Effect of Overweight and Obesity on the Response to Anti-TNF Therapy and Disease Course in Children With IBD.

BACKGROUND: This study aimed to evaluate the effect of overweight and obesity at the start of anti-TNF therapy on treatment response and relapse rate in children with inflammatory bowel disease (IBD). METHODS: This multicenter, retrospective cohort study included 22 IBD centers in 14 countries. Children diagnosed with IBD in whom antitumor necrosis factor (anti-TNF) was introduced were included; those who were overweight/obese were compared with children who were well/undernourished. RESULTS: Six hundred thirty-seven children (370 [58%] males; mean age 11.5 ±â€…3.5 years) were included; 140 (22%) were in the overweight/obese group (OG) and 497 (78%) had BMI ≤1 SD (CG). The mean follow-up time was 141 ±â€…78 weeks (median 117 weeks). There was no difference in the loss of response (LOR) to anti-TNF between groups throughout the follow-up. However, children in OG had more dose escalations than controls. Male sex and lack of concomitant immunomodulators at the start of anti-TNF were risk factors associated with the LOR. There was no difference in the relapse rate in the first year after anti-TNF introduction; however, at the end of the follow-up, the relapse rate was significantly higher in the OG compared with CG (89 [64%] vs 218 [44%], respectively, P < .001). Univariate and multivariate analysis revealed that being overweight/obese, having UC, or being of male sex were factors associated with a higher risk for relapse. CONCLUSIONS: Overweight/obese children with IBD were not at a higher risk of LOR to anti-TNF. Relapse in the first year after anti-TNF was introduced, but risk for relapse was increased at the end of follow-up.

Overweight and obese children with inflammatory bowel disease required more frequent dose escalations, but overall loss of response to anti-TNF therapy was not increased. Furthermore, in the long term, they tend to have a higher risk for relapse.

STEP-CD study: ustekinumab use in paediatric Crohn's disease-a multicentre retrospective study from paediatric IBD Porto group of ESPGHAN.

Ustekinumab is an effective therapy for adult Crohn's disease (CD), but data in paediatric CD patients are scarce. The aim of the study was to describe the real-life effectiveness and safety of ustekinumab in paediatric CD. This is a multicentre review of children with Crohn's disease treated with ustekinumab. The aim of our study was to describe the effectiveness and safety of ustekinumab in paediatric real-life practice. This is a study of the Paediatric IBD (inflammatory bowel disease) Porto group of ESPGHAN. Corticosteroid (CS)- and exclusive enteral nutrition (EEN)-free remission, defined as weighted Paediatric Crohn's Disease Activity Index (wPCDAI) < 12.5, and physician global assessment (PGA) were determined at weeks 12 and 52. A total of 101 children were included at a median age of 15.4 years (IQR 12.7-17.2) with a median follow-up of 7.4 months (IQR 5.6-11.8). Ninety-nine percent had received prior anti-TNF, 63% ≥ 2 anti-TNFα therapies and 22% vedolizumab. Baseline median wPCDAI was 39 (IQR 25-57.5) (71 (70%) patients with moderate-severe activity). Weeks 12 and 52 CS- and EEN-free remission were both 40.5%. Clinical response at week 6, iv induction route and older age at onset of ustekinumab treatment were predictive factors associated with clinical remission at week 12. Seven minor adverse events probably related to ustekinumab were reported. One patient died from an unrelated cause.  Conclusion: Our results suggest that ustekinumab is effective and safe in children with chronically active or refractory CD. What is Known: • Ustekinumab is an effective therapy for adult moderate to severe Crohn's disease (CD). • Off-label use of ustekinumab in children is increasing especially in anti-TNF refractory CD. What is New: • Is the largest cohort of real-world use of ustekinumab in paediatric CD to date. • Clinical response at week 6, iv induction and older age at onset of ustekinumab were predictive factors associated with clinical response at week 12.

Kono-S anastomosis in Crohn's disease: initial experience in pediatric patients.

