Notification



Notification Issue Date:



Medical Policy Bulletin


Title:Immune Cell Function Assay

Policy #:06.02.37a

This policy is applicable to the Company’s commercial products only. Policies that are applicable to the Company’s Medicare Advantage products are accessible via a separate Medicare Advantage policy database.


The Company makes decisions on coverage based on Policy Bulletins, benefit plan documents, and the member’s medical history and condition. Benefits may vary based on contract, and individual member benefits must be verified. The Company determines medical necessity only if the benefit exists and no contract exclusions are applicable.

When services can be administered in various settings, the Company reserves the right to reimburse only those services that are furnished in the most appropriate and cost-effective setting that is appropriate to the member’s medical needs and condition. This decision is based on the member’s current medical condition and any required monitoring or additional services that may coincide with the delivery of this service.

This Medical Policy Bulletin document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy Bulletin will be reviewed regularly and be updated as scientific and medical literature becomes available. For more information on how Medical Policy Bulletins are developed, go to the About This Site section of this Medical Policy Web site.



Policy

Coverage is subject to the terms, conditions, and limitations of the member's benefit contract.

Although the US Food and Drug Administration (FDA) has approved devices for immune cell assay, the Company has determined that the safety and/or effectiveness of this service cannot be established by review of the available published peer-reviewed literature. Therefore, an immune cell assay is considered experimental/investigational by the Company and, therefore, not covered for all indications, including but not limited to, either of the following:
  • For the detection and prediction of cell-mediated immune response in individuals undergoing immunosuppressive therapy for solid organ transplant
  • For the detection and prediction of cell-mediated immune response in individuals undergoing immunosuppressive therapy for hematopoietic stem cell transplantation

Guidelines

BENEFIT APPLICATION

Subject to the terms and conditions of the applicable benefit contract, immune cell function assay is not eligible for payment under the medical benefits of the Company’s products because the service is considered experimental/investigational and, therefore, not covered.

Services that are experimental/investigational are a benefit contract exclusion for all products of the Company. Therefore, they are not eligible for reimbursement consideration.

US FOOD AND DRUG ADMINISTRATION (FDA) STATUS

ImmuKnow® (Cylex, recently acquired by Viracor-IBT Laboratories Inc., Lee’s Summit, MO) is an immune cell function assay cleared for marketing by FDA in April 2002 to detect cell-mediated immunity (CMI) in an immunosuppressed patient population.

In April 2002, Cylex obtained 510(k) clearance from FDA to market the Immune Cell Function Assay based on substantial equivalence to 2 flow cytometry reagents (“predicate devices”) manufactured by Becton Dickinson, the TriTestTM CD4 FITC/CD8 PE/CD3 PerCP Reagent and the MultiTestTM CD3 FITC/CD8 PE/CD45 PerCP/CD4 APC Reagent. These reagents are used to determine CD4+ Tlymphocyte counts in immunocompromised patients. The FDA-indicated use of the Immune Cell Function Assay is for the detection of CMI 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.

Description

THE MONITORING OF IMMUNOSUPPRESSIVE THERAPY IN TRANSPLANT RECIPIENTS

Transplant recipients generally require prolonged treatment with immunosuppressive agents to prevent rejection of the allograft. Immunosuppressants deplete the entire immune system, so that the body has difficulty fighting off infections. In addition, over time, these potent drugs can damage the kidneys and raise the risk for diabetes, high blood pressure, cancer, and cardiovascular disease. Correct dosing of immunosuppressives is critical. Higher dosing than required may leave the individual susceptible to infections or lead to drug toxicity, while under-dosing can lead to graft rejection and graft loss due to the immune response to the transplanted tissue. Although levels of immunosuppressive drugs are routinely monitored, they do not always correlate with the degree of immunosuppression. Immunosuppressive drugs can have different effects in different individuals despite drug concentrations and dosages that are the same. Infection and organ rejection remain the major causes of death in the majority of transplant recipients.

Monitoring of immunosuppression attempts to balance the dual risks of infection and rejection. 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. Currently, immunosuppression is determined by well-established testing for clinical toxicity and by therapeutic drug monitoring (TDM). The value of TDM is the avoidance of toxic levels and the monitoring of an individual's compliance with the prescribed immunosuppressive therapy. Monitoring of graft function may include a biopsy with histopathology of the transplanted organ, imaging modalities and B-type natriuretic peptide, and/or genomic markers of rejection.

