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BackgroundCOVID-19 is a multi-system disease and patients who survive may experience in-hospital complications. These complications are likely to have important short and long-term consequences for patients, healthcare utilisation, healthcare system preparedness, and society amidst the ongoing COVID-19 pandemic. Our aim was to characterise the extent and impact of COVID-19 complications, particularly in those who survive using the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK).MethodsA multicentre, prospective cohort study in 302 UK healthcare facilities of adults hospitalised with COVID-19 between 17th January and 4th August 2020. Complications were defined as organ specific diagnoses occurring alone or in addition to any hallmarks of COVID-19 illness. Outcomes included death, critical care use, and ability to self-care at hospital discharge. We used multilevel logistic regression and survival models to explore associations between these outcomes and in-hospital complications, age, and pre-existing comorbidities.ResultsOf patients admitted to hospital for management of COVID-19, 49.7% (36 367/73 197) experienced at least one complication. The mean age of our cohort was 71.1 years old (SD 18.7), included more males (56.0%, 41 025/73 ) with 81.0% (59 289/73 197) of patients having at least one comorbidity. Males over 60 were most likely to experience a complication (60 y and over, 54.5% [16 579/30 416] in males and 48.2% [11 707/24 288] in females; Under 60 y, 48.8% [5179/10 609] in males, 36.6% [2814/7689] in females). Renal (24.3%, 17 752/73 197), complex respiratory 18.4% (13 486/73 197), and systemic (16.3%, 11 895/73 197) complications were most frequent. Cardiovascular (12.3%, 8973/73 197), neurological (4.3%, 3115/73 197), and gastrointestinal/liver (0.8%, 7901/73 197) complications were also reported. The presence of any complication was associated with significantly worse survival (adjusted HR 1.74, 95% CI 1.64 to 1.84) and increased admission to critical care (adjusted OR 7.25, 95% CI 6.83 to 7.69). Reduced ability to self-care at discharge was significantly greater in patients who experienced a complication (adjusted OR 2.42, 95% CI 2.31 to 2.54) and was greatest in those who experienced neurological complications (adjusted OR 4.39, 95% CI 3.95 to 4.89). ConclusionsComplications and worse functional outcomes in patients admitted to hospital with COVID-19 are high, even in young, previously healthy individuals. Acute complications are associated with reduced ability to self-care at discharge, with neurological complications being associated with the worst functional outcomes. COVID-19 complications are likely to cause significant strain on health and social care in the coming years. These data will help in the design and provision of services aimed at the post-hospitalisation care of patients with COVID-19.

Background: Microbiological characterisation of co-infections and secondary infections in patients with COVID-19 is lacking, and antimicrobial use is high. We aimed to describe microbiologically confirmed co-infections and secondary infections, and antimicrobial use, in patients admitted to hospital with COVID-19. Methods: The International Severe Acute Respiratory and Emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study is an ongoing, prospective cohort study recruiting inpatients from 260 hospitals in England, Scotland, and Wales, conducted by the ISARIC Coronavirus Clinical Characterisation Consortium. Patients with a confirmed or clinician-defined high likelihood of SARS-CoV-2 infection were eligible for inclusion in the ISARIC WHO CCP-UK study. For this specific study, we excluded patients with a recorded negative SARS-CoV-2 test result and those without a recorded outcome at 28 days after admission. Demographic, clinical, laboratory, therapeutic, and outcome data were collected using a prespecified case report form. Organisms considered clinically insignificant were excluded. Findings: We analysed data from 48 902 patients admitted to hospital between Feb 6 and June 8, 2020. The median patient age was 74 years (IQR 59–84) and 20 786 (42·6%) of 48 765 patients were female. Microbiological investigations were recorded for 8649 (17·7%) of 48 902 patients, with clinically significant COVID-19-related respiratory or bloodstream culture results recorded for 1107 patients. 762 (70·6%) of 1080 infections were secondary, occurring more than 2 days after hospital admission. Staphylococcus aureus and Haemophilus influenzae were the most common pathogens causing respiratory co-infections (diagnosed ≤2 days after admission), with Enterobacteriaceae and S aureus most common in secondary respiratory infections. Bloodstream infections were most frequently caused by Escherichia coli and S aureus. Among patients with available data, 13 390 (37·0%) of 36 145 had received antimicrobials in the community for this illness episode before hospital admission and 39 258 (85·2%) of 46 061 patients with inpatient antimicrobial data received one or more antimicrobials at some point during their admission (highest for patients in critical care). We identified frequent use of broad-spectrum agents and use of carbapenems rather than carbapenem-sparing alternatives. Interpretation: In patients admitted to hospital with COVID-19, microbiologically confirmed bacterial infections are rare, and more likely to be secondary infections. Gram-negative organisms and S aureus are the predominant pathogens. The frequency and nature of antimicrobial use are concerning, but tractable targets for stewardship interventions exist. Funding: National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, UK Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, and NIHR HPRU in Respiratory Infections at Imperial College London.

