Populations	Interventions	Comparators	Outcomes
Individuals: With a suspicion of inflammatory bowel disease when endoscopy with biopsy is being considered	Interventions of interest are: Fecal calprotectin testing to select patients who can forgo endoscopy	Comparators of interest are: Endoscopy with biopsy	Relevant outcomes include: Test validity Symptoms Change in disease status Quality of life Hospitalizations Medication use
Individuals: With active inflammatory bowel disease	Interventions of interest are: Fecal calprotectin testing to monitor disease activity	Comparators of interest are: Clinical evaluation Endoscopy with biopsy	Relevant outcomes include: Test validity Symptoms Change in disease status Quality of life Hospitalizations Medication use
Individuals: With inflammatory bowel disease in remission	Interventions of interest are: Fecal calprotectin testing to predict relapse	Comparators of interest are: Clinical evaluation Endoscopy with biopsy	Relevant outcomes include: Test validity Symptoms Change in disease status Quality of life Hospitalizations Medication use

Background

Inflammatory Bowel Disease

IBD is a chronic condition that encompasses two main forms: Crohn disease and ulcerative colitis. These conditions overlap in clinical and pathologic characteristics but have distinct features. Crohn 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 (e.g., abdominal pain, bloody diarrhea, perianal fistulae), systemic (e.g., weight loss, fatigue, growth failure in children), or extraintestinal (e.g., 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 non-specific and suggestive of other disorders, including infectious colitis, colon cancer, and functional bowel disorders, including irritable bowel syndrome.

Thus, 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 the GI tract. Fecal markers, in contrast, have the potential to be more specific to the diagnosis of GI tract disorders, because 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 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. In contrast, lactoferrin, another potential fecal marker of intestinal inflammation, is stable at room temperature for about two days.

Among potential disadvantages of fecal calprotectin as a marker of inflammation are that fecal calprotectin levels increase after the use of nonsteroidal anti-inflammatory drugs, that levels may change with age, and that bleeding (e.g., nasal, menstrual) may cause an elevated fecal calprotectin level. Moreover, there is uncertainty about the optimal cutoff to distinguish between IBD and noninflammatory 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) 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 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 be used to change treatment, such as adjusting medication levels.

Treatment

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

Regulatory Status

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 IBD 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.”

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; Quantum Blue CalprotectinÒ, Bühlmann Laboratories). Rapid tests have not been approved by the FDA for use in the U. S.

Related Policies

• Fecal Analysis in the Diagnosis of Intestinal Dysbiosis (Policy #045 in the Pathology Section)

The first step in assessing a medical test is to formulate the clinical context and purpose of the test. The test must be technically reliable, clinically valid, and clinically useful for that purpose. Evidence reviews assess the evidence on whether a test is clinically valid and clinically useful. Technical reliability is outside the scope of these reviews, and credible information on technical reliability is available from other sources.

Suspected Inflammatory Bowel Disease
Clinical Context and Test Purpose

In patients who have suspected IBD, the purpose of fecal calprotectin testing is to inform the decision whether to proceed to endoscopy with biopsy in order to confirm a diagnosis of IBD, either ulcerative colitis or Crohn disease.

Irritable bowel syndrome (IBS) and IBD can share common presenting symptoms such as diarrhea and abdominal pain. IBS is generally managed by antidiarrheal agents, diet, and lifestyle changes. IBD has a more serious prognosis. For example, Crohn disease can result in a bowel obstruction or fistulas requiring surgical intervention. Ulcerative colitis has similar complications but is more localized.

In a patient whose symptoms have not responded to conservative management, endoscopy with biopsy would be required to confirm a diagnosis of IBD and inform treatment choice, which may include biologic disease-modifying agents. However, in a significant proportion of patients undergoing endoscopy with biopsy, IBD is not present. If fecal calprotectin testing can predict which patients are unlikely to have IBD, fewer patients would be subjected to endoscopy with biopsy (see Figure 1).

The question addressed in this policy is: Does fecal calprotectin testing predict the likelihood of bowel inflammation and thus inform the decision whether to proceed to endoscopy with biopsy?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals who present with signs and symptoms of suspected IBD for whom endoscopy with biopsy is being considered. Alternative causes of abdominal pain and diarrhea would have been ruled out and there would be no other indication for endoscopy such as rectal bleeding or risk factors (eg age) for cancer.

Interventions

The test being considered is fecal calprotectin analysis, which detects the process of inflammation in the intestines. The labeling of the Food and Drug Administration-cleared PhiCal assay recommends the following interpretative guidelines: normal/healthy: less than 50 µg/g; indeterminate; 50 to 120 µg/g; abnormal: greater than 120 µg/g. Fecal calprotectin is also available as a laboratory-developed test and the upper threshold is being defined. Some laboratories use an upper threshold of 250 µg/g or higher to define a high probability of IBD

Comparators

The following practice is currently being used to make decisions about diagnosing IBD: the reference standard is endoscopy with biopsy. In clinical practice, other tests such as magnetic resonance imaging, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), and complete hemogram are part of the evaluation for IBD.

Outcomes

The outcome of a fecal calprotectin test is to inform the decision of whether to proceed to endoscopy with biopsy.

The beneficial outcome of correctly being classified as low-risk for IBD is avoiding an unnecessary invasive test. The harmful outcome of incorrect classification as low-risk for IBD is omission or deferral of a necessary biopsy, with a consequent delay of appropriate treatment.

For purposes of evaluating the clinical validity of fecal calprotectin testing to predict the results of endoscopy, the time frame is the availability of endoscopy results.

