Original Article
Unexplained Rabies in Three Immigrants in the United States a Virologic Investigation
N Engl J Med 1991; 324:205-211January 24, 1991
- Abstract
- Abstract
Background.
Extensive investigation of three patients who died of rabies in the United States failed to reveal any source of exposure to the disease. The three patients had immigrated to the United States from areas in Laos, the Philippines, and Mexico where rabies is endemic.
Methods.
We studied rabies viruses isolated from the three patients, other patients with a known source of exposure, and animals in the United States, Thailand (as a proxy for Laos), the Philippines, and Mexico. The viruses were characterized by indirect immunofluorescence and neutralization tests according to their reactions to panels of monoclonal antibodies. Transcribed complementary DNA from these isolates was amplified by the polymerase chain reaction; the DNA product was then analyzed by differential digestion with restriction enzymes.
Results.
The viral isolate from each of the three patients was a rabies variant with distinctive antigenic or genetic characteristics. For each of the three isolates, identical variants were found in specimens from rabid animals obtained from or near the country in which the patient lived before immigrating to the United States. None of these variants were found among the isolates collected from rabid animals in the United States.
Conclusions.
Rabies infection in these three patients did not originate in the United States but resulted from exposures in Laos, the Philippines, and Mexico. Since the three patients had lived in the United States for 4 years, 6 years, and 11 months, our findings suggest that the onset of the clinical manifestations of rabies occurred after long incubation periods. (N Engl J Med 1991; 324: 205–11.)
Media in This Article
Figure 1
Reactivity Patterns of Antinucleocapsid Monoclonal Antibodies (MAb) with Virus Isolated from the Three Patients with Rabies Who Had No Known Exposure to Animals; a Patient from Butte County, California, Who Had Rabies after a Known Exposure to a Rabid L. noctivagans Bat; and Five Species of Bats Commonly Found to Be Rabid in the Western United States.Figure 2
Reactivity Patterns of Antinucleocapsid Monoclonal Antibodies (MAb) with Virus Isolated from the Three Patients with Rabies and No Known Exposure to Animals and from the Principal Terrestrial Animals in Which Rabies Is Enzootic in Areas of Texas and California Where the Patients Lived and from Dogs in Areas of Asia and Latin America Where the Patients Lived before Moving to the United States.Article Activity
- Article
IN most large studies, over 90 percent of patients with rabies have a definite or probable history of exposure to an animal, usually a dog.1 2 3 4 5 In the United States, however, as rabies in dogs has been brought under control, a progressively larger proportion of cases have occurred in patients with no known history of contact with animals. Investigation has revealed a probable source for all 15 cases diagnosed in the 1960s, but for only 18 of 23 cases in the 1970s and 4 of 10 cases in the 1980s.6 7 8 9 10 11 12
There are a number of reasons why a history of exposure might not be obtained from patients with rabies. Seemingly insignificant exposures, such as superficial bites by bats or other small mammals8 , 13 or exposure to aerosols (airborne transmission),14 , 15 may not be recognized or may be forgotten. Ignorance or fear of the treatment of rabies, especially in children, may mask a history of exposure. If the patient is too ill to be interviewed or rabies is not suspected before death,10 there may be no opportunity to obtain direct information about exposure. Finally, the exposure may have occurred so long before the onset of symptoms that it was forgotten or is considered unimportant in determining the source of disease.
Until recently, there were no laboratory methods available for an epidemiologic investigation of patients with rabies who had no history of exposure. In this report, we present the results of antigenic and genetic analyses of isolates from three persons who died of rabies in the United States. These analyses provide evidence concerning the source of their exposure.
Case Reports
Patient 1
A 12-year-old female Laotian refugee in Houston was hospitalized on July 15, 1984, for possible Guillain—Barré syndrome. She had a four-day history of headache, dizziness, fever, sore throat, and weakness of the lower extremities. On the 13th hospital day, recovery of herpes simplex from a throat culture and a temporal focus of seizure activity prompted a brain biopsy, which revealed intracytoplasmic inclusions and a rhabdovirus confirmed as rabies by fluorescent-antibody testing. Experimental therapy with ribavirin was unsuccessful, and the patient died on August.8, 1984.9 Interviews with family and friends failed to reveal a history of exposure to animals in the United States. The patient had not traveled outside Texas and had rarely traveled outside Houston since arriving in the United States in 1980. She had been bitten by a dog in Laos in 1977, seven years before the onset of her illness; however, the bitch that bit her had recently given birth to a litter of puppies and was said to have remained healthy for at least one month after biting the girl.
