Severe Alpha-1 Antitrypsin Deficiency Research Articles

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

BackgroundCurrently, 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.MethodsTwo 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.ResultsRound 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.ConclusionsThese 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.

Current Practices for Severe Alpha-1 Antitrypsin Deficiency Associated COPD and Emphysema

Alpha-1 antitrypsin deficiency is a genetic disorder that can lead to chronic obstructive pulmonary disease and emphysema. Although it is the most well-studied genetic risk factor for emphysema, data is still scarce. Traditionally, medical therapy is similar to standard chronic obstructive pulmonary disease patients. Over the past several decades, enzyme augmentation therapy has emerged as a highly utilized alpha-1 antitrypsin-specific therapy. It has become the standard of care for severe alpha-1 antitrypsin deficiency despite unclear effects on a multitude of clinical outcomes. Significant data supports interventional therapies, including lung volume reduction surgery and bronchoscopic lung volume reduction, for chronic obstructive pulmonary disease patients without alpha-1 antitrypsin deficiency. These interventions have less robust data in the treatment of alpha-1 antitrypsin-induced chronic obstructive pulmonary disease. This review will explore the data regarding various treatment options for severe alpha-1 antitrypsin deficiency associated with chronic obstructive pulmonary disease and emphysema.

Detection of Alpha-1 Antitrypsin Levels in Chronic Obstructive Pulmonary Disease in Respiratory Clinics in Spain: Results of the EPOCONSUL 2021 Audit.

Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed condition despite being one of the most common inherited disorders in adults that is associated with an increased risk of developing chronic obstructive pulmonary disease (COPD). The aim was to evaluate the frequency of performing AAT levels and associated factors in COPD patients in an audit conducted in 2021-2022, as well as to compare with a previous audit conducted in 2014-2015. EPOCONSUL 2021 is a cross-sectional audit that evaluated the outpatient care provided to COPD patients in respiratory clinics in Spain based on available data from medical registries. 4225 patients with a diagnosis of COPD from 45 centers were audited in 2021. A total of 1670 (39.5%) patients underwent AAT determination. Being treated at a specialized COPD outpatient clinic (OR 1.88, p = 0.007), age ≤ 55 years old (OR 1.84, p = 0.007) and a FEV1 < 50% (OR 1.86, p < 0.001) were associated with a higher likelihood of being tested for AAT, while Charlson index ≥ 3 (OR 0.63, p < 0.001) and genotyping of AATD availability (OR 0.42, p < 0.001) showed a statistically significant negative association. The analysis of cases included in respiratory units that participated in both audits showed an increase in the proportion of cases with AAT serum level testing available (adjusted OR 2.81, p < 0.001). The percentage of individuals with serum AAT levels < 60 mg/dL (a severe AATD) was 4%. Our analysis identifies significant improvements in adherence to the recommendation to test AAT levels in COPD patients, performed in 4 out of 10 patients, being more likely at younger ages and with higher COPD severity, and with a detection of severe AATD of 4% among those tested, suggesting that clinicians still perform AAT testing in COPD patients selectively. Therefore, efforts are still needed to optimize AATD screening and establish new early detection strategies to reduce morbidity and mortality in these patients.

Safety and Reactogenicity of COVID-19 Vaccination in Severe Alpha-1 Antitrypsin Deficiency.

