John M. Rosen

Prevalence of Functional Gastrointestinal Disorders in Colombian School Children

OBJECTIVES To determine prevalence for functional gastrointestinal disorders (FGIDs) in Colombian school children using the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III Version (QPGS-III) and to determine possible risk factors. STUDY DESIGN The QPGS-III was translated into Spanish then reverse translated by a team of bilingual physicians. Focus groups of Colombian children were conducted to assure understanding of the Spanish version. Children at 1 public school and 2 private schools in Pasto, Colombia were invited to participate in a prevalence study using the translated questionnaire. RESULTS A total of 373 children (95 private school, 278 public school), with mean age 9.9 years completed the QPGS-III. Twenty-nine percent of children were diagnosed with FGIDs. FGIDs were more common in females (OR, 1.63; 95% CI, 1.04-2.56). Functional constipation (14%) was the most common FGID. Irritable bowel syndrome was the most common abdominal pain-related FGID (5.4%). Abdominal migraine (1%) and cyclic vomiting syndrome (0.3%) were the least common FGIDs. CONCLUSION FGIDs are common in Colombian school children.

Mechanisms of pain from urinary tract infection.

The pain response to urinary tract infection is largely uncharacterized, but the symptomatic response to urinary tract infection contrasts with the lack of pain response among individuals with asymptomatic bacteriuria. Quantifying pelvic pain in a murine urinary tract infection model, uropathogenic Escerichia coli induces transient pelvic pain, whereas an asymptomatic bacteriuria E. coli isolate causes no pain, thus recapitulating the spectrum of clinical responses to intravesical E. coli. These differential pain responses are not correlated with bladder colonization or inflammation, but instead are intrinsic to E. coli lipopolysaccharide and dependent on the lipopolysaccharide receptor, TLR4. Epidemiological data suggest a link between interstitial cystitis and a history of urinary tract infection, so it was evaluated whether repetitive uropathogenic E. coli instillation would result in chronic pain through central sensitization. Although repeated infection with wild type uropathogenic E. coli results in only transient episodes of acute pain, a uropathogenic E. coli mutant lacking O‐antigen causes chronic, post‐urinary tract infection pelvic pain. Similarly, a K‐12 E. coli strain lacking O‐antigen induces chronic pain that persisted long after bacterial clearance, and expressing O‐antigen nullified the pain phenotype. Spinal cords isolated from mice with post‐urinary tract infection chronic pain showed deficits in short‐term depression consistent with central sensitization. Deleting O‐antigen gene complex from a uropathogenic E. coli strain and subsequent heterologous expression of O‐antigen gene clusters shows that a single bacterial isolate can exhibit pain phenotypes ranging from a null phenotype, an acute pain phenotype, to a chronic pain phenotype. Post‐urinary tract infection chronic pain is also associated with voiding dysfunction and anxious/depressive behavior. These effects are also mediated by TRPV1 at the level of pain establishment and CCR2 at the level of pain maintenance. Together, these findings show that transient infection with E. coli might result in chronic visceral pain with the hallmarks of neuropathic pain. This pattern of behaviors mimics the spectrum of interstitial cystitis symptoms, thus supporting the possibility of an infectious etiology of interstitial cystitis.

Visceral hypersensitivity and electromechanical dysfunction as therapeutic targets in pediatric functional dyspepsia.

Functional gastrointestinal disorders (FGID) are common clinical syndromes diagnosed in the absence of biochemical, structural, or metabolic abnormalities. They account for significant morbidity and health care expenditures and are identifiable across variable age, geography, and culture. Etiology of abdominal pain associated FGIDs, including functional dyspepsia (FD), remains incompletely understood, but growing evidence implicates the importance of visceral hypersensitivity and electromechanical dysfunction. This manuscript explores data supporting the role of visceral hypersensitivity and electromechanical dysfunction in FD, with focus on pediatric data when available, and provides a summary of potential therapeutic targets.

Urinary tract infection in infancy is a risk factor for chronic abdominal pain in childhood

Objective: Adverse early life events are key factors for development of functional gastrointestinal disorders (FGIDs). Urinary tract infection (UTI) is associated with chronic pelvic pain in adults, a finding that has been recapitulated in murine models, but the relation between UTI and chronic pelvic and abdominal pain has not been studied in children. We hypothesized that UTI in infancy increases the risk of FGIDs and chronic abdominal pain (CAP) in childhood. Methods: The present study included children, ages 4 to 18 years, with a single UTI in the first year of life and their siblings with no history of UTI. Parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms–Rome III Version (QPGS-III) by telephone. Children meeting QPGS-III criteria for FGIDs but with pain less than once weekly were considered to have CAP. Results: A total of 57 patients with UTI and 58 sibling controls were identified. Mean age at UTI was 4.8 months, and mean time since UTI was 9.3 years. At the time of survey, mean age of patients was 9.7 years (5–16 years, 40% boys) and that of controls was 9.6 years (range 4–17 years, 57% boys). FGIDs were diagnosed in 6 of 57 (11%) patients, and 1 of 58 (2%) controls (P = 0.06). CAP was identified in 10 of 57 (18%) patients and 2 of 58 (3%) controls (P = 0.02). Predominant sex (female), infecting organism (E coli), and treatment (third-generation cephalosporin) were similar in patients with UTI with and without CAP. Conclusions: We show for the first time that UTI is associated with CAP in childhood. We speculate that pelvic organ sensory convergence explains our findings.

