Global mortality and readmission rates following COPD exacerbation-related hospitalisation: a meta-analysis of 65 945 individual patients.

Background: Exacerbations of COPD (ECOPD) have a major impact on patients and healthcare systems across the world. Precise estimates of the global burden of ECOPD on mortality and hospital readmission are needed to inform policy makers and aid preventive strategies to mitigate this burden. The aims of the present study were to explore global in-hospital mortality, post-discharge mortality and hospital readmission rates after ECOPD-related hospitalisation using an individual patient data meta-analysis (IPDMA) design. Methods: A systematic review was performed identifying studies that reported in-hospital mortality, post-discharge mortality and hospital readmission rates following ECOPD-related hospitalisation. Data analyses were conducted using a one-stage random-effects meta-analysis model. This study was conducted and reported in accordance with the PRISMA-IPD statement. Results: Data of 65 945 individual patients with COPD were analysed. The pooled in-hospital mortality rate was 6.2%, pooled 30-, 90- and 365-day post-discharge mortality rates were 1.8%, 5.5% and 10.9%, respectively, and pooled 30-, 90- and 365-day hospital readmission rates were 7.1%, 12.6% and 32.1%, respectively, with noticeable variability between studies and countries. Strongest predictors of mortality and hospital readmission included noninvasive mechanical ventilation and a history of two or more ECOPD-related hospitalisations <12 months prior to the index event. Conclusions: This IPDMA stresses the poor outcomes and high heterogeneity of ECOPD-related hospitalisation across the world. Whilst global standardisation of the management and follow-up of ECOPD-related hospitalisation should be at the heart of future implementation research, policy makers should focus on reimbursing evidence-based therapies that decrease (recurrent) ECOPD.

Harmonising electronic health records for reproducible research: challenges, solutions and recommendations from a UK-wide COVID-19 research collaboration.

BACKGROUND: The CVD-COVID-UK consortium was formed to understand the relationship between COVID-19 and cardiovascular diseases through analyses of harmonised electronic health records (EHRs) across the four UK nations. Beyond COVID-19, data harmonisation and common approaches enable analysis within and across independent Trusted Research Environments. Here we describe the reproducible harmonisation method developed using large-scale EHRs in Wales to accommodate the fast and efficient implementation of cross-nation analysis in England and Wales as part of the CVD-COVID-UK programme. We characterise current challenges and share lessons learnt. METHODS: Serving the scope and scalability of multiple study protocols, we used linked, anonymised individual-level EHR, demographic and administrative data held within the SAIL Databank for the population of Wales. The harmonisation method was implemented as a four-layer reproducible process, starting from raw data in the first layer. Then each of the layers two to four is framed by, but not limited to, the characterised challenges and lessons learnt. We achieved curated data as part of our second layer, followed by extracting phenotyped data in the third layer. We captured any project-specific requirements in the fourth layer. RESULTS: Using the implemented four-layer harmonisation method, we retrieved approximately 100 health-related variables for the 3.2 million individuals in Wales, which are harmonised with corresponding variables for > 56 million individuals in England. We processed 13 data sources into the first layer of our harmonisation method: five of these are updated daily or weekly, and the rest at various frequencies providing sufficient data flow updates for frequent capturing of up-to-date demographic, administrative and clinical information. CONCLUSIONS: We implemented an efficient, transparent, scalable, and reproducible harmonisation method that enables multi-nation collaborative research. With a current focus on COVID-19 and its relationship with cardiovascular outcomes, the harmonised data has supported a wide range of research activities across the UK.

Association of COVID-19 With Major Arterial and Venous Thrombotic Diseases: A Population-Wide Cohort Study of 48 Million Adults in England and Wales.

