Hepatitis A and E

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"Infectious hepatitis" is caused by hepatitis A virus (HAV); "serum hepatitis" results from hepatitis B virus (HBV) and the delta agent (HDV). "Non-A, non-B hepatitis" is caused by hepatitis E (HEV) and hepatitis C (HCV) viruses. HAV and HEV are transmitted enterically, while HCV, HBV and HDV are transmitted parenterally. There are more than 700,000 cases of viral hepatitis per annum in the United States, of which more than half are asymptomatic. Despite the availability of highly effective vaccines against hepatitis A and hepatitis B, these diseases are among the most reported vaccine-preventable diseases in the United States.

INFECTIOUS HEPATITIS - HEPATITIS A VIRUS

Hepatitis A virus (HAV) causes infectious hepatitis which is transmitted via the oral-fecal route as a result of close contact such as in day-care centers. The virus is also spread by sexual contact and in contaminated food. Rarely (in fewer than 1% of cases) is HAV spread by blood products, blood transfusions or intravenous drug use.

This form of hepatitis accounts for about 40-50% of all hepatitis cases. The orally ingested virus first enters the bloodstream via the lining of the intestinal tract and then migrates to the liver parenchymal cells. These cells become infected because they have the immunoglobulin-like HAV cellular receptor on their surfaces. The virus replicates rather slowly and is shed into the bile and passed in the stool. The symptoms of HAV and HBV are very similar. There is only one HAV serotype worldwide and humans are the only reservoir.

Symptoms

The most obvious symptom is jaundice. HAV also causes abdominal pain, nausea and diarrhea. In addition, the patient may suffer fatigue and fever. Chronic infections with HAV do not occur but some patients may experience symptoms for up to 9 months.

ACUTE HEPATITIS A CASE DEFINITION FOR SURVEILLANCE

Clinical criteria
An acute illness with:
discrete onset of symptoms (e.g. fatigue, abdominal pain, loss of appetite, intermittent nausea, vomiting),
and jaundice or elevated serum aminotransferase levels

Laboratory criteria

IgM antibody to hepatitis A virus (anti-HAV) positive

Case Classification

Confirmed. A case that meets the clinical case definition and is laboratory confirmed or a case that meets the clinical case definition and occurs in a person who has an epidemiologic link with a person who has laboratory-confirmed hepatitis A (i.e., household or sexual contact with an infected person during the 15-50 days before the onset of symptoms).

Carcinogenesis

There is no evidence for HAV being the cause of liver cancer (hepatocellular carcinoma).

Immune response

Virus particles are found in the bloodstream from three days to five weeks after infection and in the stool from one to five weeks after infection. In the latter part of this period, raised liver enzymes in the bloodstream (e.g. alanine amino transferase) are observed. IgM (which is used in diagnosis) rises soon after the initial infection and peaks at about 5 weeks. Anti-HAV IgG rises later (two to three weeks). There is a cytotoxic T cell and natural killer cell response that kills infected cells. The humoral response is also important in counteracting the virus but most pathological effects of the virus are the result of the immune response rather than the virus itself. Once the patient has cleared the virus, the anti-HAV IgG antibody response gives life-long protection.

Pathology

There is a prodromal (incubation) phase of between two and eight weeks after infection, following which there is an abrupt onset of symptoms. After about two weeks of infection, virus is detectable in the liver, blood and stool (Feces can contain up to 108 infectious virions per milliliter and are the primary source of HAV). The virus replicates in hepatocytes but little cellular damage ensues. Thus, the symptoms of infectious hepatitis are not caused by the presence of HAV in the liver but by the immunological response of the host to its presence. Initially, patients experience fatigue, pain in the abdomen and nausea and there are elevated levels of liver enzymes in the serum

A few days after the first symptoms, jaundice (icteric symptoms) often occurs; this is particularly noticeable in the sclera. Jaundice is seen in about 60% of adults but far fewer children (up to 20%). There is also dark urine and light stool. Children show lesser symptoms than adults; for example, jaundice is seen among fewer than 10% of children younger than 6 years of age, 40%-50% of older children and 70%-80% of adults.

