Factors associated with non-fatal heart failure and atrial fibrillation or flutter within the first 30 days post COPD exacerbation: a nested case-control study.

BACKGROUND: An immediate, temporal risk of heart failure and arrhythmias after a Chronic Obstructive Pulmonary Disease (COPD) exacerbation has been demonstrated, particularly in the first month post-exacerbation. However, the clinical profile of patients who develop heart failure (HF) or atrial fibrillation/flutter (AF) following exacerbation is unclear. Therefore we examined factors associated with people being hospitalized for HF or AF, respectively, following a COPD exacerbation. METHODS: We conducted two nested case-control studies, using primary care electronic healthcare records from the Clinical Practice Research Datalink Aurum linked to Hospital Episode Statistics, Office for National Statistics for mortality, and socioeconomic data (2014-2020). Cases had hospitalization for HF or AF within 30 days of a COPD exacerbation, with controls matched by GP practice (HF 2:1;AF 3:1). We used conditional logistic regression to explore demographic and clinical factors associated with HF and AF hospitalization. RESULTS: Odds of HF hospitalization (1,569 cases, 3,138 controls) increased with age, type II diabetes, obesity, HF and arrhythmia history, exacerbation severity (hospitalization), most cardiovascular medications, GOLD airflow obstruction, MRC dyspnea score, and chronic kidney disease. Strongest associations were for severe exacerbations (adjusted odds ratio (aOR)=6.25, 95%CI 5.10-7.66), prior HF (aOR=2.57, 95%CI 1.73-3.83), age≥80 years (aOR=2.41, 95%CI 1.88-3.09), and prior diuretics prescription (aOR=2.81, 95%CI 2.29-3.45). Odds of AF hospitalization (841 cases, 2,523 controls) increased with age, male sex, severe exacerbation, arrhythmia and pulmonary hypertension history and most cardiovascular medications. Strongest associations were for severe exacerbations (aOR=5.78, 95%CI 4.45-7.50), age≥80 years (aOR=3.15, 95%CI 2.26-4.40), arrhythmia (aOR=3.55, 95%CI 2.53-4.98), pulmonary hypertension (aOR=3.05, 95%CI 1.21-7.68), and prescription of anticoagulants (aOR=3.81, 95%CI 2.57-5.64), positive inotropes (aOR=2.29, 95%CI 1.41-3.74) and anti-arrhythmic drugs (aOR=2.14, 95%CI 1.10-4.15). CONCLUSIONS: Cardiopulmonary factors were associated with hospitalization for HF in the 30 days following a COPD exacerbation, while only cardiovascular-related factors and exacerbation severity were associated with AF hospitalization. Understanding factors will help target people for prevention.

Accuracy of the recording of pneumonia events in English electronic healthcare record data in patients with chronic obstructive pulmonary disease.

BACKGROUND: In primary care, identifying pneumonia events in people with chronic obstructive pulmonary disease (COPD) may be challenging due to similarities in symptoms with COPD exacerbations and lack of diagnostic testing. This study explored the accuracy of pneumonia diagnosis coded in primary care by comparing diagnosis in primary care with diagnosis in hospital. METHODS: A study population of people with COPD in England was created using the Clinical Practice Research Datalink Aurum database linked with Hospital Episode Statistics inpatient data. Pneumonia codes only, and pneumonia code with associated clinical and/or treatment codes (chest x-ray, symptoms, antibiotics, sputum and blood culture) were used to determine pneumonia events in primary care. Events that were followed by hospitalisation within 7 days were used to estimate the positive predictive value (PPV) of pneumonia coding in primary care, using primary diagnosis of pneumonia in secondary care as the gold standard. The PPV of primary care recording of hospitalised pneumonia was also calculated. RESULTS: Two hundred seventy-four thousand one hundred fifty-six COPD patients were eligible for inclusion, of whom 7,560 had an eligible pneumonia event in primary care diagnosed between 2015-2019 which was not 'hospital-acquired' and was diagnosed and entered on the same day. Of the 2,094 events which were followed by hospitalisation within 7 days, 1,208 had a primary diagnosis of pneumonia in hospital, representing a PPV of pneumonia coding in primary care of 57.7% (95% CI 55.6%-59.8%). Another 284 (13.6%) were diagnosed as a COPD exacerbation and 114 (5.4%) were diagnosed as another respiratory disease. Use of additional pneumonia clinical and treatment codes had a modest effect on the PPV but substantially lowered the number of events. Of the 33,603 eligible pneumonia events identified in secondary care, only 11,445 were recorded in primary care within 42 days, representing a sensitivity of 34.1% (95% CI 33.6%-34.6%). CONCLUSIONS: Use of primary care pneumonia codes and associated clinical and treatment codes to determine pneumonia is not recommended due to significant levels of misdiagnosis and many hospitalised events failing to be recorded in primary care.

