EoE behaves as a unique Th2 disease: a narrative review.

Background and Objective: To highlight and interpret two significant differences between eosinophilic esophagitis (EoE), a type 2 helper cell (Th2) disease, and three other representative Th2 diseases. EoE, asthma, atopic dermatitis (AD), chronic rhinosinusitis (CRS) and other Th2 diseases employ epithelial alarmins to recognize triggers, share a prototypical inflammatory cascade, and respond to glucocorticoids. However, EoE also has several distinguishing characteristics which may be explained by a distinct pathophysiologic mechanism. Methods: The following report consist of four related narrative reviews which combine comprehensive PubMed and Google searches. Two reviews were performed to identify and contrast all eligible studies describing serologic markers in EoE compared to asthma, AD, and CRS. Two additional reviews then compare the responses to parenteral biological therapies in EoE and in the same representative Th2 diseases. Key Content and Findings: Comprehensive literature searches definitively differentiate the absence of serologic markers in EoE compared to their identification in the other representative Th2 diseases. Similarly, a summary of therapeutic trials demonstrates that while EoE is unable to clinically respond to a variety of parenteral biological therapies, asthma, AD and CRS are very effectively treated with this same approach. A novel pathophysiology for EoE is proposed, and the emerging literature that support its existence is summarized. Conclusions: The fundamental properties described in this narrative regarding serologic signaling and response to parenteral therapy in EoE could be explained if EoE employs a unique application of the Th2 pathway. One potential mechanism consistent with these observations is that EoE employs exclusively esophageal mucosal constituents to initiate and generate the prototypical Th2 cascade and the fibrostenotic changes that follow.

Predicting pediatric esophageal wall thickness: An EUS study.

BACKGROUND AND OBJECTIVE: EUS has been shown in two small series to be capable of documenting increases in the total esophageal wall thickness (TWT) in children and adults with eosinophilic esophagitis (EoE). To apply EUS-derived TWT in clinical situations or in scientific investigations in pediatric EoE, measurements of esophageal TWT in children of differing ages and heights are required. MATERIALS AND METHODS: Thirty patients (18M: 12F, 7 months to 20 years and 10 months) with a history of esophageal symptoms, but no endoscopic or histologic criteria of EoE were studied using a through the scope 20 MHZ Olympus Ultrasound miniprobe UM-3R (Olympus America, Center Valley Pa 18034) through a GIF Q180 or 160 (Olympus) standard pediatric upper endoscope. The mucosa, the mucosa plus submucosa, and the TWT were measured in the mid- and distal esophagus immediately before taking diagnostic biopsies. RESULTS: Measurements from both sites showed a statistically significant increase in TWT as a function of age (P < 0.001) and height (P < 0.001), as did the individual layers. The width of the mucosa and the submucosa were equivalent and together, they contributed more than half of the entire TWT. There were no significant differences between the means of the mid- and distal esophageal measurements. A multiple regression equation that can predict TWT based on age, with 95% confidence limits, is presented. CONCLUSIONS: EUS has demonstrated that esophageal TWT in a cohort of control children correlates with height and with age and has provided insights into the organization of the esophageal wall. Esophageal TWT values obtained by EUS can now be interpreted to recognize esophageal wall thickening throughout childhood.

Applying the Eosinophilic Esophagitis Endoscopic Reference Scores (EREFS) to Different Aged Children.

