RESUMO
BACKGROUND & AIMS: Pediatric functional constipation (PFC) is a common problem in children that causes distress and presents treatment challenges to health care professionals. We conducted a randomized, placebo-controlled trial (study 1) in patients with PFC (6-17 years of age) to evaluate the efficacy and safety of lubiprostone, followed by an open-label extension for those who completed the placebo-controlled phase (study 2). METHODS: Study 1 (NCT02042183) was a phase 3, multicenter, randomized, double-blind, placebo-controlled, 12-week study evaluating the efficacy and safety of lubiprostone 12 µg twice daily (BID) and 24 µg BID. Study 2 (NCT02138136) was a phase 3, long-term, open-label extension of study 1. In both studies, lubiprostone doses were based on patients' weight. Efficacy was assessed solely based on study 1, with a primary endpoint of overall spontaneous bowel movement (SBM) response (increase of ≥1 SBM/wk vs baseline and ≥3 SBMs/wk for ≥9 weeks, including 3 of the final 4 weeks). RESULTS: 606 patients were randomized to treatment (placebo: n = 202; lubiprostone: n = 404) in study 1. No statistically significant difference in overall SBM response rate was observed between the lubiprostone and placebo groups (18.5% vs 14.4%; P = .2245). Both the 12-µg BID and 24-µg BID doses of lubiprostone were well tolerated in the double-blind and extension phases, with a safety profile consistent with that seen in adult studies. CONCLUSIONS: Lubiprostone did not demonstrate statistically significant effectiveness over placebo in children and adolescents with PFC but did demonstrate a safety profile similar to that in adults. (ClinicalTrials.gov: Number: NCT02042183; Number: NCT02138136).
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Constipação Intestinal , Defecação , Adolescente , Adulto , Criança , Constipação Intestinal/tratamento farmacológico , Método Duplo-Cego , Pessoal de Saúde , Humanos , Lubiprostona/uso terapêutico , Resultado do TratamentoRESUMO
Eosinophilic esophagitis (EoE) is a chronic, immune-mediated condition that is becoming more widely recognized in children. Recent EoE practice guidelines provide clear recommendations on adequate biopsy sampling at diagnostic endoscopy and necessity of close follow-up endoscopy with biopsy to ensure mucosal healing with therapy.1 Despite these recommendations, adherence to biopsy guidelines, time to first follow-up endoscopy, and overall surveillance endoscopy rates have not been robustly studied. Using a population-based cohort of children diagnosed with EoE in Utah, we assessed adherence to guidelines across multiple provider types, including academic pediatric gastroenterologists (PGIs), private practice PGIs, and adult-trained providers performing endoscopy in children.
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Esofagite Eosinofílica , Adulto , Biópsia , Criança , Estudos de Coortes , Endoscopia , Esofagite Eosinofílica/diagnóstico , Seguimentos , HumanosRESUMO
BACKGROUND & AIMS: Eosinophilic esophagitis (EoE) is often detected in children and is considered to be a rare disease, with prevalence values reported to be below 60 cases per 100,000 persons. To determine whether the incidence of EoE in children in Utah exceeds estimates from regional reports, we calculated incidence and prevalence values over a 5-year period. METHODS: Using consensus guidelines for the diagnosis of EoE, we reviewed pathology records from the Intermountain Healthcare pathology database, from July 1, 2011 through June 31, 2016. We collected data on 10,619 pediatric patients with available esophageal biopsy results, and identified cases of esophageal eosinophilia (>14 eosinophils in a high-power microscopy field in an endoscopic biopsy). An EoE case required the presence of esophageal eosinophilia, symptoms of esophageal dysfunction, and the absence of co-morbid conditions that may cause esophageal eosinophilia. Annual pediatric EoE incidence and prevalence values were calculated per 100,000 children, based on averaged pediatric population estimates from census figures of Utah in 2010 and 2016. RESULTS: We identified 1281 unique pediatric patients who met criteria for esophageal eosinophilia. Of those, 1060 patients met criteria for newly diagnosed EoE. Over the 5-year period studied, the average annual pediatric EoE incidence in Utah was 24 cases per 100,000 children. The prevalence in year 5 of the study was 118 cases per 100,000 children. CONCLUSION: In a population-based study of children in Utah, we found the incidence and prevalence of pediatric EoE to be higher than previously reported. This could be due to the prominence of EoE risk factors in this region, as well as Utah's searchable medical record system that allows for reliable case ascertainment. Further studies of this type could increase disease awareness, prompting early referral to pediatric gastroenterologists and trials to strengthen evidence-based, algorithmic approaches to EoE diagnosis and treatment in children.
