Complementary feeding in infants born preterm: Aspects needing improvement.

Objective: The aim of our study was to collect data on complementary feeding (CF) in preterm infants (PIs). Methods: We enrolled PI ≤ 34 weeks of gestational age discharged from the neonatal intensive care unit (NICU) of the University Hospital of Padova. At 12 months of corrected age (CA), CF was investigated with questionnaires to the parents and a 24-h dietary recall. In a subgroup of newborns, we also evaluated bone status at a CA of 12 months using quantitative ultrasound. Results: We studied 167 ex PI at 1 year of CA. CF was introduced in 67.1% of them between 5 and 8 months of chronological age, with fruit as the first food (81%, n = 136). Sweet drinks were consumed by 17.4% of our sample, and salt was added in 33.5% of cases. PIs, at 1 year CA, introduced extra energy compared to the theoretical requirement (121 ± 31 kcal/kg/day) and higher protein intake than recommended (39 ± 11 g/day), while the intake of both total lipids and carbohydrates was slightly lower. Vitamins and minerals were adequate, except vitamin D. Regarding bone status, we found a correlation between vitamin D intakes from the diet and bone parameters (metacarpus-bone transmission time: r = 0.36, p = 0.01) at 1 year of CA. Conclusions: Our population of PIs started CF in agreement with current suggestions though with a notable heterogeneity and with some mistakes. Vitamin D intake was correlated with bone status at 1 year of CA.

Disseminated Mycobacterial Infection With Reactive Polyarthritis (Poncet's Disease) During Immune-suppressive Treatment Including Ustekinumab for Pediatric Crohn's Disease.

BACKGROUND: The incidence of pediatric inflammatory bowel disease is increasing. tumor necrosis factor alpha inhibitors medicines improved the prognosis of affected subjects. Nonetheless, a proportion of patients do not respond or lose response to treatment. Newer biologics, like ustekinumab, have been approved for adults. The pediatric off-label use of these drugs is increasing, despite limited safety evidence. We report a case of disseminated mycobacterial infection (MI) presenting with reactive polyarthritis (Poncet's disease, PD) in a girl with Crohn's disease receiving various immunosuppressants, including ustekinumab. CASE REPORT: A 12-year-old girl with Crohn's disease was admitted for acute-onset migratory polyarthritis of large and small joints and opioid-resistant pain. She had recently received adalimumab and methotrexate and was currently under treatment with ustekinumab. She was vaccinated with Bacillus Calmette-Guérin and screened for tuberculosis before starting immunosuppressants. Interferon-gamma release assay, Mantoux test and chest computed tomography scan were negative. Disseminated MI with PD was diagnosed following positive cultures for Mycobacterium tuberculosis complex in blood and intestinal biopsies (with negative in synovial fluid and gastric aspirate). Whole-exome sequencing did not identify any genetic susceptibility to MI. Antituberculosis treatment eradicated MI. CONCLUSIONS: Children with inflammatory bowel disease receiving combination immunosuppressive treatments including tumor necrosis factor alpha inhibitors and anti-IL-12/23 agents are at higher risk for MI. Disseminated MI should be considered and ruled out in these patients when presenting with pulmonary, extrapulmonary or unusual clinical manifestations, like PD. The collection of multiple specimens (including intestinal biopsies) for mycobacterial culture is recommended when mycobacterial disease is suspected.

The AngioVac System in Childhood and Adolescence: A New Venovenous Extracorporeal Membrane Oxygenation-Like Configuration.

Intravascular and intracardiac clots, thrombi, and vegetative material can be safely and effectively treated with the AngioVac System (AngioDynamics, Latham, NY) as an alternative to open surgery. However, this technology is still not performed in children or adolescents as a rule. We aimed to present our experience with two cases (a 10 year old girl and a 17 year old male adolescent) with concurrent hypoxemia in whom this device was successfully used in combination with venovenous extracorporeal membrane oxygenation to remove caval thrombi and cavoatrial septic material, respectively. This extracorporeal circuit configuration allowed adequate respiratory support during the procedure. No endovascular recurrence of the pathologic material was found at 2 and 1 year of follow-up, respectively.

