ESPEN-ESPGHAN-ECFS guideline on nutrition care for cystic fibrosis.

BACKGROUND: Nutritional status is paramount in Cystic Fibrosis (CF) and is directly correlated with morbidity and mortality. The first ESPEN-ESPGHAN-ECFS guidelines on nutrition care for infants, children, and adults with CF were published in 2016. An update to these guidelines is presented. METHODS: The study was developed by an international multidisciplinary working group in accordance with officially accepted standards. Literature since 2016 was reviewed, PICO questions were discussed and the GRADE system was utilized. Statements were discussed and submitted for on-line voting by the Working Group and by all ESPEN members. RESULTS: The Working Group updated the nutritional guidelines including assessment and management at all ages. Supplementation of vitamins and pancreatic enzymes remains largely the same. There are expanded chapters on pregnancy, CF-related liver disease, and CF-related diabetes, bone disease, nutritional and mineral supplements, and probiotics. There are new chapters on nutrition with highly effective modulator therapies and nutrition after organ transplantation.

Effect of 18 months elexacaftor-tezacaftor-ivacaftor on body mass index and glycemic control in adults with cystic fibrosis.

BACKGROUND & AIMS: Malnutrition and cystic fibrosis related diabetes (CFRD) are common comorbidities in cystic fibrosis (CF). Cystic fibrosis transmembrane regulator (CFTR) modulators have shown beneficial effects on respiratory status. This study aims to determine the effect of elexacaftor-tezacaftor-ivacaftor (ETI) on body mass index (BMI) and glycemic control. METHODS: A retrospective, observational study of a cohort of 17 adult CF patients was conducted at the CF reference center of Ghent University Hospital. BMI evolution was analyzed 18 months before and 0, 3, 6, 12 and 18 months after the start of ETI. The evolution of insulin dependence and the 2 h oral glucose tolerance test (OGTT) results were described until 36 months after start of ETI, in a small subgroup of ten patients with CFRD or impaired glucose tolerance (IGT). RESULTS: A significant increase in mean BMI of 1.2 kg/m2 (±1.3 SD) was observed. Most weight gain was observed in the first 3 months after starting treatment. This effect was sustained during the observed period of 18 months. Six patients had insulin dependent CFRD, of which three were able to stop insulin after starting ETI. Two patients with CFRD treated with dietary measures showed an initial normalization of the 2 h OGTT, but deterioration at 36 month follow-up. CONCLUSIONS: After initiation of ETI an increase in BMI was observed in adults with CF. ETI can have a beneficial impact on glucose metabolism in patients with CFRD, leading to a possible need for reduction or cessation of insulin therapy.

Comparison of SARS-CoV-2 seroconversion in children with chronic diseases with healthy children and adults during the first waves of the COVID-19 pandemic.

Background: Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is clinically diverse, and children have a low risk of developing severe coronavirus disease 2019 (COVID-19). However, children with chronic diseases have a potentially increased risk. Methods: We performed a prospective surveillance study with longitudinal serum SARS-CoV-2 anti-nucleocapsid antibody quantification and questionnaires in pediatric tertiary care patients during the first waves of the COVID-19 pandemic (November 2020-September 2021). The results were compared with those of healthy children and adults from the same geographic area. Results: We obtained 525 samples from 362 patients (M/F ratio of 1.3:1; median age of 11.1 years) comprising children with immune-suppressive or immune-modulating drugs (32.9%), inborn errors of immunity (23.5%), type 1 diabetes mellitus (15.2%), and rheumatic diseases (11.9%). A total of 51 (9.7%) samples were seropositive among 37/351 children (10.5%). Seropositivity increased from 5.8% in November-December 2020 to 21.6% in July-September 2021. Compared with adults, a longitudinal analysis revealed reduced seroprevalence but similar kinetics as in children from the same country. Demographic or social variables and disease characteristics did not correlate with seropositivity. Being obese and household contact with COVID-19-infected individuals significantly increased the odds of infection. The majority of seropositive patients had mild symptoms (21/37). One-third were asymptomatic and/or unaware of having COVID-19 (10/37). Four patients (4/37) needed hospitalization, with good clinical outcomes. Conclusions: Although harboring a chronic disease, we observed a low SARS-CoV-2 incidence in a cohort of pediatric tertiary care patients, comparable with healthy children during the first year of the pandemic. Infection was mostly associated with mild symptoms.