BACKGROUND: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) induces a prothrombotic state, but long-term effects of COVID-19 on incidence of vascular diseases are unclear. METHODS: We studied vascular diseases after COVID-19 diagnosis in population-wide anonymized linked English and Welsh electronic health records from January 1 to December 7, 2020. We estimated adjusted hazard ratios comparing the incidence of arterial thromboses and venous thromboembolic events (VTEs) after diagnosis of COVID-19 with the incidence in people without a COVID-19 diagnosis. We conducted subgroup analyses by COVID-19 severity, demographic characteristics, and previous history. RESULTS: Among 48 million adults, 125 985 were hospitalized and 1 319 789 were not hospitalized within 28 days of COVID-19 diagnosis. In England, there were 260 279 first arterial thromboses and 59 421 first VTEs during 41.6 million person-years of follow-up. Adjusted hazard ratios for first arterial thrombosis after COVID-19 diagnosis compared with no COVID-19 diagnosis declined from 21.7 (95% CI, 21.0-22.4) in week 1 after COVID-19 diagnosis to 1.34 (95% CI, 1.21-1.48) during weeks 27 to 49. Adjusted hazard ratios for first VTE after COVID-19 diagnosis declined from 33.2 (95% CI, 31.3-35.2) in week 1 to 1.80 (95% CI, 1.50-2.17) during weeks 27 to 49. Adjusted hazard ratios were higher, for longer after diagnosis, after hospitalized versus nonhospitalized COVID-19, among Black or Asian versus White people, and among people without versus with a previous event. The estimated whole-population increases in risk of arterial thromboses and VTEs 49 weeks after COVID-19 diagnosis were 0.5% and 0.25%, respectively, corresponding to 7200 and 3500 additional events, respectively, after 1.4 million COVID-19 diagnoses. CONCLUSIONS: High relative incidence of vascular events soon after COVID-19 diagnosis declines more rapidly for arterial thromboses than VTEs. However, incidence remains elevated up to 49 weeks after COVID-19 diagnosis. These results support policies to prevent severe COVID-19 by means of COVID-19 vaccines, early review after discharge, risk factor control, and use of secondary preventive agents in high-risk patients.

Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.

BACKGROUND: Thromboses in unusual locations after the Coronavirus Disease 2019 (COVID-19) vaccine ChAdOx1-S have been reported, although their frequency with vaccines of different types is uncertain at a population level. The aim of this study was to estimate the population-level risks of hospitalised thrombocytopenia and major arterial and venous thromboses after COVID-19 vaccination. METHODS AND FINDINGS: In this whole-population cohort study, we analysed linked electronic health records from adults living in England, from 8 December 2020 to 18 March 2021. We estimated incidence rates and hazard ratios (HRs) for major arterial, venous, and thrombocytopenic outcomes 1 to 28 and >28 days after first vaccination dose for ChAdOx1-S and BNT162b2 vaccines. Analyses were performed separately for ages <70 and ≥70 years and adjusted for age, age2, sex, ethnicity, and deprivation. We also prespecified adjustment for anticoagulant medication, combined oral contraceptive medication, hormone replacement therapy medication, history of pulmonary embolism or deep vein thrombosis, and history of coronavirus infection in analyses of venous thrombosis; and diabetes, hypertension, smoking, antiplatelet medication, blood pressure lowering medication, lipid lowering medication, anticoagulant medication, history of stroke, and history of myocardial infarction in analyses of arterial thromboses. We selected further covariates with backward selection. Of 46 million adults, 23 million (51%) were women; 39 million (84%) were <70; and 3.7 million (8.1%) Asian or Asian British, 1.6 million (3.5%) Black or Black British, 36 million (79%) White, 0.7 million (1.5%) mixed ethnicity, and 1.5 million (3.2%) were of another ethnicity. Approximately 21 million (46%) adults had their first vaccination between 8 December 2020 and 18 March 2021. The crude incidence rates (per 100,000 person-years) of all venous events were as follows: prevaccination, 140 [95% confidence interval (CI): 138 to 142]; ≤28 days post-ChAdOx1-S, 294 (281 to 307); >28 days post-ChAdOx1-S, 359 (338 to 382), ≤28 days post-BNT162b2-S, 241 (229 to 253); >28 days post-BNT162b2-S 277 (263 to 291). The crude incidence rates (per 100,000 person-years) of all arterial events were as follows: prevaccination, 546 (95% CI: 541 to 555); ≤28 days post-ChAdOx1-S, 1,211 (1,185 to 1,237); >28 days post-ChAdOx1-S, 1678 (1,630 to 1,726), ≤28 days post-BNT162b2-S, 1,242 (1,214 to 1,269); >28 days post-BNT162b2-S, 1,539 (1,507 to 1,572). Adjusted HRs (aHRs) 1 to 28 days after ChAdOx1-S, compared with unvaccinated rates, at ages <70 and ≥70 years, respectively, were 0.97 (95% CI: 0.90 to 1.05) and 0.58 (0.53 to 0.63) for venous thromboses, and 0.90 (0.86 to 0.95) and 0.76 (0.73 to 0.79) for arterial thromboses. Corresponding aHRs for BNT162b2 were 0.81 (0.74 to 0.88) and 0.57 (0.53 to 0.62) for venous thromboses, and 0.94 (0.90 to 0.99) and 0.72 (0.70 to 0.75) for arterial thromboses. aHRs for thrombotic events were higher at younger ages for venous thromboses after ChAdOx1-S, and for arterial thromboses after both vaccines. Rates of intracranial venous thrombosis (ICVT) and of thrombocytopenia in adults aged <70 years were higher 1 to 28 days after ChAdOx1-S (aHRs 2.27, 95% CI: 1.33 to 3.88 and 1.71, 1.35 to 2.16, respectively), but not after BNT162b2 (0.59, 0.24 to 1.45 and 1.00, 0.75 to 1.34) compared with unvaccinated. The corresponding absolute excess risks of ICVT 1 to 28 days after ChAdOx1-S were 0.9 to 3 per million, varying by age and sex. The main limitations of the study are as follows: (i) it relies on the accuracy of coded healthcare data to identify exposures, covariates, and outcomes; (ii) the use of primary reason for hospital admission to measure outcome, which improves the positive predictive value but may lead to an underestimation of incidence; and (iii) potential unmeasured confounding. CONCLUSIONS: In this study, we observed increases in rates of ICVT and thrombocytopenia after ChAdOx1-S vaccination in adults aged <70 years that were small compared with its effect in reducing COVID-19 morbidity and mortality, although more precise estimates for adults aged <40 years are needed. For people aged ≥70 years, rates of arterial or venous thrombotic events were generally lower after either vaccine compared with unvaccinated, suggesting that either vaccine is suitable in this age group.

