Risk Factors of Clinical Relapses in Pediatric Luminal Crohn's Disease: A Retrospective Cohort Study.

INTRODUCTION: There is currently little knowledge on factors associated with the relapse of Crohn's disease (CD) in children. The aims of this study were to describe the risk factors associated with relapse in pediatric CD and the changes in the relapse rate over the past decade. METHODS: Patients younger than 18 years and diagnosed between 2009 and 2019 were included in this retrospective cohort study. Clinical, endoscopic, histological, and laboratory data, as well as induction and maintenance treatments, were collected from the medical records. Survival analyses and Cox regression models were used to assess the impact of these risk factors on relapse. RESULTS: Six hundred thirty-nine patients were included. There was a decrease in the clinical relapse rate over the past decade: 70.9% of the patients diagnosed between 2009 and 2014 relapsed as compared with 49.1% of the patients diagnosed between 2015 and 2019 (P < 0.0001). The following variables were associated with clinical relapse: female sex (adjusted hazard ratio [aHR] = 1.52, P = 0.0007), exposure to oral 5-ASA (aHR = 1.44, P = 0.04), use of immunomodulatory agents compared with tumor necrosis factor-alpha inhibitors (methotrexate aHR = 1.73, P = 0.003; thiopurines aHR = 1.63, P = 0.002), presence of granulomas (aHR = 1.34, P = 0.02) and increased eosinophils on intestinal biopsies (aHR = 1.36, P = 0.02), high levels of C-reactive protein (aHR = 1.01, P < 0.0001) and fecal calprotectin (aHR = 1.08, P < 0.0001), and low serum infliximab levels (aHR = 2.32, P = 0.001). DISCUSSION: Relapse of pediatric CD has decreased in the past decade. The risk of relapse is significantly associated with clinical, endoscopic, histological, and laboratory variables and treatment strategies.

Functional Luminal Imaging Probe in the Management of Pediatric Esophageal Disorders.

BACKGROUND: Functional luminal imaging probe (FLIP) measures pressure-geometry relationships of digestive luminal space. When used in esophageal disorders, it provides several luminal parameters that help better understand the pathophysiology. Data about the potential utility of FLIP in pediatrics are scarce and there is no standardized use in children. We aim to describe the use of FLIP in our center, its safety, feasibility, and clinical impact in esophageal disorders in children. METHODS: Consecutive FLIP recordings performed at the Centre Hospitalier Universitaire-Sainte-Justine, Montréal, Canada between February 2018 and January 2021 were extracted. A chart review was conducted for demographics and medical history. Symptomatology after the procedure was evaluated with validated dysphagia scores. KEY RESULTS: Nineteen patients were included (11 girls, median age 16 years, range 3.2-19.6) with achalasia (n = 5), post-Heller's myotomy dysphagia (n = 3), esophagogastric junction outflow obstruction (n = 3), congenital esophageal stenosis (n = 2); post-esophageal atresia repair stricture (n = 3), and post-fundoplication dysphagia (n = 3). There was no significant correlation between integrated relaxation pressure measured with high resolution manometry and distensibility index (DI). The use of FLIP made it possible to differentiate between dysphagia related to an esophageal obstruction (DI < 2.8 mm2/mmHg) and dysphagia without major motility disorder (DI > 2.8 mm2/mmHg) that guided the indication for dilation. FLIP led to a change in management in 47% of the patients. Forty-seven percent of the patients were symptom free at the time of the evaluation. CONCLUSIONS INFERENCES: FLIP provides key esophageal luminal values and therefore can play an important role in pediatric esophageal disorders management.

Changes in the clinical phenotype and behavior of pediatric luminal Crohn's disease at diagnosis in the last decade.

BACKGROUND AND AIMS: The aims of this study were to describe the trends in the behavior of pediatric CD during the last decade and to describe the seasonal variation of disease presentation. METHODS: Patients under 18 years old and diagnosed between 2009 and 2019 were included. The clinical, endoscopic, histological, and laboratory data were collected from the medical records. We analyzed the trends of these parameters according to the year and season of diagnosis. RESULTS: 654 patients were included in the study. The number of incident CD cases increased yearly. Patients diagnosed between 2015 and 2019 were younger at diagnosis (OR 2.53, p = 0.02), had more perianal diseases (OR: 2.30, p < 0.0001) and more granulomas (OR: 1.61, p = 0.003), but fewer eosinophils (OR: 0.35, p < 0.0001) and less chronic lymphoplasmacytic infiltrate (OR: 0.56, p = 0.008) as compared to the 2009-2014 cohort. There was fewer CD diagnosis during winter. Patients diagnosed in the fall had lower PCDAIs, less failure to thrive and less extensive digestive involvement. Colonic disease was significantly more frequent during summer and fall. CONCLUSION: The clinical and histological phenotype of CD has changed over time and there are important seasonal trends in the frequency and severity on disease behavior suggesting possible disease triggers.