Study Selection Criteria

For the evaluation of the clinical validity of the fecal calprotectin test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology
• Included a suitable reference standard (endoscopy or clinical follow-up)
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Waugh et al (2013) published a systematic review as part of the U.K. Health Technology Assessment program. Investigators included 28 studies using fecal calprotectin tests to evaluate inflammation of the lower intestine in newly presenting patients.^1, Studies using fecal calprotectin tests to monitor disease progression or response to treatment were excluded. Endoscopy with histology was the preferred reference standard, although some studies included used imaging or clinical follow-up. Studies were pooled when there was a minimum of four using the same calprotectin cutoff.

A pooled analysis of 5 studies using fecal calprotectin detected by enzyme-linked immunosorvent assay to differentiate between IBD and IBS in adults at a cutoff of 50 μg/g was performed (see Table 1). One study was rated as low-risk of bias and three studies had at least three domains with high or unclear risk of bias. The pooled studies had a combined sensitivity of 93% and a combined specificity of 94% to predict the presence of inflammatory disease on biopsy (1 study evaluated the absence of inflammatory disease). See Table 2 clinical validity results and Tables 3 and 4 for individual study characteristics and results, with Table 4 presented in the order of increasing prevalence of IBD. Out of 100 cases with a prevalence of 20%,^2, 76 invasive tests would be avoided with 1 case of IBD missed. At a prevalence of 68%,^3, 35 invasive tests would be avoided with 5 cases missed.

Table 1. Characteristics of Studies at a Threshold of 50 μg/g

					11-Item QUADAS Quality Assessment
					No. of Studies Rated as High or Unclear Risk of Bias
Study	Studies Included	Study Populations Included	Study Designs Included	Study Reference Standards Included	No Domains	1-2 Domains	>2 Domains	Domains With >3 Studies at High-Risk of Bias
Waugh et al (2013)1,	5 studies	Adults newly presenting with IBD or IBS referred by general practitioners	Diagnostic accuracy of FC to detect inflammation of the lower intestine	Most used endoscopy with biopsy	1	1	3	Blinding of reference standard
	6 studies	Adults and children newly referred with IBD or non-IBD	Diagnostic accuracy of FC to detect inflammation of the lower intestine	Most used endoscopy with biopsy Some studies in children used clinical follow-up	0	5	1	Blinding of reference standard

FC: fecal calprotectin; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome.

Table 2. Clinical Validity Study Results at a Threshold of 50 μg/g

Study	Scenario (N)	Sensitivity (95% CI), %	Specificity (95% CI), %	PPV Range, %	NPV Range, %	Disease Prevalence Range (95% CI), %
Waugh et al (2013)1, (pages 35, 38)	To detect IBD in adults with IBS or IBD (5 studies, n=596 patients)	93 (83 to 97)	94 (73 to 99)	24-100	73-100	10.9-69.0 (5.8 to 77.3)
Waugh et al (2013)1, (pages 48, 52)	To detect IBD in children and adults with IBD or non-IBD (6 studies, n=516 patients)	99 (95 to 100)	74 (59 to 86)	62-96	93-100	21.4-61.1 (13.2 to 72.5)

CI: confidence interval; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome; NPV: negative predictive value; PPV: positive predictive value.

Table 3. Characteristics of Diagnostic Accuracy Studies (IBD vs IBS) in Adults with a Cutoff of 50 μg/g

Study	Study Population	Setting	Reference Standard	No. of Domainsa at High or Unclear Risk of Bias
Basumani et al (2012)4,	New referrals with diarrhea ≥4 wk to rule out IBD	District General Hospital, England	Histology	4
Otten et al (2008)2,	Consecutive patients referred with lower abdominal symptoms to endoscopy unit. Excluded 25 patients with polyps or CRC.	Endoscopy unit, The Netherlands	Colonoscopy and biopsy	2
Li et al (2006)5,	Outpatients and inpatients with IBS or IBD, healthy controls; patients followed up after polyp removal with no recurrence. Excluded 60 patients with CRC	Hospital, Peking	Colonoscopy with biopsy in IBD group	6
Schoepfer et al (2008)3,	Outpatients and inpatients with IBS or IBD. Excluded patients with CRC.	Gastroenterology Department, University Hospital, Switzerland	Colonoscopy including terminal ileum and biopsies	0
El-Badry et al (2010)6,	GI symptoms for at least 6 mo, and endoscopy necessary to exclude organic pathology. Excluded patients with CRC, diverticulitis, and polyps.	Internal Medicine Department, Egypt	Colonoscopy into ileum with biopsies	3

CRC: colorectal cancer; GI: gastrointestinal; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome.
^a QUADAS ratings.

Table 4. Results of Diagnostic Accuracy Studies (IBD vs IBS) in Adults with a Cutoff of 50 μg/g Stratified by Increasing Prevalence

Study	N	Prevalence (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)	PLR (95% CI)	NLR (95% CI)
Basumani et al (2012)4,	110	10.91 (5.77 to 18.28)	1.00 (0.74 to 1.00)	0.60 (0.50 to 0.70)	0.24 (0.13 to 0.37)	1.00 (0.94 to 1.00)	2.51 (1.97 to 3.21)	0
Otten et al (2008)2,	114	20.18 (13.24 to 28.72)	0.96 (0.78 to 1.00)	0.87 (0.78 to 0.93)	0.65 (0.47 to 0.81)	0.99 (0.93 to 1.00)	7.25 (4.25 to 12.38)	0.05 (0.01 to 0.34)
Li et al (2006)5,	120	50.00 (40.74 to 59.26)	0.93 (0.84 to 0.98)	0.95 (0.86 to 0.99)	0.95 (0.86 to 0.99)	0.93 (0.84 to 0.98)	18.67 (6.18 to 56.63)	0.07 (0.03 to 0.18)
Schoepfer et al (2008)3,	94	68.09 (57.67 to 77.33)	0.83 (0.71 to 0.91)	1.00 (0.88 to 1.00)	1.00 (0.93 to 1.00)	0.73 (0.57 to 0.86)	NR	0.17 (0.10 to 0.29)
El-Badry et al (2010)6,	29	68.97 (49.17 to 84.72)	0.85 (0.62 to 0.97)	1.00 (0.66 to 1.00)	1.00 (0.81 to 1.00)	0.75 (0.43 to 0.95)	NR	0.15 (0.05 to 0.43)

CI: confidence interval; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome; NLR: negative likelihood ratio; NPV: negative predictive value; NR: not reported; PLR: positive likelihood ratio; PPV: positive predictive value.

