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 FEV₁were 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)versus9.67 (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.

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.

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 (18FDG PET-CT) as a noninvasive, spatially informative biomarker. Objectives: To assess the potential usefulness of 18FDG PET-CT as a surrogate measure of pulmonary neutrophilic inflammation in patients with usual COPD and α1-antitrypsin deficiency (AATD). Methods: 18FDG PET-CT imaging was performed in 10 patients with usual COPD, 10 patients with AATD, and 10 healthy control subjects. Pulmonary 18FDG 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. 18FDG 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: 18FDG 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 (FEV1% predicted, r = −0.848, P = 0.001; FEV1/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 18FDG 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).

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.

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.