3.4 Sensitivity, specificity, and predictive value of the fecal tests for mucosal healing
The sensitivity, specificity, PPV, NPV, and accuracy of the two fecal tests for mucosal healing are summarized in Table 2. When the values indicative of mucosal healing were applied, Fcal showed a sensitivity of 78.4%, specificity of 74.8%, PPV of 56.3%, NPV of 89.3%, and accuracy of 75.9%; and FIT showed a sensitivity of 98.0%, specificity of 37.4%, PPV of 39.4%, NPV of 97.9%, and accuracy of 55.2% in identifying patients with MES of 0 (Table 2A). Similar results were obtained for UCEIS. Fcal showed a sensitivity of 74.6%, specificity of 76.5%, PPV of 62.0%, NPV of 85.4%, and accuracy of 75.9%; and FIT showed a sensitivity of 94.9%, specificity of 38.3%, PPV of 44.1%, NPV of 93.6%, and accuracy of 57.5% in identifying patients with UCEIS of 0–1 (Table 2B).
In this study, we confirmed a positive correlation between endoscopic activity and the fecal tests, and different predictability between the fecal tests depending on the mucosal status in patients with UC. Although several studies suggested that Fcal and FIT were well correlated with endoscopic activity and mucosal healing[6,15–19] and that a negative FIT has a high sensitivity to mucosal healing in patients with UC,[6,17–19] there has been no conclusion as to which of the two tests is superior. This study showed that Fcal was statistically more relevant to endoscopic activity with MES and UCEIS, and FIT was superior to Fcal in sensitivity for mucosal healing with MES and UCEIS.
Regarding the clinical application of our results, a conclusion similar to that in a recent study can be made. Hiraoka et al suggested that FIT confirms mucosal healing and is favorable for subsequent relapse prediction, suggesting that Fcal is more effective in monitoring patients with active inflammation. In this study, Fcal was more superior to FIT in predictability of endoscopy activity and had a low sensitivity for mucosal healing, so it could be used for monitoring UC patients with active inflammation. However, FIT had a high sensitivity for mucosal healing, and thus, could be used to monitor relapse in UC patients with mucosal healing. Based on these results, the strategy to use one of the two fecal tests depending on the mucosal status may be more economical rather than only using Fcal regardless of the mucosal status because FIT is inexpensive. On the basis of these results, we created a simple algorithm for managing patients with UC by using the two fecal tests (Fig. 5). After induction treatment, patients with UC should undergo endoscopy to confirm mucosal healing. If patients have mucosal healing and no symptoms, FIT should be used to regularly monitor them every 6–12 months. However, an endoscopic evaluation should be performed when FIT result is elevated to 100 ng/mL in these patients. If patients failed to show mucosal healing after induction treatment, Fcal level should be assessed after 3–6 months. According to Fcal level, an endoscopy to confirm mucosal healing should be performed in patients with Fcal level <170 μg/g and no symptoms, or re-monitoring of Fcal level should be performed after 3–6 months in patients with Fcal level ≥170 μg/g.
Recently, simple and noninvasive tests that replace endoscopy have been studied in the evaluation of UC. Among several tests, Fcal is most frequently used. Fcal is a neutrophil-derived protein released in stool in response to mucosal inflammation, and it indicates the amount of inflammatory cells. Fcal has been reported to be associated with various conditions of UC. The level of Fcal is related to endoscopic severity, prediction of mucosal healing, and prediction of relapse, and it is useful in monitoring patients’ response to treatment.[22,23] Conversely, FIT indicates the amount of blood coming from the damaged mucosa, and it is used for colorectal cancer screening. There are a relatively small number of studies about FIT compared to Fcal in UC, and there are few reports related to mucosal healing.[17–19] A recent meta-analysis reported that the sensitivity and specificity of the FIT result for predicting mucosal healing in UC were 0.77 and 0.81, respectively. In our study, the sensitivity and specificity of FIT for predicting mucosal healing in UC were 0.98 and 0.38, respectively. The lower specificity of FIT for predicting mucosal healing in UC in this study than in the meta-analysis may be caused by the strict definition of mucosal healing and cut-off values of the present study. Actually, the definition of mucosal healing and the cut-off value were MES of 0 and 100 ng/mL in the present study, respectively, whereas those were MES of 0–1 and 50–280 ng/mL in studies included in the meta-analysis, respectively.
