Jose M. Garza

Molecular diagnosis of eosinophilic esophagitis by gene expression profiling.

BACKGROUND & AIMS Gene expression profiling provides an opportunity for definitive diagnosis but has not yet been well applied to inflammatory diseases. Here we describe an approach for diagnosis of an emerging form of esophagitis, eosinophilic esophagitis (EoE), which is currently diagnosed by histology and clinical symptoms. METHODS We developed an EoE diagnostic panel (EDP) comprising a 96-gene quantitative polymerase chain reaction array and an associated dual-algorithm that uses cluster analysis and dimensionality reduction using a cohort of randomly selected esophageal biopsy samples from pediatric patients with EoE (n = 15) or without EoE (non-EoE controls, n = 14) and subsequently vetted the EDP using a separate cohort of 194 pediatric and adult patient samples derived from both fresh or formalin-fixed, paraffin-embedded tissue: active EoE (n = 91), control (non-EoE and EoE remission, n = 57), histologically ambiguous (n = 34), and reflux (n = 12) samples. RESULTS The EDP identified adult and pediatric patients with EoE with approximately 96% sensitivity and approximately 98% specificity, and distinguished patients with EoE in remission from controls, as well as identified patients exposed to swallowed glucorticoids. The EDP could be used with formalin-fixed, paraffin-embedded tissue RNA and distinguished patients with EoE from those with reflux esophagitis, identified by pH-impedance testing. Preliminary evidence showed that the EDP could identify patients likely to have disease relapse after treatment. CONCLUSIONS We developed a molecular diagnostic test (referred to as the EDP) that identifies patients with esophagitis in a fast, objective, and mechanistic manner, offering an opportunity to improve diagnosis and treatment, and a platform approach for other inflammatory diseases.

Venous thrombotic events in hospitalized children and adolescents with inflammatory bowel disease.

Background: Adults with inflammatory bowel disease (IBD) have an increased risk of venous thrombotic events (TEs). We sought to evaluate the risk for TE in children and adolescents with IBD using a large population database. Methods: The triennial Healthcare Cost and Utilization Project Kids’ Inpatient Database was used in a retrospective cohort study of hospitalized children in the United States across 1997, 2000, 2003, 2006, and 2009. Billing codes were used to identify discharges with Crohn disease, ulcerative colitis, pulmonary embolism, deep vein thrombosis, thrombophlebitis, thrombosis of intracranial venous sinus, Budd-Chiari syndrome, and portal vein thrombosis. A logistic regression model was fitted to quantify the increased risk of TE in children with IBD, while adjusting for other risk factors of thrombosis. Results: The total weighted number of pediatric discharges was 7,448,292, and 68,394 (0.92%) were identified with IBD. The incidence of any TE in a hospitalized child or adolescent with IBD was 117.9/10,000 with a relative risk (95% confidence interval) of 2.36 (2.15–2.58). The adjusted odds ratio for any TE in a patient with IBD without surgery was 1.22 (1.08–1.36). Risk factors for TE among patients with IBD include older age, central venous catheter, parenteral nutrition, and an identified hypercoagulable condition. There is an increasing trend of TE in both the IBD and non-IBD patients. Conclusions: Hospitalized children and adolescents with IBD are at increased risk for TE. Conservative methods of TE prevention including hydration, mobilization, or pneumatic devices should be considered in hospitalized patients with IBD.

Colonic hyperactivity results in frequent fecal soiling in a subset of children after surgery for Hirschsprung disease.

Background and Aim: Fecal soiling is a challenging problem in some children after pull-through surgery for Hirschsprung disease (HSCR). The prevailing perception is that soiling results from overflow incontinence; however, its treatment with laxatives yields mixed results. Colonic manometry studies are reported to be normal in most patients in this population. The interpretation of these findings does not support the physiology of fecal overflow incontinence in these children. The aim of the present study was to define the physiology underlying daily, frequent fecal soiling in children after surgery for HSCR using manometric techniques. Patients and Methods: Four pediatric motility centers in the United States participated in the study; medical records and manometric tracings (anorectal and colonic) of children (n = 59; 6.5 years; 48 boys) who had pull-through surgery for HSCR and presented with daily, frequent fecal soiling were examined. Children referred for evaluation of constipation who had normal colonic manometry served as controls (n = 25; 6.7 years; 12 boys). The patients with HSCR were divided into 2 groups (Hirschsprung disease groups 1 and 2 [HD1, HD2]) based on the absence or presence of high-amplitude propagated contractions (HAPCs). A control group that included children with chronic constipation was also studied. We compared the mean HAPC frequency between the HD2 and control groups. Results: HD1 included 21 patients who had no HAPCs in fasting or postprandial periods. HD2 included 38 patients who had an average of 0.07 HPACs/min while fasting and 0.13/min in the postprandial state. In this subset the number of HAPCs in the fasting state (P = 0.04) and the postprandial state (P < 0.001) was greater when compared with controls. Additionally, there was a significant increase in HAPCs/min from the fasting to the postprandial state (P = 0.01). In the HD2 group 40% had colonic hyperactivity. Conclusions: Daily, frequent fecal soiling after pull-through surgery for HSCR may be due to colonic hyperactivity in some children. It is imperative that this unique subset be identified because the management strategy would include avoidance of laxatives, contrary to standard current practice.

