Chapter 4 Travel-Related Infectious Diseases
Noele P. Nelson
Hepatitis A virus (HAV) is a nonenveloped RNA virus classified as a picornavirus.
HAV is transmitted through direct person- to-person contact (fecal–oral transmission) or through ingestion of contaminated food or water. HAV can survive in the environment for prolonged periods at low pH. Freezing does not inactivate HAV, and it can be transmitted through ice and frozen foods. Heat inactivation must occur at high temperatures (>185°F [>85°C] for 1 minute). HAV can be transmitted from contaminated raw or inadequately cooked foods and through handling foods after cooking. Recent large-scale outbreaks have been caused by contaminated food (such as frozen berries, seafood, and fresh fruit and vegetables) and through person-to-person spread among injection and noninjection drug users and homeless people.
HAV is shed in the feces of infected people. People are most infectious 1–2 weeks before the onset of clinical signs and symptoms (jaundice or elevation of liver enzymes), when the concentration of virus is highest in the stool and blood. Viral excretion and the risk of transmission diminish rapidly after liver dysfunction or symptoms appear, which is concurrent with the appearance of circulating antibodies to HAV. Infants and children can shed virus for up to 6 months after infection.
HAV is common in areas with inadequate sanitation and limited access to clean water. In highly endemic areas (such as parts of Africa and Asia), a large proportion of adults in the population are immune to HAV, and epidemics of hepatitis A are uncommon. In areas of intermediate endemicity (such as Central and South America, Eastern Europe, and parts of Asia), childhood transmission is less frequent, more adolescents and adults are susceptible to infection, and outbreaks are more likely. In areas of low endemicity (such as the United States and Western Europe), infection is less common, but disease occurs among people in high-risk groups and as communitywide outbreaks.
In the United States, the most frequently identified risk factors for hepatitis A infection vary from year to year. Risk groups recommended to receive the hepatitis A vaccine by the Advisory Committee for Immunization Practices (ACIP), include international travelers, users of injection and noninjection drugs, men who have sex with men (MSM), people with chronic liver disease, people with clotting-factor disorders, people who work with nonhuman primates, and people who anticipate close personal contact with an international adoptee. In addition, homelessness was approved as an indication for hepatitis A vaccination by ACIP at the October 2018 meeting.
Hepatitis A is among the most common vaccine-preventable infections acquired during travel. Cases of travel-related hepatitis A can occur in travelers to developed countries and developing countries, who have “standard” tourist itineraries, accommodations, and eating behaviors. Risk is highest for those who live in or visit rural areas, trek in backcountry areas, or frequently eat or drink in settings of poor sanitation. Common-source food exposures are increasingly recognized as a risk for hepatitis A, and sporadic outbreaks have been reported in Europe, Australia, North America, and other regions with low levels of endemic transmission. Multinational HAV outbreaks among MSM have been described, including since 2016 among MSM who have traveled to areas with ongoing HAV transmission among MSM in European Union countries. In the United States, outbreaks of hepatitis A in multiple states have been identified among homeless people and people who use injection and noninjection drugs. The homeless population has emerged as a high-risk group for hepatitis A infection in these recent US outbreaks.
The incubation period averages 28 days (range, 15–50 days). Infection can be asymptomatic or range in severity from a mild illness lasting 1–2 weeks to a severely disabling disease lasting several months. Clinical manifestations include the abrupt onset of fever, malaise, anorexia, nausea, and abdominal discomfort, followed within a few days by jaundice. The likelihood of having symptoms with HAV infection is related to the age of the infected person. In children aged <6 years, most (70%) infections are asymptomatic; jaundice is uncommon in symptomatic young children. Among older children and adults, the illness usually lasts <2 months, although approximately 10%–15% of infected people have prolonged or relapsing symptoms over a 6- to 9-month period. Severe hepatic and extrahepatic complications, including fulminant hepatitis and liver failure, are rare but more common in older adults and people with underlying liver disease. Chronic infection does not occur. The overall case-fatality ratio varies according to the population affected.
HAV cannot be differentiated from other types of viral hepatitis on the basis of clinical or epidemiologic features. Diagnosis requires a positive test for antibody to HAV (anti-HAV) IgM in serum, detectable from 2 weeks before the onset of symptoms to approximately 6 months afterward.