Almost all (99%) patients make a complete recovery within two to four weeks with no chronic sequelae. In about 0.1% of patients, fulminant hepatitis occurs leading to death in the majority of these patients (about 50-80%). This results from liver failure and encephalopathy. Other rare complications are relapsing hepatitis and cholestatic hepatitis (in which there are very high bilirubin levels). The former, which has symptoms similar to the original infection, usually occurs within three months of the initial HAV infection. In cholestatic hepatitis, liver damage by the virus occurs leading to obstruction of bile secretion. This is most often seen in immuno-compromised patients.

Epidemiology

The incidence of HAV infection in the United States has fallen from about 12 cases per 100,000 population in the 1980’s to 2.9 in 2002. This is largely due to the availability of the vaccine. In 2001, there were 93,000 new HAV infections in the United States. There were an estimated 45,000 acute clinical cases (but many fewer were actually reported). in the United States, hepatitis A outbreaks used to occur in 10 to 15 years cycles. Since transmission is via the oral-fecal route, members of the family of an infected person are most at risk. Community outbreaks are common but in half of all cases no risk factor is identified. The infected person is contagious before overt symptoms appear. Many infected persons are asymptomatic (most children and up to a half of infected adults) but still shed infectious virus. In addition, conditions of poor housing and cramped conditions lead to spread of the virus. There are frequent outbreaks in daycare centers that are then transmitted to other family members. The virus is also transmitted as a result of sexual contact, especially homosexual sex and, since it is blood-borne, can be spread by sharing needles during use of intravenous drugs. The virus is very resistant to a variety of agents including low pH, organic solvents and detergents. It is also resistant is temperatures as high as 61 degrees for 20 minutes. Besides direct fecal-oral transmission (such as by contaminated hands), the virus may be spread in contaminated drinking water and where raw sewage is present since the virus can survive for months in fresh or salt water. Particularly problematic is sewage contamination of oysters and other shellfish that are filter-feeders. In developing countries, most people get mild HAV infections as children and then retain life-long immunity. Approximately 30% of the population of the United States is seropositive with a much higher incidence in third world countries.

The highest rates of hepatitis A in the United States are found in Hispanic and Native American populations. The lowest are among Asian Americans. This undoubtedly reflects socio-economic conditions such as crowding and also contact with persons from countries such as Mexico with high HAV infection rates. These factors result in higher hepatitis A incidence in western states.

In 1990, hepatitis A incidence was highest in children with about an equal male to female ratio; however, by 2001, the gender/age incidence had changed markedly with the highest incidence in young to middle aged men. This is because the incidence of hepatitis A has fallen as a result of vaccine use and HAV is now mainly spreading among intravenous drug users and homosexual men.

The virus is found worldwide with the highest levels in under-developed countries. In underdeveloped countries, nearly all children have anti-HAV antibodies indicative of a prior infection and epidemics are rare. In countries with higher levels of sanitation, infection occurs in older individuals and clinical disease is more often seen; very often there are localized outbreaks. In some countries with high hygiene standards (e.g. Scandinavia), clinical disease outbreaks are again rare and hepatitis A is seen primarily in intravenous drug users.

Diagnosis

An ELIZA test for anti-HAV IgM is available. Diagnosis is also made from the symptoms and the clusters of cases that occur. The presence of IgG within the first few weeks of infection suggests a prior infection or vaccination.

Treatment

There is no treatment. Supportive care should be given. Hepatitis A immune globulin can be administered early after infection (two weeks) and gives some temporary immunity (up to five months).

Control

Improved hygiene is the most important factor in stemming the spread of HAV. Chlorination of water is very effective. Before the present vaccine, passive immunity was obtained using immune gamma globulin which was effective against the disease in most cases if given before infection as prophylaxis or during the early incubation period. The present very effective vaccines (HAVRIX and VAQTA) used in the United States are killed (formalin) virus preparations. The vaccine is given in the first year of life and immunity, probably life-long, results within a month. In adults, the vaccines give protective immunity within one month of vaccination in most recipients. A second dose leads to 100% protection.