Physical, Psychological, and Social Factors Associated with Exacerbation-Related Hospitalization in Patients with COPD.

BACKGROUND AND OBJECTIVE: Exacerbation(s) of chronic obstructive pulmonary disease (eCOPD) entail important events describing an acute deterioration of respiratory symptoms. Changes in medication and/or hospitalization are needed to gain control over the event. However, an exacerbation leading to hospitalization is associated with a worse prognosis for the patient. The objective of this study is to explore factors that could predict the probability of an eCOPD-related hospitalization. METHODS: Data from 128 patients with COPD included in a prospective, longitudinal study were used. At baseline, physical, emotional, and social status of the patients were assessed. Moreover, hospital admission during a one year follow-up was captured. Different models were made based on univariate analysis, literature, and practice. These models were combined to come to one final overall prediction model. RESULTS: During follow-up, 31 (24.2%) participants were admitted for eCOPD. The overall model contained six significant variables: currently smoking (OR = 3.93), forced vital capacity (FVC; OR = 0.97), timed-up-and-go time (TUG-time) (OR = 14.16), knowledge (COPD knowledge questionnaire, percentage correctly answered questions (CIROPD%correct)) (<60% (OR = 1.00); 60%-75%: (OR = 0.30); >75%: (OR = 1.94), eCOPD history (OR = 9.98), and care dependency scale (CDS) total score (OR = 1.12). This model was well calibrated (goodness-of-fit test: p = 0.91) and correctly classified 79.7% of the patients. CONCLUSION: A combination of TUG-time, eCOPD-related admission(s) prior to baseline, currently smoking, FVC, CDS total score, and CIROPD%correct allows clinicians to predict the probability of an eCOPD-related hospitalization.

The stability of the ADO score among UK COPD patients from The Health Improvement Network.

The ADO (age, dyspnoea, airflow obstruction) score predicts 3-year overall mortality among chronic obstructive pulmonary disease (COPD) patients. Information on the changes in COPD prognostic scores is sparse and it is unclear if the ADO score should be measured serially. We followed 4804 UK COPD patients with three or more ADO measurements from The Health Improvement Network (2005-2014) in a retrospective open cohort design. Patient's ADO scores were calculated once per year unless an obstruction or dyspnoea measurement was missing. Cox regression models assessed the independent role of serial ADO scores on mortality. The associations between baseline patient characteristics and long-term change in ADO scores were assessed using linear mixed effect models. Fewer than 7% of patients had worsened (i.e. increased) by ≥1 point per year after a median follow-up of 4.4 years. There was strong evidence that patients with more rapid worsening in ADO scores had increased mortality (hazard ratio 2.00 (95% CI 1.59-2.52) per 1 point increase in ADO per year). More rapid ADO score worsening was seen among current smokers (rate difference 0.059 (95% CI 0.031-0.087); p=0.001) and ex-smokers (0.028 (95% CI 0.003-0.054); p=0.032) and patients with depression (0.038 (95% CI 0.005-0.071); p=0.022), while overweight (-0.0347 (95% CI -0.0544- -0.0150); p=0.001) and obese (-0.0412 (95% CI -0.0625- -0.0198); p<0.001) patients had a less rapid ADO score worsening. Serial assessment of the ADO score can identify patients with worsening disease and update their prognosis, especially for patients who smoke, are depressed or have lower body mass index.