IMMUNE CELL FUNCTION ASSAY

Immune cell function assay (e.g., ImmuKnow®) measures the concentration of adenosine triphosphate (ATP) from circulating CD4+ T lymphocytes cells following in vitro stimulation with phytohemagglutinin (PHA) as an indicator of immune cell function. This measurement is made on heparin anti-coagulated whole blood using a luminometer and luciferin/luciferase. The assay is used for the detection of cell-mediated immune response in populations undergoing immunosuppressive therapy for organ transplant. The immune cell function assay detects cell-mediated immunity in an individual's whole blood sample after a 15-18 hour incubation with stimulant. During incubation, increased ATP synthesis occurs within the cells that respond to the stimulant phytohemagglutinin (PHA). Concurrently, whole blood is incubated in the absence of the stimulant for the purpose of assessing basal ATP activity. Anti-CD4+ monoclonal antibody coated magnetic particles are added to immunoselect CD4+ cells from both the stimulated and non-stimulated wells. After washing the selected CD4+ cells on a magnet tray, Lysis Reagent is added to release intracellular ATP. Addition of Luminescence Reagent (luciferin/luciferase) to the released ATP produces light. The amount of light is then measured by a luminometer, which is proportional to the concentration of ATP. The concentration of ATP is calculated from a calibration curve and compared to ATP level ranges to characterize the cellular immune function of the sample. Immune cell function assay values are suggested to reflect more closely the activity of immune cells in vivo.

In April 2002, Cylex obtained 510(k) clearance from the US Food and Drug Administration (FDA) to market the immune cell function assay (Cylex, Inc., Columbia, MD) based on substantial equivalence of two flow cytometry reagents (“predicate devices”) manufactured by Becton Dickinson, the TriTestTM CD4 FITC/CD8 PE/CD3 PerCP Reagent and the MultiTestTM 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 Cylex immune cell function assay is for the detection of cell-mediated immunity in individuals undergoing immunosuppressive therapy after solid organ transplantation. The FDA's approval for 510(k) clearance was based on results submitted by Cylex from a multicenter study of 44 healthy adults and 127 solid organ transplant recipients (kidney, liver, pancreas, and simultaneous kidney and pancreas). ImmuKnow® assays were performed less than 1 month to greater than 4 years after transplant. Ninety-two percent of the transplant patients had CD4+ ATP values greater than 225 ng/mL. From this data, three zones of individual immune response were defined: an ATP level at or less than 225 ng/mL indicates that the individual's circulating immune cells are showing a low response to PHA stimulation, and suggests that the individual may be at increased risk of infection. An ATP level at or greater than 535 ng/mL indicates that the individual's circulating immune cells are showing a strong response to PHA, and that the individual may be at increased risk of rejection. Lastly, a moderate ATP level between 225-525 ng/mL is the proposed ideal response to PHA stimulation.

In a subsequent manufacturer-supported meta-analysis, Kowalski et al (2006) presented data of 504 immunosuppressed solid organ transplant recipients (kidney, liver, heart, and small bowel) from centers throughout the United States where ImmuKnow® assay was used. The prospective data was collected and combined with the data used to support the FDA 510(k) clearance for immune cell function assay. The study reported that only 5% of individuals with ATP levels between 130 ng/mL and 450 mg/mL, and a median ATP value of 249 ng/mL, demonstrated either rejection or infection, so the authors proposed this as the ATP targeted range for immunosuppressed transplant recipients. These ATP values and resulting targeted immunological response zone were different than those proposed in the earlier analysis.The authors suggested that this target immunological response zone was the ideal response to PHA stimulation in immunosuppressed transplant recipients, and that this data may be useful to assess relative risks of infection and rejection. Prospective controlled, double-blind outcome studies are needed to confirm this proposed range.

Cylex proposes that the information yielded by the assay can then be used to help guide professional providers in administering the correct amount of immunosuppressant drugs to prevent organ rejection while avoiding infection.