1999 ACIP RECOMMENDATIONS FOR ROUTINE HEPATITIS A VACCINATION OF CHILDREN

Children Who Should be Routinely Vaccinated
- living in states, counties, and communities where the average hepatitis A rate was > 20 cases/100,000 during baseline period

Children Who Should be Considered for Routine Vaccination
- living in states, counties, and communities where the average hepatitis A rate was <20 but  10 cases/100,000 during the baseline period.

The vaccine is recommended for the following persons 2 years of age and older:
• Travelers to areas with increased rates of hepatitis A
• Men who have sex with men
• Injecting and non-injecting drug users
• Persons with clotting-factor disorders (e.g. hemophilia)
• Persons with chronic liver disease
• Children living in areas with increased rates of hepatitis A during the baseline period from 1987-1997

Information on immune globulin from CDC

IG is a sterile preparation of concentrated antibodies made from pooled human plasma. IG provides protection against hepatitis A through passive transfer of antibody. IG is 80%‑90% effective in preventing clinical hepatitis A when administered before exposure or early in the incubation period after exposure. IG can be used for pre-exposure prophylaxis for travelers to areas of high or intermediate endemicity of hepatitis A, particularly when the planned departure is less than 2-4 weeks later. In this situation, immunity from vaccination might not have developed by the time of departure. Post-exposure prophylaxis with IG is effective if administered within 14 days of exposure. The primary routine indication for post-exposure prophylaxis is for household or other intimate contacts of persons with hepatitis A. In addition, post-exposure prophylaxis might be indicated when hepatitis A cases occur in some institutional settings (e.g., child day-care centers) and after some common source exposures (e.g., persons who ate food prepared by an infected food handler). Local and/or state health departments should be consulted regarding the use of IG for post-exposure prophylaxis in these settings.

Information on HAV vaccination from CDC

The two inactivated vaccines licensed in the United States, HAVRIX® (manufactured by GlaxoSmithKline) and VAQTA® (manufactured by Merck & Co., Inc.), are highly immunogenic. Approximately 97%-100% of children, adolescents, and adults develop protective levels of antibody within 1 month after the first dose of vaccine; essentially 100% of vaccinees develop protective antibody with high geometric mean concentrations after completing the two-dose series. The vaccines are highly efficacious: In published studies, 94%-100% of children were protected against clinical hepatitis A after receiving the equivalent of one dose.

The efficacy of HAVRIX® * was evaluated in a double-blind, controlled, randomized clinical trial in Thailand among 38,157 children 1-16 years of age living in an area with high endemic rates of hepatitis A. Following two doses of vaccine (360 EL.U. per dose) given 1 month apart, the efficacy of vaccine in protecting against clinical hepatitis A was 94% (95% confidence interval [CI], 79%-99%). A double-blind, placebo-controlled, randomized clinical trial using VAQTA® * was conducted among 1,037 children 2-16 years of age living in a single U.S. community with a high rate of hepatitis A. Within 18 days following one dose (25 U) of vaccine, the efficacy in protecting against clinical disease was 100% (95% CI, 85%-100%).

Both HAVRIX® and VAQTA® should be administered intramuscularly into the deltoid. A needle length appropriate for the vaccinee’s age and size should be used. HAVRIX® is available in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 720 EL.U. per dose in a two-dose schedule; and for persons greater than 18 years of age, 1,440 EL.U. per dose in a two-dose schedule. VAQTA® is also licensed in two formulations, and the formulation differs according to the person’s age: for persons 2-18 years of age, 25 U in a two-dose schedule; and for persons greater than 18 years of age, 50 U per dose in a two-dose schedule.

Soreness at the site of injection is the most commonly reported side effect of hepatitis A vaccination (50%). Headache and malaise were reported by 15% and 7% of vaccinees, respectively.

Reviews of data from multiple sources for more than 5 years did not identify any serious adverse events among children or adults that could be definitively attributed to hepatitis A vaccine. The safety of the vaccine will continue to be assessed through ongoing monitoring of data from the Vaccine Adverse Events Reporting System (VAERS) and other surveillance systems.

The safety of hepatitis A vaccination during pregnancy has not been determined; however, because hepatitis A vaccine is produced from inactivated HAV, the theoretical risk to the developing fetus is expected to be low. The risk associated with vaccination should be weighed against the risk of hepatitis A in women who might be at high risk for exposure to HAV.

