Ethical Considerations Within the ESPGHAN Community.

There are limited data on ethical issues related to the daily practice of members of the European Society for Pediatric Gastroenterology Hepatology and Nutrition (ESPGHAN). The role of the ESPGHAN Ethics Committee (EC) is to provide advice on such matters to its members. The present survey aimed to evaluate the current function, and reasons that ESPGHAN members consulted the ECs. One hundred and five participants from 24 different countries answered the questionnaire. Thirty-five point seven percent of the participants used the ESGHAN EC to ask about clinical practice problems and patient-related issues whereas 21.4% ask about human research questions. An important additional finding was that 66.3% of respondents consulted their hospital's EC when they had ethical concerns and 17.4% consulted with other colleagues with expertise. This is the first survey in the ESPGHAN and Europe that analyses ethical issues that are important to members of the National Societies for Pediatric Gastroenterology Hepatology and Nutrition.

High Metronidazole and Clarithromycin Resistance of Helicobacter Pylori Isolated from Previously Treated and Naïve Patients.

BACKGROUND: Antimicrobial resistance is the main determinant for Helicobacter pylori treatment failure. Regional antimicrobial susceptibility testing is essential for appropriate antibiotic selection to achieve high eradication rates. OBJECTIVES: To assess primary and secondary H. pylori resistance in isolates recovered from Israeli naïve and treatment failures. To identify predictors of resistance. METHODS: In this retrospective study, in vitro activity of isolated H. pylori in Israel was tested against metronidazole, clarithromycin, tetracycline, amoxicillin, and levofloxacin in 128 isolates: 106 from treatment failures and 22 from naïve untreated patients. The minimal inhibitory concentration values were determined according to the Etest instructions. Treatment failures previously failed at least one treatment regimen. RESULTS: No resistance to amoxicillin and tetracycline was detected. Resistance to metronidazole and clarithromycin was high in H. pylori isolates both from treated and untreated patients: 68.9%, 68.2% for metronidazole (P = 0.95); 53.8%, 59.1% for clarithromycin (P = 0.64), respectively. Dual resistance to clarithromycin and metronidazole was seen in 45.3% and 50%, respectively (P = 0.68). Resistance to levofloxacin was detected in two (1.9%) isolates from treated patients. Simultaneous resistance to clarithromycin, metronidazole, and levofloxacin was seen in an isolate from a treated patient. Age was the only predictor of resistance to metronidazole and clarithromycin. CONCLUSIONS: The resistance rates to both single and dual metronidazole and clarithromycin in isolates recovered from both Israeli naïve and treated patients is high. Low resistance renders levofloxacin an attractive option for second or third line treatment. Therapeutic outcome would benefit from susceptibility testing after treatment failure.

The Association of Helicobacter pylori Seropositivity with All-Cause Mortality among Colorectal Cancer Patients Undergoing PET/CT Scans.

BACKGROUND: Evidence has been emerging that Helicobacter pylori may also impact colorectal cancer (CRC). Positron emission tomography/computed tomography (PET/CT) imaging can predict overall survival in CRC patients. OBJECTIVES: To determine a possible association between H. pylori seropositivity and all-cause mortality among CRC patients evaluated by PET/CT scans. METHODS: This prospective cohort study was comprised of 110 consecutive CRC patients who had undergone a PET/CT evaluation in a tertiary academic medical center. Data included demographics, body mass index (BMI), tumor node metastasis stage at diagnosis, treatment, time from diagnosis to PET/CT, and PET/CT findings. All patients were tested for anti-H. pylori immunoglobulin G (IgG) antibodies and followed for 36 months from the day of the PET/CT scan. Mortality was documented. Univariate and multivariate Cox regression was used to estimate the hazard ratio (HR) of H. pylori serological status. RESULTS: During the follow-up period, of the 110 CRC patients 41 (37.3%) died and 69 (62.7%) survived. Of the 41 patients, 26 (63.4%) were H. pylori seropositive and 15 (36.6%) were seronegative. Multivariate analysis showed that H. pylori seropositivity was associated with increased mortality (HR 3.46, 95% confidence interval 1.63-7.32), stage IV at diagnosis, metastatic disease found on PET/CT, longer time from diagnosis to PET/CT, lower BMI, and older age. CONCLUSIONS: Our findings suggest that H. pylori infection may be a risk factor for all-cause mortality among CRC patients who are evaluated by PET/CT. Multicenter studies with larger patient groups are needed to confirm our findings.

