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.

Follow-up of Helicobacter pylori infection in children over two decades (1988-2007): persistence, relapse and acquisition rates.

Helicobacter pylori culture on gastric biopsy was performed on 4964 subjects aged <18 years from 1988 to 2007 at a central laboratory in Brussels. The total number of biopsies increased markedly from 941 in 1988-1993 to 1608 in 2004-2007. Biopsies were repeated at least once for 922 subjects (603 initially negative and 319 initially positive for H. pylori). Persistence rate of H. pylori at 1 year after initial positive biopsy was greater in the 1998-2007 cohort than in the 1988-1997 cohort (72.7% vs. 45.8%, P = 0.002), suggesting a tailored selection of candidates for biopsy with non-invasive tests (13C urea breath test). Of 68 subjects initially positive and re-examined subsequently after a documented cure, re-infection/relapse rate was 48.6% within 5 years post-elimination of H. pylori. Acquisition rate over 10 years follow-up in the initially negative cohort (603 patients) was 38.7% (re-infection/relapse vs. acquisition: P < 0.001). Multivariate analysis showed a fourfold greater risk of H. pylori acquisition in children of non-European origin vs. European origin (P < 0.001). Clarithromycin and metronidazole susceptibility were determined in 226 and 223 paired positive cultures in cases of re-infection/relapse or persistence. An initial non-susceptibility profile was highly predictive of a subsequent non-susceptibility profile, and the non-susceptible proportion increased markedly from 13.3% to 21.2% for clarithromycin (P < 0.001) and from 27.3% to 35.0% for metronidazole (P = 0.014), with no difference regarding European or non-European origin.

Hospital-related undernutrition in children: still an often unrecognized and undertreated problem.

AIM: To evaluate the nutritional status of hospitalized children in Belgian hospitals and to analyse the impact of undernutrition on the degree of weight loss and duration of hospitalization. METHODS: In each hospital (one tertiary and three secondary hospitals), 100 consecutively hospitalized children were eligible for inclusion. Of these, 379 were included for analysis. Body weight, length and mid-upper arm circumference were measured at admission and body weight also at discharge. RESULTS: The median (range) age was 2.1 (0.8-17) years. On admission, 29 (7.7%) children were chronically malnourished and, depending on the parameter, between 2.4% and 9.8% acutely undernourished, while 12.1% had at least one subnormal parameter. Median (range) duration of hospitalization was four (1-64) days. Median (range) weight change was 0.0% (-15.6% - +13.9%). Weight loss of >2% was significantly (p < 0.05) more prevalent in tertiary (20.0%) than in secondary (10.2%) hospitals. Median hospital duration was 50% longer for chronically malnourished children (6.0 vs 4.0 days; p < 0.01). Only 36 children received a nutritional intervention. CONCLUSION: Acute undernutrition and chronic undernutrition remain frequent findings in hospitalized children in Belgium. Children with chronic undernutrition had a 50% longer hospital stay. Hospital-related undernutrition is an often unrecognized problem, because only one-third of the acutely malnourished children received nutritional support.

Deficiency of Subunit 6 of the Conserved Oligomeric Golgi Complex (COG6-CDG): Second Patient, Different Phenotype.

We describe a 27-month-old girl with COG6 deficiency. She is the first child of healthy consanguineous Moroccan parents. She presented at birth with dysmorphic features including microcephaly, post-axial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. The clinical phenotype was further characterised by multiorgan involvement including mild psychomotor retardation, and microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, associated with life-threatening and recurrent infections due to combined T- and B-cell dysfunction and neutrophil dysfunction.Mutation analysis showed the patient to be homozygous for the c.G1646T mutation in the COG6 gene. She is the second reported patient with a deficiency of subunit 6 of the COG complex. Although both patients are homozygous for the same mutation, they present a markedly different clinical picture. Indeed immunodeficiency as well as inflammatory bowel disease has not been described previously in patients with any COG-CDG.

Multicenter survey of routine determinations of resistance of Helicobacter pylori to antimicrobials over the last 20 years (1990 to 2009) in Belgium.

