Joint ESPGHAN/NASPGHAN guidelines for the management of helicobacter pylori in children and adolescents (Update 2016)

BACKGROUND: Because of the changing epidemiology of Helicobacter pylori infection and low efficacy of currently recommended therapies, an update of the European Society for Paediatric Gastroenterology Hepatology and Nutrition/North American Society for Pediatric Gastroenterology, Hepatology and Nutrition recommendations for the diagnosis and management of H pylori infection in children and adolescents is required. METHODS: A systematic review of the literature (time period: 2009-2014) was performed. Representatives of both societies evaluated the quality of evidence using GRADE (Grading of Recommendation Assessment, Development, and Evaluation) to formulate recommendations, which were voted upon and finalized using a Delphi process and face-to-face meeting. RESULTS: The consensus group recommended that invasive diagnostic testing for H pylori be performed only when treatment will be offered if tests are positive. To reach the aim of a 90% eradication rate with initial therapy, antibiotics should be tailored according to susceptibility testing. Therapy should be administered for 14 days, emphasizing strict adherence. Clarithromycin-containing regimens should be restricted to children infected with susceptible strains. When antibiotic susceptibility profiles are not known, high-dose triple therapy with proton pump inhibitor, amoxicillin, and metronidazole for 14 days or bismuth-based quadruple therapy is recommended. Success of therapy should be monitored after 4 to 8 weeks by reliable noninvasive tests. CONCLUSIONS: The primary goal of clinical investigation is to identify the cause of upper gastrointestinal symptoms rather than H pylori infection. Therefore, we recommend against a test and treat strategy. Decreasing eradication rates with previously recommended treatments call for changes to first-line therapies and broader availability of culture or molecular-based testing to tailor treatment to the individual child.

Upper gastrointestinal bleeding in haemophiliacs: incidence and relation to use of non-steroidal anti-inflammatory drugs.

This multicentre study sought to estimate the incidence of upper gastrointestinal (UGI) bleeding in haemophiliacs and its relationship to use of non-steroidal anti-inflammatory drugs (NSAIDs). Cox models were used to estimate relative hazards (RH) with 95% confidence intervals (CI) for postulated risk factors. Conditional logistic regression and stored sera were used to assess UGI bleeding risk with Heliobacter pylori seropositivity in cases compared with closely matched controls. During a mean of 17.4 months (range 2-34), 2285 participants, ages 13-89 (mean 36.5) were followed for 3309 person-years (py). Forty-two experienced a UGI bleeding event (incidence 1.3 per 100 py), most from ulcer (11), gastritis (four), varices (five) and Mallory Weiss tears (eight). RH was significantly increased with traditional NSAID use for <1 month (OR: 3.66; 95% CI: 1.1-11.9), but not with coxibs use. RH was significantly and independently increased with age >46 years (3.5; 95% CI: 1.1-10.6) and hepatic decompensation (4.4; 95% CI: 1.7-11.6). Likelihood of bleeding was substantially but not significantly increased (OR: 4.6; 95% CI: 0.3-83.9) with H. pylori seropositivity. These findings suggest that coxibs are a safer alternative than traditional NSAIDs in the treatment of haemophilic arthropathy.

Meta-analysis: Helicobacter pylori eradication treatment efficacy in children.

BACKGROUND: Several meta-analyses assessing the efficacy of anti-Helicobacter pylori treatment in adults have been published but a comparable meta-analysis in children is lacking. AIMS: To summarize the efficacy of treatments aimed at eradicating H. pylori in children and to identify sources of variation in treatment efficacy across studies. METHODS: We searched Medline, reference lists from published study reports, and conference proceedings for anti-H. pylori treatment trials in children. Weighted meta-regression models were used to find sources of variation in efficacy. RESULTS: Eighty studies (127 treatment arms) with 4436 children were included. Overall, methodological quality of these studies was poor with small sample sizes and few randomized-controlled trials. The efficacy of therapies varied across treatment arms, treatment duration, method of post-treatment assessment and geographic location. Among the regimens tested, 2-6 weeks of nitroimidazole and amoxicillin, 1-2 weeks of clarithromycin, amoxicillin and a proton pump inhibitor, and 2 weeks of a macrolide, a nitroimidazole and a proton pump inhibitor or bismuth, amoxicillin and metronidazole were the most efficacious in developed countries. CONCLUSIONS: Before worldwide treatment recommendations are given for eradication of H. pylori, additional well-designed randomized placebo-controlled paediatric trials are needed, especially in developing countries where both drug resistance and disease burden is high.

