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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.
Currently, immunosuppression is determined by testing for clinical toxicity (e.g., leukopenia, renal failure) and by therapeutic drug monitoring (TDM) 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, gender 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 TDM is the avoidance of toxic levels and monitoring patient compliance. Further, the appropriate level of immunosuppression may vary from person to person. Individual immune profiles, such as an immune cell function assay, could support clinical decision-making and help to manage the risk of infection from excess immunosuppression and the risk of rejection from inadequate immunosuppression in immunosuppressed patients.
ImmuKnow® measures the concentration of adenosine triphosphate (ATP) in whole blood following 15-18 hour incubation with the mitogenic stimulant, phytohemagglutinin (PHA). In cells that respond to stimulation, increased ATP synthesis occurs during incubation. Concurrently, whole blood is incubated in the absence of stimulant for the purpose of assessing basal ATP activity. CD4+ T-lymphocytes are immunoselected from both samples using anti-CD4 monoclonal antibody-coated magnetic particles. After washing the selected CD4+ 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 to 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 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 increased risk of rejection, and an IR less than 1.1 indicates decreased risk of rejection. For pretransplant samples, the threshold for IR is 1.23.
In April 2002, ImmuKnow® (Cylex, recently acquired by ViraCor-IBT Laboratories, Lee's Summit, MO), an immune cell function assay, was cleared for marketing by the FDA through the 510(k) process for detecting cell-mediated immunity (CMI) in an immunosuppressed patient population.
In April 2002, Immune Cell Function Assay (Cylex) was cleared for marketing by FDA through the 510(k) process. FDA determined that this device was substantially equivalent to two flow cytometry reagents (“predicate devices”) manufactured by Becton Dickinson, the TriTest CD4 FITC/CD8 PE/CD3 PerCP Reagent and the MultiTest™ CD3 FITC/CD8 PE/CD45 PerCP/CD4 APC Reagent. These reagents are used to determine CD4+ T-lymphocyte counts in immunocompromised patients. The FDA-indicated use of the Immune Cell Function Assay is for the detection of cell-mediated immunity in an immunosuppressed population. A subsequent 510(k) marketing clearance for a device modification was issued by FDA for this assay in 2010. There were no changes to the indications or intended use.
In August 2014, Pleximmune™ (Plexision) was approved by 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.
POLICYUse of the immune cell function assay to monitor and predict immune function after solid organ transplantation is considered investigational.
Use of the immune cell function assay to monitor and predict immune function after hematopoietic stem cell transplantation is considered investigational.
Use of the immune cell function assay for all other indications is considered investigational.
POLICY EXCEPTIONSFederal 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 GUIDELINESInvestigative 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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY8/21/2009: 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 considered investigational.
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.
SOURCE(S)Blue Cross & Blue Shield Association policy # 2.04.56
CODE REFERENCEThis may not be a comprehensive list of procedure codes applicable to this policy.