SNPs of the IFNL favour spontaneous clearance of HCV infection in children.

BACKGROUND: Both spontaneous and treatment-induced clearance of hepatitis C virus (HCV) in adults have been associated with genetic polymorphisms in the interferon-λ genes. The aim of the present study was to confirm the association between the rs12979860 and evaluate the association between the rs368234815 and the rs4803217 single-nucleotide polymorphisms (SNPs) of the interferon-λ genes and the outcome of the infection in children. METHODS: Alleles and genotypes frequencies of 32 children, who presented spontaneous clearance of the virus and 135 children, with viral persistence were compared with ethnically matched controls obtained from the 1000 Genomes Project and the International HapMap Project databases. RESULTS: The frequencies of the C/C genotype of rs12979860, the TT/TT of the rs368234815 and the A/C of the rs4803217 were higher in the clearance group than in children with viral persistence (C/C versus T/T + C/T odds ratio (OR): 2.6; 90% confidence intervals (CI): 1.3-5; p = 0.01; TT/TT versus ΔG/TT + ΔG/ΔG OR: 2.8; 90% CI: 1.4-5.5; p = 0.01; and A/A versus A/C OR: 8.3; 90% CI: 1.5-45.9; p = 0.017, respectively) and with the ethnically matched controls. CONCLUSIONS: The rs12979860, the rs368234815 and the rs4803217 SNPs are associated with spontaneous clearance of HCV in children. IMPACT: Innate immune system response has a key role in the outcome of vertically acquired HCV infection in children. The rs12979860, the rs368234815 and the rs4803217 SNPs are associated with spontaneous clearance of HCV in children. Interferons-λ activate the Janus kinase-Stat pathway, which in turn induces several interferon-stimulated genes, leading to suppression of HCV replication both in vivo and in vitro.

Epidemiology and Natural History of Childhood-Acquired Chronic Hepatitis C: A Single-Center Long-Term Prospective Study.

OBJECTIVES: To prospectively describe the epidemiology and long-term outcome of childhood-acquired hepatitis C virus (HCV) infection in a large cohort of children followed at a single center. METHODS: All children with chronic HCV infection followed at the Liver Unit of our tertiary Hospital in Florence (Italy) from January 1, 1988, to September 30, 2021, were included in the analysis. RESULTS: The final sample consisted of 163 children (median age at enrollment 4 years, interquartile range (IQR): 10; median age at last follow-up 14 years, IQR: 7). The median duration of follow-up was 86 months (IQR: 112). One hundred twenty-five children were vertically infected and 26 acquired the infection horizontally. Twenty-six of the 125 children who were vertically infected (20.8%) underwent spontaneous clearance of HCV RNA at a median age of 4 years (IQR: 2), whereas all the others remained persistently viremic. One patient was diagnosed with cirrhosis; 2 presented clinically detectable extrahepatic manifestations (chronic urticaria). Thirty-two children (19.6%) received antiviral therapy: 8 out of 32 (25%) were treated with pegylated-interferon alfa-2b [sustained virological response (SVR) 24 weeks after the end of treatment in 7/8]; 24 out of 32 (75%) were treated with direct-acting antivirals (SVR 12 weeks after the end of treatment in 23/24). CONCLUSIONS: The present study describes the largest cohort of children with chronic HCV infection prospectively evaluated with a long follow-up at a single center. HCV infection in children is often a chronic infection that can be cured with modern antiviral therapy. Early treatment could prevent the development of advanced liver disease.

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.

Chronic hepatitis B in children, report of a single-centre longitudinal study on 152 children.

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.

Shortened 8-Week Course of Sofosbuvir/Ledipasvir Therapy in Adolescents With Chronic Hepatitis C Infection.

Treatment-naïve, noncirrhotic adults with chronic hepatitis C virus genotype 1 infection and with viremia levels <6 million IU/mL could be effectively treated with sofosbuvir/ledipasvir for 8 weeks. The aim of this pilot, prospective, open-label, multicenter study was to evaluate the efficacy and safety of this shortened treatment course in adolescents (≥12 years). The efficacy endpoint was sustained virological response 12 weeks after the end of treatment. Safety was assessed by adverse events and clinical/laboratory data. Fourteen consecutive adolescents (median age 16.5 years, Q1 14.1-Q3 17.4; female 57.1%), vertically infected, were enrolled and treated (June 2018-January 2019). Overall, the end of treatment response and sustained virological response 12 weeks after the end of treatment were 100%. No grade 3 to 4 adverse event or a serious adverse event was observed. Further studies are needed to confirm the optimal efficacy of the shortened 8-week treatment with sofosbuvir/ledipasvir for treatment-naïve, noncirrhotic adolescents with chronic hepatitis C virus genotype 1 infection and pretreatment viremia level < 6 million IU/mL.