Prevalence and risk factors for long COVID among adults in Scotland using electronic health records: a national, retrospective, observational cohort study.

Background: Long COVID is a debilitating multisystem condition. The objective of this study was to estimate the prevalence of long COVID in the adult population of Scotland, and to identify risk factors associated with its development. Methods: In this national, retrospective, observational cohort study, we analysed electronic health records (EHRs) for all adults (≥18 years) registered with a general medical practice and resident in Scotland between March 1, 2020, and October 26, 2022 (98-99% of the population). We linked data from primary care, secondary care, laboratory testing and prescribing. Four outcome measures were used to identify long COVID: clinical codes, free text in primary care records, free text on sick notes, and a novel operational definition. The operational definition was developed using Poisson regression to identify clinical encounters indicative of long COVID from a sample of negative and positive COVID-19 cases matched on time-varying propensity to test positive for SARS-CoV-2. Possible risk factors for long COVID were identified by stratifying descriptive statistics by long COVID status. Findings: Of 4,676,390 participants, 81,219 (1.7%) were identified as having long COVID. Clinical codes identified the fewest cases (n = 1,092, 0.02%), followed by free text (n = 8,368, 0.2%), sick notes (n = 14,469, 0.3%), and the operational definition (n = 64,193, 1.4%). There was limited overlap in cases identified by the measures; however, temporal trends and patient characteristics were consistent across measures. Compared with the general population, a higher proportion of people with long COVID were female (65.1% versus 50.4%), aged 38-67 (63.7% versus 48.9%), overweight or obese (45.7% versus 29.4%), had one or more comorbidities (52.7% versus 36.0%), were immunosuppressed (6.9% versus 3.2%), shielding (7.9% versus 3.4%), or hospitalised within 28 days of testing positive (8.8% versus 3.3%%), and had tested positive before Omicron became the dominant variant (44.9% versus 35.9%). The operational definition identified long COVID cases with combinations of clinical encounters (from four symptoms, six investigation types, and seven management strategies) recorded in EHRs within 4-26 weeks of a positive SARS-CoV-2 test. These combinations were significantly (p < 0.0001) more prevalent in positive COVID-19 patients than in matched negative controls. In a case-crossover analysis, 16.4% of those identified by the operational definition had similar healthcare patterns recorded before testing positive. Interpretation: The prevalence of long COVID presenting in general practice was estimated to be 0.02-1.7%, depending on the measure used. Due to challenges in diagnosing long COVID and inconsistent recording of information in EHRs, the true prevalence of long COVID is likely to be higher. The operational definition provided a novel approach but relied on a restricted set of symptoms and may misclassify individuals with pre-existing health conditions. Further research is needed to refine and validate this approach. Funding: Chief Scientist Office (Scotland), Medical Research Council, and BREATHE.

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

A Harmonised Approach to Curating Research-Ready Datasets for Asthma, Chronic Obstructive Pulmonary Disease (COPD) and Interstitial Lung Disease (ILD) in England, Wales and Scotland Using Clinical Practice Research Datalink (CPRD), Secure Anonymised Information Linkage (SAIL) Databank and DataLoch.

Background: Electronic healthcare records (EHRs) are an important resource for health research that can be used to improve patient outcomes in chronic respiratory diseases. However, consistent approaches in the analysis of these datasets are needed for coherent messaging, and when undertaking comparative studies across different populations. Methods and Results: We developed a harmonised curation approach to generate comparable patient cohorts for asthma, chronic obstructive pulmonary disease (COPD) and interstitial lung disease (ILD) using datasets from within Clinical Practice Research Datalink (CPRD; for England), Secure Anonymised Information Linkage (SAIL; for Wales) and DataLoch (for Scotland) by defining commonly derived variables consistently between the datasets. By working in parallel on the curation methodology used for CPRD, SAIL and DataLoch for asthma, COPD and ILD, we were able to highlight key differences in coding and recording between the databases and identify solutions to enable valid comparisons. Conclusion: Codelists and metadata generated have been made available to help re-create the asthma, COPD and ILD cohorts in CPRD, SAIL and DataLoch for different time periods, and provide a starting point for the curation of respiratory datasets in other EHR databases, expediting further comparable respiratory research.

