Rabies immunoprophylaxis strategy in travelers

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1 Journal of Wilderness Medicine 2, (1991) ORIGINAL ARTICLE Rabies immunoprophylaxis strategy in travelers D.R. SHLIM*, E. SCHWARTZ and R. HOUSTON CIWEC Clinic, POB 1340, Kathmandu, Nepal We present data from a two-year study of foreign travelers with possible exposure to rabies virus who presented to the only clinics in Nepal that provided modem rabies vaccine. Of foreign tourists and residents who visited Nepal during the study period, 62 required post-exposure rabies immunoprophylaxis. Dog bites accounted for 76% of the exposures, while 20% were due to monkey bites. Sixty-three percent of wounds involved the lower extremity. Seventy-eight per cent of wounds were 2 cm or less in length. The mean length of time between exposure and treatment was 3 days, and 90% received consultation or treatment within 9 days. The safety, expense, and convenience of pre-exposure rabies immunization versus post-exposure immunoprophylaxis alone are discussed. Introduction Rabies encephalitis is endemic in most developing countries. The annual incidence of human rabies is unknown, but estimates range from cases per year world-wide [1] to cases in India alone [2]. Travelers in developing countries are at risk of acquiring rabies from the bite of an infected animal, most often from a dog. Despite the large potential for risk, the number of reported cases of fatal rabies encephalitis in travelers is so low that it is rare to find published case reports. Recommendations for preexposure rabies immunization are poorly defined and based on an estimate of the risk of exposure (veterinarians, travelers to highly endemic areas). Whereas the importance of post-exposure immunoprophylaxis is Hnderstood, the rationale for pre-exposure immunization in travelers is unclear, in part due to lack of data on the actual risk of exposure to rabies, and the length of time between exposure and treatment. We studied the number of foreigners who were potentially exposed to rabies virus through bites or contact with animals in Nepal. In addition, we recorded details of the severity of the exposure, locale in which it occurred, type of animals, and time from exposure to treatment. The advantages and disadvantages of pre-exposure immunization versus post-exposure immunoprophylaxis alone are discussed. Methods The CIWEC Clinic is an expatriate-run outpatient facility that treats foreign residents and tourists in Kathmandu, Nepal. The Kalimati Clinic is a small facility staffed by foreign volunteers, open only a few hours a week. These were the only medical clinics *To whom correspondence should be addressed /91 $ Chapman and Hall Ltd

16 Shlim, Schwartz and Houston available to foreign travelers which stocked the rabies human diploid cell vaccine (HDCV) and human rabies immune globulin (HRIG) at the time of the study.