PURPOSE: Children diagnosed with Crohn's disease (CD) often undergo ileocecal resection (ICR) during childhood. Anastomotic recurrence is a frequent finding following this procedure. Data addressing the effect of the anastomosis type on disease recurrence are scarce in the pediatric population. The Kono-S anastomosis has shown promise in reducing endoscopic, clinical, and surgical recurrence rates in adults. We aimed to report our experience with Kono-S anastomosis in children, focusing on its feasibility and postoperative complications. METHODS: We retrospectively analyzed pediatric CD patients who underwent ICR with Kono-S anastomosis between August 2022 and May 2023. Data on demographics, clinical characteristics, surgery, hospitalization, and follow-up including colonoscopy were collected. Complications were classified using the Clavien-Dindo classification. RESULTS: Twelve patients (7 females, 58.3%) were included. Six (50%) of the patients had the B3 luminal form of the disease (according to Paris classification). Median surgery duration was 174 (interquartile range [IQR] 161-216) minutes. Anastomosis creation took a median of 62 (IQR, 54.5-71) minutes. Median hospitalization length was 6 (IQR 4-7) days. No short- or mid-term complications were observed. Median follow-up duration was 9.5 (IQR 6.8-12) months. CONCLUSION: According to our results, Kono-S anastomosis is safe and feasible in pediatric CD patients, with no observed postoperative complications. These findings support the potential benefit of using Kono-S anastomosis as a treatment approach in children with CD.

Faecal Bacteriome and Metabolome Profiles Associated with Decreased Mucosal Inflammatory Activity Upon Anti-TNF Therapy in Paediatric Crohn's Disease.

BACKGROUND AND AIMS: Treatment with anti-tumour necrosis factor α antibodies [anti-TNF] changes the dysbiotic faecal bacteriome in Crohn's disease [CD]. However, it is not known whether these changes are due to decreasing mucosal inflammatory activity or whether similar bacteriome reactions might be observed in gut-healthy subjects. Therefore, we explored changes in the faecal bacteriome and metabolome upon anti-TNF administration [and therapeutic response] in children with CD and contrasted those to anti-TNF-treated children with juvenile idiopathic arthritis [JIA]. METHODS: Faecal samples collected longitudinally before and during anti-TNF therapy were analysed with regard to the bacteriome by massively parallel sequencing of the 16S rDNA [V4 region] and the faecal metabolome by 1H nuclear magnetic resonance imaging. The response to treatment by mucosal healing was assessed by the MINI index at 3 months after the treatment started. We also tested several representative gut bacterial strains for in vitro growth inhibition by infliximab. RESULTS: We analysed 530 stool samples from 121 children [CD 54, JIA 18, healthy 49]. Bacterial community composition changed on anti-TNF in CD: three members of the class Clostridia increased on anti-TNF, whereas the class Bacteroidia decreased. Among faecal metabolites, glucose and glycerol increased, whereas isoleucine and uracil decreased. Some of these changes differed by treatment response [mucosal healing] after anti-TNF. No significant changes in the bacteriome or metabolome were noted upon anti-TNF in JIA. Bacterial growth was not affected by infliximab in a disc diffusion test. CONCLUSIONS: Our findings suggest that gut mucosal healing is responsible for the bacteriome and metabolome changes observed in CD, rather than any general effect of anti-TNF.

Anastomotic stricture prediction in patients with esophageal atresia with distal fistula.

PURPOSE: To investigate potential early risk factors for anastomotic stricture formation and assess the predictive role of post-operative esophagrams. METHODS: A retrospective study of patients with esophageal atresia with distal fistula (EA/TEF) operated between 2011 and 2020. Fourteen predictive factors were tested for stricture development. Esophagrams were used to calculate early (SI1) and late (SI2) stricture index (SI = anastomosis diameter/upper pouch diameter). RESULTS: Of 185 patients operated for EA/TEF in the 10-year period, 169 patients met the inclusion criteria. Primary anastomosis was performed in 130 patients and delayed anastomosis in 39 patients. Stricture formed in 55 patients (33%) within 1 year from anastomosis. Four risk factors showed strong association with stricture formation in unadjusted models: long gap (p = 0.007), delayed anastomosis (p = 0.042), SI1 (p = 0.013) and SI2 (p < 0.001). A multivariate analysis showed SI1 as significantly predictive of stricture formation (p = 0.035). Cut-off values using a receiver operating characteristic (ROC) curve were 0.275 for SI1 and 0.390 for SI2. The area under the ROC curve demonstrated increasing predictiveness from SI1 (AUC 0.641) to SI2 (AUC 0.877). CONCLUSIONS: This study identified an association between long gap and delayed anastomosis with stricture formation. Early and late stricture indices were predictive of stricture formation.

Postvaccination Immunogenicity of BNT162b2 SARS-CoV-2 Vaccine and Its Predictors in Pediatric Inflammatory Bowel Disease.

