rabies: epidemiology, pathogenesis, and prophylaxis

Rabies: Epidemiology,Pathogenesis, and Prophylaxis

Alexander K. C. Leung, MBBS, FRCPC, FRCP (UK&Irel), FRCPCHDepartment of PediatricsUniversity of CalgaryAlberta Children’s HospitalCalgary, Alberta, Canada

H. Dele Davies, MD, FRCPCDepartment of Pediatrics and Human DevelopmentMichigan State UniversityEast Lansing, Michigan

Kam-Lun Ellis Hon, MD, FAAPDepartment of PediatricsChinese University of Hong KongPrince of Wales HospitalShatin, Hong Kong SAR, China

ABSTRACT

Rabies is a viral zoonosis that causes approximately 50,000 to 100,000deaths per year worldwide. Most deaths occur in developing countries.Dogs are the major vector, especially in developing countries. The virus isusually transmitted to humans by infected saliva through the bite of a rabid animal; the incubation period averages 30 to 90 d. Hyperexcitability,autonomic dysfunction, hydrophobia, and aerophobia are characteristicof encephalitic rabies, which accounts for 80% of cases. The paralytic formis characterized by flaccid paralysis in the bitten limb, which ascendssymmetrically or asymmetrically. Once symptoms develop, the disease isinvariably fatal. Animal rabies can be controlled by proper induction ofherd immunity, humane removal of stray animals, promotion of respon-sible pet ownership through education, and enactment of leash laws.Preexposure vaccination with modern cell culture vaccine is recommend-ed for people at high risk of exposure to rabies and for travelers whospend longer than 1 mo in countries where rabies is a constant threat, orwho travel in a country where immediate access to appropriate care is lim-ited. Postexposure prophylaxis consists of prompt and thorough woundcleansing and immunization with modern cell culture vaccine, togetherwith administration of rabies immune globulin to those individuals whohave not previously received preexposure prophylaxis.

Keywords: rabies; fatal; dogs; vaccine; immune globulin

Advancesin Therapy®

Volume 24 No. 6November/December 2007

Address correspondence toDr. Alexander K.C. Leung#200, 233-16th Avenue NWCalgary, Alberta T2M 0H5CanadaEmail: [email protected]

©2007 Health Communications IncTransmission and reproduction of this material in wholeor part without prior written approval are prohibited.

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INTRODUCTION

The word rabies is derived from the Sanskrit word rabhas, which means “to rage,”or from the Latin word rabere, which means “to rave.”1 Rabies is a viral zoonosis. The rabies virus belongs to the genus Lyssavirus (Greek Lyssa, meaning “frenzy”)within the family Rhabdoviridae. Rabies is an important public health problem that ranks 11th among infectious diseases that cause the greatest number of humandeaths worldwide2 and rabies has the highest case fatality rate.2 Once rabies encepha-litis develops, the disease is almost always fatal. Prevention is the primary approachto this disease.

EPIDEMIOLOGY

Globally, it is estimated that approximately 50,000 to 100,000 people die fromrabies each year, although the actual number is probably much higher because ofunderreporting.3,4 Most human deaths from rabies occur in developing countries.5Dogs are the major vectors of rabies throughout the world, especially in developingcountries.4 Worldwide, transmission from dogs accounts for more than 90% ofhuman cases.6,7 In developed countries, bats, foxes, coyotes, raccoons, and skunksare major reservoirs.4,8

A child is at least 4 times more likely to be bitten than an adult in developed anddeveloping countries.9 Boys are affected more often than girls,9 and younger chil-dren are at increased risk for facial injury.10

VIROLOGY

The rabies virus, which is highly neurotropic, is bullet-shaped and measures 75 nm in diameter and 200 nm in length.11 The negative, single-stranded genome is non-segmented RNA that is approximately 12,000 nucleotides long.12 The genome encodes5 structural proteins: (1) a nucleoprotein (N), (2) a phosphoprotein (P), (3) a large,RNA-dependent polymerase (L), (4) a matrix protein (M), and (5) a glycoprotein (G).13

The major component of the riboprotein core is the N protein.13 Approximately 1800 N molecules are noncovalently bound to the genomic virion RNA, forming thehelical RNP complex, which also contains the P and L proteins.13 The virus comprisesan envelope that consists of an outer surface membrane that is covered with peplom-ers composed of trimers of the G protein.13 Spikes of the G protein project through the envelope.4