2 16 Shlim, Schwartz and Houston available to foreign travelers which stocked the rabies human diploid cell vaccine (HDCV) and human rabies immune globulin (HRIG) at the time of the study. All patients presenting to the CIWEC clinic for the treatment of a possible exposure to rabies virus during a 24-month period from 1 February 1987 to 1 February 1989 were included in the study. Patients presenting with a possible rabies exposure at the CIWEC Clinic were requested to complete a questionnaire regarding the history of exposure. We were only able to obtain the number of post-exposure rabies immunoprophylaxis patients treated at the Kalimati Clinic, without any details concerning the bites. Local hospitals used only the Semple vaccine (phenol-inactivated adult animal nerve tissue vaccine) during the time of the study; this option is rarely chosen by travelers because it involves a painful series of 14 injections into the abdominal subcutaneous tissue. Data on the numbers of tourists visiting Nepal was obtained from the Ministry of Tourism, His Majesty's Government of Nepal, in Kathmandu. Results A total of 62 people received post-exposure rabies immunoprophylaxis at both clinics (48 at CIWEC and 14 at Kalimati). An additional six patients presented to CIWEC with possible exposures to rabid animals, but post-exposure treatment was not recommended. In two other patients, post-exposure immunoprophylaxis was recommended, but we have no evidence that it was obtained. The total number of tourists entering Nepal during the study period was (excluding Indian citizens), with an average length of stay of 12 days [3]. An additional 4000 foreigners are believed to reside in Nepal. Thus, the estimated risk of requiring post-exposure rabies prophylaxis for foreigners visiting or residing in Nepal is approximately 16 per Of the 56 patients presenting to CIWEC Clinic with a suspected exposure, 89% were advised to get post-exposure immunoprophylaxis. Fifty-one patients at CIWEC completed questionnaires regarding the history of the bite. Of these, 37 of 51 (73%) were tourists. The patients ranged in age from 2 to 62 (mean 30 ± 12) years. Forty-one percent were males, and 59% were females. The type of animal and country in which the bite occurred are listed in Table 1. The three cases of exposure to a human represented one foreign family who drove a rabid man in a car for six hours to Kathmandu. None of the family received any bite wounds. Table 2 lists the number of bite incidents by the locale in which they occurred. Among tourists, 53% of the bite incidents occurred in Kathmandu. Over half (53%) of the incidents among tourists in Kathmandu occurred at Swayambunath, a popular tourist attraction known as the 'monkey temple'. Twenty-five percent of the tourist bite incidents occurred on trek (which correlates closely with the fact that 25% of tourists go trekking). Among the bite incidents, 32% were described by the patient as being 'provoked,' while 68% were 'unprovoked.' In only 3 of 50 (6%) of cases was the animal able to be detained and observed. The site of the wound on the body is listed in Table 3. Eight of ten (80%) monkey bites involved the upper extremity, while 29 of 36 (81 %) of dog bites involved the lower extremity. Seventy-eight percent (35 of 45) of wounds whose size was recorded were 2 cm or less, 16% (7 of 45) were between 2 and 4 cm, and only 7% (3 of 45) were

3 Rabies immunoprophylaxis strategy in travelers 17 Table 1. Patients presenting with animal bites to CIWEC Clinic by type of animal, and country in which the attack occurred. N=51. TYPE OF ANIMAL: Dog Monkey Human Cat Squirrel COUNTRY: Nepal India Bangladesh Table 2. Locale in which the bite incident occurred. Kathmandu is the capital city of Nepal, with a population of Swayambunath is a popular tourist attraction in Kathmandu known as the 'monkey temple.' A 'town' was defined as a town other than Kathmandu that was reachable by a road. A 'village' is defined as a village that was reachable only by foot or airplane. Percentages in parentheses. Locale Tourists Residents All Kathmandu Swayambunath Town Village 9 (25) 10 (28) 7 (19) 10 (28) 7 (50 o (0) 6 (43) 1 (7) 16 (32) 10 (20) 13 (26) 11 (22) Table 3. Number of bite incidents and location of the bites on the body. N=48. Percentages in parentheses. Body site Arm Hand Trunk Thigh Lower leg Foot Number ofbites 8 (17) 9 (19) 1 (2) 5 (10) 19 (40) 6 (13) greater than 4 cm in length. Seven percent (3 of 44) of the bite wounds became infected. Sixty-eight percent of patients washed the wound within thirty minutes of being bitten. The mean length of time between bite exposure and treatment was three days for tourists, and two days for expatriate residents. Two tourists did not obtain treatment for 64 and 76 days after exposure; these patients were excluded from the calculation of the mean, since they did not seek treatment initially. The mean length of time to treatment for the nine persons bitten on trek was five days, compared to two days for those bitten in Kathmandu. Overall, 76% (39 of 51) received consultation or treatment within three

