Imported Human Rabies Cases in Europe, the United States, and Japan, 1990 to 2010

Rabies is an irreversible, fatal disease most frequently characterized by acute encephalitis that causes approximately 55,000 deaths annually in Africa and Asia. Disease occurs when rabies virus, a Lyssavirus, is transmitted to a human via the saliva of an infected mammalian carnivore or bat, usually a dog, if it comes in contact with mucous membranes or enters the body via a bite, scratch, or lick on broken skin. Animal reservoirs for rabies exist in all continental areas worldwide. Deaths are presumed to be underreported in areas with poor access to medical facilities. Children are considered to be at a higher risk than adults.^1,2 Although the risk of contracting rabies in developed countries is generally low, those who travel to areas with high epizootic endemicity are at increased risk of exposure and death. Steffen and co‐workers evaluated the risk of rabies infection due to animal bites in travelers to developing countries and found an incidence rate per month between 0.1% and 1%.³ An epidemiological study of travelers presenting to GeoSentinel sites worldwide performed by the US Centers for Disease Control and Prevention (CDC) and the International Society of Travel Medicine (ISTM) found that 4.7% of this population required rabies post‐exposure prophylaxis.⁴

After acquisition of the virus, the incubation period is variable, usually between 20 and 90 d, although occasionally disease develops after only a few days, and, in rare cases, more than a year following exposure. Usually patients develop a furious form of the disease, with episodes of generalized hyperexcitability separated by lucid periods. Encephalitis results from viral replication in the brain. In 20% of cases, a paralytic form of the disease results in progressive immobility. Both forms of rabies, furious and paralytic, are always fatal. One documented case of recovery from symptomatic disease has been reported; however, no cure has been reported in medical history.⁵ The incubation period often provides an opportunity for post‐exposure prophylaxis to generate adequate immune defenses to avoid the onset of symptoms. These measures have a high rate of success.²

Although vaccination programs and animal control methods have led to a steep decline in canine rabies in many areas, viral reservoirs exist in wild animals, including bats, which cause a large proportion of cases in North America. Currently available rabies vaccines are propagated in cell cultures or embryonated eggs, and include the following types: human diploid cell vaccine, purified chick embryo cell‐culture vaccine, purified duck embryo vaccine, and purified Vero cell rabies vaccine. These vaccines have well‐established safety and efficacy profiles and can be administered either before or after an exposure occurs. Lyssavirus phylogroup I, which includes Rabies virus, Duvenhage virus, Australian bat lyssavirus, and European bat lyssavirus types 1 and 2, is covered by existing vaccines. The African genotypes, Mokola virus and Lagos bat virus, which comprise phylogroup II, and West Caucasian Bat Lyssavirus, which is supposed to be a third phylogroup, are assumed not to be covered.^6–8

The WHO and the Advisory Committee on Immunization Practices (ACIP) recommend pre‐exposure prophylaxis for travelers to rural areas with circulating rabies, especially if access to medical care may be limited.^1,2,8 Pre‐exposure prophylaxis recipients require a reduced course of vaccine, and no immunoglobulin, if exposed to rabies. Evidence suggests that many travelers and health‐care providers ignore these recommendations.^1,9–12

We report on the collection of all rabies deaths available in the clinical literature and other communications that occurred from 1990 to 2010 in persons traveling to areas with high rabies incidence.

Methods

We systematically reviewed the clinical literature for all reports of imported deaths in travelers due to rabies and supplemented that information with personal communications regarding deaths in C.I.S. countries and a single report from PROMED, a body of international infectious disease experts which sends daily reports on infectious diseases in humans, plants, and animals. Imported deaths was defined as persons who contracted rabies while traveling and who subsequently died in the country where the report was made. Reports of travelers who contracted rabies and died in the country where the infection originated are not included in the current analysis. As the population was not predefined and all literature cases of people who died after contracting rabies abroad were reviewed and reported, our study included different types of travelers, including those visiting friends and relatives and guest workers, as well as ordinary travelers. For each reported imported human rabies death, information on the country where the disease was contracted, age of the patient, animal source and any information on medical intervention or treatment was collected.