Primary and Secondary Antibiotic Resistance of Helicobacter pylori in Israeli Children and Adolescents.

BACKGROUND: Empiric treatment for Helicobacter pylori is influenced by antibiotic susceptibility of infecting strains. A rise in the resistance rate to clarithromycin and metronidazole has been reported in pediatric populations. OBJECTIVES: To assess the primary and secondary antibiotic resistance of H. pylori isolates in Israeli children and adolescents. METHODS: A retrospective review of H. pylori isolates cultured from antral biopsies of consecutive children aged 1 to 18 years, who were referred to the Pediatric Gastroenterology Unit, Kaplan Medical Center, over a 2.8 year period, was performed. Antibiotic susceptibility to clarithromycin, metronidazole, amoxicillin, tetracycline, and levofloxacin was determined by E-test. Data on the age of the patient, indication for endoscopy, and antibiotic treatment for H. pylori in previously treated children was collected. RESULTS: Cultures for H. pylori yielded 123 isolates. In children not previously treated (n=95), the primary global resistance was 38% with resistance to clarithromycin 9.5%, metronidazole 32.6 %, and to both 4.2%. Respective rates of resistance in previously treated children (n=28) were 71% (P = 0.002), 29% (P = 0.02), and 61% (P = 0.007). Simultaneous resistance to both drugs was found in 18% (P = 0.02). All H. pylori strains were susceptible to amoxicillin, tetracycline, and levofloxacin. Past eradication treatment was the only independent risk factor for antibiotic resistance in multivariate analysis. CONCLUSIONS: Significantly higher resistance rates were found in previously treated patients, stressing the need to refrain from empiric treatment using the "test and treat strategy." Culture-based treatment strategy should be considered in all previously treated children.

Helicobacter pylori infection is associated with advanced colorectal neoplasia.

OBJECTIVE: The aim of this article was to evaluate the prevalence of Helicobacter pylori infection in patients diagnosed with advanced colorectal neoplasia undergoing a colonoscopy compared to patients without neoplasia. MATERIAL AND METHODS: This cross-sectional study investigated the association of neoplastic lesions diagnosed on colonoscopy with H. pylori infection in a consecutive series of subjects who had undergone a pancolonoscopy in a single academic medical center. All patients were tested by ELISA and the immunoblot technique for serum anti-H. pylori and CagA protein IgG antibodies. Multivariate analyses were adjusted for potential-relevant confounders, including age, sex, smoking, childhood socioeconomic status, and family history of colorectal cancer. RESULTS: Two hundred and seventy-three patients were included in the study: 75% (84/112), diagnosed with neoplastic colorectal lesions and 48% (77/161) without neoplastic lesions, were found to be seropositive for H. pylori infection (p < 0.001). H. pylori infection was found in 66/77 (86 %) patients with advanced neoplasia, 18/35 (51%) patients with nonadvanced neoplasia, and 48% (77/161) patients without neoplasia (p < 0.001). In the adjusted analysis, H. pylori infection was found to be associated with advanced colorectal neoplasia (odds ratio, OR 9.57; 95% CI 4.31-21.2; p < 0.001) and CRC (OR 7.98;95% CI 3.16-20.16; p < 0.001). There was no association in patients who were CagA positive. CONCLUSION: H. pylori infection is associated with the development of advanced colorectal neoplasia. More studies are needed to confirm our findings.

Association of Helicobacter pylori with coronary artery disease and myocardial infarction assessed by myocardial perfusion imaging.

