Gastroenterology & Hepatology
December 2014, Volume 10, Issue 12, Supplement 7
Moderator
Benjamin D. Gold, MD
GI Care for Kids, LLC, Children’s Center for Digestive Healthcare LLC, Atlanta, Georgia
Discussants
Mark A. Gilger, MD
Pediatrician-in-Chief, Children’s Hospital of San Antonio, San Antonio, Texas
Professor & Vice Chair, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
Steven J. Czinn, MD
Professor and Chair, Department of Pediatrics, University of Maryland School of Medicine, Physician-in-Chief, University of Maryland Children’s Hospital, Baltimore, Maryland
Drs Gold, Gilger, and Czinn are paid consultants of Otsuka America Pharmaceutical, Inc.
Supported through funding from Otsuka America Pharmaceutical, Inc., manufacturer and marketer of the BreathTek® UBT for H pylori.
Helicobacter pylori Infection in Pediatric Patients: Introduction
Benjamin D. Gold, MD
GI Care for Kids, LLC, Children’s Center for Digestive Healthcare LLC, Atlanta, Georgia
Helicobacter pylori (H pylori) was first identified in gastric biopsy specimens by Dr Barry Marshall and his mentor, Dr Robin Warren, in the early 1980s.1,2 Several years after, it became apparent that in pediatric patients, the infection was associated with gastritis as well as peptic ulcer disease (to a lesser extent). Dr Steven J. Czinn was one of the first pediatric investigators to describe the association between H pylori and gastritis as well as peptic ulcer disease in children.3 At that time, the bacteria were known as Campylobacter pylori based on morphology, growth conditions, and sensitivity to metronidazole, among other factors.4 However, there were several key differences between Campylobacter pylori and the Campylobacter species.4 Through a series of molecular and biochemical assays, Campylobacter pylori was characterized in 1989 into its own genus, H pylori.5
To this day, H pylori infection remains an important cause of gastroduodenal disease, including peptic ulcer disease, in children. When the role of H pylori infection as a pathogen in pediatric patients was identified, several consensus-based guidelines were subsequently developed. In 1999, the Canadian Helicobacter Study Group released guidelines for the management of pediatric H pylori infection.6 In 2000, recommendations for the diagnosis and management of H pylori infection in children were published by the European Paediatric Task Force,7 the North American Society for Pediatric Gastroenterology and Nutrition (NASPGHAN),8 and the European Society of Pediatric Gastroenterology (ESPGHAN).9 Since those original clinical practice guidelines were published, several reports have evaluated treatment and diagnosis. Revised guidelines from Canada were published in 2005,10 and joint NASPGHAN-ESPGHAN guidelines were published in 2011.11 These consensus guidelines focused not only on the prevalence, epidemiology, and symptoms of H pylori infection, but also on the patient’s family, home environment, geographic location, and quality of life.
Epidemiology
H pylori is estimated to have infected two-thirds of individuals living in developing countries, and 30% to 40% of individuals living in industrialized countries.12 Pediatricians have continued to contend that H pylori is essentially a childhood-acquired infection in the majority of populations where it is found.11,13 In the developing world, household overcrowding and poor water hygiene (particularly fecally contaminated water) has led to a higher overall infection prevalence of H pylori as compared with developed countries.14,15 Most individuals are infected during early childhood; in developing countries, 50% of children are infected by the age of 5 years.16 In contrast, in the United States, only 5% of the population is infected by 5 years of age.16 However, some data suggest that with immigrant populations moving to the United States, there continues to be a relatively high level of prevalence in pediatric patients.17 In addition, H pylori is 2-fold to 6-fold more prevalent in black or Hispanic individuals than in white individuals, an increase that may be attributed to a generation cohort phenomenon.18-20
Transmission
Similar to other enteric pathogens, H pylori is primarily transmitted by a fecal-oral route, although gastro-oral and oral-oral transmission is also possible.16 Although reports regarding zoonotic sources have been inconsistent, there are some provocative data about cats (and, to a lesser extent, dogs) that acquire the infection and pass it back to humans.21,22 Some data suggest that there may also be an environmental reservoir of H pylori in water, specifically in fecally contaminated water.23,24 This observation may partially explain why this pathogen is so prevalent in countries with poor infrastructure and water hygiene.
Symptoms Associated With H pylori Infection
The presence of symptoms is a controversial area in the diagnosis and management of H pylori infection. In the development of the H pylori management guidelines, the focus has been to target the disease manifestations as the potential cause of the symptoms and not necessarily the infection itself.6,8-11 Many H pylori infections are silent and without clinically apparent symptoms. When symptoms do occur, they are primarily the result of gastric or peptic ulcer disease, rather than the actual infection. It is important to distinguish between the symptoms of infection and symptoms from gastric or duodenal inflammation and ulcer disease. Although clinical experience may suggest that upper gastrointestinal symptoms will disappear after H pylori eradication, it is still important to identify the causes of these symptoms. The ESPGHAN and NASPGHAN guidelines recommend that “the primary goal of clinical investigation of gastrointestinal symptoms is to determine the underlying cause of the symptoms and not solely the presence of H pylori infection.”11
Abdominal pain and nausea, among other dyspeptic symptoms, are nonspecific and may be attributable to various diseases, including gastroesophageal reflux disease and functional gastrointestinal disorders.11 To date, treatment trials have failed to clearly and reproducibly demonstrate that any particular symptoms are specifically linked to H pylori or resolve after the infection is eradicated.25,26 In fact, a large meta-analysis determined that there was no association between H pylori infection status and abdominal pain in children.27 Similarly, large studies of 1221 German children and 695 Swedish children found that H pylori infection was not associated with abdominal pain.28,29 Moreover, there are some data to suggest that even in the face of H pylori infection eradication, the underlying gastritis can persist for weeks to months before resolving.30-32
Although several interventional studies have demonstrated some improvement of symptoms after treatment of H pylori infection, these studies were uncontrolled, and eradication of H pylori was not always confirmed following treatment.33-36 Therefore, if a child has symptoms that suggest upper gastrointestinal tract disease, it is important to focus the evaluation on potential causes of those symptoms, such as H pylori–associated gastroduodenal disease.
Influence of Family History
Family history of gastric cancer is an important component of the diagnosis and management of H pylori infection in children. For years, reports have noted an association between peptic ulcer disease and families with a strong history of upper gastrointestinal tract disease—in particular, between gastric or duodenal ulcers and gastric cancer—irrespective of whether testing for H pylori infection was performed. The World Health Organization classified H pylori as a class I pathogen based on data showing that patients with the infection were found to have a 2-fold to 6-fold greater risk of developing noncardia gastric cancer.11,37 As a result, the ESPGHAN and NASPGHAN revised guidelines consider children to be at high risk of H pylori infection if they have a positive family history of gastric cancer.11 Children with a mother or father with gastric cancer are considered to be at a very high risk owing to shared genetic characteristics, environmental factors, and virulence features of the infecting strain of H pylori.11 In fact, several studies in adults have shown that eradication of H pylori reduces the prevalence of precancerous gastric lesions and may reduce gastric cancer incidence.38-40 As such, diagnostic testing is recommended for children with a primary relative who has gastric cancer.11
Impact on Quality of Life
Findings differ regarding H pylori infection and quality of life. Some studies have suggested that H pylori impacts quality of life in patients with dyspepsia and peptic ulcer disease,41-43 whereas others have indicated that treatment of H pylori infection does not impact quality of life in patients with dyspepsia or acid reflux disease.44,45 The proviso here is that it is the disease associated with H pylori infection that reduces quality of life. Therefore, as outlined in the updated guidelines (both the Canadian and the NASPGHAN-ESPGHAN documents), the goal of clinicians should be to identify the underlying cause of symptoms, and not just the presence of H pylori infection.10,11 Because H pylori is a chronic infection of the gastric mucosa that causes persistent inflammation that the host cannot spontaneously clear and resolve, the organism requires eradication when detected or it can impact quality of life.
