Fazirsiran for Adults With Alpha-1 Antitrypsin Deficiency Liver Disease: A Phase 2 Placebo Controlled Trial (SEQUOIA).

BACKGROUND & AIMS: Homozygous ZZ alpha-1 antitrypsin (AAT) deficiency produces mutant AAT (Z-AAT) proteins in hepatocytes, leading to progressive liver fibrosis. We evaluated the safety and efficacy of an investigational RNA interference therapeutic, fazirsiran, that degrades Z-AAT messenger RNA, reducing deleterious protein synthesis. METHODS: This ongoing, phase 2 study randomized 40 patients to subcutaneous placebo or fazirsiran 25, 100, or 200 mg. The primary endpoint was percent change in serum Z-AAT concentration from baseline to week 16. Patients with fibrosis on baseline liver biopsy received treatment on day 1, at week 4, and then every 12 weeks and had a second liver biopsy at or after weeks 48, 72, or 96. Patients without fibrosis received 2 doses on day 1 and at week 4. RESULTS: At week 16, least-squares mean percent declines in serum Z-AAT concentration were -61%, -83%, and -94% with fazirsiran 25, 100, and 200 mg, respectively, vs placebo (all P < .0001). Efficacy was sustained through week 52. At postdose liver biopsy, fazirsiran reduced median liver Z-AAT concentration by 93% compared with an increase of 26% with placebo. All fazirsiran-treated patients had histologic reduction from baseline in hepatic globule burden. Portal inflammation improved in 5 of 12 and 0 of 8 patients with a baseline score of >0 in the fazirsiran and placebo groups, respectively. Histologic meta-analysis of histologic data in viral hepatitis score improved by >1 point in 7 of 14 and 3 of 8 patients with fibrosis of >F0 at baseline in the fazirsiran and placebo groups, respectively. No adverse events led to discontinuation, and pulmonary function tests remained stable. CONCLUSIONS: Fazirsiran reduced serum and liver concentrations of Z-AAT in a dose-dependent manner and reduced hepatic globule burden. (ClinicalTrials.gov, Number NCT03945292).

Monocyte NLRP3 inflammasome and interleukin-1ß activation modulated by alpha-1 antitrypsin therapy in deficient individuals.

INTRODUCTION: Altered complement component 3 (C3) activation in patients with alpha-1 antitrypsin (AAT) deficiency (AATD) has been reported. To understand the potential impact on course of inflammation, the aim of this study was to investigate whether C3d, a cleavage-product of C3, triggers interleukin (IL)-1ß secretion via activation of NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome. The objective was to explore the effect of AAT augmentation therapy in patients with AATD on the C3d/complement receptor 3 (CR3) signalling axis of monocytes and on circulating pro-inflammatory markers. METHODS: Inflammatory mediators were detected in blood from patients with AATD (n=28) and patients with AATD receiving augmentation therapy (n=19). Inflammasome activation and IL-1ß secretion were measured in monocytes of patients with AATD, and following C3d stimulation in the presence or absence of CR3 or NLRP3 inhibitors. RESULTS: C3d acting via CR3 induces NLRP3 and pro-IL-1ß production, and through induction of endoplasmic reticulum (ER) stress and calcium flux, triggers caspase-1 activation and IL-1ß secretion. Treatment of individuals with AATD with AAT therapy results in decreased plasma levels of C3d (3.0±1.2 µg/mL vs 1.3±0.5 µg/mL respectively, p<0.0001) and IL-1ß (115.4±30 pg/mL vs 73.3±20 pg/mL, respectively, p<0.0001), with a 2.0-fold decrease in monocyte NLRP3 protein expression (p=0.0303), despite continued ER stress activation. DISCUSSION: These results provide strong insight into the mechanism of complement-driven inflammation associated with AATD. Although the described variance in C3d and NLRP3 activation decreased post AAT augmentation therapy, results demonstrate persistent C3d and monocyte ER stress, with implications for new therapeutics and clinical practice.

