Medical Policy: 02.04.33
Original Effective Date: April 2011
Reviewed: December 2014
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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.
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.
Assessment of a diagnostic technology typically focuses on 3 parameters: 1) its technical performance; 2) diagnostic performance (sensitivity, specificity, and positive and negative predictive value) in appropriate patients; and 3) demonstration that the diagnostic information can be used to improve patient outcomes (clinical utility).
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.
A number of studies have been published that evaluate the sensitivity and specificity of fecal calprotectin testing for diagnosing IBD. In 2010, van Rheenen and colleagues published a meta-analysis of diagnostic accuracy studies. The authors were selective in their choice of studies and only included studies that were prospective, included patients with suspected bowel disease, obtained stool samples before endoscopy, and evaluated all patients endoscopically with histological verification of segmental biopsies. Thirteen studies met eligibility criteria; 6 were conducted in adults and 7 in children and adolescents. Inflammatory bowel disease was confirmed by the reference test in 215 of 670 (32%) of adults and 226 of 371 (61%) of the children. Eleven studies used the PhiCal™ test; 7 of the 11 (64%) used a cutoff of 50 ug/g for a positive calprotectin test and the remainder used cutoffs ranging from 24 to 100 ug/g.
In the adult studies, the pooled sensitivity and specificity of the fecal calprotectin test for distinguishing between IBD and non-IBD was 93% (95% confidence interval [CI]=85% to 97%) and 96% (95% CI=79% to 99%), respectively. For children and teenagers, the corresponding numbers were a sensitivity of 92% (95% CI=84% to 96%) and specificity of 76% (95% CI=62% to 86%). Specificity was significantly lower in children andteenagers than in adults, p=0.048. The use of the fecal calprotectin test significantly changed the post-test probability of inflammatory bowel disease in both age groups. In adults, an abnormal calprotectin test increased the probability of inflammatory bowel disease from a pretest probability of 32% to a post-test probability of 91% (95% CI=77% to 97%). Similarly, a normal calprotectin test reduced the probability from 32% to 3% (95% CI=1% to 11%). In children and teenagers an abnormal calprotectin test increased the probability of inflammatory bowel disease from 61% to 86% (95% CI=78% to 92%) and a normal calprotectin test reduced the probability form 61% to 15% (95% CI=7% to 28%).
The investigators calculated that, in a hypothetical population of 100 adults with suspected inflammatory bowel disease (and a prevalence of 32%) fecal calprotectin testing would result in 30 true positives, 65 true negatives, 3 false positives, and 2 false negatives. If only patients with a positive test received endoscopy, 33 of 100 (33%) would receive endoscopy including 3 patients without disease. Two patients with disease would be missed. In a hypothetical population of 100 children with suspected inflammatory bowel disease (and a prevalence of 61%), there would be 56 true positives, 30 true negatives, 9 false positives, and 5 false negatives. Nine out of 100 without disease would get endoscopy and 5 patients with disease would be missed. In a lower prevalence population, the positive predictive value of fecal calprotectin testing would be lower; consequently, the authors did not recommend use of the test to screen asymptomatic patients and did not recommend use of the test in a primary care setting. It is also worth noting that, when 95% confidence intervals are taken into account, the data are consistent with a post-test probability of having IBD with a negative fecal calprotectin test as high as 11% in adults and 28% in children. The authors commented that, due to the relatively small number of studies meeting their eligibility criteria, they were not able to examine different test cutoffs. Seven of 13 (53%) used the manufacturer’s recommended cutoff of 50 ug/g but the remaining studies used cutoffs ranging from 24ug/g to 100 ug/g. The authors also stated that, despite their efforts to include patients most likely to be potential candidates for the test, none of the studies used a clear diagnostic algorithm to select patients at highest risk of inflammatory bowel disease. Another limitation of the van Rheenen analysis of the potential impact of fecal calprotectin testing on patient management is that it was hypothetical and none of the studies included in the meta-analysis prospectively evaluated the impact of fecal calprotectin testing on endoscopy rates of health outcomes.
