Chapter 3 Infectious Diseases Related To Travel
Charles E. Rupprecht, David R. Shlim
Rabies is an acute, progressive encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus. Regardless of the viral variants found throughout the world, all lyssaviruses cause rabies, resulting in tens of millions of human exposures and tens of thousands of human deaths each year.
Virus is present in the saliva of the biting rabid mammal. Transmission almost always occurs by an animal bite that inoculates virus into wounds. Virus inoculated into a wound does not enter the bloodstream but is taken up at a nerve synapse to travel to the central nervous system, where it causes encephalitis. Virus may enter the nervous system fairly rapidly or may remain at the bite site for an extended period. The approximate density of nerve endings in the region of the bite may increase the risk of developing encephalitis more rapidly. The hands and face, because of the relative density of nerve endings, are considered higher-risk exposures. Rarely, virus has been transmitted by exposures other than bites that introduce the agent into open wounds or mucous membranes.
All mammals are believed to be susceptible to infection, but major reservoirs are carnivores and bats. Although dogs are the main reservoir in developing countries, the epidemiology of the disease from one region or country to another differs enough to warrant the medical evaluation of all mammal bites. Bat bites anywhere in the world are a cause of concern and an indication for prophylaxis.
Rabies is found on all continents, except Antarctica. Regionally, different viral variants are adapted to various mammalian hosts and perpetuate in dogs and wildlife, such as bats and some carnivores, including foxes, jackals, mongooses, raccoons, and skunks. In certain areas of the world, canine rabies remains enzootic, including, but not limited to, parts of Africa, Asia, and Central and South America. Table 3-14 lists countries that have reported no cases of rabies during the most recent period for which information is available (formerly referred to as “rabies-free” countries).
Additional information about the global occurrence of rabies can be obtained from the following sources:
- World Health Organization (www.who.int/topics/rabies/en)
- Rabies Bulletin—Europe (www.who-rabies-bulletin.org)
- World Organisation for Animal Health (www.oie.int/en/animal-health-in-the-world/rabies-portal)
- Local health authorities of the country, the embassy, or the local consulate’s office in the United States
These lists are provided only as a guide, because up-to-date information may not be available, surveillance standards vary, and reporting status can change suddenly as a result of disease reintroduction or emergence. The actual rate of possible rabies exposure in travelers has not been calculated with accuracy. However, studies have found a range of roughly 16–200 per 100,000 travelers based on differing criteria.
Table 3-14. Countries and political units that reported no indigenous cases of rabies during 20121
|Africa||Cape Verde, Mauritius, Réunion, São Tomé and Príncipe, and Seychelles|
|Americas||North: Bermuda, Saint Pierre and Miquelon
Caribbean: Antigua and Barbuda, Aruba, The Bahamas, Barbados, Cayman Islands, Dominica, Guadeloupe, Jamaica, Martinique, Montserrat, Netherlands Antilles, Saint Kitts (Saint Christopher) and Nevis, Saint Lucia, Saint Martin, Saint Vincent and Grenadines, Turks and Caicos, and Virgin Islands (UK and US)
|Asia and the Middle East||Hong Kong, Japan, Kuwait, Malaysia (Sabah), Qatar, Singapore, Taiwan, United Arab Emirates|
|Europe2||Albania, Austria, Belgium, Corsica, Cyprus, Czech Republic, Denmark, Finland, France, Germany, Gibraltar, Greece, Hungary, Iceland, Ireland, Isle of Man, Liechtenstein, Luxembourg, Monaco, Netherlands, Norway (except Svalbard), Portugal, Slovakia, Slovenia, Spain(except Ceuta and Melilla), Sweden, Switzerland, and United Kingdom|
|Oceania3||Australia,3 Cook Islands, Fiji, French Polynesia, Guam, Hawaii, Kiribati, Micronesia, New Caledonia, New Zealand, Northern Mariana Islands, Palau, Papua New Guinea, Samoa, Solomon Islands, and Vanuatu|
1Global surveillance efforts and reporting standards differ dramatically, conditions may change rapidly because of animal translocation, and bat rabies may exist in some areas that are reportedly “free” of rabies in other mammals.
2Bat lyssaviruses have been reported throughout Europe, including areas that are reportedly free of rabies in other wild mammals.
3Most of Pacific Oceania is reportedly “rabies-free,” with the exception of Australia, where lyssaviruses in bats have been reported, as well as fatal human rabies cases.
