Concert Genetic Testing: Lung Disorders Form

Concert Genetic Testing: Lung Disorders
V1.2025
Date of Last Revision: 11/2024
CENTENE
Corporation
Revision log
Coding Implications

# CONCERT GENETIC TESTING: LUNG DISORDERS

See Important Reminder at the end of this policy for important regulatory and legal
information.

## OVERVIEW

One of the most common inherited lung disorders is alpha-1 antitrypsin deficiency (AATD).
AATD is an autosomal recessive genetic disorder that results in decreased production of the
alpha-1 antitrypsin (AAT) protein, or production of abnormal types of the protein that are
functionally deficient. Individuals with AATD have an increased risk to develop lung and liver
disease. Genetic testing to diagnose AATD aids in directing proper treatment and identifying at-
risk family members.

With the use of donor-derived cell-free DNA (dd-cfDNA), biomarker tests have been developed
as an alternative to more invasive procedures for post-lung transplant care to optimize graft
longevity while avoiding side effects and toxicity of immunosuppressive therapies.

## POLICY REFERENCE TABLE

### Coding Implications

This clinical policy references Current Procedural Terminology (CPT®. CPT is a registered
trademark of the American Medical Association. All CPT codes and descriptions are copyrighted
2023, American Medical Association. All rights reserved. CPT codes and CPT descriptions are
from the current manuals and those included herein are not intended to be all-inclusive and are
included for informational purposes only. Codes referenced in this clinical policy are for
informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage.
Providers should reference the most up-to-date sources of professional coding guidance prior to
the submission of claims for reimbursement of covered services.

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The tests, associated laboratories, CPT codes, and ICD codes contained within this document
serve only as examples to help users navigate claims and corresponding criteria; as such, they are
not comprehensive and are not a guarantee of coverage or non-coverage. Please see the Concert
Platform for a comprehensive list of registered tests.

| Criteria Sections | Example Tests (Labs) | Common CPT Codes | Common ICD Codes | Ref |
|------------------|---------------------|-----------------|-----------------|-----|
| **Alpha-1 Antitrypsin Deficiency** | | | | |
| SERPINA1 Common Variant Analysis or Sequencing and/or Deletion/Duplication Analysis | Alpha-1 Antitrypsin (AAT) Mutation Analysis (Quest Diagnostics) | 81332 | E88.01 | 1 |
|  | SERPINA1 Full Gene Sequencing and Deletion/Duplication (Invitae) | 81479 |  |  |
| **Donor-Derived Cell-free DNA for Lung Transplant Rejection** | | | | |
| Evidence-Based Donor-Derived Cell-free DNA for Lung Transplant Rejection | Prospera Lung (Natera) | 81479 | T86.810, Z48.24, Z94.2 | 5 |
|  | AlloSure Lung (CareDx) |  |  |  |
| Emerging Evidence Donor-Derived Cell-free DNA for Lung Transplant Rejection | Eurofins TRAC dd-cfDNA (Transplant Genomics Inc) | 0118U |  |  |
| **Other Covered Lung Disorders** | | | | |
| Other Covered Lung Disorders | See list below | 81400-81408 |  | 2, 3, 4 |

## OTHER RELATED POLICIES

This policy document provides criteria for Genetic Testing for Lung Disorders. Please refer to:

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* Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and
  Developmental Delay for criteria related to diagnostic testing for cystic fibrosis and other
  multisystem inherited disorders.
* Genetic Testing: General Approach to Genetic and Molecular Testing for criteria related
  to genetic testing for lung disorders and disease that are not specifically discussed in this or
  another non-general policy, including known familial variant testing.

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## CRITERIA

It is the policy of health plans affiliated with Centene Corporation® that the specific genetic
testing noted below is medically necessary when meeting the related criteria:

### ALPHA-1 ANTITRYPSIN DEFICIENCY

#### SERPINA1 Common Variant Analysis or Sequencing and/or Deletion/Duplication Analysis

1. SERPINA1 common variant analysis (81332) or sequencing and/or deletion/duplication
   analysis (81479) to establish a diagnosis of alpha-1 antitrypsin (AAT) deficiency is
   considered medically necessary when:
   A. The member/enrollee has any of the following:
      1. Abnormally low (less than 120 mg/dL) or borderline (90-140 mg/dL)
         alpha-1 antitrypsin levels (as measured by nephelometry), OR
      2. Early-onset emphysema (45 years of age or younger), OR
      3. Emphysema in the absence of additional risk factor (e.g., smoking,
         occupational dust exposure), OR
      4. Emphysema with prominent basilar hyperlucency, OR
      5. Otherwise unexplained liver disease, OR
      6. Necrotizing panniculitis, OR
      7. C-ANCA positive vasculitis (i.e., granulomatosis with polyangiitis), OR

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8. Bronchiectasis without evident etiology, OR
9. A sibling with known AAT deficiency.