Background\ud \ud Mortality rates in hospitalised patients with COVID-19 in the UK appeared to decline during the first wave of the pandemic. We aimed to quantify potential drivers of this change and identify groups of patients who remain at high risk of dying in hospital.\ud \ud \ud Methods\ud \ud In this multicentre prospective observational cohort study, the International Severe Acute Respiratory and Emerging Infections Consortium WHO Clinical Characterisation Protocol UK recruited a prospective cohort of patients with COVID-19 admitted to 247 acute hospitals in England, Scotland, and Wales during the first wave of the pandemic (between March 9 and Aug 2, 2020). We included all patients aged 18 years and older with clinical signs and symptoms of COVID-19 or confirmed COVID-19 (by RT-PCR test) from assumed community-acquired infection. We did a three-way decomposition mediation analysis using natural effects models to explore associations between week of admission and in-hospital mortality, adjusting for confounders (demographics, comorbidities, and severity of illness) and quantifying potential mediators (level of respiratory support and steroid treatment). The primary outcome was weekly in-hospital mortality at 28 days, defined as the proportion of patients who had died within 28 days of admission of all patients admitted in the observed week, and it was assessed in all patients with an outcome. This study is registered with the ISRCTN Registry, ISRCTN66726260.\ud \ud \ud Findings\ud \ud Between March 9, and Aug 2, 2020, we recruited 80 713 patients, of whom 63 972 were eligible and included in the study. Unadjusted weekly in-hospital mortality declined from 32·3% (95% CI 31·8–32·7) in March 9 to April 26, 2020, to 16·4% (15·0–17·8) in June 15 to Aug 2, 2020. Reductions in mortality were observed in all age groups, in all ethnic groups, for both sexes, and in patients with and without comorbidities. After adjustment, there was a 32% reduction in the risk of mortality per 7-week period (odds ratio [OR] 0·68 [95% CI 0·65–0·71]). The higher proportions of patients with severe disease and comorbidities earlier in the first wave (March and April) than in June and July accounted for 10·2% of this reduction. The use of respiratory support changed during the first wave, with gradually increased use of non-invasive ventilation over the first wave. Changes in respiratory support and use of steroids accounted for 22·2%, OR 0·95 (0·94–0·95) of the reduction in in-hospital mortality.\ud \ud \ud Interpretation\ud \ud The reduction in in-hospital mortality in patients with COVID-19 during the first wave in the UK was partly accounted for by changes in the case-mix and illness severity. A significant reduction in in-hospital mortality was associated with differences in respiratory support and critical care use, which could partly reflect accrual of clinical knowledge. The remaining improvement in in-hospital mortality is not explained by these factors, and could be associated with changes in community behaviour, inoculum dose, and hospital capacity strain.\ud \ud \ud Funding\ud \ud National Institute for Health Research and the Medical Research Council.

BACKGROUND: Studies of patients admitted to hospital with COVID-19 have found varying mortality outcomes associated with underlying respiratory conditions and inhaled corticosteroid use. Using data from a national, multicentre, prospective cohort, we aimed to characterise people with COVID-19 admitted to hospital with underlying respiratory disease, assess the level of care received, measure in-hospital mortality, and examine the effect of inhaled corticosteroid use. METHODS: We analysed data from the International Severe Acute Respiratory and emerging Infection Consortium (ISARIC) WHO Clinical Characterisation Protocol UK (CCP-UK) study. All patients admitted to hospital with COVID-19 across England, Scotland, and Wales between Jan 17 and Aug 3, 2020, were eligible for inclusion in this analysis. Patients with asthma, chronic pulmonary disease, or both, were identified and stratified by age ( FINDINGS: 75 463 patients from 258 participating health-care facilities were included in this analysis: 860 patients younger than 16 years (74 [8·6%] with asthma), 8950 patients aged 16-49 years (1867 [20·9%] with asthma), and 65 653 patients aged 50 years and older (5918 [9·0%] with asthma, 10 266 [15·6%] with chronic pulmonary disease, and 2071 [3·2%] with both asthma and chronic pulmonary disease). Patients with asthma were significantly more likely than those without asthma to receive critical care (patients aged 16-49 years: adjusted odds ratio [OR] 1·20 [95% CI 1·05-1·37]; p=0·0080; patients aged ≥50 years: adjusted OR 1·17 [1·08-1·27]; p INTERPRETATION: Underlying respiratory conditions are common in patients admitted to hospital with COVID-19. Regardless of the severity of symptoms at admission and comorbidities, patients with asthma were more likely, and those with chronic pulmonary disease less likely, to receive critical care than patients without an underlying respiratory condition. In patients aged 16 years and older, severe asthma was associated with increased mortality compared to non-severe asthma. In patients aged 50 years and older, inhaled corticosteroid use in those with asthma was associated with lower mortality than in patients without an underlying respiratory condition; patients with chronic pulmonary disease had significantly increased mortality compared to those with no underlying respiratory condition, regardless of inhaled corticosteroid use. Our results suggest that the use of inhaled corticosteroids, within 2 weeks of admission, improves survival for patients aged 50 years and older with asthma, but not for those with chronic pulmonary disease. FUNDING: National Institute for Health Research, Medical Research Council, NIHR Health Protection Research Units in Emerging and Zoonotic Infections at the University of Liverpool and in Respiratory Infections at Imperial College London in partnership with Public Health England.

Background Early in the pandemic it was suggested that pre-existing use of non-steroidal anti-inflammatory drugs (NSAIDs) could lead to increased disease severity in patients with COVID-19. NSAIDs are an important analgesic, particularly in those with rheumatological disease, and are widely available to the general public without prescription. Evidence from community studies, administrative data, and small studies of hospitalised patients suggest NSAIDs are not associated with poorer COVID-19 outcomes. We aimed to characterise the safety of NSAIDs and identify whether pre-existing NSAID use was associated with increased severity of COVID-19 disease. Methods This prospective, multicentre cohort study included patients of any age admitted to hospital with a confirmed or highly suspected SARS-CoV-2 infection leading to COVID-19 between Jan 17 and Aug 10, 2020. The primary outcome was in-hospital mortality, and secondary outcomes were disease severity at presentation, admission to critical care, receipt of invasive ventilation, receipt of non-invasive ventilation, use of supplementary oxygen, and acute kidney injury. NSAID use was required to be within the 2 weeks before hospital admission. We used logistic regression to estimate the effects of NSAIDs and adjust for confounding variables. We used propensity score matching to further estimate effects of NSAIDS while accounting for covariate differences in populations. Results Between Jan 17 and Aug 10, 2020, we enrolled 78 674 patients across 255 health-care facilities in England, Scotland, and Wales. 72 179 patients had death outcomes available for matching; 40 406 (56·2%) of 71 915 were men, 31 509 (43·8%) were women. In this cohort, 4211 (5·8%) patients were recorded as taking systemic NSAIDs before admission to hospital. Following propensity score matching, balanced groups of NSAIDs users and NSAIDs non-users were obtained (4205 patients in each group). At hospital admission, we observed no significant differences in severity between exposure groups. After adjusting for explanatory variables, NSAID use was not associated with worse in-hospital mortality (matched OR 0·95, 95% CI 0·84–1·07; p=0·35), critical care admission (1·01, 0·87–1·17; p=0·89), requirement for invasive ventilation (0·96, 0·80–1·17; p=0·69), requirement for non-invasive ventilation (1·12, 0·96–1·32; p=0·14), requirement for oxygen (1·00, 0·89–1·12; p=0·97), or occurrence of acute kidney injury (1·08, 0·92–1·26; p=0·33). Interpretation NSAID use is not associated with higher mortality or increased severity of COVID-19. Policy makers should consider reviewing issued advice around NSAID prescribing and COVID-19 severity. Funding National Institute for Health Research and Medical Research Council.

