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A Meta-Analysis of the Utility of C-ReactiveProtein, Erythrocyte Sedimentation Rate, Fecal

Calprotectin, and Fecal Lactoferrin to Exclude

Inflammatory Bowel Disease in Adults With...

Article in The American Journal of Gastroenterology March 2015

Impact Factor: 10.76 DOI: 10.1038/ajg.2015.6 Source: PubMed

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5 authors, including:

Jacob E Kurlander

University of Michigan

30PUBLICATIONS 235CITATIONS

SEE PROFILE

William Chey

University of Michigan

424PUBLICATIONS 11,070CITATIONS

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Available from: Jacob E Kurlander

Retrieved on: 01 July 2016
https://www.researchgate.net/profile/Jacob_Kurlander?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_4https://www.researchgate.net/institution/University_of_Michigan?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_6https://www.researchgate.net/?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_1https://www.researchgate.net/profile/William_Chey2?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_7https://www.researchgate.net/institution/University_of_Michigan?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_6https://www.researchgate.net/profile/William_Chey2?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_5https://www.researchgate.net/profile/William_Chey2?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_4https://www.researchgate.net/profile/Jacob_Kurlander?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_7https://www.researchgate.net/institution/University_of_Michigan?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_6https://www.researchgate.net/profile/Jacob_Kurlander?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_5https://www.researchgate.net/profile/Jacob_Kurlander?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_4https://www.researchgate.net/?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_1https://www.researchgate.net/publication/273153917_A_Meta-Analysis_of_the_Utility_of_C-Reactive_Protein_Erythrocyte_Sedimentation_Rate_Fecal_Calprotectin_and_Fecal_Lactoferrin_to_Exclude_Inflammatory_Bowel_Disease_in_Adults_With_IBS?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_3https://www.researchgate.net/publication/273153917_A_Meta-Analysis_of_the_Utility_of_C-Reactive_Protein_Erythrocyte_Sedimentation_Rate_Fecal_Calprotectin_and_Fecal_Lactoferrin_to_Exclude_Inflammatory_Bowel_Disease_in_Adults_With_IBS?enrichId=rgreq-f020fe5490d286567da86c98bf47ef40-XXX&enrichSource=Y292ZXJQYWdlOzI3MzE1MzkxNztBUzoyMzk5ODMxNDc2MTQyMDhAMTQzNDIyNzg0OTIyMg%3D%3D&el=1_x_2


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TheAmerican Journal ofGASTROENTEROLOGY VOLUME 110 |MARCH 2015 www.amjgastro.com

ORIGINAL CONTRIBUTIONS

INTRODUCTION

Irritable bowel syndrome (IBS) is a prevalent symptom-based

disorder that is characterized by the presence o abdominal pain

and altered bowel habits (1). IBS affects 7 to 15% o adults in the

United States (1,2) and is associated with a lower quality o lie

and annual expenditures well in excess o 20 billion dollars (3,4).

It has been suggested that patients with typical symptoms and noalarm eatures such as overt gastrointestinal bleeding, unexplained

iron deciency anemia, unintentional weight loss, symptom onset

afer age 50 years, nocturnal diarrhea or a amily history o inam-

matory bowel disease (IBD), colorectal cancer, or celiac disease

do not require exhaustive testing beore establishing a condent

diagnosis o IBS. Te American College o Gastroenterology rec-

ommended only routine serologic screening or celiac disease in

patients with diarrhea-predominant IBS or mixed IBS and colonic

mucosal biopsies or microscopic colitis when perorming colo-

noscopy in patients with diarrhea-predominant IBS (5). Despite

these recommendations, a signicant proportion o primary care

physicians and gastroenterologists view IBS as a diagnosis oexclusion and, as such, order multiple diagnostic tests to rule out

various organic diseases beore condently diagnosing IBS (6).

