Medical Policy: 02.04.33
Original Effective Date: April 2011
Reviewed: October 2020
Revised: October 2020
This policy contains information which is clinical in nature. The policy is not medical advice. The information in this policy is used by Wellmark to make determinations whether medical treatment is covered under the terms of a Wellmark member's health benefit plan. Physicians and other health care providers are responsible for medical advice and treatment. If you have specific health care needs, you should consult an appropriate health care professional. If you would like to request an accessible version of this document, please contact customer service at 800-524-9242.
Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.
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.
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. IBD is a structural disease. That means there is underlying physical damage that causing symptoms. Doctors can see chronic inflammation or ulcers when they examine the gut with an X-ray, endoscopy, surgery, or biopsy. Irritable Bowel Syndrome (IBS), on the other hand, is called a functional disease. Someone with this type of disease will have a group of symptoms, but tests won’t show any physical explanation for those problems. Providers will diagnose IBS generally using physical standards if they fail to overlap signs of IBD. But in many cases, particularly if other symptoms hint at IBD, additional tests will be completed to find out whether there’s any bleeding or inflammation in the digestive tract. The distinction of IBD from IBS will drive the level of specialty providers involvement, and ongoing follow up necessary to manage the condition.
Noninvasive diagnosis of inflammatory intestinal disease areis 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. Low specificity and clinical sensitivity of numerous tests to evaluate symptoms, diagnose, and manage intestinal disease have failed to change clinical use of testing.
Fecal calprotectin is a calcium- and zinc-binding protein that is a potential marker of intestinal inflammation. 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.
Fecal calprotectin is increasingly used to differentiate IBD from IBS when symptoms are overlapping. This is especially useful in pediatrics, where specific symptomology is at times hard to extract. If the test finds a large amount of calprotectin present in the stool, it is more likely that the patient has inflammatory bowel disease (IBD), while if the test comes back with low or normal levels of calprotectin, it points more toward irritable bowel syndrome (IBS). The other recommended use for fecal calprotectin is ongoing monitoring. Currently, the gold standard for monitoring patients with IBD continues to be endoscopy. Fecal calprotectin is frequently thought of as a noninvasive predictive marker of mucosal healing for patients with inflammatory bowel disease (IBD). Studies proving that calprotectin alone can replace invasive monitoring have failed to conclude fecal calprotectin testing can alone drive effective treatment changes. Other potential uses of calprotectin are to evaluate response to specific treatments for patients with IBD and as a marker of relapse in the asymptomatic individual.
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. This cutoff value to drive treatment changes has been modified continuously in an attempt to increase testing sensitivity and specificity.
Rapid fecal calprotectin tests that can be used in the home or physician’s office are commercially available in Europe and Canada (eg, Calprosmart, Calpro AS, Norway; Quantum Blue Calprotectin, Bühlmann Laboratories, Switzerland). Rapid tests have not been approved by the FDA for use in the United States. IBDoc® is the first in-vitro diagnostic home testing device measuring the inflammatory marker fecal calprotectin at home. The CalApp® turns your smartphone into a test cassette reader and is reported directly to the patients gastroenterologist.
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.
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.
mRNA, gene expression profiling panel testing for the diagnosis and ongoing management of IBD is unproven at this time.
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.
The American College of Gastroenterology (ACG) Ulcerative Colitis Practice Guidelines in Adults, updated in 2014, 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.
The 2019 ACG clinical guideline on ulcerative colitis in adults, recommended against serologic antibody testing to establish or rule out a diagnosis of UC. Perinuclear antineutrophilic cytoplasmic antibody (pANCA) has been identified in up to 70% of UC patients. It has been proposed that using a combination of negative anti–saccharomyces cerevisiae antibodies (ASCA) with elevated pANCA levels facilitates establishing a diagnosis of UC. However, the pooled sensitivity of antibody testing for diagnosis of UC is low, and such markers are not used for establishing or ruling out a diagnosis of UC. The guideline also stated that patients with moderately to severely active UC who are responders to anti-TNF therapy and now losing response, suggested measuring serum drug levels and antibodies (if there is not a therapeutic level) to assess the reason for loss of response. This is a conditional recommendation based on very low quality of evidence.
In 2014, the American Gastroenterological Association Institute published guidelines on the identification, assessment, and initial medical treatment in Crohn disease. Fecal calprotectin is listed among other clinical lab tests to assess inflammatory status.
ECCO-ESGAR (2019) published a joint guideline for the diagnostic assessment in IBD. The guideline stated that genetic and serological testing is not recommended for the routine diagnosis of CD or UC. The accuracy of serologic markers (pANCA, ASCAs) is rather limited and therefore ineffective at differentiating colonic CD from UC.
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.”
Multiple laboratory tests, some general and some proprietary, have been utilized for the diagnosis and ongoing management of irritable bowel disease. Many individual tests do not require FDA approval for laboratory practices.
Testing in the adult population is considered investigational.
The positive predictive value remains weak, and the definitive calprotectin levels that would change treatment/diagnosis remains non-definitive. The weakness of recommendations in the adult population do not warrant the use of fecal calprotectin at this time.
Fecal calprotectin testing is considered medically necessary when ALL the following are met:
Fecal calprotectin for on-going management after diagnosis is considered not medically necessary. There is a lack of evidence to support fecal calprotectin testing for the on-going management and continued surveillance of inflammatory bowel disease.
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 in the home environment (e.g. IBDoc) is considered investigational.
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, The IBD First Step™) is considered investigational.
Gastrointestinal Pathogen (GIP) Panels Utilizing Multiplex Nucleic Acid Amplification Techniques (NAATs) (e.g. BioFire® FilmArray® Gastrointestinal (GI) Panel, BioFire® Diagnostics) in the use of ongoing care for Inflammatory Bowel Disease is considered investigational.
mRNA, gene expression profiling panel testing in the diagnosis and management of IBD is considered investigational.
Diagnostic testing combining the use of multiple biomarkers and anitibodies (i.e. GI Effects, IBSchek®, ibs-smart™) including but not limited to triglycerides, meat and vegetable fibers, chymotrypsin, long-chain fatty acids, cholesterol, lactobacilli, ph, fecal yeast, and fecal secretory immunoglobulin A in the diagnosis of IBD is considered investigational. The clinical utility of panel testing in this scenario is unfounded at this time.
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 on 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.
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. Specifically in the scenario where an endoscopy is planned and could possibly be avoided based on calprotectin testing results.
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. Studies have used various cutoffs to indicate an abnormally high fecal calprotectin level for diagnosing or monitoring patients and the optimal cutoff remains unknown. Recent studies have used higher cutoff values in an attempt to increase specificity but fail to prove that the test is sensitive enough to create accurate treatment decisions alone. Studies completed have failed to show that consistently the calprotectin test value can directly translate to treatment changes (outside of the possibility in preventing an endoscopy or to manage referrals in those with differential disease).
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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