Gastrointestinal Pathologies in Pediatric Patients With Cystic Fibrosis Undergoing Endoscopy: A Single-Center Retrospective Review Over 15 Years.

Introduction Previous studies have demonstrated an increased incidence of gastrointestinal (GI) pathologies, specifically celiac disease (CD) and eosinophilic esophagitis (EoE), in patients with cystic fibrosis (CF). However, there is minimal data available regarding endoscopic findings in pediatric patients with CF and GI mucosal disease.  Methods A retrospective chart review was performed on patients with CF under 18 years of age who underwent esophagogastroduodenoscopy (EGD) or colonoscopy with biopsy over a 15-year period at our institution. Patient characteristics including assigned sex at birth, CF genetic mutations (if identified), and cystic fibrosis transmembrane conductance regulator (CFTR) modulator use were recorded. Data obtained at the time of biopsy included body mass index (BMI), indication for the procedure, exocrine pancreatic status, visual endoscopic findings, and histologic findings. Results A total of 72 patients with CF were included in the study. 24% (n=17) were found to have abnormal endoscopic biopsy results. EoE (13% of all patients, n=9) and CD (6% of all patients, n=4) were the most common GI diagnoses present on endoscopic biopsy. All 3 patients taking CFTR modulator medications at the time of endoscopy had normal biopsy results. Of the 17 patients found to have abnormal pathology results, 14 (82%) were taking proton-pump inhibitor (PPI) medication at the time of endoscopy. Conclusion This study highlights the probable increased frequency of GI disease in the pediatric CF population. These findings underscore the importance of maintaining a broad differential diagnosis while considering utilization of endoscopy with biopsy in pediatric patients with CF who have GI symptoms.

Flexible Sigmoidoscopy Utility in the Diagnosis of Pediatric Gastrointestinal Disorders.

AIM:  Although flexible sigmoidoscopy (FS) is utilized in children for the diagnosis of pediatric gastrointestinal conditions, such as inflammatory bowel disease and juvenile polyp disorders, the diagnostic yield of FS in pediatric patients is unknown. MATERIALS AND METHODS:  We retrospectively reviewed FS cases in children under 18 years of age over a five-year period at our institution. Indications for the procedure, endoscopic visual findings, histologic findings, final diagnosis, and any management changes based on FS findings were included. RESULTS:  A total of 354 cases were included in the analysis for which 40 cases (11.3%) had abnormal visual findings, 48 cases (13.6%) had abnormal histologic findings, and 13 cases (3.7%) had both abnormal endoscopic visual and histologic findings. Of the 88 cases with abnormal visual and/or histologic abnormalities, only the results of 34 of these FS cases led to a change in management based on endoscopic findings (9.6%). Most patients with a non-diagnostic FS had a final diagnosis of functional abdominal pain; most patients with a diagnostic FS had a final diagnosis of colitis, not otherwise specified. CONCLUSION:  Our findings suggest that FS is not a helpful diagnostic endoscopic intervention in pediatric patients, especially in children with reassuring history and physical exam findings.

"I've never been able to burp": Preliminary description of retrograde cricopharyngeal dysfunction in children.

OBJECTIVE: Retrograde cricopharyngeal dysfunction was recently described by Bastian in 2019 and is characterized by an inability to belch, abdominal or chest pressure, odd gurgling noises, and occasional difficulty vomiting. Symptoms tend to worsen with carbonated beverages. Currently, the recommended treatment is cricopharyngeus muscle botulinum toxin injections. Prior studies have included few pediatric patients within larger datasets comprised primarily of adults. We describe our preliminary experience in pediatric patients, including presenting symptoms, treatment approach, and post-treatment outcomes. METHODS: Retrospective chart review of pediatric patients (aged <18 years) diagnosed with retrograde cricopharyngeal dysfunction based on clinical history by the senior author. Medical records were reviewed for presenting symptoms, prior testing and treatment, details of treatment, and postoperative outcomes. RESULTS: Five patients with average age of 14 ± 4 (3 females, 2 males) were included. Presenting symptoms included lifelong or nearly lifelong inability to burp (n = 5), bloating (n = 5), awkward gurgling noises (n = 3), and worsening of symptoms with carbonated beverages (n = 5). Two patients had prior normal upper endoscopy. All patients underwent cricopharyngeal botulinum toxin injection under general anesthesia, with 25-50 units of botulinum toxin injected to the posterior cricopharyngeus across 4-5 locations. All patients had resolution of symptoms with follow-up of 1.5-10 months. CONCLUSIONS: Retrograde cricopharyngeal dysfunction may be underdiagnosed due to lack of awareness of the condition. Now that the phenomenon of inability to belch has a name and is being reported in the literature, we will likely see more adult and pediatric patients with these symptoms. Pediatric patients may respond similarly to adults. Larger studies with longer-term follow-up and targeted patient-reported outcome measures are needed to characterize disease presentation and treatment outcomes.