PATHOGENESIS

The virus is usually transmitted to humans by infected saliva through the bite ofa rabid animal. Less commonly, the virus can be transmitted by contamination of anopen wound, scratch, abrasion, or mucous membrane with fresh saliva from a rabidanimal. Rarely, the virus can be transmitted through aerosol inhalation or by cornealor organ transplants.1,3

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After entry through a skin break, the virus may remain latent near the inoculationsite. Subsequently, the virus replicates slowly within muscle cells. The neuromuscu-lar junction is the major site of entry into the neurons.14 G protein plays an impor-tant role in viral entry and interaction with various cell receptors such as nicotinicacetylcholine receptors at the neuromuscular junction, the neural cell adhesion mol-ecule, and the p75 neurotropic receptors on neural cell membranes.14,15 The rabiesvirus then migrates along peripheral nerves to the central nervous system via retro-grade fast axonal transport at a rate of 12 to 100 mm/d.14,16 The P protein may be animportant determinant in the retrograde transport of the virus within the axons.13

When the central nervous system is reached, massive viral replication occurs with-in neurons, causing widespread neuronal inflammation and necrosis.17 Microscopicexamination of rabies-infected neurons often shows eosinophilic intracytoplasmicinclusions, known as Negri bodies, which contain masses of viral RNA, ribosomes,and virions.18 From the central nervous system, the virus spreads centrifugally to therest of the body, especially the salivary glands, via the peripheral nerves.8 It is at thisstage that productive viral replication occurs with budding, particularly in the sali-vary glands, resulting in high viral concentrations in the saliva.17

CLINICAL MANIFESTATIONS

The incubation period is, on average, 30 to 90 d long but may last from a few daysto several years.8 In general, multiple deep lacerations and bites on the head andneck are associated with short incubation periods.12 Typically, a prodrome lasts 2 to10 d, and this duration correlates with viral invasion of the central nervous system.8Prodromal symptoms are nonspecific and include influenza-like symptoms andparesthesia, hyperesthesia, anesthesia, pain, and pruritus at the site of viral entry.1,12

Progression of the disease occurs in 2 forms: the encephalitic (“furious”) form inabout 80% of patients and the paralytic (“dumb”) form in about 20% of patients.8Patients with intact T-cell immunity to rabies and a high concentration of seruminterleukin-2 and interleukin-6 often present with the furious form, whereas thosewho are lacking such responses often present with the paralytic form.15 Hyper-excitability, autonomic dysfunction (hypersalivation, sweating, lacrimation, mydri-asis, and hyperpyrexia), hydrophobia, and aerophobia are characteristic ofencephalitic rabies. Hydrophobia and aerophobia may be triggered by an attempt todrink water or by air blowing on the face, both of which cause painful spasms of thepharynx and larynx.8 The disease runs its entire course in no more than a few daysand ends fatally.12 The paralytic form is insidious. Flaccid paralysis develops, usual-ly in the bitten limb, which ascends symmetrically or asymmetrically.17 The patientultimately develops paraplegia/triplegia/quadriplegia, urinary and fecal inconti-nence, and respiratory and bulbar paralysis over a period of days to a few weeks.

With both forms, cardiac arrhythmia and coma ensue, and death is almost alwaysinevitable.

DIFFERENTIAL DIAGNOSIS

Rabies should be suspected in an acute, unexplained neurologic disease of sus-pected viral origin, especially if the illness rapidly runs a downhill course.4 This isespecially so in an endemic area, regardless of whether a history of animal exposure

1342A. K. C. Leung, et al

Rabies: Epidemiology, Pathogenesis, and Prophylaxis

has been documented. Tetanus may be confused with the encephalitic form. Bothcan follow an animal bite. Tetanus can be distinguished from rabies by its shorterincubation period, trismus and spasmodic contractions of the muscles of the body,and absence of meningoencephalitis.12,17 In addition, hydrophobia and aerophobiaare uncommon in patients with tetanus. Other differential diagnoses include diphtheria, botulism, delirium tremens, and drug intoxication (eg, phenothiazine,amphetamine).17 The differential diagnosis of paralytic rabies includes Guillain-Barré syndrome, Japanese encephalitis, cerebral malaria, and poliomyelitis.4

LABORATORY DIAGNOSIS

If possible, the animal that is suspected of having rabies should be captured. If it is not overtly rabid, it can be quarantined for 10 days and observed for signs of rabies. If the animal exhibits signs of rabies, it should be euthanized and its brain tissue should be tested through immunofluorescence or polymerase chainreaction (PCR).