Gastroduodenal Disease
There is a clear association between H pylori and gastritis, gastric ulcers, and duodenal ulcers.46,47 Studies have shown that this pathogen causes mucosa-associated lymphoid tissue (MALT) lymphoma in both children and adults.48-51 In fact, when the organism is eradicated, extragastric metastases or sites of MALT lymphoma resolve.11,51-53
Gastric adenocarcinoma is also associated with H pylori. The presence of precancerous lesions, intestinal metaplasia, and atrophic gastritis in pediatric patients with H pylori was first described by Guarner and colleagues in 2003.54 Frank adenocarcinoma has not been described in pediatric patients, with the exception of a few isolated case reports; however, gastric cancer is clearly associated with H pylori infection.55,56 It is important to remember when counseling parents about whether to treat H pylori infection in children that gastric cancer is a potential long-term sequelae, especially if the infection is left untreated.
Extragastric Disease Associations
Since the original guidelines were published in 1999, research has focused on the association between H pylori and extragastric conditions (ie, those that manifest in areas outside of the stomach and duodenum). Examples of extragastric disease include growth reduction, iron-deficiency anemia, and idiopathic thrombocytopenic purpura (ITP).
The impact of H pylori infection on growth was clearly demonstrated in a study of indigenous populations in Colombia, South America, where gastric cancer rates are high.57 In children aged 4 to 8 years, those infected with H pylori grew an average of 0.022 cm/month slower than H pylori–negative children after adjustment for age, sex, and height (95% CI, 0.008-0.035; Figure 1).58 In a multivariate mixed model of 295 school-aged children that adjusted for age, sex, father’s education, and number of siblings, children who were negative for H pylori infection or who cleared the infection grew significantly faster than children positive for H pylori infection (Figure 2).59
Studies have also demonstrated an association between H pylori infection and iron-deficiency anemia in children. For example, in a study of 688 children aged 7 to 11 years in native villages in southwestern Alaska, 91% of those with iron deficiency also tested positive for H pylori infection.60 In addition, H pylori–infected children were more likely to have iron deficiency and iron-deficiency anemia than uninfected children. Once the infection was cleared, the iron deficiency and the iron-deficiency anemia resolved. In a study of 219 native Alaskan children aged 7 to 11 years who had H pylori infection and iron deficiency, treatment and eradication of H pylori resulted in a significant reduction in iron deficiency and anemia (Figure 3).61 Compared with H pylori–positive children in the control group, H pylori–negative children in the treatment group had a lower prevalence of iron deficiency (adjusted relative risk, 0.62 [95% CI, 0.38-1.01]) and iron deficiency and anemia (adjusted relative risk, 0.22 [95% CI, 0.03-1.50]).
H pylori may play a role in the pathogenesis of ITP. A number of studies evaluating H pylori eradication and ITP have been conducted in children, albeit with conflicting results. For example, in a randomized controlled trial that included 16 children with ITP and H pylori infection, there was no positive effect of H pylori eradication on platelet recovery.62 In contrast, a prospective, controlled multicenter study of children with ITP, including 50 patients who also tested positive for H pylori, found that platelet recovery occurred in 39% of patients who had successful H pylori eradication (33 of 37) vs 10% of H pylori–negative patients who experienced spontaneous remission (17 of 166; P<.005).63 Although the data from these studies did not demonstrate definitive causality between H pylori infection and ITP disease, they suggest that gastric colonization by this organism may result in more systemic immune-mediated effects than previously believed.
Impact on Health as an Adult
Early exposure to infections may predispose individuals to chronic disease, as well as significantly increase the risk of gastric cancer.54 The impact on health as an adult highlights the need for eradication. Although data now suggest that H pylori might have once been part of the human microflora, the fact remains that if this infection is left untreated, it can have a significant impact on adult health.64-66
Acknowledgment
Dr Gold was paid by Otsuka America Pharmaceutical, Inc. for participation in this roundtable and development of this monograph. Dr Gold is a consultant and scientific advisor for Otsuka Pharmaceuticals, Inc. and Takeda Pharmaceuticals. He is a consultant and speaker for Nestle USA and Mead Johnson Nutritionals.
References
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18. Malaty HM, Evans DG, Evans DJ Jr, Graham DY. Helicobacter pylori in Hispanics: comparison with blacks and whites of similar age and socioeconomic class. Gastroenterology. 1992;103(3):813-816.
19. Malaty HM, Graham DY, Wattigney WA, Srinivasan SR, Osato M, Berenson GS. Natural history of Helicobacter pylori infection in childhood: 12-year follow-up cohort study in a biracial community. Clin Infect Dis. 1999;28(2):279-282.
20. Epplein M, Signorello LB, Zheng W, et al. Race, African ancestry, and Helicobacter pylori infection in a low-income United States population. Cancer Epidemiol Biomarkers Prev. 2011;20(5):826-834.
21. Handt LK, Fox JG, Dewhirst FE, et al. Helicobacter pylori isolated from the domestic cat: public health implications. Infect Immun. 1994;62(6):2367-2374.
22. Dore MP, Bilotta M, Vaira D, et al. High prevalence of Helicobacter pylori infection in shepherds. Dig Dis Sci. 1999;44(6):1161-1164.
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24. Fujimura S, Kato S, Watanabe A. Water source as a Helicobacter pylori transmission route: a 3-year follow-up study of Japanese children living in a unique district. J Med Microbiol. 2008;57(pt 7):909-910.
25. Levine A, Milo T, Broide E, et al. Influence of Helicobacter pylori eradication on gastroesophageal reflux symptoms and epigastric pain in children and adolescents. Pediatrics. 2004;113(1 pt 1):54-58.
26. McCallion WA, Bailie AG, Ardill JE, Bamford KB, Potts SR, Boston VE. Helicobacter pylori, hypergastrinaemia, and recurrent abdominal pain in children. J Pediatr Surg. 1995;30(3):427-429.
27. Macarthur C. Helicobacter pylori infection and childhood recurrent abdominal pain: lack of evidence for a cause and effect relationship. Can J Gastroenterol. 1999;13(7):607-610.
28. Bode G, Brenner H, Adler G, Rothenbacher D. Recurrent abdominal pain in children: evidence from a population-based study that social and familial factors play a major role but not Helicobacter pylori infection. J Psychosom Res. 2003;54(5):417-421.
29. Tindberg Y, Nyrén O, Blennow M, Granström M. Helicobacter pylori infection and abdominal symptoms among Swedish school children. J Pediatr Gastroenterol Nutr. 2005;41(1):33-38.
30. Gil JH, Seo JW, Cho MS, Ahn JH, Sung HY. Role of Treg and TH17 cells of the gastric mucosa in children with Helicobacter pylori gastritis. J Pediatr Gastroenterol Nutr. 2014;58(2):252-258.
31. Serelli-Lee V, Ling KL, Ho C, et al. Persistent Helicobacter pylori specific Th17 responses in patients with past H. pylori infection are associated with elevated gastric mucosal IL-1β. PLoS One. 2012;7(6):e39199.
32. Guarner J, Bartlett J, Whistler T, et al. Can pre-neoplastic lesions be detected in gastric biopsies of children with Helicobacter pylori infection? J Pediatr Gastroenterol Nutr. 2003;37(3):309-314.
33. Elitsur Y, Dementieva Y, Rewalt M, Lawrence Z. Helicobacter pylori infection rate decreases in symptomatic children: a retrospective analysis of 13 years (1993–2005) from a gastroenterology clinic in West Virginia. J Clin Gastroenterol. 2009;43(2):147-151.