BACKGROUND: The relationship between Helicobacter pylori infection and coronary artery disease (CAD) has as yet not been fully examined. The myocardial perfusion imaging (MPI) stress test has proven its efficacy as an integral part of diagnosing CAD. OBJECTIVES: To investigate the association between CAD and H. pylori infection using MPI. METHODS: This prospective study evaluated CAD positivity among consecutive patients referred to a tertiary medical center for a stress/rest MPI. All patients were tested for serum anti-H. pylori and CagA protein immunoglobulin G antibodies. The CAD positivity group included patients with ischemia and/or myocardial infarction (MA) on a stress MPI, coronary artery bypass graft surgery (CABG), or percutaneous coronary interventions (PCI). CAD-negative subjects were defined as participants with a normal MPI, no pathological Q waves in resting ECG tracing, and no history of CAD. Both groups were compared for H. pylori and CagA seropositivity. Patients' demographic data, risk factors for CAD, and childhood socioeconomic status were recorded. RESULTS: The study group consisted of 300 consecutive patients, 170 men and 130 women; 64% (110/173) CAD-positive patients and 47% (60/127) CAD-negative participants were found seropositive for H. pylori infection (P = 0.005). In the adjusted analysis, H. pylori infection was found to be associated with CAD positivity (odds ratio 1.83, 95% confidence interval 1.06-3.17, P = 0.031), and MI (fixed perfusion defects on MPI) (OR 3.36, 95% CI 1.44-7.84, P = 0.005). No association was noted with CagA positivity. CONCLUSIONS: In patients undergoing a stress MPI, serum anti-H. pylori antibodies positivity was found to be associated with CAD, independent of traditional cardiovascular risk factors.

The epidemiology of Helicobacter pylori resistance in a university affiliated hospital: a comparison between two time periods-a cross-sectional design.

PURPOSE: During the last few decades, the increased use of various types of antibiotics in the general population caused a significant change in regional Helicobacter pylori (H. pylori) antibiotic resistance. Our aim is to study the changes in H. pylori resistance in patients who had undergone an esophagogastroduodenoscopy (EGD) and susceptibility testing and found positive for H. pylori. The study was conducted in a university affiliated hospital between 2013-2020. METHODS: A cross-sectional study was performed on all consecutive patients who had undergone an EGD and tested positive for H. pylori at the Kaplan Medical Center, Israel. The study period was divided into two sub-periods: 2013-2016 and 2017-2020. Data on age, sex, comorbidities, previous treatments, and antimicrobial susceptibility testing for six antimicrobial agents were compared. RESULTS: The resistance rates of H. pylori to clarithromycin and dual resistance to clarithromycin and metronidazole were found significantly higher during the late period. Multivariable analysis showed that the later period, older age, and diabetes mellitus were independent predictors for antimicrobial resistance. CONCLUSIONS: Our study has shown that there is an increasing resistance of H. pylori to clarithromycin and metronidazole while its susceptibility is unaffected with time to other antibiotics. More recent cross-sectional studies with larger samples are warranted in order to evaluate the changes in the resistance patterns of H. pylori to various antibiotics with time.

Neurologic presentation in children with ataxia-telangiectasia: is small head circumference a hallmark of the disease?

OBJECTIVE: To define the neurologic characteristics and course of ataxia-telangiectasia (A-T). STUDY DESIGN: Retrospective cross-sectional chart study of 57 children (ages 2 to 19 years) followed at an A-T clinic. Cerebellar and extracerebellar symptoms were graded according to degree of functional impairment. Head circumferences were plotted from the charts and z-scores were calculated and compared with that of family members. RESULTS: Ataxia was present in 87.7%, followed by dysarthria (82.1%), dysmetria (75.4%), bradykinesia (69.2%), hyperkinetic movements (58.9%), and dystonia (15.8%). All features aggravated with age. The most striking clinical observation in our patients was low head circumference (z-score below 1), which was present in 60.9%; 17% had true microcephaly (z-score below 2). Microcephaly appeared postnatally, was proportionate to height and weight, and did not correlate with severity of ataxia or genotype. CONCLUSIONS: In addition to cerebellar ataxia, extrapyramidal symptoms, especially bradykinesia, were frequent and disabling. Microcephaly is an integral part of A-T; understanding its pathogenesis may shed light on the mechanism by which ATM mutation causes dysfunction in the nervous system.

Antibiotic resistance of Helicobacter pylori in Israeli children.

