Viral Hepatitis in Travelers and Immigrants

Hepatitis A Virus (HAV)

HAV is a 27-nm RNA virus. The transmission of hepatitis A is almost exclusively via the fecal-oral route, although parenteral transmission may occasionally occur, particularly in the setting of intravenous drug use. The virus is found throughout the world, but from the standpoint of the traveler, inadequate sewage facilities and environmental contamination with human excrement in rural tropical areas are most often responsible for hepatitis A transmission ( Fig. 22.1 ). Drinking contaminated water and eating fresh fruits and vegetables grown and processed with contaminated water are major routes of infection. Consumption of shellfish grown in contaminated waters is another common etiology of hepatitis A outbreaks, such as the outbreak associated with contaminated clams that caused approximately 300,000 cases of hepatitis A infection in Shanghai in 1988.

Person-to-person transmission can occur through eating food touched by unhygienic food handlers (who failed to wash their hands after defecation) or through close personal contact involving unsanitary conditions, such as found in daycare facilities and institutional domiciles such as prisons and homes for the developmentally disabled. Epidemiologic data have shown that other high-risk populations for HAV infection are men who have sex with men, illegal drug users, and persons with clotting factor disorders. Occupational risk for HAV occurs among those who work with HAV-infected primates or with HAV in research laboratories.

As an indication of the difference in risk in developed versus developing countries, serologic evidence of prior hepatitis A infection was present in 2.3% of young Scandinavian soldiers, in 20-30% of middle-aged middle-class New Yorkers, but in almost 100% of Southeast Asian populations. Epidemiologic evidence shows that the risk of HAV infection changes as formerly low-resource countries undergo modernization: only 50% of young urban Thais are seropositive, and the massive 1988 hepatitis A outbreak in China indicated that there was a large pool of susceptible young adults who had not previously been infected.

Hepatitis B Virus (HBV)

The agent of HBV is a 42-nm DNA virus. The intact virion, also known as the Dane particle, consists of identifiable sub-viral fragments, including the hepatitis B surface antigen (HBsAg), a core antigen (HBcAg), a DNA polymerase molecule, and the “e” antigen (HBeAg). Circulating HBsAg is the prime marker of active infection. HBeAg is an indicator of high infectivity, except in the setting of the precore mutation, which leads to lack of HBeAg but very high viral levels.

Identifiable groups at risk of contracting HBV include persons receiving contaminated blood products (a low risk in countries where banked blood is screened for HBsAg and other blood-borne pathogens), organ transplant recipients, healthcare workers having frequent contact with blood products, hemodialysis patients, homosexual males with multiple sexual partners, and sexual and household contacts of HBsAg-positive carriers.

The risk of transmission of HBV during travel reflects the prevalence of the disease worldwide ( Fig. 22.2 ). In the United States, there is evidence of past HBV infection in 10% of the population, but the HBsAg-positive carrier rate is <2% (1.25 million people). The same figures hold for northern European countries, but areas of North Africa, sub-Saharan Africa, Oceania, and much of East Asia have much higher rates of infection: evidence for previous infection may be present in up to 70-80% of the population, and the underlying carrier rates run from 5 to 15%. An estimated 350 million persons are chronic carriers of HBV worldwide. One reason for the high rate of infection and carrier state in highly endemic areas is the phenomenon of peripartum maternal-fetal (vertical) transmission. As many as 30-50% of the women who are HBsAg carriers or who are acutely infected in the third trimester will transmit the infection to their offspring unless specific prophylactic measures are administered to the infant immediately following birth (see below).

Of most concern to the traveler is the risk of exposure through sexual or close personal contact with carriers in the native populations abroad and inadvertent exposure to the virus through contaminated instruments used for personal grooming, for example, haircuts, shaves, manicures, pedicures, tattooing, and waxing. Other travelers at risk include those who seek medical or dental care in countries where hepatitis B is endemic or those who receive unexpected emergency care in sub-optimal situations. The current trend in “medical tourism,” that is, travel to foreign countries to obtain surgical procedures at a significantly lower cost than at home, makes the issue of effective practices by blood banks worldwide to screen for blood-borne pathogens (hepatitis B, hepatitis C, human immunodeficiency virus [HIV], West Nile virus, and Chagas disease) a topic of increasing importance.

