A Microbial Signature for Paediatric Perianal Crohn's Disease.

BACKGROUND AND AIMS: Perianal fistulising disease can affect up to 25% of patients with Crohn's disease [CD] and lead to significant morbidity. Although the role of the gut microbiota in inflammatory bowel disease [IBD] has been increasingly recognised, its role in fistula development has scarcely been studied. Here, we aimed to define the microbial signature associated with perianal fistulising CD in children. METHODS: A prospective observational study including children age 6-18 years with a diagnosis of perianal fistulising CD was conducted. Stool samples and rectal and perianal fistula swabs were collected. Stool samples and rectal swabs from children with CD without perianal disease and healthy children were included as comparison. Whole shotgun metagenomic sequencing was performed. RESULTS: A total of 31 children [mean age 15.5 ± 3.5 years] with perianal CD were prospectively enrolled. The fistula-associated microbiome showed an increase in alpha diversity and alteration in the abundance of several taxa compared with the rectal- and faecal-associated microbiome with key taxa belonging to the Proteobacteria phylum. Genes conferring resistance to the clinically used antibiotic regimen ciprofloxacin and metronidazole were found in the three sample types. In comparison with children without the perianal phenotype [N = 36] and healthy controls [N = 41], the mucosally-associated microbiome of children with perianal CD harboured a reduced butyrogenic potential. Linear discriminant analysis identified key taxa distinguishing the rectal mucosally-associated microbiome of children with perianal CD from children without this phenotype. CONCLUSIONS: The microbial community within CD-related anorectal fistula is compositionally and functionally unique. Taken together, these findings emphasise the need to better understand the ecosystem of the fistula milieu to guide development of novel microbiome-based strategies in this CD phenotype.

Utilization of an Electronic Medical Record-integrated Dashboard Improves Identification and Treatment of Anemia and Iron Deficiency in Pediatric Inflammatory Bowel Disease.

BACKGROUND: Iron deficiency (ID) and anemia are one of the most common extraintestinal manifestations of inflammatory bowel disease (IBD), usually complicating the course both in ulcerative colitis and Crohn's disease. Despite their high prevalence and significant impact on patients, this particular aspect is still underestimated by clinicians. Although guidelines have been recently published to address this problem, these recommendations do not address pediatric specific concerns and do not provide guidance as to how implement these guidelines in clinical practice. The aims of this quality improvement (QI) initiative were to improve the rates of detection and treatment of anemia in children with IBD. METHODS: After the creation of a multidisciplinary team of skateholders in IBD and anemia, we launched a multifaceted QI strategy that included the development of a pediatric evidence-based care pathway, utilization of an electronic medical record (EMR)-integrated dashboard to track patients, and generation of an automated provider-based monthly report. Data were collected and graphed into statistical process control charts. RESULTS: These key strategies resulted in improved rates of ID screening from 31.7% to 63.6%, in increased treatment rates from 38.2% to 49.9%, and in decreased prevalence of anemia from 35.8% to 29.7%, which was reflected by a greater decline in patients with quiescent disease. CONCLUSIONS: Quality improvement strategies incorporating the creation of a pediatric evidence-based care pathway with an EMR-supported electronic dashboard were the foundation of a successful intervention in the management of ID and anemia in pediatric IBD. Our positive results demonstrate the potential of QI initiatives using automated technology to assist clinicians in their commitment to provide evidence-based IBD care and enhance patient outcomes.

Multi-omic Analysis of the Interaction between Clostridioides difficile Infection and Pediatric Inflammatory Bowel Disease.

Children with inflammatory bowel diseases (IBD) are particularly vulnerable to infection with Clostridioides difficile (CDI). IBD and IBD + CDI have overlapping symptoms but respond to distinctive treatments, highlighting the need for diagnostic biomarkers. Here, we studied pediatric patients with IBD and IBD + CDI, comparing longitudinal data on the gut microbiome, metabolome, and other measures. The microbiome is dysbiotic and heterogeneous in both disease states, but the metabolome reveals disease-specific patterns. The IBD group shows increased concentrations of markers of inflammation and tissue damage compared with healthy controls, and metabolic changes associate with susceptibility to CDI. In IBD + CDI, we detect both metabolites associated with inflammation/tissue damage and fermentation products produced by C. difficile. The most discriminating metabolite found is isocaproyltaurine, a covalent conjugate of a distinctive C. difficile fermentation product (isocaproate) and an amino acid associated with tissue damage (taurine), which may be useful as a joint marker of the two disease processes.

Dynamics of the Stool Virome in Very Early-Onset Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Dysbiosis of the gut microbiota is a well-known correlate of the pathogenesis of inflammatory bowel disease [IBD]. However, few studies have examined the microbiome in very early-onset [VEO] IBD, which is defined as onset of IBD before 6 years of age. Here we focus on the viral portion of the microbiome-the virome-to assess possible viral associations with disease processes, reasoning that any viruses potentially associated with IBD might grow more robustly in younger subjects, and so be more detectable. METHODS: Virus-like particles [VLPs] were purified from stool samples collected from patients with VEO-IBD [n = 54] and healthy controls [n = 23], and characterized by DNA and RNA sequencing and VLP particle counts. RESULTS: The total number of VLPs was not significantly different between VEO-IBD and healthy controls. For bacterial viruses, the VEO-IBD subjects were found to have a higher ratio of Caudovirales vs to Microviridae compared to healthy controls. An increase in Caudovirales was also associated with immunosuppressive therapy. For viruses infecting human cells, Anelloviridae showed higher prevalence in VEO-IBD compared to healthy controls. Within the VEO-IBD group, higher levels of Anelloviridae DNA were also positively associated with immunosuppressive treatment. To search for new viruses, short sequences enriched in VEO-IBD samples were identified, and some could be validated in an independent cohort, although none was clearly viral; this provides sequence tags to interrogate in future studies. CONCLUSIONS: These data thus document perturbations to normal viral populations associated with VEO-IBD, and provide a biomarker-Anelloviridae DNA levels-potentially useful for reporting the effectiveness of immunosuppression.

