Diagnosis
Review: Calprotectin testing differentiates inflammatory bowel disease from the irritable bowel syndrome
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. 2013;17:xv-xix, 1-211.
Clinical impact ratings: F ★★★★★✩✩ g ★★★★★★✩ Question
Source of funding: Health Technology Assessment Programme of National Institute for Health Research.
How reliable is fecal calprotectin (FC) testing for differentiating inflammatory bowel disease (IBD) from the irritable bowel syndrome (IBS)?
For correspondence: Prof. N. Waugh, University of Warwick, Coventry, England, UK. E-mail [email protected]. ■
Review scope
Commentary
Included studies compared FC testing (laboratory or point-ofcare testing) with reference tests (endoscopy and histology) in newly presenting patients. Outcomes included sensitivity, specificity, and likelihood ratios (LRs).
FC was described as a diagnostic test > 20 years ago (1) but has yet to find a niche for clinical applicability. Calprotectin is found in particularly high concentrations in neutrophils and is not digested in the gut. For this reason, an increased FC level should be a sensitive marker for intestinal inflammation. Most serious gastrointestinal disorders have an element of inflammation, so this should be a good test to differentiate between organic and functional gastrointestinal disease in primary care. Gastrointestinal disorders account for 5% to 10% of primary care consults (2). Clearly not all such patients can be referred for investigation, particularly children, so a noninvasive test to help triage referral is needed. The well-conducted systematic review by Waugh and colleagues involved an extensive literature search, rigorous methodology, and appropriate analysis. The quality of the 14 studies included in meta-analyses is generally reasonable, although only 2 studies fulfilled all 11 quality criteria. However, there was a lack of data from studies in primary care populations.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, and Web of Science (all to Mar 2013), and reference lists were searched for studies of newly diagnosed patients and reported diagnostic test characteristics. Experts provided unpublished data from 2 studies. 28 studies (n = 5135), many of which included children, met the inclusion criteria. 6 types of enzymelinked immunosorbent assays (ELISAs) (Nycomed Pharma, Immundiagnostik ELISA kit, EK-Cal, Calprest, Calpro Calprotectin ELISA test [ALP], and an unspecified test) and 3 point-of-care tests (Quantum Blue, Prevent ID Caldetect, and Prevista [no longer available]) were assessed. 14 studies were included in the meta-analyses reported in this abstract; median score on the modified Quality Assessment of Diagnostic Accuracy Studies tool was 9 out of 11 (range 5 to 11).
Despite a history of studies showing its accuracy, the calprotectin test is still not routinely used. The main reason for this lies in the nature of lower gastrointestinal disease. Organic disease is relatively rare, even in older adults, and is very rare in children. Waugh and colleagues quote a pretest probability of IBD of 20%, although in reality it is much lower in adults (3) and probably ≤ 1% in children.
Main results The test characteristics for key assessments are shown in the Table. All assessments used ELISA tests, and 1 also used a PoC test. 5 studies differentiating IBD from IBS in adults showed that, based on a pretest probability of 20%, an abnormal calprotectin test result with a cutpoint of 50 µg/g would increase the posttest probability to 80%, and a normal result would reduce the probability to 2%. 6 studies that assessed differentiation of IBD from non-IBD in largely pediatric populations showed that, based on a pretest probability of 20%, an abnormal calprotectin test result with a cutpoint of 50 µg/g would increase the posttest probability to 49%, and a normal result would reduce the probability to 0%.
Meta-analysis showed that the calprotectin test has 93% sensitivity for IBD. This is good but not sufficient to rule out the remote possibility of IBD, particularly given the 95% CI of 83% to 97%. Further, some of the studies used a case–control design, which tends to overestimate the accuracy of any test. The technology is still evolving. Currently, FC is used to monitor disease activity in patients with established IBD. Data are not sufficiently robust to recommend FC testing in primary care to rule out IBD in those with lower gastrointestinal symptoms.
Conclusion Fecal calprotectin testing had high sensitivity and specificity for differentiating inflammatory bowel disease from the irritable bowel syndrome.
Paul Moayyedi, MD McMaster University Hamilton, Ontario, Canada
Test characteristics of fecal calprotectin testing with ELISA for diagnosing bowel diseases* Differentiation Cutpoint Number of studies (n)
Sensitivity (95% CI)
Specificity (CI) LR+ LR−
IBD vs IBS
50 µg/g
5 (596)
93% (83 to 97)
94% (73 to 99)
16
0.08
IBD vs non-IBD
50 µg/g
6 (531)
99% (95 to 100) 74% (59 to 86)
4
0.02
100 µg/g
6 (656)
94% (86 to 98)
5
0.07
82% (67 to 91)
*ELISA = enzyme-linked immunosorbent assay; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; other abbreviations defined in Glossary.
15 April 2014 | ACP Journal Club | Volume 160 • Number 8 Downloaded From: http://annals.org/ by a Oakland University User on 06/15/2014
References 1. Røseth AG, Kristinsson J, Fagerhol MK, et al. Faecal calprotectin: a novel test for the diagnosis of colorectal cancer? Scand J Gastroenterol. 1993;28: 1073-6. 2. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol. 2008;103:1229-39. 3. Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, et al. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gastroenterology. 2013;145:1262-70.
© 2014 American College of Physicians
JC13
Review: Calprotectin testing differentiates inflammatory bowel disease from the irritable bowel syndrome
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. 2013;17:xv-xix, 1-211.
Clinical impact ratings: F ★★★★★✩✩ g ★★★★★★✩ Question
Source of funding: Health Technology Assessment Programme of National Institute for Health Research.
