Improved Efficacy of 10-Day Sequential Treatment for Helicobacter pylori Eradication in Children: A Randomized Trial
2005; Elsevier BV; Volume: 129; Issue: 5 Linguagem: Inglês
10.1053/j.gastro.2005.09.007
ISSN1528-0012
AutoresRuggiero Francavilla, Elena Lionetti, Stefania Castellaneta, Anna Maria Magistà, Giuseppe Boscarelli, Domenico Piscitelli, A. Amoruso, Alfredo Di Leo, Vito Leonardo Miniello, A. Francavilla, Luciano Cavallo, Enzo Ierardi,
Tópico(s)Gastrointestinal disorders and treatments
ResumoBackground & Aims: The currently recommended first-line eradication treatment of Helicobacter pylori in children is usually successful in about 75%. Recently, in adults, a novel 10-day sequential treatment has achieved an eradication rate of 95%. The aim of the study was to assess the H pylori eradication rate of the sequential treatment regimen compared with conventional triple therapy in children. Methods: Seventy-eight consecutive children with H pylori infection were randomized to receive either sequential treatment (omeprazole plus amoxicillin for 5 days, followed by omeprazole plus clarithromycin plus tinidazole for another 5 days) (n = 38; 15 boys [39.5%]; median age, 11.0 years [range, 3.3–16 years]) or triple therapy (omeprazole, amoxicillin, and metronidazole) for 1 week (n = 37; 15 boys [40.5%]; median age, 9.9 years [range, 4.3–16 years]). H pylori infection was based on 2 out of 3 positive tests results: 13C-urea breath test, rapid urease test, and histologic analysis. Eradication was assessed by 13C-urea breath test 8 weeks after therapy. Results: Seventy-four patients completed the study. H pylori eradication was achieved in 36 children receiving sequential treatment (97.3%; 95% confidence interval, 86.2–99.5) and 28 children receiving triple therapy (75.7%; 95% confidence interval, 59.8–86.7) (P < .02). Compliance with therapy was good (>95%) in all. Conclusions: Our study shows, for the first time in children, that 10-day sequential treatment achieves a higher eradication rate than standard triple therapy, which is consistent with the results of adult studies. Background & Aims: The currently recommended first-line eradication treatment of Helicobacter pylori in children is usually successful in about 75%. Recently, in adults, a novel 10-day sequential treatment has achieved an eradication rate of 95%. The aim of the study was to assess the H pylori eradication rate of the sequential treatment regimen compared with conventional triple therapy in children. Methods: Seventy-eight consecutive children with H pylori infection were randomized to receive either sequential treatment (omeprazole plus amoxicillin for 5 days, followed by omeprazole plus clarithromycin plus tinidazole for another 5 days) (n = 38; 15 boys [39.5%]; median age, 11.0 years [range, 3.3–16 years]) or triple therapy (omeprazole, amoxicillin, and metronidazole) for 1 week (n = 37; 15 boys [40.5%]; median age, 9.9 years [range, 4.3–16 years]). H pylori infection was based on 2 out of 3 positive tests results: 13C-urea breath test, rapid urease test, and histologic analysis. Eradication was assessed by 13C-urea breath test 8 weeks after therapy. Results: Seventy-four patients completed the study. H pylori eradication was achieved in 36 children receiving sequential treatment (97.3%; 95% confidence interval, 86.2–99.5) and 28 children receiving triple therapy (75.7%; 95% confidence interval, 59.8–86.7) (P < .02). Compliance with therapy was good (>95%) in all. Conclusions: Our study shows, for the first time in children, that 10-day sequential treatment achieves a higher eradication rate than standard triple therapy, which is consistent with the results of adult studies. Infection with Helicobacter pylori plays a crucial role in the pathogenesis of both chronic active gastritis and peptic ulcer disease in children and adults.1NIH Consensus Statement.Helicobacter pylori in peptic ulcer disease. 