Alpha-1-antitrypsin-deficiency is associated with lower cardiovascular risk: an approach based on federated learning.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is an inflammatory multisystemic disease caused by environmental exposures and/or genetic factors. Inherited alpha-1-antitrypsin deficiency (AATD) is one of the best recognized genetic factors increasing the risk for an early onset COPD with emphysema. The aim of this study was to gain a better understanding of the associations between comorbidities and specific biomarkers in COPD patients with and without AATD to enable future investigations aimed, for example, at identifying risk factors or improving care. METHODS: We focused on cardiovascular comorbidities, blood high sensitivity troponin (hs-troponin) and lipid profiles in COPD patients with and without AATD. We used clinical data from six German University Medical Centres of the MIRACUM (Medical Informatics Initiative in Research and Medicine) consortium. The codes for the international classification of diseases (ICD) were used for COPD as a main diagnosis and for comorbidities and blood laboratory data were obtained. Data analyses were based on the DataSHIELD framework. RESULTS: Out of 112,852 visits complete information was available for 43,057 COPD patients. According to our findings, 746 patients with AATD (1.73%) showed significantly lower total blood cholesterol levels and less cardiovascular comorbidities than non-AATD COPD patients. Moreover, after adjusting for the confounder factors, such as age, gender, and nicotine abuse, we confirmed that hs-troponin is a suitable predictor of overall mortality in COPD patients. The comorbidities associated with AATD in the current study differ from other studies, which may reflect geographic and population-based differences as well as the heterogeneous characteristics of AATD. CONCLUSION: The concept of MIRACUM is suitable for the analysis of a large healthcare database. This study provided evidence that COPD patients with AATD have a lower cardiovascular risk and revealed that hs-troponin is a predictor for hospital mortality in individuals with COPD.

Assessment and monitoring of lung disease in patients with severe alpha 1 antitrypsin deficiency: a european delphi consensus of the EARCO group.

BACKGROUND: Currently, there is conflicting information and guidance on the effective management of Alpha 1 Antitrypsin Deficiency (AATD). Establishing a consensus of assessment and disease management specific to AATD is important for achieving a standardized treatment pathway and for improving patient outcomes. Here, we aim to utilize the Delphi method to establish a European consensus for the assessment and management of patients with severe AATD. METHODS: Two rounds of a Delphi survey were completed online by members of the European Alpha-1 Research Collaboration (EARCO). Respondents were asked to indicate their agreement with proposed statements for patients with no respiratory symptoms, stable respiratory disease, and worsening respiratory disease using a Likert scale of 1-7. Levels of agreement between respondents were calculated using a weighted average. RESULTS: Round 1 of the Delphi survey was sent to 103 members of EARCO and 38/103 (36.9%) pulmonologists from across 15 countries completed all 109 questions. Round 2 was sent to all who completed Round 1 and 36/38 (94.7%) completed all 79 questions. Responses regarding spirometry, body plethysmography, high-resolution computed tomography, and the initiation of augmentation therapy showed little variability among physicians, but there was discordance among other aspects, such as the use of low-dose computed tomography in both a research setting and routine clinical care. CONCLUSIONS: These results provide expert opinions for the assessment and monitoring of patients with severe AATD, which could be used to provide updated recommendations and standardized treatment pathways for patients across Europe.

Distribution of alpha1 antitrypsin rare alleles in six countries: Results from the Progenika diagnostic network.

