human Leukocyte Antigen procedure codes

Coverage Indications, Limitations, and/or Medical Necessity


Human Leukocyte Antigen (HLA) typing is performed to assess compatibility of recipients and potential donors as a part of solid organ and hematopoietic stem cell/ bone marrow pre-transplant testing. HLA testing is also performed to identify HLA alleles and allele groups (antigen equivalents) associated with specific diseases and individualized responses to drug therapy (e.g., HLA-B*27 and ankylosing spondylitis and HLA-B57:01 and abacavir hypersensitivity), as well as other clinical uses. One or more HLA genes may be tested in specific clinical situations (e.g., HLA A, B, C,-DRB1, and DQB1 for kidney transplantation). Each HLA gene typically has multiple variant alleles or allele groups that can be identified by typing.

HLA antigens are divided into types: Class I (A, B, C) and Class II (DR, DP, DQ). The primary use for HLA testing is to match organ and tissue transplant recipients with compatible donors. Different kinds of transplants necessitate different levels of matching between donor and intended recipient. This may determine which HLA tests are performed and which HLA genes are tested for. HLA typing identifies the unique constellation of HLA antigens for an individual.

HLA typing using newer DNA technologies provides tests that are more robust, accurate and reliable in resolving allele-level differences in HLA genes that cannot be detected by serology. DNA tests can be performed using a variety of source materials (lymphocytes, whole blood, buccal swabs, biopsy samples, frozen tissue) and are less affected by viability and sample age. Several approaches to HLA typing are used, offering a range of typing resolution levels from low (antigen-level) to high (allele-level). Examples include, tests used to identify HLA types that rely on amplification of limited stretches of genomic DNA within the HLA genes. The genetic polymorphisms associated with the different HLA alleles are identified through hybridization with specific amplification primers: sequence-specific primer (SSP) or sequence specific oligonucleotide probes (SSO) or by direct sequencing-based typing (SBT).


Reverse SSO hybridization is used to determine HLA-A, -B, -C, -DR, -DQ and -DP locus types at an intermediate level of resolution, somewhat higher than serological testing. Tests of this type are used when low or intermediate resolution typing is required or as a screening test to identify potential donors or individuals who may later require higher resolution testing.

This technology is used for high volume testing and allows for relatively low-cost typing for bone marrow donor drives or other applications involving large sample numbers.


PCR-SSP is also used to determine HLA-DP and to determine, at a resolution similar to serological testing, HLA-A, -B, -C, -DR and DQ locus types. PCR-SSP is a very rapid test that can be performed in 3-4 hours from the time a sample is received. PCR-SSP is used for typing deceased organ donors when speed is an important consideration. PCR-SSP can also be used to provide higher resolution testing and may be employed to resolve alleles. In this technique, PCR primers are designed to anneal only to a specific set of alleles or to a single allele.


SBT provides the highest resolution HLA typing for HLA-A, -B, -C, -DR, -DQ and -DP locus alleles. SBT is used when the highest resolution typing is important as in donors and recipients of stem cell transplants or in examining disease associations.


The commercial availability does not ensure that a molecular diagnostic test is indicated for clinical application. Molecular diagnostic testing is a rapidly evolving science in which the significance of detecting specific mutations has yet to be clarified in many circumstances. Analytical and clinical validity as well as clinical utility are the responsibility of the provider, and all testing must meet standards of care.

For the purpose of this LCD, the Molecular Pathology Procedures for HLA typing will be considered medically and reasonable necessary when the following apply:


Standard of care determination of HLA matching for solid organ transplant (donor/recipient). Solid organ transplant registries include both serological HLA testing (e.g. crossmatch) and genomic molecular DNA typing. Family members, or unrelated living donors or cadaveric donors who donate bone marrow or a solid organ are HLA tested pretransplant to determine compatibility with the potential recipients.

Standard of care identification of determination of HLA matching for hematopoietic stem cell/bone marrow transplantation. Allele-level typing will provide clinical guidance for the HLA-A,B,C Class I and DRB1, DQB1,DPB1, and DQA1 Class II loci in the average transplant program because it is well established that mismatches at certain HLA loci between donor-recipients are closely linked to the risk of graft versus host disease. Potential marrow donors may enroll with a national registry such as the United States National Marrow Donor Program or the Canadian Blood Services registry.