OBJECTIVES: To determine the antibiotic susceptibility of Helicobacter pylori isolates from Israeli children; assess the role of previous antibiotic use in the development of antibiotic resistance and examine the possibility of simultaneous colonization of strains with different resistance patterns in the same patients. MATERIAL AND METHODS: A prospective case-series design was used. The study group included 174 patients aged 1-18 years referred to the Schneider Children's Medical Center of Israel for gastroscopy over a 2.5-year period. Antibiotic susceptibility to amoxicillin, clarithromycin, metronidazole, tetracycline, and levofloxacin was determined by E-test on gastric biopsies (2 per patient). Clinical and demographic data were obtained by questionnaire. RESULTS: Cultures for H. pylori yielded 55 isolates from 53 children. In treatment-naïve children, the prevalence rate of primary resistance to clarithromycin was 25% and to metronidazole, 19%. Respective rates in children previously treated for H. pylori infection were 42% (p = 0.22) and 52% (p = 0.016). Simultaneous resistance to both drugs was found in 13% of isolates (n = 7), all from children with previous treatment failure. No resistance was found to amoxicillin, tetracycline or levofloxacin. Clarithromycin resistance was associated with macrolide use for any indication during the previous year (p = 0.033). In 2 patients (3.8%), a different H. pylori strain was cultured from each biopsy. CONCLUSIONS: H. pylori resistance to clarithromycin and metronidazole is high in Israeli children, particularly in those previously treated for H. pylori infection, in whom culture-based treatment should be considered. The simultaneous colonization of multiple strains in a minority of patients needs to be further characterized.

Effect of cranberry juice on eradication of Helicobacter pylori in patients treated with antibiotics and a proton pump inhibitor.

Cranberry constituents are known to exert anti-adhesion activity on H. pylori in vitro. To determine their possible additive effect to triple therapy with omeprazole, amoxicillin and clarithromycin (OAC), a double-blind randomized clinical study was carried out. One-hundred-seventy-seven patients with H. pylori infection treated with OAC for 1 week were randomly allocated to receive 250 mL of either cranberry juice (cranberry-OAC, n = 89) or placebo beverage (placebo-OAC, n = 88) twice daily and only cranberry juice or placebo beverage for the next 2 weeks. Treatment outcome was determined with the(13)C urea breath test ((13)C-UBT). An additional control group consisted of patients referred to the same center during the same period who were treated with OAC alone for 1 week (non-placebo-OAC, n = 712). Overall, the rate of H. pylori eradication ((13)C-UBT < 3.5) was 82.5%, with no statistically significant difference among the three arms. Analysis by gender revealed that for female subjects, the eradication rate was higher in the cranberry-OAC arm (n = 42, 95.2%) than in the placebo-OAC arm (n = 53, 86.8%) and significantly higher than in the non-placebo-OAC group (n = 425, 80%; p = 0.03). For males, the rate was nonsignificantly lower in the cranberry-OAC arm (n = 35, 73.9%) than in the placebo-OAC arm (n = 45, 80.0%) and non-placebo-OAC group (n = 287, 85.0%). These results suggest that the addition of cranberry to triple therapy improves the rate of H. pylori eradication in females.

In vitro activity of levofloxacin against Helicobacter pylori isolates from patients after treatment failure.

We tested the in vitro activity of levofloxacin (LEV), amoxicillin (AMP), clarithromycin (CLA), metronidazole (MET), and tetracycline (TET) against 70 clinical isolates of Helicobacter pylori recovered from 70 dyspeptic patients. All patients had previously failed 2 treatment regimens: first-line triple therapy with omeprazole, AMP, and CLA, and second-line quadruple therapy with omeprazole, MET, TET, and bismuth. Resistance to CLA, MET, and LEV was found in 65.7%, 57.1%, and 18.6% of isolates, respectively. Resistance to both CLA and MET was found in 32.8%, and to CLA, MET, and LEV in 12.8%. Only 4 of the isolates were resistant to both CLA and LEV, and none was resistant to LEV alone or to MET and LEV. Physicians should consider triple therapy with omeprazole, LEV, and AMP in patients unsuccessfully treated with first- and second-line regimens.

Non-pharmacological treatment of Helicobacter pylori.