OBJECTIVES: The eosinophilic esophagitis (EoE) endoscopic reference score (EREFS) was developed to analyze adults with EoE and has been successfully applied to a pediatric cohort. The present study compares EREFS in younger and older children with EoE. METHODS: The 99 patients were divided among 3 cohorts: 44 active EoE (EoE-A); 16 EoE remission (EoE-R); and 39 controls (esophageal dysfunction but <15 eos/hpf). The cohorts were then subdivided into 2 groups: younger (≤10 years) and older (>10 years) that were compared based on the composite and the individual components of their EREFS. RESULTS: EREFS identified EoE-A in all children with an area under the receiving operating characteristics curve (AUC) of 0.85, in older children with an AUC of 0.90 and in younger children with an AUC of 0.77. Mean EREFS for ≤10 years was 1.26 ±â€Š1.19 and 2.71 ±â€Š1.33 for >10 years (P < 0.01). The 3 most common findings in our entire EoE-A cohort and in both ages were furrows, edema, and exudates. EREFS in patients with EoE-A had similar specificities (0.88 vs 0.89) and positive predictive values (0.89 vs 0.91) in both ages. CONCLUSIONS: The present investigation confirms the utilization of EREFS in Pediatric EoE. Furthermore, EREFS can detect EoE and document response to treatment in both younger and older children. EREFS, however, predicted EoE in the older children with a higher sensitivity (0.89 vs 0.63) and a higher negative predictive value (0.87 vs 0.59) than was seen in the younger cohort.

Treatment of Pyoderma Gangrenosum in Pediatric Inflammatory Bowel Disease.

Pyoderma gangrenosum (PG) is a rare, necrotizing dermatologic condition associated with neoplastic and immune dysregulatory states, including adult and pediatric inflammatory bowel disease (IBD). Over the last decade, the elucidation of inflammatory mediators in PG has led to a plethora of localized and systemic corticosteroid sparing therapies including antibiotics, antiinflammatory, and immunomodulatory agents. Herein, we describe the case of a 17-year-old female with ulcerative colitis in clinical remission, who presented with a long-standing, large, deep, and painful lower extremity PG lesion. Following failed attempts both at local and at systemic therapies, her PG was successfully treated with the tumor necrosis factor-alpha (TNF-α) monoclonal antibody adalimumab, and the lesion remains in remission after four years of subcutaneous anti-TNF therapy. This case serves as the basis for our presenting a review of the pathogenesis, diagnostic criteria, differential diagnosis, therapies and treatment outcomes for pediatric IBD-associated PG. Our experience adds to earlier reports suggesting anti-TNF-α biologic therapy is most likely to achieve long-term resolution of IBD-associated PG in children and adolescents with severe lesions or who failed other treatments.

Measurement of Microvascular Function in Pediatric Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Altered vascular flow is known to both play a role in the pathogenesis and influence the severity of inflammatory bowel disease (IBD). This phenomenon has been described in other systemic conditions and contributes to disease progression by facilitating inflammation and thrombosis. Microvascular dysfunction may represent an early sign of generalized vascular disease (VD). It manifests by failure to achieve a normal response of vasodilation and increased blood flow following a period of vaso-occlusion. Although thromboembolic complications are well described in IBD, their pathogenesis is not fully understood. This study sought to assess microvascular responsiveness in pediatric subjects with IBD, by recording postocclusion peripheral arterial pulsatile volume changes. PATIENTS AND METHODS: A total of 32 pediatric subjects were studied, including 16 with IBD and 16 age-matched controls. All patients with IBD were in clinical remission, and none had known VD. Vascular reactivity was evaluated using the Itamar Medical EndoPAT2000, a noninvasive device utilizing plethysmography to measure microvascular flow. Results were reported as the reactive hyperemia index (RHI), indicating post- to preocclusion pulsatile volume changes. RESULTS: Baseline characteristics, including body mass index, plasma lipid levels, hemoglobin, and serum albumin, were similar in both study groups. All patients with IBD were in clinical remission, assessed by standard disease activity scoring methods. Measurements of microvascular function indicated patients with IBD exhibited a mean RHI both within the range associated with VD risk in adults (≤1.67) and significantly lower than that in controls (IBD vs control = 1.66 vs 2.02, P = 0.036). CONCLUSIONS: Microvascular plethysmography is a safe and noninvasive method for assessing microvascular function in children with IBD. Patients with IBD in clinical remission demonstrate an attenuated, postocclusion microvascular hyperemic response, compared with the normal response in controls. These findings suggest pediatric IBD subjects with a mean RHI within the VD "at risk" range should be monitored for thromboembolic phenomena. Further studies in a larger patient population and over longer periods should be conducted to validate our findings and to determine the importance of these measurements in guiding IBD management.

