Diagnostic Accuracy of Fecal Calprotectin for Pediatric Inflammatory Bowel Disease in Primary Care: A Prospective Cohort Study

Gea A. Holtman; Yvonne Lisman-van Leeuwen; Boudewijn J. Kollen; Obbe F. Norbruis; Johanna C. Escher; Angelika Kindermann; Yolanda B. de Rijke; Patrick F. van Rheenen; Marjolein Y. Berger

doi:10.1370/afm.1949

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Figure 1
Patient flow in the study.
Note: The group of children who were mainly seen in primary care and selected for referral to specialist care based on ≥1 red flags were evaluated in both analyses. Fecal calprotectin was not measured in 14 children because no stool sample was collected (9 children), the sample was not stored (2 children), or the sample of feces was too small (3 children). Two children with no stool sample were evaluated in both analyses.
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Figure 2
Flow charts and contingency tables for the calculation. of diagnostic accuracy in the primary care cohort and referred cohort, using the nonimputed data set.
FCal = fecal calprotectin; GI = gastrointestinal; IBD = inflammatory bowel disease; PPV = positive predictive value; NPV = negative predictive value.
Note: The left flow chart shows the specificity of FCal (>50 μg/g) for IBD in the primary care cohort (11 missing values). Specificity of standard follow-up and endoscopy were 0.88 (95% CI, 0.80–0.93) and 0.50 (95% CI, 0.09–0.91), respectively. The right flow chart shows the test characteristics of FCal (>50 μg/g) for IBD in the referred cohort (5 missing values). Sensitivity of the reference standards of follow-up and endoscopy were 1.00 (95% CI, 0.34–1.00) and 1.00 (95% CI, 0.78–1.00), respectively; values for specificity were 0.87 (95% CI, 0.76–0.93) and 0.67 (95% CI, 0.35–0.88), respectively.

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Table 1

Definitions of Red Flags in Inflammatory Bowel Disease

Red Flag	Method of Ascertainment	Definition of Positive Finding
Alarm symptoms
Involuntary weight loss	History	Involuntary decrease in weight of >1 kg
Rectal blood loss	History	Rectal blood loss with defecation without constipation according to Rome III criteria
Family history of IBD	History	Affected first-degree relative(s)
Growth failure	History and physical examination	Target height range > −1 standard deviation score
Extraintestinal symptoms	Physical examination	Eyes (episcleritis, scleritis, uveitis), skin (erythema nodosum, pyoderma gangrenosum, psoriasis), mouth ulcers, finger clubbing, arthritis
Perianal lesions	Physical examination	Skin tags, hemorrhoids, fissures, fistulas, abscesses
Blood markers
Hemoglobin	Local laboratory	Age 4–12 y: <7.1 mmol/L; age 12–18 y: boys <8.1 mmol/L, girls <7.4 mmol/L25
C-reactive protein	Local laboratory	>10 mg/L²⁶
Erythrocyte sedimentation rate	Local laboratory	>20 mm/h²⁶
Platelet count	Local laboratory	>450 × 10⁹/L²⁷

IBD = inflammatory bowel disease.

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Table 2

Baseline Characteristics of the Primary Care Cohort and the Referred Cohort

Characteristic	Main Analysis		Referred Cohort by Origin		Referred Cohort by Referral