Many food and plant extracts have shown in vitro anti-Helicobacter pylori (H. pylori) activity, but are less effective in vivo. The anti-H. pylori effects of these extracts are mainly permeabilitization of the membrane, anti-adhesion, inhibition of bacterial enzymes and bacterial grown. We, herein, review treatment effects of cranberry, garlic, curcumin, ginger and pistacia gum against H. pylori in both in vitro, animal studies and in vivo studies.

Association of CagA+ Helicobacter pylori infection with aortic atheroma.

BACKGROUND: To investigate possible association between infection with CagA(+) strains of Helicobacter pylori and aortic atheroma diagnosed by transesophageal echocardiography. METHODS AND RESULTS: One hundred and eighty-eight consecutive subjects prospectively examined for presence of aortic atheroma (localized intimal thickening of >/=3mm) by transesophageal echocardiography were tested for serum IgG antibodies against H. pylori (enzyme-linked immunosorbent assay) and CagA protein (Western blot assay). The association between infection with H. pylori, CagA status of the infecting H. pylori strains, and aortic atherosclerosis was evaluated after adjusting for coronary artery disease risk factors. There was a linear trend for presence of atheroma in subjects with CagA-positive H. pylori infection (51/81, 63%) compared to subjects with CagA-negative H. pylori infection (21/45, 46.7%) and uninfected subjects (18/62, 29%) (p=0.003). H. pylori seropositivity was not associated with aortic atheroma (OR 2.9; 95% CI, 0.8-10.3; p=0.11) when CagA status is not taken into account. On multivariate analysis, parameters associated with risk of aortic atheroma were CagA-positive H. pylori seropositivity (OR 4.4; 95% CI, 1.4-14.7; p=0.01), older age (OR 1.2; 95% CI, 0.9-14.7; p=0.01), having ever smoked cigarettes (OR 3.6; 95% CI, 1.3-10.0; p<0.001), and elevated serum triglyceride level (OR 3.4; 95% CI, 1.3-9.4; p=0.02). CONCLUSIONS: After controlling for H. pylori infection and coronary artery disease risk factors, infection with a CagA-positive strain of H. pylori was independently associated with aortic atherosclerosis. This study suggests a gradient of atherosclerosis between uninfected individuals and patients with CagA-positive H. pylori infection and should prompt research into the role of CagA-positive H. pylori infection in the inflammatory atherosclerotic process.

Effects of an intensive 4-week summer camp on cystic fibrosis: pulmonary function, exercise tolerance, and nutrition.

STUDY OBJECTIVES: Cystic fibrosis (CF) patients prefer exercise to most other forms of therapy, although objective improvement remains controversial. Israeli CF patients have attended a summer program in Switzerland for many years with subjective improvement. However, CF camps worldwide have been cancelled recently, due to fears of cross-infection with resistant organisms. Therefore, we evaluated the effect of attending the camp on pulmonary function, exercise tolerance, and nutritional state in CF patients. DESIGN: Weight, resting pulmonary function, incremental exercise test results, and sputum culture findings were assessed before and after a 4-week intensive summer camp. SETTING: Davos, Switzerland (altitude, 1,500 m). PATIENTS: Thirteen Israeli CF patients (seven women and six men) with an age range of 9 to 25 years who had mild-to-moderate lung disease. No patients had Burkholderia cepacia detected in their sputum. INTERVENTIONS: The program included a high-calorie diet, chest physiotherapy, daily mountain climbing, and indoor activities. Arterial oxygen saturation (SaO(2)) was maintained at > 88% during exertion. RESULTS: Exercise tolerance improved significantly. The peak work capacity increased by 12.7%, the maximal oxygen uptake increased by 10%, and minute ventilation increased by 18.5% (p < 0.0005). Of the calculated parameters, the anaerobic threshold improved by 17%. Ventilation was always the limiting factor during exercise, although it improved. There was no significant change in resting lung function and pulse or in SaO(2) decline at maximal exercise. The mean weight gain was 1 kg. No patient acquired B cepacia. CONCLUSIONS: An intensive summer camp improved exercise tolerance and nutrition in CF patients. This may explain improved patient well-being despite unchanged values for resting lung function. The reinstitution of summer camps, with special care to avoid cross-infection, should be considered.

