Spatio-temporal modelling of referrals to outpatient respiratory clinics in the integrated care system of the Morecambe Bay area, England.

BACKGROUND: Promoting integrated care is a key goal of the NHS Long Term Plan to improve population respiratory health, yet there is limited data-driven evidence of its effectiveness. The Morecambe Bay Respiratory Network is an integrated care initiative operating in the North-West of England since 2017. A key target area has been reducing referrals to outpatient respiratory clinics by upskilling primary care teams. This study aims to explore space-time patterns in referrals from general practice in the Morecambe Bay area to evaluate the impact of the initiative. METHODS: Data on referrals to outpatient clinics and chronic respiratory disease patient counts between 2012-2020 were obtained from the Morecambe Bay Community Data Warehouse, a large store of routinely collected healthcare data. For analysis, the data is aggregated by year and small area geography. The methodology comprises of two parts. The first explores the issues that can arise when using routinely collected primary care data for space-time analysis and applies spatio-temporal conditional autoregressive modelling to adjust for data complexities. The second part models the rate of outpatient referral via a Poisson generalised linear mixed model that adjusts for changes in demographic factors and number of respiratory disease patients. RESULTS: The first year of the Morecambe Bay Respiratory Network was not associated with a significant difference in referral rate. However, the second and third years saw significant reductions in areas that had received intervention, with full intervention associated with a 31.8% (95% CI 17.0-43.9) and 40.5% (95% CI 27.5-50.9) decrease in referral rate in 2018 and 2019, respectively. CONCLUSIONS: Routinely collected data can be used to robustly evaluate key outcome measures of integrated care. The results demonstrate that effective integrated care has real potential to ease the burden on respiratory outpatient services by reducing the need for an onward referral. This is of great relevance given the current pressure on outpatient services globally, particularly long waiting lists following the COVID-19 pandemic and the need for more innovative models of care.

Clinimetric Properties of Outcome Measures in Bronchiectasis.

Rationale: There is a lack of outcome measures with robust clinimetric properties in bronchiectasis. Objectives: To determine the clinimetric properties (reliability over 1 year during clinical stability and responsiveness over the course of antibiotics for pulmonary exacerbation) of objective and patient-reported outcome measures. Methods: This multicenter cohort study included adults with bronchiectasis from seven hospitals in the United Kingdom. Participants attended four visits, 4 months apart over 1 year while clinically stable and at the beginning and end of exacerbation and completed lung function (spirometry and multiple breath washout), provided a blood sample for C-reactive protein (CRP) measurement, and completed health-related quality of life (HRQoL) questionnaires (Quality of Life-Bronchiectasis, St. George's Respiratory Questionnaire, and EuroQoL 5-Dimensions 5-Levels). Results: Participants (n = 132) had a mean (standard deviation) age of 66 (11) years, and 64% were female. Lung function parameters (forced expiratory volume in one second [FEV1], standard lung clearance index [LCI2.5]) were reliable over time [coefficient of variation (CV): <10%]). Regarding responsiveness, FEV1 demonstrated better properties than LCI2.5; therefore, a clear justification for the use of LCI2.5 in future trials is needed. CRP was less reliable (CV > 20%) over time than FEV1 and LCI2.5, and whereas CRP had a large mean change between the start and end of an exacerbation, this may have been driven by a small number of patients having a large change in CRP. Reliability of HRQoL questionnaires and questionnaire domains ranged from acceptable (CV: 20-30%) to good (CV: 10-20%), and HRQoL were responsive to treatment of exacerbations. Considering the specific questionnaire domain relevant to the intervention and its associated clinimetric properties is important. Additional statistics will support future power and/or sample size analysis. Conclusions: This information on the clinimetric properties of lung function parameters, CRP, and HRQoL parameters should be used to inform the choice of outcome measures used in future bronchiectasis trials.

Multiple-Breath Washout Outcome Measures in Adults with Bronchiectasis.

