[Screening for alpha1-antitrypsin deficiency using dried blood spot: Assessment of the first 20 months]. / Dépistage du déficit en alpha1-antitrypsine sur sang capillaire recueilli sur papier-filtre : bilan des 20 premiers mois.

INTRODUCTION: Alpha1-antitrypsin deficiency is a predisposing factor for pulmonary disease and under-diagnosis is a significant problem. The results of a targeted screening in patients with respiratory symptoms possibly indicative of severe deficiency are reported here. METHODS: Data were collected from March 2016 to October 2017 on patients who had a capillary blood sample collected during a consultation with a pulmonologist and sent to the laboratory for processing to determine alpha1-antitrypsin concentration, phenotype and possibly genotype. RESULTS: In 20 months, 3728 test kits were requested by 566 pulmonologists and 718 (19 %) specimens sent: among these, 708 were analyzable and 613 were accompanied by clinical information. Of the 708 samples, 70 % had no phenotype associated with quantitative alpha1- antitrypsin deficiency, 7 % had a phenotype associated with a severe deficiency and 23 % had a phenotype associated with an intermediate deficiency. One hundred and eight patients carried at least one PI*Z allele which is considered to be a risk factor for liver disease. CONCLUSIONS: The results of this targeted screening program for alpha1- antitrypsin deficiency using a dried capillary blood sample reflect improvement in early diagnosis of this deficiency in lung disease with good adherence of the pulmonologists to this awareness campaign.

State-of-the-art testing for alpha-1 antitrypsin deficiency.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition characterized by low serum levels of the protein alpha-1 antitrypsin. Because there are no unique clinical symptoms that point to a definitive diagnosis of AATD, laboratory testing is crucial to differentiate this disease from others. OBJECTIVE: To summarize advances in laboratory techniques used to test for AATD. METHODS: Data were sourced from a nonsystematic literature review of MEDLINE and the author's personal literature collection, and by checking reference lists of sourced articles. RESULTS: Since the original description of AATD by Laurell and Eriksson in 1963, testing methods have undergone major changes. Currently, alpha-1 antitrypsin protein is quantified by immunologic measurement in serum, and the phenotype is characterized by isoelectric focusing and/or targeted genotyping of predefined mutations. In addition, whole-gene sequencing of the gene SERPINA1 can be undertaken. However, this is costly and generally used only if targeted genotyping cannot conclusively identify the variant. The introduction of next-generation sequencing (NGS), which enables rapid and accurate sequencing of large quantities of DNA fragments in a single reaction, may help reduce costs. With its increasing availability, NGS may begin to appear in testing protocols. Clinical guidelines recommend that patients are tested for AATD if they have chronic irreversible airflow obstruction, especially those with early onset disease or a positive family history of AATD. Despite this, AATD is still underrecognized, and significant delays exist between symptom onset and diagnosis. CONCLUSION: Traditional testing practices have limitations. Screening programs that incorporate NGS are the most comprehensive methods available for accurate diagnosis of AATD.

Appropriateness of newborn screening for α1-antitrypsin deficiency.

OBJECTIVE: The Alpha-1 Foundation convened a workshop to consider the appropriateness of newborn screening for α-1-antitrypsin (AAT) deficiency. METHODS: A review of natural history and technical data was conducted. RESULTS: Homozygous ZZ AAT deficiency is a common genetic disease occurring in 1 in 2000 to 3500 births; however, it is underrecognized and most patients are undiagnosed. AAT deficiency can cause chronic liver disease, cirrhosis, and liver failure in children and adults, and lung disease in adults. The clinical course is highly variable. Some neonates present with cholestatic hepatitis and some children require liver transplantation, but many patients remain well into adulthood. Some adults develop emphysema. There is no treatment for AAT liver disease, other than supportive care and liver transplant. There are no data on the effect of early diagnosis on liver disease. Avoidance of smoking is of proven benefit to reduce future lung disease, as is protein replacement therapy. Justifying newborn screening with the aim of reducing smoking and reducing adult lung disease-years in the future would be a significant paradigm shift for the screening field. Recent passage of the Genetic Information Nondiscrimination Act (GINA) and the Affordable Care Act may have a major effect on reducing the psychosocial and financial risks of newborn screening because many asymptomatic children would be identified. Data on the risk-benefit ratio of screening in the new legal climate are lacking. CONCLUSIONS: Workshop participants recommended a series of pilot studies focused on generating new data on the risks and benefits of newborn screening.

Assessment of regional progression of pulmonary emphysema with CT densitometry.

BACKGROUND: Lung densitometry is an effective method to assess overall progression of emphysema, but generally the location of the progression is not estimated. We hypothesized that progression of emphysema is the result of extension from affected areas toward less affected areas in the lung. To test this hypothesis, a method was developed to assess emphysema severity at different levels in the lungs in order to estimate regional changes. METHODS: Fifty subjects with emphysema due to alpha(1)-antitrypsin deficiency (AATD) [AATD deficiency of phenotype PiZZ (PiZ) group] and 16 subjects with general emphysema (general emphysema without phenotype PiZZ [non-PiZ] group) were scanned with CT at baseline and after 30 months. Densitometry was performed in 12 axial partitions of equal volumes. To indicate predominant location, craniocaudal locality was defined as the slope in the plot of densities against partitions. Regional progression of emphysema was calculated after volume correction, and its slope identifies the area of predominant progression. The hypothesis was tested by investigating the correlation between predominant location and predominant progression. RESULTS: As expected, the PiZ patients showed more basal emphysema than the non-PiZ group (craniocaudal locality, - 40.0 g/L vs - 6.2 g/L). Overall progression rate in PiZ patients was lower than in non-PiZ subjects. A significant correlation was found between craniocaudal locality and progression slope in PiZ subjects (R = 0.566, p < 0.001). In the non-PiZ group, no correlation was found. CONCLUSIONS: In the PiZ group, the more emphysema is distributed basally, the more progression was found in the basal area. This finding suggests that emphysema due to AATD spreads out from affected areas.

Results of a case-detection programme for alpha1-antitrypsin deficiency in COPD patients.

Alpha1-antitrypsin (alpha1-AT) deficiency is an underdiagnosed condition in patients with chronic obstructive pulmonary disease (COPD). The present authors have conducted a nationwide case detection programme of alpha1-AT deficiency in unselected patients with COPD using dried blood spots. The first phase analysed samples from 971 patients by determining alpha1-AT concentrations and identifying the deficient Z allele by genotyping using rapid real-time PCR. The second phase analysed 1,166 samples with alpha1-AT concentrations and identified both the S and the Z allele, but only in samples with low alpha1-AT concentrations. A total of eight (0.37%) individuals with the severe deficiency PiZZ were detected. In addition, three patients were identified with the PiSZ genotype in the second phase (0.3%). The global cost of the programme was 41,512, which represents 19.42 per sample and 5,189 per PiZZ detected. A sensitivity analysis demonstrated that performing Z genotype to all samples would have resulted in increased costs of 28 per sample and 7,479.5 per PiZZ case identified. In conclusion, a case detection programme of alpha1-antitrypsin deficiency in patients with chronic obstructive pulmonary disease using dried blood spots is feasible and at a reasonable cost per case detected. Diagnostic yield and costs depend largely on inclusion criteria and the protocol for processing of samples.