Reply to: Immune Activation in Irritable Bowel Syndrome: Wrong Title or Wrong Disease? Part 2

April 2003

CORRESPONDENCE

hypoventilation too easily: despite the best efforts of endoscopy nurses and technicians, patients can and do become deeply sedated, especially during prolonged procedures. The possibility that emergency airway management will be needed when using a potent hypnotic agent such as propofol–for which there is no antagonist –is a legitimate concern. The assertion by Clarke et al. that airway obstruction is a concern is a point well made: it serves to highlight the need for caution when using propofol. Bag-and-mask ventilation is a skill mastered by most endoscopy personnel, but how competent are most gastroenterologists and endoscopy nurses at performing endotracheal intubation should this prove necessary? If, as is suggested, nonanesthesiologists are to use propofol during endoscopy, advanced training in airway management will be mandatory for these personnel. The routine use of propofol for endoscopic sedation certainly has attractions, but further controlled studies assessing propofol with or without benzodiazepines and narcotics are needed before we change current practice. We were interested in the authors’ neologism, “sedationist”: the jury is definitely “out” on whether this is a term that should become part of the endoscopist’s vocabulary. To us, “The Sedationist” sounds like an action movie starring Arnold Schwarzenegger. MICHAEL F. BYRNE JOHN BAILLIE Division of Gastroenterology Duke University Medical Center Durham, North Carolina 1. Byrne MF, Baillie J. Propofol for conscious sedation? Gastroenterology 2002;123:373–375. 2. Clarke AC, Chiragakis L, Hillman LC, Kaye GL. Sedation for endoscopy: the safe use of propofol by general practitioner sedationists. Med J Aust 2002;176:158 –161. 3. Godsiff L, Magee L, Park GR. Propofol versus propofol with midazolam for laryngeal mask insertion. Eur J Anaesthesiol Suppl 1995;12:35– 40. doi:10.1053/gast.2003.50194

Immune Activation in Irritable Bowel Syndrome: Wrong Title or Wrong Disease? Part 2 Dear Sir: Chadwick et al.,1 in a very interesting paper entitled “Activation of the mucosal immune system in irritable bowel syndrome” published in the June 2002 issue of GASTROENTEROLOGY, described increased number of activated immunocompetent cells in the colonic mucosa of patients meeting the Rome criteria for clinical diagnosis of IBS. As reported by the authors, “microscopic inflammation sufficient to describe as microscopic colitis was reported by our pathologists in 50% of samples.” We recognize that microscopic colitis may still be a confounding issue of uncertain significance,2 but we believe that these patients with histological abnormalities diagnostic of microscopic colitis should not be classified as IBS. According to the authors, the message from the paper would be maintained; we are very happy of this, although it is difficult to separate both populations in the report. As discussed, in the editorial by Collins,3 this paper is important to support the immunological basis for IBS, but I believe that for research purposes (where clear identification of patient subgroups is a key target), as well as for clinical purposes (are steroids

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used for treatment of lBS patients?) patients with microscopic colitis should not be called IBS. We had similar comments4 regarding another paper published recently in GASTROENTEROLOGY5 where celiac disease markers were found in patients with diarrhea of unknown origin. Diagnostic criteria for IBS are applicable “in the absence of structural or metabolic abnormalities to explain the symptoms.”6 Patients suspected of IBS where the investigation identifies lesions diagnostic of microscopic colitis, celiac diseases, as well as other conditions such as IBD for example, are not IBS patients anymore. Although they could indeed suffer concomitantly from functional, as well as lesional disorders. PIERRE POITRAS Hoˆpital Saint-Luc du CHUM Montre´al, Canada 1. Chadwick VS, Chen W, Chu D, Paulus B, Bethwaite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. 2. Blumberg D, Wald A. Other diseases of the colon and rectum. In: Feldman M, Friedman LS, Sleisenger MH, eds. Sleisenger and Fordtran’s Gastrointestinal and liver diseases. Philadelphia, PA: Saunders, 2002:2294 –2318. 3. Collins SM. A case for immunological basis for irritable bowel syndrome. Gastroenterology 2002;122:2078 –2079. 4. Poitras P. Celiac disease-like abnormalities in IBS: wrong title or wrong disease? (letter) Gastroenterology 2002;123:954. 5. Wahnschaffe U, Ullrich R, Riecken EO, Schulzke JD. Celiac disease-like abnormalities in a subgroup of patients with irritable bowel syndrome. Gastroenterology 2001;121:1329 –1338. 6. Thompson WG, Longstreth G, Drossman DA, Heaton K, Irvine EJ, Muller-Lissner S. Functional bowel disorders and functional abdominal pain. In: Drossman DA, et al., eds. Rome II. The functional gastrointestinal disorders, 2nd ed. McLean, Virginia: Degnon Associates, 2000:351– 432. doi:10.1053/gast.2003.50195

