RESUMO
An important goal of clinical genomics is to be able to estimate the risk of adverse disease outcomes. Between 5% and 10% of individuals with ulcerative colitis (UC) require colectomy within 5 years of diagnosis, but polygenic risk scores (PRSs) utilizing findings from genome-wide association studies (GWASs) are unable to provide meaningful prediction of this adverse status. By contrast, in Crohn disease, gene expression profiling of GWAS-significant genes does provide some stratification of risk of progression to complicated disease in the form of a transcriptional risk score (TRS). Here, we demonstrate that a measured TRS based on bulk rectal gene expression in the PROTECT inception cohort study has a positive predictive value approaching 50% for colectomy. Single-cell profiling demonstrates that the genes are active in multiple diverse cell types from both the epithelial and immune compartments. Expression quantitative trait locus (QTL) analysis identifies genes with differential effects at baseline and week 52 follow-up, but for the most part, differential expression associated with colectomy risk is independent of local genetic regulation. Nevertheless, a predicted polygenic transcriptional risk score (PPTRS) derived by summation of transcriptome-wide association study (TWAS) effects identifies UC-affected individuals at 5-fold elevated risk of colectomy with data from the UK Biobank population cohort studies, independently replicated in an NIDDK-IBDGC dataset. Prediction of gene expression from relatively small transcriptome datasets can thus be used in conjunction with TWASs for stratification of risk of disease complications.
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Colectomia/estatística & dados numéricos , Colite Ulcerativa/cirurgia , Doença de Crohn/cirurgia , Locos de Características Quantitativas , Transcriptoma , Bancos de Espécimes Biológicos , Estudos de Coortes , Colite Ulcerativa/complicações , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/genética , Colo/metabolismo , Colo/patologia , Colo/cirurgia , Doença de Crohn/complicações , Doença de Crohn/diagnóstico , Doença de Crohn/genética , Conjuntos de Dados como Assunto , Progressão da Doença , Perfilação da Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Herança Multifatorial , Prognóstico , Medição de Risco , Reino UnidoRESUMO
OBJECTIVES: No study has explored whether availability of endoscopic retrograde cholangiopancreatography (ERCP) is adequate and equitable across US children's hospitals. We hypothesized that ERCP availability and utilization differs by geography and patient factors. METHODS: Healthcare encounter data from 2009 to 2019 on children with pancreatic and biliary diseases from the Pediatric Health Information System were analyzed. ERCP availability was defined as treatment at a hospital that performed pediatric ERCP during the year of service. RESULTS: From 2009 to 2019, 37,946 children (88,420 encounters) had a potential pancreatic or biliary indication for ERCP; 7066 ERCPs were performed. The commonest pancreatic diagnoses leading to ERCP were chronic (47.2%) and acute pancreatitis (43.2%); biliary diagnoses were calculus (68.3%) and obstruction (14.8%). No ERCP was available for 25.0% of pancreatic encounters and 8.1% of biliary encounters. In multivariable analysis, children with public insurance, rural residence, or of Black race were less likely to have pancreatic ERCP availability; those with rural residence or Asian race were less likely to have biliary ERCP availability. Black children or those with public insurance were less likely to undergo pancreatic ERCP where available. Among encounters for calculus or obstruction, those of Black race or admitted to hospitals in the West were less likely to undergo ERCP when available. CONCLUSIONS: One-in-four children with pancreatic disorders and one-in-12 with biliary disorders may have limited access to ERCP. We identified racial and geographic disparities in availability and utilization of ERCP. Further studies are needed to understand these differences to ensure equitable care.
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Colangiopancreatografia Retrógrada Endoscópica , Acessibilidade aos Serviços de Saúde , Hospitais Pediátricos , Humanos , Colangiopancreatografia Retrógrada Endoscópica/estatística & dados numéricos , Criança , Hospitais Pediátricos/estatística & dados numéricos , Masculino , Feminino , Estados Unidos , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Pré-Escolar , Adolescente , Lactente , Pancreatopatias/terapia , Pancreatopatias/cirurgia , Disparidades em Assistência à Saúde/estatística & dados numéricos , Doenças Biliares/terapia , Estudos RetrospectivosRESUMO
OBJECTIVES: Vedolizumab (VDZ) and ustekinumab (UST) are second-line treatments in pediatric patients with ulcerative colitis (UC) refractory to antitumor necrosis factor (anti-TNF) therapy. Pediatric studies comparing the effectiveness of these medications are lacking. Using a registry from ImproveCareNow (ICN), a global research network in pediatric inflammatory bowel disease, we compared the effectiveness of UST and VDZ in anti-TNF refractory UC. METHODS: We performed a propensity-score weighted regression analysis to compare corticosteroid-free clinical remission (CFCR) at 6 months from starting second-line therapy. Sensitivity analyses tested the robustness of our findings to different ways of handling missing outcome data. Secondary analyses evaluated alternative proxies of response and infection risk. RESULTS: Our cohort included 262 patients on VDZ and 74 patients on UST. At baseline, the two groups differed on their mean pediatric UC activity index (PUCAI) (p = 0.03) but were otherwise similar. At Month 6, 28.3% of patients on VDZ and 25.8% of those on UST achieved CFCR (p = 0.76). Our primary model showed no difference in CFCR (odds ratio: 0.81; 95% confidence interval [CI]: 0.41-1.59) (p = 0.54). The time to biologic discontinuation was similar in both groups (hazard ratio: 1.26; 95% CI: 0.76-2.08) (p = 0.36), with the reference group being VDZ, and we found no differences in clinical response, growth parameters, hospitalizations, surgeries, infections, or malignancy risk. Sensitivity analyses supported these findings of similar effectiveness. CONCLUSIONS: UST and VDZ are similarly effective for inducing clinical remission in anti-TNF refractory UC in pediatric patients. Providers should consider safety, tolerability, cost, and comorbidities when deciding between these therapies.