Modifiable risk factors that may be addressed in routine care to prevent progression to and extension of multimorbidity in people with COPD: a systematic literature review.

Chronic obstructive pulmonary disease (COPD) is a multisystem disease, and many patients have multiple conditions. We explored multimorbidity patterns that might inform intervention planning to reduce health-care costs while preserving quality of life for patients. Literature searches up to February 2022 revealed 4419 clinical observational and comparative studies of risk factors for multimorbidity in people with COPD, pulmonary emphysema, or chronic bronchitis at baseline. Of these, 29 met the inclusion criteria for this review. Eight studies were cluster and network analyses, five were regression analyses, and 17 (in 16 papers) were other studies of specific conditions, physical activity and treatment. People with COPD more frequently had multimorbidity and had up to ten times the number of disorders of those without COPD. Disease combinations prominently featured cardiovascular and metabolic diseases, asthma, musculoskeletal and psychiatric disorders. An important risk factor for multimorbidity was low socioeconomic status. One study showed that many patients were receiving multiple drugs and had increased risk of adverse events, and that 10% of medications prescribed were inappropriate. Many patients with COPD have mainly preventable or modifiable multimorbidity. A proactive multidisciplinary approach to prevention and management could reduce the burden of care.

Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in England from 2008 to 2018: a cohort study.

BACKGROUND: Owing to discrepancies in methodologies and how idiopathic pulmonary fibrosis (IPF) is diagnosed it is challenging to establish a consistent understanding of the disease burden In the UK, over 10 years ago, the incidence and prevalence of IPF were reported as 2.8-8.7 per 100 000 person-years (from 2000 to 2012) and 39 per 100 000 persons (in 2012), respectively. Here, we estimated the incidence and prevalence of IPF in England from 2008 to 2018 and investigated IPF mortality. METHODS: Using Clinical Practice Research Datalink Aurum and Hospital Episode Statistics (HES) linked datasets, we estimated incidence and prevalence using four validated diagnostic-code-based algorithms. Using the registered number of deaths (from Office of National Statistics) with the underlying cause being recorded as IPF, we estimated IPF mortality for the same period. RESULTS: Using Aurum-based definitions, incidence increased over time by 100% for Aurum narrow (3-6.1 per 100 000 person-years) and by 25% for Aurum broad (22.4-28.6 per 100 000 person-years). However, using HES-based definitions showed a decrease in incidence over the same period and lay between the two extremes derived for Aurum-based definition. IPF mortality in 2018 was 7.9 per 100 000 person-years and increased by 53% between 2008 and 2018. INTERPRETATION: When using best-case definitions, incidence rose throughout the study period. Scaling this to England's population (2018), our best estimate would be in the range of 8000-9000 new cases per year which is higher than previously reported estimates (5000-6000). This increased burden in the new cases of IPF each year impacts future health service planning and resource allocation.

Greenhouse gas emissions associated with suboptimal asthma care in the UK: the SABINA healthCARe-Based envirONmental cost of treatment (CARBON) study.

BACKGROUND: Poorly controlled asthma is associated with increased morbidity and healthcare resource utilisation (HCRU). Therefore, to quantify the environmental impact of asthma care, this retrospective, cohort, healthCARe-Based envirONmental cost of treatment (CARBON) study estimated greenhouse gas (GHG) emissions in the UK associated with the management of well-controlled versus poorly controlled asthma. METHODS: Patients with current asthma (aged ≥12 years) registered with the Clinical Practice Research Datalink (2008‒2019) were included. GHG emissions, measured as carbon dioxide equivalent (CO2e), were estimated for asthma-related medication use, HCRU and exacerbations during follow-up of patients with asthma classified at baseline as well-controlled (<3 short-acting ß2-agonist (SABA) canisters/year and no exacerbations) or poorly controlled (≥3 SABA canisters/year or ≥1 exacerbation). Excess GHG emissions due to suboptimal asthma control included ≥3 SABA canister prescriptions/year, exacerbations and any general practitioner and outpatient visits within 10 days of hospitalisation or an emergency department visit. RESULTS: Of the 236 506 patients analysed, 47.3% had poorly controlled asthma at baseline. Scaled to the national level, the overall carbon footprint of asthma care in the UK was 750 540 tonnes CO2e/year, with poorly controlled asthma contributing excess GHG emissions of 303 874 tonnes CO2e/year, which is equivalent to emissions from >124 000 houses in the UK. Poorly controlled versus well-controlled asthma generated 3.1-fold higher overall and 8.1-fold higher excess per capita carbon footprint, largely SABA-induced, with smaller contributions from HCRU. CONCLUSIONS: These findings suggest that addressing the high burden of poorly controlled asthma, including curbing high SABA use and its associated risk of exacerbations, may significantly alleviate asthma care-related carbon emissions.

