Cade M. Nylund

Azithromycin in Early Infancy and Pyloric Stenosis

BACKGROUND AND OBJECTIVE: Use of oral erythromycin in infants is associated with infantile hypertrophic pyloric stenosis (IHPS). The risk with azithromycin remains unknown. We evaluated the association between exposure to oral azithromycin and erythromycin and subsequent development of IHPS. METHODS: A retrospective cohort study of children born between 2001 and 2012 was performed utilizing the military health system database. Infants prescribed either oral erythromycin or azithromycin as outpatients in the first 90 days of life were evaluated for development of IHPS. Specific diagnostic and procedural codes were used to identify cases of IHPS. RESULTS: A total of 2466 of 1 074 236 children in the study period developed IHPS. Azithromycin exposure in the first 14 days of life demonstrated an increased risk of IHPS (adjusted odds ratio [aOR], 8.26; 95% confidence interval [CI], 2.62–26.0); exposure between 15 and 42 days had an aOR of 2.98 (95% CI, 1.24–7.20). An association between erythromycin and IHPS was also confirmed. Exposure to erythromycin in the first 14 days of life had an aOR of 13.3 (95% CI, 6.80–25.9), and 15 to 42 days of life, aOR 4.10 (95% CI, 1.69–9.91). There was no association with either macrolide between 43 and 90 days of life. CONCLUSIONS: Ingestion of oral azithromycin and erythromycin places young infants at increased risk of developing IHPS. This association is strongest if the exposure occurred in the first 2 weeks of life, but persists although to a lesser degree in children between 2 and 6 weeks of age.

Bacterial enteritis as a risk factor for childhood intussusception: a retrospective cohort study.

OBJECTIVE To assess the relationship between bacterial enteritis and intussusception. STUDY DESIGN The Patient Administration Systems and Biostatistics Activity database from January 2002 to December 2005 was examined for clinic visits or hospital admission to a Department of Defense medical facility for children age 0-5 years. The study included the International Statistical Classification of Diseases and Related Health Problems diagnosis-related group (DRG) codes for infections with Yersinia enterocolitica, Escherichia coli, Shigella species, Salmonella species, and Campylobacter. Identified patients were then assessed for the intussusception DRG code for 0-180 days postinfection. The total number of children enrolled in military treatment facilities in the same age group (denominator) was obtained. RESULTS Bacterial enteritis significantly increased the relative risk of intussusception. An increased risk was found following infection with Salmonella, E coli, Shigella, and Campylobacter. The relative risk for intussusception following any bacterial enteritis was 40.6 (95% confidence interval = 28.6-57.5; P < .0001). CONCLUSIONS Bacterial enteritis is a significant risk factor for the subsequent development of intussusception in children.

A randomized controlled trial of growth hormone in active pediatric Crohn disease.

Objectives: Growth hormone (GH) may reduce symptoms and improve growth in Crohn disease (CD). The effect on mucosal inflammation is not known. We hypothesized that GH would improve both clinical and mucosal disease activity and stimulate linear growth in pediatric CD. Patients and Methods: Twenty patients ages 7 to 18 receiving corticosteroids (CTX) for active CD were randomized to begin GH, 0.075 mg · kg−1 · day−1 (group A), or continue CTX alone (group B). Clinical and endoscopic disease activities were assessed after 12 weeks. Group B began GH at 12 weeks, and clinical disease activity was assessed at 24 weeks. Subjects who experienced a clinical response after 12 weeks of GH therapy continued treatment for an additional 52 weeks, and linear growth was assessed. Results: Sixty-five percent of patients receiving GH achieved clinical remission, compared with 20% treated with CTX alone (P = 0.03). Although endoscopic disease activity trended toward an improvement at week 12 in group A, this did not differ between the groups. Sixty-one percent of week 12 GH responders maintained their clinical response through week 64. Mean (95th confidence interval) height z score on GH increased from −1.1 (−1.6, −0.6) to −0.4 (−1, 0.2), P = 0.004 during this 52-week extension phase. GH was well tolerated with no unexpected safety signals. Conclusions: The addition of GH to CTX therapy did not induce a reduction in mucosal inflammation, relative to CTX alone. However, GH was safe and effective as an adjunct to CTX for treatment of clinical disease activity and growth failure in pediatric CD.