Background\ud \ud Prognostic models to predict the risk of clinical deterioration in acute COVID-19 cases are urgently required to inform clinical management decisions.\ud \ud \ud Methods\ud \ud We developed and validated a multivariable logistic regression model for in-hospital clinical deterioration (defined as any requirement of ventilatory support or critical care, or death) among consecutively hospitalised adults with highly suspected or confirmed COVID-19 who were prospectively recruited to the International Severe Acute Respiratory and Emerging Infections Consortium Coronavirus Clinical Characterisation Consortium (ISARIC4C) study across 260 hospitals in England, Scotland, and Wales. Candidate predictors that were specified a priori were considered for inclusion in the model on the basis of previous prognostic scores and emerging literature describing routinely measured biomarkers associated with COVID-19 prognosis. We used internal–external cross-validation to evaluate discrimination, calibration, and clinical utility across eight National Health Service (NHS) regions in the development cohort. We further validated the final model in held-out data from an additional NHS region (London).\ud \ud \ud Findings\ud \ud 74 944 participants (recruited between Feb 6 and Aug 26, 2020) were included, of whom 31 924 (43·2%) of 73 948 with available outcomes met the composite clinical deterioration outcome. In internal–external cross-validation in the development cohort of 66 705 participants, the selected model (comprising 11 predictors routinely measured at the point of hospital admission) showed consistent discrimination, calibration, and clinical utility across all eight NHS regions. In held-out data from London (n=8239), the model showed a similarly consistent performance (C-statistic 0·77 [95% CI 0·76 to 0·78]; calibration-in-the-large 0·00 [–0·05 to 0·05]); calibration slope 0·96 [0·91 to 1·01]), and greater net benefit than any other reproducible prognostic model.\ud \ud \ud Interpretation\ud \ud The 4C Deterioration model has strong potential for clinical utility and generalisability to predict clinical deterioration and inform decision making among adults hospitalised with COVID-19.\ud \ud \ud Funding\ud \ud National Institute for Health Research (NIHR), UK Medical Research Council, Wellcome Trust, Department for International Development, Bill & Melinda Gates Foundation, EU Platform for European Preparedness Against (Re-)emerging Epidemics, NIHR Health Protection Research Unit (HPRU) in Emerging and Zoonotic Infections at University of Liverpool, NIHR HPRU in Respiratory Infections at Imperial College London.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Background\ud Hospitalisation due to acute\ud exacerbations of COPD (AECOPD) is common, and\ud subsequent mortality high. The DECAF score was derived\ud for accurate prediction of mortality and risk strati\ud fi\ud cation\ud to inform patient care. We aimed to validate the DECAF\ud score, internally and externally, and to compare its\ud performance to other predictive tools.\ud Methods\ud The study took place in the two hospitals\ud within the derivation study (internal validation) and in\ud four additional hospitals (external validation) between\ud January 2012 and May 2014. Consecutive admissions\ud were identi\ud fi\ud ed by screening admissions and searching\ud coding records. Admission clinical data, including DECAF\ud indices, and mortality were recorded. The prognostic\ud value of DECAF and other scores were assessed by the\ud area under the receiver operator characteristic (AUROC)\ud curve.\ud Results\ud In the internal and external validation cohorts,\ud 880 and 845 patients were recruited. Mean age was\ud 73.1 (SD 10.3) years, 54.3% were female, and mean\ud (SD) FEV\ud 1\ud 45.5 (18.3) per cent predicted. Overall\ud mortality was 7.7%. The DECAF AUROC curve for\ud inhospital mortality was 0.83 (95% CI 0.78 to 0.87) in\ud the internal cohort and 0.82 (95% CI 0.77 to 0.87) in\ud the external cohort, and was superior to other\ud prognostic scores for inhospital or 30-day mortality.\ud Conclusions\ud DECAF is a robust predictor of mortality,\ud using indices routinely available on admission. Its\ud generalisability is supported by consistent strong\ud performance; it can identify low-risk patients (DECAF\ud 0\ud –\ud 1) potentially suitable for Hospital at Home or early\ud supported discharge services, and high-risk patients\ud (DECAF 3\ud –\ud 6) for escalation planning or appropriate early\ud palliation.\ud Trial registration number\ud UKCRN ID 14214.

Background and objective Measuring adherence to inhaled asthma treatment is a key priority for asthma care. The aim of this study was to determine the relationship between self-report and actual medication use as measured by electronic monitoring for single and combination inhaled corticosteroid (ICS) and long-acting beta-agonist (LABA) metered-dose inhaler therapy. Methods In this retrospective analysis from a previously completed prospective 24-week randomized, controlled trial of single or combination ICS/LABA therapy, medication use in the week prior to study visits determined by self-report questionnaire and electronic monitoring was compared. One hundred eleven participants received 125 µg fluticasone dipropionate and 25 µg salmeterol, two actuations twice daily, by either separate or combination ICS/LABA inhalers. Paired data for self-report and electronic monitoring were analysed. Measurement of agreement was by Bland–Altman-like plots by visit with calculation of limits of agreement. Results For single and combination ICS/LABA therapy, self-report consistently overestimated actual inhaler use assessed by electronic monitoring by a mean of 2.2–8.4 inhalations over a 1-week period, with limits of agreement ranging from ±15.8 to 25.6 inhalations. Participants who underused their inhalers tended to overreport their use, while those who overused tended to underreport their medication use. The greater the degree of underuse, the greater the magnitude of overreport, and likewise, the greater the degree of overuse, the greater the magnitude of underreport. Conclusions Self-report is inaccurate in measuring actual use of inhaled asthma treatment with patients who underuse their maintenance therapy overreporting their use and those who overuse their therapy underreporting their use.

