| Coverage Policy Manual | |
| Policy #: | 2012066 |
| Category: | Laboratory |
| Initiated: | November 2012 |
| Last Review: | February 2024 |
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| Genetic Test: Alpha-1 Antitrypsin Deficiency | |
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| Description: |
DESCRIPTION OF DISEASE
Alpha1-antitrypsin deficiency (AATD) is an autosomal recessive genetic disorder that decreases production of the alpha1-antitrypsin (AAT) protein or production of abnormal types of the protein that are functionally deficient. Data from screening studies have found the prevalence of AATD in the United States to be between 1 in 2857 and 1 in 5097 individuals (American Thoracic Society, 2003).
AAT is an acute phase glycoprotein, primarily synthesized in the liver and secreted into the bloodstream. One of the primary functions of the AAT protein is to protect the lungs from damage by the enzyme elastase. Elastase, part of the normal response to injury and inflammation, breaks down proteins and can damage lung tissue if its action is not regulated by AAT. Individuals with AATD thus have an increased risk of lung disease.
AATD Genetics
Production of AAT is encoded by the SERPINA1 gene, which is codominant (each gene copy is responsible for producing half of the AAT). Although there are more than 75 sequence variants of the SERPINA1 gene (ie, 75 possible alleles), only a few are common in North America. Approximately 95% of individuals have 2 copies of the normal M allele sequence (MM) and have mean serum AAT concentrations ranging from 20 to 53 μmol/L. The most common abnormal forms are the Z and the S alleles. Individuals with 2 copies of the Z allele (ZZ) tend to be most severely affected, with mean serum AAT concentrations of 2.5 to 7 μmol/L and a high risk of chronic obstructive pulmonary disease (COPD). Individuals with genotype SS and heterozygous individuals with genotype MZ have low risk of COPD and moderately lower levels of AAT. Individuals with rarer mutations of the SERPINA1 gene or null alleles may not produce any AAT and are also at high risk (Kelly, 2010).
Clinical Presentation
AATD is a multisystem disease, primarily affecting the lungs and liver, and less commonly the skin. It may present differently at different ages.
Pulmonary Manifestations
Respiratory disease tends to be more severe and occur sooner (ie, between ages 40 and 50 years) in individuals with AATD who smoke cigarettes and/or are exposed to occupational dust or fumes. In nonsmokers and individuals without environmental exposure, onset of respiratory disease occurs more commonly in the sixth decade. Childhood-onset lung disease is rare with AATD.
Liver Manifestations
Adults with AATD-associated liver disease generally present with cirrhosis and fibrosis. In contrast, newborns with AATD can present with cholestasis or (less frequently) hepatomegaly and elevated aminotransferase levels. The AATD-associated cholestasis is typically associated with PI*Z homozygotes or PI*SZ heterozygotes, which tend to have less severe lung disease in adulthood. AATD-associated-cholestatic jaundice can progress to require liver transplant in newborns. In a large series of 127
newborns with AATD found by screening, the prevalence of liver damage was 11%, severe in about two-thirds of cases (Sveger, 1976).
Skin Manifestations
Panniculitis is a rare, but well-recognized complication of AATD. This dermatologic condition is characterized by inflammatory and necrotizing lesions of the skin and subcutaneous tissue (Schlade-Bartusiak, 2016).
Clinical Management
The primary interventions to prevent or treat lung-related symptoms in adults with AATD involve behavioral change, especially avoiding or quitting cigarette smoking. Smoking is the most important risk factor for the development of emphysema in AATD in individuals who are homozygous for the most severe AAT mutations.1 In addition, individuals with AATD are advised to avoid other substances that can irritate the lungs (eg, cigarette smoke, dust, workplace chemicals), as well as substances that can cause liver damage (eg, alcohol). There are also general recommendations to exercise, avoid stress, and have a nutritious diet. Furthermore, patients with AATD may be recommended to have earlier or more aggressive treatments for conditions such as asthma outbreaks or acute exacerbations of chronic obstructive pulmonary disease (COPD). One treatment option that is specific to AATD is AAT augmentation. There are commercially available intravenous AAT augmentation products; patients generally receive injections of plasma every 3 to 4 weeks for life. Inhaled AAT augmentation therapy is under development. There is no consensus on the efficacy of augmentation treatment. Product labels state that the effect of augmentation therapy on emphysema progression and pulmonary exacerbations has not been demonstrated in randomized controlled trials (Zemaira, 2017; Glassia, 2017).