OBJECTIVES: We prospectively compared the postvaccination immunity to messenger ribonucleic acid BNT162b2 severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine of our pediatric patients over 12 years old with inflammatory bowel disease (IBD) to that of healthy controls and looked for predictors of its robustness. METHODS: Anti-receptor binding domain, anti-spike S2, and anti-nucleocapsid immunoglobin-G (IgG) and immunoglobin-A levels were measured in 139 pediatric patients with IBD [65 fully vaccinated (2 doses), median age 16.3, interquartile range (IQR) 15.2-17.8 years, median time from vaccination (IQR) 61.0 (42.0-80.0) days] and 1744 controls (46, 37-57 years) using microblot array. RESULTS: All IBD and control patients developed positive anti-receptor binding domain IgG antibodies at comparable titers. The proportion of observations with positive anti-spike S2 IgG was higher in patients with IBD than in controls [63% vs 21%, odds ratio 2.99 (1.51-5.90)], as was its titer [median (IQR) 485 (92-922) vs 79 [33-180] IU/mL]. Anti-receptor binding domain and anti-spike S2 IgG levels were associated with IBD status. We found an association between anti-spike S2 IgG levels and time since vaccination (ß -4.85, 95% CI -7.14 to 2.71, P = 0.0001), history of SARS-CoV-2 polymerase chain reaction positivity (206.76, 95% CI 39.93-374.05, P = 0.0213), and anti-tumor necrosis factor treatment (-239.68, 95% CI -396.44-83.55, P = 0.0047). Forty-three percent of patients reported vaccination side effects (mostly mild). Forty-six percent of observations with positive anti-nucleocapsid IgG had a history of SARS-CoV-2 infection. CONCLUSIONS: Patients with IBD produced higher levels of postvaccination anti-spike S2 antibodies than controls. Previous SARS-CoV-2 infection is associated with higher production of postvaccination antibodies and anti-tumor necrosis factor treatment with lower production.

Prediction of thiopurine failure in pediatric Crohn's disease: pediatric IBD Porto group of ESPGHAN.

BACKGROUND: Maintaining of remission early in the disease course of Crohn's disease (CD) is essential and has major impact on the future prognosis. This study aimed to identify baseline predictors to develop model allowing stratification of patients who will not benefit from long-term azathioprine (AZA) treatment and will require more intensive therapy. METHODS: This study was designed to develop clinical prediction rule using retrospective data analysis of pediatric CD patients included in prospective inception cohort. Clinical relapse was defined as necessity of re-induction of remission. Sequence of Cox models was fitted to predict risk of relapse. RESULTS: Out of 1190 CD patients from 13 European centers, 441 were included, 50.3% patients did not experience clinical relapse within 2 years of AZA treatment initiation. Median time to relapse was 2.11 (CI 1.59-2.46) years. Of all the tested parameters available at diagnosis, six were significant in multivariate analyses: C-reactive protein (p = 0.038), body mass index Z-score >0.8 SD (p = 0.002), abnormal sigmoid imaging (p = 0.039), abnormal esophageal endoscopy (p = 0.005), ileocolonic localization (p = 0.023), AZA dose in specific age category (p = 0.031). CONCLUSIONS: Although the possibility of predicting relapse on AZA treatment appears limited, we developed predictive model based on six baseline parameters potentially helpful in clinical decision. IMPACT: The possibility of predicting relapse on AZA treatment appears to be possible but limited. We identified six independent predictors available at diagnosis of early AZA/6-MP treatment failure in pediatric CD patients. Using combination of these factors, a model applicable to clinical practice was created. A web-based tool, allowing estimation of individual relapse risk in pediatric CD patients on a particular therapeutic regimen, has been developed.

Serum and Mucosal CD30 in Pediatric Inflammatory Bowel Diseases: Useful Biomarker for Diagnosis and Disease Activity Monitoring?

BACKGROUND: Inflammatory bowel diseases (IBD) frequently manifest in pediatric age, but may have atypical clinical, histological and laboratory features. Their underlying immune pathophysiology is incompletely understood, rendering quick diagnosis followed by tailored therapy difficult. The tumor necrosis factor superfamily receptor CD30 has been proposed as a potential marker of ulcerative colitis (UC) and has also been associated with elevated Th2 helper T cells. METHODS: A cohort of pediatric patients with UC and Crohn's disease (CD) was evaluated for serum soluble CD30 (sCD30) using ELISA and expression of CD30 and subpopulations of Th1/Th2/Th17 lymphocytes in the gastrointestinal mucosa using flow cytometry (FCM). The dataset is supported by endoscopic and microscopic activity of the disease and basic laboratory markers of inflammation. RESULTS: The cohort consisted of 102 observations from 94 patients. sCD30 levels did not differ between patients with CD or UC. However, sCD30 levels correlated with levels of CRP, ESR, fecal calprotectin and albumin and also with clinical activity of the disease in patients with both UC and CD. FCM was not helpful in evaluation of mucosal CD30, which was lowly expressed and not associated with the diagnosis or disease activity. We show augmented Th2 and Th1/17 response in terminal ileum and right-sided colon and decreased Th1/17 response in left-sided colon of UC patients. T lymphocyte subsets were also affected by anti-TNF treatment and patients' age. CONCLUSIONS: Neither sCD30 nor mucosal CD30 expression was helpful in differentiating between UC and CD. sCD30 seems to reflect a degree of systemic inflammation and clinical activity in IBD.

