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Inflammatory Bowel Diseases:
doi: 10.1097/MIB.0000000000000087
Clinical Review Articles

Fecal Biomarkers in the Diagnosis and Monitoring of Crohn's Disease

Wright, Emily K. MD*; De Cruz, Peter MD, PhD*; Gearry, Richard MD, PhD; Day, Andrew S. MD PhD; Kamm, Michael A. MD, PhD*

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Author Information

*St. Vincent's Hospital and University of Melbourne, Melbourne, Australia; and

Christchurch Hospital and University of Otago, Christchurch, New Zealand.

Reprints: Michael A. Kamm, MD, PhD, St. Vincent's Hospital, Victoria Parade, Fitzroy, 3065 Melbourne, Australia (e-mail: mkamm@unimelb.edu.au).

The authors have no conflicts of interest to disclose.

Received April 07, 2014

Accepted April 21, 2014

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Abstract

The diagnosis and monitoring of Crohn's disease has traditionally relied on clinical assessment, serum markers of inflammation, and endoscopic examination. Fecal biomarkers such as calprotectin, lactoferrin, and S100A12 are predominantly derived from neutrophils, are easily detectable in the feces, and are emerging as valuable markers of intestinal inflammation. This review focuses on the role of fecal biomarkers in the diagnosis and monitoring of Crohn's disease, in particular how these biomarkers change with disease activity and remission, how they can be used to monitor the response to medical therapy, their value in predicting clinical relapse, and their role in monitoring the postoperative state.

Diagnosis and monitoring of Crohn's disease activity is based on a combination of clinical assessment, serological markers of inflammation, and endoscopy. However, there is often insufficient correlation between these tests to engender confidence in their routine use.1–3 Endoscopy is widely accepted as the gold standard for detecting and quantifying bowel inflammation, but endoscopy is expensive, labor intensive, inconvenient for the patient, and carries some risk. Furthermore, standard ileocolonoscopy does not examine the small intestine proximal to the distal terminal ileum. The correlation between clinical scoring systems, such as the Crohn's Disease Activity Index (CDAI) and the Harvey–Bradshaw Index (HBI), and endoscopic findings in Crohn's disease is poor.4,5 The correlation between serum biochemical markers of inflammation, such as C-reactive protein (CRP), and endoscopic findings in Crohn's disease is also inconsistent5,6 with more than one-third of patients with clinically or endoscopically active disease having a normal CRP.7,8 Simple, inexpensive, and safe tests that correlate closely with endoscopic findings are therefore required to assist in the diagnosis and monitoring of disease.

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DEFINITIONS AND APPLICATIONS

The most extensively described fecal biomarkers in the literature are fecal calprotectin (FC) and lactoferrin (FL).9–15 These 2 biomarkers will form the basis of this review. S100A12, like FC, is a calgranulin and is emerging as a useful marker of gut inflammation. Literature on the use of S100A12 in inflammatory bowel disease (IBD) is limited and mainly contained to pediatric studies and will be explored briefly in this review. These biomarkers have the advantage of showing excellent stability in the feces at room temperature for up to 1 week before freezing until the time of analysis.11,12,16,17Table 1 summarizes the characteristics of these fecal biomarkers.

TABLE 1
TABLE 1
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Quantification is traditionally performed using the inexpensive and simple enzyme-linked immunosorbent assay (ELISA) technique with as little as 1–2 g of feces. Commercially available immunoassays have also become available recently, often referred to as “rapid tests”; these allow for fast and mobile point-of-care testing with as little as 40 mg of stool.13–16,18 These rapid tests are simple and reliable alternatives to ELISA. They are useful in the clinical setting at a comparable cost and allow for the possibility of home testing as part of patient self-management.18–22

Day-to-day variability of FC has been reported.23,24 Moum et al25 looked at FC variability in patients with Crohn's disease. They found that although there was some variation, this was most significant when FC concentration exceeded 200 mg/L with only 5% of patients with a normal FC, defined as <50 mg/L, having a paired test result of >50 mg/L.25 Most recently, Naismith et al26 confirmed these findings in patients with clinically quiescent Crohn's disease. In this latter study, patients provided 3 stool samples on 3 consecutive days with the overall consistency across 3 samples being high with an intraclass correlation of 0.84 (95% confidence interval [CI], 0.79–0.89) where a value of >0.80 reflects almost perfect agreement, confirming low day-to-day variability of FC in patients with Crohn's disease. This supports the use of a single FC measurement in the clinical setting in the assessment of patients with Crohn's disease.