Other aspects of management of AATD involve monitoring for and screening for comorbidities, including liver disease.
Diagnostic Testing for AAT
Several types of tests are available for patients suspected of having AATD. A blood test is available that quantifies the total amount of AAT in the blood, detecting decreases in AAT protein levels, but not distinguishing among abnormal protein types. AAT is an acute phase reactant, and levels will be elevated in acute and chronic inflammatory conditions, infections, and some cancers, which may cause levels to appear normal in individuals with mild-to-moderate AATD. In general, a serum AAT concentration less than 15% to 20% of the normal value is highly suggestive of a homozygous AAT mutation (Global Initiative for Chronic Obstructive Lung Disease, 2016).
The alpha1 phenotype test identifies the type of circulating AAT protein in the blood by isoelectric focusing of the various AAT protein types. Patterns of protein migration in an electric field are evaluated and compared with normal patterns to determine if and what type of abnormal AAT protein may be present.
Genetic testing for AATD can be done with the alpha1 genotype test. This test uses polymerase chain reaction analysis or nucleic acid‒based analysis to identify abnormal alleles of AAT DNA. Currently available genotype tests are only designed to detect the most common mutations (ie, S and Z alleles).
There are several testing approaches to detect AATD. One is to initially perform serum quantitation and then, if the AAT level is found to be low, a follow-up phenotype or genotype test is ordered. Another approach is to perform serum protein quantification, followed by genotype testing in subjects with clinical suspicion of AATD. If these tests are discordant, phenotype testing is then performed.
REGULATORY STATUS
In 2007, the phenotyping test Hydragel 18 A1AT ISOFOCUSING kit (Sebia, GA) was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process for the qualitative detection and identification of the phenotypes of alpha1-antitrypsin protein. FDA product code: OBZ.
Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Laboratories that offer LDTs must be licensed by CLIA for high-complexity testing. Molecular diagnostic laboratories may also be accredited by the College of American Pathologists Laboratory Accreditation Program. To date, FDA has chosen not to require any regulatory review of this test.
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Policy/ Coverage: |
Effective December 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for alpha-1 antitrypsin deficiency meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when both of the following conditions are met:
NOTE: Clinical factors relevant for suspicion of that would prompt a suspicion alpha-1 antitrypsin deficiency based on 2016 COPD Foundation Clinical Practice Guidelines include any of the following:
Family history relevant for suspicion of alpha1-antitrypsin deficiency:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for alpha-1 antitrypsin deficiency not meeting the criteria listed above and in all other situations or circumstances does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes in all other situations.
For members with contracts without primary coverage criteria, genetic testing for alpha-1 antitrypsin deficiency is considered investigational in all other situations. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
Effective November 2012 through November 2023
Meets Primary Coverage Criteria Or Is Covered For Contracts Without Primary Coverage Criteria
Genetic testing for alpha-1 antitrypsin deficiency meets member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes when both of the following conditions are met:
Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria
Genetic testing for alpha-1 antitrypsin deficiency for any indication or circumstance not described above does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.
For members with contracts without primary coverage criteria, genetic testing for alpha-1 antitrypsin deficiency for any indication or circumstance not described above, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.
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| Rationale: |
Validation of the clinical use of any genetic test focuses on 3 main principles: 1) the analytic validity of the test, which refers to the technical accuracy of the test in detecting a mutation that is present or in excluding a mutation that is absent; 2) the clinical validity of the test, which refers to the diagnostic performance of the test (sensitivity, specificity, positive and negative predictive values) in detecting clinical disease; and 3) the clinical utility of the test, i.e., how the results of the diagnostic test will be used to change management of the patient and whether these changes in management lead to clinically important improvements in health outcomes.
Analytic validity
Analytic performance of the Hydrogel AAT phenotyping test is reported in a U.S. Food and Drug Administration (FDA) decision summary document. Within-run test result reproducibility was determined by testing 8 samples 15 or 18 times on a single gel. Two normal samples and 6 pathological samples with MS, SS, MZ, ZZ and MX phenotypes were included; the test was able to reproduce the corresponding phenotype correctly. Between-run gel reproducibility was determined by testing 15 samples and 3 controls 12 times on 2 lots of gels. Again, the phenotypes were reproduced correctly.
