CurrentCapital BluecrossPolicy AHS G2098

Immune Cell Function Assay

This policy governs coverage determinations for immune cell function assays (e.g., ImmuKnow, Pleximmune, iQue) used to assess cell-mediated immune responses, primarily in transplant and primary immunodeficiency contexts, and applies to Capital BlueCross members in North Carolina.

Policy Summary

PayerCapital Bluecross

PolicyImmune Cell Function Assay

Policy CodePolicy AHS G2098

Change TypeNo material change

Effective Date

Next Review DateApr 1, 2025

Key ActionExpect prior authorization to be denied for immune cell function assays; confirm coding and payer requirements when submitting requests.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

1Assay not covered

3Proprietary assays

510(k)FDA clearance (ImmuKnow)

SeveralStudies summarized

Coverage Determinations

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Uncovered Indication

Not covered

General exclusion: Immune cell function assays (eg, Pleximmune™/Pleximark, ImmuKnow, or similar ICFA tests) do not meet coverage criteria due to insufficient published scientific literature confirming that the tests are required and beneficial for diagnosis or treatment

Policy explicitly states these tests DO NOT MEET COVERAGE CRITERIA.

Context and evidence (no hard coverage criteria in this section)

The following summarizes regulatory status, guideline context, and the cited evidence; this section does not establish additional coverage criteria.

Regulatory and guideline context: ImmuKnow (Cylex/ViraCor) has FDA 510(k) clearance for detection of cell-mediated immunity in immunosuppressed patients; Pleximmune received FDA Humanitarian Device Exemption approval for use in certain pediatric liver and small‑bowel transplant indications. Major transplant society guidance describes immune monitoring as an emerging tool (eg, for CMV risk stratification) but does not uniformly endorse routine use of ImmuKnow in screening or monitoring recommendations.

Supported by FDA statements and society guideline citations.

For all situations, immune cell function assays (for example, Pleximmune™ Pleximar and similar proprietary or laboratory-developed tests) do not meet coverage criteria. This policy determination is based on the lack of sufficient published scientific literature demonstrating that these tests are required for, or provide benefit to, the diagnosis or treatment of an individual’s illness.

Society guidance cited in this policy notes that immune monitoring is an emerging tool, but the American Society of Transplantation (AST) publications referenced in this document do not include the ImmuKnow assay among recommended methods for screening or monitoring infectious complications in transplant recipients (AST publications 2006 and 2009).

Use of immune cell function assays is considered not medically necessary under this policy because available evidence is insufficient to confirm clinical benefit. The policy explicitly states these assays do not meet coverage criteria due to limited published evidence demonstrating improved diagnostic or therapeutic outcomes.

The evidence base for immune cell function assays is mixed. Published studies include single-center observational reports, meta-analyses, and randomized trials with variable results: some analyses and observational series suggest potential associations between assay results and infection or rejection risk, while randomized and prospective studies have produced inconsistent findings. This heterogeneity in study design and outcomes underlies the policy conclusion that current evidence is inadequate to support routine clinical use for clinical decision-making.

Procedure Codes and Test Parameters

Prior Authorization

Prior Authorization Required

Provider must obtain code-level prior authorization when indicated by payer policy before ordering or billing for these assays. Prior authorization requirements include submission of the specific assay name, indication, and supporting clinical documentation demonstrating intended use (e.g., pre- or post-transplant monitoring, infection evaluation, or suspected rejection). Failure to document the specific assay and clinical indication may result in denial or reimbursement at payer discretion.

Prior authorization: submit assay name (e.g., ImmuKnow®, Pleximmune™, Pleximark) and clinical indication
Include supporting documentation: transplant type, timing relative to transplant, clinical signs/symptoms, serial test plan if monitoring

Documentation Required

Government Policy Precedence

Government and regulatory precedence: the Cylex ImmuKnow assay (Viracor/Cylex) received 510(k) clearance by the FDA for detection of cell-mediated immunity in immunosuppressed patients (2002; device modification cleared 2010). Pleximmune™ (Plexision) obtained FDA Humanitarian Device Exemption (HDE) approval for use in pediatric liver and small bowel transplant patients. Laboratory-developed tests (LDTs) exist and are regulated under CLIA as high-complexity tests; LDTs may be used clinically without FDA clearance but must be validated in-house.