Reply. In his response to our paper entitled “Activation of the mucosal immune system in irritable bowel syndrome” in the June 2002 issue of GASTROENTEROLOGY,1 Dr. Poitras argues that patients with symptoms meeting the Rome Criteria for IBS, who are subsequently shown to have microscopic histologic abnormalities in colonoscopic biopsies should not be classified as IBS. He wishes us to draw a clear line between what he calls “functional” and “lesional” disorders. For patients with normal endoscopic appearances, but biopsies that show granulomatous, eosinophilic, collagenous, or lymphocytic microscopic colitis, reclassification is obviously appropriate. Patients with nonspecific microscopic colitis could also be reclassified, although they are indistinguishable in terms of demographics, symptoms, and disease duration from patients whose biopsies show no obvious inflammatory changes. Poitras is happy to accept that this last group (those with normal conventional histology) have IBS, but in doing so he ignores or fails to address the immunohistologic abnormalities in this group, which include increased IELs, lamina propria CD3⫹ and CD25⫹ cells as detailed in the paper. Does Poitras regard histologic abnormalities as “lesional” and immunohistologic abnormalities as “nonlesional” or “functional”? If immunohistologic abnormalities are “lesional” and IBS patients cannot have lesions, then few if any of the patients in our study group meet the Poitras’ criteria for IBS. IBS then becomes a very rare, rather than a very common disorder. Furthermore, we are left without a

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suitable diagnostic category for the majority of patients with symptoms meeting the Rome criteria. While we are sympathetic to Poitras’ call for accurate patient subgroup classification for research purposes, his “wrong title or wrong disease” descriptor for our paper does not really advance this issue. VINTON S. CHADWICK WANGXUE CHEN DAIRU SHU BARBARA PAULUS IAN WILSON Wakefield Gastroenterology Centre and Research Institute Gastroenterology/Research Wellington, New Zealand PETER BETHWAITE ANDY TIE Medical Laboratory Wellington Wellington, New Zealand 1. Chadwick VS, Chen W, Chu D, Paulus B, Bethwaoite P, Tie A, Wilson I. Activation of the mucosal immune system in irritable bowel syndrome. Gastroenterology 2002;122:1778 –1783. doi:10.1053/gast.2003.50196