No published studies on the analytic validity of any AAT genotyping test conducted in the United States, other than FDA documents, were identified.
Clinical validity
In 2008, Ljujic and colleagues in Serbia published findings of a study with 27 emphysema patients (Ljujic, 2008). Phenotyping was performed using isoelectric focusing and genotyping by denaturing gradient gel electrophoresis (DGGE). Isoelectric focusing was successfully performed in 25 cases and genotyping results were available for all 27 patients. Phenotyping and genotyping were concordant for the 4 patients found to have 1 or 2 ‘Z’ alleles. However, genotyping found 2 unusual mutations and in both of these cases, phenotyping found normal variants.
The FDA decision summary for the Hydrogel phenotyping test included an evaluation of clinical sensitivity and specificity. Samples were evaluated from 64 patients with the following diagnoses: congenital AATD [alpha-1 antitrypsin deficiency] (n=16), pulmonary disorder (n=15), hepatic disorder (n=8), infertility (n=1), panniculitis (n=1) and normal (n=23). The sensitivity of the phenotype test was 39/39 (100%) and the specificity was 23/25 (92%). (Note: This analysis excludes 4 individuals with indeterminate diagnoses).
Clinical utility
The clinical utility of genetic testing for alpha-1 antitrypsin deficiency (AATD) depends on how the results can be used to improve patient management. With AATD, this could occur in several ways, including the following:
Smoking cessation
In 2003, a joint statement on diagnosis and management of alpha-1 antitrypsin deficiency (AATD) from the American Thoracic Society (ATS) and the European Respiratory Society (ERS) was published (ATS/ERS, 2003). The authors stated that the joint statement was based on systematic reviews and an evidence-based approach to evaluating evidence. A review of smoking cessation studies in the ATS/ERS joint statement did not identify any RCTs on the impact of AATD status on smoking cessation. However, they identified an RCT on a related topic. This study which found that, at one year, individuals who received genetic susceptibility information (in this case, CYP2D6 genotype results) were significantly more likely to report a quit attempt than individuals who received counseling only; quit rates did not differ significantly in the 2 groups (Audrain, 1997).
The MEDLINE search identified a study by Carpenter and colleagues reporting on findings of a survey of individuals who had volunteered for genetic testing for AATD (Carpenter, 2007). A total of 4,344 individuals completed a test kit; 331 (7.6%) respondents were rejected because their blood sample was insufficient. The remaining participants were mailed a follow-up letter with their test results and a genotype-specific brochure. Results of the testing revealed that 2,228 (56%) of the valid samples tested normal, 1,530 (38%) were found to be heterozygous carriers for AATD (MZ genotype) and 255 (6%) were found to be severely alpha-1 antitrypsin (AAT) deficient (SZ or ZZ genotype). A total of 729/2,228 (33%) of participants with valid blood samples identified themselves as current cigarette smokers. These smokers were sent an additional questionnaire 3 months after the initial letter. Test results among smokers were 55% normal genotype, 38% carrier and 7% severely AAT deficient. Of the 729 surveys sent to smokers, 205 (28%) were completed. Six smokers were excluded because they smoked less than 6 cigarettes per day, leaving 199 participants in the study sample. Survey responders were more likely to be older than non-respondents; there were no significant differences in response rates by genotype group. Among survey respondents, individuals with severe AATD were significantly more likely to make any self-reported quit attempt than were individuals with a normal genotype (59% vs. 33%, p<0.05). Of 8 quit behaviors listed in the survey, AAT deficient smokers reported engaging in a mean of 2.4 (standard deviation [SD]=2.3). This was significantly higher than the number of quit behaviors reported by carriers (0.7, SD=1.3) or normals (1.3, SD=2.0), p=0.04. There was not a significant difference between groups, however, in the abstinence rate at 3 months (defined as 24-hour point prevalence). This study was limited in that it lacked a control group of smokers who were not tested for AATD, and there was a low response rate to the 3-month survey.
