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Review Article

Rabies: An overview
Tarun Kumar Dutta

Department of Clinical Hematology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry, India

ABSTRACT

Rabies is a fatal disease caused by rabies virus, a neurotropic virus and a prototype of Lyssavirus of Rhabdoviridae family.
It is transmitted to human beings through infected saliva of dogs and cats during bite. Dog is the cause of more than
90% of human rabies in India. The incubation period is 4-8 weeks (but it may vary from 5 days to 7 years). There are
two clinical types of rabies – encephalitic (furious) and paralytic (dumb) types. In the encephalitic (furious) form, the
principal malfunction is in the brain stem and limbic system. Patient has hydrophobia in the full-blown form, but the mind
remains clear till the end. Death occurs within a week after the onset of symptoms. Paralytic rabies resembles Guillain–
Barre syndrome. Diagnosis is mostly clinical. However, direct fluorescent antibody test is used to identify the antigen in
skin biopsy from the nape of neck. In the postmortem specimen, demonstration of Negri bodies in the brain confirms the
diagnosis. Anti-rabies vaccine is used for pre- and post-exposure prophylaxis. The commonly used intramuscular (IM)
regimen is being superseded by intradermal (ID) vaccine because it makes the treatment economical. Whereas touching
of animal or lick on intact skin does not require vaccination, any transdermal bite with bleeding requires immediate
administration of rabies immunoglobulin (RIG) and simultaneous vaccination with a tissue culture vaccine (TCV). Minor
abrasion without bleeding may require only vaccination and no RIG. Rabies human monoclonal antibody (RMAb) is the
newest entry in the prophylaxis of rabies which may ultimately replace RIG. Prognosis is grave since there are just six
reports of survivors. Treatment is mainly palliative with heavy sedation and/or therapeutic coma (Milwaukee protocol).

Key words: Intradermal vaccine, intramuscular vaccine, post-exposure prophylaxis, pre-exposure prophylaxis, rabies

INTRODUCTION skunks, jackals, etc., which are the main reservoirs

and transmitters of rabies.[1] These animals maintain
Rabies is a fatal disease of nearly worldwide distribution a cycle among them and transmit the disease to dogs
that is caused by a filterable neurotropic virus present and domestic animals. Humans may contract rabies by
in the saliva of the infected animals and transmitted to intrusion into the wild-life cycle of rabies. Bat rabies
humans through their infected saliva. occurs in certain Latin American countries where the
vampire bat serves as an important host and vector for
Urban rabies is propagated chiefly by unimmunized
rabies. In the USA, insectivorous bats and wild animals
domestic or street dogs and cats. Street virus is the
natural virus present in rabid animals. Wild-life or are the most important vectors at present.
sylvatic-type rabies is propagated by wolves, foxes,
The source of infection in humans is the saliva of rabid
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animals. Domestic dog is the cause of more than 90% of
Quick Response Code:
human rabies in India. Dogs also infect cats and other
Website: domestic species.
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Rabies-free countries are Australia, New Zealand,

DOI: Japan, Taiwan, Hong Kong, Singapore, Fiji, UK, Ireland,
10.4103/2349-4220.147998 Norway, Sweden, Jamaica, and Barbados. In India, the
islands of Andaman and Lakshadweep are rabies free.
Address for correspondence: Prof. Tarun Kumar Dutta, Department of Clinical Hematology, Jawaharlal Institute of Postgraduate Medical Education and
Research, Puducherry - 605 006, India. E-mail: [email protected]

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Dutta: Rabies: An overview

EPIDEMIOLOGY It may be of two types:

• Encephalitic type (furious rabies) — observed in the
The true incidence is unknown. In India, the estimated majority of cases
mortality is 25,000 to 50,000 deaths per year. Recent • Paralytic type (dumb rabies) — observed in about
figures in China show less than 1000 cases per year. In 20% of cases
Bangladesh, about 2000 deaths and in Nepal, about 200
deaths occur per year. Only 0.01% cases of human rabies Encephalitic type (furious rabies)
occur in the temperate zones. The onset is usually sudden. But prodromal symptoms
are noted for 2–3 days before the hydrophobic syndrome
AETIOPATHOGENESIS appears. Only a proportion of people bitten by a rabid
animal develop the disease, but once manifested, the
Rabies virus is the prototype of the genus Lyssavirus of disease is almost invariably fatal. Specific prodromal
the large family of Rhabdoviridae. It is a bullet-shaped features include paresthesias and itching over the
virus containing a single-strand of ribonucleic acid healed bite wound scar. Other features are fever,
(RNA) combined with nucleoprotein that forms a helical headache, tachycardia, anxiety, insomnia, restlessness,
coil. The virus is rapidly inactivated by heat. At 56°C, and myalgias. After 2–3 days, the stage of excitement
the half-life is less than 1 min. The lipid coat is disrupted supervenes. There is mental excitement, restlessness,
by 1% soap solution. hyperesthesia, and hydrophobia. Hyodrophobia
consists of sudden spasm of muscles of the mouth,
Humans are infected by inoculation of virus-laden saliva pharynx, larynx, and the whole of the respiratory
by the bite of a rabid dog or animal. Licking on abraded musculature, particularly the diaphragm and muscles
skin or mucus membrane may also result in infection. of inspiration. The attack can be induced by offering
Scratching by claws can also cause infection. The virus water to patients. As the glass of water approaches the
cannot enter through intact skin. mouth, typical spasmodic jerks with violent contraction
of diaphragm and other inspiratory muscles occur
The rabies virus travels in the nerves and is carried and water is ejected from the mouth. Afterward, the
centripetally by the flow of axoplasm to the dorsal sight and even the sound of water may provoke the
root ganglion. It multiplies further in the dorsal root distressing spasm. In the later stage, a wide number
ganglion and causes characteristic prodromal symptoms of stimuli like sudden sound, strong lights, and even
and paresthesias at the site of inoculation. From there the suggestion of water may induce the attack. Cold
it travels to the brain, where massive viral replication air or blowing of air due to fan may also induce an
occurs. Then the virus migrates along the efferent nerves attack (aerophobia). The mind remains clear during
to almost every organ such as adrenal medulla, cornea, the intervals. Hallucinations, delusions accompanied
pancreas, nerve twiglet of the hair follicle, and salivary by biting, mania, and spitting may develop later. There
gland, and this leads to virus shedding in the saliva. is malfunction of brain stem, limbic system, and higher
Virus may also be shed in milk and urine. centers.

At autopsy, widespread infection is usually found in the Death occurs within a week after the onset of symptoms.
brain, particularly in the brainstem, hippocampus, and
basal ganglia. Congestion of blood vessels of the central Paralytic type (dumb rabies)
nervous system (CNS) and petechial hemorrhages of It characteristically occurs in bat-transmitted rabies.
the pia-arachnoid are found. Histological examination It also occurs in partially vaccinated persons. Patient
shows perivascular cellular infiltration of lymph spaces. presents with flaccid paralysis. It resembles Guillain–
Negri bodies can be detected within the cytoplasm Barre syndrome.[2] The stage of excitement is absent. In a
of nerve cells as round or oval eosinophilic inclusion few days, paralysis may ascend to involve the respiratory
bodies, particularly in the hippocampus and Purkinje muscles. There is fever and profuse sweating.
cells of the cerebellum. Negri bodies are also found in
the brain of more than 95% of rabid animals.[1] The patient has a comparatively longer survival.