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Anticorpos Monoclonais Humanizados , Colite Ulcerativa , Fármacos Gastrointestinais , Ustekinumab , Humanos , Colite Ulcerativa/tratamento farmacológico , Ustekinumab/uso terapêutico , Feminino , Masculino , Criança , Anticorpos Monoclonais Humanizados/uso terapêutico , Adolescente , Fármacos Gastrointestinais/uso terapêutico , Resultado do Tratamento , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Indução de Remissão/métodos , Pontuação de Propensão , Sistema de RegistrosRESUMO
BACKGROUND: Pouchitis is the most frequent complication following restorative proctocolectomy and ileal pouch anal anastomosis (RP-IPAA) in patients with Ulcerative colitis (UC). Pediatric data on nutritional status during RP-IPAA and in patients with pouchitis are limited. AIMS: We aimed to delineate nutritional changes in children undergoing 2-stage and 3-stage surgeries and to evaluate the association between nutrition and the development of recurrent or chronic pouchitis. METHODS: This single-center retrospective study involved 46 children with UC who underwent a RP-IPAA. Data were collected at each surgical stage and for up to 2-year post-ileostomy takedown. We used Wilcoxon matched-pairs signed-rank test to evaluate the differences in nutritional markers across surgical stages and logistic regression to identify the factors associated with recurrent or chronic pouchitis. RESULTS: Twenty patients (43.5%) developed recurrent or chronic pouchitis. Children who underwent a 3-stage procedure had improvements in albumin, hematocrit, and body mass index (BMI)-for-age Z-scores (p < 0.01) between the first two stages. A positive trend in BMI-for-age Z-scores (p = 0.08) was identified in children with 2-stage procedures. All patients showed sustained nutritional improvement during the follow-up period. Among patients who underwent 3-stage surgeries, BMI worsened by 0.8 standard deviations (SDs) (p = 0.24) between the initial stages in those who developed recurrent or chronic pouchitis and improved by 1.1 SDs (p = 0.04) in those who did not. CONCLUSIONS: Early improvement in BMI-for-age Z-scores following the initial stage was associated with lower rates of recurrent or chronic pouchitis. Larger prospective studies are needed to validate these findings.
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Colite Ulcerativa , Pouchite , Proctocolectomia Restauradora , Humanos , Criança , Pouchite/etiologia , Colite Ulcerativa/cirurgia , Colite Ulcerativa/complicações , Estudos Retrospectivos , Estado Nutricional , Proctocolectomia Restauradora/efeitos adversos , Colectomia/efeitos adversosRESUMO
OBJECTIVES: Known as pediatric medical traumatic stress (PMTS), posttraumatic stress symptoms from medical experiences have not been explored in children with chronic gastrointestinal diseases. This cross-sectional study of children and adolescents with inflammatory bowel disease, chronic pancreatitis and cystic fibrosis, aimed to (1) estimate the prevalence of medical potentially traumatic events (PTEs) and PMTS, (2) explore potential risk factors for PMTS, and (3) explore potential consequences of PMTS. METHODS: This cross-sectional study used validated, self-report measures to evaluate PTEs and PMTS. Descriptive statistics and regression analyses were used to achieve study objectives. RESULTS: Over two-thirds of children reported a medical potentially traumatic event (91 of 132, 69%). Forty-eight had PMTS symptoms (36%). PMTS was associated with medication burden, emergency and intensive care visits, and parent posttraumatic stress disorder in multivariate analysis. Potential consequences associated with PMTS included school absenteeism, home opioid use, poor quality of life, and parent missed work. CONCLUSIONS: A substantial portion of our cohort reported medical PTEs and PMTS. The exploratory analysis identified potential associations between PMTS and illness factors, parent posttraumatic stress disorder, and functional impairments. Further studies of PMTS detection, prevention and treatment are integral to optimizing these children's health and quality of life.