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Esofagite Eosinofílica/epidemiologia , Adolescente , Biópsia , Criança , Pré-Escolar , Esofagite Eosinofílica/patologia , Esofagite Eosinofílica/fisiopatologia , Esôfago/patologia , Feminino , Histocitoquímica , Humanos , Incidência , Lactente , Recém-Nascido , Masculino , Prevalência , Fatores de Risco , Utah/epidemiologiaRESUMO
Eosinophilic esophagitis (EoE) is an inflammatory condition of the esophagus with rising incidence in children. Owed to potential adverse effects and high costs of EoE medications, strict elimination diets are often employed as a mainstay of long-term EoE therapy in children. Currently, there are no effective tests to pinpoint food protein triggers in children with EoE. Therefore, EoE elimination diets are often broad (including milk, soy, wheat, egg, fish/shellfish, and nuts) and can greatly alter a child's baseline eating habits. Herein, we describe 2 cases of avoidant/restrictive food intake disorder (ARFID) in children with remitted EoE maintained on an elimination diet. We also present comorbidity data on ARFID and diet-treated EoE from our pediatric EoE clinic. This is the first report of disordered eating associated with EoE therapy. As EoE is becoming more common, close monitoring of intake and growth in patients treated with elimination diets will be key.
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Transtorno Alimentar Restritivo Evitativo , Esofagite Eosinofílica/psicologia , Esofagite Eosinofílica/terapia , Adolescente , Ansiedade/etiologia , Criança , Pré-Escolar , Terapia Cognitivo-Comportamental , Nutrição Enteral , Esofagite Eosinofílica/dietoterapia , Gastrostomia , Humanos , Masculino , Inibidores da Bomba de Prótons/uso terapêutico , Redução de PesoRESUMO
OBJECTIVES: Eosinophilic esophagitis (EoE) is a delayed-type hypersensitivity with increasing rates among pediatric populations. Although studies have used International Classification of Diseases (ICD) coding to define local cohorts and report disease epidemiology, the accuracy of the EoE ICD code for pediatric EoE is unknown. METHODS: We searched the Intermountain Healthcare Database for pediatric cases with the EoE ICD code over a 5-year period. We cross-referenced these results with a recently published pediatric EoE cohort from the same region and period, where incident cases were identified via retrospective review of pathology reports and medical records. Using the retrospective review cohort as the reference standard, we evaluated the accuracy of the EoE ICD code. RESULTS: Via retrospective review, we identified 1129 new pediatric EoE cases in the Intermountain Healthcare system over 5 years. Six hundred ten of these had the EoE ICD code associated with their chart. Out of 878,872 unique pediatric records in the Intermountain Healthcare system, 219 had the EoE ICD code incorrectly applied. The specificity of the EoE ICD code in children was 99%, but sensitivity and positive predictive value were 61% and 79%, respectively. CONCLUSIONS: The EoE ICD code has strengths and weaknesses in pediatrics. The EoE ICD code is specific, with few false positives across a large population, but not sensitive. The low sensitivity is likely multifactorial and requires further evaluation. Compared to retrospective chart review, which allows for application of clinicopathologic EoE diagnostic criteria, sole use of ICD codes results in underascertainment of EoE cases and key misclassifications.