Background One in three patients hospitalised due to acute exacerbation of COPD (AECOPD) is readmitted within 90 days. No tool has been developed specifically in this population to predict readmission or death. Clinicians are unable to identify patients at particular risk, yet resources to prevent readmission are allocated based on clinical judgement. Methods In participating hospitals, consecutive admissions of patients with AECOPD were identified by screening wards and reviewing coding records. A tool to predict 90-day readmission or death without readmission was developed in two hospitals (the derivation cohort) and validated in: (a) the same hospitals at a later timeframe (internal validation cohort) and (b) four further UK hospitals (external validation cohort). Performance was compared with ADO, BODEX, CODEX, DOSE and LACE scores. Results Of 2417 patients, 936 were readmitted or died within 90 days of discharge. The five independent variables in the final model were: Previous admissions, eMRCD score, Age, Right-sided heart failure and Left-sided heart failure (PEARL). The PEARL score was consistently discriminative and accurate with a c-statistic of 0.73, 0.68 and 0.70 in the derivation, internal validation and external validation cohorts. Higher PEARL scores were associated with a shorter time to readmission. Conclusions The PEARL score is a simple tool that can effectively stratify patients9 risk of 90-day readmission or death, which could help guide readmission avoidance strategies within the clinical and research setting. It is superior to other scores that have been used in this population. Trial registration number UKCRN ID 14214.

Objective To determine whether high concentration oxygen increases the PaCO2 in the treatment of community-acquired pneumonia. Design Randomized controlled clinical trial in which patients received high concentration oxygen (8 L/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93 and 95%) for 60 minutes. Transcutaneous CO2 (PtCO2) was measured at 0, 20, 40 and 60 minutes. Setting The Emergency Departments at Wellington, Hutt and Kenepuru Hospitals. Participants 150 patients with suspected community-acquired pneumonia presenting to the Emergency Department. Patients with chronic obstructive pulmonary disease (COPD) or disorders associated with hypercapnic respiratory failure were excluded. Main outcome variables The primary outcome variable was the proportion of patients with a rise in PtCO2 ≥4 mmHg at 60 minutes. Secondary outcome variables included the proportion of patients with a rise in PtCO2 ≥8 mmHg at 60 minutes. Results The proportion of patients with a rise in PtCO2 ≥4 mmHg at 60 minutes was greater in the high concentration oxygen group, 36/72 (50.0%) vs 11/75 (14.7%), relative risk (RR) 3.4 (95% CI 1.9 to 6.2), P < 0.001. The high concentration group had a greater proportion of patients with a rise in PtCO2 ≥8 mmHg, 11/72 (15.3%) vs 2/75 (2.7%), RR 5.7 (95% CI 1.3 to 25.0), P = 0.007. Amongst the 74 patients with radiological confirmation of pneumonia, the high concentration group had a greater proportion with a rise in PtCO2 ≥4 mmHg, 20/35 (57.1%) vs 5/39 (12.8%), RR 4.5 (95% CI 1.9 to 10.6) P < 0.001. Conclusions We conclude that high concentration oxygen therapy increases the PtCO2 in patients presenting with suspected community-acquired pneumonia. This suggests that the potential increase in PaCO2 with high concentration oxygen therapy is not limited to COPD, but may also occur in other respiratory disorders with abnormal gas exchange.

The effect on Paco2 of high concentration oxygen therapy when administered to patients with severe exacerbations of asthma is uncertain.106 patients with severe exacerbations of asthma presenting to the Emergency Department were randomised to high concentration oxygen (8 l/min via medium concentration mask) or titrated oxygen (to achieve oxygen saturations between 93% and 95%) for 60 min. Patients with chronic obstructive pulmonary disease or disorders associated with hypercapnic respiratory failure were excluded. The transcutaneous partial pressure of carbon dioxide (Ptco2) was measured at 0, 20, 40 and 60 min. The primary outcome variable was the proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min.The proportion of patients with a rise in Ptco2 ≥4 mm Hg at 60 min was significantly higher in the high concentration oxygen group, 22/50 (44%) vs. 10/53 (19%), RR 2.3 (95% CI 1.2 to 4.4, p0.006). The high concentration group had a higher proportion of patients with a rise in Ptco2 ≥8 mm Hg, 11/50 (22%) vs. 3/53 (6%), RR 3.9 (95% CI 1.2 to 13.1, p=0.016). All 10 patients with a final Ptco2 ≥45 mm Hg received high concentration oxygen therapy, and in five there was an increase in Ptco2 ≥10 mm Hg.High concentration oxygen therapy causes a clinically significant increase in Ptco2 in patients presenting with severe exacerbations of asthma. A titrated oxygen regime is recommended in the treatment of severe asthma, in which oxygen is administered only to patients with hypoxaemia, in a dose that relieves hypoxaemia without causing hyperoxaemia. Clinical trial number ACTRN12607000131459.

Background It is unknown whether oxygen therapy causes worsening hypercapnia in patients with obesity-associated hypoventilation (OAH), similar to the response observed in COPD. The objectives of this study were to investigate whether breathing 100% oxygen results in an increase in hypercapnia in patients with OAH and the mechanisms of any effect. Methods In this double-blind, randomized, controlled, crossover trial, 24 outpatients with newly diagnosed OAH inhaled 100% oxygen or room air for 20 min on 2 separate days. Transcutaneous CO 2 tension (Ptco 2 ), minute ventilation, and volume of dead space to tidal volume ratio were measured at baseline and at 20 min. A mixed linear model was used to determine differences between the two treatments. Results The study was terminated in three subjects breathing 100% oxygen due to a Ptco 2 increase ≥ 10 mm Hg, which occurred after 10:35, 13:20, and 15:51 min. Ptco 2 increased by 5.0 mm Hg (95% CI, 3.1–6.8; P P = .03), and volume of dead space to tidal volume ratio increased by 0.067 (95% CI, 0.035–0.10; P Conclusions Breathing 100% oxygen causes worsening hypercapnia in stable patients with OAH. Trial registry Australia New Zealand Clinical Trials Registry; No.: ACTRN 12608000592347; URL: www.anzctr.org.au.

