R
Rabies
Henry Wilde, Supaporn Wacharapluesadee, Thiravat Hemachudha, Veera Tepsumethanon, and Boonlert Lumlertdacha,
King Chulalongkorn Memorial Hospital, Bangkok, Thailand; and Queen Saovabha Memorial Institute of the Thai Red Cross Society,
Bangkok, Thailand
Ó 2017 Elsevier Inc. All rights reserved.
This article is an updated version of the previous edition article by Henry Wilde, Supaporn Wacharapluesadee, Thiravat Hemachudha, Veera
Tepsumethanon, volume 5, pp. 463–470, Ó 2008, Elsevier Inc.
Rabies remains a threat and is expanding into previously
rabies-free regions (Windiyaningsih et al., 2004; Clifton,
2010). Sadly, no new countries have been declared rabies-free
in Asia during the past three decades. We have the knowledge
and technology to control canine rabies which causes almost
all of the more than 55 000 reported human rabies deaths
worldwide. One major cause for this is a lack of sustainable
dog control. This is particularly true in many less-developed
canine-endemic countries. Postexposure prophylaxis (PEP)
with immune globulin and vaccine is effective in preventing
deaths when administered as soon as possible after exposure.
It is widely available in developed countries and in some larger
population centers of most canine-endemic regions. However,
we have not been able to bring PEP to the regions where it is
needed the most. These are the more rural, very poor, subsis-
tence farming, and fishing communities of tropical and less-
developed countries where most human rabies deaths have
always occurred.
Introduction
Rabies is a classical zoonosis which should have been virtually
eliminated worldwide as a major public health threat.
However, it is still an emerging disease and is spreading to areas
that have not experienced rabies in recent decades. Examples
are Flores and Bali Islands of Indonesia, where there are
ongoing epidemics (Windiyaningsih et al., 2010; Clifton,
2010). Annually, there are at least 55 000 human deaths world-
wide attributed to rabies; mostly in less-developed countries.
Rabies is considered an underreported disease and is not
required to be reported in several canine-endemic countries.
Domestic and stray dogs remain the principal vectors. We
have the knowledge and technology to eliminate this disease
from dogs but lack the funds and motivation from the public
and governments to do so. Sadly, virtually all of the human
rabies deaths reported worldwide are in subjects who did not
receive PEP or where it was not provided, incomplete, or
with delay (Dimaano et al., 2011; Joseph et al., 2014).
The last two decades have led to better understanding of the
pathophysiology, virology, and immunology of rabies. Cost-
effective, evidence-based shortened methods for PEP are being
236 International Encyclopedia of Public Health, 2nd edition, Volume 6
developed and are now being applied (WHO, 2010). One PEP
schedule that can be completed in 7 days is now undergoing
final studies by WHO (Sudarshan et al., 2012; Shantavasinkul
et al., 2010). Effective vaccines and immunoglobulins are avail-
able, but are expensive and often not used where needed the
most. In spite of recent publicity about human rabies survivors,
and much hope for a cure, rabies remains a virtually invariably
fatal disease.
Rabies is usually transmitted to humans by dog or bat bites
and less commonly by cats and bats. Wildlife also plays a role,
particularly in Africa. The virus, a single-stranded RNA Lyssavi-
rus, can lie dormant within muscle cells at the bite site and then
invade free nerve endings or, in case of direct nerve injury, enter
the nerve and ascend to the spinal cord and brain. The severity
of the bite, the size of the inoculum, and location are determi-
nants of risk of infection, and the length of the silent incuba-
tion periods that ranges from a few days to years. Immediate
wound cleansing and prompt local use of antirabies immuno-
globulin (RIG) and rabies vaccine can save lives. Older vaccines
are being replaced by safer and more potent tissue culture prod-
ucts, which are now also manufactured in rabies-endemic
countries at lower costs (Hemachudha et al., 2013; Wilde
et al., 2012).
The new reduced-dose intradermal administration sched-
ules have made vaccination more affordable (WHO, 2010;
Wilde et al., 2013). Elimination of rabies in uncontrolled dog
populations represents a major public health challenge which
is far from being aggressively managed today (Clifton, 2010;
Windiyaningsih et al., 2004). It remains the ultimate and
most cost-effective way to control rabies. Many rabies expo-
sures occur in rural regions, where PEP is not readily available
and where subsistence farmers or fishermen do not have the
means to travel several times to a remote medical center to
obtain PEP.
