Helicobacter eradication versus prompt endoscopy for dyspepsia

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cially for the health food industry. The term synbiotics refers to preparations with both prebiotic and probiotic contents. Despite much observational data, few mechanistic studies have been performed with no direct comparisons of different probiotic and prebiotic strategies in inflammatory bowel disease. Several studies using animal models of inflammatory bowel disease have yielded encouraging results but have shown that a single probiotic may not be ideally suited to all patients. Probiotic cocktails may have wider indications, but the properties of the individual components need rigorous scientific study before they can be recommended for routine use. In addition, the question of possible antagonism among different bacterial components has not been resolved. Evidence for therapeutic efficacy of probiotics in humans with inflammatory bowel disease has been generated mainly in patients with pouchitis (Gastroenterology 2000;119:305–309) and ulcerative colitis (reviewed in an earlier selected summary, Gastroenterology 2000;118:630 – 635). Controlled trials in Crohn’s disease are under way in Europe. However, there are many unanswered questions including optimal dosage, frequency of administration, delivery vehicle, choice of organism, combinations of organism, and relationship to diet and conventional drug therapy. Before these questions have even been addressed, and reflective of the pace of research in inflammatory bowel disease today, the present report by Steidler et al. pushes the boundaries of probiotic research a leap further and blends probiotic therapy with cytokine therapy. The most successful form of cytokine therapy for inflammatory bowel disease to date has been the use of monoclonals against tumor necrosis factor ␣ in Crohn’s disease (N Engl J Med 1997;337:1029 – 1035, N Engl J Med 1999;340:1398 –1405). In contrast to antibodymediated blockade of cytokines, parenteral administration of counterregulatory or anti-inflammatory cytokines, such as IL-10, carries the disadvantage of rapid clearance, limited bioavailability, and a requirement for frequent administration. Gene therapy may circumvent these problems by delivering cytokines to the intestinal mucosa (Gut 1998;42:460 – 461). This has been accomplished with viral vectors, which express immunoregulatory cytokines (IL-4 and IL-10) and a mutant I␬B to inhibit cytokine transcription within the intestinal mucosa ( J Clin Invest 1997;100:2766 –2776, Gut 2000;46: 344 –349, J Immunol 1998;160:410 – 418). In general, the efficiency with which adenoviral vectors target biological molecules to the intestinal mucosa in different experimental settings has been variable, and other forms of peroral gene delivery are being studied (Nat Med 1988;4:1131–1135, Nat Med 1999;5:387–391). The use of genetically modified food-grade bacteria to deliver specific gene products is an important advance that adds scientific rigor to probiotic therapy and offsets the problems with systemic administration of cytokines. IL-10 is a particularly attractive cytokine for delivery to the intestinal mucosa. Evidence for its role in mucosal immunoregulation includes the development of enterocolitis in IL-10 – deficient mice (Cell 1993: 75:263–274, J Clin Invest 1996;98:1010 –1020), and IL-10 has recently been shown to be essential to the function of T cells that regulate mucosal inflammatory responses to intestinal antigens ( J Exp Med 1999;190:995–1003). One of the beauties of genetically modified probiotic organisms is the potential for delivery of a wide range of biologically relevant molecules, including enzymes and vaccines, with applications in treatment and prevention of a variety of disorders. More importantly, the cost of biological therapies can be prohibitive for widespread usage, particularly in developing countries; exploitation of orally administered nonpathogenic bacteria could, therefore, have a significant impact on public health. Acceptability of genetically modified

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food-grade bacteria is unlikely to be a problem for patients suffering with chronic disabling diseases. Remaining technical, safety, and logistical concerns will probably be overcome, but ultimately public education, commercial constraints, and even political will may be required for optimal deployment of genetically modified organisms for the welfare and benefit of all. FERGUS SHANAHAN, M.D.

