Epidemiology of Human Rabies in the United States, 1980 to 1996

One of the oldest recognized zoonotic diseases, rabies continues to plague humankind and causes more than 35 000 deaths annually [1]. These potentially preventable deaths occur primarily in Asia, Africa, and Latin America, where animal control, vaccination programs, and effective human postexposure prophylaxis are not widely available. In contrast, in the United States, deaths in humans caused by rabies totaled 99 in the 1950s, 15 in the 1960s, 23 in the 1970s, 10 in the 1980s, and 22 from 1990 through 1996 [2, 3]. The epidemiology of human rabies is ultimately linked to cycles of rabies virus transmission in animals. With the interruption of dog-to-dog transmission in most regions, the incidence of human rabies in the United States has reached a level that cannot be further reduced without targeting wildlife. An understanding of epidemiologic patterns of rabies virus maintenance in natural populations has emerged in the past 20 years, largely because of advances in immunology and molecular biology. Monoclonal antibody and genetic sequence analyses of rabies virus variants permit detailed descriptions of enzootic maintenance cycles of specific virus variants in the United States [4, 5]. These analyses have led to an understanding of how variants of rabies virus are maintained in natural reservoirs within geographic regions and have provided information on variability of the virus itself. Current epidemiologic patterns of rabies in the United States can be summarized as follows: The annual reports of rabies in wildlife exceed those of rabies in domestic animals [6]; rabies variants in bats are associated with a disproportionate number of infections in humans, although bats constitute only about 10% of all reported rabies cases in animals annually; most other cases of human rabies diagnosed in the United States can be attributed to infections acquired in areas of enzootic canine rabies outside of the United States; most persons with a case of rabies that originated in the United States have no history of an animal bite; and rabies is diagnosed after death in more than one third of the latter group. The last published summary of cases of human rabies in the United States covered the period from 1960 to 1979 [3]. This review discusses the clinical and epidemiologic features of cases of human rabies in the United States from 1980 to 1996. Methods Case Definition This report includes all laboratory-confirmed cases of human rabies in the United States or its territories from 1980 to 1996 [7-31]. All of the cases were reported to the Centers for Disease Control and Prevention (CDC) by health authorities as part of ongoing national surveillance. Variable Definitions Onset of illness was defined as either the first day of reported symptoms attributable to rabies or the date of initial presentation for medical care before confirmation of rabies. Clinical signs attributable to rabies included paresthesia, anxiety, agitation, confusion, disorientation, hydrophobia, aerophobia, hypersalivation, dysphagia, paresis, paralysis, and fluctuating levels of consciousness [32, 33]. The type of transmitting animal and the geographic location of exposure were listed if the case history included a definite animal bite. The reliability of information that linked rabies exposure to a human was assessed by subsequent laboratory typing of the rabies virus variant. All other exposures were defined as unknown. The diagnosis of rabies was considered antemortem if it was tentatively made and samples were obtained specifically for rabies testing before the patient's death. Laboratory Tests The diagnosis of rabies was confirmed by using standard tests [34] conducted at the CDC or at a state laboratory. Serology Two tests were used to detect rabies antibody: the rapid fluorescent focus inhibition test and the indirect immunofluorescence assay. The rapid fluorescent focus inhibition test measures neutralizing antibody. An antibody titer of 1:5 or more, as defined by the reciprocal of the serum or cerebrospinal fluid dilution that reduces the challenge virus by 50%, was considered positive. An indirect immunofluorescence assay, using patient serum or cerebrospinal fluid diluted 1:4 or more, detects serum reactive with rabies antigen in infected cell cultures. The presence of antibody in serum was considered diagnostic if no vaccine or antirabies serum was given to the patient. Antibody in the cerebrospinal fluid, regardless of the rabies immunization history, was considered indicative of rabies virus infection. Virus Isolation Suspensions of brain or saliva specimens were added to mouse neuroblastoma cells and cultured for 24 and 48 hours. Culture slides were fixed and examined by direct immunofluorescence assay for antigen. Samples that were initially negative were maintained for an additional 3 to 4 days and retested. The negative result was considered definitive if it occurred both times. Antigen Detection