Laboratory Tests Post Transplant and for Heart Failure

POLICY NUMBER

A.2.01.68

DESCRIPTION

Clinical assessment and noninvasive imaging of chronic heart failure can be limited in accurately diagnosing patients with heart failure because symptoms and signs can poorly correlate with objective methods of assessing cardiac dysfunction. For management of heart failure, clinical signs and symptoms (eg, shortness of breath) are relatively crude markers of decompensation and occur late in the course of an exacerbation. Thus, circulating biomarkers have potential benefit in heart failure diagnosis and management.

Heart Failure

Heart failure is a major cause of morbidity and mortality worldwide. The term heart failure refers to a complex clinical syndrome that impairs the heart's ability to move blood through the circulatory system. The prevalence of heart failure in the U.S. between 2013 and 2016 was an estimated 6.2 million for Americans ≥20 years old, up from 5.7 million between 2009 and 2012. Heart failure is the leading cause of hospitalization among people older than age 65 years, with direct and indirect costs estimated at $37 billion annually in the U.S. Although survival has improved with treatment advances, absolute mortality rates of heart failure remain near 50% within 5 years of diagnosis.

Physiology

Heart failure can be caused by disorders of the pericardium, myocardium, endocardium, heart valves or great vessels, or metabolic abnormalities. Individuals with heart failure may present with a wide range of left ventricular (LV) anatomy and function. Some have normal LV size and preserved ejection fraction; others have severe LV dilatation and depressed ejection fraction. However, most patients present with key signs and symptoms secondary to congestion in the lungs from impaired LV myocardial function. They include dyspnea, orthopnea, and paroxysmal dyspnea. Other symptoms include weight gain due to fluid retention, fatigue, weakness, and exercise intolerance secondary to diminished cardiac output.

Diagnosis

Initial evaluation of a patient with suspected heart failure is typically based on clinical history, physical examination, and chest radiograph. Because people with heart failure may present with nonspecific signs and symptoms (eg, dyspnea), accurate diagnosis can be challenging. Therefore, noninvasive imaging procedures (eg, echocardiography, radionuclide angiography) are used to quantify pump function of the heart, thus identifying or excluding heart failure in patients with characteristic signs and symptoms. These tests can also be used to assess prognosis by determining the severity of the underlying cardiac dysfunction. However, clinical assessment and noninvasive imaging can be limited in accurately evaluating patients with heart failure because symptoms and signs can poorly correlate with objective methods of assessing cardiac dysfunction. Thus, invasive procedures (eg, cardiac angiography, catheterization) are used in select patients with presumed heart failure symptoms to determine the etiology (ie, ischemic vs. nonischemic) and physiologic characteristics of the condition.

Treatment

Patients with heart failure may be treated using a number of interventions. Lifestyle factors such as the restriction of salt and fluid intake, monitoring for increased weight, and structured exercise programs are beneficial components of self-management. A variety of medications are available to treat heart failure. They include diuretics (eg, furosemide, hydrochlorothiazide, spironolactone), angiotensin-converting enzyme inhibitors (eg, captopril, enalapril, lisinopril), angiotensin receptor blockers (eg, losartan, valsartan, candesartan), b-blockers (eg, carvedilol, metoprolol succinate), and vasodilators (eg, hydralazine, isosorbide dinitrate). Numerous device-based therapies also are available. Implantable cardioverter defibrillators reduce mortality in patients with an increased risk of sudden cardiac death. Cardiac resynchronization therapy improves symptoms and reduces mortality for patients who have disordered LV conduction evidenced by a wide QRS complex on electrocardiogram. Ventricular assist devices are indicated for patients with end-stage heart failure who have failed all other therapies and are also used as a bridge to cardiac transplantation in select patients.

Heart Failure Biomarkers

Because of limitations inherent in standard clinical assessments of patients with heart failure, a number of objective disease biomarkers have been investigated to diagnose and assess heart failure patient prognosis, with the additional goal of using biomarkers to guide therapy. They include a number of proteins, peptides, or other small molecules whose production and release into circulation reflect the activation of remodeling and neurohormonal pathways that lead to LV impairment. Examples include B-type natriuretic peptide (BNP), its analogue N-terminal pro B-type natriuretic peptide (NT-proBNP), troponin T and I, renin, angiotensin, arginine vasopressin, C-reactive protein, and norepinephrine.