Paediatric porto-sinusoidal vascular disease: Two different clinical phenotypes with subtle histological differences.

BACKGROUND AND AIMS: In paediatrics, porto-sinusoidal vascular disease (PSVD) is relatively unknown and probably underdiagnosed. We aimed to describe clinical phenotypes, histology and outcome of children diagnosed with PSVD. METHODS: Retrospective multicentre study of children diagnosed with PSVD. Diagnosis of PSVD was based on histopathology reports; liver specimens were re-evaluated by two expert liver pathologists. RESULTS: Sixty two children diagnosed with PSVD (M/F = 36/26, median age 6.6 years, range 3.3-10.6), from 7 centres, were included. Thirty-six presented with non-cirrhotic portal hypertension, PH, (PH-PSVD Group = 58%) while 26 had a liver biopsy because of chronic elevation of transaminases without PH (noPH-PSVD Group = 42%). On histology review, the two groups differed for the prevalence of obliterative portal venopathy (more prevalent in PH-PSVD, p = 0.005), and hypervascularised portal tracts (more common in noPH-PSVD, p = 0.039), the other histological changes were equally distributed. At multivariate analysis, platelet count ≤185 000/mm3 was the only independent determinant of PH (p < 0.001). After a median follow-up of 7 years (range 3.0-11.2), in PH-PSVD group 3/36 (8%) required TIPS placement, 5/36 (14%) developed pulmonary vascular complications of PH, and 7/36 (19%) required liver transplantation. In noPH-PSVD none progressed to PH nor had complications. CONCLUSIONS: Paediatric patients with PSVD present with two different clinical phenotypes, one characterised by PH and one by chronic elevation of transaminases without PH. PSVD should be included among the conditions causing isolated hypertransaminasaemia. On histology, the differences between the two groups are subtle. Medium-term outcome is favourable in patients without PH; progression of the disease is observed in those with PH.

Prevalence and detection rate of celiac disease in Italy: Results of a SIGENP multicenter screening in school-age children.

BACKGROUND: Celiac disease is a common lifelong disorder. Recent studies indicate that the number of clinically detected cases has increased over the last decades, however little is known about changes in the prevalence and the detection rate of celiac disease. AIM: To evaluate the current prevalence and detection rate of celiac disease in Italy by a multicenter, mass screening study on a large sample of school-age children. METHODS: children aged 5-11 years were screened at school by HLA-DQ2 and -DQ8 determination on a drop of blood in six Italian cities; total serum IgA and IgA anti-transglutaminase were determined in children showing HLA-DQ2 and/or -DQ8 positivity. Diagnosis of celiac disease was confirmed according to the European guidelines. RESULTS: 5994 children were eligible, 4438 participated and 1873 showed predisposing haplotypes (42.2%, 95% CI=40.7-43.7). The overall prevalence of celiac disease was 1.65% (95% CI, 1.34%-2.01%). Only 40% of celiac children had been diagnosed prior to the school screening. Symptoms evoking celiac disease were as common in celiac children as in controls. CONCLUSION: In this multicenter study the prevalence of celiac disease in school-age Italian children was one of the highest in the world. Determination of HLA predisposing genotypes is an easy and fast first-level screening test for celiac disease. Without a mass screening strategy, 60% of celiac patients remain currently undiagnosed in Italy.

Esophageal Dysphagia in Children: State of the Art and Proposal for a Symptom-Based Diagnostic Approach.

