Screening For Alpha-1 Antitrypsin Deficiency Research Articles

Molecular confirmation of alpha 1-antitrypsin deficiency in liver transplant setting: A province-wide experience.

Patients suspected of Alpha 1-Antitrypsin (A1AT) abnormality based on low serum concentration are routinely confirmed through polymerase chain reaction (PCR) testing of peripheral blood. Genotyping formalin-fixed paraffin-embedded (FFPE) tissue is a novel approach that could aid in detecting variant A1AT. We performed qPCR on FFPE liver explants with Periodic Acid Schiff after Diastase (PASD)- and A1AT-positive globules to confirm and estimate the frequency of A1AT deficiency in transplant cases. Eighteen (12.68%) of 142 patients with end-stage liver disease showed PASD/A1AT positive globules. FFPE of the explants was tested through qPCR to detect S and Z alleles. A second age- and sex-matched control group consisting of five liver transplant patients with negative globules was included in the study. qPCR assay was successful with all the samples meeting QC parameters. All patients included in the study elucidated Z allele variants; 2 homozygous (11.1%) and 16 heterozygous (88.9%). The control group demonstrated normal wild-type MM allele. Screening for A1AT deficiency using serum levels is not sufficiently sensitive to detect deficiency, especially in carriers. If A1AT testing was not performed preoperatively and the risk is high based on the PASD/A1AT-positive globules in the explants, then molecular testing of FFPE tissue can be a viable method for confirming the diagnosis.

Shaping the Future in Rare Lung Diseases: From Imaging to Patient Management

This symposium was held during the 2023 European Respiratory Society (ERS) International Congress in Milan, Italy. The main objective was to discuss unmet needs in the diagnosis and management of rare lung diseases, with a particular emphasis on alpha 1 antitrypsin deficiency (AATD) and idiopathic pulmonary fibrosis (IPF). Presentations focused on promising approaches to meet these needs, including the feasibility of genomic diagnosis, the development of improved biomarkers of disease progression, such as quantitative CT and novel blood biomarkers, the use of digital lung auscultation, and increased screening for AATD in vulnerable populations. The overarching message from the symposium was that advancements in technology, multidisciplinary collaboration, and partnerships between academic institutions, patient associations, and industry are crucial to the continued improvement of patient management in rare diseases, and that the education of healthcare professionals is vital to enhance the understanding and awareness of these conditions.

A Novel Provider Education Module to Enhance Detection of Alpha-1 Antitrypsin Deficiency.

Alpha-1 antitrypsin deficiency (AATD) is the most common genetic risk factor for early-onset emphysema. However, AATD continues to be underrecognized and underdiagnosed. Provider awareness about AATD, concerns with testing costs, and limited understanding about therapeutic options contribute to its underdiagnosis. We hypothesized that provider education would improve awareness of AATD and improve screening. To evaluate the impact of a targeted provider education module on AATD screening. We developed a web-based education module to address barriers to screening for AATD, deployed the education module using the Medscape Education platform, assessed perceived healthcare provider confidence in AATD screening, and conducted a prospective pre and postintervention study of AATD testing practices at a high-volume academic outpatient subspecialty pulmonary clinic. A total of 11,385 healthcare providers, including eight pulmonologists at our institution, completed the web-based education module. Confidence in identifying patients at high risk for AATD improved after completing the module ("not confident" in AATD screening was 7.7% postintervention compared with 19.4% preintervention). The rate of screening patients at high risk for AATD improved more than twofold (AATD screening rate 9.7% preintervention vs. 20.4% postintervention; P = 0.004). Among patients screened for AATD in our cohort, 27.2% had a genotype/phenotype or low alpha-1 antitrypsin concentration consistent with AATD. Targeted healthcare provider education can improve the confidence in testing for AATD. Improvements in provider confidence corresponded to improvements in AATD screening in a subspecialty pulmonary clinic. More than one-fourth of screening tests suggested AATD, underpinning the value of testing in high-risk individuals.

Improving Screening for Alpha-1 Antitrypsin Deficiency with Direct Testing in the Pulmonary Function Testing Laboratory.

