Dear XXXXX,

The objective of this letter is to share some basic information about the rabies virus and human rabies epidemiology as well as address issues related to the treatment of humans after potential exposure to the virus. After a mammal, whether human or other animal, is exposed to the rabies virus an incubation period first occurs during which time the disease cannot be transmitted to another organism. Following the incubation period, the virus is shed in the animals saliva and symptoms of the disease are followed by death. The rabies virus attacks the brain of the infected individual, and rabies in humans is nearly 100% fatal, despite treatment, if the disease is contracted [1 and 2]. In rabid domestic dogs, excretion of the virus in the saliva, and therefore the possibility of being contagious, has been observed up to 14 days prior to signs of the disease appearing in one study [3] and 13 days prior in another [4]. In the U.S., human exposure to the disease typically occurs as a result of a bite by an animal that is excreting the virus in their saliva [1]. As mentioned in the previous paragraph, after a person is exposed to the virus, an incubation period occurs prior to the onset of the disease. The individual exposed must be treated during the incubation period in order to acquire antibodies able to combat the virus and prevent the manifestation of the disease state. The incubation period in humans has been reported to be as short as 5 days in some cases [5]. Incubation periods in humans as short as 8 days to as long as over a year were observed by Sudarshan et al. (2007) [6]. Rabies virus is relatively rare in domestic animals and the reservoir of the virus is in wildlife populations. The route of virus transmission to humans is typically directly from wildlife or from a domestic animal that has been infected by a wild animal (raccoons, foxes, skunks, and bats are common carriers). The likelihood of wild animals carrying the disease varies by location, and the type of animal most likely to carry the disease also varies spatially [7]. The mid-Atlantic region near northcentral West Virginia is an obvious hotspot for rabies in raccoons which are the most common carriers in northcentral West Virginia [Figures 1 and 2 from 7]. Indoor domestic animals that are vaccinated against rabies are substantially less likely to contract the illness than are unvaccinated, outdoor pets, especially if they are allowed to roam freely [7]. The treatment for potential rabies exposure in humans consists of a series of injections. On the first day of treatment, the individual is injected with both a volume of vaccine that initiates formation of rabies virus antibodies and a volume of rabies immunoglobulins that supply virus neutralizing antibodies prior to the body beginning its own natural production. A series of follow-up vaccine injections are administered on subsequent days [1 and 8]. The World Health Organization-recommended minimally accepted concentration of rabies virus antibodies necessary to ward of human rabies infection is 0.5 IU/ml (International Units per milliliter) [8]. It has been observed in humans to require on average 7 to 14 days from the beginning of prophylactic injections to attain this concentration of antibodies [8]. Studies in animal models found that after exposure to the rabies virus via intramuscular injection, peak effectiveness of antirabies serum was attained if administered immediately after exposure and

effectiveness fell for each hour that the serum was withheld, reaching a 40% survival rate with serum administered 30 hours post-exposure [9]. The prophylaxis recommended by the Center for Disease Control for potential rabies exposure is mirrored in local recommendations by various governmental organizations. In the case of a bite by an unvaccinated dog available for observation, the recommendation is to observe the animal for 10 days and to begin rabies post-exposure treatment if the animal develops any symptoms consistent with the disease during this observation period [1]. This 10 day observation period is based largely on the research of Vaughn et al. (1965) and Tepsumethanon et al. (2004) [10 and 11]. In the former study, dogs injected with rabies virus were found to begin secreting the virus in their saliva no sooner than 10 days prior to death. In the later, and more recent study, dogs brought in after beginning to act in an odd fashion were found to live no more than 10 days after being brought in, if in fact they were rabid. It is important to note that the work of Fekadu et al. (1982 and 1988) has found that dogs purposefully infected with rabies can begin secretion of the virus in their saliva 13 to 14 days prior to the onset of any symptoms [3 and 4]. Further, an important assumption of the Tepsumethanon et al. study, if it is to support the 10 day period first described by Vaughn et al., is that the dogs did not begin secreting the virus significantly prior in time to when the dogs behavior prompted the owner to seek medical attention. If this untested assumption is violated, then rabid dogs in their study could have been infectious for greater than 10 days prior to death. The treatment recommendations made by the CDC, including this 10 day observation period, are based upon a cost-benefit analysis from a societal perspective [1], rather than the individual perspective at which medical decisions are usually made. In their approach, a range of probabilities of becoming infected with rabies is estimated for various scenarios based on expert opinion. The costs and benefits of immunizing people in each scenario are then estimated and intersected with probability estimates of disease outcomes in order to arrive at an average cost effectiveness for treating people in each scenario. Also, most and least cost effective scenarios are calculated with these estimates in an attempt to describe the possible range of this metric. The CDC only recommends treatment in potential exposure scenarios in which treatment will result in saving money. It is very important to reiterate that this savings is calculated at the societal level, no matter who is receiving the benefit from treatment or paying the cost of treatment. In this regard, a dollar value must be assigned to a human life lost due to inaction after exposure. The CDC takes this value to be the average lifetime earnings of a human in the U.S. plus housekeeping services and is estimated at right over $1.1 million in 2004 dollars. It is interesting to note that the societal perspective of the CDC and the dollar values assigned to human life are explained briefly and then not mentioned appreciably afterward, nor are the implications of these analysis decisions explored [1]. The CDCs recommendations are the treatments they believe doctors should seek in various scenarios in order to conserve the rabies vaccine and also be cost effective on a broad scale. Therefore, it is obvious that some loss of life is acceptable to the CDC given their recommendations and in fact would be statistically predictable. It is also unsurprising that the recommendations given for societylevel decision making with a value of roughly $1.1 million (2004 adjusted) will conflict with what a local doctor may prescribe for a patient or the optimal decision making process for an individual possibly