HBV Infection in Pregnancy

As a general policy, immigrants to the United States from areas where hepatitis B is endemic should be screened for HBsAg, but the screening process becomes extremely important in pregnant women. The influx of refugees from Southeast Asia and other areas where hepatitis B is endemic has made this even more critical ( Chapter 19 ).

The cause for concern is the risk of maternal-fetal transmission. Up to 90% of infants born to HBeAg-positive mothers will themselves become chronic carriers, with the risk of long-term complications and death and also the risk of passing the infection on to their offspring. High-dose (0.5 mL) hepatitis B immune globulin (HBIG) given within 12 hours of birth has been shown to decrease the immediate infection rate by 80%. When the passive immunity granted by HBIG disappears, significant risk of infection via maternal-fetal contact returns, so it is recommended that infants at risk also receive the first of their three hepatitis B vaccinations at birth. This combination of HBIG and HBV vaccine has been shown, in general, to be 90% effective in preventing infection in children born to mothers who are HBV carriers. However, depending on the study, in women with high viral levels the percentage of infants developing HBsAg ranges from 7 to 32%. Antiviral therapy should be considered during the third trimester in women with high-level viremia.

Hepatitis C Virus (HCV)

The HCV was identified in 1989 and proved to be the viral agent causing 96% of cases of what was previously referred to as non-A, non-B hepatitis (NANBH). HCV became the most common cause of transfusion-associated hepatitis in the United States after screening for HBsAg decreased the percentage of post-transfusion hepatitis due to HBV to 10%. Older studies suggested that as many as 3-7% of units of what would now be regarded as high-risk blood products were capable of transmission of NANBH, and rates of infection from 5 to 15% in patients receiving 1-5 units of blood were documented. The risk of post-transfusion hepatitis due to HCV initially decreased when blood was screened for surrogate markers for NANBH (using the liver enzyme alanine aminotransferase [ALT] and the core antibody to hepatitis B); it has now undergone about a 10-fold decrease with routine screening of donor blood for antibody to hepatitis C. Transmission via blood products in the United States is now rare.

Transmission of HCV also occurs with parenteral drug abuse and less often by the mechanisms by which HBV is spread. Although data from studies have been contradictory, there may be a mildly increased incidence of infection in homosexual males and in those with multiple heterosexual partners who are infected; inoculation of body fluids containing virus through mucosal lesions is presumed to be the mechanism of spread. However, this mechanism of viral spread is extremely inefficient. Sexual transmission of HCV between stable monogamous couples is uncommon. The likelihood of transmission to healthcare workers following needle-stick or other parenteral exposure to blood or body fluids is correlated to the viral load of the source patient. Rates of transmission from 1 to 10% have been reported for HCV, in contrast to 5-30% for HBV.

Worldwide, an estimated 180 million people are infected with HCV. In the United States, it is estimated that 1.6% of the population (4.1 million persons) have antibody to hepatitis C virus, and at least 80% are chronically infected. At the time of this publication, HCV is the leading cause of death from liver disease and leading indication for liver transplantation in the United States. Unfortunately, a large proportion of infections with HCV abroad have no clear reason for transmission established; however, medical care, drug use, tattooing, body piercing, and traditional medicine (i.e., ritual scarification, acupuncture) have all been cited as causes. The traveler must be counseled to avoid risk factors for transmission similar to those with HBV. It has been established that some countries have a particularly high prevalence of anti-HCV antibody. Included in this group are certain sub-Saharan African nations, Egypt and parts of the Arabian Peninsula, Thailand, and Japan ( Fig. 22.3 ).

Hepatitis D Virus (HDV)

Hepatitis D (formerly the “delta agent”) is a defective RNA virus that is dependent on host enzymes and viral enzymes of HBV for its own replication. The HDV RNA is replicated by the host polymerases and requires HBV for its HBsAg coat, which is necessary for HDV assembly. Active hepatitis D is found only in patients who are positive for HBsAg, and anti-hepatitis D antibody has been found only in the sera of active HBsAg carriers or those with serologic evidence of past infection. The overall prevalence of anti-HD in HBsAg carriers is about 8-15% in Western Europe. Hepatitis D is most prevalent in southern Italy and North Africa, but increased rates are also seen in the Middle East and sub-Saharan Africa. Epidemics have also occurred in the Amazon basin, Russia, Greenland, and Mongolia. Risk factors for the transmission of the virus appear to be much the same as for HBV. In the United States, hepatitis D has been found almost exclusively in drug abusers with concomitant hepatitis B infection or in HBV carriers with a history of many transfusions. However, as immigration from endemic countries increases, this population must not be forgotten. The mortality rate in acute HBV infection appears to be greater when hepatitis D co-infection is present, but not as high as when hepatitis D superinfection of a chronic hepatitis B carrier occurs.