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Fibrose Cística , Doenças Inflamatórias Intestinais , Pancreatite , Adolescente , Analgésicos Opioides , Criança , Doença Crônica , Estudos Transversais , Fibrose Cística/complicações , Humanos , Doenças Inflamatórias Intestinais/complicações , Pancreatite/epidemiologia , Pancreatite/etiologia , Qualidade de VidaRESUMO
OBJECTIVES: Abdominal pain, emergency department visits, and hospitalizations impact lives of children with acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP). Data on health-related quality of life (HRQOL) in this population, however, remains limited. We aimed to evaluate HRQOL in children with ARP or CP; and test biopsychosocial risk factors associated with low HRQOL. METHODS: Data were acquired from the INternational Study Group of Pediatric Pancreatitis: In search for a cuRE registry. Baseline demographic and clinical questionnaires, the Child Health Questionnaire (measures HRQOL) and Child Behavior Checklist (measures emotional and behavioral functioning) were completed at enrollment. RESULTS: The sample included 368 children (54.3% girls, mean ageâ=â12.7years, standard deviation [SD]â=â3.3); 65.2% had ARP and 34.8% with CP. Low physical HRQOL (Mâ=â38.5, SDâ=â16.0) was demonstrated while psychosocial HRQOL (Mâ=â49.5, SDâ=â10.2) was in the normative range. Multivariate regression analysis revealed that clinical levels of emotional and behavioral problems (Bâ=â-10.28, Pâ <â0.001), episodic and constant abdominal pain (Bâ=â04.66, Pâ=â0.03; Bâ=â-13.25, Pâ<â0.001) were associated with low physical HRQOL, after accounting for ARP/CP status, age, sex, exocrine, and endocrine disease (F [9, 271]â=â8.34, Pâ<â0.001). Borderline and clinical levels of emotional and behavioral problems (Bâ=â-10.18, Pâ<â0.001; Bâ=â-15.98, Pâ<â0.001), and constant pain (Bâ=â-4.46, Pâ<â0.001) were associated with low psychosocial HRQOL (F [9, 271]â=â17.18, Pâ<â0.001). CONCLUSIONS: Findings highlight the importance of assessing HRQOL and treating pain and psychosocial problems in this vulnerable group of children.
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Pancreatite Crônica , Qualidade de Vida , Dor Abdominal/complicações , Criança , Feminino , Humanos , Masculino , Pancreatite Crônica/complicações , Pancreatite Crônica/terapia , Recidiva , Fatores de RiscoRESUMO
BACKGROUND: Research on the utilization and effectiveness of antitumor necrosis factor (TNF) biologics in children with very early onset inflammatory bowel disease (VEOIBD) is urgently needed. Here we describe anti-TNF use and durability in a multicenter cohort. METHODS: We performed a retrospective cohort study of patients diagnosed with VEOIBD (<6 years) between 2008 and 2013 at 25 North American centers. We performed chart abstraction at diagnosis and 1, 3, and 5 years after diagnosis. We examined the rate of initiation and durability of infliximab and adalimumab and evaluated associations between treatment durability and the following covariates with multivariate Cox proportional hazard regression: age at diagnosis, sex, disease duration, disease classification, and presence of combined immunomodulatory treatment versus monotherapy. RESULTS: Of 294 children with VEOIBD, 120 initiated treatment with anti-TNF therapy and 101 had follow-up data recorded [50% Crohn disease (CD), 31% ulcerative colitis (UC), and 19% IBD unclassified (IBD-U)]. The cumulative probability of anti-TNF treatment was 15% at 1 year, 30% at 3 years, and 45% at 5 years from diagnosis; 56 (55%) were treated between 0 and 6 years old. Anti-TNF durability was 90% at 1 year, 75% at 3 years, and 55% at 5 years. The most common reason for discontinuation of anti-TNF were loss of response in 24 (57%) children. Children with UC/IBD-U had lower durability than those with CD (hazard ratio [HR] 0.17; 95% confidence interval [CI], 0.06-0.51; P = 0.001). CONCLUSIONS: Utilization and durability of anti-TNF in VEOIBD is relatively high and comparable with older children. Having Crohn disease (compared with UC/IBD-U) is associated with greater durability.