Response to vitamin D replacement therapy in obese children and adolescents with vitamin D deficiency: a randomized controlled trial.

OBJECTIVES: Vitamin D deficiency is common in the pediatric group with obesity and is a risk factor for metabolic syndrome. Supplementation of vitamin D may require higher dosing than in normal-weight children. The aim of our study was to investigate the response of supplementation on vitamin D levels and the metabolic profile in youths with obesity. METHODS: Children and adolescents with obesity (Body mass index >2.3 SDS, age ≤18 years) and hypovitaminosis D (level <20 µg/L) who entered a residential weight-loss program in Belgium, were included during summer. Subjects were randomized: Group 1 received 6,000 IU vitamin D daily for 12 weeks, whereas Group 2 simultaneously participating in the weight-loss program received no supplementation. Differences in vitamin D levels, weight, insulin resistance, lipid patterns, and blood pressure after 12 weeks were assessed. RESULTS: A total of 42 subjects (12-18 years) with hypovitaminosis D were included, group 1 (n=22) received supplementation after randomization. After 12 weeks, a median increase in vitamin D levels of 28.2 (24.1-33.0) and 6.7 (4.1-8.4) µg/L was observed in group 1 and group 2, respectively (p-value<0.001), resulting in vitamin D sufficiency in 100 and 60% of subjects. No significant differences in weight loss (p-value 0.695), insulin resistance (p-value 0.078), lipid patterns (p-value 0.438), or blood pressure (p-value 0.511) were observed between both groups after 12 weeks of treatment. CONCLUSIONS: Supplementation with 6,000 IU vitamin D daily during 12 weeks in children and adolescents with obesity and hypovitaminosis D is safe and sufficient to reach vitamin D sufficiency. However, no positive effects on weight loss, insulin resistance, lipid patterns, or blood pressure were observed.

Glycemic indices at night measured by CGM are predictive for a lower pulmonary function in adults but not in children with cystic fibrosis.

INTRODUCTION: In patients with cystic fibrosis (CF), it is still unclear to which extent glucose abnormalities - preceding the diagnosis of cystic fibrosis related diabetes (CFRD) - are associated with pulmonary and nutritional outcome parameters. This study related circadian glycemic patterns to clinical outcomes in a group of CF patients not previously diagnosed with diabetes. METHODS: Continuous glucose monitoring (CGM) readings (7 days) of 47 CF patients (26 children, 21 adults) with an impaired oral glucose tolerance test (OGTT) (n = 25) and/or increased Hb1Ac (> 5.5%) were analyzed. Biometric, pulmonary function and clinical parameters were retrospectively collected over a period of 1 year before (T-1) and 1 year after (T + 1) CGM (T0). RESULTS: 96% (45/47) of CGM readings showed glucose values > 140 mg/dL ≥ 4.5% of the time and at least one ≥ 200 mg/dL. In the pediatric cohort, no significant associations were found between CGM parameters and pulmonary and nutritional outcome parameters. In the adult cohort, an area under the curve (AUC) > 140 mg/dL and%-time > 140 mg/dL during the night were associated with a lower forced expiratory volume in 1 s (FEV1)% predicted (pp) at time of evaluation but not with change in FEV1pp. CONCLUSION: This is the first study reporting the circadian glycemic pattern in children and adults at risk for CFRD. In the adult cohort an association between detection of abnormal glucose exposure and a lower FEV1pp was found. Our results support continued screening for glucose intolerance in patients with CF.

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.

Altered intravenous drug disposition in people living with cystic fibrosis: A meta-analysis integrating top-down and bottom-up data.

Cystic fibrosis (CF) has been linked to altered drug disposition in various studies. However, the magnitude of these changes, influencing factors, and underlying mechanisms remain a matter of debate. The primary aim of this work was therefore to quantify changes in drug disposition (top-down) and the pathophysiological parameters known to affect pharmacokinetics (PKs; bottom-up). This was done through meta-analyses and meta-regressions in addition to theoretical PK simulations. Volumes of distribution and clearances were found to be elevated in people living with CF. These increases were larger in studies which included patients with pulmonary exacerbations. Differences in clearance were smaller in more recent studies and when results were normalized to body surface area or lean body mass instead of body weight. For the physiological parameters investigated, measured glomerular filtration rate and serum cytokine concentrations were found to be elevated in people living with CF, whereas serum albumin and creatinine levels were decreased. Possible pathophysiological mechanisms for these alterations relate to renal hyperfiltration, increases in free fraction, and inflammation. No differences were detected for cardiac output, body fat, fat free mass, hematocrit, creatinine clearance, and the activity of drug metabolizing enzymes. These findings imply that, in general, lower total plasma concentrations of drugs can be expected in people living with CF, especially when pulmonary exacerbations are present. Given the potential effect of CF on plasma protein binding and the variability in outcome observed between studies, the clinical relevance of adapting existing dosage regimens should be evaluated on a case-by-case basis.

