History of rabies in China

Rabies was highly endemic in almost all provinces of China until the end of the
1980s, with more than 5,200 human deaths reported annually during the period
1987-89.
Since then, the number of deaths has been drastically, reduced with about 3,500
deaths in 1990 and only 200 in 1995. This was followed by a decade of increased
incidence, which peaked in 2007 with 3,300 deaths reported.
The incidence of rabies decreased to fewer than 2000 cases in 2011.
Currently most of the human rabies cases are reported in the southeastern part of
China.
The animal species found to be at the origin of human exposure to rabies in China
are mainly dogs, cats, pigs, cattle, ferrets and skunks.
Dog is the primary reservoir and transmitter of rabies in the country.
Epidemiological investigations in Beijing showed that most of the rabies deaths
occurred in persons exposed to rabies-suspected dogs (85-95%) and cats (5%).
Multisectoral cooperation is an important feature of rabies control in China. A notice
on Strengthening Rabies Prevention and Control in 2003 was issued by four
ministries the Ministry of Health, Ministry of Agriculture, Ministry of Public Security
and the State Food and Drug Administration.
Dog population
How Did
Rabies Get its Name?
Rabid dogs sometimes appear to be angry or in a rage. Rabies comes from the Latin
word rabere. Rabere means to rage or rave.
This Latin word rabere may have roots in a Sanskrit word rabhas. Rabhas means to
do violence.
The Greeks called rabies lyssa or lytta, which means frenzy or madness. They
named human rabies hydrophobia, which means fear of water, a symptom shown
by rabies victims.
Rabies Timeline

2300 BC
Dog owners in the Babylonian city of Eshnunna are fined heavily for deaths caused
by their dogs biting people.
800-700 BC
Homer likens Hector to a raging dog in The Iliad, one of the oldest Greek poems
known today. He writes that Sirius, the dog star of Orion, exerts a malignant
influence upon the health of mankind".

500 BC
Democritus, a Greek philosopher records a case of canine rabies.
400 BC
Aristotle writes that dogs suffer from the madness. This causes them to become
very irritable and all animals they bite become diseased.
By now, the Greeks have two special rabies gods; one to prevent rabies, (Arisaeus,
son of Apollo) and a one to heal rabies, (Artemis).
001-100 AD
Rabies is widespread across the Roman Empire, Greece and Crete.
The Roman Cardanus describes saliva from a rabid dog as a virus the Latin word
for poison.
Pliny the Elder also devises a series of treatments based around the idea that rabies
is a tongue worm.
A Roman physician named Celsus takes a special interest in rabies and discovers
saliva alone contains the virus. He recommends cleaning, sucking and burning
(cauterizing) the wound before leaving it open so the virus could drain out. This will
remain the only accepted treatment for the next 1800 years.
201-300
The treatment for rabies in cattle is described by early veterinary medicine writer,
Vegetius Renatus.
501-600
Aetious, a Mesopotamian physician, writes an accurate description of dog rabies
symptoms.
601-700
Greek physician, Paulus Aegineta records the difference between fatal hydrophobia
caused by dog bites and simple hydrophobia stemming from a different cause.
801-900
Syrian doctors believed hydrophobia was incurable. They helped suffering patients
by giving water disguised inside drops of honey.
Rhazes, (Al-Razi) a Persian physician identifies hydrophobia and further describes
rabies symptoms in humans.
1001-1100
The writings of another Arab physician, Avicenna, (Abu Ali Sina) mark a step forward
in knowledge about the disease. His books were used in European medical schools
for nearly 500 years.

1026

Madness in dogs is recorded in the laws of Howel the Good, of Wales. This is the
earliest record of rabies in Great Britain.

1198
Poisons and Their Antidotes, by Talmud scholar and physician Moses Maimonides,
contains remedies against bites from mad dogs.