34. Ukarapol N, Lertprasertsuk N, Wongsawasdi L. Recurrent abdominal pain in children: the utility of upper endoscopy and histopathology. Singapore Med J. 2004;45(3):121-124.
35. Das BK, Kakkar S, Dixit VK, Kumar M, Nath G, Mishra OP. Helicobacter pylori infection and recurrent abdominal pain in children. J Trop Pediatr. 2003;49(4):250-252.
36. Kivi M, Tindberg Y, Sörberg M, et al. Concordance of Helicobacter pylori strains within families. J Clin Microbiol. 2003;41(12):5604-5608.
37. Cervantes DT, Fischbach LA, Goodman KJ, Phillips CV, Chen S, Broussard CS. Exposure to Helicobacter pylori-positive siblings and persistence of Helicobacter pylori infection in early childhood. J Pediatr Gastroenterol Nutr. 2010;50(5):481-485.
38. You WC, Brown LM, Zhang L, et al. Randomized double-blind factorial trial of three treatments to reduce the prevalence of precancerous gastric lesions. J Natl Cancer Inst. 2006;98(14):974-983.
39. Zhou LY, Lin SR, Ding SG, et al. The changing trends of the incidence of gastric cancer after Helicobacter pylori eradication in Shandong area. Chin J Dig Dis. 2005;6(3):114-115.
40. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA. 2004;291(2):187-194.
41. Lane JA, Murray LJ, Noble S, et al. Impact of Helicobacter pylori eradication on dyspepsia, health resource use, and quality of life in the Bristol helicobacter project: randomised controlled trial. BMJ. 2006;332(7535):199-204.
42. Fujiwara Y, Higuchi K, Arafa UA, et al. Long-term effect of Helicobacter pylori eradication on quality of life, body mass index, and newly developed diseases in Japanese patients with peptic ulcer disease. Hepatogastroenterology. 2002;49(47):1298-1302.
43. Buzás GM. Quality of life in patients with functional dyspepsia: short- and long-term effect of Helicobacter pylori eradication with pantoprazole, amoxicillin, and clarithromycin or cisapride therapy: a prospective, parallel-group study. Curr Ther Res Clin Exp. 2006;67(5):305-320.
44. Moayyedi P, Feltbower R, Brown J, et al; Leeds HELP Study Group. Effect of population screening and treatment for Helicobacter pylori on dyspepsia and quality of life in the community: a randomised controlled trial. Lancet. 2000;355(9216):1665-1669.
45. Bektas M, Soykan I, Altan M, Alkan M, Ozden A. The effect of Helicobacter pylori eradication on dyspeptic symptoms, acid reflux and quality of life in patients with functional dyspepsia. Eur J Intern Med. 2009;20(4):419-423.
46. Suerbaum S, Michetti P. Helicobacter pylori infection. N Engl J Med. 2002;347(15):1175-1186.
47. Sherman P, Czinn S, Drumm B, et al. Helicobacter pylori infection in children and adolescents: Working Group Report of the First World Congress of Pediatric Gastroenterology, Hepatology, and Nutrition. J Pediatr Gastroenterol Nutr. 2002;35(suppl 2):S128-S133.
48. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PG. Helicobacter pylori–associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991;338(8776):1175-1176.
49. Eidt S, Stolte M, Fischer R. Helicobacter pylori gastritis and primary gastric non-Hodgkin’s lymphomas. J Clin Pathol. 1994;47(5):436-439.
50. Claviez A, Meyer U, Dominick C, Beck JF, Rister M, Tiemann M. Brief Report: MALT lymphoma in children: a report from the NHL-BFM Study Group. Pediatr Blood Cancer. 2006;47(2):210-214.
51. Berrebi D, Lescoeur B, Faye A, Faure C, Vilmer E, Peuchmaur M. MALT lymphoma of labial minor salivary gland in an immunocompetent child with a gastric Helicobacter pylori infection. J Pediatr. 1998;133(2):290-292.
52. Blecker U, McKeithan TW, Hart J, Kirschner BS. Resolution of Helicobacter pylori-associated gastric lymphoproliferative disease in a child. Gastroenterology. 1995;109(3):973-977.
53. Ohno Y, Kosaka T, Muraoka I, et al. Remission of primary low-grade gastric lymphomas of the mucosa-associated lymphoid tissue type in immunocompromised pediatric patients. World J Gastroenterol. 2006;12(16):2625-2628.
54. Guarner J, Bartlett J, Whistler T, et al. Can pre-neoplastic lesions be detected in gastric biopsies of children with Helicobacter pylori infection? J Pediatr Gastroenterol Nutr. 2003;37(3):309-314.
55. Harting MT, Blakely ML, Herzog CE, Lally KP, Ajani JA, Andrassy RJ. Treatment issues in pediatric gastric adenocarcinoma. J Pediatr Surg. 2004;39(8):e8-e10.
56. Sasaki H, Sasano H, Ohi R, et al. Adenocarcinoma at the esophageal gastric junction arising in an 11-year-old girl. Pathol Int. 1999;49(12):1109-1113.
57. Piazuelo MB, Correa P. Gastric cancer: overview. Colomb Med (Cali). 2013;44(3):192-201.
58. Goodman KJ, Correa P, Mera R, et al. Effect of Helicobacter pylori infection on growth velocity of school-age Andean children. Epidemiology. 2011;22(1):118-126.
59. Mera RM, Bravo LE, Goodman KJ, Yepez MC, Correa P. Long-term effects of clearing Helicobacter pylori on growth in school-age children. Pediatr Infect Dis J. 2012;31(3):263-266.
60. Baggett HC, Parkinson AJ, Muth PT, Gold BD, Gessner BD. Endemic iron deficiency associated with Helicobacter pylori infection among school-aged children in Alaska. Pediatrics. 2006;117(3):e396-e404.
61. Fagan RP, Dunaway CE, Bruden DL, Parkinson AJ, Gessner BD. Controlled, household-randomized, open-label trial of the effect of treatment of Helicobacter pylori infection on iron deficiency among children in rural Alaska: results at 40 months. J Infect Dis. 2009;199(5):652-660.
62. Treepongkaruna S, Sirachainan N, Kanjanapongkul S, et al. Absence of platelet recovery following Helicobacter pylori eradication in childhood chronic idiopathic thrombocytopenic purpura: a multi-center randomized controlled trial. Pediatr Blood Cancer. 2009;53(1):72-77.
63. Russo G, Miraglia V, Branciforte F, et al; AIEOP-ITP Study Group. Effect of eradication of Helicobacter pylori in children with chronic immune thrombocytopenia: a prospective, controlled, multicenter study. Pediatr Blood Cancer. 2011;56(2):273-278.
64. Brawner KM, Morrow CD, Smith PD. Gastric microbiome and gastric cancer. Cancer J. 2014;20(3):211-216.
65. Wu WM, Yang YS, Peng LH. Microbiota in the stomach: new insights. J Dig Dis. 2014;15(2):54-61.
66. Sheh A, Fox JG. The role of the gastrointestinal microbiome in Helicobacter pylori pathogenesis. Gut Microbes. 2013;4(6):505-531.