FC and FL have been shown to consistently reflect endoscopic disease activity in Crohn's disease and have been studied extensively.4,6,27 These proteins are produced by neutrophils, are resistant to colonic bacterial degradation, and are detectable and quantifiable in the feces. Although other novel fecal biomarkers are promising, their validation as disease markers and the literature detailing their use are limited; hence, they will not be discussed further.

Combining FC and CRP measurements may increase the sensitivity and specificity for detecting endoscopic lesions in Crohn's disease. D'Haens et al,4 using combined thresholds of FC <250 μg/g and CRP <5 mg/L, found that the specificity for the detection of endoscopic lesions in Crohn's disease increased from 0.56 without CRP to 0.77 with CRP, but with a reduced sensitivity from 0.86 to 0.65, respectively. Furthermore, binary logistic regression revealed that only FC was significantly associated with endoscopic ulcers in Crohn's disease, without added value for CRP.4 The authors concluded that the combination of FC and serum CRP did not perform better than FC alone.

More recently, the GETAID group have undertaken a meta-study that included 6 studies looking and FC, CRP and Crohn's disease activity, all with endoscopic evaluation. In patients in clinical remission (CDAI ≤150) (n = 355), the sensitivity of the combination of CRP ≤10 mg/L and calprotectin ≤200 μg/g for detecting a Crohn's Disease Endoscopic Index of Severity (CDEIS) ≤3 was 0.78, the specificity 0.58, the positive predictive value (PPV) ranged from 88% to 65% and negative predictive value (NPV) from 40% to 73%. However, these results were not compared with the performance of either biomarker alone, making interpretation of these results difficult.28 It does not appear that the addition of CRP to FC adds significantly to the utility of FC alone in reflecting the presence of endoscopically active Crohn's disease.

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METHODS

Search Strategy

An electronic search of the English language medical literature from January 1970 to September 2013 was conducted using MEDLINE (EBSCOhost) to identify articles on fecal biomarkers, IBD and Crohn's disease. FC, FL, and S100A12 were identified as key biomarkers for this review as they have been the most comprehensively studied in the literature. This search strategy used a combination of the following prespecified MeSH headings and keywords alone or in combination: feces, fecal, biomarkers, biological markers, inflammatory bowel disease, Crohn's disease, intestinal inflammation, postoperative, calprotectin, lactoferrin, and S100 proteins. Boolean operators (“not,” “and,” “or”) were also used in succession to narrow or widen the search. Three hundred seventy-eight articles were found and screened, of which 106 were excluded. Additional articles were identified through a manual review of the reference list of identified studies and review articles. Seven relevant abstracts were identified manually from recent conferences and were included (Fig. 1).

FIGURE 1
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Inclusion and Exclusion Criteria

Included studies (full papers and meeting abstracts) evaluated the utility of at least 1 of FC, FL, or S100A12 in screening for or assessing disease activity in human subjects with possible or established Crohn's disease. Studies containing only patients with ulcerative colitis were excluded as were case reports. Details of other excluded abstracts are given in Figure 1.

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Review Process and Data Abstraction

Title, abstract, and full article selection was performed independently by 2 reviewers (E.W., M.K.) with conflicts resolved by consensus adjudication.

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Outcomes

The primary outcome was to review the role of fecal biomarkers in the diagnosis and management of Crohn's disease, including postoperative recurrence.

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FECAL BIOMARKERS FOR THE DIAGNOSIS OF IBD

The assessment of patients with gastrointestinal symptoms, to determine whether the cause is likely to be organic or functional, often requires more than clinical assessment. Only a minority of patients with symptoms will have organic disease.29 Noninvasive testing may provide confidence that endoscopic investigations are not required for all patients. Fecal biomarkers may, therefore, be useful in determining which patients with gastrointestinal symptoms are likely to benefit from colonoscopy versus those in whom colonoscopy is likely to be normal.