Document whether testing is a cleared/approved device (FDA 510(k) or HDE) or an in-house LDT
If using an LDT, include CLIA certification and validation documentation in prior auth or claims support

Note

Related Procedural Guidance

When ordering or billing, providers should follow related procedural guidance: specify the clinical purpose (diagnosis of infection vs monitoring immunosuppression vs rejection risk assessment), the specimen type and collection timing (relative to transplant and clinical events), and whether testing will be performed serially as part of a monitoring protocol. For assays intended for monitoring, include a stepwise plan describing frequency and decision thresholds that will guide changes in immunosuppression.

Specify specimen: whole blood per manufacturer's instructions
State timing: pre-transplant baseline when applicable; post-transplant time points (e.g., weeks 1,2,4,8,12,24) if monitoring
Provide management thresholds and intended actions (e.g., ATP cutoffs guiding immunosuppression adjustment)

Billing Rule

Assay Identification and Coding

Assay identification and coding: providers must document the specific assay performed (e.g., Cylex ImmuKnow® immune cell function assay; Pleximmune™; Pleximark) and use the appropriate procedure code(s) on claims. If the proprietary test corresponds to an FDA-cleared/HDE-coded procedure (e.g., 81560 for Pleximmune™/Plexision proprietary rejection risk score), bill that code. For cellular function assays that measure ATP after stimulation, CPT 86352 is the general code used. For proprietary algorithm-based transplant rejection risk scores, use the specific CPT proprietary codes when available (e.g., 0018M, 81560).

Document assay name and manufacturer on requisition and claim
Use CPT 86352 for general cellular function assay (ATP measurement after stimulation) when appropriate
Use proprietary CPT codes (0018M, 81560) for Pleximark and Pleximmune when applicable

Step Therapy

Stepwise Testing Workflow

Stepwise testing workflow — recommended provider actions to support coverage and clinical utility: 1) Establish indication: document transplant type, clinical question (infection vs rejection vs immunosuppression monitoring), and baseline immune function if available. 2) Select assay and document manufacturer: specify ImmuKnow (Cylex/Viracor), Pleximmune (Plexision), Pleximark, or in-house LDT and include CLIA status. 3) Obtain prior authorization (code-level) when required; include assay name, indication, timing, and planned serial testing schedule. 4) Collect specimen per assay instructions (whole blood, timing relative to transplant or clinical event); send to certified lab performing that specific assay. 5) Report results with numeric ATP or algorithm score and interpretive category (e.g., ImmuKnow categories: Strong ≥ ~525 ng/mL; Moderate 226–524 ng/mL; Low <225 ng/mL) and any study-derived cutoffs used (e.g., pediatric liver transplant diagnostic cutoff ~152 ng/mL; hypothesized immunological target ~280 ng/mL). Include planned management actions tied to thresholds. 6) For serial monitoring, document dates and clinical decisions linked to each result and include in authorization/medical record to support medical necessity for subsequent tests.

Step 1: Document indication and baseline
Step 2: Specify assay and lab (manufacturer or LDT/CLIA)
Step 3: Secure code-level prior authorization with assay name and testing plan
Step 4: Follow specimen collection and lab submission guidance
Step 5: Report numeric result + interpretive category and planned clinical action
Step 6: For follow-up testing, link each test to documented clinical decision-making

What Providers Should Do

Prior Authorization

Expect prior authorization denial

Immune cell function assays are explicitly stated as not meeting coverage criteria; providers should expect that prior authorization requests for these assays will be denied under this policy.

Policy states: 'For all situations, an immune cell function assay (e.g., PleximmuneTM Pleximar) DOES NOT MEET COVERAGE CRITERIA.'
Expect prior authorization denials for requests that rely on this policy's coverage stance.