Role of Fecal Calprotectin Test in the Work-up of IBS Patients Dear Sir: We read with great interest the article from Tibble et al.,1 in the August 2002 issue of GASTROENTEROLOGY. Based on the sensitivity (Se) and specificity (Sp) of the calprotectin test to differentiate organic gastrointestinal disease from IBS, the authors propose the use of this test in combination with Rome I criteria to “screen” tertiary referred IBS patients for further work-up. There are a number of methodological issues in the study that we believe are worth further analysis. First, the use of an inadequate criterion standard (“gold standard”).2 In the study from Tibble et al., the criterion standard varies from individual to individual, since patients were seen by 4 different gastroenterologists and the tests performed in each individual was determined by each investigating clinician’s choice. This may have significantly influenced the final diagnosis in each individual and impacts negatively on the internal validity of the study. Second, the inclusion of a narrow spectrum of patients.2 Thus, patients with diseases outside the gastrointestinal tract were excluded from the study. This may lead to a biased estimate of the performance characteristics of the test and hence, limits the external validity of the results. Third, the authors describe the performance characteristics of the different tests using Se, Sp, positive, and negative predictive values. The use of predictive values can be misleading since they depend on the prevalence of the disease in the population in whom the test is performed.3 On the other hand, likelihood ratios (LR), which depend only on the operating characteristics of the test, are thought to be more appropriate and allow assessment of the usefulness of the test in all possible scenarios.4 Thus, using the Se and Sp reported in the article, we calculated the LRs for each test under different scenarios, and reached conclusions that differed from those in Tibble’s article. For example, in the tertiary referral population in this study (pretest probability of or-

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ganic disease ⫽ 44%), the posttest probability of organic disease based solely on absence of Rome I criteria is 79% (positive LR ⫽ 4.7). This is similar to the posttest probability of organic disease based solely on a positive calprotectin test, 77% (positive LR ⫽ 4.2). The combination of the absence of Rome I criteria plus a positive C-reactive protein test (positive LR ⫽ 2.1) yields a posttest probability of organic disease of 91%. This probability of organic disease, with a much simpler blood screening test that is universally applicable, is high enough to make it reasonable to perform further investigation regardless of the results of fecal calprotectin. This information limits the usefulness of the calprotectin test to “rule in” organic disease in a tertiary care practice. On the other hand, if Rome criteria are present (negative LR ⫽ 0.27), the posttest probability of organic disease is 21%, and the addition of a negative calprotectin test (negative LR ⫽ 0.11) decreases that probability to 4% compared with the 14% in case of a negative C-reactive protein test (negative LR ⫽ 0.6). Thus, it appears that in the presence of Rome I criteria for IBS, fecal calprotectin might be useful to “rule out” organic disease. It would have been of interest to include in the analysis the combination of presence/absence of “red flags” or alarm symptoms and Rome I criteria, since these are of critical value to discriminate organic from nonorganic patients with GI complaints on formal analysis5 and are used extensively in clinical practice. Thus, it is important to know whether adding absence of “red flags” to the presence of Rome criteria for IBS would decrease the value of fecal calprotectin test to “rule out” organic disease. Finally, Tibble et al. state that the use of calprotectin test in a primary care population should be deferred until the test is validated in such population. We beg to disagree with the authors in this respect. The Se and Sp of a diagnostic test do not change from population to population, as the authors claim, provided that the assay or the cut-off values are not changed, and the performance characteristics of the test have been adequately assessed.2 The potential for bias in the assessment of the Se and Sp of the calprotectin test in the study by Tibble et al., as well as the lack of consideration of “red flags” associated to Rome I criteria as part of their analysis raise some questions about the potential role of fecal calprotectin in the work-up of IBS patients. SILVIA DELGADO-AROS FILIPPO CREMONINI Mayo Clinic Clinical Enteric Neuroscience, Translational & Epidemiological Research Program (C.E.N.T.E.R.) Rochester, Minnesota 1. Tibble JA, Sigthorsson G, Foster R, Forgacs I, Bjarnason I. Use of surrogate markers of inflammation and Rome criteria to distinguish organic from nonorganic intestinal disease. Gastroenterology 2002;123:450 – 460. 2. Ransohoff DF, Feinstein AR. Problems of spectrum and bias in evaluating the efficacy of diagnostic tests. N Engl J Med 1978; 299:926 –930. 3. Weissler AM. A perspective on standardizing the predictive power of noninvasive cardiovascular tests by likelihood ratio computation: 1. Mathematical principles. Mayo Clin Proc 1999;74:1061– 1071. 4. Jaeschke R, Guyatt GH, Sackett DL. Users’ guides to the medical literature. III. How to use an article about a diagnostic test. B. What are the results and will they help me in caring for my