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Grupos Diagnósticos Relacionados/normas , Esofagite Eosinofílica/diagnóstico , Criança , Esofagite Eosinofílica/epidemiologia , Feminino , Humanos , Classificação Internacional de Doenças , Masculino , Estudos Retrospectivos , Sensibilidade e Especificidade , Utah/epidemiologiaRESUMO
BACKGROUND & AIMS: Eosinophilic esophagitis is usually triggered by foods, by unclear mechanisms. We evaluated the roles of IgE and IgG4 in the development of eosinophilic esophagitis. METHODS: We performed a prospective, randomized, double-blind, placebo-controlled trial of adults with eosinophilic esophagitis given an antibody against IgE (omalizumab, n = 16) or placebo (n = 14) every 2-4 weeks for 16 weeks, based on weight and serum level of IgE. Endoscopy was performed, esophageal biopsy specimens were collected, and symptoms were assessed at baseline and at 16 weeks. Maximum numbers of eosinophils/high-power field were determined. Homogenates of esophageal biopsy specimens from 11 subjects with eosinophilic esophagitis and 8 without (controls) were assessed for IgM, IgA, and IgG subclasses. In a retrospective analysis, we performed immunofluorescence analysis of IgG4 in fixed esophageal tissues from 2 patients with eosinophilic esophagitis who underwent esophagectomy and 47 consecutive autopsies (controls). We also performed immunofluorescence analysis of IgG4 in esophageal mucosal biopsy specimens from 24 subjects with eosinophilic esophagitis and 9 without (controls). Finally, sera were collected from 15 subjects with eosinophilic esophagitis and from 41 without (controls), and assayed for total and food-reactive IgG4. RESULTS: Omalizumab did not alter symptoms of eosinophilic esophagitis or eosinophil counts in biopsy samples compared with placebo. Homogenates of esophageal tissues from patients with eosinophilic esophagitis had a 45-fold increase in IgG4 compared with controls (P < 3 × 10(-5)), but no significant increases in other IgG subclasses, IgM, or IgA. Sparse stromal deposits resembling immune complexes were found in 2 of 5 eosinophilic esophagitis biopsy specimens based on ultrastructural analysis. Esophagectomy samples from 2 patients with eosinophilic esophagitis contained 180 and 300 IgG4 plasma cells/maximal high-power field, mainly in the deep lamina propria; these levels were greater than in tissues from controls. Fibrosis essentially was exclusive to the lamina propria. Granular extracellular IgG4 was detected in biopsy specimens from 21 of 24 patients with eosinophilic esophagitis, but in none of the specimens from 9 controls (P = 6 × 10(-6)). The total serum level of IgG4 increased only slightly in patients with eosinophilic esophagitis, compared with controls. Subjects with eosinophilic esophagitis had increased serum levels of IgG4 that reacted with milk, wheat, egg, and nuts-the 4 foods that most commonly trigger this condition (P ≤ 3 × 10(-4) for each food). CONCLUSIONS: In a prospective trial, omalizumab did not reduce symptoms of eosinophilic esophagitis or tissue eosinophil counts compared with placebo. This finding, along with observed granular deposits of IgG4, abundant IgG4-containing plasma cells, and serum levels of IgG4 reactive to specific foods, indicate that, in adults, eosinophilic esophagitis is IgG4-associated, and not an IgE-induced allergy. ClinicalTrials.gov number: NCT 00123630.
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Esofagite Eosinofílica/imunologia , Esôfago/imunologia , Hipersensibilidade Alimentar/imunologia , Imunoglobulina E/metabolismo , Imunoglobulina G/metabolismo , Adulto , Idoso , Antialérgicos/uso terapêutico , Anticorpos Anti-Idiotípicos/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Biomarcadores/sangue , Biomarcadores/metabolismo , Biópsia , Método Duplo-Cego , Esofagite Eosinofílica/sangue , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/tratamento farmacológico , Esofagoscopia , Esôfago/efeitos dos fármacos , Hipersensibilidade Alimentar/sangue , Hipersensibilidade Alimentar/diagnóstico , Hipersensibilidade Alimentar/tratamento farmacológico , Humanos , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Masculino , Pessoa de Meia-Idade , Omalizumab , Estudos Prospectivos , Fatores de Risco , Fatores de Tempo , Resultado do Tratamento , UtahRESUMO
BACKGROUND & AIMS: We evaluated the efficacy and safety of high-dose swallowed fluticasone propionate (FP) and dose reduction in patients with eosinophilic esophagitis (EoE) and analyzed esophageal transcriptomes to identify mechanisms. METHODS: We conducted a randomized, multisite, double-blind, placebo-controlled trial of daily 1760 mcg FP in participants age 3-30 years with active EoE. Twenty-eight participants received FP, and 14 participants received placebo. After 3 months, participants given FP who were in complete remission (CR) received 880 mcg FP daily, and participants in the FP or placebo groups who were not in CR continued or started, respectively, 1760 mcg FP daily for 3 additional months. The primary end point was histologic evidence for CR. Secondary end points were partial remission (PR), symptoms, compliance, esophageal gene expression, esophageal eosinophil count, and the relationship between clinical features and FP responsiveness. RESULTS: After 3 months, 65% of subjects given FP and no subjects given placebo were in CR (P = .0001); 12% of those given FP and 8% of those given placebo were in PR. In the FP group, 73% of subjects remained in CR, and 20% were in PR after the daily dose was reduced by 50%. Extending FP therapy in FP-resistant participants did not induce remission. FP decreased heartburn severity (P = .041). Compliance, age, sex, atopic status, or anthropomorphic features were not associated with response to FP. Gene expression patterns in esophageal tissues of FP responders were similar to those of patients without EoE; there was evidence for heterogeneous steroid signaling in subjects who did not respond to FP and preliminary evidence for transcripts predictive of FP responsiveness. CONCLUSIONS: Daily administration of a high dose of FP induces histologic remission in 65%-77% of patients with EoE after 3 months. A 50% dose reduction remained effective in 73%-93% of patients who initially responded to FP. Nonresponders had evidence of steroid resistance; histologic and molecular markers may predict resistance. Clinicaltrials.gov number: NCT00426283.