Hepatitis E Virus (HEV)

What had previously been called enterically transmitted non-A, non-B hepatitis is now known as hepatitis E. HEV has been demonstrated in stool using immune electron microscopy, and while the virus resembles HAV in terms of both transmission and epidemiology, it is serologically unrelated. Five genotypes have been identified, four of which infect humans, and genotype distribution varies geographically.

HEV is endemic in Southeast and Central Asia ( Fig. 22.4 ). It has been the source of several large epidemics in India, Nepal, and Burma, usually in association with flooding or other problems with the water supply. Well-studied outbreaks have occurred in northern and western Africa, the Middle East, and Mexico. With the advent of serologic testing, evidence for frequent sporadic transmission of endemic infection has been documented in a number of countries, including Egypt, Hong Kong, and nations in sub-Saharan Africa.

Classic epidemic HEV infection is secondary to genotypes 1 or 2 HEV, which have no known animal reservoir. Patients who develop acute hepatitis after recent travel to endemic areas are generally infected with these genotypes. Studies have shown that HEV genotypes 3 and 4 are likely to be a zoonosis for which pigs are the most common reservoir. Genotype 4 has also been reported in other reservoirs such as wild boars, chickens, rodents, mongooses, shellfish, and, to a lesser extent, dogs. Based on limited serum surveys of HEV antibodies among high-risk populations in endemic regions, most zoonotic HEV infections appear to be asymptomatic among occupational risk groups where reported seroprevalence was elevated, ranging from 6% among Brazilian pig farmers up to 33% among Italian abattoir workers. Symptomatic cases seem to occur in young adults or older children. The very few cases of HEV in the United States have generally been imported by recent travelers from abroad, primarily Mexico and India; secondary transmission has not been documented. However, there have been reports of HEV infection secondary to undercooked deer, pig liver, and shellfish.

In general, hepatitis E is clinically similar to hepatitis A; however, the mortality in some outbreaks has been higher than that seen with hepatitis A, perhaps due to malnutrition and concomitant disease among the victims. A mortality rate of 10 - 20% among women late in pregnancy has been a consistent finding in HEV epidemics, particularly with genotypes 1 and 2. There is no commercially available vaccine against hepatitis E, although one is in development and appears promising. Administration of immune globulin derived from pooled serum banks in non-endemic regions for hepatitis E appears to offer no protection against infection.

Prodrome

The incubation period for hepatitis A is 2-6 weeks, with a mean of 3.7, and the onset of the disease is typically rather rapid. The incubation time for hepatitis E is similar to HAV at 2-8 weeks, with a mean of 40 days. The incubation times for hepatitis B (2-6 months; mean 11.8 weeks) and hepatitis C (6-12 weeks; mean 7.8 weeks) are longer, and the onset is generally more indolent. The incubation periods for hepatitis D are less well defined, but for HDV, it appears to range from 3 to 6 weeks.

Beyond the differing incubation periods, and the rapidity of onset of symptoms, the prodrome in the different types of infections may be remarkably similar. Fatigue, flu-like myalgia, and malaise are often the initial symptoms, followed by gastrointestinal symptoms including anorexia, nausea, and occasional diarrhea. A low-grade fever may also be present. Right upper quadrant tenderness is almost universally found, and hepatomegaly is detectable in many cases.

Arthralgia and an urticarial rash are seen about 10% of the time as part of the prodrome of hepatitis B. They are thought to be due to the formation of hepatitis B antigen–antibody immune complexes. This is seen rarely in HAV infection, although may occur occasionally in hepatitis C.

Patients with hepatitis A are infectious for approximately 2 weeks before the onset of clinical disease, during which time they are shedding viral particles in their stool. Shedding declines with the onset of jaundice, and the patient is non-infectious 1-2 weeks after clinical disease develops. There is no carrier state. By contrast, patients with HBV infection may have low levels of HBsAg detectable within 1-2 weeks after infection and theoretically may be infectious; a smaller infectious inoculum will delay the appearance of HBsAg in serum. The timing for infectivity with HCV is not known.