Apoptotic enteropathy, gluten intolerance, and IBD-like inflammation associated with lipotoxicity in DGAT1 deficiency-related diarrhea: a case report of a 17-year-old patient and literature review.

We present a long-term follow-up in a 17-year-old girl with DGAT1-related diarrhea, an autosomal recessive disorder characterized by impaired triglyceride absorption. Neonatal presentation included severe congenital diarrhea, protein-losing enteropathy, and failure to thrive requiring total parenteral nutrition. Duodenal biopsies revealed apoptotic enteropathy and acute inflammation with the presence of macrophages and Touton giant cells, related to the intake of fat. She was able to switch to enteral nutrition on a fat-free diet. However, at age 10, she developed gluten-induced enteropathy and then IBD-like inflammation 5 years later. Immunohistochemistry was able to confirm the diagnosis, while DGAT1 sequencing remained inconclusive. This highlights the role of histopathology and immunohistochemistry, despite the increasing importance of genetic analysis in the diagnostic work-up. This report also illustrates that parenteral nutrition weaning is possible in DGAT1-related diarrhea, but gut barrier dysfunction might increase the risk of autoimmune intestinal disease.

Novel CFTR modulator combinations maximise rescue of G85E and N1303K in rectal organoids.

Introduction: Cystic fibrosis (CF) is a severe monogenic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Several types of CFTR modulators (correctors/potentiators) have been developed to overcome protein dysfunction associated with these mutations. CFTR modulator therapy is now available for the major CF-causing mutations; however, 10% of people with CF remain without causal treatments. By combining investigational and market-approved CFTR modulators, we aimed to maximise functional rescue of iva-, luma- and tezacaftor refractory mutants G85E and N1303K. Methods: We used the well-established forskolin-induced swelling (FIS) in primary rectal organoids to assess responses to different CFTR corrector and potentiator types. The FIS analysis was performed with brightfield microscopy, allowing both 1-h and 24-h follow-up. Corrector and potentiator activity of elexacaftor was investigated. Results: For G85E, maximal rescue was observed by a combination of elexacaftor and corr4a. For N1303K, the quadruple combination teza-elexa-ivacaftor with apigenin was required to obtain a rescue similar to that of luma-ivacaftor rescued F508del. Elexacaftor rescued G85E and N1303K by different mechanisms, with chronic corrector effects on G85E and acute potentiation of N1303K only in the presence of ivacaftor. Synergy in N1303K rescue for iva-elexacaftor and apigenin suggests at least three potentiator mechanisms for this mutant. 24-h FIS identified ivacaftor as the main CFTR modulator for N1303K and elexacaftor and apigenin as co-potentiators. Conclusions: Novel combinations of CFTR modulators can further improve functional rescue of G85E and N1303K in rectal organoids, although for N1303K, more effective CFTR modulators are still needed.

Time Is Money in Case of a Button Battery Ingestion.

Button battery (BB) ingestion is a preventable pediatric health hazard with important morbidity and mortality due to complications. We present 3 pediatric patients with a complicated course after BB ingestion and discuss current guidelines. Urgent endoscopic removal is necessary for every BB impacted in the esophagus. A new strategy before endoscopic removal is the administration of honey or sucralfate. During endoscopy, rinsing the esophageal mucosae with acetic acid can neutralize the alkalic environment and prevent late complications. Prevention of ingestion needs to be pursued by increasing awareness and changing legislation of packaging of BB.