BACKGROUND: Knowledge of the frequency of rare SERPINA1 mutations could help in the management of alpha1 antitrypsin deficiency (AATD). The present study aims to assess the frequencies of rare and null alleles and their respiratory and hepatic pathogenicity. METHODS: This is a secondary analysis of a study that evaluated the viability of the Progenika diagnostic genotyping system in six different countries by analyzing 30,827 samples from cases of suspected AATD. Allele-specific genotyping was carried out with the Progenika A1AT Genotyping Test which analyses 14 mutations in buccal swabs or dried blood spots samples. SERPINA1 gene sequencing was performed for serum AAT-genotype discrepancies or by request of the clinician. Only cases with rare mutations were included in this analysis. RESULTS: There were 818 cases (2.6%) carrying a rare allele, excluding newly identified mutations. All were heterozygous except for 20 that were homozygous. The most frequent alleles were the M-like alleles, PI*Mmalton and PI*Mheerlen. Of the 14 mutations included in the Progenika panel, there were no cases detected of PI*Siiyama, PI*Q0granite falls and PI*Q0west. Other alleles not included in the 14-mutation panel and identified by gene sequencing included PI*Mwürzburg, PI*Zbristol, and PI*Zwrexham, and the null alleles PI*Q0porto, PI*Q0madrid, PI*Q0brescia, and PI*Q0kayseri. CONCLUSIONS: The Progenika diagnostic network has allowed the identification of several rare alleles, some unexpected and not included in the initial diagnostic panel. This establishes a new perspective on the distribution of these alleles in different countries. These findings may help prioritize allele selection for routine testing and highlights the need for further research into their pathogenetic role.

Quantification of circulating alpha-1-antitrypsin polymers associated with different SERPINA1 genotypes.

OBJECTIVES: Alpha-1-antitrypsin deficiency is a genetic disorder caused by mutations in the SERPINA1 gene encoding alpha-1-antitrypsin (AAT), the major serine protease inhibitor in plasma. Reduced AAT levels are associated with elevated risk of developing emphysema mainly due to uncontrolled activity of neutrophil elastase in the lungs. The prevalent Z-AAT mutant and many rare pathogenic AAT variants also predispose to liver disease due to their accumulation as polymeric chains in hepatocytes. Part of these polymers are secreted into the bloodstream and could represent biomarkers of intra-hepatic accumulation. Moreover, being inactive, they further lower lung protection against proteases. Aim of our study is to accurately quantify the percentage of circulating polymers (CP) in a cohort of subjects with different SERPINA1 genotypes. METHODS: CP concentration was measured in plasma or Dried Blood Spot (DBS) by a sensitive sandwich ELISA based on capture by the polymer-specific 2C1 monoclonal antibody. RESULTS: CP were significantly elevated in patients with the prevalent PI*SZ and PI*ZZ genotypes, with considerable intra-genotype variability. Notably, higher percentage of polymers was observed in association with elevated C-reactive protein. CP levels were also increased in carriers of the Mmalton variant, and of Mprocida, I, Plowell and Mherleen in heterozygosity with Z-AAT. CONCLUSIONS: These findings highlight the importance of implementing CP quantification in a clinical laboratory. Indeed, the variable amount of CP in patients with the same genotype may correlate with the variable severity of the associated lung and liver diseases. Moreover, CP can reveal the polymerogenic potential of newly discovered ultrarare AAT variants.

Increased expression or activation of TRPML1 reduces hepatic storage of toxic Z alpha-1 antitrypsin.

Mutant Z alpha-1 antitrypsin (ATZ) accumulates in globules in the liver and is the prototype of proteotoxic hepatic disease. Therapeutic strategies aiming at clearance of polymeric ATZ are needed. Transient receptor potential mucolipin-1 (TRPML1) is a lysosomal Ca2+ channel that maintains lysosomal homeostasis. In this study, we show that by increasing lysosomal exocytosis, TRPML1 gene transfer or small-molecule-mediated activation of TRPML1 reduces hepatic ATZ globules and fibrosis in PiZ transgenic mice that express the human ATZ. ATZ globule clearance induced by TRPML1 occurred without increase in autophagy or nuclear translocation of TFEB. Our results show that targeting TRPML1 and lysosomal exocytosis is a novel approach for treatment of the liver disease due to ATZ and potentially other diseases due to proteotoxic liver storage.

Probing of the reactive center loop region of alpha-1-antitrypsin by mutagenesis predicts new type-2 dysfunctional variants.