Using healthcare systems data for outcomes in clinical trials: issues to consider at the design stage.

BACKGROUND: Healthcare system data (HSD) are increasingly used in clinical trials, augmenting or replacing traditional methods of collecting outcome data. This study, PRIMORANT, set out to identify, in the UK context, issues to be considered before the decision to use HSD for outcome data in a clinical trial is finalised, a methodological question prioritised by the clinical trials community. METHODS: The PRIMORANT study had three phases. First, an initial workshop was held to scope the issues faced by trialists when considering whether to use HSDs for trial outcomes. Second, a consultation exercise was undertaken with clinical trials unit (CTU) staff, trialists, methodologists, clinicians, funding panels and data providers. Third, a final discussion workshop was held, at which the results of the consultation were fed back, case studies presented, and issues considered in small breakout groups. RESULTS: Key topics included in the consultation process were the validity of outcome data, timeliness of data capture, internal pilots, data-sharing, practical issues, and decision-making. A majority of consultation respondents (n = 78, 95%) considered the development of guidance for trialists to be feasible. Guidance was developed following the discussion workshop, for the five broad areas of terminology, feasibility, internal pilots, onward data sharing, and data archiving. CONCLUSIONS: We provide guidance to inform decisions about whether or not to use HSDs for outcomes, and if so, to assist trialists in working with registries and other HSD providers to improve the design and delivery of trials.

Cause-specific mortality in COPD subpopulations: a cohort study of 339 647 people in England.

BACKGROUND: Identifying correlates of cause-specific mortality in patients with chronic obstructive pulmonary disease (COPD) may aid the targeting of therapies to reduce mortality. We determined factors associated with causes of death in a primary care COPD population. METHODS: Clinical Practice Research Datalink Aurum was linked to Hospital Episode Statistics and death certificate data. People with COPD alive between 1 January 2010 and 1 January 2020 were included. Patient characteristics were defined before the start of follow-up: (a) frequency and severity of exacerbations; (b) emphysema or chronic bronchitis; (c) Global Obstructive Lung Disease (GOLD) groups A-D; and (d) airflow limitation. We used Cox Proportional Hazards regression and competing risks to investigate the association between patient characteristics and risk of all-cause, COPD and cardiovascular (CV) mortality. RESULTS: 339 647 people with COPD were included of which 97 882 died during follow-up (25.7% COPD related and 23.3% CV related). Airflow limitation, GOLD group, exacerbation frequency and severity, and COPD phenotype were associated with all-cause mortality. Exacerbations, both increased frequency and severity, were associated with COPD-related mortality (≥2 exacerbations vs none adjusted HR: 1.64, 1.57-1.71; 1 severe vs none adjusted HR: 2.17, 2.04-2.31, respectively). Patients in GOLD groups B-D had a higher risk of COPD and CV mortality compared with GOLD group A (GOLD group D vs group A, adjusted HR for COPD mortality: 4.57, 4.23-4.93 and adjusted HR for CV mortality: 1.53, 1.41-1.65). Increasing airflow limitation was also associated with both COPD and CV mortality (GOLD 4 vs 1, adjusted HR: 12.63, 11.82-13.51 and adjusted HR: 1.75, 1.60-1.91, respectively). CONCLUSION: Poorer airflow limitation, worse functional status and exacerbations had substantial associations with risk of all-cause mortality. Differing results for CV and COPD-related mortality suggests interventions to prevent mortality may need to target particular characteristics or time points in the disease course.

Temporal Risk of Nonfatal Cardiovascular Events After Chronic Obstructive Pulmonary Disease Exacerbation: A Population-based Study.

