Rabies

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October ~, 1981

iSSN 0t96-4399

Copyright © t98I by G. K. Ha11 & Co. ~

Vo!. 3, No. 19

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RuNes Charles D. Mitchell, M.D. Division of Pediatric Irq~cdous Disease University of Mirmesota Minneavolis, Minnesota 55455 Imroauetlon Rabies was one of the first viral aiseases of humans that was shown to be preventabie by vaccination. The pioneering work o f Pasteur during the 18C£~s demonstrated tha~ sequentiai postexposure inoculations of the attenuated agent (obtained via seri~l passage in dried rabbit spinal cords) were effective in preventing the disease. Despite this earIy breakthrough, it is only wkhin the last few years that a relativeiy sate and efficacious rabies vaccine has been developed. Virology ClassiEed as a rhabdovirus, the rabies virion has a single-stranded RNA genome coupled to nucleoprotein within a helical capsid. An enve!oping lipoprotein coav contains two matrix proteins, a glycoprotein, phospholipids, and choiesterol. The gl~/coprotein is *° ~n~ ~ so!e antigen responsible for the induction of protective viral neutraiizing antibodies, although other protein moieties may eiicit an antibody response (the antibody induced by the nucleopro~ein forms the basis of the diagnostic immunoflnorescent test used to detect intracellular viral antigen). As viewed wi~h electron microscopy, the rabies virus appears bulietshaped, being approximateiy 75 nm in diameter and 160-180 nm in length. Typicaliy, it matures within the cytoplasm; budding complete virions are often released from the cytoplasmic membrane of infected celis in juxtaposition to nucleo-

capsid matrix inclusions or Negri bodies (5). Pathogenesis

Rabies is a neurotropic virus. Whiie the exact sequence of events following inoculation is not clearly delineated, the virus enters the peripheral nerves after a variable period. (Following aerosol exposure, the virus enters the oifactory end organs.) Once within the nerve endings, the virus is sequestered and passively transrnkted via axoplasmic flow to the spinal cord, where it rapidly ascends to the brain. The virus may initially affec'~ the iimbic system and the brain stem. Within a short period, however, the infection spreads, and nearly aii cerebral neurons are affected. Death usually foliows shortly. Prior to death, the virus may spread centrifugally to involve the salivary glands, adrenal glands, kidney, and heart (3). Cliniea~ m a n i f e s t a t i o n s

Most cases of rabies occur 20-90 days postexposure; however there have been documented cases occurring from i0 days to one year or more after contact (5). The incubation period varies depending on the following factors: a) the severity of the bite or iaceration, b) the age of the victim--children have a shorter incubation period, and c) the location o f the bite or laceration, in general, incubation periods are shorter aRer bites on the head, neck, fingertips, and genitals than after bites on the trunk and lower extremities, because of more extensive innervation in those regions. The initiai symptoms are nonspecific; malaise, fever, headache,

irritability, and anxiety or depression occur most often. Pain, paresthesia, and tingling may occur at the exposure site. The prodroma! phase precedes the acute no,urologic phase by 2 to 10 days. As in animals, the acute neuro!ogic phase can take two forms, paralytic (~'dumb") rabies or furious rabies. Paralytic rabies is manifested by lethargy, dysphagia (secondary to selective paralysis of throat muscies), and progressive deterioration of level of consciousness. Furious rabies presen~s with agitation, hyperactivity, bizarre behavior, and a severe sore throat. Laryngospasms are a result of the pain induced by a~tempts to swaltow iiqaids. H> arop,ob~a is apparently a conditioned response where fear of swallowing water precipitates the actual spasms. The acute neurologic phase usually iasts no more than 10 days, during which the patient may have ahernating periods of agitation and alertness. The acute phase often

~n This Issue Rabies . . . . . . . . . . . . . . . . . . . . . . .

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A review of current knowledge and therapeutic recommendations Status o f R u b e l l a Vaccines . . . . . . 130 Recommendations for immunization Extraintestir~a] Salmonella Infection . . . . . . . . . . . . . . . . . . . . . 131 ]soiation of an "enteric" pathogen f,,:om an unexpected site LysostapMn Test . . . . . . . . . . . . . . To d~¢ferentiate Staphylococcus from Micrococcus

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Letters . . . . . . . . . . . . . . . . . . . . . . .