BNP and NT-proBNP are considered the reference standards for biomarkers in assessing heart failure patients. They have had a substantial impact on the standard of care for diagnosis of heart failure and are included in the recommendations of all major medical societies, including the American College of Cardiology Foundation and American Heart Association, European Society of Cardiology, and the Heart Failure Society of America. Although natriuretic peptide levels are not 100% specific for the clinical diagnosis of heart failure, elevated BNP or NT-proBNP levels in the presence of clinical signs and symptoms reliably identify the presence of structural heart disease due to remodeling and heightened risk for adverse events. Natriuretic peptides also can help in determining prognosis of heart failure patients, with elevated blood levels portending a poorer prognosis.

In addition to diagnosing and assessing prognosis of heart failure patients, blood levels of BNP or NT-proBNP have been proposed as an aid for managing patients diagnosed with chronic heart failure. Levels of either biomarker rise in response to myocardial damage and LV remodeling, whereas they tend to fall as drug therapy ameliorates symptoms of heart failure. Evidence from a large number of randomized controlled trials (RCTs) that have compared BNP- or NT-proBNP-guided therapy with clinically guided adjustment of pharmacologic treatment of patients who had chronic heart failure has been assessed in recent systematic reviews and meta-analyses. However, these analyses have not consistently reported a benefit for BNP-guided management. Savarese and colleagues published the largest meta-analysis to date, a patient-level meta-analysis that evaluated 2,686 patients from 12 RCTs. This meta-analysis showed that NT-proBNP-guided management was associated with significant reductions in all-cause mortality and heart failure–related hospitalization compared with clinically guided treatment. Although BNP-guided management in this meta-analysis was not associated with significant reductions in these parameters, differences in patient numbers and characteristics may explain the discrepancy. Troughton and colleagues conducted a second patient-level meta-analysis that included 11 RCTs with 2,000 patients randomized to natriuretic peptide-guided pharmacologic therapy or usual care. The results showed that, among patients 75 years of age or younger with chronic heart failure, most of whom had impaired left ventricular ejection fraction, natriuretic peptide-guided therapy was associated with significant reductions in all-cause mortality compared with clinically guided therapy. Natriuretic-guided therapy also was associated with significant reductions in hospitalization due to heart failure or cardiovascular disease.

Suppression of Tumorigenicity-2 Protein Biomarker

A protein biomarker, ST2, has elicited interest as a potential aid to predict prognosis and manage therapy of heart failure. This protein is a member of the interleukin-1 (IL-1) receptor family. It is found as a transmembrane isoform (ST2L) and a soluble isoform (sST2), both of which have circulating IL-33 as their primary ligand. ST2 is a unique biomarker that has pluripotent effects in vivo. Thus, binding between IL-33 and ST2L is believed to have an immunomodulatory function via T-helper type 2 lymphocytes and was initially described in the context of cell proliferation, inflammatory states, and autoimmune diseases. However, the IL-33/ST2L signaling cascade is also strongly induced through the mechanical strain of cardiac fibroblasts or cardiomyocytes. The net result is mitigation of adverse cardiac remodeling and myocardial fibrosis, which are key processes in the development of heart failure. The soluble isoform of ST2 is produced by lung epithelial cells and cardiomyocytes and is secreted into circulation in response to exogenous stimuli, mechanical stress, and cellular stretch. This form of ST2 binds to circulating IL-33, acting as a "decoy," thus inhibiting the IL-33-associated antiremodeling effects of the IL-33/ST2L signaling pathway. Thus, on a biologic level, IL-33/ST2L signaling plays a role in modulating the balance of inflammation and neurohormonal activation and is viewed as pivotal for protection from myocardial remodeling, whereas sST2 is viewed as attenuating this protection. In the clinic, blood concentrations of sST2 appear to correlate closely with adverse cardiac structure and functional changes consistent with remodeling in patients with heart failure, including abnormalities in filling pressures, chamber size, and systolic and diastolic function.