Adherence to Biopsy and Follow-Up Guidelines in a Population-Based Cohort of Children With Eosinophilic Esophagitis.

Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition that is becoming more widely recognized in children. Recent EoE practice guidelines provide clear recommendations on adequate biopsy sampling at diagnostic endoscopy and necessity of close follow-up endoscopy with biopsy to ensure mucosal healing with therapy.1 Despite these recommendations, adherence to biopsy guidelines, time to first follow-up endoscopy, and overall surveillance endoscopy rates have not been robustly studied. Using a population-based cohort of children diagnosed with EoE in Utah, we assessed adherence to guidelines across multiple provider types, including academic pediatric gastroenterologists (PGIs), private practice PGIs, and adult-trained providers performing endoscopy in children.

Sensitivity and Specificity of Administrative Medical Coding for Pediatric Eosinophilic Esophagitis.

OBJECTIVES: Eosinophilic esophagitis (EoE) is a delayed-type hypersensitivity with increasing rates among pediatric populations. Although studies have used International Classification of Diseases (ICD) coding to define local cohorts and report disease epidemiology, the accuracy of the EoE ICD code for pediatric EoE is unknown. METHODS: We searched the Intermountain Healthcare Database for pediatric cases with the EoE ICD code over a 5-year period. We cross-referenced these results with a recently published pediatric EoE cohort from the same region and period, where incident cases were identified via retrospective review of pathology reports and medical records. Using the retrospective review cohort as the reference standard, we evaluated the accuracy of the EoE ICD code. RESULTS: Via retrospective review, we identified 1129 new pediatric EoE cases in the Intermountain Healthcare system over 5 years. Six hundred ten of these had the EoE ICD code associated with their chart. Out of 878,872 unique pediatric records in the Intermountain Healthcare system, 219 had the EoE ICD code incorrectly applied. The specificity of the EoE ICD code in children was 99%, but sensitivity and positive predictive value were 61% and 79%, respectively. CONCLUSIONS: The EoE ICD code has strengths and weaknesses in pediatrics. The EoE ICD code is specific, with few false positives across a large population, but not sensitive. The low sensitivity is likely multifactorial and requires further evaluation. Compared to retrospective chart review, which allows for application of clinicopathologic EoE diagnostic criteria, sole use of ICD codes results in underascertainment of EoE cases and key misclassifications.

Incidence and Prevalence of Pediatric Eosinophilic Esophagitis in Utah Based on a 5-Year Population-Based Study.

BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. METHODS: Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. RESULTS: We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. CONCLUSION: In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah's searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.

Vitamin D deficiency in pediatric patients with cystic fibrosis: associated risk factors in the northern United States.

OBJECTIVES: Cystic fibrosis (CF) is associated with vitamin D deficiency, which can lead to adverse effects including recurrent pulmonary infections and osteoporosis. We longitudinally investigated calcifediol or 25-hydroxyvitamin D (25(OH)D) levels for our pediatric patients with CF based on the time of year as well as vitamin D supplementation dosing ranges for these patients at our CF center. METHODS: We retrospectively evaluated vitamin D deficiency in our pediatric CF center for 2 years (baseline and annually) while evaluating 25(OH)D serum changes based on vitamin D supplementation, seasonality, patient age, and other factors associated with CF. RESULTS: Vitamin D supplementation was noted to be higher than current Cystic Fibrosis Foundation dosing recommendations, and no patient experienced vitamin D toxicity. Seasonality was a strong indicator of 25(OH)D levels, especially during summer or fall. Significantly fewer patients with initially low 25(OH)D levels maintained low levels at the conclusion of the study, suggesting benefit. Older patient age and higher supplemental dosing correlated with significantly lower 25(OH)D levels. CONCLUSIONS: This study suggests that targeted intervention among pediatric patients with CF living in northern latitudes of the United States, especially older children, is needed to prevent vitamin D deficiency.

