CurrentHealthfirstPolicy PO-RE-036v4

Immune Cell Function Assay

Defines Healthfirst's coverage stance for immune cell function assays (e.g., ImmuKnow®, Pleximmune™, iQue®) including indications, limitations, scientific background, guidelines, and applicable codes; affects providers requesting coverage for these assays for Healthfirst members.

Policy Summary

PayerHealthfirst

PolicyImmune Cell Function Assay

Policy CodePolicy PO-RE-036v4

Change TypeNo material change

Effective DateMay 1, 2025

Next Review Date

Key ActionDo not submit prior authorization requests for immune cell function assays because they do not meet coverage criteria.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes in this revision.

1Assay excluded

3Proprietary tests named

3Procedure codes listed

Class IIIISHLT stance

1Applicable state

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.

inv-01: Not Medically Necessary (General)

Not covered when the following condition is present:

General Exclusion: For all situations, an immune cell function assay (e.g., Pleximmune™, Pleximark™, ImmuKnow®) DOES NOT MEET COVERAGE CRITERIA.

Policy-level exclusion based on lack of sufficient published scientific literature confirming clinical benefit.

For all situations, immune cell function assays (for example, Pleximmune™ and Pleximark™) do not meet coverage criteria because available published scientific literature does not confirm that these tests are required or beneficial for diagnosis and treatment.

The European Society for Immunodeficiencies (ESID) 2024 guidance recommends a stepwise diagnostic approach for congenital athymia starting with newborn TREC screening and flow-cytometric enumeration of T-cell numbers and naive subsets. ESID states that qualitative T‑lymphocyte function tests are of limited value and are not routinely necessary, and that such assays can be unreliable in lymphopenic patients, indicating limited support for their use in diagnosing congenital athymia.

Immune cell function assays are considered not medically necessary for all indications covered by this policy due to a lack of sufficient published evidence demonstrating clinical utility for diagnosis or management of an individual's illness.

Qualitative T-lymphocyte function tests are not routinely necessary for evaluation of congenital athymia and are described by ESID as unreliable in lymphopenic patients; therefore such qualitative assays are not appropriate as a primary diagnostic tool in this setting.

inv-02: Clinical utility and regulatory context

Contextual statements describing regulatory status and guideline limitations relevant to coverage considerations:

Regulatory status: ImmuKnow® is FDA-cleared (510[k], initial clearance April 2002; subsequent device modification clearance 2010) for detection of cell-mediated immunity in immunosuppressed patients; Pleximmune™ was approved by the FDA via the Humanitarian Device Exemption (HDE) in August 2014 for prediction of transplant rejection risk in pediatric liver and small bowel transplant patients within 60 days of transplantation or sampling.

These approvals are indication-specific and do not imply broad coverage for other uses.

Guideline limitations: The European Society for Immunodeficiencies (ESID) states that qualitative T-lymphocyte function tests are of limited value, are not routinely necessary, and can be unreliable in lymphopenic patients; ESID recommends a stepwise diagnostic approach for congenital athymia using TREC screening followed by flow-cytometric T-cell enumeration and naive subset analysis, noting immune function assays provide limited diagnostic value in this context.

Guideline-based limitation indicating assays are not recommended for routine diagnostic use for athymia.

Procedure and Code Information

Proprietary assays described (not CPT/HCPCS codes listed in this section)mixed

ImmuKnow®	Immune Cell Function Assay — proprietary assay (ATP-based)
Pleximmune™	Donor-specific immune cell assay (HDE for pediatric liver & small bowel transplant)
iQue®	Multiplex flow-based immune cell function assay/platform

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 ATP categories — Strong/Moderate/Low thresholds

Strong (ImmuKnow ATP)≥525 ng/mL

Moderate (ImmuKnow ATP)226–524 ng/mL

Low (ImmuKnow ATP)≤225 ng/mL

Example clinical decision thresholds — reported tacrolimus adjustment and study-derived cut-off examples

Tacrolimus adjustment (Ravaioli et al. 2015)Reduce tacrolimus dose 25% when ImmuKnow <130 ng/mL; increase tacrolimus dose 25% when ImmuKnow >450 ng/mL.

Study-derived infection cut-off (infants)Diagnostic cut-off reported at 152 ng/mL for infection in an infant study (study-derived example).

ImmuKnow clinical risk observationsAuthors reported immunological target intersection at ~280 ng/mL as a target immunological response zone for minimizing risk.

Pleximmune predictive window — predicts risk of transplant rejection within 60 days

Predictive windowPleximmune predicts risk of transplant rejection within 60 days after transplantation or within 60 days after sampling.

Immunoreactivity index (IR) thresholdAn IR ≥1 (examples: posttransplant IR ≥1.1; pretransplant IR ≥1.23) was associated with increased rejection risk in pediatric studies.

Reported performance (pediatric)Training/validation testing in children reported sensitivity ~84% and specificity ~81% for predicting acute cellular rejection.

Provider Requirements and Billing Guidance

Prior Authorization

Prior Authorization Not Supported

Requests for immune cell function assays (e.g., Pleximmune™, Pleximark™, ImmuKnow®) do not meet coverage criteria and are not supported for coverage. Prior authorization will not change this coverage determination; submitting a PA for these assays will not meet coverage criteria and is subject to denial.

Examples: Pleximmune™, Pleximark™, ImmuKnow®

Prior Authorization

Prior authorization / Submission Guidance

Claims for the procedure codes listed in this policy must be submitted with complete clinical documentation demonstrating the assay performed, the clinical rationale, and any relevant prior diagnostic testing. Submitters should include operative notes, transplant history (if applicable), prior screening test results (e.g., flow cytometry, immunoglobulin levels, mitogen responses), and laboratory reports that describe the assay methodology.

