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Fecal Calprotectin Testing

Policy Number: MP-472

Latest Review Date: December 2020

Category: Laboratory

Policy Grade: A

POLICY:

For dates of service on and after 1/1/2019:

Fecal calprotectin testing may be considered medically necessary for the evaluation of patients 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 not medically necessary and investigational in the management of inflammatory bowel disease, including the management of active inflammatory bowel disease and surveillance for relapse of disease in remission.


For dates of service prior to 01/1/2019:

For patients age 18 and under, fecal calprotectin testing may be considered medically necessary in the diagnosis and management of inflammatory bowel disease. 

For patients age 19 and older, fecal calprotectin testing is considered not medically necessary and investigational in the diagnosis and management of intestinal conditions, including the diagnosis and management of inflammatory bowel disease.

DESCRIPTION OF PROCEDURE OR SERVICE:

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

Inflammatory Bowel Disease (IBD) is a chronic condition that encompasses two main forms: Crohn’s disease (CD) and ulcerative colitis (UC), which overlap in clinical and pathological characteristics but have distinct features. Crohn disease can involve the entire gastrointestinal 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 gastrointestinal (e.g., abdominal pain, bloody diarrhea, perianal fistulae), systemic (e.g., weight loss, fatigue, growth failure in children), and extraintestinal (e.g., characteristic rashes, uveitis, arthritis). Patients may present with or develop a range of severity levels, including 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).

Thus, there is a 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 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 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 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 one week, leaving enough time for patients to collect samples at home and send them to a distant laboratory for testing. In contrast, lactoferrin, another potential fecal marker of intestinal inflammation, is stable at room temperature for only about two days.

Among potential disadvantages of fecal calprotectin as a marker of inflammation are that fecal calprotectin levels increase after use of non-steroidal anti-inflammatory drugs, that levels may change with age, and that bleeding (e.g., nasal or menstrual) 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 differentiate between organic (e.g., inflammation) and functional (no visible problem in the GI tract like irritable bowel syndrome [IBS]) disease. Some consider fecal calprotectin to be a marker of neutrophilic intestinal inflammation rather than a marker of organic disease and believe its appropriate use is to distinguish between IBD and non-IBD. 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 potentially be used to change treatment, such as adjusting medication levels.

Treatment

Guidelines-based treatments of IBD include oral and rectal salicylates, glucocorticoids, immunomodulators (e.g., methotrexate), and multiple biologic therapies (e.g., infliximab), depending on the disease severity.

KEY POINTS:

The most recent literature review was performed through October 27, 2020. The BCBSA Medical Advisory Panel also reviewed the evidence in October 2018.

Summary of Evidence

For individuals who have a suspicion of IBD when endoscopy with biopsy is being considered who receive fecal calprotectin testing to select patients who can forgo endoscopy, the evidence includes prospective and retrospective diagnostic accuracy studies and systematic reviews. Relevant outcomes are test validity, symptoms, change in disease status, quality of life, hospitalizations, and medication use. Twenty-eight studies in a systematic review evaluated the diagnostic accuracy of fecal calprotectin in patients suspected of having IBD for whom noninflammatory bowel disease, such as irritable bowel syndrome, remains a consideration. Studies varied in the fecal calprotectin protein level cutoff used to indicate the presence of disease but most used a cutoff of 50 µg/g, which is the recommended lower bound. Studies have indicated that, at this threshold, the test has a sensitivity of 93% to 99% for IBD and a negative predictive value of 73% to 100% for intestinal inflammation. Out of 100 cases of suspected IBD, approximately 49 invasive tests would be avoided with one case missed. In another more recent meta-analysis involving 19 studies where the majority of studies again used the cutoff of 50 μg/g, investigators determined that out of 100 hypothetical patients, 18 non-disease patients would have a colonoscopy performed and one patient with IBD would not be referred for a colonoscopy. Additionally, it was determined that incorporating a fecal calprotectin test into the regular diagnostic work-up would reduce the need for colonoscopy by 66.7%. Therefore, fecal calprotectin can be used to inform a decision of whether to proceed with endoscopy. Clinical input supported that the use of fecal calprotectin testing for individuals with suspected IBD provides a clinically meaningful improvement in net health outcome by providing clinically valid and clinically useful information to guide the clinical decision-making. Specifically, fecal calprotectin testing can inform the decision by using a positive fecal calprotectin result to refer for endoscopy with biopsy or to use a negative fecal calprotectin results to exclude inflammatory bowel disease (IBD) and avoid endoscopy with biopsy with acceptably low tradeoffs in missed diagnoses of IBD in those who have false negative FCP results. Additionally, input further highlighted that the use of fecal calprotectin is particularly important in pediatric populations, where children may not be able to fully participate as medical historians and may have non-specific and/or atypical symptoms. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have active IBD who receive fecal calprotectin testing to monitor disease activity, the evidence includes a systematic review and a randomized controlled trial (RCT). Relevant outcomes are test validity, symptoms, change in disease status, quality of life, hospitalizations, and medication use. RCTs are needed to determine whether guiding treatment based on fecal calprotectin levels can improve disease management. A 2017 RCT included fecal calprotectin as one of several indicators of inflammation to test the effect of tight control of IBD on health outcomes. The independent contribution of fecal calprotectin could not be determined from this study design. The evidence is insufficient to determine the effects of the technology on health outcomes.