Factors associated with time to clinical remission in pediatric luminal Crohn's disease: A retrospective cohort study.

BACKGROUND AND AIM: Data on factors influencing time to remission in pediatric Crohn's disease (CD) are very limited in the literature. The aim of this retrospective cohort study was to describe the trends of time to clinical remission over the past decade and to identify factors associated with time to clinical remission in children with luminal CD. METHODS: Patients under 18 years old diagnosed between 2009 and 2019 were included. All data were collected from the patients' medical records. Survival analyses and linear regression models were used to assess the impact of clinical, laboratory, endoscopic, histological, and therapeutic factors on time to clinical remission. RESULTS: A total of 654 patients were included in the study. There was no change in the time to clinical remission over the decade. Female sex in adolescents (adjusted bêta regression coefficient [aß] = 31.8 days, P = 0.02), upper digestive tract involvement (aß = 46.4 days, P = 0.04) perianal disease (aß = 32.2 days, P = 0.04), presence of active inflammation on biopsies at diagnosis (aß = 46.7 days, P = 0.01) and oral 5-aminosalicylates (5-ASA) exposure (aß = 56.6 days, P = 0.002) were associated with longer time to clinical remission. Antibiotic exposure (aß = -29.3 days, P = 0.04), increased eosinophils (aß = -29.6 days, P = 0.008) and combination of exclusive enteral nutrition with tumor-necrosis-factor-alpha (TNF-alpha) inhibitors as induction therapy (aß = -36.8 days, P = 0.04) were associated with shorter time to clinical remission. CONCLUSION: In children with newly diagnosed Crohn's disease, time to clinical remission did not shorten during the decade. It was associated with baseline clinical and histological data and treatment strategies. Combination of enteral nutrition and TNF-alpha inhibitors was associated with faster clinical remission.

An OX40/OX40L interaction directs successful immunity to hepatitis B virus.

Depending on age of acquisition, hepatitis B virus (HBV) can induce a cell-mediated immune response that results in either cure or progressive liver injury. In adult-acquired infection, HBV antigens are usually cleared, whereas in infancy-acquired infection, they persist. Individuals infected during infancy therefore represent the majority of patients chronically infected with HBV (CHB). A therapy that can promote viral antigen clearance in most CHB patients has not been developed and would represent a major health care advance and cost mitigator. Using an age-dependent mouse model of HBV clearance and persistence in conjunction with human blood and liver tissue, we studied mechanisms of viral clearance to identify new therapeutic targets. We demonstrate that age-dependent expression of the costimulatory molecule OX40 ligand (OX40L) by hepatic innate immune cells is pivotal in determining HBV immunity, and that treatment with OX40 agonists leads to improved HBV antigen clearance in young mice, as well as increased strength of T cell responses in young mice and adult mice that were exposed to HBV when they were young and developed a CHB serological profile. Similarly, in humans, we show that hepatic OX40L transcript expression is age-dependent and that increased OX40 expression on peripheral CD4+ T cells in adults is associated with HBV clearance. These findings provide new mechanistic understanding of the immune pathways and cells necessary for HBV immunity and identify potential therapeutic targets for resolving CHB.

Very Early-Onset Inflammatory Manifestations of X-Linked Chronic Granulomatous Disease.

