Harland S. Winter

Evaluation, Diagnosis, and Treatment of Gastrointestinal Disorders in Individuals With ASDs: A Consensus Report

Autism spectrum disorders (ASDs) are common and clinically heterogeneous neurodevelopmental disorders. Gastrointestinal disorders and associated symptoms are commonly reported in individuals with ASDs, but key issues such as the prevalence and best treatment of these conditions are incompletely understood. A central difficulty in recognizing and characterizing gastrointestinal dysfunction with ASDs is the communication difficulties experienced by many affected individuals. A multidisciplinary panel reviewed the medical literature with the aim of generating evidence-based recommendations for diagnostic evaluation and management of gastrointestinal problems in this patient population. The panel concluded that evidence-based recommendations are not yet available. The consensus expert opinion of the panel was that individuals with ASDs deserve the same thoroughness and standard of care in the diagnostic workup and treatment of gastrointestinal concerns as should occur for patients without ASDs. Care providers should be aware that problem behavior in patients with ASDs may be the primary or sole symptom of the underlying medical condition, including some gastrointestinal disorders. For these patients, integration of behavioral and medical care may be most beneficial. Priorities for future research are identified to advance our understanding and management of gastrointestinal disorders in persons with ASDs.

Intraepithelial eosinophils: a new diagnostic criterion for reflux esophagitis.

Intraepithelial eosinophils in esophageal biopsy specimens were noted to be an indicator of prolonged acid reflux. The presence of even a few intraepithelial eosinophils correlated with abnormal acid clearance determined by overnight intraesophageal pH probe study. This new marker also appeared to be an early lesion, as evidence by its presence in children under age 2 yr, and in biopsy specimens from the proximal esophagus where traditional histometric features (basal zone thickening and papillary lengthening) were lacking. Furthermore, when intraepithelial eosinophils were seen in the proximal 75% of the esophagus, they served to identify more severe disease by correlation with greater abnormalities in the pH probe study. Although this new marker is a histologic indication of prolonged acid reflux and may be appreciated in routine endoscopic biopsy specimens in children, it has been observed in patients over 18 yr of age and may be applicable to the adult population.

Consensus guidelines of ECCO/ESPGHAN on the medical management of pediatric Crohn's disease

Children and adolescents with Crohns disease (CD) present often with a more complicated disease course compared to adult patients. In addition, the potential impact of CD on growth, pubertal and emotional development of patients underlines the need for a specific management strategy of pediatric-onset CD. To develop the first evidenced based and consensus driven guidelines for pediatric-onset CD an expert panel of 33 IBD specialists was formed after an open call within the European Crohns and Colitis Organisation and the European Society of Pediatric Gastroenterolog, Hepatology and Nutrition. The aim was to base on a thorough review of existing evidence a state of the art guidance on the medical treatment and long term management of children and adolescents with CD, with individualized treatment algorithms based on a benefit-risk analysis according to different clinical scenarios. In children and adolescents who did not have finished their growth, exclusive enteral nutrition (EEN) is the induction therapy of first choice due to its excellent safety profile, preferable over corticosteroids, which are equipotential to induce remission. The majority of patients with pediatric-onset CD require immunomodulator based maintenance therapy. The experts discuss several factors potentially predictive for poor disease outcome (such as severe perianal fistulizing disease, severe stricturing/penetrating disease, severe growth retardation, panenteric disease, persistent severe disease despite adequate induction therapy), which may incite to an anti-TNF-based top down approach. These guidelines are intended to give practical (whenever possible evidence-based) answers to (pediatric) gastroenterologists who take care of children and adolescents with CD; they are not meant to be a rule or legal standard, since many different clinical scenario exist requiring treatment strategies not covered by or different from these guidelines.

Infliximab (REMICADE) therapy in the treatment of pediatric Crohn’s disease

OBJECTIVES:The aim of this study was to assess the efficacy and safety of a single infusion of infliximab in the treatment of pediatric Crohns disease (CD).METHODS:A total of 21 pediatric CD patients were enrolled at seven study centers and randomized to receive a single infusion of infliximab 1 mg/kg (n = 6), 5 mg/kg (n = 7), or 10 mg/kg (n = 8) over at least 2 hrs at week 0 in this multicenter, open-label, dose-blinded trial. Efficacy assessments, including the Pediatric Crohns Disease Activity Index (PCDAI), modified CDAI, C-reactive protein concentration (CRP), and erythrocyte sedimentation rate (ESR) determinations, were made at screening and at weeks 1, 2, 4, 8, and 12. Adverse events were assessed throughout study participation.RESULTS:Improvements in the PCDAI, modified CDAI, ESR, and CRP were observed with all infliximab doses, beginning at week 1. On average, all treated patients experienced approximately 50% improvement in the PCDAI by week 2. By week 12, the PCDAI remained approximately 30% improved from baseline. During the study, all 21 patients (100%) achieved a clinical response, and 10 patients (48%) achieved clinical remission. There were no infusion reactions in any of the treatment arms.CONCLUSIONS:The results of this trial suggest that infliximab may be safe and effective as short-term therapy of medically refractory moderate to severe CD in a pediatric population.