We analyzed the rates of antimicrobial resistance of Helicobacter pylori strains isolated from patients from 1990 to 2009 and identified risk factors associated with resistance. Gastric biopsy specimens were collected from several digestive disease centers in Brussels, Belgium. We routinely performed antimicrobial susceptibility testing for clarithromycin (CLR), metronidazole, amoxicillin, tetracycline, and ciprofloxacin. Evaluable susceptibility testing was obtained for 9,430 strains isolated from patients who were not previously treated for Helicobacter pylori infection (1,527 isolates from children and 7,903 from adults) and 1,371 strains from patients who were previously treated (162 isolates from children and 1,209 from adults). No resistance to amoxicillin was observed, and tetracycline resistance was very rare (<0.01%). Primary metronidazole resistance remained stable over the years, with significantly lower rates for isolates from children (23.4%) than for isolates from adults (30.6%). Ciprofloxacin resistance remained rare in children, while it increased significantly over the last years in adults. Primary clarithromycin resistance increased significantly, reaching peaks in 2000 for children (16.9%) and in 2003 for adults (23.7%). A subsequent decrease of resistance rates down to 10% in both groups corresponded to a parallel decrease in macrolide consumption during the same period. Multivariate logistic regression revealed that female gender, age of the patient of 40 to 64 years, ethnic background, the number of previously unsuccessful eradication attempts, and the different time periods studied were independent risk factors of resistance to clarithromycin, metronidazole, and ciprofloxacin. Our study highlights the need to update local epidemiological data. Thus, the empirical CLR-based triple therapy proposed by the Maastricht III consensus report remains currently applicable to our population.

Marching cohort of Helicobacter pylori infection over two decades (1988-2007): combined effects of secular trend and population migration.

The prevalence of Helicobacter pylori infection is decreasing in developed countries. In this study we included 22,612 patients in whom a first culture of gastric biopsy (routinely performed in our medical centres) yielded an interpretable result over a 20-year period (1988-2007) in Brussels. The effects of patients' age, gender and ethnic background were analysed. The overall proportion of H. pylori-infected patients was 37·7%, with a progressive decline over time (P<10(-5)). A gender effect was observed in adults. The lowest infection rate was observed in Western European patients (n=11,238) with respectively 36·2% and 15·2% infected subjects in 1988 and 2007, compared to 71·7% and 40% in North African patients (n=3200) (P<10(-5)). However, no trend of decline was observed over time in North African children aged ≤9 years. These data show the effects of time, age and ethnicity on the prevalence of H. pylori infection, and its complex heterogeneity in the same cosmopolitan urban area.

Prospective multicentre study on antibiotic resistance of Helicobacter pylori strains obtained from children living in Europe.

AIM: To prospectively assess the antibacterial resistance rate in Helicobacter pylori strains obtained from symptomatic children in Europe. METHODS: During a 4-year period, 17 paediatric centres from 14 European countries reported prospectively on patients infected with H pylori, for whom antibiotic susceptibility was tested. RESULTS: A total of 1233 patients were reported from Northern (3%), Western (70%), Eastern (9%) and Southern Europe (18%); 41% originated from outside Europe as indicated by mother's birth-country; 13% were <6 years of age, 43% 6-11 years of age and 44% >11 years of age. Testing was carried out before the first treatment (group A, n = 1037), and after treatment failure (group B, n = 196). Overall resistance to clarithromycin was detected in 24% (mean, A: 20%, B: 42%). The primary clarithromycin resistance rate was higher in boys (odds ratio (OR) 1.58; 1.12 to 2.24, p = 0.01), in children <6 years compared with >12 years (OR 1.82, 1.10 to 3.03, p = 0.020) and in patients living in Southern Europe compared with those living in Northern Europe (OR 2.25; 1.52 to 3.30, p<0.001). Overall resistance rate to metronidazole was 25% (A: 23%, B: 35%) and higher in children born outside Europe (A: adjusted. OR 2.42, 95% CI: 1.61 to 3.66, p<0.001). Resistance to both antibiotics occurred in 6.9% (A: 5.3%, B: 15.3%). Resistance to amoxicillin was exceptional (0.6%). Children with peptic ulcer disease (80/1180, 6.8%) were older than patients without ulcer (p = 0.001). CONCLUSION: The primary resistance rate of H pylori strains obtained from unselected children in Europe is high. The use of antibiotics for other indications seems to be the major risk factor for development of primary resistance.