An enzyme-linked immunosorbent-based assay is commercially available for determining sST2 blood levels (Presage ST2 Assay). The manufacturer claims a limit of detection of 1.8 ng/mL for sST2, and a limit of quantification of 2.4 ng/mL, as determined according to Clinical and Laboratory Standards Institute guideline EP-17-A. Mueller and Dieplinger reported a limit of detection of 2.0 ng/mL for sST2 in their study. In the same study, the assay had a within-run coefficient of variation of 2.5% and a total coefficient of variation less than 4.0%, demonstrated linearity within the dynamic range of the assay calibration curve, and exhibited no relevant interference or cross-reactivity.

The ST2 biomarker is not intended to diagnose heart failure because it is a relatively nonspecific marker that is increased in many other disparate conditions that may be associated with acute or chronic manifestations of heart failure. Although the natriuretic peptides (BNP, NT-proBNP) reflect different physiologic aspects of heart failure compared with sST2, they are considered the reference standard biomarkers when used with clinical findings to diagnose, prognosticate, and manage heart failure and as such are the comparator to sST2.

Heart Transplant Rejection

Most cardiac transplant recipients experience at least a single episode of rejection in the first year after transplantation. The International Society for Heart and Lung Transplantation (2005) modified its grading scheme for categorizing cardiac allograft rejection. The revised (R) categories are listed in the table below.

Revised Grading Schema for Cardiac Allograft Rejection

Acute cellular rejection is most likely to occur in the first 6 months after transplantation, with a significant decline in the incidence of rejection after this time. Although immunosuppressants are required on a life-long basis, dosing is adjusted based on graft function and the grade of acute cellular rejection determined by histopathology. Endomyocardial biopsies are typically taken from the right ventricle via the jugular vein periodically during the first 6 to 12 months post transplant. The interval between biopsies varies among clinical centers. A typical schedule is weekly for the first month, once or twice monthly for the following 6 months, and several times (monthly to quarterly) between 6 months and 1-year post transplant. Surveillance biopsies may also be performed after the first postoperative year (eg, on a quarterly or semiannual basis). This practice, although common, has not been demonstrated to improve transplant outcomes. Some centers no longer routinely perform endomyocardial biopsies after 1 year in patients who are clinically stable.

While the endomyocardial biopsy is the criterion standard for assessing heart transplant rejection, it is limited by a high degree of interobserver variability in the grading of results and potential morbidity that can occur with the biopsy procedure. Also, the severity of rejection may not always coincide with the grading of the rejection by biopsy. Finally, a biopsy cannot be used to identify patients at risk of rejection, limiting the ability to initiate therapy to interrupt the development of rejection. For these reasons, an endomyocardial biopsy is considered a flawed criterion standard by many. Therefore, noninvasive methods of detecting cellular rejection have been explored. It is hoped that noninvasive tests will assist in determining appropriate patient management and avoid overuse or underuse of treatment with steroids and other immunosuppressants that can occur with false-negative and false-positive biopsy reports. Two techniques are commercially available for the detection of heart transplant rejection.

Noninvasive Heart Transplant Rejection Tests

Presage ST2 Assay

In addition to its use as a potential aid to predict prognosis and manage therapy of heart failure, elevated serum ST2 levels have also been associated with an increased risk of antibody-mediated rejection following a heart transplant. For this reason, ST2 has also been proposed as a prognostic marker post heart transplantation and as a test to predict acute cellular rejection (graft-versus-host disease). The Presage ST2 Assay, described above, is a commercially available sST2 test that has been investigated as a biomarker of heart transplant rejection.

Heartsbreath Test

The Heartsbreath test, a noninvasive test that measures breath markers of oxidative stress, has been developed to assist in the detection of heart transplant rejection. In heart transplant recipients, oxidative stress appears to accompany allograft rejection, which degrades membrane polyunsaturated fatty acids and evolving alkanes and methylalkanes that are, in turn, excreted as volatile organic compounds in breath. The Heartsbreath test analyzes the breath methylated alkane contour, which is derived from the abundance of C4 to C20 alkanes and monomethylalkanes and has been identified as a marker to detect grade 3 (clinically significant) heart transplant rejection.

