Coverage Policy Manual - Arkansas Blue Cross and Blue Shield

Coverage Policy Manual
Policy #:	2015007
Category:	Medicine
Initiated:	January 2015
Last Review:	December 2023

Laboratory Tests for Chronic Heart Failure and Organ Transplant Rejection

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 (e.g., 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.

In transplant recipients, despite the progress in immunosuppressant therapy, the risk of rejection remains. Diagnosis of allograft rejection continues to rely on clinical monitoring and histologic confirmation by tissue biopsy. However, due to limitations of tissue biopsy, including a high degree of interobserver variability in the grading of results and its potential complications, less invasive alternatives have been investigated. Several laboratory-tested biomarkers of transplant rejection have been evaluated and are commercially available for use. The laboratory tests for heart transplant rejection currently evaluated in this policy include the Presage® ST2 Assay kit, which measures the soluble suppression of tumorigenicity-2 (sST2) protein biomarker; ; the Heartsbreath test, which measures breath markers of oxidative stress; the AlloSure, Prospera Heart and myTAIHEART tests for assessment of donor-derived cell-free DNA (dd-cfDNA); the AlloMap test, which uses gene expression profiling (GEP); and the HeartCare test, which combines AlloMap GEP testing with the AlloSure test. Also included in this policy are the AlloSure and Prospera dd-cfDNA tests for assessment of renal and lung transplant rejection

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 (Yancy, 2013). 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 from between 2009 and 2012 (Roger, 2011; Virani, 2020). 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. (Roger, 2011). Although survival has improved with treatment advances, absolute mortality rates of heart failure remain near 50% within 5 years of diagnosis.

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 (Yancy, 2013). 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.

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 (e.g., dyspnea), accurate diagnosis can be challenging. Therefore, noninvasive imaging procedures (e.g., 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 (Yancy, 2013). 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 (Rohde, 2004; Marcus, 2005; Stevenson, 1989). Thus, invasive procedures (e.g., cardiac angiography, catheterization) are used in select patients with presumed heart failure symptoms to determine the etiology (i.e., ischemic vs. nonischemic) and physiologic characteristics of the condition.

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 (e.g., furosemide, hydrochlorothiazide, spironolactone), angiotensin-converting enzyme inhibitors (e.g., captopril, enalapril, lisinopril), angiotensin receptor blockers (e.g., losartan, valsartan, candesartan), b-blockers (e.g., carvedilol, metoprolol succinate), and vasodilators (e.g., 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 (Yancy, 2013).

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 (Gaggin, 2013). 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 (Yancy, 2013; Gaggin, 2013).

BNP and NT-proBNP are considered the reference standards for biomarkers in assessing heart failure patients. They have had 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 (Heidenreich, 2022, 2013; McMurray, 2012; Lindenfeld, 2010). 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 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 (Heidenreich, 2022; Savarese, 2013; Troughton, 2014). 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 et al published the largest meta-analysis to date, a patient-level meta-analysis that evaluated 2686 patients from 12 RCTs (Savarese, 2013). 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 et al conducted a second patient-level meta-analysis that included 11 RCTs with 2000 patients randomized to natriuretic peptide-guided pharmacologic therapy or usual care (Troughton, 2014). 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 (ST2) Protein Biomarker

A protein biomarker, ST2, has elicited interest as a potential aid to predict prognosis and manage therapy of heart failure (Bhardwaj, 2010; Chowdhury, 2013; Ciccone, 2013; Daniels, 2014; Dieplinger, 2015; Mueller, 2013; Shah, 2010). 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 (Xu, 1998). However, the IL-33/ST2L signaling cascade is also strongly induced through 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 (Weinberg, 2002). 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 (Gaggin, 2013; Ciccone, 2013; Dieplinger, 2014).

An enzyme-linked immunosorbent-based assay is commercially available for determining sST2 blood levels (Presage ST2 Assay) (Mueller, 2013). 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 (Mueller, 2013). 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 diagnosis 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 (Dieplinger, 2015; Mueller, 2013). 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 modified its grading scheme for categorizing cardiac allograft rejection (Stewart, 2005). The revised grading schema for cardiac allograft rejection:

0R – No rejection

1R – Mild rejection

2R – Moderate rejection

3R – Severe 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 posttransplant. 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 posttransplant. Surveillance biopsies may also be performed after the first postoperative year (e.g., 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 (Measurement of Volatile Organic Compounds for Heart Transplant)

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 (Celec, 2018). In patients who have received transplants, 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 (Natera, 2022). 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.

myTAIHEART

Using proprietary myTAIHEART software (TAI Diagnostics), the myTAIHEART 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 cfDNA in the patient’s plasma after cardiac transplant, and accurately distinguish dd-cfDNA originating from the engrafted heart from cfDNA originating from the recipient’s native cells (North, 2020). The ratio of dd-cfDNA to total cfDNA 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 myTAIHEART does not require a donor specimen. TAI Diagnostics suspended production of the myTAIHEART test in 2020. As of September 2022, TAI Diagnostics appears to no longer be operational and it is unclear if myTAIHEART will be available through another company in the future.

AlloMap (Uses gene expression profiling)

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 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 polymerase chain reaction-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 (CareDx, 2020). 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 (Duong, 2014; Patel, 2014).

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, graft survival at 1 year is 94.7%; at 5 years, graft survival is 78.6% (OPTN, 2018).

Surveillance of transplant kidney function relies on routine monitoring of serum creatinine, urine protein levels, and urinalysis (Goldberg, 2016). 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 (Ahmad, 2004).

Kidney biopsies allow for diagnosis of acute and chronic graft rejection, which may be graded using the Banff Classification (Solez, 2008; Haas, 2016). 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 (Measurement of donor-derived cell-free DNA)

AlloSure 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 (Natera, 2020). 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 (Natera, 2019). 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 (Parulekar, 2019; Yusen, 2015). 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 (Levine, 2016). 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 1%, 0.85%, and <0.5%, respectively (CareDx, 2021).

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 (Natera, 2022).

Measurement of Donor and Third-party-induced CD154+T-cytotoxic Memory Cells

Pleximmune™: Pleximmune (Plexision, Pittsburgh, PA) is a cell-based blood test that is proposed to predict acute cellular rejection in children and adults up to 21 years of age following liver or intestine transplantation. For blood samples collected before transplantation, the test predicts the risk of transplant rejection within 60 days after transplantation. For blood samples collected within 60 days (early) after transplantation or at 200 or more days (late), the test predicts the risk of transplant rejection within 60 days after the sample was collected. The test measures the increased anti-donor activity or inflammatory immune response in the recipient’s lympocytes also called T-cytotoxic memory cells (TcM). The activity is measured after stimulating lymphocytes from the recipient with donor or donor-like cells and is expressed by the inflammatory marker CD154, or CD40 ligand (CD154+TcM). The results are expressed as a fraction of CD154+TcM induced by a reference alloantigen in a parallel reaction. A resulting immunoreactivity index (IR) of 1.1 or greater implies increased anti-donor activity therefore an increased risk of rejection while an IR <1 indicates a decreased risk of rejection (Plexision, 2020; Sindhi et al., 2016).

Pleximark™: Pleximark (Plexision, Pittsburgh, PA) is a cell-based blood test that is proposed to predict acute cellular rejection (ACR) after renal transplantation. The methodology of the test is similar to Pleximmune. The Index of Rejection (IR) is the ratio of the recipient T-cytotoxic memory cell activity toward donor or donor-like cells and reference cells. An IR of 1.15 or greater indicates an increased likelihood of ACR (Plexision, 2020).

U. S. Food and Drug Administration (FDA): Pleximmune was granted FDA Humanitarian Device Exemption (HDE) on August 26, 2014. It is “intended to be performed at a single laboratory to measure the CD154 expression on T-cytotoxic memory cells (TcM) in patient’s peripheral blood lymphocytes (PBL) isolated from heparinized whole blood (anticoagulant – sodium heparin). The Pleximmune is a qualitative prognostic test intended to be used in patients less than 21 years old with liver or small bowel transplantation. The Pleximmune test is an aid in the evaluation of the risk of acute cellular rejection (ACR) and must be used in conjunction with biopsy, standard clinical assessment and other laboratory information.

