mp-381 - mp-381 - Medical Policies
Immune Cell Function Assay
Policy Number: MP-381
Latest Review Date: December 2020
Policy Grade: C
Use of the immune cell function assay testing to monitor and predict immune function after solid organ transplantation is considered not medically necessary and investigational.
Use of the immune cell function assay testing to monitor and predict immune function after hematopoietic stem cell transplantation is considered not medically necessary and investigational.
Use of the immune cell function assay testing for all other indications is considered not medically necessary and investigational.
DESCRIPTION OF PROCEDURE OR SERVICE:
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 the immunosuppressive therapy.
Immunosuppression for Transplant
In current clinical practice, levels of immunosuppression in patients being managed after solid organ transplant or hematopoietic cell transplantation (HCT) is determined by evaluating 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 levels 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. 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.
Several commercially available tests of immune cell function have been developed to support clinical decision-making.
ImmuKnow® (Cylex) is an immune cell function assay cleared for marketing by the FDA in April 2002 to detect cell-mediated immunity (CMI) in an immunosuppressed patient population. The assay 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 level 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 posttransplant 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.
This policy been updated regularly with searches of the MEDLINE database. The most recent literature search was performed through October 27, 2020.
Summary of Evidence
For individuals who have a solid organ transplant or hematopoietic cell transplant who receive testing using an immune cell function assay with ImmuKnow®, the evidence includes numerous studies on the association between assay test values and subsequent rejection or infection, and a randomized controlled trial in liver transplant patients. Relevant outcomes are overall survival, other test performance measures, and morbid events. The ImmuKnow® test has shown variable associations with infection and rejection, depending on the type of transplant and context of the study. Across all the studies among various types of patients, ImmuKnow® levels are associated with the risk of rejection when levels are high and risk of infection when levels are low. However, the absolute risk and increments of risk are uncertain because of heterogeneity of the studies. The predictive characteristics of the test are still uncertain and do not allow a strong chain of evidence for clinical utility. The trial of the ImmuKnow® test in liver transplant patients showed improvement in overall survival; however, the trial had several limitations. The evidence is insufficient to determine the effects of the technology on health outcomes.
For individuals who have a solid organ transplant or hematopoietic cell transplant who receive testing using an immune cell function assay testing with Pleximmune™, the evidence includes the U.S. Food and Drug Administration documentation and a report on the test’s development and validation. Relevant outcomes are overall survival, other measures of test performance, and morbid events. Small studies have shown that Pleximmune™ values correlate with long-term survival. Pleximmune™ test results correlated with rejection, but conclusions are uncertain because of extremely limited evidence deriving from a small number of patients described briefly in the Food and Drug Administration approval documents and a second study, in which the confidence interval bounds for sensitivity and specificity estimates were wide. No direct studies of clinical utility were identified. An argument for clinical utility using a chain of evidence would rely on both a demonstration of clinical validity and a rationale that specific clinical interventions based the results of the test decrease the risk of a poor health outcome. At present, the clinical interventions that would occur as a result of the test result are uncertain, and so the clinical validity is uncertain. The evidence is insufficient to determine the effects of the technology on health outcomes.
Practice Guidelines and Position Statements
The International Cytomegalovirus (CMV) Consensus Group of the Transplantation Society published an international consensus statement on the management of CMV in solid organ transplant in 2018. The authors state that “there are no clinical studies demonstrating that management decisions based on immunologic monitoring affect patient outcomes.” Routine immunologic monitoring is not recommended.
U.S. Preventive Services Task Force Recommendations
Cylex, ImmuKnow®, ImmuKnow® assay, Immune Cell Function Assay, Transplantation Immune Cell Function Assay, Pleximmune™
APPROVED BY GOVERNING BODIES:
In April 2002, ImmuKnow® (Cylex, acquired by ViraCor-IBT Laboratories, Lee’s Summit, MO), 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, the FDA cleared Immune Cell Function Assay (Cylex) for marketing through the 510(k) process. The FDA-indicated use of the Immune Cell Function Assay is for the detection of CMI in an immunosuppressed population. In 2010, a device modification for this assay was cleared for marketing by FDA through the 510(k). There were no changes to the indications or intended use.
In August 2014, Pleximmune™ (Plexision, Pittsburgh, PA) was approved by FDA through the humanitarian device exemption process. The test is intended for use in the pretransplantation, early, and late posttransplantation 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.
Coverage is subject to member’s specific benefits. Group specific policy will supersede this policy when applicable.
ITS: Home Policy provisions apply
FEP: Special benefit consideration may apply. Refer to member’s benefit plan. FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.