One o the main concerns o primary care physicians and gas-

trointestinal specialists when evaluating a patient with abdominal

pain and altered bowel habits is IBD. Despite data to suggest that

A Meta-Analysis of the Utility of C-Reactive Protein,

Erythrocyte Sedimentation Rate, Fecal Calprotectin,and Fecal Lactoferrin to Exclude Inflammatory Bowel

Disease in Adults With IBS

Stacy B. Menees, MD, MS1, Corey Powell, PhD2, Jacob Kurlander, MD1, Akash Goel, MD3and William D Chey, MD, AGAF, FACG, FACP1

OBJECTIVES: Irritable bowel syndrome (IBS) is viewed as a diagnosis of exclusion by most providers. The aim of our

study was to perform a systematic review and meta-analysis to evaluate the utility of C-reactive protein

(CRP), erythrocyte sedimentation rate (ESR), fecal calprotectin, and fecal lactoferrin to distinguish

between patients with IBS and inflammatory bowel disease (IBD) and healthy controls (HCs).

METHODS: A systematic online database search was performed. Included studies were prospective, adult,

diagnostic cohort studies with any of the four tests. The means and s.d. values of biomarker

logarithms were estimated based on studies that gave medians and either confidence intervals for the

median, interquartile ranges, or ranges. We used a Naive Bayes approach to estimate the probability

of being a HC, having IBS, or having IBD based on the biomarker values.

RESULTS: Systematic review identified 1,252 citations. After cross-referencing medical subject headings,

detailed evaluation identified 140 potentially relevant journal articles/abstracts for CRP, ESR,

calprotectin, and lactoferrin of which 4, 4, 8, and 2 fulfilled our inclusion criteria, respectively. None

of the biomarkers reliably distinguished between IBS and healthy controls. At a CRP level of 0.5 or

calprotectin level of 40g/g, there was a 1% probability of having IBD. Individual analysis of ESR

and lactoferrin had little clinical utility.

CONCLUSION: CRP and calprotectin of 0.5 or 40, respectively, essentially excludes IBD in patients with IBS

symptoms. The addition of CRP and calprotectin to symptom-based criteria may improve the

confident diagnosis of IBS.

Am J Gastroenterol2015; 110:444454; doi:10.1038/ajg.2015.6; published online 3 March 2015

1Division of Gastroenterology, University of Michigan Health System, Ann Arbor, Michigan, USA; 2Center for Statistical Consultation and Research (CSCAR),

University of Michigan, Ann Arbor, Michigan, USA; 3Division of Internal Medicine, Columbia University, New York Presbyterian, New York, New York, USA.

Correspondence: William D. Chey, MD, AGAF, FACG, FACP, Division of Gastroenterology, University of Michigan Health System, 3912 Taubman Center, SPC

5362, Ann Arbor, Michigan 48109-5362, USA. E-mail: [email protected] 31 July 2014; accepted 5 January 2015


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2015 by the American College of Gastroenterology TheAmerican Journal ofGASTROENTEROLOGY

4

Meta-Analysis of Biomarkers for Identifying IBS

the prevalence o IBD is low in patients with IBS symptoms and no

alarm eatures (7,8), numerous studies have described signicant

symptom overlap between patients with IBD and IBS (911). In

addition, the potential clinical and medicolegal consequences o

misdiagnosing an IBD patient with IBS can be substantial. As such,

a simple, inexpensive means by which to rule out IBD in patients

with suspected IBS would be o considerable value.

Candidate biomarkers that may be helpul to screen or condi-

tions that lead to a systemic inammatory response include sero-

logic-, tissue-, and stool-based tests. Both S100A and B-2 deensin

are available or investigational use only. S100A has been ound

in two separate studies to be overexpressed in rectal mucosa in

IBS patients (12,13), whereas B-Deensin-2 has been shown to be

elevated within tissue and stool (14). Commercially available bio-

markers include serologic (C-reactive protein (CRP) and eryth-

rocyte sedimentation rate (ESR)) and stool-based (calprotectin,

lactoerrin) tests. CRP is produced by hepatocytes in response

to proinammatory cytokines such as interleukins 1 and 6. An

elevated ESR occurs when hepatocytes and the immune systemproduce proteins that cause red blood cells to aggregate and

collect at the bottom o a test tube. Both tests can be elevated in

IBD and provide a measure o disease activity. More recently, two

neutrophil granular proteins, calprotectin and lactoerrin, that

are released rom activated neutrophil cells into the eces have

been studied as an adjunct in IBD diagnosis. Calprotectin is a

calcium and zinc protein ound in neutrophils and monocytes

and comprises 60% o the cytosolic protein content o neutro-

phils. Its elevation in the eces is likely a result o cell disrup-

tion and death, although it can be actively secreted. Lactoerrin

is an iron-binding glycoprotein that is secreted by most mucosal

membranes and is a major component o polypmorphonuclearneutrophil secondary granules. Tese polypmorphonuclear

neutrophils are the primary components o the acute inamma-

tory response.