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terminates with a significant deterioration in the patient's mental status. Coma and death commonly occur shortly as a result of cardiopulmonary complications. Diagnosis There is no way of diagnosing rabies prior to the onset of clinical symptoms. Once developed, rabies is usually suspected on the basis of a known exposure and a typical clinical picture. A lumbar puncture is usually not helpful, as a mononuclear pleocytosis is present in only a minority of cases--usually those in which meningismus is present (5). A premortem diagnosis may be made by isolating the virus from human saliva between 4 and 25 days after the onset of symptoms or by detecting the viral antigen in smears of corneal epithelial cells and skin sections obtained from the neck at the hairline, using a fluorescent antibody (F'A) technique (2). These techniques have been quite useful in the diagnosis of animal rabies and are based on the centrifugal spread of the virus to those richly innervated areas. Serologic evidence of rabies is shown by an in vitro rapid fluorescent focus-inhibition test or by mouse or plaque reduction neutralization tests (5). At the postmortem examination, the diagnosis may be confirmed by the presence of the pathognomonic cytoplasmic inclusions (Negri bodies--multiple 2-10/~ eosinophilic bodies with inner basophilic granules) or positive FA staining of the viral antigen within brain sections. The FA examination is more sensitive and specific than the screen for Negri bodies (2).

Epidemiology Experimentally, rabies may be transmitted via the oral, respiratory, or parenteral route. The overwhelming majority of natural infections in humans and animals occurs through the physical introduction of infectious saliva into subcutaneous and muscular tissue by a bite. There have been occasional cases of disease transmission as a result of the contact of contaminated saliva

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with an abrasion or laceration and four documented cases of aerosol transmission (two occurred in a laboratory environment, the other two in bat caves) (3). Ecologically, there are two primary forms--urban rabies, spread by unimmunized domestic dogs and cats, and sylvatic or rural rabies, spread by skunks, foxes, raccoons, insectivorous bats, and occasionally by livestock. Mass vaccination of domestic animals and control of strays have markedly reduced urban rabies within the last two decades in the United States. In 1980, only 15°70 of the total number of animal cases reported to the Centers for Disease Control (CDC) were in domesticated animals. Of the 6,405 cases reported, dogs comprised only 4°70 and cats 3.3% (6). The greatest source of infection for humans during the last several years remains wild animals. Nationally, the disease has been found most commonly in skunks, foxes, raccoons, and bats. The skunk is the most common source of exposure (63°7o of the documented cases of animal rabies nationally during 1980) (7). Curiously, while the fox is the second most common source reported nationally, in Minnesota the second most common reported source is the cow. Within the last 10 years in Minnesota the combination of skunks and cows has accounted for 50°7o of the total number of rabid animals reported (8). Human exposure to rabies in cattle apparently occurs as a result of attempts to relieve the gagging produced by laryngospasms.* Why cattle should be such a frequent source of rabies exposure in Minnesota is unknown. Nationally, cattle accounted for only 6°70 of the total number of rabid animals reported during 1980. Despite the reports from CDC during 1978 of rabies in flying squirrels and a case in a rabbit from Minnesota this past year (this case occurred in a pet who had contact with a skunk), rabies is not endemic in either wild or domestic *R. A. Siem. Personal Communication.

rodents, insectivores (moles, shrews), or lagomorphs (rabbits, hares). A bite from these species has never been linked with a case of human rabies in the United States, and antirabies prophylaxis is almost never indicated (1). The number of human cases of rabies in the United States has decreased significantly within the last three decades. Human cases averaged 22 per year from 19401950. Since 1960 there have only been 1-5 cases per year (1). In 1980, there were none (7). In contrast, the actual number of postexposure prophylactic courses administered remains approximately the same.