ASSESSMENT OF TECHNOLOGY

Cadillo-Chavez et al (2006) evaluated records of all individuals of in a limited sample size of 64 kidney transplant recipients at a single institution and reviewed data for associations between ATP levels and immunosuppression type, doses, and levels; creatinine levels; white blood cell count; tissue typing; performed antibodies; as well as ATP levels on infection and rejection and any changes in the ATP levels. There was no correlation found between ATP levels and immunosuppression type, doses, or levels; creatinine levels; white blood counts; HLA; and panel-reactive antibody. However, individuals with moderate or high pre-transplant ATP levels had more rejection episodes, while those with ATP levels in the low immune response had more infections. Although acute rejections occurred mostly above 300 ng/mL, this was not significant. When pre-transplant ATP values were compared with post-transplant ATP values at the second week, a decrease in ATP values did not correlate with infection.

Gupta et al (2008) studied 125 adult heart transplant recipients, the majority of whom underwent ImmuKnow® assay testing for more than one year post-transplant. There was no apparent correlation between ATP level and rejection. For individuals who developed an infection, the ATP levels did not differ from those individuals who did not develop an infection. During this study a unique incident occurred where there was a significant correlation between ATP levels and white blood cell count but not between ATP level and absolute lymphocyte count, suggesting that non-lymphocytes also may influence the ATP response.

A study by Bhorade et al (2008) found that ImmuKnow® assay had high sensitivity but poor specificity for infection in 57 lung transplant recipients. Since ImmuKnow® assay levels were lower in infected lung transplant recipients compared to non-infected recipients and increased with the treatment of these infections, it was unclear if the ImmuKnow® assay reflected those who were over-immunosuppressed and at risk of infection of the bone marrow due to infectious agents. The authors concluded that further study of this assay is needed to determine its role in optimizing immunosuppression in a given transplant recipient.

Reinsmoen et al (2008) reported on a study of 126 kidney transplant recipients that focused on whether pretransplant immune parameters (i.e., human leukocyte antigen [HLA] mismatch, HLA-specific antibodies, CD4+ cellular response as measured by ATP synthesis, and interferon-gamma precursor frequencies to donor or third-party cells) were associated with post-transplant early acute rejection, unstable creatinine courses, and poor graft outcome. The immune parameters were not used to guide a tailored immunosuppressive therapy. Graft survival and incidence of infection were not reported in this study.

Russano et al (2009) found no correlation between ATP levels as determined by the ImmuKnow® assay and outcomes in 83 pediatric cardiac transplant recipients. ImmuKnow® assays were performed for which there was no difference in ATP levels between patients with or without acute rejection or with or without infection. Furthermore the manufacturer's reported target response zone with ATP levels 225 ng/mL or less for infection or 525 ng/mL or greater for rejection were not predictive of infection or rejection. Consideration is also given to the fact that pediatric risk for infection and rejection may correspond to different ATP levels.

In another study, Cabrera et al (2009) assessed the ability of ImmuKnow® assay to differentiate between acute cellular rejection and recurrent hepatitis C in 42 individuals with hepatitis C--related endstage liver disease as the indication for liver transplant. The ImmuKnow® assay was performed prior to liver biopsy, and the biopsy samples were interpreted by histopathologists blinded to the results of the ImmuKnow assay. In individuals whose liver biopsy showed evidence of cellular rejection, the ATP value was very high, and in individuals with recurrent hepatitis C the ATP value was very low. A statistically significant difference of p<0.001 was noted.The data showed the potential utility of the ImmuKnow® assay in distinguishing hepatitis C from acute cellular rejection and the assay's potential usefulness as a marker for the progression of hepatitis C.

Husain et al (2009) reported on the correlation between ImmuKnow® assay values and various infectious episodes such as cytomegalovirus disease, viral infection, and bacterial pneumonia, fungal disease, and tracheobronchitis in a prospective cohort of 175 lung transplant recipients. The study findings demonstrated lower ImmunKnow® assay values that independently correlated with increased risk of infection. In addition, the study results also suggested that ImmuKnow® assay may be potentially useful in identifying those with fungal colonization. Further testing is needed in order to validate the study results.

Kobashigawa et al (2010) studied the effect of ImmuKnow® assay values for 296 heart transplant recipients. The authors concluded that ImmuKnow® assay values may be able to predict the risk of infection in heart transplant recipients, but the association between higher scores and rejection was inconclusive since the average assay value was not significantly different during rejection as compared to the steady state of non- rejection. A larger sample size of rejection episodes and a randomized trial in which immunosuppression could be prospectively guided by the assay values are needed.