For individuals who have IBD in remission who receive fecal calprotectin testing to predict relapse, the evidence includes a systematic review and an RCT. Relevant outcomes are test validity, symptoms, change in disease status, quality of life, hospitalizations, and medication use. One RCT found no significant difference in the rate of relapse in patients whose medication was modified based on fecal calprotectin or standard clinical indicators, however, this RCT had design and conduct limitations that affected the interpretation of its results. Further study in high-quality RCTs is needed to determine whether adding fecal calprotectin to standard clinical practice improves the management of IBD patients in remission. The evidence is insufficient to determine the effects of the technology on health outcomes.

Practice Guidelines and Position Statements

American Gastroenterological Association

In 2018, the American Gastroenterological Association (AGA) published a guideline on functional gastrointestinal symptoms in patients with IBD. AGA recommends a stepwise approach to rule-out ongoing inflammatory activity in IBD patients that includes fecal calprotectin, endoscopy with biopsy, and imaging. AGA recommends that in those patients with indeterminate fecal calprotectin levels and mild symptoms, calprotectin monitoring at three to six month intervals may allow anticipatory management of impending flares. However, "the optimal cutoff for biomarkers remains a source of debate" and overtreatment for symptoms that are due to functional pathophysiology rather than inflammation can increase adverse effects with no symptomatic benefit.

A 2019 guideline from the AGA on laboratory evaluation of functional diarrhea and diarrhea-predominant irritable bowel syndrome (IBS) in adults gave a conditional recommendation based on low quality evidence to use either fecal calprotectin or fecal lactoferrin to screen for IBD. A threshold value of 50 μg/g for fecal calprotectin was recommended to optimize sensitivity for IBD.

American College of Gastroenterology

In 2018, The American College of Gastroenterology published guidelines on the management of Crohn disease in adults. The College gave a strong recommendation based on a moderate level of evidence that fecal calprotectin is a helpful test that should be considered to differentiate the presence of inflammatory bowel disease (IBD) from irritable bowel syndrome (IBS). A summary statement without a recommendation indicated that fecal calprotectin measurements may have an adjunctive role in monitoring disease activity.

National Institute for Health and Care Excellence

The National Institute for Health and Care Excellence (2013; recommendation 1.1 was updated in 2017), published guidance on fecal calprotectin testing for inflammatory diseases of the bowel. The guidance made the following recommendations:

1.1 “Fecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of IBD or IBS in adults with recent onset lower gastrointestinal symptoms for whom specialist assessment is being considered, if cancer is not suspected, having considered the risk factors (for example, age).....

1.2 Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of IBD or non-IBD (including IBS) in children with suspected IBD who have been referred for specialist assessment….”

U.S. Preventive Services Task Force Recommendations

Not Applicable.

KEY WORDS:

Fecal calprotectin testing, PhiCal™, CalPrest®, fCAL®

APPROVED BY GOVERNING BODIES:

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 Food and Drug Administration (FDA) through the 510(k) process. This test is indicated to aid in the diagnosis of irritable bowel disease and to differentiate IBD from irritable bowel syndrome (IBS) 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 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. 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 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."

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 (e.g., Calprosmart, Calpro AS, Norway; Quantum Blue Calprotectin®, Bühlmann Laboratories, Switzerland). Rapid tests have not been approved by the Food and Drug Administration for use in the United States.

BENEFIT APPLICATION:

Coverage is subject to member’s specific benefits.  Group specific policy will supersede this policy when applicable.

ITS: Home Policy provisions apply.