Intensive Lifestyle Management Improves Steatosis and Fibrosis in Pediatric Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: Childhood obesity, with associated comorbidities such as nonalcoholic fatty liver disease (NAFLD), is an increasing global health problem. Although lifestyle management is the mainstay of treatment, its efficacy on liver fibrosis has not yet been established. METHODS: Children and adolescents admitted for severe obesity at a tertiary center (Zeepreventorium, De Haan, Belgium) were enrolled in this prospective study. Intensive lifestyle therapy encompassed caloric restriction, physical activity, education on a healthy lifestyle, and psychosocial support. At baseline, 6 months, and 12 months, liver ultrasound and transient elastography with controlled attenuation parameter were performed to assess liver steatosis and fibrosis. RESULTS: A total of 204 patients (median age, 14.0 y; body mass index Z-score, +2.8) were evaluated at admission. NAFLD on ultrasound was present in 71.1%, whereas 68.6% had controlled attenuation parameter values of 248 dB/m or greater. A total of 32.8% of patients had at least F2 fibrosis, including 10.3% with transient elastography of 9 kPa or greater. After 6 months, the median body weight loss was 16.0% in the 167 patients evaluated. Fibrosis improved in 75.0% (P < .001). Baseline severity of liver fibrosis and steatosis were predictors of fibrosis resolution. Seventy-nine patients had reached the 1-year time point. The improvements were sustained because fibrosis regressed at least 1 stage in all patients with baseline fibrosis. Fasting serum alanine aminotransferase and homeostasis model assessment of insulin resistance decreased significantly over the 1-year period (P < .001). CONCLUSIONS: NAFLD and associated fibrosis are highly prevalent in children and adolescents with severe obesity. An intensive multidisciplinary lifestyle management program that causes significant weight loss not only improves liver steatosis, but also fibrosis.

Urinary sodium/creatinine ratio is a predictor for fractional sodium excretion and related to age in patients with cystic fibrosis.

Electrolyte disturbances are common in patients with cystic fibrosis (CF). Current guidelines on monitoring sodium status are based on research in a small group of infants and require blood sampling. The aim of this study was to evaluate urinary salt parameters as a surrogate for sodium-status in different age-groups. Blood and urine samples for electrolytes were collected from 222 patients followed at the Ghent University Hospital CF-center. Fractional sodium excretion (FENa) and several urinary parameters were calculated. Clinical characteristics did not differ according to sodium status, defined as FENa <0.5%. ROC analysis demonstrated that sodium/creatinine ratio (UNa/Creat) predicted the sodium status most accurately with high sensitivity and specificity (97 and 91% respectively). The UNa/Creat cut-off predicting a FENa <0.5% differed significantly according to age. The UNa/Creat is an excellent marker for the sodium status defined as a FENa <0.5%. However, different cut-offs according to age category should be applied.

Non-invasive assessment of liver abnormalities in pediatric Fontan patients.

Liver abnormalities are well known among long-term survivors of Fontan palliation, which remains the definite surgery for complex congenital heart disease and single ventricle physiology. Pediatric data however are scarce. We assessed the prevalence and degree of liver abnormalities in pediatric Fontan patients through non-invasive investigations suitable for longitudinal follow-up. Thirty-five patients with a median age of 11.8 years (5.2-16.6) and median time since Fontan of 6 years (1.17-13.83) were studied. Each child underwent a blood test, liver Doppler ultrasound (US), and transient elastography (TE). Healthy children were used as controls for TE measurement. AST, ALT, γGT, and direct bilirubin were abnormal in respectively 12 (34%), 5 (14%), 24 (69%), and 7 (20%) patients, while platelet count was decreased in 7 (20%). Splenomegaly was present in 7 (20%) patients. Portal vein mean flow velocity was < 15 cm/s in 19 (54%) patients indicative of portal hypertension. Twenty-two patients (63%) showed inferior vena cava collapsibility index values below 17%, indicating venous congestion. Hepatic artery and superior mesenteric artery resistance index were inversely correlated with time post Fontan (p < 0.05). TE values in Fontan patients were significantly higher than controls, with a median of 12.6 versus 4.6 kPa (p < 0.001) and were already increased shortly after Fontan completion. Conclusion: Liver abnormalities are frequently observed in pediatric Fontan patients. The non-invasive investigations used were not able to confirm liver fibrosis or differentiate hepatic congestion from fibrosis. Based on our findings, we propose a prospective screening protocol with serial measurements of laboratory, (Doppler) US, and TE parameters. What is Known: • Hepatic dysfunction is a well-known consequence of the Fontan circulation. • The natural history of Fontan-associated liver disease in the pediatric age group remains unclear. What is New: • Liver abnormalities are frequently observed in pediatric Fontan patients; however, differentiating liver fibrosis and hepatic congestion with non-invasive investigations remains challenging. Sonographic Doppler measurements may improve our insight in both Fontan-associated liver disease development and the functioning of the Fontan circulation. • A prospective screening protocol is proposed to improve our ability to detect Fontan-associated liver disease early on and understand its natural history.