Background and Objective: The CRB65 score, a risk stratification method validated for use in community-acquired pneumonia, has recently been shown to have utility in acute exacerbations of COPD (AECOPD). The objective of this study was to independently validate the CRB65 score as a predictor of mortality in patients who required hospital admission with AECOPD. Methods: The medical records of patients admitted to Wellington Hospital with AECOPD during a 12-month period from June 2006 were reviewed. Logistic regression was used to determine the strength of the association between the CRB65 score and death at three measurement times: in-hospital, 30 days and 12 months. Results: Complete data were available in 133/174 patient admissions. In-hospital and 30-day mortality increased progressively with increasing CRB65 score and was markedly higher in the CRB 3–4 group (3%, 5%, 29%, and 4%, 9%, 43% for CRB65 scores 0–1, 2, 3–4 for in-hospital and 30-day mortality, respectively). Differences in 1-year mortality were less apparent (24%, 25%, 57% for CRB65 scores 0–1, 2, 3–4, respectively). The CRB65 score demonstrated a modest value for predicting in-hospital and 30-day mortality with a c statistic of 0.68 at both time points. Conclusions: The CRB65 score shows similar characteristics for predicting short-term mortality in AECOPD as its use in community-acquired pneumonia. We recommend its use in clinical practice, particularly in patients with a score ≥3, which is associated with a high risk of early mortality, and need for intensive hospital management.

To streamline the investigation and referral process of new unilateral pleural effusions by setting up a dedicated pleural clinic, based on British Thoracic Society 2010 guidelines. It was noticed that there were delays in investigating patients with new unilateral pleural effusions and associated

Background The inhaled corticosteroid (ICS)/long-acting β-agonist (LABA) combination inhaler has the potential to improve adherence with ICS therapy in asthma. Objective To determine whether ICS/LABA combination inhaler therapy improves adherence compared with separate inhaler use. Methods In a 24-week randomized controlled parallel group study, 111 subjects were prescribed 125 μg fluticasone dipropionate (FP) and 25 μg salmeterol, 2 actuations twice daily through either a combination inhaler or separate inhalers concurrently. Medication use was recorded by covert electronic monitors. The primary outcome variable was adherence during the final 6-week period, defined as the number of doses taken as a percentage of those prescribed. Results Complete adherence data from the final 6-week period were available for 49 and 54 subjects in the separate and combination groups, respectively. The mean (SD) adherence was 73.7% (36.0) for FP, 76.7% (30.5) for salmeterol, and 82.4% (24.5) for FP/salmeterol. There were no significant differences in adherence between FP/salmeterol and FP (–8.7%; 95% CI, –10.6 to 3.3) and salmeterol (–5.6%; 95% CI, –16.4 to 5.1). There was no significant difference in overuse among the FP, salmeterol, or FP/salmeterol groups. In 2 (4%) of 49 subjects, salmeterol was effectively taken as monotherapy during a 6-week period. Conclusion In the setting of a randomized controlled trial, use of a combination ICS/LABA inhaler does not markedly increase adherence above that observed with separate inhaler use. LABA monotherapy was observed in a small proportion of patients prescribed ICS and LABA therapy via separate inhalers.

There is uncertainty whether long-acting beta-agonist (LABA) drugs may increase the risk of asthma mortality. This uncertainty is partly due to the difficulty in estimating the risk of rare adverse outcomes. The aim of this paper is to consider the utility of three approaches to determine the magnitude and statistical significance of this potential association.Using a death rate of 9 per 10,000 subjects with asthma, derived from a meta-analysis of randomized controlled trials (RCTs) of formoterol, power calculations for a single RCT, a case-control study, and a meta-analysis of RCTs were determined.For each study design, the number of subjects and events required to have adequate statistical power to detect a 1.5- and 2.0-fold increased risk of death were calculated. For a single RCT, or meta-analyses of RCTs, very large sample sizes are required. In contrast, case-control methodology represents a realistic method of estimating the risk of rare serious adverse events.Major practical limitations exist in the use of RCTs to determine the potential risk of death with LABAs in the treatment of asthma. Case-control methodology may be more effective in establishing causation; however, if selection bias occurs, estimates of risk may be inaccurate.

Background Pulse oximetry non-invasively assesses the arterial oxygen saturation of patients with acute respiratory disease; however, measurement of the arterial partial pressure of carbon dioxide (PaCO(2)) requires an arterial blood gas. The transcutaneous partial pressure of carbon dioxide (PtCO(2) ) has been used in other settings with variable accuracy. We investigated the accuracy of a PtCO(2) device in the assessment of PaCO(2) in patients with asthma and suspected pneumonia attending the emergency department. Methods Patients with severe asthma (FEV(1) 18/min) were enrolled. Subjects were excluded if they had a history of chronic obstructive pulmonary disease or other conditions associated with respiratory failure. Arterial blood gases were taken at the discretion of the investigator according to clinical need, and paired with a simultaneous reading from the PtCO(2) probe. Results Twenty-five patients were studied with one set of data excluded because of poor PtCO(2) signal quality. The remaining 24 paired samples comprised 12 asthma and 12 pneumonia patients. The range of PaCO(2) was 19-64 mmHg with a median of 36.5 mmHg. Bland-Altman analysis showed a mean (SD) PaCO(2) - PtCO(2) difference of -0.13 (1.9) mmHg with limits of agreement of plus or minus 3.8 mmHg (-3.9 to +3.7). Conclusion A PtCO(2) device was accurate in the assessment of PaCO(2) in patients with acute severe asthma and suspected pneumonia when compared with an arterial blood gas. These bedside monitors have the potential to improve patient care by non-invasively monitoring patients with acute respiratory disease at risk of hypercapnia.