Hepatitis C in Children Co-infected With Human Immunodeficiency Virus.

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.

Interleukin 28B rs12979860 single-nucleotide polymorphism predicts spontaneous clearance of hepatitis C virus in children.

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.

Paediatric-onset autoimmune liver disease: Insights from a monocentric experience.

BACKGROUND: Autoimmune liver disease (AILD) encompasses autoimmune hepatitis (AIH), autoimmune sclerosing cholangitis (ASC) and primary sclerosing cholangitis (PSC). A unified disease process evolving over time through these entities has been recently suggested. From this perspective, this study aimed to compare the characteristics of childhood-onset AILD at baseline and after a medium-to-long term follow-up period. METHODS: Paediatric-onset cases of AILD diagnosed between 1992 and 2023 at a tertiary-care centre were reviewed. Patients transitioned to adult-care by the time of data collection were asked for clinical updates. RESULTS: Fifty-five patients were included (AIH = 20, ASC =22, PSC =13). AIH, ASC and PSC exhibited increasing age at the onset (AIH to PSC, p < 0.01). The area under the receiver operating characteristic curve for gamma-glutamyltranspeptidase (GGT) combined with alkaline phosphatase/aspartate aminotransferase (ALP/AST) ratio in predicting sclerosing cholangitis was 0.94, with a sensitivity of 86 % and a specificity of 94 %. At the last follow-up (median duration 5,8 years, interquartile range [IQR] 2,9-10,2, n = 45), 15 patients (33 %) developed portal hypertension, 2 patients (4 %) underwent liver transplantation, no patient died. CONCLUSION: A cohort of childhood-onset AILD managed at a single centre reveals a temporal trend in the onset of AIH, ASC and PSC, with progressively older ages. Elevated GGT levels combined with a high ALP/AST ratio predict the diagnosis of sclerosing cholangitis. The occurrence of liver-related adverse events in one-third of patients highlights the progressive nature of paediatric-onset AILD.

Autoimmunity and extrahepatic manifestations in treatment-naïve children with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection has been associated with autoimmunity and extrahepatic manifestations in adults. Few data are available on these topics in children. Nonorgan specific auto-antibodies development is part of the natural course of chronic hepatitis C in children. Smooth muscle autoantibody is the most common autoantibody found, while liver-kidney microsomal type-1 antibody positivity is the most peculiar autoimmune feature of children with HCV infection. The clinical significance of non-organ specific autoantibodies in the course of paediatric chronic hepatitis C is still debated. Autoantibody positivity can be considered neutral for most patients, while it can be associated with negative connotations for others, especially those positive for liver-kidney microsomal type-1 autoantibody. Subclinical hypothyroidism but not autoimmune thyroiditis has been demonstrated in HCV infection in children, while only few cases of HCV-associated membranoproliferative glomerulonephritis have been described. Single reports are available in the literature reporting the anecdotal association between chronic hepatitis C and other extrahepatic manifestations such as myopathy and opsoclonus-myoclonus syndrome. Despite the low incidence of extrahepatic manifestations of chronic hepatitis C in children, overall, available data suggest a careful monitoring.

Community­acquired bacteremic pneumococcal pneumonia in children: diagnosis and serotyping by real­time polymerase chain reaction using blood samples.

