Chapter 3 Infectious Diseases Related to Travel
Cathleen A. Hanlon, David R. Shlim
Rabies is an acute, fatal, progressive encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus. Numerous and diverse variants of lyssaviruses are found throughout the world, all of which may cause fatal human rabies cases. Tens of millions of human exposures and tens of thousands of deaths may occur each year.
The most natural and successful mode of transmission is through the bite of a rabid animal. Virus at the wound site may remain undetectable during a variable incubation period; there is no viremia. Clinical illness begins following invasion of the peripheral and then central nervous system and culminates in acute fatal encephalitis. Exposure of highly innervated tissue and close proximity to the brain increases the risk of successful infection and may result in postexposure prophylaxis (PEP) failure if there is a delay in administration. Rarely, virus has been transmitted by exposures other than bites, such as introducing the agent into open wounds (such as through scratches) or mucous membranes and transplantation of tissues from undiagnosed rabid donors.
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 differs from one region or country to another, so that all patients with mammal bites should be medically evaluated. Bat bites anywhere in the world are a cause of concern and an indication to consider 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 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).
Timely and specific information about the global occurrence of rabies is often difficult to find. Surveillance levels vary, and reporting status can change suddenly as a result of disease reintroduction or emergence. The rate of rabies exposures in travelers is at best an estimate and may range from 16 to 200 per 100,000 travelers.
After infection, the incubation period is variable, but clinical illness most commonly develops in several weeks to several months after exposure. The disease progresses rapidly from a nonspecific, prodromal phase with fever and vague symptoms to an acute, progressive encephalitis. The neurologic phase may be 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, patients die quickly, but with intensive supportive care may succumb in 7–14 days.
The diagnosis may be relatively simple in a patient with a compatible history and a classic clinical presentation. However, clinical suspicion and prioritization of differential diagnoses may be complicated by variations in clinical presentation and a lack of exposure history. The exposure history is especially evasive if the risk of exposure to rabies was not recognized, the exposure was not discussed with friends and family, and several weeks to months have elapsed since the exposure.
Definitive antemortem diagnosis requires high-complexity experimental test methods on multiple samples (such as serum, cerebrospinal fluid [CSF], saliva, and skin biopsy from the nape of the neck), which are best collected sequentially if initial testing is negative. Additional detailed information on diagnostic testing may be obtained from CDC (http://www.cdc.gov/rabies/specific_groups/doctors/ante_mortem.html). Rising levels of rabies virus–neutralizing antibodies, particularly in the CSF, is diagnostic in an unvaccinated, encephalitic patient.
Table 3-14. Countries and political units that reported no indigenous cases of rabies during 20151
|Africa||Ascension Island, Canary Islands, Cape Verde, Mayotte, Madeira Islands, Réunion, Saint Helena|
Central: Costa RicaSouth: Argentina, Chile, Easter Island, Falkland Islands, Galápagos Islands, South Georgia and South Sandwich Island, Uruguay
|Asia and the Middle East||British Indian Ocean Territory, Hong Kong, Japan, Macau, Maldives, Singapore|
|Europe2||Albania, Andorra, Austria, Azores, Balearic Islands, Belgium, Channel Islands, Corsica, Cyprus, Czech Republic, Denmark, Estonia, Faroe Islands, Finland, France, Germany, Gibraltar, Ireland, Isle of Man, Italy, Latvia, Liechtenstein, Luxembourg, Malta, Monaco, Netherlands, Portugal, San Marino, Spain (except Ceuta and Melilla), Switzerland, and United Kingdom|
|Oceania3||American Samoa, Australia, Christmas Island, Cocos (Keeling) Islands, Cook Islands, Fiji, French Polynesia, Guam, Kiribati, Marshall Islands, Micronesia, Nauru, New Caledonia, New Zealand, Niue, Norfolk Island, Northern Mariana Islands, Palau, Papua New Guinea, Pitcairn Islands, Samoa, Solomon Islands, Tahiti, Tokelau, Tonga, Tuvalu, Vanuatu, Wake Islands, Wallis and Futuna|
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.
There is not yet an evidence-based “best practices” medical approach to treating patients with rabies; most patients are managed with symptomatic and palliative supportive care. An experimental approach, known as the Milwaukee protocol, involves inducing coma and treating with antiviral drugs, but it remains controversial (www.chw.org/display/PPF/DocID/33223/router.asp). Rabies is still considered 100% fatal for practical purposes, and preventive measures are the only way to optimize survival after a bite from a rabid animal.
Rabies in travelers is best prevented by having a comprehensive strategy. This consists of 1) education about risks and the need to avoid bites from mammals, especially high-risk rabies reservoir species; 2) knowing how to prevent rabies after a bite; and 3) being able to obtain PEP, which may involve urgent international travel to where PEP is available. No traveler is known to have died while trying to obtain PEP. Travelers who have died of rabies either did not seek PEP or received inadequate care when they did.
