Chapter 6.1. Pediatric Chronic Hepatitis B and C: 30 Years of ESPGHAN Clinical Research and Recommendations.

The expression of hepatitis B and C virus infections in children differs from that in adults and requires specific paediatric expertise. The European Society of Pediatric Gastroenterology, Hepatology, and Nutrition (ESPGHAN) has been a pioneer in this field, having stressed the need for straightforward recommendations since the mid-1980s. Following much observation, surveillance, and research, a panel of ESPGHAN experts was able to develop such recommendations on hepatitis B infection in children in 2009, which was then followed in June 2013 by proper guidelines. In the field of Chronic Hepatitis C, in 2011 ESPGHAN experts published also the Guidance for Clinical Trials for Children and Adolescents, and approved in 2012 the NASPGHAN guidelines for treatment. The ESPGHAN Society is to be commended for its pioneering work in furthering our understanding of chronic hepatitis B and C disease presentations in infants, children, and adolescents.

Humoral and cell-mediated immune responses after a booster dose of HBV vaccine in HIV-infected children, adolescents and young adults.

OBJECTIVE: HBV vaccine induces protective antibodies only in 23-56% of HIV-infected children. The aim of our study is to evaluate the immunologic effects of a booster dose of HBV vaccine in HIV-infected youth. DESIGN: 53 young HIV-infected patients in whom HBV vaccination did not elicit protective Ab titers were enrolled. All patients were on ART with optimal immunological and viral response. METHOD: All patients received a booster dose of HBV vaccine (HBVAXPRO 10 µg i.m.). HBV-specific Ab titer, viral load and CD4+ T cells were measured at baseline (T0), T1, T6 and T12 months. In a subgroup of 16 patients HBV-specific cell mediated immune responses were evaluated at baseline, at T1 and T6. RESULTS: The booster dose induced seroconversion in 51% of patients at T1, 57% at T6, and49% at T12; seroconversion rate was significantly correlated with CD4+T cells at T0 and to the CD4 nadir. The booster dose induced HBV-specific cell mediated immunity at T6 mainly in Responders (Rs): Effector Memory CD8+T cells, HBV-specific TNFα-, IFNγ-, granzyme secreting CD8+ T cells and IL2-secreting CD4+ T cells were significantly increased in Rs compared to T0. In Non Responders (NRs), HBV-specific IL2-secreting CD4+ T cells, Central and Effector Memory CD8+ T cells were the only parameters modified at T6. CONCLUSIONS: Seroconversion induced by a booster dose of vaccine correlates with the development of T cell immunological memory in HIV-infected patients who did not respond to the standard immunization. Alternate immunization schedules need to be considered in NRs.

Hepatitis C virus in children: the global picture.

Chronic hepatitis C virus (HCV) infection is a major cause of cirrhosis, hepatocellular carcinoma and end-stage liver disease. One hundred thirty million to 150 million people have chronic HCV infection, among them 11 million are younger than 15 years of age. This review summarises the epidemiology and characteristics of HCV infection in children, and highlights the role of the new upcoming therapies in HCV-related liver complications.

An update on the assessment and management of metabolic syndrome, a growing medical emergency in paediatric populations.

In the last decades the increasing rate of obesity in children and adolescents worldwide has led to the onset in paediatric age of metabolic syndrome, a disease commonly associated to adulthood. Central obesity, dyslipidaemia, hyperglycaemia, and hypertension are typical features of metabolic syndrome that seem to hesitate often in type 2 diabetes, cardiovascular disease, non-alcoholic fatty liver disease, and many other clinical conditions. Thus preventing and curing metabolic syndrome in paediatric patients is becoming an urgent need for public health. While diagnostic criteria and therapy of metabolic syndrome in adults are very well defined, there is no consensus on the definition of metabolic syndrome in children and adolescents as well as on healing approaches. The aim of this review is to describe the recent advances on the pathogenesis and clinical outcomes of paediatric metabolic syndrome. We then detail the therapeutic strategies (i.e. dietary regimens, physical exercise, nutraceuticals, and medications) employed to manage the disease. Finally, we analyse the safety profile of the drugs used in children and adolescents by performing a retrospective review of paediatric adverse reactions reported in the FDA's Adverse Event Reporting System database.