II. SERPINA1 common variant analysis (81332) or sequencing and/or deletion/duplication
   analysis (81479) to establish a diagnosis of alpha-1 antitrypsin deficiency is considered
   investigational for all other indications.

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## DONOR-DERIVED CELL-FREE DNA FOR LUNG TRANSPLANT REJECTION

### Evidence-Based Donor-Derived Cell-free DNA for Lung Transplant Rejection

I. The use of peripheral blood measurement of donor-derived cell-free DNA tests (81479)
   with sufficient evidence of clinical utility and validity in the management of patients after
   lung transplantation is considered medically necessary when:
   A. The member/enrollee has undergone lung transplantation, AND
   B. The test has not been performed in the last 12 months, AND
   C. The member/enrollee meets at least one of the following:
      1. The member/enrollee has clinical signs of acute rejection, OR
      2. A biopsy was done and is inconclusive for rejection, OR
      3. The member/enrollee is being monitored for adequate
         immunosuppression.

II. The use of peripheral blood measurement of donor-derived cell-free DNA tests (81479)
   in the management of patients after lung transplantation is considered investigational for
   all other indications.

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## Emerging Evidence Donor-Derived Cell-free DNA for Lung Transplant Rejection

I. Donor-derived cell-free DNA tests with insufficient evidence of clinical validity (0118U)
   in the management of patients after lung transplantation are considered investigational.

## OTHER COVERED LUNG DISORDERS

The following is a list of conditions that have a known genetic association. Due to their relative
rareness, it may be appropriate to cover these genetic tests to establish or confirm a diagnosis.

I. Genetic testing to establish or confirm one of the following genetic lung disorders to
   guide management is considered medically necessary when the member/enrollee
   demonstrates clinical features* consistent with the disorder (the list is not meant to be
   comprehensive, see II below):
   A. Familial Pulmonary Fibrosis
   B. Primary Ciliary Dyskinesia
   C. Pulmonary lymphangioleiomyomatosis (LAM)
   D. Pulmonary alveolar proteinosis (PAP)

II. Genetic testing to establish or confirm the diagnosis of all other lung disorders not
   specifically discussed within this or another medical policy will be evaluated by the criteria
   outlined in General Approach to Genetic and Molecular Testing (see policy for criteria).

\*Clinical features for a specific disorder may be outlined in resources such as GeneReviews, OMIM, National Library
of Medicine, Genetics Home Reference, or other scholarly source.

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## BACKGROUND AND RATIONALE

### ALPHA-1 ANTITRYPSIN DEFICIENCY

#### SERPINA1 Common Variant Analysis or Sequencing and/or Deletion/Duplication Analysis

American Thoracic Society and European Respiratory Society

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The American Thoracic Society and European Respiratory Society published a joint statement on
the diagnosis and management of individuals with alpha-1 antitrypsin deficiency (2003) which
provided recommendations for diagnostic testing.

A normal range of plasma alpha-1 antitrypsin (measured via nephelometry) is 83/120 - 200/220
mg/dL. Individuals with borderline normal levels of plasma alpha-1 antitrypsin (90-140 mg/dL)
or with abnormally low levels (below 120 mg/dL) should be evaluated for alpha-1 antitrypsin
deficiency. (p. 826 and 827)

“The following features should prompt suspicion by physicians that their patient may be more
likely to have AAT deficiency:
* Early-onset emphysema (age of 45 years or less)
* Emphysema in the absence of a recognized risk factor (smoking, occupational dust
  exposure, etc.)
* Emphysema with prominent basilar hyperlucency
* Otherwise unexplained liver disease
* Necrotizing panniculitis
* Anti-proteinase 3-positive vasculitis (C-ANCA [anti-neutrophil cytoplasmic antibody]-
  positive vasculitis)
* Family history of any of the following: emphysema, bronchiectasis, liver disease, or
  panniculitis
* Bronchiectasis without evident etiology…” (p. 820)