Pediatric Helicobacter pylori gastropathy demonstrates a unique pattern of gastric foveolar hyperplasia.

OBJECTIVES: Helicobacter pylori (Hp) are the most common agents causing gastric mucosal injury worldwide. Foveolar hyperplasia is a key component of the stomach's reaction to injury. This study examines histopathologic characteristics associated with Helicobacter pylori and with non- Helicobacter pylori-associated gastropathy in children and adolescents, and compares the prevalence of foveolar hyperplasia among these disease subgroups and normal control subjects. METHODS: Eighty-one gastric antral and corpus biopsies from subjects 2-19 years of age were studied. Twenty-two subjects with Helicobacter pylori gastritis were compared to 23 with non-Helicobacter pylori gastropathy and to 36 controls (normal biopsies). Foveolar length, full mucosal thickness, and the foveolar length: full mucosal thickness ratio were derived by a morphometric technique previously developed to analyze adult gastric tissue. RESULTS: Compared to controls, Helicobacter pylori gastritis demonstrated significant increases in antral foveolar length (P < .0001), full mucosal thickness (P < .0001), as well as corpus foveolar length (P < .05) and corpus full mucosal thickness (P < .05). Non-Helicobacter pylori-associated gastropathy also was characterized by increased antral foveolar length (P < .0001) and full mucosal thickness (P < .001) but corresponding corpus measurements did not differ from controls. Antral foveolar length in non-Helicobacter pylori gastropathy was increased, when compared to Helicobacter pylori gastritis (P < .05), while corpus values were not. The non-Helicobacter pylori gastropathy group demonstrated increased antral foveolar length: full mucosal thickness ratios, compared with Helicobacter pylori gastritis (P < .001) and with normal controls (P < .0001). DISCUSSION: An objective, quantitative approach to measuring foveolar hyperplasia in adults was successfully applied to pediatric biopsies and yielded a richer characterization of gastric pathology in children. Foveolar hyperplasia appears to be a generalized phenomenon in the presence of pediatric Helicobacter pylori gastritis but is limited to the antrum in non-Helicobacter pylori gastropathy.

Aripiprazole reversed gastroparesis in a child with 1q21.1-q21.2 microdeletion.

An 11-year-old Caucasian boy, with a microdeletion in the 1q21.1-q21.2 region, had multiple medical conditions including gastroparesis documented initially at the age of 5. The patient had a history of poor feeding since infancy and had been treated for gastro-oesophageal reflux disease (GERD), constipation and multiple food allergies. As a consequence of the GERD and his concurrent immunoglobulin (IgG) subclass deficiency, the patient had multiple otolaryngologic (ENT) infections and required two sinus surgeries. The patient had poor weight gain (below the third percentile for weight-for-age) and required a short course of parenteral nutrition and eventually a gastrostomy tube. He was started on metoclopramide as treatment for gastroparesis with an increase in his appetite, oral intake and weight gain. However, severe headaches and worsening in his behaviour caused the agent to be discontinued. He had little weight gain and after a course of parenteral nutrition he was converted to a transpyloric feeding tube. Because of ongoing behavioural problems that interfered with his school performance, a psychiatrist started him on aripiprazole. After aripiprazole was prescribed at age 11, his appetite and oral intake dramatically increased and a repeat gastric emptying study was normal. The increased oral intake and weight gain continued, allowing removal of the feeding tube. More than 2 years later, on aripiprazole, he continues to gain weight without any supplemental feedings.

Using the Objective Structured Clinical Examination to Assess ACGME Competencies in Pediatric Gastroenterology Fellows.