Most patients will present after a documented, highly suspected, or likely exposure from a rabid animal. Clinical illness is compatible with acute, progressive encephalitis. After infection, the incubation period is highly variable, but it lasts approximately 1–3 months. The disease progresses acutely from a nonspecific, prodromal phase with fever and vague symptoms, to a neurologic phase, characterized by anxiety, paresis, paralysis, and other signs of encephalitis; spasms of swallowing muscles can be stimulated by the sight, sound, or perception of water (hydrophobia); and delirium and convulsions can develop, followed rapidly by coma and death. Once clinical signs manifest, most patients die in 7–14 days.
Diagnosis is straightforward in an encephalitic patient recently exposed to a rabid animal. However, in lieu of a history of a documented exposure and the potential for long incubation periods of weeks to months after initial viral transmission, clinical diagnosis may be complicated by the variety of symptoms and the differential exclusion of other etiologic agents associated with encephalitis.
Definitive diagnosis can be made by demonstrating virus in neuronal tissue, corneal impressions, or nuchal biopsy, either by detecting viral antigens or amplicons. Additional detailed information on diagnostic testing may be obtained from CDC (www.cdc.gov/rabies). A specific serologic response to virus can also support the diagnosis in an unvaccinated encephalitic patient.
There is no known cure after the onset of clinical signs. One experimental approach, known as the Milwaukee protocol, involves coma induction and antiviral drug treatment and has been used in approximately 40 rabies patients around the world, with at least 4 reported survivors (www.chw.org/display/PPF/DocID/33223/router.asp). Despite these observations, rabies must still be considered 100% fatal for practical purposes, and preventive measures remain the only way to guarantee survival after a bite by a rabid animal.
Prevention of rabies in travelers is best accomplished by having a comprehensive strategy. Such a strategy consists of 1) avoiding animal bites; 2) knowing how to prevent rabies after a bite; and 3) being able to travel (even to another country) to wherever postexposure prophylaxis (PEP) is available. To our knowledge, no traveler has died while trying to obtain PEP. The few travelers who have died of rabies received either no or inadequate PEP.
Avoiding Animal Bites
Travelers to rabies-enzootic countries should be warned about the risk of acquiring rabies and educated in animal bite-prevention strategies. Travelers should avoid feral animals, be aware of their surroundings so that they do not accidentally surprise a dog, and avoid contact with bats and other wildlife. A particular risk for a bite exposure is from monkeys who live near temples and other urban areas of Asia. Tourists to these sites should not carry any food on their person or in their backpack, purse, or other bag and should be careful not to approach or otherwise interact with monkeys. Casual exposure to cave air is not a concern, but visitors should be educated not to handle bats or other wildlife. Many bats have tiny teeth, and not all wounds may be apparent, compared with the lesions caused by carnivores. Any suspected or documented bite or scratch from a bat should be grounds for seeking PEP.
Children are at higher risk for rabies exposures because of their smaller stature, which makes extensive bites more likely; their curiosity and attraction to animals; and the possibility that they may not report a possible exposure. Although licks to fresh wounds or mucus membranes are a theoretical risk of acquiring rabies and PEP should be considered, there are no documented examples of rabies in travelers who were exposed in this manner.
For certain international travelers, preexposure rabies vaccine may be recommended, based on the prevalence of rabies in the country to be visited, the availability of appropriate antirabies biologics, intended activities, and duration of stay. A decision to receive preexposure rabies immunization may also be based on the likelihood of repeat travel to at-risk destinations or taking up residence in a high-risk destination. Preexposure vaccination may be recommended for veterinarians, animal handlers, field biologists, cavers, missionaries, and certain laboratory workers. Table 3-15 provides criteria for preexposure vaccination. Serology for rabies virus neutralizing antibodies is used as one gauge for revaccination considerations. Lists of US laboratories performing rabies serology may be found on the CDC website (www.cdc.gov/rabies). Regardless of whether preexposure vaccine is administered, travelers going to areas with a high risk for rabies should be encouraged to purchase medical evacuation insurance (see Chapter 2, Travel Insurance, Travel Health Insurance, & Medical Evacuation Insurance).
In the United States, preexposure vaccination consists of a series of 3 injections with human diploid cell rabies vaccine (HDCV) or purified chick embryo cell (PCEC) vaccine. The schedule for this series is given in Table 3-16. Travelers should receive all 3 preexposure immunizations before travel. If 3 doses of rabies vaccine cannot be completed before travel, the traveler should not start the series, as it would be problematic to plan PEP after a partial immunization series.