Cellular function assay involving stimulation (e.g., mitogen or antigen) and detection of biomarker (e.g., ATP)
Ashokkumar C, Soltys K, Mazariegos G, et al. Predicting cellular rejection with a cell-based assay: preclinical evaluation in children. Transplantation. Jan 2017; 101(1):131-140.
Ashokkumar C, Talukdar A, Sun Q, et al. Allospecific CD154+ T cells associate with rejection risk after pediatric liver transplantation. Am J Transplant. Jan 2009; 9(1):179-191.
Bhorade SM, Janata K, Vigneswaran WT et al. Cylex ImmuKnow assay levels are lower in lung transplant recipients with infection. J Heart Lung Transplant 2008; 27(9):990-994.
Cabrera R, Ararat M, Soldevila-Pico C et al. Using an immune functional assay to differentiate acute cellular rejection from recurrent hepatitis C in liver transplant patients. Liver Transpl 2009; 15(2):216-222.
Cheng JW, Shi YH, Fan J et al. An immune function assay predicts post-transplant recurrence in patients with hepatocellular carcinoma. J Cancer Res Clin Oncol 2011; 137(10):1445-1453.
Costanzo Mr, Dipchand A, Starling R, Et Al. The International Society Of Heart And Lung Transplantation Guidelines For The Care Of Heart Transplant Recipients. J Heart Lung Transplant. Aug 2010; 29(8):914-956.
Dong JY, Yin H, Li RD et al. The relationship between adenosine triphosphate within CD4(+) T lymphocytes and acute rejection after liver transplantation. Clin Transplant 2011; 25(3):E292-296.
Educational guidelines. American Society of Transplantation. www.a-s-t.org/content/educational-guidelines.
Food and Drug Administration (FDA). Pleximmune Summary of Safety and Probable Benefit. https://www.accessdata.fda.gov/cdrh_docs/pdf13/H130004b.pdf. Last Accessed November 21, 2018.
Food and Drug Administration (FDA). Special 510(k): Device Modification 2010. https://www.accessdata.fda.gov/cdrh_docs/reviews/K101911.pdf. Last Accessed November 21, 2018.
Gesundheit B, Budowski E, Israeli M et al. Assessment of CD4 T-lymphocyte reactivity by the Cylex ImmuKnow assay in patients following allogeneic hematopoietic SCT. Bone Marrow Transplant 2010; 45(3):527-533.
Guidelines for the Care of Heart Transplant Recipients, 2010. The International Society of Heart and Lung Transplantation: www.ishlt.org/publications/guidelines.asp.
Gupta S, Mitchell JD, Markham DW et al. Utility of the Cylex assay in cardiac transplant recipients. J Heart Lung Transplant 2008; 27(8):817-822.
Hashimoto K, Miller C, Hirose K et al. Measurement of CD4+ T-cell function in predicting allograft rejection and recurrent hepatitis C after liver transplantation. Clin Transplant 2010; 24(5):701-708.
Heikal NM, Bader FM, Martins TB et al. Immune function surveillance: association with rejection, infection and cardiac allograft vasculopathy. Transplant Proc 2013; 45(1):376-382.
Hooper E, Hawkins DM, Kowalski RJ et al. Establishing pediatric immune response zones using the Cylex ImmuKnow assay. Clin Transplant 2005; 19(6):834-839.
Humar A, Michaels M. American Society of Transplantation recommendations for screening, monitoring and reporting of infectious complications in immunosuppression trials in recipients of organ transplantation. Am J Transplant 2006; 6(2):262-274.
Husain S, Raza K, Pilewski JM et al. Experience with immune monitoring in lung transplant recipients: correlation of low immune function with infection. Transplantation 2009; 87(12):1852-1857.
Huskey J, Gralla J, Wiseman AC. Single time point immune function assay (ImmuKnow) testing does not aid in the prediction of future opportunistic infections or acute rejection. Clin J Am Soc Nephrol 2011; 6(2):423-429.
Israeli M, Ben-Gal T, Yaari V et al. Individualized immune monitoring of cardiac transplant recipients by noninvasive longitudinal cellular immunity tests. Transplantation 2010; 89(8):968-976.
Jwa E, Hwang S, Kwon Yj, Et Al. In Vitro Immune Cell Monitoring As A Guide For Long-Term Immunosuppression In Adult Liver Transplant Recipients. Korean J Hepatobiliary Pancreat Surg. Nov 2015; 19(4):139-148.
Kobashigawa JA, Kiyosaki KK, Patel JK et al. Benefit of immune monitoring in heart transplant patients using ATP production in activated lymphocytes. J Heart Lung Transplant 2010; 29(5):504-508.