Patients with alpha-1 antitrypsin deficiency (AATD) exhibit dysregulated inflammatory responses and a predilection for autoimmunity. While the adverse event (AE) profiles of COVID-19 vaccines in several chronic inflammatory conditions are now available, safety and tolerability data for patients with severe AATD have yet to be described. The feasibility of coadministering vaccines against COVID-19 and influenza in this population is similarly unclear. We conducted a prospective study of 170 patients with Pi*ZZ genotype AATD receiving their initial vaccination series with ChAdOx1 nCoV-19 (AstraZeneca). Patients were monitored clinically for AEs over the week that followed their first and second doses. In parallel, we conducted the same assessments in patients with Pi*MM genotype chronic obstructive pulmonary disease (COPD) (n=160) and Pi*MM individuals without lung disease (n=150). The Pi*ZZ cohort was subsequently followed through 2 consecutive mRNA-based booster vaccines (monovalent and bivalent BNT162b2, Pfizer/BioNTech). To assess the safety of combined vaccination against COVID-19 and influenza, the quadrivalent influenza vaccine was administered to participants attending for their second COVID-19 booster vaccination, either on the same day or following a 1-week interval. Pi*ZZ AATD participants did not display increased AEs compared to Pi*MM COPD or Pi*MM non-lung disease controls. Although unexpected and serious vaccine-associated AEs did occur, the majority of AEs experienced across the 3 groups were mild and self-limiting. The AATD demographic at highest risk for AEs (especially systemic and prolonged AEs) was young females. No increase in AE risk was observed in patients with established emphysema, sonographic evidence of liver disease, or in those receiving intravenous augmentation therapy. AE incidence declined sharply following the initial vaccine series. Same-day coadministration of the COVID-19 mRNA bivalent booster vaccine and the annual influenza vaccine did not result in increased AEs compared to sequential vaccines 1 week apart. Despite their pro-inflammatory state, patients with severe AATD are not at increased risk of AEs or serious AEs compared to patients with nonhereditary COPD and patients without lung disease. Same-day coadministration of COVID-19 booster vaccines with the annual influenza vaccine is feasible, safe, and well-tolerated in this population.

Pi*S and Pi*Z Alleles of SERPINA1 Gene Are Associated With Specific Variants of a BRD4‐Independent Enhancer

Alpha‐1 antitrypsin deficiency (AATD) is a genetic disorder caused by specific variants in the SERPINA1 gene, which encodes AAT. The most common disease‐associated SERPINA1 variants are Pi ∗ S and Pi ∗ Z alleles, which cause moderate and severe AATD, respectively. Recent studies have reported the presence of a possible regulator of SERPINA gene cluster expression (LOC126862032), which is suggested to act as a BRD4‐Independent Enhancer (SERPINA‐BIE). This study is aimed at characterizing the SERPINA‐BIE locus and assessing possible associations with SERPINA1 AATD‐related alleles. For this purpose, SERPINA‐BIE was PCR genotyped from 917 samples, including 452 asthmatic patients, and 465 newborns. Nine SERPINA‐BIE alleles were sequenced, revealing a specific combination of 56‐bp sequence types, and each SERPINA‐BIE allele has a unique total number of CpG sites. Statistical analyses revealed an association between the Pi ∗ Z allele of the SERPINA1 gene and the SERPINA‐BIE allele 13 (p value = 5.51 × 10−10), as well as between Pi ∗ S and SERPINA‐BIE allele 14 (p value = 8.95 × 10−15). However, AAT levels were not associated with SERPINA‐BIE alleles when models were corrected by SERPINA1 genotypes. This study could contribute to a better understanding of the regulation of the SERPINA1 gene expression, and its role in AATD.

Alpha-1 Antitrypsin Deficiency in a Young Never Smoker With Novel Pi*Null Homozygous Mutation: a Case Report.

Alpha-1 antitrypsin deficiency is an autosomal codominant disorder caused by SERPINA1 gene mutations. PI*Z and PI*S mutations commonly underlie this deficiency, but rarer homozygous PI*null (Q0) mutations may result in a complete loss of alpha-1 antitrypsin (AAT). Such rare mutations lead to severe AAT deficiency and early onset of lung disease. We present a case of 35-year-old female never-smoker born to consanguineous parents who developed severe panlobular emphysema and end-stage respiratory insufficiency requiring lung transplantation. Subsequent genetic testing identified her as homozygous for a novel c.82del mutation - here named Q0Bani-Yas based on the region of the primary carrier's origin - which resulted in undetectable levels of alpha-1 antitrypsin protein.

Prevalence of Cardiovascular Disease and Rate of Major Adverse Cardiovascular Events in Severe Alpha-1 Antitrypsin Deficiency COPD.