Pediatric esophageal dysphagia (PED) is an infrequent condition that can be determined by a large number of disorders. The etiologic diagnosis is challenging due to overlapping clinical phenotypes and to the absence of pediatric diagnostic guidelines. This review aims to summarize the most relevant causes of ED during childhood, highlight the clinical scenarios of PED presentation and discuss the indications of available diagnostic tools. Available information supports that PED should always be investigated as it can underlie life-threatening conditions (e.g., foreign body ingestion, mediastinal tumors), represent the complication of benign disorders (e.g., peptic stenosis) or constitute the manifestation of organic diseases (e.g., eosinophilic esophagitis, achalasia). Therefore, the diagnosis of functional PED should be made only after excluding mucosal, structural, or motility esophageal abnormalities. Several clinical features may contribute to the diagnosis of PED. Among the latter, we identified several clinical key elements, relevant complementary-symptoms and predisposing factors, and organized them in a multi-level, hierarchical, circle diagram able to guide the clinician through the diagnostic work-up of PED. The most appropriate investigational method(s) should be chosen based on the diagnostic hypothesis: esophagogastroduodenoscopy has highest diagnostic yield for mucosal disorders, barium swallow has greater sensitivity in detecting achalasia and structural abnormalities, chest CT/MR inform on the mediastinum, manometry is most sensitive in detecting motility disorders, while pH-MII measures gastroesophageal reflux. Further studies are needed to define the epidemiology of PED, determine the prevalence of individual underlying etiologies, and assess the diagnostic value of investigational methods as to develop a reliable diagnostic algorithm.

De novo Food Allergy After Pediatric Liver Transplantation: A Systematic Review.

Background: Liver transplant (LT) recipients, particularly children, have an increased risk of developing de novo food allergies (FAs) after transplantation both compared to all the other transplant groups and to the general population. Little is known about the pathogenesis underlying this phenomenon and comprehensive recommendations or clinical practice guidelines are still lacking, mainly due to the scarcity of high-quality evidence. Aim: We aimed to prepare a systematic review on de novo FA in pediatric LT recipients to assess epidemiology and risk factors, evaluate the correlation to specific food groups, describe clinical manifestations, investigate the rate of tolerance acquisition over time and report available therapeutic strategies. Methods: We conducted this systematic review according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). MEDLINE, Scopus, Web of Science, Wiley online library, Cochrane Library, and ClinicalTrials.gov databases were systematically searched for studies published from January 1980 to September 2021. All the articles were checked independently by two reviewers in two steps. A total of 323 articles were screened, and 40 were included for data extraction. Results and Conclusions: We found that de novo FAs develop in the 15% of pediatric LT recipients, especially in the first 2 years after surgery, with higher risk related to younger age at transplantation (especially <2 years of age) and tacrolimus immunosuppression. Subjects are often allergic to multiple foods, and 15% of them suffer from anaphylaxis. The majority of patients do not spontaneously outgrow their symptoms during follow-up. The discontinuation of tacrolimus in favor of cyclosporine or the association of tacrolimus with mycophenolate have been associated with the resolution or the improvement of FA in small retrospective case series and could be considered in case of severe or multiple, difficult to manage FAs. Prospective multicenter studies are needed to confirm these findings, guide the risk-based stratification of pediatric LT recipients, and provide for high-evidence therapeutic strategies for children with de novo FA.

Protective SARS-CoV-2 Antibody Response in Children With Inflammatory Bowel Disease.

BACKGROUND: To date, there's no evidence of an increased risk of SARS-CoV-2 infection or more severe COVID-19 in patients with inflammatory bowel disease (IBD). However, whether COVID-19 alters the clinical course of IBD or whether IBD treatment affects the immunological response to SARS-CoV-2 is still under investigation, especially in children. AIM: To assess the serological response to SARS-CoV-2 in children with IBD, and to evaluate the impact of COVID-19 on the clinical course of IBD. MATERIAL AND METHODS: This prospective study enrolled children (0-18 years) followed-up at the University Hospital of Padova for IBD, who acquired a confirmed SARS-CoV-2 infection between 02.2020 and 02.2021. The anti-SARS-CoV-2 S-RBD IgG titer was evaluated at 3 months after infection and compared to that of a control group of healthy children matched for age, sex, and COVID-19 severity. RESULTS: Twelve children with IBD (M = 5; median age 14 years) contracted COVID-19 during the study period. 11/12 patients were under immunomodulatory treatment (4/12 steroids; 6/12 azathioprine; 3/12 anti-TNFs; 2 vedolizumab; 1 ustekinumab). SARS-CoV-2 infection remained asymptomatic in 4/12 children and caused mild COVID-19 in the remaining 8. Mean anti-SARS-CoV-2 IgG S-RBD titer was similar between IBD patients and controls (27.3 ± 43.8 vs. 36.8 ± 35.3 kAU/L, p = ns). No children experienced IBD flares nor required gastroenterological support during the infection period. DISCUSSION: Children with IBD can mount a protective humoral response against SARS-CoV-2, which is comparable to that of their healthy peers regardless of ongoing immunomodulatory treatment. This study also supports the favorable course of PIBD during COVID-19 and vice-versa.