Patient 2
A 13-year-old male Filipino immigrant was hospitalized in San Francisco on November 29, 1987, for possible pyelonephritis or appendicitis. He had a three-day history of pain and spasm in the buttocks and lower back, and a one-day history of shaking chills, priapism, and pruritus, causing him to scratch his right lower abdomen. On the 4th hospital day, he became comatose; he died on the 17th day of hospitalization despite supportive therapy. A postmortem diagnosis of rabies was made by fluorescent-antibody testing.11 The patient had no history of animal bites and had not traveled outside California since arriving in the United States in 1981. He had traveled outside San Francisco County only twice in the year preceding his death — once to San Mateo County in August 1987 and once for a three-day camping trip to Sonoma County in October 1987. Interviews with relatives, classmates, and teachers failed to reveal any contact with animals during either trip. The patient's father recalled that the child had been bitten by a neighbor's dog shortly before leaving the Philippines for the United States. The dog was said to have remained healthy and was eaten about a month later.
Patient 3
On January 26, 1989, an 18-year-old Mexican man was hospitalized in Portland, Oregon, for evaluation of periumbilical pain. He had been ill for nine days and had twice sought medical care, first for fever, cough, dyspnea, nausea, and vomiting and later for sore throat and myalgia. A cardiopulmonary arrest occurred on the fifth day of hospitalization, and he died three days later. A postmortem diagnosis of rabies was made by fluorescent-antibody testing.12 Interviews with friends in Oregon and the patient's family failed to reveal a history of exposure to animals. In March 1988, he left Michoacán, Mexico, and traveled by car with two companions through California to Oregon. Except for two trips to Washington in September and December 1988, he remained in northern Oregon, working intermittently as an agricultural laborer until the time of his death.
Methods
Collection of Tissue Samples
Brain tissue was collected from samples submitted to public health laboratories for immunofluorescent-antibody tests for rabies.16 Among these samples, we selected only those from the animal species commonly found to be rabid in the area in the United States in which each patient lived; selection was based on surveillance data published in the Centers for Disease Control Surveillance Summaries.17 18 19 In Texas, the animals tested included 33 striped skunks (Mephitis mephitis, responsible for 88 percent of the 601 cases in terrestrial animals in the state in 1984); 13 gray foxes (Urocyon cinereoargenteus, from a small focus of rabies predominantly in foxes in central Texas); 5 domestic dogs (involved in an outbreak of rabies at the Mexican border); and 15 migratory bats (Mexican freetail bats [Tadarida brasiliensis mexicana] and red bats [Lasiurus borealis], the two species responsible for more than 90 percent of the 118 cases of rabies in bats in the state in 1984). In California, the animals tested included 12 striped skunks (which accounted for 95 percent of the 277 cases in terrestrial animals in the state in 1987) and 11 bats (migratory Mexican freetail and hoary bats [Lasiurus cinereus] and resident big brown bats [Eptesicus fuscus], the three species accounting for more than 90 percent of the 116 cases of rabies in bats in the state in 1987). There have been no cases of enzootic rabies in terrestrial animals in Oregon or Washington for the past 30 years, and only 5 to 10 cases in bats each year. Tissue samples were collected from nine bats in Oregon and Washington (resident big brown bats and migratory silver-haired bats [Lasionycteris noctivagans), the two species in which rabies is most often found). Additional samples from migratory bats were collected from throughout their migratory range in the western states.