Alpha-1 antitrypsin deficiency is an autosomal co-dominant condition that predisposes individuals to early-onset emphysema. As with COPD, AATD-COPD is associated with pulmonary exacerbations, which impacts on overall mortality and quality of life. Though there is evidence that COPD is associated with a higher prevalence of cardiovascular disease and major adverse cardiovascular events (MACE), it is unclear if this is true for patients with AATD-COPD. Prevalence of cardiovascular disease was determined in two separate severe AATD cohorts: AlphaNet, USA and the Birmingham AATD registry, UK. All patients had preexisting lung disease. Cardiovascular disease was defined as presence of any of the following: heart failure, ischaemic heart disease, atrial fibrillation, stroke, and myocardial infarction. A Cox proportional hazards model was used to assess the impact of prior cardiovascular disease and frequent exacerbator phenotype on risk of future MACE. Out of 3493 patients with severe AATD, 14.7% had prior cardiovascular disease, including stroke (2.3%), myocardial infarction (2.2%), and heart failure (2.5%). Frequent exacerbators were more likely to have preexisting cardiovascular disease compared with those with one or no exacerbations in the preceding year (63% vs 44.8%, p = 0.001). There was increased risk of future MACE in frequent exacerbators (HR 1.85, 95% CI 1.24 to 2.75), former and current smokers (HR 1.80, 95% CI 1.07 to 3.02, p = 0.026, and HR 4.04, 95% CI 1.44 to 11.32, p = 0.008, respectively), and those with prior cardiovascular disease (HR 3.81, 95% CI 2.60 to 5.58, p < 0.001). In severe AATD-COPD, MACE are associated with an increased exacerbation frequency, previous cardiovascular disease, and a history of smoking.

Nine controversial questions about augmentation therapy for alpha-1 antitrypsin deficiency: a viewpoint.

Augmentation therapy with intravenous alpha-1 antitrypsin is the only specific treatment for alpha-1 antitrypsin deficiency (AATD)-associated emphysema. This treatment has been available and remained basically unchanged for more than 35 years, but many questions persist regarding its indications, regimen of administration and efficacy. Because AATD is a rare disease, it has not been possible to conduct randomised, placebo-controlled trials that are adequately powered for the usual outcomes analysed in non-AATD-related COPD, such as lung function decline, exacerbations, symptoms or quality of life. New outcomes such as lung densitometry measured by computed tomography are more sensitive for identifying emphysema progression but are not widely accepted by regulatory agencies. In addition, clinical manifestations, severity and the natural history of lung disease associated with AATD are very heterogeneous, which means that individual prediction of prognosis is challenging. Therefore, the indication for augmentation is sometimes a dilemma between initiating treatment in individuals who may not develop significant lung disease or in whom disease will not progress and delaying it in patients who will otherwise rapidly and irreversibly progress.Other areas of debate are the possible indication for augmentation in patients with severe AATD and respiratory diseases other than emphysema, such as bronchiectasis or asthma, and the use of therapy after lung transplant in AATD patients. All these uncertainties imply that the indication for treatment must be personalised in expert reference centres after in-depth discussion of the pros and cons of augmentation with the patient.

Governmental Non-Pharmaceutical Interventions during the COVID-19 Pandemic and the COPD Exacerbation and Respiratory Infection Rate in Patients with Alpha-1 Antitrypsin Deficiency