Chronic granulomatous disease (CGD) is a rare primary immune deficiency caused by mutations in genes coding for components of the nicotinamide adenine dinucleotide phosphate oxidase, characterized by severe and recurrent bacterial and fungal infections, together with inflammatory complications. Dysregulation of inflammatory responses are often present in this disease and may lead to granulomatous lesions, most often affecting the gastrointestinal (GI) and urinary tracts. Treatment of inflammatory complications usually includes corticosteroids, whereas antimicrobial prophylaxis is used for infection prevention. Curative treatment of both infectious susceptibility and inflammatory disease can be achieved by hematopoietic stem cell transplantation. We report herein three patients with the same mutation of the CYBB gene who presented with very early-onset and severe GI manifestations of X-linked CGD. The most severely affected patient had evidence of antenatal inflammatory involvement of the GI and urinary tracts. Extreme hyperleukocytosis with eosinophilia and high inflammatory markers were observed in all three patients. A Mycobacterium avium lung infection and an unidentified fungal lung infection occurred in two patients both during their first year of life, which is indicative of the severity of the disease. All three patients underwent bone marrow transplantation and recovered fully from their initial symptoms. To our knowledge, these are the first reports of patients with such an early-onset and severe inflammatory manifestations of CGD.

The Liver in Tyrosinemia Type I: Clinical Management and Course in Quebec.

HT1 is a severe autosomal recessive disorder due to the deficiency of fumarylacetoacetate hydrolase (FAH), the final enzyme in the degradation of tyrosine. Before the era of treatment with 2-(2-N-4-trifluoromethylbenzoyl)-1,3-cyclohexanedione (NTBC), even with newborn screening and optimal diet therapy, HT1 patients often developed liver failure. Death was common in patients who did not undergo liver transplantation. For the last two decades, NTBC has revolutionized the management of HT1 patients. In screened newborns treated within the first month of life, we have not observed hepatocarcinoma. If patients are not detected at birth by neonatal screening, the diagnosis and treatment must be performed on an emergency basis, and patients are at risk for complications. Long term adhesion to treatment and reliable early detection of hepatocellular carcinoma (HCC) are two important challenges. In this chapter, we describe the clinical, biological, histo-pathological and imaging findings of HT1 in Québec before the era of NTBC. We also describe the hepatic status of nontransplanted tyrosinemic patients in Quebec and current management practices in the Quebec NTBC Study.

The Québec NTBC Study.

In this chapter we describe the current Quebec NTBC Study protocol. Quebec's unique characteristics have influenced the development of the protocol, including a high prevalence of hepatorenal tyrosinemia (HT1), universal newborn screening for HT1, availability of treatment with nitisinone (NTBC) and special diet, a large territory, where HT1 treatment is coordinated by a small number of centers. Screened newborns are seen within 3 weeks of birth. Patients with liver dysfunction (prolonged prothrombin time and/or international normalized ratio (INR) provide sensitive, rapidly available indicators) are treated by NTBC and special diet. The specific diagnosis is confirmed by diagnostic testing for succinylacetone (SA) in plasma and urine samples obtained before treatment. After an initial period of frequent surveillance, stable patients are followed every 3 months by assay of plasma amino acids and NTBC and plasma and urine SA. Abdominal ultrasound is done every 6 months. Patients have an annual visit to the coordinating center that includes multidisciplinary evaluations in metabolic genetics, hepatology, imaging (for abdominal ultrasound and magnetic resonance imaging) and other specialties as necessary. If hepatocellular carcinoma is suspected by imaging and/or because of progressive elevation of alphafetoprotein, liver transplantation is discussed. To date, no patient in whom treatment was started before 1 month of age has developed hepatocellular carcinoma, after surveillance for up to 20 years in some. This patient group is the largest in the world that has been treated rapidly following newborn screening. The protocol continues to evolve to adapt to the challenges of long term surveillance.

Torque Teno virus in children who underwent orthotopic liver transplantation: new insights about a common pathogen.

BACKGROUND: Torque Teno virus (TTV) is a ubiquitous infectious agent. Transplant recipients are at risk of hepatitis E virus (HEV) infection and could be vulnerable to TTV-associated adverse effects. The aim of this study was to evaluate the influence of immunosuppression and HEV infection on TTV replication and liver injury in pediatric patients after orthotopic liver transplantation (OLT). METHODS: Pediatric recipients of liver transplants were classified into the following 2 groups: (1) those with normal serum aminotransferases levels and (2) those with persistently increased serum aminotransferases levels and histological features of chronic hepatitis of unknown etiology. The TTV load was assessed in 342 serum samples by use of TaqMan real-time polymerase chain reaction, along with TTV genogroups and coinfection with HEV. RESULTS: TTV DNA was detected in 96% of tested serum samples. Viral load was significantly lower in patients with features of chronic hepatitis, of whom 78% had liver fibrosis scores of ≥2. Viral load decreased during posttransplantation follow-up. Viral load and genogroups were influenced by immunosuppression. Lower viral load was observed in patients coinfected with HEV. CONCLUSIONS: TTV infection is widespread, and its replication is closely related to immune status and viral coinfection. High TTV viremia is not associated with hepatitis after OLT, but, conversely, liver inflammatory activity impairs TTV replication.