Diagnostic approach to neonatal and infantile cholestasis: A position paper by the SIGENP liver disease working group.

Neonatal and infantile cholestasis (NIC) can represent the onset of a surgically correctable disease and of a genetic or metabolic disorder worthy of medical treatment. Timely recognition of NIC and identification of the underlying etiology are paramount to improve outcomes. Upon invitation by the Italian National Institute of Health (ISS), an expert working grouped was formed to formulate evidence-based positions on current knowledge about the diagnosis of NIC. A systematic literature search was conducted to collect evidence about epidemiology, etiology, clinical aspects and accuracy of available diagnostic tests in NIC. Evidence was scored using the GRADE system. All recommendations were approved by a panel of experts upon agreement of at least 75% of the members. The final document was approved by all the panel components. This position document summarizes the collected statements and defines the best-evidence diagnostic approach to cholestasis in the first year of life.

Case Report: Intestinal Nodular Lymphoid Hyperplasia as First Manifestation of Activated PI3Kδ Syndrome Due to a Novel PIK3CD Variant.

Nodular lymphoid hyperplasia (NLH) is a lymphoproliferative disease caused by non-clonal expansion of lymphoid cells in the gut mucosa. Little is known about the pathogenesis of NLH, which is often disregarded as an insignificant or para-physiologic phenomenon. We present the case of a girl with isolated diffuse NLH (extending from the stomach to the rectum) caused by activated PI3Kδ syndrome (APDS) due to the novel p.Glu525Gly variant in PIK3CD. The gain-of-function effect of the variant was confirmed by demonstration of over activation of the Akt/mTOR pathway in the patient's cells. APDS diagnosis led to treatment with sirolimus, which resulted in the complete remission of NLH and in the prevention of extra intestinal complications. In conclusion, we identify APDS as a novel cause of isolated NLH and suggest that patients with severe pan-enteric NLH should be screened for this disorder that may not be apparent on first-line immunological testing.

Under-Vaccination in Pediatric Liver Transplant Candidates with Acute and Chronic Liver Disease-A Retrospective Observational Study of the European Reference Network TransplantChild.

Infection is a serious concern in the short and long term after pediatric liver transplantation. Vaccination represents an easy and cheap opportunity to reduce morbidity and mortality due to vaccine-preventable infection. This retrospective, observational, multi-center study examines the immunization status in pediatric liver transplant candidates at the time of transplantation and compares it to a control group of children with acute liver disease. Findings show only 80% were vaccinated age-appropriately, defined as having received the recommended number of vaccination doses for their age prior to transplantation; for DTP-PV-Hib, less than 75% for Hepatitis B and two-thirds for pneumococcal conjugate vaccine in children with chronic liver disease. Vaccination coverage for live vaccines is better compared to the acute control group with 81% versus 62% for measles, mumps and rubella (p = 0.003) and 65% versus 55% for varicella (p = 0.171). Nevertheless, a country-specific comparison with national reference data suggests a lower vaccination coverage in children with chronic liver disease. Our study reveals an under-vaccination in this high-risk group prior to transplantation and underlines the need to improve vaccination.

IFIH1 loss-of-function variants contribute to very early-onset inflammatory bowel disease.