Alpha-1 antitrypsin deficiency (AATD) is a common but highly underdiagnosed genetic disorder that may lead to chronic obstructive pulmonary disease (COPD), bronchiectasis, and liver disease. Early diagnosis is key to altering the course of disease as well as informing family members of potential risk. This randomized, prospective observational study compares the different testing modalities for AATD testing of at-risk patients initiated in the pulmonary function testing (PFT) laboratory. Providing a recommendation with a prescription for serologic testing, providing a finger-stick testing method (AlphaKit), and providing a buccal swab testing method (AlphaID) were compared to the community standard of referring the patient back to the PFT-ordering provider only. Results show that testing directly in the PFT laboratory has an odds ratio (OR) for completing testing of 35.14 (5.33 - 999.99), p-value of <0.0001, for buccal swab testing and an OR of 17.09 (2.58 - 729.99), p-value of 0.0002, for finger-stick testing compared to the community standard. Providing a prescription was no better than referral back to the PFT-ordering provider with an OR of 2.61(0.33 - 119.36), p-value of 0.6412. Resources needed to have testing performed by the Respiratory Therapy department were minimal with an average time of 1 to 5 minutes per patient tested. Causes of testing refusal were also identified. In conclusion, direct testing for AATD by respiratory therapists at the conclusion of PFT testing shows a significant improvement in rates of testing, especially with testing that utilizes buccal swab sample collection.

Utility of routine screening for alpha-1 antitrypsin deficiency in patients with bronchiectasis

Alpha-1 antitrypsin deficiency (AATD) is a cause of bronchiectasis. Guidelines for bronchiectasis from the British Thoracic Society do not recommend to routinely test patients for AATD. In contrast, guidelines for...

A Novel Approach to Screening for Alpha-1 Antitrypsin Deficiency: Inpatient Testing at a Teaching Institution.

Chronic obstructive pulmonary disease (COPD) currently affects more than 16 million Americans and it is estimated that roughly 100,000 Americans have undiagnosed, severe alpha-1 antitrypsin deficiency (AATD) (Chest. 2005;128[3]:1179-1186) (Chest. 2002;122[5]:1818-1829). Patients with AATD have an accelerated rate of decline of lung function caused by proteolytic enzymes. The morbidity associated with this inherited disorder is preventable due to the availability of augmentation therapy. Appropriate inpatient screening of patients with COPD for AATD is lacking and most screening is exclusively limited to outpatient pulmonary clinics. Between May 2016 and February 2017, genetic screening was completed on 54 individuals who were admitted with either a former diagnosis of COPD or active COPD exacerbation to Arnot Ogden Medical Center (AOMC) in Elmira, New York. The incorporation of inpatient genetic screening by resident physicians for AATD in COPD patients led to a high rate of screened and newly diagnosed AATD carriers with a variety of AATD genotypes. It is recommended that there should be an expansion of screening for AATD in hospitalized patients with COPD, regardless of age or smoking history.

Screening for alpha1-antitrypsin deficiency in Lithuanian patients with COPD

Alpha1-antitrypsin (AAT) deficiency is an under-diagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The objective of the present screening was to estimate the AAT gene frequency and prevalence and to identify AAT deficiency cases in a large cohort of Lithuanian patients with COPD. A nationwide program of AAT deficiency was conducted in 1167 COPD patients, defined according to the GOLD criteria. Patients were collected from outpatient clinics in five different Lithuanian regions (Kaunas, Vilnius, Siauliai, Klaipeda and Alytus). AAT serum concentrations were measured by nephelometry; PI-phenotypes characterized by isoelectric-focusing. Mean age and FEV(1) were 62.0 (10.3) and 54.7% (10.9), respectively. Ninety-one AAT deficiency genotypes (40 MZ, 39 MS, 1 SS, 3 SZ and 8 ZZ) were identified. Calculated PI(*)S and PI(*)Z frequencies, expressed in per 1000, were 18.8 (95% CI: 13.9-25) and 25.3 (95% CI: 19.4-32.7), respectively. The calculated AAT gene prevalence (Hardy-Weinberg principle) was: 1/1.09 for MM, 1/28 for MS, 1/2814 for SS, 1/20 for MZ, 1/1049 for SZ and 1/1565 for ZZ. Calculated Odds ratio (OR) for PI(*)Z in COPD vs. Lithuanian healthy people was of 1.87 (P=0.004). The OR for each genotypic class demonstrated a significant increase of MZ, SZ and ZZ genotypes in COPD patients. The results of the present study, with a significant number of ZZ individuals detected, support the general concept of targeted screening for AAT deficiency in countries like Lithuania, with a large population of COPD patients and low awareness among care-givers about this genetic condition.