Hepatitis B: changing epidemiology and interventions.

Hepatitis B virus infection is still a major public health problem worldwide, since more than 350 million people have chronic, lifelong infection and nearly 1 million deaths occur each year owing to complications. Most infections are acquired at birth or during early childhood. Nowadays, low- and middle-income countries bear the majority of the burden of hepatitis B-related liver cancer deaths despite the availability of an effective vaccine and antiviral treatments. In this review the epidemiology, strategies of prevention and the recent advances in therapy, genotype diversity and resistance are discussed.

Long-term renal effects of tenofovir-disoproxil-fumarate in vertically HIV-infected children, adolescents, and young adults: a 132-month follow-up study.

BACKGROUND AND OBJECTIVES: The introduction of highly active anti-retroviral therapy has led to a significant decline in morbidity and mortality. Although several studies in adult populations have shown that tenofovir-disoproxil-fumarate (TDF) use is associated with a significant loss of renal function, there is still uncertainty on the long-term TDF safety profile in pediatric HIV populations, mostly in vertically HIV-infected patients. The aim of this study was to evaluate the long-term TDF renal safety profile, during a ten-year follow up. METHODS: Twenty-six vertically HIV-infected patients were evaluated for a total of 132 months of follow up, monitoring anthropometric parameters, renal function, viral load and CD4+ count. Generalized estimating equations were used to evaluate the changes in anthropometric and laboratory variables. Multivariable fractional polynomials were used to test for the existence of non-linear relationships of outcomes with time and other continuous covariates. In all patients, weight, height and body mass index increased linearly with time. CD4+ count and glomerular filtration rate decreased linearly with time (p < 0.01). RESULTS: No significant increase of serum creatinine was registered. An inverse linear relationship between time and plasma phosphate was found. Hypophosphatemia was detected in 17 patients, mostly mild. In 14 out of 17 we also genotyped single nucleotide polymorphisms rs717620 mapping in ABCC2, a gene encoding for a renal transporter. CONCLUSIONS: Our study demonstrates the relative safety of prolonged use of TDF in vertically HIV-infected children and young adults. The most relevant alteration that emerged was hypophosphatemia, appearing after 72 months of TDF therapy, mostly mild and without clinical significance.

Sclerostin and DKK-1: two important regulators of bone metabolism in HIV-infected youths.

Reduced bone mineral density (BMD) and altered bone metabolism are common findings in HIV-infected patients. Increased bone formation has been described both in HIV-infected adults and children. Wnt ligands promote bone formation by stimulating osteoblast differentiation and their survival. Sclerostin and dickkopf factor 1 (DKK-1), Wnt antagonists, are important negative regulators of bone formation. We studied 86 HIV-infected patients whose ages ranged from 5.7 to 27.9 years. Patients were all on antiretroviral therapy, but seven who were naïve to treatment. Bone alkaline phosphatase (BAP), sclerostin, and DKK-1 were measured in serum by enzyme immunoassay. BMD was measured by dual-energy X-ray absorptiometry at the lumbar spine and in the whole skeleton. Biochemical indexes were also measured in 143 healthy controls (age range 4.5-27.4 years). HIV-infected patients had lower than normal BMD (spine P < 0.005, and whole skeleton P < 0.03). BAP measurements were significantly higher in HIV-infected patients than controls (P ≤ 0.05). Sclerostin and DKK-1 concentrations were markedly lower than in controls (P ≤ 0.0006, and P ≤ 0.03, respectively). The serum concentration of both analytes of patients naïve to antiretroviral treatment was not different from that of treated patients. No correlations were found between sclerostin, DKK-1, and bone mineral measurements. Our data confirm the alteration of bone metabolism pathways in HIV-infected individuals. The lower concentration of Wnt antagonists is consistent with the increased bone formation markers.

Areal bone mineral density in pediatric patients with chronic hepatitis B or chronic hepatitis C.