Rationale: Cardiovascular events after chronic obstructive pulmonary disease (COPD) exacerbations are recognized. Studies to date have been post hoc analyses of trials, did not differentiate exacerbation severity, included death in the cardiovascular outcome, or had insufficient power to explore individual outcomes temporally.Objectives: We explore temporal relationships between moderate and severe exacerbations and incident, nonfatal hospitalized cardiovascular events in a primary care-derived COPD cohort.Methods: We included people with COPD in England from 2014 to 2020, from the Clinical Practice Research Datalink Aurum primary care database. The index date was the date of first COPD exacerbation or, for those without exacerbations, date upon eligibility. We determined composite and individual cardiovascular events (acute coronary syndrome, arrhythmia, heart failure, ischemic stroke, and pulmonary hypertension) from linked hospital data. Adjusted Cox regression models were used to estimate average and time-stratified adjusted hazard ratios (aHRs).Measurements and Main Results: Among 213,466 patients, 146,448 (68.6%) had any exacerbation; 119,124 (55.8%) had moderate exacerbations, and 27,324 (12.8%) had severe exacerbations. A total of 40,773 cardiovascular events were recorded. There was an immediate period of cardiovascular relative rate after any exacerbation (1-14 d; aHR, 3.19 [95% confidence interval (CI), 2.71-3.76]), followed by progressively declining yet maintained effects, elevated after one year (aHR, 1.84 [95% CI, 1.78-1.91]). Hazard ratios were highest 1-14 days after severe exacerbations (aHR, 14.5 [95% CI, 12.2-17.3]) but highest 14-30 days after moderate exacerbations (aHR, 1.94 [95% CI, 1.63-2.31]). Cardiovascular outcomes with the greatest two-week effects after a severe exacerbation were arrhythmia (aHR, 12.7 [95% CI, 10.3-15.7]) and heart failure (aHR, 8.31 [95% CI, 6.79-10.2]).Conclusions: Cardiovascular events after moderate COPD exacerbations occur slightly later than after severe exacerbations; heightened relative rates remain beyond one year irrespective of severity. The period immediately after an exacerbation presents a critical opportunity for clinical intervention and treatment optimization to prevent future cardiovascular events.

QRISK3 underestimates the risk of cardiovascular events in patients with COPD.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD). The extent to which the excess CVD risk is captured by risk factors in QRISK, a widely used CVD risk scoring tool, is not well studied. METHODS: We created an incidence cohort of diagnosed COPD patients from the United Kingdom (UK) Clinical Practice Research Datalink GOLD database (January 1998-July 2018). The outcome was a composite of fatal or non-fatal CVD events. Sex-specific age-standardised incidence ratios (SIR) were compared with values for the UK primary-care population. The observed 10-year CVD risk was derived using the Kaplan-Meier estimator and was compared with predicted 10-year risk from the QRISK3 tool. RESULTS: 13 208 patients (mean age 64.9 years, 45% women) were included. CVD incidence was 3.53 events per 100 person-years. The SIR of CVD was 1.71 (95% CI 1.61 to 1.75) in women and 1.62 (95%CI 1.54-1.64) in men. SIR was particularly high among patients younger than 65 years (women=2.13 (95% CI 1.94 to 2.19); men=1.86 (95% CI 1.74 to 1.90)). On average, the observed 10-year risk was 52% higher than QRISK predicted score (33.5% vs 22.1%). The difference was higher in patients younger than 65 years (observed risk 82% higher than predicted). CONCLUSION: People living with COPD are at a significantly heightened risk of CVD over and beyond their predicted risk. This is particularly the case for younger people whose 10-year CVD risk can be >80% higher than predicted. Risk scoring tools must be validated and revised to provide accurate CVD predictions in patients with COPD.

Impact of COVID-19 on immunocompromised populations during the Omicron era: insights from the observational population-based INFORM study.