	Primary Care Cohort (n = 114)	Referred Cohort (n = 90)	Primary Care Patients With Red Flag(s) (n = 24)^a	Specialist Care Patients (n = 66)	Referred by Primary Care Physician (n = 65)^b	Referred by General Pediatrician (n = 25)
Male, No. (%)	38 (33)	37 (41)	8 (33)	29 (44)	29 (45)	8 (32)
Age, median (IQR), y	9 (6–12)	11 (7–15)	9 (6–14)	12 (7–15)	10 (7–14)	14 (10–15.5)
Presenting symptoms
Recurrent abdominal pain, No. (%)	88 (77)	58 (64)	16 (67)	42 (64)	38 (59)	20 (80)
Chronic diarrhea, No. (%)	74 (65)	62 (69)	17 (71)	45 (68)	40 (62)	22 (88)
Involuntary weight loss, No. (%)	5 (4)^c	23 (26)	1 (4)	22 (33)	10 (15)	13 (52)
Rectal blood loss, No. (%)	7 (6)	27 (30)	6 (25)	21 (32)	13 (20)	14 (56)
Family history of IBD, No. (%)	5 (4)	11 (12)	5 (21)	6 (9)	9 (14)^d	2 (8)
Growth failure, No. (%)	4 (3)	6 (7)	3 (13)	3 (5)	6 (9)	0 (0)
Extraintestinal symptoms, No. (%)	0 (0)	13 (14)	0 (0)	13 (20)	4 (6)	9 (36)
Perianal lesions, No. (%)	7 (6)	13 (14)	7 (29)	6 (9)	9 (14)	4 (17)^e
Positive blood markers, n/N (%)
Hemoglobin^f	1/111 (1)	11/86 (13)	1/24 (4)	10/62 (16)	5/61 (8)	6/25 (24)
CRP (>10 mg/L)	2/110 (2)	10/76 (13)	2/24 (8)	8/52 (15)	5/56 (9)	5/20 (25)
ESR (>20 mm/h)	5/111 (5)	16/83 (19)	5/24 (21)	11/59 (19)	8/59 (14)	8/24 (33)
Platelet count (>450 × 10⁹/L)	4/111 (4)	7/86 (8)	2/24 (8)	5/62 (8)	4/61 (7)	3/25 (12)
Anti–tissue transglutaminase,^g n/N	0/100	0/72	0/21	0/51	0/55	0/18
≥1 Red flag,^h No. (%)	29 (25)	68 (76)	24 (100)	44 (67)	43 (66)	25 (100)
Endoscopy, No. (%)	2 (2)	29 (32)	2 (8)	27 (41)	9 (14)	20 (80)
IBD, No. (%)	0 (0)	17 (19)	0 (0)	17 (26)	5/64 (8)	12 (48)

CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; IBD = inflammatory bowel disease; IQR = interquartile range.
↵a Five children with red flags were ultimately not seen by a pediatric gastroenterologist: 3 declined because of reduced symptoms, 2 were lost to follow-up.
↵b Including primary care physicians who did not participate in this study.
↵c Three children had no further weight loss after 3 weeks.
↵d Denominator is 64.
↵e Denominator is 24.
↵f Age and sex specific: aged 4–12 years <7.1 mmol/L; aged 12–18 years: boys <8.1 mmol/L, girls <7.4 mmol/L.
↵g Twenty-five children had IgA deficiency.
↵h Growth failure, involuntary weight loss, rectal blood loss, family history of IBD, extraintestinal symptoms, perianal lesions, positive blood markers (hemoglobin, CRP, ESR, platelet count).

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Table 3

Prevalence of Symptoms, Blood Marker Positivity, and FCal Positivity by Final Diagnosis

Diagnosis	No. (%)	Symptom Positive,^a No.	Blood Marker Positive,^b No.	FCal >50 μg/g, No.	Range of FCal, μg/g
Primary care cohort
Functional gastrointestinal disorder	108 (95)	24	9	12	20–257
Gastroenteritis^c	5 (45)	0	0	1	20–88
Declined endoscopy	1 (1)	1	0	–	–
Referred cohort
IBD
Crohn disease	7 (8)	7	7	6	152–2,823
Ulcerative colitis	8 (9)	7	4	8	53–916
IBD unclassified	2 (2)	2	1	2	79–778
Non-IBD
Functional gastrointestinal disorder	66 (73)	40	12	10	20–185
Gastroenteritisc	3 (3)	1	0	0	20–45
Reflux esophagitis	1 (1)	0	0	0	22
Celiac disease	1 (1)	1	0	0	20
Solitary rectal ulcer	1 (1)	1	0	1	299

