History of paediatric gastroenterology in Australia.

Paediatric gastroenterology in Australia has undergone remarkable changes over the more than six decades since Charlotte Anderson's pioneering work, and is now a well-established specialty in its own right. Australian paediatric gastroenterologists have made important contributions nationally and internationally.

Pediatric Collagenous Gastritis and Colitis: A Case Series and Review of the Literature.

INTRODUCTION: Collagenous gastritis is a rare disease characterized by the subepithelial deposition of collagen bands. Two phenotypes of the disease have been described: a pediatric-onset and an adult-onset type. The adult-onset form is associated with collagenous colitis and autoimmune disorders. No effective treatment has been identified to date. OBJECTIVE: We aim to describe the clinical features and outcomes of patients in our cohort and provide a summary of published pediatric cases with collagenous gastritis and colitis reported to date to gather information that will contribute to improved knowledge of this rare condition. METHODS: A retrospective chart review of all patients with collagenous gastritis and/or colitis who were treated at the Royal Children's Hospital, Melbourne, was performed. A literature review was also conducted. RESULTS: A total of 12 cases of collagenous gastritis were reviewed. Three of 12 (25%) patients had associated collagenous colitis. The most common clinical presentation was iron deficiency anemia. Nine (75%) patients were followed up, and repeat endoscopies were performed in 8 (67%). Iron deficiency anemia resolved in all patients on oral iron supplementation. Histologic improvement was only identified in one patient with the adult phenotype who had been treated with oral corticosteroids and azathioprine. CONCLUSIONS: Collagenous gastritis is a rare condition in children. A small proportion of children develop features of the "'adult" phenotype at a very young age. Patients with collagenous gastritis require long-term follow-up and monitoring of their disease. Further randomized clinical trials are needed to establish an effective therapeutic strategy.

Clinical patterns and outcome of early-onset inflammatory bowel disease.

We sought to determine whether extremely-early-onset childhood inflammatory bowel disease (age <6 years; 20 ulcerative colitis [UC], 8 Crohn disease [CD], 2 indeterminate, sequentially diagnosed) was clinically more severe than in older children (6-17 years; 19 UC, 39 CD, 2 indeterminate). Early-onset UC was marked by less abdominal pain at presentation, but an aggressive course with a significant reduction in weight-for-age, increased use of immunosuppressants, and more surgery. Children with early-onset CD were more likely to have bloody stools at presentation and an isolated colitis. This study supports the suggestion that inflammatory bowel disease phenotype differs in early-onset disease.

TLR4, IL10RA, and NOD2 mutation in paediatric Crohn's disease patients: an association with Mycobacterium avium subspecies paratuberculosis and TLR4 and IL10RA expression.

Mycobacterium avium subspecies paratuberculosis (MAP) has been implicated in the pathogenesis of Crohn's disease (CD). The role of CD susceptibility genes in association with these microbes is not known. Sixty-two early onset paediatric CD patients and 46 controls with known MAP status were analysed for an association with 34 single nucleotide polymorphisms (SNPs) from 18 CD susceptibility genes. Functional studies on peripheral blood mononuclear cells (PBMCs) were conducted on 17 CD patients with known CD mutations to assess IL-6, IL-10, and TNF-α expression upon stimulation with MAP precipitated protein derivative (PPD) and lipopolysaccharide (LPS). In addition, surface expression of IL10R and TLR4 on resting B cells, NK cells, T cells, and monocytes was assessed. A mutation in TLR4 (rs4986790) and IL10RA (rs22291130) was significantly associated with MAP-positive CD patients compared to MAP-negative CD patients (27.6 vs. 6.1 %, p = 0.021, and 62.1 vs. 33.3 %, p = 0.024, respectively). PPD and LPS significantly increased IL-6, IL-10, and TNF-α production in PBMCs. IL-10 and TNF-α production were significantly lower in a subgroup of CD patients (5/12) with a known NOD2 mutation. Receptor for IL-10 was significantly higher expressed on NK cells (CD56low) and on NK T cells harbouring a NOD2 mutations compared to wildtype cells (p = 0.031 and 0.005, respectively). TLR4 was significantly higher expressed on NK cells (CD56high) harbouring a NOD2 mutations compared to wildtype cells (p = 0.038).