The Pleximmune™ test is intended for use at the following time periods:

Pre-transplantation period: For blood samples collected before transplantation, the test predicts the risk of transplant rejection within 60 days after transplantation.
Early and late post-transplantation period: For blood samples collected within 60 days (early) after transplantation and for blood samples collected at 200 or more days (late) after transplantation, the test predicts the risk of transplant rejection within 60 days after sampling.” (FDA, 2014).

Regulatory Status

The U.S. Food and Drug Administration (FDA) has cleared multiple biomarker tests for the detection of heart and renal allograft rejection. A few of these tests are described below:

Heartsbreath™, manufactured by Menssana Research, received a Humanitarian device exemption (H030004) in 2004 to aid in diagnosing grade 3 heart transplant rejection in patients who have received heart transplants within the preceding year. The device is intended as an adjunct to, and not as a substitute for, endomyocardial biopsy and is also limited to patients who have had endomyocardial biopsy within the previous month.
AlloMap® Molecular Expression Testing, manufactured by CareDx, formerly XDx, received 510(k) FDA clearance (k073482) in 2008. The test is to be used in conjunction with clinical assessment, for aiding in the identification of heart transplant recipients with stable allograft function and a low probability of moderate-to-severe transplant rejection. It is intended for patients at least 15 years old who are at least 2 months post transplant.
Presage® ST2 Assay kit, manufactured by Critical Diagnostics, received 510(k) FDA clearance (k093758) in 2011 for use with clinical evaluation as an aid in assessing the prognosis of patients diagnosed with chronic heart failure.

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.

myTAIHEART 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 (North, 2020). This test was developed and its performance characteristics were determined by TAI Diagnostics.

Other Tests

Other commercially available LDTs without FDA clearance or approval for use have been excluded from this evidence review 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 below.

Biomarker Tests Excluded from Review:

KidneyCare®, manufactured by CareDx, uses dd-cfDNA and GEP technology. Available as a research tool through the OKRA Registry.
AlloSeq® HCT, manufactured by CareDx, uses NGS technology to aid in the assessment of engraftment following HCT via NGS analysis of 202 biallelic SNPs. The fraction of recipient and donor genomic DNA is reported. The test is marketed for research use only.
AlloSeq® Tx17, manufactured by CareDx, uses NGS technology. An NGS test utilizing Hybrid Capture Technology conducted pre-transplant to identify optimal transplant matches. The test sequences full HLA genes and other transplant-associated genes (KIR, MICA/B, C4, HPA, ABO). This test is marketed for research use only.
Viracor TRAC®, manufactured by Eurofins, uses dd-cfDNA technology to aid in the diagnosis of solid organ transplant rejection via NGS analysis. The fraction of dd-cfDNA is reported (Yancy, 2013).
MMDx® Heart, manufactured by Kashi Clinical Laboratories/Thermo Fisher uses tissue-based microarray technology. It is tissue-based microarray mRNA gene expression test of 1283 genes post-transplant to provide a probability score of rejection as a complement to conventional biopsy processing. The test is not marketed to provide information for the diagnosis, prevention, or treatment of disease or to aid in the clinical decision-making process.
MMDx® Kidney, manufactured by Kashi Clinical Laboratories/Thermo Fisher, uses tissue-based microarray technology. It is a tissue-based microarray mRNA gene expression test of 1494 genes post-transplant to provide a probability score of rejection as a complement to conventional biopsy processing. The test is not marketed to provide information for the diagnosis, prevention, or treatment of disease or to aid in the clinical decision-making process.

Coding:

83006 (Growth stimulation expressed gene 2 [ST2, Interleukin 1 receptor like-1]) may be billed for the Presage® ST2 Assay

0055U (Cardiology [heart transplant], cell-free DNA, PCR assay of 96 DNA target sequences [94 single nucleotide polymorphism targets and two control targets], plasma) may be billed for the myTAIHEART Biomarker test.

0085T (Breath test for heart transplant rejection) may be billed for the Heartsbreath test.

81595 (Cardiology [heart transplant], mRNA, gene expression profiling by real time quantitative PCR of 20 genes [11 content and 9 housekeeping], utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score) may be billed for the AlloMap test.

There are currently no dedicated CPT codes for testing the probability of allograft rejection in renal transplantation. Some providers may use CPT code 81479 (Unlisted molecular pathology procedure) to bill for AlloSure® Donor-Derived Cell-Free DNA Test.

81560 Transplantation medicine (allograft rejection, pediatric liver and small bowel), measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, algorithm reported as a rejection risk score

Policy/
Coverage:

Coverage policies 2004057 (Laboratory Tests for Heart and Kidney Transplant Rejection) and 2015007 (ST2 Assay and myTAIHEART Assay for Chronic Heart Failure) were combined into one policy (2004057 is now archived) and updated to include heart and renal transplant rejection indications effective November 2020.

Effective December 2022

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

to evaluate the prognosis of individuals diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of individuals diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of individuals diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of individuals diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The measurement of volatile organic compounds to assist in the detection of moderate grade 2R (formerly grade 3) heart transplant rejection does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the measurement of volatile organic compounds to assist in the detection of moderate grade 2R (formerly grade 3) heart transplant rejection is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood gene expression profile tests 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, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood gene expression profile tests 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood measurement of donor-derived cell-free DNA 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, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood measurement of donor-derived cell-free DNA 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood measurement of donor-derived cell-free DNA in the management of individuals after organ transplant, including but not limited to heart transplantation, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood measurement of donor-derived cell-free DNA in the management of individuals after organ transplant, including but not limited to heart transplantation, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, in the management of individuals after organ transplant does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, in the management of individuals after organ transplant, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood gene expression profile tests in the management of organ transplant individuals including but not limited to renal transplant rejection, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood gene expression profile tests in the management of organ transplant individuals, including but not limited to renal transplant rejection, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to December 2022

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of the myTAIHEART assay in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of the myTAIHEART assay in the post cardiac transplantation period is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates.

The use of peripheral blood gene expression profile 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, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood gene expression profile 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

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, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, 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. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after organ transplant, including but not limited to heart transplantation, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood measurement of donor-derived cell-free DNA in the management of patients after organ transplant, including but not limited to heart transplantation, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, in the management of patients after organ transplant does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, in the management of patients after organ transplant, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

The use of peripheral blood gene expression profile tests in the management of organ transplant patients including but not limited to renal transplant rejection, does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes.

For members with contracts without primary coverage criteria, the use of peripheral blood gene expression profile tests in the management of organ transplant patients, including but not limited to renal transplant rejection, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective January 2022 through March 2022

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

For members with contracts without primary coverage criteria, measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, in the management of patients after organ transplant, is considered investigational. Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective November 2020 through December 2021

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness in improving health outcomes:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to November 2020

Does Not Meet Primary Coverage Criteria Or Is Investigational For Contracts Without Primary Coverage Criteria

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Effective Prior to June 2020

The use of the Presage® ST2 Assay does not meet member benefit certificate primary coverage criteria that there be scientific evidence of effectiveness:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

For members with contracts without primary coverage criteria, the use of the Presage® ST2 Assay is considered investigational:

to evaluate the prognosis of patients diagnosed with chronic heart failure;
to guide management (pharmacological, device-based, exercise, etc.) of patients diagnosed with chronic heart failure;
in the post cardiac transplantation period, including but not limited to predicting prognosis and predicting acute cellular rejection;
for any other indication.

Investigational services are specific contract exclusions in most member benefit certificates of coverage.

Rationale:

This evidence review was created in November 2004 and has been updated regularly with searches of the PubMed database. The most recent literature update was performed through August 25, 2020.

Use of Soluble Suppression of Tumorigenicity-2 Levels in Chronic Heart Failure Patients

A number of clinical studies in which sST2 blood levels were determined using the Presage ST2 Assay have reported that there is an association between ST2 levels and adverse outcomes in patients diagnosed with chronic heart failure. A substantial body of biomarker evidence has been reported retrospectively from subsets of patients enrolled in randomized controlled trials (RCTs) of heart failure interventions. These RCTs include the Valsartan Heart Failure Trial (Val-HeFT);Heart Failure: A Controlled Trial Investigating Outcomes of Exercise Training (HF-ACTION);Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA); and ProBNP Outpatient Tailored Chronic Heart Failure study(PROTECT) (Cohn, 2001; O’Connor, 2009; Kjekshus, 2007; Januzzi, 2011). Although patients in these RCTs were well-characterized and generally well-matched between study arms, the trials were neither intended nor designed specifically to evaluate biomarkers as risk predictors. At present, no prospectively gathered evidence is available from an RCT in which sST2 levels were compared with levels of a B-type natriuretic peptide (BNP or N-terminal pro B-type natriuretic peptide [NT-proBNP]) to predict risk for adverse outcomes among well-defined cohorts of patients with diagnosed chronic heart failure.