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Produtos Biológicos , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Adalimumab/uso terapêutico , Adolescente , Produtos Biológicos/uso terapêutico , Criança , Pré-Escolar , Estudos de Coortes , Colite Ulcerativa/tratamento farmacológico , Doença de Crohn/tratamento farmacológico , Humanos , Lactente , Recém-Nascido , Doenças Inflamatórias Intestinais/tratamento farmacológico , Infliximab/uso terapêutico , Necrose , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral , Fator de Necrose Tumoral alfaRESUMO
OBJECTIVE: To assess whether early modifiable dietary factors and obesity measures are associated with leukocyte telomere length at 3-5 years of age after controlling for the heritability of leukocyte telomere length in a prospective cohort of low-income Latina mothers and their children in San Francisco. STUDY DESIGN: We analyzed data from the Latinx, Eating and Diabetes cohort, a prospective study of 97 woman-infant dyads. We used linear regression models to evaluate associations between early dietary factors and obesity measures and child leukocyte telomere length at 3-5 years of age. Multivariable models included child age at the time of telomere collection, breastfeeding at 6 months (yes/no), obesity at 6 months, maternal education, child sex, and maternal and paternal leukocyte telomere length. RESULTS: Data for 73 of the 97 children at 3-5 years of age were analyzed. Any breastfeeding at 6 months was positively associated (ß = 0.14; P = .02) and obesity at 6 months was negatively associated (ß = -0.21; P < .001) with leukocyte telomere length in bivariate analyses. In multivariable models including parental leukocyte telomere length, obesity at 6 months was associated with a shorter leukocyte telomere length at 3-5 years of age (ß = -0.15; P = .02). Analyses of dietary factors showed high flavored milk consumption at 3 years of age was associated with shorter leukocyte telomere length after adjustment for possible confounders. CONCLUSIONS: In a low-income Latinx population, obesity at 6 months of age is negatively associated with cellular health at 3-5 years of age after controlling for genetic factors (parental leukocyte telomere length) associated with leukocyte telomere length. Early life obesity may be more deleterious for cellular health than obesity later in childhood.
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Hispânico ou Latino , Obesidade Infantil/genética , Encurtamento do Telômero , Aleitamento Materno , Pré-Escolar , Estudos de Coortes , Feminino , Humanos , Lactente , Leucócitos/fisiologia , Modelos Lineares , Masculino , Obesidade Infantil/epidemiologia , São Francisco/epidemiologia , Bebidas Adoçadas com AçúcarRESUMO
The COVID-19 pandemic will leave an indelible mark on the careers of current medical trainees. Given the disruptions to medical education, economic impact on institutions, and the uncertainties around future job prospects, trainees are facing unprecedented challenges. This situation is especially concerning for futures of pediatric physician-scientist trainees, where concerns regarding maintaining the pipeline were well documented prior to the emergence of COVID-19. In this Perspectives article, we leverage the unique expertise of our workgroup to address concerns of physician-scientist trainees and to provide suggestions on how to navigate career trajectories in the post-COVID-19 era. We identified and addressed four major areas of concern: lack of in-person conferences and the associated decrease access to mentors and networking activities, decreased academic productivity, diminished job prospects, and mental health challenges. We also suggest actions for trainees, mentors and educational leaders, and institutions to help support trainees during the pandemic, with a goal of maintaining the pediatric physician-scientist pipeline.
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Pesquisa Biomédica/educação , COVID-19 , Educação de Pós-Graduação em Medicina , Mentores , Pediatras/educação , Pediatria/educação , Mobilidade Ocupacional , Eficiência , Humanos , Relações Interpessoais , Saúde Mental , Pediatras/psicologia , Sociedades MédicasRESUMO
OBJECTIVE: Given the importance of scholarly work in academic medicine, better understanding of the manuscript review process (MRP) is useful for authors, reviewers, and editorial boards. We aim to describe the MRP at the Journal of Pediatric Gastroenterology and Nutrition (JPGN), assess the correlation between editor decisions and reviewer recommendations, and provide transparency to this process. METHODS: All manuscripts submitted in 2018 to JPGN were included in this analysis. Data included reviewers' manuscript scores and recommendations, time spent on each review by reviewers, the editor's rating of the reviewers' reviews, the editor's first decision, and final outcome. Data were collated using the JPGN manuscript submission website, Editorial Manager. RESULTS: 1023 manuscripts were submitted to JPGN in 2018 and included in this analysis. Of these, 486 manuscripts had at least two peer reviewers. The recommendations of the two reviewers were in agreement 43% of the time. Intra-class correlation (ICC) between the two reviewers suggests moderate agreement (ICCâ=â0.40). When both reviewers agreed to Not Reject (289/486), the editor agreed in 93% of cases (269/289). When both reviewers agreed to Reject (55/486), the editor agreed 100% of the time (55/55). The reviewers disagreed in about one-third of submissions (142/486), and the editor recommended to Reject in two-thirds of these cases (95/142). Overall, inter-reviewer agreement strongly correlated with the editor's initial decision (Pâ<â0.001). CONCLUSIONS: The editor most often agreed with reviewers' assessments when there was concordance between the two reviewers' recommendations. About a third of peer reviews result in discordant recommendations between the two reviewers.