How reliable is fecal calprotectin (FC) testing for differentiating inflammatory bowel disease (IBD) from the irritable bowel syndrome (IBS)?
For correspondence: Prof. N. Waugh, University of Warwick, Coventry, England, UK. E-mail [email protected]. ■
Review scope
Commentary
Included studies compared FC testing (laboratory or point-ofcare testing) with reference tests (endoscopy and histology) in newly presenting patients. Outcomes included sensitivity, specificity, and likelihood ratios (LRs).
FC was described as a diagnostic test > 20 years ago (1) but has yet to find a niche for clinical applicability. Calprotectin is found in particularly high concentrations in neutrophils and is not digested in the gut. For this reason, an increased FC level should be a sensitive marker for intestinal inflammation. Most serious gastrointestinal disorders have an element of inflammation, so this should be a good test to differentiate between organic and functional gastrointestinal disease in primary care. Gastrointestinal disorders account for 5% to 10% of primary care consults (2). Clearly not all such patients can be referred for investigation, particularly children, so a noninvasive test to help triage referral is needed. The well-conducted systematic review by Waugh and colleagues involved an extensive literature search, rigorous methodology, and appropriate analysis. The quality of the 14 studies included in meta-analyses is generally reasonable, although only 2 studies fulfilled all 11 quality criteria. However, there was a lack of data from studies in primary care populations.
Review methods MEDLINE, EMBASE/Excerpta Medica, Cochrane Library, and Web of Science (all to Mar 2013), and reference lists were searched for studies of newly diagnosed patients and reported diagnostic test characteristics. Experts provided unpublished data from 2 studies. 28 studies (n = 5135), many of which included children, met the inclusion criteria. 6 types of enzymelinked immunosorbent assays (ELISAs) (Nycomed Pharma, Immundiagnostik ELISA kit, EK-Cal, Calprest, Calpro Calprotectin ELISA test [ALP], and an unspecified test) and 3 point-of-care tests (Quantum Blue, Prevent ID Caldetect, and Prevista [no longer available]) were assessed. 14 studies were included in the meta-analyses reported in this abstract; median score on the modified Quality Assessment of Diagnostic Accuracy Studies tool was 9 out of 11 (range 5 to 11).
Despite a history of studies showing its accuracy, the calprotectin test is still not routinely used. The main reason for this lies in the nature of lower gastrointestinal disease. Organic disease is relatively rare, even in older adults, and is very rare in children. Waugh and colleagues quote a pretest probability of IBD of 20%, although in reality it is much lower in adults (3) and probably ≤ 1% in children.
Main results The test characteristics for key assessments are shown in the Table. All assessments used ELISA tests, and 1 also used a PoC test. 5 studies differentiating IBD from IBS in adults showed that, based on a pretest probability of 20%, an abnormal calprotectin test result with a cutpoint of 50 µg/g would increase the posttest probability to 80%, and a normal result would reduce the probability to 2%. 6 studies that assessed differentiation of IBD from non-IBD in largely pediatric populations showed that, based on a pretest probability of 20%, an abnormal calprotectin test result with a cutpoint of 50 µg/g would increase the posttest probability to 49%, and a normal result would reduce the probability to 0%.
Meta-analysis showed that the calprotectin test has 93% sensitivity for IBD. This is good but not sufficient to rule out the remote possibility of IBD, particularly given the 95% CI of 83% to 97%. Further, some of the studies used a case–control design, which tends to overestimate the accuracy of any test. The technology is still evolving. Currently, FC is used to monitor disease activity in patients with established IBD. Data are not sufficiently robust to recommend FC testing in primary care to rule out IBD in those with lower gastrointestinal symptoms.
Conclusion Fecal calprotectin testing had high sensitivity and specificity for differentiating inflammatory bowel disease from the irritable bowel syndrome.
Paul Moayyedi, MD McMaster University Hamilton, Ontario, Canada
Test characteristics of fecal calprotectin testing with ELISA for diagnosing bowel diseases* Differentiation Cutpoint Number of studies (n)
Sensitivity (95% CI)
Specificity (CI) LR+ LR−
IBD vs IBS
50 µg/g
5 (596)
93% (83 to 97)
94% (73 to 99)
16
0.08
IBD vs non-IBD
50 µg/g
6 (531)
99% (95 to 100) 74% (59 to 86)
4
0.02
100 µg/g
6 (656)
94% (86 to 98)
5
0.07
82% (67 to 91)
*ELISA = enzyme-linked immunosorbent assay; IBD = inflammatory bowel disease; IBS = irritable bowel syndrome; other abbreviations defined in Glossary.
15 April 2014 | ACP Journal Club | Volume 160 • Number 8 Downloaded From: http://annals.org/ by a Oakland University User on 06/15/2014
References 1. Røseth AG, Kristinsson J, Fagerhol MK, et al. Faecal calprotectin: a novel test for the diagnosis of colorectal cancer? Scand J Gastroenterol. 1993;28: 1073-6. 2. Ford AC, Forman D, Bailey AG, Axon AT, Moayyedi P. Irritable bowel syndrome: a 10-yr natural history of symptoms and factors that influence consultation behavior. Am J Gastroenterol. 2008;103:1229-39. 3. Ford AC, Bercik P, Morgan DG, Bolino C, Pintos-Sanchez MI, et al. Validation of the Rome III criteria for the diagnosis of irritable bowel syndrome in secondary care. Gastroenterology. 2013;145:1262-70.
© 2014 American College of Physicians
JC13