Smoking prevention
The ATS/ERS joint statement on AATD identified 2 case-control studies that included children identified at birth as having AATD and matched to a demographically similar control group. The number of children with AATD was 61 in one study and 22 in the other. These studies reported a lower frequency of adolescent smoking in individuals identified at birth as having AAT deficiency, compared to the control individuals (ATS/ERS, 2003).
Conclusions: The available studies suggest that knowledge of AATD status may lead to more quit attempts but not higher smoking cessation rates. There is also limited evidence from 2 small case-control studies that individuals who know from birth they have AATD are less likely to initiate smoking than individuals without genetic information knowledge.
Treatments for individuals with AATD
Alteration of timing or intensity of treatments for patients with AATD
The ATS/ERS joint statement on AATD (ATS/ERS, 2003) recommended the following interventions for individuals with emphysema who have AATD:
The authors noted that these are recommendations for treating patients with COPD in general and are applicable to those with pulmonary disease associated with AATD; no controlled studies specific to AATD were cited in support of the above recommendations to determine whether the timing, intensity, or compliance with these treatments is altered by knowledge of AATD status.
Apha-1 antitrypsin augmentation therapy
A 2010 Cochrane review addressed the benefits and harms of augmentation therapy with alpha-1 antitrypsin (AAT) in patients with AADT and lung disease (Gøtzsche, 2010). The investigators searched for randomized controlled trials (RCTs) comparing augmentation therapy with AAT to placebo or no intervention and reporting one or more of the primary outcomes: mortality, forced expiratory volume in one second (FEV1) or adverse effects. Two RCTs were identified; both were conducted by the same research team (Dirksen, 1999; Dirksen, 2009). The first trial, published in 1999, enrolled 58 ex-smokers with AATD (ZZ genotype). Patients were treated with AAT (250 mg/kg) or placebo 4 times a week for 3 years. The primary outcome was FEV1. The second trial, published in 2009, included 82 ex-smokers or never-smokers with the ZZ or heterozygous Z genotype. Patients were treated for 2 years with AAT (60 mg/kg) or placebo. The primary outcome was lung density measured by computed tomography (CT) scans, which the trial authors noted was an exploratory outcome; in the trial, FEV1 was reported as a secondary outcome. Adverse events were not reported in the first trial. A pooled analysis of the 2 studies did not find a significant difference in FEV1 deterioration over the course of the study in the treatment compared to the placebo group. The pooled mean difference in FEV1 (mL) was -19.92 (95% confidence interval [CI]: -40.86 to 1.02). A pooled analysis of lung density change (g/L) according to CT findings favored the treatment group. The mean difference was 1.14, 95% CI=: 0.14 to 2.14, p=0.026. Potential biases in the trials noted by the Cochrane review authors include potential financial conflicts of interest and, in the second trial, selective reporting of outcomes, which refers to the trial authors’ emphasis of the intermediate outcome CT lung density. The Cochrane review concluded that there was insufficient evidence to recommend augmentation therapy with alpha-1 antitrypsin. No additional trials on AAT augmentation therapy were identified in the MEDLINE search.
Conclusions: A national guideline recommends different interventions for individuals with emphysema found to have AATD such as preventive vaccinations and early antibiotic treatment. The only AATD-specific treatment is AAT augmentation therapy, which is often prescribed for patients with documented AATD and COPD. A Cochrane review concluded that the RCT evidence was insufficient to determine whether alpha-1 antitrypsin augmentation therapy is effective for improving health outcomes in individuals with AATD. In their pooled analysis of data from 2 studies, there was significantly greater decrease in lung density among patients who received augmentation therapy; the difference in FEV1 was not statistically significant although the upper confidence interval was close to 1.
Ongoing Clinical Trials
International Study Evaluating the Safety and Efficacy of Inhaled, Human, Alpha-1 Antitrypsin (AAT) in Alpha-1 Antitrypsin Deficient Patients With Emphysema (NCT01217671): This is a double-blind randomized controlled trial comparing the safety and efficacy of inhaled AAT versus placebo in adults with emphysema. Estimated enrollment is 200 patients. The primary efficacy measures are exacerbations and lung density after 1 year. Adverse events are included as secondary outcomes. The study is being conducted at sites in Canada and several European countries and is sponsored by Kameda, Ltd.
