Cluster randomised controlled trial of specialist-led integrated COPD care (INTEGR COPD).

OBJECTIVE: Studies in hospital settings demonstrate that there is greater guideline adherence when care is delivered by a respiratory specialist, however, this has not been explored in primary care. The aim of this study is to determine the impact integrating respiratory specialists into primary care has on the delivery of guideline adherent chronic obstructive pulmonary disease (COPD) care. METHODS: 18 general practitioner (GP) practices were randomised to provide either usual or specialist-led COPD care. Patients at participating practices were included if they had an existing diagnosis of COPD. Outcomes were measured at the individual patient level. The primary outcome was guideline adherence, assessed as achieving four or more items of the COPD care bundle. Secondary outcome measures included quality of life, number of exacerbations, number of COPD-related hospitalisations and respiratory outpatient attendances. RESULTS: 586 patients from 10 practices randomised to the intervention and 656 patients from 8 practices randomised to the control arm of the study were included. The integration of respiratory specialists into GP practices led to a statistically significant (p<0.001) improvement in the provision of guideline adherent care when compared with usual care in this cohort (92.7% vs 70.1%) (OR 4.14, 95% CI 2.14 to 8.03). CONCLUSION: This is the first study to demonstrate that guideline adherence is improved through the integration of respiratory specialists into GP practices to deliver annual COPD reviews. To facilitate changes in current healthcare practice and policy, the findings of this paper need to be viewed in combination with qualitative research exploring the acceptability of specialist integration. TRIAL REGISTRATION NUMBER: NCT03482700.

Relationship between Depression and Anxiety, Health Status and Lung Function in Patients with Alpha-1 Antitrypsin Deficiency.

Alpha-1 Antitrypsin deficiency (AATD) is a genetic condition that can lead to Chronic Obstructive Pulmonary Disease. The burden of psychological disease, its impact and contributing factors in patients with AATD are largely unknown. This study determined the prevalence of depression and anxiety in AATD and its clinical impact. All subjects with PiZZ/PiZnull (n = 635) and PiSZ (n = 111) genotypes within the AATD registry who had sufficient data to calculate pulmonary physiological and health status (HS) decline were grouped as those with or without a diagnosis of depression and/or anxiety. Univariate and multivariate analyses were performed on physiological, demographic and HS parameters. Depression and/or anxiety was present in 16.4% overall in both PiSZ and PiZZ/PiZnull cohorts and was associated with lower baseline pulmonary function and worse HS. In the multivariable analysis of the PiZZ/PiZnull cohort, a greater average decline in FEV1% predicted was observed in those with depression and/or anxiety than those without (-1.53 SD ± 2.26 per year, -0.99 ± 1.79, respectively; p = 0.03) but there was no difference in HS decline (p = 0.33). No differences were seen in the PiSZ cohort. Dyspnoea (mMRC score) was generally worse in those with depression and/or anxiety than those without. Comorbidity burden did not differ between those with or without depression and/or anxiety. Disease severity and progression may be contributing to the prevalence of psychological factors in PiZZ/PiZnull patients. Patients who are declining rapidly should be actively monitored for psychological co-morbidity and treated by cognitive or pharmacological means.Supplemental data for this article is available online at https://doi.org/10.1080/15412555.2021.1991904 .

Physiological tests of small airways function in diagnosing asthma: a systematic review.