Genetic defects of innate immunity impairing intestinal bacterial sensing are linked to the development of Inflammatory Bowel Disease (IBD). Although much evidence supports a role of the intestinal virome in gut homeostasis, most studies focus on intestinal viral composition rather than on host intestinal viral sensitivity. To demonstrate the association between the development of Very Early Onset IBD (VEOIBD) and variants in the IFIH1 gene which encodes MDA5, a key cytosolic sensor for viral nucleic acids. Whole exome sequencing (WES) was performed in two independent cohorts of children with VEOIBD enrolled in Italy (n = 18) and USA (n = 24). Luciferase reporter assays were employed to assess MDA5 activity. An enrichment analysis was performed on IFIH1 comparing 42 VEOIBD probands with 1527 unrelated individuals without gastrointestinal or immunological issues. We identified rare, likely loss-of-function (LoF), IFIH1 variants in eight patients with VEOIBD from a combined cohort of 42 children. One subject, carrying a homozygous truncating variant resulting in complete LoF, experienced neonatal-onset, pan-gastrointestinal, IBD-like enteropathy plus multiple infectious episodes. The remaining seven subjects, affected by VEOIBD without immunodeficiency, were carriers of one LoF variant in IFIH1. Among these, two patients also carried a second hypomorphic variant, with partial function apparent when MDA5 was weakly stimulated. Furthermore, IFIH1 variants were significantly enriched in children with VEOIBD as compared to controls (p = 0.007). Complete and partial MDA5 deficiency is associated with VEOIBD with variable penetrance and expressivity, suggesting a role for impaired intestinal viral sensing in IBD pathogenesis.

Novel CARMIL2 loss-of-function variants are associated with pediatric inflammatory bowel disease.

CARMIL2 is required for CD28-mediated co-stimulation of NF-κB signaling in T cells and its deficiency has been associated with primary immunodeficiency and, recently, very early onset inflammatory bowel disease (IBD). Here we describe the identification of novel biallelic CARMIL2 variants in three patients presenting with pediatric-onset IBD and in one with autoimmune polyendocrine syndrome (APS). None manifested overt clinical signs of immunodeficiency before their diagnosis. The first patient presented with very early onset IBD. His brother was found homozygous for the same CARMIL2 null variant and diagnosed with APS. Two other IBD patients were found homozygous for a nonsense and a missense CARMIL2 variant, respectively, and they both experienced a complicated postoperative course marked by severe infections. Immunostaining of bowel biopsies showed reduced CARMIL2 expression in all the three patients with IBD. Western blot and immunofluorescence of transfected cells revealed an altered expression pattern of the missense variant. Our work expands the genotypic and phenotypic spectrum of CARMIL2 deficiency, which can present with either IBD or APS, aside from classic immunodeficiency manifestations. CARMIL2 should be included in the diagnostic work-up of patients with suspected monogenic IBD.

Efficacy of Sofosbuvir/Ledipasvir in Adolescents With Chronic Hepatitis C Genotypes 1, 3, and 4: A Real-world Study.

OBJECTIVES: Sofosbuvir/Ledipasvir (SOF/LDV) has been approved by the European Medicine Agency (EMA) for the treatment of children and adolescents (at least 3 years of age) with chronic hepatitis C (CHC) genotype 1, 3, and 4 infection. The aim of this study was to evaluate the efficacy and safety of SOF/LDV in adolescents (12 to <18 years old) with CHC in the real-world setting. METHODS: Prospective, open-label, multicentre study involving 12 Italian centres. Patients received the fixed-dose combination of SOF/LDV (400/90 mg) once daily ± ribavirin as per EMA approval and recommendations. The key efficacy endpoint was sustained virological response 12 weeks after the end of treatment (SVR12) as per intention-to-treat analysis. Safety was assessed by adverse events and clinical/laboratory data. RESULTS: Seventy-eight consecutive adolescents (median age 15.2 years, range 12-17.9; girls 53.8%) were enrolled and treated between June 2018 and December 2019. Genotype distribution was as follows: genotype 1 (82.1%), 3 (2.5%), and 4 (15.4%). Seventy-six (97.4%) patients completed treatment and follow-up. Overall, SVR12 was 98.7%. One patient was lost to follow-up after 4 weeks of treatment; 1 patient completed treatment and missed the follow-up visit. No virological breakthrough or relapse were observed. No patient experienced grade 3 to 4 adverse event or serious adverse event. CONCLUSIONS: The results of this real-world study confirmed the high efficacy and the optimal safety profile of SOF/LDV for treatment of CHC in adolescents.

"Rendezvous" Procedure in Children with Cholecysto-Choledocholithiasis.