Diagnosis of Helicobacter pylori Infection in Pediatric Patients
Mark A. Gilger, MD
Pediatrician-in-Chief, Children’s Hospital of San Antonio, San Antonio, Texas, Professor & Vice Chair, Department of Pediatrics, Baylor College of Medicine, Houston, Texas
There are no specific symptoms of H pylori infection in children. Upper gastrointestinal symptoms, such as recurrent abdominal pain, are not an immediate indication for treatment of H pylori infection. The current ESPGHAN and NASPGHAN guidelines do not recommend diagnostic testing for H pylori infection in children experiencing pain, nausea, or other dyspeptic symptoms, owing to the nonspecific nature of these events.1 Several studies have failed to find an association or causal relationship between abdominal pain and H pylori infection.2-4 In contrast, symptoms of peptic ulcer disease, such as epigastric pain and upper gastrointestinal bleeding, are suggestive of H pylori infection.5 Children with these symptoms should undergo diagnostic evaluation for the infection.5
Since symptoms are nonspecific, other factors will help determine whether a symptomatic child should be tested for H pylori infection.1 Children living in poor socioeconomic conditions may benefit from testing.1 Since rates of H pylori are higher in developing countries, children who have lived in these areas are at higher risk.1 The presence of an immediate family member with gastric adenocarcinoma or gastric MALT lymphoma is a definite indication for pediatric diagnostic testing.1
ESPGHAN and NASPGHAN guidelines also recommend H pylori diagnostic testing for children with iron-deficiency anemia or anemia that is unresponsive to oral iron therapy, when other causes have been ruled out.1 Although several studies have found an association between iron deficiency and H pylori infection, there are conflicting study data regarding whether treatment of H pylori infection corrects iron-deficiency anemia.6-8
Invasive Testing
Diagnostic testing can be divided into invasive and noninvasive methods. Invasive testing consists of an upper gastrointestinal endoscopy and biopsy followed by culture, rapid urease testing, histopathology, polymerase chain reaction, or fluorescence in situ hybridization (FISH) to assess whether H pylori is present in the gastric tissue (Table 1). At this time, upper endoscopy with biopsy is the gold standard for diagnosing H pylori infection in children. The ESPGHAN and NASPGHAN guidelines recommend at least 2 tests to confirm H pylori infection: positive histopathology plus a positive rapid urease test or a positive culture.1 To determine negative H pylori status, 2 or 3 negative results from invasive tests are necessary.1 It is important to remember that the use of antibiotics and proton pump inhibitors can confound test results. As such, these medications should be discontinued for 2 to 4 weeks prior to H pylori testing.1,9,10
Invasive testing is led by histology, which is more than 90% sensitive and specific, widely available, and easily performed but expensive.11 The benefit of histopathology is that it may identify the underlying disease pathology (eg, gastritis and intestinal metaplasia). Culture of biopsy specimens is somewhat less sensitive than histopathology, but 100% specific; however, this approach is expensive, somewhat complicated, and not widely available.12,13 Rapid urease testing tends to be more specific than histology; these tests are approximately 95% sensitive and 85% specific.11,13,14 Although these assays obtain very rapid results, they require an invasive approach, which is more difficult in the pediatric population.
Noninvasive Testing
Noninvasive testing includes antibody testing of the serum, urine, or saliva; the fecal antigen test of stool; and the urea breath test (Table 2). Although the ESPGHAN and NASPGHAN guidelines state that endoscopy should be a component of the initial diagnosis of H pylori,1 other authors suggest that a noninvasive test, such as the fecal antigen test or the urea breath test, may be sufficient.5,15 Antibody testing is not recommended for diagnosis of H pylori infection.1
Antibody Testing
ESPGHAN and NASPGHAN guidelines state that detection of H pylori–specific antibodies in the serum, whole blood, urine, and saliva is not reliable enough for a clinical diagnosis in children.1 This recommendation is supported by a high grade of evidence from studies showing that the sensitivity and specificity of assays that detect H pylori antibodies vary in children.1 In particular, variability has been observed in serologic testing of children in different age groups.16 In a study of 130 consecutive children who underwent upper gastrointestinal endoscopy, 68 were positive for H pylori infection. With the use of a second-generation enzyme-linked immunosorbent assay (ELISA), H pylori–specific immunoglobulin G (IgG) antibodies were detected in only 79% of the infected children and 8% of the uninfected children. The sensitivity of the assay was low in children aged 2 to 6 years (44%). Sensitivity improved in older children, to 76.7% in those aged 7 to 11 years and 93.1% in those aged 12 to 16 years. In addition, results varied according to the commercial assay used, particularly in younger children.17 Although newer serologic assays have improved sensitivity,18,19 results of a multicenter European study found that patient age continues to be a factor.20
Sensitivity varies widely among the different serologic modalities, from 40% to 99%, but specificity is high (>90%).15 Although serology testing kits are widely available and relatively inexpensive, they are of no value after treatment owing to the presence of long-lasting H pylori–specific IgG antibodies; patients can remain positive for H pylori–specific IgG antibodies for months to years after the resolution of infection.5
Commercial kits are available to detect H pylori–specific IgG antibodies in saliva, but this approach has proven to be relatively insensitive. In a population-based study of 477 children, the sensitivity of the salivary ELISA was 80.9% (95% CI, 66.3%-90.4%), and the specificity was 95.3% (95% CI, 92.7%-97.1%).21 In another study, the sensitivity of the oral-fluid–based ELISA was only 76.2% (specificity, 94.0%) in children ages 2 months to 2.5 years; the sensitivity improved to 81% in children ages 5 years and older.22 In a comparison with gastric biopsy histology, the sensitivity of the oral-fluid–based ELISA was 71% (specificity, 90.4%).22
Sensitivity of the anti–H pylori IgG antibody testing in urine varies from 90% to 100%. This test provides rapid results and is easy to perform, but the length of time needed to prove eradication is unknown. In a study of 101 Japanese children (age range, 2-15 years; median, 7 years), this test had a 91.9% sensitivity (96.9% specificity) and an accuracy of 95.0%.23 In the same study, an immunochromatography-based assay for antibodies in the urine had a much lower sensitivity of 78.4% (100% specificity) and an accuracy of 92.1%.23
The Fecal Antigen Test
Fecal antigen testing remains a very good, reliable, and reasonably priced screening test for H pylori infection, both before and after eradication.5,15,24 Although this test is inexpensive, it requires a stool collection, which may be difficult or off-putting for some patients. ESPGHAN and NASPGHAN guidelines indicate that a validated ELISA for H pylori detection in stool can reliably determine whether H pylori has been eradicated in children.1 This test may be easier to collect in children younger than 3 years than the urea breath test. In addition, the age of the patient does not appear to influence the accuracy of the results.25 In a study of 302 symptomatic children (age range, 6 months-18.7 years), 92 children tested positive for H pylori infection by culture, histology, the rapid urease test, and the 13C urea breath test.25 A monoclonal enzyme immunoassay had a 98% sensitivity and a 99% specificity for H pylori detection in the stool samples of these children.
The monoclonal enzyme immunoassay appears to have greater sensitivity and specificity than the polyclonal enzyme immunoassays.1,26 A meta-analysis was recently conducted to determine the accuracy of the fecal antigen test for the diagnosis of H pylori infection in children.27 The analysis included 45 studies and 5931 patients. The overall pooled sensitivity was 92%, and the pooled specificity was 94%. A subgroup analysis revealed that sensitivity (96.2% [95% CI, 94.9%-97.2%]) and specificity (94.7% [95% CI, 93.6%-95.6%]) were higher with the monoclonal enzyme immunoassay compared with the polyclonal enzyme immunoassays (sensitivity, 88.0% [95% CI, 85.0%-90.5%]; specificity, 93.0% [95% CI, 91.3%-94.5%]) and the rapid 1-step tests (sensitivity, 88.1% [95% CI, 85.2%-90.6%]); specificity, 94.2% [95% CI, 92.5%-95.5%]).