Lung disease in alpha-1-antitrypsin deficiency (AATD) mainly results from insufficient control of the serine proteases neutrophil elastase (NE) and proteinase-3 due to reduced plasma levels of alpha-1-antitrypsin (AAT) variants. Mutations in the specificity-determining reactive center loop (RCL) of AAT would be predicted to minimally affect protein folding and secretion by hepatocytes but can impair anti-protease activity or alter the target protease. These properly secreted but dysfunctional 'type-2' variants would not be identified by common diagnostic protocols that are predicated on a reduction in circulating AAT. This has potential clinical relevance: in addition to the dysfunctional Pittsburgh and Iners variants reported previously, several uncharacterized RCL variants are present in genome variation databases. To prospectively evaluate the impact of RCL variations on secretion and anti-protease activity, here we performed a systematic screening of amino acid substitutions occurring at the AAT-NE interface. Twenty-three AAT variants that can result from single nucleotide polymorphisms in this region, including 11 present in sequence variation databases, were expressed in a mammalian cell model. All demonstrated unaltered protein folding and secretion. However, when their ability to form stable complexes with NE was evaluated by western blot, enzymatic assays, and a novel ELISA developed to quantify AAT-NE complexes, substrate-like and NE-binding deficient dysfunctional variants were identified. This emphasizes the ability of the RCL to accommodate inactivating substitutions without impacting the integrity of the native molecule and demonstrates that this class of molecule violates a generally accepted paradigm that equates circulating levels with functional protection of lung tissue.

Genetic Epidemiology of Alpha-1 Antitrypsin Deficiency in Macaronesia.

INTRODUCTION: The prevalence of alpha-1 antitrypsin deficiency (AATD) in Macaronesia (i.e., Azores, Madeira, Canary Islands, and Cape Verde archipelagos) is poorly known. Our goal was to update it by selecting the most reliable available articles. METHOD: Literature search using MEDLINE, Embase (via Ovid), and Google Scholar, until December 2023, for studies on prevalence of AATD in the general population and in screenings, published in peer-reviewed journals. RESULTS: Three studies carried out in the general population of Madeira, La Palma, and Cape Verde, and three screenings carried out in La Palma (2) and Gran Canaria (1) were selected. The frequencies of PI*S in the general population showed an ascending gradient, from South to North, with values (per thousand) of 35 in Cape Verde, 82 in La Palma, and 180 in Madeira. The PI*Z frequencies showed this same gradient, with values of 2 × 1,000 in Cape Verde, 21 in La Palma, and 25 in Madeira. Screenings detected high percentages of defective alleles, including several rare and null alleles, some unique to these islands. CONCLUSION: The frequencies of PI*S and PI*Z in Madeira are comparable to the highest in the world. Those of the Canary Islands are similar to those of the peninsular population of Spain, and contrast with the low rates of Cape Verde. Screenings detected high numbers of deficient alleles. These results support the systematic investigation of AATD in clinically suspected patients and in relatives of index cases, to reduce underdiagnosis and apply early preventive and therapeutic measures in those affected.

Predicting Exacerbations in Alpha-1 Antitrypsin Deficiency Using Clinical and Pulmonary Function Tests: Portuguese EARCO Registry.

INTRODUCTION: Exacerbations are common in individuals with alpha-1 antitrypsin deficiency (AATD)-related lung disease. This study intended to identify independent predictive factors for exacerbations in AATD using the Portuguese European Alpha-1 Research Collaboration (EARCO) registry. METHODS: This study includes patients from the Portuguese EARCO registry, a prospective multicenter cohort (NCT04180319). From October 2020 to April 2023, this registry enrolled 137 patients, 14 of whom were excluded for analysis for either missing 12 months of follow-up or baseline pulmonary function. RESULTS: Among the 123 AATD patients, 27 (22.0%) had at least one exacerbation in the last 12 months of follow-up. Patients with Pi*ZZ phenotype were three times more likely than the rest of the population to experience any exacerbation (32.7 vs. 14.1%, p = 0.014; OR 3.0). BODE index was significantly higher in exacerbators than in non-exacerbators (3.9 ± 2.4 vs. 1.3 ± 1.2; p < 0.001), including on multivariate analysis (p = 0.002). Similar results were found for BODEx (multivariate p < 0.001). DLCO was the only functional parameter independently associated with exacerbations (p = 0.024). CONCLUSIONS: DLCO, BODE, and BODEx were independent predictors of exacerbations at 12 months in AATD patients. Understanding these risk factors can aid decision-making on AATD-related lung disease management and improve patient outcomes.