For each of the three patients with rabies, we obtained from public health laboratories tissue samples from rabid dogs in areas of endemic rabies in or near the countries from which the patients emigrated — Thailand (samples provided by Dr. Thiravat Hemachudha), the Philippines (Dr. Ronald Vescovi), and Mexico (Dr. Mario Martell). No samples could be obtained from Laos. Brain tissue was also obtained from eight patients with rabies associated with known exposures to dogs in Asia and Mexico. Tissue samples from humans with rabies in Thailand were obtained from Dr. Hemachudha. Viral samples from humans infected by dog bites in Mexico20 , 21 or the Philippines22 but whose illness was diagnosed in Texas or California were obtained from the respective state laboratories. Tissue from a patient with rabies originating from a bat bite in California23 was obtained from the state laboratory.
Monoclonal Antibodies
Monoclonal antibodies for the characterization of rabies isolates were obtained from two sources. The panel of 20 antibodies specific for the rabies nucleoprotein was produced at the Centers for Disease Control.24 Its use in epidemiologic investigations has been reviewed elsewhere.25 Antibodies 37 and 54 were prepared at the Wistar Institute from mice immunized with a field strain of rabies virus.26 A panel of 40 antibodies specific for the rabies glycoprotein was prepared at the Wistar Institute27 28 29 and has been used in epidemiologic investigations.30
Antigenic Analysis
The reaction of each rabies sample with the panel of N protein-specific monoclonal antibodies was determined by indirect immunofluorescence methods as described elsewhere,24 with antibody diluted to a concentration producing 4+ fluorescence with its homologous virus. Negative or weak positive reactions were confirmed by repeat tests with a preparation of antibody that was 10 times less dilute. The initial tests were performed on acetone-fixed brain impression slides. Tests were repeated with samples passaged in cell culture when the distribution of antigens in brain tissue was sparse or uneven or when observations were inconclusive.
Test samples containing 100 infectious units of cell culture—passaged virus were exposed to dilutions of glycoprotein-specific monoclonal antibody by incubation for 60 minutes at 37°C. Indicator cells were then added, and the cultures were incubated for 40 hours in a humidified incubator with 0.5 percent carbon dioxide at 37°C. After acetone fixation, the cultures were examined for residual virus by immunofluorescence methods. A 100-fold difference in the neutralization titer of an antibody signified an antigenic difference in the viral glycoprotein.
Genetic Analysis
Cytoplasmic RNA was obtained from rabies-infected cell cultures by hypotonic lysis, phenol extraction, and ethanol precipitation.31 One tenth (usually 10 μl) of the RNA extracted from one T25 flask was heated to 65°C for five minutes, cooled on ice, and added to a 50-μl reverse transcriptase reaction mixture containing 100 mM TRIS buffer (pH 8.3), 140 mM calcium chloride, 10 mM magnesium chloride, 0.5 mM deoxy-NTP, 1 mM dithiothreitol, 25 units of avian myeloblastosis virus reverse transcriptase (United States Biochemical, Cleveland), 25 units of RNAsin (Promega, Madison, Wis.), and 0.025 μg of oligo(deoxythymidine)l0 (Boehringer–Mannheim, Indianapolis). After incubation at 42°C for 90 minutes, amplification of the complementary DNA (cDNA)32 , 33 with the polymerase chain reaction was performed by adding a 200-μl reaction mixture containing 10 mM TRIS buffer (pH 8.3), 6.25 units of Taq polymerase (Perkin–Elmer–Cetus, Norwalk, Conn.), and 0.25 μM primers l0g and 106m. After 1 minute of denaturation at 94°C, 40 cycles of denaturation at 94°C for 30 seconds, annealing at 37°C for 30 seconds, and DNA polymerization at 72°C for 90 seconds were repeated in a thermocycler (Perkin–Elmer–Cetus). Primer sequence was derived from the PV strain of rabies virus.34 Primers 10g (sequence 66 to 80) and 106m (complementary to sequence 1402 to 1419) allowed the amplification of a 1354 base-pair (bp) sequence of the rabies N protein messenger RNA. Amplified DNA was visualized by electrophoresis of a 10-μl sample in 1.0 percent agarose gel containing ethidium bromide.35 The specificity of the reaction was confirmed by excision of the 1354-bp fragment from agarose with a low melting point and amplification of a 1049-bp piece with internal primers 23g (sequence 319 to 336) and 107m (complementary to sequence 1344 to 1367).