Aimo et al pooled findings of studies on the prognostic value of sST2 for chronic heart failure in a meta-analysis (Aimo, 2017). The meta-analysis selected 7 studies, including post hoc analyses of RCTs, and calculated the association between the Presage ST2 Assay and health outcomes. A pooled analysis of 7 studies found that sST2 was a statistically significant predictor of overall mortality (hazard ratio [HR] = 1.75; 95%CI, 1.37-2.22). Moreover, a pooled analysis of 5 studies found that sST2 was a significant predictor of cardiovascular mortality (HR = 1.79; 95% CI, 1.22 to 2.63).

No evidence is available from randomized or nonrandomized controlled studies in which outcomes from groups of well-matched patients managed using serial changes in sST2 blood levels were compared with those managed using the reference standard of BNP or NT-proBNP levels.

Use of Soluble Suppression of Tumorigenicity-2 in Chronic Heart Failure Patients

Several analyses, mostly retrospective, have evaluated whether sST2 levels are associated with disease prognosis, especially mortality outcomes. Studies mainly found that elevated sST2 levels were statistically associated with elevated risk of mortality. A pooled analysis of study results found that sST2 levels significantly predicted overall mortality and cardiovascular mortality. Several studies, however, found that sST2 test results did not provide additional prognostic information compared with BNP or NT-proBNP levels. In general, it appears that elevated sST2 levels predict higher risk of poor outcomes better than lower levels. The available evidence is limited by interstudy inconsistency and differences in patient characteristics, particularly the severity of heart failure, its etiology, duration, and treatment. Furthermore, most of the evidence was obtained from retrospective analyses of sST2 levels in subsets of larger patient cohorts within RCTs, potentially biasing the findings. The evidence primarily shows associations between elevated sST2 levels and poor outcomes, but does not go beyond that in demonstrating a clinical connection among biomarker status, treatment received, and clinical outcomes.

Use of Soluble ST2 Suppression of Tumorigenicity-2 in Post–Heart Transplantation Patients

Serum ST2 levels have been proposed as a prognostic marker post heart transplantation and as a test to predict acute cellular rejection (graft-versus-host disease). There is very little evidence available for these indications. Januzzi et al retrospectively assessed sST2 levels in 241 patients post–heart transplant (Januzzi, 2013). Over a follow-up out to 7 years, sST2 levels were predictive of total mortality (HR = 2.01; 95% CI, 1.15-3.51; P=.01). Soluble ST2 levels were also associated with risk of acute cellular rejection, with a significant difference between the top and bottom quartiles of sST2 levels in the risk of rejection (P=.003).

Pascual-Figal et al 26 patients with post–cardiac transplantation and an acute rejection episode (Pascual-Figal, 2011). Soluble ST2 levels were measured during the acute rejection episode and compared with levels measured when acute rejection was not present. Soluble ST2 levels were higher during the acute rejection episode (130 ng/mL) than during the nonrejection period (50 ng/mL; P=.002). Elevated sST2 levels greater than 68 ng/mL had a positive predictive value of 53% and a negative predictive value of 83% for the presence of acute cellular rejection. The addition of sST2 levels to serum BNP resulted in incremental improvement in identifying rejection episodes.

No RCTs were identified using sST2 levels that directed patient management in heart transplantation patients and which assessed patient outcomes.

No inferences can be drawn about the clinical utility of sST2 levels for patients with heart transplantation.

Few studies are available, and they are observational and retrospective. No prospective studies were identified that provide high-quality evidence on the ability of sST2 levels to predict transplant outcomes. One retrospective study (N = 241) found that sST2 levels were associated with acute cellular rejection and mortality; another study (N = 26) found that sST2 levels were higher during an acute rejection episode than before rejection.

Use of myTAIHEART in Post–Heart Transplantation Patients

The purpose of myTAIHEART is to determine prognosis and/or to predict acute cellular rejection in patients with heart transplantation as an alternative to or an improvement on existing tests.

Serum donor fraction (%), defined as the ratio of donor specific cell free DNA to total cell free DNA, has been proposed as a test to predict acute cellular rejection. In study funded by TAI Diagnostics, Inc., North et al performed a blinded clinical validation study on 158 matched pairs of endomyocardial biopsy-plasma samples collected from 76 volunteer adult and pediatric heart transplant recipients (ages 2 months or older, and 8 days or more post-transplant) between June of 2010 and Aug 2016 from 2 Milwaukee transplant centers (North, 2020). Based on acute cellular rejection grade as defined by the 2004 International Society for Heart and Lung Transplantation (ISHLT) classification, Receiver Operating Characteristic (ROC) analysis was performed to evaluate diagnostic accuracy across all possible cutoffs. To maximize diagnostic accuracy, Youden’s Index was used to select the optimal cutoff, found to correspond to a donor fraction value of 0.32%. Using this cutoff, clinical performance characteristics of the assay included a negative predictive value (NPV) of 100.00% for grade 2R or higher acute cellular rejection, with 100.00% sensitivity and 75.48% specificity; Area under the Curve (AUC) for this analysis was 0.842, indicative of robust ability of the donor fraction assay to rule out 2R or greater acute cellular rejection for donor fraction values less than 0.32%. There was no statistically significant correlation of donor fraction with age. Donor fraction elevation can also be caused by other forms of injury to the donor heart such as acute cellular rejection 1R, acute antibody-mediated rejection (AMR), and presence of coronary artery vasculopathy (CAV), thereby requiring correlation of myTAIHEART results with other clinical indicators.

In study funded by a grant from the National Institutes of Health and TAI Diagnostics, Inc., Richmond et al assessed 174 post-cardiac transplant patients from 7 centers (ages 2.4 months-73.4 years) days with myTAIHEART testing ( before transplant; 1, 4, and 7 days following transplant; and at discharge from transplant hospitalization) using blinded analysis of biopsy-paired samples (Richmond, 2020). All the patients were followed for at least 1 year. Donor fraction, defined as the ratio of cell free DNA specific to the transplanted organ to the total amount of cell free DNA present in a blood sample was higher in acute cellular rejection 1R/2R (n = 15) than acute cellular rejection 0R (healthy) (n = 42) (P = 0.02); an optimal donor fraction threshold (0.3%) was determined by the use of Receiver Operating Characteristic (ROC) analysis, revealing an AUC of 0.814 with a sensitivity of 0.65, specificity of 0.93, and an NPV of 81.8% for the absence of any allograft rejection.

Few studies are available, and they are observational and of small sample size. No high-quality evidence was found supporting the ability of myTAIHEART levels to predict transplant outcomes. A clinical validation study (n=76) reports donor fraction cutoff value of 0.32% cutoff provides a negative predictive value (NPV) of 100.00% for grade 2R or higher acute cellular rejection, with 100.00% sensitivity and 75.48% specificity; an additional prospective study (N = 174) found that myTAIHEART levels were associated with acute cellular rejection with an optimal donor fraction threshold of 0.3% to rule out the presence of either acute cellular rejection or antibody-mediated rejection.

Measurement of Volatile Organic Compounds for Heart Transplant

The U.S. Food and Drug Administration approval of the Heartsbreath test was based on the results of the Heart Allograft Rejection: Detection with Breath Alkanes in Low Levels (HARDBALL) study sponsored by the National Heart, Lung, and Blood Institute (Phillips, 2004). The HARDBALL study was a 3-year, multicenter study of 1061 breath samples in 539 heart transplant patients. Before the scheduled endomyocardial biopsy, patient breath was analyzed by gas chromatography and mass spectroscopy for volatile organic compounds. The amount of C4 to C20 alkanes and monomethylalkanes was used to derive the marker for rejection, known as the breath methylated alkane contour. The breath methylated alkane contour results were compared with subsequent biopsy results, as interpreted by 2 readers using the International Society for Heart and Lung Transplantation biopsy grading system as the criterion standard for rejection (Stewart, 2005).

