolactinaemia with the main outcome being normalisation of serum prolactin at the end of serial sampling. RESULTS: Ninety-three patients with documented hyperprolactinaemia (range 360-1690 mU/L) were included in the analysis. Prolactin decreased during serial sampling in 73 patients (78%), suggesting a prevalent effect of venepuncture stress. The final prolactin sample was normal in 50 patients (54%), consistent with stress hyperprolactinaemia rather than pathological hyperprolactinaemia. Patients with a referral prolactin result greater than two times the upper reference limit (URL) were less likely (15%) to have a normal prolactin result on serial sampling. Measurement of a single rested prolactin sample from an indwelling cannula showed the same diagnostic utility as serial sampling. CONCLUSION: Serum prolactin results are frequently elevated by the stress of venepuncture. Confirmation of pathological hyperprolactinaemia in a rested sample obtained from an indwelling venous cannula is recommended in patients with mild hyperprolactinaemia, particularly when the referral prolactin is less than two times the URL.

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.

A randomised phase 2a study to investigate the effects of blocking interleukin-33 with tozorakimab in patients hospitalised with COVID-19: ACCORD-2.

Background: Increased serum interleukin (IL)-33 predicts poor outcomes in patients hospitalised with coronavirus disease 2019 (COVID-19). We examined the efficacy and safety of tozorakimab, a monoclonal antibody that neutralises IL-33, in improving outcomes in ACCORD-2 (EudraCT: 2020-001736-95). Methods: ACCORD-2 was an open-label, phase 2a study in adults hospitalised with COVID-19. Patients were randomised 1:1 to tozorakimab 300 mg plus standard of care (SoC) or SoC alone. The primary end-point was time to clinical response (sustained clinical improvement of ≥2 points on the World Health Organization ordinal scale, discharge from hospital or fit for discharge) by day 29. Other end-points included death or respiratory failure, mortality and intensive care unit admission by day 29, and safety. Serum IL-33/soluble stimulated-2 (sST2) complex levels were measured by high-sensitivity immunoassay. Results: Efficacy analyses included 97 patients (tozorakimab+SoC, n=53; SoC, n=44). Median time to clinical response did not differ between the tozorakimab and SoC arms (8.0 and 9.5 days, respectively; HR 0.96, 80% CI 0.70-1.31; one-sided p=0.33). Tozorakimab was well tolerated and the OR for risk of death or respiratory failure with treatment versus SoC was 0.55 (80% CI 0.27-1.12; p=0.26), while the OR was 0.31 (80% CI 0.09-1.06) in patents with high baseline serum IL-33/sST2 complex levels. Conclusions: Overall, ACCORD-2 results suggest that tozorakimab could be a novel therapy for patients hospitalised with COVID-19, warranting further investigation in confirmatory phase 3 studies.

Estimating the Health and Economic Impact of Improved Management in Prevalent Chronic Obstructive Pulmonary Disease Populations in England, Germany, Canada, and Japan: A Modelling Study.

Introduction: COPD is a leading cause of morbidity and mortality globally. Management is complex and costly. Although international quality standards for diagnosis and management exist, opportunities remain to improve outcomes, especially in reducing avoidable hospitalisations. Objective: To estimate the potential health and economic impact of improved adherence to guideline-recommended care for prevalent, on-treatment COPD populations in four high-income settings. Methods: A disease simulation model was developed to evaluate the impact of theoretical improvements to COPD management, comparing outcomes for usual care and policy scenarios for interventions that reduce avoidable hospitalisations: 1) increased attendance (50% vs 31-38%) of early follow-up review after severe exacerbation hospitalisation; 2) increased access (30% vs 5-10%) to an integrated disease management (IDM) programme that provides guideline adherent care. Results: For cohorts of 100,000 patients, Policy 1 yielded additional life years (England: 523; Germany: 759; Canada: 1316; Japan: 512) and lifetime cost savings (-£2.89 million; -€6.58 million; -$40.08 million; -¥735.58 million). For Policy 2, additional life years (2299; 3619; 3656) and higher lifetime total costs (£38.15 million; €35.58 million; ¥1091.53 million) were estimated in England, Germany and Japan, and additional life years (4299) and cost savings (-$20.52 million) in Canada. Scenarios found that the cost impact depended on the modelled intervention effect size. Conclusion: Interventions that reduce avoidable hospitalisations are estimated to improve survival and may generate cost savings. This study provides evidence on the theoretical impact of policies to improve COPD care and highlights priority areas for further research to support evidence-based policy decisions.

