Henry Wilde

Management of Rabies in Humans

Rabies is a fatal disease in humans, and, to date, the only survivors of the disease have received rabies vaccine before the onset of illness. The approach to management of the rabies normally should be palliative. In unusual circumstances, a decision may be made to use an aggressive approach to therapy for patients who present at an early stage of clinical disease. No single therapeutic agent is likely to be effective, but a combination of specific therapies could be considered, including rabies vaccine, rabies immunoglobulin, monoclonal antibodies, ribavirin, interferon-alpha, and ketamine. Corticosteroids should not be used. As research advances, new agents may become available in the future for the treatment of human rabies.

Postexposure prophylaxis for rabies with antiserum and intradermal vaccination

The Thai Red Cross intradermal postexposure rabies treatment schedule was prospectively assessed in 100 Thai patients severely bitten by proven rabid animals. It consists of 0.1 ml of purified Vero cell rabies vaccine containing more than 2.5 IU of rabies antigen per 0.5 ml of reconstituted vaccine given intradermally at two sites on days 0, 3, and 7, followed by one 0.1 ml injection on days 30 and 90. The commercial vaccine used had an antigen content of 3.17 IU per 0.5 ml ampoule. Purified equine or human rabies immuno-globulin was also given on day 0 to patients with severe exposures. As much of the immunoglobulin as possible was infiltrated around the wounds. All patients were followed for 1 year post exposure. There were no deaths; the efficacy of the regimen was 100%. Antibody titre determination in a randomly selected subgroup showed seroconversion in all 10 patients.

Failure of therapeutic coma and ketamine for therapy of human rabies

The recent success in treating a human rabies patient in Milwaukee prompted the use of a similar therapeutic approach in a 33-year-old male Thai patient who was admitted in the early stages of furious rabies. He received therapeutic coma with intravenous diazepam and sodium thiopental to maintain an electroencephalographic burst suppression pattern, which was maintained for a period of 46 h, as well as intravenous ketamine (48 mg/kg/day) as a continuous infusion and ribavirin (48 to 128 mg/kg/day) via a nasogastric tube. He never developed rabies virus antibodies and he died on his 8th hospital day. At least three other patients have been treated unsuccessfully with a similar therapeutic approach. Because of the lack of a clear scientific rationale, high associated costs, and potential complications of therapeutic coma, the authors recommend caution in taking this approach for the therapy of rabies outside the setting of a clinical trial. More experimental work is also needed in cell culture systems and in animal models of rabies in order to develop effective therapy for human rabies.

Heterologous Antisera and Antivenins Are Essential Biologicals: Perspectives on a Worldwide Crisis

