An infographic is available for this article at: https://links.lww.com/MPG/C332.
What Is Known/What Is New
What Is Known
- Fecal calprotectin (FC) is a widely used non-invasive marker of Crohn disease (CD) activity.
- FC is known to be extremely sensitive in detecting colonic inflammation, while its performance for isolated ileal CD is still questioned.
What Is New
- FC should not be used alone to monitor disease activity in patients with isolated ileal CD.
- A significantly lower threshold should be applied for increasing its performance for isolated small bowel CD monitoring.
Crohn disease (CD) is a chronic inflammatory disorder of the gastrointestinal tract. Its incidence is increasing worldwide with up to 20–25% of inflammatory bowel disease cases presenting during childhood resulting in ∼1% of prevalent cases diagnosed in the pediatric populations (1–3).
It is widely known that accurate disease monitoring, through endoscopy, imaging and laboratory markers, should be performed in patients with CD, to check the control of inflammation, possibly avoiding or leading to early recognition and treatment of CD complications (such as strictures, fistulae, abscesses) and, therefore, prevent bowel wall damage (4–7).
Laboratory markers are widely used for monitoring pediatric inflammatory bowel disease, as they are non-invasive, cheap and easy to perform. Among those, fecal calprotectin (FC) and C-reactive protein (CRP) are the most commonly evaluated. Fecal calprotectin (a small calcium-binding protein member of the S100 family of zinc-binding proteins), is part of the protein content of the cytosol in neutrophils (it has also been detected at lower concentrations in monocytes and macrophages) and is excreted in feces when any disturbance to the intestinal mucosal architecture due to the inflammatory process occurs, resulting in the migration and in the leakage of neutrophils (8). Fecal calprotectin is known to be extremely sensitive in detecting colonic inflammation (allowing avoidance of repeated colonoscopies in children with ulcerative colitis), while its performance for isolated ileal CD is still questioned. Adult data show that its predictive value in cases of relapses decreases significantly in patients with isolated ileal rather than colonic or ileocolonic disease (9–11). Therefore, we aimed to define the role of FC for monitoring small bowel disease in children by comparing its performance for different CD locations. Moreover, we sought to evaluate the concordance between FC and disease activity according to disease location, to identify the optimal FC cut-off for each location and to determine the performance of other non-invasive markers of activity (erythrocyte sedimentation rate [ESR], CRP, weighted pediatric Crohn disease activity index [wPCDAI] and Mucosal Inflammation Noninvasive index [MINI index]) in the detection of active or inactive CD for each disease location.
PATIENTS AND METHODS
This is a retrospective observational study of all patients with CD, ages <18 years, followed at the Pediatric Gastroenterology and Liver Unit of Sapienza University of Rome between January 2018 and January 2020. All children undergoing endoscopy or cross-sectional imaging at the diagnosis and for routine monitoring, with a sample for FC collected within 1 week from the procedure, were included in the study. As per local protocol, only stool sample collected before bowel preparation or after 24 hours from any procedure are analyzed for FC.
Diagnosis of CD was made according to the Porto criteria (12). Exclusion criteria were the following: isolated upper gastrointestinal CD involvement (Paris classification L4a-L4b); use of nonsteroidal anti-inflammatory drugs in the previous two weeks; acute or chronic enteric infections (eg, Clostridium difficile) at inclusion; any treatment modification occurred within the FC sample collection and ileocolonoscopy or magnetic resonance enterography (MRE); inability to provide a fecal sample within 7 days of the study procedure; inability to perform a complete ileocolonoscopy with direct visualization of the terminal ileum.
All patients’ clinical and demographic data were collected from the computerized medical records. Disease location and behavior at diagnosis and at the time of inclusion were defined according to Paris Classification (13) as follows: L1 identified patients with the isolated ileal disease, L2 and L3 those with colonic and ileocolonic disease respectively.
Weighted PCDAI (14) and MINI Index (15) were retrospectively determined. A cut-off of 12.5 points for wPCDAI and 8 for MINI Index were used to differentiate patients with active and inactive disease. Laboratory data included ESR, CRP and FC. The normal ranges for CRP and ESR were <6 mg/l and <25 mm/h, respectively.