Summary
The literature evidence on the analytic and clinical validity of genetic testing for AATD is limited. In addition, there are few RCTs evaluating the impact of AATD testing on patient outcomes. However, national guidelines recommend specific interventions for patients with emphysema and AATD, and AAT augmentation therapy is often prescribed for patients with AATD and COPD. The available evidence suggests that knowledge of AATD status may discourage non-smokers from initiating smoking and may increase quit attempts among smokers, but it has not been shown to increase successful quitting. Evidence from small RCTs on AAT augmentation therapy are not definitive of a treatment benefit, but reports trend toward improvement in lung function. As a result, genetic testing for AATD may lead to improved outcomes by altering interventions for AATD and therefore may be considered medically necessary for individuals with suspected AATD or those at high risk for AATD due to personal or family history, who have serum levels of alpha-1 antitrypsin level in the range for homozygous disease.
Practice Guidelines and Position Statements
In 2003, the American Thoracic Society published recommendations on the diagnosis and management of individuals with alpha-1 antitrypsin deficiency (ATS/ERS, 2003).
Recommendations were classified as follows:
Type A: Genetic testing is recommended
Type B: Genetic testing should be discussed and could be accepted or declined
Type C: Genetic testing is not recommended i.e., should not be encouraged
Type D: Recommend against genetic testing i.e., should be discouraged
Type A recommendations for diagnostic testing in the following situations:
Type B recommendations for diagnostic testing in the following situations:
Type C recommendations for diagnostic testing in the following situations:
Type D recommendations for diagnostic testing in the following situations:
*Population screening is not recommended currently. However, a possible exception (type B recommendation) may apply in countries satisfying all 3 of the following conditions: 1) the prevalence of AAT deficiency is high (about 1/1,500, or more); 2) smoking is prevalent; and 3) adequate counseling services are available.
2013 Update
A search of the MEDLINE database conducted through October 2013 did not reveal any new information that would prompt a change in the coverage statement. One clinical practice guideline was identified and summarized below.
In 2012, the Canadian Thoracic Society published a clinical practice guideline on AAT deficiency testing and augmentation therapy (Marciniuk, 2012). The recommendations regarding targeted testing for AATD are:
2014 Update
A literature search conducted through March 2014 did not reveal any new information that would prompt a change in the coverage statement.
2015 Update
A literature search conducted through February 2015 did not reveal any new information that would prompt a change in the coverage statement. The key identified literature is summarized below.
No large clinical validity studies have been identified. A study by the Serbian research group, published in 2014, performed genotyping using direct sequencing in 50 patients diagnosed with COPD before the age of 45 (Beletic, 2014). The authors found that genotyping did not identify more AATD patients than using AAT concentrations alone. The authors did not report sensitivity or specificity.
2016 Update
A literature search conducted through January 2016 did not reveal any new information that would prompt a change in the coverage statement.
2017 Update
A literature search conducted using the MEDLINE database did not reveal any new literature that would prompt a change in the coverage statement. The following applicable publications were identified and reviewed.
Smoking Cessation
In 2007, Carpenter et al reported on findings of a survey of volunteers for genetic testing for AATD (Carpenter, 2007). A total of 4344 individuals completed a test kit; 331 (7.6%) respondents were rejected because their blood samples were insufficient. The remaining participants were mailed a follow-up letter with test results and a genotype-specific brochure. Results of the testing revealed that 2228 (56%) of the valid samples tested normal, 1530 (38%) were found to be heterozygous carriers for AATD (MZ genotype), and 255 (6%) were found to be severely AATD (SZ or ZZ genotype). A total of 729 (33%) of 2228 participants with valid blood samples identified themselves as current cigarette smokers. These smokers were sent an additional questionnaire 3 months after the initial letter. Test results among smokers were 55% normal genotype, 38% carrier, and 7% severely AATD. Of the 729 surveys sent to smokers, 205 (28%) were completed. Six smokers were excluded because they smoked fewer than 6 cigarettes per day, leaving 199 participants in the study sample. Survey responders were more likely to be older than non-responders; there were no significant differences in response rates by genotype group. Among survey respondents, individuals with severe AATD were significantly more likely to make any self-reported quit attempt than individuals with a normal genotype (59% vs 33%, p<0.05). Of 8 quit behaviors listed in the survey, AATD smokers reported engaging in a mean (SD) of 2.4 (2.3) attempts. This was significantly higher than the number of quit behaviors reported by carriers (0.7, SD=1.3) or individuals with a normal genotype (1.3, SD=2.0; p=0.04). There was no significant difference between groups, however, in the abstinence rate at 3 months (defined as 24-hour point prevalence).