1994; 12: 1-23Google Scholar, 2Vaira D. Gatta L. Ricci C. D'Anna L. Miglioli M. Helicobacter pylori diseases, tests and treatment.Dig Liver Dis. 2001; 33: 788-794Abstract Full Text PDF PubMed Scopus (36) Google Scholar An increasing amount of evidence also supports the hypothesis that H pylori is an important cofactor in the development of gastric cancer.3Ekstrom A.M. Held M. Hansson L.E. Engstrand L. Nyren O. Helicobacter pylori in gastric cancer established by CagA immunoblot as a marker of past infection.Gastroenterology. 2001; 121: 784-791Abstract Full Text Full Text PDF PubMed Scopus (376) Google Scholar, 4Uemura N. Okamoto S. Yamamoto S. Matsumura N. Yamaguchi S. Yamakido M. Taniyama K. Sasaki N. Schlemper R.J. Helicobacter pylori infection and the development of gastric cancer.N Engl J Med. 2001; 345: 784-789Crossref PubMed Scopus (3818) Google Scholar, 5Watanabe T. Tada M. Nagai H. Helicobacter pylori infection induces gastric cancer in Mongolian gerbils.Gastroenterology. 1998; 115: 642-648Abstract Full Text Full Text PDF PubMed Scopus (939) Google Scholar Furthermore, younger age at acquisition has been suggested to increase the risk of developing cancer later in life.6Blaser M.J. Chyou P.H. Normura A. Age at establishment of Helicobacter pylori infection and gastric carcinoma, gastric ulcer and duodenal ulcer risk.Cancer Res. 1995; 55: 562-565PubMed Google Scholar Thus, strategies to limit the burden of H pylori infection and its complications are needed, and prevention by treatment of childhood H pylori infection has been suggested. Few evidence-based data are available for the treatment of H pylori in children,7Oderda G. Rapa A. Bona G. A systematic review of Helicobacter pylori eradication treatment schedules in children.Aliment Pharmacol Ther. 2000; 14: 56-60Crossref Scopus (49) Google Scholar and this issue is complicated by the results of a recent study in children that found a significant improvement of dyspeptic symptoms at long-term follow-up after H pylori treatment irrespective of eradication.8Oderda G. Marinello D. Lerro P. Kuvidi M. de'Angelis G.L. Ferzetti A. Cucchiara S. Franco M.T. Romano C. Strisciuglio P. Pensabene L. Dual vs. triple therapy for childhood Helicobacter pylori gastritis a double-blind randomized multicentre trial.Helicobacter. 2004; 9: 293-301Crossref PubMed Scopus (34) Google Scholar The ideal eradication therapy should be characterized by high effectiveness, good compliance, and a low incidence of side effects. A recent review of data in children reports variable eradication rates according to the different therapeutic regimens,7Oderda G. Rapa A. Bona G. A systematic review of Helicobacter pylori eradication treatment schedules in children.Aliment Pharmacol Ther. 2000; 14: 56-60Crossref Scopus (49) Google Scholar with figures of 68% and 75% reported in 2 different trials with the use of 7-day triple therapies based on proton pump inhibitors plus 2 antibiotics.8Oderda G. Marinello D. Lerro P. Kuvidi M. de'Angelis G.L. Ferzetti A. Cucchiara S. Franco M.T. Romano C. Strisciuglio P. Pensabene L. Dual vs. triple therapy for childhood Helicobacter pylori gastritis a double-blind randomized multicentre trial.Helicobacter. 2004; 9: 293-301Crossref PubMed Scopus (34) Google Scholar, 9Gottrand F. Kalach N. Spyckerelle C. Guimber D. Mougenot J.F. Tounian P. Lenaerts C. Roquelaure B. Lachaux A. Morali A. Dupont C. Maurage C. Husson M.O. Barthelemy P. Omeprazole combined with amoxicillin and clarithromycin in the eradication of Helicobacter pylori in children with gastritis a prospective randomized double-blind trial.J Pediatr. 2001; 139: 664-668Abstract Full Text Full Text PDF PubMed Scopus (81) Google Scholar Moreover, prolonging the duration of these schedules does not significantly increase the efficacy.7Oderda G. Rapa A. Bona G. A systematic review of Helicobacter pylori eradication treatment schedules in children.Aliment Pharmacol Ther. 2000; 14: 56-60Crossref Scopus (49) Google Scholar In an attempt to improve the success of eradication, a novel 10-day sequential treatment regimen, including a proton pump inhibitor and amoxicillin double therapy for 5 days, followed by a proton pump inhibitor, clarithromycin, and tinidazole triple therapy for a further 5 days was used in a large, multicenter trial in adults and achieved an eradication rate of 95%.10Zullo A. Vaira D. Vakil N. Hassan C. Gatta L. Ricci