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.

Paediatrician and Caregiver Awareness of Cryptosporidiosis and Giardiasis in Children: US Survey Responses.

There appears to be no published information concerning the awareness and knowledge about diarrhoea caused by Cryptosporidium spp. or Giardia lamblia among US paediatricians and caregivers of young children. Two concurrent, separate surveys were conducted among paediatricians and caregivers (~1000 respondents in each survey) of children ages 1-12 years concerning their knowledge, perceptions and attitudes in the diagnosis and treatment of parasitic diarrhoea. Awareness of parasite-induced diarrhoea was low for specific aspects among both paediatricians and caregivers. Educational efforts to improve awareness on the appropriate clinical presentation, management and treatment of cryptosporidiosis and giardiasis in children with persistent diarrhoea should be undertaken.

Gastric LTi cells promote lymphoid follicle formation but are limited by IRAK-M and do not alter microbial growth.

Lymphoid tissue inducer (LTi) cells are activated by accessory cell IL-23, and promote lymphoid tissue genesis and antibacterial peptide production by the mucosal epithelium. We investigated the role of LTi cells in the gastric mucosa in the context of microbial infection. Mice deficient in IRAK-M, a negative regulator of TLR signaling, were investigated for increased LTi cell activity, and antibody mediated LTi cell depletion was used to analyze LTi cell dependent antimicrobial activity. H. pylori infected IRAK-M deficient mice developed increased gastric IL-17 and lymphoid follicles compared to wild type mice. LTi cells were present in naive and infected mice, with increased numbers in IRAK-M deficient mice by two weeks. Helicobacter and Candida infection of LTi cell depleted rag1(-/-) mice demonstrated LTi-dependent increases in calprotectin but not RegIII proteins. However, pathogen and commensal microbiota populations remained unchanged in the presence or absence of LTi cell function. These data demonstrate LTi cells are present in the stomach and promote lymphoid follicle formation in response to infection, but are limited by IRAK-M expression. Additionally, LTi cell mediated antimicrobial peptide production at the gastric epithelium is less efficacious at protecting against microbial pathogens than has been reported for other tissues.

Famotidine for infant gastro-oesophageal reflux: a multi-centre, randomized, placebo-controlled, withdrawal trial.

BACKGROUND: Gastro-oesophageal reflux afflicts up to 7% of all infants. Histamine-2 receptor antagonists are the most commonly prescribed medications for this disorder, but few controlled studies support this practice. AIM: To evaluate the safety and efficacy of famotidine for infant gastro-oesophageal reflux disease. METHODS: Thirty-five infants, 1.3-10.5 months of age, entered an 8-week, multi-centre, randomized, placebo-controlled, two-phase trial: first 4 weeks, observer-blind comparison of famotidine 0.5 mg/kg and famotidine 1.0 mg/kg; second 4 weeks, double-blind withdrawal comparison (safety and efficacy) of each dose with placebo. RESULTS: No serious adverse events were reported. Eleven patients had 16 non-serious, possibly drug-related adverse experiences: 6 patients with agitation or irritability (manifested as head-rubbing in two), 3 patients with somnolence, 2 patients with anorexia, 2 with headache, 1 patient with vomiting, 1 patient with hiccups, and 1 patient with candidiasis. Of the 35 infants, 27 completed Part I. There were significant score improvements for famotidine 0.5 mg/kg in regurgitation frequency (P = 0.04), and for famotidine 1.0 mg/kg in crying time (P = 0.027) and regurgitation frequency (P = 0.004) and volume (P = 0.01). Eight infants completed Part II on double-blind treatment, which was insufficient for meaningful comparisons. CONCLUSIONS: Histamine-2 receptor antagonists may cause agitation and headache in infants. A possibly efficacious famotidine dose for infants is 0.5 mg/kg (frequency adjusted for age). As 1.0 mg/kg may be more efficacious in some, the dosage may require individualization based on response. Further sizeable placebo-controlled evaluations of histamine-2 receptor antagonists in infants with gastro-oesophageal reflux disease are warranted.

Pneumatosis intestinalis and diarrhea in a child following renal transplantation.

Pneumatosis intestinalis is an uncommon finding beyond the neonatal period, but it has been reported in immunocompromized pediatric patients. The association of pneumatosis intestinalis in children following renal transplantation has to the best of our knowledge been only reported once in children. We describe a 4-year-old female who developed intermittent emesis, weight loss, and intermittently loose bloody stools after cadaveric renal transplantation at age 3.5 years. An abdominal x-ray demonstrated extensive pneumatosis in the colon. The infectious work-up was negative. Histologically, she had increased eosinophils throughout the lamina propria in the rectum. A glucose breath test was suggestive of small bowel bacterial overgrowth. She was treated with 10 days of metronidazole with resolution of the diarrhea and occult blood in stools. One month after the treatment she had radiologic resolution of her pneumatosis. Based on this report, pneumatosis intestinalis should be considered in the differential diagnosis of children after organ transplant suffering from diarrhea, abdominal pain, or blood in the stool.