BACKGROUND: Asthma is a common, heterogeneous disease that is characterised by chronic airway inflammation and variable expiratory airflow limitation. Current guidelines use spirometric measures for asthma assessment. This systematic review aimed to assess whether the most commonly reported tests of small airways function could contribute to the diagnosis of asthma. METHODS: Standard systematic review methodology was used, and a range of electronic databases was searched (Embase, MEDLINE, CINAHL, CENTRAL, Web of Science, DARE). Studies that included physiological tests of small airways function to diagnose asthma in adults were included, with no restrictions on language or date. The risk of bias and quality assessment tools used were Agency for Healthcare Research and Quality tool for cross-sectional studies and Quality Assessment of Diagnostic Accuracy Studies 2 for diagnostic test accuracy (DTA) studies. RESULTS: 7072 studies were identified and 10 studies met review criteria. 7 included oscillation techniques and 5 included maximal mid-expiratory flow (MMEF). Studies were small and of variable quality. In oscillometry, total resistance (R5) and reactance at 5 Hz (X5) was altered in asthma compared with healthy controls. The percentage predicted of MMEF was lower in patients with asthma compared with controls in all studies and lower than the % predicted forced expiratory volume in 1 s. In DTA of oscillometry, R5 showed a sensitivity between 69% and 72% and specificity between 61% and 86%. CONCLUSION: There were differences in the results of physiological tests of small airway function in patients with asthma compared with controls. However, studies are small and heterogeneous. Further studies are needed to assess the effectiveness of these tests on a larger scale, including studies to determine which test methodology is the most useful in asthma.

A Systematic Review of the Use of Physiological Tests Assessing the Acute Response to Treatment During Exacerbations of COPD (with a Focus on Small Airway Function).

Exacerbations are prevalent in Chronic Obstructive Pulmonary Disease (COPD) patients and associated with poor clinical outcomes. Currently, there is a lack of sensitive and specific tools that can objectively identify exacerbations and assess their progress or treatment response. FEV1 is often reported as a study outcome, but it has significant limitations. Studies have suggested that small airways measures might provide physiological biomarkers during exacerbations. Therefore, this study was done to assess which physiological tests of small airways function have been used in the acute setting during exacerbations of COPD and the evidence to support their use. An electronic databases search was conducted in April 2019. A standard systematic review methodology was used. Eligible studies were those of ≥10 participants that compared at least one small airway test with FEV1 to assess response to treatment with baseline and a follow-up measurement ≤2 months after. Analyses were narrative. Of 1436 screened studies, seven studies were eligible. There was heterogeneity in which tests of small airways were used and three different small airways measures were reported. Studies were small (including 20 to 87 subjects). Six articles reported improvements in small airway measurements during the recovery from exacerbation which correlated with FEV1. Included studies varied in their timing and duration of the assessment. There is some evidence to support the use of small airway tests in acute exacerbations of COPD. However, studies have been small with different tests being utilized. Further studies to determine the usefulness of each test may be of interest.

The clinical and inflammatory relationships between periodontitis and chronic obstructive pulmonary disease.

AIM: To investigate associations between periodontitis and chronic obstructive pulmonary disease (COPD) with and without alpha-1 antitrypsin deficiency (AATD), including neutrophil functions implicated in tissue damage. METHODS: The presence and severity of periodontitis (using two international criteria) and lung disease were assessed in 156 COPD patients with and without AATD accounting for common confounding factors. Saliva and systemic inflammatory markers were measured by ELISA together with neutrophil migration. RESULTS: COPD and AATD patients exhibited higher prevalence of periodontitis (COPD 95%; AATD 88%) than reported in unselected community-dwelling populations even when risk factors (age, smoking history, socio-economic status and dental habits) were considered. Periodontitis severity associated with lung disease severity (AATD, periodontitis versus no periodontitis; FEV1 = 56% versus 99% predicted; TLCO = 59% versus 81% predicted, p < .0001 for both). Neutrophil migratory accuracy declined in stage II-IV periodontitis patients with COPD or AATD compared to COPD or AATD with no or stage I periodontitis. Improved dental habits appeared to be associated with a reduction in exacerbation frequency in COPD. CONCLUSION: The results support shared pathophysiology between periodontitis and COPD, especially when associated with AATD. This may reflect an amplification of neutrophilic inflammation and altered neutrophil functions, already described in periodontitis, COPD and AATD.

Expedient synthesis of highly substituted 3,4-dihydro-1,2-oxathiine 2,2-dioxides and 1,2-oxathiine 2,2-dioxides: revisiting sulfene additions to enaminoketones.