During the COVID-19 pandemic the number of hospital admissions due to chronic obstructive pulmonary disease (COPD) exacerbations was significantly reduced. The reason for this decline is not fully understood. Governmental non-pharmaceutical interventions (NPI’s), an increase in community treated exacerbations, or healthcare avoidance by patients, are potential reasons. For the current study, the impact of Dutch governmental NPI’s on the COPD exacerbations and respiratory infections rate in patients with severe alpha-1 antitrypsin deficiency (AATD) was analyzed. The patients participated in the NCT04204252 study, a randomized controlled trial evaluating the efficacy and safety of inhaled alpha-1 antitrypsin. Data collected in the time-period from March 2020 until February 2022 was analyzed. In this period the Dutch government imposed variable NPI’s to contain the spread of SARS-CoV-2. Patients were required to document their daily symptoms in an electronic diary. The strictness of the governmental NPI’s was measured by the COVID-19 Stringency Index. 19 patients participated in this study during the analysis period. A total of 40 respiratory infections and COPD exacerbations occurred. The Spearman’s correlation coefficient of the monthly average COVID-19 Stringency Index and respiratory infections and COPD exacerbations rate was −0.316 (p = 0.132). When months known for a low respiratory infection rate were excluded, the correlation coefficient was −0.625 (p = 0.010). This study showed a significant negative correlation between the COPD exacerbations and respiratory infection rate and the COVID-19 Stringency Index in patients with AATD related COPD in the autumn-winter months.

Impact of PNPLA3 I148M on alpha-1 antitrypsin deficiency-dependent liver disease progression.

Genetic risk factors are major determinants of chronic liver disease (CLD) progression. Patatin-like phospholipase domain-containing protein 3 (PNPLA3) I148M polymorphism and alpha-1 antitrypsin (AAT) E342K variant, termed PiZ, are major modifiers of metabolic CLD. Both variants are known to affect metabolic CLD through increased endoplasmic reticulum stress, but their combined effect on CLD progression remains largely unknown. Here, we aimed to test our working hypothesis that their combined incidence triggers CLD disease progression. We showed that patients with PiZZ/PNPLA3 I148M from the European alpha-1-antitrypsin deficiency (AATD) liver consortium and the UK Biobank had a trend towards higher liver enzymes, but no increased liver fat accumulation was evident between subgroups. After generating transgenic mice that overexpress the PiZ variant and simultaneously harbor the PNPLA3 I148M knockin (designated as PiZ/PNPLA3 I148M ), we observed that animals with PiZ and PiZ/PNPLA3 I148M showed increased liver enzymes compared to controls during aging. However, no significant difference between PiZ and PiZ/PNPLA3 I148M groups was observed, with no increased liver fat accumulation over time. To further study the impact on CLD progression, a Western-styled diet was administered, which resulted in increased fat accumulation and fibrosis in PiZ and PiZ/PNPLA3 I148M livers compared to controls, but the additional presence of PNPLA3 I148M had no impact on liver phenotype. Notably, the PiZ variant protected PNPLA3 I148M mice from liver damage and obesity after Western-styled diet feeding. Our results demonstrate that the PNPLA3 polymorphism in the absence of additional metabolic risk factors is insufficient to drive the development of advanced liver disease in severe AATD.

Alpha1-antitrypsin deficiency: An updated review

Alpha1-antitrypsin deficiency (AATD) is a rare autosomal recessive disease associated with the homozygous Z variant of the SERPINA1 gene. Clinical expression of AATD, reported 60 years ago associate a severe deficiency, pulmonary emphysema and/or liver fibrosis. Pulmonary emphysema is due to the severe alpha1-antitrypsin deficiency of the ZZ homozygous status and is favored by smoking. Liver fibrosis is due to the ZZ homozygous status and is favored by obesity and excessive chronic alcohol intake, with a risk of liver cancer. Diagnosis is based on serum level and either isoelectric focusing determination of the biochemical phenotype or PCR detection of some variants. SERPINA1 gene sequencing is necessary in case of discrepancies between the results of these tests. No treatment is available for the liver disease in AATD. Although no specific trial has been performed, COPD in AATD should be treated as per COPD recommendations. Based on a randomized clinical trial, augmentation therapy is indicated in non-smoking adults less than 70 years of age with emphysema at chest CT, confirmed homozygous AATD, and FEV1 between 35% and 70% of predicted. In contrast Z heterozygosis (MZ or SZ) brings a risk of lung or liver disease only in association with further risk factors. Early detection, in all patients with COPD and chronic liver disease, is critical for the correct information of Z variant carriers. News ways of correcting the liver production of alpha1-antitrypsin will modify the care of AATD patients.

