ICS Use May Modify FEV1 Decline in α1-Antitrypsin Deficiency Patients with Relatively High Blood Eosinophils.

BACKGROUND: α1-Antitrypsin deficiency (AATD) predisposes to chronic obstructive pulmonary disease (COPD). In COPD unrelated to AATD, the role of a higher blood eosinophil count in disease and subsequent personalization of therapy has recently received much attention. We sought to investigate this concept in patients with AATD-associated COPD. OBJECTIVES: The study aims to evaluate eosinophilia status against outcomes including mortality and FEV1 decline in patients with AATD. METHODS: All patients with PiSZ and PiZZ genotypes were identified from the UK AATD registry. The participants were substratified according to inhaled corticosteroid (ICS) use. Blood eosinophil counts were assessed from baseline and annually during follow-up (range 1-18 years). Eosinophilia was defined as a level >0.2 × 109/L, and classified by the frequency of such counts into "always," "intermittent," or "never present." Univariate and multivariate analyses were conducted. RESULTS: In total, 646 participants were included, 53.9% of whom demonstrated intermittent and 7.4% persistent eosinophilia. Survival did not differ according to eosinophilic group (p > 0.05). Those with persistent eosinophilia showed a slower FEV1 decline (p < 0.001). There was no clear association with exacerbation frequency. Patients on ICS at baseline were more likely to be eosinophilic (p = 0.002) and having a lower FEV1 (p < 0.001) and greater pack-year exposure (16.5 vs. 7.8 pack-years, p < 0.001). When the multivariate analyses of FEV1 decline were stratified for baseline ICS use, the association of persistent eosinophilia with slower decline persisted in those on ICS. CONCLUSIONS: Blood eosinophil levels persistently >0.2 × 109/L may be an indication for ICS use in PiZZ AATD in order to reduce FEV1 decline.

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.

The significance of the F variant of alpha-1-antitrypsin and unique case report of a PiFF homozygote.

BACKGROUND: Inheritance of the F variant of alpha-1-antitrypsin is associated with normal circulating protein levels, but it is believed to be dysfunctional in its ability to inhibit neutrophil elastase and therefore has been implicated as a susceptibility factor for the development of emphysema. In this study, its functional characteristics were determined following the identification of a unique patient with the PiFF phenotype, and the implications as a susceptibility factor for emphysema are considered both in homozygotes and heterozygotes. METHODS: Second order association rate constants were measured for M, Z, S and F variants of alpha-1-antitrypsin with neutrophil elastase and proteinase 3. Clinical characteristics of the PiFF homozygote and six PiFZ heterozygote subjects were studied. RESULTS: The F variant had a reduced association rate constant with neutrophil elastase (5.60 ± 0.83 × 106 M-1 s-1) compared to the normal M variant (1.45 ± 0.02 × 107 M-1 s-1), indicating an increased time to inhibition that was comparable to that of the Z variant (7.34 ± 0.03 × 106 M-1 s-1). The association rate constant for the F variant and proteinase 3 (1.06 ± 0.22 × 106 M-1 s-1) was reduced compared to that with neutrophil elastase, but was similar to that of other alpha-1-antitrypsin variants. Of the six PiFZ heterozygotes, five had airflow obstruction and radiological evidence of emphysema. The PiFF homozygote had airflow obstruction but no emphysema. None of the patients had clinical evidence of liver disease. CONCLUSIONS: The F variant may increase susceptibility to elastase-induced lung damage but not emphysema, whereas co-inheritance with the Z deficiency allele may predispose to emphysema despite reasonable plasma concentrations of alpha-1-antitrypsin.

Small airway function measured using forced expiratory flow between 25% and 75% of vital capacity and its relationship to airflow limitation in symptomatic ever-smokers: a cross-sectional study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is diagnosed and its severity graded by traditional spirometric parameters (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) and FEV1, respectively) but these parameters are considered insensitive for identifying early pathology. Measures of small airway function, including forced expiratory flow between 25% and 75% of vital capacity (FEF25-75), may be more valuable in the earliest phases of COPD. This study aimed to determine the prevalence of low FEF25-75 in ever-smokers with and without airflow limitation (AL) and to determine whether FEF25-75 relates to AL severity. METHOD: A retrospective analysis of lung function data of 1458 ever-smokers suspected clinically of having COPD. Low FEF25-75 was defined by z-score<-0.8345 and AL was defined by FEV1/FVC z-scores<-1.645. The severity of AL was evaluated using FEV1 z-scores. Participants were placed into three groups: normal FEF25-75/ no AL (normal FEF25-75/AL-); low FEF25-75/ no AL (low FEF25-75/AL-) and low FEF25-75/ AL (low FEF25-75/AL+). RESULTS: Low FEF25-75 was present in 99.9% of patients with AL, and 50% of those without AL. Patients in the low FEF25-75/AL- group had lower spirometric measures (including FEV1 FEF25-75/FVC and FEV3/FVC) than those in the normal FEF25-75/AL- group. FEF25-75 decreased with AL severity. A logistic regression model demonstrated that in the absence of AL, the presence of low FEF25-75 was associated with lower FEV1 and FEV1/FVC even when smoking history was accounted for. CONCLUSIONS: Low FEF25-75 is a physiological trait in patients with conventional spirometric AL and likely reflects early evidence of impairment in the small airways when spirometry is within the 'normal range'. FEF25-75 likely identifies a group of patients with early evidence of pathological lung damage who warrant careful monitoring and reinforced early intervention to abrogate further lung injury.