Association of Constipation and Fecal Incontinence With Attention-Deficit/Hyperactivity Disorder

OBJECTIVE: Functional constipation and fecal incontinence are common childhood gastrointestinal conditions. Both conditions may be associated with behavioral problems. Attention-deficit/hyperactivity disorder (ADHD) is the most common behavioral disorder of childhood, characterized by shortened attention span and hyperactivity. We hypothesize that a diagnosis of ADHD increases the risk for functional constipation and fecal incontinence. METHODS: A retrospective cohort study of children was performed by using the military health system database. Children of active-duty military personnel, aged 4 to 12 years, from October 2005 to September 2007, were included. ADHD, constipation, and fecal incontinence were identified by International Classification of Diseases, Ninth Revision, Clinical Modification diagnostic codes. Relative risks and adjusted incidence rate ratios (IRRs) were calculated. A subgroup analysis of subjects receiving medical therapy was performed. RESULTS: There were 742 939 children identified in the study, 32 773 (4.4%) of whom had ADHD. Children with ADHD had an increased prevalence of constipation (4.1% of children with ADHD vs 1.5% children without ADHD; P < .001) and fecal incontinence (0.9% of children with ADHD vs 0.15% of children without ADHD; P < .0001). Children with ADHD had more visits than those without ADHD for both constipation (IRR 3.39; 95% confidence interval 2.59–4.43) and fecal incontinence (IRR 7.74; 95% confidence interval 5.01–11.98). Children with ADHD receiving medicinal therapy did not differ significantly from children with ADHD not receiving medicinal therapy on rates of constipation visits (P = .57) or fecal incontinence visits (P = .32). CONCLUSIONS: Children with ADHD are significantly more likely to have constipation and fecal incontinence. Medical therapy for ADHD does not impact visit rates for defecation disorders.

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.

Granulocyte macrophage-colony-stimulating factor autoantibodies and increased intestinal permeability in Crohn disease.

Background:Alterations in intestinal permeability have been implicated in the pathogenesis of Crohn disease (CD). We have reported that granulocyte macrophage-colony-stimulating factor (GM-CSF) is required for mucosal barrier function in mice, and elevated neutralizing GM-CSF autoantibodies (Ab) are associated with stricturing ileal disease and surgery in patients with CD. We hypothesized that children with CD with elevated GM-CSF Ab would exhibit increased intestinal permeability. Patients and Methods:Subjects were divided into 3 groups: 15 with CD and high GM-CSF Ab (≥1.6 μg/mL, GM-CSF Ab Hi), 12 with CD and low GM-CSF Ab (<1.6 μg/mL, GM-CSF Ab Lo), and 15 healthy controls. Subjects ingested a lactulose:mannitol (L:M) solution, and urinary excretion of LM was measured by high-performance liquid chromatography. Serum GM-CSF Ab, endotoxin core Ab (EndoCAb), and lipopolysaccharide-binding protein (LBP), and fecal S100A12 were determined by enzyme-linked immunosorbent assay. Results:The CD groups did not vary by age, sex, disease location, or activity. Neither systemic (serum LBP) nor mucosal (fecal S100A12) inflammation differed between the CD groups. Intestinal permeability as measured by the urine L:M ratio and endotoxin exposure as measured by serum EndoCAb were increased in the GM-CSF Ab Hi group compared to the GM-CSF Ab Lo group and controls. Conclusions:Patients with CD with elevated GM-CSF Ab exhibit an increase in bowel permeability relative to patients with CD with lower levels of GM-CSF Ab in the absence of differences in systemic or intestinal inflammation. Therapies that target the mucosal barrier may be of particular benefit in this subgroup of patients with CD.

Video capsule endoscopy impacts decision making in pediatric IBD: a single tertiary care center experience.

Background: Little is known about the impact of video capsule endoscopy (VCE) on decision making in pediatric patients with IBD. Moreover, few studies have reported on the outcomes of treatment changes made based on VCE findings. Our aim was to identify the added value of VCE in pediatric patients in a tertiary IBD center with established or suspected IBD, by assessing changes in treatments and outcomes before and after VCE. Methods: A retrospective chart review was performed in children with established (n = 66) or suspected (n = 17) IBD who underwent VCE. Diagnostic classifications, treatments, and clinical outcomes before and 1 year after VCE were compared. Results: Primary indications for VCE included patients treated for Crohns disease (CD) with poor growth or active symptoms (60%), patients with ulcerative colitis/IBD-unclassified (19%), and suspected IBD (20%). Abnormal VCE was seen in 86% of patients with CD, of whom 75% underwent treatment escalation. One year after VCE, patients with CD improved in growth (mean z-scores at baseline and 12 months, −0.5 and 0.2, respectively; P < 0.0001), mean body mass index (18.3 and 19.8, respectively; P = 0.004), mean erythrocyte sedimentation rate (25 versus 16, respectively; P = 0.012), and median Harvey–Bradshaw Index (2 and 0, respectively; P = 0.003). VCE revealed more extensive disease than concurrent imaging modalities in 43% of the patients with CD. VCE “ruled out” IBD in 94% who had suspected IBD, whereas 50% with presumed ulcerative colitis/IBD-unclassified had a diagnosis changed to CD. Conclusions: VCE provides additional clinical information that impacted management of pediatric patients with IBD in a tertiary IBD center and was associated with improved outcomes.

Prospective evaluation of 1-day polyethylene glycol-3350 bowel preparation regimen in children.