An FC cut-off value >150 μg/g was considered suggestive of active disease (16).
The reference standard techniques for the evaluation of disease activity were ileocolonoscopy and magnetic resonance enterography (MRE). If both available, ileocolonoscopy was considered the gold standard. The Simple Endoscopic Crohn Disease Activity Index (SES-CD) (17,18) was used to grade and assess endoscopic disease activity and an SES-CD >3 identified patients with active disease.
For MRE, the presence of one or more of the following variables in any evaluated intestinal segment was considered suggestive of inflammation: wall thickness (>3 mm), presence of mural edema, fat stranding, and mucosal ulcerations (19). In the presence of a stricture, the absence of such inflammatory imaging markers, was considered suggestive of fibrotic/non-inflammatory stricture and considered negative for the presence of active inflammation, regardless of the presence of absence of a prestenotic dilation.
The primary aim of our study was to assess the performance (sensitivity, specificity, positive predictive value [PPV], negative predictive value [NPV], accuracy) of FC in the detection of active or inactive CD for isolated ileal CD (L1) and to compare it with that showed for isolated colonic CD (L2) and ileocolonic CD (L3).
Secondary aims were to identify the optimal FC cut-off for active L1, L2 and L3 CD and its correlation with the reference standard technique and to determine the performance of ESR, CRP, wPCDAI and MINI index in the detection of active or inactive CD for each disease location (L1, L2, L3).
Approval by the local Ethics Review Board was obtained (protocol number 5617).
Statistical Analysis
All data were summarized and expressed as mean and standard deviation (SD) for the continuous variables. Categorical data were expressed as frequencies and percentages. The comparison of the groups was performed by using the Student t-test for unpaired data in a two-group comparison and one-way analysis of variance with Bonferroni correction for multiple-group comparison. A chi square test with the Fisher correction was used to evaluate the differences for categorical variables wherever needed. A P value <0.05 was considered significant. Sensitivity, specificity, NPV, PPV, and accuracy of FC, ESR, CRP, wPCDAI and MINI index for all disease locations were determined by comparing the results with either ileocolonoscopy or MRE used as the gold standard. The Fisher exact test was used to evaluate the performance of tests. Exact binomial 95% confidence intervals were also reported. Receiver operating characteristic (ROC) curves analysis was used to determine the best threshold of FC to assess active or inactive CD. Cohen kappa was calculated to determine the agreement between FC and the standard reference for L1, L2 and L3 CD. Statistical analysis was performed using GraphPad Prism and Instat software (GraphPad 6.07, San Diego, CA, USA).
RESULTS
Study Population
One-hundred seventy-six FC measurements from a total of 98 patients were collected. Table 1 reports the baseline characteristics of the population of CD patients.
TABLE 1 -
Baseline and demographic characteristics of 98 patients with
Crohn disease
|
All patients (n = 98) |
| Sex F, N (%) |
F 31 (98) 31.6%, M 67 (98) 68.4% |
| Age at diagnosis (mean ± SD) |
11.62 y (±3.09) |
| Age at inclusion (mean ± SD) |
13.23 (± 2.65) |
| Disease location at inclusion, N (%) |
| L1 |
14 (98) 14.3% |
| L2 |
10 (98) 10.2% |
| L3 |
74 (98) 75.5% |
| P |
10 (98) 10.2% |
| L4a/L4b |
30 (98) 30.6%/18 (98) 18.4% |
| Disease behavior at inclusion, N (%) |
| B1 |
69 (98) 70.4% |
| B2 |
16 (98) 16.3% |
| B3 |
13 (98) 13.3% |
| B2B3 |
2 (98) 2% |
At the time of diagnosis, 14 of 98 (14.3%) patients were labeled as L1, 74 (75.5%) as L3 and 10 (10.2%) had an isolated colonic involvement (L2). Twelve (7%) FC measurements were obtained at the diagnosis and 164 (93%) during follow-up.