Endoscopy in the diagnosis of intestinal graft-versus-host disease: is lower endoscopy with biopsy as effective in diagnosis as upper endoscopy combined with lower endoscopy?

BACKGROUND: Graft-versus-host disease (GvHD) causes morbidity and mortality in recipients of hematopoietic stem cell transplantation (SCT). This study assessed the distribution of GvHD in gastrointestinal (GI) biopsies from the upper and lower GI tract in pediatric patients who had undergone SCT and evaluated if there was correlation between biopsy findings and possible extra-intestinal manifestations of GvHD. PROCEDURE: We performed a retrospective chart review for all patients diagnosed with GvHD, who underwent both upper and lower endoscopy. We also reviewed pathology and clinical reports to determine which biopsy sites were diagnostic of GvHD and to evaluate for the possible presence of extra-intestinal manifestations GvHD at the time of biopsy. RESULTS: Twenty patients were identified who had undergone both upper and lower endoscopy for evaluation of GvHD. Patients with GvHD diagnosed on upper endoscopy also had GvHD identified in the sigmoid colon region 100% of the time (positive predictive value [PPV] = 1). In patients that were found to have underlying liver disease, GvHD was diagnosed in the sigmoid colon region 90% of the time (PPV = 0.9). CONCLUSION: Use of sigmoid biopsy for GvHD diagnosis is effective, safe, and less expensive compared to other endoscopic interventions.

Effect of dietary advanced glycation end products on mouse liver.

UNLABELLED: The exact pathophysiology of non-alcoholic steatohepatitis (NASH) is not known. Previous studies suggest that dietary advanced glycation end products (AGEs) can cause oxidative stress in liver. We aim to study the effects of dietary AGEs on liver health and their possible role in the pathogenesis of NASH. METHODS: Two groups of mice were fed the same diet except the AGE content varied. One group was fed a high AGE diet and the second group was fed a regular AGE diet. Liver histology, alanine aminotransferase, aspartate aminotransferase, fasting glucose, fasting insulin, insulin resistance and glucose tolerance were assessed. RESULTS: Histology revealed that neutrophil infiltration occurred in the livers of the high AGE group at week 26; steatosis did not accompany liver inflammation. At week 39 livers from both groups exhibited macro- or micro-steatosis, yet no inflammation was detected. Higher insulin levels were detected in the regular AGE group at week 26 (P = 0.034), compared to the high AGE group. At week 39, the regular AGE group showed higher levels of alanine aminotransferase (P<0.01) and aspartate aminotransferase (P = 0.02) than those of the high AGE group. CONCLUSIONS: We demonstrate that a high AGE diet can cause liver inflammation in the absence of steatosis. Our results show that dietary AGEs could play a role in initiating liver inflammation contributing to the disease progression of NASH. Our observation that the inflammation caused by high AGE alone did not persist suggests interesting future directions to investigate how AGEs contribute to pro-oxidative and anti-oxidative pathways in the liver.

Clostridium difficile Infection and Proton Pump Inhibitor Use in Hospitalized Pediatric Cystic Fibrosis Patients.

Children with cystic fibrosis (CF) often take proton pump inhibitors (PPIs), which helps improve efficacy of fat absorption with pancreatic enzyme replacement therapy. However, PPI use is known to be associated with Clostridium difficile-(C. diff-) associated diarrhea (CDAD). We retrospectively evaluated the incidence of C. diff infection from all pediatric hospital admissions over a 5-year period at a single tertiary children's hospital. We found significantly more C. diff-positive stool tests in hospitalized patients with CF compared to patients with no diagnosis of CF. However, use of a PPI was not associated with an increased risk of CDAD in hospitalized CF patients. In summary, C. diff infection is more common in hospitalized pediatric CF patients although PPI use may not be a risk factor for CDAD development in this patient population.

Esophagitis in children with celiac disease.

