The Rabies Symposium at CISTM 2007

Special Report

By Lin Chen, MD

Assistant Clinical Professor, Harvard Medical School; Director Travel Resource Center, Mount Auburn Hospital, Cambridge, MA

Dr. Lin H. Chen reports no financial relationship relevant to this field of study.

The Rabies Symposium at the Conference of the International Society of Travel Medicine in Vancouver, Canada, featured Drs. David Warrell, David Shlim, and Kanitta Suvansrinon. Professor Warrell presented Rabies Update: Epidemiology and Risk including Host Range. He described a 26-year-old woman from the United Kingdom who traveled to Himachal Pradesh, India, where she was bitten by a dog. The wound was cleaned with whisky and the patient treated with antibiotics and homeopathy. One month later, she returned to the UK still needing dressing changes. Two months later, she became tired, had back pain, and was described as "catching her breath when drinking liquids or felt wind." Two days later she experienced cardiac arrest and died 36 hours later.

The annual human deaths from rabies are ~24,000 in India, 3,200 in China, < 40 in North America, 36 in South America, 9 in Russia. In India during 2005, most bites were due to dogs; there were 16 million bites, 20,000 deaths, and 4 million courses of post exposure rabies prophylaxis given. In China for the year 2006, there were 3293 deaths (27% increase from 2005), and 8 million courses post-exposure prophylaxis administered. Rabies was the leading cause of infectious diseases from May 2006 to March 2007. About 95% of bites were from dogs, whose population ranges from 80-150 million. In rural China, 70% of households have guard dogs or pet dogs; only 2% are vaccinated, and usually they are not leashed. There are also many feral dogs. Use of post-exposure prophylaxis is inadequate in rural China. Among 178 rabies victims in Guizhou Province, 66% had no wound treatment, 72% received no vaccine, 28% received too few doses or delayed vaccination, and 99% had no rabies immune globulin (RIG).

Regarding the epidemiology of rabies, the UK had been free of indigenous rabies since 1902. However, in 1996 European bat lyssavirus (EBLV-2a)-infected Daubenton's bats (Myotis daubentonii) were discovered. In South Africa, rabies carriers include dog (southeast), fox (west), kudu (north), mongoose (central). In the Middle East, camels are common carriers. In the United States, carriers include skunks and raccoons, as well as bats. In Latin America, vampire bats are common rabies carriers. Less than 500 human deaths have occurred since 1975; children are bitten more commonly on their ears, while adults are bitten on their toes.

In Puerto Maldonado, Peru, bats are present in caves. Between July 2006 and February 2007, 527 people had bites. In arid coastal Peru, irrigation tunnels house vampire bats. Local bat control uses an anticoagulant that is lethal for bats. In Melbourne, flying foxes are of concern. In 1996 and 1998, 2 females died of rabies-like illnesses. The usual perception of rabies is the "mad dog" form but a paralytic type of rabies is also very dangerous.

Rabies transmission can occur through bites, scratches, inhalation, transplanted cornea (1979-1996: 8 recipients in 6 countries), organ transplants (2004: 4 recipients died after receiving transplants of liver, kidneys, iliac artery; more than 1000 contacts were traced, and 20% did get post-exposure prophylaxis). A study found that among 1,882 foreigners living in Thailand, 1.3% had dig bites, and 8.9% had dog licks. 1

Rabies is uncontrolled in most countries, and some countries have experienced a recent increase in incidence. It is important to educate travelers, advise that they clean bite wounds immediately and seek effective western post-exposure prophylaxis. Following bites, victims should receive rabies vaccine and rabies immune globulin (RIG). However, the latter may be unavailable or unreliable. Therefore, consider pre-exposure prophlaxis in consideration of time and peace of mind. Preexposure prophylaxis has never failed, when boosted after exposure. Intradermal route is an economic solution in some countries, and it is well worth interrupting a trip to get complete post-exposure prophylaxis.

Dr. Shlim discussed pre-exposure rabies immunization for travelers, and highlighted the unique nature of rabies: 1) the time and source of exposure is almost always known and almost always preventable; 2) it is the most lethal infection of humans; 3) it has 100% fatality when encephalitis develops. He addressed the benefits of pre-exposure prophylaxis, what is adequate pre exposure prophylaxis, and when boosters should begin.

What are benefits of pre-exposure prophylaxis?