Rabies is generally transmitted through bites from an
infected mammal to another mammal. Rabies is believed
to be capable of infecting all mammals with differing
susceptibility. It is transmitted to humans primarily by
canines, cats, and bats, and less commonly by wildlife and
domestic or agricultural animals. Once symptomatic, death
is virtually inevitable. Very rare natural survivors have been
reported among humans and in most mammals including
http://dx.doi.org/10.1016/B978-0-12-803678-5.00370-2
 Rabies 237

dogs and cats (Hemachudha et al., 2013). Rabies, and
closely related Lyssaviruses, can be found throughout the
world except in Greenland, Antarctica, and isolated islands.
They are, however, not immune to future invasion.
Australia, previously considered rabies-free, harbors
Lyssavirus in fruit- and insect-eating bats, which have caused
fatal rabies in humans and other mammals (Figures 1
and 2). Regions with large unvaccinated dog populations
present the greatest risk. They are the principal vector and
cause of human infection. Vampire bat rabies in Central
and South America is a hazard to humans and cattle.
Wildlifes including insect-eating bats are also responsible
for human and livestock deaths.
Worldwide rabies reporting is incomplete and unreliable.
The number of annual human deaths is unknown but is
thought to be well over the 55 000 reported to the WHO.
Nearly 50% of these deaths are in children as they are less
able to defend themselves against bites than adults. They are
also more likely to be bitten on high-risk body parts such as
the face, head, trunk, and hands (WHO, 2013). Rabies can
also be transmitted through the inhalation of bat secretions
(such as in people exploring caves that house bats) and, rarely,
through transplantation from infected organ or tissue donors
(Maier et al., 2010). Rabies has occurred in people who
have bats in their homes and without a recognized history of
bites. The cause could be inhalation or unrecognized and
virtually painless bites. Imported human rabies cases, where
infection occurred abroad and symptoms developed on return-
ing home, have been reported from several countries not
familiar with clinical manifestations of this disease. This may

Figure 1 Major animal vectors.

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PEP (per 100 000 populaon) Deaths (cases)

Figure 2 Human rabies deaths and PEP per 100 000 population in Thailand.
238 Rabies
result in a delay of diagnosis and potential exposure of family
members and health-care workers (Srinivasan et al., 2005;
Maier et al., 2010).
Rabies is responsible for more worldwide deaths than polio,
yellow fever, Japanese encephalitis, dengue, or meningococcal
meningitis. India alone had an estimated 30 000 annual rabies
deaths during most of the past decade. Pakistan estimates over
5000 deaths per year (Wilde et al., 2012). Rabies has again
emerged in China, which was virtually rabies-free during the
reign of Mao Zedong who had eliminated pet dogs. Japan,
Taiwan, Malaysia, Singapore, and South Korea eliminated
canine rabies decades ago. However, no Asian country has
been declared rabies-free during the past three decades. Taiwan,
which was rabies-free for six decades, reported recurrence of
wildlife rabies among badgers in 2013. How it came to Taiwan
is still a mystery.
Lyssaviruses are Still Being Discovered in New
Locations
There may be undetected bat Lyssaviruses related to the classic
rabies virus in many parts of the world. Bats do not often
interact with people, migrate and transmission to humans,
pets and livestock has been documented in the Americas,
Europe, and Australia. Indigenous bat Lyssaviruses, with
different genetic lineages, have now been found in the
Philippines, Thailand, Siberia, Central Asia, and Cambodia,
as well as in Australia. The United Kingdom, considered
rabies-free, experienced a human death from a European bat
Lyssavirus. Previously rabies-free Flores and Bali Islands of
Indonesia are experiencing ongoing rabies outbreaks and
human deaths (Windiyaningsih et al., 2004; Clifton, 2010).
Dogs and other canines remain the most important animal
vectors responsible for transmission of rabies to humans and
other mammals. We know virtually all that is needed to elim-
inate canine rabies, but cultural, political, and economic
barriers have prevented implementation. Sustained vaccination
of over 70% of the canine population will control rabies
(WHO, 2013). In order to regularly vaccinate a large canine
population, given their short life spans and rapid reproductive
rates, it must also be managed. Sustainably vaccinating a large
population of stray dogs is difficult, labor intensive, and expen-
sive. This can only be done when societies and governments are
motivated to enforce vaccination laws and reduce stray dog
populations. It requires popular support, funding, legislation,
and energetic enforcement, which are often lacking. WHO
publishes detailed guidelines for human and veterinary profes-
sionals to help control and vaccinate canine populations
(WHO, 2013). However, Hindu and Buddhist countries have
religious and cultural barriers against some current control
measures. These will have to be overcome by developing
a more humane method to control canine populations than
culling and create awareness of responsible pet ownership.