FC, FL, and S100A12 have been shown to be significantly and consistently increased in both adult and pediatric patients with IBD versus non-IBD.30–42 Even when disease is in remission, FC concentrations in patients with IBD are higher than in healthy controls.4,43 FC has been studied the most extensively. Reported cutoff values for FC for distinguishing IBD from non-IBD in patients with gastrointestinal symptoms vary but a concentration of 50 μg/g is most commonly reported in the adult and pediatric literature.16 When 50 μg/g of stool is used as a cutoff, FC seems to be both sensitive and specific for this purpose with sensitivity, 0.78 to 1.00; specificity, 0.44 to 1.00; PPV, 28% to 100%; and NPV, 67% to 100%.37,39,40,42,44–51Table 2 summarizes the studies that have evaluated the role of FC, FL, and S100A12 in the diagnosis of IBD in patients with gastrointestinal symptoms.

TABLE 2
TABLE 2
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FC is sensitive for the detection of colonic and small bowel Crohn's disease in patients with gastrointestinal symptoms.27,30,33 Jensen et al27 studied 83 patients referred to a gastrointestinal clinic suspected of having Crohn's disease in a prospective study. FC was measured during diagnostic workup. Ileocolonoscopy and capsule endoscopy or surgery served as the gold standards for the presence and location of Crohn's disease. Concentrations of FC were similar in patients with small bowel or colonic Crohn's disease: median, 890 and 830 μg/g, respectively. With a 50 μg/g cutoff, Crohn's disease in the small intestine and colon was diagnosed with 0.92 and 0.94 sensitivities, respectively.27 Other studies have found a higher correlation between endoscopic activity of Crohn's disease and FC in ileocolonic than in colonic or ileal disease.6,22

Fecal biomarkers not only assist in selecting patients with gastrointestinal symptoms for whom colonoscopy may be of value but also have diagnostic utility after negative gastroscopy and colonoscopy when clinical suspicion of Crohn's disease persists. Measurement of FC before referral for small bowel capsule endoscopy seems to be useful for selecting patients with possible small bowel Crohn's disease. An FC >100 μg/g is good predictor of positive small bowel capsule endoscopy findings, whereas FC >200 μg/g was associated with a higher small bowel capsule endoscopy yield (65%) and confirmed Crohn's disease in 50% of cases.52

Although FC seems to be highly sensitive for the detection of IBD in patients with gastrointestinal symptoms, an elevated concentration has only modest specificity. Elevated FC can also be found in patients with colorectal carcinoma and adenomatous polyps.53,54 Age <10 or ≥60 years, obesity, nonsteroidal anti-inflammatory drug use, and physical inactivity may also be associated with increased FC.55,56 Results therefore need to be interpreted in a clinical context, although an elevated FC will usually mandate the need for endoscopic evaluation.

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FECAL BIOMARKERS IN RELATION TO ENDOSCOPICALLY ACTIVE DISEASE AND REMISSION

FC and FL are sensitive markers for detecting the presence of endoscopically identifiable intestinal inflammation in patients with IBD.4 They are more sensitive than CDAI or CRP.6,57 Crohn's disease endoscopic severity can be scored using the validated CDEIS or the Simple Endoscopic Index for Crohn's Disease (SES-CD).58,59 These 2 scores have a high degree of correlation with each other (Spearman's r = 0.938, P = 0.0001), but a lower degree of correlation with the CDAI (r = 0.473, P < 0.0001) and CRP (r = 0.525, P < 0.0001).60

Most recently D'Haens et al4 in a prospective study of 87 patients with Crohn's disease has shown that the FC concentration correlates significantly with Crohn's disease endoscopic scores. An FC of ≥250 μg/g indicated the presence of large ulcers with a sensitivity of 0.60, specificity of 0.80, PPV of 78.4%, and NPV of 62.0%. These results confirm previous findings of a correlation between FC and endoscopic inflammation with correlation coefficients for FC and CDEIS or SES-CD of 0.48 to 0.73.6,37,61

It is likely that fecal biomarker concentrations also correlate with the presence or degree of histological disease activity, although studies addressing this have been inconsistent.6,37,62–65 In a small group of 17 patients with Crohn's disease in clinical remission, where the median FC concentration was 175 μg/g (15–500 μg/g), most patients had normal ileocolonoscopy and histology.62 Sipponen et al6,63 found that the scored Crohn's disease histological severity correlated significantly with both FC and FL concentrations in ileocolonic and colonic Crohn's disease. The same findings have been demonstrated in a pediatric population.64 In contrast D'Inca et al37 did not find a significant correlation between FC concentration and histological score (r = 0.117, P = 0.545), although the FL concentration did correlate significantly (r = 0.477, P = 0.009). Similarly, Sipponen et al65 did not find a correlation between FC or FL and histological score in a small group of patients with Crohn's disease.