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Androstadienos/administração & dosagem , Anti-Inflamatórios/administração & dosagem , Resistência a Medicamentos , Esofagite Eosinofílica/tratamento farmacológico , Administração Oral , Adolescente , Adulto , Androstadienos/efeitos adversos , Anti-Inflamatórios/efeitos adversos , Criança , Pré-Escolar , Método Duplo-Cego , Esquema de Medicação , Esofagite Eosinofílica/diagnóstico , Esofagite Eosinofílica/genética , Fluticasona , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Humanos , Indução de Remissão , Índice de Gravidade de Doença , Fatores de Tempo , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
OBJECTIVE: The objective of the present study was to determine the effect of gastrojejunal tube (GJT) feedings in children with neurologic impairment (NI) on gastroesophageal reflux disease (GERD)- and/or dysfunctional swallowing-related visits and their associated costs. METHODS: The present study is a retrospective cohort study of children with NI and GERD who underwent GJT placement at the study hospital from December 1999 to October 2006. Visits (emergency department, radiology, and hospitalizations) were reviewed from the time of birth until 1 year following GJT placement and classified as either not GERD and/or dysfunctional swallowing related or GERD and/or dysfunctional swallowing related (eg, pneumonias). Incident rate ratios (IRRs) were calculated by dividing the post-GJT visit rate by the pre-GJT visit rate. Other outcomes included associated costs, fundoplications, and deaths. RESULTS: Thirty-three patients met inclusion criteria. The IRR for total visits was 1.78 (95% confidence interval [CI] 1.12-2.81) and for GERD- and/or dysfunctional swallowing-related visits 2.88 (95% CI 1.68-4.94). Feeding tube-related visits (IRR 5.36, 95% CI 2.73-10.51) accounted for the majority. GERD- and/or dysfunctional swallowing-related costs per child per year were low overall, with no difference from pre-GJT versus post-GJT placement ($1851 vs $4601, P = 0.89). Seven (21%) children underwent Nissen fundoplication and 4 (12%) died within 1 year of GJT placement. Two deaths involved jejunal perforation. CONCLUSIONS: Children with NI and GERD who are treated with GJT feedings have significantly more GERD- and/or dysfunctional swallowing-related visits in the following year. The majority of these visits are because of the procedural complications, which are inexpensive. There is, however, mortality associated with the GJT and some children proceed to a fundoplication.