Objectives. To our knowledge, the occurrence of esophagitis in children with celiac disease (CD) has never been evaluated. The aim of this study is to determine the prevalence of esophagitis in children with CD. Patients and Methods. Between 2003 and 2007, children with biopsy confirmed CD were retrospectively identified. Biopsy reports were reviewed for esophageal inflammation. Biopsy reports of 2218 endoscopies performed during the same period were also evaluated for inflammation. Results. Forty-nine children diagnosed with CD (47% boys). Nineteen of 49 (39%) patients with CD had esophagitis (95% CI 0.23-0.5). Thirty percent of boys and 46% of girls with CD had esophagitis (95% CI 0.12-0.40). Overall, 45% of patients who underwent upper endoscopy had esophagitis. The prevalence of esophagitis in CD (39%) compared to the prevalence of esophagitis (45%) in our practice was not significantly different, P = 0.2526. Conclusion. There was no difference in the prevalence of esophagitis between children diagnosed with CD at the time of their diagnostic EGD and the prevalence of esophagitis in children without CD. A prospective study to determine whether the esophagitis should be treated with acid suppression or whether the esophagitis heals with the gluten-free diet is warranted.

Varicella immunity in inflammatory bowel disease.

OBJECTIVES: Varicella zoster is a childhood disease that can cause devastating illness and death in immunocompromised individuals, including those who are taking steroids. Inflammatory bowel disease (IBD) is managed by decreasing or controlling the inflammation using immunosuppression. Our objective was to show that at least 90% of patients newly diagnosed as having IBD had antibodies against varicella zoster and were protected by vaccination or natural disease. MATERIALS AND METHODS: Retrospective review of all of the charts of the patients diagnosed with IBD at the University of Buffalo's Digestive Diseases and Nutrition Center for 5 years from January 1, 2005 to December 31, 2009. RESULTS: There were 163 new diagnoses of IBD during this time; 57% were boys. Mean age was 12 years (range 1-19 years); 62% had Crohn disease, 33% ulcerative colitis, and 5% indeterminate colitis. A total of 66% of all of the patients had a history of disease or vaccination. Measurable titers against varicella were found in only 77% of all of the patients. CONCLUSIONS: Lack of varicella immunity is common in children and adolescents at the time of diagnosis of IBD. Routine screening for varicella immune status may be warranted. Offering immunization to susceptible patients should confer protection, but this may be difficult to achieve once immune suppression has begun.

Lipid in the livers of adolescents with nonalcoholic steatohepatitis: combined effects of pathways on steatosis.

Fatty liver is a prerequisite for the development of nonalcoholic steatohepatitis (NASH). The homeostasis of hepatic lipid is determined by the dynamic balance of multiple pathways introducing lipids into or removing lipids from hepatocytes. We aim to study the different contributions of major lipid pathways to fat deposition in NASH livers. Expression of the lipid metabolism-related genes was analyzed by microarray and quantitative real-time polymerase chain reaction analysis. The expression levels of genes responsible for the rate-limiting steps of fatty acid uptake (CD36, FABPpm, SLC27A2, and SLC27A5), de novo synthesis (ACACB), oxidation (CPT-1), and very low-density lipoprotein (VLDL) secretion (ApoB) were used to evaluate the relative activity of each pathway. The expression levels for CD36 and CPT-1 were confirmed by Western blot analysis. Fatty acid uptake pathways were up-regulated to a higher degree than other pathways. The de novo synthesis pathway was also up-regulated more than both VLDL secretion and fatty acid oxidation pathways. In contrast to other NASH livers, one NASH liver exhibited lower ApoB and CPT-1 expression levels than normal controls. The increased fatty acid uptake and de novo synthesis were the most common causes for steatosis in NASH patients. In a rare case, impaired VLDL secretion and fatty acid oxidation contributed to the development of steatosis. Our study promises a simple method for the determination of why hepatic steatosis occurs in individual patients. This method may allow specific targeting of therapeutic treatments in individual patients.

Two Cases of Helicobacter pylori-Negative Gastric Outlet Obstruction in Children.

Gastric outlet obstruction (GOO) in children is most commonly caused by idiopathic hypertrophic pyloric stenosis. Prior to proton pump inhibitors and H2 blockers, peptic ulcer disease (PUD) secondary to H. pylori was a cause of GOO. Both patients presented with a history of weight loss, vomiting, and abdominal pain. Their diagnosis of PUD and GOO was made by EGD and UGI. H. pylori testing was negative for both on multiple occasions but still received H. pylori eradication therapy. Patient 1 after failing pharmaceutical management underwent surgery for definitive treatment. Patient 2 underwent six therapeutic pyloric dilations before undergoing surgery as definitive treatment. These cases suggest that GOO secondary to PUD occurs in the absence of H. pylori infection and surgical management can provide definitive therapy.

Increasing incidence of community-associated atypical Clostridium difficile disease in children.