Characteristics associated with SF-36 in alpha-1 antitrypsin deficiency-associated COPD: a cross-sectional analysis.

BACKGROUND: Generic measures of health-related quality of life (HRQoL), such as the 36-Item Short Form Survey (SF-36), are widely used in assessing chronic conditions. These tools have an advantage over disease-specific instruments, as they allow comparisons across different health conditions and with the general population. In alpha-1 antitrypsin deficiency (AATD)-associated chronic obstructive pulmonary disease (COPD), HRQoL research remains scarce. This cross-sectional study evaluates the factors associated with HRQoL in a cohort of patients with AATD-associated COPD. METHODS: Our study included participants of AlphaNet (2008-2019), a health management organization for people with AATD in the US who are prescribed augmentation therapy. Norm-based SF-36 scores for the mental and physical component summary scores (MCS and PCS, mean of 50 ± 10 in the general US population) and 8 individual scales were evaluated. Individuals with lung disease and data available on ≥1 measurement on any SF-36 scale and clinically relevant characteristics such as modified Medical Research Council (mMRC) scale, exacerbation frequency, productive cough, and use of oxygen were included in these analyses. Generalized linear regression models were fit to examine the association of baseline characteristics with MCS and PCS scores. Age, sex, regular use of oxygen, exacerbation frequency, mMRC, and productive cough were included in these models. RESULTS: Participants (n=4398, mean age 57.6 [SD=10.6] years, 45.4% female) had a mean MCS score of 51.2 ± 10.8 and PCS of 36.3 ± 9.8. The average mMRC score was 2.4 ± 1.3, and 56.4% had 2 or more exacerbations per year. Overall, the physical component of SF-36 was more severely impacted compared to the mental component. In multivariable regression analyses, PCS scores were significantly associated with exacerbation frequency, mMRC, regular use of oxygen, and productive cough; MCS was associated with age, sex, exacerbation frequency, mMRC, and productive cough. CONCLUSIONS: These findings demonstrate that patient-perceived physical health is significantly impaired in this cohort of people with AATD-associated COPD compared to mental health. Longitudinal studies are needed to evaluate the change in physical and mental health status over time in this population.

Case report of a novel alpha1-antitrypsin null variant in Türkiye: Q0RIZE.

BACKGROUND: Alpha1-antitrypsin (AAT) is a serine protease inhibitor that serves as a counterbalance to the activity of elastases, e.g., neutrophil elastase in lung tissue. AAT deficiency (AATD) is a rare disorder usually arising from mutations to the SERPINA1 gene that codes for AAT. The most common AATD alleles are S and Z which produce ~ 40% and ~ 90% reductions in serum AAT, respectively. Rare genetic variants (> 500 identified) can also be associated with mild to severe AATD. RESULTS: This report describes a novel mutation of SERPINA1 producing AATD, which we have designated, Q0RIZE. This mutation was identified in a 44-year-old woman admitted with massive hemoptysis and treated with bronchial artery embolization. Computed tomography revealed centriacinar and panacinar emphysema with prominent air entrapment, atelectasis, and localized bronchiectasis. Serum AAT was < 0.27 g/L (below detection limit). Genetic analysis showed homozygous deletion of exons I to III. CONCLUSIONS: Although many SERPINA1 variants have been identified, variants with large deletions and identified in a homozygous individual, as seen in this case with Q0RIZE, are uncommon. AATD is an underdiagnosed and undertreated disease. Wider screening of COPD patients could result in earlier diagnosis and treatment that could preserve lung function.

Danish children with ZZ-homozygous alpha-1 antitrypsin deficiency are more affected on liver parameters than children with heterozygosity.