Recent studies have assessed the ability o CRP, ESR, ecal cal-

protectin, and ecal lactoerrin to discriminate between healthy

persons, patients with conrmed IBD, and patients with IBS. Te

aim o our study was to perorm a systematic review and meta-

analysis to evaluate the utility o CRP, ESR, ecal calprotectin, or

ecal lactoerrin to aid in distinguishing between IBS, IBD, and

healthy patients.

METHODSStudy protocol

Using the Cochrane handbook or systematic reviews o diagnos-

tic test accuracy as a guide, a standard protocol or study identi-

cation, inclusion, exclusion, and data abstraction was developed

and used to identiy potential studies or this systematic review

and meta-analysis (15). Data were recorded according to the pre-

erred reporting items or systematic reviews and meta-analyses

described by the PRISMA (Preerred Reporting Items or System-

atic Reviews and Meta-Analyses) guidelines (16). A systematic

search o relevant abstracts in any language was perormed or

CRP, ESR, ecal calprotectin, and ecal lactoerrin in the ollow-

ing electronic databases: Medline (1950 to March 2014), EMBASE

(1947 to March 2014), Cochrane library (1993 to March 2014),

Web o Science (1900 to March 2014), and PubMed (1950 to

March 2014). Bibliographies rom relevant gastrointestinal meet-

ings including Digestive Diseases Week, Te Annual Meeting o

the American College o Gastroenterology, and the United Euro-

pean Gastroenterology Week rom years 20002013 were manu-

ally searched or relevant studies. Medical subject headings or

our literature review included CRP, C-reactive protein, ESR,

blood sedimentation, westergren, Leukocyte L1 Antigen

Complex, calprotectin, ecal calprotectin, calgranulin, ecal

lactoerrin, or lactoerrin. Tese subject headings were cross-

reerenced with IBS, irritable bowel syndrome, IBD, inam-

matory bowel disease, crohn, and colitis, or completeness.

Study selection and data abstraction

Studies included in this meta-analysis were prospective diagnostic

cohort studies o the CRP, ESR, ecal calprotectin, or ecal lacto-

errin that met the ollowing inclusion criteria: (i) human stud-ies in adults that compare CRP, ESR, ecal calprotectin, or ecal

lactoerrin with conrmed diagnosis o IBD with IBS or healthy

control (HC) subjects; (ii) studies that utilize the enzyme-linked

immunosorbent assay or ecal calprotectin, not the point o care

testing; (iii) used Manning or Rome Criteria or IBS diagnosis;

and (iv) provided suffi cient data (studies must give medians and

either condence intervals or the median, interquartile ranges,

or ranges). I there were multiple papers published based on the

same or overlapping data sets, then only the paper with the high-

est number o subjects, the most detailed results, and the long-

est ollow-up time was included. No study size or language was

restricted. Any discrepancies in article selection were resolved byjoint reevaluation o the article by the reviewers and through con-

sensus with a senior reviewer (W.D.C.).

Tree authors (S.M., J.K., and A.G.) independently extracted

data. Te ollowing data were abstracted rom each study: (i) study

characteristics: authors, publication year, study site, and design;

(ii) patient characteristics: sex, age, race, IBD, and IBS criterion;

and (iii) test characteristics: type o assay, median values or CRP,

ESR, ecal calprotectin, and ecal lactoerrin. In cases o discord-

ance, a consensus was reached with the senior author (W.D.C.).

Study quality was assessed with the quality assessment or studies

o diagnostic accuracy (QUADAS) tool (17).

Statistical analysis

Te meta-analysis assumed that the logarithms o the biomark-

ers were normally distributed or the IBS, IBD, and HC groups.