Development of a risk score to increase detection of severe alpha-1 antitrypsin deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an under-recognised genetic cause of chronic obstructive lung disease, and many fewer cases than estimated have been identified. Can a reported respiratory and hepatic disease history from a large AATD testing database be used to stratify a person's risk of severe AATD? We analysed data extracted from the AATD National Detection Program. Demographics and medical history were evaluated to predict AATD PI*ZZ genotype. Logistic regression and integer programming models identified predictors and obtained risk scores. These were internally validated on a subset of the data. Out of 301 343 subjects, 1529 (0.5%) had PI*ZZ genotype. Predictors of severe AATD were asthma, bronchitis, emphysema, allergies, bronchiectasis, family history of AATD, cirrhosis, hepatitis and history of abnormal liver function tests. The derived model establishes a subject's risk of severe AATD, and scores ≥0 had an estimated risk of 0.41%, sensitivity 84.62% and specificity 24.32%. A model simulating guideline recommendations had an estimated risk of 0.51% with a sensitivity of 37.98% and specificity 46.60%. By recommending screening for scores ≥0, we estimate that more subjects would be screened (75.7% versus 53.4%) and detected (84.6% versus 58.2%) compared to a guideline-simulated model. This medical history risk model is a useful predictive tool to detect subjects at greater risk of having severe AATD and improves sensitivity of detection. Scores <0 are at lower risk and may need not be screened; testing is recommended for scores ≥0 and consistent with current guidelines.

THU-472 - PNPLA3 I148M polymorphism does not promote liver disease progression in severe alpha1-antitrypsin deficiency

THU-472 - PNPLA3 I148M polymorphism does not promote liver disease progression in severe alpha1-antitrypsin deficiency

Comprehensive Clinical Diagnostic Pipelines Reveal New Variants in Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is an underdiagnosed disorder associated with mutations in the SERPINA1 gene encoding alpha-1 antitrypsin (AAT). Severe AATD can manifest as pulmonary emphysema and progressive liver disease. Besides the most common pathogenic variants S (E264V) and Z (E342K), many rarer genetic variants of AAT have been found in patients and in the general population. Here we report a panel of new SERPINA1 variants, including 4 null and 16 missense alleles, identified among a cohort of individuals with suspected AATD whose phenotypic follow-up showed inconclusive or atypical results. Because the pathogenic significance of the missense variants was unclear purely on the basis of clinical data, the integration of computational, biochemical, and cellular studies was used to define the associated risk of disease. Established pathogenicity predictors and structural analysis identified a panel of candidate damaging mutations that were characterized by expression in mammalian cell models. Polymer formation, intracellular accumulation, and secretory efficiency were evaluated experimentally. Our results identified two AAT mutants with a Z-like polymerogenic severe deficiency profile (Smilano and Mcampolongo) and three milder variants (Xsarezzo, Pdublin, and Ctiberias). Overall, the experimentally determined behavior of the variants was in agreement with the pathogenicity scores of the REVEL (an ensemble method for predicting the pathogenicity of rare missense variants) predictor, supporting the utility of this bioinformatic tool in the initial assessment of newly identified amino acid substitutions of AAT. Our study, in addition to describing 20 new SERPINA1 variants, provides a model for a multidisciplinary approach to classification of rare AAT variants and their clinical impact on individuals with rare AATD genotypes.

Impact of a Computerized Clinical Decision Support System to Improve Chronic Obstructive Pulmonary Disease Diagnosis and Testing for Alpha-1 Antitrypsin Deficiency.