Safety and Potential Efficacy of Escalating Dose of Ustekinumab in Pediatric Crohn Disease (the Speed-up Study): A Multicenter Study from the Pediatric IBD Porto Group of ESPGHAN.

OBJECTIVES: Escalation of the ustekinumab (UST) maintenance dosage was effective in adults with Crohn disease (CD), but no data are available for children. We evaluated the effectiveness and safety of dose escalation of UST in pediatric CD. METHODS: This was a retrospective multicenter study from 25 centers affiliated with the IBD Interest and Porto groups of ESPGHAN. We included children with CD who initiated UST at a standard dosing and underwent either dose escalation to intervals shorter than 8 weeks or re-induction of UST due to active disease. Demographic, clinical, laboratory, endoscopic, imaging, and safety data were collected up to 12 months of follow-up. RESULTS: Sixty-nine children were included (median age 15.8 years, interquartile range 13.8-16.9) with median disease duration of 4.3 years (2.9-6.3). Most children were biologic (98.6%)- and immunomodulator (86.8%)- experienced. Clinical response and remission were observed at 3 months after UST escalation in 46 (67%) and 29 (42%) children, respectively. The strongest predictor for clinical remission was lower weighted Pediatric Crohn Disease Activity Index (wPCDAI) at escalation ( P = 0.001). The median C-reactive protein level decreased from 14 (3-28.03) to 5 (1.1-20.5) mg/L ( P = 0.012), and the fecal calprotectin level from 1100 (500-2300) to 515 (250-1469) µg/g ( P = 0.012) 3 months post-escalation. Endoscopic and transmural healing were achieved in 3 of 19 (16%) and 2 of 15 (13%) patients, respectively. Thirteen patients (18.8%) discontinued therapy due to active disease. No serious adverse events were reported. CONCLUSIONS: Two-thirds of children with active CD responded to dose escalation of UST. Milder disease activity may predict a favorable outcome following UST dose escalation.

Adalimumab vs Infliximab in Pediatric Patients With Crohn's Disease: A Propensity Score Analysis and Predictors of Treatment Escalation.

INTRODUCTION: Two antitumor necrosis factor therapies (infliximab [IFX] and adalimumab [ADA]) have been approved for the treatment of pediatric Crohn's disease (CD) but have not been compared in head-to-head trials. The aim of this study was to compare the efficacy and safety of ADA and IFX by propensity score matching in a prospective cohort of pediatric patients with luminal CD and at least a 24-month follow-up. METHODS: Among 100 patients, 75 met the inclusion criteria, and 62 were matched by propensity score. We evaluated time to treatment escalation as the primary outcome and primary nonresponse, predictors of treatment escalation and relapse, serious adverse events, pharmacokinetics, and effect of concomitant immunomodulators as secondary outcomes. RESULTS: There was no difference between ADA and IFX in time to treatment escalation (HR = 0.63 [95% CI 0.31-1.28] P = 0.20), primary nonresponse (P = 0.95), or serious adverse events. The median (interquartile range) trough levels at the primary outcome were 14.05 (10.88-15.40) and 6.15 (2.08-6.58) µg/mL in the ADA and IFX groups, respectively. On a multivariate analysis, the combination of anti-Saccharomyces cerevisiae antibody negativity and antineutrophil cytoplasmic antibody positivity was a strong independent predictor of treatment escalation (HR 5.19, [95% CI 2.41-11.18], P < 0.0001). The simple endoscopic score for CD, L3 disease phenotype, and use of concomitant immunomodulators for at least the first 6 months revealed a trend toward significance on a univariate analysis. DISCUSSION: Propensity score matching did not reveal substantial differences in efficacy or safety between ADA and IFX. The anti-S. cerevisiae antibody negativity and antineutrophil cytoplasmic antibody positivity combination is a strong predictor of treatment escalation.