Rationale: Lung clearance index (LCI) has good intravisit repeatability with better sensitivity in detecting lung disease on computed tomography scan compared with forced expiratory volume in 1 second (FEV1) in adults with bronchiectasis. Alternative multiple-breath washout parameters have not been systematically studied in bronchiectasis. Objectives: To determine the validity, repeatability, sensitivity, specificity, and feasibility of standard LCI (LCI2.5), shortened LCI (LCI5.0), ventilation heterogeneity arising within proximal conducting airways (ScondVT), and ventilation heterogeneity arising within the acinar airways (SacinVT) in a cross-sectional observational cohort of adults with bronchiectasis. Methods: Cross-sectional multiple-breath nitrogen washout data (Exhalyzer D; Eco Medics AG) from 132 patients with bronchiectasis across five United Kingdom centers (BronchUK Clinimetrics study) and 88 healthy control subjects were analyzed. Results: Within-test repeatability (mean coefficient of variation) was <5% for both LCI2.5 and LCI5.0 in patients with bronchiectasis, and there was no difference in mean coefficient of variation for LCI2.5 and LCI5.0 in patients with bronchiectasis compared with healthy volunteers. Moderate-strength correlations were seen between FEV1 and LCI2.5 (r = -0.54), LCI5.0 (r = -0.53), ScondVT (r = -0.35), and SacinVT (r = -0.38) z-scores. The proportion of subjects with abnormal multiple-breath washout (z-score > 2) but in normal FEV1 (z-score < -2) was 42% (LCI2.5) and 36% (LCI5.0). Overall results from the receiver operating characteristic curve analysis indicated that LCI2.5 had the greatest combined sensitivity and specificity to discriminate between bronchiectasis and control subjects, followed by LCI5.0, FEV1, and ScondVT z-scores. There was a 57% time saving with LCI5.0. Conclusions: LCI2.5 and LCI5.0 had good within-test repeatability and superior sensitivity compared with spirometry measures in differentiating between health and bronchiectasis disease. LCI5.0 is quicker and more feasible than LCI2.5. Clinical trial registered with www.clinicaltrials.gov (NCT02468271).

Multiple breath washout in bronchiectasis clinical trials: is it feasible?

BACKGROUND: Evaluation of multiple breath washout (MBW) set-up including staff training, certification and central "over-reading" for data quality control is essential to determine the feasibility of MBW in future bronchiectasis studies. AIMS: To assess the outcomes of a MBW training, certification and central over-reading programme. METHODS: MBW training and certification was conducted in European sites collecting lung clearance index (LCI) data in the BronchUK Clinimetrics and/or i-BEST-1 studies. The blended training programme included the use of an eLearning tool and a 1-day face-to-face session. Sites submitted MBW data to trained central over-readers who determined validity and quality. RESULTS: Thirteen training days were delivered to 56 participants from 22 sites. Of 22 sites, 18 (82%) were MBW naïve. Participant knowledge and confidence increased significantly (p<0.001). By the end of the study recruitment, 15 of 22 sites (68%) had completed certification with a mean (range) time since training of 6.2 (3-14) months. In the BronchUK Clinimetrics study, 468 of 589 (79%) tests met the quality criteria following central over-reading, compared with 137 of 236 (58%) tests in the i-BEST-1 study. CONCLUSIONS: LCI is feasible in a bronchiectasis multicentre clinical trial setting; however, consideration of site experience in terms of training as well as assessment of skill drift and the need for re-training may be important to reduce time to certification and optimise data quality. Longer times to certification, a higher percentage of naïve sites and patients with worse lung function may have contributed to the lower success rate in the i-BEST-1 study.

Quality control for multiple breath washout tests in multicentre bronchiectasis studies: Experiences from the BRONCH-UK clinimetrics study.