AIM: The longitudinal health status of Danish children with alpha-1 antitrypsin deficiency had never previously been characterised. This study aimed to assess the changes in growth, lung and liver function through childhood in these children. METHODS: Danish children diagnosed between 2005 and 2020 with pathogenic variants in the Serpin family A member 1 gene were included. Retrospective data on growth, lung and liver parameters were obtained from local databases. Anthropometric Z-scores and composite liver scores were computed. Growth and blood results were analysed using robust linear mixed models. RESULTS: The study included 184 children (68 with ZZ-homozygosity, 116 with heterozygosity). The median follow-up time was 7 years [IQR 3.75-9.00] for children with ZZ-homozygosity and 0.5 years [IQR 0.0-2.0] for children with heterozygosity. Both groups had low weight-for-height Z-scores at diagnosis but experienced catch-up growth during the first year of life. In addition, children with ZZ-homozygosity had higher serum concentrations of γ-glutamyl transferase and alanine aminotransferase throughout childhood, when compared with children with heterozygosity. Data proved insufficient to assess lung function properly. CONCLUSION: Children with ZZ-homozygosity were more affected on serum liver parameters throughout childhood when compared with children with heterozygosity. Both groups experienced catch-up growth during the first year of life.

Machine-Learning Model Identifies Patients With Alpha-1 Antitrypsin Deficiency Using Claims Records.

Identifying patients with rare diseases like alpha-1 antitrypsin deficiency (AATD) is challenging. Machine-learning models may be trained to identify patients with rare diseases using large-scale, real-world databases, whereas electronic medical records have low numbers of confirmed cases and have limited use in training such models. We applied a machine-learning model to a large US claims database to identify undiagnosed symptomatic patients with AATD. Using deidentified data from the Komodo US claims database (April 26, 2016-January 31, 2023), a model was trained to identify symptomatic patients with high probability of AATD. Eighty claims records for high-probability candidates identified by the model were independently reviewed and validated by 2 clinical experts. The experts independently indicated that of the 80 high-probability candidate patients, 65 (81%) and 62 (78%) patients, respectively, should be tested for AATD. Feedback from this validation step informed model optimization. The optimized model was applied to claims data to identify symptomatic patients with probable AATD. Eleven and 14 "features" of the claims data were informative in distinguishing patients with AATD from patients with COPD without AATD and from unspecified chronic liver diseases. Moreover, patients with diagnosed AATD and COPD without AATD had unique cadences of similar medical events in their diagnostic journeys. Our work shows that a machine-learning model trained on a large US claims database can accurately identify symptomatic patients with AATD and provides useful insights into the diagnostic journey of patients with AATD.

Normal Alpha-1-Antitrypsin Variants Display in Serum Allele-Specific Protein Levels.

Alpha-1-antitrypsin (A1AT or SERPINA1) has been proposed as a putative biomarker distinguishing healthy from diseased donors throughout several proteomics studies. However, the SERPINA1 gene displays high variability of frequent occurring genotypes among the general population. These different genotypes may affect A1AT expression and serum protein concentrations, and this is often not known, ignored, and/or not reported in serum proteomics studies. Here, we address allele-specific protein serum levels of A1AT in donors carrying the normal M variants of A1AT by measuring the proteoform profiles of purified A1AT from 81 serum samples, originating from 52 donors. When focusing on heterozygous donors, our data clearly reveal a statistically relevant difference in allele-specific protein serum levels of A1AT. In donors with genotype PI*M1VM1A, the experimentally observed ratio was approximately 1:1 (M1V/M1A, 1.00:0.96 ± 0.07, n = 17). For individuals with genotype PI*M1VM2, this ratio was 1:1.28 (M1V/M2, 1.00:1.31, ±0.19, n = 7). For genotypes PI*M1VM3 and PI*M1AM3, a significant higher amount of M3 was observed compared to the M1-subtypes (M1V/M3, 1.00:1.84 ± 0.35, n = 8; M1A/M3, 1.00:1.61 ± 0.33, n = 5). We argue that these observations are important and should be considered when analyzing serum A1AT levels before proposing A1AT as a putative serum biomarker.

A test of automated use of electronic health records to aid in diagnosis of genetic disease.