Background: High concentration oxygen is commonly administered during acute exacerbations of chronic obstructive pulmonary disease (AECOPD). The aim of this study was to determine the association between oxygen, severity markers and poor outcomes in AECOPD. Methods: In an audit of patients with AECOPD arriving by ambulance to the Emergency Department of Wellington Hospital, details of oxygen administration, clinical outcomes and severity markers were documented. The main outcome measure was a composite of death, assisted ventilation, or respiratory failure. Associations between oxygen therapy, severity markers and poor clinical outcomes were assessed by logistic regression. Results: Of 250 patients 77 (31%) died, required assisted ventilation or were in respiratory failure. Increased oxygen flow was associated with increasing risk of death, assisted ventilation or respiratory failure with an odds ratio (OR) of 1.2 (95% CI 1.0–1.4) per 1 L/min oxygen flow. Increasing PaO2 was associated with a greater risk of a poor outcome with an OR of 1.1 (95% CI 1.0–1.3) per 10 mmHg higher PaO2. Home oxygen (OR 2.8, 95% CI 1.5–5.1), previous respiratory failure (OR 2.6, 95% CI 1.5–4.6), previous ventilation (OR 3.2, 95% CI 1.7–5.9) and home nebulizer use (OR 2.4, 95% CI 1.4–4.3) were associated with an increased risk of a poor outcome. Conclusion: In AECOPD high flow oxygen in the ambulance is associated with poor clinical outcomes. A number of easily identified markers of chronic disease severity indicate an increased risk of a poor clinical outcome.

Problem The need to improve the prescription, administration and monitoring of oxygen therapy. Design An interventional, prospective audit. Background and setting Wellington Hospital, a teaching and tertiary referral hospital in New Zealand in 2007 and 2008. Key measures for improvement Demonstration of adequate oxygen prescribing, administration and monitoring of oxygen therapy. Strategies for improvement The introduction of a new drug chart with a specific oxygen prescription section. Targeted educational lectures primarily to medical staff. Effects of change 610 and 566 patients were reviewed in the first and second audits. After introduction of the new oxygen prescription section on the drug chart the proportion of patients whose oxygen therapy was prescribed increased from 15/85 (17.6%) to 39/98 (39.8%), relative risk 2.3 (95% CI 1.3 to 3.9). The proportion with adequate oxygen prescription, with documentation of device, flow rate or inspired oxygen concentration, and the target oxygen saturation increased from 5/85 (5.9%) to 36/98 (36.7%), relative risk 6.2 (95% CI 2.5 to 15.0). Introduction of the new charts was not associated with changes in clinical practice in terms of assessment of oxygen saturations on room air and commencement if ≤92%, or the titration of oxygen therapy in response to oxygen saturations ≤92%. Lessons learnt An oxygen prescription section on hospital drug charts improved the prescription of oxygen but did not improve clinical practice. Additional strategies are required to improve the administration of oxygen therapy in hospitals.

Background: There is concern that long-acting β agonist (LABA) drugs may increase the risk of asthma mortality. Methods: A meta-analysis was conducted of asthma deaths in randomised controlled clinical trials from the GlaxoSmithKline database that compared salmeterol with a non-LABA comparator treatment in asthma. The Peto one-step method was used to determine the risk overall (all studies) and in derived datasets based on inhaled corticosteroid (ICS) use. Results: There were 35 asthma deaths in 215 studies with 106 575 subjects. Two studies (SMART and SNS) contributed 30/35 (86%) asthma deaths, the overall findings largely reflecting the characteristics of these studies. The odds ratio for risk of asthma mortality with salmeterol was 2.7 (95% CI 1.4 to 5.3). In 54 placebo controlled studies the risk of death from asthma in patients not prescribed ICS was 7.3 (95% CI 1.8 to 29.4). In 127 studies in which patients were prescribed ICS, the risk of asthma death was 2.1 (95% CI 0.6 to 7.9). In 63 studies in which patients were randomised to receive the combination salmeterol/fluticasone propionate inhaler or ICS, there were no asthma deaths among 22 600 patients. Conclusions: Salmeterol monotherapy in asthma increases the risk of asthma mortality and this risk is reduced with concomitant ICS therapy. There is no evidence that combination salmeterol/fluticasone propionate therapy is associated with an increased risk of asthma mortality, although this interpretation is limited by the low statistical power of available studies.

There is concern long-acting beta-agonist (LABA) drugs may increase the risk of asthma mortality. We undertook a systematic review which included the AstraZeneca Formoterol Clinical Trial Safety Database and Novartis Food and Drug Administration Formoterol Briefing Document. Randomised controlled clinical trials of durationor = 4 weeks that compared formoterol with a non-LABA comparator treatment in asthma were included in a meta-analysis of the risk of all-cause mortality and asthma death. Simple contingency tables, Peto's one-step method and a Bayesian analysis were used. There were 42 deaths (nine from asthma) recorded in 62 studies with 49,327 subjects. The simple contingency table odds ratio for risk of all-cause mortality with formoterol was 1.1 (95% CI 0.6-2.2) and for asthma death was 2.7 (95% CI 0.5-26.7). Analyses by the other methods using both "as randomised" and "as exposed" classifications of treatment gave similar risk estimates with wide confidence and credible intervals. We conclude that there was insufficient power to determine whether formoterol increases the risk of mortality. However, the point estimates of a 2.0- to 3.2-fold increased risk of asthma death are not reassuring and add weight to evidence that LABA use in certain circumstances may increase the risk of asthma mortality.

