Immune Cell Function Assay

POLICY NUMBER

A.2.04.56

DESCRIPTION

Careful monitoring of lifelong immunosuppression is required to ensure long-term viability of solid organ allografts without incurring an increased risk of infection. The monitoring of immunosuppression parameters attempts to balance the dual risks of rejection and infection. It is proposed that individual immune profiles, such as an immune cell function assay, will help assess the immune function of the transplant recipient and individualize immunosuppressive therapy.

Immunosuppression for Transplant

In current clinical practice, levels of immunosuppression in patients being managed after a solid organ transplant or hematopoietic cell transplantation are determined by testing for clinical toxicity (e.g., leukopenia, renal failure) and by therapeutic drug monitoring when available. However, drug levels are not a surrogate for overall drug distribution or efficacy because pharmacokinetics often differ among individuals due to clinical factors such as underlying diagnosis, age, sex, and race; circulating drug levels may not reflect the drug concentration in relevant tissues; and serum level of an individual immunosuppressant drug may not reflect the cumulative effect of other concomitant immunosuppressants. The main value of therapeutic drug monitoring is the avoidance of toxicity. Individual immune profiles, such as an immune cell function assay, could support clinical decision making and help to manage the risk of infection from excessive immunosuppression and the risk of rejection from inadequate immunosuppression.

Treatment

Several commercially available tests of immune cell function have been developed to support clinical decision making.

ImmuKnow measures the concentration of adenosine triphosphate (ATP) in whole blood after a 15- to 18- hour incubation with phytohemagglutinin (a mitogenic stimulant). Cells that respond to stimulation show increased ATP synthesis during incubation. Concurrently, whole blood is incubated in the absence of stimulants for the purpose of assessing basal ATP activity. CD4-positive T-lymphocytes are immunoselected from both samples using anti-CD4 monoclonal antibody-coated magnetic particles. After washing the selected CD4-positive cells on a magnet tray, a lysis reagent is added to release intracellular ATP. A luminescence reagent added to the released ATP produces light measured by a luminometer, which is proportional to the concentration of ATP. The characterization of the cellular immune response of a specimen is made by comparing the ATP concentration for that specimen with fixed ATP production ranges.

Pleximmune measures CD154 expression on T-cytotoxic memory cells in patient’s peripheral blood lymphocytes. CD154 is a marker of inflammatory response. To characterize the risk of rejection, the patient’s inflammatory response to transplant donor cells is expressed as a fraction of the patient’s inflammatory response to third-party cells. This fraction or ratio is called the Immunoreactivity Index (IR). If the donor-induced response exceeds the response to third-party cells, the individual is at increased risk for rejection. Cells are cultured and then analyzed with fluorochrome-stained antibodies to identify the cells expressing CD154. For post-transplant blood samples, an IR greater than 1.1 indicates an increased risk of rejection, and an IR less than 1.1 indicates a decreased risk of rejection. For pretransplant samples, the threshold for IR is 1.23.

In April 2002, ImmuKnow® (Cylex, acquired by ViraCor-IBT Laboratories), an immune cell function assay, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. The FDA-indicated use of ImmuKnow® is for the detection of cell-mediated immune response in populations undergoing immunosuppressive therapy for organ transplant.

In April 2002, Immune Cell Function Assay (Cylex) was cleared for marketing by the FDA through the 510(k) process. The FDA-indicated use of the Immune Cell Function Assay is for the detection of a cell-mediated immune response in an immunosuppressed population. In 2010, a device modification for this assay was cleared for marketing by the FDA through the 510(k) process. There were no changes to the indications or intended use.

In August 2014, Pleximmune™ (Plexision) was approved by the FDA through the humanitarian device exemption process. The test is intended for use in the pretransplantation and early and late post-transplantation period in pediatric liver and small bowel transplant patients for the purpose of predicting the risk of transplant rejection within 60 days after transplantation or 60 days after sampling.

POLICY

Use of immune cell function assay testing to monitor and predict immune function after solid organ transplantation is considered investigational. 

Use of immune cell function assay testing to monitor and predict immune function after hematopoietic cell transplantation is considered investigational.

Use of immune cell function assay testing for all other indications is considered investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

8/21/2009: Policy added.

11/19/2009: Approved by MPAC.

3/11/2010: Code section updated. New CPT code 86352 added to non-covered table. 

11/17/2010: Policy reviewed; no changes.

02/24/2012: Added the following policy statement: Use of the immune cell function assay for all other indications, including but not limited to hematopoietic stem cell transplantation, is considered investigational.

03/13/2013: Policy reviewed; no changes.

03/05/2014: Policy reviewed; no changes.

01/09/2015: Policy title changed from "Immune Cell Function Assay in Solid Organ Transplantation" to "Immune Cell Function Assay." Policy description updated. Policy statement revised to state that the use of the immune cell function assay to monitor and predict immune function after hematopoietic stem cell transplantation is considered investigational. It previously stated: Use of the immune cell function assay for all other indications, including but not limited to hematopoietic stem cell transplantation, is considered investigational. Added the following investigational statement: Use of the immune cell function assay for all other indications is consideredinvestigational.

07/30/2015: Code Reference section updated for ICD-10.

01/20/2016: Policy description updated regarding tests. Policy statements unchanged. Investigative definition updated in policy guidelines section.

06/06/2016: Policy number A.2.04.56 added.

01/18/2017: Policy description updated. Policy statements unchanged.

01/17/2018: Policy description updated. Policy statements unchanged.

01/15/2019: Policy reviewed; no changes.

01/16/2020: Policy reviewed; no changes.

02/02/2021: Policy description updated. Policy statements unchanged.

09/29/2021: Code Reference section updated to add new CPT code 0018M as investigational. Effective 10/01/2021.

12/15/2021: Code Reference section updated to add new CPT code 81560, effective 01/01/2022.

04/06/2022: Policy statements updated for clarity; intent unchanged.

01/26/2023: Policy reviewed; no changes.

01/11/2024: Policy reviewed; no changes.

02/10/2025: Policy reviewed; no changes.

SOURCE(S)

Blue Cross & Blue Shield Association policy # 2.04.56

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

Investigational Codes

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