Medical Resources :: Common Diseases :: Infectious Diseases & Parasites :: Hepatitis C in Children

Virology of Hepatitis C

• Existence of a 3rd hepatitis virus first suspected in 1975
• Known as non-A non-B Hepatitis and associated with blood transfusions
• Renamed HCV in 1989 when the viral genome was cloned and sequenced
• Single-stranded RNA virus in Flavivirideae family
• Six genotypes with wide variations in their geographic distribution
• Individuals may be simultaneously infected with multiple genotypes and subtypes
• Genetic diversity may be responsible for the host's inability to mount an effective immune response
• Mutations contribute to viral escape from the host immune response
• Propensity for this virus to cause chronic infection may also be related to defective viral particles and to extrahepatic viral replication particularly in peripheral mononuclear cells and lymphocytes
• Clinical Disease Associated with Hepatitis C
• Incubation period of HCV averages 6 weeks to 7 weeks with a range of 2 weeks to 6 months
• Clinical picture of disease in children may be indistinguishable from hepatitis A or B
• Usually asymptomatic, subclincal, mild

Clinical Disease

• Jaundice in 25% of patients
• Liver enzyme ALT (SGPT) elevation lower than in Hepatitis B
• Fulminant hepatitis is extremely uncommon
• Chronic disease may lead to autoimmune complications such as autoimmune hepatitis, arthritis, serum sickness, erythema multiforme (target lesion rash)
• Immunecompromised children have a higher and more rapid rate of disease progression

Extrahepatic Manifestations in Hepatitis C

• Arthritis
• Keratoconjunctivitis sicca
• Lichen planus
• Glomerulonephritis
• Extrahepatic Manifestations in Hepatitis C
• Essential mixed cryoglobulinemia
• Porphyria cutanea tarda
  Note: extrahepatic manifestations have not adequately been studied in children
• Complications of Hepatitis C
• Chronic Hepatitis
• Cirrhosis of the liver
• Hepatocellular carcinoma

Clinical Disease

• 85% of those infected as children or adults become chronically infected
• 20%-30% of that group develop cirrhosis over the next 20 years
• 15% of those infected become immune and presumably are protected against chronic hepatitis and liver cancer
• Average period between initial infection and the development of cancer is 30 years (Tong et al. New England Journal of Medicine 1995)
• 1%-5% risk of hepatocellular carcinoma at 20 years (DiBisceglie et al. Am J Gastroenterol 1991)
• It is not known whether the risk of chronic disease and subsequent complications is higher for patients infected as newborns than for patients infected at an older age
• Rapid progression to cirrhosis in children not common
• Typical course is gradual resolution or very slow progressive or stable liver disease Bortolotti et al. Journal of Pediatric
• Gastroenterology and Nutrition 1994

Long-term Follow-up

• Bortolotti et al. Journal of Pediatric Gastroenterology and Nutrition Vol. 18, 1994
• 77 children in Italy and Spain infected with HCV followed during a mean observation time of 6 years (mean age 4 years)
• 22% ALT elevation at presentation
• 32% chronic active disease by liver biopsy at presentation
• At six year follow-up, 10% had achieved biochemical remission (nl ALT)
• 40% had evidence of chronic active hepatitis

Worldwide Distribution of HCV from WHO 1997 Data

Continent	Prevalence
North America	0.5% to 2.5%
South America	0.5% to >10%
Europe	0.5% to 2.5%
Africa	2.5% to >10%
Asia	2.5% to >10%

Worldwide Prevalence in Kids

Country	Setting	# Tested	HCV +
Spain	school	560	0.36%
Japan	school	1,442	0%
Brazil	daycare, street youth, school	1,378	0%, 0%, 4%
Ukraine	boarding school, day school	478	1.4%, 0.4%
Pakistan	school	236	0.44%
Ghana	school	809	5.4%
Cameroon	school	696	14.5%

Epidemiology in Children

• Seroprevalence of HCV in the U.S. is approximately 0.2% in children younger than 12 years and 0.4% in those between 12 and 19 years of age (CDC, unpublished data)
• Possibly 150,000 children in the U.S. are currently infected
• CDC estimates 3.9 million individuals in U.S. are infected with HCV (third national Health and Nutrition Examination Survey 1988-1994-NHANES III)
• Overall prevalence in the general population is 1.8%
• Seroprevalence rates of 1% to 2% in pregnant women
• HCV is the major cause of chronic liver disease in U.S. and the main reason for liver transplantation in the U.S.