Protective anti-Helicobacter immunity is induced with aluminum hydroxide or complete Freund's adjuvant by systemic immunization.

To determine whether systemic immunization against Helicobacter pylori could be achieved with an adjuvant approved for human use, the efficacy of vaccination with Helicobacter antigen in combination with aluminum hydroxide (AlOH) was evaluated in a murine model of Helicobacter infection. Immunization with antigen and AlOH induced interleukin-5-secreting, antigen-specific T cells, and immunization with antigen and complete Freund's adjuvant induced interferon-gamma-secreting, antigen-specific T cells, as determined by ELISPOT assay. Both immune responses conferred protection after challenge with either H. pylori or H. felis, as confirmed by the complete absence of any bacteria, as assessed by both histology and culture of gastric biopsy samples. Protection was antibody independent, as demonstrated with antibody-deficient muMT mice (immunoglobulin-gene knockout mice), and CD4(+) spleen T cells from immunized mice were sufficient to transfer protective immunity to otherwise immunodeficient rag1(-/-) recipients. These results suggest an alternative and potentially more expeditious strategy for development of a human-use H. pylori vaccine.

Techniques for the evaluation of dyspepsia in children.

Dyspepsia can describe a subset of children with episodic or persistent abdominal symptoms--often related to feeding--that are thought to be caused by disorders of the proximal part of the digestive tract. Symptoms, such as vomiting, early satiety, postprandial epigastric abdominal pain, heartburn, abdominal fullness, poor weight gain, and/or anorexia, have been incorporated into the definition of dyspepsia. Unfortunately, presenting signs and symptoms in children with dyspepsia are nonspecific and can occur as a result of many diseases, such as parasitic infections, esophagitis, eosinophilic gastroenteritis, Helicobacter pylori infection, Crohn's disease, biliary tract or hepatic disease, pancreatitis, and lactose intolerance. This lack of specificity makes the evaluation of dyspepsia more difficult. Here, we describe an approach for the evaluation of dyspepsia that correlates in part with the child's presenting symptoms.

gamma-Glutamyltransferase is a Helicobacter pylori virulence factor but is not essential for colonization.

The contribution of glutamyl transpeptidase (GGT) (gamma-glutamyltransferase [EC 2. 3. 2. 2]) to Helicobacter pylori virulence was investigated in piglets and mice using GGT-deficient isogenic strains. All animals became colonized. However, the bacterial load was significantly lower for mutant bacteria than for parent strains. These results suggest that GGT activity provides an advantage to H. pylori in colonization.

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.

Immunology of Helicobacter pylori and prospects for vaccine.

Since the initial discovery of H. pylori by Marshall and Warren 17 years ago, much progress has been made in treating this infection. However, as we enter the millennium, H. pylori infection continues to be one of the most common infections of mankind. In addition, eradication of H. pylori still requires multiple antimicrobial agents. A better understanding of the host immune response to H. pylori infection should allow investigators to develop immunotherapies to prevent the acquisition of infection and eradicate existing chronic H. pylori infection.

Helicobacter pylori infection in children: update.

Despite its worldwide distribution, the pathogenesis of Helicobacter pylori associated gastroduodenal disease remains poorly understood. What is clear is that H. pylori infection rarely resolves spontaneously and that the chronic gastritis that accompanies infection is typically maintained for the duration of infection. Ultimately, if untreated, this chronic inflammation predisposes a subset of individuals to develop gastric or duodenal ulcers and even gastric cancer. Chronic long-lasting H. pylori infection, particularly when acquired early in childhood, can predispose an individual to a significantly increased risk of developing gastric cancer. These studies were so compelling that the World Health Organization has recently classified H. pylori as a type 1 human carcinogen. Since the discovery of H. pylori less than 20 years ago, this infection has continued to generate considerable interest in the medical and scientific community. As we enter the new millenium, there are now a number of effective treatments for children in whom H. pylori-associated peptic ulcer disease is diagnosed. Although there is now overwhelming evidence to confirm that H. pylori plays an etiologic role in the development of peptic ulcer disease, only a small number of these children develop H. pylori disease. In this review, we highlight some of the recently published pediatric studies addressing the role H. pylori plays in the development of gastroduodenal disease in children.

Differences in genotypes of Helicobacter pylori from different human populations.

