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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.

Mutations in ATP8B1 can lead to familial intrahepatic cholestasis type 1 (FIC1) deficiency, or progressive familial intrahepatic cholestasis type 1 (PFIC1). The rarity of FIC1 deficiency has largely prevented a detailed analysis of its natural history, effects of predicted protein truncating mutations (PPTMs), and possible associations of serum bile acid (sBA) concentrations and surgical biliary diversion (SBD) with long-term outcome. We aimed to provide novel insights by using the largest genetically defined cohort of FIC1 deficiency patients to date. This multicenter, combined retrospective and prospective study included 130 patients with compound heterozygous or homozygous predicted pathogenic ATP8B1 variants. Patients were categorized according to the number of PPTMs (i.e., splice site, frameshift due to deletion or insertion, nonsense, duplication); FIC1-A (n=67; no PPTM), FIC1-B (n=29; one PPTM) or FIC1-C (n=34; two PPTMs). Survival analysis showed an overall native liver survival (NLS) of 44% at age 18y. NLS was comparable between FIC1-A, FIC1-B, and FIC1-C (%NLS at age 10y: 67%, 41%, and 59%, respectively; P=0.12), despite FIC1-C undergoing SBD less often (%SBD at age 10y: 65%, 57%, and 45%, respectively; P=0.03). sBAs at presentation were negatively associated with NLS (NLS at age 10y; sBAs, University of Colorado; Baylor College of Medicine; Children’s Hospital of Philadelphia; Children’s Hospital of Pittsburgh; St Louis Children’s Hospital; Riley Hospital for Children; Seattle Children’s Hospital; M.D./Ph.D. Scholarship from the University of Groningen; European Society for Pediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) Networking Grant 2019; ChilDReN National Institutes of Health Grants; Ann & Robert H. Lurie Children’s Hospital; Albireo and Mirum Pharmaceuticals

BACKGROUND The effect of direct-acting anti-virals (DAAs) in children and adolescents with chronic hepatitis C virus (HCV) infection is difficult to determine, since few, aged between 3 and 18 years, have been enrolled in clinical trials, and some data come from observational studies. AIM To summarise the evidence on efficacy and safety of DAAs in children and adolescents with chronic HCV infection. METHODS We performed a systematic review and meta-analysis of prospective studies on the efficacy and safety of DAAs in subjects

The aims of this prospective study were as follows: (1) to describe the natural history of chronic hepatitis B virus (HBV) infection in a large cohort of untreated children followed at a single centre and (2) to evaluate whether or not the new European Association for the Study of Liver (EASL) classification for the phases of HBV infection in adults can be used for children. All children who presented at the Liver Unit of our hospital from 1 January 1987 to 31 December 2019 and were diagnosed with chronic HBV infection were enrolled. The final sample consisted of 152 children. The median duration of the follow-up was 83 months (range 7-232). At baseline, 125 patients (82.2%) were HBeAg positive (85.3% abnormal alanine aminotransferase (ALT) levels), and 24 (15.8%) were HBeAg-negative (93.3% abnormal ALT). At the end of the observation period, 62 of the HBeAg-positive patients (40.7%) achieved HBeAg seroconversion (median age 9.45 years, range 0.8-19) and 2 (1.4%) achieved HBsAg seroconversion. Elevated ALT serum levels at baseline (P = .011), lower baseline HBV DNA levels (P < .001) and Asian ethnicity (P = .0001) were identified as predisposing factors towards HBeAg seroconversion. EASL criteria could not be applied to 43.3% and 43.5% of the children at baseline and at end of observation, respectively, that were grouped into an undetermined phenotype category. According to the results of the present study, the new EASL guidelines for adults with HBV infection cannot be applied in a satisfactory manner in children.

Summary In 2017, the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) approved the fixed-dose direct-acting antiviral (DAA) combination sofosbuvir and ledipasvir and the combination sofosbuvir plus ribavirin for the treatment of adolescents (aged 12–17 years) with chronic hepatitis C. Preliminary results on the use of DAAs in paediatric patients are available for the fixed-dose combination sofosbuvir and ledipasvir in children aged 6–17 years for genotype 1 or 4 infection; for combination sofosbuvir plus ribavirin for adolescents aged 12–17 years for genotype 2 or 3 infection; for the fixed-dose combination ombitasvir, paritaprevir, and ritonavir with or without dasabuvir and with or without ribavirin for adolescents aged 12–17 years with genotype 1 or 4 infection; and for the combination of sofosbuvir plus daclatasvir for children with genotype 4 infection. All the results available indicated positive efficacy and favourable safety profiles of the different combinations of DAAs. With the approval of the new drugs, indications for treatment of children with chronic hepatitis C have changed. DAA therapy is recommended for all adolescents aged 12–17 years with chronic hepatitis C virus infection independent of treatment history and disease severity. If and when DAAs are approved for younger age cohorts, all children older than 3 years infected with hepatitis C will benefit from antiviral therapy. In this Review, we aim to provide an up-to-date overview of the existing evidence on the paediatric use of DAAs, summarising indications to treatment and recommendations for monitoring.