The remainder of the original reaction was extracted with chloroform, precipitated with ethanol, and resuspended to 25 μl in water. Then 1 or 2 μl of this preparation was added to a 20-μl restriction-enzyme digestion mixture containing 10 units of either DdeI or HinfI (New England Biolabs, Beverly, Mass.) in the buffer supplied by the manufacturer. Samples were digested for one hour at 37°C. The entire digested product was resolved by electrophoresis on a composite gel of 3 percent NuSieve and 1 percent Seakem agaroses (FMC Bioproducts, Rockland, Me.) in TRIS—borate buffer containing ethidium bromide.
Results
Antigenic Analysis
Viral isolates from the three patients with rabies were first tested with a panel of 20 antibodies specific for the N protein, and the reaction patterns obtained were compared with those of the rabies variants found in the principal species of bats affected by rabies in the western United States, the major terrestrial-animal vectors for rabies in Texas and California, and dogs in enzootic areas of Thailand, the Philippines, and Mexico.
A single pattern of reactivity, designated antigenic variant 1, characterized all three rabies isolates from the patients (Fig. 1Figure 1
Reactivity Patterns of Antinucleocapsid Monoclonal Antibodies (MAb) with Virus Isolated from the Three Patients with Rabies Who Had No Known Exposure to Animals; a Patient from Butte County, California, Who Had Rabies after a Known Exposure to a Rabid L. noctivagans Bat; and Five Species of Bats Commonly Found to Be Rabid in the Western United States.). This pattern was not found in any of the 112 rabies isolates from bats that were tested, making it unlikely that the patients died as a result of contact with infected bats. Isolates from bats contained antigenic variants 2 through 7, with a particular variant associated with isolates from a particular species. For example, all nine isolates from rabid L. noctivagans bats contained antigenic variant 7, as did an isolate from a patient with a documented bite by this species of bat in California. In contrast, variant 7 was found in only 2 of 103 isolates from bat species other than L. noctivagans. This same panel of antibodies could not distinguish the human isolates from isolates from terrestrial animals in the western United States (Fig. 2Figure 2
Reactivity Patterns of Antinucleocapsid Monoclonal Antibodies (MAb) with Virus Isolated from the Three Patients with Rabies and No Known Exposure to Animals and from the Principal Terrestrial Animals in Which Rabies Is Enzootic in Areas of Texas and California Where the Patients Lived and from Dogs in Areas of Asia and Latin America Where the Patients Lived before Moving to the United States.). Antigenic variant 1, found in the three patients, was also found in all 13 rabies isolates from foxes from central Texas and all 5 isolates from dogs from the Texas—Mexico border near the home of Patient 1, as well as in 8 of 12 isolates from skunks from the area of California near the home of Patient 2 and possibly associated with the travels of Patient 3. Antigenic variant 1 was also found in isolates from rabid dogs in Asia and Mexico. Only one focus of animal rabies could be eliminated as a source of the human infection; all 33 skunks collected in areas near the home of Patient 1 in Texas contained antigenic variant 8.We next attempted to differentiate isolates of antigenic variant 1 according to their reaction with a panel of 40 monoclonal antibodies reactive to the glycoprotein. The neutralization tests of isolates from the three patients were identical, and the reaction pattern matched that previously found for rabies isolates from dogs from Asia and Mexico.25 This pattern was also found in isolates from terrestrial wildlife from the United States (data not shown).
