Chapter 4 Travel-Related Infectious Diseases
Ryan M. Wallace, Brett W. Petersen, David R. Shlim
Rabies is a fatal, acute, progressive encephalomyelitis caused by neurotropic viruses in the family Rhabdoviridae, genus Lyssavirus. Numerous and diverse variants of lyssaviruses are found in a wide variety of animal species throughout the world, all of which may cause fatal human rabies. Rabies virus is by far the most common lyssavirus infection of humans. Tens of millions of potential human exposures and tens of thousands of deaths from rabies virus occur each year.
The normal and most successful mode of transmission is inoculation of saliva from the bite of a rabid animal. Rabies virus is neurotropic and gains access to the peripheral nervous system by being taken up at a nerve synapse at the site of the bite. The virus travels through peripheral nerves to the central nervous system, where most viral replication occurs, before traveling back out through the peripheral nervous system. After reaching the salivary glands, virus can be secreted allowing the transmission cycle to repeat. Exposure of rabies virus to highly innervated tissue may increase the risk of successful infection. Exposure of rabies virus to anatomic sites nearer the central nervous system may reduce the incubation period. In addition to saliva, rabies virus may also be found in nervous tissues (central and peripheral) and tears. Infection from nonbite exposures, such as organ transplantation from infected humans, does occur. However, human-to-human transmission does not generally occur otherwise.
All mammals are believed to be susceptible to infection, but major rabies reservoirs are terrestrial 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. 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.
Lyssaviruses, the causative agent for the disease rabies, have been found on all continents except Antarctica. Rabies virus is classified into 2 major genetic lineages: canine and New World bat. These 2 lineages can be further classified into rabies virus variants based on the reservoir species in which they circulate. Regionally, different viral variants are adapted to various mammalian hosts and perpetuate in dogs and wildlife, such as bats, foxes, jackals, mongooses, raccoons, and skunks. Canine rabies remains enzootic in many areas of the world, including Africa, Asia, and parts of Central and South America. In addition to rabies virus, the Lyssavirus genus includes 14 other viruses that all cause the disease rabies. Nonrabies lyssaviruses are found in Europe, Asia, Africa, and Australia; although they have caused human deaths, nonrabies lyssaviruses contribute relatively little to the global rabies burden compared to rabies virus.
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.
Clinical illness in humans begins following invasion of the peripheral and then central nervous system and culminates in acute fatal encephalitis. After infection, the asymptomatic incubation period is variable, but signs and symptoms most commonly develop within several weeks to several months after exposure. Pain and paresthesia at the site of exposure are often the first symptoms of disease. The disease then 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 in the absence of intensive supportive care.
The diagnosis may be relatively simple in a patient with a compatible history and a classic clinical presentation (Box 4-06). 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 can be difficult to elicit given that several weeks to months may have elapsed since the exposure occurred. Furthermore, the possibility of exposure to rabies virus may not be initially considered by clinicians and possible exposures might not be discussed with friends and family.
Definitive antemortem diagnosis requires high-complexity experimental test methods on multiple samples (serum, cerebrospinal fluid [CSF], saliva, and skin biopsy from the nape of the neck), which can be collected sequentially if initial testing is negative and clinical suspicion is high. Additional detailed information on diagnostic testing may be obtained from CDC (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. Rabies is a nationally notifiable disease.
CDC is designated as the national rabies reference laboratory for the United States, as well as a World Health Organization collaborating center for rabies and a World Organisation for Animal Health (OIE) rabies reference laboratory. As such, CDC performs public health testing for domestic and international health agencies, for both human and animal rabies diagnosis. Before submitting samples to CDC for rabies testing, the submitter must consult with program staff, obtain approval, and submit appropriate paperwork. Step-by-step instructions can be found at www.cdc.gov/rabies/resources/specimen-submission-guidelines.html.