HeartCare

Cell-free DNA (cfDNA), released by damaged cells, is normally present in healthy individuals. In patients who have received transplants, donor-derived cell-free DNA (dd-cfDNA) may be also present. It is proposed that allograft rejection, which is associated with damage to transplanted cells, may result in an increase in dd-cfDNA. HeartCare (CareDx) is a commercially-available test that combines AlloMap gene expression profiling with a next-generation sequencing assay that quantifies the fraction of dd-cfDNA in cardiac transplant recipients relative to total cfDNA. The AlloMap score, AlloMap score variability, and AlloSure % dd-cfDNA are reported.

Prospera

Prospera Heart (Natera) is a commercially available assay that uses massively multiplexed PCR (mmPCR) followed by next-generation sequencing (NGS) to quantify the fraction of dd-cfDNA in transplant recipients. Donor versus recipient cfDNA is differentiated via an advanced bioinformatics analysis of >13,000 single-nucleotide polymorphisms (SNPs) without the need for prior recipient or donor genotyping or computational adjustments for related donors. The Prospera Heart test reports the dd-cfDNA fraction in the patient’s blood as a predictor of acute rejection, although the optimal dd-cfDNA cut-point is not described by the manufacturer.

myTAI_HEART

Using proprietary myTAI_HEART software (TAI Diagnostics), the myTAI_HEART test uses multiplexed, high-fidelity amplification followed by allele-specific qPCR of a panel of 94 highly informative bi-allelic single nucleotide polymorphisms (SNPs) and two controls to quantitatively genotype cell free DNA in the patient’s plasma after cardiac transplant, and accurately distinguish dd-cfDNA originating from the engrafted heart from cell free DNA originating from the recipient’s native cells. The ratio of dd-cfDNA to total cell free DNA is reported as the donor fraction (%) and categorizes the patient as at low or increased risk of moderate (grade 2R) to severe (grade 3R) acute cellular rejection: low donor fractions indicate less damage to the transplanted heart and a lower risk for rejection, while increased donor fractions indicate more damage to the transplanted heart and an increased risk for rejection. Testing with myTAI_HEART does not require a donor specimen. TAI Diagnostics suspended production of the myTAI_HEART test in 2020. As of September 2022, TAI Diagnostics appears to no longer be operational and it is unclear if myTAI_HEART will be available through another company in the future.

AlloMap

Another approach has focused on patterns of gene expression of immunomodulatory cells, as detected in the peripheral blood. For example, microarray technology permits the analysis of the expression of thousands of genes, including those with functions known or unknown. Patterns of gene expression can then be correlated with known clinical conditions, permitting a selection of a finite number of genes to compose a custom multigene test panel, which then can be evaluated using polymerase chain reaction techniques. AlloMap (CareDx) is a commercially available molecular expression test that has been developed to detect acute heart transplant rejection or the development of graft dysfunction. The test involves expression measurement of a panel of genes derived from peripheral blood cells and applies an algorithm to the results. The proprietary algorithm produces a single score that considers the contribution of each gene in the panel. The score ranges from 0 to 40. The AlloMap website states that a lower score indicates a lower risk of graft rejection; the website does not cite a specific cutoff for a positive test. All AlloMap testing is performed at the CareDx reference laboratory in California.

Other laboratory-tested biomarkers of heart transplant rejection have been evaluated. They include brain natriuretic peptide, troponin, and soluble inflammatory cytokines. Most have had low accuracy in diagnosing rejection. Preliminary studies have evaluated the association between heart transplant rejection and micro-RNAs or high-sensitivity cardiac troponin in cross-sectional analyses, but the clinical use has not been evaluated.