Introduction: Cholecysto-choledocolithiasis is a rare entity in children and its management is still challenging and controversial. The laparoendoscopic rendezvous (LERV) procedure, consisting of laparoscopic cholecystectomy and simultaneous endoscopic retrograde cholangiopancreatography for the management of symptomatic choledocholithiasis is well described in adult patients. However, in the literature, few reports about its application in the pediatric population have been recorded. Aim of the Study: The aim of the present study is to report our first successful cases of symptomatic cholecysto-choledocholithiasis LERV treatment. Methods: Two girls suffering of hemolytic disease presented to our third referral center with acute abdominal pain due to cholecysto-choledocholithiasis. Preoperative, perioperative, and postoperative data were retrospectively reviewed. Results: Surgery was performed without complications. The girls were dismissed once re-alimentation and re-canalization were achieved and had no other episodes of biliary cholic. Reported advantages of LERV include: a shorter in-hospital stay, a reduction in the number of procedures and anesthesia, and a reduced overall risk of complications. Conclusions: The promising result with our 2 cases suggest that, when performed in highly specialized centers, LERV is a safe procedure, which leads to considerable benefits, despite logistic and organizational difficulties.

Incidence of metabolic bone disease in preterm infants of birth weight <1250 g and in those suffering from bronchopulmonary dysplasia.

BACKGROUND & AIMS: Preterm infants are exposed to a higher risk of developing Metabolic Bone Disease (MBD) with an increased bone fragility, a higher fracture risk and a long-term reduced linear growth and childhood height. Monitoring bone growth has become mandatory in neonatology. Several risk factors have been identified among the population of extremely low birth weight infants, but we still do not know which is the real incidence of MBD since its evaluation is not routinely performed worldwide. The aim of this study was to evaluate the incidence of MBD in preterm infants and in those suffering from bronchopulmonary dysplasia (BPD). METHODS: Prospective evaluation of patients who developed BPD (BPD group) versus infants who did not develop it (no-BPD group). We examined, in preterms <1.250 g, the metacarpus bone transmission time (mc-BTT) at birth, 21 days and 36 weeks of gestational age (GA) together with biochemical markers of bone status. RESULTS: We included 135 patients, 55 with BPD. BPD patients received less total proteins in the first two weeks and less energy in the first month of life (p = 0.007 and p < 0.001 respectively). BPD patients had a worse growth velocity at two weeks of age (12.36 ± 7.86 vs 16.59 ± 7.05 g/kg/day, p = 0.001). At 21 days, BPD patients had lower phosphatemia (1.65 ± 0.031 mmol/L vs 1.85 ± 0.034 mmol/L, p = 0.007) and higher alkaline phosphatase levels (411.62 ± 135.31 IU/l vs 338.98 ± 102.20 IU/l, p = 0.005). BPD patients had significantly worse mc-BTT at 36 weeks GA (0.45 ± 0.06 vs 0.50 ± 0.08 µsec, p < 0.001) and a higher incidence of MBD (60% vs 34%; p = 0.012). CONCLUSIONS: BPD infants are a special subset of patients among preterms who receive, in the first month of life, a lower energy intake than patients without BPD. BPD patients have a suboptimal bone growth and a higher incidence of MBD. Monitoring growth, bone status and optimizing nutritional intakes need to be further improved in preterm infants with BPD.

Assessment of bone health in preterm infants through quantitative ultrasound and biochemical markers.

OBJECTIVE: To assess bone status in preterm infants with quantitative ultrasound and to search for biochemical markers of bone health. METHODS: Metacarpus bone transmission time (mcBTT) was prospectively performed during hospitalization, together with biochemical and clinical outcomes analysis. RESULTS: 154 patients were studied. At 3rd week of life mcBTT positively correlated with serum phosphate. Urinary excretion of calcium and phosphate were assessed in a subgroup of 55 patients: on day 21 mcBTT positively correlated with phosphaturia, negatively with calciuria. Gestational age (GA), weight and length at 3rd week and at 36 weeks of GA correlated positively with mcBTT. We found negative correlation between mcBTT at 3rd week and days of parenteral nutrition, mechanical ventilation period and days to reach 1800 g. CONCLUSIONS: Serum phosphate, phosphaturia and calciuria correlate most with mcBTT. Further studies are necessary to verify the possible influence of early bone status on future bone health.