Diversely substituted 1,2-oxathiine 2,2-dioxides, including 3,5,6-triaryl-, 3,6-diaryl-, 3,5-diaryl-, 5,6-diaryl- and selected fused heterocyclic analogues, have been efficiently obtained by the application of a mild Cope elimination of a 4-amino moiety from the requisite 4-amino-3,4-dihydro-1,2-oxathiine 2,2-dioxides, which themselves were readily obtained by the addition of sulfenes to enaminoketones.

Late presentation of acute hypercapnic respiratory failure carries a high mortality risk in COPD patients treated with ward-based NIV.

INTRODUCTION: Non-invasive ventilation (NIV) is recommended for treatment of acute hypercapnic respiratory failure (AHRF) refractory to medical management in patients with COPD. This study investigated the relationship between time from hospital presentation to diagnosis of AHRF and in-hospital mortality. METHODS: Retrospective analysis of hospitalised COPD patients treated with a first episode of ward-based NIV for AHRF at a large UK teaching hospital between 2004 and 2017. Data collected prospectively as part of NIV service evaluation. Multivariable logistic regression performed to identify predictors of in-hospital mortality. RESULTS: In total, 547 unique patients were studied comprising 245 males (44.8%), median age 70.6 years, median FEV1% predicted 34%. Overall in-hospital mortality was 19% (n = 104); median survival was 1.7 years. In univariate analysis, a longer time between hospital presentation to diagnosis of AHRF was associated with in-hospital mortality (median [IQR]: 8.7 [0.7-75.8] hours vs. 1.9 [0.3-13.6] hours, p < 0.0001). In multivariable logistic regression, significant predictors of in-hospital mortality were AHRF >24 h after hospital presentation (odds ratio [95% CI]: 2.29 [1.33-3.95], p = 0.003), pneumonia on admission (1.81 [1.07-3.08], p = 0.027), increased age (1.10 [1.07-1.14], p < 0.001) and NIV as ceiling of treatment (5.86 [2.87-11.94], p < 0.001). CONCLUSIONS: Hospitalised COPD patients with late presentation of AHRF, requiring acute ward-based NIV, may have increased in-hospital mortality. These patients may benefit from closer monitoring and earlier specialist respiratory review.

Temporal trends in survival following ward-based NIV for acute hypercapnic respiratory failure in patients with COPD.

INTRODUCTION: Non-invasive ventilation (NIV) is recommended for treatment of acute hypercapnic respiratory failure (AHRF) in acute exacerbations of COPD. National UK audit data suggests that mortality rates are rising in COPD patients treated with NIV. OBJECTIVE: To investigate temporal trends in in-hospital mortality in COPD patients undergoing a first episode of ward-based NIV for AHRF. METHODS: Retrospective study of hospitalised COPD patients treated with a first episode of ward-based NIV at a large UK teaching hospital between 2004 and 2017. Patients were split into two cohorts based on year of admission, 2004-2010 (Cohort 1) and 2013-2017 (Cohort 2), to facilitate comparison of patient characteristics. RESULTS: In total, 547 unique patients were studied. There was no difference in in-hospital mortality rate between the time periods studied (17.6% vs 20.5%, P = .378). In Cohort 2 there were more females, a higher rate of co-morbid bronchiectasis and pneumonia on admission and more severe acidosis, hypercapnia and hypoxia. More patients in Cohort 2 had NIV as the ceiling of treatment. Patients in Cohort 2 experienced a longer time from AHRF diagnosis to application of NIV, higher maximum inspiratory positive airway pressure, lower maximum oxygen and shorter duration of NIV. Finally, patients in Cohort 2 experienced a shorter hospital length of stay (LOS), with no differences observed in rate of transfer to critical care or intubation. CONCLUSION: In-hospital mortality remained stable and LOS decreased over time, despite greater comorbidity and more severe AHRF in COPD patients treated for the first time with ward-based NIV.

