Rabies

More than 3 billion people are at risk of rabies in over 100 countries. Rabies is responsible for
approximately 60,000 fatalities annually worldwide, with India accounting for approximately
one third of cases.
Rabies is primarily a disease of animals.The epidemiology of human rabies reflects both the
distribution of the disease in animals and the degree of human contact with these animals. A
summary of major rabies vectors is provided in Table 158-1:

Worldwide, greater than 99% of human rabies cases are acquired by dog bite.

Rabies virus is the prototype member of the genus Lyssavirus. All lyssaviruses are adapted to
replicate in the mammalian CNS, are transmitted by direct contact, and are not associated
with transmission by or natural replication in insects.
Viral infection of the salivary glands of the biting animal is responsible for the infectivity of
saliva. After a bite, saliva containing infectious rabies virus is deposited in muscle and
subcutaneous tissues. The virus remains close to the site of exposure for the majority of the
long incubation period (typically 20 to 90 days). Rabies virus binds to the nicotinic
acetylcholine receptor in muscle, which is expressed on the postsynaptic membrane of the
neuromuscular junction. Subsequently, the virus spreads across the motor end plate and
ascends and replicates along the peripheral nervous axoplasm to the dorsal root ganglia, the
spinal cord, and the CNS. Following CNS replication in the gray matter, the virus spreads
outward by peripheral nerves to virtually all tissues and organ systems
Histologically, rabies is an encephalitis, resulting in infiltration of lymphocytes,
polymorphonuclear leukocytes, and plasma cells, and focal hemorrhage and demyelination in
the gray matter of the CNS, the basal ganglia, and the spinal cord. Negri bodies, in which
CNS viral replication occurs, are eosinophilic intracellular lesions found within cerebral
neurons and are highly specific for rabies. Negri bodies are found in about 75% of proven
cases of animal rabies. Although their presence is pathognomonic for rabies, their absence
does not exclude it

Transmission of rabies virus usually begins when the contaminated saliva of an infected host
is passed to a susceptible host, usually by the bite of a rabid animal. Of note, the bite of a
bat may escape notice; human rabies cases with no known animal exposure are most
commonly attributed to bats. Other, less common routes of documented transmission include
contamination of mucous membranes (i.e., eyes, nose, mouth), aerosol transmission during
spelunking (caving) in bat-infested caves, exposure while working in the laboratory with
rabies virus, and infected organ transplantation (e.g., cornea, liver, kidney, vascular graft,
lung)

Preexposure prophylaxis with rabies vaccine is highly recommended for persons whose
recreational or occupational activities place them at risk for rabies (Table 158-3).
Preexposure vaccination does not eliminate the need for additional therapy after a rabies
exposure but simplifies postexposure prophylaxis by eliminating the need for human rabies
immunoglobulin (HRIG) and by decreasing the number of doses of vaccine required

A)RISK ASSESSMENT
The risk of developing rabies following a bite or scratch by a rabid animal depends on
whether the wound was a bite, scratch, or nonbite exposure; the number of bites; the depth of
the bites; and the location of the wounds (Table 158-4).

The distinction between a “provoked” and “nonprovoked” attack should not be used for
risk assessment.
Most animal bites are “provoked” from the standpoint of the animal (e.g., interfering with the
animal’s food, offspring, feeding habits). In addition, approximately 15% of animals with
rabies do not exhibit aggressive behavior but are apathetic (“dumb rabies”). The local health
department can provide information about the epidemiology of animal rabies in the area.
Evaluation for postexposure prophylaxis is indicated for persons bitten by, scratched by,
or exposed to saliva from a wild or domestic animal that could be rabid (Figure 158-1).
Give postexposure prophylaxis as soon as possible after exposure to rabies-prone wildlife
(Tables 158-5 and 158-6).
1)Bites:

For the purpose of rabies postexposure prophylaxis, a bite exposure is defined as any
penetration of the skin by the teeth of an animal. Bites to the face and hands carry the
highest risk, but the site of the bite does not influence the decision to begin therapy.

2)Nonbite Exposures:

A nonbite exposure is contamination of scratches, abrasions, open wounds, or mucous

membranes with saliva or brain tissue from a rabid animal. For example, animal licks to
nonintact skin have transmitted rabies. Nonbite exposures from animals very rarely cause
rabies. If the material containing the virus is dry, the virus can be considered noninfectious.
Petting a rabid animal or contact with blood, urine, or feces (e.g., guano) of a rabid
animal does not constitute an exposure and is not an indication for prophylaxis.