The Urea Breath Test
The 13C urea breath test is a reliable noninvasive test for eradication of H pylori infection in children.1 Guidelines from the American College of Gastroenterology state that it can be used for diagnosis.5 The 13C urea breath test is associated with high sensitivity and specificity.1 This test is not radioactive, in contrast to the 14C urea breath test.28 The 13C urea test is relatively inexpensive. As with the fecal antigen test, the ESPGHAN and NASPGHAN guidelines indicate that the 13C urea breath test can reliably determine whether H pylori has been eradicated in children with high accuracy, specificity, and sensitivity.1
Among children and adolescents, the 13C urea breath test has a sensitivity of more than 95% and a specificity of 93% to 97%.19,29 In a multicenter European study that compared the specificity and sensitivity of the 13C urea breath test, the fecal antigen test, antibody detection in serum, and antibody detection in urine, the 13C urea breath test had the highest sensitivity (96%) among the 4 noninvasive approaches.19 In a prospective study conducted in the United States, the 13C urea breath test had a sensitivity of 98% and a specificity of 96%.30 It should be noted that diagnostic accuracy may be lower in children younger than 6 years, owing to increased false-positive results.31-33 As the pediatric community becomes more familiar with the 13C urea breath test, it could become as common as fecal antigen testing.
Selecting the Best Option for Each Patient
In a child, the best option is a noninvasive test. The fecal antigen test and the urea breath test are simple and noninvasive approaches for detecting H pylori infection, and they have potential for use as screening tests in the pediatric population. However, the gold standard for diagnosis remains a positive histopathology plus a positive rapid urease test or a positive culture.1 At this time, ESPGHAN and NASPGHAN guidelines recommend against the test-and-treat approach for pediatric patients based on a lack of supporting evidence.1 The guidelines emphasize that the goal of testing in pediatric patients is to determine the underlying cause of the symptoms, not merely the presence of H pylori.1
Acknowledgment
Dr Gilger was paid by Otsuka America Pharmaceutical, Inc. for participation in this roundtable and development of this monograph. Dr Gilger is a consultant for Otsuka.
References
1. Koletzko S, Jones NL, Goodman KJ, et al; H pylori Working Groups of ESPGHAN and NASPGHAN. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53(2):230-243.
2. Macarthur C. Helicobacter pylori infection and childhood recurrent abdominal pain: lack of evidence for a cause and effect relationship. Can J Gastroenterol. 1999;13(7):607-610.
3. Bode G, Brenner H, Adler G, Rothenbacher D. Recurrent abdominal pain in children: evidence from a population-based study that social and familial factors play a major role but not Helicobacter pylori infection. J Psychosom Res. 2003;54(5):417-421.
4. Tindberg Y, Nyrén O, Blennow M, Granström M. Helicobacter pylori infection and abdominal symptoms among Swedish school children. J Pediatr Gastroenterol Nutr. 2005;41(1):33-38.
5. Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):1808-1825.
6. Choe YH, Kim SK, Son BK, Lee DH, Hong YC, Pai SH. Randomized placebo-controlled trial of Helicobacter pylori eradication for iron-deficiency anemia in preadolescent children and adolescents. Helicobacter. 1999;4(2):135-139.
7. Kurekci AE, Atay AA, Sarici SU, et al. Is there a relationship between childhood Helicobacter pylori infection and iron deficiency anemia? J Trop Pediatr. 2005;51(3):166-169.
8. Gessner BD, Baggett HC, Muth PT, et al. A controlled, household-randomized, open-label trial of the effect that treatment of Helicobacter pylori infection has on iron deficiency in children in rural Alaska. J Infect Dis. 2006;193(4):537-546.
9. Leung WK, Hung LC, Kwok CK, Leong RW, Ng DK, Sung JJ. Follow up of serial urea breath test results in patients after consumption of antibiotics for non-gastric infections. World J Gastroenterol. 2002;8(4):703-706.
10. Gatta L, Vakil N, Ricci C, et al. Effect of proton pump inhibitors and antacid therapy on 13C urea breath tests and stool test for Helicobacter pylori infection. Am J Gastroenterol. 2004;99(5):823-829.
11. Pourakbari B, Ghazi M, Mahmoudi S, et al. Diagnosis of Helicobacter pylori infection by invasive and noninvasive tests. Braz J Microbiol. 2013;44(3):795-798.
12. Gold BD, Colletti RB, Abbott M, et al; North American Society for Pediatric Gastroenterology and Nutrition. Helicobacter pylori infection in children: recommendations for diagnosis and treatment. J Pediatr Gastroenterol Nutr. 2000;31(5):490-497.
13. Guarner J, Kalach N, Elitsur Y, Koletzko S. Helicobacter pylori diagnostic tests in children: review of the literature from 1999 to 2009. Eur J Pediatr. 2010;169(1):15-25.
14. Elitsur Y, Hill I, Lichtman SN, Rosenberg AJ. Prospective comparison of rapid urease tests (PyloriTek, CLO test) for the diagnosis of Helicobacter pylori infection in symptomatic children: a pediatric multicenter study. Am J Gastroenterol. 1998;93(2):217-219.
15. Leal YA, Flores LL, García-Cortés LB, Cedillo-Rivera R, Torres J. Antibody-based detection tests for the diagnosis of Helicobacter pylori infection in children: a meta-analysis. PLoS One. 2008;3(11):e3751.
16. de Oliveira AM, Rocha GA, Queiroz DM, et al. Evaluation of enzyme-linked immunosorbent assay for the diagnosis of Helicobacter pylori infection in children from different age groups with and without duodenal ulcer. J Pediatr Gastroenterol Nutr. 1999;28(2):157-161.
17. Kindermann A, Konstantopoulos N, Lehn N, Demmelmair H, Koletzko S. Evaluation of two commercial enzyme immunoassays, testing immunoglobulin G (IgG) and IgA responses, for diagnosis of Helicobacter pylori infection in children. J Clin Microbiol. 2001;39:3591-3596.
18. Ueda J, Okuda M, Nishiyama T, Lin Y, Fukuda Y, Kikuchi S. Diagnostic accuracy of the E-plate serum antibody test kit in detecting Helicobacter pylori infection among Japanese children. J Epidemiol. 2014;24(1):47-51.
19. Iqbal S, Fatima S, Raheem A, Khan AH. Agreement between serology and histology for detection of Helicobacter pylori infection. J Coll Physicians Surg Pak. 2013;23(10):784-786.
20. Mégraud F; European Paediatric Task Force on Helicobacter pylori. Comparison of non-invasive tests to detect Helicobacter pylori infection in children and adolescents: results of a multicenter European study. J Pediatr. 2005;146(2):198-203.
21. Bode G, Marchildon P, Peacock J, Brenner H, Rothenbacher D. Diagnosis of Helicobacter pylori infection in children: comparison of a salivary immunoglobulin G antibody test with the [(13)C]urea breath test. Clin Diagn Lab Immunol. 2002;9(2):493-495.
22. Gilger MA, Tolia V, Johnson A, et al. The use of an oral fluid immunoglobulin G ELISA for the detection of Helicobacter pylori infection in children. Helicobacter. 2002;7(2):105-110.
23. Okuda M, Kamiya S, Booka M, et al. Diagnostic accuracy of urine-based kits for detection of Helicobacter pylori antibody in children. Pediatr Int. 2013;55(3):337-341.
24. Leal YA, Cedillo-Rivera R, Simón JA, Velázquez JR, Flores LL, Torres J. Utility of stool sample-based tests for the diagnosis of Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;52(6):718-728.
25. Koletzko S, Konstantopoulos N, Bosman D, et al. Evaluation of a novel monoclonal enzyme immunoassay for detection of Helicobacter pylori antigen in stool from children. Gut. 2003;52(6):804-806.
26. Makristathis A, Barousch W, Pasching E, et al. Two enzyme immunoassays and PCR for detection of Helicobacter pylori in stool specimens from pediatric patients before and after eradication therapy. J Clin Microbiol. 2000;38(10):3710-3714.