Deficiency of immune interferon production by leukocytes of normal newborns

Abstract The maturity of the newborns immune system was assessed by measuring proliferative responses and interferon production of isolated mononuclear cells from cord blood ( N = 19), newborns 1 to 7 days of age ( N = 19), and adult controls ( N = 18). Ficoll-Hypaque-separated mononuclear cells were stimulated with phytohemagglutinin (PHA), allogeneic leukocytes in a mixed leukocyte culture (MLC), or Newcastle disease virus (NDV), pulsed with thymidine after 3 to 7 days in culture, and thymidine incorporation into DNA measured and used to calculate a proliferative index. The supernatants were h-arvested at optimal times for assay of classical and immune interferon (IF) production. IF was assessed by a microtiter assay using human diploid cells after encephalomyocarditis virus challenge. The proliferative responses of cord and newborn cells were equivalent or greater than those of adult controls. PHA-induced immune IF was produced in only 1 of 19 cord bloods and 3 of 19 newborns, whereas immune IF was produced in all adults (225 ± 2 units). No IF was produced in MLC in newborns, cords, or adults. NDV-induced classical IF was produced in normal amounts by newborn (373 ± 2IU), cord (457 ± 2IU), and adult cells (170 ± 3IU). These results indicate an abnormality of cellular immunity in newborns not detected by T-cell numbers or proliferative responses and parallels similar defects in T-cell-mediated cytotoxicity, another specialized T-cell function. These results suggest a possible mechanism for viral infection in newborns with concomitant bacterial infections and in patients undergoing graft-versus-host reactions.

Cancer incidence in the south Asian population of England (1990-92).

SummaryCancer incidence among English south Asians (residents in England with ethnic origins in India, Pakistan or Bangladesh) is described and compared with non-south Asian and Indian subcontinent rates. The setting for the study was areas covered by Thames, Trent, West Midlands and Yorkshire cancer registries. The study identified 356 555 cases of incident cancer (ICD9:140–208) registered between 1990 and 1992, including 3845 classified as English south Asian. The main outcome measures were age specific and directly standardized incidence rates for all cancer sites (ICD9:140–208). English south Asian incidence rates for all sites combined were significantly lower than non-south Asian rates but higher than Indian subcontinent rates. English south Asian rates were substantially higher than Indian subcontinent rates for a number of common sites including lung cancer in males, breast cancer in females and lymphoma in both sexes. English south Asian rates for childhood and early adult cancer (0–29 years) were similar or higher than non-south Asian rates. English south Asian rates were significantly higher than non-south Asian rates for Hodgkin’s disease in males, cancer of the tongue, mouth, oesophagus, thyroid gland and myeloid leukaemia in females, and cancer of the hypopharynx, liver and gall bladder in both sexes. The results are consistent with a transition from the lower cancer risk of the country of ethnic origin to that of the country of residence. They suggest that detrimental changes in lifestyle and other exposures have occurred in the migrant south Asian population.

Induction and Maintenance Therapy With Infliximab for Children With Moderate to Severe Ulcerative Colitis

BACKGROUND & AIMS We evaluated the efficacy and safety of infliximab for inducing and maintaining benefit in children with moderately to severely active ulcerative colitis (UC). METHODS Patients (6-17 years old) who had active UC (Mayo scores of 6-12; endoscopic subscores ≥ 2) and had not responded to or tolerated conventional treatment were given 5 mg/kg infliximab at weeks 0, 2, and 6. The primary end point was response at week 8 (decreases in Mayo scores ≥ 30% and ≥ 3 points and decreases in rectal bleeding subscores of ≥ 1 or an absolute subscore of ≤ 1). At week 8, only responders were randomly assigned to groups given infliximab every 8 or 12 weeks (q8w or q12w) and followed through week 54. Maintenance end points included pediatric UC activity index scores <10 points, defined as remission. RESULTS At week 8, infliximab induced a response in 73.3% of patients (44 of 60) (95% confidence interval, 62.1%-84.5%; a positive result was defined by 95% confidence interval lower limit >40%). Among responders, twice as many were in remission at week 54 after q8w (8 of 21, 38.1%) than q12w (4 of 22, 18.2%; P = .146) therapy. Assuming the q8w remission rate for responders, the overall remission rate at week 54 would be 28.6%. Serious adverse events and infusion reactions occurred in similar proportions in the q8w and q12w groups. No deaths, malignancies, opportunistic infections, tuberculosis, or delayed hypersensitivity reactions were reported. CONCLUSIONS Infliximab was safe and effective, inducing a response at week 8 in 73.3% of pediatric patients with moderate to severely active UC who did not respond to conventional therapy. The overall remission rate at week 54 for all enrolled patients was 28.6%, assuming the more effective q8w remission rate.