An optimal FC concentration to define remission in Crohn's disease is yet to be established although different concentrations have been suggested. Concentrations as high as 350 μg/g have been proposed as a cutoff for the presence of mucosal inflammation in patients with Crohn's disease.26 D'Haens et al4 found that concentrations ≤250 μg/g predicted endoscopic remission (CDEIS ≤3) with 0.94 of sensitivity, specificity of 0.62, PPV of 48.5%, and NPV of 96.6%. Sipponen et al6 in their prospective study of 77 patients with Crohn's disease found that a lower cutoff FC concentration of 200 μg/g had a sensitivity of 0.70, specificity 0.92, PPV 94.0%, and NPV 61.0% in predicting endoscopically active disease (CDEIS ≤3).

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FECAL BIOMARKERS TO MONITOR THE RESPONSE TO TREATMENT

The traditional goals of Crohn's disease therapy, to induce and maintain clinical remission, have not clearly changed the natural history of the disease.66 Emerging evidence suggests that achieving and maintaining endoscopic remission, that is, mucosal healing, is associated with sustained steroid-free clinical remission, and reduced rates of disease flares, complications, hospitalizations, and surgical resections.67–72 Mucosal healing is now regarded as a key “target” in disease management and an important endpoint in clinical trials.69,71,73–76 However, assessment of the mucosa with colonoscopy is expensive, resource intensive, carries some risk, and cannot be repeated frequently. This has led to the pursuit of noninvasive markers of mucosal disease activity.

Sipponen et al77 showed that both FC and FL are reliable surrogate markers of mucosal improvement in 19 patients with active Crohn's disease who were followed prospectively throughout their treatment with a range of oral medications including prednisolone, budesonide, mesalasine, and thiopurines. In this study, all 7 endoscopic responders, assessed using the SES-CD, achieved normalization of fecal biomarkers, whereas in 8 of the 9 endoscopic nonresponders posttreatment FC remained abnormal (132–15,330 μg/g) with 6 of the 9 having an abnormal FL (10.6–1259 μg/g).77 Lobaton et al22 have shown from prospective data collected from 115 patients with Crohn's disease that FC measured by both ELISA and quantitative point-of-care testing (QPOCT) can predict endoscopic remission (CDEIS <3). Cutoff values of 274 μg/g for ELISA and 272 μg/g for QPOCT presented an area under the curve of 0.935 and 0.933, respectively, reflecting both the accuracy of FC as a marker of endoscopic remission and the good relationship between the ELISA test and the QPOCT.22

In children, fecal S100A12 has been shown to fall significantly in patients entering clinical remission following treatment with exclusive enteral nutrition.17 In this study, remission was defined as a Pediatric Crohn's Disease Activity Index <15, although remission is now more commonly regarded as a Pediatric Crohn's Disease Activity Index ≤10. This index incorporates clinic and laboratory measures, but not endoscopic findings, in determining the final severity score.78 De Jong et al,17 in a study of 23 children with newly diagnosed IBD, demonstrated that an S100A12 cutoff of 10 μg/g was associated with a high sensitivity and specificity for remission of 0.96 and 0.92, respectively, in children with Crohn's disease.