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Gastroenterologia , Revisão da Pesquisa por Pares , Criança , Humanos , Estado NutricionalRESUMO
ABSTRACT: Transgender and gender nonconforming (TGNC) individuals have a different gender identity than the sex they were assigned at birth. Despite an increase in provider awareness of TGNC health over the past decade, no original research or societal guidelines exist on TGNC patients with inflammatory bowel disease (IBD). We review TGNC IBD cases in the University of California, San Francisco (UCSF) Pediatric IBD Program and in the literature. We then provide some recommendations for the provision of high-quality care to the TGNC IBD population, divided into 3 categories: medications, anatomy, and mental health.
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Doenças Inflamatórias Intestinais , Pessoas Transgênero , Adolescente , Feminino , Identidade de Gênero , Humanos , Doenças Inflamatórias Intestinais/terapia , Masculino , Adulto JovemRESUMO
INTRODUCTION: Ustekinumab (UST), a human monoclonal antibody against interleukin-12 and 23, is approved to treat adult patients with psoriasis or Crohn disease (CD). Outcomes data for off-label use in pediatric patients with CD are limited. AIM: We conducted a retrospective cohort study to analyze the long-term efficacy of UST, including dose adjustments, in the treatment of pediatric patients with medically refractory CD. Adverse events were documented. METHODS: We identified 40 pediatric patients with CD treated with UST between January 1, 2016 and December 31, 2019. Electronic medical records were reviewed for demographics, Paris Classification, significant comorbidities, previous CD therapy, adverse events after initiation, and surveillance markers at the time of their first dose and most recent clinic visit. A validated abbreviated pediatric CD activity index (aPCDAI) was used to assess response to therapy. RESULTS: Thirty-eight pediatric patients with CD, including 34.2% with stricturing or penetrating disease, were analyzed after initiation of treatment with UST. Median age at diagnosis of CD was 12.5âyears, and median age at UST induction was 17.2âyears. No patients were anti-TNF-naive, and 34.2% were previously exposed to 2 or more anti-TNF agents. At time of last follow-up, 84.2% of patients remained on UST for a median duration on UST of 62.1âweeks, and 60.5% achieved clinical remission. Patients had significant improvement in aPCDAI scores, clinical remission rates, albumin, and hematocrit, and 89.5% of patients had no significant adverse events. Similar results were observed among those who required dose adjustment, including 61.1% achieving clinical remission, and among those with perianal disease, including 38.5% achieving clinical remission. CONCLUSIONS: Our data suggest that, within our cohort of pediatric patients with CD, UST has long-term efficacy with no observed safety concerns. Dose adjustment may be helpful in achieving clinical remission.
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Doença de Crohn , Ustekinumab , Adulto , Anticorpos Monoclonais , Criança , Doença de Crohn/tratamento farmacológico , Humanos , Estudos Retrospectivos , Inibidores do Fator de Necrose Tumoral , Ustekinumab/uso terapêuticoRESUMO
INTRODUCTION: The optimal trial design for assessing novel therapies in paediatric IBD (PIBD) is a subject of intense ongoing global discussions and debate among the different stakeholders. However, there is a consensus that the current situation in which most medications used in children with IBD are prescribed as off-label without sufficient paediatric data is unacceptable. Shortening the time lag between adult and paediatric approval of drugs is of the upmost importance. In this position paper we aimed to provide guidance from the global clinical research network (Pediatric Inflammatory Bowel Disease Network, PIBDnet) for designing clinical trials in PIBD in order to facilitate drug approval for children. METHODS: A writing group has been established by PIBDnet and topics were assigned to different members. After an iterative process of revisions among the writing group and one face-to-face meeting, all statements have reached consensus of >80% as defined a priori. Next, all core members of PIBDnet voted on the statements, reaching consensus of >80% on all statements. Comments from the members were incorporated in the text. RESULTS: The commentary includes 18 statements for guiding data extrapolation from adults, eligibility criteria to PIBD trials, use of placebo, dosing, endpoints and recommendations for feasible trials. Controversial issues have been highlighted in the text. CONCLUSION: The viewpoints expressed in this paper could assist planning clinical trials in PIBD which are both of high quality and ethical, while remaining pragmatic.