Autoimmune thyroid disease and thyroid dysfunction are common in adults receiving interferon (IFN)-based treatment for chronic hepatitis C (CHC). Few data are available in children with CHC. This study is aimed to evaluate the appearance and timing of thyroid dysfunction and antithyroid autoimmunity in children with CHC treated with pegylated IFN-α-2b and ribavirin (RBV).Sixty-one otherwise healthy children with CHC, 3-17 years of age, infected perinatally and treatment naïve, receiving therapy with pegylated IFN-α-2b and RBV and 183 age- and sex-matched controls were included in a multicenter, prospective, case-control study. Thyroid-stimulating hormone, free thyroxine, antithyroglobulin antibodies and antithyroid peroxidase antibodies were assessed before, during and 24 weeks after the end of treatment.From baseline to the end of treatment, subclinical hypothyroidism and autoimmune thyroiditis were diagnosed in 17 of 61 (27.94%) and in 4 of 61 (6.6%) of the children treated, respectively, and in 5 of 183 (2.7%) and in none of the controls (P0.0001, relative risk: 10.2, 95% confidence interval: 3.9-26.5; P = 0.03, relative risk: 26.8, 95% confidence interval: 1.5-489.1, respectively). Twenty-four weeks after the end of treatment, subclinical hypothyroidism persisted in only 4 of 61 (6.6%). Autoimmune thyroiditis persisted in 3 of 4 (75%) of the cases.Subclinical hypothyroidism is common in children with CHC receiving treatment with pegylated IFN-α-2b and RBV, but in most cases is transient. Autoimmune thyroiditis, which is less common, generally persists after treatment completion. Thyroid function should be carefully monitored in patients presenting with antithyroid autoantibodies and thyroid dysfunction during and after pegylated IFN-α-based treatment.

Preexistence and appearance of resistance-associated substitutions limit the efficacy of direct-acting antivirals in treatment of hepatitis C. This is the first case report of an adolescent with chronic hepatitis C virus genotype 4 infection and cirrhosis who failed treatment with ombitasvir/paritaprevir/ritonavir and ribavirin. Resistance analysis showed baseline resistance-associated substitutions M28V and Y93C and emergent D168H.

This is the first case of NBAS disease detected by NBS for primary immunodeficiency. NBS with KRECs is revealing unknown potentialities detecting conditions that benefit from early recognition like NBAS deficiency. Immune phenotyping should be mandatory in patients with NBAS deficiency since they can exhibit severe immunodeficiency with hypogammaglobulinemia as the most frequent finding. Fever during infections is a known trigger of acute liver failure in this syndrome, so immune dysfunction, should never go unnoticed in NBAS deficiency in order to start adequate therapy and prophylaxis.

Treatment-naive, noncirrhotic adults with chronic hepatitis C virus genotype 1 infection and with viremia levels

Background Primary meningococcal arthritis is a rare infectious disease that occurs in less than 3% of meningococcal infections and is characterized by arthritis without meningitis, fever, rash, or hemodynamic instability Barahona [Case Rep Orthop 4696014:2017 ]. There are no validated clinical criteria that can be used for the diagnosis. We present two pediatric cases of atypical presentation of meningococcal disease revealed by molecular tests. Case presentation The clinical presentation of the two children (6- and 9-years-old) was characterized by signs of arthritis. By Real Time Polymerase Chain Reaction (RT-PCR), we identified N. meningitidis serogroup Y in the joint fluid in both cases. After specific antimicrobial treatment, the clinical conditions of the two patients quickly improved during hospitalization. Conclusions. We believe that the incidence of meningococcal arthritis could be underestimated in those settings where the use of RT-PCR is limited. Clearer data on the incidence of meningococcal disease would help to design specific treatments and the best possible national vaccine strategies [Fiji Sci Rep 23:39784, 2016, J Infect 67:385-90, 2013].