Te means and s.d. values o biomarker logarithms were esti-

mated based on studies that gave medians and either condence

intervals or the median, interquartile ranges, or ranges. Age was

assumed to be normally distributed or all three groups, and all

studies were used to estimate the age distributions and gender

prevalence. Population-based estimates o IBS and IBD re-

quency (10% or IBS and (780,000+46,000)/320,000,000 or IBD)

were used to estimate prior probabilities or HCs, IBS, and IBD

(18,19). Bayes theorem was then applied to estimate the probabil-


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ities o being a HC, having IBS, or having IBD based on the given

values or the biomarkers (Table 1). Tis estimation assumed that

the values o the biomarkers, gender, and age were conditionally

independent given the health status o the patient. Heteroge-

neity among each subject group or the most useul biomark-ers was explored utilizing the inconsistency index (I2 statistic).

Heterogeneity was dened as I250%.

RESULTS

Systematic literature review identied 1,252 citations (Figure 1).

Afer cross-reerencing medical subject headings, detailed

evaluation identied 140 potentially relevant journal articles/

abstracts or CRP, ESR, ecal calprotectin, and ecal lactoerrin.

Ultimately, 67 ull manuscripts and abstracts were reviewed in

detail o which 12 studies (N=2,145: 1,059 IBD, 595 IBS, and 491

HC) ullled inclusion criteria and were included in the meta-

analysis. Details regarding the study populations enrolled, sam-ple size, CRP, ESR, ecal calprotectin, or ecal lactoerrin median

values with condence intervals or the median, interquartile

ranges, or ranges can be ound in (Table 2). Data on gender

were available in 11 out o 12 studies. Te IBD, IBS, and HC

cohorts were 52.7%, 29.9%, and 53.5% male, respectively. Te

mean age or the IBD, IBS, and HC cohorts was 40.7 (13.3),

40.0 (18.2), and 38.7 (13.8) years, respectively. Our analysis

ound that none o the biomarkers were able to accurately dis-

criminate patients with IBS rom HCs. However, some o the

biomarkers offered value in terms o discriminating IBD rom

IBS or HCs.

C-reactive protein

For the CRP analysis, 4 studies (2023) had suitable data (N=823;

465 IBD, 224 IBD, and 134 HC) (Table 2). Elevated CRP levels

were predictive o IBD (Figure 2). A level o 1.7 mg/dl has a

>52% predictive probability o IBD. Levels >2.7 mg/dl havemore than a 90% likelihood o IBD. In addition, the inverse also

appeared to be true. Low levels o CRP strongly argued against

the presence o IBD. A CRP o 0.5 predicted a 1% or lower like-

lihood o IBD. For IBS, the predictive probability o CRP rises

steadily to a 45.7% peak likelihood o IBS at 1.3 mg/dl, but then

gradually declines to


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259 IBS, and 238 HC) (Table 2). For IBD, as the level o ecal

calprotectin increases, so does the likelihood o IBD with the

maximal predictive value o 78.7% at 1,000/g (Figure 4). How-

ever, a patient with a level o


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4


Table2.

Continued

Author

(year)

Studypopula-

tion

Studysettin

g

Studysite

Numberof

patients

IBSDxcriteria

IBDcriteria

Testbrand

Median

values(CAL/LAC:

g/g,E

SR:mm/h,

CRP:

mg/dl)

CD

UC

IBD

IBS

HC

Oikonomou

etal.(21)

Patientswith

knownIBS/

IBD

Unclear

Greece

88

93

181

41

82

RomeIII

Clinical,

endoscopic,

radiological,

andhistologi-

calworkup,

basedon

standard

criteria

LaboratoryESR

andCRP

ESR,CRP

CD:17(255),17.5(1157)

UC:14

(266),7(1172)

IBS:17(726),4(08)

HC:11

(324),3(0.512)

Sidhuetal.

(31)

Consecutive

patientswith

knownIBD/

IBS

Outpatient

clinic

UK

104

126

130

137

98

RomeIIfordiar-

rheapredomi-

nantIBS

Established

diagnosisbyGI

LAC:SCHEBO

BIOTECHUK

andtechlab,

Blacksburg,VA

CD:4(13)

U

C:6.6(42)

IBS:0(1.4)

HC:0.5(2)

Tibbleetal.