Gesundheit et al (2010) studied immune monitoring in 40 individuals in post-allogeneic stem cell transplantation. These immunosuppressed individuals are susceptible to opportunistic infections, and uncontrolled function of the graft can result in graft-versus-host disease. ImmuKnow® assay values were compared in clinically immunocompromised versus immunocompetent individuals after allogeneic stem cell transplantation. The researchers also compared the reconstitution of white blood cell count to the ImmuKnow® assay values. The individuals' clinical course correlated with the stratification of immune response established by the ImmuKnow® assay values for the solid organ transplantation, which often differed from their white blood cell count. However, due to the small number of individuals studied, and that fact that many of the individuals died, relapsed, or were lost to follow-up, this study was not able to establish a clear cause-effect relationship. The authors concluded that ImmuKnow® assay should be evaluated prospectively in clinical trials.

Manga et al (2010) reported on a study of 16 individuals with hematologic malignancies (multiple myeloma, B- or T-cell lymphoma, and acute myeloid leukemia) undergoing hematopoietic stem cell mobilization prior to autologous transplantation in which the immune cell function assay was used to measure ATP activity. The ATP activity was found to be significantly higher than that measured in immunocompetent individuals. The authors concluded that larger studies are needed to assess the significance of ATP activity in individuals with hematologic malignancies.

Torio et al (2011) grouped 227 samples from 116 kidney transplant recipients by clinical course. The first group included individuals that were stable, and had no infectious sequelae or acute rejection episode 1 month before or after the immune cell assay. Those who demonstrated an infection defined as a fever plus at least one positive culture or positive polymerase chain reaction were included in the second group. The last group included those individuals who demonstrated rejection qualified by a biopsy-proven rejection. Healthy blood donors served as controls. Mean ATP levels in the stable group and in the control group were higher than in the infection group. No difference was observed between the rejection group and the stable group or the control group.

Huskey et al (2011), in a large retrospective analysis, evaluated ImmuKnow® assay values and compared them with subsequent events of infection and acute rejection over a five-year period of 583 kidney transplant recipients. The authors concluded that ImmuKnow® assay values at a single point did not identify individuals at risk for future development of clinically significant events. Further studies are needed to define the role of ImmuKnow® assay in immune monitoring of kidney transplant recipients.

Two retrospective studies of kidney transplant recipients found statistically significant correlations between ATP production and white blood cell (WBC). In a study of 39 patients at a single center in Japan, Nishikawa et al (2014) reported correlation coefficients (R2) of 0.573 (p=0.03) and 0.510 (p=0.02) for associations between WBC and neutrophil counts, respectively. In this study, ATP levels in 5 patients who developed viral infections in the early post-transplantation period (<50 days) were within normal limits. Methodologic limitations prevented any conclusion about the association of ATP levels with infections in 8 patients in the late posttransplantation period (>120 days).

In a study of 306 patients at a single U.S. center, Sageshima et al (2014) reported a correlation coefficients (R2) of 0.264 (p<0.001) for the association between ATP production and WBC. In this study, mean (SE) ATP production in patients with biopsyproven rejection (389 [56] ng/mL) and borderline/clinical rejection (254 [41] mg/mL) were not statistically higher compared with ATP production in patients without rejection (not reported). Mean (SE) ATP production in patients with opportunistic (349 [48] ng/mL) and other (345 [27] ng/mL) infections were not statistically lower compared with ATP production in patients without infection (not reported).

In a prospective cohort study of 55 patients followed for 3 years, Libri et al (2014) observed that ATP production was often lower in patients with acute rejection compared with patients without acute rejection, and was often greater in patients with infection compared with patients without infection. Using labelled cutoffs for ImmuKnow®, area under the summary receiver operating characteristic (ROC) curve (AUC) was 0.44 (95% CI, 0.18 to 0.71) for acute rejection and 0.37 (95% CI, 0.22 to 0.53) for viral or major respiratory tract infections. In a prospective study of 67 patients undergoing kidney transplant, patients with low preoperative ATP production had statistically fewer rejection episodes than those with high preoperative ATP production (p<0.001). The cutoff used for this analysis was 300ng/mL.

To optimize ImmuKnow® performance, Quaglia et al (2014) and Wang et al (2014) both proposed assessing change in ATP production over time, rather than single values. In a retrospective study of 118 patients, Quaglia et al reported AUC of 0.632 (95% CI, 0.483 to 0.781) for infection risk using a cutoff of -30 ng/mL for the decrease in ATP production from month 1 to month 3.29 In a prospective study of 140 patients, Wang et al reported AUC of 0.929 for risk of acute rejection using a cutoff of 172.55 ng/mL for the increase in ATP production from “right before” the rejection episode to the occurrence of rejection.