Assuntos
Transtornos de Deglutição/terapia , Nutrição Enteral/economia , Refluxo Gastroesofágico/terapia , Intubação Gastrointestinal/efeitos adversos , Intubação Gastrointestinal/economia , Visita a Consultório Médico/estatística & dados numéricos , Pré-Escolar , Transtornos de Deglutição/economia , Transtornos de Deglutição/etiologia , Nutrição Enteral/métodos , Falha de Equipamento/economia , Feminino , Fundoplicatura , Refluxo Gastroesofágico/economia , Refluxo Gastroesofágico/etiologia , Humanos , Lactente , Perfuração Intestinal/etiologia , Doenças do Jejuno/etiologia , Masculino , Doenças do Sistema Nervoso/complicações , Visita a Consultório Médico/economia , Estudos RetrospectivosRESUMO
BACKGROUND: Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus. OBJECTIVE: We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis. METHODS: Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician's global assessment score at week 15 (end of therapy). RESULTS: Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician's global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication. CONCLUSION: Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Esofagite Eosinofílica/tratamento farmacológico , Adolescente , Criança , Pré-Escolar , Método Duplo-Cego , Esofagite Eosinofílica/imunologia , Eosinófilos/efeitos dos fármacos , Eosinófilos/imunologia , Feminino , Humanos , Contagem de Leucócitos , Masculino , Qualidade de Vida , Resultado do TratamentoRESUMO
OBJECTIVES/HYPOTHESIS: Timing and indication for surgical intervention is a major challenge in managing pediatric oropharyngeal dysphagia. No study has evaluated a natural course of swallowing dysfunction in otherwise healthy infants. Our objective was to review the outcomes and time to resolution of abnormal swallow in infants with aspiration. STUDY DESIGN: Retrospective case series at a tertiary children's hospital. METHODS: Fifty patients under 1 year old with aspiration on a modified barium swallow study were included. Patients born <34 weeks, with medical or genetic comorbidities, or who underwent surgical intervention for aspiration were excluded. Patients were followed until aspiration resolved on a swallow study. Kaplan-Meier survival analysis was performed. RESULTS: Forty patients (25 patients [50%] by 6 months, 10 [20%] by 1 year, three [6%] by 2 years, and two [4%] at the end of the follow-up interval) were recommended a normal diet, and 10 patients (20%) were still aspirating by the end of the follow-up interval. Median time to resolution was 202 ± 7 days (range, 19-842 days), probability 48% (95% confidence interval [CI]: 0.34-0.62). The probability of resolution at 6 months was 46% (95% CI: 0.4-0.68), at 1 year was 64% (95% CI: 0.51-0.77), at 2 years was 76% (95% CI: 0.64-0.88), and at the end of the follow-up interval 81.3% (95% CI: 0.7-0.92). CONCLUSIONS: The majority of infants with aspiration and without any other major comorbidities improved within 1 year. Future research should be directed toward better understanding swallowing dysfunction in neurologically normal infants. LEVEL OF EVIDENCE: 4 Laryngoscope, 130:514-520, 2020.
Assuntos
Transtornos de Deglutição/fisiopatologia , Transtornos de Deglutição/cirurgia , Aspiração Respiratória/prevenção & controle , Transtornos de Deglutição/diagnóstico por imagem , Feminino , Humanos , Lactente , Recém-Nascido , Estimativa de Kaplan-Meier , Masculino , Estudos RetrospectivosRESUMO
OBJECTIVE: The SI gene encodes the sucrase-isomaltase enzyme, a disaccharidase expressed in the intestinal brush border. Hypomorphic SI variants cause recessive congenital sucrase-isomaltase deficiency (CSID) and related gastrointestinal (GI) symptoms. Among children presenting with chronic, idiopathic loose stools, we assessed the prevalence of CSID-associated SI variants relative to the general population and the relative GI symptom burden associated with SI genotype within the study population. METHODS: A prospective study conducted at 18 centers enrolled 308 non-Hispanic white children ≤18 years old who were experiencing chronic, idiopathic, loose stools at least once per week for >4 weeks. Data on demographics, GI symptoms, and genotyping for 37 SI hypomorphic variants were collected. Race/ethnicity-matched SI data from the Exome Aggregation Consortium (ExAC) database was used as the general population reference. RESULTS: Compared with the general population, the cumulative prevalence of hypomorphic SI variants was significantly higher in the study population (4.5% vs. 1.3%, P < .01; OR = 3.5 [95% CI: 6.1, 2.0]). Within the study population, children with a hypomorphic SI variant had a more severe GI symptom burden than those without, including: more frequent episodes of loose stools (P < .01), higher overall stool frequency (P < .01), looser stool form (P = .01) and increased flatulence (P = .02). CONCLUSION: Non-Hispanic white children with chronic idiopathic loose stools have a higher prevalence of CSID-associated hypomorphic SI variants than the general population. The GI symptom burden was greater among the study subjects with a hypomorphic SI variant than those without hypomorphic SI variants.