The authors of the HARDBALL study reported that the abundance of breath markers that measured oxidative stress was significantly greater in grade 0, 1, or 2 rejection than in healthy normal persons. In contrast, in grade 3 rejection, the abundance of breath markers that measure oxidative stress was found to be reduced, most likely due to accelerated catabolism of alkanes and methylalkanes that make up the breath methylated alkane contour. The authors also reported that in identifying grade 3 rejection, the negative predictive value (NPV) of the breath test (97.2%) was similar to endomyocardial biopsy (96.7%) and that the breath test could potentially reduce the total number of biopsies performed to assess for rejection in patients at low-risk for grade 3 rejection. The sensitivity of the breath test was 78.6% vs 42.4% with biopsy. However, the breath test had a lower specificity (62.4%) and a lower positive predictive value (PPV; 5.6%) in assessing grade 3 rejection than a biopsy (specificity, 97%; PPV=45.2%). In addition, the breath test was not evaluated in grade 4 rejection.

Findings from the HARDBALL study were published by Phillips et al (Phillips, 2004). No subsequent studies evaluating the use of the Heartsbreath test to assess for graft rejection were identified in literature updates.

No RCTs assessing the measurement of volatile organic compounds to diagnose cardiac allograft rejection were identified.

A published study found that for identifying grade 3 (now grade 2R) rejection, the NPV of the breath test the study evaluated (97.2%) was similar to endomyocardial biopsy (96.7%), and the sensitivity of the breath test (78.6%) was better than that for biopsy (42.4%). However, the breath test had a lower specificity (62.4%) and a lower PPV (5.6%) in assessing grade 3 rejection than a biopsy (specificity, 97%; PPV=45.2%). The breath test was also not evaluated for grade 4 rejection. At present, no studies evaluating the clinical utility for the measurement of volatile organic compound testing for heart transplant have been identified.

Gene Expression Profiling for Heart Transplant

A TEC Assessment reviewed the evidence on the use of GEP using the AlloMap test (BCBSTEC, 2011). The Assessment concluded that the evidence was insufficient to permit conclusions about the effect of the AlloMap test on health outcomes.

Patterns of gene expression for the development of the AlloMap test were studied in the Cardiac Allograft Rejection Gene Expression Observation (CARGO) study, which included 8 U.S. cardiac transplant centers enrolling 629 cardiac transplant recipients (Deng, 2006). The study included the discovery and validation phases. In the discovery phase, patient blood samples were obtained during the endomyocardial biopsy, and the expression levels of more than 7000 genes involved in immune responses were assayed and compared with the biopsy results. A subset of 252 candidate genes was identified, from which a panel of 11 genes was selected for evaluation. A proprietary algorithm was applied to the results, producing a single score that considers the contribution of each gene in the panel.

The validation phase of the CARGO study, published by Deng et al, was prospective, blinded, and enrolled 270 patients (Deng, 2006). Primary validation was conducted using samples from 63 patients independent from discovery phases of the study and enriched for biopsy-proven evidence of rejection. A prospectively defined test cutoff value of 20 resulted in a sensitivity of 84% of patients with moderate/severe rejection but a specificity of 38%. Of note, in the “training set” used in the study, these rates were 80% and 59%, respectively. The authors evaluated the 11-gene expression profile on 281 samples collected at 1 year or more from 166 patients who were representative of the expected distribution of rejection in the target population (and not involved in discovery or validation phases of the study). When a test cutoff of 30 was used, the NPV (no moderate/severe rejection) was 99.6%; however, only 3.2% of specimens had grade 3 or higher rejection. In this population, grade 1B scores were found to be significantly higher than grade 0, 1A, and 2 scores but were similar to grade 3 scores.

A second prospective multicenter study evaluating the clinical validity of GEP with the AlloMap test (CARGO II) was published by Crespo-Leiro et al (Crespo-Leiro, 2016). The study enrolled 499 heart transplant recipients undergoing surveillance for allograft rejection. The reference standard for rejection status was histologic grade from an endomyocardial biopsy performed on the same day as blood samples were collected. Blood samples need to be collected 55 days or more posttransplant, more than 30 days after blood transfusion, more than 21 days after administration of prednisone 20 mg/day or more, and more than 60 days after treatment for a prior rejection. Patients had a total of 1579 eligible blood samples for which paired GEP scores and endomyocardial biopsy rejection grades were available.

As in the original CARGO study, the proportion of cases of rejection was small. The prevalence of moderate-to-severe rejection (grade 2R/>3A) reported by local pathologists was 3.2%, which was reduced to 2.0% when confirmation from 1 or more other independent pathologist was required. At a GEP cutoff of 34, for patients who were at least 2 to 6 months posttransplant, the sensitivity of GEP for detecting grade 2R/>3A was 25.0%, and the specificity was 88.7%. The PPV and NPV were 4.0% and 98.4%, respectively. Using the same cutoff of 34, for patients more than 6 months posttransplant, the sensitivity of GEP was 25.0%, the specificity was 88.8%, the PPV was 4.3%, and the NPV was 98.3%. The number of true-positives used in the above calculations was 5 (9.1%) of 55 for patients at least 2 to 6 months posttransplant and 6 (10.2%) of 59 for patients more than 6 months posttransplant.

Kobashigawa et al published the results of a pilot RCT evaluating the use of the AlloMap test in patients who were 55 days to 6 months posttransplant (Kobashigawa, 2015). The trial design was similar to that of the Invasive Monitoring Attenuation through Gene Expression (IMAGE) RCT, discussed next. Sixty subjects were randomized to rejection monitoring with AlloMap or with endomyocardial biopsy at prespecified intervals of 55 days and 3, 4, 5, 6, 8, 10, and 12 months posttransplant. The threshold for a positive AlloMap test was set at 30 for patients 2 to 6 months posttransplant and 34 for patients after 6 months posttransplant, based on data from the CARGO study. Endomyocardial biopsy outside of the scheduled visits was obtained in either group if there was clinical or echocardiographic evidence of graft dysfunction and for the AlloMap group if the score was above the specified threshold. The incidence of the primary outcome at 18 months posttransplant (a composite outcome of the first occurrence of any of the following: death or retransplant, rejection with hemodynamic compromise, or allograft dysfunction due to other causes) did not differ significantly between the AlloMap and biopsy groups (10% vs 17%; p=0.44). The number of biopsy-proven rejection episodes (International Society for Heart and Lung Transplantation grading system ≥2R) within the first 18 months did not differ significantly between groups (3 in the AlloMap group vs 1 in the biopsy group; p=0.31). Of the rejections in the AlloMap group, 1 was detected after an elevated routine AlloMap test, while 2 were detected after patients presenting with hemodynamic compromise. As in the IMAGE study, a high proportion of rejection episodes were detected by clinical signs or symptoms (however, this study had only 3 rejection episodes in the AlloMap group).

In 2010, the results of the IMAGE study were published (Pham, 2007; Pham, 2010). This was an industry-sponsored, nonblinded, noninferiority RCT that compared outcomes in 602 patients managed with the AlloMap test (n=297) or with routine endomyocardial biopsies (n=305). The trial included adults from 13 centers who underwent cardiac transplantation between 1 and 5 years prior to participating, were clinically stable and had a left ventricular ejection fraction of at least 45%. To increase enrollment, the trial protocol was later amended to include patients who had undergone transplantation between 6 months and 1 year prior to participating; this subgroup ultimately comprised only 15% of the final sample (n=87). Each transplant center used its own protocol for determining the intervals for routine testing. At all sites, patients in both groups underwent clinical and echocardiographic assessments in addition to the assigned surveillance strategy. According to the study protocol, patients underwent biopsy if they had signs or symptoms of rejection or allograft dysfunction at clinic visits (or between visits) or if the echocardiogram showed a left ventricular ejection fraction decrease of at least 25% compared with the initial visit. Additionally, patients in the AlloMap group underwent biopsy if their test score was above a specified threshold; however, if they had 2 elevated scores with no evidence of rejection found on 2 previous biopsies, no additional biopsies were required. The AlloMap test score varied from 0 to 40, with higher scores indicating a higher risk of transplant rejection. The investigators initially used 30 as the cutoff for a positive score; the protocol was amended to use a cutoff of 34 to minimize the number of biopsies needed. Fifteen patients in the AlloMap group and 26 in the biopsy group did not complete the trial.