The first pediatric study to demonstrate that fecal biomarker concentration reflected a successful clinical response to anti–tumor necrosis factor α (anti-TNF-α) treatment was published by Buderus et al.79 In this cohort of just 5 patients with severe Crohn's disease, a falling FL was associated with clinical response to infliximab therapy.79 In a larger pediatric population, of 36 patients with IBD followed prospectively, FC concentrations fell following anti-TNF-α therapy induction, normalizing (<100 μg/g) in one-third of patients by week 2.80 Sipponen et al65 showed in an adult population of 15 that, compared with their pretreatment concentrations, FC and FL after anti-TNF-α induction therapy were significantly lower. When measured at 12 weeks following anti-TNF-α induction therapy, FC and FL correlated with mucosal healing assessed endoscopically. Active mucosal disease (defined as CDEIS ≥3) was associated with an FC of ≥200 μg/g and FL of ≥10 μg/g with a sensitivity of 0.87 and 0.77, respectively, and a specificity of 1.0 for both FC and FL.65 Af Bjorkesten et al81 also demonstrated that FC concentration accurately reflects endoscopic remission in patients treated with anti-TNF-α. A cutoff value of 95 μg/g was associated with endoscopic remission (defined as SES-CD of 0–2) with a sensitivity of 0.84 and specificity of 0.74.81 In this study, CDAI, HBI, and CRP did not correlate with endoscopic remission.

Having identified the relationship between mucosal healing and fecal biomarkers in patients treated with anti-TNF-α, it has been postulated that fecal biomarkers can be used to identify patients likely to have a sustained clinical and/or endoscopic remission after commencing anti-TNF-α therapy. Molander et al82 found that FC of <100 μg/g after induction therapy with anti-TNF-α in 34 patients with active Crohn's disease predicted sustained clinical remission (defined as HBI <4) in most patients. These results conflict with the findings of Laharie et al83 who could not demonstrate a relationship between FC 14 weeks after commencing infliximab and clinical relapse defined as CDAI >150 in 65 patients with Crohn's disease. It is likely that these inconsistencies relate to the subjective nature of these clinical indices and their poor ability to correlate with mucosal disease.

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FECAL BIOMARKERS TO PREDICT DISEASE RELAPSE AND LONG-TERM OUTCOMES

There is some debate about the accuracy of fecal biomarkers in predicting subsequent clinical relapse. Some studies have shown that FC and FL can predict clinical relapse with modest accuracy in adults and pediatric patients with both Crohn's disease and ulcerative colitis.84–89 In a prospective multicentre study, the role of FC and FL in predicting relapse was examined by Gisbert et al86 in 74 patients with ulcerative colitis and 89 patients with Crohn's disease who had been in clinical remission for 6 months. Following baseline FC and FL measurement, follow-up continued until clinical relapse, defined as Truelove modified index >11 points in UC90 and CDAI >150 points in Crohn's disease, or until 12 months. Twenty-six patients (16%) relapsed during the 12-month follow-up period. FC and FL concentrations at baseline were higher in relapsing versus nonrelapsing patients. FC of >150 μg/g had a sensitivity and specificity of approximately 0.70 to predict relapse in IBD. FL performed similarly.

Louis et al,91 in their analysis from the prospective STORI study of 115 patients with Crohn's disease, found that increased FC concentrations were associated with an increased risk of clinical relapse after infliximab discontinuation in patients with Crohn's disease in remission on combination thiopurine maintenance therapy. A FC concentration of ≥300 μg/g at study inclusion was independently associated with a shorter time to relapse (hazard ratio, 2.5; 95% CI, 1.1–5.8; P = 0.04).91 A sudden and pronounced increase in CRP and FC concentration was observed during the 4 months preceding clinical relapse (P < 0.0001 and P = 0.0004, respectively) with a median value before relapse of 8 mg/L for CRP and 534 μg/g for FC. Using receiver operating characteristic curve analysis, optimal sensitivity and specificity for predicting relapse were 0.71 and 0.66 for CRP (cutoff 6.1 mg/L) and 0.70 and 0.74, respectively, for FC (cutoff, 305 μg/g).92

Other studies have provided good sensitivity but low specificity for predicting clinical relapse in Crohn's disease. Costa et al93 studied 38 patients in clinical remission. A baseline FC >150 μg/g had a sensitivity of 0.87 for predicting relapse within the next year, but a specificity of just 0.43.