Review article: epidemiology and management of gastro-oesophageal reflux in children.

The management of gastro-oesophageal reflux disease (GERD) continues to garner vast amounts of attention among physicians who care for adults. However, there is an increasing awareness of the fact that this disease, as well as several other lifelong digestive diseases (i.e. Crohn's disease) may actually have their origins in childhood. Paediatric gastro-oesophageal reflux (GER) is likely to share a similar pathophysiology to adult GER, and mounting evidence from published preliminary data suggests a genetic susceptibility to GERD. However, further studies will be necessary to confirm this hypothesis. In children, GER has a distinct presentation from that in adults, with the diagnostic work-up based upon the patient's age as well as their presenting signs and symptoms. Like their adult counterparts, the early detection and treatment of GER in children may result in a better long-term outcome, improved quality-of-life, and a reduction in overall healthcare burden. While the treatment of GER in infants tends to be conservative (i.e. positioning during feeding, smaller feedings), its management in older children parallels that of adults and includes lifestyle changes and pharmacological therapy. However, with persistent symptoms, acid suppression is the mainstay of GERD management in both children and adults. Several studies in children have verified that acid suppression with a proton pump inhibitor is superior to histamine-2 receptor antagonists. Among the proton pump inhibitors, both lansoprazole and omeprazole have been the subject of published adult and paediatric studies demonstrating their short and long-term safety, in addition to their efficacy in a variety of oesophageal and supra-oesophageal GERD related conditions. These two proton pump inhibitors are manufactured as capsules containing enteric-coated granules that can be emptied into soft foods or liquids without compromising their pharmacological effects or pharmacokinetic properties. Lansoprazole is also available as a strawberry-flavoured suspension that is acceptable to children and as an oral disintegrating tablet.

Helicobacter pylori infection in children.

A number of scientific breakthroughs since H pylori first became recognized as a human pathogen have increased our understanding of the pathogenesis of gastroduodenal disease. In particular, advances in molecular bacteriology and the complete sequencing of the H pylori genome in 1999, and soon thereafter the human genome, provide tools allowing better delineation of the pathogenesis of disease. These molecular tools for both bacteria and host should now be applied to multicenter pediatric studies that evaluate disease outcome. More recent developments indicate that a better understanding of the microbial-host interaction is critical to furthering knowledge with respect to H pylori-induced diseases. Studies are needed to evaluate either DNA-based or more traditional protein-based vaccines, to evaluate more specific antimicrobials that confer minimal resistance, and to evaluate probiotics for the management of H pylori infection. Multicenter multinational studies of H pylori infection in the pediatric population, which include specific, randomized controlled eradication trials, are essential to extend current knowledge and develop better predictors of disease outcome.

New approaches to Helicobacter pylori infection in children.

Helicobacter pylori infection is usually acquired during childhood, and evidence-based guidelines regarding diagnosis and treatment of infected children have been recently published. Diseases associated with H. pylori infection are gastritis, duodenal ulcers, mucosal-associated lymphoid-type (MALT) lymphoma, and gastric adenocarcinoma. The association of specific symptoms with H. pylori infection in children and adults (ie, recurrent abdominal pain and nonulcer dyspepsia) remains controversial. Additionally, the role of H. pylori in gastroesophageal reflux disease or in extra-gastrointestinal diseases (ie, coronary artery disease) lacks sufficient evidence to demonstrate causality. The diagnosis of H. pylori-associated diseases in children can reliably be made through gastroduodenal endoscopy with biopsies. Clinical trials are underway for the validation of noninvasive diagnostic tests for the H. pylori-infected child, and current guidelines recommend eradication therapy for infected children with duodenal and gastric ulcer, gastric lymphoma, and atrophic gastritis with intestinal metaplasia. The natural history of childhood H. pylori infection is poorly described. Moreover, rational approaches to the prevention and control of childhood H. pylori infection are critically needed, requiring characterization of the determinants for acquisition and persistence and the disease outcomes following eradication.

Genotypic, clinical, and demographic characteristics of children infected with Helicobacter pylori.