Ward-Based Non-Invasive Ventilation in Acute Exacerbations of COPD: A Narrative Review of Current Practice and Outcomes in the UK.

Non-invasive ventilation (NIV) is frequently used as a treatment for acute hypercapnic respiratory failure (AHRF) in hospitalised patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD). In the UK, many patients with AHRF secondary to AECOPD are treated with ward-based NIV, rather than being treated in critical care. NIV has been increasingly used as an alternative to invasive ventilation and as a ceiling of treatment in patients with a 'do not intubate' order. This narrative review describes the evidence base for ward-based NIV in the context of AECOPD and summarises current practice and clinical outcomes in the UK.

Health status decline in α-1 antitrypsin deficiency: a feasible outcome for disease modifying therapies?

BACKGROUND: Trials of disease modifying therapies in Chronic Obstructive Pulmonary Disease (COPD) provide challenges for detecting physiological and patient centred outcomes. The purpose of the current study was to monitor decline in health status in Alpha-1 antitrypsin deficiency (AATD) and determine its' relationship to conventional physiology. METHODS: Patients recruited to the UK-AATD database with a median follow up of 7 years (IQR 5-10) were studied to determine annual change in St George's Respiratory Questionnaire (SGRQ), FEV1, gas transfer and their feasibility of use in future trials. RESULTS: Annual decline in SGRQ had a wide range, was greater for patients with established COPD and correlated with decline in FEV1 (p < 0.0001). Total score decline was greater (p < 0.05) for those with accelerated FEV1 decline (median = 1.07 points/year) compared to those without (median = 0.51). Power calculations indicated effective intervention would not achieve MCID for the SGRQ unless the timeframe was extended for up to 8 years. More than 5000 patients/arm would be required for a statistically significant modest effect over 3 years even in those with rapid FEV1 decline. CONCLUSION: Despite AATD being a rapidly declining form of COPD, deterioration in SGRQ was slow consistent with ageing and the chronic nature of disease progression. Power calculations indicate the numbers needed to detect a difference with disease modifying therapies would be prohibitive especially in this rare cause of COPD. These data have important implications for future study design of disease modifying therapies even in COPD not associated with AATD.

Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a rare genetic condition predisposing individuals to chronic obstructive pulmonary disease (COPD). The treatment is generally extrapolated from COPD unrelated to AATD; however, most COPD trials exclude AATD patients; thus, this study sought to systematically review AATD-specific literature to assist evidence-based patient management. METHODS: Standard review methodology was used with meta-analysis and narrative synthesis (PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. Randomized controlled trials (RCTs) were the primary focus; however, case series and uncontrolled studies were eligible. All studies had ≥10 participants receiving treatment or usual care, with baseline and follow-up data (>3 months). Risk of bias was assessed appropriately according to study methodology. RESULTS: In all, 7,296 studies were retrieved from searches; 52 trials with 5,632 participants met the inclusion criteria, of which 26 studies involved alpha-1 antitrypsin augmentation and 17 concerned surgical treatments (largely transplantation). Studies were grouped into four management themes: COPD medical, COPD surgical, AATD specific, and other treatments. Computed tomography (CT) density, forced expiratory volume in 1 s, diffusing capacity of the lungs for carbon monoxide, health status, and exacerbation rates were frequently used as outcomes. Meta-analyses were only possible for RCTs of intravenous augmentation, which slowed progression of emphysema measured by CT density change, 0.79 g/L/year versus placebo (P=0.002), and associated with a small increase in exacerbations 0.29/year (P=0.02). Mortality following lung transplant was comparable between AATD- and non-AATD-related COPD. Surgical reduction of lung volume demonstrated inferior outcomes compared with non-AATD-related emphysema. CONCLUSION: Intravenous augmentation remains the only disease-specific therapy in AATD and there is evidence that this slows decline in emphysema determined by CT density. There is paucity of data around other treatments in AATD. Treatments for usual COPD may not be as efficacious in AATD, and further studies may be required for this disease group.