Efficacy of anti-TNF dosing interval lengthening in adolescents and young adults with inflammatory bowel disease in sustained remission (FREE-study): protocol for a partially randomised patient preference trial.

INTRODUCTION: Anti-tumour necrosis factor (TNF) therapy has greatly improved treatment outcomes in patients with inflammatory bowel disease (IBD), but long-term use is associated with cutaneous reactions, susceptibility to infections and frequent injections or hospital visits. Several non-controlled studies have demonstrated that dose reduction is feasible for a subset of patients, provided that early detection of a disease flare is possible. Here, we aim to compare the effectiveness of interval lengthening with standard dosing in maintaining remission in young patients with IBD. METHODS AND ANALYSIS: In this international, prospective, non-inferiority, partially randomised patient preference trial, we aim to recruit 148 patients aged 12-25 years with luminal Crohn's disease or ulcerative colitis in sustained remission (ie, three consecutive in-range faecal calprotectin (FC) results or recently confirmed endoscopic remission). In the interventional arm, the dosing interval will be lengthened from 8 to 12 weeks for infliximab users and from 2 to 3 weeks for adalimumab users. In the control group, standard dosing will be continued. Rapid tests will be performed for FC every 4 weeks and for anti-TNF trough levels every 12 weeks. The primary outcome is the cumulative incidence of out-of-range FC results at 48-week follow-up. Secondary endpoints include time to get out-of-range FC results, cumulative incidence of adverse effects, proportion of patients progressing to loss of response and identification of predictors of successful interval lengthening. ETHICS AND DISSEMINATION: The protocol has been approved by the Medical Ethics Review Committee of the University Medical Centre Groningen and is pending at the other participating centres. Results will be disseminated in peer-reviewed journals and presented at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number: 2020-001811-26; ClinicalTrials.gov Identifier: NCT04646187. Protocol version 4, date 17 September 2021.

Two cases of DCDC2-related neonatal sclerosing cholangitis with developmental delay and literature review.

Ciliopathies are a group of clinical and molecular heterogeneous conditions with pleiotropic manifestations affecting the central nervous system, renal, liver, skeletal, and ocular systems. Biallelic pathogenic variants in DCDC2 cause a ciliopathy primarily presenting with neonatal sclerosing cholangitis (NSC). Pathogenic variants in DCDC2 have further been reported in the context of nephronophthisis and non-syndromic recessive deafness. Polymorphisms in DCDC2 have also been associated with dyslexia and DCDC2 has a role in neuronal development. We report on two unrelated patients with DCDC2-related NSC with additional central nervous system impairment manifesting as microcephaly, global developmental delay, and axial hypotonia. Histological findings of our patients can mimic biliary atresia or congenital hepatic fibrosis. We further show that transmission electron microscopy in patients with NSC does not always show absence of primary cilia. Hence patients with DCDC2 pathogenic variants should also undergo an evaluation of neuromotor development. Review of all reported patients further reveals a risk for supra-aortic arterial aneurysms.

The effect of an intensive residential rehabilitation program on body composition in patients with cystic fibrosis.