Positioning Biologic Therapies in the Management of Pediatric Inflammatory Bowel Disease.

The incidence and prevalence of pediatric inflammatory bowel disease (IBD) are rising worldwide, with a steep increase in children under 5 years of age. Compared to adult IBD, pediatric IBD presents with a more severe, aggressive phenotype and unique complications, notably growth impairment. Treatment goals include achieving intestinal healing, reaching growth potential, and optimizing quality of life, all while limiting drug toxicities. In the last 2 decades, the advent of anti-tumor necrosis factor (TNF) α agents has significantly increased the potential to reach these goals. However, nonresponse or loss of response to anti- TNFα agents is still encountered in approximately one-third of patients. Although the development of novel biologic therapies has offered new alternatives in recent years, the use of these therapies in the pediatric setting has been limited due to delayed approval. This article summarizes the key evidence for biologic agents currently used in the treatment of pediatric IBD and discusses challenges and barriers unique to pediatric drug development.

Efficacy of Combination Antibiotic Therapy for Refractory Pediatric Inflammatory Bowel Disease.

BACKGROUND: Recent studies have shown that oral combination antibiotics may improve disease course in refractory inflammatory bowel disease (IBD). Here, we describe the use of combination oral antibiotics as salvage therapy in refractory ulcerative colitis (UC), Crohn's colitis, and IBD-unclassified (IBD-U) at a large pediatric IBD center. METHODS: Clinical response, disease activity indices, adverse events, and clinical outcomes were measured up to 1 year after antibiotic treatment in this retrospective cohort study of children with medically refractory IBD colitis. RESULTS: Sixty-three patients with refractory UC, Crohn's colitis, and IBD-U (median age [interquartile range {IQR}], 15.3 [11.2-16.5] years; median disease duration [IQR], 1.2 [0.41-4.6] years) received a combination of 3 or 4 oral antibiotics (most commonly amoxicillin, metronidazole, and either doxycycline or ciprofloxacin) for a median (IQR) of 29 (21-58) days. Thirty-four patients (54%) were deemed corticosteroid-refractory or -dependent, with the majority (62/63) having a previous or present loss of response or primary nonresponse to anti-tumor necrosis factor alpha (anti-TNFα) therapy. Use of combination antibiotics led to a significant decrease in median Pediatric Ulcerative Colitis Activity Index (PUCAI) score (IQR) from 55 (40-65) to 10 (0-40; P < 0.0001) over 3 ± 1 weeks, with 25/63 (39.7%) patients achieving clinical remission (PUCAI <10 points). The clinical benefits of oral antibiotics were independent of anti-TNFα therapy optimization. Among children entering clinical remission (n = 25), only 1 patient required surgery at 1-year follow-up, vs 10 patients in the nonresponder group. Negative predictors of response to combination antibiotics were exposure to doxycycline (odds ratio [OR], 0.25; 95% CI, 0.08-0.76) and PUCAI ≥65 at baseline (OR, 0.2; 95% CI, 0.05-0.74). CONCLUSIONS: Oral combination antibiotics appears to be an effective rescue and steroid-sparing therapy to induce remission in the short term in patients failing a biologic.

Teaching the Role of Health Advocate: Reflections on two cross-cultural collaborative advocacy workshops for medical trainees and instructors in Oman.

In March 2014, medical educators from Canada and Oman collaborated to shape the foundation of health advocacy training in Oman. Using existing research and innovative tools, two workshops were developed, representing the first formalised approach to health advocacy for medical trainees in Oman. The development and application of the workshops highlighted many unique challenges and opportunities in advocacy training. This article summarises the process of developing and implementing the workshops as well as feedback from the participants and short-term consequences. Furthermore, this article seeks to explore the complexities of designing a cross-cultural curriculum. In particular, it reflects on how the role of health advocate may be perceived differently in various cultural and societal settings. Understanding and adapting to these influences is paramount to creating a successful health advocacy curriculum that is relevant to learners and responsive to the communities in which they work.

Treatment of Pulmonary Exacerbations Improves Short But Not Long-Term Growth Trajectory in Children With Cystic Fibrosis.

OBJECTIVES: The present study sought to determine the long-term growth consequences after a pulmonary exacerbation in children with cystic fibrosis (CF). METHODS: Retrospective cohort study of pediatric patients with CF with a hospital admission for a pulmonary exacerbation. Logistic regression used to determine risk factors for failure to recover baseline body mass index (BMI) percentile. RESULTS: Of 72 patients, 43% failed to recover their baseline BMI percentile 12 months after discharge and these patients also had a lower forced expiratory volume in 1 second at follow-up. A greater decrease in weight percentile from baseline to admission was the only risk factor identified (odds ratio 0.83, P = 0.0015). CONCLUSIONS: Greater decrease in weight percentile from baseline to admission predicts failure to recover BMI percentile 1 year after a pulmonary exacerbation. Children with CF with poor growth preceding a pulmonary exacerbation continue to be at risk for long-term nutritional failure despite treatment for pulmonary exacerbation.