INTRODUCTION: Multiple Breath Washout (MBW) to measure Lung Clearance Index (LCI) is increasingly being used as a secondary endpoint in multicentre bronchiectasis studies. LCI data quality control or "over-reading" is resource intensive and the impact is unclear. OBJECTIVES: To assess the proportion of MBW tests deemed unacceptable with over-reading, and to assess the change in LCI (number of turnovers), LCI coefficient of variation (CV%) and tidal volume (VT) CV% results after over-reading. METHODS: Data were analysed from 250 MBW tests (from 98 adult bronchiectasis patients) collected as part of the Bronch-UK Clinimetrics study in 5 UK centres. Each MBW test was over-read centrally using pre-defined criteria. MBW tests with <2 technically valid and repeatable trials were deemed unacceptable to include in analysis. In accepted tests, values for LCI, LCI CV% and VT CV% before and after over-reading, were compared. RESULTS: Insufficient data was collected in 10/250 tests. With over-reading, 30/240 (12%) were deemed unacceptable to include in analysis. In those accepted tests, overall the change in LCI, LCI CV% and VT CV% with over-reading was not statistically significant. When MBW new sites were compared to MBW expert sites, the change in LCI with over-reading was significantly greater in MBW new sites (p = 0.047). Data suggests that over-reading could be important up to at least 12 months post initiation of MBW activity. CONCLUSION: MBW over-reading was important in this study as 12% of tests were considered unacceptable. Over-reading improved test result accuracy in sites new to MBW.

Personalised asthma action plans for adults with asthma.

BACKGROUND: A key aim of asthma care is to empower each person to take control of his or her own condition. A personalised asthma action plan (PAAP), also known as a written action plan, an individualised action plan, or a self-management action plan, contributes to this endeavour. A PAAP includes individualised self-management instructions devised collaboratively with the patient to help maintain asthma control and regain control in the event of an exacerbation. A PAAP includes baseline characteristics (such as lung function), maintenance medication and instructions on how to respond to increasing symptoms and when to seek medical help. OBJECTIVES: To evaluate the effectiveness of PAAPs used alone or in combination with education, for patient-reported outcomes, resource use and safety among adults with asthma. SEARCH METHODS: We searched the Cochrane Airways Group Specialised Register of trials, clinical trial registers, reference lists of included studies and review articles, and relevant manufacturers' websites up to 14 September 2016. SELECTION CRITERIA: We included parallel randomised controlled trials (RCTs), both blinded and unblinded, that evaluated written PAAPs in adults with asthma. Included studies compared PAAP alone versus no PAAP, and/or PAAP plus education versus education alone. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted study characteristics and outcome data and assessed risk of bias for each included study. Primary outcomes were number of participants reporting at least one exacerbation requiring an emergency department (ED) visit or hospitalisation, asthma symptom scores on a validated scale and adverse events (all causes). Secondary outcomes were quality of life measured on a validated scale, number of participants reporting at least one exacerbation requiring systemic corticosteroids, respiratory function and days lost from work or study. We used a random-effects model for all analyses and standard Cochrane methods throughout. MAIN RESULTS: We identified 15 studies described in 27 articles that met our inclusion criteria. These 15 included studies randomised a total of 3062 participants (PAAP vs no PAAP: 2602 participants; PAAP plus education vs education alone: 460 participants). Ten studies (eight PAAP vs no PAAP; two PAAP plus education vs education alone) provided outcome data that contributed to quantitative analyses. The overall quality of evidence was rated as low or very low.Fourteen studies lasted six months or longer, and the remaining study lasted for 14 weeks. When reported, mean age ranged from 22 to 49 years and asthma severity ranged from mild to severe/high risk. PAAP alone compared with no PAAPResults showed no clear benefit or harm associated with PAAPs in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (odds ratio (OR) 0.75, 95% confidence interval (CI) 0.45 to 1.24; 1385 participants; five studies; low-quality evidence), change from baseline in asthma symptoms (mean difference (MD) -0.16, 95% CI -0.25 to - 0.07; 141 participants; one study; low-quality evidence) or the number of serious adverse events, including death (OR 3.26, 95% CI 0.33 to 32.21; 125 participants; one study; very low-quality evidence). Data revealed a statistically significant improvement in quality of life scores for those receiving PAAP compared with no PAAP (MD 0.18, 95% CI 0.05 to 0.30; 441 participants; three studies; low-quality evidence), but this was below the threshold for a minimum clinically important difference (MCID). Results also showed no clear benefit or harm associated with PAAPs on the number of participants reporting at least one exacerbation requiring oral corticosteroids (OR 1.45, 95% CI 0.84 to 2.48; 1136 participants; three studies; very low-quality evidence) nor on respiratory function (change from baseline forced expiratory volume in one second (FEV1): MD -0.04 L, 95% CI -0.25L to 0.17 L; 392 participants; three studies; low-quality evidence). In one study, PAAPs were associated with significantly fewer days lost from work or study (MD -6.20, 95% CI -7.32 to - 5.08; 74 participants; low-quality evidence). PAAP plus education compared with education aloneResults showed no clear benefit or harm associated with adding a PAAP to education in terms of the number of participants requiring an ED visit or hospitalisation for an exacerbation (OR 1.08, 95% CI 0.27 to 4.32; 70 participants; one study; very low-quality evidence), change from baseline in asthma symptoms (MD -0.10, 95% CI -0.54 to 0.34; 70 participants; one study; low-quality evidence), change in quality of life scores from baseline (MD 0.13, 95% CI -0.13 to 0.39; 174 participants; one study; low-quality evidence) and number of participants requiring oral corticosteroids for an exacerbation (OR 0.28, 95% CI 0.07 to 1.12; 70 participants; one study; very low-quality evidence). No studies reported serious adverse events, respiratory function or days lost from work or study. AUTHORS' CONCLUSIONS: Analysis of available studies was limited by variable reporting of primary and secondary outcomes; therefore, it is difficult to draw firm conclusions related to the effectiveness of PAAPs in the management of adult asthma. We found no evidence from randomised controlled trials of additional benefit or harm associated with use of PAAP versus no PAAP, or PAAP plus education versus education alone, but we considered the quality of the evidence to be low or very low, meaning that we cannot be confident in the magnitude or direction of reported treatment effects. In the context of this caveat, we found no observable effect on the primary outcomes of hospital attendance with an asthma exacerbation, asthma symptom scores or adverse events. We recommend further research with a particular focus on key patient-relevant outcomes, including exacerbation frequency and quality of life, in a broad spectrum of adults, including those over 60 years of age.

