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ObjectiveInflammatory bowel disease (IBD) patients are commonly treated with immunomodulatory medications, and the effect of these medications on seroconversion to SARS-CoV-2 infection and vaccination are scant, particularly in pediatrics. We sought to determine serologic responses to SARS-CoV-2 infection and vaccination in pediatric IBD patients.DesignWe conducted a single-center, retrospective study of all pediatric (≤21 years old) IBD patients in whom a SARS-CoV-2 IgG Antibody Assay was performed between April 2020 and May 2021 at our tertiary care center. This assay measures IgG antibody to the full-length SARS-CoV-2 spike protein and was routinely collected at infusion and outpatient clinic visits. The primary outcome was SARS-CoV-2 seroconversion, and the secondary outcome was titer level, with high titer defined as ≥960 titer or >40 AU/mL. Clinical characteristics, including demographics, IBD location, behavior, activity, and therapy, SARS-CoV-2 exposures, COVID-19 testing and symptoms, SARS-CoV-2 infection status (WHO COVID-19: Case Definitions, 2020) and COVID-19 vaccination status and type, were gathered, and univariate analyses examined associations between clinical characteristics and outcome measures.ResultsThere were 340 pediatric patients with SARS-CoV-2 Antibody Testing; 15% for confirmed or probable COVID-19, 2% for suspected COVID-19, 16% for asymptomatic exposure to a close contact with SARS-CoV-2 infection, 61% without any prior symptoms or exposures, and 6% for history of COVID-19 vaccination. Patients with confirmed or probable COVID-19 infection had a 90% rate of seroconversion, with 76% of these patients on biologic therapy. Patients post-infection without seroconversion had a significantly longer interval between infection and antibody assay (P=0.03). Within those with asymptomatic SARS-CoV-2 exposure, 43% had seroconversion, and there were no identified clinical characteristics associated with positive titer.All pediatric patients who received vaccination seroconverted, and all who received mRNA vaccinations, including one after a single dose, achieved high titer levels; 100% of those who received vaccination were on biologic or small molecule therapy, including one on combination therapy with ustekinumab and tofacitinib.ConclusionPediatric IBD patients have strong serologic antibody responses to SARS-CoV-2 infection and COVID-19 vaccination despite high rates of immunomodulatory therapy.

Background Vedolizumab (VDZ) is effective for treating both adult and pediatric onset inflammatory bowel disease (IBD). Clinical outcomes, however, have been reported to be superior in patients naive to anti-tumor necrosis factor (TNF). With the growing interest in endoscopic endpoints, we aimed to describe rates of mucosal healing in pediatric patients being treated with VDZ and examine the influence of anti-TNF on outcomes. Methods We conducted a retrospective review of all IBD patients ≤21 years of age who initiated VDZ and underwent endoscopy. Primary outcome was mucosal healing (composite of endoscopic [SES-CD] and Mayo score UC) and histological remission [Nancy index-UC and Crohn disease (CD) histologic activity]. Descriptive statistics summarized the data. Comparisons were made for endpoints based on anti-TNF exposure using univariate testing. Results Sixty-eight patients were included in the final analysis; 35 with UC and 33 with CD. Thirty-two patients (22 UC and 10 CD) were anti-TNF-naive and 36 patients (13 UC and 23 CD) were anti-TNF-exposed. The median duration on VDZ before endoscopic assessment was 49 (IQR 32-73) weeks. A total of 38% (25/66) of patients met the primary outcome of mucosal healing and did not differ between anti-TNF-naive or anti-TNF-exposed. Endoscopic remission was achieved by 51% with significantly more anti-TNF naive patients reaching this endpoint (66% vs 40%, P = 0.03). Histologic remission was achieved by 42% of patients with a nonsignificant trend towards improved histologic remission rates in anti-TNF-naive patients (52% vs 33%, P = 0.13). Conclusions VDZ is associated with mucosal healing in pediatric IBD. Anti-TNF exposure significantly impacted endoscopic remission, but not histologic remission in children on VDZ.