4 18 Shlim, Schwartz and Houston days of exposure, and 90% received consultation or treatment within nine days of exposure. A total of five of the 51 people who entered the study had received a rabies preimmunization series. Only 5% of tourists (2 of 37) were pre-immunized. Discussion The main issues involved in determining the proper strategy for rabies immunoprophylaxis in travelers are safety, expense, and convenience. Safety is determined by the type of exposure (the location and severity of the bite, along with the likelihood that the animal was rabid), and the speed with which antirabies antibodies can be induced in the host. One must also consider the safety of the vaccine used. Two strategies exist for rabies immunoprophylaxis in travelers. (1) The person planning to travel can receive three injections of HDCV on days 0, 7, and 21 or 28 (according to the Centers for Disease Control's protocol). If the person is exposed to rabies after this pre-immunization, two boosters of the same vaccine are given on days 0 and 3. HRIG is not required in this regimen. (2) The person can travel without any previous vaccination. If an exposure to rabies occurs, the person would undergo the rabies post-exposure immunoprophylaxis series which consists of five injections of HDCV on days 0,3, 7, 14, and 28. In addition, a one time dose of HRIG is given on day 0, calculated by body weight (20 LV. kg-i; 150 LV. ml- I ). Average dose for an adult is 6-10 ml, with half of the dose infiltrated around the wound if anatomically possible, and the other half injected into the gluteal muscles. To help decide whether pre-immunization rabies vaccination increases the safety of travelers, it is necessary to know the risk of being exposed to rabies while traveling. In our study, approximately one in 6000 foreigners in Nepal received an animal bite for which rabies immunoprophylaxis was recommended. We could not estimate the number of travelers who received animal bites and decided not to seek medical advice, but awareness of the risk of rabies in Nepal is high, and we doubt that many travelers fail to seek medical care after being bitten. Our current recommendations for treatment are based on the following: (1) the bite penetrated the skin; (2) the animal is unavailable for observation; (3) the type of animal is known to carry rabies. Occasionally, immunoprophylaxis is given to people who may have had mucous membrane exposure to a sick animal. We tried to determine if it was possible to decide if the attack was 'provoked' or 'unprovoked,' and whether this determination would change our advice. We also tried to determine if observation of the animal could preclude immunization of the victim. Patients were asked whether they thought the attack was 'provoked' or 'unprovoked.' In two-thirds of the cases they felt that it was 'unprovoked,' but this issue was so subjective that it was rarely useful clinically. If you are walking in an area where monkeys are used to seeing tourists and you happen to be carrying food, is it a provoked or unprovoked attack if a monkey jumps on your back? Is it a provoked attack if you step into a courtyard of a monastery in a remote village and a dog attacks your leg? In addition, even an animal 'provoked' into attack could be incubating rabies if it resides in a highly endemic country. Observation of the biting animal in lieu of immediate treatment is an option only if the animal can be firmly identified, and is a dog or a cat. No safe observation period for

Rabies immunoprophylaxis strategy in travelers 19 monkeys has been established, and therefore all monkey exposures require rabies immunoprophylaxis.