Avoiding Animal Bites
Travelers to rabies-enzootic countries should be warned about the risk of rabies exposure and educated in avoiding animal bites. Travelers should avoid free-ranging mammals, be aware of their surroundings so that they do not accidentally surprise a dog, and avoid contact with bats and other wildlife. Although nonhuman primates are rarely rabid, they are a common source of bites, mainly on the Indian subcontinent. Awareness of this risk and simple prevention is particularly effective. Travelers should be advised to not approach or otherwise interact with monkeys or carry food while monkeys are near, especially those habituated to tourists. Entering caves where bats may be found is usually not a concern for rabies (although bat caves may be a source of Marburg or other viruses [see Viral Hemorrhagic Fevers later in this chapter]), but travelers should be educated to not handle bats or other wildlife. Many bats have tiny teeth, and not all wounds may be apparent. Any suspected or documented bite or wound from a bat should be grounds for seeking PEP.
Children are at higher risk for rabies exposure and subsequent illness because of their smaller stature, which makes severe bites to high-risk areas, such as the face and head, more likely. Also contributing to the higher risk is their natural curiosity and attraction to animals and the possibility that they may not report an exposure.
Preexposure rabies vaccination may be recommended for certain international travelers, based on the occurrence of animal rabies in the destination country; the availability of antirabies biologics; intended activities, especially in remote areas; 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 long-term travel to 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. The level of rabies virus neutralizing antibodies is typically used to dictate the need for booster vaccination. Globally, few laboratories perform the rapid fluorescent focus inhibition test, which is the gold standard test method for measuring rabies antibody levels. Those in the United States are listed on the CDC website (http://www.cdc.gov/rabies/specific_groups/doctors/serology.html). Regardless of whether preexposure vaccine is administered, travelers going to areas where the risk of rabies is high 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 intramuscular injections in the deltoid 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 few data exist to guide 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 protection when an exposure to rabies virus is unrecognized and PEP might be delayed. Travelers who have completed a 3-dose preexposure rabies immunization series or have received full PEP are considered preexposure immunized and do not require routine boosters. Periodic serum testing for rabies virus–neutralizing antibody is not necessary in most international travelers.
Any animal bite or scratch should be thoroughly cleaned with copious amounts of soap and water. All travelers should be informed that immediately cleaning bites as soon as possible substantially reduces the risk of infection, especially when followed by timely administration of PEP. For previously unvaccinated patients, 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) should be injected into all wounded tissues before suturing. The use of local anesthetic is not contraindicated in wound management.
In Travelers Who Received Preexposure Vaccination
PEP for someone previously immunized consists of 2 doses of modern cell culture vaccine given on days 0 and 3 after the exposure. The booster doses do not have to be the same brand as the one in the original preexposure immunization series.
In Travelers Who Did Not Receive Preexposure Vaccination
PEP for a previously unvaccinated patient 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 dose-appropriate volume of RIG (Table 3-17) as is anatomically feasible should be injected at the wound site, striving to put the RIG in the areas where the animal’s teeth have wounded the tissue. If the wound is small and on a distal extremity such as a finger or toe, the health care provider will have to use judgment as to how much to inject at the wound to avoid local tissue compression and complications. Any remaining dose should be administered intramuscularly. If the wounds are extensive, the dose-appropriate volume of RIG must not be exceeded. If the volume is inadequate to inject all the wounds, the RIG may be diluted with normal saline so that some can be injected in each of the wounds. This is a particular issue in children, whose body weight may be small in relation to the size and number of wounds.
RIG is difficult to access in many countries. If modern cell culture vaccine is available but access to RIG is delayed, the vaccine series should be started as soon as possible, and RIG may be added to the regimen up to and including day 7. After day 7, RIG is contraindicated because it may compromise the patient’s adaptive immunity to the vaccination series.
Because rabies virus can persist in tissue for a long time before gaining access to a peripheral nerve, a traveler who has sustained a bite that is suspicious for rabies should receive full PEP, including RIG, even if a considerable length of time has passed since the initial exposure. If there is a scar, or the patient remembers where the bite occurred, an appropriate amount of RIG should be injected in that area.
Human RIG is manufactured by plasmapheresis of blood from hyperimmunized volunteers. The quantity of commercially produced human RIG falls short of worldwide demand, and it is not available in many developing countries. Equine RIG or purified fractions of equine RIG may be available 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 unequivocally be recommended. 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. For example, commercially available purified Vero cell rabies vaccine and purified duck embryo cell vaccine are acceptable alternatives if available. 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-volume injection (5 mL) daily for approximately 14–21 days. Because of variability of potency in these preparations, which may limit effectiveness, and the risk of adverse reactions, the traveler should not accept these vaccines but 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. If this 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 (28 if immuno-
|Previously immunized4,5||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; patient follow-up should include monitoring antibody response. See http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5902a1.htm for more information. The World Health Organization recommends this fifth dose for all patients, not just those who are immunocompromised.
3CDC recommends 4 postexposure vaccine doses, on days 0, 3, 7, and 14, unless the patient is immunocompromised in some way, in which case a fifth dose is given at day 28.
4Preexposure 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.
5RIG should not be administered.
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