Screening and Familial Testing of Patients for α1-Antitrypsin Deficiency

alpha(1)-Antitrypsin deficiency (AATD) is an autosomal-codominant genetic disorder that predisposes individuals to the development of liver and lung disease. AATD is greatly underrecognized and underdiagnosed. Early identification allows preventive measures to be taken, the most important of which is the avoidance of smoking (including the inhalation of second-hand smoke) and exposure to environmental pollutants. Early detection also allows careful lung function monitoring and augmentation therapy while the patient still has preserved lung function. Cost factors and controversies have discouraged the initiation of large-scale screening programs of the newborn and adult populations in the United States and Europe (except for Sweden). There are sound medical reasons for targeted screening. Evidence-based recommendations for testing have been published by the American Thoracic Society/European Respiratory Society task force, which take potential social, psychological, and ethical adverse factors into consideration. This review discusses rationales for testing and screening for AATD in asymptomatic individuals, family members, and the general population, weighing benefits against potential psychological, social, and ethical implications of testing. For most, negative issues are outweighed by the benefits of testing. AATD testing should be routine in the management of adults with emphysema, COPD, and asthma with incompletely reversible airflow obstruction.

Estimating the Risk for Alpha-1 Antitrypsin Deficiency among COPD Patients: Evidence Supporting Targeted Screening

Alpha-1 antitrypsin deficiency is known as a significant genetic risk factor for COPD for carriers of phenotype PIMZ, and for phenotypes PIZZ and PISZ. Genetic epidemiological studies for alpha-1 antitrypsin deficiency conducted by others on both COPD patients and concurrent non-COPD controls were used to estimate the risk factors for all six phenotypic classes (namely, the normal phenotype PIMM, and the 5 deficiency allele phenotypes: PIMS, PIMZ, PISS, PISZ, and PIZZ). Studies on alpha-1 antitrypsin deficiency in white (Caucasian) COPD and non-COPD populations in 6 countries were combined to obtain estimates of the prevalence of the PIS and PIZ deficiency alleles in the combined COPD and non-COPD cohorts. The odds ratios for each of the six phenotypic classes of alpha-1 antitrypsin deficiency were calculated for a hypothetical population of 19.3 million white COPD patients in the United States of America. This approach demonstrated that 1,829,673 alpha-1 antitrypsin deficiency patients would be detected by testing 19.3 million white COPD patients and 536,033 in white non-COPD concurrent controls. The odds ratios for each of the phenotypic classes among white COPD patients demonstrate highly significant decreases in the normal phenotype PIMM, no significant change in the PIMS and PISS deficiency phenotypes, but highly significant increases in the prevalences of the PIMZ, PISZ, and PIZZ deficiency phenotypes. The result of the present study supports the concept of targeted screening for alpha-1 antitrypsin deficiency in countries with large populations of white (Caucasian) COPD patients.

Cost-Effectiveness of Population Screening for Alpha-1 Antitrypsin Deficiency: A Decision Analysis

The objective was to assess the cost-effectiveness of population screening for alpha-1 antitrypsin (AAT) deficiency. The design was a Markov-based decision analytic model. Hypothetical cohorts were analyzed from birth and followed over time until death using Monte Carlo simulation. The following strategies were compared: 1) screen all newborns, 2) screen all 10-year-old children, and 3) do not screen. Screenees found to have PI*ZZ AAT deficiency received the benefits of lower smoking rates and were offered augmentation therapy. In keeping with reported experience, most (96%) non-screened AAT deficient individuals remained undiagnosed and, therefore, missed these benefits. Under base conditions, screening all newborns cost nearly $422,000 per quality-adjusted life-year (QALY) gained; this estimate fell to $92,135 per QALY when the cost of screening was minimized to $6 in the model. Delaying screening until age 10 decreased the incremental cost-effectiveness ratio (ICER) to nearly $317,000. In sensitivity analysis, when the prevalence of PI*ZZ individuals increased from a baseline of 1.96 to 16 per 10,000, the ICER for newborn screening decreased below $100,000 per QALY. When the cost of screening and augmentation therapy were decreased simultaneously with increasing PI*ZZ prevalence, there were many scenarios in which the ICER decreased below $50,000. While population-based screening for AAT deficiency is not cost-effective under current conditions, cost-effectiveness criteria could be satisfied when case-finding in a high prevalence population is undertaken.

