Impact of medication dosage on Helicobacter pylori eradication rates among pediatric patients.

OBJECTIVES: Helicobacter pylori rates of eradication to common first-line regimens continue to decline globally. Prescription of the appropriate medication dosage is an important consideration, particularly in the pediatric population due to medication weight-based dosing. Limited data is available on the impact of guideline-recommended weight-based dosing on the successful eradication of H. pylori in children. METHODS: Retrospective study of patients with histologic evidence of H. pylori from two pediatric tertiary care centers in New England. We excluded patients who were not treated or those missing eradication data. We compared the eradication rates of patients prescribed recommended weight-based dosages, duration, and frequency of treatment with those who were not. RESULTS: One hundred forty-four patients were included. The overall eradication rate was 73.6% (106/144). All treatment regimens were properly prescribed for 14 days. There was a high rate of improper weight-based dosing: proton pump inhibitor (PPI) 31.2% (45/144), amoxicillin 31.7% (39/123), metronidazole (MET) 19.4% (12/62), clarithromycin (CLA) 23.9% (22/70), tetracycline 50% (6/12), bismuth 26.1% (6/23). When PPIs were properly weight-dosed, there was a 78.8% eradication rate that dropped to 62.2% with suboptimal dosing (p = 0.036, odds ratio [OR]: 2.26, confidence interval [CI]: 1.04-4.87). When amoxicillin was properly weight-dosed, successful eradication was achieved in 81% versus only 53.8% when improperly dosed (p = 0.002; OR: 3.64, CI: 1.58-8.37). There was no statistically significant impact on eradication rates with improper weight-based dosing of MET, CLA, tetracycline, or bismuth. CONCLUSION: Proper weight-based dosing of amoxicillin and PPI is important for the successful eradication of H. pylori among children in the New England area.

Clinical presentation and outcomes of Helicobacter heilmannii gastritis in children in the New England region of the United States.

OBJECTIVE: To describe the clinical, endoscopic, histologic, and treatment outcomes of Helicobacter heilmannii (H. heilmannii) associated gastritis in children in the New England region of the United States. METHODS: Retrospective study of children (1-18 years) with H. heilmannii identified on gastric mucosal biopsies from two pediatric centers over a 21-year period, January 2000-December 2021. Cases were identified by querying pathology databases at each institution. Demographic and clinical data were obtained from the medical record. Endoscopic and histologic findings were extracted from endoscopy and pathology reports, respectively. RESULTS: Thirty-eight children were diagnosed with H. heilmannii-associated gastritis during the study period. The mean age at diagnosis was 10.1 ± 5.3 years, and 25/38 (66%) cases were male. Abdominal pain (32%) and nausea with or without vomiting (26%) were the most common symptoms. Thirty-two children (84%) had endoscopic findings including gastric nodularity (55%) and erythema (26%). All children had histologic signs of chronic gastritis, including those with normal endoscopic exams. Antibiotic regimens used for treating Helicobacter pylori were frequently prescribed. Of the 17 children who underwent a follow-up endoscopy (range 2-68 months), 15 (88%) did not have H. heilmannii identified on gastric biopsies. CONCLUSION: H. heilmannii was an infrequent but potential cause of epigastric abdominal pain and nausea in our cohort of New England children. While morphologically distinct from H. pylori, the bacteria can result in similar endoscopic and histologic findings of nodularity and chronic gastritis, respectively. The rate of eradication, as assessed by histology following treatment with H. pylori therapies, was below the 90% recommended goal for antimicrobial therapies.

Helicobacter pylori Antimicrobial Resistance Using Next-Generation Sequencing in Stool Samples in a Pediatric Population.

Helicobacter pylori ( H pylori ) eradication rates have declined globally, stressing the importance of antimicrobial susceptibility testing to inform treatment. Molecular tests such as next-generation sequencing (NGS) provide susceptibility data for the antibiotics used in the treatment of H pylori in a noninvasive, effective, and rapid manner. We obtained stool susceptibility testing using a novel NGS-based analysis and compared results with the current "gold standard" of gastric biopsy culture via agar dilution in 20 pediatric patients with evidence of H pylori in gastric biopsies. Stool NGS-based antimicrobial susceptibility analysis was highly concordant with agar dilution for no resistance (100% agreement), as well as clarithromycin, levofloxacin, and amoxicillin resistance (100%, 67%, and 100% agreement, respectively) but not concordant for metronidazole in our cohort of patients. Future studies involving a larger number of patients and geographical regions are needed to further validate this analysis.