External Validation Of The Updated ADO Score In COPD Patients From The Birmingham COPD Cohort.

Background: Reviews suggest that the ADO score is the most discriminatory prognostic score for predicting mortality among chronic obstructive pulmonary disease (COPD) patients, but a full evaluation and external validation within primary care settings is critical before implementation. Objectives: To validate the ADO score in prevalent and screen-detected primary care COPD cases at 3 years and at shorter time periods. Patients and methods: One thousand eight hundred and ninety-two COPD cases were recruited between 2012 and 2014 from 71 United Kingdom general practices as part of the Birmingham COPD Cohort study. Cases were either on the practice COPD register or screen-detected. We validated the ADO score for predicting 3-year mortality with 1-year and 2-year mortality as secondary endpoints using discrimination (area-under-the-curve (AUC)) and calibration plots. Results: One hundred and fifty-four deaths occurred within 3 years. The ADO score was discriminatory for predicting 3-year mortality (AUC= 0.74; 95% CI: 0.69-0.79). Similar performance was found for 1- (AUC= 0.73; 0.66-0.80) and 2-year mortality (0.72; 0.67-0.76). The ADO score showed reasonable calibration for predicting 3-year mortality (calibration slope 0.95; 0.70-1.19) but over-predicted in cases with higher predicted risks of mortality at 1 (0.79; 0.45-1.13) and 2-year (0.79; 0.57-1.01) mortality. Discussion: The ADO score showed promising discrimination in predicting 3-year mortality in a primary care population including screen-detected cases. It may need to be recalibrated if it is used to provide risk predictions for 1- or 2-year mortality since, in these time-periods, over-prediction was evident, especially in cases with higher predicted mortality risks.

Low Vitamin K Status Is Associated with Increased Elastin Degradation in Chronic Obstructive Pulmonary Disease.

Elastin degradation is accelerated in chronic obstructive pulmonary disease (COPD) and is partially regulated by Matrix Gla Protein (MGP), via a vitamin K-dependent pathway. The aim was to assess vitamin K status in COPD as well as associations between vitamin K status, elastin degradation, lung function parameters and mortality. A total of 192 COPD patients and 186 age-matched controls were included. In addition to this, 290 COPD patients from a second independent longitudinal cohort were also included. Vitamin K status was assessed by measuring plasma inactive MGP levels and rates of elastin degradation by measuring plasma desmosine levels. Reduced vitamin K status was found in COPD patients compared to smoking controls (p < 0.0005) and controls who had never smoked (p = 0.001). Vitamin K status was inversely associated with desmosine (cohort 1: p = 0.001; cohort 2: p = 0.004). Only few significant associations between vitamin K status and lung function parameters were found. Mortality was higher in COPD patients within the quartile with the lowest vitamin K status compared to those within the other quartiles (hazard ratio 1.85, 95% confidence interval (CI), 1.21-2.83, p = 0.005). In conclusion, we demonstrated reduced vitamin K status in COPD and an inverse association between vitamin K status and elastin degradation rate. Our results therefore suggest a potential role of vitamin K in COPD pathogenesis.

Trends in moderate and severe exacerbations among COPD patients in the UK from 2005 to 2013.

INTRODUCTION: Exacerbations of chronic obstructive pulmonary disease are characterised by increased symptoms such as dyspnoea, cough and sputum production and/or purulence, leading to greater risk of hospitalisation and mortality. Very few studies have measured long term trends in the incidence of exacerbations of chronic obstructive pulmonary disease. We therefore investigated the incidence of moderate and severe exacerbations in the UK general population. METHODS: A population based-study including Clinical Practice Research Datalink (CPRD) patients ≥ 40 years of age with a current diagnosis of COPD within the United Kingdom from 2004 to 2013 was conducted. Individuals with a history of asthma were excluded from main analyses. We calculated the incidence rates for any, moderate, and severe exacerbations. Patients contributed time at risk from January 1st up to the date of the first outcome within each year. The incidence rate for any, moderate and severe exacerbations for COPD in each calendar year was calculated as follows: the sum of any or moderate or severe exacerbations for COPD in that year divided by the total duration of follow-up in the same calendar year from 2005 through to 2013. We then analysed these rates by gender and age categories (40-59 years, 60-79 years and ≥80 years). RESULTS: Among 213,561 with incident COPD diagnosis, 86,300 patients were included in the study. From 2005 to 2013, the incidence rate of any exacerbations increased from 89 to 98 per 1000 person years (PYs) (p = 0.005). Women had significantly higher incidence rates of any exacerbation for each calendar year when compared to men (p < 0.0001). The incidence rate of any and moderate exacerbations increased with age from 2005 to 2007. For severe exacerbations incidence decreased from 2005 to 2007 before increasing from 2008 until the end of follow-up (43 per 1000 PYs (95% confidence interval, 42-45/1000PYs) in 2013). Incidence rates of severe exacerbations were similar by gender and patients aged 80 + years had a higher incidence rate of severe exacerbation from 2005 to 2008 after which their incident rate dropped in subsequent years. CONCLUSION: This is the first study that reports the long-term changes in the incidence rates of moderate and severe exacerbations within the UK general practice. Women showed a substantially higher risk of any COPD exacerbations, and their risk is increasing. The incidence rates of any exacerbations increased during the study period, while severe exacerbations were variable. Furthermore, incidence rates varied substantially by age group.

