Prophylaxis against Rabies
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《新英格兰医药杂志》
To the Editor: As noted by Rupprecht and Gibbons (Dec. 16 issue),1 delay before postexposure prophylaxis against rabies is initiated may result in treatment failure and death.2 The incubation period for rabies in dogs could be much longer than 10 days. Furthermore, in previous studies, the rabies virus was isolated from the saliva and cerebrospinal fluid of many dogs before they had any signs of rabies,3 and up to 18 percent of the infected dogs died without having shown any signs of illness beforehand.4 Therefore, management by 10-day observation in many areas where rabies is still prevalent might put patients' lives at risk. According to World Health Organization (WHO) recommendations, all patients with a category 3 exposure (i.e., a transdermal bite or contamination of the mucous membranes with saliva) should receive immune globulin and vaccine immediately, and treatment should be stopped only if the animal remains healthy throughout the 10-day period of observation or is euthanized and found to be negative for rabies by appropriate laboratory tests.5
Sathit Kurathong, M.D.
Bangkok Metropolitan Administration Medical College
Bangkok 10300, Thailand
skurathong@hotmail.com
References
Rupprecht CE, Gibbons RV. Prophylaxis against rabies. N Engl J Med 2004;351:2626-2635.
Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies postexposure treatment in Thailand. Vaccine 1989;7:49-52.
Fekadu M, Shaddock JH, Baer GM. Excretion of rabies virus in the saliva of dogs. J Infect Dis 1982;145:715-719.
Fekadu M, Shaddock JH, Baer GM. Peripheral distribution of virus in dogs inoculated with two strains of rabies virus. Am J Vet Res 1984;45:724-729.
WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva: World Health Organization, 1997. (Accessed March 25, 2005, at http://www.who.int/emc-documents/rabies/whoemczoo966c.htm.)
To the Editor: In their review, Rupprecht and Gibbons recognize that rabies immune globulins are in short supply and note that "multisite intradermal vaccination is another possible strategy to accelerate the immune response." However, the risks associated with not using immune globulins in cases of severe rabies exposure should be emphasized. A similar statement, since withdrawn, from the Thai Health Ministry led to one tragic death. The eight-site method was used without immune globulin in a Thai child with facial dog bites, and the child died of rabies 15 days later.1 Recent studies have shown that the multisite accelerated method will result in increased antibody titers by day 14 but not in significantly earlier ones.2,3 This topic was discussed at a 2004 WHO meeting, at which the need for immune globulin in the optimal treatment of severe rabies exposure was reaffirmed.
Henry Wilde, M.D.
Thai Red Cross Society
Bangkok 10330, Thailand
Thiravat Hemachudha, M.D.
Chulalongkorn University
Bangkok 10330, Thailand
References
Sriaroon C, Daviratanasilpa S, Sansomranjai P, et al. Rabies in a Thai child treated with the eight-site post-exposure regimen without rabies immune globulin. Vaccine 2003;21:3525-3526.
Khawplod P, Wilde H, Tepsumethanon S, et al. Prospective immunogenicity study of multiple intradermal injections of rabies vaccine in an effort to obtain an early immune response without the use of immunoglobulin. Clin Infect Dis 2002;35:1562-1565.
Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 2002;1:101-109.
To the Editor: In their review of rabies prophylaxis, Rupprecht and Gibbons mention that multiple intradermal vaccination is an alternative strategy for accelerating the immune response. Because of the high cost of rabies vaccine, the intradermal route is often used in tropical countries. However, in these countries, chloroquine is used regularly. In our view, it is important to mention that weekly oral chloroquine prophylaxis against malaria has been associated with an impaired antibody response to intradermal rabies vaccination.1,2 If chloroquine is being used concurrently, intramuscular injections are preferable.3 If the intradermal route is chosen, chloroquine should not be used.
Erwin Van den Enden, M.D.
Institute of Tropical Medicine
2000 Antwerp, Belgium
References
Pappaioanou M, Fishbein DB, Dreesen DW, et al. Antibody response to preexposure human diploid-cell rabies vaccine given concurrently with chloroquine. N Engl J Med 1986;314:280-284.
Taylor DN, Wasi C, Bernard K. Chloroquine prophylaxis associated with a poor antibody response to human diploid cell rabies vaccine. Lancet 1984;1:1405-1405.
WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva, World Health Organization, 1997. (Accessed March 25, 2005, at http://www.who.int/emc-documents/rabies/whoemczoo966c.htm.)
The authors reply: In response to Dr. Kurathong: As we discuss in our review, postexposure prophylaxis against rabies should begin when rabies is considered seriously. In developed countries, where rabies is controlled among domestic animals, suspect dogs are observed and postexposure prophylaxis administered only when there is a significant suspicion of rabies.
