CurrentBlue Cross Blue Shield - TennesseePolicy N/A

Testing for Alpha-1 Antitrypsin Deficiency

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Defines coverage criteria for serum, proteotype/phenotype, and genetic testing for alpha-1 antitrypsin deficiency (AATD) including indications, limitations, and testing pathways for symptomatic individuals, at-risk relatives, and cases with discordant results. Applies to Blue Cross Blue Shield - Tennessee members.

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyTesting for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeNo material change

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument clinical indication, prior serum AAT level and any discordant proteotype/phenotype or genotype results, and family history to support coverage.

SourceLink

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CurrentBlue Cross Blue Shield - TennesseePolicy N/A

Testing for Alpha-1 Antitrypsin Deficiency

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Sign up for all blue cross blue shield - tennessee policy alerts

Know when blue cross blue shield - tennessee releases new policies or updates existing guidance.

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Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyTesting for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeNo material change

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument clinical indication, prior serum AAT level and any discordant proteotype/phenotype or genotype results, and family history to support coverage.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

1 in 2,000–1 in 5,000estimated prevalence of AATD

80k–100kUS with severe AATD

<=11 µmol/Llow serum AAT threshold

12–35 µmol/Lborderline serum AAT

7/1/2023policy adoption date

Coverage Criteria for AATD Testing

Covered indications and testing cascade

Covered when ANY of the following are met

Serum testing covered indications: Serum quantification of A1AT and/or A1AT phenotyping/proteotyping (Pi-typing) for Z and S alleles meets coverage criteria for: (a) symptomatic adults with emphysema, COPD, or asthma; (b) individuals with unexplained liver disease; (c) individuals with persistent obstruction on pulmonary function tests without identifiable risk factors (e.g., cigarette smoking, occupational exposure); (d) adults with necrotizing panniculitis; (e) siblings of an individual with known AAT deficiency; (f) individuals with anti-proteinase three-positive (C-ANCA) vasculitis; (g) individuals with bronchiectasis without evident etiology.

From Serum Testing section

Phenotyping in discordant/negative genotype contexts: Isoelectric focusing/phenotyping (proteotyping) meets coverage criteria when genotype testing for common variants is negative or results are discordant with A1AT serum levels and there is strong suspicion of disease based on laboratory testing and symptoms.

Reflex/confirmatory phenotyping

Genetic testing covered indications: Genetic testing for AATD meets coverage criteria when: (a) the patient is suspected of having AATD because of clinical factors (early-onset emphysema age ≤45; emphysema in the absence of a recognized risk factor such as smoking or occupational dust exposure; emphysema with prominent basilar hyperlucency; otherwise unexplained liver disease; necrotizing panniculitis; anti-proteinase three-positive vasculitis; bronchiectasis without evident etiology); (b) there are discordant results between serum levels and proteotype testing for Z and S alleles; (c) at-risk individuals with a first-degree relative with AAT deficiency.

From Genetic testing section

Full gene sequencing: Full SERPINA1 gene sequencing meets coverage criteria when there is strong suspicion of disease based on laboratory testing and symptoms in an individual with negative genotype testing for common variants or discordant serum/proteotype or phenotype results (to detect rare or null variants).

Used for rare/null variants

Guideline-based testing criteria

Testing recommended as Type A when ALL of the following apply (per ATS/ERS; other societies provide overlapping guidance):

Type A diagnostic testing — recommended: Symptomatic adults with emphysema, COPD, or asthma with airflow obstruction that is not completely reversible with aggressive bronchodilator treatment; 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 AAT deficiency.

ATS/ERS Type A list

Type B indications — testing should be discussed: Adults with bronchiectasis without evident etiology; adolescents with persistent airflow obstruction; asymptomatic individuals with persistent airflow obstruction and no risk factors; adults with C-ANCA (anti-proteinase 3)-positive vasculitis; individuals with a family history of COPD or liver disease not known to be due to AATD; distant relatives, offspring, or parents of homozygous individuals; siblings/relatives of heterozygotes; individuals at high risk; partners of affected individuals.