C. De Francesco V. Menegatti M. Tampieri A. Perna F. Rinaldi V. Perri F. Papadia C. Fornari F. Pilati S. Mete L.S. Merla A. Poti R. Marinone G. Savioli A. Campo S.M. Faleo D. Ierardi E. Miglioli M. Morini S. High eradication rates of Helicobacter pylori with a new sequential treatment.Aliment Pharmacol Ther. 2003; 17: 719-726Crossref PubMed Scopus (219) Google Scholar This regimen has also been shown to be safe and well tolerated in adults.10Zullo A. Vaira D. Vakil N. Hassan C. Gatta L. Ricci C. De Francesco V. Menegatti M. Tampieri A. Perna F. Rinaldi V. Perri F. Papadia C. Fornari F. Pilati S. Mete L.S. Merla A. Poti R. Marinone G. Savioli A. Campo S.M. Faleo D. Ierardi E. Miglioli M. Morini S. High eradication rates of Helicobacter pylori with a new sequential treatment.Aliment Pharmacol Ther. 2003; 17: 719-726Crossref PubMed Scopus (219) Google Scholar We investigated, for the first time in the pediatric population, in a randomized clinical trial, the following issues: (1) the efficacy of the 10-day sequential treatment regimen for eradication of H pylori and (2) the safety profile as compared with conventional triple therapy. The study enrolled only patients never previously treated for H pylori infection. A total of 78 consecutive children (31 boys [39.7%]; median age, 12.3 years [range, 3.3–18 years]) with H pylori infection diagnosed in the Department of Paediatric Gastroenterology of the University of Bari in Italy between January 2002 and September 2004 were candidates for inclusion in the study. Exclusion criteria were one of the following: (1) consumption of proton pump inhibitors and/or antibiotics in the previous 4 weeks, (2) previous gastric surgery, and (3) known allergy to antibiotics. At baseline, patients underwent endoscopy with biopsies for histology (2 samples from the antrum and 2 samples from the corpus) and a rapid urease test (one sample from the antrum) (CP test; Yamanouchi Pharma S.p.A., Carugate, Italy). Endoscopy was performed by the same physician (R.F.) (endoscope model GIF XP20; Olympus, Tokyo, Japan) after sedation with intravenous midazolam. Histologic examinations were performed by the same observer (D.P.) using H&E staining for assessment of gastritis and Gram strain for detection of H pylori. Within 24 hours of the endoscopy, patients completed a standard 13C-urea breath test after overnight fasting. A fatty meal (100 mL) and a solution of 13C-urea (75 mg 13C-urea; AB Analitica srl, Padova, Italy) were fed to each patient. Breath samples were collected before and 30 minutes after the dose of urea. In children younger than 6 years of age, breath samples were collected by using a face mask with a bag (made in house). The ratio of 13C to 12C in the expired air samples was measured using a dual-inlet-ratio mass spectrometer (Automated Breath 13Carbon Analyzer; Europa Scientific, Ltd, Crawley, West Sussex, England). Results were expressed as parts per million of excess of Δ13CO2 (by subtraction of the baseline pretest breath sample). The presence of gastric urease activity was revealed by a change of 3.5 per thousand (or more) related to the baseline signal.11Rowland M. Lambert I. Gormally S. Daly L.E. Thomas J.E. Hetherington C. Durnin M. Drumm B. Carbon 13-labeled urea breath test for the diagnosis of Helicobacter pylori infection in children.J Pediatr. 1997; 131: 815-820Abstract Full Text Full Text PDF PubMed Scopus (158) Google Scholar 13C-urea breath test, as described, had been validated in children of our geographic area by our group.12Rutigliano V. Ierardi E. Francavilla R. Castellaneta S. Margiotta M. Amoruso A. Marrazza E. Traversa A. Panella C. Rigillo N. Francavilla A. Helicobacter pylori and nonulcer dyspepsia in childhood clinical pattern, diagnostic techniques, and bacterial strains.J Pediatr Gastroenterol Nutr. 1999; 28: 296-300Crossref PubMed Scopus (38) Google Scholar 13C-urea breath test was differed of at least 4 weeks in case of use of medications such as antibiotics or antacids. At entry, patients were considered H pylori positive if the results of 2 out of 3 tests (histologic analysis, rapid urease test, and 13C-urea breath test) were positive. Sera