HELICOBACTER ERADICATION VERSUS PROMPT ENDOSCOPY FOR DYSPEPSIA Lassen AT, Pedersen FM, Bytzer P, Schaffalitzky de Muckadell OB (Department of Medical Gastroenterology S, Odense University Hospital, and Department of Medical Gastroenterology F, Glostrup University Hospital, Denmark). Helicobacter pylori test-and-eradicate versus prompt endoscopy for management of dyspeptic patients: a randomised trial. Lancet 2000;356: 455– 460. The objective of this randomized trial was to compare the quality of life and resource utilization of patients presenting with dyspepsia managed with either prompt endoscopy or noninvasive testing for Helicobacter pylori and subsequent antibiotic eradication therapy (test-and-treat). Patients 18 years and older were referred for the study by 65 primary care physicians in Odense, Denmark, if they had dyspepsia for at least 2 weeks or of shorter duration if the severity of symptoms was judged to require additional intervention. Patients with “alarm” or “warning” symptoms or signs were excluded. Subjects assigned to the test-and-treat arm were evaluated for the presence of H. pylori using a 13C urea breath test (UBT), with a sensitivity and specificity of 97%. If positive, they were treated with lansoprazole 30 mg twice daily, amoxicillin 1000 mg twice daily, and metronidazole 500 mg 3 times daily for 2 weeks. Subjects negative for H. pylori were stratified into 3 groups and received subsequent therapy based on the clinical history: (1) those that had taken nonsteroidal anti-inflammatory drugs (NSAIDs) in the preceding month were offered endoscopy; (2) those with reflux symptoms received protonpump inhibitors (PPIs); and (3) NSAID-negative and refluxnegative subjects were given reassurance and lifestyle modifications (although some eventually received PPIs). All patients in the test-and-treat group were offered endoscopy if their symptoms failed to improve. Subjects assigned to the prompt endoscopy arm were treated according to the findings at endoscopy. Patients with duodenal ulcers or H. pylori–positive gastric ulcers received eradication therapy, those with esophagitis received PPIs, and those whose endoscopic examinations that were either normal or “nonsignificant” (e.g., gastric or duodenal erythema) received reassurance and lifestyle modifications (although some eventually received PPIs). Biopsies of gastric ulcers were performed every 6 weeks until healed. Patients kept a monthly log of symptoms, medication use, sick leave days, and visits to their primary care physician for 1 year. Patients also completed a quality of life survey, rated

April 2001

their satisfaction with medical care, and compared their overall symptoms at entry, 1 month, and 1 year. The primary outcome of the trial was the rate of well-being days (proportion of days without dyspepsia). Secondary outcomes included number of endoscopies, UBTs, H. pylori eradication treatments, and PPI use. Two hundred fifty subjects were randomized to each group. Twenty-six percent of the patients in the test-and-eradicate group were H. pylori positive, with successful eradication in 87%. One hundred (40%) of the patients in this study arm underwent endoscopy. Patients randomized to the prompt endoscopy group had an expected distribution of endoscopic findings: duodenal ulcer in 9%, gastric ulcer in 10%, reflux esophagitis in 28%, normal/insignificant in 52%, and malignancy in 1%. There was no difference in the number of well-being days between groups, the primary treatment outcome. With regard to secondary treatment outcomes, there were no differences in the number of sick days or subsequent physician clinic visits. There were fewer endoscopies (0.5 vs. 1.25, P ⬍ 0.0001) and less PPI use per patient in the test-and-eradicate group but, not surprisingly, greater use of UBTs and H. pylori eradication therapies. Although no formal cost analyses were performed, the investigators concluded that a test-and-treat strategy was as “efficient” as prompt endoscopy for the treatment of dyspepsia. Comment. The optimal strategy for managing patients presenting with dyspepsia has yet to be established. A previous study by 2 of the investigators concluded that prompt endoscopy was a more costeffective approach than empiric therapy with H2-receptor antagonists; however, the importance of H. pylori in the pathogenesis of dyspepsia was not considered at that time (Lancet 1994;343:811– 816). Decision analyses comparing early endoscopy with test-and-treat strategies for H. pylori have reported variable results. Two studies found that prompt endoscopy was equivalent to test-and-treat when the cost for endoscopy is approximately $500 (Ann Intern Med 1995;123: 260 –268, Gastroenterology 1996;110:72– 83), a figure that current Medicare physician and facility reimbursement is approaching. Two subsequent decision analyses showed a significant cost-effectiveness advantage with initial H. pylori identification and eradication when compared with endoscopy (Ann Intern Med 1997;126:280 –291, J Fam Pract 1997;44:545–555). All of these analyses incorporated the assumption that H. pylori eradication would not result in improved symptoms in patients with functional dyspepsia. This would tend to underestimate the cost-effectiveness of test-and-treat strategies if there were, in fact, a benefit. A small randomized trial comparing a test-and-treat strategy to early endoscopy in 104 patients under the age of 45 found that dyspepsia scores were significantly better in the test-and-treat group and required 73% fewer endoscopies. Although the benefit of H. pylori eradication in functional dyspepsia remains controversial, the investigators postulated that this might account for the observed difference in symptoms (Gut 1999;45:186 –190). The present study by Lassen et al. confirmed the equivalence of test-and-treat and prompt endoscopy strategies in a larger patient population ranging in age from 18 to 88 years. It is the first to compare these strategies in an older patient population, and thus the results are more generalizable to clinical practice. There were no differences between the 2 treatment arms in terms of symptom-free