Kotton CN, Kumar D, Caliendo AM et al. International consensus guidelines on the management of cytomegalovirus in solid organ transplantation. Transplantation 2010; 89(7):779-795.
Kotton CN, Kumar D, Caliendo AM, et al. The Third International Consensus Guidelines on the Management of Cytomegalovirus in Solid-organ Transplantation. Transplantation. Jun 2018; 102(6):900-931.
Kowalski RJ, Post DR, Mannon RB et al. Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay. Transplantation 2006; 82(5):663-668.
Kowalski R, Post D, Schneider MC et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant 2003; 17(2):77-88.
Libri I, Gnappi E, Zanelli P, et al. Trends in immune cell function assay and donor-specific HLA antibodies in kidney transplantation: A 3-year prospective study. Am J Transplant. Dec 2013; 13(12):3215-3222.
Ling X, Xiong J, Liang W et al. Can immune cell function assay identify patients at risk of infection or rejection? A meta-analysis. Transplantation 2012; 93(7):737-743.
Liu J, Pan Y, Tang LJ, et al. Low adenosine triphosphate activity in CD4+ cells predicts infection in patients with lupus nephritis. Clin Exp Rheumatol. May-Jun 2014; 32(3):383-389.
Liu W, Wang K, Zhao YH, et al. Clinical relevance of a CD4 + T cell immune function assay in the diagnosis of infection in pediatric living-donor liver transplantation. Exp Ther Med. Nov 2019; 18(5): 3823-3828.
Manga K, Serban G, Schwartz J et al. Increased adenosine triphosphate production by peripheral blood CD4+ cells in patients with hematologic malignancies treated with stem cell mobilization agents. Hum Immunol 2010; 71(7):652-658.
Myslik F, House AA, Yanko D, et al. Preoperative Cylex assay predicts rejection risk in patients with kidney transplant. Clin Transplant. May 2014; 28(5):606-610.
Natsuda K, Soyama A, Takatsuki M, et al. The efficacy of the ImmuKnow assay for evaluating the immune status in human immunodeficiency virus and hepatitis C virus-coinfected patients. Transplant Proc. Apr 2014; 46(3):733-735.
Nishikawa K, Mizuno S, Masui S et al. Usefulness of monitoring cell-mediated immunity for predicting post-kidney transplantation viral infection. Transplant Proc. Mar 2014; 46(2):552-555.
Piloni D, Magni S, Oggionni T, Et Al. Clinical Utility Of Cd4+ Function Assessment (Viracor-Ibt Immuknow Test) In Lung Recipients. Transpl Immunol. Jul 2016; 37:35-39.
Quaglia M, Cena T, Fenoglio R et al. Immune function assay (immunknow) drop over first 6 months after renal transplant: a predictor of opportunistic viral infections? Transplant Proc. Sep 2014; 46(7):2220-2223.
Ravaioli M, Neri F, Lazzarotto T et al. Immunosuppression Modifications Based on an Immune Response Assay: Results of a Randomized, Controlled Trial. Transplantation. Aug 2015; 99(8):1625-1632.
Reinsmoen NL, Cornett KM, Kloehn R et al. Pretransplant donor-specific and non-specific immune parameters associated with early acute rejection. Transplantation 2008; 85(3):462-470.
Rodrigo E, Lopez-Hoyos M, Corral M et al. ImmuKnow® as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: Systematic review and meta-analysis. Liver Transpl 2012; 18(10):1245-1253.
Rossano JW, Denfield SW, Kim JJ et al. Assessment of the Cylex ImmuKnow cell function assay in pediatric heart transplant patients. J Heart Lung Transplant 2009; 28(1):26-31.
Ryan CM, Chaudhuri A, Concepcion W, et al. Immune cell function assay does not identify biopsy-proven pediatric renal allograft rejection or infection. Pediatr Transplant. Aug 2014; 18(5):446-452.
Sageshima J, Ciancio G, Chen L, et al. Lack of clinical association and effect of peripheral WBC counts on immune cell function test in kidney transplant recipients with T-cell depleting induction and steroid-sparing maintenance therapy. Transpl Immunol. Mar 2014; 30(2-3):88-92.
Serban G, Whittaker V, Fan J et al. Significance of immune cell function monitoring in renal transplantation after Thymoglobulin induction therapy. Hum Immunol 2009; 70(11):882-890.
Serrano M, Meneu JC, Medina E et al. Clinical value of a single determination of intracellular ATP levels in stimulated CD4+ T lymphocytes in pediatric patients with stable liver transplantation. Transplant Proc 2012; 44(9):2622-2624.
Shearer G, Clerici M. In vitro analysis of cell-mediated immunity: clinical relevance. Clin Chem 1994; 40(11):2162-2165.
