Medical Policy: 02.04.33
Original Effective Date: April 2011
Reviewed: October 2017
Revised: October 2017
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This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.
Fecal calprotectin is a calcium- and zinc-binding protein that is a potential marker of intestinal inflammation. Fecal calprotectin testing is proposed as a noninvasive test to diagnose inflammatory bowel disease (IBD). Other potential uses are to evaluate response to treatment for patients with IBD and as a marker of relapse.
Inflammatory bowel disease (IBD) is a chronic inflammatory condition. There are two main forms of the disorder, Crohn’s disease (CD) and ulcerative colitis (UC). Typical symptoms of episodes/exacerbations are diarrhea, defecation urgency, and sometimes rectal bleeding and abdominal pain.
Noninvasive diagnosis of inflammatory intestinal disease is difficult because the clinical manifestation of intestinal disorders and colon cancer are relatively non-specific. Endoscopy with histology is the gold standard for diagnosing bowel inflammation. Limitations of this approach are that it is invasive, with an associated risk of adverse events, and not well tolerated by some patients.
There is, thus, the need for simple, accurate, noninvasive tests to detect intestinal inflammation. Potential noninvasive markers of inflammation fall into several categories including serological and fecal. Serologic markers such as C-reactive protein and anti-neutrophil cytoplasmic antibodies (ANCA) tend to have low sensitivity and specificity for intestinal inflammation because they are affected by inflammation outside of the gastrointestinal tract. Fecal markers, in contrast, have the potential for being more specific to the diagnosis of gastrointestinal disorders since their levels are not elevated in extra-digestive processes. Fecal leukocyte testing has been used to evaluate whether there is intestinal mucosal inflammation. The level of fecal leukocytes can be determined by the microscopic examination of fecal specimens; however, leukocytes are unstable and must be evaluated promptly by skilled personnel. There is interest in identifying stable proteins in stool specimens which may be representative of the presence of leukocytes rather than evaluating leukocyte levels directly.
Fecal calprotectin is one protein that could possibly be used as a marker of inflammation. It is a calcium- and zinc-binding protein that accounts for about 60% of the neutrophils’ cytoplasmic proteins. It is released from the neutrophils during activation or apoptosis/necrosis and has a role in regulating inflammatory processes. In addition to potentially higher sensitivity and specificity than serologic markers, a potential advantage of fecal calprotectin as a marker is that it has been shown to be stable in feces at room temperature for up to a week, leaving enough time for patients to collect samples at home and send them to a distant laboratory for testing.
Potential disadvantages of fecal calprotectin as a marker of inflammation include that fecal calprotectin levels increase after use of non-steroidal anti-inflammatory drugs, that levels may change with age, and that bleeding may cause an elevated fecal calprotectin level. Moreover, there is uncertainty about the optimal cutoff to use to distinguish between inflammatory bowel disease and non-inflammatory disease.
Fecal calprotectin testing has been used to distinguish between organic and functional intestinal disease. Some authors consider fecal calprotectin to be a marker of neutrophilic intestinal inflammation rather than a marker of organic disease and believe the appropriate use of the marker is to use it to distinguish between inflammatory and non-inflammatory bowel disease. In clinical practice, the test might be suitable for selecting patients with IBD symptoms for endoscopy, i.e. deciding which patients do not require endoscopy. Fecal calprotectin testing has been proposed to evaluate the response to IBD treatment and for predicting relapse. If found to be sufficiently accurate, results of calprotectin testing could potentially be used to change treatment such as adjusting medication levels.
There is a commercially available ELISA test measuring fecal calprotectin levels. The PhiCal™ (Genova Diagnostics)was cleared for marketing by the Food and Drug Administration (FDA) through the 510(k) process in March 2006. The test is indicated to aid in the diagnosis of inflammatory bowel disease and to differentiate IBD from irritable bowel syndrome (IBS); it is intended to be used in conjunction with other diagnostic testing and clinical considerations. CalFast was recently released for calprotectin testing as a point of care test with results in as little as 20 minutes, and ELISA test, Calprest is a confirmatory test for the measurement of calprotectin.
In January 2014, CalPrest® (Eurospital SpA) was cleared for marketing by FDA through the 510(k) process. According to the FDA summary, CalPrest “is identical” to the PhiCal™ test “in that they are manufactured by Eurospital S.p.A. Trieste, Italy. The only differences are the name of the test on the labels, the number of calibrators in the kit and the dynamic range of the assay.”
Fecal calprotectin is not mentioned in the latest version of the following guidelines: Irritable bowel syndrome in adults: Diagnosis and management of irritable bowel syndrome in primary care (2015), colorectal cancer screening (2009).