Importance of Animal Vector Control
Thailand has been fortunate and is able to provide PEP at virtu-
ally no cost throughout the kingdom. However, it has been less
Figure 3 Street in Bangkok showing a woman feeding stray dogs.
Note: none of the dogs have collars, suggesting that they have not been
vaccinated.
successful in dog control and vaccination (Figure 3). This has
caused rabies virus to survive among the large number of
community and stray dogs and remains a threat to man
(Figures 10 and 11). Furthermore, dogs, cats, and other
mammalian vectors are occasionally transported from rabies-
endemic regions to rabies-free ones. For example, the introduc-
tion of rabies by Indonesian fishermen to the previously
rabies-free Flores and Bali Islands resulted in rabies outbreaks
with ongoing human deaths. Recreational hunters transported,
unknowingly, rabid raccoons from Florida to hunting reserves
further north. This has led to ongoing rabies outbreaks in
animals and some humans along the East Coast of the United
States and is spreading in Canada and Westwards. To eliminate
rabies expansion through animal transport, strict animal
control measures within countries and at the national borders
must be developed and maintained (WHO, 2013).
Continuing surveillance and oral vaccination of foxes, using
bait-containing vaccine, has virtually abolished fox rabies in
Western Europe. Efforts are being made in North America to
apply this to foxes, skunks, and raccoons. Mass culling of wild-
life, although it reduces the density of vectors transiently, is
ineffective as a long-term solution and widely unacceptable.
Attempts at extensive dog culling as a control measure of
a rabies epidemic, in previously rabies-free and isolated Indo-
nesian islands of Flores and Bali, were failures (Windiyaningsih
et al., 2010; Clifton, 2010). There is no strategy as yet for
controlling rabies in bats and most other wildlife. Funding of
active research in this field is needed but appears to be a low
priority.
Clinical Diagnosis of Rabies
Rabies generally presents in one of two forms, ‘furious’
(Figures 4 and 5) or ‘paralytic’ (Figure 6). Diagnosis of canine
and feline rabies is not difficult when it is in the furious form
(about 70% of cases). Irritability, aggression, increased saliva-
tion, indiscriminate biting of inert objects and damaged and
inflamed oral structures are indicators of this disease. The

Figure 4 A confined furious rabid dog biting indiscriminantly at
the cage.
Figure 5 A cat with furious rabies. Such an animal can inflict incredibly
severe wounds in several people. All will become full-blown cellulitis
within hours which usually responds best to a beta-lactam/beta–
lactamase combination like amox/clav (oral) or ampicillin/sulbactam (IV).
paralytic form of rabies (about 30%) presents diagnostic prob-
lems in dogs, cats, domestic animals, and humans. The clinical
presentation is similar to several other infections such as
distemper in dogs and ascending paralysis in humans. It is
best to start PEP in an exposed person immediately if rabies
is suspected in the responsible mammal. If the suspect dog is
still alive, vaccination can be safely discontinued. Studies in
rabid dogs and cats have shown that they will not survive
longer than 10 days after onset of symptoms (Tepsumethanon
et al., 2004).
The ‘furious’ human form (seen in 70% of cases) is often
initially accompanied by nonspecific symptoms such as
anxiety, fever, headache, muscle aches, or even diarrhea, where
the patient appears and acts quite normally. Characteristic local
symptoms of abnormal sensation (burning itching) at or near
the bitten area can be seen in one-third of the cases (similar
to the cases with paralytic rabies) (Figure 7). This is followed
by the neurological phase, consisting of alternating intervals
of agitation, aggression, and coherent calmness. It may also
Rabies 239
Figure 6 A dog with paralytic rabies. It looks pitiful and several
people can become exposed to saliva, bites, or scratches in attempts to
hand-feed such an animal. Note the dropped jaw.