Assuntos
Erros Inatos do Metabolismo dos Carboidratos/patologia , Complexo Sacarase-Isomaltase/deficiência , Complexo Sacarase-Isomaltase/genética , Adolescente , Erros Inatos do Metabolismo dos Carboidratos/epidemiologia , Erros Inatos do Metabolismo dos Carboidratos/genética , Criança , Bases de Dados Factuais , Feminino , Genótipo , Heterozigoto , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prevalência , Estudos ProspectivosRESUMO
BACKGROUND: Fidaxomicin is an approved therapy for Clostridium difficile-associated diarrhea (CDAD) in adults. The safety of fidaxomicin in children has not been reported. METHODS: In this study (ClinicalTrials.gov identifier NCT01591863), pediatric patients with CDAD received twice-daily oral fidaxomicin at a dose of 16 mg/kg per day (up to 200 mg) for 10 days in an open-label study. Plasma and fecal samples were collected for pharmacokinetic assessments. The primary outcome measure was safety, which was assessed by adverse-event (AE), laboratory, and physical examination/vital-sign monitoring. Efficacy was determined through early and sustained clinical response rates (clinical response without recurrence of CDAD). RESULTS: The study enrolled 40 patients (11 months to 17 years of age), many with underlying comorbidity, including neoplasm (23.7%), gastrointestinal disorder (78.9%), and history of CDAD (60.5%). Plasma fidaxomicin and OP-1118 (the major fidaxomicin metabolite) 3- to 5-hour postdose concentrations were 0.6 to 87.4 and 2.4 to 882.0 ng/mL, respectively, and no age-related trends were seen. Fecal fidaxomicin concentrations within 24 hours of the last dose averaged 3228 µg/g, and higher concentrations and greater variability in the youngest age group were found. AEs were reported in 73.7% of the patients; most of them were mild (44.7%) to moderate (21.1%) and were considered treatment-related in 15.8% of the patients. Overall, the early clinical response rate was 92.1%. The rate of sustained clinical response (clinical response without recurrence through 28 days after treatment) was 65.8% overall. CONCLUSIONS: Fidaxomicin was well tolerated in children with CDAD and has a pharmacokinetic profile in children similar to that in adults. The clinical response rate was high.
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Aminoglicosídeos/efeitos adversos , Aminoglicosídeos/farmacocinética , Antibacterianos/efeitos adversos , Antibacterianos/farmacocinética , Clostridioides difficile , Infecções por Clostridium/tratamento farmacológico , Diarreia/tratamento farmacológico , Administração Oral , Adolescente , Aminoglicosídeos/administração & dosagem , Aminoglicosídeos/sangue , Antibacterianos/administração & dosagem , Antibacterianos/sangue , Criança , Pré-Escolar , Infecções por Clostridium/microbiologia , Diarreia/microbiologia , Esquema de Medicação , Fezes/química , Feminino , Fidaxomicina , Humanos , Lactente , Masculino , Resultado do TratamentoRESUMO
BACKGROUND & AIMS: IgA antibodies against tissue transglutaminase (TTGA) and endomysium (EMA) are sensitive and specific markers for celiac disease (CD). Data correlating TTGA and EMA levels with degree of villous atrophy are limited. We compared duodenal histopathology in pediatric CD patients with TTGA and EMA serologies, symptoms, height, and weight. METHODS: We identified 117 pediatric patients retrospectively who had serologic testing for IgA TTGA and IgA EMA and duodenal biopsies graded by modified Marsh criteria as 0-3c. Data were analyzed with Spearman rank correlation and multinomial logistic regression. RESULTS: IgA TTGA (r = .704, P < .001) and IgA EMA (r = 0.740, P < .001) correlated with intestinal villous atrophy in pediatric CD patients by Spearman rank correlation. Similar correlations were found in a subset of 23 patients younger than 3 years of age. Multinomial logistic regression revealed increased probability of Marsh 3a or greater changes with increasing TTGA or EMA levels. Strongly positive antibody levels (TTGA >100 units or EMA titer >1:1280) were highly specific (>98%) for Marsh 3a or greater lesions. Among symptoms, abdominal distention and diarrhea were associated with abnormal histology. CONCLUSIONS: IgA TTGA and EMA levels correlate with duodenal villous atrophy in pediatric CD patients. IgA TTGA >100 or EMA >1:1280 were nearly always associated with CD histopathology. With further validation of this observation, strongly positive titers might be considered sufficient for diagnosis of pediatric patients at risk for CD. Symptoms, height, and weight are not reliable predictors of CD.