Results

Between 1990 and 2010, a total of 42 human deaths from rabies were reported in Europe, the United States, and Japan; all of these victims were assumed to have contracted the rabies infection abroad (Table 1).^13–39 Of these imported human rabies cases, 36 (86%) were reported in the clinical literature, 5 (12%) via personal communication, and 1 case (2%) via PROMED. Twenty‐seven deaths (64%) occurred after 2000. During the observation period, the greatest number of deaths were reported in European Union countries (n = 22), followed by the United States (n = 13), the former USSR (n = 5), and Japan (n = 2). One death, reported in Finland, was of a person from the country of rabies origin. No cases from Canada, Australia, and New Zealand were reported.

Table 1

Forty‐two human rabies deaths in Europe, Japan, and the United States caused by infection acquired during a visit to an endemic area, 1990 to 2010 ^13–39

Year	Origin of infection	Age of victim	Animal source	Medical interventions (if known)	First author, publication year
Austria
2004	Morocco	23	Dog†	None sought‡	Strauss 2005 13
Finland
2007	Philippines	45	Dog	None sought§	Rimhanen‐Finne 2010 14
France
1990	Mexico	28	Dog	‖	Rotivel 2007 15
1992	Algeria	3	Dog	‖	Rotivel 2007 15
1994	Mali	46	Dog	‖	Rotivel 2007 15
1996	Algeria	60	Dog	‖	Rotivel 2007 15
1996	Algeria	71	Dog	‖	Rotivel 2007 15
1996	Madagascar	3	Dog	‖	Rotivel 2007 15
1997	India	50	Dog	‖	Rotivel 2007 15
2003	Gabon	3	Dog	None sought‡	[None listed] 2003 16
Germany
1996	Sri Lanka	49	Dog	No PEP¶	Roß 1997 17
2004	India	51	Dog/ monkey	No PEP¶	Summer 2004 18
2004	India	26	Dog	#	Johnson 2005 19
2007	Morocco	55	Dog	Sought medical attention but vaccination not initiated	Schmiedel 2007 20
Netherlands
1998	Morocco	49	Dog	Post‐exposure prophylaxis started in Morocco; however, vaccination was incomplete and no immunoglobulin was administered	Groen 1998 21
2007	Kenya	34	Bat	Wound cleaned and medical treatment sought. No PEP was received.**	van Thiel 2008 22
Russia
2007	Ukraine	66	Fox	None sought‡	Movsesyants 2010*
2009	Azerbaijan	21	Dog	None sought‡	Movsesyants 2010*
2009	Kazakhstan	58	Dog	None sought‡	Movsesyants 2010*
2009	Kyrgyzstan	28	Dog	None sought‡	Movsesyants 2010*
Georgia
2010	Azerbaijan	11	Dog	Received PEP, but interval after exposure is unknown	PROMED 2010 21
Sweden
2000	Thailand	19	Dog (puppy)	None sought‡	Ekdahl 2000 24
United Kingdom
1996	Nigeria	19	Dog	No PEP	Johnson 2005 19
2001	Nigeria	52	Dog	Injections were received; provenance of the vaccine was unclear	Johnson 2005 19
2001	Philippines	55	Dog	None sought‡	Johnson 2005, 19 Smith 2003 25
2005	India	37	Dog	None sought‡ ,††	Johnson 2005, 19 Solomon 2005 26
2008	South Africa	37	Exposed to various animals	No pre‐exposure prophylaxis or PEP	Hunter 2010 27
Japan
2006	Philippines	69	Dog	No PEP¶	Yamamoto 2008 28
2006	Philippines	65	Dog	No PEP¶	Tobiume 2009 29
United States
1992	India	11	Dog	‖	DSHS 2009 30
1993	Mexico	69	Dog or coyote	‖	DSHS 2009 30
1994	Haiti	51	Dog or mongoose	‖	DSHS 2009 30
1996	Mexico	26	Dog	None sought‡	CDC 1996 31
1996	Nepal	32	Dog	Medical treatment sought, but PEP not given	CDC 1997 32
2000	Ghana	54	Dog	‖	CDC 2000 33
2001	Philippines	72	Dog	‖	DSHS 2009, 30 Krebs 2003 34
2004	El Salvador	22	No history of animal bite	‖	Krebs 2005 35
2004	Haiti	41	Dog	None sought‡	CDC 2005 36
2006	Philippines	11	Dog	No PEP¶	CDC 2007, 37 Blanton 2010 38
2008	Mexico	16	Dog or fox	No PEP¶	Blanton 2010 38
2009	India	42	Dog	‖	Blanton 2010 38
2010	Mexico	—	Unknown	No PEP¶	ISID 2010 39