An earlier meta-analysis of studies on the diagnostic accuracy of fecal calprotectin testing was published by von Roon and colleagues in 2007. The authors included studies that compared fecal calprotectin with histological diagnosis of Crohn’s disease, ulcerative colitis and colorectal cancer screening. In contrast to the van Rheenen analysis they excluded studies without a control group either of healthy individuals or individuals with irritable bowel syndrome. The authors identified 30 studies with a total of 5,983 participants (3393 of which were healthy controls). Nine studies (n=1,297) provided data on the ability of fecal calprotectin to distinguish between inflammatory bowel disease versus no inflammatory bowel disease using a cutoff of 50 ug/g to indicate a positive test. Pooled sensitivity was 89% (95% CI=86% to 91%) and the pooled specificity was 81% (95% CI=78% to 84%). Stratifying by age group, a pooled analysis of 6 studies conducted in adults (n=1030) using the 50 ug/g cutoff calculated a sensitivity of 71% (95% CI=67% to 75%) and specificity of 80% (95% CI=77% to 83%). When findings from the 3 studies with children (n=201) were pooled, the sensitivity was 83% (95% CI=73% to 90%) and specificity was 85% (95% CI=77% to 91%). Four studies (n=328) provided data on differentiating between IBD and non-IBD in adults and/or children using a calprotectin cutoff of 100 ug/g. The pooled sensitivity was 98% (95% CI=93% to 99%) and the pooled specificity was 91% (95% CI=86% to 95%). The authors noted that there may have been spectrum bias in the studies included in the review. That is, studies on using fecal calprotectin to differentiate between IBD and non-IBD had differing proportions of patients with mild versus severe disease and this could affect the sensitivity and specificity of the test.
Several studies have evaluated the accuracy of calprotectin and other fecal markers for predicting treatment outcome in patients with bowel disease. Among them, a 2010 prospective multicenter study by Turner and colleagues examined the ability of 4 fecal markers to predict steroid refractoriness in children with severe ulcerative colitis. The markers were fecal calprotectin, lactoferrin, M2-pyruvate kinase (M2-PK) and S100A12. Stool samples were obtained from 101 children when they were admitted to the hospital for intravenous steroid treatment. Twenty six (26%) subsequently failed steroid treatment within a median of 10 days. Levels of all fecal markers were elevated at baseline. The mean value of fecal calprotectin at sampling for patients who later responded to treatment was 3307 ug/g and for those who failed treatment was 7516 ug/g; this difference was statistically significant (p=0.039). The ability of the fecal markers to predict treatment response was assessed using receiver operating curve (ROC) analysis. A ROC of > 0.7 was considered fair, 0.8 good, and > 0.9 excellent at discriminating between steroid responders and non-responders. The ROC values for the markers were 0.64 for calprotectin, 0.51 for lactoferrin, 0.75 for M2-PK, and 0.39 for S100A12; only M2-PK was considered to be at least a “fair” marker. In addition, a clinical scoring system known as the Pediatric Ulcerative Colitis Activity Index (PUCAI) had an area under the curve of 0.81.
No studies evaluating the use of fecal calprotectin testing to predict response to treatment provided data on how treatment decisions and/or health outcomes would differ with and without use of the test.
Several prospective studies using fecal calprotectin testing to predict relapse in patients with inflammatory bowel disease who are in clinical remission have been published. For example, a study by Costa and colleagues in Italy, published in 2004, found that calprotectin was a stronger predictive marker of ulcerative colitis relapses than relapses of Crohn’s disease. The study included 79 patients with inflammatory bowel disease in remission; 38 had Crohn’s disease and 41 had ulcerative colitis. A single stool sample was obtained at the start of the study and the level of calprotectin was measured; 150 ug/g was used as the cutoff for an elevated level of calprotectin. At baseline, 26 of 38 (68%) of CD patients and 21 of 41 (51%) of UC patients had calprotectin > 150 ug/g. Patients were followed for up to 12 months during which time 15 (39%) CD patients and 19 (46%) UC patients experienced a relapse. A fecal calprotectin level of 150 ug/g had 89% sensitivity and 82% specificity for predicting relapses of UC. Corresponding values for predicting relapse of CD were a sensitivity of 87% and a specificity of 43%. Among the patients with a baseline calprotectin level > 150 ug/g, half of the CD patients and more than 80% of the UC patients relapsed by the end of the 12 month period.