Gastric Intestinal Metaplasia in Children: Natural History and Clinicopathological Correlation.

INTRODUCTION: Gastric intestinal metaplasia (GIM) is defined as the replacement of the normal gastric epithelium by intestinal-type epithelium. GIM is considered a preneoplastic lesion for gastric adenocarcinoma in adults and is found in 25% of Helicobacter pylori ( H pylori ) exposed adults. However, the significance of GIM in pediatric gastric biopsies is still unknown. METHODS: We conducted a retrospective study of children with GIM on gastric biopsies at Boston Children's Hospital between January 2013 and July 2019. Demographic, clinical, endoscopic, and histologic data were collected and compared to age and sex-matched cohort without GIM. Gastric biopsies were reviewed by the study pathologist. GIM was classified as complete/incomplete based on Paneth cell presence or absence and limited/extensive based on its distribution in the antrum or both antrum and corpus. RESULTS: Of 38 patients with GIM, 18 were male (47%), mean age of detection was 12.5 ± 5.05 years (range, 1-18 years). The most common histologic was chronic gastritis (47%). Complete GIM was present in 50% (19/38) and limited GIM was present in 92% (22/24). H pylori was positive in 2 patients. Two patients had persistent GIM on repeat esophagogastroduodenoscopy (2/12). No dysplasia or carcinoma was identified. Proton-pump inhibitor use and chronic gastritis were more common in GIM patients compared to control ( P = 0.02). CONCLUSION: Most children with GIM had low-risk histologic subtype (complete/limited) for gastric cancer; GIM was rarely associated with H pylori gastritis in our cohort. Larger multicenter studies are needed to better understand outcomes and risk factors in children with GIM.

Low Adherence to Society Guidelines for the Management of Helicobacter Pylori Among Pediatric Gastroenterologists.

BACKGROUND: The revised ESPGHAN/NASPGHAN 2016 guideline on the diagnosis and management of Helicobacter pylori (H pylori) infection discourages a "test and treat" strategy. Instead, upper endoscopy (EGD) is recommended when a valid clinical indication is present. Likewise, new treatment recommendations for first-line therapies strongly encourage obtaining antimicrobial susceptibility before treatment. We conducted this study to assess the effect of revised guidelines on clinical practice at our center. METHODS: Retrospective chart review of patients with H pylori infection diagnosis either by serology, stool antigen test, urea breath test, or EGD at Boston Children's Hospital between January 2013 and July 2019. We compared demographic and clinical data between initial guideline and 2016 revision (January 2013 to November 2016) and period after revised guideline (December 2016 to July 2019). RESULTS: Two hundred and fifty-six patients were included. EGD was the initial diagnostic test in 49% (50/103, prerevised guideline) and in 52% (79/153, postrevised guideline). Biopsy culture was sent in 3% of patients for both periods (3/103 and 4/153, respectively). PPI-clarithromycin-amoxicillin triple therapy was the most common regimen in both periods. Clarithromycin use was lower in postrevised guideline period (P = 0.003) whereas the opposite was noted for metronidazole and tetracycline (P = 0.009 and P = 0.02, respectively). There was no significant difference in eradication rate between periods (86% vs 81%). CONCLUSIONS: Low adherence to the updated H pylori guideline recommendations was observed among pediatric gastroenterologists at our center with low use of gastric biopsy culture. The guideline revision was associated with avoidance of clarithromycin use as a second-line therapy, but no change in eradication rates. Future interventions should address the importance of obtaining gastric biopsy culture for antibiotic susceptibilities to guide therapy.

Long-term Use of Bisacodyl in Pediatric Functional Constipation Refractory to Conventional Therapy.

