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A.2.04.69
Calprotectin is a calcium- and zinc-binding protein that is a potential marker of intestinal inflammation. Fecal calprotectin testing is proposed as a noninvasive means to diagnose inflammatory bowel disease (IBD). Other potential uses are to evaluate treatment response for patients with IBD and as a marker of relapse.
Inflammatory Bowel Disease
Inflammatory bowel disease (IBD) is a chronic condition that encompasses two main forms: Crohn's disease and ulcerative colitis. These conditions overlap in clinical and pathologic characteristics but have distinct features. Crohn's disease can involve the entire gastrointestinal (GI) tract and is characterized by transmural inflammation. Ulcerative colitis involves inflammation limited to the mucosal layer of the colon, almost always involving the rectum.
IBD is suggested by the presence of one or more of a variety of signs and symptoms that can be GI (eg, abdominal pain, bloody diarrhea, perianal fistulae), systemic (eg, weight loss, fatigue, growth failure in children), or extraintestinal (eg, characteristic rashes, uveitis, arthritis) in nature. Patients may present with or develop a range of severity of symptoms in the disease course, including a life-threatening illness.
Diagnosis
Diagnosing IBD is associated with well-defined management changes. A typical diagnostic approach to IBD includes stool testing for enteric pathogens, blood tests (complete blood count, inflammatory markers) to differentiate etiologies and evaluate disease severity, as well as small bowel imaging and endoscopy (upper GI, colonoscopy) with biopsies.
Fecal Calprotectin
In some cases, the clinical manifestations of IBD can be nonspecific and suggestive of other disorders, including infectious colitis, colon cancer, and functional bowel disorders, including irritable bowel syndrome (IBS).
Therefore, there is a need for simple, accurate, noninvasive tests to detect intestinal inflammation. Potential noninvasive markers of inflammation fall into several categories, including serologic and fecal. Serologic markers such as C-reactive protein and anti-neutrophil cytoplasmic antibodies 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 to be more specific to the diagnosis of gastrointestinal tract 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.
Calprotectin is a protein that could be used as a marker of inflammation. It is a calcium- and zinc-binding protein that accounts for approximately 30% to 60% of the neutrophil’s cytoplasmic proteins. It is released from 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, another advantage of calprotectin as a marker is that it has been shown to be stable in feces at room temperature for up to one week, leaving enough time for patients to collect samples at home and send them to a laboratory for testing. A sample of a few grams of stool is sufficient enough for testing. A 50 mg/g fecal calprotectin concentration in a stool sample is usually recommended as the cutoff for the normal concentration for adults and children older than 4 years. Moderate increases in fecal calprotectin levels, up to 100 mg/g, have been described for individuals older than 65 years. The concentration of fecal calprotectin is physiologically higher for neonates, infants, and young children, and thus fecal calprotectin concentrations in this population should be interpreted with caution.
Among potential disadvantages of fecal calprotectin as a marker of inflammation are that fecal calprotectin levels increase after the use of some medications (ie, non-steroidal anti-inflammatory drugs; proton pump inhibitors), and that levels may change with other factors such as age, low fiber intake, and lack of exercise; other clinical situations associated with mucosal inflammation may also cause elevated fecal calprotectin levels such as gastrointestinal bleeding. Moreover, there is uncertainty about the optimal cutoff to distinguish between inflammatory bowel disease and non-inflammatory disease.
Fecal calprotectin testing has been used to differentiate between organic (eg, inflammation) and functional (no visible problem in the GI tract like irritable bowel syndrome) disease. Some consider fecal calprotectin to be a marker of neutrophilic intestinal inflammation rather than a marker of organic disease and believe it has utility to distinguish between inflammatory bowel disease and non-inflammatory bowel disease. In 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 also been proposed to evaluate the response to IBD treatment and for predicting relapse. If found to be sufficiently accurate, results of calprotectin testing could be used to change treatment, such as adjusting medication levels.
Treatment
Guideline-based treatments of IBD include oral and rectal salicylates, glucocorticoids, immunomodulators (eg, methotrexate), and multiple biologic therapies (eg, infliximab), depending on disease severity.
In March 2006, the PhiCal® (Genova Diagnostics), an enzyme-linked immunosorbent assay test for measuring concentrations of fecal calprotectin in fecal stool, was cleared for marketing by the U.S. Food and Drug Administration (FDA) through the 510(k) process. This test is indicated as an aid in the diagnosis of inflammatory bowel disease and to differentiate IBD from irritable bowel syndrome, when used with other diagnostic testing and clinical considerations.
The PhiCal®, as modified by Quest Diagnostics, is classified as a laboratory-developed test. 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 modified PhiCal® is available under the auspices of the Clinical Laboratory Improvement Amendments. Laboratories that offer laboratory-developed tests must be licensed by the Clinical Laboratory Improvement Amendments for high-complexity testing.