Box 4-06. World Health Organization, human rabies case definitions
Clinical case definition: a person presenting with an acute neurologic syndrome (encephalitis) dominated by forms of hyperactivity (furious rabies) or paralytic syndromes (paralytic rabies) progressing toward coma and death, usually by cardiac or respiratory failure, typically within 7–10 days after the first symptom if no intensive care is instituted. Symptoms may include any of the following: aerophobia, hydrophobia, paresthesia or localized pain, dysphagia, localized weakness, nausea or vomiting.
Suspected human rabies: A case compatible with the clinical case definition.
Probable human rabies: A suspected case plus a reliable history of contact with a suspected, probable, or confirmed rabid animal.
Confirmed human rabies: A suspected or probable case confirmed in the laboratory.
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. Rabies is still considered universally fatal for practical purposes, and preventive measures (for example, proper wound care, pre- and postexposure prophylaxis) are the only way to optimize survival if bitten by 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) consultation with travel health professionals to determine if preexposure vaccination is recommended; 3) knowing how to prevent rabies after a bite; and 4) knowing how to obtain postexposure prophylaxis (PEP). The last may involve urgent importation of rabies biologics or travel to where PEP is available. A list of pretravel considerations in regards to rabies precautions can be found at www.cdc.gov/travel.
Not seeking PEP or receiving inadequate care is likely to result in death from rabies.
Avoiding Animal Bites
Travelers to rabies-enzootic countries should be warned about the risk of rabies exposure and educated as to how to avoid animal bites. Travelers should avoid free-roaming mammals, avoid behaviors and actions that may provoke an animal to bite, and avoid contact with bats and other wildlife. Travelers who will spend time outdoors should be aware of dog-bite prevention techniques, such as avoidance of puppies when the mother is near, avoidance of dogs that are protecting a food source, and appropriate behavior around dogs.
Although nonhuman primates are rarely rabid, they are a common source of bites, mainly on the Indian subcontinent. In most instances these nonhuman primates cannot be followed up for rabies assessments, and the bite victims are recommended to receive PEP. 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 around monkeys that are habituated to tourists.
Travelers should be educated to not handle bats or other wildlife and consider the need for personal protective equipment before entering caves where bats may be found, given the risk for exposures to rabies virus, Histoplasma spp., viral hemorrhagic fever viruses, or other bat-associated pathogens. Many bats have tiny teeth, and wounds may not be readily 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 inquisitive nature and inability to read behavioral cues from dogs and other animals. The smaller stature of children makes them more likely to experience severe bites to high-risk areas, such as the face and head. Also contributing to the higher risk is their attraction to animals and the possibility that they may not report an exposure.
Preexposure prophylaxis (PrEP) may be recommended for certain international travelers based on the occurrence of animal rabies in the country of destination; the availability of antirabies biologics; the intended activities of the traveler, especially in remote areas; and the traveler’s 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. Updated recommendations, published in May, 2022, provide criteria for preexposure vaccination. 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 6, Travel Insurance, Travel Health Insurance & Medical Evacuation Insurance).
In the United States, PrEP previously consisted of a series of 3 intramuscular (deltoid) injections of human diploid cell rabies vaccine (HDCV) or purified chick embryo cell (PCEC) vaccine given on days 0, 7, and 21 or 28. Based on recent changes in WHO recommendations and the availability of empirical studies, the US Advisory Committee on Immunization Practices (ACIP) reviewed its own recommendations for PrEP and approved a 2-dose preexposure regimen, given on days 0 and 7 (Table 4-17).
Travelers should receive all 2 preexposure immunizations before travel. If 2 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 or PEP might be delayed. Travelers who have completed a 2-dose preexposure rabies immunization series or have received full PEP are considered previously vaccinated and do not require routine boosters. Routine testing for rabies virus-neutralizing antibody is not recommended for international travelers who are at low risk or have elevated, but not sustained, risk for rabies exposure (Updated PrEP recommendations, published in May, 2022).