ATS/ERS Type B list

ERS/Alpha-1 Foundation testing principles: Quantitative AAT level measurement is recommended as the first-line test. Quantitative deficiency should be supported by qualitative testing (phenotyping) to identify variants; genotyping for S and Z alleles is recommended for diagnostic testing, and gene sequencing is indicated when a null variant or deficient variant other than S or Z is suspected.

Testing for alpha-1 antitrypsin deficiency (AATD) is covered only when documentation shows a qualifying clinical indication or family history as specified in this policy. Covered situations include symptomatic adults with emphysema, COPD, or asthma with incompletely reversible airflow obstruction; individuals with otherwise unexplained liver disease; adults with necrotizing panniculitis; anti-proteinase-3 (C-ANCA)–positive vasculitis; bronchiectasis without evident etiology; siblings or first-degree relatives of an individual with known AAT deficiency; discordant or negative genotype testing with strong clinical or laboratory suspicion; and patients meeting guideline-specified clinical factors (for example early-onset emphysema age ≤45 or emphysema without recognized risk factors).

Guideline recommendations classify indications for genetic testing by Type. Type A situations (testing recommended) include symptomatic adults with emphysema, COPD, or asthma with incompletely reversible airflow obstruction; individuals with unexplained liver disease; asymptomatic individuals with persistent obstruction and identifiable risk factors; adults with necrotizing panniculitis; and siblings of persons with known AAT deficiency. Type B situations (testing should be discussed) include adults with bronchiectasis of unclear cause, adolescents with persistent obstruction, C-ANCA–positive vasculitis, and various family-contact scenarios. Type C and Type D recommendations discourage or recommend against testing for population screening and predispositional fetal testing; these scenarios are not routine indications for genetic testing.

Some molecular assays for SERPINA1 variants are FDA-cleared or approved (for example, the Grifols SERPINA1 Variant Detection System and AlphaID, and the 23andMe PGS report for PI*Z and PI*S variants). Many laboratories also use laboratory-developed tests (LDTs); these are regulated under CLIA as high-complexity tests but are not FDA-approved or cleared. When LDTs are used, documentation should identify the specific test performed and confirm that it was validated and run in a CLIA-certified high-complexity laboratory.

This policy does not cover population screening or predispositional testing. Specifically, predispositional testing, population screening of neonates, adolescents, or adults, and population screening of smokers with normal spirometry are listed as not recommended or do not meet coverage criteria except in rare public-health scenarios noted by guidelines. Fetal predispositional testing is explicitly recommended against by Type D guidance.

The European Respiratory Society (ERS) has stated that there is no evidence to support efficacy of alpha-1 antitrypsin augmentation therapy for individuals with PiSZ or PiMZ genotypes, and for current smokers of any protein phenotype. This lack of evidence for therapeutic benefit in these groups informs testing and treatment considerations and supports withholding augmentation therapy where not clinically indicated.

Coding, Tests, and Thresholds

Provider Actions, Documentation, and Prior Authorization

Prior Authorization

Genetic test prior authorization

Genetic tests and some laboratory assays may require payer authorization prior to performance. Providers should verify whether Blue Cross Blue Shield of Tennessee requires prior authorization for genetic testing for alpha-1 antitrypsin deficiency (including targeted genotyping, multi-variant panels, and full SERPINA1 sequencing) and obtain it when required.

Prior authorization may apply to FDA-cleared genotyping assays (e.g., Grifols AlphaID/ SERPINA1 Variant Detection System) as well as laboratory-developed tests (LDTs).
When prior authorization is required, include clinical indication(s) and prior laboratory results (AAT serum level, phenotype/proteotype) with the request.

Prior Authorization

Check payer and government prior authorization

Verify applicable payer and government prior authorization and coverage rules before testing. This includes Medicare (LCD/NCD) and state Medicaid requirements which may differ from BCBS TN policy.

