Search

In children affected by malignancies and/or who received hematopoietic stem cell transplantation (HSCT), acute kidney injury (AKI) may occur causing a high mortality rate, despite the implementation of renal replacement therapy (RRT). We performed a nationwide, multicenter, retrospective, observational cohort study including consecutive patients between January 2010 and December 2019. One hundred and fourteen episodes of AKI requiring RRT coming from nine different Italian centers were included. The overall mortality rate was 61.4%. At the 3-month follow-up, the mortality rate was 47.4%. The mortality rate was higher in transplanted patients than those receiving chemotherapy. In particular, HSCT (

T-cell replete hematopoietic stem cell transplantation (HSCT) from a haploidentical donor followed by high doses of cyclophosphamide has been demonstrated to provide the best chances of a cure for many children in need of an allograft but who lack both a sibling and an unrelated donor. In this study we retrospectively compared the outcome of pediatric patients undergoing T-replete haploidentical HSCT (Haplo) for acute leukemia with those undergoing transplantation from unrelated HLA-matched donor (MUD) and HLA mismatched unrelated donor (MMUD) from 2012 to 2017 at our Center. Both univariable and multivariable analyses showed similar 5-year overall survival rates for MUD, MMUD, and Haplo patients: 71% (95% CI 56-86), 72% (95% CI 55-90), and 75% (95% CI 54-94), respectively (p = 0.97). Haplo patients showed reduced event-free survival rates compared to MUD and MMUD patients: 30% (95% CI 12-49) versus 70% (95% CI 55-84) versus 53% (95% CI 35-73), respectively (p = 0.007), but these data were not confirmed by a multivariable analysis. Non-relapse mortality (NRM) and relapse incidence (RI) were similar for the three groups. Therefore, our data confirm that Haplo is a suitable clinical option for pediatric patients needing HSCT when lacking both an MUD and an MMUD donor.

Prognosis of relapsed leukemia patients after second allogeneic hematopoietic stem cell transplantation (HSCT2) is historically considered very poor. We report the outcome of 18 pediatric patients after failure of HSCT2. The 2-year overall survival was 26% (95% confidence interval [CI], 6-47). The lymphoid malignancies were associated with better survival (40% [95% CI, 12-68]) than myeloid malignancies (0%, P=0.002), together with time to relapse after the HSCT2 (≥5 mo: 44% [95% CI, 12-76] vs. 0% for patients who relapsed within 5 mo from HSCT2, P=0.005), other factors such as sex, donor type, conditioning regimen, and graft versus host disease prophylaxis did not have statistical significance. When the multivariate analysis was carried out, 2 independent protective factors were identified: the lymphoid malignancies and the graft versus host disease 0 to I after HSCT2. When we look at the treatments, patients receiving blinatumomab after relapse got benefit in terms of overall survival and, more importantly, with a long-term control of acute lymphoblastic leukemia.

BACKGROUND Despite efforts made to prevent the spread of multi-drug-resistant bacteria, carbapenemase-producing Enterobacteriaceae (CPE) has become one of the most dangerous threat worldwide. However, data on the epidemiology of CPE and on the correlation between CPE colonization and infection are scanty. The objectives of this study were first to describe the epidemiological characteristics of colonizations and invasive CPE infections in the pediatric population, and second, to apply the Giannella Risk Score (GRS) to the pediatric population for the assessment of the risk of invasive CPE infection in patients with already known colonization. METHODS Pediatric patients with evidence of colonization by CPE were retrospectively enrolled. For each colonized patient, the subsequent development of an infection by CPE was then assessed for a 90-day period after the first CPE isolation; GRSs were compared between patients who had developed any type of CPE infection and those without infection. RESULTS A total of 215 patients (113 males and 102 females) with at least 1 isolation of CPE during hospitalization were analyzed. Median age was 5.6 years [interquartile range (IQR), 1.89-12.2 years]. Overall, 28 CPE infections (13%) were documented: 23 blood stream infections and 5 complicated urinary tract infections. The 30-day mortality of invasive CPE infections was 34.8%. The GRS values in patients with any CPE infection were statistically higher than in noninfected patients: median GRS 9 (IQR, 4-12.5) versus 4 (IQR, 2-4), respectively; P < 0.0001. The analysis of the receiver operating characteristic curves identified a GRS cut-off value ≥8 as the best predictor of CPE infection. The likelihood ratio of the results was