Figure 7 This anxious looking young man was seen in the emergency
room where he presented with fever, headache, some phobic spasms
and aerophobia. He was bitten by a street dog 18 days earlier and had
PEP without immunoglobulin. At the time picture was taken, he was
fully conscious, frightened and fully understood that he had rabies. He
died suddenly after 3 days. He provided verbal permission for this
picture, and it was obtained and recorded on his medical record.
be accompanied by a feeling of impending doom. Within
a few days, coma ensues with respiratory failure, leading to
rapid demise unless life is prolonged by intensive cardiopul-
monary support. Several cases of humans surviving rabies
have been reported, but they are very rare exceptions. Hydro-
phobic and aerophobic spasms of the neck and diaphragm
may occur intermittently and may not appear together prior
to onset of coma (Figures 8 and 9). Autonomic dysfunction
may start early but usually becomes prominent in the
240 Rabies
Figure 8 Patient with furious rabies. Note the contracted muscles of
neck due to phobic spasms. She was sedated and lived for 2 weeks on
cardiopulmonary support but died of cardiovascular failure. Verbal
permission was obtained from family members to take and use this
picture and this was recorded on her hospital chart.
Figure 9 A near-terminal patient with paralytic rabies. At request of
family, he was not intubated. Permission to take and use this picture
was obtained from his family.
neurological phase with excessive salivation, fluctuating blood
pressure, cardiac arrhythmias, pupillary dysfunction, and
neurogenic pulmonary edema. Hallucinations and seizures
are not common in dog-related cases but are seen occasionally
in bat rabies patients (Hemachudha et al., 2013).
One-third of human rabies cases present as the paralytic
form. The clinical presentation resembles Guillain-Barré
syndrome (GBS). The paralytic form of rabies is difficult to
diagnose without experience and sophisticated laboratory
help. Electrophysiological studies seen in rabies are identical
to those seen in GBS. Efforts to identify the virus or RNA in
saliva, urine, extracted hair follicles, biopsy of skin with hair
follicles, or cerebrospinal fluid may be required to confirm or
exclude rabies. Phobic spasms can only be seen in few paralytic
cases. Survival time is longer in the paralytic form than in the
furious form (mean of 11 vs 5 days). The same dog has been
known to cause a paralytic course in one patient and furious
rabies in another. The mechanism for the different manifesta-
tions is now slowly beginning to be understood. Rabies can
also present in atypical ways, particularly when associated
with bat exposures. Our study, in a rabies infected canine
model, showed that paralytic dogs had statistically less virus
in the brain but more of an immune response than furious
ones (Shuangshoti et al., 2013; Laothamatas et al., 2008).
Rabies must be considered in any patient presenting with
unclear encephalopathy. It is now well documented that as
many as 20% of clinically diagnosed cases of encephalitis
syndrome may exhibit autoimmune pathophysiology which
could be treatable (Saraya et al., 2013). Use of illicit or ‘recrea-
tional’ drugs, medications, or alcohol may mislead clinicians
and delay proper diagnosis. This has led to rabies-associated
organ transplantation (Srinivasan et al., 2005; Maier et al.,
2010). Rapid deterioration to coma suggests rabies but is not
diagnostic. Constant rigidity of muscles is the hallmark of
tetanus. Acute hepatic porphyria can be excluded by history
and appropriate tests. A history of recent animal encounters
(which may be absent in cryptic bat cases or small children),
fever, muscular paralysis with preserved consciousness and
intact sensory function, urinary retention, percussion myoe-
dema, inspiratory spasms, and respiratory failure suggest para-
lytic rabies. It is important to exclude GBS and other
autoimmune causes which could respond to appropriate
therapy (Hemachudha et al., 2013).
Rabies awareness in health-care staff is inadequate in non-
endemic countries. This became evident in the
transplantation-related cases in both Germany and the United
States. One case was diagnosed as drug abuse-related psychosis
and the other as drug intoxication and a possible subarachnoid
hemorrhage. One patient had returned from India but a dog
bite history was disregarded or not known till later. The second
case had been bitten by a bat which was not known till later or
disregarded. They were used as tissue donors for 10 recipients,
of which 7 died of rabies. Interestingly, one of the survivors had
been previously vaccinated against rabies. He had an amnesic
rabies-neutralizing antibody response after the transplantation
and survived (Srinivasan et al., 2005; Maier et al., 2010). The
authors know of a case where an unknown street person was
hit by a truck and arrived at the emergency room of a referral
hospital brain dead. His corneas were transplanted into two
persons. Both died of rabies at the same hospital.
