CurrentMedical Mutual - OhioPolicy AHS - G2098

Immune Cell Function Assay

Defines coverage stance for immune cell function assays (e.g., ImmuKnow, Pleximmune, iQue) for diagnosis or management of immune function in transplant and primary immunodeficiency contexts; applies to claims reviewed under this payer policy.

Policy Summary

PayerMedical Mutual - Ohio

PolicyImmune Cell Function Assay

Policy CodePolicy AHS - G2098

Change TypeEditorial and literature update (no material coverage changes)

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionDo not request prior authorization for immune cell function assays to obtain payment, as these tests do not meet coverage criteria and will be denied.

SourceLink

POLICY UPDATE CHANGES

Corrected error in name of test (Pleximark ™).

Updated the background, guidelines and recommendations, and evidence-based scientific references.

Not coveredCoverage stance

3Proprietary tests named

3CPT/HCPCS codes listed

≥15Evidence citations

Trek Health ingests and normalizes Transparency in Coverage data and payer policy updates to give provider organizations a clear view of how commercial reimbursement behaves across markets, payers, and services. Our platform transforms raw payer disclosures into structured intelligence that supports contract evaluation, payer negotiations, and service line strategy. By combining market benchmarks with ongoing policy visibility, Trek helps teams identify variability, risk, and opportunity in commercial reimbursement. The result is faster insight, stronger negotiating positions, and more informed financial decisions.

Professional societies discussed

Coverage Determination

Not Medically Necessary / Not Covered

Not covered

Immune cell function assays not covered: For all situations, an immune cell function assay (e.g., Pleximmune™, Pleximark™, ImmuKnow®, iQue®) DOES NOT MEET COVERAGE CRITERIA due to lack of sufficient published scientific literature confirming clinical benefit.

Policy explicitly states assays do not meet coverage criteria

Revision History / Coverage impact

Revision summary

Revision note: Literature review updated background, guidelines and references without necessitating changes to coverage criteria.

No coverage criteria edits made.

For all clinical situations addressed by this policy, immune cell function assays (for example, Pleximmune™ and Pleximark™) DO NOT MEET COVERAGE CRITERIA due to insufficient published scientific literature demonstrating that these tests are required or beneficial for diagnosis or management.

The European Society for Immunodeficiencies (ESID) 2024 guideline recommends a stepwise diagnostic evaluation for congenital athymia beginning with TREC screening and flow-cytometric enumeration of T-cell numbers and naive subsets, and states that qualitative T-lymphocyte (immune function) tests are of limited value and are not routinely necessary; ESID also notes these assays can be unreliable in lymphopenic patients.

Immune cell function assays (including proprietary and laboratory-developed tests) are considered not medically necessary for the indications covered by this policy and therefore do not meet coverage criteria for use in diagnosis or management as described in the policy.

The American Society of Transplantation (AST) guidelines support pathogen-specific immune assays and nonspecific markers such as lymphocyte count for immune monitoring, and do not include immune cell function assays (for example, ImmuKnow or Pleximmune) as recommended monitoring strategies.

Procedure Codes and Test Identifiers

Applicable CPT/HCPCS Procedure Codes (referenced section present)mixed

No codes listed

Procedure Codes referencedCPT

81560	Transplantation medicine (allograft rejection, pediatric liver and small bowel), measurement of donor and third-party-induced CD154+T-cytotoxic memory cells, utilizing whole peripheral blood, algorithm reported as a rejection risk score; Proprietary test: Pleximmune ™; Lab/Manufacturer: Plexision, Inc.
86352	Cellular function assay involving stimulation (eg, mitogen or antigen) and detection of biomarker (eg, ATP).
0018M	Transplantation medicine (allograft rejection, renal), measurement of donor and third-party-induced CD154+T-cytotoxic memory cells, utilizing whole peripheral blood, algorithm reported as a rejection risk score; Proprietary test: Pleximark ™; Lab/Manufacturer: Plexision, Inc.

ImmuKnow® response categories

Strong response≥525 ng/ml ATP

Moderate response226–524 ng/ml ATP

Low response≤225 ng/ml ATP

Immunological target (hypothesized)

Proposed immunological targetApproximately 280 ng/ml ATP (intersection of odds ratio curves in meta-analysis)

ContextTarget derived from meta-analysis of solid organ transplant recipients as a proposed zone to balance infection and rejection risks

Billing, Documentation, and Clinical Action

Denial Risk

Denial Condition

Requests for immune cell function assays (e.g., ImmuKnow™, Pleximmune™, Pleximark™) will be denied because these tests DO NOT MEET COVERAGE CRITERIA. Prior authorization will not render these assays payable.

Examples: ImmuKnow™, Pleximmune™, Pleximark™

Prior Authorization

Prior Authorization — Not Applicable

Prior authorization is not a pathway to coverage for immune cell function assays. Because these assays do not meet coverage criteria, submission of a prior authorization request will not result in payment.

Clinical and Test Background

Immune cell function assays measure peripheral blood lymphocyte responses following stimulation (for example, intracellular ATP levels or proliferation) to assess cell-mediated immune response. These tests have been evaluated primarily in transplant populations to predict infection or rejection and as part of advanced immunologic evaluation after abnormal screening, but available evidence has not established consistent clinical benefit to meet coverage criteria.

Key Terms and Proprietary Test Descriptions

Immune cell function assay — definition

DefinitionAssays that measure peripheral blood lymphocyte response (eg, intracellular ATP levels, proliferation) following stimulation to assess cell-mediated immune response.