A major limitation of many studies is the use of the CDAI to define Crohn's disease relapse. The CDAI is a subjective clinical tool that correlates poorly with endoscopic findings, FC and FL concentrations.5 A meta-analysis by Mao et al94 attempted to clarify the use of FC in this setting. In this analysis, 672 patients with IBD, including 353 patients with Crohn's disease from 6 different studies, were included. The pooled sensitivity and specificity of FC to predict clinical relapse or quiescent IBD was 0.78 (95% CI, 0.72–0.83) and 0.73 (95% CI, 0.68–0.77), respectively, with an area under the curve of 0.83.94

In summary, the FC concentration seems to be a moderately sensitive marker of future short-term clinical relapse risk in Crohn's disease. Whether fecal biomarkers have value in predicting the more definitive risk of endoscopic disease recurrence remains to be determined.

Fecal biomarkers may play some role in identifying patients who are at high risk for a complicated disease course.95 Kennedy et al,95 drawing from a large data set from the Edinburgh Fecal Calprotectin Registry, were able to identify 801 patients with Crohn's disease with at least 1 FC result. They aimed to determine whether a single FC measurement in patients with established Crohn's disease could predict disease progression. The primary endpoint was a composite of progression in luminal behavior, from nonstricturing and nonpenetrating disease to stricturing and/or penetrating disease, hospitalization for a flare, or surgical resection. A total of 211patients reached the primary endpoint of disease progression, hospitalization, or intestinal surgery. The median earliest FC was significantly higher in the group that reached the primary endpoint at 595 μg/g (IQR, 210–1246) versus 320 μg/g (80–992) in those that did not (P < 0.0001). Survival analysis revealed significant differences in time to progression, hospitalization, or surgery with FC ≥200 μg/g (P < 0.0001).95

These cohort data demonstrate for the first time that FC concentrations bear some relationship, in group data, to the long-term outcome in Crohn's disease, although such measurements lack the sensitivity and specificity to be useful on an individual basis.

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FECAL BIOMARKERS IN THE POSTOPERATIVE SETTING

Eighty percent of patients with Crohn's disease will require bowel surgery at some time in their life and, of these, up to 70% will require a second operation.96 Postoperative disease recurrence can be identified endoscopically at the anastomosis and neo-terminal ileum in many patients within weeks of resection, 80% of patients at 1 year, and 90% at 3 years.97,98 Endoscopic recurrence precedes the development of clinical recurrence, which occurs in 30% by 1 year.99 Symptom recurrence is a poor guide to true disease recurrence. CDAI and the HBI are largely subjective and correlate poorly with endoscopic findings.5 Furthermore, these indices were not developed for use after intestinal resection and have not been validated in this setting. Endoscopic assessment has therefore become the gold standard for assessment of the surgical anastomosis and the evaluation of recurrent disease. The timing of endoscopy following resection and optimal medical management after diagnosis of recurrent disease are likely to be key aspects to the prevention of recurrent disease.

Early endoscopic assessment at 6 months postoperatively has been suggested as a possible strategy to identify patients with endoscopic recurrence so that medical therapy may be optimized.98 Results from the Post-Operative Crohn's Endoscopic Recurrence study have demonstrated that treating immediately after surgery according to the clinical risk of recurrence, with colonoscopy performed 6 months after resection and treatment step-up for recurrence, is significantly superior to optimal drug therapy alone, in preventing postoperative recurrence of Crohn's disease.100 However, colonoscopy is expensive, resource intensive, carries a risk, and cannot be performed frequently. There is a need for noninvasive and safe measures to identify disease recurrence after surgery.101 As yet, no simple diagnostic test has been shown in a large prospective population to reliably reflect the presence of recurrent intestinal inflammation or to predict the recurrence of Crohn's disease postoperatively.

The early detection and assessment of asymptomatic mucosal recurrence may allow timely and appropriate treatment after resection. To date, only small studies have evaluated the role of fecal biomarkers (FC and FL) postoperatively and few have made routine comparison with endoscopy. S100A12 has not been evaluated in the postoperative setting.