Etiology and serotyping of parapneumonic effusion (PPE) and the impact of vaccination was evaluated over a 12-year period, before and after the PCV13 introduction (2011) for Italian children From 0 to 16 years of age. Five hundred and two children were evaluated; 226 blood and 356 pleural fluid samples were obtained and tested using Realtime-PCR and culture. In the pre-PCV13 era S. pneumoniae was the most frequent pathogen identified (64/90; 71.1%) with a large predominance of serotypes 1 (42.4%), 3 (23.7%), 7F (5.1%) and 19A (11.9%). The impact of vaccination, calculated on children 0-8 years of age, demonstrated a significant reduction of PPE: with an incidence rate of 2.82 (95%CL 2.32-3.41) in the pre-PCV13 era and an age-standardized rate (ASR) of 0.66 (95% CL 0.37-1.99) in the post-PCV13 era, p

To compare the effectiviness of spiramycin/cotrimoxazole (Sp/C) versus pyrimethamine/sulfonamide (Pyr/Sul) and spiramycin alone (Spy) on mother-to-child transmission of toxoplasmosis infection in pregnancy.Retrospective study of pregnant women evaluated for suspected toxoplasmosis between 1992 and 2011.A total of 120 mothers and their 123 newborns were included. Prenatal treatment consisted of spiramycin in 43 mothers (35%), spiramycin/cotrimoxazole in 70 (56.9%) and pyrimethamine/sulfonamide in 10 (8.1%). A trend toward reduction in toxoplasmosis transmission was found when Sp/C was compared with Pyr/Sul and particularly with Spy alone (P=0.014). In particular, Spy increased the risk of congenital infection when compared with Sp/C (odds ratio (OR) 4.368; 95% CI: 1.253 to 15.219), but there was no significant reduction when Sp/C was compared with Pyr/Sul (OR 1.83; 95% CI: 0.184 to 18.274).The treatment based on Sp/C has significant efficacy in reducing maternal-fetal transmission of Toxoplasma gondii when compared with Pyr/Sul and particularly to Spy. Randomized controlled trials would be required.

Antimicrobial agents are important causes of drug-induced liver injury. They are responsible for about 45% of cases of drug hepatotoxicity. Hepatic damage mechanisms are intrinsic or idiosyncratic. Usually, antibiotics are responsible for idiosyncratic toxicity. This review summarizes the rate of incidence and clinical features of hepatotoxicity due to antibiotics and chemotherapics, with particular attention to data regarding paediatric population. Liver injury features have been systematically evaluated for the most commonly administered antibiotics and chemotherapics in adults, even though there is little information about other widely used compounds, as cephalosporine or clarithromycin, and about antibiotics active against multi-resistant bacteria, as carbapenems, vancomycin, clindamycin, and linezolid. By contrast, there is an abundance of case reports in paediatrics, but very few structured studies have been carried out in children. Children are an important class of antibiotic users, with specific metabolic characteristics, so more studies on them should be carried out.

Introduction of Highly Active Antiretroviral Therapy (HAART) and implementation of preventive strategies during pregnancy have resulted in a dramatic reduction of the mortality rate in HIV-1 infected children by over 80-90% and in a decrease in the risk of mother-to-child transmission (MCTC) of HIV-1 to approximately 1-2%. However the MCTC remains the main source of HIV-1 infection within the paediatric population. The risk of disease progression is inversely correlated with the age of the child, with the youngest children at greatest risk of rapid disease progression, but in the first year of life it is not possible to identify infants at greatest risk; therefore, according to all the international guidelines, it is necessary to start antiretroviral therapy in all infants < 12 months of age. This article provides a summary of the clinical features of the infection and of the methods for diagnosis. Furthermore it offers an overview of antiretroviral therapy in HIV-1 infected children, including a description of the main classes of antiretroviral drugs, the most common side effects and some issues concerning the disclosure of diagnosis. The objectives of this study are to make a set of practical suggestions to paediatricians for the optimum management of the infection and the antiretroviral therapy.

Summary Background Natural killer (NK) cells number, phenotypes and function have been evaluated in many studies in adults with hepatitis C as compared with healthy controls or dynamically during interferon-based and interferon-free treatments. Overall, in adults with chronic infection number of circulating NK cells has been reported to be lower when compared to spontaneous resolvers and healthy subjects. Different studies yielded inconsistent findings due to patient and virus heterogeneity. Aim To evaluate NK cells in children according to the different outcomes of the infection. Methods In this cross-sectional study, we examined numbers and phenotypes of circulating NK cells from a homogenous cohort of Italian children with vertically acquired hepatitis C. Results We compared 31 children who developed chronic infection with nine who presented spontaneous clearance and 13 controls. CD56+CD3− NK cell numbers were consistently lower in the persistently infected group (P = 0.03 and 0.04). This decrease was due to depletions of CD56dim NK cells (P = 0.03 chronic infection vs. spontaneous clearance), while CD56bright NK cells were expanded (P = 0.03). No significant difference was found in the frequencies of CD56+CD16+ and CD56dimCD16− cells. Perforin expression was higher in children with chronic infection (P = 0.03 vs. spontaneous clearance). Conclusions Altered NK cells number and phenotypes could impact the outcome of HCV infection in children following vertical transmission. This study suggests for the first time that NK cells cytolytic function, featured by CD56dim cells, contributes to the elimination of HCV in children presenting spontaneous clearance.