Prior Authorization

Verify prior authorization for listed procedure codes (81560, 86352, 0018M)

Confirm payer prior authorization requirements for the specific procedure codes listed in the policy—81560, 86352, and 0018M—before ordering or billing these assays.

Procedure codes referenced in the policy: 81560, 86352, 0018M.
Procedure codes in policy are provided for reference; verify Capital BlueCross prior auth rules for each code.

Step Therapy

Use stepwise testing: screen first, advanced assays only if indicated

Follow a stepwise diagnostic workflow: perform relatively inexpensive, rapid screening tests first (e.g., lymphocyte counts, immunoglobulins); pursue advanced immune function testing only if screening results are abnormal and clinical evaluation indicates need.

Background states screening tests are relatively inexpensive and abnormal results indicate need for more sophisticated tests.
Use stepwise testing to narrow diagnostic options before costly specialized assays.

Step Therapy

No explicit step therapy requirements in policy

This policy does not establish any explicit step therapy requirements for immune cell function assays.

Policy background describes a stepwise clinical approach but provides no mandated step therapy protocol.
No step therapy conditions are specified in the coverage language.

Documentation Required

Refer to Flow Cytometry policy (AHS-F2019) for flow cytometry procedures

If the requested test involves flow cytometry procedures, consult and follow the Flow Cytometry policy (AHS-F2019) for related procedural guidance.

Policy note: 'For guidance on procedures utilizing flow cytometry, please refer to AHS-F2019 Flow Cytometry.'

Denial Risk

Coverage exclusion—requests for ICFAs subject to denial

Requests for immune cell function assays (for example, Pleximmune™/Pleximark or similar ICFA tests) are subject to denial because the policy explicitly states these assays do not meet coverage criteria.

Policy language: 'For all situations, an immune cell function assay (e.g., PleximmuneTM Pleximar) DOES NOT MEET COVERAGE CRITERIA.'
Pleximmune/Pleximark are listed proprietary tests associated with codes 81560 and 0018M.

Note

Government policy (LCD/NCD/state Medicaid) overrides this policy if conflicting

If this policy conflicts with an applicable government policy (LCD, NCD, or state Medicaid), the government policy takes precedence and will govern coverage determinations.

Policy disclaimer: government policies (LCD/NCD/state Medicaid) supersede this policy when conflicts exist.
Check applicable Medicare and state Medicaid rules for final determination.

Key Terms and Abbreviations

ATP

TermAdenosine triphosphate (ATP)

Use in assaysMeasurement used in some immune cell function assays to quantify T-cell activation

ContextAppears in terminology table as defined abbreviation used throughout policy

ICFA

TermImmune cell function assay (ICFA)

DefinitionAssay measuring peripheral blood lymphocyte responses (eg, intracellular ATP, proliferation) after stimulation

RoleUsed to assess cell-mediated immunity in transplant and immunodeficiency contexts

ImmuKnow / Immune Cell Function Assay

ImmuKnow (Immune Cell Function Assay)FDA-cleared (510[k], 2002) assay to detect cell-mediated immunity in immunosuppressed patients by measuring T-cell function (ATP activity) after stimulation

Regulatory history510(k) clearance in 2002; additional 510(k) device modification clearance in 2010 with no change in intended use

Clinical evaluationStudied in transplant populations with mixed sensitivity and specificity findings across studies and meta-analyses

Pleximmune / Pleximark

Pleximmune / Pleximark (proprietary tests)Tests measuring donor and third-party–induced CD154+ T‑cytotoxic memory cells; Pleximmune (CPT 81560) and Pleximark (0018M) report an algorithmic rejection risk score

Regulatory statusPleximmune received FDA Humanitarian Device Exemption (2014) for pediatric liver and small bowel transplant use

CodingProcedure codes referenced: 81560 (Pleximmune), 0018M (Pleximark); related cellular function assay code: 86352

OpenPayer

Immune Cell Function Assay

Coverage Determinations

Procedure Codes and Test Parameters

What Providers Should Do

Clinical and Technical Background

Key Terms and Abbreviations