Background: Immunocompromised individuals are not optimally protected by COVID-19 vaccines and potentially require additional preventive interventions to mitigate the risk of severe COVID-19. We aimed to characterise and describe the risk of severe COVID-19 across immunocompromised groups as the pandemic began to transition to an endemic phase. Methods: COVID-19-related hospitalisations, intensive care unit (ICU) admissions, and deaths (01/01/2022-31/12/2022) were compared among different groups of immunocompromised individuals vs the general population, using a retrospective cohort design and electronic health data from a random 25% sample of the English population aged ≥12 years (Registration number: ISRCTN53375662). Findings: Overall, immunocompromised individuals accounted for 3.9% of the study population, but 22% (4585/20,910) of COVID-19 hospitalisations, 28% (125/440) of COVID-19 ICU admissions, and 24% (1145/4810) of COVID-19 deaths in 2022. Restricting to those vaccinated with ≥3 doses of COVID-19 vaccine (∼84% of immunocompromised and 51% of the general population), all immunocompromised groups remained at increased risk of severe COVID-19 outcomes, with adjusted incidence rate ratios (aIRR) for hospitalisation ranging from 1.3 to 13.1. At highest risk for COVID-19 hospitalisation were individuals with: solid organ transplant (aIRR 13.1, 95% confidence interval [95% CI] 11.2-15.3), moderate to severe primary immunodeficiency (aIRR 9.7, 95% CI 6.3-14.9), stem cell transplant (aIRR 11.0, 95% CI 6.8-17.6), and recent treatment for haematological malignancy (aIRR 10.6, 95% CI 9.5-11.9). Results were similar for COVID-19 ICU admissions and deaths. Interpretation: Immunocompromised individuals continue to be impacted disproportionately by COVID-19 and have an urgent need for additional preventive measures beyond current vaccination programmes. These data can help determine the immunocompromised groups for which targeted prevention strategies may have the highest impact. Funding: This study was funded by AstraZeneca UK.

Investigating the impact of London's ultra low emission zone on children's health: children's health in London and Luton (CHILL) protocol for a prospective parallel cohort study.

BACKGROUND: Air pollution harms health across the life course. Children are at particular risk of adverse effects during development, which may impact on health in later life. Interventions that improve air quality are urgently needed both to improve public health now, and prevent longer-term increased vulnerability to chronic disease. Low Emission Zones are a public health policy intervention aimed at reducing traffic-derived contributions to urban air pollution, but evidence that they deliver health benefits is lacking. We describe a natural experiment study (CHILL: Children's Health in London and Luton) to evaluate the impacts of the introduction of London's Ultra Low Emission Zone (ULEZ) on children's health. METHODS: CHILL is a prospective two-arm parallel longitudinal cohort study recruiting children at age 6-9 years from primary schools in Central London (the focus of the first phase of the ULEZ) and Luton (a comparator site), with the primary outcome being the impact of changes in annual air pollutant exposures (nitrogen oxides [NOx], nitrogen dioxide [NO2], particulate matter with a diameter of less than 2.5micrograms [PM2.5], and less than 10 micrograms [PM10]) across the two sites on lung function growth, measured as post-bronchodilator forced expiratory volume in one second (FEV1) over five years. Secondary outcomes include physical activity, cognitive development, mental health, quality of life, health inequalities, and a range of respiratory and health economic data. DISCUSSION: CHILL's prospective parallel cohort design will enable robust conclusions to be drawn on the effectiveness of the ULEZ at improving air quality and delivering improvements in children's respiratory health. With increasing proportions of the world's population now living in large urban areas exceeding World Health Organisation air pollution limit guidelines, our study findings will have important implications for the design and implementation of Low Emission and Clean Air Zones in the UK, and worldwide. CLINICALTRIALS: GOV: NCT04695093 (05/01/2021).

Investigating the prognostic value of digital mobility outcomes in patients with chronic obstructive pulmonary disease: a systematic literature review and meta-analysis.