Objectives The objective of this systematic review was to summarize evidence regarding hepatitis C in hepatitis C virus/human immunodeficiency virus (HCV/HIV)-co-infected children focusing on mother-to-child transmission, clinical and laboratory features, outcome, and therapies. Methods A literature search was performed using multiple keywords and standardized terminology in MEDLINE, EMBASE, and Cochrane databases dating back to their inception up to April 1, 2015, using the following terms hepatitis C virus, HIV, and child. Results Fifty-five of 367 publications were selected for inclusion. In co-infected children, HIV impacted all the different aspects of HCV infection. Maternal HIV infection increased the risk of vertical transmission of hepatitis C. Children with HCV/HIV co-infection presented a lower rate of spontaneous clearance of HCV, were more commonly HCV viraemic, and had higher values of alanine aminotransferase when compared with HCV-monoinfected children. No relevant difference was reported between monoinfection and co-infection with regard to clinical findings. Although the data on the outcome of hepatitis C in the context of co-infection were limited, they were highly suggestive of a more severe outcome in terms of fibrosis in co-infected children. No pediatric data were available on the role of antiretroviral therapy as a cofactor of liver injury in HCV/HIV co-infection. The efficacy of pegylated interferon-α and ribavirin in children with HCV/HIV co-infection was lower than in monoinfected children. Conclusions The effect of HIV co-infection on HCV-related disease was clear with most studies indicating that HIV accelerates HCV progression and reduces the efficacy of the available anti-HCV therapies.

PHACE is a rare congenital neurocutaneous syndrome where posterior fossa malformations, hemangiomas, cerebrovascular anomalies, aortic arch anomalies, cardiac defects, and eye abnormalities are variably associated. We describe the prenatal detection and the postnatal course of a child with PHACE syndrome with a unique type of aortic arch anomaly consisting of proximal interruption of the aortic arch and persistence of the fifth aortic arch. The fifth aortic arch represented in this case a vital systemic-to-systemic connection between the ascending aorta and the transverse portion of the aortic arch allowing adequate forward flow through the aortic arch without surgical treatment.

Although several cases of severe hypoalbuminemia resulting from rice milk have been described in the past, today the use of rice milk without nutritional counseling to treat eczema is still a continuing, poor practice. We describe a kwashiorkor case in an infant with severe eczema exclusively fed with rice milk. It is well documented that rice milk is not a sufficient protein source. Moreover, only a small portion of eczema is triggered by food allergy. In conclusion this case raises the importance of managing dietary changes facing food allergies with responsibility for specialized consensus among pediatricians, nutritionists, endocrinologists and allergists all of them specialist professionals.

Children bear a substantial part of the tuberculosis (TB) epidemic worldwide, and it is estimated that there were ≅ 500.000 childhood TB cases globally in 2010, although accurate data are problematic to obtain given the many difficulties associated with TB diagnosis in children and the weaknesses of surveillance systems in countries where TB is endemic. The World Health Organization is working hard in order to reduce the TB prevalence rates and deaths by half by 2015. In this challenge, general practitioners and pediatricians play a key role in detecting early cases of suspected TB and sending them to experts in infectious diseases. This will reduce delayed diagnosis and the spread of disease, which is especially important now that the prevalence of multidrug resistant TB is increasing. For this reason, the purpose of this report was to delineate the characteristic clinical features of the most common forms of pediatric TB and to suggest a rational and practical approach to the disease underlining the role of patients and parents personal and clinical history.

Objective Recent genome-wide association studies performed in adults correlated single-nucleotide polymorphisms (SNPs rs12979860 and rs8099917) located on chromosome 19, upstream of the interleukin 28B gene, with spontaneous clearance of hepatitis C virus and with response to treatment with paginated interferon and ribavirin. The aim of the present collaborative study was to evaluate the rs12979860 SNP in a large cohort of Italian children with perinatal acquisition of hepatitis C. Methods Children were prospectively enrolled in 2 Italian centers. The interleukin 28B rs12979860 SNP was studied according to the diagnosis of chronic infection or spontaneous clearance. Results One hundred thirty children (86.7%) with chronic infection and 23 (13.3%) with spontaneous clearance of the virus were enrolled. Overall, the interleukin 28B C/C and C/T-T/T genotypes were found in 57 (37.3%) and 96 (62.7%) children, respectively. The proportion of C/C genotype was higher among children who cleared infection (14/23; 60.9%) compared with children with chronic infection (43/130; 33.1%; P = 0.01; odds ratio 3.15; 90% confidence intervals 1.34-7.53). Conclusions The present study showed that, as already demonstrated in adults, children with the rs12979860 C/C SNP of the interleukin 28B gene have a higher probability of spontaneous clearance of hepatitis C virus.