The GI Effects Comprehensive Stool Profile (Genova Diagnostics) is a multianalyte stool assay. The test uses polymerase chain reaction (PCR) to quantify 26 commensal gut bacteria and standard biochemical and culture methods to measure levels of other stool components (eg, lipids, fecal occult blood) and potential pathogens (ova and parasites, opportunistic bacteria, yeast). The test is purported to optimize management of gut health and to differentiate IBS from inflammatory bowel disease (IBD).
A number of studies have examined the association between the serologic markers ASCA and ANCA and inflammatory bowel disease. Systematic reviews have found relatively low sensitivity and moderately high specificity. The clinical utility of these assays has not been demonstrated. No studies demonstrated the use of these markers in lieu of a standard workup for IBD. No guideline or position statement currently recommend the use of serum markers for the diagnosis or differentiation of inflammatory bowel disease.
The Prometheus© IBD Serology 7 (Prometheus© Inc., San Diego, CA) is a quantitative analysis of biomarkers for IBD prediction and differentiation. Prometheus© IBD Serology 7 is only offered at Prometheus©. This system uses a 2-step process to diagnose IBD and to differentiate between ulcerative colitis and Crohn’s disease. The first step is a panel of 4 markers intended to maximize the sensitivity and negative predictive value of the test. Patients who test positive on the initial screen are further analyzed by a set of proprietary markers and enzyme reagents to distinguish between true positive results and artifacts of fixation. In this way, the Prometheus© system is intended to increase the specificity of the test compared to other laboratories.
IBD sgi Diagnostic (Prometheus Therapeutics & Diagnostics) is a panel of 17 serologic (n=8), genetic (n=4), and inflammatory biomarkers (n=5). A proprietary algorithm produces an IBD score; results are reported as consistent with IBD (consistent with ulcerative colitis, consistent with CD, or inconclusive for UC vs CD) or not consistent with IBD. The test is intended for use in patients with clinical suspicion of IBD.
Celiac PLUS is a panel of 2 genetic and 5 serologic markers associated with celiac disease. Per the manufacturer, Celiac PLUS is a diagnostic test that also stratifies future risk of celiac disease. Genetic markers (human leukocyte antigen DQ2 and DQ8) are considered predictive of the risk of developing celiac disease; serologic markers (immunoglobulin A [IgA] anti-tissue transglutaminase antibody, IgA anti-endomysial antibodies, IgA anti-DGP antibodies, IgG anti-DGP, and total IgA) are considered diagnostic for celiac disease. Celiac PLUS is intended for patients at risk for disease (eg, with an affected first-degree relative) or with symptoms suggestive of disease.
Crohn’s Prognostic (Prometheus Therapeutics & Diagnostics) is a panel of 6 serologic (n=3) and genetic (n=3) biomarkers. Limited information about the test is available on the manufacturer’s website.
NOD2/CARD15 genotyping for Crohn's Disease, as the analytical validity of NOD2 genotyping has not been identified. In addition, no data regarding the impact of NOD2 gene status on the health outcome of patients were identified.
The American College of Gastroenterology (ACG) states that for CD, serological studies are evolving to provide adjunctive support for the diagnosis of CD but are not sufficiently sensitive or specific to be recommended for use as screening tools. Similarly, as reported in published ACG practice guidelines for ulcerative colitis (UC), pANCA, and ASCA currently are neither a first step nor a definitive step in differential diagnosis or clinical decision making.
Furthermore, the ACG states that the measurement of genetic mutations of CD has not yet been proven to be of clinical benefit for the general assessment of diagnosis, guidance of individual care, or prediction of response to specific medical therapies. Thompson (2011) reports that advances in genetic contributions for UC will not in the short term provide additional diagnostic or prognostic value.
The American College of Gastroenterology Ulcerative Colitis Practice Guidelines in Adults, updated in 2010, states that pANCA have been identified in 60–70% of UC patients but are also found in up to 40% of patients with CD. These pANCA-positive CD patients typically have a clinical phenotype resembling left-sided UC patients, so ANCA detection alone is of little value in distinguishing between UC and CD. The low sensitivity of pANCA for the diagnosis of UC prevents it from serving as a useful diagnostic tool.
Fecal calprotectin testing in the diagnosis and management of intestinal conditions, including the diagnosis and management of inflammatory bowel disease, is considered investigational due to the lack of a well-established cutoff as well as the absence of prospective trials demonstrating clinical utility.
Fecal calprotectin testing is considered investigational as a test used in colorectal cancer screening.