Functional gastrointestinal disorders induced by esophageal atresia surgery: is it valid in humans?

BACKGROUND/AIMS: Functional gastrointestinal disorders (FGID) affect 15%-20% of the general pediatric and adult population. Animal models suggest that a neonatal stress such as invasive procedures and maternal separation could be responsible for visceral hypersensitivity and FGID. We tested the hypothesis that congenital esophageal atresia (EA), a condition corrected during the neonatal period and associated with multiple stresses, is a clinically significant risk factor for the development of FGID later in life. We postulated that, to be clinically significant, the effect of neonatal stress on the incidence of FGID should be as strong as that of enteric infections in the development of irritable bowel syndrome in children. METHODS: Subjects with EA and healthy controls were enrolled in this multicenter cohort study. Gastrointestinal symptoms were assessed by a questionnaire and FGID was diagnosed using the Rome III criteria. RESULTS: Fifty-three children (25 girls; median age, 12 years) with EA were compared to 72 age- and sex-matched controls. Although 11 children with EA (21%) had a FGID diagnosis versus 8 controls (11%), this difference was not significant (χ(2) = 2.20, P > 0.05). In subjects with EA, the presence of associated malformations, the occurrence of complications during the first month, and the length of hospital stay > 30 days did not influence the incidence of FGID. Chronic abdominal pain was present in 38% of subjects with EA versus 25% of controls (P > 0.05). CONCLUSIONS: Neonatal stress secondary to surgical correction of EA is not a clinically significant risk factor for the development of FGID in childhood.

Bardet-Biedl Syndrome, Crohn Disease, Primary Sclerosing Cholangitis, and Autoantibody Positive Thyroiditis: A Case Report and A Review of a Cohort of BBS Patients.

Bardet-Biedel syndrome (BBS) is a rare autosomal recessive, genetically heterogeneous ciliopathy. Although the disease has been described in a patient with psoriasis, individuals with BBS are not known to be at risk of developing autoimmune disorders. Our objective was to describe a 14-year-old patient with BBS who presented with Crohn disease (CD), primary sclerosing cholangitis (PSC), and thyroiditis in the context of a cohort review at Sainte-Justine Hospital and to alert clinicians to the increased risk of autoimmune disorders in these patients. The cohort contained fifteen patients (9 boys), followed from 1968 to 2009 during a median period of 12 years (range 9 months-26 years). Three of the 15 patients (20%) developed a chronic autoimmune disease: one had juvenile rheumatoid arthritis; a second one had type 1 diabetes mellitus in association with Hashimoto thyroiditis and psoriasis; a third one developed CD, PSC, and Hashimoto thyroiditis. As chronic autoimmune diseases occurred in 20% of our cohort of children with BBS, it is appropriate to keep this association in mind during the followup.

Cirrhosis due to chronic hepatitis E infection in a child post-bone marrow transplant.

Chronic hepatitis E virus (HEV) infection occurs in immunosuppressed adults. We detected HEV ribonucleic acid in serum of an adolescent patient who had undergone bone marrow transplantation and subsequently presented with persistently increased aminotransferases and histologic chronic hepatitis, and eventually developed cirrhosis. Phylogenetic analysis revealed these HEV strains were similar to swine genotype 3a, suggesting a possible zoonosis.

Chronic hepatitis E infection in children with liver transplantation.