Few physicians in western countries are aware of the continuing worldwide need for heterologous serum products. Antisera against rabies, tetanus, diphtheria, and snake antivenins are in short supply or unavailable in many countries where they are needed the most [1]. Efforts to replace heterologous products with homologous products have only been partially successful because such products are generally unaffordable [1]. Murine and human monoclonal antibodies are potential replacements for human and equine blood donors [2-4]. Several major scientific groups and manufacturers of biologicals are working to refine the use of human monoclonal antibodies, anticipating that these will eventually replace human rabies, tetanus, and diphtheria immune globulins. None of these products is available, and it is doubtful that, for the foreseeable future, such products will be less expensive and more readily available than human or equine antisera and antivenins, particularly in poorer tropical countries. The Basic Problem: A Continuing Need for Heterologous Antisera It is possible to raise antibodies in avian eggs instead of horses. The advantages and limitations of antibody production in avian eggs were recently discussed in Bangkok in connection with a western firms efforts to sell their technology to the Thai Red Cross Society. At the end of the day, however, the proposal generated little interest. It was felt that the chicken or duck egg, a heterologous biosystem similar to the horse but smaller and possibly less productive, offered no advantage over the time-proven system of equine or human antibody production. Horses can be bled every 4 weeks. One liter of horse serum yields 75 mL (15 000 IU) of equine rabies immune globulin (the usual dose for an adult victim of a dog bite is 2000 IU) or 100 mL of snake antivenin. The average working life expectancy of such a horse is approximately 6 years (according to the Thai Red Cross Societys experience using plasmapheresis). With the completion of a new facility at the Thai Red Cross Society, yields of heterologous antisera and antivenins are expected to increase as a result of more efficient production. Volunteer human blood donors with high titers of rabies antibody are having plasmapheresis every 2 to 3 months at the Thai Red Cross National Blood Center. One donor provides 300 to 400 mL of plasma, which yield 10 mL (1500 IU) of human rabies immune globulin (average adult dose, 1000 IU). Snake venoms are complex substances; each is made of many protein and enzyme toxins [5]. Even the largest and most experienced manufacturer would find it difficult to produce monoclonal antivenins against the venoms of the many poisonous snakes (at least 200 species worldwide) that bite humans in the tropics. Experiments in Myanmar, Burma, have shown that it may be possible to immunize humans against Russell viper venom [6]. It is, however, unlikely that these interesting experiments will lead to production of antivenin from human donors or to other practical and effective measures, such as immunization of Burmese farmers against the venom of this snake. The hope that every man, woman, and child will have been adequately immunized against tetanus and diphtheria by the beginning of the new century is, in our view, unrealistic. The World Health Organization and some health ministries provide optimistic projections for national immunization programs, but these projections appear to be inflated. The recent increase in the number of reported diphtheria cases in the former Union of Soviet Socialist Republics (USSR) may well have resulted from better surveillance and reporting instead of from the correction of previous politically motivated under-reporting [7, 8]. Diphtheria and tetanus have never really left us and could surface, even in western countries, whenever the opportunity arises [9, 10]. Mackay [11] has developed a map of the world that shows how expanded immunization programs for children have reached less than 50% of the population. Rabies in particular remains a growing public health problem almost everywhere except Antarctica, Australia, New Zealand, and some island states, such as Hawaii. Each year, throughout the world, at least 34 000 persons die of rabies and more than 6 million receive prophylaxis after exposure [12, 13]. It was hoped that with the advent of potent tissue and avian culture rabies vaccines, administration of immune sera would no longer be required. However, it has been shown that these vaccines alone (without antiserum) do not protect all patients bitten by rabid animals [14, 15]. Human or equine rabies antisera are essential to neutralize virus at the inoculation site and provide protection during the first critical week after exposure until endogenous antibodies are produced, because the virus may be entering an immune-protected environment when it invades nerves [14-16]. In Mexico, a series of patients with rabies who received vaccine but no antiserum developed rabies encephalitis but survived with severe brain damage ([17], Baer GM. Personal communication). Similarly, treatment failures occurred in Asia when antisera were not properly administered [13], again emphasizing the therapeutic importance of rabies immune globulins. Nevertheless, more than 90% of worldwide prophylaxis series for rabies after exposure do not include antiserum or immune globulins, largely because these are not affordable and perhaps not even available [1, 13, 14]. There are no good estimates of the number of lives lost because of this lack of an essential biological, but we believe that the numbers are substantial. Antivenins for hemotoxic and neurotoxic snake bites save lives and reduce the number and severity of such complications as clotting disorders and paralysis [18]. Only equine-origin antivenins are available and only in limited quantities [5, 18, 19]. Manufacturers of antivenins face additional problems. These products are usually species-specific. No antivenins are currently made against several dangerous venomous snakes [for example, the Malayan krait from Asia]. The efficacy and cross-protective potency of several so-called polyvalent snake antivenins have never been tested in prospective human studies, and well-controlled animal experiments are lacking for some products. For example, we lack good data on the efficacy of 1) the antivenin product against Siamese monocellate cobra venom when used for bites from the spitting cobras, recently reclassified as three different species [20]; and 2) the only monovalent sea snake antivenin that is being marketed (when available) for use in bites from at least 37 highly toxic species found in the Indian and Pacific Oceans [18]. Considerable research is required to sort out these problems in Asia and on other continents, and current equine snake antivenin production procedures may have to be revised when more data become available. Only a handful of scientists with limited resources work in this field. Many species of snakes are increasingly difficult to procure, and some are almost impossible to breed in captivity. They nevertheless continue to pose a substantial hazard to humans. The Economics of Antiserum Therapy Human antitetanus globulin costs

Rabies in Thailand

155 per average treatment course in Thailand. The equivalent equine product costs only

Surgical management of an epidemic of penile amputations in siam

7. An average adult dose of human rabies immune globulin costs

Pathophysiology of human paralytic rabies

180 in Thailand, with the exception of limited quantities that are made and distributed gratis by the Thai Red Cross National Blood Bank. Purified, pepsin-digested equine rabies antiserum costs only

Rabies Update for Travel Medicine Advisors

28 per dose. Human-origin diphtheria immune globulin (not available in the United States) costs

Failure of rabies postexposure treatment in Thailand

1290 for an average treatment dose in this same region. The equine equivalent would cost

What is an acceptable delay in rabies immune globulin administration when vaccine alone had been given previously

10. The minimum daily wage of a worker in Thailand is