Background: Previous studies have shown that children and adolescents with COVID-19 generally have mild disease. Children and adolescents with cancer, however, can have severe disease when infected with respiratory viruses. In this study, we aimed to understand the clinical course and outcomes of SARS-CoV-2 infection in children and adolescents with cancer. Methods: We did a cohort study with data from 131 institutions in 45 countries. We created the Global Registry of COVID-19 in Childhood Cancer to capture de-identified data pertaining to laboratory-confirmed SARS-CoV-2 infections in children and adolescents (

So far, we do not have any published database regarding HCT patients during the present pandemic. We herein describe the first case of COVID-19 presenting in the early hematopoietic cell transplantation (HCT) setting.

Introduction: Central venous accesses devices (CVADs) have a fundamental importance for diagnostic and therapeutic purposes in pediatric onco-hematological patients. The treatment of pediatric onco-hematological diseases is complex and requires the use of integrated multimodal therapies. Long-lasting and safe central venous access is therefore a cornerstone for any successful treatment. Methods: The aim of this work is to define pediatric guidelines about the management of CVADs in onco-hematology. A panel of experts belonging to the working groups on Infections and Supportive Therapy, Surgery and Nursing of the Italian Pediatric Hematology Oncology Association (AIEOP) revised the scientific literature systematically, scored the level of evidence and prepared these guidelines. The content of the following guidelines was approved by the Scientific Board of AIEOP. Results and Conclusions: Important innovations have been developed recently in the field of CVADs, leading to new insertion methods, new materials and new strategy in the overall management of the device, especially in the adult population. These guidelines recommend how to apply these innovations in the pediatric population, and are directed to all physicians, nurses and health personnel active in the daily management of CVADs. Their aim is to update the knowledge on CVAD and improve the standard of care in pediatric patients with malignancies.

Background Little is known as yet about the outcome of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in children being treated for cancer. Methods We collected information on the clinical characteristics and outcomes of a cohort of 29 children (16 female and 13 male; median age, 7 years [range, 0–16 years]) diagnosed with SARS-CoV-2 infection while on chemotherapy/immunotherapy (n = 26), or after stem cell transplantation (n = 3) during the peak of the epidemic in Italy. These patients suffered from leukemia (n = 16), lymphoma (n = 3), solid tumors (n = 10), and Langerhans cell histiocytosis (n = 1). Results The course of the disease was mild in all cases, with only 12 children developing symptoms (pneumonia in 3 cases), and none needing intensive care. Fifteen patients were hospitalized, including 7 asymptomatic patients. Nine patients (including 5 with no symptoms) were given hydroxychloroquine, and 3 of them were also given lopinavir/ritonavir. Among the 26 patients on chemotherapy/immunotherapy, the treatment was suspended in 16 cases for a median of 26 days (range, 15–68 days), whereas 8 patients continued their chemotherapy and 2 had minor modifications to their treatment regimen. Conclusions SARS-CoV-2 infection seems to take a milder clinical course in children than in adults with cancer. Specific SARS-CoV-2 treatment seems unnecessary for most children. In light of our findings, and albeit with the necessary caution, we suggest avoiding major changes to planned anticancer treatments in pediatric patients acquiring COVID-19., We describe clinical characteristics and outcomes of 29 SARS-CoV-2–infected children with cancer. In comparison to adult oncology patients, children presented a milder clinical course. A substantial number of them continued their anticancer treatment without major modifications.

aGvHD remains a major obstacle to successful HSCT. We report our experience on steroid-refractory aGvHD III and IV from 1989 to 2017. Ninety patients with aGvHD III or IV were stratified according to the HSCT year: 1989-1998, 1999-2007, and 2008-2017 and to aGvHD extension (GvHD III vs IV) and finally the probability of OS, RI, and TRM was calculated accordingly. aGvHD III patients had a substantial improvement over time: day 100 OS raised from 64% (95% CI 39-89) in the first cohort to 100% in the latest (P = .022), and it was mainly due to a reduction of TRM (it was 28% [95% CI 12-65] in the first cohort to 0% in the latest (P = .01). The aGvHD IV patients did not present a significant improvement. Day 100 OS was 42% (95% CI 16-68) in the first group and 54% (95% CI 25-83) in the year 2008-2017 (P = NS), and the day-100 TRM was very similar (it was 57% [95% CI 36-90] in the first cohort and 45% [95% CI 23-89] in the latest (P = NS). We report significant improvements in OS and TRM in patients diagnosed with grade III aGvHD. Patients with the most severe aGvHD appear to have no or fewer benefits on long-term outcomes.