The pulmonary function of patients with cystic fibrosis (CF) is associated with nutritional status not only expressed as body mass index (BMI) but also as fat-free mass index (FFMI). This study evaluated the effect of a residential rehabilitation program on nutritional status (BMI, FFMI). The rehabilitation program provided supervised respiratory and nutritional treatment and daily physical activity for 3 weeks (median stay 20 (19-25) days). At the start and the end of the program, weight, height, pulmonary function, and body composition using dual-energy X-ray absorptiometry were prospectively collected. Supervised weighed food records were obtained, and physical activity intensity was measured using a SenseWear Pro3 Armband. CF-related complications were collected from the patient. Thirty-four patients (21 males, median age 18 years old (12-27)) were included. The diet contained a median of 30 EN% fat, 16 EN% protein, and 52 EN% of carbohydrates. A significant median weight gain (+1.45 kg (0.58; 2.6) (p < 0.0001) and a significant increase in BMI (+0.24 kg/m2 (0.11; 0.38)) (p < 0.0001), FFMI (+0.26 kg/m2 (0.01; 0.55)) (p < 0.0001), and FMI (+0.19 kg/m2 (0.04; 0.41)) (p < 0.0001) were obtained.Conclusion: A short rehabilitation program in individuals with CF between 6 and 40 years old is able to improve nutritional status and body composition.Trial registration: NCT04527796 What is Known: • Fat-free mass depletion is frequently present in CF. • In CF pulmonary function is associated with nutritional status measured as body mass index but also fat-free mass index. What is New: • Nutritional status and body composition improve significantly after a short-term rehabilitation program. • The rehabilitation program was able to improve nutritional outcome even with a diet containing less fat than currently advised in the guidelines.

Successful liver transplantation in hyperornithinemia-hyperammonemia-homocitrullinuria syndrome: Case report.

BACKGROUND: HHH syndrome is a rare autosomal recessive disorder of the urea cycle, caused by a deficient mitochondrial ornithine transporter. We report the first successful liver transplantation in HHH syndrome performed in a seven-year-old boy. The patient presented at 4 weeks of age with hyperammonemic coma. The plasma amino acid profile was suggestive of HHH syndrome, and the diagnosis was confirmed when sequencing of the SLC25A15 gene identified two mutations p.R275Q and p.A76D. Although immediate intervention resulted in normalization of plasma ammonia levels within 24 hours, he developed cerebral edema, coma, convulsions, and subsequent neurological sequelae. Metabolic control was difficult requiring severe protein restriction and continued treatment with sodium benzoate and L-arginine. Despite substantial developmental delay, he was referred to our center for liver transplantation because of poor metabolic control. Following cadaveric split liver transplantation, there was complete normalization of his plasma ammonia and plasma amino acid levels under a normal protein-containing diet. This excellent metabolic control was associated with a markedly improved general condition, mood and behavior, and small developmental achievements. Twelve years after liver transplantation, the patient has a stable cognitive impairment without progression of spastic diplegia. CONCLUSION: This first case of liver transplantation in HHH syndrome demonstrates that this procedure is a therapeutic option for HHH patients with difficult metabolic control.

Autoantibodies and Donor-specific Antibodies are Associated With Graft Dysfunction in Pediatric Liver Transplantation.

OBJECTIVES: Autoantibodies (AAb) and donor-specific HLA antibodies (DSA) are frequently present in pediatric liver transplant (LT) recipients. Their clinical significance remains incompletely understood. We aimed to investigate the prevalence of serum AAb and DSA in pediatric LT recipients and its correlation with patient characteristics and histological and biochemical parameters. METHODS: We retrospectively reviewed the data from 62 pediatric LT patients in follow-up at Ghent University Hospital between January 2007 and February 2018. Blood samples with AAb measurement were taken systematically, liver biopsies (LB) were performed on clinical indication. RESULTS: AAb were detected in 27 (43.3%) patients, with antinuclear antibodies (ANA) being the most frequently (24%) encountered AAb. There was an association between AAb positivity and female gender (P = 0,032) and deceased donor LT (P = 0,006). Patients with positive AAb underwent a higher number of LB during their follow-up (P < 0,001), and an association was found with the presence of nonspecific histologic alterations (P = 0,032) in the absence of de novo autoimmune hepatitis. Positive AAb were also associated with higher alkaline phosphatase (P < 0,001), ALT (P < 0,001), AST (P < 0,001), γ-GT (P = 0,001), IgG (P = 0,011) and lower albumin (P = 0,029). Fourteen out of 50 (28%) patients were DSA-positive, mostly anti-HLA class II. DSA positivity was associated with T-cell-mediated rejection (P = 0,019), higher total (P = 0,033), and direct (P = 0,012) bilirubin and γ-GT (P < 0,001). CONCLUSIONS: The presence of AAb and DSA is associated with histological and biochemical parameters of graft dysfunction. Larger prospective studies are warranted to investigate the causal relationships between AAb and DSA development and outcome parameters post pediatric LT.

Infliximab in young paediatric IBD patients: it is all about the dosing.