Serologic tests for total anti-HAV (IgG and IgM) are available commercially. A positive total anti-HAV result and a negative IgM anti-HAV result indicate past infection or vaccination and immunity. The presence of serum IgM anti-HAV usually indicates current or recent infection and does not distinguish between immunity from infection and vaccination. Acute hepatitis A is a nationally notifiable disease.
Vaccination or immune globulin (IG), food and water precautions, maintaining standards of hygiene and sanitation.
Two monovalent hepatitis A vaccines, Vaqta (Merck & Co, Inc., Whitehouse Station, NJ) and Havrix (GlaxoSmithKline Beecham Biologicals, Rixensart, Belgium), are approved for people ≥12 months of age in a 2-dose series. A combined hepatitis A and hepatitis B (Twinrix, GlaxoSmithKline) vaccine is approved for people ≥18 years of age in the United States (Table 4-02). The immunogenicity of the combination vaccine is equivalent to that of the monovalent hepatitis A and hepatitis B vaccines when tested after completion of the recommended schedule.
INDICATIONS FOR USE
All susceptible people traveling for any purpose, frequency, or duration to countries with high or intermediate HAV endemicity should be vaccinated or receive IG before departure. Many travel health clinicians feel that all travelers should be educated about hepatitis A and be given the opportunity for immunization. Prevalence patterns of HAV infection vary among regions within a country, and in some areas limited data result in uncertainty in endemicity maps, especially in low- and middle-income countries. Countries where the prevalence of HAV infection is decreasing have growing numbers of susceptible people and are at risk for outbreaks of hepatitis A. In recent years, large outbreaks of hepatitis A were reported in developed countries among people who had been exposed to imported food contaminated with HAV, MSM, drug users, and the homeless. Taking into account the complexity of interpreting hepatitis A risk maps and potential risk of foodborne hepatitis A in countries with low endemicity, some experts advise people traveling outside the United States to consider hepatitis A vaccination regardless of destination.
Vaccination is recommended for unvaccinated household members and other people who anticipate close personal contact (such as household contacts or regular babysitters) with an international adoptee from a country of high or intermediate endemicity during the 60 days after arrival of the child in the United States. The first dose of the 2-dose hepatitis A vaccine series should be administered as soon as adoption is planned, ideally ≥2 weeks before the arrival of the child (see Chapter 7, International Adoption).
One dose of single-antigen hepatitis A vaccine administered at any time before departure can provide adequate protection for most healthy travelers. However, single-dose, long-term protection data are limited. The monovalent vaccine series should be completed according to the licensed schedule for long-term protection.
Hepatitis A vaccine should be administered to infants aged 6–11 months traveling outside the United States when protection against hepatitis A is recommended. Although hepatitis A vaccine is considered safe and immunogenic in infants, hepatitis A vaccine doses administered before 12 months of age might result in a suboptimal immune response, particularly in infants with passively acquired maternal antibody. Therefore, hepatitis A vaccine doses administered at <12 months of age are not considered for long-term protection, and the 2-dose hepatitis A vaccine series should be initiated at age 12 months according to the routine, age-appropriate vaccine schedule. Adults aged >40 years, immunocompromised people, people with chronic liver disease, and people with other chronic medical conditions planning travel in <2 weeks may receive IG (0.1 mL/kg) in addition to vaccine at a separate injection site based on provider risk assessment, including considerations of the traveler’s age, immune status and underlying conditions, risk of exposure, and availability of IG.
Infants aged <6 months and travelers who are allergic to a vaccine component or elect not to receive vaccine should receive a single dose of IG (0.1 mL/kg), which provides effective protection against HAV infection for up to 1 month. Those who do not receive vaccination and plan to travel for 1–2 months should receive an IG dose of 0.2 mL/kg, which can be repeated every 2 months thereafter if the traveler remains in a high-risk setting, though hepatitis A vaccination should be encouraged if not contraindicated.
No data on single-dose hepatitis A vaccine efficacy are available for Twinrix. An alternate, accelerated 4-dose schedule is available for Twinrix; doses can be administered at 0, 7, and 21–30 days, followed by a dose at 12 months. (For more information, see www.cdc.gov/mmwr/volumes/66/wr/mm6636a5.htm?s_cid=mm6636a5_e.) Although vaccinating an immune traveler is not contraindicated and does not increase the risk for adverse effects, screening for total anti-HAV before travel can be useful in some circumstances to determine susceptibility and eliminate unnecessary vaccination. Postvaccination testing for serologic response is not indicated.