FCal = fecal calprotectin; IBD = inflammatory bowel disease.
↵a Presence of 1 or more of the following: growth failure, involuntary weight loss, rectal blood loss, extraintestinal symptoms, perianal lesions, family history of IBD.
↵b Hemoglobin (4–12 years old <7.1 mmol/L; 12–18 years old: boys <8.1 mmol/L, girls <7.4 mmol/L), C-reactive protein (>10 mg/L), erythrocyte sedimentation rate (>20 mm/h), platelet count(>450 × 109/L).
↵c Due to Salmonella enterica (0 cases included by primary care physician; 2 cases included by pediatrician), Shiga toxin–producing Escherichia coli (STEC) (1 and 0), and Giardia lamblia (4 and 1).
Note: One child declined endoscopy and evaluation of red flags at 12 months’ follow-up, so the diagnosis was unknown. Nine children without IBD, including 1 child with a solitary rectal ulcer, underwent upper and lower endoscopy, including ileal intubation. The remaining 3 children did not undergo complete endoscopic evaluation for various reasons: the colonoscopy was prematurely terminated because of mucosal bleeding in 1 child with a functional gastrointestinal disorder, but was not repeated because symptoms subsided; 1 child with a functional gastrointestinal disorder underwent colonoscopy only, but not esophagogastroduodenoscopy; and 1 child received a diagnosis of celiac disease by esophagogastroduodenoscopy only.

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Table 4

Test Characteristics at Increasing Calprotectin Cutoff Levels in the Referred Cohort Using the Imputed Data Set (n = 90)

Test Characteristic	Fecal Calprotectin Cutoff
Test Characteristic	>50 μg/g	>100 μg/g	>250 μg/g
Sensitivity (95% CI)	0.99 (0.81–1.00)	0.87 (0.65–0.96)	0.81 (0.58–0.93)
Specificity (95% CI)	0.84 (0.74–0.91)	0.93 (0.84–0.97)	0.98 (0.92–0.99)
PPV (95% CI)	0.60 (0.42–0.76)	0.74 (0.53–0.88)	0.92 (0.69–0.98)
NPV (95% CI)	1.00 (0.94–1.00)	0.97 (0.89–0.99)	0.96 (0.88–0.98)
Referrals avoided, No. (%)^a	61 (68)	69 (77)	74 (82)
Missed cases of IBD, No. (%)^b	0 (0)	2 (12)	3 (18)

NPV = negative predictive value; PPV = positive predictive value; IBD = inflammatory bowel disease.
↵a Denominator is the 90 children in the referred cohort.
↵b Denominator is the 17 children in the referred cohort ultimately given a diagnosis of IBD.
Note: Pretest probability of IBD in this sample was 19%.

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The Article in Brief

Diagnostic Accuracy of Fecal Calprotectin for Pediatric Inflammatory Bowel Disease in Primary Care: A Prospective Cohort Study

Gea A. Holtman , and colleagues

Background Guidelines recommend primary care physicians refer children with chronic diarrhea, recurrent abdominal pain, or both for specialist care if red flags are present, however the red flags are nonspecific and discriminate poorly between functional and organic gastrointestinal diseases, often leading to referral and extensive diagnostic testing. Fecal calprotectin is a simple, noninvasive diagnostic test commonly used in specialist care for ruling out inflammatory bowel disease (IBD) in children with chronic gastrointestinal symptoms. This is the first study to evaluate the use of fecal calprotectin for IBD in symptomatic children in primary care.

What This Study Found Fecal calprotectin has satisfactory discriminatory power between children with and without IBD. Among 2 groups of symptomatic children (114 children initially seen in primary care and 90 children referred to specialist care), none of the 114 children in the primary care group received a diagnosis of IBD. Among the 90 children in the cohort referred by a primary care physician to specialist care, 17 (19 percent) received a diagnosis of IBD.

Implications

While fecal calprotectin showed good sensitivity and specificity, the authors question whether it can add to the diagnostic information that is already available from a thorough history and physical examination. They call for further research to determine the cost-effectiveness of fecal calprotectin and whether it should be incorporated in to the routine diagnostic evaluation of pediatric patients with chronic gastrointestinal symptoms and red flags in primary care.
A pragmatic approach may be to monitor children with an initial calprotectin value between 50 ug/g and 250 ug/g feces, and later refer children whose symptoms persist and whose calprotectin values remain high.