Helicobacter pylori isolates vary between geographic regions. Certain H. pylori genotypes may be associated with disease outcome. Thirty-eight children underwent diagnostic upper endoscopy at four medical centers and were retrospectively analyzed to determine if H. pylori virulence genes were associated with endoscopic disease severity, histologic parameters, and host demographics. The H. pylori virulence genotype was analyzed by a reverse hybridization line probe assay and type-specific PCR. Endoscopic ulcers or erosions were found in 17 (45%) patients, with 13 (34%) of these patients having antral nodularity. Histological gastritis, of varying severity, was present in all children. Four patients harbored more than one H. pylori strain: one subject had both cagA(+) and cagA-negative strains, while three patients harbored either two different cagA-negative strains (two children) or two cagA(+) strains (one child). There were 28 (74%) cagA(+) isolates; 19 were associated with the vacA s1b genotype, 7 were associated with the vacA s1a genotype, 1 was associated with the vacA s1c genotype, and 1 was associated with the s2 genotype. Of 14 cagA-negative isolates, 6 were vacA s2 genotype, 4 were vacA s1b, 3 were vacA s1a, and 1 was vacA s1c. Nine of ten (90%) Hispanics had similar H. pylori strains (vacA s1b,m1), and all Asian-Canadian children were infected by strains with vacA s1c genotype. No correlation between H. pylori strain and endoscopic or histopathologic abnormalities was found. This study provides a baseline framework of North American children and their H. pylori strains, serving as a powerful epidemiological tool for prospective investigations to better understand the transmission and evolution of diverse disease outcomes.

Pretreatment with urea-hydrochloric acid enhances the isolation of Helicobacter pylori from contaminated specimens.

Human saliva seeded with H. pylori was incubated in urea-HCl and then cultured on nonselective media. Pretreatment with 0.06 N HCl-0.08 M urea for 5 min at 37 degrees C resulted in reproducible isolation of H. pylori, even at low inocula (< or =10(2) CFU/ml of saliva), despite the presence of large numbers of contaminating organisms.

Characteristics of Helicobacter pylori infection in Jamaican adults with gastrointestinal symptoms.

Helicobacter pylori infection is common in Jamaica. Describing its epidemiology in a population-based study depends largely on serology, but serologic assays have not been validated in this population. To address this issue, we examined the presence of H. pylori infection in 30 sequential adult patients with gastroduodenal symptoms by three biopsy-based methods (rapid urease test, histology, and culture) as well as by one research and two commercial enzyme-linked immunosorbent assays (ELISAs). A patient was considered H. pylori positive if the organism was detected by at least one biopsy-based method. Eighteen (60%) of the 30 patients were H. pylori positive by these criteria, whereas 21 (70%) were seropositive for H. pylori immunoglobulin G by our research ELISA. The presence of H. pylori infection in patients with gastric cancer and those with chronic gastritis was missed by biopsy-based methods but was detected by serologic assays. This observation indicates that serologic assays may be better suited for the detection of this infection in a population in which H. pylori-associated pathology is prevalent. The performance of our research ELISA in detecting biopsy-based H. pylori-positive cases was excellent, with a sensitivity and specificity of 100% and 75%, respectively. Molecular genotyping of the isolates revealed that the predominant H. pylori genotypes in this cohort of Jamaicans were cagA(+) vacA slb-m1, and iceA2. The validated serologic assay enables us to interpret epidemiologic data from population-based studies in Jamaica by comparison to those from other populations.

Helicobacter pylori gastritis in children and adults: comparative histopathologic study.

The inflammatory response to Helicobacter pylori in adults has been well characterized. In children, studies of H. pylori gastritis have been based on small numbers of patients and have used loose definitions of the inflammatory components. Comparative study of the inflammatory response to H. pylori in children and adults can help our understanding of the natural history of this infection. Using the Updated Sydney Classification, we performed a retrospective, blinded pathology review of gastric biopsy specimens from 42 children and 40 adults with H. pylori infection, and we quantified each inflammatory cell separately (neutrophils, lymphocytes, plasma cells, and eosinophils). Differences in inflammatory cell components of children and adults were assessed by logistic regression analysis. More children had marked amounts of H. pylori (P = .05) and mild degree of neutrophils (P = .02), plasma cells (P = .005), and eosinophils (P = .0001) compared with adults. No differences existed when quantifying mononuclear cells or atrophy. Ulcers and intestinal metaplasia were present only in adults. We found that the numbers of inflammatory cells present in H. pylori-infected biopsy specimens is different in children and adults. We hypothesize that these differences demonstrate how H. pylori infection evolves from an acute childhood infection to an adult chronic disease.

High prevalence of Helicobacter pylori in the Alaska native population and association with low serum ferritin levels in young adults.