exposed. Expressed briefly, anyone will likely value his or her own life much more than $1.1 million dollars (2004 adjusted) and would likely assign a nearly infinite value to their own life given that trading it in the marketplace for any other good would mean that the trade could not be enjoyed afterward. The only exception would be sacrificing your life for something you deem more valuable, such as the life of a loved one, but in these cases the dollar value ascribed, if the value must be translated in this way, would still likely be much more than $1.1 million (2004 adjusted). This is evidenced by greater than $1.1 million (2004 adjusted) being spent regularly for life-saving procedures or awarded in wrongful death civil cases. In my own case, the dog that attacked me was a free-ranging, unvaccinated animal that attacked without provocation. I had no hand in my doctors moving forward with rabies preventative treatment, but am glad that they did given the uncertainty around my exposure at that time and what I have since learned about the disease and its prevention. If exposed, the rabies preventative treatment is most effective the sooner it is given after exposure since rabies antibodies take time to develop in the proper concentration in the body. Further, the period of time between an animal becoming infectious and it dying has been observed to sometimes be longer than the incubation period in humans (14 day period of infectiousness prior to death observed in dogs as well as an incubation period as short as 5 days in humans after exposure). Given these relevant time periods and that preventative treatment is only effective during the incubation period and takes time for immunity to develop, I could have possibly developed rabies while the animal was still being observed or if given the vaccines and other treatments at the first sight of symptoms, especially if these symptoms came late in the observational period. Further, given that 14 days between infectiousness and death is possible, the dog that bit me could have passed through the 10 day observation and developed symptoms afterward without being reported. In summary, given that I value my life much more than $1.1 million dollars (2004 adjusted) and my risk of fatal illness if not treated was some value greater than a probability of 0, I feel it was rational to spend less than $8,000 to guarantee my continued existence. I believe the experts that produced the rabies recommendations for the CDC would feel the same way too if they or a loved one were bitten in like fashion, that is if they understood the implications of the approach they have taken and the analysis decisions and assumptions they have made. The recommendations of local health departments are carbon copies of the CDC recommendations, and it is doubtful that local officials spend time reading and dissecting the manner in which the CDC arrived at these prescriptions.

Sincerely, XXXXXXX

Figure 1. Distribution of major rabies virus variants among nonchiropteran reservoirs in the United States and Puerto Rico,
2008.

Figure 2. Reported cases of rabies involving raccoons by county in 2009.

References 1. Center for Disease Control. Human rabies prevention-United States, 2008: recommendations of the Advisory Committee on Immunization Practices. MMWR 2008; 57 [No. RR-3] 2. Rupprecht, C.E. et al. Rabies re-examined. The Lancet, Infectious Diseases 2002; 2 [pp. 327-343] 3. Fekadu, M. Pathogenesis of rabies virus infection in dogs. Reviews of Infectious Diseases 1988; 10 [pp. S678-S683] 4. Fekadu, M. et al. Excretion of rabies virus in the saliva of dogs. The Journal of Infectious Diseases 1982; 145 [pp. 715-719] 5. Grill, A.K. Approach to management of suspected rabies exposures. Canadian Family Physician 2009; 55 [pp. 247-251] 6. Sudarsha, M.K. et al. Assessing the burden of human rabies in India: results of a national multicenter epidemiological survey. International Journal of Infectious Diseases 2007; 11 [pp. 29-35] 7. Blanton, J.D. et al. Rabies surveillance in the United States during 2009. Journal of the American Veterinary Medical Association 2010; 237 [646-657] 8. Jones, R.L. et al. Immunogenicity, safety and lot consistency in adults of a chromatographically purified Vero-cell rabies vaccine: a randomized, double-blind trial with human diploid cell rabies vaccine. Vaccine 2001; 19 [pp. 4635-4643] 9. Schindler, R. Studies on the pathogenesis of rabies. Bulletin-World Health Organization 1961. 25 [119-126] 10. Vaughn, J.B. et al. Excretion of street rabies virus in saliva of dogs. Journal of the American Medical Association 1965; 193 [pp. 363-368] 11. Tepsumethanon, V. et al. Survival of naturally infected rabid dogs and cats. Clinical Infectious Diseases 2004; 39 [pp. 278-280]