Title: Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study

Transcription

1 Author's response to reviews Title: Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: an observational study Authors: Michael Manz Emanuel Burri Claude Rothen Nuschin Tchanguizi Christian Niederberger Livio Rossi Christoph Beglinger Frank Serge Lehmann Version: 3 Date: 21 December 2011 Author's response to reviews: see over

2 Jigisha Patei, MRCP, PhD BMC Gastroenterolgy BioMed Central Ltd Floor 6, 236 Gray's Inn Road London, WC1X 8HB United Kingdom Prof. Dr. med. Christoph Beglinger Petersgraben 4, CH-4031 Basel Fax , Phone Basel, 18 December 2011 BMC Gastroenterology : Value of fecal calprotectin in the evaluation of patients with abdominal discomfort: An observational study Dear Professor Patei Thank you very much for the positive evaluation of our manuscript. Please find enclosed the revised version. We incorporated the excellent and helpful comments made by the editors and reviewers, which helped to further strengthen our manuscript. Please find a detailed point-by-point list of all changes made to the manuscript keyed to the reviewer comments below. Comments from reviewer 1 (Methods, Endpoint) The definition of this endpoint was based on the assumption, that the finding would justify an endoscopic assessment. The definition of a clinically significant organic finding in the GI tract should be addressed in details here with basis/ evidence for classification of significant/ minor/ normal findings under endoscopy. As suggested by the reviewer, we have modified the wording in the method section to clarify the definition of our primary endpoint (page 6, lines 18ff). In the evaluation of patients with abdominal complaints, separating organic bowel disease, e.g. inflammatory bowel disease or peptic ulcer, from functional gastrointestinal disorders is crucial. A number of studies have addressed this issue (Gisbert JP, McNicholl AG: Questions and answers on the role of faecal calprotectin as a biological marker in inflammatory bowel disease. Dig Liver Dis 2009, 41(1):56-66). There is convincing data that fecal calprotectin reliably detects mucosal inflammation, which is usually associated with organic findings of the intestinal tract. In functional GI disorders, fecal calprotectin is not elevated. We therefore defined our endpoint accordingly. 1/5

3 (Discussion, the 8th paragraph) Here, the authors attempted to address why RE LA-A was excluded from clinically significant findings. In table 2, patients with LA-A (n=25) have a lower median calprotectin level (17). Classifying this group of patients into no clinically significant findings will increase the specificity of results. There is no strong evidence to exclude it from clinically significant findings. As suggested by the reviewer, we have reclassified esophagitis LA grade A as clinically significant finding and recalculated the diagnostic accuracy of fecal calprotectin (page 10, lines 11ff, Table 2, Table 3, Figure 2, Figure 3). We agree that there is no strong evidence to do otherwise. Reasons to explain the lower diagnostic accuracy of fecal calprotectin to detect reflux LA grade A are discussed in the manuscript (page 16, lines 9ff). (Conclusion) Our study demonstrated that fecal calprotectin is a useful noninvasive marker to identify patients with clinically significant findings throughout the gastrointestinal tract irrespective of age. Conclusion should not be applied to throughout the GI tract for only a small number of patients in your study has been evaluated the lesions in the small intestine. As suggested by the reviewer, we have changed the wording in the Conclusion section. It states now that fecal calprotectin is a useful marker not only for colonic lesions but also for mucosal lesions in the upper intestinal tract. We agree, that the small number of patients that received capsule endoscopy does not allow to extrapolate the diagnostic performance of fecal calprotectin throughout the gut (page 19, lines 3ff). We thank the reviewer for helping us to clarify that point. (Results, Diagnostic value of calprotectin in patients with negative initial endoscopy, 1st sentence) One hundred and thirty-six patients (25%) were investigated with both EGD and colonoscopy; in 106 patients (78%) after no clinically significant findings had been identified during the initial investigation. The sentence is confusing. Please rewrite. As suggested by the reviewer, we have changed the first paragraph of this subsection. We now give a detailed description of the study population and the number of endoscopies performed in each of the different subgroups. This paragraph states an important message that the diagnostic yield can be increased with the use of fecal calprotectin in patients with a negative initial endoscopy (done according to clinical judgment (page 12, lines 8ff). (Discussion, 1st paragraph, last sentence) calprotectin levels indicated disease severity in patients with peptic lesions of the stomach. In this study, the level of fecal calprotectin was found to be higher in gastric cancer than ulcers and erosions. Gastric cancer does not belong to peptic lesions; therefore this conclusion is not justified. Thank you for that important comment. As suggested, we have eliminated the word peptic when talking about the value of fecal calprotectin to indicate 2 / 5