Six studies using fecal calprotectin with an enzyme-linked immunosorvent assay to differentiate between IBD and non-IBD in children and adults were pooled (see Table 5). Five of the studies included only children, most of whom had been referred to pediatric gastroenterologists. The children had undergone fecal calprotectin testing prior to endoscopy with biopsy or were followed clinically. No studies were at low-risk of bias and five studies had one to two domains with high or unclear risk of bias, as evaluated on the QUADAS quality assessment. The highest risk of bias was for blinding of the reference standard. The combined sensitivity was 99%, with a lower combined specificity (74%) to detect the absence of inflammatory disease on biopsy (see Table 6). Modeling indicated that the use of fecal calprotectin in children would result in fewer children undergoing an unnecessary invasive test (i.e., endoscopy with biopsy). Out of 100 cases, at a prevalence of 36%,^7, 47 invasive tests would be avoided with 1 case of IBD missed. At a prevalence of 51%,^8, 36 invasive tests would be avoided with 1 case of IBS missed. Individual study characteristics (Table 5) and results, (Table 6) presented in the order of the increasing prevalence of IBD.

Table 5. Characteristics of Diagnostic Accuracy Studies (IBD vs Non-IBD) in Children and Adults with a Cutoff of 50 μg/g

Study	Study Population	Setting	Reference Standard	No. of Domainsa at High or Unclear Risk of Bias
Damms and Bischoff al (2008)9,	Patients ages >18 y referred for colonoscopy for GI disorders or CRC screening	Gastroenterology departments at 3 hospitals and 3 outpatient clinics in Germany	Colonoscopy: for CRC screening medical check-up	2
Van de Vijver et al (2012)7,	Children ages 6-18 y referred for further investigation of high suspicion of IBD from pediatrician’s global assessment, physical examination, and blood results	Pediatric outpatient clinics at 6 general hospitals and 1 tertiary care hospital in the North Netherlands Paediatric IBD Consortium	68 patients had endoscopy; others had follow-up for at least 6 mo to confirm a diagnosis of IBS	1
Henderson et al (2012)10,	All children who had a fecal calprotectin measurement as part of initial diagnostic workup before endoscopy	Pediatric gastroenterology department at a children’s hospital in U.K.	IBD patients: standard clinical, histologic, and radiologic findings Non-IBD (control) patients: upper and lower endoscopy	2
Sidler et al (2008)8,	Children ages 2-18 y referred for further investigation of GI symptoms (chronic diarrhea, bloody stools, abdominal pain) suggestive of an OBD	Pediatric gastroenterology outpatient clinic at children’s hospital in Australia	Upper GI endoscopy and complete ileocolonoscopy with biopsy	1
Tomas et al (2007)11,	Patients referred for further investigation of GI symptoms (intense abdominal pain, chronic diarrhea, weight loss, rectal bleeding)	Pediatric gastroenterology unit of university hospital in Spain	Clinical criteria, laboratory, image, and endoscopic test results	6
Fagerberg et al (2005)12,	Children ages 6-17 y with GI symptoms and blood tests suggestive of inflammation who were scheduled for colonoscopy to rule out IBD	Pediatric gastroenterology departments at hospitals in Sweden	Complete ileocolonoscopy with biopsy	1

CRC: colorectal cancer; GI: gastrointestinal; IBD: inflammatory bowel disease; IBS: irritable bowel syndrome; OBD; organic bowel disease.
^a QUADAS ratings.

Table 6. Results of Diagnostic Accuracy Studies (IBD vs Non-IBD) in Children and Adults with a Cutoff of 50 μg/g Stratified by Increasing Prevalence

Study	N	Prevalence (95% CI)	Sensitivity (95% CI)	Specificity (95% CI)	PPV (95% CI)	NPV (95% CI)	PLR (95% CI)	NLR (95% CI)
Damms et al (2008)9,	84	21.43 (13.22 to 31.74)	1.00 (0.81 to 1.00)	0.79 (0.67 to 0.88)	0.79 (0.60 to 0.88)	1.00 (0.93 to 1.00)	4.71 (2.96 to 7.50)	0
Van de Vijver et al (2012)7,	117	35.9 (27.24 to 45.29)	1.00 (0.92 to 1.00)	0.73 (0.62 to 0.83)	0.68 (0.55 to 0.79)	1.00 (0.94 to 1.00)	3.8 (2.6 to 5.5)	0
Henderson et al (2012)10,	190	47.89 (40.61 to 55.25)	0.98 (0.92 to 1.00)	0.44 (0.34 to 0.55)	0.62 (0.53 to 0.70)	0.96 (0.85 to 0.99)	1.8 (0.15 to 2.1)	0.05 (0.01 to 0.20)
Sidler et al (2008)8,	61	50.82 (37.70 to 63.86)	1.00 (0.89 to 1.00)	0.67 (0.47 to 0.83)	0.76 (0.60 to 0.88)	1.00 (0.83 to 1.00)	3.00 (1.81 to 4.98)	0
Tomas et al (2007)11,	28	53.57 (33.87 to 72.49)	1.00 (0.78 to 1.00)	0.92 (0.64 to 1.00)	0.94 (0.70 to 1.00)	1.00 (0.74 to 1.00)	13.00 (1.98 to 85.46)	0
Fagerberg et al (2005)12,	36	61.11 (43.46 to 76.86)	0.95 (0.77 to 1.00)	0.93 (0.66 to 1.00)	0.96 (0.77 to 1.00)	0.93 (0.66 to 1.00)	13.36 (2.02 to 88.54)	0.05 (0.01 to 0.33)