Hepatitis A vaccine should not be administered to persons with a history of a severe reaction to a dose of hepatitis A vaccine or allergy to a vaccine component. Because hepatitis A vaccine is inactivated, no special precautions are needed when vaccinating immunocompromised persons.

Among adults and children, studies have demonstrated that detectable antibody persists for at least 5-8 years after completing the vaccination series. Although data regarding long-term efficacy are limited, no cases among vaccinated children were observed in one community at 5-6 years of follow-up. Estimates of antibody persistence derived from mathematical models of antibody decline indicate that protective levels of anti-HAV persist for at least 20 years. Whether other mechanisms such as cellular memory also contribute to long-term protection is unknown.

The presence of anti-HAV at the time of vaccination appears to blunt the immune response. Administration of immune globulin (IG) concurrently with the first dose of hepatitis A vaccine did not decrease the proportion of adults who developed protective levels of antibody compared with adults who had been administered hepatitis A vaccine alone, but the geometric mean antibody concentrations (GMCs) among adults who received IG were lower 1 month after completion of the vaccination series than the GMCs of any adults who had been administered hepatitis A vaccine alone. The reduced immunogenicity of hepatitis A vaccine that occurs with concurrent administration of IG does not appear to be clinically significant. IG and hepatitis A vaccine can be given concurrently if indicated.

Reduced vaccine immunogenicity also has been observed in infants who had passively-transferred antibody because of prior maternal HAV infection and were administered hepatitis A vaccine according to a number of different schedules. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers.

Based on limited data, final antibody concentrations might be lower among older vaccinated persons.

Vaccination of adults with chronic liver disease of viral or nonviral etiology produced seroprotection rates similar to those observed in healthy adults. Final antibody concentrations, however, were substantially lower for each group of patients with chronic liver disease than for healthy adults.

In some studies, administration of hepatitis A vaccine to persons with HIV infection resulted in lower seroprotection rates and antibody concentrations. Among HIV-infected men, those who responded to hepatitis A vaccination had significantly more CD4+ T lymphocytes at baseline compared with those who did not respond. Being HIV positive, however, is not a contraindication for administering hepatitis A vaccine if the person is in a risk group for whom hepatitis A vaccine is recommended.

In one small study, none of the 8 patients who had received a liver transplant responded to hepatitis A vaccination; however, liver transplantation is not a contraindication for administering hepatitis A vaccine.

Hepatitis A vaccine is safe and immunogenic for infants who do not have antibody to HAV that was passively-transferred from a mother who had hepatitis A in the past. A number of studies of infants vaccinated according to different dosages and schedules have shown that the presence of passively-acquired maternal antibody blunts the immune response. In most studies, all infants developed protective levels of antibody, but the final GMCs were approximately 1/3 to 1/10 those of infants born to anti-HAV-negative mothers. Although the age at which this passively-transferred antibody disappears is unclear, it is probably no longer detectable in most infants by 15 months of age. Currently, hepatitis A vaccines are not licensed by the FDA for children under 2 years of age.

Twinrix® is a combined hepatitis A and hepatitis B vaccine approved in 2001 by the Food and Drug Administration (FDA) for persons 18 years of age or older. Twinrix® contains 720 EL.U. of hepatitis A antigen and 20 μg of hepatitis B surface antigen.

Primary immunization consists of three doses, given on a 0-, 1-, and 6-month schedule, the same schedule as that used for single-antigen hepatitis B vaccine. Immunogenicity of the combined vaccine appears to be similar to that of the single-antigen vaccines when given separately.

Twinrix® can be used for immunization of persons 18 years of age or older who have indications for vaccination against both hepatitis A and hepatitis B, such as users of illicit injectable drugs, men who have sex with men, and persons with clotting factor disorders who receive therapeutic blood products. Formulation for children is available in many other countries.

For international travel, hepatitis A vaccine is recommended for travelers to areas of high or intermediate hepatitis A endemicity (see slide 10). Hepatitis B vaccine is recommended for travelers to areas of high or intermediate hepatitis B endemicity who plan to live or work for at least 6 months in highly endemic countries.