PURPOSE: Automated use of electronic health records may aid in decreasing the diagnostic delay for rare diseases. The phenotype risk score (PheRS) is a weighted aggregate of syndromically related phenotypes that measures the similarity between an individual's conditions and features of a disease. For some diseases, there are individuals without a diagnosis of that disease who have scores similar to diagnosed patients. These individuals may have that disease but not yet be diagnosed. METHODS: We calculated the PheRS for cystic fibrosis (CF) for 965,626 subjects in the Vanderbilt University Medical Center electronic health record. RESULTS: Of the 400 subjects with the highest PheRS for CF, 248 (62%) had been diagnosed with CF. Twenty-six of the remaining participants, those who were alive and had DNA available in the linked DNA biobank, underwent clinical review and sequencing analysis of CFTR and SERPINA1. This uncovered a potential diagnosis for 2 subjects, 1 with CF and 1 with alpha-1-antitrypsin deficiency. An additional 7 subjects had pathogenic or likely pathogenic variants, 2 in CFTR and 5 in SERPINA1. CONCLUSION: These findings may be clinically actionable for the providers caring for these patients. Importantly, this study highlights feasibility and challenges for future implications of this approach.

The impact of diagnostic delay on survival in alpha-1-antitrypsin deficiency: results from the Austrian Alpha-1 Lung Registry.

BACKGROUND: Alpha-1-antitrypsin (AAT) deficiency (AATD) is a genetic disorder that can manifest as lung disease. A delay between onset of symptoms and diagnosis of AATD is common and associated with worse clinical status and more advanced disease stage but the influence on survival is unclear. OBJECTIVE: We aimed to investigate the impact of diagnostic delay on overall survival (OS) and transplant-free survival (TS) in AATD patients. METHODS: We analysed 268 AATD patients from the prospective multi-centre Austrian Alpha-1 Lung (AAL) Registry, employing descriptive statistics, Chi-square-test as well as univariable (Kaplan-Meier plots, log-rank test) and multivariable survival analysis (Cox regression). RESULTS: The predominant phenotype was Pi*ZZ (82.1%). At diagnosis, 90.2% had an AAT level below 0.6 g/L. At inclusion, 28.2% had never smoked, 68.0% had quit smoking and 3.8% continued to smoke. Lung disease was diagnosed in 98.5%, thereof most patients were diagnosed with emphysema (63.8%) and/or chronic obstructive pulmonary disease (44.0%). Median diagnostic delay was 5.3 years (inter-quartile range [IQR] 2.2-11.5 years). In multivariable analysis (n = 229), a longer diagnostic delay was significantly associated with worse OS (hazard ratio [HR] 1.61; 95% CI 1.09-2.38; p = 0.016) and TS (HR 1.43; 95% CI 1.08-1.89; p = 0.011), independent from age, smoking status, body mass index (BMI), forced expiratory volume in one second (FEV1) and long-term oxygen treatment. Furthermore, BMI, age and active smoking were significantly associated with worse OS as well as BMI, active smoking and FEV1 were with worse TS. CONCLUSIONS: A delayed diagnosis was associated with significantly worse OS and TS. Screening should be improved and efforts to ensure early AATD diagnosis should be intensified.

Baseline characteristics from a 3-year longitudinal study to phenotype subjects with COPD: the FOOTPRINTS study.