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Doença Celíaca/sangue , Doença Celíaca/patologia , Tecido Conjuntivo/imunologia , Duodeno/patologia , Proteínas de Ligação ao GTP/imunologia , Imunoglobulina A/sangue , Transglutaminases/imunologia , Adolescente , Estatura , Peso Corporal , Doença Celíaca/imunologia , Criança , Pré-Escolar , Feminino , Humanos , Modelos Logísticos , Masculino , Proteína 2 Glutamina gama-Glutamiltransferase , Estudos RetrospectivosRESUMO
We report the first observation of a patient with contgenital chylous ascites (CCA) and Ehlers-Danlos syndrome type VI due to primary lymphatic defect with additional vascular anomaly. CCA is a rare condition, and there is limited understanding of its pathophysiology and treatment options. We also review the patient's treatment course mitigated with octreotide and total parenteral nutritional support, as there are no current established guidelines for CCA. Early recognition of possible association with Ehlers-Danlos syndrome is important for quick intervention and successful management of pediatric patients.
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Russell-Silver syndrome (RSS) is a genetic syndrome with clinical manifestations of intrauterine and postnatal growth retardation, normal head circumference, body asymmetry, and distinctive facial appearance. We followed an infant diagnosed with RSS who had occurrence of multiple gastrointestinal complications. Although there are a number of published reports describing gastrointestinal problems associated with RSS, specific gastrointestinal diseases have not been recognized as major features. We hypothesize that gastrointestinal complications may be more frequent in RSS cases than previously reported. To address our hypothesis, we developed a pilot study of RSS cases to identify and characterize associated gastrointestinal complications. Surveys were distributed by MAGIC, a support group for individuals with RSS. Surveys included information on the objective and subjective characteristics used to diagnose RSS, as well as descriptions of gastrointestinal problems. Completed surveys were returned on 135 individuals. We used strict diagnostic guidelines to determine affected status of children reported in our survey. Of the 135 surveys completed, 65 were determined to have clear-cut RSS. The diagnoses were made without knowledge of the gastrointestinal symptoms of any of the subjects. Of the 65 subjects with "clear cut" RSS, 50 (77%) had gastrointestinal symptoms. Major specific symptoms included gastroesophageal reflux disease (34%), esophagitis (25%), food aversion (32%), and failure to thrive (63%). A common theme in gastrointestinal complications of RSS is significant gastroesophageal reflux that includes esophagitis and food aversion. Results of this survey suggest that there is an association of gastrointestinal complications with RSS that should be addressed in diagnosis as well as management protocols for children with this condition.
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Anormalidades Múltiplas/genética , Gastroenteropatias/etiologia , Aberrações Cromossômicas , Feminino , Retardo do Crescimento Fetal , Gastroenteropatias/epidemiologia , Gastroenteropatias/genética , Humanos , Recém-Nascido de Baixo Peso , Recém-Nascido , Projetos Piloto , Gravidez , SíndromeRESUMO
Infection of newborn woodchucks with woodchuck hepatitis virus (WHV) results in hepatocellular carcinoma (HCC). Since oxidative damage may be carcinogenic, we investigated the relationship between WHV infection and oxidative damage to hepatic lipids and DNA. Eastern woodchucks were infected with WHV. Hepatic lipid peroxidation was assessed in vitro in isolated hepatocytes by thiobarbituric acid reactive substances (TBARS). Oxidative DNA damage was assessed in vivo in snap-frozen livers by 8-hydroxy-2'-deoxyguanosine (8-OH-dG). The proliferation index (PI) and apoptotic index (AI) were also determined. WHV infection was associated with increased hepatic lipid peroxidation (0.51+/-0.04 nmols TBARS per mg protein for WHV+ hepatocytes vs. 0.38+/-0.04 for WHV negative controls, P<0.01). In contrast, the WHV+ livers exhibited less oxidative DNA damage than uninfected controls (11+/-5 vs. 38+/-8 8-OH-dG/10(6) dG, P<0.02). In WHV-infected animals PI and AI were increased, by >20-fold. We conclude that WHV infection is associated with increased in vitro lipid peroxidation and decreased in vivo oxidative DNA damage. The increased PI and AI in the WHV+livers suggest that rapid cell turnover dilutes 8-OH-dG concentration.