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Ensaios Clínicos como Assunto/métodos , Fármacos Gastrointestinais/uso terapêutico , Doenças Inflamatórias Intestinais/tratamento farmacológico , Fatores Etários , Produtos Biológicos/administração & dosagem , Produtos Biológicos/uso terapêutico , Criança , Ensaios Clínicos como Assunto/normas , Relação Dose-Resposta a Droga , Aprovação de Drogas/métodos , Fármacos Gastrointestinais/administração & dosagem , Humanos , Seleção de Pacientes , Projetos de Pesquisa , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: Crohn's disease is a relapsing and remitting inflammatory disorder with a variable clinical course. Although most patients present with an inflammatory phenotype (B1), approximately 20% of patients rapidly progress to complicated disease, which includes stricturing (B2), within 5 years. We analyzed DNA methylation patterns in blood samples of pediatric patients with Crohn's disease at diagnosis and later time points to identify changes that associate with and might contribute to disease development and progression. METHODS: We obtained blood samples from 164 pediatric patients (1-17 years old) with Crohn's disease (B1 or B2) who participated in a North American study and were followed for 5 years. Participants without intestinal inflammation or symptoms served as controls (n = 74). DNA methylation patterns were analyzed in samples collected at time of diagnosis and 1-3 years later at approximately 850,000 sites. We used genetic association and the concept of Mendelian randomization to identify changes in DNA methylation patterns that might contribute to the development of or result from Crohn's disease. RESULTS: We identified 1189 5'-cytosine-phosphate-guanosine-3' (CpG) sites that were differentially methylated between patients with Crohn's disease (at diagnosis) and controls. Methylation changes at these sites correlated with plasma levels of C-reactive protein. A comparison of methylation profiles of DNA collected at diagnosis of Crohn's disease vs during the follow-up period showed that, during treatment, alterations identified in methylation profiles at the time of diagnosis of Crohn's disease more closely resembled patterns observed in controls, irrespective of disease progression to B2. We identified methylation changes at 3 CpG sites that might contribute to the development of Crohn's disease. Most CpG methylation changes associated with Crohn's disease disappeared with treatment of inflammation and might be a result of Crohn's disease. CONCLUSIONS: Methylation patterns observed in blood samples from patients with Crohn's disease accompany acute inflammation; with treatment, these change to resemble methylation patterns observed in patients without intestinal inflammation. These findings indicate that Crohn's disease-associated patterns of DNA methylation observed in blood samples are a result of the inflammatory features of the disease and are less likely to contribute to disease development or progression.
Assuntos
Doença de Crohn/genética , Metilação de DNA/genética , Regulação da Expressão Gênica/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana/métodos , Adolescente , Fatores Etários , Estudos de Casos e Controles , Criança , Pré-Escolar , Doença de Crohn/sangue , Progressão da Doença , Feminino , Seguimentos , Genótipo , Humanos , Lactente , Inflamação/genética , Masculino , América do Norte , Medição de Risco , Índice de Gravidade de Doença , Fatores SexuaisRESUMO
OBJECTIVES: The aim of this study was to assess common laboratory tests in identifying severe ulcerative colitis in children at diagnosis. METHODS: A cohort of 427 children 4 to 17 years of age newly diagnosed with ulcerative colitis (UC) was prospectively enrolled. Boosted classification trees were used to characterize predictive ability of disease attributes based on clinical disease severity using Pediatric Ulcerative Colitis Activity Index (PUCAI), severe (65+) versus not severe (<65) and total Mayo score, severe (10-12) versus not severe (<10); mucosal disease by Mayo endoscopic subscore, severe (3) versus not severe (<3); and extensive disease versus not extensive (left-sided and proctosigmoiditis). RESULTS: Mean age was 12.7 years; 49.6% (nâ=â212) were girls, and 83% (nâ=â351) were Caucasian. Severe total Mayo score was present in 28% (nâ=â120), mean PUCAI score was 49.8â±â20.1, and 33% (nâ=â142) had severe mucosal disease with extensive involvement in 82% (nâ=â353). Classification and regression trees identified white blood cell count, erythrocyte sedimentation rate, and platelet count (PLT) as the set of 3 best blood laboratory tests to predict disease extent and severity. For mucosal severity, albumin (Alb) replaced PLT. Classification models for PUCAI and total Mayo provided sensitivity of at least 0.65 using standard clinical cut-points with misclassification rates of approximately 30%. CONCLUSIONS: A combination of the white blood cell count, erythrocyte sedimentation rate, and either PLT or albumin is the best predictive subset of standard laboratory tests to identify severe from nonsevere clinical or mucosal disease at diagnosis in relation to objective clinical scores.