In 2014, CalPrest® (Eurospital SpA) and, in 2016, CalPrest®NG (Eurospital SpA) were cleared for marketing by the FDA through the 510(k) process. According to the FDA summary, CalPrest® “is identical” to the PhiCal™ test in that they have the same manufacturer. Compared with CalPrest®, the “differences in CalPrest® NG include the name of the test on the labels, detection antibody, the use of a Horse-radish peroxidase/TMB conjugate/substrate system, the provided Stop solution, the concentration of calibrators and controls in the kit and the dynamic range of the assay.”
The fCAL® ELISA Calprotectin Test (Bühlmann Laboratories) received FDA clearance in 2018 for the quantitative measurement of fecal calprotectin in human stool. In 2018, LIAISON® Calprotectin test (DiaSorin Inc.) also received FDA clearance and was determined to be substantially equivalent to the predicate PhiCal™ device.
In 2019, ALPCO received 510(k) clearance from the FDA for its new fecal Calprotectin Chemiluminescence ELISA test. This test exhibits a clinical specificity of 95.1% and provides the "lowest false positive rate of any currently cleared calprotectin test without sacrificing clinical sensitivity." In 2023, ALPCO received 510(k) clearance from the FDA for its Calprotectin Immunoturbidimetric Assay and it was determined to be substantially equivalent to the Calprotectin Chemiluminescence ELISA test and is indicated for in-vitro diagnostic use as an aid in the diagnosis of IBD.
In 2022, DiaSorin Inc. submitted an application for modification of its LIAISON® Calprotectin test for the addition of the LIAISON® Q.S.E.T. Device Plus (the accessory used for stool sample collection and extraction) to the cleared assay. While the LIAISON® Calprotectin test is identical to its predicate cleared in 2018, the Q.S.E.T. Device Plus differs from its predicate Q.S.E.T. Device.
FDA product code: NXO.
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; Quantum Blue Calprotectin, Bühlmann Laboratories). Rapid tests have not been FDA-approved for use in the United States.
Fecal Analysis in the Diagnosis of Intestinal Dysbiosis is a related medical policy.
Fecal calprotectin testing may be considered medically necessary for the evaluation of individuals when the differential diagnosis is inflammatory bowel disease or noninflammatory bowel disease (including irritable bowel syndrome) for whom endoscopy with biopsy is being considered.
Fecal calprotectin testing is considered investigational in the management of inflammatory bowel disease, including the management of active inflammatory bowel disease and surveillance for relapse of disease in remission.
None
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
A fecal calprotectin level of less than 50 µg/g is suggestive of a low likelihood of inflammatory bowel disease.
Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:
A. consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and
B. appropriate with regard to standards of good medical practice; and
C. not solely for the convenience of the Member, his or her Provider; and
D. the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.
For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.
Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.
07/29/2011: Approved by Medical Policy Advisory Committee.
05/09/2012: Policy reviewed; no changes.
08/07/2013: Policy reviewed; no changes.
07/11/2014: Policy reviewed; no changes.
09/15/2014: Policy reviewed; description updated. Policy statement unchanged.
07/20/2015: Code Reference section updated for ICD-10.
10/27/2015: Policy description updated regarding tests. Policy statement unchanged. Investigative definition updated in policy guidelines section.
06/06/2016: Policy number A.2.04.69 added.
07/06/2017: Policy description updated regarding inflammatory bowel disease and fecal calprotectin tests. Policy statement unchanged.
04/04/2018: Policy description updated regarding the CalPrest® NG test. Policy statement unchanged.
06/15/2019: Policy description updated regarding laboratory-developed tests. Added statement that fecal calprotectin testing may be considered medically necessary for the evaluation of patients when the differential diagnosis is inflammatory bowel disease or noninflammatory bowel (including irritable bowel syndrome) disease for whom endoscopy with biopsy is considered. Investigational statement revised to state that fecal calprotectin is considered investigational in the management of inflammatory bowel disease, including the management of active inflammatory bowel disease and surveillance for relapse of disease in remission. Code Reference section updated to change CPT code 83993 from investigational to covered.
01/17/2020: Policy reviewed; no changes.
02/03/2021: Policy description updated regarding tests. Policy statements unchanged. Policy Guidelines updated to changed "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."
02/07/2022: Policy reviewed; no changes.
01/26/2023: Policy description updated regarding devices. Policy statement updated to change "patients" to "individuals."
01/16/2024: Policy description updated regarding fecal calprotectin and tests. Policy statements unchanged.
02/10/2025: Policy reviewed; no changes.
Blue Cross Blue Shield Association policy # 2.04.69
This may not be a comprehensive list of procedure codes applicable to this policy.
The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.
Code Number | Description |
CPT-4 | |
83993 | Calprotectin, fecal |
HCPCS | |
ICD-10 Procedure | |
ICD-10 Diagnosis |
CPT copyright American Medical Association. All rights reserved. CPT is a registered trademark of the American Medical Association.