Ross Edgar

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).

Systematic review:: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease

Alpha‐1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD.

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 density associates with survival in Alpha 1 antitrypsin deficient patients

INTRODUCTION CT density correlates with quality of life (QOL) scores and impaired upper zone lung density associates with higher mortality in alpha one antitrypsin deficiency (A1ATD). We hypothesised that decline in CT densitometry would relate to survival or deterioration in QOL in A1ATD. METHODS All augmentation naïve PiZZ patients in the UK A1ATD registry with ≥ two successive quantitative CT scans were selected. Patients were divided into groups based on CT density decline and the relationship to survival and change in QOL compared by univariate analyses and multivariate Cox regression. Analyses were performed for whole lung, upper zone and lower zone density separately. Exploratory analyses of FEV1 subgroups were conducted. RESULTS 110 patients were identified; 77 had whole lung and lung zone density recorded on two CT scans, 33 patients had upper zone data only on four scans. Decline in lower zone density associated with survival, even after adjustment for baseline lung density (p = 0.048), however upper zone density and whole lung density decline did not. This difference appeared to be driven by those with FEV1 >30% predicted. CONCLUSION Rate of change in lung densitometry could predict survival in A1ATD.

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.

Lung Transplantation in Alpha-1-Antitrypsin Deficiency

Abstract 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.

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 Georges 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. Mid-expiratory flow indicates early disease, worse health status and predicts decline in AATD patients without COPD http://ow.ly/F6K6308355E

P149 Validation of the COPD assessment test (CAT) within α-1 antitrypsin deficiency (A1ATD)

Introduction and objectives The COPD Assessment Test (CAT) has recently been validated with a USA cohort as a health status questionnaire (HSQ) for use in chronic obstructive pulmonary disease (COPD).1 Its purpose is to guide and improve communication between the health care professional and patient and identify key areas for health improvement. Historically, other HSQ have been used in COPD especially the St Georges Respiratory Questionnaire (SGRQ) which has been extensively validated for use in clinical care and trials. However the SGRQ has a complex scoring algorithm and requires several minutes to complete restricting its use in daily clinical practice.1 2 The CAT was developed as a user friendly, time efficient, easily analysed and reliable HSQ for COPD. We have an extensive database for patients with α-1 Antitrypsin Deficiency (A1ATD) and have an annual review at which the SGRQ is used. We wished to compare CAT with the SGRQ in these patients. Methods 163 consecutive patients with A1ATD attending the Antitrypsin Deficiency Assessment and Programme for Treatment (ADAPT) centre were asked to complete both SGRQ and CAT prior to full Lung function and medical review. All patients were clinically stable (at least 6 weeks post exacerbation). SGRQ and CAT scores were compared as well as routine post bronchodilator lung function parameters to determine the relationships. Results 157 patients completed both questionnaires. CAT correlated strongly with SGRQ total score (R2=0.799, p<0.0001, n=157) (Abstract P149 Figure 1) and its domains (impact R2=0.751, symptoms R2=0.59 and activity R2=0.66). CAT values also correlated with lung function including FEV1 %predicted (R2=0.26, p<0.0001, n=157), FEV1/FVC (R2=0.224, p<0.0001, n=157), KCO %predicted (R2=0.151, p<0.0001, n=147) all of which were comparable to those seen with SGRQ.Abstract P149 Figure 1 Conclusion CAT offers a short HSQ that is simple to use and analyse, correlates well with the more complex SGRQ and stable lung function.