OBJECTIVES: Standard therapy for pediatric constipation includes osmotic laxatives with stimulant laxatives use only as rescue therapy. Limited information is available on regular and long-term use of bisacodyl in pediatric population despite its common use in adult and pediatric constipation. METHODS: Retrospective review of patients with functional constipation refractory to conventional therapy (regular use of osmotic laxatives and intermittent use of stimulant laxatives only as a rescue therapy) referred to tertiary care children's hospital (January 2007-December 2014). Patients had a bowel movement (BM) frequency of ≤2 per week and were treated with bisacodyl regularly for longer than 4 weeks. Demographic variables, bisacodyl dose and treatment duration, number of BM/week before and after treatment, side effects, and length of follow-up were recorded. Response to therapy was successful when frequency of BM increased from baseline to ≥3 BM/wk. RESULTS: A total of 164 patients were included, 52% girls, median age 9.45 years (0.9-21 years). Bisacodyl median dose was 5 mg/day, median duration of treatment was 14 months (1-77 months) with 90% of patients taking the medication for <36 months. Median number of BM/wk doubled after initiation of bisacodyl from 2 to 4 bm/w (P < 0.001). Approximately 57% of patients had successful response. At long-term follow-up 55% of patients were successfully weaned off bisacodyl (median time of 18 months). Side effects reported in 9% of patients. CONCLUSIONS: Bisacodyl is effective and well tolerated in the long-term treatment of pediatric functional constipation refractory to conventional therapy. Most of patients with a favorable response were successfully weaned off the medication.

Management of chronic intractable constipation in children.

BACKGROUND: Chronic intractable constipation (CIC) is a debilitating disease that is challenging to manage. Treatment options in children include medications, enemas, and surgical management in selected cases. METHOD: We reviewed medical records of pediatric patients diagnosed as having CIC at Tufts Medical Center from 2005 to 2012. Demographic variables, diagnostic procedures, and medical and surgical outcomes were collected. Clinical outcome was defined using the Rome III criteria. RESULTS: A total of 14 patients were included in the study (10 boys). The age range was 10 to 21 years. All of the patients had the diagnosis of CIC. Eleven patients had cecostomy placement. During the follow-up period, 10 patients underwent total abdominal colectomy with ileorectal anastomosis, 1 had total colectomy with ileostomy, and 1 had partial colectomy with colorectal anastomosis. Successful clinical outcome was reported in 7 patients with 3 patients reporting persistent fecal incontinence. Colonic motility studies were performed on 12 patients (colonic neuropathy in 11 patients and normal study in 1 patient). Defecography was consistent with isolated pelvic floor dysfunction in 1 patient, abnormal motility and anatomy in 1 patient, pelvic floor dysfunction and abnormal motility in 2 patients, and found abnormal motility only in 5. Defecography study was normal in 5 patients. All of the patients with abnormal colonic manometry underwent a surgical procedure. CONCLUSIONS: Anorectal manometry, colonic manometry, and defecography help in understanding the pathophysiology of defecation disorders in children. The majority of patients with abnormal colonic manometry underwent TAC-IRA. There was no statistical correlation between individual investigations (anorectal manometry, colonic manometry, and defecography) with surgical intervention (P > 0.35). TAC-IRA may be safe and useful intervention in a subset of patients when other treatment options have failed.

Abdominal pain and functional gastrointestinal disorders in children with celiac disease.

OBJECTIVE: To assess whether patients with celiac disease (CD) are more likely than controls to develop abdominal pain (AP) and AP-associated functional gastrointestinal disorders (FGID) in long-term follow-up. STUDY DESIGN: In a retrospective study, data on children (3-22 years old) with CD diagnosed between 2000 and 2010 were obtained. Parents were contacted by telephone at least 6 months after the diagnosis of CD and invited to participate in the study. Consenting parents completed: (1) a telephone questionnaire on the presence of gastrointestinal symptoms; and (2) the parent report version of the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III for cases and selected controls. RESULTS: Forty-nine cases (mean 11.3 years, 20 male participants) and 48 controls (mean 11.1 years, 24 male participants) were enrolled. Twelve children in the CD group (24.5%) and 7 children in the control group (14.6%) had AP at the time of the study (P = .3). Nine children in the CD group (18.3%) and 4 children in the control group (8.3%) met criteria for an AP-associated FGID according to the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III (P = .23). CONCLUSION: It was found that children with CD and controls have a similar risk of AP and AP-FGIDs. Methodologic limitations prevent generalization of results, but large prospective studies should confirm the findings.