Antigen detection was performed by direct immunofluorescence of assay serial frozen sections of nuchal skin biopsy specimens, touch impressions of corneal epithelial cells, or fresh brain matter. Paraffin-embedded fixed brain matter was sectioned and enzyme-digested before direct immunofluorescence. RNA Detection Standard extraction procedures and reagents were used to obtain nucleic acids from samples of undiluted saliva; from fresh or paraffin-embedded fixed samples of the brain; or, occasionally, from other tissues. Reverse transcription of RNA and complementary DNA amplification were performed by polymerase chain reaction (PCR) with primers derived from the sequence of the N protein gene. The nucleotide sequence of all PCR products was obtained by standard dideoxynucleotide sequencing methods. Rabies virus variants were identified by comparing samples of rabies virus obtained from all known reservoirs for rabies in the United States [5] with samples of rabies virus obtained from dogs in Asia, Africa, and Latin America [35]. Statistical Analysis Data analyses were performed by using EPI INFO 6 (Centers for Disease Control and Prevention, Atlanta, Georgia) or SPSS 6.0 for Windows (SPSS Inc., Chicago, Illinois) [36, 37]. Specific tests are identified in the text. Some variables were dichotomized before statistical comparisons for determination of odds ratios and 95% CIs. All reported P values are for two-tailed tests of significance. Results Demographic Information Thirty-two persons died of rabies in the United States from 1980 through 1996. Patients ranged in age from 4 to 82 years (median, 27 years) and 20 (63%) were male (Table 1). Cases were reported from 20 states; 7 cases (22%) were reported in California and 6 in Texas. Eleven patients were exposed to rabies in eight foreign countries on the basis of variant typing. The onset of illness occurred in all months and had no apparent seasonal pattern. Dates of exposure, based on the history of an animal bite, were obtained for 7 patients (22%) (Table 1). Table 1. Human Rabies in the United States, 1980-1996 Exposure History A definite history of animal exposure was identified in 7 of the 32 patients (22%), and 25 remained unknown or indefinite (Table 1). Of the 7 cases of definite exposure, 6 resulted from a dog bite received in a foreign country and 1 was from a bat bite received in the United States. Although rabies was not diagnosed in any of the animals that inflicted bites, in each case the rabies virus variant identified in the human sample was consistent with that in the animal species implicated as the source of infection (Table 1). Contact with an animal, thereby suggesting the source for infection, was identified in 12 persons (8 with a bat, 2 with a dog, 1 with a cow, and 1 with a cat). This human-animal contact, however, could not be linked to a bite or mucous membrane contact with the saliva of an animal potentially infected with rabies virus. The remaining 13 patients did not report animal contact; thus, a potential source of exposure was not identified. Histories were obtained before death from friends or relatives in 9 cases and from 4 children aged 11 to 13 years. Prophylaxis None of the 32 patients received a complete series of rabies prophylaxis after exposure; patient 7 reported receiving a single injection of an unknown type after a dog bite in Guatemala, and patients 15, 29, and 30 received human rabies immune globulin during the course of their clinical illness. Clinical Presentation For the 7 patients in which a definite animal bite occurred, the median incubation period was 85 days (range, 53 to 150 days). The first signs and symptoms of rabies were often nonspecific, including fever, sore throat, chills, malaise, anorexia, headache, nausea, vomiting, dyspnea, cough, and weakness. Specific symptoms, such as paresthesias at or near the presumed exposure site, were also reported early in the clinical course, and 19 of the 32 patients (59%) had three or more clinical findings suggestive of rabies during the course of their illness (Table 2). The 32 patients were seen by physicians on an outpatient basis a median of one time (range, 0 to 5 times) before hospitalization, and the median length of time from the onset of illness attributable to rabies to hospitalization was 4 days (range, 1 to 10 days). Table 2. Clinical Findings Suggestive of Rabies in 32 Patients* On admission, 21 of the 32 patients (66%) were febrile (oral temperature > 37.8C), including 12 patients with temperatures greater than 39.5C. Of the 11 patients who were afebrile on admission, 5 reported being febrile before admission, 2 became febrile within 2 days of admission, and 4 had no additional temperatures recorded. The antemortem diagnosis of rabies was first considered at the time of hospitalization in 5 patients, within 1 day of hospitalization in 5 patients, and after a median of 6 days of hospitalization (range, 2 to 12 days) in 10 patients. In 12 patients, rabies was diagnosed after death. Th