BACKGROUND: The aim of this study was to use real-time polymerase chain reaction (RT-PCR) on blood samples to diagnose and serotype pneumococcal infection in a large cohort of Italian children hospitalized for community-acquired pneumonia. METHODS: We conducted an observational study from April 2007 through June 2009 of children aged 0-16 years with a diagnosis of community-acquired pneumonia admitted to 83 pediatric hospitals in Italy. RESULTS: Seven hundred fifty-three children were studied. RT-PCR found pneumococcal infection in 80 (10.6%) of 753 patients. In 292 patients, culture and RT-PCR were simultaneously performed. Streptococcus pneumoniae was identified in 47 of 292 patients; 45 (15.4%) tested positive by RT-PCR and 11 (3.8%) tested positive by culture. RT-PCR was significantly more sensitive than culture in revealing bacteremic pneumonia (odds ratio, 30.6; 95% confidence interval, 5.8-97.5; P<.001). Complicated pneumonia was found in 162 (21.5%) of 753 children; 152 (93.8%) of these 162 had parapneumonic effusion, and 51 (33.6%) had empyema. Children with complicated pneumonia were significantly older. Pneumococcal bacteremia was found by RT-PCR to occur significantly more frequently in children with complications (38 [23.5%] of 162) than in children with uncomplicated pneumonia (44 [7.4%] of 591; odds ratio, 3.8; 95% confidence interval, 2.30-6.30; P<.001). RT-PCR allowed serotyping from blood in 92.5% of patients. More than two-thirds of the pneumonia cases were due to nonpneumococcal conjugate vaccine 7 serotypes. Serotype 1 was the most frequent serotype (26 [32.5%] of 80) and was significantly associated with complications (50.0% in patients with complicated pneumonia vs 18.2% in patients with uncomplicated pneumonia; odds ratio, 4.5, 95% confidence interval, 1.48-14.03; P=.005) and older age. Serotype 19A was second in frequency (15.0%) and was significantly associated with younger age. CONCLUSIONS: RT-PCR allows diagnosis and serotyping of pneumococcal bacteremic community-acquired pneumonia in children and is an important tool for evaluating serotype distribution in culture-negative samples.

Absorption and bioeffects of an isoflavone-based supplementation in postmenopausal women.

Epidemiological studies suggest that consumption of isoflavones rich diets can improve several postmenopausal complications. The aim of this study was to investigate the absorption and the efficacy of isoflavonic supplementation in the treatment of menopausal symptoms.36 postmenopausal women received 75 mg/day of isoflavones in the form of tablets, for six months. 21 subjects concluded the treatment. Plasmatic and urinary samples were collected before and after the treatment, along with a dietary interview. Isoflavones were determined in biological samples and in commercial administered supplements by a HPLC/DAD system.Results showed the presence of genistein (from 0.043 to 1.820 micromol/L) in plasma samples, and of genistein (from 2.486 to 20.363 micromol/24h) and daidzein (from 11.106 to 98.091 micromol/24h) in the urines of the treated women. In the 21 completers the Greene Climateric scale value for hot flushes changed from 3 to 1 or 0. No changes of the endometrial thickness and of the breast tissue were detected. The analysis of the supplement content in the tablets was in agreement with what declared by the producer.Administration of isoflavone supplements produced a decrease of symptoms in this cohort of postmenopausal women monitored for isoflavone absorption.

Hepatitis C Genotype 4 Virus Nonstructural 3 and Nonstructural 5A Resistance-associated Substitutions in a 16-year-old Adolescent Failing Ombitasvir/Paritaprevir/Ritonavir Plus Ribavirin.

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.

Intrafamilial transmission of hepatitis C virus: infection of the father predicts the risk of perinatal transmission.

The aims of the present study were to evaluate in a cohort of mothers infected with hepatitis C virus (HCV) the prevalence of HCV infection of their sexual partners, the influence of infection of the partners on perinatal transmission, and whether this influence is mediated by other well known risk factors for perinatal transmission. Forty-nine consecutive mothers infected with HCV who transmitted infection to their offspring and, as a control group, 557 consecutive mothers infected with HCV who did not transmit infection, together with their children and the fathers of the children who were also the sexual partners of the mothers were evaluated. History of intravenous drug use was significantly more frequent in women with partners infected with HCV than in women with partners not infected [115/180 (63.9%) vs. 87/401 (21.7%); relative risk (RR): 6.38, 95% confidence intervals (CI): 4.34-9.39, P < 10(-3)]. HCV infection was more frequent in the partners of mothers who transmitted perinatally HCV [23/49 (46.9%) vs. 174/557 (31.2%); RR: 1.95, 95%CI: 1.08-3.51, P = 0.03]. Multivariate analysis demonstrated that paternal HCV infection is not a risk factor per se for perinatal HCV transmission, but its role is dependent on maternal intravenous drug use [adjusted RR: 1.23 (95%CI: 0.44-3.39, P = 0.6)]. In conclusion, the present study shows that partners of mothers infected with HCV with a history of intravenous drug use were at a higher risk of HCV infection. HCV infection of the father seems to be associated with perinatal transmission but this relationship is dependent on maternal history of intravenous drug use.

Thyroid function and anti-thyroid autoantibodies in untreated children with vertically acquired chronic hepatitis C virus infection.