Natsuda et al (2014)40 assessed ATP production in 28 patients coinfected with HIV and HCV. These patients were all receiving antiretroviral therapy with undetectable viral load in most, and were classified Child-Pugh class A. Results were compared with those of 24 HCV-infected liver transplant recipients and 11 healthy volunteers. Median ATP levels in the HIV/HCV coinfected group (259 ng/ML [range, 30-613]) were statistically higher compared with the HCV monoinfected group (33 ng/mL [range, 6-320]; MannWhitney U test, p<0.001) and significantly lower compared with healthy volunteers (446 ng/mL [range, 309-565]; Mann-Whitney U test, p=0.001). In HIV/HCV coinfected patients, ATP production was significantly correlated with CD4+ cell count (Spearman rank correlation, p=0.03) but not with CD4/CD8 ratio (Spearman rank correlation coefficient, p=0.76). The clinical significance of these findings, for either HCV monoinfected liver transplant recipients or HIV/HCV coinfected patients, is unclear.

Liu et al (2014) compared ATP production in 22 patients with lupus nephritis and severe infection requiring hospitalization, 74 patients with lupus nephritis and no infection, and 28 healthy controls. Mean ATP production was significantly lower in patients with lupus nephritis and severe infection compared with non-infected patients and healthy controls (p<0.01 for both comparisons). Mean ATP production in noninfected LN patients did not differ statistically from that in healthy controls. Using a cutoff of 300 ng/mL, sensitivity and specificity for severe infection were both 77%. Strength of the correlation between ATP production and severe infection (r=-0.040, p<0.001) was less than that between C-reactive protein and severe infection (r=0.962, p<0.001).

PROFESSIONAL SOCIETIES

The American Society of Transplantation (AST) does not include the use of the immune cell function assay in their publication of recommendations for screening, monitoring, and reporting of infectious complications in the evaluation of recipients of organ transplantation (AST 2006). In addition, the 2010 guidelines for the care of heart transplant recipients by the International Society for Heart and Lung Transplantation do not include ImmuKnow®. Furthermore, the International Cytomegalovirus (CMV) Consensus Group of the Transplantation Society states that there are no clinical studies that demonstrate that management decisions based on immunologic monitoring affect patient outcomes, and that routine immunologic monitoring is not recommended.

SUMMARY

Published studies to date have primarily been small single-center retrospective studies. Studies indicate that adenosine triphosphate (ATP) levels vary among transplant recipients who have evidence of acute infection or transplant rejection, compared with clinically stable patients. Sensitivity and specificity of immune cell function assay have varied in studies reporting these parameters. Based on results from two 2012 systematic reviews of observational studies of ImmuKnow® in adult transplant recipients, estimates of sensitivity range from 52% to 88% for infection and 34% to 75% for rejection. Estimates of specificity, on the other hand, range from 66% to 79% for infection and 72% to 84% for rejection. Given the significant heterogeneity observed across studies, performance characteristics of ImmuKnow® have not been conclusively demonstrated. Further, it remains unclear whether different types of organ transplants or different immunosuppressive regimens affect CD4+ T cells’ response to phytohemagglutinin stimulation variably or whether cutoff values require adjustment for various clinical scenarios. Prospective trials are needed to better define the predictive ability of ImmuKnow® compared with current methods of assessing immune status. Other studies evaluate immune cell function for conditions other than solid organ transplantation not supported in the FDA 510(k) clearance for immune cell function assay.

Clinical utility of ImmuKnow® to impact net health outcome in comparison with current methods of care for solid organ transplant recipients has not been evaluated using prospective trials with multiple time point measurements of ATP production. Thus, it is unknown how current methods of assessing immune status in solid organ transplant recipients, e.g., immunosuppressant drug-level monitoring or empiric use of anti-infective agents, might be changed by use of ImmuKnow®.
References


Bhorade SM, Janata K, Vigneswaran WT, et al. Cylex ImmuKnow assay levels are lower in lung transplant recipients with infection. J Heart Lung Transplant. Sep 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. Feb 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. Oct 2011;137(10):1445-1453.