Background International guidelines recommend the routine use of oxygen in the initial treatment of myocardial infarction, yet it is uncertain what effect this might have on physiologic and clinical outcomes. Methods We undertook a systematic search of Medline, Cochrane Database of Systematic Reviews, EMBASE, and CINHAL using the key words "oxygen," "coronary blood flow," "hyperoxia," and "coronary circulation" to identify human studies involving a measure of coronary blood flow while breathing oxygen and room air. The primary outcome measure was coronary blood flow; secondary outcomes included coronary vascular resistance and myocardial oxygen consumption. Results From 2,072 potential publications, there were 6 studies from 4 publications that met the inclusion criteria, with 6 healthy subjects and 61 subjects with cardiac disease. It was not possible to undertake a meta-analysis due to methodological limitations. In the 6 studies, high-concentration oxygen therapy resulted in hyperoxia, with a range in mean Pao 2 of 273 to 425 mm Hg. Hyperoxia caused a significant reduction in coronary blood flow (mean change −7.9% to −28.9%, n=6 studies). Hyperoxia caused a significant increase in coronary vascular resistance (mean change 21.5% to 40.9%, n=4 studies) and a significant reduction in myocardial oxygen consumption (mean change −15.3% to −26.9%, n=3 studies). Conclusions Hyperoxia from high-concentration oxygen therapy causes a marked reduction in coronary blood flow and myocardial oxygen consumption. These physiologic effects may have the potential to cause harm and are relevant to the use of high-concentration oxygen therapy in the treatment of cardiac and other disorders.

Background International time trends in asthma mortality have played an important sentinel role in the identification of two epidemics of asthma mortality in some countries in the 1960s and the 1970s and 1980s. Since then, little attention has been paid to the ongoing international time trends. Methods Country-specific data on asthma mortality rates since 1960 in the 5- to 34-year-old age group were collated. To be included in the analysis, countries were required to have data available prior to 1980. A scatter plot smoothing technique was used to model the change in asthma mortality rates with time. Results Asthma mortality rates from 20 countries were included in the analysis. An increase in asthma mortality rates was found in the 1960s, with a mean increase of 53% from 0.55 per 100,000 in 1960 and 1961 to a peak of 0.84 in 1966 and 1967. This trend was followed by a progressive decline to a nadir of 0.45 per 100,000 in 1974 and 1975. A gradual increase was then found in asthma mortality rates to a peak of 0.62 per 100,000 in 1985 and 1986, with a mean increase of 38% during this period. Since the late 1980s, there has been a widespread and progressive reduction in mortality rates to a level of 0.23 per 100,000 in 2004 and 2005, with a mean reduction of 63% during this period. Conclusions The widespread increase in asthma mortality in the 1980s and the subsequent, even greater reduction has largely gone unrecognized. We propose that awareness of such trends and their causes is important and that they are investigated contemporaneously.

Context: International guidelines recommend the routine use of oxygen therapy in the treatment of myocardial infarction (MI). Objective: To undertake a systematic review and metaanalysis of randomised placebo-controlled trials of oxygen therapy in MI. Data sources: Medline, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, EMBASE and CINHAL. Study selection: Randomised placebo-controlled trials of oxygen therapy in MI. Data extraction: The primary clinical outcome was mortality. Results: Two of 51 potential studies met the inclusion criteria. The one study with substantive clinical outcome data reported that in uncomplicated MI, high-flow oxygen was associated with a non-significant increased risk of death (risk ratio 2.9, 95% CI 0.8 to 10.3, p = 0.08) and a greater serum aspartate aminotransferase level (difference 19.2 IU/ml, 95% CI 0 to 38.4, p = 0.05) than room air. Conclusion: The limited evidence that does exist suggests that the routine use of high-flow oxygen in uncomplicated MI may result in a greater infarct size and possibly increase the risk of mortality.

This article reviews the available evidence as to whether inhaled long acting β-agonists (LABA) increase the risk of asthma mortality and considers the implications for the use of this treatment in the management of asthma. Randomised controlled trials suggest that LABAs prescribed as monotherapy may increase the risk of asthma death in certain circumstances, such as the unsupervised “off-label” use without concomitant inhaled corticosteroid (ICS) treatment in patients with unstable asthma. However, there is also evidence that the use of LABAs in conjunction with ICS treatment in adult asthma as recommended in current guidelines is not associated with an increased risk of asthma mortality. The only way in which a prescriber can ensure that a patient with asthma takes LABA treatment in conjunction with ICS is through a combination ICS/LABA product, an approach which may have additional therapeutic advantages. We propose that in the management of asthma, a case can now be made to limit the availability of LABAs to combination LABA/ICS therapy.

Summary Objective To determine the strength of association between the dose of inhaled corticosteroids (ICS) and risk of non-vertebral fracture in adults. Methods A systematic review and meta-analysis of case–control studies of non-vertebral fractures in adults, in which at least two doses of ICS were reported as the dose of beclomethasone dipropionate (BDP) or equivalent. Results Five case–control studies were identified, with a total of 43 783 cases and 259 936 controls. There was an association between the risk of non-vertebral fracture and increasing dose of BDP. The random-effects odds ratio of relative risk for a non-vertebral fracture was 1.12 (95% confidence interval 1.00–1.26) per 1000 μg increase in the daily dose of BDP or equivalent. Conclusion In older adults, the relative risk of non-vertebral fractures increases by about 12% for each 1000 μg/day increase in the dose of BDP or equivalent. The magnitude of this risk was considerably less than other common risk factors for fracture in the older adult.