(20)

Consecu-

tivepatients

referredfor

opinionasto

whetherthey

hadIBSorIBD

GIoutpatient

clinic

US

31

0

31

159

0

Manning

Standard

clinical,

radiological,

endoscopic

andhistologi-

calcriteria

LaboratoryESR

andCRP

ESR

CD

:23(1045),

10(330)

IBS:6(68),3(37)

Wassell

etal.(30)

Patients

diagnosed

IBSorCrohns

GIclinic

UK

25

0

25

25

27

RomeII

Provenhisto-

logicdiagnosis

CAL:Calprotech

LTD.London,

UK

CD:22

9.6(6.51,1966)

IBS:

20.5(6.587.3)

HC:

9.3(6.563.8)

CAL,fecalcalprotectin;CD,Crohnsdisease;CRP,C-reactiveprotein;Dx,diagnosis;ELISA,enzyme

-linkedimmunosorbentassay;ESR,erythrocytese

dimentationrate;GI,gastrointestinal;HC,healthycontrol;IBD,inflam-

matoryboweldisease;IBS,irritablebowelsyndro

me;LAC,fecallactoferrin;N/A,notavailable;SBFT,smallbowelfollow-through;UC,ulcerativecolitis

.


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and details regarding whether the reerence standard was inde-pendent o the index test (2023,2831).

DISCUSSION

Te symptoms o IBS, including abdominal pain/discomort

and altered bowel habits, can overlap with a number o organic

diseases. Te identication o noninvasive tests that can aid in

a condent, cost-effective diagnosis o IBS is vital to primary

care providers and specialists alike. Despite the relatively low

likelihood, patients and providers remain concerned about

the possibility o IBD in patients with typical IBS symptoms.

Our meta-analysis o 12 studies ound that none o the serumand ecal biomarkers evaluated, including CRP, ESR, ecal

calprotectin, and ecal lactoerrin, accurately identied patients

with IBS vs. IBD patients or HCs. However, both CRP and

ecal calprotectin appeared to be clinically useul in ruling

out IBD. On the other hand, the commonly ordered serum

biomarker, ESR, provided no value in distinguishing between

IBD and IBS patients. Te other ecal biomarker, ecal lacto-

errin, was more predictive o IBS rather than IBD, but had

signicant overlap between IBD and IBS. Tis renders it clini-

cally unhelpul in trying to rule out IBD in patients with IBS

symptoms.

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

0.1

0

0.2

0

0.3

0

0.4

0

0.5

0

0.6

0

0.7

0

0.8

0

0.9

0

1.0

0

1.1

0

1.2

0

1.3

0

CRP level, mg/dl

1.4

0

1.5

0

1.6

0

1.7

0

1.8

0

1.9

0

2.0

0

2.1

0

2.2

0

2.3

0

2.4

0

2.5

0

2.6

0

2.7

0

Percent,%

CRP

0.1 89.9 9.8

9.9

11.2

13.6

16.8

20.8

25.8

30.235.0

39.3

42.7

89.8

88.4

85.8

82.1

77.4

71.7

65.157.9

50.2

42.435.0

28.1

17.0

12.9

9.6

7.1

5.2

3.8

2.8

2.0

1.5

1.1

0.8

0.6

0.4

22.1

0.2

0.3

0.4

0.5

0.6

0.7

0.80.9

1.0

1.1P (Control)

P (IBS)

P (IBD)1.2

1.3

1.4

1.5

1.6

1.7

1.8

1.9

2.0

2.1

2.2

2.3

2.4

2.5

2.6

2.7

Percentlikelihood

HC

Percentlikelihood

IBS

Percentlikelihood

IBD

44.9

45.7

45.2

43.5

40.9

37.6

34.1

30.5

27.0

23.7

20.6

17.9

15.5

13.4

11.6

10.0 89.6

87.8

85.8

83.4

80.6

77.4

73.6

69.2

64.3

58.8

52.7

46.2

39.5

32.7

26.2

20.114.9

10.6

7.24.7

3.0

1.8

1.1

0.6

0.4

0.3

0.2

Figure 2. CRP predictive probability of being a healthy control, or having IBS or IBD. The line graph is a graphical representation of the table. The dottedline represents the following: at a CRP level of 0.2 mg/dl, a person has a 0.3% probability of IBD, a 9.9% probability of IBS, and 89.9% probability of being

a healthy control. CRP, C-reactive protein; IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.