The statement also recommended that individuals with a sibling with AAT deficiency should
also be offered genetic testing. (p. 827)

### DONOR-DERIVED CELL-FREE DNA FOR LUNG TRANSPLANT REJECTION

#### Evidence-Based Donor-Derived Cell-free DNA for Lung Transplant Rejection

Centers for Medicare and Medicaid Services

The CMS local coverage determination (LCD) entitled “MolDX: Molecular Testing for Solid
Organ Allograft Rejection” states the following regarding donor-derived cell-free DNA tests in
individuals who have had solid organ transplantation:

“This Medicare contractor will provide limited coverage for molecular diagnostic tests used in
the evaluation and management of patients who have undergone solid organ transplantation.
These tests can inform decision making along with standard clinical assessments in their
evaluation of organ injury for active rejection (AR).

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These tests may be ordered by qualified physicians considering the diagnosis of AR affiliated
with a transplant center, helping to rule in or out this condition when assessing the need for or
results of a diagnostic biopsy. They should be considered along with other clinical evaluations
and results and may be particularly useful in patients with significant contraindications to
invasive procedures.

The intended use of the test must be:
* To assist in the evaluation of adequacy of immunosuppression, wherein a non-invasive or
  minimally invasive test can be used in lieu of a tissue biopsy in a patient for whom
  information from a tissue biopsy would be used to make a management decision
  regarding immunosuppression, OR
* As a rule-out test for AR in validated populations of patients with clinical suspicion of
  rejection with a non-invasive or minimally invasive test to make a clinical decision
  regarding obtaining a biopsy, OR
* For further evaluation of allograft status for the probability of allograft rejection after a
  physician-assessed pretest, OR
* To assess rejection status in patients that have received a biopsy, but the biopsy results
  are inconclusive or limited by insufficient material.”

#### Concert Note

For monitoring patients post lung transplantation, absent clear, specific and evidence-based
guideline recommendations for a particular regimen of screening, a default frequency of once
every 12 months will be adopted.

### Emerging Evidence Donor-Derived Cell-free DNA for Lung Transplant Rejection

Tests that have limited established clinical utility or validity as defined in the Concert policy for
General Approach to Genetic and Molecular testing do not meet the threshold for coverage.
Evidence for validity may include a Technology Assessment conducted by an independent third
party (e.g.MolDx Tech, ECRI, Optum Genomic) and/or evidence-based guidelines published by
professional societies. Such evidence was not identified for the tests referenced by this policy.

| Reviews, Revisions, and Approvals | Revision Date | Approval Date |
|----------------------------------|--------------|---------------|
| Policy developed.                | 03/23        | 03/23         |

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| Semi-annual review. Updated title to reflect V1.2024 version. Overview, coding, reference-table, background and references updated. Throughout policy: replaced “coverage criteria” with “criteria”. For Policy Reference Table: under “SERPINA1 Common Variant. ”, added “E88.01”. For Background and Rationale: under “SERPINA1 Known Familial Variant Analysis: replaced “inheritance patterns” with “genetic testing”. | 10/23 | 10/23 |
| Semi-annual review. Updated title to reflect V2.2024 version. In SERPINA1 Common Variant Analysis or Sequencing and/or Deletion/Duplication Analysis criteria, updated criteria to better align with current guidelines, allowing for an expansion to coverage. In SERPINA1 Known Familial Variant criteria, moved criteria to policy “Genetic Testing: General Approach to Genetic and Molecular Testing” to consolidate criteria for known familial variant tests. Minor rewording for clarity throughout. Coding, reference-table, background and references updated. | 04/24 | 04/24 |
| Semi-annual review. Updated title to reflect V1.2025 version. Evidence-Based Donor-Derived Cell-free DNA for Lung Transplant Rejection: NEW criteria based on LCD guidelines. Emerging Evidence Donor-Derived Cell-free DNA for Lung Transplant Rejection: NEW Criteria set created for lung cancer diagnostic algorithmic tests for which clinical validity has not been established. | 11/24 | 11/24 |