Preexposure vaccination does not eliminate the need for additional medical attention after a rabies exposure, but it simplifies PEP. Preexposure vaccination may also provide some degree of protection when there is an unrecognized exposure to rabies virus and when PEP might be delayed. Travelers who have completed a 3-dose preexposure rabies immunization series or have received full PEP are considered preimmunized and do not require routine boosters, except after a suspected rabies exposure. Periodic serum testing for rabies virus neutralizing antibody is not necessary in routine international travelers.
Any animal bite or scratch should be thoroughly cleaned with copious amounts of soap and water. This local care will substantially reduce the risk for rabies. Wounds that might require suturing should have the suturing delayed for a few days. If suturing is necessary to control bleeding or for functional or cosmetic reasons, rabies immune globulin (RIG), if indicated, should be administered into the wound before closing. The use of local anesthetic is not contraindicated in wound management.
In Travelers Who Received Preexposure Vaccination
In the event of a possible rabies exposure in someone who received preexposure rabies vaccination, 2 boosters of an acceptable rabies vaccine are given on days 0 and 3 after the exposure. The booster doses should be modern cell culture vaccines, but they do not have to be the same brand as the vaccine given in the original preexposure immunization series.
In Travelers Who Did Not Receive Preexposure Vaccination
If preexposure rabies vaccination has not been given, PEP consists of injections of RIG (20 IU/kg) and a series of 4 injections of rabies vaccine over 14 days (or 5 doses over a 1-month period in immunosuppressed patients, Table 3-17). After wound cleansing, as much of the calculated amount of RIG (Table 3-17) as is anatomically feasible should be infiltrated around the wound, striving to put the RIG in the areas where the animal’s teeth and saliva have come in contact with the wound. The dose injected around the wound may be as small as 0.5 mL if the wound is small or on a finger. If the wounds are extensive, the calculated dose of RIG must not be exceeded. If the calculated dose is inadequate to inject all the wounds, the RIG should be diluted with normal saline to extend the number of wounds that can be injected. This is a particular issue in children, whose body weight may be small in relation to the size and number of wounds.
The remainder of the RIG dose, if any, should be injected intramuscularly. Care should be taken to guarantee that this remaining amount of RIG is deposited in a muscle and not injected subcutaneously, which may decrease its effectiveness. The remaining RIG can be given in the deltoid muscle, on the opposite side of the initial vaccine dose. The anterior thigh is an alternative site.
RIG should not be given >7 days after the start of the PEP series. This 7-day period does not relate to the time of the bite exposure itself. Initiation of PEP, including RIG infiltration, should begin after a bite exposure, even if there has been a considerable delay between the exposure and the traveler presenting for evaluation.
Human RIG is manufactured by plasmapheresis of blood from hyperimmunized volunteers. The manufactured quantity of human RIG falls short of worldwide requirements, and it is not available in many developing countries. Equine RIG or purified fractions of equine RIG have been used effectively in some developing countries where human RIG might not be available. If necessary, such heterologous products are preferable to no RIG.
The incidence of adverse events after the use of modern equine-derived RIG is low (0.8%–6.0%), and most reactions are minor. However, such products are not evaluated by US standards or regulated by the Food and Drug Administration, and their use cannot be recommended unequivocally. In addition, unpurified antirabies serum of equine origin might still be used in some countries where neither human nor equine RIG is available. The use of this antirabies serum is associated with higher rates of serious adverse reactions, including anaphylaxis.
Different PEP schedules, alternative routes of administration, and other rabies vaccines besides HDCV and PCEC may be used abroad. Although not approved for sale in the United States, purified Vero cell rabies vaccine and purified chick embryo cell vaccine (manufactured abroad) are acceptable alternatives if available in a destination country. Assistance in managing complicated PEP scenarios may be obtained from experienced travel medicine professionals, health departments, and CDC.
Rabies vaccine was once manufactured from viruses grown in animal brains, and some of these vaccines are still in use in developing countries. Typically, the brain-derived vaccines can be identified if the traveler is offered a large injection (5 mL) daily for approximately 14–21 days. The traveler should not accept these vaccines, but rather travel to where acceptable vaccines and RIG are available.
Vaccine Safety and Adverse Reactions
Travelers should be advised that they may experience local reactions after vaccination, such as pain, erythema, swelling, or itching at the injection site, or mild systemic reactions, such as headache, nausea, abdominal pain, muscle aches, and dizziness. Approximately 6% of people receiving booster vaccinations with HDCV may experience an immune complex–like reaction characterized by urticaria, pruritus, and malaise. The likelihood of these reactions may be less with PCEC. Once initiated, rabies PEP should not be interrupted or discontinued because of local or mild systemic reactions to rabies vaccine.