20%

10%

100%

0%

40%

30%

50%

Percent,%

70%

60%

80%

90%

10 20 30 40 50 60 70 80 90 100

ESR, mm/h

110 110 130 140 150 160 170 180 190 200

P (Control)

ESRPercent

likelihoodHC

Percentlikelihood

IBS

Percentlikelihood

IBD

10 89.3

93.1

95.8

97.1

97.9

98.3

98.5

98.698.7

98.8

98.898.898.8

98.7

98.7

98.7

98.7

98.6

98.6

98.5

10.4 0.3

0.3

0.4

0.5

0.5

0.6

0.7

0.70.8

0.8

0.91.01.0

1.1

1.1

1.2

1.2

1.3

1.3

1.4

6.5

3.8

2.4

1.6

1.1

0.8

0.60.5

0.4

0.30.20.2

0.2

0.2

0.1

0.1

0.1

0.1

0.1

20

30

40

50

60

70

8090

100

110120130

140

150

160

170

180

190

200

P (IBS)

P (IBD)

Figure 3. Fecal calprotectin predictive probability of being a healthy control, or having IBS or IBD. The line graph is a graphical representation of the table.

The dotted line represents the following: at a fecal calprotectin level of 40g/g, a person has a 1% probability of IBD, a 14.9% probability of IBS, and

84.1% probability of being a healthy control. IBD, inflammatory bowel disease; IBS, irritable bowel syndrome.


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Fecal calprotectin is increasingly being utilized as a screen-

ing test or IBD and as an index o disease activity. Numerous

controlled studies in IBD patients have been perormed yielding

varying sensitivities and specicities (14,22,23,2528,30,3638).Te meta-analyses o ecal calprotectin by both von Roon et al.

(39) and van Rheenen et al.(40) ound an overall sensitivity and

specicity or IBD o >90%. In addition, using the area under the

receiver operating characteristic curve, the authors ound that

100g/g had better diagnostic precision or IBD compared with

50g/g. Although ruling in IBD was not our primary aim, we

did nd that patients with a ecal calprotectin o 100g/g had

a 3% predictive probability o IBD. Clinicians are also utilizing

ecal calprotectin or assessing IBD clinical activity. Sipponen

et al. (41) ound that a level o >200g/g correlates best with

endoscopically active disease.

O the serum biomarkers evaluated, our analysis ound that

CRP at a level o 1 mg/dl is universally considered abnormal.It is important to acknowledge that patients with IBD can present

with normal CRP levels (3234). An elevated CRP is more likely

to be present in patients with Crohns disease than ulcerative coli-

tis (3335). Henriksen et al.(33) ound a CRP o 10 mg/l in 25%

o Crohns disease patients and 71% o ulcerative colitis patients in

a prospective population-based study. Unortunately, no inorma-

tion is available regarding the absolute CRP values among patients

with a CRP o


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numerical values o these biomarkers to a log scale and the need to

use crude methods to estimate the means and s.d. values. Related

to this, it is important to acknowledge that our analysis summary

o data derived rom varying clinical and geographical popula-

tions. In addition, the cited studies do not stratiy their biomarker

results by age and gender, and hence we are unable to account or

these dependencies in our biomarker models, specically in reer-

ence to ESR. Finally, because o the nature o the available data, we

are limited in speciying the exact symptom complex that warrants

screening as the included studies utilized either Rome or Manning

IBS criteria, but did not give urther details regarding IBS subtypes.

In summary, CRP and ecal calprotectin might provide non-

invasive means by which to screen or IBD in patients with IBS

symptoms. Based upon these results, it may be reasonable or cli-

nicians to consider ordering CRP or ecal calprotectin to improve

their condence in making a diagnosis o IBS. ESR is o no value

in discriminating between IBD and IBS. Finally, too little data are

available to make a judgment on the utility o ecal lactoerrin in

excluding IBD. Prospective studies to evaluate the clinical utilityand cost effectiveness o adding CRP or ecal calprotectin to the

evaluation o patients with suspected IBS in different populations

would be o considerable interest.

CONFLICT OF INTEREST

Guarantor of the article:William D. Chey, MD, AGAF, FACG, FACP.

Specic author contributions:S.B.M., and W.D.C. conceived

and drafed the study. S.B.M., J.K., and A.G. collected all data.

S.B.M.,W.D.C., and C.P. analyzed and interpreted data. C.P. pro-

vided statistical advice and support. S.B.M. drafed the manuscript.