It is important to differentiate between the incubation period (i.e., the time between exposure and onset) and the period when transmission is likely. Incubation periods are quite variable, lasting from days to years (average duration, approximately one to three months). In contrast, animals excrete rabies virus for only a few days before obvious illness. The 10-day observation period refers to the suspect biting dog. Postexposure prophylaxis is unnecessary unless the animals sickens, after which euthanasia and laboratory diagnosis should be performed. No documented human cases have occurred when the dog remains normal during this period.1 If there is an increased prevalence of rabies, as there is in developing countries, postexposure prophylaxis begins after a bite and is discontinued if the animal remains normal or test results are negative.
The comments of Drs. Wilde and Hemachudha and of Dr. Van den Enden highlight potential difficulties in postexposure prophylaxis in countries where rabies is endemic. Rabies vaccines are potent, but many factors affect immunity, including genetic characteristics, nutrition, concomitant diseases, and concomitant use of other drugs. Serologic analyses of vaccine recipients, such as Peace Corps volunteers, showed substantial differences in responses after vaccination.2 Antimalarial drugs, such as chloroquine, may interfere with optimal responses after primary vaccination with intradermal vaccine. If antimalarial drugs are administered, vaccination should ideally be given by the intramuscular route. Nevertheless, there have been no documented instances of failure of postexposure prophylaxis as a result of the use of antimalarial drugs. Unfortunately, malaria is endemic in most regions where canine rabies persists: the costs of intramuscular vaccination make it impractical for routine use in these regions, as opposed to occasional use in travelers. The high costs and lack of availability of rabies immune globulin, which we agree is routinely indicated for high-risk exposures, also remain a problem in these areas.
Clearly, elimination of canine rabies is the ultimate solution to problematic postexposure prophylaxis.3 Scarce and costly biologic agents for use in humans are not a practical approach to the effective management of rabies in areas where it is endemic.
Charles E. Rupprecht, V.M.D., Ph.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
cyr5@cdc.gov
Robert V. Gibbons, M.D., M.P.H.
Armed Forces Research Institute of Medical Sciences
Bangkok 10400, Thailand
References
Rupprecht CE. A tale of two worlds: public health management decisions in human rabies prevention. Clin Infect Dis 2004;39:281-283.
Briggs DJ, Schwenke JR. Longevity of rabies antibody titre in recipients of human diploid cell rabies vaccine. Vaccine 1992;10:125-129.
Kamoltham T, Singhsa J, Promsaranee U, Sonthon P, Mathean P, Thinyounyong W. Elimination of human rabies in a canine endemic province in Thailand: five-year programme. Bull World Health Organ 2003;81:375-381.
Sathit Kurathong, M.D.
Bangkok Metropolitan Administration Medical College
Bangkok 10300, Thailand
skurathong@hotmail.com
References
Rupprecht CE, Gibbons RV. Prophylaxis against rabies. N Engl J Med 2004;351:2626-2635.
Wilde H, Choomkasien P, Hemachudha T, Supich C, Chutivongse S. Failure of rabies postexposure treatment in Thailand. Vaccine 1989;7:49-52.
Fekadu M, Shaddock JH, Baer GM. Excretion of rabies virus in the saliva of dogs. J Infect Dis 1982;145:715-719.
Fekadu M, Shaddock JH, Baer GM. Peripheral distribution of virus in dogs inoculated with two strains of rabies virus. Am J Vet Res 1984;45:724-729.
WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva: World Health Organization, 1997. (Accessed March 25, 2005, at http://www.who.int/emc-documents/rabies/whoemczoo966c.htm.)
To the Editor: In their review, Rupprecht and Gibbons recognize that rabies immune globulins are in short supply and note that "multisite intradermal vaccination is another possible strategy to accelerate the immune response." However, the risks associated with not using immune globulins in cases of severe rabies exposure should be emphasized. A similar statement, since withdrawn, from the Thai Health Ministry led to one tragic death. The eight-site method was used without immune globulin in a Thai child with facial dog bites, and the child died of rabies 15 days later.1 Recent studies have shown that the multisite accelerated method will result in increased antibody titers by day 14 but not in significantly earlier ones.2,3 This topic was discussed at a 2004 WHO meeting, at which the need for immune globulin in the optimal treatment of severe rabies exposure was reaffirmed.
Henry Wilde, M.D.
Thai Red Cross Society
Bangkok 10330, Thailand
Thiravat Hemachudha, M.D.
Chulalongkorn University
Bangkok 10330, Thailand
References
Sriaroon C, Daviratanasilpa S, Sansomranjai P, et al. Rabies in a Thai child treated with the eight-site post-exposure regimen without rabies immune globulin. Vaccine 2003;21:3525-3526.