27. Zhou X, Su J, Xu G, Zhang G. Accuracy of stool antigen test for the diagnosis of Helicobacter pylori infection in children: a meta-analysis [Epub ahead of print]. Clin Res Hepatol Gastroenterol. Published online March 10, 2014. doi:10.1016/j.clinre.2014.02.001.
28. Logan RP. Urea breath tests in the management of Helicobacter pylori infection. Gut. 1998;43(suppl 1):S47-S50.
29. Kawakami E, Machado RS, Reber M, Patrício FR. 13 C-urea breath test with infrared spectroscopy for diagnosing helicobacter pylori infection in children and adolescents. J Pediatr Gastroenterol Nutr. 2002;35(1):39-43.
30. Elitsur Y, Tolia V, Gilger MA, et al. Urea breath test in children: the United States prospective, multicenter study. Helicobacter. 2009;14(2):134-140.
31. Yang HR, Ko JS, Seo JK. Does the diagnostic accuracy of the 13C-urea breath test vary with age even after the application of urea hydrolysis rate? Helicobacter. 2008;13(4):239-244.
32. Machado RS, Patrício FR, Kawakami E, et al. 13C-urea breath test to diagnose Helicobacter pylori infection in children aged up to 6 years. Helicobacter. 2004;9(1):39-45.
33. Imrie C, Rowland M, Bourke B, Drumm B. Limitations to carbon 13-labeled urea breath testing for Helicobacter pylori in infants. J Pediatr. 2001;139(5):734-737.
34. Taj Y, Essa F, Kazmi SU, Abdullah E. Sensitivity and specificity of various diagnostic tests in the detection of Helicobacter pylori. J Coll Physicians Surg Pak. 2003;13(2):90-93.
35. Perez-Perez GI. Accurate diagnosis of Helicobacter pylori. Culture, including transport. Gastroenterol Clin North Am. 2000;29(4):879-884.
36. Koumi A, Filippidis T, Leontara V, Makri L, Panos MZ. Detection of Helicobacter pylori: a faster urease test can save resources. World J Gastroenterol. 2011;17(3):349-353.
37. Ozaslan E, Koseoglu T, Purnak T, Yildiz A. A forgotten cause of false negative rapid urease test: formalin contamination of the sample. Hepatogastroenterology. 2010;57(99-100):2.
38. FDA.gov. FDA approves first Helicobacter pylori breath test for children. http://www.fda.gov/NewsEvents/Newsroom/pressAnnouncements/ucm293278.htm. Posted February 12, 2012. Accessed September 10, 2014.
39. BreathTek [package insert]. Rockville, MD: Otsuka America Pharmaceutical; April 2014.
40. Luzza F, Oderda G, Maletta M, et al. Salivary immunoglobulin G assay to diagnose Helicobacter pylori infection in children. J Clin Microbiol 1997;35:3358-3360.
41. Rothenbacher D, Inceoglu J, Brenner H. Acquisition of Helicobacter pylori infection in a high-risk population occurs within the first 2 years of life. J Pediatr. 2000;136:744-748.
Treatment Options for Pediatric Patients With Helicobacter pylori Infection
Steven J. Czinn, MD
Professor and Chair, Department of Pediatrics, University of Maryland School of Medicine, Physician-in-Chief, University of Maryland, Children’s Hospital, Baltimore, Maryland
The current dogma is to treat H pylori infection because of its associated disease burden, which includes dyspepsia, gastroduodenal ulcerative diseases, MALT lymphoma, and gastric malignancies. The first step in the management of a pediatric patient with H pylori infection is to confirm that a reliable test was used to diagnose the infection. The ESPGHAN and NASPGHAN guidelines recommend that diagnosis be based on a positive histopathology plus a positive rapid urease test or a positive culture.1 Other authors suggest that a noninvasive test, such as the fecal antigen test or the urea breath test, can be used.2,3 Routine serology is not sensitive or specific enough in children to be used for diagnosis.1
After confirmation of an accurate diagnosis, the next step is to discuss with the family whether the child should receive treatment. In most cases, the recommendation should be to eradicate H pylori, which always causes aggressive histologic inflammation in the stomach whether the child has symptoms or not. Eradicating H pylori in children dramatically decreases the risk that they will develop peptic ulcer disease or gastric cancer later in life.1 Treatment is currently recommended for pediatric patients who have H pylori–positive peptic ulcer disease, H pylori infection detected by biopsy-based methods in the absence of peptic ulcer disease, or H pylori infection and a first-degree relative with gastric cancer.4 Treatment is not indicated for pediatric patients with recurrent functional abdominal pain because this nonspecific symptom can be caused by several diseases or disorders.1,5
A provocative question is whether there is ever a situation in which therapy for H pylori infection should be withheld. Generally speaking, a diagnosed infection should be treated. However, treatment of H pylori remains controversial even 20 years after its discovery. Some studies have suggested that infection with H pylori might be beneficial for children, at least for a period of time. This benefit is related to asthma and allergies.6-9 For example, in a study of 6959 children ages 5 to 18 years (average age, 12.4±3.5 years) who underwent urea breath testing, 45.6% were positive for H pylori infection and 8.3% had asthma.8 There was a significant inverse relationship between H pylori infection and asthma in these children; among H pylori–positive children, the rate of asthma was 7.3% compared with 9.1% in H pylori–negative children (odds ratio [OR], 0.82 [95% CI, 0.69-0.98]; P=.032). In addition, a recent longitudinal birth-cohort study of 863 Ethiopian children assessed at ages 1 year, 3 years, and 5 years found that H pylori infection at age 3 years was significantly associated with a decreased risk of eczema (adjusted OR, 0.31 [95% CI, 0.10-0.94]; P=.02).10 In addition, the study found an inverse association between H pylori infection and skin sensitization at age 5 (adjusted OR, 0.26 [95% CI, 0.07-0.92]; P=.02).10 However, several studies found no relationship between H pylori–infection status and allergies or asthma, and therefore the evidence is currently inconclusive.11-14 It may be prudent to withhold or delay treatment in a child with a very strong family history of asthma and allergy or in a child suffering from symptoms of these conditions. With the exception of those rare situations, once a pediatric patient receives a diagnosis of H pylori infection based on a reliable test, the approach is to provide treatment in an effort to eradicate the infection.
Treatment Approaches
The NASPGHAN and ESPGHAN 2011 guidelines for H pylori infection in children recommend triple therapy as a first-line eradication regimen (Table 3).1 The general treatment regimen for H pylori infection for children, as well as adults, consists of 3 medications: a proton pump inhibitor, amoxicillin, and an additional antibiotic, usually either clarithromycin or metronidazole (Table 4).1,15 The guidelines also recommended bismuth salts plus amoxicillin and metronidazole as an alternative first-line therapy. Triple therapy should be administered for 7 to 14 days.1,15 Clinicians should emphasize the necessity for patients to complete the entire prescribed regimen.
After treatment, it is important to follow-up with testing to confirm eradication because antibiotic resistance is a pervasive concern, and eradication rates are far from optimal.2 Four to 8 weeks after completing therapy, pediatric patients should be tested to confirm H pylori eradication using the urea breath test or the fecal antigen test.1,16 It is important to remember that the absence of symptoms is not a reliable measure of H pylori eradication.