CLINICAL FEATURES DIAGNOSIS

Incubation period is usually 4-8 weeks, but may vary Diagnosis is confirmed by virus isolation, identification
from 5 days to 7 years. Face, neck, and head bites of antigen, and detection of antibodies.[3] Virus culture
which are close to the CNS have a shorter incubation is positive in the first week from saliva, throat swab, eye
period. swab, and cerebrospinal fluid (CSF).
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Dutta: Rabies: An overview

Antigen detection Milwaukee protocol[4]

Direct fluorescent antibody test is used to identify the antigen In September, a 15-year-old girl developed features of
in skin biopsies taken from the nape of the neck, where rabies 37 days after being bitten by a bat on her finger.
hair follicles are highly innervated. It is a sensitive test and In an attempt to treat the patient, doctors placed her on
positive results are found in 60-100% cases. The corneal induced coma and gave ketamine, midazolam, ribavarin,
smear test is not so sensitive and false-positive results occur. and amantadine. After 31 days of intensive care, the
patient recovered, but had some neurological deficits like
Antibody detection inability to walk and maintain balance. She became the
Seroconversion occurs during the second week of illness first case of rabies who survived without being vaccinated.
in unvaccinated patients. Antirabies antibody detection
in serum and CSF confirms the diagnosis. This original Milwaukee protocol has undergone several
modifications and out of 25 patients thus treated, only
Negri body detection 2 have survived.
The offending animal is captured (if possible) and
humanely killed for demonstration of Negri bodies in PROPHYLAXIS
the brain. Fluorescent antigen can also be detected in
the animal’s brain, and confirms the diagnosis of rabies. Rabies vaccine can be used for pre-exposure prophylaxis
(PrEP) as well as post-exposure prophylaxis (PEP).
DIFFERENTIAL DIAGNOSIS The commonly used regimen of intramuscular (IM)
administration (1 ml) of vaccine is being superseded
This includes other causes of encephalitis or bulbar by intradermal (ID) vaccination, which requires lesser
paralysis (including post-vaccinal encephalomyelitis), quantity of vaccine (0.1 ml) and is equally effective.[5]
Guillain–Barre syndrome, and hysterical pseudorabies.
Post-exposure prophylaxis
PEP is begun immediately after an exposure. Before
TREATMENT initiating anti-rabies treatment, one should establish the
category of the animal bite [Table 1]. This categorization
Once symptoms develop, only palliative treatment helps in deciding the future course of action.[3] In addition,
is possible. Seizures should be controlled by heavy tetanus toxoid and proper antibiotics should be used.
sedation. Diazepam 10 mg, six hourly, supplemented by
chlorpromazine 50 mg, if necessary, can be used to control PEP consists of a regimen of one dose of immunoglobulin
seizures. Fluid balance and nutrition must be maintained (passive immunization) and five doses of rabies vaccine
by intravenous route. Airway and oxygenation should over a period of 28 days. Vaccines should be given
be maintained. On rare occasions, partially immunized intramuscularly. Alternatively, vaccine can be given
patients survive due to extensive intensive care. To date, intradermally also. Human rabies immunoglobulin
there are six survivors of rabies including one 6-year-old (RIG) should be infiltrated around the wound and
girl from India, the majority with some neurological any remaining portion should be administered
sequelae. Induced coma (Milwaukee protocol) has been intramuscularly, preferably in the gluteal region.
found useful in some cases. Alternatively, equine immunoglobulin 40 IU/kg may

Table 1: WHO classification of wounds

Recommended Type of contact with a suspect or confirmed Type of Recommended post-exposure prophylaxis
post-exposure rabid domestic or wilda animal, or animal exposure
prophylaxis category unavailable for testing
I Touching or feeding of animals Licks on intact skin None None
II Nibbling of uncovered skin Minor scratches or Minor Administer vaccine immediatelyb
abrasions without bleeding Stop treatment if animal remains healthy
throughout an observation period of 10 daysc or
if animal is proven to be negative for rabies by
a reliable laboratory using appropriate diagnostic
techniques
III Single or multiple transdermal bites or scratches, Severe Administer rabies immunoglobulin and vaccine
licks on broken skin, contamination of mucus immediately. Stop treatment if the animal
membrane with saliva (i.e. licks), exposures to batsd remains healthy throughout an observation
period of 10 days
a
Exposure to rodents, rabbits, and hares seldom, if ever, requires specific anti-rabies post-exposure prophylaxis, bIf an apparently healthy dog or cat in or from a low-risk area is placed under observation,
the situation may warrant delaying initiation of treatment, cThis observation period applies only to dogs and cats. Except in the case of threatened or endangered species, other domestic and wild animals
suspected as rabid should be humanely killed and their tissues examined for the presence of rabies antigen using appropriate laboratory techniques, dPost-exposure prophylaxis should be considered when
contact between a human and a bat has occurred unless the exposed person can rule out a bite or scratch or exposure to the mucus membrane