CI: confidence interval; IBD: inflammatory bowel disease; NLR: negative likelihood ratio; NPV: negative predictive value; PLR: positive likelihood ratio; PPV: positive predictive value.

Clinically Useful

A test is clinically useful if the results inform management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from randomized controlled trials (RCTs).

No RCTs were identified that assessed the use of fecal calprotectin testing to diagnose suspected IBD.

Chain of Evidence

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Indirect evidence supports the clinical usefulness of fecal calprotectin in patients with suspected IBD for whom endoscopy is being considered. The evidence on clinical validity (sensitivity, specificity, NPV) permits inference on clinical usefulness as a result of avoidance of endoscopy with biopsy in patients who are unlikely to have an inflammatory disease.

Section Summary: Suspected IBD

A systematic review and meta-analysis of 28 studies pooled 11 studies that used a 50 μg/g threshold to evaluate intestinal inflammation. Five studies (n=596 patients) showed an NPV in the range of 73% to 100% in adults with IBS or IBD. The pooling of 6 studies in adults and children (n=1100) with IBD or non-IBD showed an NPV of 93% to 100%. Together, these results would suggest that fecal calprotectin testing at a threshold of 50 μg/g can identify patients who are unlikely to have the inflammatory disease and can forgo a more invasive test (endoscopy with biopsy). Clinical input supported that the use of fecal calprotectin testing for individuals with suspected IBD provides a clinically meaningful improvement in net health outcomes by providing clinically valid and clinically useful information to guide 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 negative fecal calprotectin results to exclude IBD and avoid endoscopy with biopsy with acceptably low tradeoffs in missed diagnoses of IBD in those who have false-negative fecal calprotectin results. 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. Further details from clinical input are included in the Clinical Input section later in the review and the Appendix.

Monitoring Active IBD
Clinical Context and Test Purpose

For patients who have been diagnosed with IBD, testing for fecal calprotectin testing could allow clinicians to monitor disease activity and guide therapeutic decision making.

The question addressed in this section is: Does the addition of fecal calprotectin testing to clinical assessment (based on standard scores and/or history and physical examination) and standard laboratory tests (e.g., complete blood count, ESR, CRP) in individuals with active IBD improve health outcomes?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with Crohn disease or ulcerative colitis.

Interventions

The test being considered is fecal calprotectin analysis.

Comparators

The following practice is currently being used to make decisions about monitoring IBD: the reference standard is a repeat endoscopy with biopsy. In clinical practice, other tests such as ESR, CRP, and complete hemogram are part of the evaluation for monitoring disease activity in IBD

Outcomes

The beneficial outcome of a true test result, if correctly classified as low disease activity, is the avoidance of endoscopy and unnecessary medications.

If correctly classified as high activity, the administration of appropriate treatment is another beneficial outcome.

Outcomes may be assessed in clinical practice and in the research setting with standardized measures, such as the Crohn Disease Activity Index, a validated 8-item score used as a marker of Crohn disease remission, with values less than 150 considered consistent with remission and values greater than 450 considered a marker of severe Crohn disease.^13,

The relevant time period for the impact of testing is weeks to months.

Study Selection Criteria

For the evaluation of the clinical validity of the fecal calprotectin test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology
• Included a suitable reference standard (endoscopy)
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic reviews and meta-analyses have reviewed studies on fecal calprotectin testing to identify IBD patients with active disease.

A systematic review by Mosli et al (2015) evaluated the sensitivity and specificity of fecal calprotectin in adults and some children with previously diagnosed ulcerative colitis or Crohn disease to detect endoscopically confirmed active disease (see Table 7).^14, Nineteen studies with 1069 ulcerative colitis patients and 1033 Crohn disease patients met eligibility criteria. Individual studies used a variety of cutoffs for fecal calprotectin, ranging from 6 to 280 μg/g. Pooled sensitivity and specificity estimates for fecal calprotectin were 88% and 73%, respectively. (see Table 8). The optimal threshold was determined to be 50 μg/g. At a threshold of 50 μg/g, the NPV for inflammation at a prevalence of 0.50 was 86% and the PPV was 76%. This information might be used to triage patients for endoscopy when they have symptoms of active disease.

Table 7. Characteristics of Clinical Validity Reviews Assessing Monitoring of Active Disease

					11-Item QUADAS Quality Assessment
					No. of Studies Rated as High or Unclear Risk of Bias
Study	Studies Included	Study Populations Included	Study Designs Included	Study Reference Standards Included	No Domains	1-2 Domains	>2 Domains	Indicators with >6 Studies at High or Unclear Risk of Bias
Mosli et al (2015)14,	19	1069 UC and 1033 CD patients (mostly adults) with symptomatic disease	Prospective cohorts or case-controls for evaluating disease activity	Endoscopy	2	9	8	Inappropriate exclusions Blinding of index test Interval between tests Exclusions in the analysis

CD: Crohn diseases; UC: ulcerative colitis.