Sexual function in adult females after feminizing genitoplasty for congenital adrenal hyperplasia.

OBJECTIVE: To investigate sexual function and subjective attitudes towards surgery in adult women after feminizing genitoplasty (FG) for congenital adrenal hyperplasia (CAH). MATERIALS AND METHODS: We retrospectively reviewed the medical files of patients who underwent FG from 1996 to 2018. Of those, patients older than 16 years of age were asked to answer non-standardized questions aiming at the awareness of genital surgery and standardized questionnaire evaluating sexual function (GRISS). The anonymized answers were compared to a control group of 50 healthy females. Student's t-test, Pearson's χ2 test, Fisher's exact test and Spearman's rank correlation coefficient were performed. A P-value less than 0.05 was considered significant. RESULTS: Out of 106 patients who underwent FG, 64 were included, 55 successfully contacted and 32, aged 17-40 years (median 25.5), answered the questionnaires (58% response rate). In all, 11 patients underwent historical clitorectomy in early childhood by a pediatric gynecologist before 1996 and pull-through vaginoplasty at puberty. A total of 21 patients underwent modern one- or two-staged FG. There were statistically significant differences between the CAH group and controls as to the proportion living in committed partnerships (28% and 84%, respectively; p = 0.0000), having sexual intercourse (41% and 92%, respectively; p = 0.0000) and having their own children (13% and 36%, respectively; p = 0.0369). The median overall GRISS score was 4 (range 1-7) in the CAH group compared to 1 (range 1-9) in the control group, with infrequency and vaginismus representing the least favorable subscales (median 5). In all, 81% of the women operated on for CAH would recommend such an operation to any other individual with CAH and 66% of them suggested the surgery should be performed in early childhood. DISCUSSION: By this study we have contributed to the debate over suggestions that FG may cause adverse effects on sexual life of the patients in adulthood, beside already published effects on their mental well-being and LUTS. Despite possible selection bias due to only 58% response rate the comparison with control group shows only a moderate sexual dysfunction and more significant impact on long-term partnership that might be caused by other factors related to CAH beside FG itself. CONCLUSIONS: Partnership, offspring, sexual frequency and function were impaired in adult females with CAH after FG. However, the median GRISS score was below the pathological level of 5.

Predictive value of tissue calprotectin for disease recurrence after ileocecal resection in pediatric Crohn's disease.

AIM: Detection of possible predictive factors of endoscopic recurrence after ileocecal resection in Crohn's disease could be very beneficial for the individual adjustment of postoperative therapy. The aim of this study was to verify, whether immunohistochemical detection of calprotectin in resection margins is useful in diagnostics of endoscopic recurrence. METHODS: In this study we included pediatric patients with Crohn's disease who underwent ileocecal resection, regardless of pre-operative or post-operative therapy (n=48). We collected laboratory, clinical, surgical, endoscopic and histopathological data at the time of surgery and at 6 months after surgery. The immunohistochemical staining of calprotectin antigen was performed on all paraffin blocks from the resection margins. RESULTS: Out of 48 patients 52% had endoscopic recurrence in the anastomosis (defined by Rutgeerts score) within 6 months after surgery. The number of cells positive for calprotectin in the proximal resection margin was negatively associated with recurrence (P=0.008), as was the elevated level of total calprotectin (from both resection margins). There was no correlation of calprotectin in distal resection margin and endoscopic recurrence. Fecal calprotectin over 100 ug/g (P=0.0005) and high CRP (P<0.001) at 6 months after ileocecal resection and peritonitis (P=0.048) were associated with endoscopic recurrence. CONCLUSION: Approximately half of the patients developed endoscopic recurrence within 6 months after ileocecal resection. The predictive value of tissue calprotectin is questionable, as it is negatively associated with endoscopic recurrence. There are other potentially useful predictors, such as CRP and fecal calprotectin at 6 months after resection and the presence of peritonitis.

Risk factors for dermatological complications of anti-TNF therapy in a cohort of children with Crohn's disease.