## REFERENCES

1. American Thoracic Society; European Respiratory Society. American Thoracic
   Society/European Respiratory Society statement: standards for the diagnosis and
   management of individuals with alpha-1 antitrypsin deficiency (2003). Am J Respir Crit Care
   Med. 2003;168(7):818-900. doi:10.1164/rccm.168.7.818
2. Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews [Internet]. Seattle
   (WA): University of Washington, Seattle; 1993-2024. Available from:
   https://www.ncbi.nlm.nih.gov/books/NBK1116/
3. Online Mendelian Inheritance in Man, OMIM. McKusick-Nathans Institute of Genetic
   Medicine, Johns Hopkins University (Baltimore, MD). World Wide Web URL:
   https://omim.org/
4. MedlinePlus [Internet]. Bethesda (MD): National Library of Medicine (US). Available
   from: https://medlineplus.gov/genetics/
5. Centers for Medicare & Medicaid Services. Medicare Coverage Database: Local
   Coverage Determination. MolDX: Molecular Testing for Solid Organ Allograft Rejection
   (L38582). Available at: https://www.cms.gov/medicare-coverage-
   database/view/lcd.aspx?lcdid=38582

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## Important Reminder

This clinical policy has been developed by appropriately experienced and licensed health care
professionals based on a review and consideration of currently available generally accepted
standards of medical practice; peer-reviewed medical literature; government agency/program
approval status; evidence-based guidelines and positions of leading national health professional
organizations; views of physicians practicing in relevant clinical areas affected by this clinical
policy; and other available clinical information. The Health Plan makes no representations and
accepts no liability with respect to the content of any external information used or relied upon in
developing this clinical policy. This clinical policy is consistent with standards of medical
practice current at the time that this clinical policy was approved. “Health Plan” means a health
plan that has adopted this clinical policy and that is operated or administered, in whole or in part,
by Centene Management Company, LLC, or any of such health plan’s affiliates, as applicable.

The purpose of this clinical policy is to provide a guide to medical necessity, which is a
component of the guidelines used to assist in making coverage decisions and administering
benefits. It does not constitute a contract or guarantee regarding payment or results. Coverage
decisions and the administration of benefits are subject to all terms, conditions, exclusions, and
limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy,
contract of insurance, etc.), as well as to state and federal requirements and applicable Health
Plan-level administrative policies and procedures.

This clinical policy is effective as of the date determined by the Health Plan. The date of posting
may not be the effective date of this clinical policy. This clinical policy may be subject to
applicable legal and regulatory requirements relating to provider notification. If there is a
discrepancy between the effective date of this clinical policy and any applicable legal or
regulatory requirement, the requirements of law and regulation shall govern. The Health Plan
retains the right to change, amend or withdraw this clinical policy, and additional clinical
policies may be developed and adopted as needed, at any time.

This clinical policy does not constitute medical advice, medical treatment, or medical care. It is
not intended to dictate to providers how to practice medicine. Providers are expected to exercise
professional medical judgment in providing the most appropriate care and are solely responsible
for the medical advice and treatment of member/enrollees. This clinical policy is not intended to
recommend treatment for member/enrollees. Member/enrollees should consult with their treating
physician in connection with diagnosis and treatment decisions.

Providers referred to in this clinical policy are independent contractors who exercise independent
judgment and over whom the Health Plan has no control or right of control. Providers are not
agents or employees of the Health Plan.

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This clinical policy is the property of the Health Plan. Unauthorized copying, use, and
distribution of this clinical policy or any information contained herein are strictly prohibited.
Providers, member/enrollees, and their representatives are bound to the terms and conditions
expressed herein through the terms of their contracts. Where no such contract exists, providers,
member/enrollees and their representatives agree to be bound by such terms and conditions by
providing services to member/enrollees and/or submitting claims for payment for such services.

Note: For Medicaid member/enrollees, when state Medicaid coverage provisions conflict with
the coverage provisions in this clinical policy, state Medicaid coverage provisions take
precedence. Please refer to the state Medicaid manual for any coverage provisions pertaining to
this clinical policy.

Note: For Medicare member/enrollees, to ensure consistency with the Medicare National
Coverage Determinations (NCD) and Local Coverage Determinations (LCD), all applicable
NCDs and LCDs and Medicare Coverage Articles should be reviewed prior to applying the
criteria set forth in this clinical policy. Refer to the CMS website at http://www.cms.gov for
additional information.



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