COPD-related bronchiectasis; independent impact on disease course and outcomes.

BACKGROUND: COPD and radiographic bronchiectasis frequently coexist but the effect of this on the clinical course of COPD is not fully understood. We determined the impact of bronchiectasis on clinical outcomes in COPD patients, independent of coexisting emphysema and bronchial wall thickening (BWT). METHODS: COPD patients admitted with first exacerbation 1998-2008 were identified retrospectively using ICD10 codes J44.0,1,8,9. Patients with suitable CT scans were graded for severity of bronchiectasis, emphysema and BWT on a 5 point scale (0-absent, 1-minor, 2-mild, 3-moderate, 4-severe). RESULTS: 406 patients (71 ± 11 years, 56% male, FEV1 52 ± 23% predicted) were included; 278 (69%) patients had bronchiectasis: minor, 112 (40%); mild, 81 (29%); moderate, 62 (22%); severe 23 (8%). Bronchiectasis severity correlated with severity of BWT (p < 0.001) but not emphysema (p = 0.090). Bronchiectasis independently determined sputum isolation of Pseudomonas aeruginosa (Odds ratio (OR) 1.39 (95% CI 1.07 to 1.80), p = 0.013) and atypical mycobacteria (OR 2.44 (95% CI 1.04 to 5.69), p = 0.040), annual respiratory admissions (p = 0.044) and inpatient days (p < 0.001), but did not predict survival (p = 0.256). CONCLUSIONS: Radiographic bronchiectasis in COPD patients is associated with increased respiratory infection and hospitalisation, independent of coexisting emphysema and BWT. COPD-related bronchiectasis is therefore an important diagnosis with potential implications for treatment.