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days, quality of life, or sick leave days. With regard to resource utilization, the study suffers from the lack of a formal cost analysis, although one is left with the impression that the test-and-treat strategy was less costly given the lower frequency of endoscopy and PPI use. The often-stated concern with empiric or test-and-treat regimens is the possibility of missing or delaying the diagnosis of gastric cancer; therefore, most authorities recommend this approach only in younger patients without “warning” or “alarm” symptoms. Even after excluding patients with alarm symptoms, 2 malignancies were found in the endoscopy arm, 1 in a 22-year-old. Although this patient would likely have undergone endoscopy at some point had he been randomized to the test-and-treat arm, it highlights the uneasiness of relying on a simple age cutoff or warning symptoms. Although this dilemma might be resolved in straightforward fashion from a health policy perspective, i.e., by using a benchmark dollar value per year of life saved, it has not yet been applied to the present algorithm. This well-done study confirms that a test-and-treat strategy results in equivalent patient outcomes when compared with prompt endoscopy. Although it has generated needed information that may facilitate future cost-effectiveness analyses, further study on the question of delay in diagnosis is warranted. DOUGLAS B. NELSON, M.D.

Reply. Comment is required on economic evaluation in this (and other) clinical trials. The size of this study (500 patients) was based on a power calculation of the main clinical endpoint. Resource variables tend to follow a screwed distribution resulting in a higher variance than those for clinical outcomes. As a result, cost-effectiveness analyses have lower power than those for clinical outcomes. Furthermore, conclusions in cost-effectiveness analysis can change dramatically with different payers’ costs and changes. Because our study had a limited power for an economic evaluation, we presented the use of individual resources by mean and corresponding 95% confidence intervals, to illuminate variability of the mean estimates. As mentioned by Dr. Nelson, we have thereby generated information that may faciliatate future cost-effectiveness analyses. We have also generated information illustrating that analyses from different payers’ points of view might result in different conclusions regarding cost-effectiveness. ANNMARIE LASSEN, M.D. FINN MØLLER PEDERSEN, M.D. PETER BYTZER, M.D., Ph.D. OVE B. SCHAFFALITZKY DE MUCKADELL, M.D., D.M.Sci.

SINGLE-STAGE OPERATIONS FOR HIRSCHSPRUNG’S DISEASE: PUSHING THE ENVELOPE Teitelbaum DH, Cilley RE, Sherman NJ, Bliss D, Uitvlugt ND, Renaud EJ, Kirstioglu I, Bengston T, Coran AG. (Section of Pediatric Surgery, CS Mott Children’s Hospital, Ann Arbor, Michigan). A decade of experience with the primary pullthrough for Hirschsprung disease in the newborn period. A multicenter analysis of outcomes. Ann Surg 2000; 232:372– 380. Hirschprung’s disease is characterized by absent ganglion cells in the distal rectum, which may extend proximally for