Forty-one children with a variety of gastrointestinal complaints were diagnosed with Clostridium difficile infections as part of a routine screen over 3 years. The infection had not been suspected prior to the screen. Each child responded to treatment with metronidazole with resolution of their symptoms. These data suggest that community-associated C difficile is increasing and may produce atypical disease and lead to misdiagnosis.

Delays in discharge in a tertiary care pediatric hospital.

BACKGROUND: Delays in discharges affect both efficiency and timeliness of care; 2 measures of quality of inpatient care. OBJECTIVE: Describe number, length, and type of delays in hospital discharges. Characterize impact of delays on overall length of stay (LOS) and costs. DESIGN: Prospective observational cohort study. SETTING: Tertiary-care children's hospital. PATIENTS: All children on 2 medical teams during August 2004. INTERVENTION: Two research assistants presented detailed data of patient care (from daily rounds) to 2 physicians who identified delays and classified the delay type. Discharge was identified as delayed if there was no medical reason for the patient to be in the hospital on a given day. MEASUREMENTS: Delays were classified using a validated and reliable instrument, the Delay Tool. LOS and costs were extracted from an administrative database. RESULTS: Two teams cared for 171 patients. Mean LOS and costs were 7.3 days (standard deviation [SD] 14.3) and $15,197 (SD 38,395), respectively: 22.8% of patients experienced at least 1 delay, accounting for 82 delay-related hospital days (9% of total hospital days) and $170,000 in costs (8.9% of hospital costs); 42.3% of the delays resulted from physician behavior, 21.8% were related to discharge planning, 14.1% were related to consultation, and 12.8% were related to test scheduling. CONCLUSIONS: Almost one-fourth of patients in this 1-month period could have been discharged sooner than they were. Impact of delays on LOS and costs are substantial. Interventions will need to address variations in physician criteria for discharge, more efficient discharge planning, and timely scheduling of consultation and diagnostic testing.

Treatment with high-dose proton pump inhibitors helps distinguish eosinophilic esophagitis from noneosinophilic esophagitis.

BACKGROUND: Eosinophilic esophagitis (EE) is a clinical entity that is recognized increasingly in children. The treatment of EE has been debated since its identification as a clinical entity separate from reflux esophagitis. We hypothesize that the treatment with a high-dose proton pump inhibitor (HDPPI) helps differentiate EE from noneosinophilic esophagitis (NEE). PATIENTS AND METHODS: Retrospective review of 2221 patients who underwent esophagogastroduodenoscopy (EGD) with biopsies was undertaken. Sixty-nine patients had more than or equal to 15 eosinophils/high-power field (eos/HPF) in 1 or more esophageal levels. Of those, 36 were initially treated with HDPPI for 3 months followed by repeat EGD. Patients who demonstrated histologic response were classified as NEE. Patients with no histologic response were diagnosed as having EE and treated with HDPPI+swallowed fluticasone for 3 months followed by repeat EGD. RESULTS: Of the 36 patients, histologic response was seen in 14 (39%) after treatment with HDPPI; 95% confidence interval (0.23-0.54). Swallowed fluticasone was added to the treatment of the 22 patients who did not show histologic response to HDPPI alone. Of those, 15 patients underwent repeat endoscopies. Seven patients were lost to follow-up or did not have repeated EGDs. Histologic response was observed in 9 of 15 (60%) patients. Of the nonresponders (6 of 15), 5 of 6 (83%) self-reported noncompliance with the swallowed fluticasone. Patients with more than or equal to 15 eos/HPF at all 3 levels (25 of 36) were less likely to respond to HDPPI alone and more likely to be categorized as EE (18 of 25), P=or<0.043. Symptomatically, 28 of 36 patients reported resolution of symptoms after HDPPI therapy alone, P=or<0.0001, regardless of histology. Visual endoscopic findings during the first and second EGDs did not show any significance in differentiating EE from NEE, P=0.625 and P=0.2405, respectively. CONCLUSIONS: The study demonstrates that HDPPI can be used to help differentiate EE from NEE histologically. Moreover, patients with more than or equal to 15 eos/HPF at all 3 levels are less likely to respond to HDPPI than patients with more than or equal to 15 eos/HPF at fewer than 3 levels. Therefore, having more than or equal to 15 eos/HPF at 1 or 2 biopsy levels does not necessarily establish the diagnosis of EE. Symptomatic response to HDPPI does not correlate with histologic findings. Clinical management guided by EGD with biopsy helps distinguish patients with EE from those with NEE.