Iron deficiency anemia is a common public health problem in the Alaska Native population. Yet, a clear etiology has eluded researchers for decades. Previous studies suggested a link between Helicobacter pylori infection, gastrointestinal blood loss due to hemorrhagic gastritis, and generalized iron deficiency anemia in adult Alaska Natives. Therefore, we examined the association between the prevalence of H. pylori-specific immunoglobulin G (IgG) and serum ferritin levels, a marker of iron deficiency. A random sample of 2,080 serum samples from Alaska Native residents drawn between 1980 and 1986 from residents in 13 regions was selected, and the samples were stratified by age, sex, and region. Overall, 75% were positive for H. pylori-specific IgG. The rate of H. pylori seropositivity increased with age; by age 14 years, 78% of the residents were positive. There were no gender differences in H. pylori seropositivity. However, marked regional differences were observed. Serum ferritin levels of <12 ng/ml were found most commonly among persons <20 years of age and among women of childbearing age. A significant association between low serum ferritin levels and prevalence of H. pylori-specific IgG was found, particularly for people aged less than 20 years. H. pylori may be a factor contributing to the iron deficiency anemia in the Alaska Native population.

The disease spectrum of Helicobacter pylori: the immunopathogenesis of gastroduodenal ulcer and gastric cancer.

Helicobacter pylori is a gram-negative bacterium that resides under microaerobic conditions in a neutral microenvironment between the mucus and the superficial epithelium of the stomach. From this site, it stimulates cytokine production by epithelial cells that recruit and activate immune and inflammatory cells in the underlying lamina propria, causing chronic, active gastritis. Although epidemiological evidence shows that infection generally occurs in children, the inflammatory changes progress throughout life. H. pylori has also been recognized as a pathogen that causes gastroduodenal ulcers and gastric cancer. These more severe manifestations of the infection usually occur later in life and in a minority of infected subjects. To intervene and protect those who might be at greatest risk of the more severe disease outcomes, it is of great interest to determine whether bacterial, host, or environmental factors can be used to predict these events. To date, several epidemiological studies have attempted to define the factors affecting the transmission of H. pylori and the expression of gastroduodenal disease caused by this infection. Many other laboratories have focused on identifying bacterial factors that explain the variable expression of clinical disease associated with this infection. An alternative hypothesis is that microorganisms that cause lifelong infections can ill afford to express virulence factors that directly cause disease, because the risk of losing the host is too great. Rather, we propose that gastroduodenal disease associated with H. pylori infection is predominantly a result of inappropriately regulated gastric immune responses to the infection. In this model, the interactions between the immune/inflammatory response, gastric physiology, and host repair mechanisms would dictate the disease outcome in response to infection.

Increased macrophage infiltration of gastric mucosa in Helicobacter pylori-infected children.

The purpose of the study was to quantify gastric mucosal macrophages and define their association with the histopathologic features of stomach biopsies obtained from Helicobacter pylori-infected and uninfected children. Endoscopically obtained gastric biopsies from symptomatic children were independently evaluated by two groups of pathologists. Thirty children were evaluated; 14 were H. pylori-infected. H. pylori positivity was determined by hematoxylin and eosin (H&E), Giemsa, Warthin-Starry and an H. pylori-specific immunoperoxidase stain. A macrophage-specific, KP-1, immunoperoxidase stain was used to quantify positive cells. Inflammatory cell infiltrates were graded by severity with scores of mild to severe. Increased numbers of gastric mucosal macrophages were observed in biopsies of H. pylori-infected versus uninfected children (P < 0.05) and correlated with gastritis severity. The role of this inflammatory cell the in persistence of gastric mucosal inflammation in H. pylori infection warrants further study to develop targeted immunotherapeutic strategies.

Seroprevalence of Helicobacter pylori infection in cystic fibrosis and its cross-reactivity with anti-pseudomonas antibodies.