Decreased bone mineral density (BMD) is a known complication of chronic liver disease in adults. Data on bone mass, an important factor for the development of osteoporosis in adult life, in young patients with chronic hepatitis B (HBV) and C virus (HCV) infections are scarce. We measured BMD at the lumbar spine and whole skeleton by dual-energy X-ray absorptiometry in 11 HBV- and 21 HCV-vertically infected untreated youths (3.9-21.1 years). BMD measurements were compared to those of 202 healthy subjects (3.0-21.9 years). The median BMD Z-score of the lumbar spine of HBV-infected patients was -0.3, ranging from -1.6 to 0.6, while the median whole skeleton BMD Z-score was 0.1 (-0.8 to 0.6). HBV-infected patients showed a median Z-score of the lumbar spine of 0.6 (-1.6 to 1.9), and a median whole skeleton BMD Z-score of 0.6, ranging from -1.5 to 1.4. Multivariate analyses have been performed to correct for differences in sex, age, and anthropometric measurements. Lumbar spine BMD values of HBV and HCV-infected patients were not significantly different from those of controls. Similarly, no differences were found between groups in total body BMD measurements. Our data suggest that, unlikely adult patients, untreated young patients with chronic HBV and HCV infection may not have impaired bone mass measurements.

Unexpected vertical transmission of HIV infection.

Mother-to-child transmission of HIV infection occurred in a child born from an HIV-infected mother with HIV-RNA undetectable during pregnancy. She was suffering from gastroenteritis in the last 3 weeks of gestation.

Serotype distribution and antimicrobial susceptibilities of nasopharyngeal isolates of Streptococcus pneumoniae from healthy children in the 13-valent pneumococcal conjugate vaccine era.

Few epidemiological data are available since the introduction of 13-valent pneumococcal vaccine (PCV13) in 2010. We conducted a cross-sectional study to estimate the prevalence of Streptococcus pneumoniae (SP) nasopharyngeal carriage in healthy Italian infants and young children and to evaluate the impact of PCV13 on pneumococcal colonization. In the trimester September-December 2011 nasopharyngeal swabs were collected from healthy children aged 3-59 months presenting for routine well careat 16 primary care pediatricians in Milan. SP carriage isolates were serotyped and tested for antimicrobial resistance using EUCAST breakpoints. Among 1250 enrolled children, 618 had received at least 1 dose of PCV13, 292 at least 1 dose of PCV7, 94 a combination of the two vaccines and 246 were not vaccinated. The prevalence of SP carriage was 27% (95% confidence interval [CI] 25-30). At multivariable analysis, age≥25 months (prevalence ratio [PR]=0.74) and use of antibiotics in the previous 3 months (PR=0.67) were associated with lower SP carriage prevalence. Having siblings (PR=1.79 for 1 sibling and PR=2.23 for ≥2 siblings), day-care attendance (PR=2.27) and respiratory tract infections in the previous 3 months (PR=1.39) were associated with higher SP carriage prevalence. The immunization status for SP was not associated with SP carriage at univariable or at multivariable analysis. The most common carriage isolates were 6C, 19A and 23A. The prevalence of the six additional PCV13 serotypes carriage in children appropriately vaccinated with PCV13 was lower than in children appropriately vaccinated with PCV7 (0 vs. 0.060); the greater reduction in prevalence of carriage was observed for serotype 19A (0 vs. 0.041). Serotype 6C was the most common drug-resistant serotype (17.2%). Further epidemiological studies are needed to assess changes in circulating SP serotypes following the large-scale introduction of PCV13.

Tenofovir-induced renal tubular dysfunction in vertically HIV-infected patients associated with polymorphisms in ABCC2, ABCC4 and ABCC10 genes.

Tenofovir disoproxyl fumarate is a known cause of kidney tubular dysfunction in HIV-infected patients. Recent studies reported significant association between specific allelic variants in ABCC2, ABCC4 and/or ABCC10 genes and the development of kidney tubular dysfunction in HIV-infected adults. We describe the first 2 cases of vertically HIV-infected patients affected by kidney tubular dysfunction associated with polymorphisms in the ABCC genes.