Several scoring systems are used for evaluating endoscopic activity of UC, among which MES is the most representative. More recently, UCEIS has been introduced and is known to reflect clinical outcomes and long-term prognosis.[26,27] Ikeya et al suggested that UCEIS more accurately reflects clinical outcomes and long-term prognosis than MES. In this study, both scoring systems were useful because MES and UCEIS were statistically significantly correlated (r = 0.923, P < .001). The definition of mucosal healing is not clearly defined, but recent studies have defined mucosal healing as only MES of 0.[7,28,29] UCEIS does not yet have a standard value for mucosal healing. Herein, endoscopic activity was evaluated by both MES and UCEIS, and mucosal healing was defined as MES of 0 and UCEIS of 0–1.
In the present study, FIT had a better sensitivity for mucosal healing than Fcal. However, the sensitivity may change depending on the determined cut-off value. For the FIT, usually a cut-off value of 100 ng/mL is used for screening for colorectal cancer. However, Fcal does not have a defined cut-off value. Therefore, most studies have used cut-off values of Fcal based on ROC curves. The cut-off value of Fcal for mucosal healing (MES 0) varied in each study: 180 μg/g in Hiraoka et al, 187 μg/g in Lee et al, and 194 μg/g in Yamaguchi et al. In these studies, the sensitivity and specificity were reported as 71% to 85% and 58% to 89%, respectively.[7,11,30] In our study, the cut-off value was also determined based on the ROC curve, and the cut-off value of Fcal for MES of 0 could be set to 170 μg/g. Additionally, the sensitivity and specificity in our study were not significantly different from those in other studies.
There are some limitations to this study. First, there are inaccuracies and limitations of the fecal tests. FIT can be positive in different situations unrelated with UC, such as anal bleeding. Fcal has no standard cut-off value and produces different results depending on measurement kits and diurnal variation. Second, the sensitivity of FIT to mucosal healing was significantly higher but the specificity was lower than that reported in other studies, and FIT can show high false-positive results. However, FIT is an inexpensive and fast test, so we can perform it easily and frequently. Third, this study had a single-center, retrospective design with a small sample size. Nevertheless, when compared with other studies confirming the usefulness of fecal tests in patients with UC, the number of participating patients was relatively high, and only those patients who submitted a stool test on the day of colonoscopy were included in this study.
In conclusion, this study revealed that both Fcal and FIT were well correlated with endoscopic activity in patients with UC. Between the two tests, Fcal was statistically more correlated and had better predictive accuracy with endoscopic activity. On the other hand, FIT was more sensitive for predicting mucosal healing with MES and UCEIS. Therefore, we suggest that Fcal may be used to evaluate disease activity and treatment response in active UC patients with mucosal inflammation, and FIT may be used to monitor recurrence in patients with UC with mucosal healing. Further well-designed prospective, randomized, large-volume trials are required to determine proper application of the two fecal tests in patients with UC.
Conceptualization: Hyung Wook Kim, Su Bum Park.
Data curation: Dae Gon Ryu.
Formal analysis: Dae Gon Ryu.
Investigation: Su Bum Park, Cheol Woong Choi, Su Jin Kim, Hyeong Seok Nam.
Methodology: Dae Gon Ryu, Hyung Wook Kim.
Project administration: Dae Gon Ryu, Hyung Wook Kim, Su Jin Kim.
Software: Su Bum Park, Cheol Woong Choi, Hyeong Seok Nam.
Supervision: Dae Hwan Kang.
Validation: Dae Gon Ryu, Hyung Wook Kim, Su Bum Park.
Visualization: Dae Gon Ryu, Su Bum Park.
Writing – original draft: Dae Gon Ryu, Hyung Wook Kim.
Writing – review & editing: Dae Gon Ryu, Hyung Wook Kim.
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Keywords:Copyright © 2019 the Author(s). Published by Wolters Kluwer Health, Inc.
fecal calprotectin; fecal immunochemical test; ulcerative colitis