OBJECTIVE: The reported data on thyroid function and anti-thyroid autoantibodies in adults with untreated hepatitis C virus (HCV) infection are controversial. Data are scarce for HCV-infected children, and only in those treated with interferon-alpha (IFN-alpha). We investigated thyroid function and anti-thyroid autoantibodies in a cohort of untreated children with vertically acquired, chronic, HCV infection. DESIGN AND PATIENTS: FT4 and TSH serum levels (measured by immunometric assays) and anti-thyroglobulin (TgA) and anti-thyroperoxidase (TPOA) antibodies (evaluated by fluorescence enzymatic immunoassays) were studied in 36 consecutive HCV-infected children and 150 age- and sex-matched controls. The prevalence of thyroid involvement was also related to family history of autoimmune disease, distribution of HCV genotypes, and duration and activity of HCV infection. RESULTS: Four out of 36 (11.1%) HCV-infected children and 4/150 controls (2.7%) showed subclinical hypothyroidism [P = 0.04; relative risk (RR) 4.56, 95% confidence interval (CI) 1.08-19.21]. None of these had anti-thyroid autoantibodies. Two out of 36 (5.6%) HCV-infected children and 1/150 (0.7%) controls had increased TgA values with normal levels of TSH (P > 0.05). Subclinical hypothyroidism and anti-thyroid autoantibodies were not related to family history of autoimmune disease, duration of infection, HCV viral load, liver function or different HCV genotype distribution, but seemed to be related to the presence of active HCV infection. CONCLUSIONS: Our data suggest a role for HCV infection in the development of nonautoimmune thyroid disease in untreated HCV-infected children, confirming previous studies in adults. Clinicians should be aware of thyroid dysfunction even in untreated children.

Incidence and clinical significance of reactive thrombocytosis in children aged 1 to 24 months, hospitalized for community-acquired infections.

The aims of this study were to identify demographic, clinical and laboratory characteristics associated with reactive thrombocytosis useful for clinical management and to evaluate potential complications of this condition in a cohort of children selected for they young age as at high risk of reactive thrombocytosis. Retrospective analysis of medical records of 239 children among 902 aged 1-24 months, hospitalized during a 12-month period, and discharged with a diagnosis of infectious disease was performed. One hundred and nineteen children out of 239 (49.8%) presented thrombocytosis (>500 platelets x 10(9)/L; normal range 150-499 x 10(9)/L), 81/119 (68%) on admission. The incidences of thrombocytosis or extreme thrombocytosis (>1,000 x 10(9)/L) were 13.2% (119/902) and 0.8% (7/902). Thrombocytotic children had higher counts of white blood cells and had been treated more frequently with steroids (36/82, 43.9% vs. 5/53, 9.4%; p = 5 x 10(-5); relative risk 7.51, 95% confidence intervals 2.71-20.82). No significant difference was found in relation to sex, age, fever, C reactive protein level, diagnoses and antibiotic therapy. Two out of 239 (0.8%) enrolled children, both thrombocytotic and with other acquired risk factors, developed thrombosis. In conclusion, reactive thrombocytosis in children aged 1 up to 24 months is frequent and unrelated to markers of disease activity or degree of inflammation.

Phytoestrogens: food or drug?

Within the past several years, the relation between diet and health has been accepted by the mainstream nutrition community and in this connection interest in the physiological role of bioactive compounds present in plants has dramatically increased over the last decade.The phytoestrogens are bioactive molecules present as nutritional constituents of widely consumed vegetables. Their name derives from the fact that they are able to bind to estrogen receptors and to induce an estrogenic/antiestrogenic response in target tissues. Natural estrogens are involved in a multiplicity of programmed events in target tissues as uterus, breast, pituitary gland and hormone responsive tumors. Phytoestrogens are present in many human foodstuffs including fruits (plum, pear, apple grape berries, …), vegetables (beans, sprouts, cabbage, spinach, soybeans, grains, hops, garlic, onion,…), wine, tea, and they have been identified in a number of botanical dietary supplements. They include a wide variety of structurally different compounds such as isoflavones, mainly found in soy, lignans found in grains, stilbenes found in the skin of grapes. Other less investigated compounds include flavones, flavans, isoflavanes and coumestans. The estrogenic or antiestrogenic activity of any chemicals depends on the ability of the compound to interact with the ERs (ERα , ERß ).This article reported the knowledge about the activity of phytoestrogens from a pharmacological point of view for their estrogenicity or antiestrogenicity.