Twelve year observation of primary and secondary antibiotic-resistant Helicobacter pylori strains in children.

BACKGROUND: The effectiveness of Helicobacter pylori eradication regimens is influenced by antibiotic susceptibility of infecting strains. Data concerning antibiotic resistance in children are limited. We report the evolution of primary and secondary resistance in a series of Belgian children during the last 12 years. PATIENTS AND METHODS: From 1989 through 2000, H. pylori gastritis was diagnosed in 569 children, and antibiotic susceptibility tests were performed in 555. Eradication, using different schemes, failed in 128 of 457 treated children. After eradication failure antibiotic susceptibility determination was performed in 87 of 128. Comparison of antibiotic susceptibility of strains isolated from the gastric body and from the antrum was performed in 238 samples. RESULTS: Resistance to amoxicillin was not observed. The rate of primary resistance to nitroimidazole derivatives was 18.0% (101 of 555) and remained constant throughout this period, whereas primary resistance to macrolides increased from an average of 6.0% (range, 0 to 10%) before 1995 to 16.6% (range, 10 to 25%, P < 0.001) thereafter. Antibiotic consumption in Belgium, especially macrolides, did not show important fluctuations during the study period. Secondary resistance developed in 39 of 87 patients (46%). Strains isolated from different gastric locations show identical susceptibility testing in all but 5 of 238. CONCLUSIONS: Resistance of H. pylori to macrolides increased in our pediatric population which did not appear to correlate with macrolides prescription habits in our country. After eradication failure acquired secondary resistance was observed in one-half of the patients.

Accuracy of serology and 13C-urea breath test for detection of Helicobacter pylori in children.

BACKGROUND: Indirect noninvasive methods, such as the 13C-urea breath test and serology, can be useful for the detection of Helicobacter pylori infection in children. We analyzed retrospectively the diagnostic accuracy of these two methods. PATIENTS AND METHODS: Between September, 1989, and October, 1996, H. pylori status was determined in 139 children by means of culture and histologic study of gastric biopsies. We performed 146 13C-urea breath tests and serologic assays (Cobas core; Roche). RESULTS: H. pylori infection was detected in 91 of 139 (65%) children. The 13C-urea breath test was discordant with H. pylori status in 4 of 146 tests; serology was discordant in 24 and indeterminate in 7 of 146. The 13C-urea breath test was more sensitive than serology (98% vs. 79%, P < 0.01) but comparable in specificity (96% vs. 92%). The serology yielded false negative results more often in children younger than 5 years of age (P < 0.05). CONCLUSIONS: The 13C-urea breath test is more reliable than serology for the detection of active H. pylori infection in children. Below 10 years of age serology is insufficiently sensitive for clinical purposes, whereas the 13C-urea breath test remains a reliable test.

Detection of Helicobacter pylori infection in children with a standardized and simplified 13C-urea breath test.

BACKGROUND: The 13C-urea breath test, a reliable noninvasive method of detection of Helicobacter pylori in adults, needs validation in children. METHODS: In order to evaluate the diagnostic accuracy of 13C-urea breath test in children, the results of this test performed in 144 children were correlated with the histology and culture of contemporaneous gastric (antral and fundic) biopsy specimens. The test was performed with 2 mg/kg body weight 13C-Urea (maximum, 100 mg) ingested after a fat-rich test meal. Samples of expired breath taken at 0, 5, 10, 20, and 30 minutes were assayed with mass spectrometry. Results were considered positive when the curve of excretion of labeled carbon dioxide in the expired breath increased by 5%O or more above the baseline. RESULTS: Discrepancies in H. pylori status were observed in 14 children. To improve and simplify the test, the results were reanalyzed using different cutoff values for each sampling time. The best results, with sensitivity of 95.7% and specificity of 95.2%, were obtained with a cutoff of 3.5%O at 20 minutes. CONCLUSIONS: The 13C-urea breath test is a reliable method for the noninvasive detection of H. pylori infection in children. The test can be simplified and its accuracy improved using only the 0- and 20-minute breath samples and a cutoff of 3.5%O instead of the classical 5%O used in adults. The need for modification of the cutoff value may reflect the higher production of endogenous CO2 in children.