Infliximab (IFX) is administered intravenously using weight-based dosing (5 mg/kg) in inflammatory bowel disease (IBD) patients. Our hypothesis is that especially young children need a more intensive treatment regimen than the current weight-based dose administration. We aimed to assess IFX pharmacokinetics (PK), based on existing therapeutic drug monitoring (TDM) data in IBD patients < 10 years. TDM data were collected retrospectively in 14 centres. Children treated with IFX were included if IFX was started as IBD treatment at age < 10 years (young patients, YP) and PK data were available. Older IBD patients aged 10-18 years were used as controls (older patients, OP). Two hundred and fifteen paediatric inflammatory bowel disease (PIBD) patients were eligible for the study (110 < 10 year; 105 ≥ 10 years). Median age was 8.3 years (IQR 6.9-8.9) in YP compared with 14.3 years (IQR 12.8-15.6) in OP at the start of IFX. At the start of maintenance treatment, 72% of YP had trough levels below therapeutic range (< 5.4 µg/mL). After 1 year of scheduled IFX maintenance treatment, YP required a significantly higher dose per 8 weeks compared with OP (YP; 9.0 mg/kg (IQR 5.0-12.9) vs. OP; 5.5 mg/kg (IQR 5.0-9.3); p < 0.001). The chance to develop antibodies to infliximab was relatively lower in OP than YP (0.329 (95% CI - 1.2 to - 1.01); p < 0.001), while the overall duration of response to IFX was not significantly different (after 2 years 53% (n = 29) in YP vs. 58% (n = 45) in OP; p = 0.56).Conclusion: Intensification of the induction scheme is suggested for PIBD patients aged < 10 years. What is Known? •Infliximab trough levels of paediatric IBD patients are influenced by several factors as dosing scheme, antibodies and inflammatory markers. •In 4.5-30% of the paediatric IBD patients, infliximab treatment was stopped within the first year. What is New? •The majority of young PIBD (< 10 years) have inadequate IFX trough levels at the start of maintenance treatment. •Young PIBD patients (< 10 years) were in need of a more intensive treatment regimen compared with older paediatric patients during 1 year of IFX treatment. •The chance to develop antibodies to infliximab was relatively higher in young PIBD patients (< 10 years).

Pharmacokinetics in Patients with Cystic Fibrosis: A Systematic Review of Data Published Between 1999 and 2019.

BACKGROUND: Cystic fibrosis is a lethal inherited disease that affects multiple organs. To provide optimal pharmacological treatment of comorbidities associated with cystic fibrosis, relevant alterations in pharmacokinetics must be known. OBJECTIVE: The objective of this study was to compare the pharmacokinetics of drugs between patients with cystic fibrosis and controls, based on clinical study reports published from 1999 to 2019. METHODS: Clinical studies were considered if patients with cystic fibrosis and patients without cystic fibrosis/healthy volunteers were included, a drug was administered orally/intravenously and pharmacokinetic parameters were compared. RESULTS: In total, 32 clinical studies were included. Twenty-one studies reported absorption parameters. For multiple drugs, speed and/or extent of oral absorption were lower in cystic fibrosis. This phenomenon is possibly related to pathophysiological changes in the gastrointestinal tract associated with cystic fibrosis. However, a large proportion of drugs had comparable absorption kinetics. Twenty-one studies discussed volume of distribution, which was comparable between groups for most drugs. Initial differences became smaller when scaled to body composition. For some highly protein-bound drugs, inflammation-related changes in plasma proteins helped explain residual variability between cystic fibrosis and controls. Twenty-four studies elaborated on clearance, whereby higher clearances were observed in cystic fibrosis. In contrast with previously published reviews, no evidence was found for increased activities of drug-metabolising enzymes nor for up-regulation of active transport processes involved in drug disposition. In most cases, scaling clearance parameters to body composition and/or incorporating differences in plasma protein concentration accounted for these larger clearances. IMPLICATIONS: There is no evidence that genetic defects causing cystic fibrosis directly lead to altered pharmacokinetics. However, co-morbidities can have a potential impact on drug absorption and disposition. Because of gastrointestinal complications, it is not advisable to extrapolate drug absorption parameters from healthy volunteers to patients with cystic fibrosis. Differences observed in the volume of distribution and clearance in patients with cystic fibrosis can potentially be explained by correcting for lean body mass.