Sixty-year study of incidence of childhood ulcerative colitis finds eleven-fold increase beginning in 1990s.

BACKGROUND: We sought to define the point at which a recently noted marked increase in the incidence of ulcerative colitis (UC) had occurred in children in Victoria, Australia. METHODS: A 60-year retrospective review (1950-2009) of children age 16 years or less diagnosed with UC in the state's major pediatric centers was performed. RESULTS: In all, 342 children were diagnosed with UC (male to female ratio of 1.25:1.0, median age 10.9 years, interquartile range [IQR] 7.0, 13.2). The overall median annual incidence of UC was 0.36/10(5) children ≤ 16 years of age (IQR 0.18, 0.66). The number of reported cases increased by 11-fold during the study period (P < 0.001). This marked increase appeared to occur from the early 1990s and has yet to plateau. Children diagnosed during the last two decades were older at diagnosis (median 10 years vs. 11.6, P < 0.0001), and had higher weight- and height-for-age z scores than those diagnosed during the first 40 years (mean weight-for-age [standard deviation] 1950-1989: -0.80 [1.56] vs. 1990-2009: -0.11 [1.17], P < 0.001; mean height-for-age 1950-1989: -0.50 [1.15] vs. 1990-2009: -0.13 [1.12], P < 0.05). More recently diagnosed children also had more extensive disease (1950-1989: 52% vs. 1990-2009: 71%, P < 0.01). CONCLUSIONS: The incidence of UC has increased markedly in Victorian children since 1990. Although some of this change may be attributable to earlier diagnosis, it is unlikely that this can provide a complete explanation for this still-increasing condition.

An Australian audit of vaccination status in children and adolescents with inflammatory bowel disease.

BACKGROUND: Children and adolescents with inflammatory bowel disease (IBD) are at increased risk of vaccine preventable diseases (VPD). This includes invasive pneumococcal disease and influenza. The primary aim of this study was to describe compliance with current Australian guidelines for vaccination of children and adolescents diagnosed with IBD. A secondary aim was to review the serological screening for VPD. METHODS: A random sample of patients (0-18 years at diagnosis), were selected from the Victoria Australia state based Pediatric Inflammatory Bowel Disease Register. A multi-faceted retrospective review of immunization status was undertaken, with hospital records audited, a telephone interview survey conducted with consenting parents and the vaccination history was checked against the primary care physician and Australian Childhood Immunization Register (ACIR) records. The routine primary childhood vaccinations and administration of the recommended additional influenza and pneumococcal vaccines was clarified. RESULTS: This 2007 audit reviewed the immunization status of 101 individuals on the Victorian Pediatric IBD database. Median age at diagnosis was 12.1 years, 50% were on active immunosuppressive therapy. 90% (38/42) [95% confidence intervals (CI) 77%; 97%] with complete immunization information were up-to-date with routine primary immunizations. Only 5% (5/101) [95% CI 2%; 11%] received a recommended pneumococcal vaccine booster and 10% (10/101) [95% CI 5%; 17%] had evidence of having ever received a seasonal influenza vaccine. Those living in rural Victoria (p = 0.005) and younger at the age of diagnosis (p = 0.002) were more likely to have ever received an influenza vaccine Serological testing, reviewing historical protection from VPD, identified 18% (17/94) with evidence of at least one serology sample. CONCLUSION: This study highlights poor compliance in IBD patients for additional recommended vaccines. A multi-faceted approach is required to maximize protection from VPD in this vulnerable special risk population.

Interaction of Crohn's disease susceptibility genes in an Australian paediatric cohort.