Precautions and Contraindications
Pregnancy is not a contraindication to PEP. In infants and children, the dose of HDCV or PCEC for preexposure or PEP is the same as that recommended for adults. The dose of RIG for PEP is based on body weight (Table 3-17).
CDC website: www.cdc.gov/rabies
Table 3-15. Criteria for preexposure immunization for rabies
|RISK CATEGORY||NATURE OF RISK||TYPICAL POPULATIONS||PREEXPOSURE REGIMEN|
Virus present continuously, often in high concentrations
Specific exposures likely to go unrecognized
Bite, nonbite, or aerosol exposure
|Rabies research laboratory workers,1 rabies biologics production workers||Primary course: serologic testing every 6 months; booster vaccination if antibody titer is below acceptable level2|
Exposure usually episodic with source recognized, but exposure might also be unrecognized
Bite, nonbite, or aerosol exposure possible
|Rabies diagnostic laboratory workers,1 cavers, veterinarians and staff, and animal control and wildlife workers in rabies-epizootic areas||Primary course: serologic testing every 2 years; booster vaccination if antibody titer is below acceptable level2|
|Infrequent (more than general population)||
Exposure nearly always episodic with source recognized
Bite or nonbite exposure
|Veterinarians, animal control, and wildlife workers in areas with low rabies rates; veterinary students; and travelers visiting areas where rabies is enzootic and immediate access to appropriate medical care, including biologics, is limited||Primary course: no serologic testing or booster vaccination|
|Rare (general population)||Exposure always episodic, with source recognized||US population at large, including individuals in rabies-epizootic areas||No preexposure immunization necessary|
1Judgment of relative risk and extra monitoring of vaccination status of laboratory workers is the responsibility of the laboratory supervisor (see www.cdc.gov/biosafety/publications/bmbl5 for more information).
2Preexposure booster immunization consists of 1 dose of human diploid cell (rabies) vaccine or purified chick embryo cell vaccine, 1.0-mL dose, intramuscular (deltoid area). Per Advisory Committee on Immunization Practices recommendations, minimum acceptable antibody level is complete virus neutralization at a 1:5 serum dilution by the rapid fluorescent focus inhibition test, which is equivalent to approximately 0.1 IU/mL. A booster dose should be administered if titer falls below this level in populations that remain at risk.
Table 3-16. Preexposure immunization for rabies1
|VACCINE||DOSE (ML)||NUMBER OF DOSES||SCHEDULE (DAYS)||ROUTE|
|HDCV, Imovax (Sanofi)||1.0||3||0, 7, and 21 or 28||IM|
|PCEC, RabAvert (Novartis)||1.0||3||0, 7, and 21 or 28||IM|
Abbreviations: HDCV, human diploid cell vaccine; IM, intramuscular; PCEC, purified chick embryo cell.
1Patients who are immunosuppressed by disease or medications should postpone preexposure vaccinations and consider avoiding activities for which rabies preexposure prophylaxis is indicated. When this course is not possible, immunosuppressed people who are at risk for rabies should have their antibody titers checked after vaccination.
Table 3-17. Postexposure immunization for rabies1
|DOSE||NUMBER OF DOSES||SCHEDULE (DAYS)||ROUTE|
|Not previously immunized||RIG plus||20 IU/kg body weight||1||0||Infiltrated at bite site (if possible); remainder IM|
|HDCV or PCEC||1.0 mL||42||0, 3, 7, 14||IM|
|Previously immunized3,4||HDCV or PCEC||1.0 mL||2||0, 3||IM|
Abbreviations: RIG, rabies immune globulin; IM, intramuscular; HDCV, human diploid cell vaccine; PCEC, purified chick embryo cell.
1All postexposure prophylaxis should begin with immediate, thorough cleansing of all wounds with soap and water.
2Five vaccine doses for the immunosuppressed patient. The first 4 vaccine doses are given on the same schedule as for an immunocompetent patient, and the fifth dose is given on day 28.
3Preexposure immunization with HDCV or PCEC, prior postexposure prophylaxis with HDCV or PCEC, or people previously immunized with any other type of rabies vaccine and a documented history of positive rabies virus neutralizing antibody response to the prior vaccination.
4RIG should not be administered.
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