BACKGROUND: The Accreditation Council for Graduate Medical Education has described 6 core competencies with which trainees should demonstrate proficiency. Using the Objective Structured Clinical Examination (OSCE), we aimed to assess 4 of these competencies among Pediatric Gastrointestinal (GI) fellows (PGs). METHODS: Eight first-year PGs from 6 medical centers in the New York area participated in a 4-station OSCE with trained standardized patient (SP) actors. The cases included an emergency department (ED) consult, or "ED Consult" for lower gastrointestinal bleeding; "Breaking Bad News" focusing on CF nutritional complications; "Second Opinion" for abdominal pain; "Transition of Care" for inflammatory bowel disease. At each station, attending faculty observed the encounters behind a 1-way mirror. SPs and faculties provided immediate feedback to the examined fellows. Previously validated OSCE checklists were used to assess performance. On completion, fellows attended debriefing sessions and completed surveys about the educational value. RESULTS: Median overall milestone competency scores were 6.9 (PC1), 4.8 (PC2), 5.9 (MK1), 5.7 (MK2), 6.4 (ICS1), 6.9 (Prof1), and 6.7 (Prof3). Overall, fellows score highest (7/9) on the inflammatory bowel disease "Transition of Care" case, found the "Breaking Bad News" Cystic Fibrosis OSCE to be the most challenging, and were most comfortable with the "ED Consult" OSCE, as a commonly encountered scenario. Overall, the fellows rated the educational value of the program highly. CONCLUSIONS: To our knowledge, although the OSCE has been validated in other medical fields, this is the first OSCE program developed for PGs fellows. These OSCEs have included Accreditation Council for Graduate Medical Education competencies, serving to assess fellows' skills in these areas while exposing them to challenging medical and psychosocial cases that they may not frequently encounter.

Packed red blood cell transfusions as a risk factor for parenteral nutrition associated liver disease in premature infants.

AIM: To determine if packed red blood cell transfusions contribute to the development of parenteral nutrition associated liver disease. METHODS: A retrospective chart review of 49 premature infants on parenteral nutrition for > 30 d who received packed red blood cell (PRBC) transfusions was performed. Parenteral nutrition associated liver disease was primarily defined by direct bilirubin (db) > 2.0 mg/dL. A high transfusion cohort was defined as receiving > 75 mL packed red blood cells (the median value). Kaplan-Meier plots estimated the median volume of packed red blood cells received in order to develop parenteral nutrition associated liver disease. RESULTS: Parenteral nutritional associated liver disease (PNALD) was noted in 21 (43%) infants based on db. Among the 27 high transfusion infants, PNALD was present in 17 (64%) based on elevated direct bilirubin which was significantly greater than the low transfusion recipients. About 50% of the infants, who were transfused 101-125 mL packed red blood cells, developed PNALD based on elevation of direct bilirubin. All infants who were transfused more than 200 mL of packed red blood cells developed PNALD. Similar results were seen when using elevation of aspartate transaminase or alanine transaminase to define PNALD. CONCLUSION: In this retrospective, pilot study there was a statistically significant correlation between the volume of PRBC transfusions received by premature infants and the development of PNALD.

Lipogenesis in Huh7 cells is promoted by increasing the fructose: Glucose molar ratio.

AIM: To determine whether hepatocyte lipogenesis, in an in vitro cell culture model, is modulated by adjusting culture media monosaccharide content and concentration. METHODS: Hepatocytes (Huh7), demonstrating glucose and fructose uptake and lipid biosynthesis, were incubated in culture media containing either glucose alone (0.65-0.72 mmol/L) or isosmolar monosaccharide (0.72 mmol/L) comprising fructose:glucose (F:G) molar ratios ranging from 0.58-0.67. Following a 24-h incubation, cells were harvested and analyzed for total protein, triglyceride (TG) and cholesterol (C) content. Significant differences (P < 0.05) among groups were determined using analysis of variance followed by Dunnett's test for multiple comparisons. RESULTS: After a 24 h incubation period, Huh7 cell mass and viability among all experimental groups were not different. Hepatocytes cultured with increasing concentrations of glucose alone did not demonstrate a significant change either in C or in TG content. However, when the culture media contained increasing F:G molar ratios, at a constant total monosaccharide concentration, synthesis both of C and of TG increased significantly [F:G ratio = 0.58, C/protein (µg/µg) = 0.13; F:G = 0.67, C/protein = 0.18, P < 0.01; F:G ratio = 0.58, TG/protein (µg/µg) = 0.06; F:G ratio = 0.67, TG/protein = 0.11, P < 0.01]. CONCLUSION: In an in vitro hepatocyte model, glucose or fructose plus glucose support total cell mass and lipogenic activity. Increasing the fructose:glucose molar ratio (but not glucose alone) enhances triglyceride and cholesterol synthesis. These investigations demonstrate fructose promotes hepatocellular lipogenesis, and they provide evidence supporting future, in vivo studies of fructose's role in the development of hepatic steatosis and non-alcoholic fatty liver disease.