In a living human, the diagnosis can be made by demonstration of rabies virusRNA with reverse transcriptase–PCR in the saliva, or by full-thickness skin biopsiesof specimens taken from the nuchal region.4,17 Detection of rabies viral antibodies inthe serum can be diagnostic in unvaccinated individuals. On the other hand, rabiesantibodies in the cerebrospinal fluid are produced only in infected, not vaccinated,individuals.4 Therefore, detection of rabies antibodies in the cerebrospinal fluid sup-ports the diagnosis of rabies. Rabies virus can also be isolated for culture from sali-va or from material obtained for brain biopsy.7

TREATMENT

Once rabies symptoms have developed, the disease is invariably fatal.18 Treatmentis mainly supportive and may include the use of supplemental oxygen with mechan-ical ventilation, heavy sedation, analgesia, and anticonvulsants. Theoretically, combi-nation therapy with rabies vaccine, rabies immune globulin, ribavirin, interferon-α,and ketamine may be superior to therapy with a single agent.14 On the whole, suchtreatment has not proved useful.16

PREVENTION

Because rabies is untreatable, prevention is of utmost importance. Death can beminimized through timely and proper wound care, as well as with the use of mod-ern cell culture rabies vaccine and by means of postexposure administration ofrabies immune globulin to those individuals who have not previously received pre-exposure prophylaxis.

Control of Rabies

Animal rabies can be controlled by proper induction of herd immunity throughvaccination of domestic animals and wildlife vectors, routine veterinary care,humane removal of stray animals, early spaying and neutering programs, promo-tion of responsible pet ownership through education, and enactment of leash laws.19



Unfortunately, no means of controlling rabies is available in some inaccessible vectorspecies. Contact with wildlife and unknown domestic animals should be avoided.Children should be taught not to approach an unfamiliar dog or play with any dogunless they are closely supervised.20 Children should also be taught not to disturb adog that is eating, sleeping, or caring for puppies, and they should be encouraged totreat dogs with respect and not to chase or tease them.20

Preexposure Prophylaxis

Preexposure vaccination is recommended for people at high risk of exposure torabies, such as veterinarians, animal handlers, and rabies research personnel.1Travelers who are at high risk for exposure during travel, who spend longer than 1 mo in countries where rabies is a constant threat, or who travel to or within a coun-try where immediate access to appropriate medical care, including biologic agents,is limited should be considered for preexposure vaccination.21,22

In developed countries, modern cell culture vaccines have replaced the originalnerve tissue vaccines pioneered by Pasteur in 1885. Unfortunately, nerve tissue vac-cines are still widely used in many developing countries because of perceivedaffordability. Such vaccines should be discontinued whenever feasible because oflow potency and a high incidence of serious neurologic complications such asGuillain-Barré syndrome and encephalomyelitis.6,23 These neurologic complicationsare attributed to myelin basic protein and to some of the ganglioside and phospho-lipid constituents.6

Modern cell culture vaccines are more expensive but are safe and immunogenic.Vaccine strains may be grown in cultured human diploid cell lines or in develop-ing eggs. Currently, human diploid cell vaccine (HDCV; Imovax Rabies, SanofiPasteur, Lyon, France) and purified chick embryo cell culture vaccine (PCECV;RabAvert, Novartis Vaccines & Diagnostics, Inc., Emeryville, Calif) are licensed andare used widely in North America and the United Kingdom.16,18,24 Rabies virusstrains are inactivated by β-propiolactone. Imovax Rabies and RabAvert are lyophi-lized and contain at least 2.5 IU of rabies antigen per milliliter.4,24 Rabies vaccina-tion induces long-term immunologic memory, as well as high titers of protectiverabies virus–neutralizing antibody.2 Preexposure vaccination simplifies postexpo-sure prophylaxis because fewer doses of vaccine are needed and rabies immuneglobulin is not required.4

The standard preexposure regimen consists of 3 doses of 1 mL modern cell cul-ture vaccine on days 0, 7, and 21 or 28. The vaccine should be given intramuscular-ly in the deltoid muscle of adults and in the anterolateral aspect of the thigh ofinfants because administration in the adipose tissue might result in lower antibodytiters.24,25 The seroconversion rate is about 98% after primary vaccination.17 Boostervaccinations are recommended for those at high risk of rabies exposure if antibodytiters are below acceptable levels.25 The World Health Organization (WHO) approvesthe intradermal route of vaccination whereby 0.1 mL of vaccine is administered ondays 0, 7, and 21 or 28.26 This approach would help to lower the cost of vaccinationbecause the total volume of vaccine required is less than the amount required for intramuscular administration; however, the intradermal route is technicallymore difficult to use, and this approach might result in lower antibody levels.27,28



The intradermal route should be avoided in immunocompromised individuals andin those who are taking corticosteroids or chloroquine.24 The use of chloroquine hasto be delayed for at least 1 mo after vaccination if the intradermal route is used.