AAT Augmentation Therapy
A 2016 Cochrane review addressed the benefits and harms of AAT augmentation therapy in patients with AATD and lung disease (Gotzsche, 2016). Three RCTs comparing AAT augmentation therapy to placebo were identified; all included patients with genetic variants associated with a high risk of developing COPD. Primary outcomes of the review were mortality and adverse effects of the intervention. Data on these outcomes were not available for pooling. Meta-analyses were conducted on several secondary outcomes. A pooled analysis of the 3 studies did not find a significant difference in forced expiratory volume in 1 second (FEV1) deterioration over the course of the studies in the treatment compared with the placebo group. The pooled standardized mean difference (SMD) in FEV1 was -0.19 (95% confidence interval [CI], -0.42 to 0.05; p=0.12). There was also no significant difference between groups in change in carbon monoxide diffusion (SMD = -0.11; 95% CI, -0.35 to 0.12; p=0.34). However, a pooled analysis of lung density change (in grams per liter) according to computed tomography findings favored the treatment group. The mean difference was 0.86 (95% CI, 0.31 to 1.42; p=0.004). Authors concluded there were insufficient data to draw conclusions on the impact of AAT augmentation therapy on health outcomes.
Two of the 3 RCTs were conducted by the same research team, Dirksen et a l (Dirksen, 1999; 2009). The first trial, published in 1999, enrolled 56 ex-smokers with AATD (ZZ phenotype verified by isoelectric focusing)and FEV1 of 30% to 80% of the predicted normal value. Patients were treated with augmentation therapy or placebo for 3 years. The primary outcome (decline in FEV1) did not differ significantly between groups at follow-up. The second trial, published in 2009, included 77 ex-smokers or never smokers with AATD defined as AAT serum concentrations less than 11 μM. Patients were treated for 2 years with augmentation therapy or placebo. The primary outcome was lung density measured by computed tomography (CT) scans. Lung density decline was reported in 4 ways (2 methods of adjustment for lung variability and 2 statistical methods). One of the 4 lung density outcome variables found a statistically significant between-group difference at follow-up (p=0.049) and the other 3 had marginally significant findings (p=0.59 to p=0.084). Decrease in FEV1, reported as a secondary outcome, did not differ significantly between groups.
The third RCT was published in 2015 by Chapman et al (Chapman, 2015). It was a double-blind placebo-controlled study in patients with emphysema secondary to AATD and FEV1 of 35% to 70% of the predicted normal value. AATD was defined as AAT serum levels or 11 μM or less. Patients were treated with augmentation therapy or placebo for 2 years. The primary outcome was the annual rate of decrease in lung density. Lung density values were calculated at both the total lung capacity (TLC) and functional residual capacity (FRC). When measured at TLC and FRC combined, the relative reduction in lung density in the augmentation versus the placebo group was 29% (95% CI, 93% to 76%) and this difference was not statistically significant. When measured separately, there was a significantly greater decrease in lung density at TLC alone in the augmentation versus placebo group and no significant difference between groups in lung density at FRC alone. Change in FEV1, a secondary outcome, did not differ significantly between groups but the authors noted that the study was not powered for this outcome.
2018 Update
A literature search conducted using the MEDLINE database through January 2018 did not reveal any new information that would prompt a change in the coverage statement.
2019 Update
Annual policy review completed with a literature search using the MEDLINE database through February 2019. No new literature was identified that would prompt a change in the coverage statement.
2020 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2020. No new literature was identified that would prompt a change in the coverage statement.
2021 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2021. No new literature was identified that would prompt a change in the coverage statement.
2022 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2022. No new literature was identified that would prompt a change in the coverage statement.