Differential cyclooxygenase expression levels and survival associations in type I and type II ovarian tumors.

BACKGROUND: High cyclooxygenase (COX)-2 expression in ovarian tumors has been associated with poor prognosis, but the role of COX-1 expression and its relation to survival is less clear. Here, we evaluated COX expression and associations with survival outcomes between type I (clear cell, mucinous, low grade endometrioid and low grade serous) and type II (high grade serous and high grade endometrioid) ovarian tumors. METHODS: We developed and validated a new COX-1 antibody, and conducted immunohistochemical (IHC) staining for COX-1 and COX-2 on a tissue microarray (TMA) of 190 primary ovarian tumors. In addition to standard IHC scoring and H-scores to combine the percentage of positive cells and staining intensity, we also measured COX-1 and COX-2 mRNA expression by QPCR. High expression was defined as greater than or equal to median values. Clinical characteristics and disease outcomes were ascertained from medical records. Associations with disease-free survival (DFS) and overall survival (OS) were quantified by hazard ratios (HRs) and confidence intervals (CIs) from proportional hazards regression. RESULTS: Type I tumors had high COX-2 expression, while type II tumors had high COX-1 expression. In multivariable adjusted regression models, higher COX-1 mRNA expression was associated with shorter DFS (HR: 6.37, 95% CI: 1.84-22.01) and OS (HR: 2.26, 95% CI: 1.04-4.91), while higher H-scores for COX-2 expression were associated with shorter DFS (HR: 1.92, 95% CI: 1.06-3.49). Stratified analysis indicated that COX-2 was significantly associated with DFS among cases with Type II tumors (HR: 1.93, 95% CI: 1.06-3.53). CONCLUSIONS: These findings suggest that ovarian tumor type contributes to differences in COX expression levels and associations with survival.

Thresholds and timing of pre-operative thrombocytosis and ovarian cancer survival: analysis of laboratory measures from electronic medical records.

BACKGROUND: Thrombocytosis has been associated with poor ovarian cancer prognosis. However, comparisons of thresholds to define thrombocytosis and evaluation of relevant timing of platelet measurement has not been previously conducted. METHODS: We selected Tumor Registry confirmed ovarian, primary peritoneal, and fallopian tube cancer cases diagnosed between 1995-2013 from the Vanderbilt University Medical Center. Laboratory measured platelet values from electronic medical records (EMR) were used to determine thrombocytosis at three thresholds: a platelet count greater than 350, 400, or 450 × 10(9)/liter. Timing was evaluated with 5 intervals: on the date of diagnosis, and up to 1, 2, 4, and 8 weeks prior to the date of diagnosis. Cox regression was used to calculate hazard ratios (HR) and confidence intervals (CI) for association with overall survival; adjustment included age, stage, grade, and histologic subtype of disease. RESULTS: Pre-diagnosis platelet measures were available for 136, 241, 280, 297, and 304 cases in the five intervals. The prevalence of thrombocytosis decreased with increasing thresholds and was generally consistent across the five time intervals, ranging from 44.8-53.2 %, 31.6-39.4 %, and 19.9-26.1 % across the three thresholds. Associations with higher grade and stage of disease gained significance as the threshold increased. With the exception of the lowest threshold on the date of diagnosis (HR350: 1.55, 95 % CI: 0.97-2.47), all other survival associations were significant, with the highest reaching twice the risk of death for thrombocytosis on the date of diagnosis (HR400: 2.01, 95 % CI: 1.25-3.23). CONCLUSIONS: Our EMR approach yielded associations comparable to published findings from medical record abstraction approaches. In addition, our results indicate that lower thrombocytosis thresholds and platelet measures up to 8 weeks before diagnosis may inform ovarian cancer characteristics and prognosis.