The primary outcome was a composite variable: (1) the first occurrence of rejection with hemodynamic compromise; (2) graft dysfunction due to other causes; (3) death; or (4) retransplantation. Use of the AlloMap test was considered noninferior to the biopsy strategy if the 1-sided upper boundary of the 95% confidence interval (CI) for the hazard ratio comparing the 2 strategies was less than the prespecified margin of 2.054. The margin was derived using the estimate of a 5% event rate per year in the biopsy group, taken from published observational studies, and allowing for an event rate of up to 10% per year in the AlloMap group.

According to Kaplan-Meier analysis, the 2-year event rate was 14.5% in the AlloMap group and 15.3% in the biopsy group. The corresponding hazard ratio was 1.04 (95% CI, 0.67 to 1.68). The upper boundary of the CI of the hazard ratio (1.68) fell within the prespecified noninferiority margin (2.054); thus, GEP was considered noninferior to endomyocardial biopsy. Death from all causes, a secondary outcome, did not differ significantly between groups. There were 13 (6.3%) deaths in the AlloMap group and 12 (5.5%) in the biopsy group (P=0.82). During follow-up, there were 34 treated episodes of graft rejection in the AlloMap group. Only 6 (18%) of the 34 patients with graft rejection presented solely with elevated AlloMap scores. Twenty (59%) patients presented with clinical signs/symptoms and/or graft dysfunction on echocardiogram and 7 patients had an elevated AlloMap score plus clinical signs/symptoms with or without graft dysfunction on echocardiogram. In the biopsy group, 22 patients were detected solely due to an abnormal biopsy.

A total of 409 biopsies were performed in the AlloMap group and 1249 in the biopsy group. Most biopsies in the AlloMap group (67%) were performed because of elevated gene profiling scores. Another 17% were performed due to clinical or echocardiographic manifestations of graft dysfunction, and 13% were performed as part of routine follow-up after treatment for rejection. There was 1 (0.3%) adverse event associated with biopsy in the AlloMap group and 4 (1.4%) in the biopsy group. In terms of quality of life, the physical health and mental health summary scores of the 12-Item Short-Form Health Survey were similar in the 2 groups at baseline and did not differ significantly between groups at 2 years.

A limitation of the trial was that the threshold for a positive AlloMap test was changed partway through the study; thus, the optimal test cutoff remains unclear. Moreover, the trial was not blinded, which could have affected treatment decisions based on clinical findings, such as whether to recommend a biopsy. In addition, the study did not include a group that only received clinical and echocardiographic assessment, so the value of AlloMap testing beyond that of clinical management alone cannot be determined. The uncertain incremental benefit of the AlloMap test is highlighted by the finding that only 6 of the 34 treated episodes of graft rejection detected during follow-up in the AlloMap group were initially identified solely due to an elevated GEP score. Since 22 episodes of asymptomatic rejection were detected in the biopsy group, the AlloMap test does not appear to be a sensitive test, possibly missing more than half of the episodes of asymptomatic rejection. Because clinical outcomes were similar in the 2 groups, there are at least 2 possible explanations: the clinical outcome of the study may not be sensitive to missed episodes of rejection, or it is not necessary to treat asymptomatic rejection. In addition, the trial was only statistically powered to rule out more than a doubling of the rate of the clinical outcome, which some may believe is an insufficient margin of noninferiority. Finally, only 15% of the final study sample had undergone transplantation less than 1 year before study participation; therefore, findings might not be generalizable to the population of patients 6 to 12 months posttransplant.

The 2 studies (CARGO, CARGO II) examining the diagnostic performance of GEP using the AlloMap test for detecting moderate or severe rejection were flawed by lack of a consistent threshold (ie, 20, 30, or 34) for determining positivity and by a small number of positive cases. In the available studies, although the NPVs were relatively high (ie, at least 88%), the performance characteristics were calculated based on detection of 10 or fewer cases of rejection each. Moreover, the PPV in the CARGO II study was only 4.0% for patients who were at least 2 to 6 months posttransplant and 4.3% for patients more than 6 months posttransplant.

The most direct evidence on the clinical utility of GEP using the AlloMap test comes from a large RCT comparing a GEP-directed strategy with an endomyocardial biopsy-directed strategy for detecting rejection; it found that the GEP-directed strategy was noninferior. However, given the high proportion of rejection episodes in the GEP-directed strategy group detected by clinical signs/symptoms, the evidence is insufficient to determine that health outcomes are improved because of the uncertain incremental benefit of GEP. In addition, a minority of subjects assessed were in the first year posttransplant. Results from a pilot RCT would suggest that GEP may have a role in evaluating for heart transplant rejection beginning at 55 days posttransplant, but the trial was insufficiently powered to permit firm conclusions about the noninferiority of early GEP use.

Donor-Derived Cell-Free DNA Testing for Renal Transplant

Development of the AlloSure test was conducted in the multicenter prospective study by Bloom et al, which both recruited patients who were less than 3 months after renal transplant (n=245) and recruited renal transplant patients requiring a biopsy for suspicion of graft rejection (n=139) (Bloom, 2017). For the primary analysis, an active rejection was defined as the combined categories of T cell-mediated rejection, acute/active antibody-mediated rejection, and chronic/active antibody-mediated rejection as defined by the Banff working groups. Only patients undergoing biopsy were considered; further exclusion of biopsies that were not for cause had an inadequate or incomplete collection of biopsies or corresponding blood samples or had prior allograft in situ. These exclusions resulted in the main study cohort of 102 patients (107 biopsies). Within this population, acute rejection was noted in 27 patients (27 biopsies). After statistical analysis accounting for multiple biopsies from the same patient, the threshold dd-cfDNA fraction corresponding to acute rejection was set to 1.0% or higher. In the main study group, this resulted in a sensitivity of 59% (95% CI, 44% to 74%) and specificity of 85% (95% CI, 79% to 81%) for detecting active rejection vs no rejection. Using the original data set including all biopsies performed for clinical suspicion of rejection, 58 cases of acute rejection were diagnosed in 204 biopsies (170 patients). This PPV was 61% and the NPV 84%. Biopsies performed for surveillance (n=34 biopsies) were excluded from analysis in this study, as only 1 biopsy for surveillance demonstrated acute rejection. Study limitations included the absence of a validation data set.

Huang et al conducted a smaller single center that recruited 63 renal transplant patients with suspicion of rejection that had AlloSure assessment of dd-cfDNA within 30 days of an allograft biopsy (Huang, 2019). Median years from transplant to dd-dfDNA measurement was 2.0 (interquartile range, 0.3 to 6.5). Within this population, biopsy found acute rejection in 34 (54%) of patients; 10 (15.9%) were cell-mediated only, 22 (25.4%) were antibody-mediated only, and 2 (3.2%) were mixed cell-mediated and antibody-mediated. In contrast to the study by Bloom et al (2017), the optimal threshold for a positive dd-cfDNA result was identified as ≥0.74%. For the outcome of any rejection (ie, cell-mediated, antibody-mediated, or mixed), use of this threshold was associated with an overall sensitivity of 79.4%, specificity of 72.4%, PPV of 77.1%, and NPV of 75.0%. Discrimination of rejection differed by biopsy findings, however. For the subgroup of patients with antibody-mediated rejection, the sensitivity was 100%, specificity was 71.8%, PPV was 68.6%, and NPV was 100%. The dd-cfDNA test did not discriminate rejection in patients with cell-mediated rejection, as evidenced by an AUC of 0.43 (95% CI, 0.17 to 0.66). Major limitations of this study is its small sample size and single-center setting.

