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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.
Assuntos
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: 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.
Assuntos
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
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.
Assuntos
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.
Assuntos
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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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
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.
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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.
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Colectomia , Colite Ulcerativa , Adolescente , Criança , Estudos de Coortes , Colite Ulcerativa/patologia , Colite Ulcerativa/cirurgia , Humanos , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de RiscoRESUMO
BACKGROUND/PURPOSE: Early reports suggest that the use of steroids after Kasai portoenterostomy may improve bile flow and outcome in infants with biliary atresia. METHODS: Of 28 infants with biliary atresia, half received adjuvant high-dose steroids, and half received standard therapy. Infants in the steroid group (n = 14) received intravenous solumedrol (taper of 10, 8, 6, 5, 4, 3, 2 mg/kg/d), followed by 8 to 12 weeks of prednisone (2 mg/kg/d). The steroid protocol also included ursodeoxycholic acid indefinitely and intravenous antibiotics for 8 to 12 weeks followed by oral antibiotic prophylaxis. Infants in the standard therapy group (n = 14) received no steroids, occasional ursodeoxycholic acid, and perioperative intravenous antibiotics followed by oral antibiotic prophylaxis. The infants were not assigned randomly, but rather received standard therapy or adjuvant steroid therapy according to individual surgeon preference. RESULTS: Eleven of 14 (79%) in the steroid group and 3 of 14 (21%) in the standard therapy group had a conjugated bilirubin level less than 1.0 within 3 to 4 months of surgery (P <.001). Fewer patients in the steroid group (21% v 85%) required liver transplantation or died during the first year of life (P <.001). Infants in the steroid group did better despite the fact that this group included 5 infants with biliary atresia-polysplenia-heterotaxia syndrome, a subgroup that might have been expected to have a poor prognosis. Neither bile duct size nor liver histology was a reliable predictor of success or failure in either group. CONCLUSIONS: Adjuvant therapy using high-dose steroids, ursodeoxycholic acid, and intravenous antibiotics may accelerate the clearance of jaundice and decrease the need for early liver transplantation after Kasai portoenterostomy.
Assuntos
Corticosteroides/uso terapêutico , Antibacterianos/uso terapêutico , Bile/metabolismo , Atresia Biliar/cirurgia , Colagogos e Coleréticos/uso terapêutico , Colestase/prevenção & controle , Portoenterostomia Hepática , Complicações Pós-Operatórias/prevenção & controle , Ácido Ursodesoxicólico/uso terapêutico , Administração Oral , Corticosteroides/administração & dosagem , Antibacterianos/administração & dosagem , Antibioticoprofilaxia , Atresia Biliar/tratamento farmacológico , Atresia Biliar/fisiopatologia , Quimioterapia Adjuvante , Feminino , Humanos , Lactente , Infusões Intravenosas , Transplante de Fígado/estatística & dados numéricos , Masculino , Hemissuccinato de Metilprednisolona/administração & dosagem , Hemissuccinato de Metilprednisolona/uso terapêutico , Prednisona/administração & dosagem , Prednisona/uso terapêutico , Estudos Retrospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Once it is established that a jaundiced infant has an elevated direct bilirubin level, the principal diagnostic concern is the differentiation of hepatocellular from obstructive cholestasis, of disorders of physiology from disorders of anatomy, and of disease that is managed medically from disease that is managed surgically. Traditional tests such as ultrasonography, liver biopsy, and technotium 99m HIDA scan are often not sufficiently discriminating. General anesthesia is required for invasive imaging with endoscopic retrograde cholangio pancreatography (ERCP) or operative cholangiogram. The authors describe a facile alternative using percutaneous cholecystocholangiography (PCC) with intravenous sedation. METHODS: Nine cholestatic infants underwent PCC (age, 27 to 73 days; mean, 44 days) after ultrasoundscan, liver biopsy, and (99mTc)HIDA scan failed to provide a definitive diagnosis. RESULTS: In the 4 infants without complete biliary filling, we found biliary atresia (3) and biliary hypoplasia (1). The biliary tree was completely opacified in 5 infants with the following diagnosis: neonatal hepatitis (2), duplication of the gallbladder (1), choledochocele (1), total parenteral nutrition (TPN) cholestasis (1). There were no complications. CONCLUSIONS: When the etiology of cholestasis remains elusive after traditional firstline tests, PCC has proven to be an accurate simple alternative in differentiating obstructive from hepatocellular causes of infantile cholestatic jaundice.