Currentblue cross blue shield - tennesseePolicy N/A

Immune_Cell_Function_Assay_G2098_Reimbursement_Policy

Defines coverage limitations for immune cell function assays measuring peripheral blood lymphocyte responses (ATP, proliferation, cytokines) for assessment of cell-mediated immunity; summarizes indications, scientific background, guideline positions, and FDA/CLIA status. Applies to commercial plan benefits with Medicare/Medicaid exceptions noted.

Policy Summary

Payerblue cross blue shield - tennessee

PolicyImmune_Cell_Function_Assay_G2098_Reimbursement_Policy

Policy CodePolicy N/A

Change TypeNo material change

Effective Date

Next Review Date

Key ActionObtain pre-service benefit verification and follow applicable payer prior authorization processes; check Medicare/Medicaid LCD/NCDs when applicable.

SourceLink

POLICY UPDATE CHANGES

No material clinical or coverage changes identified in this update; policy continues to state that immune cell function assays do not meet coverage criteria for listed indications.

9Not-covered indications listed

3Named assays discussed

multipleEvidence references

Coverage Summary

This policy defines coverage limitations for immune cell function assays that measure peripheral blood lymphocyte responses (for example, intracellular ATP, proliferation, or cytokine release) to assess cell-mediated immunity. The policy stance is not covered (cosmetic): an immune cell function assay DOES NOT MEET COVERAGE CRITERIA for the listed indications. Named assays discussed include ImmuKnow, PlexImmune, and other laboratory-developed or iQue-style assays. As noted in the policy introduction, an immune cell function assay does not meet coverage criteria for all indications including, but not limited to, management of solid organ transplant rejection, pre-transplant rejection risk identification, hematopoietic stem cell transplantation management, immunodeficiency disorders (e.g., HIV, SCID), prediction or management of infection risk in immune-mediated disorders, diagnosis/management of Lyme disease, inflammatory bowel disease management, testing for urticaria, and monitoring immune response after surgery.

Not Medically Necessary / Exclusions

Not covered indications

An immune cell function assay DOES NOT MEET COVERAGE CRITERIA for all indications including, but not limited to:

Management of solid organ transplant rejection in an individual undergoing immunosuppressive therapy.
Identification of risk for rejection prior to any solid organ transplantation.
Management of autologous or allogeneic hematopoietic stem cell transplantation.
Management of immunodeficiency disorders including human immunodeficiency virus (HIV) and severe combined immunodeficiency disease (SCID).
Management of or prediction of infection risk in immune mediated disorders including rheumatoid arthritis (RA), multiple sclerosis, and lupus nephritis.
Testing for urticaria.
Diagnosis and management of Lyme disease (for example, iSpot Lyme Test).
Management of inflammatory bowel diseases.
Monitoring of immune response following surgery.

The policy includes assay-specific numeric thresholds in a thresholds section; listing these numeric thresholds does not imply coverage or endorsement of the tests. The document provides population-based ImmuKnow categorizations and study-derived cutoffs, and reports trial-based tacrolimus adjustment thresholds and PlexImmune immunoreactivity index (IR) thresholds for context, but inclusion in the thresholds list should not be interpreted as a coverage determination.

Provider Actions / Billing & Prior Authorization

Prior Authorization

Prior authorization implication

Policy implies coverage determination depends on the member's benefit coverage; providers must obtain pre-service benefit verification and follow payer prior authorization processes as required.

Obtain pre-service benefit verification
Follow applicable payer prior authorization processes

Documentation Required

Benefit determination

Application of coverage criteria depends on the individual's benefit coverage at time of request. Verify member benefits and check applicable Medicare/Medicaid LCDs/NCDs and other government policies when making coverage determinations.

Check member benefits at time of request
Check applicable Medicare/Medicaid Local Coverage Determinations (LCDs) and National Coverage Determinations (NCDs)

Billing Rule

Laboratory-developed tests (LDTs) regulatory status

Many immune cell function tests are laboratory-developed tests (LDTs) regulated under CLIA as high-complexity tests and are not FDA-approved/cleared. Verify that the performing laboratory has validated the test and confirm CLIA status and any applicable state or federal requirements when billing.

Verify laboratory validation of the specific LDT
Confirm CLIA high-complexity status of the performing lab
Recognize that many LDTs are not FDA approved or cleared

Background & Evidence Summary

Immune cell function assays measure T-cell responses after stimulation (for example, intracellular ATP production, proliferation, or cytokine/marker expression) to estimate cell-mediated immune competence. Examples include the ImmuKnow assay, which quantifies CD4+ T-cell ATP after mitogenic stimulation; the PlexImmune assay, which assesses recipient T-cell response to donor cells (reported as an immunoreactivity index); and various laboratory-developed tests (LDTs) and multiplex platforms such as the iQue that quantify cytokines and cell phenotypes. Clinical utility remains uncertain: studies and meta-analyses report mixed sensitivity and specificity and there is no broad consensus on the tests' predictive value for infection or rejection. Regulatory notes: ImmuKnow received FDA 510(k) clearance for detecting cell-mediated immunity in immunosuppressed patients, PlexImmune was cleared under a Humanitarian Device Exemption (HDE) for pediatric liver/small-bowel transplant use, and many LDTs are performed under CLIA regulation rather than FDA approval.

Study / Evidence	Key findings
ImmuKnow pooled specificity/sensitivity (meta-analyses)	Meta-analyses report relatively high specificity (~0.75–0.90) but low to moderate sensitivity (~0.43–0.51) with significant heterogeneity across studies; pooled estimates for predicting infection: sensitivity ~0.51, specificity ~0.75; for acute rejection one analysis reported sensitivity 0.51 and specificity 0.90 in a subset (diagnostic odds ratios and likelihood ratios varied).
PlexImmune performance (Ashokkumar 2017)	In a pediatric training/validation set (214 children, 280 samples) PlexImmune (CD154+ T-cytotoxic memory cell assay) predicted rejection with reported sensitivity 84% and specificity 80–81% (posttransplant IR ≥1.1; pretransplant IR ≥1.23); high NPV reported in study context.
Ravaioli randomized trial	Randomized controlled trial (100 patients with ImmuKnow-guided serial testing vs 102 controls) used thresholds to adjust tacrolimus (reduce 25% if ATP <130 ng/mL; increase 25% if >450 ng/mL) and reported improved survival and infection rates in the immune-function–guided arm.

Definitions

ATPAdenosine triphosphate; measured intracellularly as marker of T-cell activation

ImmuKnowCylex/Viracor immune cell function assay measuring CD4 T-cell ATP after PHA stimulation; FDA 510(k) cleared

PlexImmunePlexision assay assessing recipient T-cell response to donor cells; HDE/Humanitarian Device Exemption for pediatric liver/small bowel transplant

Assay Thresholds & Operational Cutoffs

The policy lists assay-specific numeric thresholds for reference but reiterates that listing thresholds does not imply coverage.

ImmuKnow categorization (population-based): Strong ≥525 ng/mL; Moderate 226-524 ng/mL; Low ≤225 ng/mL.

Kowalski hypothesized immunological target: intersection at 280 ng/mL ATP.

Ravaioli immunosuppression adjustment thresholds used in a trial: reduce tacrolimus 25% if ImmuKnow <130 ng/mL; increase 25% if >450 ng/mL.

Pediatric Cylex (ImmuKnow) infection diagnosis cutoff reported by Xue: 152 ng/mL.

PlexImmune immunoreactivity (IR) thresholds: IR ≥1 implies increased rejection risk; training-set thresholds reported as posttransplant IR ≥1.1; pretransplant IR ≥1.23.