Two more recent studies found that fecal calprotectin predicted relapses in both major types of inflammatory bowel disease. For instance, a 2009 study by Gisbert and colleagues in Spain included 163 patients (89 CD and 74 UC) who had been in remission for at least 6 months. Like the Costa study, one sample of fecal calprotectin was obtained at baseline and patients were followed for 12 months. The mean baseline level of fecal calprotectin was 153 ug/g (range 6 to 1217 ug/g); levels were not reported for UC versus CD patients. During the follow up period, 13 of 74 (18%) UC patients and 13 of 89 (15%) CD patients experienced a relapse severe enough to warrant a change in treatment. Mean levels of calprotectin were significantly higher in patients who relapsed compared to those who did not relapse. In CD patients, mean levels were 266 ug/g in relapsing patients and 145 ug/g in non-relapsing patients (p=0.002). Corresponding values in UC patients were 213 ug/g and 126 ug/g, respectively (p=0.03). A cutoff of 150 ug/g was found to best predict relapses of inflammatory bowel disease. At 150 ug/g, fecal calprotectin had 31% sensitivity and 91% specificity for predicting UC and 28% sensitivity and 93% specificity for predicting CD.
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.
Clinical utility for all potential uses of the test is best evaluated by prospective studies, ideally randomized controlled trials, evaluating the impact of the test on patient management decisions and/or health outcomes. No studies of this type using the fecal calprotectin test were identified during the literature review for this policy.
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.
Procedure Codes and Billing Guidelines:
- To report provider services, use appropriate CPT* codes, Modifiers, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
- 83993 Calprotectin, fecal
- United States Food and Drug Administration (FDA). PhiCal 510(k) Substantial Equivalence Determination Decision Summary. Accessed April 18, 2011.
- 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.
- 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.
- 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.
- 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.
- 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.
- 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. Imflamm Bowel Dis 2009; 15(2):199-205.
- Turner D, Leach ST, Mack D et al. Faecal calprotectin, lactoferrin, M2-pyruvate kinase and S100A12 in severe ulcerative colitis: a prospective multicentre comparison predicting outcomes and monitoring response. Gut 2010; 59(9):1207-12.
- 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.
- 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.
- 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.
- Garcia-Sanchez V, Iglesias-Flores E, Gonzales 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.
- 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):340-5.
- 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.
- 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.
- Jellema P, van Tulder MW, van der Horst HE, et al. Inflammatory bowel disease: a systematic review on the value of diagnostic testing in primary care. Colorectal Dis. 2011 Mar;13(3):239-54.
- Laharie D, Mesli S, El Hajbi F, et al. Prediction of Crohn’s disease relapse with faecal calprotectin in infliximab responders: a prospective study. Aliment Pharmacol Ther. 2011 Aug;34(4):462-9.
- Gastroenterol Hepatol. 2013 Feb 19. pii: S0210-5705(13)00004-6. doi: 10.1016/j.gastrohep.2012.10.008. [Epub ahead of print,]
- Mao, R., Xiao, Y.-l., Gao, X., Chen, B.-l., He, Y., Yang, L., Hu, P.-j. and Chen, M.-h. (2012), Fecal calprotectin in predicting relapse of inflammatory bowel diseases: A meta-analysis of prospective studies. Inflamm Bowel Dis, 18: 1894–1899. doi: 10.1002/ibd.22861
- Higuchi LM and Bousvaros A. Clinical features and diagnosis of inflammatory bowel disease in children and adolescents. Waltham, MA : Wolters Kluwer Health; 2013. Available at: http://www.uptodate.com.
- National Institute for Health and Care Excellence (NICE). Faecal calprotectin diagnosis tests for inflammatory diseases of the bowel. NICE diagnostics guidance 11. London, UK: NICE; 2013. Available at: http://www.nice.org.uk/nicemedia/live/14285/65337/65337.pdf.
Date Reason Action
April 2011 Literature review New policy
March 2012 Annual review Policy renewed
March 2013 Annual review Policy renewed
February 2014 Annual review Policy renewed
December 2014 Annual review Policy renewed
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