Ravi Jhaveri

Performance of the AST-to-platelet ratio index as a noninvasive marker of fibrosis in pediatric patients with chronic viral hepatitis.

We investigated the performance of aspartate aminotransferase to platelet ratio index (APRI) as a noninvasive marker of fibrosis and cirrhosis in children with chronic viral hepatitis. All of the patients 0 to 20 years old with chronic hepatitis B or C presenting at a tertiary medical center from 1992 to 2008 were identified. Thirty-six patients were evaluated with 48 biopsy results. The areas under the receiver operating characteristic curve were 0.71 for fibrosis and 0.52 for cirrhosis. When examining subgroups, the APRI performed better in older patients and in those with vertically transmitted hepatitis C virus. Further research into APRI and the other noninvasive markers of fibrosis in children with chronic viral hepatitis is warranted.

Varicella-zoster virus: An overlooked cause of aseptic meningitis

Varicella-zoster virus causes varicella (chickenpox) and zoster (shingles). Neurologic manifestations occur in both illnesses. We describe a previously healthy child who had aseptic meningitis without exanthem caused by reactivation of varicella-zoster virus. This has not been previously reported in the pediatric literature.

Diagnosis and management of hepatitis C virus-infected children.

VIROLOGY, TRANSMISSION, AND EPIDEMIOLOGY HCV is a flavivirus (family Flaviviridae) but is sufficiently distinct from other flaviviruses (eg, yellow fever virus, dengue virus, West Nile encephalitis virus, etc) as to be classified by itself in the Hepacivirus genus. It is an enveloped single-stranded RNA virus. Its genome is translated as 1 polyprotein that is cleaved by host and viral proteases to yield the individual viral proteins. HCV is most frequently transmitted by blood or contaminated body fluid exposure, primarily during illicit injection drug use. Before 1992, contaminated blood products were responsible for much of HCV transmission, but currently, only intravenous drug exposure continues to significantly contribute to transmission in the US adult population. The main route of acquisition for children is vertical transmission. Approximately 5% to 10% of infants born to mothers with chronic HCV infection will acquire the virus. Other routes have been suggested (sexual transmission, tattooing), but definitive evidence of transmission is lacking. Worldwide, it is estimated that 130 to 180 million people are infected with HCV. Current US estimates show that approximately 25,000 to 50,000 children are chronically infected, with an estimated 750 infants/y acquiring the virus through vertical transmission (pediatric seropositivity rates of 0.2%–0.4%).

Effect of Heptitis C Virus Core Protein on Cellular Gene Expression: Specific Inhibition of Cyclooxygenase 2

Hepatitis C virus (HCV) core protein plays a significant role in the alteration of cellular gene expression. We expressed HCV core protein using a tetracycline-inducible expression system in HeLa cell lines. Profiles of gene expression in cells expressing the HCV core protein were compared with those in control cells by use of microarray analysis. Cells expressing the HCV core protein showed 86 down-regulated and 41 up-regulated genes, compared with control cells. One gene affected was cyclooxygenase 2 (COX-2). Levels of both COX-2 RNA and the Cox-2 protein were significantly inhibited after the expression of HCV core protein in HeLa cells. Similar results were obtained in hepatoma cells and in a functional assay that measured the production of the Cox-2 protein in response to a mitogenic stimulus. The inhibition of the Cox-2 protein could serve as a means of muting the cellular inflammatory response during HCV infection. Correlation of these findings with analysis of clinical specimens from chronically infected patients should lend further significance to the down-regulation of the inflammatory response via Cox-2.

Hepatitis C Virus (HCV) Vertical Transmission in 12-Month-Old Infants Born to HCV-Infected Women and Assessment of Maternal Risk Factors

We summarize the results of HCV RNA testing of 12 month old infants born to HCV infected mothers in Cairo, Egypt. We used real-time PCR testing and demonstrated a transmission rate of 14.3%.

Hepatitis C Virus in Pregnancy and Early Childhood: Current Understanding and Knowledge Deficits.

Hepatitis C virus (HCV) is a well known cause of chronic liver disease in adults, but the burden of HCV in pregnant women and children is underappreciated. The leading route of HCV acquisition in children is vertical transmission. This review will discuss previous studies on the impact of HCV on pregnancy, risk factors for perinatal transmission, HCV transmission rates from mother to infant, what influence the virus has on the exposed or infected infant, and those areas where additional studies are required to advance our understanding of HCV pathogenesis during pregnancy. The rapid expansion of HCV treatment regimens free of interferon and ribavirin will expand future therapeutic opportunities for pregnant women and infected infants.