Neonatal iron overload and tissue siderosis due to gestational alloimmune liver disease.

BACKGROUND & AIMS: Gestational alloimmune liver disease is the main cause of the neonatal hemochromatosis phenotype, wherein severe neonatal liver disease is associated with iron overload and extrahepatic tissue siderosis. How fetal liver disease produces extrahepatic siderosis is not known. We hypothesized that fetal liver injury causes deficient hepcidin production and poor regulation of placental iron flux. Under the resulting conditions of iron overload, the tissue pattern of extrahepatic siderosis is determined by the normal expression of proteins involved in the import of non-transferrin-bound iron and the export of cellular iron. METHODS: Liver and extrahepatic tissues from infants with gestational alloimmune liver disease were examined and compared to normal age-appropriate tissues. RESULTS: Serum iron indices indicate iron overload and excess non-transferrin bound iron in gestational alloimmune liver disease. The diseased liver showed significantly reduced hepcidin, hemojuvulin, and transferrin gene expression compared to the normal fetal and neonatal liver. Those extrahepatic tissues that are typically involved in pathological siderosis in neonatal hemochromatosis, whether from normal or diseased newborns, consistently expressed solute carrier family 39 (zinc transporter), member 14 (ZIP14) for non-transferrin-bound iron uptake and expressed little ferroportin for iron export. CONCLUSIONS: Excess non-transferrin-bound iron in gestational alloimmune liver disease may result from fetal liver injury that causes reduced synthesis of key iron regulatory and transport proteins. Whereas, the pattern of extrahepatic siderosis appears to be determined by the normal capacity of various tissues to import non-transferrin-bound iron and not export cellular iron.

Parental report of abdominal pain and abdominal pain-related functional gastrointestinal disorders from a community survey.

BACKGROUND AND AIMS: Functional gastrointestinal disorders (FGIDs) are common in children. Abdominal pain (AP) is the most common gastrointestinal (GI) symptom in children. The severity of AP drives medical consultations and quality of life in adult patients with irritable bowel syndrome (IBS). Thirty-eight percent of 8- to 15-year-old schoolchildren report AP weekly with 24% of those children reporting persistence of AP >8 weeks. Despite the high prevalence of AP, only 2% of school children seek medical attention for AP. Lack of parental knowledge on their child's symptoms may constitute one of the factors affecting the low ratio of consultation in children reporting AP. The aim was to assess parental reports of AP symptoms in a population of healthy community children. METHODS: Data of 5 studies with identical methodology to assess GI symptoms in children with celiac disease (CD), cow's milk allergy (CMA), pyloric stenosis (PS), Henoch-Schönlein purpura (HSP), and stem cell transplant (SC) and their healthy siblings were reviewed: a phone questionnaire on GI symptoms and Pediatric Gastrointestinal Symptoms Rome III version questionnaire (QPGS-RIII). Inclusion criteria were healthy children 4 to 18 years of age with a sibling previously diagnosed with CD, CMA, PS, HSP, or SC. RESULTS: Data on 246 healthy children, mean age (9.8 years, range 3-24, 112 girls) were obtained. Parents reported presence of AP in the last 8 weeks before the telephone contact in 20 (8.1%) children (age range 4-18 years, 11 girls). There was no significant difference in AP prevalence between boys and girls (P = 0.64). Six children (2.4%) met QPGS-RIII diagnostic criteria for FGIDs: 3 functional abdominal pain (FAP) and 3 IBS. CONCLUSIONS: AP was common in community children. FAP was the most common FGID among healthy community children. The prevalence of AP by parental report is lower than the previously published prevalence of AP reported by children. Lack of awareness of children's symptoms may play a role in the low ratio of consultation for AP in symptomatic children. Future prospective studies should confirm our findings and investigate the factors influencing the medical consultation decision including parental awareness of children's symptoms.