Dong JY, Yin H, Li RD, et al. The relationship between adenosine triphosphate within CD4+ T lymphocytes and acute rejection after liver transplantation. Clinical Transplantation. 2011;25(3):E292-E296.

Food and Drug Administration (FDA). Special 510(k): Device Modification 2010. Available online at: http://www.accessdata.fda.gov/cdrh_docs/reviews/K101911.pdf. Last accessed October 19, 2014.

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. Mar 2010;45(3):527-533.

Guidelines for the Care of Heart Transplant Recipients, 2010. The International Society of Heart and Lung Transplantation http://www.ishlt.org/publications/guidelines.asp. Accessed October 19, 2014.

Gupta S, Mitchell JD, Markham DW, et al. Utility of the Cylex assay in cardiac transplant recipients. J Heart Lung Transplant. Aug 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. Sep-Oct 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. Jan-Feb 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. Dec 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. Feb 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. Jun 27 2009;87(12):1852-1857.

Huskey J, Gralla J, Wiseman AC. Single time point immune function assay (ImmuKnow(trademark)) testing does not aid in the prediction of future opportunistic infections or acute rejection. Clinical Journal of the American Society of Nephrology. 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. Apr 27 2010;89(8):968-976.

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. May 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. Apr 15 2010;89(7):779-795.

Kowalski R, Post D, Schneider MC, et al. Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management. Clin Transplant. Apr 2003;17(2):77-88.

Kowalski RJ, Post DR, Mannon RB, et al. Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay. Transplantation. Sep 15 2006;82(5):663-668.

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. Apr 15 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.

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. Jul 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 postkidney transplantation viral infection. Transplant Proc. Mar 2014;46(2):552-555.

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.

Reinsmoen NL, Cornett KM, Kloehn R, et al. Pretransplant donor-specific and non-specific immune parameters associated with early acute rejection. Transplantation. Feb 15 2008;85(3):462-470.

Rodrigo E, Lopez-Hoyos M, Corral M, et al. ImmuKnow((R)) as a diagnostic tool for predicting infection and acute rejection in adult liver transplant recipients: Systematic review and meta-analysis. Liver Transpl. Jun 27 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. Jan 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. Nov 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. Nov 2012;44(9):2622-2624.

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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. Sep 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. Nov-Dec 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. Jul-Aug 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.

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.

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Zeevi A, Britz JA, Bentlejewski CA, et al. Monitoring immune function during tacrolimus tapering in small bowel transplant recipients. Transpl Immunol. Oct 2005;15(1):17-24.

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. Sep 2011;43(7):2574-2578.

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. Apr 2013;17(2):304-309.





Coding

Inclusion of a code in this table does not imply reimbursement. Eligibility, benefits, limitations, exclusions, precertification/referral requirements, provider contracts, and Company policies apply.

The codes listed below are updated on a regular basis, in accordance with nationally accepted coding guidelines. Therefore, this policy applies to any and all future applicable coding changes, revisions, or updates.

In order to ensure optimal reimbursement, all health care services, devices, and pharmaceuticals should be reported using the billing codes and modifiers that most accurately represent the services rendered, unless otherwise directed by the Company.

The Coding Table lists any CPT, ICD-9, ICD-10, and HCPCS billing codes related only to the specific policy in which they appear.

CPT Procedure Code Number(s)

86352


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD - 10 Procedure Code Number(s)

N/A


Professional and outpatient claims with a date of service on or before September 30, 2015, must be billed using ICD-9 codes. Professional and outpatient claims with a date of service on or after October 1, 2015, must be billed using ICD-10 codes.

Facility/Institutional inpatient claims with a date of discharge on or before September 30, 2015, must be billed with ICD-9 codes. Facility/Institutional inpatient claims with a date of discharge on or after October 1, 2015, must be billed with ICD-10 codes.


ICD -10 Diagnosis Code Number(s)

This service is experimental/investigational for all diagnoses.


HCPCS Level II Code Number(s)

N/A


Revenue Code Number(s)

N/A

Coding and Billing Requirements


Cross References


Policy History

Revisions from 06.02.37a
08/29/2018The policy has been reviewed and reissued to communicate the Company’s continuing position on Immune Cell Function Assay.


Effective 10/05/2017 this policy has been updated to the new policy template format.


Version Effective Date: 11/06/2015
Version Issued Date: 11/06/2015
Version Reissued Date: 08/29/2018

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