1271
First large rabies outbreak reported. 30 people die after rabid wolves invade villages
in Franconia (Germany).

1400
During the 15th century, Spain is ravaged by canine rabies

1500
During the 16th century, Christian Europeans believe a patron saint named St.
Hubert will cure rabies. Many travel to his shrine at Liege, Belgium and die of the
madness. Jean Gerson, a French theologian, speaks out against superstitious
practices in religion.

1586
Canine rabies spreads through Flanders, (North Belgium) Austria, Turkey and
Hungary.

1604
Rabies reaches Paris, causing panic.

1671
Superstitious practices for treating rabies are condemned by the Sorbonne.

1700
Rabies spreads through Europe during the 18th century.

1703

The first case of rabies is reported in the Americas by a priest in Mexico. He is told
off for raising the problem by his superiors in Spain.

1734-5
Canine rabies appears in England.

1750
Rabies is reported in Barbados among dogs and hogs. They are said to die around
three days after getting sick.

1752
Orders to shoot dogs on sight are given in England when rabies appears around St.
James, London.

1753
Canine rabies is present in the State of Virginia, North America.

1759-1762
Serious outbreak of rabies reported in London. All dogs are confined for one month.
Dogs on the street are killed and a reward of 2 shillings per dog is offered. The
reward prompts barbaric scenes of killing in the streets.

1763
Serious rabies outbreaks reported in France, Italy and Spain. Authorities slaughter
dogs. In Madrid, Spain, 900 dogs are killed in just one day.

1768-1771
Rabies breaks out in Boston and other North American towns. Foxes and dogs carry
the disease to farm animals. The symptoms are unusual and rabies is reported as a
new disease.

1774
Rabies is a general disease throughout England. People are discouraged to keep
dogs. Bigger rewards up to five shillings - are paid for each dog killed.

1776-1778

The French West Indies is invaded by rabies. Cattle and people are bitten by
infected dogs.

1785-1789
Rabies is now common across North America.

1789
A New Yorker dies from hydrophobia after skinning an infected cow.

1790-1821
Rabies is common in France and Silesia (now Poland and the Czech Republic). It
spreads through wolves and foxes in central Europe.

1797
Rabies appears on Rhode Island.

1800
Rabies becomes widespread in Northern, Western and Eastern Europe during the
9th century. It is common in the Ukraine. There are accounts of European villagers
dying from contact with mad wolves, foxes and dogs. There is also a reappearance
of rabies in North America and it moves up to Canada. And in England, it never goes
away.

1803
Hundreds of dead foxes are spotted at the foot of the Jura Alps, eastern France. This
outbreak, the largest yet recorded lasts for thirty years and wipes out all foxes in
some areas, terrifying villagers. In the same year, rabies appears in Peru for the first
time.

1804
Zinke, a German scientist demonstrates rabies is passed through saliva by
conducting experiments on animals.

1806
Dogs belonging to English officers introduce rabies to Argentina.

1810
Rabies reappears in eastern USA and Ohio.

1825
Rabies enters the Black Forest, Germany.

1835
Rabies appears in Chile and kills many.

1881
French chemist Louis Pasteur and his assistant, Physician-scientist Emile Roux, begin
research on a cure for rabies.

1883
Roux presents a medical paper about the rabies research he as been doing with
Pasteur. Roux creates a rabies vaccine from the spinal cord of an infected animal
and tests it on dogs.

1885
Joseph Meister is mauled by a rabid dog and brought to Pasteur. Pasteur gives him
the rabies vaccine immediately, despite the risks to his own career as he is not a
doctor, but a chemist. The treatment was successful, and Pasteur was hailed as a
hero.

1892
Canadian physician William Osler, describes hydrophobia in a medical textbook. He
recommends careful washing and treatment of the wound. Osler is unaware of
Pasteurs breakthrough.

1953
The first US case of rabies in a bat is reported by the CDC.

1959
Dr. Robert Kissling developed the fluorescent antibody test for rabies
Cultural impact

Because of its potentially violent nature, rabies has been known since 3500 B.C. The
first written record of rabies is in the Codex of Eshnunna (ca. 1930 BC), which
dictates that the owner of a dog showing symptoms of rabies should take
preventive measure against bites. If a person was bitten by a rabid dog and later
died, the owner was fined heavily.