PEP = post‐exposure prophylaxis.

*

A.A. Movsesyants, personal communication, L.A. Tarassevich State Research Institute for Standardization and Control of Medical Biological Preparations, Moscow, Russian Federation, November 2010.

†

The dog died soon after bite but was not tested for rabies.

‡

No medical intervention was sought in the country of infection after the bite was received.

§

No medical attention was sought before symptoms appeared.

‖

No information about medical interventions was specified.

¶

No PEP; no post‐exposure prophylaxis.

#

Medical interventions not specified; however, three of six organ recipients from this patient subsequently died.

**

Reference states that medical personnel were not aware of rabies in the area and prophylaxis was not initiated.

††

Reference specifies that the patient not seek wound cleansing or medical attention.

Among the 39 reports for whom the animal cause of rabies was known, 37 patients (95%) had had contact with a dog or puppy. One patient reported contact with a fox and one with a member of an unknown insectivorous bat species.

The most common continent of rabies origin was Asia (n = 19), followed by Africa (n = 14); in contrast, only eight cases were contracted in the Americas, and of those, seven were from the United States. At the country level, the most cases were contracted in India (n = 6) and the Philippines (n = 6), followed by Mexico (n = 5). The Philippines was the only source of disease common to the United States, Europe, and Japan.

Age was available for 41 of 42 cases. Twenty‐eight deaths were in adults 19 to 64 y of age, nine were in children under 5 y of age, four were in children 11 to 18 y of age, and six were in persons 65 y of age or older.

Among cases for whom information about treatment and prophylaxis was available (n = 29), only a few received post‐exposure prophylaxis. Twelve did not seek medical attention and six sought medical attention that was ineffective or denied because healthcare workers lacked supplies or knowledge about the disease.

Four of the cases we reviewed have not been previously published in the clinical literature. These cases were communicated by A.A. Movsesyants, Head of Rabies Department at the L. A. Tarassevich State Research Institute for Standardization and Control of Medical Biological Preparations in Moscow, Russian Federation. Three of these patients were bitten by stray or aggressive domestic dogs, and one was bitten by a fox. Exposures occurred in the Ukraine, Azerbaijan, Kazakhstan, or Kyrgyzstan. None of the male Russian patients, age 21 to 58 y, sought medical attention and all died (Table 1). An 11‐y‐old boy from Georgia, as described by PROMED, who received post‐exposure prophylaxis after being bitten by a dog in Azerbaijan, died later in Georgia, probably because of an inappropriate interval between exposure and treatment.

Discussion

Based on literature review and personal communications, we collected the most complete set of reports of imported rabies cases available to date. We reviewed 42 human deaths due to imported rabies, which we defined as rabies that was contracted outside the country where death occurred. We found that the risk for an individual traveler to contract rabies was small relative to the number of people traveling to such areas. For example, over 45 million international travelers went to Africa in 2009.⁴⁰ We report 14 fatalities in travelers to Africa; however, there may be substantial underreporting. Interestingly, we only found published cases that had occurred in the United States, Europe, and Japan, countries where scientific publishing is very common. Of the 14 fatalities from Africa, 13 travelers came from Europe and 1 from the United States. To determine whether more human rabies cases occur in travelers within Asia or Africa would require further investigation by other means. Given that once symptoms of rabies are evident, the disease is expected to be fatal in virtually all cases, it is important to consider rabies prophylaxis and vaccination as a vital preparation to ensure the safety of those planning to visit areas with high rabies incidence.^1,2,8–12