Background: Accurate prognostication and risk stratification in patients hospitalised due to acute exacerbations of chronic obstructive pulmonary disease (AECOPD) could improve patient care. The DECAF score accurately predicted mortality in its derivation cohort and the British Thoracic Society 2014 national audit recommended the score is collected on all patients admitted with AECOPD. We present the internal and external validation of the DECAF score to describe its performance in a diverse UK population. Methods: Six UK hospitals recruited consecutive admissions from January 2012-May 2014. Admission clinical data, including DECAF indices, and mortality were recorded. The prognostic value of DECAF, and other prognostic scores (APACHE II, BAP-65, CAPS, CURB-65), were assessed and compared by the area under the receiver operator characteristic (AUROC) curve. Results: In the internal and external validation cohorts, 880 and 845 patients were recruited. Mean age was 73.1 (SD 10.3) years, 54.3% were female, and mean (SD) FEV1 45.5 (18.3) % predicted. Overall mortality was 7.7%. The DECAF AUROC curve for in-hospital mortality was 0.83 (95% CI 0.78-0.87) in the internal cohort, 0.82 (95% CI 0.77-0.87) in the external cohort and superior to other prognostic scores for in-hospital or 30-day mortality. Conclusions: DECAF is simple to apply and a robust predictor of mortality. Its generalisability is supported by consistent strong performance in a diverse multicentre study. Its application could improve patient outcomes by identifying low risk patients potentially suitable for Hospital at Home or Early Supported Discharge services, and high risk patients for escalation planning or appropriate early palliation.

INTRODUCTION: The purpose of the quality standards document is to provide healthcare professionals, commissioners, service providers and patients with a guide to standards of care that should be met for home oxygen provision in the UK, together with measurable markers of good practice. Quality statements are based on the British Thoracic Society (BTS) Guideline for Home Oxygen Use in Adults.METHODS: Development of BTS Quality Standards follows the BTS process of quality standard production based on the National Institute for Health and Care Excellence process manual for the development of quality standards.RESULTS: 10 quality statements have been developed, each describing a key marker of high-quality, cost-effective care for home oxygen use, and each statement is supported by quality measures that aim to improve the structure, process and outcomes of healthcare.DISCUSSION: BTS Quality Standards for home oxygen use in adults form a key part of the range of supporting materials that the society produces to assist in the dissemination and implementation of a guideline's recommendations.

Background Exacerbation of COPD is the second commonest reason for hospital admission, with high subsequent readmission and mortality rates among those who survive to discharge. Risk stratification would inform efficient use of services. Methods Consecutive patients admitted with an exacerbation of COPD who survived to discharge were recruited by screening admissions units and searching coding records. Six UK hospitals took part: the derivation and internal validation cohort involved the same two hospitals at different time periods, and the external validation involved four hospitals. Clinical data, and 90-day death and readmission rates were recorded. Multivariate logistic regression analysis was used to develop a tool to predict 90-day readmission, or death without readmission. Performance was assessed by the area under the receiver operator characteristic (AUROC) curve. Results 2,417 patients were analysed (derivation 824, internal validation 824, external validation 791). Female 54.0%, mean (SD) age 72.6 (10.2) years, FEV1 45.3 (18.2) %predicted, 90-day readmission or death 38.7%. In the derivation cohort, the five strongest predictors (odds ratio, 95% confidence interval given for whole population) were: two or more Previous admissions in the preceding year (OR 3.17, 95% CI 2.59–3.87), stable-state dyspnoea assessed by the Extended MRCD score (eMRCD 4 OR 1.46, 95% CI 1.12–1.90; eMRCD 5a OR 2.35 95% CI 1.79–3.08; eMRCD 5b OR 3.00 95% CI 2.19–4.11), Age 80 or more (OR 1.48, 95% CI 1.22–1.81), cor-pulmonale “Right heart failure” (OR 1.93, 95% CI 1.41–2.66), Left heart failure (OR 1.45, 95% CI 1.07–1.97). Two or more previous admissions and eMRCD 5b were assigned a score of 3, eMRCD 5a scored 2, while eMRCD 4 and remaining indices scored 1. The risk of readmission and/or death is shown in Table 1. The AUROC was: derivation 0.73 (95% CI 0.69–0.77); internal validation 0.68 (95% CI 0.64–0.72); and external validation 0.70 (95% CI 0.66–0.73). Discussion In patients hospitalised with an exacerbation of COPD the PEARL score is a robust predictor of readmission and death and may be used to inform efficient use of resources according to risk.

Background Titrated oxygen has been shown to significantly reduce mortality in patients presenting with acute exacerbations of chronic obstructive pulmonary disease (COPD) 1 . All patients at risk of type 2 respiratory failure (T2RF) should be administered oxygen in accordance with British Thoracic Society Guidelines. However, the NEWS system proposed by the Royal College of Physicians makes no allowance for patients at risk of T2RF and may lead to potential over oxygenation in this group of patients 2 . Objective To assess the use of the NEWS in patients with T2RF in our district general hospital and to assess the safety of a modified system. Methods Patients were selected from the Medical Admissions Unit. Inclusion criteria were oxygen prescription or oxygen in situ . Data were collected over 5 consecutive days. Conventional NEWS for these patients were compared with a system currently being piloted at Salford Royal Foundation Trust with modified oxygen saturation levels (SpO2) for patients at risk of T2RF (Table 1) Results 69 patients were assessed. 32% (22/69) had risk factors for T2RF. 21 had COPD and one had sleep apnoea. 55% (12/22) had oxygen saturations in their target range or were above target saturations but on air. 32% (7/22) were on oxygen and had saturations above 92%. 14% (3/22) had saturations below 88%. 73% (16/22) of at risk patients had their scores altered when using the Salford EWS system. 69% (11/16) of these patients had their scores reduced. 4 patient’s scores were reduced by 3, 4 were reduced by 2 and 3 were reduced by 1. 31% (5/16) of patient’s scores were increased. 4 scores were increased by 2 and 1 increased by 1. The score differences were due to over oxygenation. Conclusions The current NEWS system appears to increase the risk of over oxygenation in patients at risk of T2RF. Using a modified score for patients at risk of T2RF will reduces this risk. With thanks Ronan O’Driscoll, Salford Foundation Trust for use of the modified Salford NEWS chart

We appreciate the comments by Snelson and Tunnicliffe1 regarding our study of the effects of high concentration oxygen therapy in acute exacerbations of asthma.2 We concur with the view that the effect of high concentration oxygen therapy on arterial carbon dioxide pressure (PaCO2) is not clinically relevant in all patients presenting to the emergency department (ED) with acute severe asthma. However, we consider that the 3.9-fold …