Table 8. Results of Clinical Validity Reviews Assessing Detection of Endoscopically Confirmed Active Disease

Study	Scenario	Sensitivity (95% CI), %	Specificity (95% CI), %	Range PPV, %	Range NPV, %
Mosli et al (2015)14,	To monitor disease activity in patients with CD or UC on maintenance therapy (N=2102)	88 (84 to 90)	73 (66 to 79)	52-91	67-95

CI: confidence interval; CD: Crohn disease; NPV: negative predictive value; PPV: positive predictive value; UC: ulcerative colitis

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

For monitoring disease activity in patients with active IBD, inferences cannot be made from clinical validity studies to clinical usefulness. How fecal calprotectin would be used to make decisions about endoscopy or intensification of therapy is not described in the Mosli et al (2015) review. Intervention studies will provide direct evidence of fecal calprotectin for monitoring disease activity in patients with active IBD.

Colombel et al (2018) reported on an open-label multicenter RCT, the Efficacy and Safety Study to Evaluate Two Treatment Algorithms in Subjects With Moderate to Severe Crohn's Disease (CALM) that compared the effect of tight control of Crohn disease with standard clinical management.^15, The primary endpoint was mucosal healing with an absence of deep ulcers at 48 weeks after randomization (see Tables 9 and 10). This trial did not test whether using fecal calprotectin, as decision criteria for treatment changes, improved the capability to achieve tight control. Although a post hoc analysis found that, in the tight management arm, fecal calprotectin levels frequently influenced the decision to escalate treatment, the contribution of fecal calprotectin to the tight control cannot be determined from this study design.

Table 9. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Colombel et al (2018)15,	U.S., E.U.	74	2011 - 2016	244 adults with moderate-to-severe active CD (CDEIS, >6; CDAI, 150-450) and naive to immunomodulators and biologics	Tight controla including FC ≥250 μg/g and CRP >5 mg/L	Clinical managementb

CD: Crohn disease; CDAI: Crohn’s Disease Activity Index; CDEIS: Crohn’s Disease Endoscopic Index of Severity; CRP: C-reactive protein; FCP: fecal calprotectin; RCT: randomized controlled trial.

^a Tight control was determined by FC level ≥250 μg/g, CRP level ≥5 mg/L, CDAI score ≥150, or prednisone use in the previous week.
^b Clinical management was based on a CDAI score decrease of <100 points vs baseline or CDAI score ≥200, or prednisone use in the previous week.

Study	Mucosal Healing at 48 Weeks	Adverse Events	Steroid-Free Remission at 48 Weeks	Deep Remission
Colombel et al (2018)15,	244	244	244	244
Tight control	56/122 (46)	105 (86)	73 (59.8)	45 (36.9)
Clinical monitoring	37/122 (30)	100 (82)	48 (39.3)	28 (23.0)
RR (95% CI)	16.1 (3.9 to 28.3)
p	0.010		0.001	0.014

The limitations tables (see Tables 11 and 12) display notable limitations identified in each study. The Colombel et al (2018) study does not specifically address the intervention of interest for this policy (fecal calprotectin) (see Table 11). The study evaluated tight control vs standard management. As noted in Table 12, additional study limitations were a lack of blinding to treatment assignment or outcomes assessment and a 25% loss to follow-up.

Table 11. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Colombel et al (2018)15,		4. In addition to FCP, CRP, prednisone use, and different thresholds of CDAI were used in the tight control arm

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.
CDAI: Crohn’s Disease Activity Index; CRP: C-reactive protein; FCP: fecal calprotectin.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
^c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
^d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
^e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Colombel et al (2018)15,		1. Not blinded to treatment assignment 2. Not blinded outcome assessment 3. Outcome assessed by treating physician		1. 25% loss to follow-up (analysis was intention-to-treat)

^a Allocation key: 1. Participants not randomly allocated; 2. Allocation not concealed; 3. Allocation concealment unclear; 4. Inadequate control for selection bias.
^b Blinding key: 1. Not blinded to treatment assignment; 2. Not blinded outcome assessment; 3. Outcome assessed by treating physician.
^c Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^d Data Completeness key: 1. High loss to follow-up or missing data; 2. Inadequate handling of missing data; 3. High number of crossovers; 4. Inadequate handling of crossovers; 5. Inappropriate exclusions; 6. Not intent to treat analysis (per protocol for noninferiority trials).
^e Power key: 1. Power calculations not reported; 2. Power not calculated for primary outcome; 3. Power not based on clinically important difference.
^f Statistical key: 1. Intervention is not appropriate for outcome type: (a) continuous; (b) binary; (c) time to event; 2. Intervention is not appropriate for multiple observations per patient; 3. Confidence intervals and/or p values not reported; 4. Comparative treatment effects not calculated.

Indirect evidence on clinical utility rests on clinical validity. If the evidence is insufficient to demonstrate test performance, no inferences can be made about clinical utility.

Because the clinical utility of fecal calprotectin testing has not been established for monitoring active IBD, a chain of evidence cannot be constructed.

Section Summary: Monitoring Active IBD

Studies to manage IBD have not used consistent cutoff values. A systematic review determined that 50 μg/g was the optimum threshold; at a prevalence of 0.50, fecal calprotectin had NPV of 86% and PPV of 76%. One RCT using fecal calprotectin testing along with other measures to monitor disease activity in patients with IBD on maintenance therapy was identified. The investigators reported that tight control using both clinical status and biologic markers (fecal calprotectin level, ≥250 μg/g; CRP level, ≥5 mg/L) resulted in greater mucosal healing in patients with Crohn disease. The contribution of fecal calprotectin to the tight control could not be determined from this study design.