Genetic susceptibility is an important contributor to the pathogenesis of Crohn's disease (CD). We investigated multiple CD susceptibility genes in an Australian paediatric onset CD cohort. Newly diagnosed paediatric onset CD patients (n = 72) and controls (n = 98) were genotyped for 34 single nucleotide polymorphisms (SNPs) in 18 genetic loci. Gene-gene interaction analysis, gene-disease phenotype analysis and genetic risk profiling were performed for all SNPs and all genes. Of the 34 SNPs analysed, four polymorphisms on three genes (NOD2, IL23R, and region 3p21) were significantly associated with CD status (p<0.05). All three CD specific paediatric polymorphisms on PSMG1 and TNFRSF6B showed a trend of association with p<0.1. An additive gene-gene interaction involving TLR4, PSMG1, TNFRSF6B and IRGM was identified with CD. Genes involved in microbial processing (TLR4, PSMG1, NOD2) were significantly associated either at the individual level or in gene-gene interactive roles. Colonic disease was significantly associated with disease SNP rs7517847 (IL23R) (p<0.05) and colonic and ileal/colonic disease was significantly associated with disease SNP rs125221868 (IBD5) and SLC22A4 & SLC22A4/5 variants (p<0.05). We were able to demonstrate genetic association of several genes to CD in a paediatric onset cohort. Several of the observed associations have not been reported previously in association with paediatric CD patients. Our findings demonstrate that CD genetic susceptibility in paediatric patients presents as a complex interaction between numerous genes.

Oesophagitis in children: reflux or allergy?

The prevalence of eosinophilic oesophagitis appears to be increasing in many countries, sometimes rapidly, although this may be partly due to increased disease recognition. Histological methods of assessment and diagnostic criteria vary considerably between major clinical centres. Oesophagitis with over 20 intraepithelial eosinophils per high power field is more likely to be due to allergy than gastro-oesophageal reflux induced acid-peptic mucosal injury. Typical eosinophilic oesophagitis shows involvement of the entire oesophagus, with basal cell proliferation occupying more than 50% of the thickness of the surface epithelium, and high numbers of intraepithelial eosinophils, sometimes concentrated on the surface or as contiguous clusters. Ulceration and prominent neutrophils are atypical and should suggest an alternative or co-existent disease. On endoscopy, the oesophagus may display the typical 'corrugated' mucosal appearance. Clinically, dysphagia or food impaction are the most characteristic symptoms. There is a strong association with other atopic diseases, especially asthma and eczema. To date no evidence has emerged of an increased malignancy risk. Patients with eosinophilic oesophagitis typically fail to respond to acid suppressive medications but respond well to either elemental/elimination diets or aerosolised swallowed corticosteroids. Long-term uncontrolled oesophageal eosinophilic inflammation may lead to progressive subepithelial fibrosis, potentially resulting in strictures or oesophageal narrowing.

Use of intravenous midazolam and clonidine in cyclical vomiting syndrome: a case report.

We report a case of a teenage boy with cyclical vomiting syndrome (CVS) who was referred to the anesthesia-run postoperative pain service for symptom management. His symptoms were uncontrolled by oral pizotifen prophylaxis and acute therapy with intravenous (IV) hydration and ondansetron. A continuous low dose IV midazolam infusion was added to his treatment regimen (as is instituted for recalcitrant postoperative nausea and vomiting) with benefit, but not total symptom resolution. Recent literature review suggested links between migraine, CVS and adrenergic autonomic dysfunction. Consequently, IV clonidine was administered, in addition, with recovery. This combination was reinstituted successfully on subsequent admissions and emergency department presentations with shortened episode durations from 4-5 days to 16-48 h. It is uncertain if clonidine's sympatholytic effects were significantly beneficial or if associated sedation or natural resolution were contributors. Many agents have been used in CVS therapy but no trials have been done. Neither midazolam nor clonidine has been reported previously as used in the treatment of CVS. The apparent success of this combination raises possibilities both for future trials and research into the pathogenesis of CVS.

Esophageal eosinophilia in children with dysphagia.