Laboratory Diagnosis
The most sensitive method to diagnose rabies is by examining
tissue. Ante-mortem laboratory diagnosis of rabies in animals
is not recommended as distribution of virus in organs and
fluids may be variable and results may be misleading. Shed-
ding of virus in saliva, spinal fluid, and urine is intermittent
in animals and humans. The sensitivity of the Taq-Man real-
time reverse transcription polymerase chain reaction

(Taq-Man real-time RT-PCR) analysis, using saliva from rabies
confirmed dogs, was 84.6% (55/65) in furious rabies patients
and 84.9% (45/53) in patients with paralytic rabies (Wachar-
apluesadee et al., 2012; Wacharapluesadee and Hemachudha,
2010). Postmortem brain examination, demonstrating rabies
antigen using direct fluorescent antibody (DFA), immunohis-
tochemistry, or molecular tests are the current methods. The
fluorescent antibody test is the current ‘gold standard’ used
in clinical laboratories. There were no false-negative results
in a retrospective and prospective study of 8987 brain impres-
sion smears. The mouse inoculation test was used as a control
in all DFA-negative samples (Tepsumethanon et al., 1997).
Brain tissue, dried on filter paper, can be kept at room temper-
ature for many days for rabies virus RNA detection. Samples
can thus be mailed to a distant reference laboratory. These
techniques are available in many tertiary referral centers and
public health laboratories. To be of clinical relevance, results
must be rapidly available, sensitive, and specific. They can
contribute to decision making for PEP as well as human rabies
case management. In contrast to the above-mentioned
methods, detection of Negri bodies in brain smears or histo-
pathology specimens is neither sensitive nor specific. Knowl-
edge of genetic sequences of rabies virus is useful for
epidemiological surveillance and the study of transmission
and spread dynamics. There are separate identifiable strains
of rabies virus that circulate predominantly in foxes, bats,
and other wildlife.
Rapid ante-mortem laboratory diagnosis in humans is
important for formulating management decisions (Hemachudha
et al., 2013). RT-PCR and other diagnostic molecular techniques
can be performed and produce results within a day. Saliva, cere-
brospinal fluid, urine, and hair follicles should be used simulta-
neously owing to the intermittency of virus secretion. Negative
results require repeat testing when there is a clinical suspicion
of rabies. Brain imaging studies such as computerized tomog-
raphy (CT) or magnetic resonance imaging (MRI) are most useful
in excluding other causes of the clinical picture. This is important
as some of these may be treatable if recognized (Saraya et al.,
2013). In rabies, MRI findings are usually localized to the brain
stem, hippocampus, and hypothalamic regions, but this is not
sufficiently unique to make a specific diagnosis of rabies. During
the early stage of rabies after onset of clinical symptoms, MRI
findings are often normal (Hemachudha et al., 2013). It must
be understood that, where the vast majority of human rabies
occurs, access to sophisticate laboratory or imagined studies is
not available or affordable. Rabies thus largely remains a clinical
diagnosis and is often missed if of paralytic or atypical form.
Medical staff must follow respiratory and body fluid contact
precautions when caring for a rabies patient. This includes the
use of eye and respiratory protection, gowns, and gloves. To
date, there has been no documented case of transmission of
rabies to health-care staff. Several babies delivered by
Caesarean section from symptomatic rabid mothers, with one
exception, remained healthy. Postmortem brain necropsy can
be performed via the superior orbital fissure (inner canthus
of eye), using kidney or liver biopsy needles. Embalming
should be avoided and the body should be placed in a protec-
tive body bag and promptly cremated or securely buried.
Unnecessary handling and washing of bodies by family and
others should be discouraged.
Rabies 241
Postexposure Prophylaxis
The principles of PEP are to vigorously cleanse the bite wounds
as soon as possible with soap and ample water, followed by
application of an antiseptic solution. Washing with water
may decrease the size of virus inoculums, while soap and anti-
septic agents denature the virus, preventing local infection and
early viral replication. This is followed by risk evaluation and
careful infiltration of the bite wounds with human or purified
equine rabies immunoglobulin (RIG). Since it takes 7–10 days
for a neutralizing level of vaccine-induced circulating natural
antibody to form, this may leave enough time for the virus to
invade a peripheral nerve. Once inside nerve cells, it cannot
be reached by circulating antibodies and can travel through
nerve cells centrally to the brain. Passive immunity must there-
fore be provided as soon as possible after the bite. This is done
by injecting rabies immunoglobulin (RIG) into and around the
bite wounds to neutralize virus. This is followed by a course of
tissue culture rabies vaccine (Table 1). Immunoglobulin if
injected intramuscularly at a distant site from the wound is
virtually useless. It will not result in a virus-neutralizing circu-
lating antibody level that would kill virus at a distant bite
site. This was first reported in 1963 (Dean et al., 1963), and
is now part of national guidelines for managing rabies expo-
sures (US-CDC, 2008; WHO, 2010).