BACKGROUND Hematopoietic stem cell transplantation (HSCT) is curative in patients with primary immunodeficiencies. However, pre-HSCT conditioning entails unacceptably high risks if the liver is compromised. The presence of a recurrent opportunistic infection affecting the biliary tree and determining liver cirrhosis with portal hypertension posed particular decisional difficulties in a 7-year-old child with X-linked CD40-ligand deficiency. We aim at adding to the scanty experience available on such rare cases, as successful management with sequential liver transplantation (LT) and HSCT has been reported in detail only in 1 young adult to date. METHODS A closely sequential strategy, with a surgical complication-free LT, followed by reduced-intensity conditioning, allowed HSCT to be performed only one month after LT, preventing Cryptosporidium parvum recolonization of the liver graft. RESULTS Combined sequential LT and HSCT resolved the cirrhotic evolution and corrected the immunodeficiency so that the infection responsible for the progressive sclerosing cholangitis did not recur. CONCLUSIONS Hopefully, this report of the successful resolution of a potentially fatal combination of immunodeficiency and chronic opportunistic infection with end-stage organ damage in a child will encourage others to adapt a sequential transplant approach to this highly complex pathology. However, caution is to be exercised to carefully balance the risks intrinsic to transplant surgery and immunosuppression in primary immunodeficiencies.

Background Posaconazole is a triazole with limited pharmacokinetic information in children. This study assessed the correlation between posaconazole oral solution daily dosage/kg/body weight and trough plasma level. Methods A total of 97 hematology-oncology pediatric patients with ≥1 posaconazole plasma concentration level (PPC) assessment in the first 6 weeks after the start of posaconazole treatment were included. Results Posaconazole was used as prophylaxis in 84 of 97 (87%) patients and as therapy in 13 of 97 (13%). The median daily dose/kg/bw ranged from 10 to 12 mg in the prophylaxis group and 12.5 to 16.5 mg in the therapy group. The median value of PPC for the prophylaxis group was 0.9 and 0.8 μg/mL at the first and second/third determinations, respectively. Posaconazole prophylaxis failed in 4 of 84 patients (5%). The median value of PPC for the therapy group was 1.5 and 1.4 μg/mL at the first/second and the third determination, respectively. Posaconazole-related side effects were reported in 6 patients and all regressed with the suspension of the drug. In the prophylaxis group, the use of proton-pump inhibitors was significantly associated with a lower PPC, P = 0.04. Conclusions Posaconazole may be a valuable antifungal agent in children despite the incomplete knowledge of its pharmacokinetic characteristics.

Background invasive fungal infection (IFI) is a cause of morbidity, mortality and increased health costs in children undergoing chemotherapy or hematopoietic stem cell transplant (HSCT). Methods multi-center, retrospective study to assess the incidence, outcome of proven and probable IFI (PP-IFI) in children treated for acute leukemia, non-Hodgkin lymphoma or who underwent HSCT from 2006 to 2012. Results Over the 7-year period, 127 PP-IFI were diagnosed in 123 patients, median age of 9.7 years. The 1-year cumulative incidence was 2.5% (CI, 1.8-3.7) after front-line chemotherapy, 9.4% (CI, 5.8-15.0) after relapse, and 5.3% (CI, 3.9-7.1) after HSCT. Severe neutropenia was present in 98 (77%) patients. Culture-proven agents were: Candida spp., mostly non-albicans, 28, mould 23, whereas 3 proven IFI were identified by histopatholoy. Favorable response to treatment within 3 months from diagnosis was observed in 77 (89%). The overall ninety-day probability of survival was 68% (C.I. 59-76). Conclusions about two-thirds of pediatric patients with PP-IFI survived, regardless of whether the infection occurred after front-line chemotherapy, reinduction chemotherapy for disease relapse, or after HSCT. Further prospective studies are needed to define the impact of antifungal prophylaxis and early combination therapy on short-term overall survival. This article is protected by copyright. All rights reserved.