P135 Treatment of lung disease in alpha-1 antitrypsin deficiency: a systematic review

Introduction Alpha-1 Antitrypsin Deficiency (AATD) is a rare genetic condition predisposing individuals to COPD. The majority of treatment for AATD is similar to non-AATD related COPD; intravenous augmentation of Alpha-1 Antitrypsin is a specific treatment but is inequitably used across Europe and not used in the UK. There is a pressing need to systematically investigate efficacy since the publication of a new placebo controlled RCT and to identify patient centred, clinically meaningful outcomes.1 Methods A systematic review was conducted using standard review methodology with meta-analysis and narrative synthesis (registered with PROSPERO-CRD42015019354). Eligible studies were those of any treatment used in severe AATD. RCT’s were the primary focus however case series and uncontrolled studies (n > 10 patients receiving treatment or usual care, with baseline and follow-up data >3 months), were eligible for inclusion to ensure natural history of disease outside RCT’s could be determined. Results 7296 unique records were reviewed with 51 trials analysed on 5632 participants: 26 AAT-augmentation (3 for meta-analysis); 17 surgical intervention (5 Lung volume reduction (LVR) surgery, 1 Bronchoscopic valve LVR and 11 Lung transplantation); 3 medical interventions and 3 trials completed but not published. Meta-analysis of AAT-Augmentation demonstrated slower lung CT density decline, difference 0.79 g/l/year (95% CI: 0.29–1.29; p = 0.002), and a small increase in annual exacerbations 0.29/year (95% CI: 0.04–0.54; p = 0.02) compared to placebo (Figure 1). Survival benefit of transplant was observed in one study (p = 0.006) but not in a second with more stringent matching for groups; however significant improvements in health status, total SGRQ and all domain scores, at one year (p < 0.01) were observed. Mortality post lung transplant was comparable between AATD and non-AATD related COPD cohorts. Surgical lung volume reduction demonstrated inferior outcomes when compared to non-AATD related emphysema. Conclusion CT density, FEV1, DLCO, health status and exacerbation rates were frequently used as outcomes in AATD related treatment trials. AAT-Augmentation is able to slow the progression of severity of emphysema when measured by CT density change compared to placebo. This systematic review will help assist in the improved monitoring and management of patients with AATD. Reference 1 Chapman KR, et al. Intravenous augmentation treatment and lung density in severe α1 antitrypsin deficiency (RAPID): a randomised, double-blind, placebo-controlled trial. The Lancet 2015;386(9991):360–368. Abstract P135 Figure 1 Forest Plots : A) Annual CT Lung Density Change (g/L per year)in 300 patients across three placebo controlled RCT’s. B) Annual patient reported exacerbation episode in 257 patients across two placebo controlled RCT’s.

Blood eosinophils as a biomarker in alpha 1 anti trypsin deficiency

Introduction: Eosinophilic airway inflammation is associated with worse outcomes in COPD; tailoring corticosteroid (CS) therapy to eosinophilia improves this, and even blood eosinophils are a sensitive measure (Bafadhel et al, AJRCCM (2011)). However, it is unknown whether eosinophilic airway inflammation occurs or impacts on alpha 1 anti trypsin deficiency (A1ATD) outcomes. Aims And Objectives: To explore associations between blood eosinophilia and clinical phenotype, lung function and mortality in A1ATD. Methods: Retrospective study of patients attending the UK national centre for A1ATD. 720 case notes were studied for baseline visit blood eosinophil counts, clinical data, longitudinal lung function data and mortality. Eosinophilia was classified as peripheral blood eosinophil count > 2% (Bafadhel et al, ERJ (2014)). Univariate and multivariate analyses were conducted for the above variables, comparing eosinophilia to non-eosinophilia. Results: 292 (41%) cases were baseline eosinophilic. There were no significant differences in age, sex or phenotype between the two groups. Eosinophilic patients had a lower baseline FEV 1 % predicted (p = 0.018) and more bronchodilator reversibility (BDR; p= 0.026). Adjusting for our published associations of FEV1 and KCO decline (Dawkins et al, ERJ (2009)), eosinophilia was not associated with FEV1 or KCO decline in PiZZ patients (both p>0.15). Similarly, eosinophilia did not relate to death (p=0.56). Conclusions: Results confirm an association between eosinophilia and BDR; the lower observed FEV1 may suggest an impact on progression, which we could not prove in longitudinal analyses. Further study of CS responsiveness according to eosinophilia may be of interest in A1ATD.