were assayed for antibodies to CagA antigens using a commercial enzyme-linked immunosorbent assay (Radim, Angleur, Belgium) validated in our geographic area.13Ierardi E. Margotta M. De Francesco V. Russo F. Berloco P. Burattini O. Marangi S. Ricciarelli C. Gentile M. De Palo M. Di Leo A. Panella C. Francavilla A. Cut-off validation in resident population improves noninvasive assessment of CagA status in Helicobacter pylori infected patients.Dig Liver Dis. 2003; 35 (abstr): S60Google Scholar At entry, all children (or family members) were carefully interviewed, always by one physician (E.L.), to investigate the presence of the following symptoms: epigastric burning and/or pain, nausea, recurrent abdominal pain, objective halitosis, heartburn, vomiting, postprandial fullness, overflow, belching, diarrhea, anorexia or failure to thrive, and early satiety. Dyspeptic symptoms were classified as ulcer-like and dysmotility-like dyspepsia according to the Roma II criteria of childhood functional gastrointestinal disorders.14Rasquin-Weber A. Hyman P.E. Cucchiara S. Fleisher D.R. Hyams J.S. Milla P.J. Staiano A. Childhood functional gastrointestinal disorders.Gut. 1999; 45: 60-68Google Scholar Eight weeks and 6 months after completing therapy, the persistence of symptoms was accurately assessed by a personal interview conducted by the same physician (E.L.). An independent physician prescribed either sequential treatment or standard therapy according to a computer-generated randomization list that was blinded to researchers. The code was revealed to the researchers once recruitment, data collection, and laboratory analyses were completed. Children were randomized to receive 10-day sequential treatment consisting of omeprazole 1 mg · kg−1 · day−1 plus amoxicillin 50 mg · kg−1 · day−1 for 5 days followed by omeprazole 1 mg · kg−1 · day−1 plus clarithromycin 15 mg · kg−1 · day−1 and tinidazole 20 mg · kg−1 · day−1 for the next 5 days (38 patients; 15 boys [39.5%]; median age, 11.0 years [range, 3.3–16 years]) or standard 7-day triple therapy consisting of omeprazole 1 mg · kg−1 · day−1 plus amoxicillin 50 mg · kg−1 · day−1 and metronidazole 15 mg · kg−1 · day−1 (37 patients; 15 boys [40.5%]; median age, 9.9 years [range, 4.3–16 years]). In both groups, omeprazole was prescribed before breakfast and dinner, whereas the antibiotics were administered after meals. Patients were thoroughly instructed and motivated for the therapy. At the end of treatment, both side effects and therapeutic compliance were assessed by personal interview. A minimum pill intake of 95% was considered as acceptable. Eight weeks and 6 months after completion of therapy, H pylori infection was assessed by using a 13C-urea breath test. Informed consent was obtained from all parents or guardians. The local ethical committee approved the study protocol. In the current study, we tested the hypothesis that 10-day sequential treatment would (1) increase the rate of H pylori eradication and (2) be tolerated as well as currently recommended H pylori eradication therapy.15Gold B.D. Colletti R.B. Abbott M. Czinn S.J. Elitsur Y. Hassall E. Macarthur C. Snyder J. Sherman P.M. North American Society for Pediatric Gastroenterology and NutritionHelicobacter pylori infection in children recommendations for diagnosis and treatment.J Pediatr Gastroenterol Nutr. 2000; 31: 490-497Crossref PubMed Scopus (311) Google Scholar All data are expressed as the median with a range. All data analysis was performed according to a pre-established analysis plan. Proportions were compared by using χ2 test with continuity correction or Fisher exact test when appropriate; comparison of continuous variables was performed using the Mann–Whitney U test. P < .05 was considered significant. Statistical analysis was performed using the Number Cruncher Statistical System (version 11.0) program (Kaysville, UT). The sample size was calculated starting from the assumption of an eradication rate of standard triple therapy of 77%7Oderda G. Rapa A. Bona G. A systematic review of Helicobacter pylori eradication treatment schedules in children.Aliment Pharmacol Ther. 2000; 14: 56-60Crossref