Prediction of Relapse With IBD in Remission
Clinical Context and Test Purpose

Calprotectin has been used to predict relapse in individuals with IBD who are in remission. A marker to predict relapse could improve the net health outcome if preemptive treatment were found to eliminate recurrences or reduce their severity.

The questions addressed in this policy section are: Does the addition of fecal calprotectin to clinical assessment (based on standard scores and/or history and physical examination) and standard laboratory tests (e.g., complete blood count, ESR, CRP) in individuals with diagnosed IBD improve relapse prediction? And does relapse prediction lead to improved outcomes in those with IBD?

The following PICOs were used to select literature to inform this policy.

Patients

The relevant population of interest are individuals with Crohn disease or ulcerative colitis who are in remission.

Interventions

The test being considered is fecal calprotectin analysis.

Comparators

The following practice is currently being used to make decisions about monitoring IBD: the reference standard is endoscopy with biopsy. The following tests are currently used to make decisions about monitoring for IBD relapse in patients in the relevant population: patient’s symptoms, inflammatory markers (ESR), and complete blood count.

Outcomes

The beneficial outcome of a true test result, if correctly classified as low disease activity, is the avoidance of unnecessary medications.

If correctly classified as high activity, the administration of appropriate treatment is another beneficial outcome.

In making a decision to increase medications, fecal calprotectin testing as an adjunct to clinical assessment is being used as a test to support a “rule in” decision, so PPV is the key measure of clinical validity.

Outcomes of interest are an improvement in symptoms and disease activity scores. Outcomes may be assessed in clinical practice and in the research setting with standardized measures, such as the Crohn Disease Activity Index, a validated 8-item score used as a marker of Crohn disease remission, with values less than 150 considered consistent with remission and values greater than 450 considered a marker of severe Crohn disease.^13,

The relevant time period for the impact of testing is weeks to months.

Study Selection Criteria

For the evaluation of the clinical validity of the fecal calprotectin test, studies that meet the following eligibility criteria were considered:

• Reported on the accuracy of the marketed version of the technology
• Included a suitable reference standard (endoscopy)
• Patient/sample clinical characteristics were described
• Patient/sample selection criteria were described.

Technically Reliable

Assessment of technical reliability focuses on specific tests and operators and requires a review of unpublished and often proprietary information. Review of specific tests, operators, and unpublished data are outside the scope of this policy, and alternative sources exist. This policy focuses on the clinical validity and clinical utility.

Clinically Valid

A test must detect the presence or absence of a condition, the risk of developing a condition in the future, or treatment response (beneficial or adverse).

Systematic Reviews

Heida et al (2017) conducted a systematic review to determine the accuracy of fecal calprotectin monitoring in asymptomatic patients (see Table 13).^16, Six studies met the review inclusion criteria and evaluated fecal calprotectin levels every one to three months. One-third of patients had a relapse during the study period, although the definitions of relapse varied across studies. Five of the six studies used an upward trend of fecal calprotectin between two measurements as the threshold. Asymptomatic patients with IBD who had fecal calprotectin levels above the study’s cutoff had a 53% to 83% probability of developing disease relapse within the next 2 to 3 months, while patients with normal fecal calprotectin levels had a 67% to 94% probability of remaining in remission in the next 2 to 3 months (see Table 14). Calprotectin levels began to rise two to three months before clinical relapse. The investigators could not identify the best fecal calprotectin cutoff for monitoring purposes.

Table 13. Characteristics of Clinical Validity Reviews Assessing Prediction of Relapse

					11-Item QUADAS Quality Assessment
					No. of Studies Rated as High or Unclear Risk of Bias
Study	Studies Included	Study Populations Included	Study Designs Included	Study Reference Standards Included	No Domains	1-2 Domains	>2 Domains
Heida et al (2017)16,	6	552 patients with UC in remission	Prospective studies that assessed FC every 1-3 mo	· 5 studies used endoscopy · 1 study used clinical activity score	0	3	3

Adapted by Heida et al (2017).^16,
FC: fecal calprotectin; UC: ulcerative colitis.

Table 14. Results of Clinical Validity Reviews Assessing Prediction of Relapse

Study	Scenario	Sensitivity Range, %	Specificity Range, %
Heida et al (2017)16,	Prediction of relapse (552 patients) of whom 33.3% relapsed during observation	53-83	67-94

Clinically Useful

A test is clinically useful if the use of the results informs management decisions that improve the net health outcome of care. The net health outcome can be improved if patients receive correct therapy, or more effective therapy, or avoid unnecessary therapy, or avoid unnecessary testing.

Direct Evidence

Direct evidence of clinical utility is provided by studies that have compared health outcomes for patients managed with and without the test. Because these are intervention studies, the preferred evidence would be from RCTs.

A prospective nonblinded controlled trial by Lasson et al (2015) randomized patients with ulcerative colitis in remission at high-risk of relapse in a 3:2 ratio to medication dosing decisions based on fecal calprotectin levels or to usual care (see Table 15).^17, The fecal calprotectin monitoring group was included in the systematic review by Heida et al (2017) described above.^16, Both groups submitted fecal samples at baseline and on a monthly basis. In the intervention group, a fecal calprotectin cutoff of 300 μg/g was used for escalating the 5-aminosalicylic acid dose to the maximally tolerable dose. The high dose was continued for 3 months and then reduced when fecal calprotectin levels fell below 200 μg/g. The primary outcome was the number of patients to relapse by 18 months. At 1 year, there was no significant difference in relapse rates between the 2 groups (see Table 16). For 10 of the 18 patients in the intervention group who had a relapse, fecal calprotectin levels did not rise above the 300 μg/g cutoff for medication dosage escalation. In the subgroup of patients who had levels of 300 μg/g or more, there was a significantly lower rate of relapse in the intervention group (28.6%) than in the control group (57.1%). Trial limitations included lack of blinding, exclusion of patients without intention-to-treat analysis, and insufficient power (see Tables 17 and 18).