Renal Transplant Rejection

Allograft dysfunction is typically asymptomatic and has a broad differential, including graft rejection. Diagnosis and rapid treatment are recommended to preserve graft function and prevent loss of the transplanted organ. For a primary kidney transplant from a deceased donor (accounting for about 70% of kidney donors), graft survival at 1 year is 93%; at 5 years, graft survival is 74%.

Surveillance of transplant kidney function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis. Allograft dysfunction may also be demonstrated by a drop in urine output or, rarely, as pain over the transplant site. With clinical suspicion of allograft dysfunction, additional noninvasive workup including ultrasonography or radionuclide imaging may be used. A renal biopsy allows a definitive assessment of graft dysfunction and is typically a percutaneous procedure performed with ultrasonography or computed tomography guidance. Biopsy of a transplanted kidney is associated with fewer complications than biopsy of a native kidney because the allograft is typically transplanted more superficially than a native kidney. Renal biopsy is a low-risk invasive procedure that may result in bleeding complications; loss of a renal transplant, as a complication of renal biopsy, is rare.

Kidney biopsies allow for diagnosis of acute and chronic graft rejection, which may be graded using the Banff Classification. Pathologic assessment of biopsies demonstrating acute rejection allows clinicians to further distinguish between acute cellular rejection and antibody-mediated rejection, which are treated differently.

Noninvasive Renal Transplant Rejection Tests

Allosure

AlloSure Kidney (CareDx) is a commercially available, next-generation sequencing assay that quantifies the fraction of dd-cfDNA in renal transplant recipients relative to total cfDNA by measuring 266 single nucleotide variants. Separate genotyping of the donor or recipient is not required, but patients who receive a kidney transplant from a monozygotic (identical) twin are not eligible for this test. The fraction of dd-cfDNA relative to total cfDNA present in the peripheral blood sample is cited in the report. For patients undergoing surveillance, a routine testing schedule is recommended for longitudinal monitoring.

Prospera

Prospera Kidney (Natera) is a commercially available assay that quantifies the fraction of dd-cfDNA in renal transplant recipients. The manufacturer recommends use of the Prospera test when there is clinical suspicion of active rejection and for regular surveillance of subclinical rejection in renal transplant recipients. In a surveillance scenario, regular testing is recommended at 1, 2, 3, 4, 6, 9 and 12 months after renal transplant or most recent rejection. Thereafter, the test should be repeated quarterly. The proportion of dd-cfDNA relative to total cfDNA is reported, with detection of ≥1% dd-cfDNA indicating increased risk for active rejection. The percent dd-cfDNA change between tests is also reported.

Lung Transplant Rejection

Despite advances in induction and maintenance immunosuppressive regimens, lung transplant recipients have a median overall survival of 6 years, with more than a third of patients receiving treatment for acute rejection in the first year after transplant. Acute cellular rejection, lymphocytic bronchiolitis, and antibody-mediated rejection are all risk factors for subsequent development of chronic lung allograft dysfunction (CLAD). Pathologic grading of acute cellular rejection is based on the histological assessment of perivascular and interstitial mononuclear cell infiltrates. Antibody-mediated rejection may be clinical (symptomatic or asymptomatic allograft dysfunction) or subclinical (normal allograft function). Key diagnostic criteria established via consensus by the International Society for Heart and Lung Transplantation include the presence of antibodies directed toward donor human leukocyte antigens and characteristic lung histology with or without evidence of complement 4d within the graft. The most common phenotype of CLAD is a persistent obstructive decline in lung function known as bronchiolitis obliterans syndrome (BOS), which is graded based on the degree of decrease in FEV₁. Approximately 50% of patients develop BOS within 5 years post-transplant. Median survival following a diagnosis of BOS is 3-5 years. Acute rejection may present with non-specific physical symptoms or be asymptomatic. However, the role of surveillance bronchoscopy for screening asymptomatic patients for acute rejection is controversial, and performance of surveillance bronchoscopies varies across transplant centers.