Check CMS Medicare Coverage Database for relevant NCDs/LCDs.

Background on Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is an inherited serpin disorder caused by pathogenic variants in the SERPINA1 gene that reduce or alter circulating AAT. AAT, produced by the liver, protects the lung from neutrophil elastase; deficiency or dysfunctional protein leads to proteolytic lung injury manifesting as early-onset emphysema and increased risk of COPD and bronchiectasis. AATD also causes polymer-mediated liver injury and is associated with liver disease and necrotizing panniculitis. Clinical suspicion is prompted by features such as early-onset emphysema (≤45 years), emphysema without recognized risk factors, emphysema with basilar hyperlucency, unexplained liver disease, necrotizing panniculitis, C-ANCA–positive vasculitis, and bronchiectasis without evident etiology.

Definitions and Test Terms

inv-26: A1AT / AAT definition

DefinitionAlpha-1 antitrypsin (A1AT, AAT) is a serine protease inhibitor produced by the liver that protects the lungs from neutrophil elastase and is encoded by the SERPINA1 gene.

Clinical relevanceDeficient or dysfunctional AAT leads to emphysema, COPD, bronchiectasis, and liver disease via proteolytic lung injury and intrahepatocyte polymer accumulation.

InheritanceInherited in an autosomal recessive pattern with codominant expression; allele combinations (e.g., ZZ, MZ) influence disease risk.

inv-27: SERPINA1 definition

DefinitionSERPINA1 is the gene that encodes alpha-1 antitrypsin; pathogenic variants in SERPINA1 cause AAT deficiency.

Testing roleDirect identification of Z and S alleles by genotyping targets SERPINA1 variants for diagnostic evaluation.

Policy Summary

PayerBlue Cross Blue Shield - Tennessee

PolicyTesting for Alpha-1 Antitrypsin Deficiency

Policy CodePolicy N/A

Change TypeNo material change

Effective DateJul 1, 2023

Next Review DateN/A

Key ActionDocument clinical indication, prior serum AAT level and any discordant proteotype/phenotype or genotype results, and family history to support coverage.

SourceLink

On This Page

ERS and Alpha-1 Foundation recommendations

Confirm state Medicaid rules for the member's state of residence prior to testing.

If member is dual-eligible or Medicare-covered, follow Medicare prior authorization/coverage determinations where applicable.

Denial Risk

Denial risk for non-indicated testing

Tests performed without a documented, guideline-based clinical indication may be denied. Order testing only when the patient's presentation meets covered indications and retain supporting documentation in the medical record.

Testing outside of listed coverage indications (see policy Section III) is subject to denial.
Document clinical signs/symptoms and prior test results (AAT level, phenotype/genotype discordance) to support medical necessity.

Documentation Required

Conflict with government policies

If there is any conflict between this BCBS TN policy and an applicable government policy (e.g., Medicare LCD/NCD or state Medicaid coverage), the government policy supersedes and should be followed when determining coverage.

Use the government policy (NCD/LCD or state Medicaid) for determination when conflicts exist.
Maintain documentation of the applicable government policy cited in the adjudication decision.

Prior Authorization

Medicare/Medicaid policy alignment

Coverage determinations for Medicare and Medicaid beneficiaries are subject to applicable CMS and state Medicaid policies. Providers must consult the Medicare Coverage Database and the member's state Medicaid rules for the most current coverage and prior authorization requirements.

Medicare: search CMS Medicare Coverage Database for NCDs/LCDs affecting AATD testing.
Medicaid: verify state-specific Medicaid coverage and prior authorization rules before testing.

Documentation Required

Required documentation to support medical necessity

Document the clinical indications and all supporting data that establish medical necessity for AATD testing. Include symptom history, relevant diagnoses, family history, and prior laboratory results in the medical record and authorization request.