5 Rabies immunoprophylaxis strategy in travelers 19 monkeys has been established, and therefore all monkey exposures require rabies immunoprophylaxis. In our series, quarantine and observation of the animal was practical in only 6% of the exposures. There are no data in Nepal on the percentage of dogs or monkeys that are infected with the rabies virus; the risk of death from an untreated potential exposure is thus also unknown. Details on 18 fatal cases of rabies in Nepalese citizens were reported by Joshi and Regmi [4] and offer a hint that exposures to the head and hands may have a higher risk of inducing fatal rabies. In their series, in which no one received modern postexposure rabies vaccines, 17% of wounds were to the head, 67% of the wounds were to the hand, and only 17% were below the waist. The mean incubation period from bite to onset of symptoms was 77 ± 45 days (excluding one case of 1100 days); the shortest incubation period in that study was 14 days. In our study, there were no wounds to the head, 63% of the wounds involved the lower extremity, and the mean time between exposure and treatment was 3 days. In addition, the majority of wounds in our study were very minor in nature, often just tiny abrasions of the skin. The comparison with the Nepal study suggests that foreigners may have lower risk exposure as a rule, and that they are able to obtain immunoprophylaxis within a reasonable length of time. Do people who take pre-exposure rabies immunoprophylaxis have less chance of dying of rabies than those who rely on post-exposure treatment alone? Pre-exposure prophylaxis can offer protection against unnoticed or unreported exposures, or might extend the time that one can wait before obtaining post-exposure treatment. This fact has important implications for children who are traveling in endemic countries, who may not report exposures to their parents for fear of punishment for playing with wild animals. A recent report ofa fatal case ofrabies in a 1O-year-old Australian boy who failed to report a monkey bite on his finger to his mother highlights this argument [5]. After one or two years, however, unboosted levels may fall below levels that could be considered protective for a delayed or unreported exposure, and this advantage might be lost unless boosters are obtained [6]. When pre-exposed individuals receive a booster, antibody levels rise to a higher level more quickly than in those who receive only post-exposure treatment, including HRIG [7]. Whether the more rapid response offers an additional margin of safety is not known. However, there have been two recent reports of post-exposure treatment failures with HDCV and HRIG [8,9]. It was suggested that these failures may have been due to improper care of the wounds, and inappropriate injection of the vaccine into the gluteal region instead of the deltoid muscle. We have not found a clear-cut case report of the failure of prompt, appropriate post-exposure rabies immunoprophylaxis, but these two case reports suggest that there is a narrow margin for error. Of more practical importance to travelers trying to decide whether to take preexposure rabies immunization is the potential availability of rabies immune globulin in developing countries. This substance is required if one is to try to guarantee 100% safety in post-exposure treatment [10,11]. However, its expense and need for refrigeration make it unavailable in most developing countries. Travelers should be advised that HRIG is an advantage only if given within eight days of starting HDCV. The levels achieved with the passive antibodies are surpassed after the first three injections of HDCV, and HRIG would not provide additional benefit if given in the second week [12]. HRIG should be given, however, along with HDCV, even if a significant delay has occurred before starting immunoprophylaxis.

20 Shlim, Schwartz and Houston A possible drawback to pre-exposure rabies immunization is the risk of allergic reaction to a subsequent booster.

6 20 Shlim, Schwartz and Houston A possible drawback to pre-exposure rabies immunization is the risk of allergic reaction to a subsequent booster. A serum sickness-like allergic reaction occurs in up to 6% of people receiving boosters from 1-3 years after a pre-exposure series [13,14]. None of the reactions have been fatal, but the risk exists of a severe reaction that could preclude completion of a post-exposure series. The usual cost for the complete post-exposure series in Nepal is $ US (HDCV $55 US per dose; HRIG $55 US per ml). The cost of pre-exposure immunization varies from $75 to $165 US, depending on whether the intramuscular or intradermal route is used. The two additional boosters, required if one were exposed to rabies, would be another $55 US each. The issue of expense is significant in terms of trying to define who should receive pre-exposure rabies vaccine before traveling. The CDC tried to limit their recommendation for rabies pre-immunization to individuals who would be traveling off the beaten path. They felt that the longer-term traveler might go to more remote areas or in some way have greater exposure. They defined the population for whom they recommended rabies pre-immunization as 'persons living in or visiting countries (for more than 30 days) where rabies is a constant threat' [15]. Ten percent of tourists to Nepal stay for 31 days or longer [4]. If ten percent of the tourists to Nepal during our two year study had been pre-immunized against rabies, the cost would have been over $ US. This figure is more than 100 times higher than the approximate cost ($40000 US) of treating only those individuals who were actually bitten. Arguments about the possible additional margin of safety for pre-immunized people must take into account this huge cost differential. To determine the convenience of rabies pre-immunization, one must also consider the ease of obtaining pre-exposure injections. These may not be readily available, take a month to complete, and may require leaving work on three different occasions. In most cases, the proposed journey's length would be shorter than the time it takes to become immunized. Unlike other travel-related immunizations, pre-immunization for rabies does not obviate the need to seek post-exposure treatment, and exposures are generally recognized. Thus, the fact of being pre-immunized does not prevent having to seek medical care if bitten, and being bitten allows the person who has not been pre-immunized to seek appropriate care. Pre-immunization does, however, offer the significant advantage of not having to obtain HRIG, or spend a month acquiring further injections. Our study has shown that even in a high-risk country like Nepal, the risk of requiring post-exposure rabies immunoprophylaxis is low, and that appropriate post-exposure treatment could be obtained in a reasonable length of time. If a traveler is willing to budget for the possibility of needing post-exposure treatment, and is willing to travel if necessary to get the treatment, pre-exposure immunization is probably not necessary. We have observed that some travelers attempt to travel for a long time on a limited budget, and cannot afford the sudden expense of post-exposure rabies treatment. This group should also consider pre-exposure immunoprophylaxis. In summary, most short term travelers who are mainly staying in cities should not take rabies pre-exposure immunization due to the low risk of exposure, and the relatively large expense for a marginal benefit. Travelers to remote areas in Asia, where transportation could be uncertain, or where HRIG would not be available, should consider the benefits of pre-exposure rabies immunization.