Delay in starting PEP must be avoided at all cost. Rabies
incubation periods may be as short as a few days or as long
as years, depending on the site of the bite, host factors, and
size of the viral inoculum. It is safest to initiate PEP immedi-
ately unless a necropsy study of the responsible animal has
Table 1 Guide for rabies PEP
1. A history obtained from a small child may not be provided or is
unreliable.
2. If an apparently healthy dog or cat is from a rabies-free area and is
placed under close observation, it may be justified to delay specific
treatment in some situations. This should only be done in consultation
with veterinarians and local public health experts.
3. Observation applies only to dogs and cats, not to wildlife. Domestic or
wild animals should be euthanized. Their brains should be examined
using appropriate laboratory techniques.
4. RIG is injected into and around bite sites. The patient is usually
undressed to avoid missing small undetected bites.
Exposure: risk category classification Recommended treatment
I. Touching or feeding animal, licks No treatment if reliable history can
over intact skin be obtained
II. Nibbling over uncovered skin, Administer vaccine immediately;
minor scratches, or abrasions stop treatment if dog or cat still
without bleeding, licks on healthy 10 days later or if animal
broken skin examined and found rabies-free
by laboratory tests
III. Single or multiple transdermal Administer RIG and vaccine
bites or scratches, immediately; stop treatment if
contamination of mucous animal remains healthy for
membranes by saliva (licks) 10 days or if animal is
euthanized and found negative
for rabies by appropriate
laboratory tests
Modified from WHO, 2005. WHO Expert Consultation on Rabies, First Report,
Tech No. 931. Geneva.
242 Rabies

Figure 10 The hand of an elderly Thai housewife, bitten by a street

dog that she tried to feed. She required tendon repairs after wound care
and injection of wounds with immunoglobulin and survived.

excluded rabies. There are no contraindications to rabies PEP. Figure 11 Child with multiple dog bites of face head and hands from
It is safe at all ages and during pregnancy for both mother, the a confirmed rabid animal. Small children are often bitten on the head,
fetus in uterus, and infants. Immunocompromized subjects face, trunk, and hands. Children represent almost half of worldwide
may, however, not be able to develop a normal antibody human rabies deaths. The calculated dose of RIG (based on the WHO
response. In these cases, cleansing of the wound and injecting body weight formula) was inadequate to cover all of this child’s
wounds. A decision was made, after discussion and consensus by the
it with RIG is essential (WHO, 2013). An infected wound can
entire Thai Red Cross Animal Bite Clinic staff, to dilute RIG more than
be infiltrated safely with RIG as long as antibiotics are also
three times with saline to enable injection all of the wounds. This was
used to treat bacterial infection, and it is inspected and the first known patient where RIG was diluted prior to use. This prac-
dressed for several days to exclude aggressive and invasive tice was later presented to a WHO Expert Committee and is now part of
bacterial infection (Wilde et al., 1992). Primary suture of the WHO guidelines (WHO, 2010). The child survived. This decision
bite wounds is contraindicated as it may disseminate virus was made without any prior WHO or institutional approval in an emer-
within the wounds. Secondary repair is safe and can produce gency setting.
better cosmetic results. If some suture is unavoidable (Figures
10 and 11), the wounds are first thoroughly cleansed and
infiltrated with RIG, then observed for several hours allowing Table 2 Currently available rabies vaccines
antibody to neutralize virus. Only then are minimal sutures
placed if this is unavoidable. Equine origin RIG preparations Name of Vaccine Abbreviation Available countries a
are now available in most canine rabies-endemic countries. Human diploid cell vaccine HDCV France, Germany,
Consultation with an expert is mandatory when unusual India
problems are encountered. Some unusual problems may Purified vero cell rabies PVRV France, India, Columbia,
include marked delay in seeking treatment, prior incomplete vaccine China
PEP, exotic animals, exposure by sexual contact with an early Purified chick embryo cell PCEC Germany, India, Japan
rabies symptomatic partner and others. A vaccine history of vaccine
the responsible dog is not an absolute justification for not Purified duck embryo PDEV India
providing PEP to a bite victim; unless the vaccination has vaccine
Purified hamster kidney PHKC China, Russia, Central
been thoroughly documented and more than one annual
cell vaccine Asian Republics
dose of vaccine had been administered PEP is costly and is
often carried out in a substandard manner. Table 2 lists a
Different trade names are used with rabies vaccines in different countries and
current WHO-recognized vaccines, which are now either regions.
tissue or avian culture products. Rabies vaccines are
now being manufactured in India, Thailand, China, South
America, and the Russian Federation.