Transmission of Hepatitis C

• Viral transmission occurs primarily through large or repeated direct percutaneous exposure to blood
• Injecting-drug use currently accounts for 60% of HCV transmission in the U.S.
• Blood transfusions which accounted for a substantial proportion of HCV infections acquired greater than 10 years ago, rarely account for recently acquired infections
• Risk has not been completely eliminated because of the inability to detect antibodies for a period after acute infection, as well as the presence of seronegative HCV carriers (5%-10%)

Transmission of HCV

• Identification of the virus with HCV antibody screening of blood products after 1990 has had a significant impact on the incidence of posttransfusion hepatitis, decreasing the risk of acquiring HCV from a transfusion in the U.S. to 0 .001% per unit transfused (Schreiber et al. NEJM 1996)
• Intravenous immunoglobulin (IVIG) associated cases of HCV (Kawasaki, ITP, immune disorders, sepsis) Gammagard made by Baxter Healthcare administered to patients between April 1, 1993 and February 23, 1994
• Screened with an anti-HCV assay, but there was no viral inactivation step
• All IVIG preps are solvent and detergent treated and HCV is inactivated

Seroprevalence of HCV

Pop Subgroup	Seroprevalence (%)
IV drug abuse	60-90
Hemophilia	60-90
Hemodialysis	20
High-risk sex	1-10
Household contacts	1-10
Pregnant women	1-2
Health care workers	1
Volunteer blood donors	< 0.6

Transmission in Children

• Children are infected primarily via transfusion of blood or blood products or by vertical transmission from their chronically infected mothers

Maternal-Infant Transmission

• HCV is vertically transmitted from mother to infant
• Current estimated risk is about 5%-7% (range: 0%-25%)
• Risk of transmission appears to correlate with the maternal viral RNA titer (viral load)
• Higher rates of transmission are seen when mothers are co-infected with HIV
• Average risk 14% (range: 5%-36%-Ohto et al. New England Journal of Medicine 1994)

Breast Feeding and HCV

• Although infection via breast milk is theoretically possible, evidence to date does not support a contraindication for breast feeding by HCV-infected mothers (Lin et al. Journal of Pediatrics 1995)

Household Transmission

• Transmission from household exposure is rare (Camareno et al. Journal of Pediatrics 1993)
• As with Hepatitis B, razors and toothbrushes should not be shared in households with individuals infected with HCV

Postexposure Prophylaxis and Prevention of HCV

• Immune globulin is anti-HCV negative and is therefore not useful to prevent HCV after exposure
• There is currently no vaccine against HCV (mutations and lack of protection from natural infection)

Diagnostic Tests

• Detection of antibody to HCV antigens-ELISA and RIBA assays detect IgG anti-HCV antibody
• Molecular methods to detect and quantitate the nucleic acid of the virus-PCR assay for detection of HCV RNA

Diagnostic Tests

• ELISA=Enzyme-linked immunosorbent assay (EIA-1, EIA-2, EIA-3) with increasing sensitivity
• RIBA=Recombinant immunoblot assay (RIBA-I, RIBA-II, RIBA-III) with increasing specificity

Interpretation of HCV Tests

• EIA indicates past or present infection, but does not differentiate between acute, chronic, or resolved infection
• Negative antibody test results early in the course of acute disease do not rule out infection with HCV
• A prolonged interval may occur between onset of clinical illness and seroconversion although 80% of patients will be anti-HCV positive within 5 to 6 weeks after onset of clinical hepatitis

Diagnostic Tests

• PCR=Polymerase Chain Reaction
• Quantitative and Qualitative assessments of the RNA (ribonucleic acid) of HCV is used to confirm the presence of the virus and can estimate the viral load