Twenty of 98 (20.4%) patients had one FC measurement, 78 of 98 (79.6%) had two FC measurements. Eighty-three of the 176 FC (47%) were collected simultaneously to endoscopy and 93 of 176 (53%) to MRE.
Twenty-eight of 83 (33.7%) and 38 of 93 (40.9%) of the ileocolonoscopies and MREs performed showed an active disease, respectively.
Fecal Calprotectin: Performance Analysis
Overall, FC showed a sensitivity of 69%, a specificity of 92%, a NPV of 56%, a PPV of 95% and an accuracy of 76% for defining active CD.
Patients with active L1 disease showed significantly lower values of FC compared to those with active L2 (120.81 ± 87 vs 491.3 ± 109.1, P < 0.001) and L3 (451 ± 886, P = 0.005) disease. Mean FC values for the inactive disease were comparable for all disease locations (71.8 ± 34.6 for L1, 61.73 ± 79.90 and 61.73 ± 79.9 for L2 and L3, respectively, P = NS).
The sensitivity, specificity, NPV, PPV and accuracy of FC for each disease location are reported in Table 2.
TABLE 2 -
Sensitivity, specificity, negative predictive value, positive predictive value and accuracy of FC for L1, L2 and L3 CD
| Test |
Sensitivity, % (95% CI) |
Specificity, % (95% CI) |
NPV% (95% CI) |
PPV% (95% CI) |
ACC% |
| FC |
| L1 (25) |
36% (13–65) |
91% (59–100) |
53% (29–75) |
83% (36–99) |
60% |
| L2 (18) |
93% (66–100) |
75% (19–99) |
75% (19–99) |
93% (66–100) |
89% |
| L3 (133) |
70% (61–80) |
95% (82–99) |
56% (42–68) |
97% (90–99) |
77% |
ACC = accuracy; CD = Crohn disease; CI = confidence interval; FC = fecal calprotectin; L1 = isolated ileal disease; L2 = colonic disease; L3 = ileocolonic disease; NPV = negative predictive value; PPV = positive predictive value.
Concordance and Receiver-Operating Characteristic Analysis of Fecal Calprotectin
By ROC analysis, the FC threshold above which active L1 disease was confirmed was 95 mg/kg, with a sensitivity of 77% and a specificity of 56% (area under the curve [AUC] 0.77, P = 0.02) (Fig. 1A).
;)
FIGURE 1: Receiver operating characteristic (ROC) curve for fecal calprotectin (FC) stratifying patients with active or inactive disease as measured by ileocolonoscopy or MRE in L1 (A) L2 (B) and L3 (C) CD. AUROC = area under the curve ROC; CD = Crohn disease; L1 = isolated ileal disease; L2 = colonic disease; L3 = ileocolonic disease; MRE = magnetic resonance enterography.
A FC cut-off value of 164 and 139 μg/g best discriminated between the presence and absence of inflammation for L2 and L3 disease, respectively (AUROC 0.96 [CI 0.88–1.05], sensitivity 100% and specificity 87%, P = 0.01 [Fig. 1B] and AUROC 0.83 [CI 0.76–0.90] sensitivity 84% and specificity 71%, P < 0.0001 [Fig. 1C]).
When evaluating the concordance between FC according to CD location and disease activity measured by the reference standard a poor correlation (kappa = 0.24) was found for L1, whereas the concordance resulted in good (kappa = 0.61) and fair (kappa = 0.48) for L2 and L3, respectively.
Other Noninvasive Markers: Performance Analysis
The sensitivity of the MINI index, wPCDAI, CRP and ESR was 60%, 47%, 50% and 75% for L1, 80%, 47%, 53%, 73% for L2 and 78%, 60%, 50%, 58% for L3, respectively. The analysis of the performance of the MINI index, wPCDAI, CRP and ESR for each disease location are reported in Table 3.