BACKGROUND In patients with Crohn’s disease (CD), following an ileocolic resection (ICR), colonoscopy is the gold standard for the detection of endoscopic recurrence (ER). Colonoscopy, however, is invasive and not easily accepted by patients for repeated monitoring. In contrast, transabdominal intestinal ultrasound (IUS) is non-irradiating, non-invasive, and easy to repeat. The goal of this study was to assess the accuracy of IUS for ER in CD. METHODS This was a cross-sectional study of CD patients who underwent point-of-care IUS during a postoperative follow-up clinic visit within 30 days of a planned colonoscopy. Parameters on IUS included bowel wall thickness (BWT), bowel wall hyperemia (BWH), layer stratification, inflammatory fat, lymphadenopathy, and complications. C-reactive protein (CRP), fecal calprotectin (FC), endoscopic healing index (EHI) and Harvey Bradshaw Index (HBI) were also measured. ER was defined as a Rutgeerts Score (RS) ≥ i2. Primary outcome was the association between IUS parameters and ER. Secondary outcomes were the association of IUS parameters with other markers of disease activity. Univariable analysis – Fisher’s exact, Wilcoxon Rank Sum and Spearman correlation coefficient tested associations with ER. Area under the receiver operator curve (ROC) was used to determine optimal cut-off values for BWT to accurately identify ER. RESULTS Eighteen CD patients (9 female; 29 [19-40] years old), underwent IUS examination 45 [29-99] months post-ICR. All patients underwent endoscopy within 30 days of IUS examination, four (22%) for the first time post-ICR. Seven (39%) patients were on ustekinumab, four (22%) on adalimumab, two (11%) on infliximab, one (6%) on vedolizumab, and four (22%) on no therapy. ER was found in eight (44%) patients. BWT and BWH in the neo-terminal ileum and BWH at the ileocolic anastomosis were the only IUS parameters associated with ER (Table 1). BWT was 4.0 [3.2-4.8] mm in patients with ER vs. 2.0 [1.5-2.6] mm without (p=0.04). Neo-terminal ileum BWH was abnormal in six (75%) patients with ER vs. 0% without (p=0.007). BWT of 3.2 mm was the optimal cut point for predicting ER with an: AUROC of 0.82, positive predictive value of 100%, negative predictive value of 97.3%, sensitivity of 75%, and specificity of 100% (Figure 1) vs. a CRP of 10.4 mg/L (AUROC = 0.54) or FC of 1146 μg/g (AUROC = 0.56). Significant correlations were observed between neo-terminal ileum BWT and RS (ρ=0.51, p=0.04) and between BWT and CRP (ρ=-0.56, p=0.023), but not BWT and FC (ρ=-0.04, p=0.91), BWT and EHI (ρ=-0.04, p=0.91), or BWT and HBI (ρ=0.09, p=0.75). CONCLUSIONS IUS is a feasible, accurate, non-invasive monitoring tool for detection of postoperative CD recurrence. Larger prospective studies are needed to determine how IUS can be integrated in the monitoring of CD patients after surgery.

BACKGROUND: Ustekinumab is an effective therapy for Crohn disease currently approved for adults. Off-label use in the pediatric population is increasing, but its effectiveness in this age group has not been reported. AIMS: The aim of the study was to describe real-world experience with ustekinumab at a tertiary care pediatric inflammatory bowel disease (IBD) center. METHODS: As part of an ongoing observational cohort study of biologic-treated pediatric IBD patients initiated in October 2014, data on demographics, disease behavior, location and activity, treatment, and surgical history were collected for all patients receiving ustekinumab. Disease activity was assessed using the Harvey Bradshaw index or partial Mayo score. Primary outcome was steroid-free remission at 52 weeks. Descriptive statistics summarized the safety and efficacy outcomes, and univariate analyses were performed to examine associations of clinical characteristics with efficacy. RESULTS: Fifty-two children and young adults initiating ustekinumab were analyzed; 81% Crohn Disease, 8% ulcerative colitis, and 11% IBD-unspecified. Median [IQR] age at induction was 16.8 [14–18] years. Patients were followed for a minimum of 12 months. Most patients (81%) failed >1 anti-TNF, and 37% failed anti-TNF and vedolizumab; 10 patients were biologic-naïve. At week 52, 75% were still on ustekinumab, and 50% (bio-exposed) and 90% (bio-naïve) were in steroid-free remission. Two infusion reactions and neither serious adverse events nor serious infections were observed. CONCLUSIONS: Our results suggest that ustekinumab is efficacious and safe in pediatric patients with IBD. Controlled clinical trial data are needed to confirm these observations.