Noninvasive Lung Transplant Rejection Tests

AlloSure

AlloSure Lung (CareDx) is a commercially available, NGS assay that quantifies the fraction of dd-cfDNA in lung transplant patients relative to total cfDNA by measuring single nucleotide polymorphisms. The test is intended to provide a direct, noninvasive measure of organ injury in lung transplant patients who are undergoing surveillance. Suggested thresholds for severe injury, injury, and quiescence are >0.9%, >0.5 to ≤0.9%, and <0.5%, respectively.

Prospera

Prospera Lung (Natera) is a commercially available assay that uses the same methodology as Propera Heart and Prospera Kidney to quantify the fraction of dd-cfDNA in transplant recipients. The Prospera Lung test reports the dd-cfDNA fraction in the patient’s blood as a predictor of acute rejection, chronic rejection, or infection although the optimal dd-cfDNA cut-point for each outcome is not described by the manufacturer.

The U.S. Food and Drug Administration (FDA) has cleared multiple biomarker tests for the detection of heart and renal allograft rejection. The table below provides a summary of the biomarker tests currently included in this policy that have FDA clearance.

Select Biomarker Tests for Detection of Heart or Renal Allograft Rejection Cleared by the U.S. Food and Drug Administration

Laboratory Developed Tests

There are also commercially available laboratory-developed biomarker tests for the detection of heart and renal allograft rejection. Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments. The AlloSure (CareDx) and Prospera (Natera) dd-cfDNA tests are regulated under the Clinical Laboratory Improvement Amendments standards.

myTAI_HEART is also a laboratory developed test (LDT) developed for clinical diagnostic performance exclusively in the College of American Pathologists (CAP) and Clinical Laboratory Improvement Amendment (CLIA) accredited TAI Diagnostics Clinical Reference Laboratory. This test was developed and its performance characteristics were determined by TAI Diagnostics.

These LDTs have not been cleared or approved by the FDA.

Other Tests

Other commercially available LDTs without FDA clearance or approval for use have been excluded from this policy when studies reporting on the clinical validity of the marketed version of the test could not be identified and/or where the test is marketed for research use only. Excluded tests and their descriptions are summarized for reference purposes in thetable below.

Biomarker Tests Excluded from Review

dd-cfDNA: donor-derived cell-free DNA; GEP: gene expression profiling; HCT: hematopoietic cell transplantation; HLA: human leukocyte antigen; MMDx: molecular microscope diagnostic system; NGS: next-generation sequencing; OKRA: Outcomes in KidneyCare in Renal Allografts; SNP: single-nucleotide polymorphism; TRAC: transplant rejection allograft check.¹Published studies reporting on the clinical validity of the marketed version of the test were not identified.

Related medical policies - 

• Heart/Lung Transplant

• Heart Transplant

POLICY

The use of the Presage ST2 Assay to evaluate the prognosis of individuals diagnosed with chronic heart failure is considered investigational.

The use of the Presage ST2 Assay to guide management (eg, pharmacologic, device-based, exercise) of individuals diagnosed with chronic heart failure is considered investigational.

The use of the Presage ST2 Assay in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection, is considered investigational.

The measurement of volatile organic compounds to assist in the detection of moderate grade 2R (formerly grade 3) heart transplant rejection is considered investigational.

The use of peripheral blood measurement of dd-cfDNA in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection, is considered investigational.

The use of peripheral blood gene expression profile tests alone or in combination with peripheral blood measurement of donor-derived cell-free DNA (dd-cfDNA) in the management of individuals after heart transplantation, including, but not limited to, the detection of acute heart transplant rejection or heart transplant graft dysfunction, is considered investigational.

The use of peripheral blood measurement of dd-cfDNA in the management of individuals after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction, is considered investigational.

The use of peripheral blood measurement of dd-cfDNA in the management of individuals after lung transplantation, including but not limited to the detection of acute lung transplant rejection or lung transplant graft dysfunction, 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.

The U.S. Food and Drug Administration has indicated that the Heartsbreath (Menssana Research) test is only for use as an aid in the diagnosis of grade 3 (now known as grade 2R) heart transplant rejection in patients who have received heart transplants within the preceding year and who have had endomyocardial biopsy within the previous month.

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

3/31/2005: Approved by Medical Policy Advisory Committee (MPAC).