Susceptibility of Helicobacter pylori isolates to the antiadhesion activity of a high-molecular-weight constituent of cranberry.

The sensitivity of a large number of antibiotic-resistant and nonresistant Helicobacter pylori isolates to the antiadhesion effect of a high-molecular-mass, nondialysable constituent of cranberry juice was tested. Confluent monolayers of gastric cell line in microtiter plate wells were exposed to bacterial suspensions prepared from 83 H. pylori isolates from antibiotic-treated and untreated patients in the presence and absence of the cranberry constituent. Urease assay was used to calculate the percentage of adhesion inhibition. In two thirds of the isolates, adhesion to the gastric cells was inhibited by 0.2 mg/mL of the nondialysable material. There was no relationship between the antiadhesion effect of the cranberry material and metronidazole resistance in isolates from either treated or untreated patients (N=35). Only 13 isolates (16%) were resistant to both the nondialysable material and metronidazole, and 30 (36%) were resistant to the nondialysable material alone. There was no cross-resistance to the nondialysable material and metronidazole. These data suggest that a combination of antibiotics and a cranberry preparation may improve H. pylori eradication.

Liver cirrhosis and portal hypertension in cystic fibrosis.

OBJECTIVES: Liver disease is the second cause of death in cystic fibrosis. The most deleterious complication of liver disease is portal hypertension, which has an estimated prevalence of up to 8%. Portal hypertension may manifest itself by splenomegaly, hypersplenism, gastro-oesophageal bleeding and ascites. The aim of our study was to determine the prevalence, risk factors and invasive management of portal hypertension at our centre. METHODS: One hundred and fifty patients with cystic fibrosis were followed up between 1975 and 2000 in the national cystic fibrosis centre in Israel. Forty patients (27%) had liver disease. All underwent clinical evaluation and laboratory and imaging studies. RESULTS: Portal hypertension was diagnosed in 10 patients (7%), of whom eight were male. The mean age at diagnosis was 11 years (range, 4-17 years). All had severe mutations of the cystic fibrosis transmembrane conductance regulator gene (the CFTR gene), pancreatic insufficiency, meconium ileus or distal intestinal obstruction syndrome and variceal bleeding. Seven patients underwent sclerotherapy to control acute bleeding. Four underwent portosystemic shunting (functioning up to 37 years). Two patients with severe lung and liver disease underwent transjugular intrahepatic portosystemic shunting, which provided bleeding control, but both died while waiting for lung/liver transplantation. One patient underwent liver transplantation due to liver failure and still had good liver and lung function 10 years later. CONCLUSIONS: Portal hypertension is more common among Israeli patients with cystic fibrosis. The unique genetic composition of our population may explain this phenomenon. Risk factors include male gender, pancreatic insufficiency, severe CFTR mutations, meconium ileus and meconium ileus equivalent. Sclerotherapy is the main option to control oesophageal variceal bleeding, while portosystemic shunts offer a prolonged alternative treatment for refractory bleeding. A transjugular intrahepatic portosystemic shunt and liver transplantation may also be effective, but further research is required in order to establish their role.

Helicobacter pylori: friend or foe?

Helicobacter pylori (H. pylori) is a Gram-negative spiral bacterium that is present in nearly half the world's population. It is the major cause of peptic ulcer disease and a recognized cause of gastric carcinoma. In addition, it is linked to non-ulcer dyspepsia, vitamin B12 deficiency, iron-deficient anemia and immune thrombocytopenic purpura. These conditions are indications for testing and treatment according to current guidelines. An additional indication according to the guidelines is "anyone with a fear of gastric cancer" which results in nearly every infected person being eligible for eradication treatment. There may be beneficial effects of H. pylori in humans, including protection from gastroesophageal reflux disease and esophageal adenocarcinoma. In addition, universal treatment will be extremely expensive (more than $32 billion in the United States), may expose the patients to adverse effects such as anaphylaxis and Clostridium difficile infection, as well as contributing to antibiotic resistance. There may also be an as yet uncertain effect on the fecal microbiome. There is a need for robust clinical data to assist in decision-making regarding treatment of H. pylori infection.