FEP: FEP does not consider investigational if FDA approved and will be reviewed for medical necessity.

CURRENT CODING: 

CPT Codes:

83993

Calprotectin, fecal

REFERENCES:

  1. ALPCO. Now available: 510(k) cleared fecal calprotectin ELISA. October 29, 2019. https://www.alpco.com/now-available-510k-cleared-fecal-calprotectin-elisa. Accessed October 26, 2020
  2. Ashorn S, Honkanen T, Kolho KL et al. Fecal calprotectin levels and serological responses to microbial antigens among children and adolescents with inflammatory bowel disease. Inflamm Bowel Dis 2009; 15(2):199-205.
  3. Basumani P, Bardhan K, Eyre R, et al. Faecal calprotectin: Rotherham experience (unpublished slide presentation). BSG Away; 2012 June 28
  4. Bonnin Tomas A, Vila Vidal M, Rosell Camps A. Fecal calprotectin as a biomarker to distinguish between organic and functional gastrointestinal disease. Spanish. Rev Esp Enferm Dig. Dec 2007; 99(12):689-693.
  5. Colombel JF, Panaccione R, Bossuyt P, et al. Effect of tight control management on Crohn's disease (CALM): a multicentre, randomised, controlled phase 3 trial. Lancet. Dec 23 2018; 390(10114):2779-2789.
  6. Colombel JF, Shin A, Gibson PR. AGA Clinical Practice Update on Functional Gastrointestinal Symptoms in Patients With Inflammatory Bowel Disease: Expert Review. Clin Gastroenterol Hepatol. Feb 2019; 17(3): 380-390.e1.
  7. Conroy S, Hale MF, Cross SS, et al. Unrestricted faecal calprotectin testing performs poorly in the diagnosis of inflammatory bowel disease in patients in primary care. J Clin Pathol. Aug 26 2017.
  8. Costa F, Mumolo MG, Ceccarelli L et al. Calprotectin is a stronger predictive marker of relapse in ulcerative colitis than in Crohn's disease. Gut 2005; 54(3):364-8.
  9. Damms A, Bischoff SC. Validation and clinical significance of a new calprotectin rapid test for the diagnosis of gastrointestinal diseases. Int J Colorectal Dis. Oct 2008; 23(10):985-992.
  10. El-Badry A, Sedrak H, Rashed L. Faecal calprotectin in differentiating between functional and organic bowel diseases. Arab J Gastroenterol. May 23 2010; 11(2):70-73.
  11. Fagerberg UL, Loof L, Myrdal U, et al. Colorectal inflammation is well predicted by fecal calprotectin in children with gastrointestinal symptoms. J Pediatr Gastroenterol Nutr. Apr 2005; 40(4):450-455.
  12. FDA. PhiCal 510(k) Substantial Equivalence Determine Decision Summary. Available online at: www.accessdata.fda.gov/cdrh_docs/reviews/K050007.pdf.
  13. Ferreiro-Iglesias R, Barreiro-de Acosta M, Otero Santiago M, et al. Fecal Calprotectin as Predictor of Relapse in Patients With Inflammatory Bowel Disease Under Maintenance Infliximab Therapy. J Clin Gastroenterol. Feb 2016; 50(2):147-151.
  14. Garcia-Sanchez V, Iglesias-Flores E, Gonzalez R et al. Does fecal calprotectin predict relapse in patients with Crohn's disease and ulcerative colitis? J Crohns Colitis 2010; 4(2):144-52.
  15. Gisbert JP, Bermejo F, Perez-Calle JL et al. Fecal calprotectin and lactoferrin for the prediction of inflammatory bowel disease relapse. Inflamm Bowel Dis 2009; 15(8):1190-8.
  16. Heida A, Park KT, van Rheenen PF. Clinical utility of fecal calprotectin monitoring in asymptomatic patients with inflammatory bowel disease: a systematic review and practical guide. Inflamm Bowel Dis. Jun 2017; 23(6):894- 902.
  17. Henderson P, Anderson NH, Wilson DC. The Diagnostic Accuracy of Fecal Calprotectin During the Investigation of Suspected Pediatric IBD: A Systematic Review and Meta-Analysis. Am J Gastroenterol 2013.
  18. Holtman GA, Lisman-van Leeuwen Y, Day AS, et al. Use of laboratory markers in addition to symptoms for diagnosis of inflammatory bowel disease in children: a meta-analysis of individual patient data. JAMA Pediatr. Oct 1 2017; 171(10):984-991.