Scopus (49) Google Scholar aiming to detect a difference in eradication rate of 20%. Based on a 0.85 power to detect a significant difference (P = .05, 2-sided), 37 patients were required for each study group. Therapeutic results were expressed using both intention-to-treat and per-protocol analyses with 95% confidence intervals. Seventy-five children (30 boys [40.0%]; median age, 12.3 years [range, 3.3–18 years]) were recruited, while 3 were excluded (Figure 1). The baseline demographic and clinical characteristics of the enrolled patients are reported in Table 1. Children enrolled in the 2 therapeutic arms did not differ in regard to age, sex, clinical symptoms, and endoscopic features (Table 2). At histology, H pylori was observed in the gastric antrum of all patients. The presence of the bacterium was always associated with chronic gastritis (lymphocytes and plasma cells in the lamina propria) with a variable degree of activity; none had gastric atrophy or intestinal metaplasia (Table 2). In all children, results of all 3 diagnostic tests were positive.Table 1Baseline Demographic and Clinical Characteristics of Trial Groups10-day sequential treatment (n = 38)Standard 7-day triple therapy (n = 37)Median age, y (range)11.0 (3.3–18)9.9 (4.3–17.6)Sex (M/F)15/2315/21Cag A (%)20 (60.6)21 (65.6)Ulcer-like dyspepsia (%)18 (47.4)14 (43.7)Dysmotility-like dyspepsia (%)17 (51.5)19 (59.4) Open table in a new tab Table 2Endoscopic and Histologic Findings in the 2 Treatment Groups10-day sequential treatment (n = 38)Standard 7-day triple therapy (n = 37)PEndoscopic findings Macroscopic nodular antral gastritis with hyperemia25 (65.8%)26 (70.3%).9 Antral hyperemia without macroscopic nodularity2 (5.3%)6 (16.2%).2 Pangastritis25 (65.8%)26 (70.3%).9 Gastric ulcer00— Duodenal ulcer1 (2.6%)01.0 Erosive bulbitis9 (23.7%)8 (21.6%).9 Esophagitis2 (5.3%)0.5Histologic findings Pangastritis9 (23.6%)10 (27%).9 Antral gastritis Mild15 (39.4%)16 (43.3%).9 Moderate9 (23.7%)7 (18.9%).7 Severe5 (13.3%)4 (10.8%)1.0 Open table in a new tab Seventy-four patients completed the study; 1 patient in the sequential treatment group was lost to follow-up. No children underwent protocol deviation. H pylori eradication was achieved in 36 children receiving sequential treatment (97.3%; 95% confidence interval, 86.2–99.5) and in 28 children receiving standard triple therapy (75.7%; 95% confidence interval, 59.8–86.7). The eradication rates following sequential treatment were significantly higher as compared with standard therapy at both intention-to-treat (94.7% vs 75.7%; P < .04) and per-protocol (97.3% vs 75.7%; P < .02) analyses. One child (in the sequential treatment arm) became reinfected after successful eradication (13C-urea breath test negative at week 8 and positive at 6 months). Compliance with therapy was good (>95%) in all enrolled cases, and no patient discontinued therapy due to side effects. No major side effects were reported, while 5 patients (13.5%) receiving sequential treatment and 4 patients (10.8%) receiving standard triple therapy reported side effects (P = 1.0). In detail, 2 children in both groups reported symptoms of transient abdominal pain, 2 patients in the sequential treatment group and 1 patient in the standard therapy group had nausea, and 1 patient in each group reported diarrhea. Thirty-two children (42.6%) reported symptoms of ulcer-like dyspepsia (18 [47.4%] in the sequential treatment group vs 14 [43.7%] in the standard therapy group; P = .09) and 36 (48%) reported symptoms of dysmotility-like dyspepsia (17 [51.5%] in the sequential treatment group vs 19 [59.4%] in the standard therapy group; P = .07), with no difference in the prevalence of each symptom in children randomized into the 2 treatment regimens. Eight weeks and 6 months after therapy, symptoms were reevaluated in children in which H pylori was eradicated and not eradicated. At week 8, most of the symptoms disappeared irrespective of the persistence of infection; however, after 6 months, epigastric pain and heartburn were significantly more prevalent in H pylori–positive as compared with H pylori–negative children (Table 3). No significant difference