HCV RNA Tests

• HCV RNA Qualitative tests-Reverse transcriptase polymerase chain reaction (RT-PCR) amplification of HCV RNA by in-house or commercial assays (Amplicor HCVTM ) detects presence of circulating HCV RNA and monitors antiviral therapy
• Quantitative tests-RT-PCR amplification of HCV RNA by in-house or commercial assays (Amplicor HCV MonitorTM )
• Branched chain DNA (bDNA) assays (QuantiplexTM HCV RNA Assay)

HCV Quantitative RNA Tests
These tests determine concentration of HCV RNA and might be useful for assessing the likelihood of response to antiviral therapy, but there is still no standardization of these tests as yet

How to diagnose HCV in Young Children

• Under one year of age, a child may have maternal antibody from maternal HCV infection and not be infected!
• Do EIA followed by confirmatory RIBA
• Do PCR HCV RNA for the presence of actual virus
• Do biochemical assay-ALT

How to Diagnose HCV in Children

• EIA positive, RIBA positive or negative, HCV RNA negative=reflection of maternal antibody, child not infected
• EIA positive, RIBA positive, HCV RNA negative=actual infection without viral activity
• EIA positive, RIBA positive, HCV RNA positive=actual infection with viral activity

Management

• A child who is older than one year who is HCV antibody positive should be followed by a pediatric gastroenterologist
• ALT and PCR HCV RNA should be done on a yearly basis to follow the course
• All children with HCV infection should be immunized against Hepatitis A and B (Vento et al. NEJM 1998)
• The ALT level is not a reliable marker of hepatic inflammation and a liver biopsy may be necessary to assess the degree of inflammation and the amount of fibrosis
• Inflammation and fibrosis in the liver may be variable and even a biopsy is subject to sampling error that may misrepresent overall liver damage

Treatment

• The decision to treat a child infected with HCV is based on ALT, PCR HCV RNA, and liver biopsy results
• Treatment with Interferon alpha-2b and interferon alpha-2a are currently FDA approved as monotherapy for the treatment of HCV infection in adults, but not in children
• Treatment efficacy with Interferon alone in adults is about 15%-25% with endpoints being normal ALT and undetectable HCV RNA (Carithers et al. Hepatology 1997)

Combination Therapy
Ribavirin, an oral antiviral agent, in combination with Interferon can increase efficacy to 40%-50% in adults (Schalm et al. Journal of Hepatology 1996)

Treatment Trials in Children

• Jonas et al. Pediatr Infect Dis J 1998)
• 7 (33%) of 21 patients treated with Interferon-alpha-2a were complete responders after at least 12 months of follow-up

Regimens and Side Effects

• IFN is given subcutaneously three times a week for one year (1996)
• Side effects-leukopenia, anemia, thrombocytopenia, malaise, flu-like syndrome, depression
• Ribavirin is given orally and can cause hemolytic anemia

Who Should be Screened for HCV?

• American Academy of Pediatrics-Committee on Infectious Diseases March 1998
• Injecting-drug use
• Transfusion before 1992
• Hemodialysis
• Clotting factor before 1987
• Infants born to HCV-Infected Women
• Recipients of intravenous immunoglobulin (Baxter)
• Children who have hepatitis found not to be Hepatitis A or B

Should Adoptees be Screened?

• According to the Academy, no routine screening is advised-I disagree!
• We often have unreliable and/or incomplete records for children who are adopted domestically and internationally
• Since so many people are unaware of their Hepatitis C status, I recommend testing all adopted children for HCV

Prevalence in Adopted Children

• 700 children adopted from abroad evaluated at Winthrop-University Hospital at the International Adoption Medical Consultation Services between 1994 and 1999
• 5/700=0.7% prevalence
• 3 children < 1 yr., 2 children > 1yr
• All 5 children from Eastern Europe

Prevalence in Adopted Children

• Of the five children found to be HCV positive at Winthrop, all five were PCR HCV RNA negative at the time of their initial adoption consultation
• 2 children are still < 1 year of age
• 2 children are > 1 year and need to be retested
• 1 child has turned 1 year of age and need

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