Lipid Droplet Binding of Hepatitis C Virus Core Protein Genotype 3

Background. Hepatitis C virus (HCV) genotype 3 is known to cause steatosis (fatty liver) that is more frequent and severe than other genotypes. We previously identified sequence elements within genotype 3 HCV Core domain 3 that were sufficient for lipid accumulation. Aims. We examined various genotype 3 Core domains for lipid droplet localization and compared the lipid droplet binding regions of domain 2 with a genotype 1 isolate. Methods. We generated HCV Core domain constructs fused with green fluorescent protein and performed immunofluorescence to visualize lipid droplets. Results. Constructs containing HCV Core domain 2 are appropriately localized to lipid droplets with varying degrees of efficiency. When compared to genotype 1, there are polymorphisms within domain 2 that do not appear to alter lipid droplet localization. Conclusions. In summary, the differences in a steatosis-associated HCV Core genotype 3 isolate do not appear to involve altered lipid droplet localization.

Osteopontin is up-regulated in chronic hepatitis C and is associated with cellular permissiveness for hepatitis C virus replication

OPN (osteopontin)) is a Hh (Hedgehog)-regulated cytokine that is up-regulated during chronic liver injury and directly promotes fibrosis. We have reported that Hh signalling enhances viral permissiveness and replication in HCV (hepatitis C virus)-infected cells. Hence we hypothesized that OPN directly promotes HCV replication, and that targeting OPN could be beneficial in HCV. In the present study, we compared the expression of OPN mRNA and protein in HCV (JFH1)-infected Huh7 and Huh7.5 cells, and evaluated whether modulating OPN levels using exogenous OPN ligands (up-regulate OPN) or OPN-specific RNA-aptamers (neutralize OPN) leads to changes in HCV expression. Sera and livers from patients with chronic HCV were analysed to determine whether OPN levels were associated with disease severity or response to therapy. Compared with Huh7 cells, Huh7.5 cells support higher levels of HCV replication (15-fold) and expressed significantly more OPN mRNA (30-fold) and protein. Treating Huh7 cells with OPN ligands led to a dose-related increase in HCV (15-fold) and OPN (8-fold) mRNA. Conversely, treating Huh7.5 cells with OPN-specific RNA aptamers inhibited HCV RNA and protein by >50% and repressed OPN mRNA to basal levels. Liver OPN expression was significantly higher (3-fold) in patients with advanced fibrosis. Serum OPN positively correlated with fibrosis-stage (P=0.009), but negatively correlated with ETBCR (end-of-treatment biochemical response), ETVR (end-of-treatment virological response), SBCR (sustained biochemical response) and SVR (sustained virological response) (P=0.007). The OPN fibrosis score (serum OPN and presence of fibrosis ≥F2) may be a predictor of SVR. In conclusion, OPN is up-regulated in the liver and serum of patients with chronic hepatitis C, and supports increased viral replication. OPN neutralization may be a novel therapeutic strategy in chronic hepatitis C.

Bacteremia Caused By An enterococcus Faecalis Isolate With High-level Linezolid Resistance In A Teenager With Crohn’s Disease

Linezolid is an antibiotic used to treat highly resistant infections, including vancomycin-resistant enterococci and methicillin-resistant Staphylococcus aureus. Enterococcus faecalis bacteremia occurs in pediatric patients. We present a teenager admitted for bacteremia caused by E faecalis with a distinctive pattern of resistance to linezolid. This organism has the highest MIC to linezolid reported in the literature to date.

Evaluation and Management of Febrile Children: A Review

IMPORTANCE Management of febrile children is an intrinsic aspect of pediatric practice. Febrile children account for 15% of emergency department visits and outcomes range from the presence of serious bacterial infection to benign self-limited illness. OBSERVATIONS Studies from 1979 to 2015 examining febrile infants and children were included in this review. Management of febrile infants younger than 90 days has evolved considerably in the last 30 years. Increased rates of Escherichia coli urinary tract infections, increasing resistance to ampicillin, and advances in viral diagnostics have had an effect on the approach to caring for these patients. Widespread vaccination with conjugate vaccines against Haemophilus influenzae and Streptococcus pneumoniae has virtually eliminated the concern for bacterial infections in children aged 3 to 36 months. Urinary tract infections still remain a concern in febrile infants of all ages. CONCLUSIONS AND RELEVANCE Advances over the last 30 years allow for more precise risk stratification for infants at high risk of serious bacterial infection. With appropriate testing at the initial visit, much of the diagnostic testing and empirical treatment can be avoided for infants younger than 90 days. In the vaccinated child aged 3 to 36 months, the only bacterial infection of concern is urinary tract infection.