Cost-Effectiveness of Population Screening for Alpha-1 Antitrypsin Deficiency: A Decision Analysis

PURPOSE: Alpha-1 antitrypsin (AAT) deficiency is a genetic disorder that may predispose to early-onset emphysema and to liver disease. The availability of effective interventions (such as primary avoidance of smoking, smoking cessation, and augmentation therapy) invites the question of whether early detection of alpha-1 antitrypsin deficiency is cost-effective, both through population-based screening or case-finding. Because no randomized controlled trials of population-based screening for alpha-1 antitrypsin deficiency is available or likely to be, the current study was undertaken to examine the cost-effectiveness of screening for AAT deficiency.

Young adults with alpha 1-antitrypsin deficiency identified neonatally: their health, knowledge about and adaptation to the high-risk condition.

The psychological and psychosocial consequences of screening for alpha 1-antitrypsin deficiency (alpha 1 ATD) were investigated when the subjects were 5-7 years old. The present study was conducted when the subjects were 18-20 years old, the foci of interest being their health, psychosomatic problems, knowledge about alpha 1 ATD and the potential effect of that knowledge on their lives and future family planning. Samples of 61 PiZ and 61 demographically matched control subjects, 18-20 years old, were asked to participate. Written, structured questionnaires covered the following items: basic familial characteristics, psychosomatic symptoms, opinions on medical check-ups, information and views on future alpha 1 ATD screening, whether the knowledge about alpha 1 ATD had affected the life and family planning of alpha 1 ATD individuals. Items concerning the "alpha 1 ATD matter" were excluded in the questionnaires given to the controls. Questionnaire data were obtained from 50 alpha 1 ATD and 48 control individuals, 41 of each being matched alpha 1 ATD-control pairs. No significant differences were found in demographic or educational backgrounds, psychosomatic complaints such as headache, sleep difficulties, stomach ache, tiredness or anxiety. Lung symptoms occurred more frequently in alpha 1 ATD subjects (p = 0.05). Six per cent of the alpha 1 ATD individuals planned working careers with a high risk of air pollution. The majority (86%) of the alpha 1 ATD subjects perceived the contact with the medical services as positive; 14% as both positive and negative. The information concerning alpha 1 ATD was assessed as satisfactory by 73%, as both good and bad by 17% and as unsatisfactory by 10%. All alpha 1 ATD subjects advocated general screening for alpha 1 ATD, the neonatal period being chosen as optimal by 94%. Half of the alpha 1 ATD individuals thought that the knowledge of their high-risk condition had affected their lives, particularly their awareness of the dangers of smoking and environmental pollution. The majority, 88%, knew that they should avoid smoking to protect their lungs. In conclusion, no negative psychosocial consequences of the neonatal alpha 1 AT-screening were found in early adulthood. The alpha 1 ATD individuals were aware of the dangers of smoking and were of the opinion that alpha 1 AT-screening should be recommended.

Identifying children at high somatic risk: possible effects on the parents' views of the child's health and parents' relationship to the pediatric health services.

Country-wide neonatal screening for alpha 1-antitrypsin deficiency (ATD) was discontinued due to clinical observations of negative psychological effects on the parents. In a subsequent systematic study, hypotheses of long-term negative effects on the parents' views of the child's health and on the parents' relationship to the pediatric services were tested by comparing these characteristics in parents with a child with ATD versus control parents, studied through interviews in the home. The identification of the ATD was found to have had negatively influenced the parents' view of the child's general health, but no evidence was found of increased parental anxiety regarding the child's current health or emotional dependence on medical personnel, of increased (reported) usage of pediatric services, or of more negative attitudes toward the pediatric services.

Psychological factors in cost-benefit analysis of somatic prevention. A study of the psychological effects of neonatal screening for alpha 1-antitrypsin deficiency.

Nation-wide neonatal screening for alpha 1-antitrypsin deficiency (ATD) in Sweden was discontinued due to observations that identification of ATD in newborns seemed in some cases to have negative psychological effects on the parents and the parent-child relationship. A multifaceted study was developed to investigate systematically the psychological and psychosocial consequences of the identification of ATD in the neonatal period, as studied five to seven years after it took place. The study's basic goals, hypotheses, design, samples and methods are described.

Silver-stained phenotyping of alpha 1-antitrypsin in dried blood and serum specimens.

In this technique for determining the electrophoretic phenotype of alpha 1-antitrypsin in dried blood or serum specimens, the adsorbed material is eluted with a concentrated solution of dithiothreitol, focused on polyacrylamide thin-layer gel, and made visible with silver stain. With this staining technique all normal and pathological alpha 1-antitrypsin phenotypes can be detected. The procedure is relatively simple, inexpensive, and suitable for use in large-scale screening for alpha 1-antitrypsin deficiency in selected populations.