4 disease severity in gastric lesions. Instead, we simply state mucosal lesion instead of peptic lesions (page 11, line 16). (Discussion, 10th paragraph, 1st sentence) All together, those results support the concept that...and that a biomarker guided strategy might be superior to a strategy using clinical decision, including guidelines of appropriateness, to decide on endoscopy. From the present study, the authors could not say superior to, but might be adding additional value. As suggested by the reviewer, we have changed the paragraph accordingly and state now that the use of fecal calprotectin might have additional value in the diagnostic approach to a patient with abdominal complaints (page 17, line 12). (Discussion, 11th paragraph) Fourth...in expectorations of patients with in acute and chronic pulmonary disease. Please consider to delete in before acute... We have changed the sentence accordingly and have deleted in before acute... (page 18, line 3). (Discussion, 3rd paragraph, last sentence) Applying these guidelines...but the selection criteria suffered from low sensitivity. It would be better to add, before but. We have changed the sentence accordingly and have added a comma to the sentence (page 14, line 14). Comments from reviewer 2 Authors mentioned 136 patients had both EGD and colonoscopy, among them, 106 patients had negative initial endoscopy evaluation. What was the indication for repeat evaluation in 53 patients? What was the initial calprotectin level of these specific group of 106 patients? See also answer to reviewer 1: we have reclassified esophagitis LA grade A as clinically significant finding and have recalculated the data. 136 patients had both EGD and colonoscopy: In 38 patients both procedures were done on the same day for clinical reasons and in 98 patients, follow-up endoscopies (EGD for patients who had colonoscopy first and colonoscopy for patients who had EGD first) were done after no clinically significant findings had been identified during the initial investigation. Follow-up investigations (51 EGDs and 47 colonoscopies) resulted in 44 additional findings, including 2 colorectal carcinomas, 6 colorectal adenomas, 1 crohn s disease, 1 ulcerative colitis, and 5 peptic ulcers (page 12, lines 8ff). 3 / 5

5 Was there a change in the calprotectin level between the initial and follow up endoscopy? What is the time gap between the two endoscopy evaluations? The median time between the initial endoscopy and follow-up endoscopies was 11 days (standard error of mean 3.5). The study protocol allowed a maximum time interval between the two investigations of 3 months. We have added this information to the results section (page 12, line 13). We did not perform repeated measurement of fecal calprotectin. For analysis, a single stool sample was obtained before the initial endoscopy and the decision to perform follow-up endoscopy in case of negative findings was based solely on results of the initial fecal sample. Can the authors speculate what will be an appropriate evaluation option, EGD vs colonoscopy or both for a patient with abdominal discomfort based on an elevated fecal calprotectin level? The evaluation of patients with abdominal complaints is difficult. Fecal calprotectin might be a valuable tool in the diagnostic work-up of these patients. Used as a screening test, it would useful to identify those patients in need of urgent endoscopy. In younger patients (<50 years) with normal calprotectin values, especially in absence of red flags, endoscopy would no be necessary. If endoscopy were recommended, the decision to perform either EGD first or colonoscopy first would have to be based on clinical judgment. Followup endoscopy would be recommended for all those patients with negative findings on the initial investigation. In patients with abdominal complaints that were also scheduled for screening colonoscopy, endoscopy would be recommended irrespective of the clinical presentation (page 13, lines 17ff). Is there any data on the level of fecal calprotectin post treatment for these significant GI diseases e.g. esophagitis, gastritis, ulcers, etc in the follow up? Can fecal calprotectin level be used to monitor the disease activity in the non-ibd patients? We did not perform repeated measurement of fecal calprotectin and our study results therefore do not allow to answer this extremely interesting question. However, our data indicate that fecal calprotectin might increase with disease severity/ activity. In patients with normal findings on gastroscopy, calprotectin levels were lower that in patients with wither erosive gastritis, gastric ulcers or gastric cancer. Based on our experience, the degree of mucosal inflammation/ damage correlates with calprotectin levels not only in IBD but also in non-ibd patients. It could therefore be speculated that for example in peptic ulcer disease, normalization of fecal calprotectin after PPI treatment would indicate healing of the gastric mucosa. However, this has not yet been systematically studied and our data does not allow drawing any conclusions. 4 / 5

6 Given the important clinical implications of our findings, we consider them of particular interest to the readers of BMC Gastroenterology. Yours sincerely, Emanuel Burri, MD Corresponding author 5 / 5