Table 15. Summary of Key RCT Characteristics

Study	Countries	Sites	Dates	Participants	Interventions
					Active	Comparator
Lasson et al (2015)17,	Sweden	5	2009 - 2012	· 91 adults with UC on maintenance therapy with oral 5-ASA medication · Patients were in remission but at high-risk of relapse	Escalation to maximally tolerable dose based on FC ≥300 μg/g and lowered when FC <200 μg/g	Usual care based on symptoms

5-ASA: 5-aminosalicylic acid; FC: fecal calprotectin; RCT: randomized controlled trial; UC: ulcerative colitis.

Table 16. Summary of Key RCT Results

Study	Rate of Relapse at 1 Year
Lasson et al (2015)17,
Fecal calprotectin monitoring, n/N (%)	18/51 (35.3)
Usual care, n/N (%)	20/40 (50)
p	0.23

RCT: randomized controlled trial.

Tables 17 and 18 display notable limitations identified in each study.

Table 17. Relevance Limitations

Study	Populationa	Interventionb	Comparatorc	Outcomesd	Follow-Upe
Lasson et al (2015)17,			3. Treatment of a flare-up based on patient complaint and not predetermined in study protocol

The study limitations stated in this table are those notable in the current review; this is not a comprehensive limitations assessment.

^a Population key: 1. Intended use population unclear; 2. Clinical context is unclear; 3. Study population is unclear; 4. Study population not representative of intended use.
^b Intervention key: 1. Not clearly defined; 2. Version used unclear; 3. Delivery not similar intensity as comparator; 4. Not the intervention of interest.
c Comparator key: 1. Not clearly defined; 2. Not standard or optimal; 3. Delivery not similar intensity as intervention; 4. Not delivered effectively.
d Outcomes key: 1. Key health outcomes not addressed; 2. Physiologic measures, not validated surrogates; 3. No CONSORT reporting of harms; 4. Not establish and validated measurements; 5. Clinical significant difference not prespecified; 6. Clinical significant difference not supported.
e Follow-Up key: 1. Not sufficient duration for benefit; 2. Not sufficient duration for harms.

Study	Selectiona	Blindingb	Delivery of Testc	Selective Reportingd	Data Completenesse	Statisticalf
Lasson et al (2015)17,		1. Not blinded			2. 9 patients not providing at least 9 samples were excluded from experimental group 3. Not intention-to-treat 3. Target sample size not achieved

^a Selection key: 1. Selection not described; 2. Selection not random or consecutive (i.e., convenience).
^b Blinding key: 1. Not blinded to results of reference or other comparator tests.
^c Test Delivery key: 1. Timing of delivery of index or reference test not described; 2. Timing of index and comparator tests not same; 3. Procedure for interpreting tests not described; 4. Expertise of evaluators not described.
^d Selective Reporting key: 1. Not registered; 2. Evidence of selective reporting; 3. Evidence of selective publication.
^e Data Completeness key: 1. Inadequate description of indeterminate and missing samples; 2. High number of samples excluded; 3. High loss to follow-up or missing data.
^f Statistical key: 1. Confidence intervals and/or p values not reported; 2. Comparison with other tests not reported.

A 2017 systematic review of 6 prospective studies that monitored fecal calprotectin in patients in remission found no consistency in the thresholds used to determine treatment. One RCT evaluated the relapse rates in patients with ulcerative colitis whose medication doses were managed with fecal calprotectin test results (≥300 μg/g) and, in its primary analysis, found no significant difference in relapse rates. Trial limitations were in the domains of blinding, power, follow-up, and analysis. In addition, this trial did not enroll the planned number of patients and might have been underpowered. There is a need for high-quality RCTs to determine whether monitoring fecal calprotectin in patients who are in remission can reduce relapse rates and improve the quality of life (QOL) for patients with IBD.

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 1 case missed. 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 outcomes by providing clinically valid and clinically useful information to guide 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 negative fecal calprotectin results to exclude inflammatory bowel disease and avoid endoscopy with biopsy with acceptably low tradeoffs in missed diagnoses of IBD in those who have false-negative fecal calprotectin results. 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 prospective and retrospective diagnostic studies, systematic reviews, 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 prospective and retrospective diagnostic studies, systematic reviews, 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.

SUPPLEMENTAL INFORMATION
Clinical Input From Physician Specialty Societies and Academic Medical Centers

While the various physician specialty societies and academic medical centers may collaborate with and make recommendations during this process, through the provision of appropriate reviewers, input received does not represent an endorsement or position statement by the physician specialty societies or academic medical centers, unless otherwise noted.

2018 Input

In response to requests, clinical input on fecal calprotectin testing was received from 3 respondents, including 1 specialty society-level response and 2 physician-level responses identified through specialty societies including physicians affiliated with academic medical centers, while this policy was under review in 2018.

Clinical input obtained in 2018 supports that the following indication provides a clinically meaningful improvement in net health outcome and is consistent with generally accepted medical practice.

• Use of fecal calprotectin testing for individuals with suspected inflammatory bowel disease when endoscopy with biopsy is being considered.