RESUMO
Genome manipulation in the malaria parasite Plasmodium falciparum remains largely intractable and improved genomic tools are needed to further understand pathogenesis and drug resistance. We demonstrated the CRISPR-Cas9 system for use in P. falciparum by disrupting chromosomal loci and generating marker-free, single-nucleotide substitutions with high efficiency. Additionally, an artemisinin-resistant strain was generated by introducing a previously implicated polymorphism, thus illustrating the value of efficient genome editing in malaria research.
Assuntos
Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Genoma de Protozoário , Plasmodium falciparum/genética , AnimaisRESUMO
Children with gastroesophageal reflux disease (GERD) may benefit from gastric acid suppression with proton pump inhibitors such as pantoprazole. Effective treatment with pantoprazole requires correct dosing and understanding of the drug's kinetic profile in children. The aim of these studies was to characterize the pharmacokinetic (PK) profile of single and multiple doses of pantoprazole delayed-release tablets in pediatric patients with GERD aged 6 to 11 years (study 1) and 12 to 16 years (study 2). Patients were randomly assigned to receive pantoprazole 20 or 40 mg once daily. Plasma pantoprazole concentrations were obtained at intervals through 12 hours after the single dose and at 2 and 4 hours after multiple doses for PK evaluation. PK parameters were derived by standard noncompartmental methods and examined as a function of both drug dose and patient age. Safety was also monitored. Pantoprazole PK was dose independent (when dose normalized) and similar to PK reported from adult studies. There was no evidence of accumulation with multiple dosing or reports of serious drug-associated adverse events. In children aged 6 to 16 years with GERD, currently available pantoprazole delayed-release tablets can be used to provide systemic exposure similar to that in adults.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis/efeitos adversos , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Refluxo Gastroesofágico/tratamento farmacológico , Inibidores da Bomba de Prótons/efeitos adversos , Inibidores da Bomba de Prótons/farmacocinética , 2-Piridinilmetilsulfinilbenzimidazóis/administração & dosagem , Adolescente , Criança , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/farmacocinética , Relação Dose-Resposta a Droga , Esquema de Medicação , Feminino , Refluxo Gastroesofágico/sangue , Refluxo Gastroesofágico/genética , Genótipo , Humanos , Inativação Metabólica/genética , Masculino , Pantoprazol , Inibidores da Bomba de Prótons/administração & dosagem , Comprimidos/administração & dosagem , Comprimidos/farmacocinéticaRESUMO
BACKGROUND: Clinical variables may identify a subset of patients with pediatric-onset ulcerative colitis (UC) (≤18 years at diagnosis) at risk for adverse outcomes. We postulated that routinely measured clinical variables measured at diagnosis would predict colectomy in patients with pediatric-onset UC. METHODS: We conducted a chart review of patients with pediatric-onset UC at a single center over a 10-year period. We compared patients with and without colectomy across several variables, used proportional hazards regression to adjust for potential confounders, and assessed the ability of a UC risk score to predict colectomy. RESULTS: Among 470 patients with inflammatory bowel disease ICD9-coded encounters, 155 patients had UC and 135 were eligible for analysis. The 1- and 3-year colectomy rates were 16.7% (95% confidence interval [CI]: 11.0%-24.8%) and 35.6% (26.7%-45.4%). White blood cell (WBC) count and hematocrit measured at diagnosis were associated with colectomy at 3 years, even after correcting for potential confounding variables. A UC Risk Score derived from the WBC count and hematocrit was strongly associated with colectomy risk, with a high negative predictive value (NPV) for colectomy at 1 and 3 years (NPV = 0.95 and 0.89, respectively), but low positive predictive value (PPV = 0.22 and 0.38, respectively). CONCLUSIONS: A risk score calculated from WBC and hematocrit measured at diagnosis was associated with, but incompletely predictive of, colectomy in pediatric-onset UC. These data suggest 1) routinely measured clinical variables may have a prognostic role in risk stratification, and 2) multicenter prospective studies are needed to optimize risk stratification in pediatric UC. Our findings have impact on the design of such studies.