2. The abbreviated US-CDC intramuscular Essen Regimen
WHO has approved four postexposure vaccine schedules
Consists of abolition of the dose on day 28
using tissue or avian culture vaccines (WHO, 2010). These are:
Four clinic visits in 2 weeks
1. The original intramuscular Essen Regimen 3. The intramuscular Zagreb (or 3-1-1) Regimen
Consists of one intramuscular full-dose injection into Consists of two full-dose intramuscular injections into
deltoid or lateral thigh muscles on days 0, 3, 7, 14, deltoid or lateral thigh muscles on day 0 and one
and 28 dose each on days 7 and 21
Five clinic visits in 1 month Three clinic visits in 3 weeks
 Rabies 243

4. The Thai Red Cross Intradermal Regimen often reluctance to inject the wounds. This is just one more
Consists of two injections of 0.1 ml of any WHO- argument for promoting PREP for some travelers to endemic
recognized tissue culture vaccine at two different countries (Bilagumba et al., 2013). Pre-exposure prophylaxis
lymphatic drainage sits on days 0, 3, 7, and 28 (PREP) is therefore recommended for certain travelers,
Four clinic visits in 1 month workers in occupations who are likely to come in contact
with infected animals and laboratory workers who are poten-
Intramuscular injections of vaccine must be administered
tially exposed to Lyssaviruses. One study from Thailand
in the deltoid or lateral thigh regions, avoiding the fat of
showed that 9% of tourists had close canine contacts, suggest-
gluteus muscles. Intradermal vaccines are injected into arms
ing that pre-exposure vaccination of tourists to endemic
or legs. In some Asian countries, women may refuse exposing
regions should be more widely considered. Recent studies
their legs, and intradermal injections are then given in the
have demonstrated that immunity following WHO-
sub-scapular region (personal communication from SN
recommended tissue culture vaccination is very long-lasting.
Madhusudana, Bangalore). The appearance of a split-skin
Neutralizing antibodies can be detected as long as two
‘bubble’ at the injection site (as in tuberculin testing) demon-
decades after completing a PREP or PEP series (Suwansrinon
strates a successful intradermal and not inadvertent subcuta-
et al., 2006). Booster injections then result in an accelerated
neous administration. If it fails, repeat the injection.
antibody response, appearing within less than 1 week and
Reduced-dose intradermal PEP (schedule three) decreases
before endogenous antibodies appear in circulation. WHO
the cost of vaccine and is used in rabies control clinics of
recommends one intramuscular or intradermal booster injec-
several countries. Many studies have shown equivalent immu-
tion on days 0 and 3 in an individual who has experienced
nogenicity and efficacy (WHO, 2010). WHO-recognized
a possible rabies exposure after having had a reliable history
tissue culture vaccines have excellent safety records. Adverse
of PREP or PEP with a WHO-recognized tissue culture rabies
reactions with tissue culture vaccines are minor and equiva-
vaccine. An alternate method is to administer intradermal
lent to those seen with Expanded Programs for Immunisation
injections of 0.1 ml vaccine at four sites (deltoids and lateral
(EPI) vaccines. Erythema, discomfort, and itching at injection
thighs) in one sitting (WHO, 2010). This saves clinic costs
sites as well as mild regional lymphadenopathy have been re-
and travel time. Laboratory scientists at risk of rabies, such
ported. Mild transient fever, headache, and malaise are also
as those working with potentially rabid animals or live virus,
seen. Human diploid cell rabies vaccine (HDCV) may cause
are still advised to have either periodic antibody titer determi-
mild serum-sickness-like reactions in individuals who have
nations or a booster every 5 years. One reason for this is that
had a prior rabies series and are later given frequent boosters.
they may encounter unusually high levels of virus inoculums
These are not due to the viral component of the vaccine and
that may overwhelm a low antibody level. One such case
are self-limited.
occurred in a laboratory scientist in New York, but the patient
Vaccination alone will protect the majority of exposed
survived a stormy course with lasting disability. Some diplo-
patients, but it is not possible to predict which victim will
matic missions, nongovernmental organizations, military,
die if not given passive immunization by infiltrating RIG
and UN teams recommend PREP for some of their staff
into and around bite wounds. The provision of passive
when transferred to rabies-endemic countries. This is particu-
immunity to protect exposed patients during the first critical
larly important for small children who may not report an
days can be life saving. Patients with facial, head, and hand
animal contact. Many canine-endemic countries are failing
bites are at the highest risk of death. They represent
to control dog rabies. Since children represent half of rabies
a priority group if immunoglobulin is in short supply
deaths, this has led to suggestions to include rabies vaccine
(Wilde et al., 2012; Figure 11). The original crude equine
as part of the childhood EPI in high-risk regions. Cost–benefit
rabies antisera had a bad reputation for serum sickness
considerations and priority of funds for other vaccinations
and anaphylaxis. The current highly purified equine rabies
have, however, prevented implementation.