Umbilical hernia repair increases the rate of functional gastrointestinal disorders in children.

OBJECTIVES To hypothesize that hernia repair would not change the incidence of functional gastrointestinal disorders (FGIDs) due to the benign and limited nature of the procedure. STUDY DESIGN This cohort study assessed a randomized selection of children aged 4-18 years who underwent hernia repair more than 4 years prior at Ann and Robert H. Lurie Childrens Hospital of Chicago. Controls were siblings who had not undergone surgery previously. Parents completed the Questionnaire on Pediatric Gastrointestinal Symptoms-Rome III Version by telephone for subjects and controls. The primary outcome was the presence of FGIDs. RESULTS Fifty children with hernia repair and 43 sibling controls were identified. At the time of survey, subjects with hernia repair were average age 12.9 years (range 5-18 years, 60% male) and controls were average age 12.2 years (range 4-18 years, 49% male). Average age at surgical repair was 5.2 years (median 5.2 years, range 0.2-10.4 years) and average time since surgical repair was 7.8 years (range 4.8-13.7 years). FGIDs were diagnosed in 10/50 (20%) cases of hernia repair and 2/43 (5%) controls (P = .033, Fisher 2-tailed test). CONCLUSIONS Umbilical hernia repair increases the likelihood of FGIDs in childhood. Additional studies are needed to identify aspects of surgery that may be associated with development of FGIDs.

Diffuse esophageal spasm in children referred for manometry.

ABSTRACT Diffuse esophageal spasm (DES) causes chest pain and/or dysphagia in adults. We reviewed charts of 278 subjects 0 to 18 years of age after esophageal manometry to describe the frequency and characteristics of DES in children. Patient diagnoses included normal motility (61%), nonspecific esophageal motility disorder (20%), DES (13%, n = 36), and achalasia (4%). Of patients with DES, the most common chief complaint was food refusal in subjects younger than 5 years (14/24, 58%) and chest pain in subjects older than 5 years (4/12, 33%). Comorbid medical conditions, often multiple, existed in 33 subjects. DES should be considered when young children present with food refusal.

Utility of Gastric and Duodenal Biopsies during Follow-up Endoscopy in Children with Eosinophilic Esophagitis.

Objectives: Eosinophilic esophagitis (EoE) is a chronic antigen-mediated immune disorder of the esophagus. Consensus guidelines recommend obtaining esophageal, gastric, and duodenal biopsies at diagnostic endoscopy when EoE is suspected. The utility of repeated gastric and duodenal biopsies during follow-up endoscopy in patients previously diagnosed with EoE is not established. The aim of the present study was to explore the role of gastric and duodenal biopsies in children with an established diagnosis of EoE undergoing repeat endoscopy to assess histological response to treatment. Methods: Retrospective chart review of children diagnosed with EoE at a tertiary care center was conducted. A total of 160 patients with EoE with demographic clinical, endoscopic, and histological data at diagnosis and follow-up endoscopy were included. The frequency of gastric and duodenal biopsies at follow-up endoscopy with abnormal histology and their correlation to endoscopic findings was determined. Results: At follow-up endoscopy, 83% (132/160) of patients had gastric and 74% (118/160) had duodenal biopsies. Histology was normal in 81% of gastric and 92% of duodenal biopsies. The most frequent gastric abnormalities were chemical and inactive chronic gastritis. The most frequent duodenal abnormality was villous blunting with increased intraepithelial lymphocytes. Two patients with normal gastric and duodenal histology progressed to eosinophilic gastroenteritis at follow-up endoscopy. Conclusions: Gastric and duodenal biopsies obtained in EoE patients during follow-up endoscopy show pathology in a minority of patients, increase costs, and may add potential risk of adverse events. Large multicenter, prospective studies of endoscopic practice during follow-up of EoE are warranted to provide evidence supporting best practices.

X-ray detection of ingested non-metallic foreign bodies.