Disease Association:

Standard of care testing to diagnose certain HLA related diseases/conditions when the testing is supported by the clinical literature and is informative for the direct management of a patient bearing a certain allele(s). It is not expected that more than one test would be required in a given beneficiary’s lifetime. Possible covered indications when standard laboratory testing (tissue typing) is not adequate:

HLA-B*27 for the diagnosis of certain cases of symptomatic patients with presumed ankylosing spondylitis or related inflammatory disease. HLA-B*27 is covered for ankylosing spondylitis in cases where other methods of diagnosis would not be appropriate or have yielded inconclusive results (National Coverage Determination 190.1).

In the work-up of certain patients with an unclear diagnosis of celiac disease and gluten hypersensitivity usually related to ambiguous standard laboratory results and/or inconsistent biopsy results (e.g., HLA-DQ2 by HLA-DQB1*02 and of DQ8 by HLA-DQB1*0302).


Standard of care testing to diagnose certain HLA related drug hypersensitivity reactions when the testing is supported by the clinical literature and is informative for the direct management of a patient bearing a certain allele(s) associated to fatal skin drug reactions (Stevens-Johnson syndrome and toxic epidermal necrolysis). It is not expected that more than one test would be required in a given beneficiary’s lifetime. Possible covered indications:

HLA –B*5701 when testing performed prior to the initiation of an abacavir-containing regime in the treatment of HIV Infection.

HLA-B*1502 when genotyping may be useful for risk stratification when the testing is performed prior to the initiation of carbamazepine therapy in the treatment of patients at high risk of having this allele. HLA-B*1502 occurs almost exclusively in patients with ancestry across broad areas of Asia, including South Asian Indians.

Identification of HLA compatible platelets for transfusion.


The following will be considered noncovered as applicable due to statutory exclusion, lack of Medicare benefit, not reasonable and necessary, or not separately billable (a component of the service per NCCI regulations).

Tests considered screening in the absence of clinical signs and symptoms of disease (e.g., HLA-DQB1*06:02P as a positive/negative predictor for narcolepsy).

Tests that do not provide the clinician with actionable data (information that will improve patient outcomes and/or change physician care and treatment of the patient).

Tests that confirm a known diagnosis or known information (and no new data for decision making).

Tests to determine risk for developing a disease or condition.

Tests without diagnosis specific indications.

Tests performed to measure the quality of a process.

Tests for Quality Control/Quality Assurance (QC/QA), i.e., tests performed to ensure a tissue specimen matches the patient.

Tests assessing the risk of allopurinol hypersensitivity reactions (HLA-B*58:01P).


Group 1 Paragraph: N/A

Group 1 Codes:

81370 Hla i & ii typing lr

81371 Hla i & ii type verify lr

81372 Hla i typing complete lr

81373 Hla i typing 1 locus lr

81374 Hla i typing 1 antigen lr

81375 Hla ii typing ag equiv lr

81376 Hla ii typing 1 locus lr

81377 Hla ii type 1 ag equiv lr

81378 Hla i & ii typing hr

81379 Hla i typing complete hr

81380 Hla i typing 1 locus hr

81381 Hla i typing 1 allele hr

81382 Hla ii typing 1 loc hr

81383 Hla ii typing 1 allele hr

ICD-10 Codes that Support Medical Necessity


T86.00 – T86.819 – Opens in a new window Unspecified complication of bone marrow transplant – Unspecified complication of lung transplant
T86.830 – T86.839 – Opens in a new window Bone graft rejection – Unspecified complication of bone graft
T86.850 – T86.99 – Opens in a new window Intestine transplant rejection – Other complications of unspecified transplanted organ and tissue
Z48.21 – Z48.298 – Opens in a new window Encounter for aftercare following heart transplant – Encounter for aftercare following other organ transplant
Z94.0 – Z94.9 – Opens in a new window Kidney transplant status – Transplanted organ and tissue status, unspecified
Z95.3 – Z95.4 – Opens in a new window Presence of xenogenic heart valve – Presence of other heart-valve replacement

Group 2 Paragraph: CPT Code 81374 for HLA-B*27 Testing

M08.1 Juvenile ankylosing spondylitis
M45.0 – M45.9 – Opens in a new window Ankylosing spondylitis of multiple sites in spine – Ankylosing spondylitis of unspecified sites in spine
M48.8X1 – M48.8X9 – Opens in a new window Other specified spondylopathies, occipito-atlanto-axial region – Other specified spondylopathies, site unspecified

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