For individuals who have chronic heart failure who receive the sST2 assay to determine prognosis and/or to guide management, the evidence includes correlational studies and 2 meta-analyses. Relevant outcomes are overall survival, quality of life, and hospitalization. Most of the evidence is from reanalysis of existing randomized controlled trials and not from studies specifically designed to evaluate the predictive accuracy of sST2, and prospective and retrospective cross-sectional studies made up a large part of 1 meta-analysis. Studies have mainly found that elevated sST2 levels are statistically associated with elevated risk of mortality. A pooled analysis of study results found that sST2 significantly predicted overall mortality and cardiovascular mortality. Several studies, however, found that sST2 test results did not provide additional prognostic information compared with N-terminal pro B-type natriuretic peptide levels. Moreover, no comparative studies were identified on the use of the sST2 assay to guide management of patients diagnosed with chronic heart failure. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have heart transplantation who receive sST2 assay to determine prognosis and/or to predict acute cellular rejection, the evidence includes a small number of retrospective observational studies on the Presage ST2 Assay. Relevant outcomes are overall survival, morbid events, and hospitalization. No prospective studies were identified that provide high-quality evidence on the ability of sST2 to predict transplant outcomes. One retrospective study (n = 241) found that sST2 levels were associated with acute cellular rejection and mortality; another study (n = 26) found that sST2 levels were higher during an acute rejection episode than before rejection. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have heart transplantation who receive myTAIHEART assay to determine acute cellular rejection, the evidence includes observational studies. A validation study using 158 matched endomyocardial biopsy-plasma pairs from 76 pediatric and adult heart transplant recipients (ages 2 months or older, and 8 days more post-transplant) found a donor-specific fraction cutoff (0.32%) that produced a 100% negative predictive value for Grade 2 or higher acute cellular rejection. A prospective observational blinded study (n=174; pediatric=101, adult=73) using biopsy-paired samples found that myTAIHEART level was associated with acute cellular and antibody-mediated rejection in both adult and pediatric heart transplant populations, and that an optimal donor fraction threshold (0.3%) ruled out the presence of either acute cellular rejection or antibody-mediated rejection. Both studies received industry funding. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a heart transplant who receive a measurement of volatile organic compounds to assess cardiac allograft rejection, the evidence includes a diagnostic accuracy study. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The published study found that, for identifying grade 3 (now grade 2R) rejection, the negative predictive value of the breath test the study evaluated (97.2%) was similar to endomyocardial biopsy (96.7%) and the sensitivity of the breath test (78.6%) was better than that for biopsy (42.4%). However, the breath test had a lower specificity (62.4%) and a lower positive predictive value (5.6%) in assessing grade 3 rejection than a biopsy (specificity, 97%; positive predictive value, 45.2%). The breath test was also not evaluated for grade 4 rejection. This single study is not sufficient to determine the clinical validity of the test measuring volatile organic compounds and no studies on clinical utility were identified. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have a heart transplant who receive gene expression profiling (GEP) to assess cardiac allograft rejection, the evidence includes 2 diagnostic accuracy studies and several randomized controlled trials evaluating clinical utility. Relevant outcomes are overall survival, test validity, morbid events, and hospitalizations. The 2 studies, Cardiac Allograft Rejection Gene Expression Observation (CARGO, CARGO II) examining the diagnostic performance of GEP for detecting moderate-to-severe rejection lacked a consistent threshold for defining a positive GEP test (ie, 20, 30, or 34) and reported a low number of positive cases. In the available studies, although the negative predictive values were relatively high (ie, at least 88%), the performance characteristics were only calculated based on 10 or fewer cases of rejection; therefore, performance data may be imprecise. Moreover, the positive predictive value in CARGO II was only 4.0% for patients who were at least 2 to 6 months posttransplant and 4.3% for patients more than 6 months posttransplant. The threshold indicating a positive test that seems to be currently accepted (a score of 34) was not prespecified; rather it evolved partway through the data collection period in the Invasive Monitoring Attenuation through Gene Expression (IMAGE) study. In addition, the IMAGE study had several methodologic limitations (eg, lack of blinding); further, the IMAGE study failed to provide evidence that GEP offers incremental benefit over biopsy performed on the basis of clinical exam or echocardiography. Patients at the highest risk of transplant rejection are patients within 1 year of the transplant, and, for that subset, there remains insufficient data on which to evaluate the clinical utility of GEP. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals with a renal transplant and clinical suspicion of allograft rejection who receive testing of dd-cfDNA to assess renal allograft rejection, the evidence includes small diagnostic accuracy studies. Relevant outcomes are OS, test validity, morbid events, and hospitalizations. One study examined the diagnostic performance of dd-cfDNA for detecting moderate-to-severe rejection; the NPV was moderately high (84%), and performance characteristics were calculated on 27 cases of active transplant rejection. The threshold indicating a positive test was not prespecified. A subsequent smaller single-center study that explored variation in clinical validity based on different rejection mechanisms found the strongest performance characteristics for AlloSure with antibody-mediated rejection. The evidence is insufficient to determine the effects of the technology on health outcomes.

SUPPLEMENTAL INFORMATION

Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2012 Input

In response to requests, input was received from 7 academic medical centers and 1 specialty society while this policy was under review in 2012. Input was mixed on whether AlloMap should be investigational. Four reviewers agreed with the investigational status, 1 disagreed, and 3 indicated it was a split decision/other. Reviewers generally agreed that the sensitivity and specificity have not yet been adequately defined for AlloMap and that the negative predictive value was not sufficiently high to preclude the need for biopsy. There was mixed input about the need for surveillance cardiac biopsies to be performed in the absence of clinical signs and/or symptoms of rejection.

2008 Input

In response to requests, input was received from 2 academic medical centers and 2 physician specialty societies while this policy was under review in 2008. Three reviewers agreed that these approaches for monitoring heart transplant rejection are considered investigational. The American College of Cardiology disagreed with the policy, stating that the College considers the available laboratory tests to have good potential to diagnose heart transplant rejection and reduce the frequency of invasive biopsies performed on heart transplant patients, although questions remained as to their role in clinical practice.

Practice Guidelines and Position Statements

American College of Cardiology et al

In 2017, the American College of Cardiology Foundation, American Heart Association, and Heart Failure Society published a focused update of their 2013 guideline on the management of heart failure (Yancy, 2013; Yancy, 2017). Part of the focus of the update was on biomarkers. The guidelines stated that soluble suppression of tumorigenicity-2 (ST2) is a biomarker for myocardial fibrosis that may predict hospitalization and death in patients with heart failure and provides additive prognostic information to natriuretic peptide levels. The guidelines were based on a class IIb recommendation (weak; benefit ≥ risk) with level B-NR evidence (moderate-quality, nonrandomized) for the use of ST2 as an option to provide additive prognostic information to established clinical evaluation and biomarkers. The guidelines did not address other uses of ST2 or myTAIHEART.

International Society of Heart and Lung Transplantation

In 2010, the International Society of Heart and Lung Transplantation issued guidelines for the care of heart transplant recipients (Costanzo, 2010). The guidelines included the following recommendations:

“The standard of care for adult HT recipients is to perform periodic EMB during the first 6 to 12 postoperative months for surveillance of HT rejection.” Class of Recommendation (COR) IIa Level of Evidence (LOE) C

“After the first post-operative year, EMB surveillance for an extended period of time (eg, every 4-6 months) is recommended in HT patients at higher risk for late acute rejection….” COR IIa LOE C

“Gene Expression Profiling (AlloMap) can be used to rule out the presence of ACR of grade 2R or greater in appropriate low-risk patients, between 6 months and 5 years after HT.” COR 11a LOE B

Kidney Disease Improving Global Outcomes

The Kidney Disease Improving Global Outcomes (2009) issued guidelines for the care of kidney transplant recipients (Kasiske, 2010). The guidelines included the following recommendations:

“We recommend kidney allograft biopsy when there is a persistent, unexplained increase in serum creatinine.” Strength of Recommendation (SOR) Level 1 Level of Evidence (LOE) C

“We suggest kidney allograft biopsy when serum creatinine has not returned to baseline after treatment of acute rejection.” SOR Level 2 LOE D

“We suggest kidney allograft biopsy every 7-10 days during delayed function.” SOR Level 2 LOE C

“We suggest kidney allograft biopsy if expected kidney function is not achieved within the first 1-2 months after transplantation.” SOR Level 2 LOE D

“We suggest kidney allograft biopsy when there is new onset of proteinuria.” SOR Level 2 LOE C

“We suggest kidney allograft biopsy when there is unexplained proteinuria ≥3.0 g/g creatinine or ≥3.0 g per 24 hours.” SOR Level 2 LOE C

2022 Update

There is insufficient evidence to support accuracy and clinical utility of Pleximark or Pleximmune for detection of acute cellular rejection after organ transplantation. The literature found was in the form or reports of descriptive studies.