OTHER VACCINE CONSIDERATIONS
Using vaccine according to the licensed schedule is preferable. An interrupted series does not need to be restarted. More than 95% of vaccinated people develop levels of anti-HAV that correlate with protection 1 month after the first dose. Given their similar immunogenicity, a series that has been started with one brand of hepatitis A monovalent vaccine may be completed with another brand of monovalent vaccine. For children and adults who complete the primary series, booster doses of vaccine are not recommended.
VACCINE SAFETY AND ADVERSE REACTIONS
Among adults, the most frequently reported side effects after hepatitis A vaccination are tenderness or pain at the injection site (56%–67%) and headache (14%–16%). Among children (11–25 months of age), the most common reported side effects are pain or tenderness at the injection site (32%–37%) and redness (21%–29%). No serious adverse events in children or adults have been reported that could be attributed definitively to the vaccine; no increase in serious adverse events has been identified among vaccinated people compared with baseline rates.
PRECAUTIONS AND CONTRAINDICATIONS
Hepatitis A–containing vaccines should not be administered to travelers with a history of hypersensitivity to any vaccine component, including neomycin. Twinrix should not be administered to people with a history of hypersensitivity to yeast. The tip caps of prefilled syringes of Havrix and Twinrix and the vial stopper, syringe plunger stopper, and tip caps of Vaqta may contain dry natural rubber, which may cause allergic reactions in latex-sensitive people. Because hepatitis A vaccine consists of inactivated virus, and hepatitis B vaccine consists of a recombinant protein, no special precautions are needed for vaccination of immunocompromised travelers. Providers should check precautions and contraindications before administering IG.
Hepatitis A vaccine is considered safe for pregnant women. A recent review of the Vaccine Adverse Event Reporting System did not identify any concerning patterns of adverse events in pregnant women or their infants after hepatitis A vaccination (Havrix, Vaqta) or hepatitis A and B combined vaccination (Twinrix) during pregnancy. Hepatitis A vaccine should be administered to pregnant women who are at high risk of exposure and to pregnant women who want protection according to the adult immunization schedule.
Travelers who are exposed to HAV but not symptomatic and who have not received hepatitis A vaccine previously should be administered 1 dose of monovalent hepatitis A vaccine or IG (0.1 mL/kg) as soon as possible, ideally within 2 weeks of exposure. The efficacy of IG or vaccine when administered >2 weeks after exposure has not been established.
Hepatitis A vaccines should be administered for postexposure prophylaxis for all people aged ≥12 months. In addition to hepatitis A vaccine, IG (0.1 mL/kg) should be administered to people who are immunocompromised or who have chronic liver disease and may be administered to people aged >40 years depending on the provider’s risk assessment, which should include consideration of the exposed person’s age, immune status and underlying conditions, exposure type (risk of transmission), and availability of IG. People aged <12 months and people who are allergic to a vaccine component or elect not to receive vaccine should receive a single dose of IG (0.1 mL/kg) only. Twinrix should not be used for postexposure prophylaxis, because no data are available on the efficacy of combination vaccine for prophylaxis after exposure to HAV.
More detailed information can be found in the Advisory Committee on Immunization Practices recommendations at www.cdc.gov/mmwr/volumes/67/wr/mm6743a5.htm?s_cid=mm6743a5_w.
CDC website: www.cdc.gov/hepatitis/HAV
Table 4-02. Vaccines to prevent hepatitis A
|VACCINE||TRADE NAME (MANUFACTURER)||AGE (Y)||DOSE||ROUTE||SCHEDULE||BOOSTER|
|Hepatitis A vaccine, inactivated||Havrix (GlaxoSmithKline)||1–18||0.5 mL (720 ELU)||IM||0, 6–12 mo||None|
|≥19||1.0 mL (1,440 ELU)||IM||0, 6–12 mo||None|
|Hepatitis A vaccine, inactivated||Vaqta (Merck & Co., Inc.)||
0.5 mL (25 U)
0, 6–18 mo
|Combined hepatitis A and B vaccine||Twinrix (GlaxoSmithKline||≥18 (primary)||
1.0 mL (720 ELU HAV + 20 μg HBsAg)
|IM||0, 1, 6 mo||None|
|≥18 (accelerated)||same as above||IM||0, 7, 21–30 d||12 mo|
Abbreviations: ELU, ELISA units of inactivated HAV; IM, intramuscular; U, units HAV antigen; HAV, hepatitis A virus; HBsAg, hepatitis B surface antigen.
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