Maximal mid-expiratory flow detects early lung disease in α1-antitrypsin deficiency.

Pathological studies suggest that loss of small airways precedes airflow obstruction and emphysema in chronic obstructive pulmonary disease (COPD). Not all α1-antitrypsin deficiency (AATD) patients develop COPD, and measures of small airways function might be able to detect those at risk.Maximal mid-expiratory flow (MMEF), forced expiratory volume in 1 s (FEV1), ratio of FEV1/forced vital capacity (FVC), health status, presence of emphysema (computed tomography (CT) densitometry) and subsequent decline in FEV1 were assessed in 196 AATD patients.FEV1/FVC, FEV1 % predicted and lung densitometry related to MMEF % pred (r2=0.778, p<0.0001; r2=0.787, p<0.0001; r2=0.594, p<0.0001, respectively) in a curvilinear fashion. Patients could be divided into those with normal FEV1/FVC and MMEF (group 1), normal FEV1/FVC and reduced MMEF (group 2) and those with spirometrically defined COPD (group 3). Patients in group 2 had worse health status than group 1 (median total St George's Respiratory Questionnaire (SGRQ) 23.15 (interquartile range (IQR) 7.09-39.63) versus 9.67 (IQR 1.83-22.35); p=0.006) and had a greater subsequent decline in FEV1 (median change in FEV1 -1.09% pred per year (IQR -1.91-0.04% pred per year) versus -0.04% pred per year (IQR -0.67-0.03% pred per year); p=0.007).A reduction in MMEF is an early feature of lung disease in AATD and is associated with impaired health status and a faster decline in FEV1.

Individualized lung function trends in alpha-1-antitrypsin deficiency: a need for patience in order to provide patient centered management?

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by fixed airflow obstruction and accelerated decline of forced expired volume in 1 second (FEV1). Alpha-1-antitrypsin deficiency is a genetic cause of COPD and associated with more rapid decline in lung function, even in some never smokers (NS) but the potential for individualized assessment to reveal differences when compared to group analyses has rarely been considered. METHODS: We analyzed decline in post-bronchodilator FEV1 and gas transfer (% predicted) over at least 3 years (mean= 6.11, 95% CI 5.80-6.41) in our unique data set of 482 patients with alpha-1-antitrypsin deficiency (PiZ) to determine individual rates of decline, implications for prognosis, and potential clinical management. FINDINGS: There was a marked variation in individual rates of FEV1 decline from levels consistent with normal aging (observed in 23.5% of patients with established COPD, 57.5% of those without) to those of rapidly declining COPD. Gas transfer did not decline in 12.8% of NS and 20.7% of ex-smokers with established COPD (33.3% and 25.0%, respectively, for those without COPD). There was no correlation between decline in gas transfer and FEV1 for those with COPD, although a weak relationship existed for those without (r=0.218; P<0.025). CONCLUSION: These data confirm differing individual rates of lung function decline in alpha-1-antitrypsin deficiency, indicating the importance of comprehensive physiological assessment and a personalized approach to patient management.

Lung Transplantation in Alpha-1-Antitrypsin Deficiency.

BACKGROUND: Lung transplantation is a therapeutic option for patients with end-stage lung disease and a survival benefit has been described in patients with alpha-1-antitrypsin deficiency (A1ATD). The aims of the current study were to determine the survival and health benefits of lung transplantation in UK patients with A1ATD compared to carefully matched non-transplant patients. METHODS: Patients with the PiZZ (alpha-1-antitrypsin deficiency) genotype who had undergone lung transplantation between 1996 and 2011 were identified from the UK A1ATD registry. Lung physiology, health status and survival were compared pre- and post-transplant using carefully matched non-transplant patients. RESULTS: Thirty-two A1ATD patients who had undergone lung transplant were identified. Lung function decline pre-transplant was not different to the closely matched non-transplanted cohort. The transplant group pre-transplant, although matched for FEV1, had lower gas transfer measurements, (mean KCO% predicted 41.0% SE ± 3.86 vs 55.6% SE ± 3.10 p < 0.001) and worse health status (SGRQ mean score 64.2 SE ± 2.5 vs 55.3 SE ± 2.0, p < 0.001). Post-transplant, physiology and health status improved significantly (p < 0.002). However, the post-operative mortality over 5 years was no better than for a second group of non-transplant patients further matched for gas transfer or a third group also matched for SGRQ. CONCLUSION: Patients who underwent lung transplant had lower gas transfer and quality-of-life pre-transplant compared to non-transplant patients matched for FEV1, age and sex, suggesting that these parameters provide extra information helpful in decision making. Lung transplantation for A1ATD patients significantly improves quality-of-life but not survival.