Early life events: infants with pyloric stenosis have a higher risk of developing chronic abdominal pain in childhood.

OBJECTIVE: We hypothesize that children who had pyloric stenosis are at greater risk for developing chronic abdominal pain because this cohort combines various risk factors: an early stressful event, gastric surgery, and perioperative nasogastric tube placement in most cases. STUDY DESIGN: This was a case control study of all children diagnosed with pyloric stenosis during infancy (cases) between January 1, 2000, and June 31, 2005, at Children's Memorial Hospital, Chicago. Because of their similar genetic and socioeconomic backgrounds, siblings aged 4 to 20 years without a history of pyloric stenosis were selected as controls. Parents of children with symptoms completed the parental form of the Pediatric GI Symptoms Rome III version questionnaire for both cases and controls. The primary outcome was the prevalence of chronic abdominal pain, and the secondary outcome was the presence of pain-associated functional gastrointestinal disorder (FGID), in accordance with Rome III criteria. RESULTS: Cases (n = 100; mean age, 7.49 ± 1.43 years; 29 girls) and controls (n = 91; mean age, 9.20 ± 4.19 years; 29 girls) participated in the study. Mean time to follow-up was 7.2 ± 1.6 years. Chronic abdominal pain was significantly more common in cases than in controls (20/80 [25%] vs 5/91 [5.8%]; OR, 4.3; 95% CI, 1.5-12; P = .0045). Seven out of 20 subjects (35%) met the Rome III criteria for diagnosis of a pain-associated FGID (3 with irritable bowel syndrome, 2 with functional dyspepsia, and 2 with functional abdominal pain), and 1 patient in the control group (with irritable bowel syndrome) met these criteria (OR, 6.8; 95% CI, 0.82-56; P = .043). CONCLUSION: We have described a new model to study early life events in infants. Our findings suggest that the presence of pyloric stenosis in infancy and factors involved in its perioperative care represent risk factors in the development of chronic abdominal pain in children at long-term follow-up. This study provides important data to sustain the multifactorial theoretical construct of pain-associated FGID and underscores the importance of early life events in the development of chronic abdominal pain in children.

Cow's-milk allergy is a risk factor for the development of FGIDs in children.

OBJECTIVES: Functional gastrointestinal disorders (FGIDs) are common in children. Their pathogenesis remains unknown and is most likely multifactorial. We hypothesized that noninfectious causes of inflammation affecting the gastrointestinal (GI) tract early in life, such as cow's-milk allergy (CMA), can predispose to the development of FGIDs later in childhood. PATIENTS AND METHODS: Case-control study. Subjects were patients between 4 and 18 years diagnosed with CMA in the first year of life at Children's Memorial Hospital in Chicago, IL, between January 2000 and June 2009. Diagnosis of CMA was based on history and clinical findings. Siblings 4 to 18 years of age without a history of CMA were selected as controls. Cases completed the parental form of the Pediatric Gastrointestinal Symptoms Rome III version questionnaire to assess for GI symptoms. RESULTS: Fifty-two subjects (mean age 8.1 ± 4.48 years, 62% girls) and 53 controls (mean age 9.7 ± 4.20 years, 55% girls) participated in the study. Twenty-three of 52 subjects (44.2%) reported GI symptoms that included abdominal pain, constipation, or diarrhea compared with 11 of 53 controls (20.75%) (odds ratio 3.03, P = 0.01). Abdominal pain was significantly more common in cases (16/52, 30.8%) versus controls (5/53, 9.43%) (odds ratio 4.27 [1.43-12.7]) (χ² = 7.47, P = 0.01). Abnormal stool habits were more common in cases (15/52, 28.8%) versus controls (7/53, 13.2%), but the difference was not statistically significant. Ten of 52 subjects (19.2%) met the Questionnaire on Pediatric Gastrointestinal Symptoms Rome III version criteria for diagnosis of an FGID (7 irritable bowel syndrome, 2 functional dyspepsia, 1 functional abdominal pain), whereas none in the control group did. CONCLUSIONS: CMA constitutes a risk factor for the development of FGIDs in children.

Lessons From a Quality Improvement Project to Standardize the Process of Gastric Biopsy Culture for Helicobacter pylori.