Inverse correlation between Helicobacter pylori colonization and obesity in a cohort of inner city children.

BACKGROUND: Recently, publications in adults and children have documented a potential role of Helicobacter pylori (H. pylori) in decreasing the likelihood of obesity. The present study compares the prevalence of H. pylori colonization between obese (body mass index [BMI] ≥ 95th percentile) and healthy weight (BMI ≥ 5th to <85th percentiles) children seen at an inner city medical center in the United States. METHODS: This retrospective study reviewed clinical features, BMI, and gastric histology of consecutive children aged 1-18 years undergoing an esophagogastroduodenoscopy. BMI percentile was calculated for age and gender. Helicobacter pylori colonization was determined by histopathologic identification of the organism. Multiple logistic regression was employed to measure the association between BMI and H. pylori colonization, controlling for baseline age, gender, and presenting symptoms. RESULTS: Among 340 patients (51.5% female, mean age of 10.5 ± 4.7 years), 98 (29%) were obese and 173 (51%) were healthy weight. The H. pylori colonization rate of the entire cohort was 18.5% (95% CI = 14.7-23.0%). Among obese children, 10% had H. pylori colonization compared to 21% of the healthy weight children (RR = 2.1, 95% CI = 1.1-4.0). Conversely, 39% of noncolonized children, but only 21% of the infected children, were obese (RR = 1.8, 95% CI = 1.1-3.3). Multivariate analysis revealed that being colonized with H. pylori is associated with a 50% reduction in the odds of being obese (adjusted OR = 0.5, 95% CI = 0.2-1.0). CONCLUSIONS: Our findings in a North American cohort are in agreement with studies from Asia and Europe suggesting that H. pylori infection decreases the prevalence of obesity in children. Further work to characterize the extent and nature of this relationship is warranted.

The liver in pediatric gastrointestinal disease.

Hepatic involvement is often encountered in gastrointestinal (GI) diseases, in part because of the close anatomic and physiologic relations between the liver and GI tract. Drainage of the mesenteric blood supply to the portal vein permits absorbed and/or translocated nutrients, toxins, bacterial elements, cytokines, and immunocytes to gain hepatic access. Liver problems in digestive disorders may range from nonspecific hepatocellular enzyme elevations to significant pathologic processes that may progress to end-stage liver disease. Hepatobiliary manifestations of primary GI diseases in childhood and adolescence are not uncommon and include several well-described associations, such as sclerosing cholangitis with inflammatory bowel disease. Liver damage may also result from the effects of drugs used to treat GI diseases, for example, the hepatotoxicity of immunomodulatory therapies. This review highlights the important features of the hepatic and biliary abnormalities associated with 3 common pediatric GI conditions: inflammatory bowel disease, celiac disease, and cystic fibrosis.

Hirschsprung disease presenting as sigmoid volvulus: a case report and review of the literature.

While sigmoid volvulus is commonly seen in older patients, it is rarely encountered in children and younger adults. Consequently, heightened awareness of this entity is required to avoid a delay in diagnosis. Among the pediatric and adult cases of colonic volvulus previously reported in the English literature, 23 of the affected individuals have also been diagnosed with Hirschsprung disease (HD). This report describes a 12-year-old male with a history of chronic constipation who presented with vomiting and abdominal distension and was found to have sigmoid volvulus with previously unrecognized HD. The case presentation is followed by a review of the literature describing colonic volvulus secondary to HD in children.