Prevalence and radiological outcomes of lung nodules in alpha 1-antitrypsin deficiency.

Pulmonary nodules are a frequent incidental finding on computed tomography (CT) imaging. This study sought to investigate the prevalence and radiological outcomes of lung nodules in patients with alpha 1-antitrypsin deficiency (AATD), and determine any association with systemic inflammation and disease progression. A retrospective study was conducted using thoracic CT imaging from 494 patients on the AATD U.K. registry. Patients were categorised according to radiological and clinical outcome, and comparisons made with respect to baseline demographics, lung function and high-sensitivity CRP (hs-CRP). Sixty-four patients (13%) had a nodule present on baseline imaging, and in total 132 patients (27%) had a nodule on at least one scan, of which 2 were malignant. The presence of a lung nodule was associated with significantly lower baseline percent predicted forced expiratory volume in 1 s (FEV1 % predicted) (p = 0.037) and percent predicted transfer coefficient of the lung for carbon monoxide (Kco % predicted, p = 0.001). Patients with self-resolving nodules had higher baseline hs-CRP concentrations (p < 0.01) and more rapid decline in Kco (p = 0.03) compared to patients in whom no nodules were observed. The prevalence of 'incidental' pulmonary nodules on CT imaging in patients with AATD was 13%. Self-resolving pulmonary nodules were associated with increased systemic inflammation and progression of emphysema and may therefore reflect an important component of emphysema pathogenesis or a marker of emphysema.

Assessment of pulmonary neutrophilic inflammation in emphysema by quantitative positron emission tomography.

RATIONALE: Neutrophilic inflammation is understood to be of pathogenetic importance in chronic obstructive pulmonary disease (COPD) and may be quantified using 18-fluorodeoxyglucose positron emission tomography-computed tomography ((18)FDG PET-CT) as a noninvasive, spatially informative biomarker. OBJECTIVES: To assess the potential usefulness of (18)FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α(1)-antitrypsin deficiency (AATD). METHODS: (18)FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary (18)FDG uptake was estimated by three-dimensional Patlak graphical analysis as an indicator of pulmonary neutrophilic glycolytic activity. Patients with AATD were treated with 12 weekly intravenous infusions of AAT augmentation therapy before repeat imaging. (18)FDG uptake, lung physiology, lung density, and systemic markers of inflammation were compared for all groups at baseline and, in patients with AATD, at baseline and on treatment. MEASUREMENTS AND MAIN RESULTS: (18)FDG uptake in the upper lung of patients with usual COPD was greater compared with the healthy control group (P = 0.009) and correlated with measures of disease severity (FEV(1)% predicted, r = -0.848, P = 0.001; FEV(1)/FVC, r = -0.918, P < 0.001; Kco% predicted, r = -0.624, P = 0.027; 15th percentile point, r = -0.709, P = 0.011). No significant difference was observed between measurements at baseline and on treatment in patients with AATD. CONCLUSIONS: Quantitative (18)FDG PET-CT has a potential role as an imaging biomarker in mechanistic and interventional studies in patients with usual COPD. The data support previous evidence of distinct functional characteristics of neutrophils in COPD. Clinical trial registered with https://eudract.ema.europa.eu/index.html (EudraCT 2007-004869-18).