December 2022 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2022. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

Kim et al assessed the clinical validity of the Prospera Heart dd-cfDNA test versus endocardial biopsy for prediction of acute heart transplant rejection. The study included 811 samples (703 prospectively collected and 108 retrospectively collected) from 223 heart transplant patients with a planned biopsy from 2 U.S. centers (Kim, 2022). The median patient age was 54 years and 27% were female. Race/ethnicity of the study population was: 54% White, 21% Hispanic, 12% Black, 6% Asian and 5% other race/ethnicity. The majority (91% [737/811]) of reference standard biopsies were conducted for surveillance, and median dd-cfDNA was lower in the surveillance samples (0.04%) than the for-cause samples (0.22%). The time from transplant to biopsy was 10 weeks, and the total prevalence of acute rejection was 9.0%. Median dd-cfDNA % was 0.58% in patients with acute rejection, although fractions varied according to rejection type/grade and were higher in those with antibody mediated rejection (median range 0.44% to 3.43%) than those with acute cellular rejection (median range 0.045% to 0.13%). In patients without acute rejection, dd-cfDNA % was 0.04. Diagnostic accuracy for 3 dd-cfDNA fractions were explored: 0.12%, 0.15% and 0.20%. At a cut-off off of 0.12%, sensitivity was 86.6%, specificity was 72.0%, PPV was 23.4%, and NPV 98.2%. Corresponding values at a dd-cfDNA cut-of of 0.15% were 78.6%, 76.9%, 25.1% and 97.3%, and 78.6%, 82.1%, 30.3% and 97.5% at a dd-cfDNA cut-off of 0.20%. This resulted in an AUC for detection of acute rejection of 0.86 (95% CI 0.77 to 0.96). The optimal dd-cfDNA fraction for detection of heart transplant rejection has yet to be established. Limitations of the study include potential selection bias, as only patients with a scheduled biopsy were included in the study, and study authors noted that the prevalence of acute rejection in the study cohort was higher than in other cohorts.

Preliminary results from the ongoing Trifecta study (NCT04239703) published by Halloran et al provide assessment of combined dd-cfDNA fraction and absolute values for prediction of active kidney allograft rejection (Halloran, 2022). The study reported data from 218 individuals included in a test set (median age 51 years) enrolled from December 2019 to July 2021. Thirty-eight patients were female and 17% were Black or African American; other race or ethnicity data were not reported. The mean post-transplant time was 1,439 days (3.9 years). The study used a training set (n=149) to identify optimal % dd-cfDNA (≥1%) and absolute values cut-offs (≥78 cp/mL). Accuracy of dd-cfDNA testing was compared with the Molecular Microscope Diagnostic System (MMDx) and histological analysis using Banff criteria as reference standards. The use of two reference standards in this study is based on previous Trifecta analysis that suggested a strong correlation between dd-cfDNA fraction and molecular changes due to rejection assessed using MMDx (Halloran, 2022).

A retrospective study conducted by Keller et al included 157 patients enrolled in a post-transplant home surveillance program that included the AlloSure test for detection of acute allograft rejection (Keller, 2022). The study analyzed data from patients at 4 U.S. centers. Data were collected from March to September 2020, during the COVID-19 pandemic at a time when in-office visits were limited and routine, surveillance bronchoscopy was deferred. Home monitoring was intended to identify those patients most at risk for acute rejection for triage to bronchoscopy. Study inclusion was limited to adults >18 years between 30 days and 3 years post-transplant. Of the total cohort, the mean age was 59 years and the majority were male (54%) and White race (64%). Eighteen percent were Black, 3% Asian, and 15 % other race/ethnicity. The mean time since transplantation as 13 months, and 82% underwent bilateral transplantation. Diagnosis of ACR, AMR, infection, or a composite of these outcomes (Acute Lung Allograft Dysfunction [ALAD]), was made based on biopsy and/or clinical diagnosis. Mean dd-cfDNA % was 1.6% for acute rejection (ACR+AMR) and 1.7% for ALAD. In comparison, the mean dd-cfDNA in stable patients was 0.37%. Using a dd-cfDNA cut-off of 1.0% for detection of ALAD, the sensitivity was 73.9%, specificity 87.7%, PPV 43.4% and NPV 96.5%. Of the 157 patients with dd-cfDNA measurement for surveillance, 52 also had a contemporaneous reference standard surveillance bronchoscopy independent of dd-cfDNA level (i.e., patients who were not triaged to bronchoscopy). When analysis was limited to this subgroup, diagnostic performance declined slightly: 76.2% sensitivity, 70.0% specificity, 66.7% PPV and 79.2% NPV. The study was limited by the small sample size, particularly the limited number of unselected patients who underwent both dd-cfDNA testing and bronchoscopy.

Rosenheck et al assessed the predictive ability of dd-cfDNA testing using the Prospera test for lung transplant rejection (Rosenheck, 2022). The study included 195 samples from 103 patients, who were predominantly White (93%) and male (60%); mean age was 62 years. Black and Hispanic patients comprised 6% and 1% of the study population, respectively. The median time since lung transplant was 198 days, and most patients (85%) underwent lung biopsy for routine transplant surveillance. Consistent with other dd-cfDNA studies, median dd-cfDNA % was higher in patients with acute rejection (AR), which included acute cellular rejection (1.43%) or antibody-mediated rejection (2.50%), than those who were stable (0.46%). Prevalence of acute rejection was 28% (29/103), and prevalence of CLAD or neutrophilic-responsive allograft dysfunction (NRAD) was 21% (22/103); patients could be included in both diagnostic groups. Using a dd-cfDNA threshold of ≥1% for prediction of acute rejection, sensitivity was 89.1% and specificity was 82.9%, resulting in an AUC of 0.91 (95% CI 0.83 to 0.98). PPV was 51.9% and NPV was 97.3%. For a combined measure that included AR, CLAD/NRAD, and infection, sensitivity was 59.9%, specificity 83.9%, AUC 0.76, PPV 43.6%, and NPV 91.0%. As with other dd-cfDNA studies in lung transplantation, this study was limited by the small sample size though unlike other studies samples were collected prospectively.

2023 Update

Annual policy review completed with a literature search using the MEDLINE database through November 2023. No new literature was identified that would prompt a change in the coverage statement. The key identified literature is summarized below.

A retrospective cohort study conducted by Rodgers et al compared dd-cfDNA testing with Allosure, which examines 405 single nucleotide polymorphisms (SNPs), to Prospera, which evaluates 13,292 SNPs, in 112 heart transplant patients (Rodgers, 2023). Participants were enrolled from October 2020 to January 2022 and had a median age of 60 years (IQR, 47 to 65 years). Both tests used a dd-cfDNA threshold value of 15%. Testing with Allosure resulted in a low sensitivity (39%) and high specificity (82%) for identification of acute rejection; the Prospera test had similar characteristics with sensitivity at an identical 39% and a negligible difference in specificity (84%). Between-group comparisons showed no difference between the 2 tests in this small cohort. PPV with the Allosure test was 6.2% compared to 7% in Prospera testing (p=.7) and NPV was 98% for both tests (p=.76).

Two meta-analyses were identified which assessed the clinical validity of dd-cfDNA testing (Wijtvliet, 2020; Xiao, 2021). Both studies quantitatively synthesized the findings from 9 observational studies to determine the diagnostic accuracy of dd-cfDNA as a potential marker of graft rejection following kidney transplantation. Xiao et al calculated a pooled sensitivity of 0.70 (95% CI, 0.57-0.81; I2, 65) and specificity of 0.78 (0.70-0.84; I2, 75) from 6 studies evaluating the diagnostic accuracy of dd-cfDNA for any rejection episode (Xiao, 2021). The area under the receiver operating characteristics curve (AUC) was 0.81 (95% CI, 0.77 to 0.84; I2, 65) with an overall diagnostic odds ratio (DOR) of 8.18 (95% CI, 5.11 to 13.09). Similar pooled estimates were calculated for 5 studies discriminating AMR. The authors reported a pooled sensitivity of 0.84 (95% CI, 0.75 to 0.90; I2, 0) and a specificity of 0.80 (95% CI, 0.75 to 0.84; I2, 4) with an AUC of 0.89 (95% CI, 0.86 to 0.91) and overall DOR of 20.48 (95% CI, 10.76 to 38.99). Overall, the authors found greater value in dd-cfDNA as a biomarker for AMR in patients with suspected renal dysfunction than in discriminating a main rejection episode and cite the need for more large-scale, prospective research on the topic.