Clinical indications to document: early-onset emphysema (≤45 years), emphysema without recognized risk factors, basilar-predominant emphysema, unexplained liver disease, necrotizing panniculitis, C-ANCA–positive vasculitis, bronchiectasis without clear etiology, and first-degree relative with known AAT deficiency.
Laboratory data to include: quantitative AAT serum level, phenotype/proteotype results, and any discordant genotype/phenotype findings.
When prior authorization is requested, attach copies of prior test results and relevant clinical notes supporting the indication.

Documentation Required

Test documentation and lab validation

Record the specific test performed, the method used, and the laboratory's validation/authorization status. For genetic assays, indicate whether an FDA-cleared test or an LDT was used and include test name and version when available.

Document test specifics: assay name (e.g., Grifols SERPINA1 Variant Detection System, AlphaID), method (genotyping panel, targeted PCR, NGS/sequencing), and whether assay is FDA-cleared or an LDT.
If an LDT is used, include laboratory CLIA certification and statement of analytic validation.
Include lab report with result interpretation, alleles tested (at minimum S and Z), and any reflex testing performed (phenotype or full gene sequencing).

Note

ERS note — augmentation therapy efficacy and testing implications

The European Respiratory Society (ERS) notes there is no evidence to support augmentation therapy efficacy for certain genotypes and in current smokers. Consider these clinical guidance points when ordering tests that could trigger therapy decisions or coverage review.

ERS statement: no evidence of augmentation benefit in PiSZ, PiMZ phenotypes and in current smokers — document smoking status and genotype/phenotype when relevant.
These findings may influence therapeutic planning and payer coverage decisions for augmentation therapy; include genotype/phenotype details in prior authorization requests for augmentation.

Clinical noteRange of serum AAT levels overlaps across genotypes; genotyping of SERPINA1 improves diagnostic sensitivity and specificity.

inv-28: Genotyping for S and Z alleles definition

DefinitionGenotyping for S and Z alleles: targeted molecular testing to identify the common SERPINA1 variants (S and Z) that account for the majority of AATD cases.

PerformanceGenotyping for S and Z alleles is >99% specific and sensitive when both alleles are included.

Role in cascadeRecommended as part of diagnostic testing; sequencing reserved for suspected null or rare variants when genotyping is negative or discordant.

inv-29: Phenotyping / Pi-typing definition

DefinitionPhenotyping / Pi-typing: protein phenotyping by isoelectric focusing (Pi-typing) to identify AAT protein variants present in a sample.

Gold-standard roleSerum phenotyping by isoelectric focusing performed by a reliable laboratory is the accepted 'gold standard' for diagnosing AAT deficiency.

IndicationsUsed to confirm variant presence when serum levels are low, when genotyping is negative or discordant, or to detect rarer variants (e.g., F, I, P).

inv-30: Laboratory-developed test (LDT) definition and regulatory note

DefinitionLaboratory-developed test (LDT): a test developed and validated by an individual laboratory and regulated by CMS as a high-complexity test under CLIA '88; not approved or cleared by the FDA for clinical use.

Regulatory noteLDTs are regulated under CLIA '88 by CMS and are not FDA-approved; FDA clearance/approval is not currently required for clinical use of LDTs.

Documentation requirementWhen LDTs are used, document the specific test performed, validation, and that testing occurred in a CLIA-certified high-complexity laboratory.

inv-31: FDA-approved genetic tests referenced (Grifols, 23andMe) — test names and context

Grifols SERPINA1 Variant Detection SystemFDA-approved qualitative in vitro molecular diagnostic system to detect variants in the SERPINA1 gene (approved Nov 17, 2017).

Grifols AlphaID™FDA-approved cheek swab genotyping assay (approved Nov 7, 2019) that screens for the 14 most prevalently reported Alpha-1 mutations including S, Z, F, I, and null alleles.

23andMe PGS Genetic Health Risk ReportFDA-approved (Apr 6, 2017) report that qualitatively detects PI*Z (rs28929474) and PI*S (rs17580) SNPs in SERPINA1 for AATD risk reporting via the 23andMe Personal Genome Service.