Rationale: Chronic obstructive pulmonary disease (COPD) and alpha-1 antitrypsin deficiency (AATD) are underrecognized diseases. This is in part due to the underdiagnosis and lack of confirmation of COPD but also from poor adherence to AATD screening recommendations. Objectives: A clinical decision support system (CDSS) to guide primary care providers improves spirometry testing and confirmation of COPD diagnosis in subjects at risk and improves AATD screening in patients with confirmed COPD. Methods: A CDSS was created to be applied to all Veterans attending single-center Veterans Affairs primary care clinics. The CDSS had an algorithmic dialogue with components executed in phases during different clinic visits: screening for COPD risk using the COPD population screening (COPD-PS) questionnaire, spirometry recommendation, and ordering tool for subjects with a prior diagnosis of COPD or subjects considered high risk by the COPD-PS, dialogue to confirm or discard the diagnosis of COPD, and recommendations for AATD screening in subjects with confirmed COPD. The latter was performed by ordering alpha-1 antitrypsin (AAT) serum levels. Each step of the CDSS algorithm approach was recorded and available to be retrieved at a later date for analysis. Results: Over 6 years, a total of 6,235 Veterans >40 years of age completed the CDSS. According to the COPD-PS questionnaire, 962 (18.5%) subjects were identified as high risk for COPD. An additional 579 subjects with a prior diagnosis of COPD also entered the subsequent steps of the CDSS algorithm. Of the high-risk cohort, the CDSS led to an increase in spirometry testing from 24% to 83% and led to a new diagnosis of COPD in 342 (43%). In the prior COPD diagnosis group, spirometry testing increased from 58% to 84%, leading to COPD reconfirmation in only 326 (67%). A total of 489 (68%) subjects with confirmed COPD completed AAT testing prompted by the CDSS, with 23 subjects identified with AATD and one with severe AATD. Conclusions: In the Veterans Affairs system, the use of a clinical decision support system algorithm that incorporates screening for COPD and AATD improves COPD over- and underdiagnosis and screening rates of AATD in a primary care setting.

SERPINA1 and More? A Putative Genetic Contributor to Pulmonary Dysfunction in Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a common inherited disorder associated with an increased risk of pulmonary disease. Its clinical presentation, including the nature and severity of organ involvement, is highly variable and unpredictable and is not as strongly linked to genotype and environmental exposure (e.g., smoking history) as might be expected. Significant differences were observed within matched populations of severe AATD patients regarding risk of complications, age at onset, and disease course, including the dynamics of lung function decline. Genetic factors are among the putative modifiers contributing to the clinical variability in AATD, yet their role remains elusive. Here, we review and summarise our current understanding of epigenetic and genetic modifiers of pulmonary dysfunction in subjects with AATD.

Quality of Life and Mortality Outcomes for Augmentation Naïve and Augmented Patients with Severe Alpha-1 Antitrypsin Deficiency.

Intravenous alpha-1 antitrypsin (AAT) augmentation therapy is the only specific treatment available for alpha-1 antitrypsin deficiency (AATD)-related lung disease. It is widely used worldwide but remains unavailable to patients with AATD in the United Kingdom. While randomized trials of augmentation therapy have demonstrated biochemical efficacy and lung tissue preservation using computed tomography (CT) densitometry, these studies were not adequately powered to demonstrate effectiveness in well-accepted clinical endpoints such as quality of life (QOL) or survival. We used large, prospectively followed AATD patient populations in the United States and United Kingdom to explore these important clinical endpoints. Our inclusion criterion was adults with severe AATD and associated lung disease. The treatment group was U.S. AATD patients receiving augmentation therapy for lung disease. The control group was augmentation therapy naïve AATD patients. Multivariable regression and survival analyses were used to assess QOL and mortality outcomes respectively. Mean annual deterioration of the St George's Respiratory Questionnaire total score was 1.43 points greater/year in the control group compared to those receiving augmentation therapy (95% confidence interval [CI] 0.47 to 2.39, p=0.003). At 7 years, median survival was 82.7% (95% CI 75.3 to 90.7) for the control group versus 87.8% (95% CI 82.8 to 93.2) in the augmentation group, p=0.66. There was significant heterogeneity between cohorts. A comparison of 2 highly characterized AATD cohorts was not able to reliably determine if AAT augmentation therapy improves QOL or mortality in patients with severe AATD-related lung disease. Alternative surrogate biomarkers of disease progression, such as CT lung density, may be a more pragmatic option.