A prospective 18-month case-control study was performed in a tertiary Paediatric Centre in Turin (Italy) to analyse the disease burden and identify risk factors for acquisition of Extended Spectrum Beta Lactamase-producing Enterobacteriaceae (ESBL-pE). Children with ESBL-pE isolation were enrolled as cases, with controls matched according to age, type of pathogen isolated and sample of isolation. Out of 83 children (37 males, mean age 4.7 ± 5.46 years), 45 were identified as infected (54.2%) and 38 as colonised (45.8%) by ESBL-pE. Twenty-nine (64.4%) infectious disease episodes were categorised as community-acquired, 16 (35.6%) as healthcare-associated. Escherichia coli was the most frequently isolated pathogen (52, 62.7%) and the urinary tract the most frequent site involved (26, 57.9%). No deaths occurred, even in bloodstream infection cases. Hospitalisation and exposure to broad-spectrum penicillins and III/IV generation cephalosporins in the 90-day period before bacteria isolation were found to be independent risk factors at multivariate analysis. Immunodepression, prolonged central venous catheter (CVC) and urine catheter stay, and receiving a total parenteral nutrition (TPN) in the previous 30 days were otherwise recognized as potential risk factors at univariated analysis. ESBL-producing Enterobacteriaceae infections are a growing threat even in children. Careful recognition of patients at risk should promote targeted interventions in order to reduce the ESBL burden.

Summary Invasive fungal infections are a frequent complication after intensive chemotherapy. The aims of this prospective study were to describe the use of antifungal therapy and to report which strategy was routinely adopted to guide the introduction of antifungal therapy. A total of 321 febrile episodes in 160 paediatric patients affected by acute leukaemia or non-Hodgkin-lymphoma were investigated. Antifungal therapy was used in 100 of 321 febrile episodes (31%), and classified as empiric in 73 episodes, diagnostic-driven in 25 episodes and targeted in 2 episodes. Switching to a second-line antifungal therapy was needed in 28 of 100 episodes (28%) and was classified as empiric in 10 episodes (36%), diagnostic-driven in 17 episodes (61%) and targeted in 1 episode (4%). In 9 of 28 episodes (32%), switching to a third-line antifungal therapy was performed and was classified as empiric in 2 episodes (22%), diagnostic-driven in 6 episodes (67%) and targeted in 1 episode (11%). Invasive fungal infections was reported in 23 of 100 episodes: confirmed in 4 episodes, probable in 8 episodes, and possible in 11 episodes. Attributable mortality was 2.8%. Antifungal therapy was still used mostly empirically, whereas as fever persisted, its modification was guided by a diagnostic-driven approach.

The expression of tumor associated antigens (TAA) in osteosarcoma cell lines allowed us to design an in vitro model for the generation of TAA-specific CTLs. Since the MHC-I-restriction of these peptides represents the major obstacle to clinical applications, we studied a second method for the generation of CTLs starting from osteosarcoma cell line lysates and PBMCs of HLA-I compatible healthy donors. TAA-specific CTLs showed high and homogeneous cytotoxic response against each peptide; high levels of IFN-γ were released by osteosarcoma cell line lysate specific-CTLs in response to the osteosarcoma cell line they were activated for. The MHC-I dependent osteosarcoma cell line lysate-specific CTLs activity was proved by the indifference against the HLA-I-negative erytroleukaemia cell line K562 and by the absence of IFN-γ production with the addition of HLA-class I blocking antibodies. These two methods may be considered the model for the autologous setting in the context of immunotherapeutic approaches for osteosarcoma patients.

Bisphosphonates have a profound effect on bone resorption and are widely used in the treatment of osteoclast-mediated bone diseases. Zoledronic acid (ZA), a third-generation biphosphonate, has a potent antitumor activity and expands gammadelta (gammadelta) T cells endowed of major histocompatibility complex-unrestricted lytic activity. Many solid tumors express tumor-specific antigens on their surface, representing targets for immune effector T cells. Nevertheless, the immune surveillance against clinically manifested tumors is relatively inefficient. Therefore, we investigated the hitherto unknown effects of ZA activated gammadelta T cells of normal donors on osteosarcoma cell lines. gammadelta T cells were stimulated with ZA and low doses of interleukin-2, and then analyzed for proliferation and generation of effector activity against osteosarcoma cell lines. Our results show the potent anti-tumor activity of ZA-stimulated gammadelta T cells and the enhanced immunosensitivity of osteosarcoma cell lines to gammadelta T cells suggesting that osteosarcoma is another gammadelta T cell susceptible tumor type.