BACKGROUND: The prevalence of Helicobacter pylori infection and its role in gastroduodenal disease in cystic fibrosis (CF) are controversial. Additionally, serologic determination of infection in this population may be inaccurate because of cross-reactivity with other bacterial species. The seroprevalence of H. pylori in a cohort of patients with CF and its cross-reactivity with Pseudomonas antibodies were investigated. METHODS: A research enzyme-linked immunosorbent assay (ELISA), and three commercial serologic assays (PyloriStat; BioWhittaker, Walkersville, MD, U.S.A.; Flexsure; SmithKline Diagnostics, Inc., San Jose, CA, U.S.A.; and HM-CAP; EPI, Stony Brook, NY, U.S.A.) at three independent laboratories determined the seroprevalence of anti-H. pylori IgG antibodies in 70 patients with CF. Cross-reactivity between solid-phase H. pylori antigens and Pseudomonas antibodies was ascertained by a competitive inhibition assay, preadsorbing sera of patients with CF with whole cell proteins from different Pseudomonas species, and serum reanalysis by each assay. Western blot analysis before and after adsorption was performed to identify potential cross-reactive antigens. RESULTS: The research ELISA, Flexsure, Pyloristat, and HM-CAP initially showed H. pylori seropositivity of 47%, 28%, 24%, and 37%, respectively. Postadsorption seropositivity declined to 8%, 0%, 0%, and 15%, respectively. All patients with research ELISA true-positive results were confirmed endoscopically to have H. pylori infection. Western blot analysis showed a 31-kDa H. pylori protein with antigenic epitopes common to both bacterial species. CONCLUSIONS: Cross-reactivity between solid-phase H. pylori antigens and anti-Pseudomonas antibodies occurs in patients with CF. A high index of suspicion should be assumed in evaluating results of serologic H. pylori tests in this population. Preadsorption of CF sera with Pseudomonas proteins should be used in serologic testing.

A comprehensive review of the natural history of Helicobacter pylori infection in children.

Across populations of children, Helicobacter pylori prevalence ranges from under 10% to over 80%. Low prevalence occurs in the U.S., Canada, and northern and western Europe; high prevalence occurs in India, Africa, Latin America, and eastern Europe. Risk factors include socioeconomic status, household crowding, ethnicity, migration from high prevalence regions, and infection status of family members. H. pylori infection is not associated with specific symptoms in children; however, it is consistently associated with antral gastritis, although its clinical significance is unclear. Duodenal ulcers associated with H. pylori are seldom seen in children under 10 years of age. H. pylori-infected children demonstrate a chronic, macrophagic, and monocytic inflammatory cell infiltrate and a lack of neutrophils, as compared with the response observed in adults. The effect of H. pylori infection on acid secretion in children remains poorly defined. The events that occur during H. pylori colonization in children should be studied more thoroughly and should include urease activity, motility, chemotaxis, adherence, and downregulation of the host response. The importance of virulence determinants described as relevant for disease during H. pylori infection has not been extensively studied in children. Highly sensitive and specific methods for the detection of H. pylori in children are needed, especially in younger pediatric populations in which colonization is in its early phases. Criteria for the use of eradication treatment in H. pylori-infected children need to be established. Multicenter pediatric studies should focus on the identification of risk factors, which can be used as prognostic indicators for the development of gastroduodenal disease later in life.

Current therapy for Helicobacter pylori infection in children and adolescents.

Helicobacter pylori infects approximately 50% of the world's population and is a definitive cause of gastroduodenal disease (ie, gastritis, duodenal and gastric ulcers) in children and adults. Four consensus conferences held around the globe have brought together clinicians, scientists, epidemiologists and health care economists to discuss the role of the gastric pathogen H pylori in human gastroduodenal disease. At each of these conferences, the overriding objective was to reach a consensus on the development of practical guidelines for the diagnosis and treatment of H pylori-infected individuals. However, it was not until the Canadian H pylori Consensus Conference, held in November 1997, that the issues of H pylori infection in children were addressed. Therapies for H pylori infection in children, presented in part at the First Canadian Pediatric H pylori Consensus Conference, held in Victoria, British Columbia, November 1998, are reviewed in this paper.

Gastritis and peptic ulcer disease in childhood.

UNLABELLED: Inflammation of the gastric and duodenal mucosa is the end result of an imbalance between mucosal defensive and aggressive factors. The degree of inflammation and imbalance between defensive and aggressive factors can then result in varying degrees of gastritis and/or frank mucosal ulceration. Gastritis and ulcers of the duodenum or stomach can be classified either as primary or secondary. The majority of children with chronic active or chronic gastritis and ulcers in the stomach or duodenum have secondary inflammation or mucosal ulceration. These ulcers generally occur due to a systemic condition like head trauma or overwhelming sepsis, or, as sequelae to drug ingestion (i.e., non-steroidal anti-inflammatory agents), but secondary gastroduodenal ulcers can also occur in specific disease conditions such as Zollinger-Ellison syndrome or Crohn's disease. The different causes of gastritis and peptic ulcer disease will be discussed in this paper. CONCLUSION: In almost all children presenting to their treating pediatric gastroenterologist with duodenal or gastric ulcers of these patients, mucosal inflammation and less frequently, ulceration is caused by a spiral shaped, gram-negative, microaerobic rod, properly named Helicobacter pylori. Recent epidemiological evidence has linked chronic H. pylori infection with the development of gastric carcinomas.