Parents of teens with inflammatory bowel disease must prepare their children for independent disease self-management. This study characterizes the stressors and coping strategies adopted among parents of teens with inflammatory bowel disease. Teens aged 16-22 years with inflammatory bowel disease who were consecutively seen by a pediatric gastroenterologist prior to transition to adult-centered care and their parents completed sociodemographic data, and two validated questionnaires for coping (Coping Health Inventory for Parents) and stress (Pediatric Inventory for Parents). Sixty-six patient-parent pairs were enrolled in this study-impairment was highest in role function (e.g., trying to attend to the needs of other family members, being unable to go to work, and feeling uncertain about how to maintain consistent discipline). These concerns seemed to be most pronounced among parents of children 18 years and older (χ (df) = 1, p = .04) with Crohn disease (χ (df) = 1, p = .02). The top five listed concerns differed depending on the caregiver's gender. Parents of teens with inflammatory bowel disease are concerned about parenting role function. Parents of teens 18 years and older with Crohn disease reported the highest stress. Caregiver gender differences were noted.

Coronavirus disease 2019 (COVID-19) may lead to a severe inflammatory response referred to as a cytokine storm. We describe a case of severe COVID-19 infection in a recently diagnosed pediatric Crohn disease patient successfully treated with tumor necrosis factor-alpha (TNF-α) blockade. The patient presented with 5 days of fever, an erythematous maculopapular facial rash, and abdominal pain without respiratory symptoms. SARS-CoV-2 polymerase chain reaction was positive. Despite inpatient treatment for COVID-19 and a perianal abscess, the patient acutely decompensated, with worsening fever, tachycardia, fluid-refractory hypotension, elevation of liver enzymes, and transformation of the rash into purpura extending from the face to the trunk, upper and lower extremities, including the palmar and plantar surfaces of the hands and feet. Cytokine profile revealed rising levels of interleukin (IL)-6, IL-8, and TNF-α, higher than those described in either inflammatory bowel disease or severe COVID-19 alone. The patient was treated with infliximab for TNF-α blockade to address both moderately to severely active Crohn disease and multisystem inflammatory syndrome in children temporally related to COVID-19. Within hours of infliximab treatment, fever, tachycardia, and hypotension resolved. Cytokine profile improved with normalization of TNF-α, a decrease in IL-6, and IL-8 concentrations. This case supports a role for blockade of TNF-α in the treatment of COVID-19 inflammatory cascade. The role of anti-TNF agents in patients with multisystem inflammatory syndrome in children temporally related to COVID-19 requires further investigation.

Adolescence is a vulnerable period for those afflicted with inflammatory bowel disease (IBD). There is limited knowledge of factors influencing transition readiness in this population. We sought to determine whether self-efficacy and resilience would be informative predictors of transition readiness independent of age.Patients with IBD aged 16 to 23 years cared for in a pediatric setting were prospectively enrolled. On entry, patients filled out the Transition Readiness Assessment Questionnaire (TRAQ); IBD Self-Efficacy Scale-Adolescent (IBD-SES-A); and the Connor-Davidson Resilience Scale. Demographic data and disease-specific information were collected from the medical record and by the provider. General linear modeling and autocorrelation were performed to investigate predictors of transition readiness.Eighty-seven patients (62 Crohn's disease and 25 ulcerative colitis) were included, with a median age of 19 years (interquartile range 1-3: 17-20; min-max: 16-23). After controlling for age, the IBD-SES-A predicted TRAQ [F(1) = 11.69, R = 0.16, P = 0.001], accounting for 16% of the variance. The Connor-Davidson Resilience Scale also independently predicted TRAQ score [F(1) = 6.45, R = 0.09, P = 0.01], accounting for 9% of the variance. The IBD-SES-A and Connor-Davidson Resilience Scale were significantly auto correlated (r = 0.044, P = 0.001); in the final predictive model, only IBD-SES-A was predictive of TRAQ [F(1) = 4.01, R = 0.12, P = 0.004]. None of the patients' demographic, disease, or socioeconomic parameters informed transition readiness once self-efficacy and resilience were considered.This is the first study to identify a reliable predictor of transition readiness scores in adolescents with IBD that does not seem to be influenced by age.