Rabies immunoprophylaxis strategy in travelers 21 Acknowledgements We would like to thank Kenneth W. Bernard, M.D. for reviewing the manuscript and making helpful suggestions. References 1.

7 Rabies immunoprophylaxis strategy in travelers 21 Acknowledgements We would like to thank Kenneth W. Bernard, M.D. for reviewing the manuscript and making helpful suggestions. References 1. World Health Organization. World Health Statistics Annual, Vol. II. Infectious Diseases: Cases and deaths. Geneva: World Health Organization, Seghal, S. and Bhatia, R, eds. Rabies: current status in India. Proceedings of workshop on rabies surveillance and control held at National Institute of Communicable Diseases, October 15-17, Delhi: National Institute of Communicable Diseases (Directorate General of Health Service), His Majesty's Government of Nepal, Ministry of Tourism, Department of Tourism. Nepal Tourism Statistics Kathmandu: Asian Printing Press, Joshi, D.D. and Regmi, D.N. Relation between site of bite, type of bite, type of animal bite, and incubation period of hydrophobia cases. J Inst Med (Nepal) 1983: 5, Centers for Disease Control. Imported human rabies - Australia, MMWR 1988: 37, Bernard, K.W., Mallonee, J., Wright, J.C. et al. Preexposure immunization with intradermal human diploid cell rabies vaccine: risks and benefits of primary and booster vaccination. JAMA 1987; 257, Fishbein, D.B., Bernard, K.W., Miller, K.D. et al. The early kinetics of the neutralizing antibody response after booster immunization with human diploid cell rabies vaccine. Am J Trop Med Hyg 1986; 35: Shill, M., Baynes, RD., Miller, D.S. Fatal rabies encephalitis despite appropriate post-exposure prophylaxis. N EnglJ Med. 1987; 316: Centers for Disease Control. Human rabies despite treatment with rabies immune globulin and human diploid cell rabies vaccine - Thailand. MMWR 1987; 36: Devriendt, J., Staroukine, M., Costy, F. et al. Fatal encephalitis apparently due to rabies: Occurrence after treatment with human diploid cell vaccine but not rabies immune globulin. JAMA 1982; 248: Wattanasri, S., Boonthai, P., Thongcharoen, P. Human rabies after late administration of human diploid cell vaccine without hyperimmune serum. Lancet 1982; 2: Bernard, K.W. and Hattwick, M.A.W. Rabies Virus. In: Mandell, G.L., Douglas, RG., Bennett, J.E., eds Principles and Practice of Infectious Diseases, 2nd ed. New York: John Wiley and Sons, Centers for Disease Control. Systemic allergic reactions following immunization with human diploid cell rabies vaccine. MMWR 1984; 33: Dreesen, D.W., Bernard, K.W., Parker, RA., Deutsch, AJ., Brown, J. Immune complex-like disease in 23 persons following a booster dose of rabies human diploid cell vaccine. Vaccine 1986; 4: Health Information for International Travel U.S. Department of Health and Human Services, Public Health Service, Centers for Disease Control.

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