Objectives: The aim of the present study was to evaluate efficacy, safety, and tolerability of a pediatric colonoscopy bowel preparation regimen composed of polyethylene glycol-3350 (PEG-3350) and a sports drink completed in a few hours. Methods: A prospective, open-label trial of a colonoscopy bowel preparation in children ages 8 to 18 years that included 238 g of PEG-3350 mixed with 1.9 L of Gatorade completed in a few hours. Efficacy was determined using the Boston Bowel Preparation Scale. Basic metabolic profiles and questionnaires were obtained that assessed for safety, adverse effects, tolerability, and patient acceptability. Results: Forty-six patients completed the study. Patients were predominately boys (56.5%) with a mean age of 14.50 years (SD ±2.9 years). Forty-three (93.5%) were able to complete the regimen. All of the colonoscopies were completed to the cecum and 84% had terminal ileum visualization. Seventy-seven percent were found to be effective preparations. Nausea/vomiting were the most common reported adverse effect (60%) followed by abdominal pain/cramping (44%) and fatigue/weakness (40%). Overall, the regimen was acceptable with 1 exception being the large volume to drink. There were no clinically significant changes in basic metabolic profiles, although there was a statistically significant decrease in the mean potassium (0.16 mEq/L; P = 0.016), blood urea nitrogen (2.68 mg/dL; P < 0.0001), and carbon dioxide (1.89 mmol/L; P < 0.0001). Conclusions: This study demonstrated that PEG-3350 + Gatorade administered in a few hours is an effective, safe, and moderately tolerable bowel preparation regimen for colonoscopy in children.

Children with Down Syndrome Are High-Risk for Severe Respiratory Syncytial Virus Disease

OBJECTIVE To assess Down syndrome as an independent risk factor for respiratory syncytial virus (RSV) hospitalization in children younger than 3 years of age and to evaluate illness severity. STUDY DESIGN A retrospective cohort study of children enrolled in the military health system database was conducted. The effect of Down syndrome on RSV hospitalization was assessed by Cox proportional hazards model, while we controlled for risk factors. Disease severity was assessed by length of hospital stay, need for respiratory support, and age at hospitalization. RESULTS The study included 633 200 children and 3 209 378 person-years. Children with Down syndrome had a hospitalization rate of 9.6% vs 2.8% in children without Down syndrome. Down syndrome had a greater adjusted hazard ratio (HR) for RSV hospitalization than most risk factors, 3.46 (95% CI 2.75-4.37). A sensitivity analysis demonstrated HR 3.21 (95% CI 2.51-4.10) for patients with Down syndrome ages 0-23 months and HR 5.07 (95% CI 2.21-11.59) ages 24-36 months. The median (IQR) length of stay of children with and without Down syndrome was 4 days (2-7) and 2 days (1-4) (P < .001). Patients with Down syndrome had a greater risk of requiring respiratory support (relative risk 5.5; 95% CI, 2.5-12.3). The median (IQR) ages at admission for children with and without Down syndrome were 9.8 months (5.5-17.7) and 3.5 months (1.7-8.7) (P < .001). CONCLUSIONS Down syndrome is independently associated with an increased risk for RSV hospitalization. Children with Down syndrome are older at time of RSV hospitalization and have more severe RSV illness than children without Down syndrome. This increased risk for hospitalization continues beyond 24 months.

Healthy Late-preterm infants born 33–36 + 6 weeks gestational age have higher risk for respiratory syncytial virus hospitalization

BACKGROUND Respiratory syncytial virus (RSV) is a leading cause of hospitalization for children <1year old and is more severe in premature infants. OBJECTIVE To assess whether late preterm (LPT) birth is an independent risk factor for RSV hospitalization and more severe RSV disease in children less than 24months old. METHODS We conducted a retrospective cohort study of children enrolled in the military health system. LPT birth was defined as 33+0 through 36+6weeks gestation. Patients who received palivizumab or had known risk factors for RSV were excluded. Adjusted hazard ratios (HR) for LPT birth were calculated using a Cox proportional hazard model, while controlling for sex and RSV season. Severity of illness was assessed by comparing the need for respiratory support, length of stay, and age at RSV hospitalization between LPT and term children. RESULTS A total of 599,535 children for 1,216,382 person-years were studied, of which 7597 children were admitted for RSV infection. LPT infants accounted for 643 (8.5%) of these RSV hospitalizations. The incidence density for RSV hospitalization of LPT infants was higher than term children (12.1 vs 7.8 per 1000 person-years). LPT infants had an increased adjusted risk for RSV hospitalization; specifically, those born 33+0 through 34+6weeks (HR 2.45; 95% confidence interval (CI) 1.96-3.07), and 35+0 through 36+6weeks (HR, 1.92; 95% CI, 1.66-2.22). LPT infants had longer hospital stays and required more respiratory support than term children. CONCLUSIONS LPT birth is an independent risk factor for severe RSV disease and need for hospitalization.