Khawplod P, Wilde H, Tepsumethanon S, et al. Prospective immunogenicity study of multiple intradermal injections of rabies vaccine in an effort to obtain an early immune response without the use of immunoglobulin. Clin Infect Dis 2002;35:1562-1565.
Hemachudha T, Laothamatas J, Rupprecht CE. Human rabies: a disease of complex neuropathogenetic mechanisms and diagnostic challenges. Lancet Neurol 2002;1:101-109.
To the Editor: In their review of rabies prophylaxis, Rupprecht and Gibbons mention that multiple intradermal vaccination is an alternative strategy for accelerating the immune response. Because of the high cost of rabies vaccine, the intradermal route is often used in tropical countries. However, in these countries, chloroquine is used regularly. In our view, it is important to mention that weekly oral chloroquine prophylaxis against malaria has been associated with an impaired antibody response to intradermal rabies vaccination.1,2 If chloroquine is being used concurrently, intramuscular injections are preferable.3 If the intradermal route is chosen, chloroquine should not be used.
Erwin Van den Enden, M.D.
Institute of Tropical Medicine
2000 Antwerp, Belgium
References
Pappaioanou M, Fishbein DB, Dreesen DW, et al. Antibody response to preexposure human diploid-cell rabies vaccine given concurrently with chloroquine. N Engl J Med 1986;314:280-284.
Taylor DN, Wasi C, Bernard K. Chloroquine prophylaxis associated with a poor antibody response to human diploid cell rabies vaccine. Lancet 1984;1:1405-1405.
WHO recommendations on rabies post-exposure treatment and the correct technique of intradermal immunization against rabies. Geneva, World Health Organization, 1997. (Accessed March 25, 2005, at http://www.who.int/emc-documents/rabies/whoemczoo966c.htm.)
The authors reply: In response to Dr. Kurathong: As we discuss in our review, postexposure prophylaxis against rabies should begin when rabies is considered seriously. In developed countries, where rabies is controlled among domestic animals, suspect dogs are observed and postexposure prophylaxis administered only when there is a significant suspicion of rabies.
It is important to differentiate between the incubation period (i.e., the time between exposure and onset) and the period when transmission is likely. Incubation periods are quite variable, lasting from days to years (average duration, approximately one to three months). In contrast, animals excrete rabies virus for only a few days before obvious illness. The 10-day observation period refers to the suspect biting dog. Postexposure prophylaxis is unnecessary unless the animals sickens, after which euthanasia and laboratory diagnosis should be performed. No documented human cases have occurred when the dog remains normal during this period.1 If there is an increased prevalence of rabies, as there is in developing countries, postexposure prophylaxis begins after a bite and is discontinued if the animal remains normal or test results are negative.
The comments of Drs. Wilde and Hemachudha and of Dr. Van den Enden highlight potential difficulties in postexposure prophylaxis in countries where rabies is endemic. Rabies vaccines are potent, but many factors affect immunity, including genetic characteristics, nutrition, concomitant diseases, and concomitant use of other drugs. Serologic analyses of vaccine recipients, such as Peace Corps volunteers, showed substantial differences in responses after vaccination.2 Antimalarial drugs, such as chloroquine, may interfere with optimal responses after primary vaccination with intradermal vaccine. If antimalarial drugs are administered, vaccination should ideally be given by the intramuscular route. Nevertheless, there have been no documented instances of failure of postexposure prophylaxis as a result of the use of antimalarial drugs. Unfortunately, malaria is endemic in most regions where canine rabies persists: the costs of intramuscular vaccination make it impractical for routine use in these regions, as opposed to occasional use in travelers. The high costs and lack of availability of rabies immune globulin, which we agree is routinely indicated for high-risk exposures, also remain a problem in these areas.
Clearly, elimination of canine rabies is the ultimate solution to problematic postexposure prophylaxis.3 Scarce and costly biologic agents for use in humans are not a practical approach to the effective management of rabies in areas where it is endemic.
Charles E. Rupprecht, V.M.D., Ph.D.
Centers for Disease Control and Prevention
Atlanta, GA 30333
cyr5@cdc.gov
Robert V. Gibbons, M.D., M.P.H.
Armed Forces Research Institute of Medical Sciences
Bangkok 10400, Thailand
References
Rupprecht CE. A tale of two worlds: public health management decisions in human rabies prevention. Clin Infect Dis 2004;39:281-283.
Briggs DJ, Schwenke JR. Longevity of rabies antibody titre in recipients of human diploid cell rabies vaccine. Vaccine 1992;10:125-129.
Kamoltham T, Singhsa J, Promsaranee U, Sonthon P, Mathean P, Thinyounyong W. Elimination of human rabies in a canine endemic province in Thailand: five-year programme. Bull World Health Organ 2003;81:375-381.