Numerous studies have examined other approaches to the treatment of H pylori infection. One such approach is sequential therapy, in which the proton pump inhibitor and amoxicillin are started before the third antibiotic. Several clinical trials have shown that sequential therapy has better eradication rates than conventional triple therapy.17-19 In a double-blind, randomized, controlled trial, 107 children with confirmed H pylori infection were treated with a sequential regimen (amoxicillin and omeprazole for 5 days followed by clarithromycin, tinidazole, and omeprazole for 5 days) or a 7-day standard triple-eradication regimen (amoxicillin, clarithromycin, and omeprazole).20 Six to 8 weeks after treatment, the eradication rates in children who received sequential therapy were significantly higher than in children treated with the standard triple therapy (86.5% vs 68.6%; relative risk, 1.26 [95% CI, 1.02-1.60]). Comparable eradication rates were observed in randomized controlled trials conducted in Kenya17 and China.18 In both of these studies, sequential regimens had higher eradication rates than standard triple-therapy regimens (81%-85% vs 49%-61.9%, respectively). Although the mechanisms behind the improved eradication rates are not completely understood, some investigators believe that because the organism does not become resistant to amoxicillin, administration of the amoxicillin/proton pump inhibitor combination in the first 5 days will dramatically decrease the bacterial load and help protect against clarithromycin resistance. After that initial 5-day period, there is less likelihood that resistance will develop when the other antibiotic is added. At this time, many clinicians believe that sequential therapy is better than standard triple therapy; some data support the use of sequential therapy as first-line treatment.21
Several studies have examined the addition of probiotics to standard triple therapy. A recent meta-analysis evaluated randomized controlled trials in pediatric patients that compared the use of H pylori eradication therapy with probiotic supplementation vs the same eradication therapy with placebo or no extra intervention.22 The analysis included 7 studies with 508 patients. The ORs of eradication rates in the probiotic group vs the control group were 1.96 (95% CI, 1.28-3.02) in the intent-to-treat analysis and 2.25 (95% CI, 1.41-3.57) in the per protocol analysis. Although most of these 7 studies demonstrated some efficacy in terms of symptom improvement, eradication rates were not significantly improved with probiotics. For example, in a study of 68 H pylori–positive children treated with either standard triple therapy (omeprazole, amoxicillin, and clarithromycin) alone or triple therapy plus a probiotic, the eradication rates were higher in the group that received probiotics (88% vs 76%), although the difference was not significant (P=.10).23 The patients receiving probiotics experienced significantly fewer episodes of epigastric pain, nausea, vomiting, and diarrhea. However, a recent double-blind, randomized, placebo-controlled study of 66 children with confirmed H pylori infection (median age, 9.09 years [range, 3-14 years]) found that the eradication rate was significantly higher in the children who received probiotics along with triple therapy (omeprazole, amoxicillin, and furazolidon) than in the children who received placebo plus triple therapy (90% vs 70%; P=.04).24 The addition of probiotics also reduced the rate of nausea/vomiting (P=.02) and diarrhea (P=.04). It is important to keep in mind that different probiotics, as well as different triple therapies, were used across the various studies. Additional studies are needed to definitively determine the effect of probiotics on H pylori eradication in children.
Eradication and Resistance
When treating H pylori infection, the goal is to achieve an eradication rate of at least 90% with first-line therapy.4 Successful eradication is important to prevent the development of antibiotic resistance, as well as to reduce the number of treatments and procedures. Among children receiving the standard triple-therapy regimen, eradication rates are declining.1 In part, this decrease can be attributed to increasing antibiotic resistance (Table 5).25 Unfortunately, H pylori becomes resistant to most antimicrobials, with the exception of amoxicillin, easily and quickly.26,27
H pylori can also develop resistance to clarithromycin—one of the mainstay drugs for treatment—and metronidazole.2 High resistance rates of 16% to 27% for clarithromycin and 25% for metronidazole have been observed.24-28 The end result is that the standard triple therapies, with either clarithromycin or metronidazole, are no longer providing outstanding eradication results. As such, it is important for the clinician to be aware of local resistance rates when choosing the initial therapy.
Treatment outcomes are severely impacted by primary antibiotic resistance. Clarithromycin resistance significantly reduces the efficacy of the standard triple therapy.29,30 Children may be highly susceptible to secondary antibiotic resistance; in a 12-year observation study from Belgium, 46% of children acquired secondary antibiotic resistance after primary eradication failure.27 This finding highlights the importance of eradicating the H pylori infection during first-line treatment.
It is important for clinicians to be aware of the rates of antibiotic resistance in their geographic area when selecting first-line therapy for H pylori infection. In areas of high clarithromycin resistance (≥20%), such as Spain, Turkey, Italy (the central region), Alaska, China, Japan, and Cameroon, it is recommended that standard triple therapy not be used.31 Low levels of clarithromycin resistance are still found in other parts of the world, including the Netherlands, Sweden, Ireland, Germany, Malaysia, and Taiwan (the southern region); in these areas, treatment with the standard triple therapy still results in high eradication rates.31 For those geographic areas known to have high resistance rates to clarithromycin, antibiotic sensitivity testing should be performed before therapy is initiated.4,31
Management After Treatment Failure
When treatment fails, the ESPGHAN and NASPGHAN guidelines recommend: 1) performing endoscopy with culture and susceptibility testing; 2) testing for clarithromycin susceptibility in paraffin-embedded biopsy samples (if this test was not performed before the initial therapy); and 3) modifying treatment to include alternate agents than were used in the initial therapy (such as different antibiotics), adding bismuth, and/or increasing the dose and duration of treatment (Table 6).1 Salvage regimens include a proton pump inhibitor plus metronidazole, amoxicillin, and bismuth; or a triple therapy with a proton pump inhibitor plus levofloxacin (moxifloxacin) and amoxicillin.1 It is important that patients are not re-treated with the same antibiotic that was administered during first-line treatment. (One exception would be if sensitivity assays indicate that the patient still might respond to such treatment.1)
One of the more recent novel approaches for the treatment of H pylori infection is concomitant therapy. This 4-drug regimen includes a proton pump inhibitor, amoxicillin, clarithromycin, and metronidazole (or tinidazole).32,33 In essence, 2 triple therapies are being administered at the same time. If treatment is extended from 5 days to 14 days, eradication rates reach 86% for first-line therapy.33 As a salvage therapy, concomitant therapy has been shown to be effective in eradicating H pylori infection in patients with dual antibiotic resistance, resulting in eradication rates of 75% (vs 92.4% for patients without dual antibiotic resistance).32 Similar results were achieved in a study from Spain, which found that concomitant therapy resulted in the eradication of 100% of clarithromycin-resistant infections and 75% of dual-resistant H pylori infections.34 Given the success of concomitant therapy, many practices are moving toward incorporating this regimen into the treatment of H pylori infection. The standard 14-day triple therapies are becoming obsolete in many practices, particularly in areas with considerable antibiotic resistance.
Several newer antibiotics, such as rifabutin, are under investigation for the treatment of H pylori infection. Rifabutin-based triple therapy is showing good results in areas with high levels of resistance.35 A 10-day course of rifabutin (300 mg) with pantoprazole and amoxicillin in patients with eradication failure after standard triple therapy resulted in an eradication rate of 86%.36 In a prospective multicenter study of patients who had failed 3 prior H pylori treatments, a regimen of rifabutin (150 mg), amoxicillin (1 g), and a proton pump inhibitor resulted in an H pylori eradication rate of 52% (95% CI, 41%-63%).37 It should be noted that neither of these studies was conducted in pediatric patients.
Another agent under investigation in H pylori is nitazoxanide, which is used to treat diarrhea. A recent report demonstrated that a 4-drug regimen consisting of levofloxacin, omeprazole, nitazoxanide, and doxycycline resulted in better efficacy and eradication rates than standard triple therapy (Figure 4).38
Conclusion
There is still much to learn about the treatment of H pylori infection. Eradication rates are falling owing to rising antibiotic resistance. Unfortunately, there are many situations in which a child with H pylori is treated multiple times and, despite compliance, the infection is not eradicated.
Acknowledgment
Dr Czinn was paid by Otsuka America Pharmaceutical, Inc. for participation in this roundtable and development of this monograph.