Testing of serological markers in inflammatory bowel disease (IBD) is considered investigational, the effectiveness of this service cannot be established by review of the available published literature. Serodiagnostic tests of IBD include, but are not limited to, the following:
There is insufficient clinical evidence that pANCA and ASCA levels are linked with disease severity or that they change in response to specific medical treatments for IBD. Their usefulness is limited due to low specificity and sensitivity. The ANCA assay has reasonable sensitivity but low specificity for ulcerative colitis, while the ASCA assay has high specificity but very low sensitivity for Crohn's disease.
Inflammatory bowel disease (IBD) diagnostic testing combining serologic, genetic, and inflammatory markers (eg, Prometheus® IBD Sgi Diagnostic™, IBD Sgi Serology, Celiac PLUS, Crohn's Prognostic) is considered investigational.
NOD2/CARD15 genotyping/genetic testing in the diagnosis and management of IBD is considered investigational. The analytical validity of NOD2 genotyping has not been identified. In addition, no data regarding the impact of NOD2 gene status on the health outcome of patients has been identified
Assessment of a diagnostic technology typically focuses on 3 parameters:
Technical performance of a device is normally assessed with 2 types of studies, those that compare test measurements with a gold standard, and those that compare results taken with the same device on different occasions (test-retest).
Diagnostic performance is evaluated by the ability of a test to accurately diagnose a clinical condition in comparison with the gold standard. The sensitivity of a test is the ability to detect a disease when the condition is present (true positive), while specificity indicates the ability to detect patients who suspected of disease but who do not have the condition (true negative). Evaluation of diagnostic performance, therefore, requires independent assessment by the 2 methods in a population of patients who are suspected of disease but who do not all have the disease.
Evidence related to improvement of clinical outcomes with use of this testing assesses the data linking use of a test to changes in health outcomes (clinical utility). While in some cases, tests can be evaluated adequately using technical and diagnostic performance, when a test identifies a new or different group of patients with a disease randomized trials are needed to demonstrate impact of the test on net health outcomes.
The FDA’s 510(k) substantial equivalence decision summary for the PhiCal™ test reported the sensitivity and specificity of the test performed on 908 individuals; this group included 255 patients with inflammatory bowel disease, 410 with irritable bowel syndrome, 82 with other bowel diseases and 161 normal individuals. A reference test was not specified, but most patients had previously been diagnosed with a bowel disease. When 132 borderline cases were excluded, the clinical sensitivity was 86% (254/296) and the clinical specificity was 94% (451/480). Receiver operating curve (ROC) analysis was done to establish a cutoff for the assay using data from the 908 individuals. The ROC analysis indicated that 120 ug/g was the optimal cutoff indicating an abnormal test, yielding 95% specificity and 70% sensitivity. A normal level was considered 50ug/g or less and between 50 and 120 ug/g was considered borderline.
Like the studies on predicting responses to treatment, the impact of fecal calprotectin testing on health outcomes in UC and CD patients in remission has not been evaluated in controlled studies.
One prospective comparative study has evaluated the clinical utility of fecal calprotectin testing. That study did not find a statistically significant difference in the relapse rate when patients with ulcerative colitis were managed with and without use of fecal calprotectin test results to guide medication dosage.
In summary, numerous studies have evaluated the ability of fecal calprotectin testing to distinguish between patients with inflammatory bowel disease and non-inflammatory bowel disease, the FDA-approved indication for the fecal calprotectin test. Generally, studies have shown that the fecal calprotectin test is reasonably accurate for this purpose when used in an appropriate patient population; that is, patients with clinical suspicion of inflammatory bowel disease based on examination and history. Studies have also examined the association between fecal calprotectin levels and the response to treatment or risk of relapse in patients known to have inflammatory bowel disease. However, studies have used various cutoffs to indicate an abnormally high fecal calprotectin level for diagnosing or monitoring patients and the optimal cutoff remains unknown. Moreover, no prospective trials have evaluated the clinical utility of the test; namely, the ability of test findings to improve patient management and/or health outcomes for any of its potential applications. Studies completed fail to show that the test value can directly translate to treatment.
The effectiveness of serological testing cannot be established by review of the available published literature or recommended by national guidelines. Currently the decreased diagnostic value and decreased sensitivity compared with conventional testing are factors that contribute to the use to diagnose inflammatory bowel disease, to distinguish ulcerative colitis from Crohn's disease, and for all other indications not being established.
No studies examining the clinical utility of Celiac PLUS were identified. Factors that support a chain of evidence for prognostic or diagnostic utility are lacking. A comparison of clinical and/or histopathologic outcomes using either Celiac PLUS or ACG’s published diagnostic algorithm would be required to demonstrate improved health outcomes with Celiac PLUS.
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