DNA motifs at several informative loci in more than 500 strains of Helicobacter pylori from five continents were studied by PCR and sequencing to gain insights into the evolution of this gastric pathogen. Five types of deletion, insertion, and substitution motifs were found at the right end of the H. pylori cag pathogenicity island. Of the three most common motifs, type I predominated in Spaniards, native Peruvians, and Guatemalan Ladinos (mixed Amerindian-European ancestry) and also in native Africans and U.S. residents; type II predominated among Japanese and Chinese; and type III predominated in Indians from Calcutta. Sequences in the cagA gene and in vacAm1 type alleles of the vacuolating cytotoxin gene (vacA) of strains from native Peruvians were also more like those from Spaniards than those from Asians. These indications of relatedness of Latin American and Spanish strains, despite the closer genetic relatedness of Amerindian and Asian people themselves, lead us to suggest that H. pylori may have been brought to the New World by European conquerors and colonists about 500 years ago. This thinking, in turn, suggests that H. pylori infection might have become widespread in people quite recently in human evolution.

Local and systemic antibody responses in humans with Helicobacter pylori infection.

Immunization can prevent or cure an otherwise chronic helicobacter infection in several animal models despite the chronic nature of natural helicobacter infections. Differences in the antigenic specificity of the antibodies may contribute to the protection observed in these experimental animals. The goal of the present study was to compare the local and systemic antibody responses of humans with chronic Helicobacter pylori infection with those of an individual with spontaneous resolution of infection to find an immunological correlate of protection. Spontaneous resolution of infection was accompanied by a change in immunoblot profiles. Whereas a broad range of H pylori antigens was recognized in chronically infected patients (including the patient who ultimately cleared the infection spontaneously), resolution of infection in the absence of therapeutic agents resulted in the recognition of only several immunodominant antigens. The most dominant antigen was approximately 66 kDa in molecular mass. Immunoblot analysis demonstrated that these antibodies were specific for the structural subunits of the urease enzyme. These studies suggest that the success of antihelicobacter immunization may be due to the ability of vaccination to induce an immune response against antigens that are normally not immunodominant during the course of infection.

Normalizing results of 13C-urea breath testing for CO2 production rates in children.

BACKGROUND: The 13C-urea breath test detects the presence of Helicobacter pylori from an enrichment of breath 13CO2, which, in turn, is critically dependent on the amount of dilution by endogenous CO2 production. The production of CO2 differs according to age (adults > children), sex (male > female) weight, and height. The cutoff value of 2.4 delta%(delta over baseline, DOB) for the 13C-urea breath test, defined in adults, does not take into account actual CO2 production. Therefore, this cutoff value (2.4 delta%) may or may not be appropriate for children. The purpose of this study was to determine a cutoff value that would provide accurate results in pediatric patients, independent of their differences in anthropometric parameters. METHODS: Estimates of CO2 production were combined with DOB values to calculate the host-dependent urea hydrolysis rate. RESULTS: Calculated as urea hydrolysis rate, the cutoff range for adults was 10.4 to 10.9 microg/min. Individual ranges were concentric (men, 9.6-10.9 microg/min; women, 8.5-12.2 microg/min). Results in studies of 312 children show that a urea hydrolysis rate of more than 10 m microg/min may also be appropriate to predict H. pylori infection. CONCLUSION: Calculating 13C-urea breath test values as urea hydrolysis rate removes the effect of individual anthropometric differences on test outcome and provides a single cutoff value for pediatric patients of all ages.

Host response and vaccine development to Helicobacter pylori infection.

Studies in both humans and animals demonstrate that H. pylori is capable of illiciting an innate response that in part is regulated by the genetic makeup of the host. These innate responses includes stimulating immune effector mechanisms at the cellular and biochemical level resulting in the influx of neutrophils into the lamina propria and have even been shown to modify gastric acid secretion. The availability of good animal models of chronic Helicobacter infection has also allowed investigators to begin to examine how the adaptive host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. The experimental H. felis/mouse model has been utilized by a number of laboratories to investigate mechanisms of host defense against chronic Helicobacter infection. This model and the more recently developed H. pylori rodent model has not only allowed investigators to confirm the feasibility of immunotherapy to prevent and/or cure Helicobacter infection but also to begin to examine how the host immune response prevents and/or exacerbates Helicobacter-induced gastroduodenal disease. Based on these studies a hypothesis is emerging that suggests that protection and/or cure from Helicobacter infection is mediated primarily by an upregulated cellular immune response which may act via an antibody independent mechanism. Paradoxically, following natural infection with H. pylori, a component of the cellular immune response also promotes chronic gastric inflammation without clearance of the organism. The recent development of reliable and reproducible H. pylori/rodent models of disease and the availability of numerous inbred strains, transgenic and knockout animals, will allow investigators to continue to explore the role the host cellular and humoral immune response plays in promoting or preventing this infection.