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Colite Ulcerativa , Sedimentação Sanguínea , Criança , Colite Ulcerativa/diagnóstico , Colonoscopia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: The aim of the study was to determine whether clinical characteristics and management of pediatric acute recurrent pancreatitis (ARP) and chronic pancreatitis (CP) differ across INSPPIRE (INternational Study Group of Pediatric Pancreatitis: In Search for a cuRE) sites. STUDY DESIGN: Data were collected from INSPPIRE and analyzed per US regions and "non-US" sites. Between-group differences were compared by Pearson chi-square test. Differences in disease burden were compared by Kruskal-Wallis test. RESULTS: Out of the 479 subjects, 121 (25%) were enrolled in West, 151 (32%) Midwest, 45 Northeast (9%), 78 (16%) South, and 84 (18%) at non-US sites. Hispanic ethnicity was more common in South (Pâ<â0.0001); white race in Northeast (Pâ=â0.009). CP was less common and time from diagnosis of first acute pancreatitis to CP was longer in children at non-US sites (Pâ=â0.0002 and Pâ=â0.011, respectively). Genetic mutations were most common among all groups; PRSS1 variants predominated in Midwest (Pâ=â0.002). Gallstones were more frequent in South (Pâ=â0.002). Endoscopic retrograde cholangiopancreatography (ERCP) and computed tomography (CT) imaging were more commonly utilized in United States compared with non-United States (Pâ<â0.0001), but there were no differences in the use of MRI/MRCP. Disease burden was highest in the West and Midwest, possibly as total pancreatectomy and islet autotransplantation (TPIAT) referral sites were located in these regions. All therapies were less commonly administered in non-US sites (Pâ<â0.0001). CONCLUSIONS: This is the first study to describe geographical variations in the INSPPIRE cohort, which possibly reflect variations in practice and referral patterns. The underlying reason behind the lower frequency of CP and fewer treatments in non-United States sites need to be further explored.
Assuntos
Pancreatite Crônica , Doença Aguda , Criança , Colangiopancreatografia Retrógrada Endoscópica , Humanos , Pancreatite Crônica/diagnóstico , Pancreatite Crônica/epidemiologia , Pancreatite Crônica/terapia , RecidivaRESUMO
OBJECTIVES: The aim of the study was to understand the association of frequent opioid use with disease phenotype and pain pattern and burden in children and adolescents with acute recurrent (ARP) or chronic pancreatitis (CP). METHODS: Cross-sectional study of children <19 years with ARP or CP, at enrollment into the INSPPIRE cohort. We categorized patients as opioid "frequent use" (daily/weekly) or "nonfrequent use" (monthly or less, or no opioids), based on patient and parent self-report. RESULTS: Of 427 children with ARP or CP, 17% reported frequent opioid use. More children with CP (65%) reported frequent opioid use than with ARP (41%, Pâ=â0.0002). In multivariate analysis, frequent opioid use was associated with older age at diagnosis (odds ratio [OR] 1.67 per 5 years, 95% confidence interval [CI] 1.13-2.47, Pâ=â0.01), exocrine insufficiency (OR 2.44, 95% CI 1.13-5.24, Pâ=â0.02), constant/severe pain (OR 4.14, 95% CI 2.06-8.34, Pâ<â0.0001), and higher average pain impact score across all 6 functional domains (OR 1.62 per 1-point increase, 95% CI 1.28-2.06, Pâ<â0.0001). Children with frequent opioid use also reported more missed school days, hospitalizations, and emergency room visits in the past year than children with no frequent use (Pâ<â0.0002 for each). Participants in the US West and Midwest accounted for 83% of frequent opioid users but only 56% of the total cohort. CONCLUSIONS: In children with CP or ARP, frequent opioid use is associated with constant pain, more healthcare use, and higher levels of pain interference with functioning. Longitudinal and prospective research is needed to identify risk factors for frequent opioid use and to evaluate nonopioid interventions for reducing pain and disability in these children.
Assuntos
Dor Abdominal/tratamento farmacológico , Analgésicos Opioides/uso terapêutico , Manejo da Dor/estatística & dados numéricos , Pancreatite/complicações , Aceitação pelo Paciente de Cuidados de Saúde/estatística & dados numéricos , Dor Abdominal/etiologia , Doença Aguda , Adolescente , Criança , Doença Crônica , Estudos Transversais , Serviço Hospitalar de Emergência/estatística & dados numéricos , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Razão de Chances , Fenótipo , RecidivaRESUMO
In the United States, approximately 5% of individuals with inflammatory bowel disease (IBD) are younger than 20 years old. Studies of pediatric cohorts can provide unique insights into genetic architecture of IBD, which includes Crohn's disease (CD) and ulcerative colitis (UC). Large genome-wide association studies have found more than 200 IBD-associated loci but explain a minority of disease variance for CD and UC. We sought to characterize the contribution of rare variants to disease development, comparing exome sequencing of 368 pediatric IBD patients to publicly available exome sequencing (dbGaP) and aggregate frequency data (ExAC). Using dbGaP data, we performed logistic regression for common variants and optimal unified association tests (SKAT-O) for rare, likely-deleterious variants. We further compared rare variants to ExAC counts with Fisher's exact tests. We did pathway enrichment analysis on the most significant genes from each comparison. Many variants overlapped with known IBD-associated genes (e.g. NOD2). Rare variants were enriched in CD-associated loci (p = 0.009) and showed suggestive enrichment in neutrophil function genes (p = 0.05). Pathway enrichment implicated immune-related pathways, especially cell killing and apoptosis. Variants in extracellular matrix genes also emerged as an important theme in our analysis.