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Dutta: Rabies: An overview

be administered. Equine immunoglobulin is cheaper, Vaccines

but the incidence of serum reactions is more. PVRV — Verorab, Aventis Pasteur (Sanofi Pasteur India
Pvt. Ltd.)
IM regimen PCECV — Rabipur, Chiron Behring Vaccines Pvt. Ltd.
There are currently four types of vaccines available, PVRV — Pasteur Institute of India, Coonoor, India
and the regimen most commonly used in India for IM PVRV — Abhayrab, Human Biologicals Institute
administration is described below:
DCGI has recommended the updated Thai Red Cross
Vaccines 2-2-2-0-2 schedule of ID vaccination, which is as follows:
1. Tissue culture vaccines
i. Human diploid cell vaccine (HDCV): One Dose: One ID dose = 0.1 ml
dose – 1 ml (IM) Day 0 3 7 28
ii. Purified chick embryo cell vaccine (PCECV): One ID sites X2 X2 X2 X2
dose – 1 ml (IM)
iii. Purified Vero cell rabies vaccine (PVRV): One
dose – 0.5 ml (IM)
2. Purified duck embryo vaccine (Vaxirab): One This involves injection of only 0.1 ml of reconstituted
dose – 1 ml (IM) vaccine per ID site and the vaccination has to be given at
Regimen: Essen schedule (standard WHO five-dose two different sites on a single visit (one on each deltoid area,
IM regimen) – The course for PEP should consist of an inch above the insertion of deltoid muscle) on days 0,
IM administration of five injections on days 0, 3, 7, 3, 7, and 28, using a 1-ml insulin syringe. A bleb formed
14, and 28. after injection is a sign of successful ID administration. It is
best used in anti-rabies clinics for group vaccinations (for a
Dose: One IM dose into deltoid minimum of 10 persons at a time) because the contents of
Day 0 3 7 14 28 a broken ampoule of 1 ml have to be used within 8 h and
the requirement for a single person on a single visit will be
just 0.2 ml and the rest will thus go waste.

Human rabies immunoglobulin (20 IU/kg) ID vaccination is not indicated in patients

with immunocompromised states or those on
The sixth dose is optional and given to individuals who immunosuppressants like chloroquine or prednisolone.
are immune deficient. Day 0 indicates the date of first They should take full dose of IM injections.
injection.
Wound treatment
Vaccines are ideally given in the deltoid region, and may Wound treatment is the most important part of treatment
be given in antero-lateral part of the thigh for children. and should begin immediately. It minimizes the viral
load. Wound should be thoroughly cleaned with soap
ID regimen and water. Povidone iodine or 70% alcohol should be
ID recommendation by WHO is a newer attempt to have used to irrigate the wound. Suturing of the wound is to
effective antibody titers against rabies with a lower total be avoided. Bites of rats, mice, rabbits, and guinea pigs
requirement of vaccine. The principle that allows ID do not require anti-rabies PEP.
vaccination to be effective at a lower dose is that it may be
due to the better response to an equal volume of antigen Pre-exposure prophylaxis
which is placed in contact with Langerhans cells of the PrEP is recommended for animal handlers and laboratory
epidermis and because of multiple sites of vaccination at workers dealing with rabies virus. PrEP consists of three
the same time to obtain maximum drainage of antigen- doses of rabies vaccine given either intramuscularly or
presenting cells to the lymph nodes. intradermally on days 0, 7, and 21.