Prevention A physician should evaluate each exposure individually with regard to the animal species involved (wild versus domestic species, carnivore versus rodent), type of exposure (bite versus nonbite), circumstances surrounding the attack (provoked versus unprovoked), vaccination status of the attacking animal, and incidence of rabies in the region. Because of the mass vaccination programs for domestic dogs and eats in the United States, many urban areas are now considered free of rabies. The physician should consult local or state public health officials to obtain data on the local incidence of rabies. If the attacking animal is a healthy domesticated dog or cat, it should be confined and observed for 10 days. If illness develops, the animal should be sacrificed and its head shipped under refrigeration to the medical laboratory affiliated with the State Department of Health for the FA test. If the involved animal is a stray cat or dog or a wild animal, the animal should be killed immediately and its head submitted for examination. Any bite or laceration inflicted by a wild animal that is not caught or killed should be considered as a bona fide exposure to rabies, and the subject should receive prophylaxis. Profuse flushing of the wound with soap and water as soon as

possible is important. Seventypercent alcohol should then be applied. After a short period the wound should be flushed again with a 20% soap solution or a 1-2% benzalkonium chloride solution. Puncture wounds should be irrigated vigorously. At present, the combination of h u m a n rabies immune globulin ( H R I G or RIG) and h u m a n diploid cell rabies vaccine (HDCV) is the treatment o f choice for postexposure prophylaxis. R I G is a concentrated antirabies g a m m a globulin obtained f r o m h u m a n plasma. It contains a

standardized dose of neutralizing antibody (150 international units) (1). Since it is obtained from hyperimmunized h u m a n donors, it is free of significant adverse reactions. (The older antirabies serum (ARS) derived f r o m horses induced serum sickness in over 40% o f recipients.) R I G should be given only once at the beginning o f the regimen to provide passive immunity. H D C V was first developed during the mid 1970s to overcome the problems associated with the Duck Emb r y o Vaccine (DEV), such as a significant incidence o f allergic reac-

tions because of the foreign duck protein and a certain percentage o f seroconversion failures. Nonresponse was increased by the simultaneous administration of DEV with rabies antiserum (4). Like DEV, H D C V is an inactivated viral vaccine, but it is prepared in a h u m a n diploid cell line. Because of the lack of foreign protein, there are fewer allergic reactions. Most importantly, H D C V is more immunogenic than DEV. The neutralizing antibody response in recipients o f H D C V is usually 10-20 times that seen with DEV, and

Table 1 Rabies Immunization Regimens* Postexposure Prophylaxis Passive Immunization

Dose

Route o f Administration

Regimen

HRIG

20 IU/kg

One-half dose around wound, one-half intramuscularly

One time only, at the beginning of immunization.t

ARS

40 IU/kg

Same

Same:[:

Active Immunization

HDCV DEV

No. o f 1-ml Doses

Route of Administration

Interval Between Doses

If no antibody response to primary series, give

5

Intramuscular

Doses to be given on days 0, 3, 7, 14, and 28

an additional booster dose

23

Subcutaneous

21 daily doses and boosters on day 31 and 41 or 2 daily doses in the first 7 days followed by 7 daily doses. Repeat boosters on days 24 and 34.

3 doses of HDCV at weekly intervals

Pre-exposure Prophylaxis§ Active Immunization

HDCV

DEV

No. o f 1-ml Doses

Route of Administration

lnterval Between Doses

l f no antibody response to primary series, give

3

Intramuscular

1 week between 1st and 2nd doses; 2-3 weeks between 2nd and 3rd.

1 booster dose

3 or 4

Subcutaneous

1 month between 1st and 2nd doses; 6-7 months between 2nd and 3rd or 1 week between 1st, 2nd, and 3rd doses; 3 months between 3rd and 4th.

2 booster doses I week apart

*Adapted from Morbidity and Mortality Weekly Report recommendations of June 1980 tlf not given with the first vaccination, HRIG may be given up to 8 days afterwards. Beyond 8 days there should be an active humoral immune response to the first dose of the vaccine. :[cARSshould be given if RIG is not available, but the recipient should be checked beforehand for sensitivity to equine serum. §For persons at high risk of exposure to rabies, such as animal care and control personnel and selected laboratory workers.

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almost every recipient of HDCV develops this prominent antibody response (4). DEV requires a prolonged postexposure regimen, whereas HDCV is given as a 1-ml intramuscular dose as soon as possible after the exposure and on days 3, 7, 14, and 28 after the first dose. A serum specimen for antirabies antibody should be sent to an appropriate laboratory, (e.g., at the State Department of Health) on day 28 to confirm seroconversion. If HDCV is not available, DEV should be used. Table 1 contains the respective dosages for HDCV and DEV

and lists the recommended preexposure rabies immunization schedule for those individuals at high risk of exposure (1). References 1. Centers for Disease Control. 1980. Immunization Practices Advisory Committee. Morbid. Mortal. Weekly Rep. 29(23):265-280. 2. Gardner, P. S., and .l. MeQuillan.