Background Approximately 10% of children with ulcerative colitis (UC) undergo colectomy with ileal pouch-anal anastomosis (IPAA). We aimed to describe the postoperative outcomes, with an emphasis on chronic pouch inflammation including de novo Crohn disease (CD) at a tertiary care inflammatory bowel disease center. Methods Electronic medical records of all children who underwent colectomy ≤18 years between 2008 and 2017 were reviewed. Clinical and laboratory data were recorded. Primary outcome was frequency of chronic pouch inflammation including de novo CD. Secondary outcomes included early (≤30 days from index surgery) and late postoperative complications. Descriptive statistics (median and interquartile range) summarized the data and univariate analysis tested associations with outcomes. Results Fifty-eight children underwent colectomy and 56 completed IPAA. Median age at diagnosis was 14 years (12-16.2) and at colectomy 16.2 years (14.2-17.7) with median follow-up of 13 months (5-43). Sixty-six percent underwent 3-stage IPAA and 78% were biologic exposed. Eleven had chronic pouchitis, 73% antibiotic refractory and 25% met criteria for de novo CD by median of 19 months (9-41). A total of 21% and 50% experienced early and late surgical complications, most commonly ileus and recurrent IPAA stricture. The pouch failure rate was 3.6%. Chronic pouch inflammation was associated with a later diagnosis of de novo CD (P = 0.0025). Conclusions In pediatric UC, CD is not uncommon after IPAA. Chronic pouch inflammation often precedes a diagnosis of de novo CD. Families should be informed of the short- and long-term outcomes in children before UC surgery.

Though vedolizumab has received regulatory approval for the treatment of Crohn's disease (CD) and ulcerative colitis (UC) in adults, there is increasing off-label use in children.To describe the experience with vedolizumab in pediatric inflammatory bowel disease (IBD) patients at 3 tertiary IBD centers and examine predictors of remission.A retrospective review identified pediatric IBD patients (age18 yrs) receiving vedolizumab. Data on demographics, disease behavior, location, activity, and previous treatments/surgeries were collected. Disease activity was assessed using the weighted pediatric CD activity index or pediatric UC activity index. Primary outcome was week 14 remission, defined as pediatric UC activity index10 or weighted pediatric CD activity index12.5. Descriptive statistics and univariate analyses were performed to examine associations of clinical characteristics with efficacy.Fifty-two patients, 58% CD and 42% UC, initiated vedolizumab between June 2014 and August 2015. Median age at vedolizumab initiation was 14.9 (range 7-17) years. Ninety percent had failed ≥1 anti-tumor necrosis factor (TNF) agent. Week 14 remission rates for UC and CD were 76% and 42%, respectively (P0.05). Eighty percent of anti-TNF-naive patients experienced week 14 remission. At week 22, anti-TNF-naive patients had higher remission rates than TNF-exposed patients (100% versus 45%, P = 0.04). There were no infusion reactions or serious adverse events/infections.Our results suggest that vedolizumab is efficacious and safe in pediatric IBD patients, with UC patients experiencing earlier and higher rates of remission than CD patients. Anti-TNF-naive patients experienced higher remission rates than those with anti-TNF exposure. Controlled clinical trial data are needed to confirm these observations.

Background Infliximab (IFX) discontinuation is not uncommon during the first year of treatment due to inadequate drug concentrations and anti-IFX antibodies (ATI). Both combination therapy and proactive therapeutic drug monitoring (pTDM) are used to decrease ATI and increase IFX durability. We proposed that monotherapy (Mono) is as effective as combination therapy (Combo) if the first maintenance infusion is dosed based on week 10 pTDM. Methods In a retrospective cohort of 83 patients with inflammatory bowel disease (IBD), we examined the frequency of IFX discontinuation, ATI, infusion reactions, and IFX concentrations during the first year of treatment in patients receiving week 10 pTDM-guided IFX monotherapy (Mono pTDM; n = 16) compared with patients on mono (n = 32) or combination therapy (n = 35) in whom TDM was introduced at or after week 14, per standard of care (SOC). Results The frequency of IFX discontinuation was lower with Mono pTDM compared with Mono SOC (P = 0.04) but did not differ with Combo SOC (P = 1). At first TDM, no patient in the pTDM strategy had ATI, vs 41% in Mono SOC (P = 0.002) and 6% in Combo SOC (P = 1). Of the 13 subjects with ATI in Mono SOC, 7 (47%) had ATI already at week 14. IFX trough concentrations with Mono pTDM were higher during maintenance compared with Mono SOC (9.5 vs 6.4 µg/mL, P = 0.04) but not Combo SOC. Conclusions Infliximab durability did not differ between patients on IFX monotherapy dosed based on p-TDM and patients receiving combination therapy. In the absence of concomitant immunosuppression, proactive TDM may improve IFX durability by maintaining higher IFX concentrations entering into maintenance. Further studies are needed to confirm our findings.