3)Exposures to Animals Previously Vaccinated for Rabies:

A fully vaccinated dog or cat (i.e., two vaccinations) is unlikely to become infected with
rabies. No documented vaccine failures have been reported in the United States among dogs
or cats that received two vaccination

4)Exposures to Bats:

Any direct contact between a human and a bat should be evaluated for a rabies exposure.
Seeing a bat does not constitute an exposure. Postexposure prophylaxis is not indicated if
the person can be certain that a bite, scratch, or mucous membrane exposure did not occur or
if the bat is available for testing and results are negative for the presence of rabies virus.

5)Bites From Healthy-Appearing Animals:

The Centers for Disease Control and Prevention recommends that a healthy dog, cat, or
ferret that bites a person be confined and observed for 10 days. At the first sign of illness
during confinement, such animals should be evaluated by a veterinarian and a report
immediately made to the local health department. If signs suggestive of rabies develop, the
animal should be euthanized and its head removed and shipped under refrigeration (not
frozen) for examination of the brain by a qualified laboratory designated by the local or state
health department. But if not able to confine and observe animal ,start immediate
Postexposure prophylaxis.
6)Bites From Stray Animals:

Any stray or unwanted dog, cat, or ferret that bites a person may be euthanized immediately
and the head submitted for rabies examination. Animals that might have exposed a person to
rabies should be reported immediately to the local health department.

7)Person-to-Person Transmission:

There are anecdotal reports of person-to-person transmission of rabies. Fluids from the upper
and lower respiratory tracts of humans frequently test positive for rabies virus. Despite the
lack of proven healthcare-associated transmission, about 30% of healthcare personnel who
have had contact with a human diagnosed with rabies have received postexposure
prophylaxis. Given the mechanism of disease transmission and concern among healthcare
workers, contact isolation precautions should be used for patients with known or suspected
rabies, and healthcare workers who care for such patients should wear either masks and eye
protection or face shields. Healthcare personnel with nonintact skin or mucous membrane
exposure to infective saliva or neural tissue from patients with rabies should receive
postexposure prophylaxis.

B)WOUND CARE

First, assess wounds for the presence of a life-threatening condition, such as arterial laceration
or pneumothorax.Provide proper wound care, including tetanus prophylaxis, wound
cleansing with soap and water( rubbing at least for 10min) and (if available) a dilute
solution of povidone-iodine (1 mL povidone-iodine in 9 mL of water or normal saline),
antibiotics (if indicated) to prevent bacterial infection and rabies prophylaxis as indicated

Wound cleaning markedly decrease viral load in the site of bite .

C)POSTEXPOSURE PROPHYLAXIS TREATMENT

In the United States, postexposure prophylaxis consists of a regimen of one dose of HRIG
and four doses of rabies vaccine over a 14-day period, except for immunocompromised
persons, who should receive a five-dose series of vaccine over a 28-day period (Table 158-
7).

The shift from a five-dose to a four-dose series of rabies vaccine occurred in 2010 and is
based on rabies virus pathogenesis, experimental animal studies, clinical trials, epidemiologic
surveillance, and economic analyses.
HRIG and the first dose of rabies vaccine should be given as soon as possible after exposure,
preferably within 24 hours. If HRIG was not administered when vaccination was begun,
it can be administered up to 7 days after administration of the first dose of the vaccine.
Note: that rabies vaccine should never be administered in the gluteal area; only the deltoid
or anterolateral thigh (for younger children) is acceptable.

Avaliable forms of HRIG in your country ( 2ml or 10ml ampoules , that consist from
150unit /ml or 300unit/ml), Dose of HRIG is 20IU/kg single dose .

1)Rabies Vaccines:

Rabies vaccines available include human diploid cell vaccine (produced in human diploid
cells; Imovax®, Sanofi Pasteur, Lyon, France) and purified chick embryo cell culture vaccine
(produced in chick embryo cells; RabAvert®, Novartis Vaccines, Emeryville, CA).

Available forms in your country ( ampoule contain 1ml ), dose : 1ml (in deltoid area) one
dose in days 0,3,7,14 days but if immunocompromised persons add fifth dose at 28 day

The active antibody response requires approximately 7 to 10 days to develop, and

detectable rabies virus–neutralizing antibodies generally persist for several years. All
currently used vaccines are produced in cell cultures and are significantly less toxic than older
vaccines that were produced in neural tissue.

Side effects of human diploid cell vaccine, including mild erythema, swelling, and pain at
the injection site, have been reported in 10% to 90% of vaccine recipients. Systemic reactions,
such as headache, nausea, abdominal pain, muscle aches, and dizziness, have been reported in
5% to 40% of recipients. Serum sickness–like reactions (type III hypersensitivity) have been
noted in approximately 6% of persons receiving booster doses of human diploid cell vaccine
and occur 2 to 21 days after administration of the booster dose. Such reactions have not been
life threatening and have not been reported with purified chick embryo cell culture vaccine.
Anaphylaxis and neurologic symptoms have only rarely been associated with the current
rabies vaccines. Severe egg allergy is a contraindication to the use of purified chick
embryo cell culture vaccine.