Despite expert recommendations, clinician's adherence to pediatric societal clinical practice guidelines is variable, particularly with respect to the use of gastric biopsy culture in the initial diagnosis of Helicobacter pylori infection. In addition, the implementation of routine use of gastric biopsy culture has been challenging with several factors affecting the rate of successful primary H pylori culture. Methods: We conducted a quality improvement (QI) project with the aims of increasing the rate of successful primary culture. The QI project involved educational efforts among our gastroenterologists, endoscopy suite personnel, and laboratory personnel. We compared the frequency of gastric biopsy culture sent in patients with international classification of diseases 9th revision code 041.86, and 10th revision codes B96.81 evaluated by pediatric gastroenterologists at Boston Children's Hospital during the 9 months before the QI intervention (February 1, 2019 to October 31, 2019) and 9 months after the QI intervention (November 1 2019 to July 31 2020). We also compared the rate of culture growth in patients with positive histology (culture positivity), and antimicrobial susceptibilities before and after November 1, 2019. Results: We observed an increased frequency of gastric biopsy acquisition by any gastroenterologist, obtained in 39% (28 of 71) preintervention patients compared with 67% (36 of 54) intervention patients (P = 0.004). There was an increase in the percentage of culture positivity across study periods from 21% (3 of 14) preintervention to 45% (5 of 11) postintervention (P = 0.39; 95% confidence interval, 0.64-7.00). Conclusion: Educational initiatives and collaborative work with staff physicians, endoscopy personnel, and hospital laboratory appear to be effective tools to increase usage of gastric biopsy culture as a diagnostic tool for H pylori infection and to increase culture positivity. Improving the surveillance of local resistance rates will improve the selection of the most effective primary treatment in specific geographic areas.

Relationship of proximal renal tubular dysgenesis and fetal liver injury in neonatal hemochromatosis.

Renal tubular dysgenesis has been reported in isolated cases of neonatal hemochromatosis (NH). We hypothesized that fetal liver injury in NH impairs proximal renal tubular development via impaired hepatic angiotensinogen (AGT) elaboration. Morphometric analyses were performed of postmortem liver and kidney sections of cases of proven NH and postconception age-matched controls for renal proximal tubule density, hepatocyte mass, and hepatic AGT expression. Proximal tubule density was markedly reduced in NH cases, although they showed a spectrum from mild to severe paucity. Hepatic AGT expression was markedly reduced in NH cases and correlated closely with reduced hepatocyte mass. A linear relationship was established between hepatic AGT expression and the degree of renal tubular dysgenesis suggesting that there is a relationship between them. Our results demonstrate that there is a spectrum of kidney pathology in patients with NH including a large proportion of cases with severe proximal tubular dysgenesis. Hepatic synthetic failure resulting in insufficient production of AGT to support renal tubular development is the likely mechanism of kidney disease in NH.

Focus on the use of antidepressants to treat pediatric functional abdominal pain: current perspectives.

Chronic abdominal pain is frequently encountered in pediatric practice. A large proportion of cases meet Rome criteria for abdominal pain-functional gastrointestinal disorders (AP-FGIDs). These disorders are costly and, in some cases, lead to impairment of daily functioning and overall quality of life. Pathophysiologic mechanisms include early stressful events, visceral hypersensitivity, dysmotility, changes in intestinal microbiota, and altered central nervous system processing. They are considered disorders of the brain-gut interaction. The diagnosis is made on clinical grounds using symptom-based criteria (Rome criteria). Anxiety and depressive symptoms are more prevalent in patients with AP-FGIDs. Therefore, attention has been directed to the use of neuromodulators as potential interventions for AP-FGIDs. Antidepressants are one type of neuromodulators, and one of the most studied drugs for the management of AP-FGIDs in adult and pediatric population. Data available in pediatric population have significant limitations including nonuniform methodology with different study designs and primary endpoints. Evidence of the efficacy of antidepressants in the management of pediatric AP-FGIDs is not consistent. There is an urgent need for well-designed randomized clinical trials using age-appropriate validated outcome measures. Careful consideration must be given to adverse effects, particularly increased suicidal ideation.