Treating acute exacerbations of COPD with Chinese herbal medicine to aid antibiotic use reduction (Excalibur): a randomised double-blind, placebo-controlled feasibility trial.

Background: Although many acute exacerbations of COPD (AECOPD) are triggered by non-bacterial causes, they are often treated with antibiotics. Preliminary research suggests that the Chinese herbal medicine "Shufeng Jiedu" (SFJD), may improve recovery and therefore reduce antibiotic use in patients with AECOPD. Aims: To assess the feasibility of conducting a randomised placebo-controlled clinical trial of SFJD for AECOPD in UK primary care. Methods: GPs opportunistically recruited patients experiencing an AECOPD. Participants were randomised 1:1 to usual care plus SFJD or placebo for 14 days. Participants, GPs and research nurses were blinded to treatment allocation. GPs could prescribe immediate, delayed or no antibiotics, with delayed prescribing encouraged where appropriate. Participants were asked to complete a participant diary, including EXACT-PRO and CAT™ questionnaires for up to 4 weeks. Outcomes included recruitment rate and other measures of study feasibility described using only descriptive statistics and with no formal comparisons between groups. We also conducted qualitative interviews with recruited and non-recruited COPD patients and clinicians, analysed using framework analysis. Results: Over 6 months, 19 participants (6 SFJD, 13 placebo) were recruited. Sixteen (84%) participants returned diaries or provided a diary by recall. Overall, 1.3 participants were recruited per 1,000 patients on the COPD register per month open. Median duration of treatment was 9.8 days in the intervention group vs 13.3 days in the placebo group. The main reason for discontinuation in both groups was perceived side-effects. in both groups. Point estimates for both the EXACT-PRO and CAT™ outcomes suggested possible small benefits of SFJD. Most patients and clinicians were happy to try SFJD as an alternative to antibiotics for AECOPD. Recruitment was lower than expected because of the short recruitment period, the lower incidence of AECOPD during the COVID-19 pandemic, patients starting antibiotics from "rescue packs" before seeing their GP, and workforce challenges in primary care. Conclusion: Recruitment was impaired by the COVID-19 pandemic. Nevertheless, we were able to demonstrate the feasibility of recruiting and randomising participants and identified approaches to address recruitment challenges such as including the trial medication in COPD patients' "rescue packs" and delegating recruitment to a central trials team. Clinical Trial Registration: Identifier, ISRCTN26614726.

Analysis of "Hybrid Closed Loop Using a Do-It-Yourself Artificial Pancreas System in Adults With Type 1 Diabetes".

In an article in Journal of Diabetes Science and Technology, Nanayakkara and colleagues assessed the glycemic efficacy and safety of AndroidAPS, an open-source automated delivery (AID) system, in a crossover randomized controlled trial. Although the trial included only 20 participants during a relatively short 4-week intervention period, glycemic outcomes attained were similar to commercial AID systems and there were no safety concerns. Validation of open-source AID systems in studies such as this should help address clinician hesitancy regarding these systems, and affirms the role of patient-centered innovation and self-management in diabetes care.

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.

Pulmonary Surfactant in Adult ARDS: Current Perspectives and Future Directions.