Background and Objectives: Nourishing a child undergoing bone marrow transplant (BMT) is essential, but the optimal method to achieve this is not established. The objectives of the study were to investigate the incidence and risk factors for complications of gastrostomy tubes in patients with BMT. Methods: A retrospective chart review was conducted of pediatric patients who received a percutaneous endoscopic gastrostomy (PEG) either for BMT or for other indications during a 3-year period. Occurrences of complications, absolute neutrophil count (ANC) at time of PEG placement, and ANC at time of complication were reviewed for both BMT and the comparison group. Results: Of the 11 subjects in the BMT group, 4 (36%) had a major complication of infection related to PEG and 3 of those required PEG removal. Two of the 4 subjects who developed a major complication were moderately neutropenic at the time of PEG placement and all subjects were neutropenic at the time of complication. Of the 30 subjects in the comparison group, only 1 (2.8%) had a major complication with cellulitis. There were no statistically significant differences between the 2 groups before PEG placement for age, weight, albumin, or white blood cell count. The incidence of complication in BMT compared with the comparison group was significant (P = 0.01). Conclusions: Our findings support that ANC should be considered before placement of PEG, significant neutropenia may be a contraindication for PEG placement in BMT patients, and other modalities for nutrition support might need to be considered.

Epstein Barr virus (EBV) is a human herpes virus that infects 90% of the world's population and has been linked to the development of lymphoproliferative disorders (LPDs) and immunosuppression. Primary EBV infection in patients with IBD on thiopurines is a risk factor for LPD, including lymphoma. We aimed to describe EBV status in a pediatric population with IBD with an emphasis on those initiating thiopurines.Electronic medical records and EBV serologies were reviewed and categorized into asymptomatic screening versus suspicion for acute infection. EBV status before therapy was described by sex, age, and therapeutic regimen. Descriptive statistics and univariate analysis were employed.Only 150 (22%) of our 688 pediatric patients with IBD had documented EBV status regardless of age or treatment regimen. Only 17% were assessed for suspicion of acute infection and 83% for screening. Sixty-four (52%) screened patients were checked before starting any treatment and only 40% were immunoglobulin (Ig)G positive. There was no difference in mean age between the seronegative and seropositive group. The majority (63%) of thiopurine-treated patients were IgG negative before starting therapy. Eighty percent of primary EBV infections occurred on thiopurines at a mean (SD) of 2 ± 1.5 years after initiating therapy.The majority of our pediatric patients with IBD with documented EBV status were IgG negative at thiopurine initiation. Thiopurines were also associated with primary EBV infection. EBV status may be an important determinate of whether physicians prescribe thiopurines given the risk of primary EBV infections and lymphoproliferative diseases.