Rabies prophylaxis should not be interrupted or discontinued because of local or mild

systemic adverse reactions to rabies vaccine. Usually such reactions can be successfully
managed with anti-inflammatory and antipyretic agents. When a person with a history of
serious hypersensitivity to rabies vaccine must be revaccinated, antihistamines may be given.
Epinephrine should be readily available to counteract anaphylactic reactions, and the
person should be observed carefully immediately after vaccination (as after any other
injection given in a healthcare setting).

2)Human Rabies Immunoglobulin:

HRIG is administered only once, at the beginning of antirabies prophylaxis, to provide
immediate antibodies until the patient responds to rabies vaccine by producing antibodies.
A passive antibody titer is evident in 24 hours. Failure to administer HRIG has led to rabies
despite appropriate postexposure prophylaxis with human diploid cell vaccine.
If HRIG was not given when vaccination was begun, it can be given through the seventh day
after administration of the vaccine.
Beyond the seventh day after vaccination is begun, HRIG is not indicated, because an
antibody response is presumed to have occurred. The Centers for Disease Control and
Prevention recommends that as much as possible of the full dose be infiltrated around the
wound.
 HRIG should never be administered in the same syringe or into the same anatomic site
as the vaccine, as the antibody and vaccine will neutralize each other. Even if the wound has
to be sutured, it should be infiltrated locally with HRIG. This practice is safe and does not
create an additional risk of infection.
caution is needed when injecting into a tissue compartment, such as the finger pulp,
because excessive HRIG can increase compartment pressure and lead to necrosis.
Any remaining HRIG that cannot be administered into the local wound area should be
injected intramuscularly at a site distant from vaccine administration.
HRIG is prepared from plasma of hyperimmunized donors and screened for known viruses
(e.g., human immunodeficiency virus, hepatitis). No cases of virus transmission from HRIG
that is commercially available in the United States or Australia have been reported.
HRIG should not be given to those with immunoglobulin A deficiencies and known
antibodies of immunoglobulin A, because small amounts of immunoglobulin A may be
present in HRIG and can cause a severe allergic reaction

The World Health Organization has provided recommendations for rabies postexposure
prophylaxis that also consider the cost and availability of vaccines and HRIG. Per the World
Health Organization, the indication for postexposure prophylaxis depends on the contact with
the suspected rabid animal:
Category I: touching or feeding animals, licks on intact skin (i.e., no exposure)
Category II: nibbling of uncovered skin, minor scratches or abrasions without bleeding
Category III: single or multiple transdermal bites or scratches, contamination of mucous
membrane with saliva from licks, licks on broken skin, exposure to bats
For category I exposures, no prophylaxis is required.
For category II, immediate vaccination is recommended.
For category III, immediate vaccination and administration of rabies immunoglobulin are
recommended.

For IM administration, the World Health Organization recommends the following

postexposure regimens. The postexposure vaccination schedule is based on injecting 1 mL or
0.5 mL (volume depends on the type of vaccine) into the deltoid muscle (or anterolateral
thigh in children <1 year of age) of patients with category II and III exposures.
Rabies vaccine should never be injected in the gluteal area. The recommended regimen
consists of either a five- or a four-dose schedule:
A)The five-dose schedule consists of one dose on each of days 0, 3, 7, 14, and 28.
B)The four-dose schedule consists of two doses on day 0 (one dose in each of the two deltoid
or thigh sites) followed by one dose on each of days 7 and 21.

An alternative for healthy, fully immunocompetent, exposed persons who receive wound care
plus high-quality rabies immunoglobulin plus World Health Organization–prequalified rabies
vaccines is a postexposure regimen consisting of four doses administered IM on days 0, 3,
7, and 14 (consistent with current U.S. recommendations).
Intradermal administration requires a smaller dose and is used to reduce the cost of vaccine in
some countries. However, intradermal administration is technically more demanding and
requires appropriate staff training.
For intradermal administration, the World Health Organization recommends the following
postexposure regimen: The two-site regimen prescribes injection of 0.1 mL at two sites
(deltoid and thigh) on days 0, 3, 7, and 28. This regimen may be used for people with
category II and III exposures in countries where the intradermal route has been endorsed by
national health authorities
Notes:
1)Adverse pregnancy outcomes or fetal abnormalities have not been associated with
rabies vaccination
2)The dose of rabies vaccine for preexposure and postexposure prophylaxis is the same
in infants and children as in adults