Antibody production in response to HAV infection results in lifelong immunity to hepatitis A and, presumably, to HAV infection. Vaccination of a person who is immune because of prior infection does not increase the risk of adverse events. In populations that are expected to have high rates of prior HAV infection, prevaccination testing might be considered to reduce costs by avoiding vaccination of persons who have prior immunity. Testing of children is not indicated generally because of their expected low prevalence of infection. For adults, the decision to test should be based on the expected prevalence of immunity, the cost of vaccination compared with the cost of serologic testing (including the cost of an additional visit), and the likelihood that testing will not interfere with initiating vaccination. For example, if the cost of screening (including laboratory and office visits) is one third the cost of the vaccine series, then screening potential recipients in populations where the prevalence of infection is likely to be greater than 33% should be cost-effective.

Persons for whom prevaccination testing will likely be most cost-effective include adults who were born in or lived for extensive periods in geographic areas that have a high endemicity of HAV infection, older adolescents and young adults in certain population groups (i.e., Native Americans, Alaska Natives, and Hispanics), and adults in certain groups that have a high prevalence of infection (e.g., injecting drug users[IDU]). In addition, the prevalence might be high enough among all older U.S.-born adults to warrant prevaccination testing. Commercially available tests for total anti-HAV should be used for prevaccination testing.

Post-vaccination testing is not indicated because of the high rate of vaccine response among adults and children. In addition, testing methods that have the sensitivity to detect low, but protective, anti-HAV concentrations after vaccination are not approved for routine diagnostic use in the United States.

The recommendations for hepatitis A vaccination are based on several guiding principles. To reduce overall hepatitis A incidence, it was felt that a comprehensive strategy was needed and that routine vaccination of children should be the cornerstone of this strategy. Herd immunity could play an important role in extending the effects of hepatitis A vaccination of young children to older children and to adults.

Creative approaches, however, were needed because hepatitis A vaccine is not licensed for use in children under 2 years of age, which is the age group in which we generally administer routine vaccinations to children in the United States. Thus, the ACIP recommendations for routine vaccination of children built on the epidemiology in an incremental fashion, starting with areas in which the disease burden was greatest. In 1996, the ACIP recommended routine vaccination of children living in communities with historically the highest rates, such as Native American and Alaska Native communities.

In 1999, the ACIP took another incremental step, recommending routine vaccination of children living in areas with consistently elevated rates during a defined baseline period.

The third step will be to vaccinate all children nationwide.

There is a combined anti-HAV/HBV vaccine approved in the United States for recipients of 18 years and older. It contains Hepatitis A antigen and HBsAg. In other countries, this vaccine is available for children.

ENTERIC NON-A, NON-B HEPATITIS - HEPATITIS E

Hepatitis E virus (HEV) causes enteric non-A, non-B hepatitis and is transmitted via the oral-fecal route through contaminated drinking water. It is not usually transmitted directly from one patient to another (in contrast to HAV). HEV outbreaks can be extensive and is likely the cause of much of the acute sporadic hepatitis seen in areas where the virus is found (figure Cool

. In countries of low incidence, HEV infections are usually seen in travelers.

After an incubation 16 to 60 days (with an average of 40 days), typical hepatitis symptoms arise (jaundice, malaise, abdominal pain, nausea etc). Virus may be excreted in the stool for several weeks after the onset of symptoms. There is no evidence for chronic HEV infections but persistence in the population may be the result of a low level of infections between epidemics. In pregnant women the mortality rate is high.

Immunology

After a prodromal phase of about a month, symptoms occur. Virus is found earlier in the stool . Alanine aminotransferase rises at the same time anti-HEV IgM and IgG. By about two months, elevated alanine aminotransferase diminishes, as does IgM. IgG remains and results in short term immunity.

Diagnosis

There are no commercially available tests for routine diagnosis

Epidemiology

HEV is endemic to many tropical countries where good sanitation is lacking. In the United States less than 2% of the population has anti-HEV antibodies. The source of these infections is not known.

Prevention

Possibly contaminated drinking water should be avoided as should uncooked food in endemic areas. Immune globulin is not effective if it comes from donors in western countries. There is no vaccine.