On the basis of the recommendations on ID PROGNOSIS

administration of rabies vaccine by WHO and reports of
safety, efficacy, and feasibility trials conducted in India, The prognosis of rabies encephalomyelitis is grave. At
the Drug Controller General of India (DCGI) approved the time of the bite, before the virus has invaded the
the use of reduced dose ID vaccination in 2006. nervous system, correct and prompt cleansing of the
wound and proper post-exposure immunization reduce
The following vaccines are currently approved by DCGI the risk of development of rabies from 50% to less than
for use by ID route: 5%. The risk is highest following head bites. Interposition
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Dutta: Rabies: An overview

of clothing, extent of tissue laceration, and immediate 3. Sudarshan et al. have found more compliant “new 1
local treatment modify the prognosis. week ID regimen” equally effective as the conventional
4 week ID regimen. Patients in this trial received PCECV
RECENT ADVANCES or PVRV at four sites on days 0, 3, and 7 (4-44).[11]

1. It has been now possible to achieve active REFERENCES

immunization with four doses of tissue culture
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London: Saunders Elsevier; 2009. p. 799-814.
2. Fully human monoclonal antibodies (mAbs) have 2. Dutta TK, Ghotekar LH, Sahoo RK. Rabies — an update. In: Gupta
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comparable with the results obtained with HRIG. PN, Thiagarajan D, Srinivasan VA. Human monoclonal antibody
Furthermore, the MAb cocktail did not interfere with and vaccine approaches to prevent human rabies. Curr Top
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8. de Kruif J, Bakker AB, Marissen WE, Kramer RA, Throsby M,
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hRIG combined with vaccine. Results showed that release date: 2012 Aug 7.
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to conduct the current trial.[10] Source of Support: Nil, Conflict of Interest: None declared.

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Dutta: Rabies: An overview

Multiple Choice Questions

1. Following countries are rabies-free EXCEPT
a. Australia
b. New Zealand
c. USA
d. Japan
2. Rabies virus is rapidly inactivated by all of the following EXCEPT
a. Heat
b. Soap solution
c. Plain water
d. Alcohol
3. In USA, the most important vector for rabies transmission currently is which of the following
a. Bats
b. Domestic dog
c. Domestic cat
d. Squirrel
4. Rabies is identified by
a. Guarneri bodies
b. Negri bodies
c. Cowdry A bodies
d. Cowdry B bodies
5. Incubation period for rabies is usually
a. 48 hours
b. One week
c. One month
d. One year
6. Which out of these is a feature of rabies
a. Aerophobia
b. Itching around site of bite
c. Conjunctival congestion
d. All of the above
7. Early prophylactic treatment for head and neck bite with bleeding is all of the following EXCEPT
a. Suturing the wound
b. Human rabies immunoglobulin
c. Tissue culture vaccine (TCV)
d. Tetanus prophylaxis
8. All are features of dumb (paralytic) rabies EXCEPT
a. May mimic Guillaine Barre syndrome
b. Patient may rarely survive with ICU management though with sequelae
c. Patient is violent
d. Patient usually would have received incomplete rabies prophylaxis
9. Which of the following statements about rabies is UNTRUE
a. Tissue culture vaccine is better than nerve tissue derived Semple vaccine
b. Preferred site of inoculation of TCV is gluteal region
c. Intradermal and intramuscular routes of administration are equally effective in an immunocompetent individual
d. Human rabies immunoglobulin should be locally infiltrated maximally
10. All of the following about pre-exposure prophylaxis are true EXCEPT
a. Should be given to high risk animal handlers
b. Dosage schedule includes three doses on day 0, 7 and 21
c. Should never be performed with intradermal administration of vaccine
d. Booster dose should be taken when rabies neutralizing antibody titre falls below 0.5 IU/ml (after testing every two years)
Key to multiple-choice questions
1. c, 2. c, 3. a, 4. b, 5. c, 6. d, 7. a, 8. c, 9. c, 10. c

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