Orlando et al,102 in a study of 39 patients, evaluated whether FC or abdominal ultrasound performed 3 months after intestinal resection could predict endoscopic recurrence (defined as Rutgeert's score ≥i2) at 1 year. An FC of >200 mg/L was found to be more sensitive (63% versus 23%) but less specific (0.75 versus 0.90) than ultrasound in predicting endoscopic recurrence. Scarpa et al,103 in a retrospective study of 63 patients, examined FC and FL concentrations and their correlation to CRP and CDAI at an average of 40.5 months after surgery. FL correlated strongly with CRP but neither FC nor FL correlated with CDAI. Endoscopic assessment was not performed. Lamb et al104 showed that FC and FL fell to normal concentrations within 2 months of surgery in a small cohort of 13 patients followed longitudinally. In the retrospective cross-sectional component of this study, single FC and FL measurements from 104 patients correlated with symptomatic recurrence (when measured by the HBI) but not endoscopic recurrence. However, endoscopy was performed in less than half the study patients and the timing of endoscopy after surgery was variable.104

Sorrentino et al105 monitored postoperative FC longitudinally in 25 patients identifying for the first time that FC reflects the success of postoperative medical therapy in preventing endoscopic recurrence. In this study, FC progressively decreased in patients without recurrence and in those responding to infliximab while remaining high throughout the duration of the study in nonresponders. Patients who maintained complete endoscopic remission on infliximab showed a faster reduction in FC than nonrelapsing patients, although the rates of decrease were not significantly different between these 2 groups (P = 0.2). In contrast, patients who did not respond favorably to medical treatment had an upward trend in FC, which was statistically different from that in nonrelapsing patients (P = 0.002 and P = 0.004, respectively) after 54 weeks of therapy.105

Lasson et al106 followed 30 patients for 1 year after ileocecal resection. The FC concentration was determined monthly and ileocolonoscopy performed at 1 year, with disease recurrence defined as a Rutgeert's score of ≥i2. At 1 year, 13 (43%) patients had endoscopic recurrence. The median FC concentration did not differ significantly between the patients in endoscopic remission and those with endoscopic recurrence 1 year after ileocecal resection: 189 μg/g (range, 50–2304) versus 227 μg/g (43–3168) respectively (P = 0.25).106 In contrast, Primas et al107 found that FC collected postoperatively could serve as a predictive parameter for endoscopic recurrence of Crohn's disease. In this study of 57 patients followed for 18 months after ileocecal resection, patients underwent FC testing every 3 months and ileocolonoscopy at 6 to 18 months postoperatively. FC measured a median of 6 months after surgery was compared with ileocolonoscopy performed 11 months after surgery. The sensitivity, specificity, PPV, and NPV of increased FC for endoscopic recurrence were 0.93, 0.47, 61.0%, and 80.0%, respectively. There was a significant association between increased FC and endoscopic recurrence (chi-square test, P = 0.001).107

Yamamoto et al108 have shown the accuracy of FC and FL in evaluating asymptomatic patients with Crohn's disease in the postoperative setting. In this prospective study, 20 patients in clinical remission (CDAI <150) between 6 and 12 months following ileocolic resection underwent FC and FL testing and ileocolonoscopy. Both FC and FL correlated with the endoscopic scores. Patients were followed for a further 12 months for clinical recurrence (CDAI >150 with an increase of ≥70 points). Both FC and FL concentrations were significantly higher in patients with clinical recurrence than those in remission. A cutoff value of 170 μg/g for FC had a sensitivity of 0.83 and a specificity of 0.93 to predict clinical recurrence, whereas a cutoff value of 140 μg/g for FC had a sensitivity of 0.67 and a specificity of 0.71.108 This was the first study to demonstrate the role of fecal biomarker testing in asymptomatic patients with Crohn's disease in the postoperative setting. Lobaton et al,22 in a group of 29 patients undergoing ileocolonoscopy following ileocecal resection, have shown similar results using a QPOCT for FC. In this study, the median FC concentration was significantly lower in those in remission (i0, i1) than those with recurrent disease (i2–i4) (98 versus 234.5 μg/g, P = 0.012). In this study, the accuracy of the QPOCT in predicting postoperative recurrence presented an area under the curve of 71.53 with a cutoff of 283 μg/g having a sensitivity of 0.67 and specificity of 0.72. FC measured by ELISA performed similarly. CDAI or any other biomarkers were found by Lobaton et al22 to be able to discriminate between endoscopic remission and recurrence in this population.

If FC and FL show consistent correlation with endoscopic inflammation in the postoperative setting, fecal biomarker testing may have a role in the algorithm for routine postoperative care and surveillance. Fecal testing offers simplicity, safety, and cost benefits over routine colonoscopy in the postoperative setting. Health economic studies are required to demonstrate this.