Any animal bite or scratch should be thoroughly cleaned with copious amounts of soap and water, povidone iodine, or other substances with virucidal activity. All travelers should be informed that immediately cleaning bite wounds as soon as possible substantially reduces the risk of rabies virus infection, especially when followed by timely administration of PEP. For 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 vaccinated consists of 2 doses of modern cell-culture vaccine given 3 days apart (days 0 and 3), ideally initiated shortly 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 an unvaccinated patient consists of administration of RIG (20 IU/kg for human RIG or 40 IU/kg for equine RIG) and a series of 4 injections of rabies vaccine over 14 days, or 5 doses over a 1-month period in immunosuppressed patients (Table 4-18). After wound cleansing, as much of the dose-appropriate volume of RIG (Table 4-18) as is anatomically feasible should be injected at the wound site. The intent is to put the RIG in the areas where saliva may have contaminated wounded tissue. If the wound is small and on a distal extremity such as a finger or toe, the health care provider must use clinical judgment to decide how much RIG to inject to avoid local tissue compression and complications. Any remaining dose should be administered intramuscularly at a site distant from the site of vaccine administration. 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 to ensure sufficient volume to inject in all 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 the seventh day after the first dose of vaccine was administered. After day 7, RIG is unlikely to provide benefit, as antibodies would be expected to be present from the patient’s own vaccine-derived immune response.
Because rabies virus can persist in tissue for a long time before invading 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 total quantity of commercially produced human RIG falls short of worldwide demand, and it is not available in many developing countries. Equine RIG, purified fractions of equine RIG, and rabies monoclonal antibody products may be available in some countries where human RIG might not be available. Such 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 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.
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. However, other rabies vaccines or PEP regimens might require additional prophylaxis or confirmation of adequate rabies virus–neutralizing antibody titers. Assistance in managing complicated PEP scenarios can be obtained from experienced travel medicine professionals, health departments, and CDC (email@example.com).
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, also known as nerve tissue 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 severe adverse reactions, the traveler should not accept these vaccines but travel to a location 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 systemic hypersensitivity reactions 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. If an adverse event occurs with one of the vaccine types, consider switching to the alternative vaccine for the remainder of the series.
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 4-18).
CDC website: www.cdc.gov/rabies
Table 4-16. Criteria for preexposure immunization for rabies
Table 4-17. Preexposure immunization for rabies1
|VACCINE||DOSE (mL)||NUMBER OF DOSES||SCHEDULE (DAYS)2||ROUTE|
|HDCV, Imovax (Sanofi)||1.0||2||0 and 7||IM|
|PCEC, RabAvert (Novartis)||1.0||2||0 and 7||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 during the period of expected immunosuppression. If this is not possible, immunosuppressed people who are at risk for rabies should have their antibody titers checked after vaccination.
2 Every attempt should be made to adhere to recommended schedules; however, for most minor deviations (delays of a few days for individual doses), vaccination can be resumed as though the traveler were on schedule. If 2 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.
Table 4-18. Postexposure immunization for rabies1
|DOSE||NUMBER OF DOSES||SCHEDULE (DAYS)2||ROUTE|
|Not previously vaccinated||RIG plus||20 IU/kg body weight||1||0||Infiltrated at bite site (if possible); remainder IM|
|Not previously vaccinated||HDCV or PCEC||1.0 mL||43||0, 3, 7, 14 (28 if immuno-
|Previously vaccinated5,6||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, povidone iodine, or other substances with virucidal activity.
2Every attempt should be made to adhere to recommended schedules; however, for most minor deviations (delays of a few days for individual doses), vaccination can be resumed as though the traveler were on schedule. When substantial deviations occur, immune status should be assessed by serologic testing 7–14 days after the final dose is administered.
3Five 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. For more information, see www.cdc.gov/mmwr/preview/mmwrhtml/rr5902a1.htm.
4CDC 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.
5Preexposure immunization with HDCV or PCEC, prior postexposure prophylaxis with HDCV or PCEC, or people previously vaccinated with any other type of rabies vaccine and a documented history of positive rabies virus neutralizing antibody response to the prior vaccination.
6 RIG is not recommended.
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