Recommendations for Evaluation and Treatment of Common Gastrointestinal Problems in Children With ASDs

Children with autism spectrum disorders (ASDs) can benefit from adaptation of general pediatric guidelines for the diagnostic evaluation of abdominal pain, chronic constipation, and gastroesophageal reflux disease. These guidelines help health care providers determine when gastrointestinal symptoms are self-limited and when evaluation beyond a thorough medical history and physical examination should be considered. Children with ASDs who have gastrointestinal disorders may present with behavioral manifestations. Diagnostic and treatment recommendations for the general pediatric population are useful to consider until the development of evidence-based guidelines specifically for patients with ASDs. Pediatrics 2010;125:S19-S29

Risk of early surgery for Crohn's disease: implications for early treatment strategies.

OBJECTIVES:In this study we aimed to define the rate of early surgery for Crohns disease and to identify risk factors associated with early surgery as a basis for subsequent studies of early intervention in Crohns disease.METHODS:We assembled a retrospective cohort of patients with Crohns disease diagnosed between 1991 and 1997 and followed for at least 3 yr, who were identified in 16 community and referral-based practices in New England. Chart review was performed for each patient. Details of baseline demographic and disease features were recorded. Surgical history including date of surgery, indication, and procedure were also noted. Risk factors for early surgery (defined as major surgery for Crohns disease within 3 yr of diagnosis, exclusive of major surgery at time of diagnosis) were identified by univariate analysis. Multiple logistic regression was used to identify independent risk factors.RESULTS:Of 345 eligible patients, 69 (20.1%) required surgery within 3 yr of diagnosis, excluding the 14 patients (4.1%) who had major surgery at the time of diagnosis. Overall, the interval between diagnosis and surgery was short; one half of all patients who required surgery underwent operation within 6 months of diagnosis. Risk factors identified by univariate analysis as significantly associated with early surgery included the following: smoking; disease of small bowel without colonic involvement; nausea and vomiting or abdominal pain on presentation; neutrophil count; and steroid use in the first 6 months. Disease localized to the colon only, blood in the stool, use of 5-aminosalicylate, and lymphocyte count were inversely associated with risk of early surgery. Logistic regression confirmed independent associations with smoking as a positive risk factor and involvement of colon without small bowel as a negative risk factor for early surgery.CONCLUSIONS:The rate of surgery is high in the first 3 yr after diagnosis of Crohns disease, particularly in the first 6 months. These results suggest that improved risk stratification and potent therapies with rapid onset of action are needed to modify the natural history of Crohns disease.

Development of extraintestinal manifestations in pediatric patients with inflammatory bowel disease.

Background: Extraintestinal manifestations (EIMs) in pediatric patients with inflammatory bowel disease (IBD) are poorly characterized. We examined the prevalence of EIMs at diagnosis, subsequent incidence, and risk factors for EIMs. Methods: Data for 1649 patients from the PediIBD Consortium Registry, diagnosed with IBD before 18 years of age (1007 [61%] with Crohns disease, 471 [29%] with ulcerative colitis, and 171 [10%] with indeterminate colitis), were analyzed using logistic regression, Kaplan–Meier, log rank tests, and Cox models. Results: EIMs were reported prior to IBD diagnosis in 97 of 1649 patients (6%). Older children at diagnosis had higher rates compared with younger children, and arthritis (26%) and aphthous stomatitis (21%) were most common. Among the 1552 patients without EIM at diagnosis, 290 developed at least 1 EIM. Kaplan–Meier estimates of cumulative incidence were 9% at 1 year, 19% at 5 years, and 29% at 15 years after diagnosis. Incidence did not differ by IBD type (P = 0.20), age at diagnosis (P = 0.22), or race/ethnicity (P = 0.24). Arthritis (17%) and osteopenia/osteoporosis (15%) were the most common EIMs after IBD diagnosis. Conclusions: In our large cohort of pediatric IBD patients, 6% had at least 1 EIM before diagnosis of IBD. At least 1 EIM will develop in 29% within 15 years of diagnosis. The incidence of EIMs both before and after diagnosis of IBD differs by type of EIM and may be slightly higher in girls, but is independent of the type of IBD, age at diagnosis, and race/ethnicity.