Studies showing a substantial frequency of dermatologic complications in paediatric Crohn's disease (CD) patients on anti-tumour necrosis factor (TNF) therapy preferentially include patients treated with infliximab. We aimed to identify risk factors for the cumulative incidence of skin complications in a paediatric cohort receiving either adalimumab or infliximab and found an association between current skin complications and the patient's current clinical condition. This study retrospectively evaluated dermatologic complications in an inception cohort of 100 paediatric CD patients receiving the first anti-TNF (Motol PIBD cohort). Patient data were collected every 3 months. The lesions were classified as psoriatic, atopic dermatitis, or others. We used Cox regression to evaluate the association between predefined variables and the time to complication and a generalised linear mixed model to assess the association between the patient's current condition and the occurrence of complications. Among the 89 included children, 35 (39%) presented with dermatologic lesions. The only predictor associated with any complication was infliximab (versus adalimumab) therapy (hazard ratio [HR]: 2.07; 95% confidence interval [CI]: 1.03-4.17; p = 0.04). Infliximab therapy (HR: 5.5; 95%CI: 1.59-19.06; p = 0.01) and a family history of atopy (HR: 3.4; 95%CI 1.35-8.57, p = 0.002) were associated with early manifestation of atopic dermatitis. Lower C-reactive protein levels (odds ratio [OR], 0.947; 95% CI, - 0.898 to 0.998; p = 0.046) and infliximab (versus adalimumab) were associated with the occurrence of any dermatologic complications (OR, 5.93; 95% CI, 1.59-22.07; p = 0.008).Conclusion: The frequency of skin complications seems high in paediatric CD patients treated with anti-TNF and is even higher in those treated with infliximab. What is Known: •The dermatologic complications occur during treatment with anti-tumour necrosis factor. •The frequency of skin complications in paediatric patients with Crohn's disease is high. What is New: •Infliximab (vs. adalimumab) was identified as a strong risk factor for the cumulative incidence of skin complications. •Lower C-reactive protein levels were associated with the current occurrence of dermatologic complications.

Is It Useful to Monitor Thiopurine Metabolites in Pediatric Patients with Crohn's Disease on Combination Therapy? A Multicenter Prospective Observational Study.

BACKGROUND: The additional value of azathioprine concomitant treatment on infliximab pharmacokinetics in children is not well described yet. AIMS: In the present study, we aimed to describe the relationship between thiopurine metabolite levels, infliximab trough levels, anti-IFX antibody formation, and clinical and laboratory markers of disease activity in pediatric patients with Crohn's disease, and to assess non-adherence. METHODS: Data were collected prospectively during repeated visits from pediatric patients followed for Crohn's disease in two Czech pediatric inflammatory bowel disease centers between January 2016 and June 2017. Thiopurine metabolites (6-thioguanine and 6-methylmercaptopurine) were measured by high-performance liquid chromatography. Infliximab trough levels and anti-IFX antibody serum levels were measured routinely by ELISA. The risk of loss of response to infliximab therapy was also assessed. RESULTS: A significant association between infliximab serum levels and 6-thioguanine erythrocyte levels was observed when tested as categorical variables (63 patients, 321 observations). To predict infliximab levels > 5 µg/mL, we propose a 6-thioguanine cutoff of 278 pmol/8 × 108 erythrocytes (sensitivity, 0.799; specificity, 0.347). A higher loss-of-response-to-infliximab rate (tested in a subgroup of 51 patients) was observed in patients with undetectable 6-thioguanine levels than in those with detectable levels (p = 0.026). Non-adherence to azathioprine therapy was suspected in 20% of patients. CONCLUSION: Thiopurine metabolite monitoring in pediatric patients with Crohn's disease is useful when optimizing combination therapy. Pediatric patients with undetectable 6-thioguanine levels are more likely to lose response to infliximab therapy. When targeting optimal infliximab levels, the 6-thioguanine cutoff levels in children appear to be higher than in adults.

Demographic and public health characteristics explain large part of variability in COVID-19 mortality across countries.

BACKGROUND: The numbers of coronavirus disease 2019 (COVID-19) deaths per million people differ widely across countries. Often, the causal effects of interventions taken by authorities are unjustifiably concluded based on the comparison of pure mortalities in countries where interventions consisting different strategies have been taken. Moreover, the possible effects of other factors are only rarely considered. METHODS: We used data from open databases (European Centre for Disease Prevention and Control, World Bank Open Data, The BCG World Atlas) and publications to develop a model that could largely explain the differences in cumulative mortality between countries using non-interventional (mostly socio-demographic) factors. RESULTS: Statistically significant associations with the logarithmic COVID-19 mortality were found with the following: proportion of people aged 80 years and above, population density, proportion of urban population, gross domestic product, number of hospital beds per population, average temperature in March and incidence of tuberculosis. The final model could explain 67% of the variability. This finding could also be interpreted as follows: less than a third of the variability in logarithmic mortality differences could be modified by diverse non-pharmaceutical interventions ranging from case isolation to comprehensive measures, constituting case isolation, social distancing of the entire population and closure of schools and borders. CONCLUSIONS: In particular countries, the number of people who will die from COVID-19 is largely given by factors that cannot be drastically changed as an immediate reaction to the pandemic and authorities should focus on modifiable variables, e.g. the number of hospital beds.

