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 performance of the Hydragel 18 A1AT phenotyping test is reported in an FDA decision summary document. (7) 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 (alpha-1 antitrypsin) genotyping test conducted in the United States, other than FDA documents, were identified.
In 2008, Ljujic and colleagues in Serbia published findings of a study with 27 emphysema patients. (8) Phenotyping was performed using isoelectric focusing and genotyping by denaturing gradient gel electrophoresis. 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. (7) 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).
The clinical utility of genetic testing for AATD depends on how the results can be used to improve patient management. With AATD, this could occur in several ways, including the following:
- Patient knowledge of AAT status could lead to behavior change that improves health outcomes. In particular, asymptomatic smokers could quit smoking which prevents or delays onset of lung disease, and symptomatic smokers could quit smoking which might prevent progression of lung disease. Knowledge of AAT status could also lead to other behavioral changes including avoiding pollutants, increasing exercise, avoiding alcohol, and avoiding smoking for those who have not started. (9)
- A diagnosis of AATD could lead to changes in treatment which may improve patient outcomes. The only treatment specific to AATD is alpha-1 antitrypsin augmentation therapy. In addition, the intensity and/or timing of other treatments may be different for individuals with known AATD. This includes antibiotic treatments for lung infections and vaccinations (influenza, pneumococcus, hepatitis A and B, etc.). (1)
In 2003, a joint statement on diagnosis and management of AATD from the American Thoracic Society (ATS) and the European Respiratory Society (ERS) was published. (1) 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 (random controlled trials) 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. (10)
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. (11) 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 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.
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 AATD, compared to the control individuals. (1)
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 (1) recommended the following interventions for individuals with emphysema who have AATD:
- Inhaled bronchodilators;
- Preventive vaccinations against influenza and pneumococcus;
- Supplemental oxygen when indicated by conventional criteria, including during air travel;
- Pulmonary rehabilitation for individuals with functional impairment;
- Consideration of lung transplantation for selected individuals with severe functional impairment and airflow obstruction; or
- Early antibiotic treatment for individuals with purulent acute exacerbations of COPD.
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 AAT in patients with AATD and lung disease. (12) The investigators searched for 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. (13,14) 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 AAT. 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): (15) 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.
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. (1)
ATS 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:
- Symptomatic adults with emphysema, COPD or asthma with airflow obstruction that is not completely reversible with aggressive treatment with bronchodilators;
- Individuals with unexplained liver disease;
- Asymptomatic individuals with persistent obstruction on pulmonary function tests with identifiable risk factors (e.g. cigarette smoking, occupational exposure);
- Adults with necrotizing panniculitis;
- Siblings of an individual with known alpha-1 antitrypsin (AAT) deficiency.
Type B recommendations for diagnostic testing in the following situations:
- Adults with bronchiectasis without evidence etiology;
- Adolescents with persistent airflow obstruction;
- Asymptomatic individuals with persistent airflow obstruction and no risk factors;
- Adults with C-ANCA positive (anti-proteinase 3-positive) vasculitis;
- Individuals with a family history of COPD or liver disease not known to be attributed to AAT deficiency;
- Distant relatives of an individual who is homozygous for AAT deficiency;
- Offspring or parents of an individual with homozygous AAT deficiency;
- Siblings, offspring, parents, or distant relatives of an individual who is heterozygous for AAT deficiency;
- Individuals at high risk of having AAT deficiency-related diseases;
- Individuals who are not at risk themselves of having AAT deficiency but who are partners of individuals who are homozygous or heterozygous for AAT deficiency.
Type C recommendations for diagnostic testing in the following situations:
- Adults with asthma in whom airflow obstruction is completely reversible;
- Predispositional testing;
- Population screening of smokers with normal spirometry.
Type D recommendations for diagnostic testing in the following situations:
- Predispositional fetal testing;
- Population screening of either neonates, adolescents, or adults.*
*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.
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.
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