1980. Rabies, pp. 174-184. In Rapid virus diagnosis. Application of immunofluorescence. Butterworth, Inc., Woburn, Mass. 3. Hankey, A. M., and J. S. Andrews.

1980. Rabies: Epidemiology and prophylaxis. Minn. Med. 63:331-336.

4. Plotkin, S. A. 1980. Rabies vaccination in the 1980s. Hosp. Pract. 15:65-72. 5. Piotkin, S. A., and H. F. Clark.

1981. Rabies, pp. 1267-1276. In R. Fergin and J. Cherry (eds.), Textbook of pediatric infectious disease. W. B. Saunders Company, Philadelphia, Pa. 6. Rabies Summary, United States, 1979. 1980. Pp. 1-4. Veterinary Public Health Notes. 7. Rabies--United States, 1980. 1981. Morbid. Mortal. Weekly Rep. 30(12):147. 8. Siem, R. A., C. D. Morse, and D. Stickle. Human exposure to animal

rabies in Minnesota 1971-1980. In press.

Editorial

Status of Rubella Vaccines

Paul A. Offit, M.D. Fellow, Division of Infectious Diseases Stanley A. Plotkin, M.D. Professor of Pediatrics University of Pennsylvania Medical School and The Children's Hospital of Philadelphia Philadelphia, Pennsylvania 19104 Maternal rubella infection during the first trimester of pregnancy can have a devastating effect on the unborn child. As a consequence of the 1964-1965 rubella epidemic, an estimated 20,000 pregnancies in the United States resulted in either abortion, stillbirth, or fetal abnormalities. In 1969 a vaccination program was implemented in the United States using live, attenuated rubella vaccines. The focus of the program was the immunization of prepubertal children, the age group in which the infection was most widely disseminated. Between 1969 and I979, the vaccines available in the United States were HPV-77, derived from dog kidney or duck embryo cell culture, and the Cendehill strain, derived from rabbit kidney cell culture. Since January 1979, the only rubella vaccine distributed in the United States is RA 27/3 (8), derived from WI-38 cells and available as a single vaccine or in combination with the mumps

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and/or measles vaccines. Over the past eleven years approximately 100 million children have been immunized. As a result, the incidence of rubella has declined fourfold (10), and there was no upswing during the 1970-1974 period when, according to the usual six-to-nineyear cycle, a major epidemic would have been expected. However, localized outbreaks have occurred in many parts of the country, usually involving unimmunized high school and college students. Indeed, since 1969, virtually no change has been noted in cases among persons ~ 15 years of age (10). This age group now accounts for approximately 75% of reported cases (10). Recent studies have confirmed that currently 15-20°70 of women in the childbearing age group are susceptible to rubella infection (11), a level of immunity similar to that in the prevaccine era (13). In fact, data from the Birth Defects Monitoring Program do not indicate a substantial decline in the rate at which infants are born with congenital rubella syndrome (2). Let us therefore reevaluate the recommendations for rubella vaccination. Infants

Rubella vaccine has been used extensively in infants of both sexes as a single vaccine or as part of

measles-mumps-rubella immunization. It has been suggested that the optimal age for infant vaccination is 15 months rather than 12 months (1). Although significant differences between the two age groups in rubella vaccine responses have not always been observed (12), it seems preferable on grounds of convenience to vaccinate at 15 months together with measles and mumps vaccine. Prepubertal Females

Increased emphasis must be placed on vaccinating all unimmunized prepubertal females. This can be accomplished by vaccinating all females without proof of immunization at either the first or fifth grade levels. A policy of insuring vaccination at the first grade level is in the long run the easiest and probably the surest of eventual success. However, vaccination of 12-year-old females has been shown to substantially reduce seronegatives in the adolescent female population (7, ll). Follow-up studies of rubella antibodies in individuals given the HPV-77 vaccine have shown a seronegativity rate of 13-36°70 (I, 5). These results are disappointing and raise the question of the need for a booster immunization. In our opinion, there are insufficient data on