Acute respiratory distress syndrome (ARDS) is a major cause of hypoxemic respiratory failure in adults, leading to the requirement for mechanical ventilation and poorer outcomes. Dysregulated surfactant metabolism and function are characteristic of ARDS. A combination of alveolar epithelial damage leading to altered surfactant synthesis, secretion, and breakdown with increased functional inhibition from overt alveolar inflammation contributes to the clinical features of poor alveolar compliance and alveolar collapse. Quantitative and qualitative alterations in the bronchoalveolar lavage and tracheal aspirate surfactant composition contribute to ARDS pathogenesis. Compared to neonatal respiratory distress syndrome (nRDS), replacement studies of exogenous surfactants in adult ARDS suggest no survival benefit. However, these studies are limited by disease heterogeneity, variations in surfactant preparations, doses, and delivery methods. More importantly, the lack of mechanistic understanding of the exact reasons for dysregulated surfactant remains a significant issue. Moreover, studies suggest an extremely short half-life of replaced surfactant, implying increased catabolism. Refining surfactant preparations and delivery methods with additional co-interventions to counteract surfactant inhibition and degradation has the potential to enhance the biophysical characteristics of surfactant in vivo.

Burden of respiratory syncytial virus in adults in the United Kingdom: A systematic literature review and gap analysis.

Despite the growing recognition of a potentially significant respiratory syncytial virus (RSV) disease burden in adults, relevant evidence in the United Kingdom (UK) is limited. This systematic literature review (SLR) aimed to identify the disease burden of RSV in UK adults, including certain high-risk subgroups and existing evidence gaps. Published studies (2011 onwards) reporting epidemiological, economic and clinical burden outcomes in UK adults (≥15 years) with RSV were identified from indexed databases, including MEDLINE, Embase and the Cochrane library. High-risk groups included elderly (≥65 years), immunocompromised, co-morbid and co-infected patients. Outcomes included RSV incidence/prevalence, mortality, clinical presentation and direct/indirect resource use/costs. Twenty-eight publications on 28 unique studies were identified, mostly in general/respiratory indicator (n = 17), elderly (n = 10) and immunocompromised (n = 6) cohorts. Main outcomes reported in the general/respiratory indicator cohort were RSV infection incidence (seasonal/annual: 0.09-17.9%/6.6-15.1%), mortality (8,482 deaths/season) and direct resource use (including mean general practitioner [GP] episodes/season: 487,247). Seasonal/annual incidence was 14.6-26.5%/0.7-16% in high-risk cohorts. Attributed to RSV in the elderly were 7,915 deaths/season and 175,070 mean GP episodes/season. Only two studies reported on co-morbid cohorts. Clinical burden outcomes were only reported in general and immunocompromised patients, and no evidence was found in any cohort on indirect economic burden or RSV complications. Evidence captured suggests that RSV may have a substantial burden in UK adults. However, available data were limited and highly heterogenous, with further studies needed to characterise the burden of RSV in adults and to validate our findings.

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.

Airway dysbiosis accelerates lung function decline in chronic obstructive pulmonary disease.

Progressive lung function decline is a hallmark of chronic obstructive pulmonary disease (COPD). Airway dysbiosis occurs in COPD, but whether it contributes to disease progression remains unknown. Here, we show, through a longitudinal analysis of two cohorts involving four UK centers, that baseline airway dysbiosis in COPD patients, characterized by the enrichment of opportunistic pathogenic taxa, associates with a rapid forced expiratory volume in 1 s (FEV1) decline over 2 years. Dysbiosis associates with exacerbation-related FEV1 fall and sudden FEV1 fall at stability, contributing to long-term FEV1 decline. A third cohort in China further validates the microbiota-FEV1-decline association. Human multi-omics and murine studies show that airway Staphylococcus aureus colonization promotes lung function decline through homocysteine, which elicits a neutrophil apoptosis-to-NETosis shift via the AKT1-S100A8/A9 axis. S. aureus depletion via bacteriophages restores lung function in emphysema mice, providing a fresh approach to slow COPD progression by targeting the airway microbiome.