  • Omits need for human rabies immune globulin (HRIG), which may be unavailable following exposure
  • Reduces vaccine doses from 5 to 3 doses
  • Simplifies treatment from complicated 28 days to 3 days
  • Increases protection if post-exposure prophylaxis (PEP) delayed
  • Possibly protects against unreported or unrecognized exposure
  • Reduces overall cost if treatment becomes necessary (pre-exposure prophylaxis + boosters = $1000, PEP + Human RIG = $4000)
  • Decreases or eliminates chance of PEP failure* due to mistakes (studies performed on 28 PEP failures found 26 cases to have errors in PEP)

Pre-exposure rabies vaccine was initially developed by Louis Pasteur in the 1880s, by drying infected rabbit spinal cord to attenuate the rabies virus. Subsequently, vaccines were developed using nerve tissue and duck embryo. Brain-derived vaccine was associated with neuroparalytic reactions in >1/400 recipients. In the late 1970s, cell culture vaccines were developed: human diploid cell vaccine (HDCV), purified chick embryo culture vaccine (PCECV), purified Vero cell rabies vaccine (PVRV).

What is an adequate dosing schedule?

Adequate pre-exposure prophylaxis is given on a 3-dose schedule on days 0, 7, 21 or 28. Due to the expense of the vaccine, intradermal administration using a fraction of the intramuscular dose was introduced in the 1980s, but vaccines had to be used within hours of reconstitution. In 1986, manufacturers repackaged the vaccine into 0.1 ml individual syringe for intradermal administration. Ten studies in the 1970s-80s showed adequate antibody response, but antibody levels following intradermal administration were lower than intramuscular administration.

How long can you go?

Volunteers injected with 0.1 cc of rabies vaccine intradermally at 2 sites were tested at 1 year, and 13/16 had > 0.5 IU/ml. After a booster, the mean titer was 49+ at 2 weeks (good).2 Minimum protective antibody level was considered to be 0.5 IU/ml according to the WHO, but this level should be interpreted as evidence of "boostability" rather than protection.

In 1983, a United States Peace Corps volunteer, a 23-year-old woman who had been immunized with the intradermal series was bitten by a puppy. No PEP was given, and she developed rabies 6 weeks later and died. A study of her cohort in Kenya found 9 of 11 had no seroconversion. Among Peace Corps volunteers in other countries, a 34%-40% failure rate was associated with intradermal rabies vaccines given in destination countries.3 Hypotheses were tested regarding the failure, and suggested that concurrent administration of chloroquine reduced total immune response though antibodies still achieved adequate level.

When should boosters be given?

Anamnestic response persists for many years. In the 1980s, CDC advised boosters every 2 years. However, it is evident that the initial series produces boostability, and boostability lasts for years, as boostability is currently felt to last lifelong. No tourist has ever died while trying to get PEP, but tourists have died from no PEP or inadequate administration. Education is the key pre-travel measure.

Dr. Suvansrinon presented post-exposure diagnosis and treatment, focusing on human rabies deaths related to PEP in Thailand. She emphasized that WHO advocated strongly against neuro tissue rabies vaccines such as Semple.

Exposure categories (WHO) are:

  • III - deep wounds, must have PEP
  • II - minor scratch
  • I - touching, feeding of animals or licks on intact skin

The WHO recommendations for PEP mandate wound cleansing, RIG and modern vaccines immediately.4 The WHO approves of 4 rabies post-exposure vaccine schedules, 2 intramuscular and 2 intradermal regimens.

Among these, the Essen (administered on days 0, 3, 7, 14, and 28) is the regimen recommended and used in the United States.4 (See Table 1.)

Dr. Suvansrnon discussed PEP failures and described a number of cases from 1985 to date. The reasons for failure included: 1) RIG was not used or not injected into all wounds; 2) vaccine or RIG were of poor quality; 3) a large viral load was inoculated through the bite; 4) virus was introduced into the nerve; 5) possible deviations from recommended dosing schedule. A sobering case for this associate editor was the case of an adult that was bitten by a dog, managed by observing the dog. The dog was suspected of having rabies on the 4th day. The patient received post exposure prophylaxis starting on the 6th day, but still succumbed to rabies.

References:

  1. Phanuphak P, et al. Should travellers in rabies endemic areas receive pre-exposure rabies immunization? Ann Med Interne(Paris). 1994;145(6):409-411.
  2. Khawplod P, et al. Immunogenicity study of abbreviated rabies preexposure vaccination schedules. J Travel Med2007;14(3):173-176.
  3. Bernard KW et al. Pre-exposure rabies immunization with human diploid cell vaccine: decreased antibody responses in persons immunized in developing countries. Am J Trop Med Hyg 1985;34(3):633-647.
  4. Meslin FX. Rabies as a traveler's risk, especially in high-endemicity areas. J Travel Med 2005;12:S30-S40.