Cell culture vaccines are inactivated by β-propiolactone and can be safely admin-istered during pregnancy.7,29 Local adverse effects, which are not uncommon,include pain, tenderness, erythema, induration, and pruritus at the injection site.6Systemic adverse effects occur in 1% to 10% of vaccine recipients and includeheadache, nausea, dizziness, myalgia, arthralgia, fever, lymphadenopathy, and rash.24

Immune-mediated hypersensitivity reactions occur in 6% of patients given HDCVboosters after an initial series of HDCV, although such reactions do not followPCECV boosters.18,30 If possible, the same product should be used for the entire vac-cine series,19 but switching to another product is reasonable if the patient developshypersensitivity to the vaccine.19 In comparison with HDCV, PCECV is less expen-sive.31,32 As of December 2005, 66.3 million doses of PCECV had been administeredglobally.31 From October 1997 though December 2005, the Vaccine Adverse EventReporting System received 336 reports of adverse events that followed vaccinationwith PCECV.31 Serious events, including 20 hospitalizations and 13 neurologic events,were described in 24 reports (7%). There was no pattern among the 13 neurologicadverse events suggesting a plausible relationship to vaccination.

Postexposure Prophylaxis

Approximately 30% to 50% of individuals who are bitten by a known rabid ani-mal and who have not received postexposure prophylaxis contract rabies.7 Woundcare is essential to the prevention of rabies infection. The wound should be imme-diately washed with copious amounts of water and cleansed with soap. Alcohol,cetrimide, quaternary ammonium compounds, iodine, and povidone should beused if available.5 Tetanus toxoid and antibiotics should be administered if indicat-ed.20,21 Suturing of the wound should be avoided.21

For those individuals who have not previously received preexposure prophylax-is within 2 y, human rabies immune globulin (HRIG) should be given as soon as pos-sible and within 7 d of exposure.8,21 HRIG provides immediate rabies-neutralizingantibodies for a short time before the person begins to make active antibodies to thevaccine.1 HRIG is standardized at a concentration of 150 IU/mL, and the recom-mended dose is 20 IU/kg of body weight.21 The full dose of HRIG should be infil-trated around the wound if feasible.5,8 Any remaining HRIG should be administeredintramuscularly at a site distant from the site of vaccine administration becauserabies immune globulin may interfere with immune uptake of the vaccine.8,25 HRIGshould not be administered in the same syringe that is used for vaccine administra-tion.12,25 The most common complications are pain and soreness at the injection site.1If HRIG is not available, equine rabies immune globulin (ERIG) at a dose of 40 IU/kgbody weight may be used instead.17,21 The use of ERIG is associated with a higherrate of hypersensitivity reactions, including anaphylaxis.17,21 Pregnancy is not a con-traindication to the administration of HRIG or ERIG.1,6,29

Individuals who have not been vaccinated previously should receive 1 mL of mod-ern cell vaccine given intramuscularly on days 0, 3, 7, 14, and 28.17 To reduce the highcost of modern cell culture vaccine, 0.1 mL of the vaccine can be given intradermal-



ly at 8 different sites on day 0, at 4 sites on day 7, and at 1 site on days 28 and 91.16,26

Those previously vaccinated require only 2 intramuscular doses of the vaccine ondays 0 and 3.5,17

CONCLUSION

Rabies is a highly fatal disease. Unfortunately, human exposure to this deadly dis-ease cannot be eradicated, and no effective therapeutic agents are available. Elimina-tion of stray animals, avoidance of exposure, immunization of those at risk, and prop-er postexposure prophylaxis are the primary strategies used to control rabies.

ACKNOWLEDGMENT

Publication of this manuscript was made possible through an unrestricted educa-tional grant provided by Merck Frosst Canada Ltd.

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rabies: epidemiology, pathogenesis, and prophylaxis

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