Affected codes: 81560, 86352, 0018M
Include: assay type, clinical indication, prior screening test results, relevant clinical notes

Denial Risk

Denial Risk for Improper Coding/Billing

Failure to follow national and state coding, billing, and reimbursement rules may result in denial or recoupment of payment. Healthfirst claim edits align with CMS and industry standards (NCCI, NCD/LCD, CPT/HCPCS/ICD-10 guidance, New York State rules). Use appropriate modifiers and adhere to global surgery/multiple procedure and duplicate service rules.

Healthfirst edits follow NCCI, NCD/LCD, AMA CPT, CMS guidance, and NY State coding rules
Noncompliance may result in denial and/or recoupment

Documentation Required

Documentation Expectations

Providers must document the specific assay performed, the laboratory/vendor, and the clinical rationale for testing in the medical record. Even when an assay request is submitted, documentation should include prior screening test results (flow cytometry, immunoglobulin levels, lymphocyte proliferation/mitogen responses), member transplant history, and how the test result would change management. Retain and make available supporting lab reports and result interpretation.

Document: assay name, lab/manufacturer, clinical indication, prior screening tests and results
Include: how results will affect patient management

Step Therapy

Diagnostic Stepwise Approach

Follow a stepwise diagnostic approach when evaluating suspected primary immunodeficiency or transplant rejection risk. Use inexpensive, rapid screening tests first — e.g., flow cytometry to enumerate CD4/CD8 T-cells and NK cells, serum immunoglobulin measurement, and lymphocyte mitogen/proliferation assays. Abnormal screening results should prompt more sophisticated testing rather than direct use of proprietary immune cell function assays.

Screening tests: flow cytometry (T‑cell subsets, naive cell proportion), serum immunoglobulins, lymphocyte proliferation/mitogen response
Advanced testing reserved for when screening is abnormal; proprietary immune cell function assays are not a first-line diagnostic step

Key Terms and Test Definitions

Immune cell function assay — definition

DefinitionAn assay that measures peripheral blood lymphocyte (primarily T-cell) responses to stimulation (e.g., intracellular ATP, proliferation) to assess cell-mediated immune function.

Common usesEvaluated primarily in transplant settings to predict infection or rejection and in assessment of immunocompetence in immunosuppressed patients.

ExamplesIncludes proprietary assays such as ImmuKnow®, Pleximmune™, and multiplex flow-based platforms (iQue®).

ImmuKnow® — ATP-based CD4 T-cell response measurement

Assay descriptionImmuKnow® measures CD4 T-cell response to mitogenic stimulation (phytohemagglutinin-L) by quantifying intracellular/released adenosine triphosphate (ATP) produced after stimulation.

Clinical intentIntended to estimate net immune system status in immunocompromised patients and as a strategy for functional immune monitoring in solid organ transplant recipients.

Performance contextHas been evaluated for association with infection and rejection; studies show variable sensitivity and specificity across populations.

Pleximmune™ — donor-induced recipient T-cell inflammatory response and IR metric

Assay descriptionPleximmune™ measures recipient T-cell inflammatory response to donor cells in co-culture and reports an immunoreactivity index (IR) as a measure of rejection risk.

IR interpretationAn IR ≥1 (examples in studies: posttransplant IR ≥1.1; pretransplant IR ≥1.23) indicates increased rejection risk in pediatric liver and intestine transplant contexts.

Proprietary reportingReported as a rejection risk score based on donor-induced CD154+ T-cytotoxic memory cell responses in whole peripheral blood.

ImmuKnow — FDA-cleared assay (cleared April 2002) description

Regulatory statusImmuKnow® (Cylex/Viracor) received FDA 510(k) clearance in April 2002 for detection of cell-mediated immunity in immunosuppressed patients; a subsequent 510(k) modification clearance was issued in 2010 without changes to indications.

Intended use per FDAIndicated for detection of cell-mediated immunity (CMI) in an immunosuppressed population.

LDT contextMany laboratory-developed tests exist and are regulated under CLIA as high-complexity tests; LDTs are not FDA-cleared/approved but are used clinically.

Pleximmune / Pleximark — proprietary assays and regulatory context

Assay targetsMeasures donor-induced CD154+ T-cytotoxic memory cells and reports an algorithmic rejection risk score (proprietary methodology).

Regulatory context (Pleximmune)Pleximmune™ was approved by FDA via the Humanitarian Device Exemption (HDE) in August 2014 for use in pediatric liver and small bowel transplantation to predict rejection risk within 60 days.

Related proprietary testPleximark (associated CPT 0018M) is a proprietary assay for renal transplantation described as measuring donor-induced CD154+ T-cytotoxic memory cells and reported as a rejection risk score.

Clinical and Scientific Background

Immune cell function assays measure peripheral blood lymphocyte (primarily T‑cell) responses to stimulation. Depending on the platform, assays quantify responses such as intracellular or released ATP, cell proliferation, cytokine production, or donor‑specific T‑cell activation (for example, donor‑induced CD154+ T‑cytotoxic memory cell responses reported as an immunoreactivity or rejection risk score).

Proprietary examples include ATP‑based tests (e.g., ImmuKnow®), donor‑specific CD154+ T‑cell assays (e.g., Pleximmune™ and Pleximark™), and multiplex flow‑based platforms (e.g., iQue®). These assays have been evaluated primarily in transplant settings to predict infection or rejection, with variable sensitivity and specificity reported across studies.

Because methods and reported outcomes vary by assay and application, the tests are considered investigational for general diagnostic use and are not supported as routine clinical tests by this policy.

OpenPayer

Immune Cell Function Assay

Coverage Determinations

Procedure and Code Information

Provider Requirements and Billing Guidance

Key Terms and Test Definitions

Clinical and Scientific Background