Central venous catheters (CVC), used for the management of children with hemato-oncological disorders, are burdened by a significant incidence of mechanical, infective, or thrombotic complications. These complications favor an increasing risk in prolongation of hospitalization, extra costs of care, and sometimes severe life-threatening events. No guidelines for the management of CVC-related occlusion and CVC-related thrombosis are available for children. To this aim, members of the coagulation defects working group and the supportive therapy working group of the Italian Association of Pediatric Hematology and Oncology (AIEOP) reviewed the pediatric and adult literature to propose the first recommendations for the management of CVC-related occlusion and CVC-related thrombosis in children with hemato-oncological disorders.

In the last 30 years, the use of long-term central venous catheters (CVC) is increased especially for children with hemato-oncological disorders. However, the use of CVC is associated to complications, as mechanical accidents, thrombosis, and infections that can determine a prolongation of hospital stay, an increase of costs, and sometimes life-threatening conditions that require urgent systemic treatment or CVC removal. CVC removal may be troublesome especially in neonates, infants, or any other “highly needed CVC patients”; in these selected cases, the prevention and treatment of CVC-related complications play a pivotal role and specific surveillance programs are crucial. While extensive literature is focused on CVC management in adults, no guidelines are available for children. To this aim, the first recommendations for the management of CVC infectious complication in pediatric age have been written after pediatric and adult literature review and collegial discussion among members of Supportive Therapy working group of Italian Association of Pediatric Hematology and Oncology. Compared to the adult age, the necessity of peripheral vein cultures for the diagnosis of CVC-related infection remains controversial in children because of the poorer venous asset and a conservative, pharmacologically focused management through CVC remains mandatory, with CVC removal to be performed only in selected cases.

ileus is a severe complication resulting from a variety of disorders. It occurs most commonly in patients with serious underlying medical or surgical conditions. Prompt diagnosis and appropriate management may improve the outcome. We describe 2 cases of onco-hematologic patients who presented this complication after intensive chemotherapy.

Influenza A (H1N1) pandemic reached its peak in Europe in autumn 2009. H1N1 infection can be a serious complication in patients with comorbidity or immunodepression. Here, we report of a boy with newly diagnosed acute promyelocytic leukemia with a very severe respiratory distress caused by influenza A (H1N1) infection in pulmonary aspergillosis, successfully treated with antifungal therapy, oseltamivir, and extracorporeal membrane oxygenation.

Background To define the mortality and the current impact of the H1N1 pandemic in pediatric hematology-oncology centers, we performed a specific survey. Procedure Pharyngeal swabs from patients with fevers of unknown origin, flu-like symptoms or bronchopneumonia were screened for H1N1 using PCR. Results Sixty-two patients with documented H1N1 infection were reported: 16 had recently stopped therapy, 2 were at the diagnosis stage, and 44 were receiving therapy. The clinical course was severe (requiring ICU admission) in only 1 patient, moderate (requiring hospital admission) in 38, and mild in the remaining 23 (37%), treated as outpatients. While none of the patients died of H1N1-related complications, two patients died of progressive cancer; in all of the remaining cases, symptoms resolved within 11 days. The clinical course was complicated by respiratory distress or bronchopneumonia in 10 cases. Oseltamivir was given to 82% of patients. Chemotherapy was temporarily withdrawn in 54% of cases for a median time of 21 days (range, 4–43 days). Conclusion H1N1 infection in children with cancer was not reported as the cause of death in any case but resulted in reduced intensity of anti-cancer therapy. Pediatr Blood Cancer. 2010;55:226–228. © 2010 Wiley–Liss, Inc.