OBJECTIVE: Chronic hepatitis E virus (HEV) infection has been described in immunosuppressed adult patients. A study was undertaken to establish the presence of HEV infection in children after orthotopic liver transplantation (OLT). METHODS: Children undergoing liver transplantation between 1992 and 2010 with available serum were classified into two groups: group 1 (control group, n=66) with normal serum aminotransferases and group 2 (n=14) with persistently increased serum aminotransferases and histological features of chronic hepatitis. Patients were tested for HEV RNA by reverse transcription-polymerase chain reaction (RT-PCR). HEV amplicons were sequenced and compared with published sequences. Antibody titres (IgG and IgM) to 12 HEV immunodominant regions were measured by enzyme-linked immunosorbent assays. RESULTS: In group 1 (control group), 15% of children were anti-HEV IgG-positive during follow-up. No anti-HEV IgM antibodies were detected in any of these children. After OLT, 86% of patients in group 2 had anti-HEV IgG compared with 36% pre-OLT. Thus, two-thirds of children acquired anti-HEV IgG after OLT. Seven anti-HEV IgG-positive patients (58%) were also anti-HEV IgM-positive more than once during follow-up after OLT. Eight years post-OLT, one girl presented with anti-HEV IgG and IgM that remained positive afterwards. In this patient, HEV RNA was found in five different annual samples from 10 years post-OLT, concomitantly with increased serum aminotransferases and cirrhosis development during that period. Phylogenetic analysis revealed two different HEV strains (detected 3 years apart) that were highly similar to swine genotype 3, suggesting a possible case of zoonotic re-infection. CONCLUSION: The diagnosis of HEV infection is technically challenging and should be made simultaneously with RT-PCR methods, viral load quantification and serological markers. In immunosuppressed children who develop chronic hepatitis, the prevalence of HEV is high and could explain the chronic liver inflammation potentially leading to cirrhosis. Re-infection by different HEV strains from zoonotic transmission can result in progressive liver disease in immunocompromised children.

Microvillous inclusion disease: how to improve the prognosis of a severe congenital enterocyte disorder.

BACKGROUND AND OBJECTIVE: Microvillous inclusion disease (MVID) is a rare congenital enterocyte disorder causing severe diarrhea and intestinal failure. The objective of this study was to analyze clinical evolution and the most frequent complications of MVID in children receiving parenteral nutrition (PN) and after small-bowel transplantation (SBTx) with the aim to improve treatment strategies and prognosis. PATIENTS AND METHODS: From 1995 to 2009, 24 patients (16 boys, median follow-up 4.7 years, range: from birth to 23.5 years) with MVID were admitted to our unit. The recorded parameters included growth, neurological development, liver and renal functions, bone disease, and outcome. RESULTS: Almost half of the children were from consanguineous families from the Mediterranean area. All of the patients completely depended on PN. Four children died of PN complications before 4 years of age. Before or without SBTx, growth failure was common (mean height -2.5 standard deviations [SD]), as was developmental delay (12/24), liver (20/22 with fibrosis) or kidney disease (3/23 with moderate renal insufficiency), and osteoporosis (6/24). Thirteen children underwent SBTx (9 isolated, 4 combined with liver Tx) at a median age of 3.5 years. Follow-up after SBTx was 0.4 to 14 years. Patient survival rates were 63% without SBTx and 77% with SBTx. After SBTx, 4 children experienced catch-up growth. CONCLUSIONS: PN in MVID is difficult to manage and requires expertise. Despite improved results in expert centers, the risk of death or irreversible sequelae is higher with PN than after Tx. SBTx, despite being complicated, remains the only hope to improve the quality of life and long-term prognosis of these children.

Rectal sensory threshold for pain is a diagnostic marker of irritable bowel syndrome and functional abdominal pain in children.

OBJECTIVE: To evaluate the diagnostic value of the rectal sensory threshold for pain (RSTP) in children and adolescents with chronic abdominal pain. STUDY DESIGN: Fifty-one patients (25 girls; median age 14.2 years; range 8.4-17.6) with abdominal pain >2 months underwent a series of rectal distensions with an electronic barostat. RSTP and viscerosomatic referrals were assessed. Three months after the barostat, the final diagnosis was documented. RESULTS: Thirty-five patients had a functional gastrointestinal disorder (FGID) (irritable bowel syndrome or functional abdominal pain), and 16 had an organic disease. RSTP was lower in the FGID group than in the organic disease group (25.4mm Hg vs 37.1mm Hg; P = .0002). At the cutoff of 30mm Hg, the RSTP measurement for the diagnosis of FGID had a sensitivity of 94% and a specificity of 77%. Both groups similarly reported aberrant viscerosomatic projections. CONCLUSION: In children, RSTP is a diagnostic marker of irritable bowel syndrome and functional abdominal pain. Viscerosomatic referrals are similar in children with FGID and organic diseases.