  19. Jorgensen LG, Fredholm L, Hyltoft Petersen P, et al. How accurate are clinical activity indices for scoring of disease activity in inflammatory bowel disease (IBD)? Clin Chem Lab Med. 2005; 43(4):403-411.
  20. Kallel L, Ayadi I, Matri S et al. Fecal calprotectin is a predictive marker of relapse in Crohn's disease involving the colon: a prospective study. Eur J Gastroenterol Hepatol 2010; 22(3):340.
  21. Kennedy NA, Clark A, Walkden A, et al. Clinical utility and diagnostic accuracy of faecal calprotectin for IBD at first presentation to gastroenterology services in adults aged 16-50 years. J Crohns Colitis. Jan 2015; 9(1):41-49.
  22. Kostakis ID, Cholidou KG, Vaiopoulos AG et al. Fecal calprotectin in pediatric inflammatory bowel disease: a systematic review. Dig Dis Sci 2013; 58(2):309-19.
  23. Lamb CA, Mohiuddin MK, Gicquel J et al. Faecal calprotectin or lactoferrin can identify postoperative recurrence in Crohn's disease. Br J Surg 2009; 96(6):663-74.
  24. Langhorst J, Boone J, Lauche R. Faecal lactoferrin, calprotectin, PMN-elastase, CRP and white blood cell count as indicators for mucosal healing and clinical course of disease in patients with mild to moderate ulcerative colitis: Post hoc analysis of a prospective clinical trial. J Crohns Colitis. 2016 Jul; 10(7):786-94.
  25. Lasson A, Ohman L, Stotzer PO, et al. Pharmacological intervention based on fecal calprotectin levels in patients with ulcerative colitis at high risk of a relapse: A prospective, randomized, controlled study. United European Gastroenterol J. Feb 2015; 3(1):72-79.
  26. Lasson A, Simren M, Stotzer PO et al. Fecal Calprotectin Levels Predict the Clinical Course in Patients With New Onset of Ulcerative Colitis. Inflamm Bowel Dis 2013.
  27. Li XG, Lu YM, Gu F, et al. Fecal calprotectin in differential diagnosis of irritable bowel syndrome. Chinese. Beijing Da Xue Bao Yi Xue Ban. Jun 18 2006; 38(3):310-313.
  28. Lichtenstein GR, Loftus EV, Isaacs KL, et al. ACG Clinical Guideline: management of Crohn's disease in adults. Am J Gastroenterol. Apr 2018;113(4):481-517
  29. Lin JF, Chen JM, Zuo JH, et al. Meta-analysis: fecal calprotectin for assessment of inflammatory bowel disease activity. Inflamm Bowel Dis. Aug 2014; 20(8):1407-1415.
  30. Manz M, Burri E, Rothen C et al. Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study. BMC Gastroenterol 2012; 12:5.
  31. Mao R, Xiao Y, Gao X et al. Fecal calprotectin in predicting relapse of inflammatory bowel diseases: A meta-analysis of prospective studies. Inflamm Bowel Dis. 2012; 18(10):1894-9.
  32. Menees SB, Powell C, Kurlander J, et al. A meta-analysis of the utility of C-reactive protein, erythrocyte sedimentation rate, fecal calprotectin, and fecal lactoferrin to exclude inflammatory bowel disease in adults with IBS. Am J Gastroenterol. Mar 2015; 110(3):444-454.
  33. Molander P, Bjorkesten CG, Mostonen H et al. Fecal calprotectin concentration predicts outcome in inflammatory bowel disease after induction therapy with TNFα blocking agents. Inflamm Bowel Dis. 2012; 18(11):2011-7.
  34. Mosli MH, Zou G, Garg SK, et al. C-Reactive Protein, Fecal Calprotectin, and Stool Lactoferrin for Detection of Endoscopic Activity in Symptomatic Inflammatory Bowel Disease Patients: A Systematic Review and Meta-Analysis. Am J Gastroenterol. May 12 2015.
  35. National Institute for Health and Care Excellence (NICE). Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel. 2013. Available online at: guidance.nice.org.uk/DG11. Accessed October 27, 2020.
  36. Orlando A, Modesto I, Castiglione F et al. The role of calprotectin in predicting endoscopic post-surgical recurrence in asymptomatic Crohn's disease: a comparison with ultrasound. Eur Rev Med Pharmacol Sci 2006; 10(1):17-22.