Shino MY, Weigt SS, Saggar R et al. Usefulness of immune monitoring in lung transplantation using adenosine triphosphate production in activated lymphocytes. J Heart Lung Transplant 2012; 31(9):996-1002.
Te HS, Dasgupta KA, Cao D et al. Use of immune function test in monitoring immunosuppression in liver transplant recipients. Clin Transplant 2012; 26(6):826-832.
Torio A, Fernandez EJ, Montes-Ares O et al. Lack of association of immune cell function test with rejection in kidney transplantation. Transplant Proc 2011; 43(6):2168-2170.
Wang XZ, Jin ZK, Tian XH, et al. Increased intracellular adenosine triphosphate level as an index to predict acute rejection in kidney transplant recipients. Transpl Immunol. Jan 2014; 30(1):18-23.
Weston MW, Rinde-Hoffman D, Lopez-Cepero M. Monitoring cell-mediated immunity during immunosuppression reduction in heart transplant recipients with severe systemic infections. Clin Transplant. Mar 2020; 34(3): e13809.
Wong MS, Boucek R, Kemna M, et al. Immune cell function assay in pediatric heart transplant recipients. Pediatr Transplant. Aug 2014; 18(5):485-490.
Wozniak LJ, Venick RS, Gordon Burroughs S, et al. Utility of an immune cell function assay to differentiate rejection from infectious enteritis in pediatric intestinal transplant recipients. Clin Transplant. Feb 2014; 28(2):229-235.
Zeevi A, Britz JA, Bentlejewski CA et al. Monitoring immune function during tacrolimus tapering in small bowel transplant recipients. Transpl Immunol 2005; 15(1):17-24.
Zhou H, Lin J, Chen S et al. Use of the ImmuKnow assay to evaluate the effect of alemtuzumab-depleting induction therapy on cell-mediated immune function after renal transplantation. Clin Exp Nephrol 2013; 17(2):304-309.
Zhou H, Wu Z, Ma L et al. Assessing immunologic function through CD4 T-lymphocyte ahenosine triphosphate levels by ImmuKnow assay in Chinese patients following renal transplantation. Transplant Proc 2011; 43(7):2574-2578.
Medical Policy Group, August 2009 (2)
Medical Policy Administration Committee, September 2009
Available for comment September 4-October 19, 2009
Medical Policy Group, August 2010 (1) Key Points updated, no policy statement coverage change
Medical Policy Group, September 2010 (3)
Medical Policy Panel, November, 2011
Medical Policy Group, February, 2012 (4): Policy updated with literature search; additional investigational indication added for HSCT and all other indications; title changed to “Immune Cell Function Assay.” Key Points and References updated to support policy changes.
Medical Policy Administration Committee, March 2012.
Available for comments March 15 – April 30, 2012
Medical Policy Panel, November 2012
Medical Policy Group, March 2013 (2): Policy updated with literature review through September 2012; no change in policy statement; Key Points and Reference updated.
Medical Policy Panel, November 2013
Medical Policy Group, November 2013 (3): Updates to Key Points and References; no change in policy statement
Medical Policy Panel, November 2014
Medical Policy Group, November 2014 (3): Updates to Key Points, Approved Governing Bodies, and References. No change in policy statement.
Medical Policy Panel, December 2015
Medical policy Group, January 2016 (3): Updates to Description, Key Points, Approved Governing Bodies, Key Words and References. No change to policy statement.
Medical Policy Panel, December 2016
Medical policy Group, December 2016 (7): 2016 Updates to Description, Key Points, Approved Governing Bodies, Key Words and References. No change to policy statement.
Medical Policy Panel, December 2017
Medical policy Group, December 2017 (7): 2017 Updates to Key Points and References. No change in Policy Statement.
Medical Policy Panel, December 2018
Medical Policy Group, January 2019 (3): Updates to Key Points, Practice Guidelines and Position Statements, and References. No change to policy statement or intent.
Medical Policy Panel, December 2019
Medical Policy Group, January 2020 (3): 2020 Updates to Key Points and References. No changes to policy statement or intent.
Medical Policy Panel, December 2020
Medical Policy Group, December 2020 (3): 2020 Updates to Key Points and References. No changes to policy statement or intent.
This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.
This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.
The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.
As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.
The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:
1. The technology must have final approval from the appropriate government regulatory bodies;
2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;
3. The technology must improve the net health outcome;
4. The technology must be as beneficial as any established alternatives;
5. The improvement must be attainable outside the investigational setting.
Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:
1. In accordance with generally accepted standards of medical practice; and
2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and
3. Not primarily for the convenience of the patient, physician or other health care provider; and
4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.