Gastroesophageal reflux, eosinophilic esophagitis, and foreign body.

Even though chest pain in children is a common complaint, an underlying gastrointestinal cause is rare. The four common gastrointestinal conditions that present with chest pain include eosinophilic esophagitis, gastroesophageal reflux disease, esophageal dysmotility, and foreign body ingestion. Other than ingestion of certain foreign bodies, most of these conditions are not life-threatening. Associated symptoms and history may be helpful in distinguishing these disorders, but further evaluation is often indicated to identify the precise cause.

Impedance probe testing prior to pediatric airway reconstruction.

Objective: This study aimed to determine if preoperative impedance testing changed management and if testing was associated with surgical outcome in patients undergoing airway reconstruction. Methods: Retrospective review of patients who had impedance testing prior to airway reconstruction at a tertiary pediatric hospital from January 2010 to September 2011. Charts were reviewed for demographics, medical/surgical history, impedance testing, and surgical outcomes. Results: Fifty-seven patients were included. Forty-seven (82%) were premature. Forty-seven (82%) had a primary diagnosis of subglottic stenosis. Twenty-six (45%) had prior airway surgery. Thirty-six (63%) had gastroesophageal reflux and 21 (36%) had undergone fundoplication. Patients without fundoplication had a median 46 total reflux, 7 proximal, and 14.5 acidic events compared to a median 5 total reflux, 0 proximal, and 0 acidic events in patients with fundoplication. Impedance testing changed management in 22% (8/36) of nonfundoplication patients and 9.5% (2/21) of fundoplication patients. In unadjusted analysis, fewer fundoplication patients had successful surgery compared to those without (33% vs 67%, P = .01). Prematurity, age at surgery, and previous airway surgery were also important predictors of surgical success. Conclusion: Fewer patients than anticipated had a change in management. Impedance testing was unlikely to change management in fundoplication patients. Patients with fundoplication were less likely to have a successful outcome, suggesting that factors other than reflux influence airway reconstruction outcomes.

Time to Stop Blaming Gastroesophageal Reflux

Objectives. Cough, pain, and desaturation episodes in infants are often ascribed to gastroesophageal reflux, and many are empirically treated with acid suppression medications. The authors hypothesize that most of these symptoms are not related to gastroesophageal reflux. Methods. Retrospective review of 186 combined pH–multichannel intraluminal impedance studies performed in infants at Cincinnati Children’s Hospital. Results. Of 4159 symptoms reported 1504 (36%) were associated with reflux events (27% nonacid and 9% acid). When total number of symptoms and reflux events were taken into consideration, nonacid reflux events were as likely to be associated with a symptom as acid reflux events (P = .66). Conclusion. The extra-esophageal symptoms commonly attributed to gastroesophageal reflux in infants are most often not associated with a reflux event. Even though causality cannot be definitively proven, in the minority in whom a symptom association is observed, nonacid events are as likely as acid events to cause symptoms.

GER and Antacid Medications

Gastric acid secretion is a physiological process essential for food digestion. It is regulated by paracrine, hormonal, and neural pathways. Antacids, surface-protective agents, and antisecretory agents are used for treating gastroesophageal reflux disease (GER). Antacids are helpful for immediate symptomatic relief but are not recommended for chronic use. Histamine-2 receptor antagonists have a role in the management of episodic and mild symptoms, particularly for infrequent GER or reflux-related symptoms. Proton pump inhibitors (PPIs) have become some of the most frequently prescribed medications in both children and adults, and their effectiveness for treatment of peptic conditions in the pediatric population has been established. They are well tolerated in both infants and children, but as with any other pharmacologic therapy, PPIs are not exempt of side effects, and risk-benefit should be assessed in individual cases, especially when a chronic use is necessary.

Food Refusal, Dysphagia, and Odynophagia

Food refusal, dysphagia, and odynophagia may represent symptoms of a wide array of underlying anatomical or functional upper aerodigestive disorders along with a behavioral overlay. It is imperative that the specialist has a detailed understanding of the upper aerodigestive tract as this can have an impact on making correct and timely decisions for diagnostic studies and treatment choices. The management of younger children presenting with food refusal or swallowing dysfunction tends to be more challenging, and an interdisciplinary approach is felt to be most effective in addressing this issue.