Evidence is emerging of such a role for fecal biomarkers as substitutes for endoscopy to monitor for, and predict, disease recurrence.105,107–109 Prospective evaluation of fecal biomarkers in large postoperative populations with longitudinal data and early endoscopic correlation performed at specific time points is required to determine properly the role of these tests in the postoperative setting.

A subanalysis from the Post-Operative Crohn's Endoscopic Recurrence study examined the relationships between FC, endoscopic Crohn's disease recurrence, CRP, and CDAI in 318 samples collected longitudinally from 136 patients.110 FC at 6 months was lower in those with endoscopic remission compared with those with endoscopic recurrence (330 μg/g versus 75 μg/g, P < 0.001). FC correlated with endoscopic recurrence (Spearman's rank correlation coefficient of r = 0.42, P < 0.001) and scored endoscopic severity (Spearman's rank correlation coefficient r = 0.44, P < 0.001). CRP and CDAI did not correlate with either endoscopic recurrence or scored endoscopic severity. In the endoscopic validation analysis, FC measurement was sufficiently sensitive in the postoperative setting after resection of all macroscopic disease to monitor for Crohn's disease recurrence. A cutoff of 100 μg/g was able to identify patients with endoscopic recurrence with a sensitivity of 0.90, specificity of 0.57, PPV of 52.0%, and NPV of 91.0%.110 These results confirm the accuracy, utility, and superiority of FC over CRP and CDAI as a screening test for endoscopic recurrence of Crohn's disease in the postoperative population. These data suggest that FC may be able to replace colonoscopy as the measure used to monitor Crohn's disease postoperatively, with colonoscopy reserved for those with an elevated FC.

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CONCLUSIONS

Fecal biomarkers do not replace the gold standard of endoscopic and histologic evaluation but can play a role from diagnosis to postoperative management in Crohn's disease. They have sufficient discriminating value to assist in differentiating both adult and pediatric patients with gastrointestinal symptoms into those who may have an inflammatory condition versus those with a functional disorder. In established Crohn's disease, fecal biomarkers reflect the presence of active disease and correlate with the severity of endoscopic lesions. FC has been the most extensively studied biomarker in patients on therapy for Crohn's disease, and in this context reflects the response to therapy and the achievement of mucosal healing. Increasing FC concentrations after withdrawal of therapy seem to correlate with the risk of clinical relapse. A single FC value may provide evidence for long-term disease behavior and complication risk and may assist in selecting patients who would benefit from early aggressive immunosuppression.

Endoscopy is currently the best method for early diagnosis of postoperative recurrence, but it has limitations. Measuring FC is safe, simple, and noninvasive and may be sufficiently sensitive to monitor for Crohn's disease recurrence in the postoperative setting. The superior sensitivity and NPV when compared with the specificity and PPV of FC in the postoperative setting reflects its utility as a screening test. Monitoring FC postoperatively may identify patients who are not responding to postoperative prophylactic medical treatment or identify patients with early disease recurrence, assisting in identifying patients requiring colonoscopic assessment, and/or treatment escalation.

We recommend the use of fecal biomarkers in the diagnosis and management of Crohn's disease. An FC of >50 μg/g in a patient with gastrointestinal symptoms should prompt endoscopic assessment. In established Crohn's disease, FC should be performed at diagnosis (when there is active luminal disease) for reference and then when endoscopic remission is achieved. FC measurement could then be performed regularly with endoscopic or other confirmation of disease relapse in the event of a rise in concentration. Postoperatively we recommend FC measurement be performed regularly from the time of surgery, with endoscopic assessment indicated for those with a concentration >100 μg/g to investigate for disease recurrence. FC varies with different degrees of endoscopic inflammation; the greatest value of fecal biomarker measurement is in the discrimination between normal and inflamed.

Inexpensive, noninvasive, and reproducible, fecal biomarkers seem to have a wide utility in the diagnosis and monitoring of Crohn's disease. Further studies are required to accurately describe cutoffs in a variety of clinical settings and to establish firm targets as Crohn's disease management moves toward a treat-to-target approach, with increased monitoring and tighter control of inflammation.

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Keywords:

Crohn's disease; inflammatory bowel disease; stool tests; fecal biomarkers; calprotectin; lactoferrin; S100A12; postoperative

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