  37. Otten CM, Kok L, Witteman BJ et al. Diagnostic performance of rapid tests for detection of fecal calprotectin and lactoferrin and their ability to discriminate inflammatory from irritable bowel syndrome. Clin Chem Lab Med 2008; 46(9):1275-80.
  38. Petryszyn P, Staniak A, Wolosianska A, et al. Faecal calprotectin as a diagnostic marker of inflammatory bowel disease in patients with gastrointestinal symptoms: meta-analysis. Eur J Gastroenterol Hepatol. Nov 2019; 31(11): 1306-1312
  39. Sandborn W, Binion D, Persley K, et al. AGA Institute Guidelines for the Identification, Assessment and Initial Medical Treatment in Crohn’s Disease: Clinical Care Pathway. 2014; //campaigns.gastro.org/algorithms/IBDCarePathway/index.html. Accessed February 5, 2018.
  40. Sandborn WJ. Crohn's disease evaluation and treatment: clinical decision tool. Gastroenterology. Sep 2014; 147(3):702-705.
  41. Scarpa M, D'Inca R, Basso D et al. Fecal lactoferrin and calprotectin after ileocolonic resection for Crohn's disease. Dis Colon Rectum 2007; 50(6):861-9.
  42. Schroder O, Naumann M, Shastri Y et al. Prospective evaluation of faecal neutrophil-derived proteins in identifying intestinal inflammation: combination of parameters does not improve diagnostic accuracy of calprotectin. Aliment Pharmacol Ther 2007; 26(7):1035-42.
  43. Schoepfer AM, Trummler M, Seeholzer P, et al. Discriminating IBD from IBS: comparison of the test performance of fecal markers, blood leukocytes, CRP, and IBD antibodies. Inflamm Bowel Dis. Jan 2008; 14(1):32-39.
  44. Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis 2008; 14(3):359-66.
  45. Smalley W, Falck-Ytter C, Carrasco-Labra A, et al. Spotlight: Laboratory Evaluation of Functional Diarrhea and Diarrhea-Predominant Irritable Bowel Syndrome in Adults (IBS-D). Gastroenterology. Sep 2019; 157(3): 858.
  46. Terdiman JP, Gruss CB, Heidelbaugh JJ, et al. American Gastroenterological Association Institute guideline on the use of thiopurines, methotrexate, and anti-TNF-alpha biologic drugs for the induction and maintenance of remission in inflammatory Crohn's disease. Gastroenterology. Dec 2013; 145(6):1459-1463.
  47. Theede K, Holck S, Ibsen P. Fecal calprotectin predicts relapse and histological mucosal healing in ulcerative colitis. Inflamm Bowel Dis. 2016 May; 22(5):1042-8.
  48. Turner D, Leach ST, Mack D et al. Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison of predicting outcomes and monitoring response. Gut 2010; 59(9):1207-12.
  49. Van de Vijver E, Schreuder AB, Cnossen WR, et al. Safely ruling out inflammatory bowel disease in children and teenagers without referral for endoscopy. Arch Dis Child. Dec 2012; 97(12):1014-1018.
  50. van Rheenen PF, Van de Vijver E, Fidler V. Faecal calprotectin for screening of patients with suspected inflammatory bowel disease: diagnostic meta-analysis. BMJ 2010; 341:c3369.
  51. von Roon AC, Karamountzos L, Purkayastha S et al. Diagnostic precision of fecal calprotectin for inflammatory bowel disease and colorectal malignancy. Am J Gastroenterol 2007; 102(4):803-13.
  52. Wagner M, Peterson CG, Ridefelt P et al. Fecal markers of inflammation used as surrogate markers for treatment outcome in relapsing inflammatory bowel disease. World J Gastroenterol 2008; 14(36):5584-9; discussion 88.
  53. Waugh N, Cummins E, Royle P et al. Faecal calprotectin testing for differentiating amongst inflammatory and non-IBDs: systematic review and economic evaluation. Health Technol Assess 2013; 17(55): xv-xix, 1-211.
  54. Whitehead SJ, Ford C, Gama RM, et al. Effect of faecal calprotectin assay variability on the management of inflammatory bowel disease and potential role of faecal S100A12. J Clin Pathol. Dec 2017; 70(12):1049-1056.
  55. Yamamoto T, Shiraki M, Bamba T et al. Fecal calprotectin and lactoferrin as predictors of relapse in patients with quiescent UC during maintenance therapy. Int J Colorectal Dis 2013.