Pathogen sensing pathways in human embryonic stem cell derived-endothelial cells: role of NOD1 receptors.

Human embryonic stem cell-derived endothelial cells (hESC-EC), as well as other stem cell derived endothelial cells, have a range of applications in cardiovascular research and disease treatment. Endothelial cells sense Gram-negative bacteria via the pattern recognition receptors (PRR) Toll-like receptor (TLR)-4 and nucleotide-binding oligomerisation domain-containing protein (NOD)-1. These pathways are important in terms of sensing infection, but TLR4 is also associated with vascular inflammation and atherosclerosis. Here, we have compared TLR4 and NOD1 responses in hESC-EC with those of endothelial cells derived from other stem cells and with human umbilical vein endothelial cells (HUVEC). HUVEC, endothelial cells derived from blood progenitors (blood outgrowth endothelial cells; BOEC), and from induced pluripotent stem cells all displayed both a TLR4 and NOD1 response. However, hESC-EC had no TLR4 function, but did have functional NOD1 receptors. In vivo conditioning in nude rats did not confer TLR4 expression in hESC-EC. Despite having no TLR4 function, hESC-EC sensed Gram-negative bacteria, a response that was found to be mediated by NOD1 and the associated RIP2 signalling pathways. Thus, hESC-EC are TLR4 deficient but respond to bacteria via NOD1. This data suggests that hESC-EC may be protected from unwanted TLR4-mediated vascular inflammation, thus offering a potential therapeutic advantage.

A key role for the endothelium in NOD1 mediated vascular inflammation: comparison to TLR4 responses.

Understanding the mechanisms by which pathogens induce vascular inflammation and dysfunction may reveal novel therapeutic targets in sepsis and related conditions. The intracellular receptor NOD1 recognises peptidoglycan which features in the cell wall of gram negative and some gram positive bacteria. NOD1 engagement generates an inflammatory response via activation of NFκB and MAPK pathways. We have previously shown that stimulation of NOD1 directly activates blood vessels and causes experimental shock in vivo. In this study we have used an ex vivo vessel-organ culture model to characterise the relative contribution of the endothelium in the response of blood vessels to NOD1 agonists. In addition we present the novel finding that NOD1 directly activates human blood vessels. Using human cultured cells we confirm that endothelial cells respond more avidly to NOD1 agonists than vascular smooth muscle cells. Accordingly we have sought to pharmacologically differentiate NOD1 and TLR4 mediated signalling pathways in human endothelial cells, focussing on TAK1, NFκB and p38 MAPK. In addition we profile novel inhibitors of RIP2 and NOD1 itself, which specifically inhibit NOD1 ligand induced inflammatory signalling in the vasculature. This paper is the first to demonstrate activation of whole human artery by NOD1 stimulation and the relative importance of the endothelium in the sensing of NOD1 ligands by vessels. This data supports the potential utility of NOD1 and RIP2 as therapeutic targets in human disease where vascular inflammation is a clinical feature, such as in sepsis and septic shock.

Successful endobronchial seal of surgical bronchopleural fistulas using BioGlue.

Postoperative bronchopleural fistula is uncommon, but it is associated with a high mortality and morbidity, and a prolonged hospital stay. Surgical treatment is gold standard, but it can prove challenging especially in the presence of infection. We describe three cases of bronchopleural fistula that developed after surgery for lung cancer in 1 patient and for bronchiectasis in 2 patients. All were successfully treated endoscopically by direct application of albumin-glutaraldehyde tissue adhesive (BioGlue; Cryolife Inc, Kennesaw, GA) through a rigid bronchoscope. Complete resolution was obtained in each patient within 24 hours.

Year in review 2005: critical care--cardiology.

This review summarizes key research papers published in the fields of cardiology and intensive care during 2005 in Critical Care. The papers have been grouped into categories: haemodynamic monitoring; goal-directed therapy; cardiac enzymes and critical care; metabolic considerations in cardiovascular performance; thrombosis prevention; physiology; and procedures and techniques.