OBJECTIVES: Children occasionally have dysphagia in the absence of an apparent primary cause. Esophageal eosinophilia is sometimes seen in these patients at the time of upper endoscopy but its significance is not clear. Although eosinophilia is regarded by some as a histologic hallmark of childhood reflux esophagitis, it may in fact signal a primary eosinophilic esophagitis in children with dysphagia. Our aim was to evaluate esophagitis, acid reflux determined by pH probe, and esophageal eosinophilia in children with the primary complaint of dysphagia. METHODS: A retrospective study was performed in 42 children, admitted for investigation of dysphagia, in whom no primary cause could be found. Twenty-one children (mean age +/- SD, 10.1 +/- 4.0 years) had esophageal eosinophilia and 21 children (8.3 +/- 4.7 years) did not. Clinical, endoscopic, manometric and esophageal pH parameters in these two groups were compared. RESULTS: Patients with esophageal eosinophilia were more often male (p<0.01) with a history of allergy (p<0.001) and food bolus obstruction (p<0.05) requiring endoscopic removal. Their esophageal mucosa appeared wrinkled and thickened at endoscopy with basal cell proliferation, and large numbers of eosinophils in esophageal mucosal biopsies. Continuous esophageal pH records and motility studies, when obtained, were similar in both groups and were within normal values. CONCLUSION: Children with dysphagia who have esophageal eosinophilia are unlikely to have pathologic gastroesophageal reflux.

Increasing incidence of Crohn's disease in Victorian children.

BACKGROUND: The incidence of Crohn's disease has been increasing in Western communities, but there are no published studies which have examined this change in children in Australia. The centralization of pediatric gastroenterology services in Victoria provides an opportunity to examine these changes within one state. METHODS: We undertook a retrospective study over a 31-year period of all children aged 16 years or less initially diagnosed with Crohn's disease at either the Royal Children's Hospital, or Monash Medical Center, Melbourne, Victoria. RESULTS: We identified 351 patients who met the diagnostic criteria between 1971 and 2001. The incidence of Crohn's disease in children aged 16 years or less rose from 0.128 to 2.0 per 100,000 per year over the three decades (r = 0.964, P < 0.01). There was a disproportionate over-representation of children from an urban background (incidence rate ratio 1.66, 95% CI 1.28-2.16). Children currently being diagnosed had on average a lower erythrocyte sedimentation rate (ESR) and higher albumin than in previous decades. The use of flexible endoscopy has increased markedly (1970s: 60%; 1990s: 96%, P < 0.05) and the proportion of children recognized at diagnosis with upper gastrointestinal and colonic involvement has increased significantly. CONCLUSION: There has been a significant increase in the incidence of Crohn's disease in Victorian children. The pattern of disease has also changed with colonic disease now more frequent, and inflammatory indices less abnormal. The increased use of endoscopy has established the frequent involvement of the upper gastrointestinal tract.

Esophagitis in distressed infants: poor diagnostic agreement between esophageal pH monitoring and histopathologic findings.

OBJECTIVES: Our purpose was to study the relation between gastroesophageal reflux (GER) and esophagitis in infants with persistent distress. STUDY DESIGN: Infants (n = 125, 79 boys; median age, 4.2 months) with persistent distress and clinical symptoms suggestive of GER and esophagitis were retrospectively studied. All had undergone esophageal 24-hour pH monitoring and had upper gastrointestinal biopsy specimens taken. RESULTS: There were 65 (48%) infants with inflammatory changes found in at least one upper gastrointestinal biopsy specimen, of whom 32 (25.6%) had esophagitis; 11 infants with esophagitis also had gastritis or duodenitis. Although infants with frequent regurgitation (n = 65) had significantly more frequent GER episodes per 24 hours (P <.03) and greater fractional reflux time (P <.001) than infants without, this was not associated with histologic esophagitis (P =.33). Of the 32 infants with esophagitis, 9 had abnormal pH monitoring and 23 had nonreflux esophagitis. A separate group of 23 infants had abnormal pH monitoring but no esophagitis. Diagnostic agreement between pH monitoring and esophageal histologic features was poor (kappa = 0.07). CONCLUSION: Esophagitis occurred in one quarter of infants with persistent distress. Abnormal esophageal pH monitoring did not reliably predict esophagitis, suggesting a nonacid peptic cause in some of these infants.