Human cystic fibrosis transmembrane conductance regulator gene (CFTR) transcription is tightly regulated by nucleotide sequences upstream of the initiator sequences. Our studies of human CFTR transcription focus on identifying transcription factors bound to an inverted CCAAT consensus or "Y-box element." The human homeodomain CCAAT displacement protein/cut homolog (CDP/cut) can bind to the Y-box element through a cut repeat and homeobox. Analysis of stably transfected cell lines with wild-type and mutant human CFTR-directed reporter genes demonstrates that human histone acetyltransferase GCN5 and transcription factor ATF-1 can potentiate CFTR transcription through the Y-box element. We have found 1) that human CDP/cut acts as a repressor of CFTR transcription through the Y-box element by competing for the sites of transactivators hGCN5 and ATF-1; 2) that the ability of CDP/cut to repress activities of hGCN5 and ATF-1 activity is contingent on the amount of CDP/cut expression; 3) that histone acetylation may have a role in the regulation of gene transcription by altering the accessibility of the CFTR Y-box for sequence-specific transcription factors; 4) that trichostatin A, an inhibitor of histone deacetylase activity, activates transcription of CFTR through the Y-box element; 5) that the inhibition of histone deacetylase activity leads to an alteration of local chromatin structure requiring an intact Y-box sequence in CFTR; 6) that immunocomplexes of CDP/cut possess an associated histone deacetylase activity; 7) that the carboxyl region of CDP/cut, responsible for the transcriptional repressor function, interacts with the histone deacetylase, HDAC1. We propose that CFTR transcription may be regulated through interactions with factors directing the modification of chromatin and requires the conservation of the inverted CCAAT (Y-box) element of the CFTR promoter.

Background—Children and adolescents who seek medical treatment for persistent physical distress often suffer from co-occurring anxiety disorders. Treatment options for this impaired population are limited. This study tests the feasibility and potential efficacy of a cognitivebehavioral intervention targeting pain and anxiety for youth with impairing functional physical symptoms and anxiety disorders presenting to pediatricians for medical care. Methods—Children and adolescents (aged 8–16) experiencing somatic complaints, without an explanatory medical disorder (i.e., functional), were recruited from primary care and specialty (gastroenterologists and cardiologists) pediatricians. Forty children, primarily with gastrointestinal symptoms, who met criteria for a co-occurring anxiety disorder, were randomly assigned to a cognitive-behavioral treatment addressing pain and anxiety, Treatment of Anxiety and Physical Symptoms (TAPS), or to a waiting-list control. Results—TAPS was found to be an acceptable treatment for this population and was superior to the waiting-list condition. Eighty percent of children in TAPS were rated as treatment responders by independent evaluators compared with none of the controls. Overall, self- and parent ratings indicated reductions in children’s somatic discomfort and anxiety following intervention. TAPS participants maintained clinical gains three months following treatment. Conclusions—The study supports the feasibility and preliminary efficacy of a cognitivebehavioral intervention targeting co-occurring physical distress and anxiety in youth presenting for medical treatment. Such an approach has the potential to exert broad impact on children’s dysfunction and to minimize exposure to invasive, ineffective, and costly medical procedures and treatments.

Background: Alcoholic liver disease has been associated with QT prolongation and sudden cardiac death. Hypothesis: We evaluated children with hepatic failure to determine whether they have abnormalities of ventricular repolarization. Methods: Between October 1990 and January 1996, 38 pediatric patients (mean age 6.5 ± 7.2 years) underwent evaluation for liver transplantation, including a 12-lead electrocardiogram and an echocardiogram. All patients had normal serum electrolytes, calcium, and magnesium at the time of cardiac evaluation and were not on any medications known to prolong repolarization. Follow-up electrocardiograms were performed on all survivors with QT prolongation following liver transplantation. Results: Among those evaluated, seven (18%) were noted to have a prolonged QT interval corrected for rate (QTc> 450 ms; range 460–560 ms). All had a structurally normal heart, except one with an atrial and ventricular septal defect. When compared with patients with a normal QT interval, there was no significant difference in serum indices of liver function or indication for liver transplantation. None of the patients developed a ventricular arrhythmia. Two patients with a prolonged QTc died prior to transplant and another died immediately after surgery. All four survivors had normalization of the QTc following liver transplantation. Conclusion: QTc prolongation can be seen in a significant number of children with hepatic failure. While the mechanism is not known, it appears to be reversible following liver transplantation.