Assuntos
Doenças Inflamatórias Intestinais/genética , Polimorfismo Genético , Adolescente , Criança , Pré-Escolar , Feminino , Estudo de Associação Genômica Ampla , Humanos , Lactente , Masculino , Sequenciamento do ExomaRESUMO
BACKGROUND & AIMS: Individuals with monogenic disorders of phagocyte function develop chronic colitis that resembles Crohn's disease (CD). We tested for associations between mutations in genes encoding reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidases, neutrophil function, and phenotypes of CD in pediatric patients. METHODS: We performed whole-exome sequence analysis to identify mutations in genes encoding NADPH oxidases (such as CYBA, CYBB, NCF1, NCF2, NCF4, RAC1, and RAC2) using DNA from 543 pediatric patients with inflammatory bowel diseases. Blood samples were collected from an additional 129 pediatric patients with CD and 26 children without IBD (controls); we performed assays for neutrophil activation, reactive oxygen species (ROS) production, and bacteria uptake and killing. Whole-exome sequence analysis was performed using DNA from 46 of the children with CD to examine associations with NADPH gene mutations; RNA sequence analyses were performed using blood cells from 46 children with CD to test for variations in neutrophil gene expression associated with ROS production. RESULTS: We identified 26 missense mutations in CYBA, CYBB, NCF1, NCF2, and NCF4. Patients with CD who carried mutations in these genes were 3-fold more likely to have perianal disease (P = .0008) and stricturing complications (P = .002) than children with CD without these mutations. Among patients with CD with none of these mutations, 9% had undergone abdominal surgery; among patients with mutations in these NADPH oxidase genes, 31% had undergone abdominal surgery (P = .0004). A higher proportion of neutrophils from children with CD had low ROS production (47%) than from controls (15%) among the 129 patients tested for ROS (P = .002). Minor alleles of the NADPH genes were detected in 7% of children with CD whose neutrophils produced normal levels of ROS vs 38% of children whose neutrophils produced low levels of ROS (P = .009). Neutrophils that produced low levels of ROS had specific alterations in genes that regulate glucose metabolism and antimicrobial responses. CONCLUSIONS: We identified missense mutations in genes that encode NADPH oxidases in children with CD; these were associated with a more aggressive disease course and reduced ROS production by neutrophils from the patients.
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Doença de Crohn/genética , NADPH Oxidases/genética , Neutrófilos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Adolescente , Alelos , Criança , Pré-Escolar , Estudos de Coortes , Doença de Crohn/sangue , Doença de Crohn/metabolismo , Regulação para Baixo , Feminino , Perfilação da Expressão Gênica , Glucose/metabolismo , Humanos , Lactente , Masculino , Mutação de Sentido Incorreto , Fenótipo , Análise de Sequência de RNA , Regulação para Cima , Sequenciamento do ExomaRESUMO
INTRODUCTION: The significance of pancreas divisum (PD) as a risk factor for pancreatitis is controversial. We analyzed the characteristics of children with PD associated with acute recurrent or chronic pancreatitis to better understand its impact. PATIENTS AND METHODS: We compared children with or without PD in the well-phenotyped INSPPIRE (INternational Study group of Pediatric Pancreatitis: In search for a cuRE) cohort. Differences were analyzed using 2-sample t test or Wilcoxon rank sum test for continuous variables, Pearson χ or Fisher exact test for categorical variables. RESULTS: PD was found in 52 of 359 (14.5%) subjects, a higher prevalence than the general population (â¼7%). Females more commonly had PD (71% vs. 55%; P=0.02). Children with PD did not have a higher incidence of mutations in SPINK1, CFTR, CTRC compared with children with no PD. Children with PD were less likely to have PRSS1 mutations (10% vs. 34%; P<0.01) or a family history of pancreatitis (P<0.05), and more likely to have hypertriglyceridemia (11% vs. 3%; P=0.03). Children with PD underwent significantly more endoscopic procedures and pancreatic sphincterotomy. Patients with PD had fewer attacks of acute pancreatitis (P=0.03) and were less likely to develop exocrine pancreatic insufficiency (P=0.01). Therapeutic endoscopic retrograde cholangiopancreatography was considered most helpful if pancreatic duct was impacted with stones (83% helpful). CONCLUSIONS: PD is likely a risk factor for acute recurrent pancreatitis and chronic pancreatitis in children that appears to act independently of genetic risk factors. Patients with PD and stones obstructing the pancreatic duct benefit most from therapeutic endoscopic retrograde cholangiopancreatography.