immunoglobulins (ERIG) have an acceptable safety margin,
causing only 1–3% relatively transient serum sickness reac-
tions, depending on the product and batch. The risk for
Management of Human Rabies
anaphylaxis, by using purified equine immunoglobulin is
approximately the same as with penicillin and other beta-
Treatment of human rabies was the subject of a Canadian and
lactams. Human rabies immunoglobulin (HRIG) is effective
US CDC-sponsored conference in Toronto in 2002. The expert
and virtually reaction free. It is, however, in short supply,
consensus was that only comfort care should be provided, given
expensive, and usually not available in canine-endemic
the uniformly fatal prognosis. Intensive curative efforts should
countries. Immunoglobulin is used as soon as possible after
be reserved for a time when promising new technologies
exposure and never after day 7 following start of rabies
become available. There are, as yet, no known effective antiviral
vaccine as it may then interfere with the patient’s normal
agents against Lyssaviruses. However, the survival of a 15-year-
immune response.
old girl, bitten by a bat who had not received PEP, has created
hope that we might have a cure. Treatment for her consisted
Pre-exposure Vaccination of intensive cardiopulmonary and metabolic support with ket-
amine and benzodiazepine sedation as well as ribavirin. This
Human and equine rabies immunoglobulins are not available patient was unusual in that she had neutralizing antibodies
in some regions of rabies-endemic countries, and PEP is often on admission in both serum and spinal fluid and no demon-
not carried out to WHO standards, even if available. There is strable viable virus or viral RNA (Willoughby et al., 2005).
244 Rabies
Her case was similar to another survivor, a 6-year-old boy
(reported in 1972), who had a bat bite and early antibodies
in serum and spinal fluid. He was treated with supportive care
only and made a virtually complete recovery Virus could not
be isolated. Both children were infected with bat-derived
viruses. They could have been of less virulence or both young
subjects may have managed to mount an unusually rapid and
effective immune response that controlled the infection. By
way of example, we treated a rabies patient who received the
coma induction regimen; as reported in the Milwaukee
Protocol. He never developed neutralizing antibodies, and
died of multisystem failure on the 8th hospital day. Ample viral
RNA was identified repeatedly throughout his hospital course
(Hemachudha et al., 2006).
About 25% of our other over 100 dog- or cat-related human
rabies deaths developed serum-neutralizing antibodies regard-
less of the form of rabies and received only supportive care.
However, none had neutralizing antibodies in CSF, the pres-
ence of which correlates with rare survival in dogs (Gnanadurai
et al., 2013). Similar coma-induction regimens have now been
applied to patients in the United States, Europe, South Amer-
ica, Asia, Africa, and Canada without success. We conclude
that every rabies patient deserves supportive as well as comfort
care. There are no antirabies drugs, shown to be promising in
animal studies, available at this time. The patient’s clinical
status should therefore not be compromised further by using
potent drugs that have not demonstrated experimental
evidence of efficacy. Patients who exhibit rabies antibody titers
on admission, and particularly in spinal fluid (Gnanadurai
et al., 2013), should be transferred to a tertiary care hospital,
wherever possible, and receive optimal supportive intensive-
care management.
Acknowledgments
This research was supported by a Research Chair Grant from the
National Science and Technology Development Agency (NSTDA),
Thailand, received by Prof. Thiravat Hemachudha, MD, FACP and
Dr. Supaporn Wacharapluesadee.
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Relevant Websites
http://www.rabiescontrol.org – Alliance for Rabies Control.
http://www.cdc.gov/rabies – Centers for Diseases Control, Rabies.
http://www.soonak.com/AIRE.htm – Software to Assist with the Diagnosis of Rabies.
http://www.who.int/globalatlas/default.asp – WHO, Global Health Atlas.
http://www.who.int/rabies – WHO, Human and Animal Rabies.
http://www.who.int/rabnet – WHO, Rabnet, Rabies, Information Mapping System.
http://www.who.int/zoonoses – WHO, Zoonoses and Veterinary Public Health.