BACKGROUND: FOOTPRINTS® is a prospective, longitudinal, 3-year study assessing the association between biomarkers of inflammation/lung tissue destruction and chronic obstructive pulmonary disease (COPD) severity and progression in ex-smokers with mild-to-severe COPD. Here, we present baseline characteristics and select biomarkers of study subjects. METHODS: The methodology of FOOTPRINTS® has been published previously. The study population included ex-smokers with a range of COPD severities (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages 1-3), ex-smokers with COPD and alpha-1-antitrypsin deficiency (A1ATD) and a control group of ex-smokers without airflow limitation (EwAL). At study entry, data were collected for: demographics, disease characteristics, history of comorbidities and COPD exacerbations, symptoms, lung function and volume, exercise capacity, soluble biomarkers, and quantitative and qualitative computed tomography. Baseline data are presented with descriptive statistical comparisons for soluble biomarkers in the individual GOLD and A1ATD groups versus EwAL. RESULTS: In total, 463 subjects were enrolled. The per-protocol set comprised 456 subjects, mostly male (64.5%). The mean (standard deviation) age was 60.7 (6.9) years. At baseline, increasing pulmonary symptoms, worse lung function, increased residual volume, reduced diffusing capacity of the lung for carbon monoxide (DLco) and greater prevalence of centrilobular emphysema were observed with increasing disease severity amongst GOLD 1-3 subjects. Subjects with A1ATD (n = 19) had similar lung function parameters to GOLD 2-3 subjects, a high residual volume comparable to GOLD 3 subjects, and similar air trapping to GOLD 2 subjects. Compared with EwAL (n = 61), subjects with A1ATD had worse lung function, increased residual volume, reduced DLco, and a greater prevalence of confluent or advanced destructive emphysema. The soluble inflammatory biomarkers white blood cell count, fibrinogen, high-sensitivity C-reactive protein and plasma surfactant protein were higher in GOLD 1-3 groups than in the EwAL group. Interleukin-6 was expressed less often in EwAL subjects compared with subjects in the GOLD and A1ATD groups. Soluble receptor for advanced glycation end product was lowest in GOLD 3 subjects, indicative of more severe emphysema. CONCLUSIONS: These findings provide context for upcoming results from FOOTPRINTS®, which aims to establish correlations between biomarkers and disease progression in a representative COPD population. TRIAL REGISTRATION NUMBER: NCT02719184, study start date 13/04/2016.

Optimizing the screening of alpha-1 antitrypsin deficiency using serum protein electrophoresis.

OBJECTIVES: Alpha-1 antitrypsin (A1AT) deficiency was first identified in patients with emphysema by the absence of the α1 band on serum protein electrophoresis (SPE). Today, capillary zone electrophoresis is widely performed in laboratories. Here, we compared two SPE systems to detect decreased A1AT concentrations to optimize their use as a screening tool for A1AT deficiency. METHODS: Serum protein electrophoresis was performed on 200 samples on the Capillarys 2 and the V8 Nexus. The latter presents two α1 bands (α1 band 1 and 2) while the Capillarys 2 has only one (Capillarys 2 total α1). The measures of A1AT and α1 acid glycoprotein (AAG) were performed as well as the phenotyping of M, S and Z alleles. RESULTS: At a A1AT cutoff of 0.80 g/L, a cutoff of 1.21 g/L using the V8 Nexus α1 band 2 corresponded to a 100% sensitivity and a 92.4% specificity while a 1.69% cutoff corresponded to a 100% sensitivity and a 92.4% specificity. The performance of the α1 band 1 was suboptimal and rather corresponded to AAG. On the Capillarys 2, a cutoff of 2.0 g/L corresponded to a 75.0% sensitivity and a 86.6% specificity, while a 3.2% cutoff showed a 96.4% sensitivity and a 67.4% specificity. The V8 Nexus α1 band 2 was the method the most correlated with A1AT (r=0.90-0.94). CONCLUSIONS: The V8 Nexus α1 band 2 was the best predictor of A1AT deficiency, probably owing to a better resolution. The use of SPE was however unable to predict each phenotype. Phenotype or genotype studies are therefore still advisable in case of A1AT deficiency.

Liver transplantation for alpha 1 antitrypsin deficiency (A1ATD) using a heterozygous donor: Outcomes and review of the literature.

INTRODUCTION: Alpha 1 antitrypsin deficiency (A1ATD) accounts for 21% of all pediatric liver transplants due to metabolic disease in the western world. Donor heterozygosity has been evaluated in adults but not to a recipient with A1ATD. METHODS: The data of patient were retrospectively analyzed and a literature review performed. RESULTS: We present a unique case of living related donation from a A1ATD heterozygote female to a child for decompensated cirrhosis due to A1ATD. In the immediate postoperative period, the child had low-alpha 1 antitrypsin levels, but these normalized by 3 months posttransplant. He is currently 19 months post-transplant with no evidence of recurrent disease. CONCLUSION: Our case provides initial evidence that A1ATD heterozygote donors may be safely used for pediatric patients with A1ATD, thus expanding the donor pool.