POLICY HISTORY:

Medical Policy Panel, April 2011

Medical Policy Group, April 2011 (2):  New policy

Medical Policy Administration Committee, May 2011

Medical Policy Group, May 2011 (2): Age clarification

Medical Policy Group June 2011

Medical Policy Administration Committee, June 2011

Available for comment June 8 – July 25, 2011

Medical Policy Group, April 2012 (1): 2012 Update to Key Points and References related to MPP update; no change to policy statement

Medical Policy Panel, April 2013

Medical Policy Group, April 2013 (1): 2013 Updates to Key Points and References; no change to policy statement

Medical Policy Panel, April 2014

Medical Policy Group, June 2014 (1): 2014 Update to Key Points and References; no change to policy statement

Medical Policy Group, April 2015 (3): clarification statement “in the diagnosis and management of inflammatory bowel disease” added to coverage criteria for ages 18 and under; no change in intent of original policy statement

Medical Policy Panel, July 2015

Medical Policy Group, July 2015 (3): 2015 Updates to Key Points, Approved by Governing Bodies, Key Words, and References; no change to policy statement.

Medical Policy Panel, April 2017

Medical Policy Group, May 2017 (3): 2017 Updates to Description, Key Points, Governing Bodies & References; no change in Policy statement

Medical Policy Panel, March 2018

Medical Policy Group, March 2018 (4): Updates to Description, Key Points, Approved by Governing Bodies, and References.  No change to policy statement.

Medical Policy Panel, December 2018

Medical Policy Group, January 2019 (4): Updates to Description, Key Points, and References.  Policy statements updated to state fecal calprotectin testing may be considered medically necessary for the evaluation of patients when the differential diagnosis is inflammatory bowel disease or noninflammatory bowel disease (including irritable bowel syndrome) for whom endoscopy with biopsy is being considered.

Medical Policy Administration Committee: January 2019

Available for comment: January 16, 2019 through March 2, 2019.

Medical Policy Panel, December 2019

Medical Policy Group, December 2019 (9): 2019 Updates to Description, Key Points, References. No change to policy statement.

Medical Policy Panel, December 2020

Medical Policy Group, December 2020 (9): 2020 Updates to Description, Key Points, References. Key word added: fCAL®. No change to policy statement.


This medical policy is not an authorization, certification, explanation of benefits, or a contract. Eligibility and benefits are determined on a case-by-case basis according to the terms of the member’s plan in effect as of the date services are rendered. All medical policies are based on (i) research of current medical literature and (ii) review of common medical practices in the treatment and diagnosis of disease as of the date hereof. Physicians and other providers are solely responsible for all aspects of medical care and treatment, including the type, quality, and levels of care and treatment.

This policy is intended to be used for adjudication of claims (including pre-admission certification, pre-determinations, and pre-procedure review) in Blue Cross and Blue Shield’s administration of plan contracts.

The plan does not approve or deny procedures, services, testing, or equipment for our members. Our decisions concern coverage only. The decision of whether or not to have a certain test, treatment or procedure is one made between the physician and his/her patient. The plan administers benefits based on the member’s contract and corporate medical policies. Physicians should always exercise their best medical judgment in providing the care they feel is most appropriate for their patients. Needed care should not be delayed or refused because of a coverage determination.

As a general rule, benefits are payable under health plans only in cases of medical necessity and only if services or supplies are not investigational, provided the customer group contracts have such coverage.

The following Association Technology Evaluation Criteria must be met for a service/supply to be considered for coverage:

1. The technology must have final approval from the appropriate government regulatory bodies;

2. The scientific evidence must permit conclusions concerning the effect of the technology on health outcomes;

3. The technology must improve the net health outcome;

4. The technology must be as beneficial as any established alternatives;

5. The improvement must be attainable outside the investigational setting.

Medical Necessity means that health care services (e.g., procedures, treatments, supplies, devices, equipment, facilities or drugs) that a physician, exercising prudent clinical judgment, would provide to a patient for the purpose of preventing, evaluating, diagnosing or treating an illness, injury or disease or its symptoms, and that are:

1. In accordance with generally accepted standards of medical practice; and

2. Clinically appropriate in terms of type, frequency, extent, site and duration and considered effective for the patient’s illness, injury or disease; and

3. Not primarily for the convenience of the patient, physician or other health care provider; and

4. Not more costly than an alternative service or sequence of services at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of that patient’s illness, injury or disease.