Lower Urinary Tract Symptoms in Adult Females after Feminizing Genitoplasty for Congenital Adrenal Hyperplasia.

PURPOSE: We investigated quality of life, long-term lower urinary tract symptoms, sexual function and subjective attitudes toward surgery in adult women after feminizing genitoplasty for congenital adrenal hyperplasia. MATERIALS AND METHODS: We retrospectively reviewed the medical files of all patients with congenital adrenal hyperplasia who underwent feminizing genitoplasty from 1996 to 2018 in our tertiary center. Of those, patients older than 16 years of age were asked to answer 1 nonvalidated and 3 standardized and validated questionnaires evaluating their current mental well-being (WHO-5 Well-Being Index), lower urinary tract symptoms (ICIQ-FLUTS) and sexual function (GRISS). The anonymized answers of this cross-sectional study were compared to a control group of 50 healthy females. Student's t-test, Pearson's χ2 test, Fisher's exact test and Spearman's rank correlation coefficient were performed. A p-value less than 0.05 was considered significant. RESULTS: Out of 106 patients who underwent feminizing genitoplasty, 64 patients were included and 32 patients, aged 17 to 40 years (median 25.5 years), answered the questionnaires (50% response rate). The difference between congenital adrenal hyperplasia and control group mental well-being was not statistically significant (WHO-5 median score 60 and 64, respectively; p=0.82). We found no significant difference in the lower urinary tract symptoms subscales of filling, voiding or incontinence, nor in the overall lower urinary tract symptoms score (ICIQ-FLUTS overall median score 3.5 and 3, respectively; p=0.43). CONCLUSIONS: We found in our group no abnormal mental well-being or prevalence of long-term symptoms of lower urinary tract dysfunction in adult female patients with congenital adrenal hyperplasia following feminizing genitoplasty.

The Impact of Anti-Tumor Necrosis Factor Alpha Therapy on Postoperative Complications in Pediatric Crohn's Disease.

INTRODUCTION: The incidence of Crohn's disease (CD) within the pediatric population is increasing worldwide. Despite a growing number of these patients receiving anti-tumor necrosis factor α therapy (anti-TNF-α), one-third of them still require surgery. There is limited data as to whether anti-TNF-α influences postoperative complications. We evaluated postoperative complications in patients who were or were not exposed to anti-TNF-α therapy in our institutional cohort. MATERIALS AND METHODS: A retrospective review of CD patients who underwent abdominal surgery between September 2013 and September 2018 was performed. The patients were divided into two groups based on whether they were treated with anti-TNF-α within 90 days before surgery. Thirty-day postoperative complications were assessed using Clavien-Dindo classification (D-C); this examination included surgical site infections (SSIs), stoma complications, intra-abdominal septic complications, non-SSIs, bleeding, ileus, readmission rate, and return to the operating room. Mann-Whitney U-test, Fisher's exact test, and multivariate logistic regression analyses were used for statistical analysis. RESULTS: Sixty-five patients (41 males) with a median age of 16 years (range: 7-19) at the time of operation were identified. The most common surgery was ileocecal resection in 49 (75%) patients. Forty-three (66.2%) patients were treated with anti-TNF-α preoperatively. Seven patients (11%) experienced postoperative complications. There was no statistically significant difference in postoperative complication in patients who did or did not receive anti-TNF-α before surgery (D-C minor 2.3% vs. 4.6%, p = 1; D-C major 7% vs. 9.1%, p = 1). CONCLUSION: The use of anti-TNF-α in pediatric CD patients within the 90 days prior to their abdominal surgery was not associated with an increased risk of 30-day postoperative complications.

Limited clinical significance of tissue calprotectin levels in bowel mucosa for the prediction of complicated course of the disease in children with ulcerative colitis.