Goals Our goals were to answer 2 questions: (1) Is the presentation of early-onset inflammatory bowel disease (IBD) similar to typical adolescent-onset IBD? (2) Is there variability in familial aggregation in childhood IBD? Background The phenotype of IBD in children under 5 years of age (early-onset) is poorly defined. Clinical and genetic studies of IBD, however, generally assume the phenotype to be homogenous throughout childhood. Study We analyzed data from 413 consecutive pediatric IBD outpatients attending our center between 1995 and 2000. Disease type, anatomic distribution, and family history were compared between children presenting before (early-onset) and after the age of five (5 to 15 y). Results Disease presentation was predominantly colonic in early-onset IBD, most patients presenting with ulcerative colitis (UC). Isolated colonic disease was most frequent in early-onset Crohn disease (colonic 76.5%, ileocolic 24%) compared with ileocolic disease (ileocolic 45.5%, colonic 26%, ileal 19.4%, proximal 6.3%) in the older age group. First-degree family history was highest in early-onset UC 26% versus 11% in the older UC group. Conclusions We describe a distinct phenotype of early childhood onset IBD, with a strikingly high familial aggregation in UC and greater tendency to present with colonic disease. As more genetic heterogeneity is identified in IBD, careful definition of phenotype is required to identify further susceptibility genes. The early-onset form of UC presents an ideal group for further genetic analysis. These phenotype differences also suggest that treatment and outcome may vary in early-onset childhood IBD; prospective studies are required to confirm this.

Liver transplantation is recognized as the appropriate treatment for end-stage liver disease due to chronic active autoimmune hepatitis. While it was initially thought that the disease did not recur after transplant, it is now generally accepted that adult patients may develop recurrent disease, with studies reporting a recurrence rate ofor = 25%. We have noted a higher incidence of recurrent autoimmune hepatitis in our pediatric patients undergoing liver transplant, with a high incidence of associated morbidity.We reviewed the records of six children followed up for autoimmune hepatitis who underwent orthotopic liver transplant for complications of end-stage liver disease.Of the six, five developed recurrent autoimmune hepatitis at a mean time of 11.4 months after transplant. The disease was aggressive, leading to cirrhosis and retransplant in three patients, within 1 year of recurrence. A second recurrence of disease occurred in all three retransplanted patients. One patient has received a third liver transplant, one has died, and one patient is asymptomatic on medical therapy. Autoimmune hepatitis recurred in all four patients receiving tacrolimus.We conclude that liver transplant for autoimmune hepatitis is likely to be palliative for most pediatric patients. Potent immunosuppressives such as tacrolimus do not protect against the development of recurrent autoimmune hepatitis.

The cystic fibrosis transmembrane conductance regulator (CFTR) gene in man is controlled by a tightly regulated and weak promoter. The architecture of the CFTR promoter suggests regulatory characteristics that are consistent with the absence of a TATA-like sequence, including the ability to initiate RNA transcription at numerous positions. Detailed investigation of the most proximal region of the human CFTR gene promoter through deletion and mutational analysis reveals that expression is contingent on the conservation of the inverted CCAAT sequence. Basal expression of CFTR transcription and cAMP-mediated transcriptional regulation require the presence of an imperfect and inverted CCAAT element recognized as 5'-AATTGGAAGCAAAT-3', located between 132 and 119 nucleotides upstream of the translational start site. RNA isolated from a transfected pancreatic cell line carrying integrated wild-type and mutant CFTR-directed transgenes was used to map the 5' termini of the transgenic transcripts. Analysis of the transcript termini by ribonuclease protection analysis reflects the direct association of the conserved inverted CCAAT sequence in promoting transcript initiation. Because of the requirement for the inverted CCAAT sequence for promoting transcription of CFTR, the involvement of CCAAT-binding factors is suspected in the regulation of CFTR gene transcription. To test this, we used electrophoretic mobility shift assays to demonstrate that the majority of the binding to the inverted CCAAT element, between -135 and -116, was easily competed for by binding to cognate nucleotide sequences for CCAAT-enhancer binding protein (C/EBP). An antibody specific for the C/EBP-related protein, C/EBP delta, detected C/EBP delta as part of a nuclear protein complex bound to the inverted CCAAT sequence of the CFTR gene. Also, the detection of specific activating transcription factor/cyclic-AMP response element binding protein antigens by antibody supershift analysis of nuclear complexes suggest that species of this family of transcription factors could be involved in the formation of complexes with C/EBP delta within the CFTR gene inverted CCAAT-like element. These studies raise the possibility of interactions between individual members of the C/EBP and activating transcription factor/cyclic-AMP response element binding protein families potentially contribute to the tight transcriptional control rendered by the CFTR gene promoter.