was found in persistence of symptoms according to therapy regimen.Table 3Prevalence of Symptoms 6 Months After the End of Therapy According to H pylori EradicationSymptomsH pylori negative (n = 63)H pylori positiveaThis group is composed of the 10 children with persistent infection after treatment (irrespective of treatment regimen) plus 1 patient found to be reinfected (having been negative 8 weeks after completion of therapy). (n = 11)PEpigastric burning and/or pain46.03Nausea22.1Recurrent abdominal pain26.3Halitosis22.1Heartburn46.03Vomiting13.5Postprandial fullness21.07Overflow11.3Belching23.2Diarrhea11.3Anorexia or failure to thrive23.2Early satiety11.3a This group is composed of the 10 children with persistent infection after treatment (irrespective of treatment regimen) plus 1 patient found to be reinfected (having been negative 8 weeks after completion of therapy). Open table in a new tab Our study clearly shows, for the first time in the pediatric population, that sequential treatment significantly improves the H pylori eradication rate as compared with standard triple therapy. Consensus statements providing guidelines for the management of H pylori infection in children either did not provide suggestions on therapeutic options or made recommendations for therapy based on data derived from adult trials.15Gold B.D. Colletti R.B. Abbott M. Czinn S.J. Elitsur Y. Hassall E. Macarthur C. Snyder J. Sherman P.M. North American Society for Pediatric Gastroenterology and NutritionHelicobacter pylori infection in children recommendations for diagnosis and treatment.J Pediatr Gastroenterol Nutr. 2000; 31: 490-497Crossref PubMed Scopus (311) Google Scholar, 16Drumm B. Koletzko S. Oderda G. European Paediatric Task Force on Helicobacter pyloriHelicobacter pylori infection in children. Report of a Consensus Conference held in Budapest, September 1998.J Pediatr Gastroenterol Nutr. 2000; 30: 207-213Crossref PubMed Scopus (304) Google Scholar, 17Sherman P. Hassall E. Hunt R.H. Fallone C.A. Veldhuyzen Van Zanten S. Thomson A.B. Canadian Helicobacter Study Group consensus conference on the approach to Helicobacter pylori infection in children and adolescents.Can J Gastroenterol. 1999; 13: 553-559PubMed Google Scholar According to the North American Society for Pediatric Gastroenterology, Hepatology and Nutrition guidelines,15Gold B.D. Colletti R.B. Abbott M. Czinn S.J. Elitsur Y. Hassall E. Macarthur C. Snyder J. Sherman P.M. North American Society for Pediatric Gastroenterology and NutritionHelicobacter pylori infection in children recommendations for diagnosis and treatment.J Pediatr Gastroenterol Nutr. 2000; 31: 490-497Crossref PubMed Scopus (311) Google Scholar 1-week triple therapy represents the currently most widely used first-line regimen for H pylori infection, but the eradication failure rate is more than 30%.8Oderda G. Marinello D. Lerro P. Kuvidi M. de'Angelis G.L. Ferzetti A. Cucchiara S. Franco M.T. Romano C. Strisciuglio P. Pensabene L. Dual vs. triple therapy for childhood Helicobacter pylori gastritis a double-blind randomized multicentre trial.Helicobacter. 2004; 9: 293-301Crossref PubMed Scopus (34) Google Scholar To increase the eradication rate, the duration of standard triple therapy has been prolonged to 14 days in some studies, without a significant therapeutic gain.7Oderda G. Rapa A. Bona G. A systematic review of Helicobacter pylori eradication treatment schedules in children.Aliment Pharmacol Ther. 2000; 14: 56-60Crossref Scopus (49) Google Scholar, 18Howden C.W. Hunt R.H. Treating Helicobacter pylori.Arch Intern Med. 1998; 158: 2396-2398Crossref PubMed Scopus (3) Google Scholar The Maastricht Consensus Report on the management of H pylori infection has stressed the need for further studies to evaluate the efficacy and safety of treatment regimens in all age groups.19Malfertheiner P. Megraud F. O'Morain C. Hungin A.P. Jones R. Axon A. Graham D.Y. Tytgat G. European Helicobacter Pylori Study Group (EHPSG)Current concepts in the management of Helicobacter pylori infection—the Maastricht 2-2000 Consensus Report.Aliment Pharmacol Ther. 2002; 16: 167-180Crossref PubMed Scopus (6) Google