6/6/2005: Code Reference section completed.

2/20/2006: Peripheral blood gene expression section added.

12/22/2008: Policy reviewed, no changes.

04/20/2010: Policy description and guidelines updated regarding noninvasive methods of detecting cellular rejection; policy statement unchanged. FEP verbiage added to the Policy Exceptions section.

12/28/2010: Policy reviewed; no changes.

05/09/2012: Policy reviewed; no changes.

08/07/2013: Policy reviewed; no changes.

06/09/2014: Policy reviewed; description updated. Policy statement revised for clarity to state that the use of peripheral blood genetic profiling tests in the management of patients after heart transplantation, including, but not limited to, the detection of acute heart transplant rejection or heart transplant graft dysfunction is considered investigational. It previously stated: The evaluation of genetic expression in the peripheral blood, including, but not limited to, the detection of acute heart transplant rejection or graft dysfunction is considered investigational.

07/31/2015: Code Reference section updated for ICD-10.

09/10/2015: Policy description updated to add section headings. Policy statements unchanged. Investigative definition updated in the policy guidelines section.

12/31/2015: Code Reference section updated to add new 2016 CPT code 81595.

06/01/2016: Policy number A.2.01.68 added.

07/06/2016: Policy description updated regarding revised categories for cardiac allograft rejection. First investigational policy statement updated to remove "Heartsbreath test" and to change "grade 3" to "moderate grade 2R/grade 3" due to updated International Society for Heart and Lung Transplantation rejection grades. Policy Guidelines updated regarding rejection grade.

10/26/2017: Policy description updated. First investigational statement updated to change "grade 3" to "formerly grade 3." Second investigational statement updated to change "genetic profiling tests" to "gene expression profile tests."

06/15/2018: Code Reference section updated to add new CPT code 0055U, effective 07/01/2018.

11/07/2018: Policy title changed from "Laboratory Tests for Heart Transplant Rejection" to "Laboratory Tests for Heart and Kidney Transplant Rejection." Policy description updated regarding renal transplant rejection. Added policy statement that the use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after renal transplantation, including but not limited to the detection of acute renal transplant rejection or renal transplant graft dysfunction, is considered investigational. Policy Guidelines updated.

07/01/2019: Code Reference section updated to add new CPT code 0087U.

12/18/2019: Policy description revised to remove information regarding surveillance of heart and renal transplant rejection. Policy statements unchanged.

09/23/2020: Code Reference section updated to add new CPT code 0221U, effective 10/01/2020.

06/13/2022: Policy title changed from "Laboratory Tests for Heart and Kidney Transplant Rejection" to "Laboratory Tests Post Transplant and for Heart Failure." Content from the "Molecular Testing for Chronic Heart Failure and Heart Transplant" policy was merged with this policy. Policy statement regarding gene expression profile tests revised to add "alone or in combination with peripheral blood measurement of donor-derived cell free DNA (dd-cfDNA)." Added investigational statement regarding the use of peripheral blood measurement of dd-cfDNA in the management of patients after lung transplantation. Code Reference section updated to add CPT codes 0018M, 0088U, 0118U, and 83006. Removed deleted CPT code 0085T.

03/07/2023: Policy description updated regarding noninvasive heart transplant rejection tests, noninvasive renal transplant rejection tests, noninvasive lung transplant rejection tests, and laboratory developed tests. Policy section updated to remove policy statement regarding the use of the myTAI_HEART assay. Added statement that the use of peripheral blood measurement of dd-cfDNA in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection, is considered investigational.

11/10/2023: Policy description updated regarding renal transplant rejection and noninvasive lung transplant rejection tests. Policy statements unchanged.

03/05/2025: Policy reviewed; no changes.

04/01/2025: Code Reference section updated to add new CPT codes 0540U, 0542U, and 0544U, effective 04/01/2025.

10/01/2025: Code Reference section updated to add new CPT codes 0575U and 0576U.

SOURCE(S)

Blue Cross Blue Shield Association policy # 2.01.68

CODE REFERENCE

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

Investigational Codes

CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.