BACKGROUND: Reduced mobility is a central feature of COPD. Assessment of mobility outcomes that can be measured digitally (digital mobility outcomes (DMOs)) in daily life such as gait speed and steps per day is increasingly possible using devices such as pedometers and accelerometers, but the predictive value of these measures remains unclear in relation to key outcomes such as hospital admission and survival. METHODS: We conducted a systematic review, nested within a larger scoping review by the MOBILISE-D consortium, addressing DMOs in a range of chronic conditions. Qualitative and quantitative analysis considering steps per day and gait speed and their association with clinical outcomes in COPD patients was performed. RESULTS: 21 studies (6076 participants) were included. Nine studies evaluated steps per day and 11 evaluated a measure reflecting gait speed in daily life. Negative associations were demonstrated between mortality risk and steps per day (per 1000 steps) (hazard ratio (HR) 0.81, 95% CI 0.75-0.88, p<0.001), gait speed (<0.80 m·s-1) (HR 3.55, 95% CI 1.72-7.36, p<0.001) and gait speed (per 1.0 m·s-1) (HR 7.55, 95% CI 1.11-51.3, p=0.04). Fewer steps per day (per 1000) and slow gait speed (<0.80 m·s-1) were also associated with increased healthcare utilisation (HR 0.80, 95% CI 0.72-0.88, p<0.001; OR 3.36, 95% CI 1.42-7.94, p=0.01, respectively). Available evidence was of low-moderate quality with few studies eligible for meta-analysis. CONCLUSION: Daily step count and gait speed are negatively associated with mortality risk and other important outcomes in people with COPD and therefore may have value as prognostic indicators in clinical trials, but the quantity and quality of evidence is limited. Larger studies with consistent methodologies are called for.

Risk Factors Associated with a First Exacerbation Among Patients with COPD Classified as GOLD A and B in Routine Clinical Practice in the UK.

Purpose: Risk factors for exacerbations of chronic obstructive pulmonary disease (COPD) have been previously characterized for patients with more severe cases of COPD. It is unclear how the risk of first exacerbation may best be identified in patients with less severe disease. This study investigated risk factors for first exacerbation among English patients with COPD classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A or B. Patients and Methods: A retrospective cohort study using data from the UK Clinical Practice Research Datalink (CPRD) AURUM linked to Hospital Episode Statistics. Patients with COPD aged ≥35 years and classified as GOLD group A or B (2020 criteria) from January 2013-December 2019 were eligible. Patients were required to have 24 months history in CPRD (baseline). Two cohorts were defined: cohort 1 included patients with no severe exacerbations during baseline; cohort 2 included patients with no moderate or severe exacerbations during baseline. Risk factors associated with severe, or combined moderate and severe exacerbation were examined for up to 5 years of follow-up. Results: Overall, 194,948 patients were included in cohort 1 (mean age 66.2 years; 55.2% male), and 148,396 patients in cohort 2 (mean age 66.1 years; 56.6% male). Identified risk factors for exacerbation (and associated 1-year absolute risk of severe, or combined moderate and severe exacerbation, respectively) included: Medical Research Council dyspnea scale score (15.9%/28.4%); COPD Assessment Test score (9.6%/25.3%); GOLD grade of airflow limitation (forced expiratory volume in 1 second % predicted; 13.6%/27.5%); and lung cancer (8.1%/23.6%). After adjustment for risk factors, these factors remained independently associated with severe exacerbation at 1, 3, and 5 years of follow-up. Conclusion: The identified risk factors may aid physicians in the early recognition of patients with COPD classified as GOLD group A or B at risk of first exacerbation.

Exploring the impact of varying definitions of exacerbations of chronic obstructive pulmonary disease in routinely collected electronic medical records.

BACKGROUND: Validity of exposure and outcome measures in electronic medical records is vital to ensure robust, comparable study findings however, despite validation studies, definitions of variables used often differ. Using exacerbations of chronic obstructive pulmonary disease (COPD) as an example, we investigated the impact of potential misclassification of different definitions commonly used in publications on study findings. METHODS: A retrospective cohort study was performed. English primary care data from the Clinical Practice Research Datalink Aurum database with linked secondary care data were used to define a population of COPD patients ≥40 years old registered at a general practice. Index date was the date eligibility criteria were met and end of follow-up was 30/12/19, death or end of data collection. Exacerbations were defined using 6 algorithms based on definitions commonly used in the literature, including one validated definition. For each algorithm, the proportion of frequent exacerbators (≥2 exacerbations/year) and exacerbation rates were described. Cox proportional hazard regression was used to investigate each algorithm on the association between heart failure and risk of COPD exacerbation. FINDINGS: A total of 315,184 patients were included. Baseline proportion of frequent exacerbators varied from 2.7% to 15.3% depending on the algorithm. Rates of exacerbations over follow-up varied from 19.3 to 66.6 events/100 person-years. The adjusted hazard ratio for the association between heart failure and exacerbation varied from 1.45, 95% confidence intervals 1.42-1.49, to 1.01, 0.98-1.04. INTERPRETATION: The use of high validity definitions and standardisation of definitions in electronic medical records is crucial to generating high quality, robust evidence.