Additional monoclonal antibodies prepared from mice immunized with a field strain of rabies virus were tested with the isolates from the three patients and with other isolates of antigenic variant 1. Two N-reactive antibodies, 37 and 54, separated the three isolates from the patients into separate reaction groups (Fig. 3Figure 3
Reactivity Patterns of Antinucleocapsid Monoclonal Antibodies (MAb) 37 and 54 with Antigenic Variant 1 Virus Isolated from Three Patients with Rabies and No Known Exposure to Animals, from Terrestrial Animals in Which Rabies Is Enzootic in Areas of Texas and California Where the Patients Lived, from Dogs in Areas of Asia and Latin America Where the Patients Lived before Moving to the United States, and from Various Patients with Rabies and Known Exposure to Animals.). Reaction pattern 1A was found in the isolate from Patient 1 (the Laotian immigrant who died in Houston) and in isolates from dogs in Thailand and from humans infected by dogs in Thailand. Isolates of antigenic variant 1 collected from animals in which rabies is enzootic in Texas (foxes in central Texas and dogs in the area of the Mexican border) displayed reaction pattern 1C.Reaction pattern 1B was found in the isolate from Patient 2 (the Filipino immigrant who died in San Francisco) and in isolates from dogs in the Philippines and from a human infected by a dog in the Philippines. Isolates of antigenic variant 1 from skunks in California displayed reaction pattern 1A or 1C.
Reaction pattern 1C was found in the isolate from Patient 3 (the Mexican man who died in Portland, Oregon) and in isolates from dogs in Mexico and from persons infected by rabid dogs in Mexico. However, since pattern 1C was also found in six of eight skunk isolates from California, infection as a result of contact with skunks while traveling through California could not be ruled out in Patient 3.
Genetic Analysis
Genetic analysis was used to determine more precisely the differences between isolates from the three patients and isolates from animal vectors of rabies in the United States. This technique should also permit estimates of the genetic relatedness of isolates from these patients and isolates from dogs from areas of Asia and Mexico in which rabies is endemic.
The cDNA amplification products of 12 samples representing each of the three antigenic variants shown in Figure 3 were separated electrophoretically; each sample contained a single band whose migration approximated 1354 bp. Amplification of this fragment with internal primers yielded a second fragment migrating as a 1049-bp fragment.
DNA precipitated from each of the 12 polymerase chain reactions was then digested with restriction enzymes (Fig. 4Figure 4
Agarose-Gel Electrophoresis of cDNA Amplified by the Polymerase Chain Reaction and Digested by Ddel (Lanes 1 through 6) or Hinfl (Lanes 8 through 13). and 5Figure 5
Agarose-Gel Electrophoresis of cDNA Amplified by the Polymerase Chain Reaction and Digested by Ddel (Lanes 2 through 9) or Hinfl (Lanes 11 through 18).). Comparison of the resultant cleavage fragments by differential migration through agarose gels confirmed the antigenic differences observed for each of the isolates from the three patients and confirmed their difference from isolates from rabid animals in the United States. For each of the three patients, an isolate with identical restriction-fragment patterns was found in a rabid dog living in or near the country from which the patient had emigrated. Furthermore, restriction-enzyme digestion revealed genetic differences in epidemiologically distinct subgroups of rabies from terrestrial animals in the United States (i.e., foxes in central Texas and skunks in California) that were antigenically indistinguishable by the monoclonal-antibody tests.Discussion
Antigenic and genetic analysis of isolates from three persons who died of rabies revealed variants previously unknown in the United States but common in dogs in areas of Asia and Mexico where rabies is endemic and where these patients had resided before moving to the United States. There are several possible explanations for these observations.
It is possible that variants indistinguishable from those found in the three patients are present in the United States but were not detected in this survey. These variants could be transmitted by a wildlife vector not sampled in this study or by a dog or other animal brought into the United States illegally from Mexico or Asia. A diagnosis of rabies was made post mortem in two of the patients (Patients 2 and 3) and was not made in the third patient until she was too ill to be interviewed directly. The patients' exposure to animals could have gone unnoticed or might not have been reported to family members or acquaintances. Antigenic and genetic analysis of isolates of rabies virus continues as an investigative procedure at the Centers for Disease Control and may eventually reveal the presence of these variants in the United States. Efforts are also under way to develop comparative sequence data to identify representative field strains of rabies virus more precisely.
A second explanation for the observations is that these patients traveled illegally to areas outside the United States where rabies is endemic or returned to their native countries while they were residents of the United States. Although their travel documents did not indicate any travel outside the United States, this travel may not have been reported to public health officials for fear of reprisal.