TABLE 3 -
Sensitivity, specificity, negative predictive value, positive predictive value and accuracy of MINI Index, wPCDAI, CRP and ESR for L1, L2 and L3 CD
| Test |
Sensitivity, % (95% CI) |
Specificity, % (95% CI) |
NPV% (95% CI) |
PPV% (95% CI) |
ACC% |
| MINI index |
| L1 |
60% (32–84) |
100% (69–100) |
62% (35–85) |
100% (66–100) |
76% |
| L2 |
80% (52–96) |
100% (30–100) |
50% (12–88) |
100% (75–100) |
83% |
| L3 |
78% (67–86) |
94% (85–98) |
75% (64–85) |
95% (86–99) |
85% |
| CRP |
| L1 |
50% (25–75) |
89% (52–100) |
50% (25–75) |
89% (52–100) |
64% |
| L2 |
53% (27–79) |
100% (29–100) |
30% (7–65) |
100% (63–100) |
61% |
| L3 |
50% (40–60) |
90% (74–98) |
35% (25–47) |
94% (85–99) |
59% |
| ESR |
| L1 |
75% (48–93) |
89% (52–100) |
67% (35–90) |
92% (64–100) |
80% |
| L2 |
73% (45–92) |
33% (0.8–90) |
20% (0.5–72) |
85% (55–98) |
67% |
| L3 |
58% (48–68) |
19% (7–37) |
12% (5–25) |
70% (59–80) |
49% |
| wPCDAI |
| L1 |
47% (21–73) |
90% (55–100) |
53% (28–77) |
87% (47–100) |
64% |
| L2 |
47% (21–73) |
100% (29–100) |
27% (6–61) |
100% (59–100) |
56% |
| L3 |
60% (50–69) |
97% (83–100) |
42% (30–54) |
98% (91–100) |
68% |
ACC = accuracy; CD = Crohn disease; CI = confidence interval; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; L1 = isolated ileal disease; L2 = colonic disease; L3 = ileocolonic disease; MINI Index = Mucosal Inflammation Noninvasive (MINI) Index; NPV = negative predictive value; PPV = positive predictive value; wPCDAI = Weighted Pediatric Crohn Disease Activity Index.
For L1 disease a ROC analysis was performed for ESR and CRP (Supplemental Digital Content 1, https://links.lww.com/MPG/C333): the best cut-off for discriminating active and inactive disease were 23 mm/h (AUROC 0.71 [CI 0.45–0.97], sensitivity 83% and specificity 73%, P = 0.12) and 6.5 mg/L (AUROC 0.70 [CI 0.48–0.92], sensitivity 83% and specificity 73%, P = 0.14), respectively.
The logistic regression model using all available clinical and biochemical parameters related to the active L1 disease is shown in Supplemental Digital Content 2, https://links.lww.com/MPG/C334.
DISCUSSION
This is the first study specifically evaluating the clinical utility of FC in isolated ileal pediatric CD, by comparing its performance in patients with ileal involvement and other disease locations.
With an accuracy and a sensitivity of 60% and 36%, FC alone appears unable to accurately reflect isolated L1 disease activity (confirming the irreplaceable value of MRE and/or ileocolonoscopy in this context), while its excellent and good performance is proven for isolated colonic (sensitivity 93%) and ileocolonic (sensitivity 70%) disease, respectively. This result finds its explanation in the ROC curve analysis which questions the efficacy of setting 150 μg/g as the cut-off for active disease: we identified an FC threshold of 95 μg/g above which active L1 disease was confirmed with a sensitivity of 77% and a specificity of 56%, whereas FC cut-off values of 164 and 139 μg/g best discriminated between presence and absence of inflammation for L2 and L3 locations, with a sensitivity of 100% and a specificity of 87% for L2 disease and a sensitivity of 84% and a specificity of 71% for L3 location, respectively. According to our results, FC values should not be interpreted regardless of disease location and, possibly, a significantly lower cut-off should be applied when dealing with L1 CD patients. Other adult reports are in line with our data, proving that FC is a much more sensitive and accurate marker of active colonic inflammation rather than of the small bowel (11,15,20). D’Incà et al, in their prospective analysis of 65 CD patients, showed that correlation between a positive calprotectin test and the probability of relapse was significant only in the case of colonic CD, and the ROC analysis attributed a sensitivity of 68% to the best-identified cut off of 130 μg/g.