Icteric Phase

Most cases of all three major types of hepatitis remain subclinical. In the case of hepatitis A, this is because worldwide most infections occur in children, who seldom become very ill; adults are much more likely to become jaundiced. An estimated 10-20% of HBV and 30% of HCV infections result in jaundice. Patients may first notice darkening of the urine, then the appearance of scleral or palatine icterus, and, finally, frank jaundice. Pruritus may become prominent. At this stage, symptoms of hepatitis A begin to improve, and infectivity clears as HAV disappears from the stool. However, symptoms of hepatitis B and hepatitis C may persist after the onset of jaundice, and infectivity remains.

Convalescent Phase

Gradual return to well-being is the rule in all types of hepatitis that do not become fulminant or progress to a chronic carrier state. Some 90% of cases of hepatitis A are characterized by return of liver function tests to normal within 12 weeks; the balance takes somewhat longer, but no carrier state develops. In contrast, the resolution of infection in hepatitis B typically takes 6-20 weeks, and the marker of cure is disappearance of HBsAg and appearance of antibody to it (anti-HBs); 5-10% of adult patients become chronic carriers of HBsAg. Hepatitis C symptoms may resolve quickly or may follow a smoldering course; the latter is highly associated with development of a chronic carrier state.

Acute Liver Failure

The development of acute liver failure (previously called fulminant liver failure) is the most feared complication of acute hepatitis infection. It is an overwhelming infection that results in massive hepatic necrosis, extreme initial elevation of bilirubin, and persistently abnormal bilirubin despite a return of hepatic enzymes to normal. Hepatic encephalopathy and elevated international normalized ratio (INR) develop due to the extreme liver dysfunction.

Acute liver failure (ALF) develops in only a small number of cases of acute hepatitis but is more common in hepatitis B (1-3%) than in hepatitis A (0.5-1.0%). Acute HAV superinfection in persons with chronic HCV may cause a higher rate of ALF. Regardless of viral etiology, the prognosis in cases of infectious ALF is grim: without liver transplantation, the mortality rate can be as high as 60-90%. The mortality rate for hepatitis B ALF is much higher if hepatitis D co-infection is present, and the rate in hepatitis D superinfection of chronic hepatitis B is particularly high.

Chronic Hepatitis

Chronic hepatitis does not occur after hepatitis A but can be seen following HBV, HCV, HDV, or HEV infection. Some 5-10% of people in the United States infected with HBV develop chronic hepatitis. The rate is higher (15-20%) in geographic areas with high endemic rates of disease; the development of chronic hepatitis is more likely following maternal-fetal transmission (90%). The most dreaded complication of chronic HBV is the development of hepatocellular carcinoma, which is 300 times more likely to develop in those with chronic disease compared with the general population. Additionally, those with chronic HBV can progress to cirrhosis, liver failure, and death. Chronic hepatitis develops in approximately 85% of those infected with HCV. Chronic HCV infection can lead to cirrhosis in 30-40% of infected individuals, which is then associated with the development of hepatocellular carcinoma in up to 4% per year. There is some evidence that chronic HCV co-infection may increase the likelihood of hepatocellular carcinoma in HBV carriers. Chronic HEV infection can develop in immunocompromised individuals, such as organ transplant recipients or those infected with HIV, and is associated with rapid development of cirrhosis (within 2-3 years).

Viral Hepatitis Co-Infections

Acute HAV infections in persons with chronic HBV and HCV infections are associated with more severe disease and a higher risk of death. Acute HAV infection in persons infected with HIV may result in a prolonged HAV viremic stage (median duration 53 days vs. 22 days, p < 0.05) and potentially more severe disease as well as increased transmissibility.

HBV and HCV co-infection may result in more serious medical complications than HCV alone, in that there is an increased chance of progression to cirrhosis and an increased risk of development of hepatocellular carcinoma.

Among HIV-infected persons, chronic HBV infection occurs in 10-15%, and up to 30% may be co-infected with HCV. An increased risk of death has been reported in HIV/HBV co-infected men. Reports from several countries have shown significantly increased rates of death from end-stage liver disease among HIV-infected persons in the era of highly active antiretroviral therapy (HAART) compared with the pre-HAART era. One hypothesis is that chronic HBV and/or HBC infections can potentiate the inherent hepatotoxicity of the antiretroviral therapy drugs.

Viral Diseases