BACKGROUND: Fecal calprotectin (F-CPT) represents one of the most widely used biomarkers for intestinal inflammation. However, the levels may be false negative or false positive in some situations. AIMS: To evaluate the usefulness of immunohistochemical (IHC) detection of tissue calprotectin (T-CPT) in bowel mucosa in children with ulcerative colitis (UC). We focused at correlation of T-CPT with levels of F-CPT and endoscopic and microscopic disease activity at the time of diagnosis and tested whether T-CPT could serve as predictor of complicated course of the disease. METHODS: Forty-nine children with newly diagnosed UC between 6/2010-1/2018 entered the study. Endoscopic activity was objectified using the Ulcerative Colitis Endoscopic Index of Severity (UCEIS), clinical activity by Pediatric Ulcerative Colitis Activity Index (PUCAI) and microscopic activity by Geboes and Nancy score. The IHC staining for CPT antigen was performed on bioptic samples from 6 bowel segments and the number of CPT + cells were counted per 1HPF. During the minimal follow-up of 12 months we searched for presence of complications. As outcome for Cox regression model we used composite endpoints: A) Acute Severe Colitis, colectomy, anti-TNF treatment; B) systemic corticotherapy; C) systemic 5-aminosalicylic acid therapy. RESULTS: Neither levels of T-CPT nor values of UCEIS, Geboes or Nancy score predicted the given complications. We found F-CPT levels (HR 2.42 and 2.52) and PUCAI > 40 points (HR 2.98) as predictors of time to endpoints B and C. Good correlation was found between T-CPT levels and Geboes score (k = 0.65) and Nancy score (k = 0.62) and modest with F-CPT (k = 0.44), UCEIS (k = 0.38) and PUCAI (k = 0.42). CONCLUSIONS: T-CPT correlated well with microscopic scores. F-CPT and PUCAI appear to be better predictors of unfavorable outcome in patients with UC.

Enteral Nutrition as a Growth Medium for Cultivable Commensal Bacteria and Its Effect on Their Quantity in the Stool of Children with Crohn's Disease.

Current studies indicate a link between the intake of exclusive enteral nutrition (EEN) and the induction of complex changes in the intestinal microbiota, as well as the clinical improvement of Crohn's disease (CD). The first aim of this study was to test the ability of various commensal bacterial strains (n = 19) such as bifidobacteria, lactobacilli, and Escherichia coli to grow on three different polymeric EN in vitro. Tested EN formulas were found to be suitable growth media for tested commensals. Furthermore, the counts of these bacteria and total counts of anaerobic bacteria in the fecal samples of children with CD (n = 15) before and after 6 weeks of EEN diet administration were determined using cultivation on selective media. The counts of cultivable commensal bacteria in the fecal samples of CD children were not significantly affected by EEN. However, tested bacteria showed some individual shifts in counts before and after EEN therapy. Moreover, cultured bifidobacteria were found to be in reduced counts in CD children. Therefore, the application of bifidogenic prebiotic compounds to EN for CD patients might be considered.

The Accuracy of a Home-performed Faecal Calprotectin Test in Paediatric Patients With Inflammatory Bowel Disease.

OBJECTIVES: Owing to the invasiveness of endoscopy, the use of biomarkers, especially faecal calprotectin (FC), has become standard for remission assessment. This study aimed to compare the accuracy for detection of endoscopic activity using recently developed FC home test using smartphone application (FC-IBDoc) against standard enzyme-linked immunosorbent assay (ELISA). METHODS: In all, 102 consecutive observations (89 participants) were included in prospective observational study. FC-IBDoc was performed parallelly with FC-ELISA in paediatric patients with inflammatory bowel disease indicated for endoscopy. Both tests were performed by trained staff. Mucosal healing was defined using Simple Endoscopic Score for Crohn disease (CD) ≤2 in patients with CD (n = 44), ulcerative colitis (UC) Endoscopic Index of Severity ≤4 in patients with UC (n = 27) and Rutgeerts score i0 and i1 without colon involvement in patients with CD after ileocaecal resection (n = 19). RESULTS: Out of 102 endoscopic findings 23 were assessed as mucosal healing. We found an association of the mucosal healing scores of the entire group both with FC-ELISA (P = 0.002) and FC-IBDoc (P = 0.001). The area under the receiver operating characteristic curve for FC-ELISA was 0.883 (95% confidence interval 0.807-0.960), with optimal cut-off at 136.5 µg/g. The area under the receiver operating characteristic curve for FC-IBDoc was 0.792 (95% confidence interval 0.688-0.895) with optimal cut-off at 48 µg/g. The FC-ELISA was more accurate than FC-IBDoc when tested by a Delong test (P = 0.023). CONCLUSIONS: Standard FC-ELISA for FC evaluation is more reliable predictor of mucosal healing than the FC-IBDoc in paediatric patients with inflammatory bowel disease. The cut-off values for both tests were incongruous.