2023 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
Lopez-Campos et al conducted an observational analysis of A1AT Genotyping Test results from 30,827 samples collected via buccal swab from patients with suspected AATD in Argentina, Brazil, Chile, Colombia, Spain, and Turkey (Lopez-Campos, 2022). The swabs were sent to a central laboratory for analysis. COPD was the most common reason for suspected AATD (49.4%), followed by poorly controlled asthma (11.0%), and bronchiectasis (4.7%). One-quarter of patients tested had no documented reason for AATD genetic screening. Gene mutations were identified in 30.9% of samples. The following genotypes were reported: MS (14.7%), MZ (8.6%), SS (1.9%), SZ (1.9%), and ZZ (0.9%).
Ashenhurst et al published the results of a self-reported survey of lifestyle and behavior changes among individuals who received direct to consumer genetic test results (23andMe®, which evaluates Z and S alleles) (Ashenhurst, 2022). Among the 205,632 survey participants, 195,014 were analyzable. Of these, 0.63% had self-reported physician-diagnosed AATD, many of whom were diagnosed after they shared their genetic results with their physician. Individuals with a ZZ genotype shared their results with a health care provider or family member in 51.1% and 79.9% of cases, respectively. Individuals with an SZ genotype shared their results with a health care provider or family member in in 27.5% and 59.6% of cases, respectively. Individuals with heterozygous Z variants were more likely to report a decrease in smoking (odds ratio, 1.7; p<.0015) and individuals with homozygous Z variants were more likely to report a decrease in alcohol consumption (odds ratio, 3.9; p<.0015) than individuals without Z variants.
2024 Update
Annual policy review completed with a literature search using the MEDLINE database through January 2024. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.
The ATS and ERS joint statement on AATD recommended the following interventions for patients with emphysema who haveAATD:
Authors noted that these are general recommendations for treating patients with COPD and are also applicable to those with pulmonary disease not associated with AATD; no controlled studies specific to AATD were cited in support of the previous recommendations to determine whether the timing, intensity, or compliance with these treatments is altered by knowledge of AATD status. The 2016 Alpha-1 Foundation guidelines also state that, "There are no reliable data to suggest a differential treatment response to bronchodilators, inhaled corticosteroids, pulmonary rehabilitation, supplemental oxygen therapy, immunizations in individuals with AATD-COPD and AAT-replete COPD"(Sandhaus, 2016).
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| References: |
Alpha-1 Foundation. Testing for Alpha-1. Available online at: alpha-1foundation.org. Last accessed October 2012. American Thoracic Society; European Respiratory Society.(2003) American Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. Am J Respir Crit Care Med 2003; 168(7):818-900. Ashenhurst JR, Nhan H, Shelton JF, et al.(2022) Prevalence of Alpha-1 Antitrypsin Deficiency, Self-Reported Behavior Change, and Health Care Engagement Among Direct-to-Consumer Recipients of a Personalized Genetic Risk Report. Chest. Feb 2022; 161(2): 373-381. PMID 34656525 Audrain J, Boyd NR, Roth J et al.(1997) Genetic susceptibility testing in smoking-cessation treatment: one-year outcomes of a randomized trial. Addict Behav 1997; 22(6):741-51. Beletic A, Dudvarski-Ilic A, Milenkovic B, et al.(2014) Is an integrative laboratory algorithm more effective in detecting alpha-1-antitrypsin deficiency in patients with premature chronic obstructive pulmonary disease than AAT concentration based screening approach? Biochem Med (Zagreb). 2014;24(2):293-298. PMID 24969923 Carpenter MJ, Strange C, Jones Y et al.(2007) Does genetic testing result in behavioral health change? Changes in smoking behavior following testing for alpha-1 antitrypsin deficiency. Ann Behav Med 2007; 33(1):22-8. Carpenter MJ, Strange C, Jones Y, et al.(2007) Does genetic testing result in behavioral health change? Changes in smoking behavior following testing for alpha-1 antitrypsin deficiency. Ann Behav Med. Feb 2007;33(1):22-28. PMID 17291167 Dirksen A, Dijkman JH, Madsen F et al.(1999) A randomized clinical trial of alpha1- antitrypsin augmentation therapy. Am J Respir Crit Care Med 1999; 160(5 pt 1):1468-72. 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