A striking finding in this review of cases was that in 38 of the 39 cases where the animal cause of rabies was known or strongly suspected, the patient had exposure to a member of the family Canidae.^13–38 Given that contact with dogs is known to represent the highest risk for contracting rabies in humans, this finding is not surprising.^1,2,8 Travelers to areas with a high prevalence of rabies in the animal population should be cautious when approaching dogs, including puppies. Healthcare providers should be trained prospectively when advising travelers, and those who seek advice at travel clinics or their general practitioner should be informed about the risk of contracting rabies and the very high mortality rate. Travelers who do not routinely seek medical advice could also be reached through travel agencies or the media.

We found it noteworthy that several persons who sought medical advice after an animal bite occurred received inappropriate care or ineffective care.^13–39 This may highlight the need for greater educational measures for healthcare workers. However, while additional measures can be made in the countries reporting imported cases here, it is difficult to control education in poor and rural areas in developing countries. Therefore, it is very important for those planning to travel to areas with a high risk for rabies to educate themselves and receive pre‐exposure prophylaxis. Obtaining pre‐exposure vaccination can eliminate the need for immunoglobulin following an exposure and also reduces the number of vaccine doses required after exposure.^2,8 Vaccination also reduces the risk of contracting rabies due to inappropriate management abroad.⁴ The vaccines recommended for travelers in North America, Europe, and Japan have been shown to be safe and effective in clinical use and clinical trials. Health‐care provision to travelers, including both medical advice and any potential indicated pre‐travel vaccination, should be based on a careful personal risk assessment and occur at an appropriate interval before departure. Advice should include an assessment of risk factors, destinations, type of travel, and the type and quality of health care available in the areas to be visited, and avoid focusing on the duration of stay. Previous guidelines only recommend vaccination to long‐term travelers expecting to spend extensive time outdoors or expatriates, which may be questionable, as the cases here clearly demonstrate that travelers on short stays can die from rabies if prophylactic measures are omitted or are administered too late following exposure. Immediate access to appropriate medical care should be highlighted, and pre‐exposure vaccination should be recommended if there is a likelihood that state‐of‐the‐art post‐exposure prophylaxis will not be guaranteed because of plans such as backpacking in remote areas, or due to an uncertain supply of biologicals.

This study has several limitations. We only report deaths that were available in clinical literature, including reports posted by the United States Centers for Disease Control and Prevention, or that had been reported to PROMED or the State Research Institute for Standardization and Control of Biological Preparations in Moscow. Therefore, our results are limited by the surveillance and reporting methods in various countries. It is possible that improved levels of reporting, for example, and not an actual increase in cases drove the larger proportion of cases reported during 2000 to 2010 relative to 1990 to 1999. Another limitation of this study is the absence of information about travelers who contracted rabies and then died in the country where infection was acquired.

We noted a large proportion of fatalities occurring in adults, with nearly as many cases in the elderly as in children.^13–39 This indicates that travelers of all ages to rabies‐endemic areas should be informed of the animal reservoirs for rabies, especially stray dogs, the risk of acquiring rabies and the consequences of the disease. Whether the epidemiology in travelers differs from that among persons living in countries with endemic rabies, or whether travelers exhibit different behavior and attitudes than people living in endemic areas should be further investigated. Pre‐exposure prophylaxis should be administered to all travelers to areas with a high risk for rabies and where vaccine, immunoglobulin or even access to medical care in general is not available or may be delayed. All travelers must be made aware of the necessary medical treatment after contact with a potentially rabid animal. An awareness of the need for prompt treatment and appropriate levels of vaccination could help to save lives.

The authors would like to thank Sandra Whitelaw PhD of Alpharmaxim Healthcare Communications for help with the literature search and the original tabulation of rabies cases. All interpretations and opinions expressed are those of the authors, who take editorial responsibility for the content of this manuscript.

Declaration of Interests

The authors are full‐time employees of Novartis Vaccines, a manufacturer of rabies vaccine.