Scholar Recently, a large multicenter study in adults has tested a novel 10-day sequential therapy achieving an eradication rate of 95% as compared with 77% for the standard 7-day triple therapy,10Zullo A. Vaira D. Vakil N. Hassan C. Gatta L. Ricci C. De Francesco V. Menegatti M. Tampieri A. Perna F. Rinaldi V. Perri F. Papadia C. Fornari F. Pilati S. Mete L.S. Merla A. Poti R. Marinone G. Savioli A. Campo S.M. Faleo D. Ierardi E. Miglioli M. Morini S. High eradication rates of Helicobacter pylori with a new sequential treatment.Aliment Pharmacol Ther. 2003; 17: 719-726Crossref PubMed Scopus (219) Google Scholar with an overall good compliance and reassuring safety profile. Our study, designed and powered to assess the efficacy and tolerability of the 10-day sequential treatment regimen in children, has shown that the H pylori eradication rate is significantly higher than that achieved by standard triple therapy, which is consistent with the results of several studies performed in adults.10Zullo A. Vaira D. Vakil N. Hassan C. Gatta L. Ricci C. De Francesco V. Menegatti M. Tampieri A. Perna F. Rinaldi V. Perri F. Papadia C. Fornari F. Pilati S. Mete L.S. Merla A. Poti R. Marinone G. Savioli A. Campo S.M. Faleo D. Ierardi E. Miglioli M. Morini S. High eradication rates of Helicobacter pylori with a new sequential treatment.Aliment Pharmacol Ther. 2003; 17: 719-726Crossref PubMed Scopus (219) Google Scholar, 20Zullo A. Rinaldi V. Winn S. Meddi P. Lionetti R. Hassan C. Ripani C. Tomaselli G. Attili A.F. A new highly effective short-term therapy schedule for Helicobacter pylori eradication.Aliment Pharmacol Ther. 2000; 14: 715-718Crossref PubMed Scopus (152) Google Scholar, 21De Francesco V. Zullo A. Hassan C. Faleo D. Ierardi E. Panella C. Morini S. Two new treatment regimens for Helicobacter pylori eradication a randomised study.Dig Liver Dis. 2001; 33: 676-679Abstract Full Text PDF PubMed Scopus (62) Google Scholar, 22De Francesco V. Della Valle N. Stoppino V. Amoruso A. Muscatiello N. Panella C. Ierardi E. Effectiveness and pharmaceutical cost of sequential treatment for Helicobacter pylori in patients with non-ulcer dyspepsia.Aliment Pharmacol Ther. 2004; 19: 1-6Google Scholar, 23De Francesco V. Zullo A. Margotta M. Marangi S. Burattini O. Berloco P. Russo F. Barone M. Di Leo A. Minenna M.F. Stoppino V. Morini S. Panella C. Francavilla A. Ierardi E. Sequential treatment for Helicobacter pylori does not share the risk factors of triple therapy failure.Aliment Pharmacol Ther. 2004; 19: 407-414Crossref PubMed Scopus (97) Google Scholar Moreover, such a sequential regimen was well tolerated and accepted (pill intake >95%) in all children. One child was found to be reinfected 6 months after completion of therapy, having been 13C-urea breath test negative at week 8; this finding is not unexpected to us in view of the high reinfection rate reported in our geographic area.24Magistà A.M. Ierardi E. Castellaneta S. Miniello V.L. Lionetti E. Francavilla A. Ros P. Rigillo N. Di Leo A. Francavilla R. Helicobacter pylori status and symptom assessment two years after eradication in pediatric patients from a high prevalence area.J Pediatr Gastroenterol Nutr. 2005; 40: 312-318Crossref PubMed Scopus (26) Google Scholar Eight weeks after the end of treatment, symptoms improved or disappeared in most treated children irrespective of treatment regimen or H pylori status. However, after 6 months, H pylori–positive children report epigastric pain and/or heartburn more frequently as compared with H pylori–negative children. These symptoms are difficult to differentiate in this age group (especially in very young infants) and are both suggestive of gastric inflammation. Our data are supported by studies in adults indicating that after eradication therapy, patients who remain clear of H pylori infection report fewer symptoms than those who remain infected at long (6–12 months) but not short follow-up (8 weeks).25Lazzaroni M. Bargiggia S. Sangaletti O. Maconi G. Boldorini M. Bianchi Porro G. 