AIM To determine the utility of X-ray in identifying non-metallic foreign body (FB) and assess inter-radiologist agreement in identifying non-metal FB. METHODS Focus groups of nurses, fellows, and attending physicians were conducted to determine commonly ingested objects suitable for inclusion. Twelve potentially ingested objects (clay, plastic bead, crayon, plastic ring, plastic army figure, glass bead, paperclip, drywall anchor, eraser, Lego™, plastic triangle toy, and barrette) were embedded in a gelatin slab placed on top of a water-equivalent phantom to simulate density of a childs abdomen. The items were selected due to wide availability and appropriate size for accidental pediatric ingestion. Plain radiography of the embedded FBs was obtained. Five experienced radiologists blinded to number and types of objects were asked to identify the FBs. The radiologist was first asked to count the number of items that were visible then to identify the shape of each item and describe it to a study investigator who recorded all responses. Overall inter-rater reliability was analyzed using percent agreement and κ coefficient. We calculated P value to assess the probability of error involved in accepting the κ value. RESULTS Fourteen objects were radiographed including 12 original objects and 2 duplicates. The models validity was supported by clear identification of a radiolucent paperclip as a positive control, and lack of identification of plastic beads (negative control) despite repeated inclusion. Each radiologist identified 7-9 of the 14 objects (mean 8, 67%). Six unique objects (50%) were identified by all radiologists and four unique objects (33%) were not identified by any radiologist (plastic bead, Lego™, plastic triangle toy, and barrette). Identification of objects that were not present, false-positives, occurred 1-2 times per radiologist (mean 1.4). An additional 17% of unique objects were identified by less than half of the radiologists. Agreement between radiologists was considered almost perfect (kappa 0.86 ± 0.08, P < 0.0001). CONCLUSION We demonstrate potential non-identification of commonly ingested non-metal FBs in children. A registry for radiographic visibility of ingested objects should be created to improve clinical decision-making.

TRPV1 and the MCP-1/CCR2 Axis Modulate Post-UTI Chronic Pain

The etiology of chronic pelvic pain syndromes remains unknown. In a murine urinary tract infection (UTI) model, lipopolysaccharide of uropathogenic E. coli and its receptor TLR4 are required for post-UTI chronic pain development. However, downstream mechanisms of post-UTI chronic pelvic pain remain unclear. Because the TRPV1 and MCP-1/CCR2 pathways are implicated in chronic neuropathic pain, we explored their role in post-UTI chronic pain. Mice were infected with the E. coli strain SΦ874, known to produce chronic allodynia, and treated with the TRPV1 antagonist capsazepine. Mice treated with capsazepine at the time of SΦ874 infection failed to develop chronic allodynia, whereas capsazepine treatment of mice at two weeks following SΦ874 infection did not reduce chronic allodynia. TRPV1-deficient mice did not develop chronic allodynia either. Similar results were found using novelty-suppressed feeding (NSF) to assess depressive behavior associated with neuropathic pain. Imaging of reporter mice also revealed induction of MCP-1 and CCR2 expression in sacral dorsal root ganglia following SΦ874 infection. Treatment with a CCR2 receptor antagonist at two weeks post-infection reduced chronic allodynia. Taken together, these results suggest that TRPV1 has a role in the establishment of post-UTI chronic pain, and CCR2 has a role in maintenance of post-UTI chronic pain.

Acyloxyacyl hydrolase modulates pelvic pain severity

Chronic pelvic pain causes significant patient morbidity and is a challenge to clinicians. Using a murine neurogenic cystitis model that recapitulates key aspects of interstitial cystitis/bladder pain syndrome (IC), we recently showed that pseudorabies virus (PRV) induces severe pelvic allodynia in BALB/c mice relative to C57BL/6 mice. Here, we report that a quantitative trait locus (QTL) analysis of PRV-induced allodynia in F2CxB progeny identified a polymorphism on chromosome 13, rs6314295 , significantly associated with allodynia (logarithm of odds = 3.11). The nearby gene encoding acyloxyacyl hydrolase ( Aoah) was induced in the sacral spinal cord of PRV-infected mice. AOAH-deficient mice exhibited increased vesicomotor reflex in response to bladder distension, consistent with spontaneous bladder hypersensitivity, and increased pelvic allodynia in neurogenic cystitis and postbacterial chronic pain models. AOAH deficiency resulted in greater bladder pathology and tumor necrosis factor production in PRV neurogenic cystitis, markers of increased bladder mast cell activation. AOAH immunoreactivity was detectable along the bladder-brain axis, including in brain sites previously correlated with human chronic pelvic pain. Finally, AOAH-deficient mice had significantly higher levels of bladder vascular endothelial growth factor, an emerging marker of chronic pelvic pain in humans. These findings indicate that AOAH modulates pelvic pain severity, suggesting that allelic variation in Aoah influences pelvic pain in IC.