In response to requests, input was received through 4 physician specialty societies and 4 academic medical centers while this policy was under review in 2014. One specialty society submitted two responses. Input was mixed on whether fecal calprotectin testing is considered investigational for the diagnosis of intestinal conditions and whether the results of diagnostic testing are being used to change patient management. Clinicians who disagreed with the investigational designation tended to argue that a medically necessary use of the test for diagnosis would be to differentiate inflammatory from noninflammatory conditions. There was near consensus that fecal calprotectin testing is considered investigational in the management of intestinal conditions. Most reviewers did not think that, when the test is used for the management of intestinal disorders, results change patient management. There was near consensus that the manufacturer’s recommended cutoff of 50 μg/g should be used to indicate a positive fecal calprotectin test.

Practice Guidelines and Position Statements

American Gastroenterological Association

The American Gastroenterological Association (AGA) published a 2018 guideline on functional gastrointestinal symptoms in patients with inflammatory bowel disease (IBD).^18,The AGA recommends a stepwise approach to rule-out ongoing inflammatory activity in IBD patients that includes fecal calprotectin, endoscopy with biopsy, and imaging. The 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 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 mg/g for fecal calprotectin was recommended to optimize sensitivity for IBD.^19,

American College of Gastroenterology

The American College of Gastroenterology (2018) published guidelines on the management of Crohn disease in adults.^20, 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 from irritable bowel syndrome. 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.^21, The guidance made the following recommendations:

1.1 “Faecal calprotectin testing is recommended as an option to support clinicians with the differential diagnosis of inflammatory bowel disease (IBD) or irritable bowel syndrome (IBS) in adults with recent-onset lower gastrointestinal symptoms for whom specialist assessment is being considered, if:

1. 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.

Ongoing and Unpublished Clinical Trials

A search of ClinicalTrials.gov in September 2018 did not identify any ongoing or unpublished trials that would likely influence this review.]
________________________________________________________________________________________

Horizon BCBSNJ Medical Policy Development Process:

This Horizon BCBSNJ Medical Policy (the “Medical Policy”) has been developed by Horizon BCBSNJ’s Medical Policy Committee (the “Committee”) consistent with generally accepted standards of medical practice, and reflects Horizon BCBSNJ’s view of the subject health care services, supplies or procedures, and in what circumstances they are deemed to be medically necessary or experimental/ investigational in nature. This Medical Policy also considers whether and to what degree the subject health care services, supplies or procedures are clinically appropriate, in terms of type, frequency, extent, site and duration and if they are considered effective for the illnesses, injuries or diseases discussed. Where relevant, this Medical Policy considers whether the subject health care services, supplies or procedures are being requested primarily for the convenience of the covered person or the health care provider. It may also consider whether the services, supplies or procedures are more costly than an alternative service or sequence of services, supplies or procedures that are at least as likely to produce equivalent therapeutic or diagnostic results as to the diagnosis or treatment of the relevant illness, injury or disease. In reaching its conclusion regarding what it considers to be the generally accepted standards of medical practice, the Committee reviews and considers the following: all credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, physician and health care provider specialty society recommendations, the views of physicians and health care providers practicing in relevant clinical areas (including, but not limited to, the prevailing opinion within the appropriate specialty) and any other relevant factor as determined by applicable State and Federal laws and regulations.

___________________________________________________________________________________________________________________________

Index:
Fecal Calprotectin Testing
Calprotectin Testing, Fecal
PhiCal™ (Genova Diagnostics)

References:

1. Waugh N, Cummins E, Royle P, et al. Faecal calprotectin testing for differentiating amongst inflammatory and non-inflammatory bowel diseases: systematic review and economic evaluation. Health Technol Assess. Nov 2013;17(55):xv-xix, 1-211. PMID 24286461

2. 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):1275-1280. PMID 18597588

3. 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. PMID 17924558

4. Basumani P, Bardhan K, Eyre R, et al. Faecal calprotectin: Rotherham experience (unpublished slide presentation). BSG Away; 2012 June 28.

5. Li XG, Lu YM, Gu F, et al. [Fecal calprotectin in differential diagnosis of irritable bowel syndrome] [Chinese]. Beijing Da Xue Xue Bao Yi Xue Ban. Jun 18 2006;38(3):310-313. PMID 16778979

6. 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.

7. 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. PMID 23019289

8. Sidler MA, Leach ST, Day AS. Fecal S100A12 and fecal calprotectin as noninvasive markers for inflammatory bowel disease in children. Inflamm Bowel Dis. Mar 2008;14(3):359-366. PMID 18050298

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. PMID 18629518

10. Henderson P, Casey A, Lawrence SJ, et al. The diagnostic accuracy of fecal calprotectin during the investigation of suspected pediatric inflammatory bowel disease. Am J Gastroenterol. Jun 2012;107(6):941-949. PMID 22370604

11. 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. PMID 18290691

12. 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. PMID 15795593

13. 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. PMID 15899657

14. 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. Jun 2015;110(6):802-819; quiz 820. PMID 25964225

15. 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. PMID 29096949

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. PMID 28511198

17. 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. PMID 25653861

18. 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., 2018 Aug 14;17(3). PMID 30099108.

19. 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, 2019 Aug 5;157(3). PMID 31377275

20. Lichtenstein GR, Loftus EV, Isaacs KL et al. ACG Clinical Guideline: Management of Crohn's Disease in Adults.. Am. J. Gastroenterol., 2018 Apr 4;113(4). PMID 29610508

21. National Institute for Health and Care Excellence (NICE). Faecal calprotectin diagnostic tests for inflammatory diseases of the bowel [DG11]. 2013; http://guidance.nice.org.uk/DG11. Accessed November 24, 2019.

Codes:
(The list of codes is not intended to be all-inclusive and is included below for informational purposes only. Inclusion or exclusion of a procedure, diagnosis, drug or device code(s) does not constitute or imply authorization, certification, approval, offer of coverage or guarantee of payment.)

CPT*

83993