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Treatment of Helicobacter pylori gastritis improves dyspeptic symptoms in children.J Pediatr Gastroenterol Nutr. 2002; 34: 281-285Crossref PubMed Scopus (47) Google Scholar, 28Wewer V. Andersen L.P. Paerregaard A. Gernow A. Hansen J.P. Matzen P. Krasilnikoff P.A. Treatment of Helicobacter pylori in children with recurrent abdominal pain.Helicobacter. 2001; 6: 244-248Crossref PubMed Scopus (37) Google Scholar and can be explained by a decrease in the bacterial load, the therapeutic effect of omeprazole in inhibiting acid output or placebo effect. It is reasonable to speculate that a course of proton pump inhibitor therapy decreases mucosal damage by intraluminal aggressive factors with consequent improvement of pain (or symptoms). Sheu et al showed that anti-H2 blockers administered to infected adults are able to induce symptom relief, although the effect is transitory.29Sheu B.S. Lin C.Y. Lin X.Z. Shiesh S.C. Yang H.B. Chen C.Y. 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Papadia C. Fornari F. Pilati S. Mete L.S. Merla A. Poti R. Marinone G. Savioli A. Campo S.M. Faleo D. Ierardi E. Miglioli M. Morini S. High eradication rates of Helicobacter pylori with a new sequential treatment.Aliment Pharmacol Ther. 2003; 17: 719-726Crossref PubMed Scopus (219) Google Scholar The high eradication rate of this new therapeutic regimen may have profound implications on the counseling of infected children favoring the strategy of treating. Many epidemiologic studies have shown that most H pylori infections are acquired in childhood, when they can spread to parents and schoolmates. Therefore, it would be advisable to try to eradicate the infection in childhood when the prevalence is still low, especially if early acquisition of the infection is confirmed to be a critical factor in assessing development of complications such as peptic ulceration or gastric cancers later in life.6Blaser M.J. Chyou P.H. Normura A. 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Francavilla A. Ros P. Rigillo N. Di Leo A. Francavilla R. Helicobacter pylori status and symptom assessment two years after eradication in pediatric patients from a high prevalence area.J Pediatr Gastroenterol Nutr. 2005; 40: 312-318Crossref PubMed Scopus (26) Google Scholar (4) in children without duodenal ulcers, eradication of the infection is not clearly associated with symptom improvement;33Mitchell H.M. Li Y.Y. Hu P.J. Epidemiology of Helicobacter pylori in Southern China identification of early as the critical period for acquisition.J Infect Dis. 1992; 166: 149-153Crossref PubMed Scopus (391) Google Scholar and (5) importantly, there is no therapeutic regimen that warrants more than a 75% success rate. The availability of a therapeutic regimen that eradicates infection in nearly all children may alter the balance in favor of treatment; although we used a small sample, we have obtained the highest eradication rate published in a pediatric controlled study. In conclusion, if our results are confirmed by a large multicenter study, the use of this effective and attractive 10-day sequential treatment regimen may become the new standard for the treatment of H pylori in childhood. The authors thank Dr G. Leone, Dr S. Fico, for the clinical support and Mrs. N. Iavernaro for her expert technical collaboration. Is There a Role for Sequential in Sequential Anti–H. pylori Therapy?GastroenterologyVol. 130Issue 6PreviewRecently, Francavilla et al1 reported excellent results with sequential therapy for H pylori infection in children. Similar results have been reported in adults.2–5 Is there something special about sequential administration of the components of therapy? The mucosal surface area of the stomach is very large such that there are a tremendous number of bacteria present (in the range of 107 to 1011), which increases the likelihood that a few naturally resistant mutants are always present. The initial use of antibiotics associated with a low rate of spontaneous mutation to a resistant phenotype or to rapidly reduce the total number of bacteria with a drug with low or absent resistance potential (eg, bismuth) would have theoretical advantages over concomitant therapy. Full-Text PDF
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