Rabies virus causes acute encephalitis in all warm-blooded hosts, including humans, and the
outcome is almost always fatal. Although patients with rabies may manifest a variety of
clinical symptoms and signs, the disease tends to follow a characteristic course (Table 158-8).
Most commonly, the incubation period after a bite ranges from 20 to 90 days. However,
incubation periods have been reported that are as short as 4 days and as long as 6 years. The
incubation period is shorter when the site of the bite is on the head than when it is on an
extremity

CLINICAL FEATURES
During the prodrome, the symptoms and signs are nonspecific. Early in the course, some
patients may report symptoms suggestive of rabies such as limb pain, limb weakness, and
paresthesias at or near the presumed exposure site. The prodrome merges into the acute
neurologic phase, which begins when the patient develops objective signs of CNS disease.
There are two clinical forms of rabies:
1) an encephalitic form in 80%
2) a paralytic form in 20%.
 In encephalitic rabies:
there are often episodes of generalized arousal or hyperexcitability, disorientation,
hallucinations, and bizarre behavior, often separated by lucid intervals. Autonomic
dysfunction is common and includes hypersalivation, hyperthermia, tachycardia,
hypertension, piloerection, cardiac arrhythmias, and priapism.
In Paralytic rabies:
generally begins with paresis in the bitten extremity with spread to quadriparesis and bilateral
facial weakness. There is progression of paralytic rabies to coma and organ failure, typically
with a longer clinical course than in encephalitic rabies.
About 50% of patients have classic hydrophobia, in which attempts to drink fluids
result in severe spasms of the pharynx, larynx, and diaphragm.
Coma almost always occurs within 10 days of the onset of symptoms.
Death occurs due to a variety of complications, including pituitary dysfunction, seizures,
respiratory dysfunction with progressive hypoxia, cardiac dysfunction with dysrhythmias and
arrest, autonomic dysfunction, renal failure, and secondary bacterial infections.
Only 14 patients are known to have survived rabies; most survivors have had severe
neurologic sequelae. In all but three cases, the patient had received postexposure prophylaxis
with rabies vaccine (e.g., duck embryo, suckling mouse brain) before the onset of symptoms.

DIAGNOSIS AND TREATMENT

Rabies should be included in the differential diagnosis of any patient with unexplained
acute, rapidly progressive encephalitis, especially in the presence of anatomic instability,
dysphagia, hydrophobia, paresis, or parasthesias.

Diseases that may be confused with rabies include tetanus, poliomyelitis, Guillain-Barré
syndrome, botulism, transverse myelitis, postvaccinal encephalomyelitis, intracranial mass
lesions
cerebrovascular accidents, poisoning with atropine-like compounds, and infectious causes of
viral encephalitis
Important clues to diagnosis include a history of an animal bite or bat exposure and the
development of the pathognomonic signs of hydrophobia and aerophobia (precipitating
grimacing and other signs by blowing air on the patient’s face).
During the incubation period of rabies, no diagnostic test is available for animals or humans
that will indicate infection. Once symptoms become evident, antigen detection in biopsy
specimens from highly innervated skin (i.e., nuchal skin), antibody detection in serum (if
unvaccinated) or CSF (all people), isolation of virus from saliva, or detection of nucleotide
sequences in saliva, skin, or other tissues can detect evidence of the disease. Serum antibodies
may be present as early as day 5 of clinical illness, but antibodies may be absent after 10 to 14
days or longer.

CT of the brain is only useful to exclude other diseases. MRI of the brain may be normal or
may show lesions in gray matter areas of the brain parenchyma, including the brainstem.
Cerebrospinal fluid analysis often shows a mild mononuclear pleocytosis
Treatment :
No specific therapy has been of demonstrated benefit in clinical rabies.Treatment with
rabies vaccine, rabies immunoglobulin, IV ribavirin, or interferon is not effective. In
animal models, use of corticosteroids shortens the incubation time and increases mortality,
and for this reason, steroids are contraindicated. Survival with normal neurologic function
was reported for a 15-year-old girl in whom coma was induced and treatment with ketamine,
midazolam, ribavirin, and amantadine was provided. However, similar regimens have
been used for more than 30 other patients without success.
 Suggesting that modern supportive care increases the likelihood of survival, particularly in
resource-rich settings. Currently, treatment is directed at the clinical complications of the
disease

Although rabies is not treatable, every attempt should be made to achieve rapid diagnosis,
because it justifies public health measures to limit contacts with the patient and permits
reconstruction of a history to identify others who may have been exposed to the same
infective source.

Medical Notes By Dr Salman Bahaj

Tele : https://t.m/+Z2hd5CUNTytiNDFk