References
1. Koletzko S, Jones NL, Goodman KJ, et al; H pylori Working Groups of ESPGHAN and NASPGHAN. Evidence-based guidelines from ESPGHAN and NASPGHAN for Helicobacter pylori infection in children. J Pediatr Gastroenterol Nutr. 2011;53(2):230-243.
2. Chey WD, Wong BC; Practice Parameters Committee of the American College of Gastroenterology. American College of Gastroenterology guideline on the management of Helicobacter pylori infection. Am J Gastroenterol. 2007;102(8):1808-1825.
3. Leal YA, Flores LL, García-Cortés LB, Cedillo-Rivera R, Torres J. Antibody-based detection tests for the diagnosis of Helicobacter pylori infection in children: a meta-analysis. PLoS One. 2008;3(11):e3751.
4. Gilger MA. Diagnosis of Helicobacter pylori infection in pediatric patients. Gastroenterol Hepatol (N Y). 2014;10(suppl 6):9-12.
5. Gold BD. Helicobacter pylori infection in pediatric patients: introduction. Gastroenterol Hepatol (N Y). 2014;10(suppl 6):3-8.
6. Chen Y, Blaser MJ. Helicobacter pylori colonization is inversely associated with childhood asthma. J Infect Dis. 2008;198(4):553-560.
7. von Hertzen LC, Laatikainen T, Mäkelä MJ, et al. Infectious burden as a determinant of atopy—a comparison between adults in Finnish and Russian Karelia. Int Arch Allergy Immunol. 2006;140(2):89-95.
8. Zevit N, Balicer RD, Cohen HA, Karsh D, Niv Y, Shamir R. Inverse association between Helicobacter pylori and pediatric asthma in a high-prevalence population. Helicobacter. 2012;17(1):30-35.
9. Amberbir A, Medhin G, Erku W, et al. Effects of Helicobacter pylori, geohelminth infection and selected commensal bacteria on the risk of allergic disease and sensitization in 3-year-old Ethiopian children. Clin Exp Allergy. 2011;41(10):1422-1430.
10. Amberbir A, Medhin G, Abegaz WE, et al. Exposure to Helicobacter pylori infection in early childhood and the risk of allergic disease and atopic sensitization: a longitudinal birth cohort study. Clin Exp Allergy. 2014;44(4):563-571.
11. Jarvis D, Luczynska C, Chinn S, Burney P. The association of hepatitis A and Helicobacter pylori with sensitization to common allergens, asthma and hay fever in a population of young British adults. Allergy. 2004;59(10):1063-1067.
12. Annagür A, Kendirli SG, Yilmaz M, Altintas DU, Inal A. Is there any relationship between asthma and asthma attack in children and atypical bacterial infections; Chlamydia pneumoniae, Mycoplasma pneumoniae and Helicobacter pylori. J Trop Pediatr. 2007;53(5):313-318.
13. Fullerton D, Britton JR, Lewis SA, Pavord ID, McKeever TM, Fogarty AW. Helicobacter pylori and lung function, asthma, atopy and allergic disease—a population-based cross-sectional study in adults. Int J Epidemiol. 2009;38(2):419-426.
14. Raj SM, Choo KE, Noorizan AM, Lee YY, Graham DY. Evidence against Helicobacter pylori being related to childhood asthma. J Infect Dis. 2009;199(6):914-915.
15. Khurana R, Fischbach L, Chiba N, et al. Meta-analysis: Helicobacter pylori eradication treatment efficacy in children. Aliment Pharmacol Ther. 2007;25(5):523-536.
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New Diagnostic Strategies for Detection of Helicobacter pylori Infection in Pediatric Patients: Discussion
G&H Should serology be used as a screening test?
Benjamin D. Gold, MD Many published studies have demonstrated that commercially available assays are not a good testing option, particularly because they lack validation in the populations for which they are used. Despite clear recommendations in the ESPGHAN and NASPGHAN guidelines that serology is not a reliable indicator of H pylori infection, we continue to have patients sent to us from other pediatric gastroenterologists who use serology as a screening test.
G&H What are some recent findings on treatment?
Mark A. Gilger, MD As a general statement regarding treatment, the fact that there are so many regimens for eradication and yet suboptimal success highlights how little we understand about H pylori.
Benjamin D. Gold, MD Yes, I agree. Following the initial discovery of H pylori, there was a stretch of 10 to 15 years in which every randomized controlled trial published, particularly in adults, showed eradication rates of 95% to 100%. Currently, eradication rates have dropped dramatically and much faster than the overall prevalence of the organism, which has stabilized. Many years ago, when eradication rates were so high, physicians did not often test for eradication after treatment. However, it is now absolutely critical to test for a cure and to make sure that the organism has been eradicated even if the symptoms have resolved. Given that there are so many regimens available, it is absolutely critical that there is more research to find the best options for the clinician to use, particularly in areas where there are higher rates of resistance.
Mark A. Gilger, MD To emphasize the point, if you are not going to test for cure, then treatment does not make much sense. If you are treating to eradicate H pylori, you must make sure you actually did so.
Steven J. Czinn, MD I completely agree.
G&H Are there any misconceptions in the community setting about H pylori?
Benjamin D. Gold, MD There is a need for ongoing up-to-date education in the community. I still see patients who have been tested with serology, or who were treated with the wrong course of an eradication regimen. Although awareness of the organism has risen, the relative awareness of the appropriate approaches in management methodologies has not. This lack of knowledge has contributed to the increasing rates of eradication failure and resistance.
Mark A. Gilger, MD It is important for the general practitioner to understand that abdominal pain in children is multifactorial, and that eradicating H pylori is the right course of action. By eradicating H pylori infection, the risk of ulcer disease and gastric cancer later in life decreases. Also, eradication will normalize the lining of the stomach and significantly reduce inflammation. However, in 50% of cases with successful eradication, patients continue to have stomach pain, which reinforces the point that abdominal pain in children has many etiologies. As such, the physician should never guarantee that the stomach pain will resolve once the infection is gone. Nevertheless, it is important for physicians to recognize that they still should treat the infection.
G&H Do family members of children with H pylori need to be tested?
Benjamin D. Gold, MD When recurrent infection occurs, one of the first things that comes to mind with enteric infections is transmission among family members. The important thing to recognize with H pylori infection is that not all patients will develop immediate symptoms, and if symptoms do occur, they may not be specific for the infection. This creates a dilemma when deciding whom to test for infection. However, if you have a patient with diagnosed H pylori infection who is treated and the infection either persists or, more importantly, recurs, then I would consider testing other family members. To echo what both Dr Czinn and Dr Gilger said, a noninvasive test for infection, namely, the 13C urea breath test or the fecal antigen test, should be used. If H pylori is detected in the family member, I would treat and then test for cure after therapy is completed.
Mark A. Gilger, MD It is important to screen children adopted from the developing world to make sure that they are H pylori–negative, since the infection rate is so high in developing countries. We have had situations where we believe that the adopted child, who was not screened or treated, was responsible for infecting the other family members with H pylori. As a result, we have had to treat all of the family members.
Benjamin D. Gold, MD Yes, we have had the same situation.
Steven J. Czinn, MD Those are very good points. Children are often the reservoirs of H pylori infection, and they are unaware that they are infected. As such, they are going to transmit the infection. Children adopted from the developing world should definitely be screened.
Acknowledgment
Drs Gold, Gilger, and Czinn were paid by Otsuka America Pharmaceutical, Inc. for participation in this roundtable and development of this monograph. Dr Gold is a consultant and scientific advisor for Otsuka Pharmaceuticals, Inc. and Takeda Pharmaceuticals. He is a consultant and speaker for Nestle USA and Mead Johnson Nutritionals. Dr Gilger is a consultant for Otsuka.