Distribution of the Clinical Manifestations of Alpha 1 Antitrypsin Deficiency in Respiratory Outpatients from an Area of Northern Italy

Background: Alpha 1 antitrypsin deficiency (AATD) is an autosomal codominant genetic condition that affects Caucasians of the European population due to the presence of a deficient allele of the SERPINA1 gene. A frequency of about 1/5,000 individuals has been estimated in Italy. Objectives: The aim of the study was to evaluate the distribution of the clinical manifestations of severe and intermediate genetic AATD in the geographic area around Parma in Northern Italy. Method: 238 subjects were submitted to molecular analysis of the SERPINA1 gene, and data on anthropometric variables, smoking habits, number of packs per year, AAT serum concentration, and clinical manifestations were recorded and presented as mean ± SD or median values (1st quartile; 3rd quartile). Results: The results show a distribution of genetic AATD of 4.1% of the screened population in the area encompassing the city of Parma. PI*MS and PI*MZ were the most common genotypes at 40.9% and 28.2% of the population with genetic AATD, and asthma and emphysema were the most represented clinical manifestations. Conclusion: Our study allowed to increase the knowledge of the distribution of genetic AATD in Northern Italy providing information regarding frequencies of genotypes and clinical manifestations of the disorder.

Labelling Alpha-1 antitrypsin deficiency in the medical record – A call to action

Alpha-1 antitrypsin deficiency (AATD) is an autosomal codominant genetic cause of chronic obstructive pulmonary disease (COPD) with over 100 allelic variants described. The normal allele is termed “M”; whereas, the “Z” and “S” alleles are the most common abnormal alleles. The ZZ combination accounts for 95% of cases with severe disease. We described the characteristics of patients given the label of AATD in the medical record. Our analysis found there is significant heterogeneity with regards to labelling subjects with AATD in the medical record, and this was true irrespective of the subjects age, gender, PFT measurements, tobacco pack years, or if the physician was a pulmonologist. In summary, this study highlights the need for continued investigation of the role of other mutations developing disease and options for more specific labelling of subjects with non-severe AATD and severe AATD to provide additional clarity for the patient and healthcare providers.

A Novel Detection Method to Identify Individuals with Alpha-1 Antitrypsin Deficiency: Linking Prescription of COPD Medications with the Patient-Facing Electronic Medical Record.

Alpha-1 antitrypsin deficiency (AATD) is under-recognized, prompting the need for enhanced detection strategies. The primary aim of this study is to determine the feasibility of using the electronic medical record (EMR) and linked electronic patient messages (EPM) to encourage AATD testing by patients with chronic obstructive pulmonary disease (COPD). Study participants were eligible, untested adult patients who were prescribed an inhaled medication which is exclusively Food and Drug Administration-approved for treating COPD. Eligible patients received a message with basic information about AATD and availability of free, home-based AATD testing. Through a collaboration with the Alpha-1 Foundation's Alpha-1 Coded Testing (ACT) study, patients referred to home-based testing through EPM were flagged. The effectiveness of the electronic message was evaluated by the proportion of patients who underwent testing, and the rate of detecting individuals with severe deficiency of AAT among those tested. A total of 12,369 patients on eligible inhalers were screened; 5430 patients met all criteria and received an EPM. During the study, 396 patients (7.3%) fully requested an ACT kit. Of these, 209 patients (52.8%) returned the test sample and received genotyping results; 65.5%, had a normal AAT genotype (PI*MM), 31.6% were heterozygotes for a deficient allele (PI*MS, PI*MZ and PI*M/Null rare), and 2.9% had severe deficiency of alpha-1 antitrypsin (PI*SZ, PI*ZZ, PI*S/Null rare). While the response rate and test return rate were low, the rate of detecting individuals with AATD using this detection strategy exceeds that of many prior strategies. As such, while requiring independent validation in other populations, this detection strategy holds promise.