Wijvliet et al performed stratified analyses of dd-cfDNA fraction and calculated pooled median estimates in the following patient groups: patients, patients without rejection at indication biopsy, patients with pure T cell-mediated rejection, and patients with a component AMR (Wijvliet, 2020). In stable patients (n=1149; 5 studies), the median dd-cfDNA fraction was 0.29% (95% CI, 0.21% to 0.45%) and in the AMR group (n=89; 6 studies) the average was nearly 10 times greater (2.5%; 95% CI, 1.4% to 2.9%). In T cell-mediated rejection patients (n=35; 4 studies), the weighted median was found to be 0.27% (95% CI, 0.26% to 2.69%) and in patients without rejection (n=225; 4 studies) the weighted median was 0.57% (95% CI, 0.30 to 0.67). The authors also calculated the weighted median differences in medians (WMDMs) between groups and found that median dd-cfDNA fractions were significantly higher in patients with AMBR than in patients without rejection (1.89%; 95% CI, 1.02 to 2.6), stable patients (2.3%; 95% CI, 1.8 to 2.69). However, no significant difference was observed for WMDMs between AMR patients and T cell-mediated rejection patients or for comparing T cell-mediated rejection to stable patients. This review had moderate heterogeneity for most between-group comparisons. Overall, higher dd-cfDNA fractions were found in patients with AMR than in individuals without rejection or stable patients, but a less clear relationship was established for T cell-mediated rejection and other investigated subgroups.

Dandamudi et al conducted a prospective study of 57 pediatric renal transplant recipients enrolled in a single center from 2013 to 2019 (Dandamudi, 2022). Patients had a median age of 14 years (IQR, 7.5 to 16) and time post-transplantation to first Allosure dd-cfDNA measurement was within 30 days and through 12 months post-transplantation. The authors attempted to correlate dd-cfDNA scores to biopsy-proved T cell-mediated rejection (including sub-clinical rejection). Twenty-two of the patients had biopsy-proven rejection, and cfDNA median levels were higher in these patients (0.91%, IQR, 0.54% to 1.2%) than in the patients without biopsy-proven rejection (median, 0.22%; IQR, 0.14% to 0.45%; p<.001). An area under the receiver operating characteristic curve value of.82 (95% CI, 0.71 to 0.93) was found between dd-cfDNA level and biopsy-proven rejection. Using a cut-off of 1%, cfDNA had a high specificity (96%; 95% CI, 90% to 99%) and low sensitivity (33%; 95% CI, 19% to 52%). A lower cut-off of 0.5% dd-cfDNA had a lower specificity (79%; 95% CI, 69% to 87%) but had a higher sensitivity (78%; 95% CI, 59% to 89%).

Bu et al evaluated data from 1092 kidney transplant recipients at 7 centers from June 2016 to January 2020 as part of the ADMIRAL study (NCT0456605) (Bu, 2022). All patients were monitored with Allosure dd-cfDNA as part of their standard care. A total of 1092 adult kidney transplant recipients (mean age 49.5 years) were followed for a period of up to 3 years to determine the association of dd-cfDNA with evidence of allograft rejection identified histologically. Using a cfDNA threshold of 0.5%, the authors found an increase in the risk of the development of donor-specific antibodies (hazard ratio [HR], 2.7). Having a dd-cfDNA result of more than 0.5% on more than 1 test predicted a reduction in eGFR over 3 years (HR, 1.97). The presence of allograft rejection was established using results from 203 patients who had a biopsy to pain with cfDNA results. Amongst patients with no rejection on biopsy, a median dd-cfDNA level of 0.23% (IQR, 0.19% to 0.64%) was lower than that observed in individuals with biopsy-defined cellular or humoral rejection (1.6%; IQR, 0.68% to 2.6%; p<.0001). Median dd-cfDNA levels had an area under the receiver operating characteristic curve (AUROC) of 0.8 for graft rejection (95% CI, 0.72 to 0.87) and was found to be more predictive than the AUROC of median creatinine levels in this sample of patients. Performance characteristics of the Allosure test at a dd-cfDNA threshold of 0.5% resulted in a sensitivity of 78% and specificity of 71%; using a dd-cfDNA cut-off of 1.0 reduced the test sensitivity to 58% but improved the specificity to 82%.

Huang and colleagues reported a retrospective cohort study of all kidney transplant patients at a single center who received testing with Allosure (Huang, 2023). A total of 317 individuals who underwent kidney transplantation were included in this study (median age, 55 years) and were defined as either low (<0.5%, n=239), moderate (0.5% to <1%, n=43), or high (≥1%, n=35) based on dd-cfDNA threshold levels. The rejection rate was established by comparing the 62 participants who underwent a biopsy; patients in the low dd-cfDNA group had a rejection rate of only 5% which was statistically less than that observed in the high dd-cfDNA group (17%; p=.01) but did not vary significantly in the moderate dd-cfDNA group (12%; p=.13). Although each group did not experience a significant change in eGFR from baseline levels, a linear mixed-effects model of eGFR over time found that dd-cfDNA category had a significant interaction when comparing both the moderate to low (p=.005) and low to high (p=.048) after adjustments for age, donor type, and history of donor-specific antibodies.

In 2023, the American Society of Transplant Surgeons (ASTS) issued a position statement on the role of dd-cfDNA in kidney transplant surveillance (ASTS, 2023). The following recommendations regarding the clinical utility and decision analysis were issued:

"The most data have been accumulated in adult transplant recipients, and these recommendations are therefore most applicable to adult patient populations.
We suggest that clinicians consider measuring serial dd-cfDNA levels in kidney transplant recipients with stable renal allograft function to exclude the presence of subclinical antibody-mediated rejection.
We recommend that clinicians measure dd-cfDNA levels in kidney transplant recipients with acute allograft dysfunction to exclude the presence of rejection, particularly antibody-mediated rejection (ABMR).
We do not recommend the use of blood gene expression profiling (GEP) in kidney transplant recipients for the purpose of diagnosing or excluding sub-clinical rejection, as adequate evidence supporting such use is still lacking.
We do not recommend the use of blood GEP to diagnose or exclude the presence of acute graft rejection in kidney transplant recipients with acute allograft dysfunction given the paucity of data to support this practice.
We recommend that dd-cfDNA may be utilized to rule out subclinical rejection in heart transplant recipients.
We recommend that clinicians utilize peripheral blood GEP as a non-invasive diagnostic tool to rule out acute cellular rejection in stable, low-risk, adult heart transplant recipients who are over 55 days status post heart transplantation."

"Caveats and recommendations for future studies:

None of these recommendations should be construed as recommending one biomarker over another in the same diagnostic niche.
We strongly recommend ongoing clinical studies to clarify the scenarios in which molecular diagnostic studies should be utilized.
We specifically recommend that studies be carried out to evaluate the potential role of dd-cfDNA surveillance in kidney transplant recipients to improve long-term allograft survival."

CPT/HCPCS:

0018M	Transplantation medicine (allograft rejection, renal), measurement of donor and third-party-induced CD154+T-cytotoxic memory cells, utilizing whole peripheral blood, algorithm reported as a rejection risk score
0055U	Cardiology (heart transplant), cell free DNA, PCR assay of 96 DNA target sequences (94 single nucleotide polymorphism targets and two control targets), plasma
0087U	Cardiology (heart transplant), mRNA gene expression profiling by microarray of 1283 genes, transplant biopsy tissue, allograft rejection and injury algorithm reported as a probability score
0088U	Transplantation medicine (kidney allograft rejection), microarray gene expression profiling of 1494 genes, utilizing transplant biopsy tissue, algorithm reported as a probability score for rejection
0118U	Transplantation medicine, quantification of donor derived cell free DNA using whole genome next generation sequencing, plasma, reported as percentage of donor derived cell free DNA in the total cell free DNA
0319U	Nephrology (renal transplant), RNA expression by select transcriptome sequencing, using pretransplant peripheral blood, algorithm reorted as a risk score for early acute rejection
0320U	Nephrology (renal transplant), RNA expression by select transcriptome sequencing, using posttransplant peripheral blood, algorithm reported as a risk score for acute cellular rejection
81479	Unlisted molecular pathology procedure
81560	Transplantation medicine (allograft rejection, pediatric liver and small bowel), measurement of donor and third party induced CD154+T cytotoxic memory cells, utilizing whole peripheral blood, algorithm reported as a rejection risk score
81595	Cardiology (heart transplant), mRNA, gene expression profiling by real time quantitative PCR of 20 genes (11 content and 9 housekeeping), utilizing subfraction of peripheral blood, algorithm reported as a rejection risk score
81599	Unlisted multianalyte assay with algorithmic analysis
83006	Growth stimulation expressed gene 2 (ST2, Interleukin 1 receptor like 1)
86849	Unlisted immunology procedure

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