PurposeAssess degree of functionality of cell-mediated immunity, often evaluated in transplant and primary immunodeficiency contexts.

Common measurementsIntracellular ATP, cell proliferation, cytokine production and other functional markers following mitogenic or antigenic stimulation.

ImmuKnow®

What it measuresCD4 T-cell ATP production after mitogenic stimulation (phytohemagglutinin-L) in vitro to estimate net immune state.

Intended useDetect cell-mediated immunity in immunosuppressed patients; used in monitoring immunosuppression in transplant recipients.

Policy Summary

PayerMedical Mutual - Ohio

PolicyImmune Cell Function Assay

Policy CodePolicy AHS - G2098

Change TypeEditorial and literature update (no material coverage changes)

Effective DateJun 1, 2026

Next Review DateN/A

Key ActionDo not request prior authorization for immune cell function assays to obtain payment, as these tests do not meet coverage criteria and will be denied.

SourceLink

On This Page

Clinical implication

Used as a hypothesized 'immune function' target for managing immunosuppression in studies, not an established treatment threshold

Billing Rule

Coding and Test Identification

When submitting claims, include the appropriate procedure code and, when applicable, the proprietary test name or laboratory/manufacturer to facilitate claim review.

Include CPT/HCPCS code (see code group)
When available, list proprietary test name (e.g., Pleximmune™, Pleximark™, ImmuKnow™) and performing lab/manufacturer

Note

Government Policy Precedence

If there is a conflict between this policy and an applicable government policy (e.g., Medicare LCDs/NCDs or state Medicaid coverage), the government policy prevails and will be used to make the determination. Providers should verify the most up-to-date Medicare and state Medicaid policies.

Medicare policies: https://www.cms.gov/medicare-coverage-database/search.aspx
Check applicable state Medicaid websites for state-specific coverage

Documentation Required

Documentation Recommendation

Providers should document the clinical indication, relevant diagnostic workup, and how test results would be expected to alter patient management. Maintain documentation of prior screening test results and rationale for any advanced testing.

Document clinical indication and expected benefit
Include prior screening test results (e.g., immunoglobulin levels, flow cytometry counts)
Describe how the assay result would change treatment or management

Step Therapy

Stepwise Diagnostic Evaluation

Follow a stepwise diagnostic evaluation for suspected primary immunodeficiency or transplant assessment: start with guideline-recommended screening tests (e.g., flow cytometry to enumerate CD4/CD8 T-cells and NK cells, serum immunoglobulin measurement); abnormal screening results may justify more sophisticated testing. Immune cell function assays are considered advanced/specialized tests and are not covered per this policy.

Initial/screening tests: flow cytometry (CD4/CD8, NK), serum immunoglobulins, basic lymphocyte subset testing
Advanced testing: lymphocyte proliferation/mitogen response or other specialized assays only after abnormal screening results
Policy position: immune cell function assays (examples listed) are not covered

Regulatory noteImmuKnow® (Viracor/Cylex) received FDA 510(k) clearance and has subsequent device modification clearance (no change in intended use).

Pleximmune™

What it measuresRecipient T-cell inflammatory response to donor cells in co-culture; reports an immunoreactivity index (IR) based on CD154+ T-cytotoxic memory cells.

Performance (study)In pediatric liver/intestine transplant testing, IR thresholds (eg, ≥1.1 posttransplant) predicted rejection with reported sensitivity ~84% and specificity ~80% in training/validation cohorts.

ProprietaryMarketed as Pleximmune™ by Plexision, Inc.; received FDA approval via Humanitarian Device Exemption for pediatric liver and small bowel transplant use (pre- and post-transplant).

iQue® Immune Cell Function Assay

PlatformFlow-cytometry–based platform that identifies immune cells by surface markers or secreted mediators and quantifies cytokines, adhesion molecules, enzymes, growth factor receptors, viability, proliferation, and secreted effector cytokines in a single well.

UsesCharacterizes T-cell subsets including memory and cytotoxic T-cells and natural killer cells; measures multiple functional and phenotypic parameters simultaneously.

OutputMultiparametric readouts enabling detailed immune profiling rather than a single ATP-based value.

ImmuKnow — FDA-cleared assay

Regulatory statusFDA-cleared immune cell function assay (Viracor/Cylex) for detection of cell-mediated immunity in an immunosuppressed patient population (original clearance April 2002; subsequent 510(k) modification in 2010).

Intended populationImmunosuppressed patients, including solid organ transplant recipients, for detection of cell-mediated immunity.

Device basis510(k) clearance based on substantial equivalence to two flow cytometry reagents; clearance relates to marketing the Cylex Immune Cell Function Assay.

Pleximmune / Pleximark — proprietary assays

Intended assessmentsProprietary assays (Pleximmune™, Pleximark™) intended to assess rejection risk using CD154+ T-cytotoxic memory cell responses and report algorithmic rejection risk scores for pediatric liver/small bowel (Pleximmune) and renal allograft (Pleximark).

Regulatory notesPleximmune received FDA approval via Humanitarian Device Exemption for pediatric liver and small bowel transplant use; Pleximark is identified with an associated CPT (0018M) and proprietary algorithm reported as a rejection risk score.

Proprietary detailsTests are marketed by Plexision, Inc.; procedure codes listed include 81560 (Pleximmune) and 0018M (Pleximark) to identify these assays in claims.