Moreover, Zittan et al, in their prospective trial in 72 adult patients with inflammatory bowel disease (IBD), demonstrated the absence of a significant correlation between FC and objective disease activity measured by either endoscopy or imaging in isolated small bowel CD, whereas this correlation appeared significant for colonic involvement. The authors, as an explanation for such results, suggested that, depending on the disease location and extension, a different inflammatory burden might exist, resulting in less neutrophil migration and less FC loss in the intestinal lumen. A slower transit, typically occurring in the colon, affecting FC concentration could be hypothesized, as well.
Compared to other literature data (8), our pooled sensitivity analysis of FC for all disease locations appears to be lower (69%). As an explanation to such results, we might refer to the risk of MRE of not accurately reflect isolated mucosal inflammation, as its strength lies in the detection of transmural inflammation, thus increasing the risk of false negative results. As already detected in other prospective pediatric cohorts, a lower threshold (<100 μg/g) should be considered when evaluating the healing of the bowel wall (21).
We were able to demonstrate a more uniform (although not excellent) performance of serum inflammatory markers: surprisingly, ESR showed higher sensitivity and accuracy than CRP whereas both, contrarily to FC, seemed to better discriminate active and inactive L1 disease compared to L2 and L3. This figure correlates only in part with the results of previous studies, in which stool markers, such as FC, always performed better than serological ones, when compared with endoscopic findings (22–25); however, these data lacked an evaluation of the performance of each marker according to disease location. Regarding the slightly better sensitivity of ESR, this could be explained by its less rapid but more persistent peak compared to that of CRP, which might account for its worse sensitivity (26). Indeed, none of the laboratory markers alone can account for 100% sensitivity and specificity, since it is not uncommon to report normal values in the context of a pediatric inflammatory disease (27), as recently demonstrated by Ashton et al in their cohort of 151 IBD children, one of five presenting with normal inflammatory markers (28).
Together with ESR, we found that the recently developed MINI Index (15), incorporating fecal, serological and clinical markers of disease activity, is the non-invasive tool with the best accuracy for L1 disease (76%), despite a slightly lower sensitivity (60%). Despite this, monitoring isolated ileal disease remains challenging, especially when compared to other locations, where the MINI index showed a sensitivity raising up to 80% (in line with the results obtained by Turner and colleagues in the MINI Index validation process) (29).
Compared to the MINI Index, our analysis confirmed the questionable performance of wPCDAI (14) in reflecting the grade of bowel inflammation, demonstrating the low reliability of this clinical score (30,31), for all disease locations: wPCDAI was also less effective in discriminating patients with active disease compared to individual laboratory markers (ESR in particular) in patients with exclusive ileal involvement.
Such results confirm the evidence of previous studies, showing a strong correlation between MINI-Index and SESCD (rho = 0.73) and a moderate correlation between wPCDAI and SESCD (rho = 0.59) (15).
A limitation of the present study is undoubtedly its retrospective nature, as well as the use of two different instruments (ileocolonoscopy and MRE) to determine the disease activity, but, being a single-center study, it accounts for an excellent uniformity in laboratory evaluation and patient's management and results’ interpretation.
CONCLUSIONS
In conclusion, the recognized utility of the treat-to-target strategy imposes a tight monitoring approach and, particularly for children, the avoidance of useless and inaccurate disease activity markers is mandatory. If confirmed by well-structured, prospective trials, our results seem to suggest that monitoring of isolated ileal pediatric CD cannot be done without resorting to an endoscopic or imaging evaluation, which cannot be replaced by less invasive disease activity markers. Otherwise, when interpreting FC results, a significantly lower threshold (<94 μg/g) should be applied to correctly estimate isolated ileal inflammation increasing the sensitivity of this important monitoring tool. A mixed clinical and laboratory grading of disease activity (provided by the MINI-index) could serve as an interim (mid-term) evaluation and help to establish the timing of endoscopy or MRE for the evaluation of the small bowel.
On the other hand, a different, less invasive approach might be suggested for the disease affecting the colon. As for the different drugs, it is conceivable that an individualized monitoring program could represent the optimal way to manage chronic conditions such as pediatric IBD.
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