Treatment of acute salmonella epiphyseal osteomyelitis using computed tomography-guided drainage in a child without sickle cell disease.

Salmonella osteomyelitis occurs infrequently in children without sickle cell disease. Similarly, acute osteomyelitis of the epiphysis has been rarely reported. We present a case of primary epiphyseal osteomyelitis caused by Salmonella in the distal femur of an otherwise healthy 17-month-old child. Before isolating an organism, parenteral nafcillin provided ineffective clinical, radiographic, and laboratory responses. Repeated fluoroscopic-guided percutaneous surgical drainages allowed for identification of the Salmonella, but did not resolve the epiphyseal infection, as the infection focus was missed. In the effort to eradicate the infection yet minimize further trauma to the epiphysis, computed tomography-guided drainage was performed and the infection subsequently resolved. Owing to its greater localization accuracy and minimal invasiveness, the computed tomography-guided intervention allowed for precise drainage without compromising the contiguous growth plate. At latest follow-up, the patient was ambulating well, had a normal knee examination, and had no evidence of leg length discrepancy or growth disturbance.

Optimizing the diagnosis of gastroesophageal reflux in children with otolaryngologic symptoms.

OBJECTIVES: Although many children with otolaryngologic (ENT) symptoms are being treated for gastroesophageal reflux (GER), how to diagnose GER in children with primarily or exclusively ENT symptoms has yet to be determined. This study compares the incidences of pathologic GER in the upper verses the lower esophagus in a cohort of children with ENT symptoms that were screened for GER. METHODS: The results of extended dual channel intraesophageal pH probe monitoring obtained from 14 infants and 14 children with ENT symptoms were retrospectively analyzed. The percent of total monitoring time that the pH was less than 4, reflux index (RI) was determined. The upper limits of normal distal and proximal esophageal RI were based on published data. To evaluate our results, upper esophageal reflux (UER) was also determined in 27 infants and children without ENT or pulmonary symptoms, who had normal lower esophageal reflux (LER) values. RESULTS: Mean upper esophageal RIs in the infants and children with normal LER were similar to previously published values for control infants and adults. Four (29%) of the ENT infants, 11 (79%) of the older ENT children, and 54% of the entire cohort had increased esophageal acid exposure. However, nine (60%) of the 15 pediatric ENT patients with GER had pH abnormalities limited to the upper esophagus. CONCLUSIONS: Standard distal pH probe monitoring alone gives a false negative result in a substantial proportion of the infants and children with ENT symptoms being evaluated for GER. Beyond its value in clinical practice, UER testing should be employed in research studies that evaluate the impact of GER therapy on ENT symptoms.

Hepatitis C infection in children and adolescents with end-stage renal disease.

The prevalence of hepatitis C virus (HCV) infection and the risk factors associated with its transmission are described in a contemporary cohort of 55 children and adolescents with end-stage renal disease (ESRD). Thirty-seven patients were on dialysis or had been transplanted (ESRD) and 18 had chronic renal failure (CRF) but had not yet received dialysis. Seven (19%) tested positive for HCV by enzyme-linked immunosorbent assay (ELISA), polymerase chain reaction (PCR), or both. None of the children with CRF were infected. HCV infection was associated with length of time on dialysis, but not with age, gender, race, or units of blood transfused. These data corroborate earlier reports and confirm that children with ESRD continue to have a high prevalence of HCV. It is also shown for the first time that elevated transaminases should not be employed to predict HCV infection in this cohort, as all affected children had normal serum levels. Because of unique characteristics in this cohort, both ELISA and PCR are required to maximize HCV diagnostic sensitivity. Although HCV remains an important consideration in pediatric ESRD, the present study shows that recent advances in clinical practice have eliminated one of the major ways in which it was previously being transmitted.