All authors commented on drafs o the paper. All authors have

approved the nal draf o the manuscript.Financial support:Tis study was supported by Division o

Gastroenterology, University o Michigan Health System.

Potential competing interests:William D. Chey is a consultant or

Salix Pharmaceuticals. Stacy Menees, Corey Powell, Jacob Kurlander,

and Akash Goel declare no conict o interest.

Study Highlights

WHAT IS CURRENT KNOWLEDGE

Many clinicians consider irritable bowel syndrome (IBS) adiagnosis of exclusion.

A number of commercially available biomarkers have proveduseful in the diagnosis and follow-up for inflammatory bowel

disease (IBD).

Currently, no inflammatory routine biomarkers are routinelyrecommended as part of the evaluation in the patients with

IBS symptoms.

WHAT IS NEW HERE

None of the biomarkers reliably distinguished between IBSand healthy controls.

C-reactive protein (CRP) and fecal calprotectin at or below 0.5and 40g/g, respectively, can exclude IBD in patients with IBS.

Erythrocyte sedimentation rate (ESR) and fecal lactoferrinwere clinically unhelpful.

Our study would seem to provide indirect support or the

concept o low-grade inammation in a subset o IBS patients

(3236). In our meta-analysis population, ecal calprotectin levels o

>100g/g were associated with a more than 15% likelihood o IBS.

Te peak predictive probability o IBS was a ecal calprotectin o

280g/g with an 18.8% predictive probability o IBS. At this level,

there was also a 17.1% predictive probability o IBD. Tese ndings

suggest that ecal calprotectin below the stated threshold effectively

rules out IBD; however, many patients with elevated ecal calpro-

tectin levels will ultimately be assigned the diagnosis o IBS rather

than IBD. In other words, the negative predictive value o ecal

calprotectin is high but the positive predictive value o this test is

poor. Tis same concept would also be applicable or CRP. Tus,

CRP and ecal calprotectin, like alarm eatures in general, may be

useul to identiy patients who are at greater risk o organic disease,

and thus should undergo a more detailed structural evaluation.

ESR and ecal lactoerrin were least helpul in discriminating

between IBS and IBD. All levels o ESR had a 10 mm/h in differentiating between organic and nonorganic

intestinal disease. Other studies have demonstrated a sensitivity and

specicity ranging rom 56 to 78% and 75 to 96% or an elevated

ESR (>10 and 15 mm/h) in differentiating IBD rom IBS (23,32).

Based on our data, ESR should not be used as a screening test or

IBD in patients with IBS symptoms. Te eligible data assessing ecal

lactoerrin or IBD and IBS cohorts were limited to two studies. Tis

small sample size limited our ability to draw condent conclusionsregarding the value o ecal lactoerrin in ruling out IBD in patients

with IBS symptoms. A recent meta-analysis o 7 studies or ecal

lactoerrin demonstrated a pooled sensitivity o 0.78 (95% con-

dence interval: 0.750.82) and a specicity o 0.94 (95% condence

interval: 0.910.96) in differentiating IBD rom IBS. However, this

meta-analysis utilized studies with varying test cutoffs and mixed

populations o both adults and children (43). It is interesting that in

our analysis, high levels o ecal lactoerrin level were more predic-

tive o IBS than IBD. Tat being said, the considerable overlap in

positive results or IBS and IBD or all o ecal lactoerrin under-

mines its value as a test to identiy patients with IBS.

A strength o our study was the inclusion o only prospective

studies that utilized dened criteria or the diagnosis o IBD andIBS. Our study is novel in trying to identiy numerical thresholds

or commonly available serum and ecal biomarkers to exclude

IBD in patients with IBS symptoms. Our study also has a number

o weaknesses. Because o our statistical methods, we were limited

in utilizing only data that were reported as medians with con-

dence intervals, interquartile ranges, or ranges or the median.

Tere were several studies that presented data as the mean with s.d.

that could not be included in our analysis (14,37,38,42,4451). Tis

particularly limited our ability to assess the utility o ecal lactoer-

rin. Another by-product o our statistical approach was the intro-

duction o heterogeneity as a consequence o transorming the


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FUNC

TIONAL

GIDISORD

ERS

Menees et al.

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