Dendritic cells (DCs) might be partly responsible for the defective immune response in tumor bearing hosts, but no study in osteosarcoma patients is still available. Therefore, we investigated in vitro whether human osteosarcoma cell lines have an inhibitor effect on different types of DCs: CD14+DCs, DC1 and DC2. DCs derived from healthy donors were cultured with osteosarcoma cell lines and appropriate cytokine cocktails and analysed for the expression of co-stimulatory molecules (CD40, CD80, CD83, CD86, HLA-DR). Each interaction resulted in a lower phenotypic expression of the DCs maturation markers, especially on DC2. Moreover, the addition of various cytokines and compounds (rhIL-12, CD40L, Indometacin) induced the DC1 and DC2 subsets towards the Th1 pattern as shown by ELISA. Osteosarcoma highly interferes with an in vitro DCs immune function as antigen presenting cells. The understanding of tumor biology underlines the need for a specific osteosarcoma immunotherapy able to reverse this immune-surveillance inhibition.

This study was aimed at ascertaining whether extracorporeal photopheresis (ECP) is an effective treatment for pediatric patients with steroid resistant graft versus host disease (GvHD). Fifteen patients with acute GvHD (aGvHD) and 10 patients with chronic GvHD (cGvHD) were enrolled in the study. At the start of the ECP protocol, aGvHD was staged as II (n=7), III (n=4), and IV (n=4). The response rate was 100% for aGvHD II, 75% for aGvHD III, and finally 0% for aGvHD IV (P=0.02). In multivariate analysis, the strongest predictor for ECP response was the aGvHD severity: aGvHD II 100%, aGvHD III-IV 30% [relative risk (RR) 5.071, confidence interval (CI) 95% 2.2-5.5, P=0.0016], this translates in a higher risk of transplant-related mortality for ECP nonresponders (RR 5.26, CI 95% 3.4-6.2, P=0.02). cGvHD was diagnosed as limited n=3, and extensive n=7; the response rate was 100% and 28% for limited or extensive cGvHD, respectively (P=0.03). For cGvHD the strongest predictor for ECP response was the absence of visceral organ involvement (RR 5.17, CI 95% 2-4.9, P=0.001), and the highest risk of transplant-related mortality was among patients not responding to ECP (RR 12.4, CI 95%, P=0.02). Our results suggest that ECP can rescue good-risk GvHD-patients, whereas for advanced, poor-risk GvHD patients, new therapies are required.

A large number of patients affected by acute myeloid leukemia (AML) achieve complete remission following induction chemotherapy based on high-dose aracytin and anthracyclines. However, a postremission consolidation treatment appears to be essential to maintain the remission status. Sixteen patients with newly diagnosed AML received induction chemotherapy according to the AIEOP LAM 92P/Mod protocol. All patients were HLA-typed, and if no donor was identified within the family, patients underwent autologous stem cell transplantation (autoSCT) with mafosfamide-purged bone marrow. Patients with very high-risk AML (cytogenetics with t(9;22), hyperleukocytosis (540x10(9)/L), and AML-M7 with trilineage myelodysplasia) underwent unrelated donor transplantation. One patient relapsed before autoSCT. Eleven patients underwent autoSCT with purged bone marrow, 3 patients underwent unrelated donor transplantation (UD), and 1 patient underwent HLA-identical, matched familiar donor transplantation (MFD). All patients achieved complete remission following one course. No treatment-related deaths occurred during first-line treatment. The median interval between diagnosis and transplant was 175 days (129-277). Three patients relapsed following autoSCT; none relapsed after alloSCT. Taking stem cell transplantation as the starting point, overall survival was 93%, disease-free survival (according to the chosen treatment) was 80%, the relapse rate was 20%, and transplant-related mortality was 0%.

s / Digestive and Liver Disease 46 (2014) e85–e127 e101 TREATING ANDMONITORING VIRAL HEPATITIS B INFECTION IN PAEDIATRIC PATIENTS RECEIVING IMMUNOSUPPRESSIVE THERAPIES OR WITH THE PROSPECTIVE OF HAEMATOPOIETIC STEM CELL TRANSPLANTATION Sara Tardito1,∗, Michele Pinon1, Sebastian Dorin Asaftei2, Francesca Carraro2, Mareva Giacchino2, Franca Fagioli 2, Alfredo Marzano3, Pier Luigi Calvo1 1 Department of Pediatric Gastroenterology and Hepatology, Regina Margherita Children’s Hospital, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 2 Paediatric Onco-Haematology, Stem Cell Transplantation and Cellular Therapy Division, Regina Margherita Children’s Hospital, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin, Turin, Italy 3 Gastro-Hepatology Unit, Azienda Ospedaliera Citta della Salute e della Scienza, University of Turin