In the absence of evidence supporting either one of these explanations, we propose a third explanation —that these patients were bitten by a rabid animal in their native countries before they emigrated to the United States and that the disease remained latent for one to seven years. Cases of rabies in humans after incubation periods of more than one year have been reported, but they are rare (less than 3 percent of cases).2 The existence of extremely long incubation periods (including ones of 16 months,2 2 years,36 3 years,37 , 38 10 years,39 and 19 1/2 years40) has been questioned because almost all of the cases reported occurred in areas where rabies is endemic, making it impossible to rule out a second exposure in the intervening period. In only one case did the patient live in a country free of rabies for a long period (eight months) before the onset of the disease, thus eliminating the possibility of an intercurrent exposure.41 All three cases investigated in this report occurred in persons with no history of an animal bite in the United States who had spent the one to six years preceding the onset of clinical disease in American cities essentially free of enzootic rabies in terrestrial animals (Patients 1 and 2) or in states where rabies is only rarely found in either terrestrial animals or bats (Patient 3). More importantly, analysis of virus isolated from these patients revealed variants not found in animals in the United States. The finding of identical variants in animals in the countries from which the patients emigrated and in humans with rabies associated with animal bites in those countries supports the thesis that their infection occurred outside the United States.
Two of the three patients were bitten by healthy pet dogs in their native countries. In each case, the animal was said to have remained healthy for at least one month after the exposure. Most experimental evidence suggests that an animal that remains healthy for 10 days after biting someone is not capable of transmitting rabies virus at the time of the bite.42 In the United States, no case of rabies has ever been reported among the tens of thousands of victims of dog bites who did not receive rabies vaccine because the biting animal remained healthy.43 , 44 However, there are reports of infected dogs capable of carrying rabies virus in their saliva for prolonged periods while remaining healthy45; these dogs have been referred to as chronic asymptomatic excretors. At least one case of human rabies associated with contact with such animals has been reported,46 but contact with other rabid animals was not ruled out. Further studies are needed to verify and fully substantiate the validity of these observations. Since the animals that bit the patients in this study were unavailable for testing, it was not possible to determine whether they were chronic asymptomatic carriers of rabies. An alternative and more likely explanation is that these patients were bitten by an animal on another occasion that went unrecognized; in developing countries, the incidence of dog bites, particularly among children, is very high.
Our findings emphasize the need for careful questioning of patients and their family members who have lived in areas outside the United States in which rabies is endemic about exposures to rabies. Evidently, rabies virus can persist for long periods without producing clinical signs.
We are indebted to Drs. Richard W. Emmons and Denny G. Constantine for providing rabies isolates from California and for their helpful discussion in the preparation of this manuscript, and to the following people for their assistance in the investigation of the epidemiologic and clinical aspects of the cases: Dr. Merlin Lugo-Faria of the Houston Department of Public Health; Drs. Dixie Snider, Donald Anderson, and Ralph Feigin of Texas Children's Hospital; Drs. Thomas Betz and Charles Alexander of the Texas Department of Health; Dr. Fran Taylor of the San Francisco Department of Health; Drs. Sanford Werner and Ronald Roberto of the California Department of Health; Drs. Fredric Cantor and Kenneth Bernard of the Centers for Disease Control; Drs. M. Loveless and T. Schacker, Oregon Health Sciences University; Drs. L. Paul Williams, Jon Andrus, Robert Sokolow, and David Flemming of the Oregon Department of Human Resources; and Drs. Marcela Cuauhtli and Harison Stettler, Secretaría de Salud Mexico.
Source Information
From the Rabies Laboratory, Viral and Rickettsial Zoonoses Branch, Division of Viral and Rickettsial Diseases, Center for Infectious Diseases, Centers for Disease Control, Atlanta (J.S.S., D.B.F.); the Rabies Unit, Wistar Institute of Anatomy and Biology, Philadelphia (C.E.R.); and the Division of Zoonoses Control, Texas State Health Department, Austin (K.C.). Address reprint requests to Dr. Smith at the Rabies Laboratory, Mailstop G-33. Bldg. 15 SSB 611, Centers for Disease Control, Atlanta, GA 30333.
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