Rabies was considered a scourge for its prevalence in the 19th century. Fear of
rabies related to methods of transmissions was almost irrational;
In France during the time of Louis Pasteur (18221895) there were only a few
hundred rabies infections in humans each year, but cures were desperately sought.
Aware of the possible danger, Pasteur began to look for the "microbe" in mad dogs.
[94] Pasteur showed that when the dried spinal cords from dogs that had died from
rabies were crushed and injected into healthy dogs they did not become infected.
He repeated the experiment several times on the same dog with tissue that had
been dried for fewer and fewer days, until the dog survived even after injections of
fresh rabies-infected spinal tissue. Pasteur had immunised the dog against rabies,
as he later did with 50 more.[95]

A cartoon from 1826 depicting a rabid dog on a London street

Although Pasteur had little idea how his method worked, he tested it on a boy,
Joseph Meister (18761940), who was brought to Pasteur by his mother on 6 July
1885. He was covered in bites, having been set upon by a mad dog. Meister's
mother begged Pasteur to help her son. Pasteur was a scientist, not a physician, and
he was well aware of the consequences for him if things were to go wrong. He
nevertheless decided to help the boy and injected him with increasingly virulent
rabid rabbit spinal tissue over the following 10 days.[96] Later Pasteur wrote, "as
the death of this child appeared inevitable, I decided, not without deep and severe
unease ... to try out on Joseph Meister the procedure, which had consistently worked
on dogs".[97] Meister recovered and returned home with his mother on 27 July.
Pasteur successfully treated a second boy in October that same year; Jean-Baptiste
Jupille (18691923) was a 15-year-old shepherd boy who had been severely bitten
as he tried to protect other children from a rabid dog.[98] Pasteur's method of
treatment remained in use for over 50 years.[99]

Little was known about the cause of the disease until 1903 when Adelchi Negri
(18761912) first saw microscopic lesions now called Negri bodies in the brains
of rabid animals.[100] He wrongly thought they were protozoan parasites. Paul
Remlinger (18711964) soon showed by filtration experiments that they were much
smaller than protozoa, and even smaller than bacteria. Thirty years later, Negri
bodies were shown to be accumulations of particles 100150 nanometres long, now
known to be the size of rhabdovirus particles the virus that causes rabies.[31]
Lyssa
The Greek word for rabies is lyssa (variously transliterated lussa, lutta or lytta),
a word of unknown derivation. Ancient etymologists suggested its root was either
lysis, meaning loosing, dissolving (as in hydrolysis and other -lysis compounds in

English), because it led to loss of rational faculties, or lykos, eaning wolf (English
lycanthropy) which suggests an animalistic belief that the madness derived
fromabsorption of a bestial nature. In this respect, it would closely parallel our
English word berserk, which probably derives from Old Norse words meaning bear
shirt.
The word lyssa, however, was not used exclusively for rabies. Like our word
berserk it was used for wild, irrational madness. In the earliest of Greek authors,
Homer, it is used to describe furious martial rage as indeed was berserk,
originally a wild Norseman fighting in furious frenzy. After Homer, the word was used
to describe madness generally: Plato (36) uses it to describe erotic passions, and a
lyric poet sings of a lyssa for sexual intercourse
There have been claims of instances of rabies from the time of Homer (ca. 8th
Century B.C.) onwards, yet
the fact that Hippocrates make no mention of it earliest suggests it had not reached
Greece by then
(5th Century B.C.) although we must be cautious as not all of his works are extant.
Hence the first
attested appearance of the disease was in 4th Century B.C. and even then more
precise diagnosis is not
recognisable until 1st Century B.C. Various remedies were attempted, often with
increasingly arcane
methods as time when on (e.g. specifying shearwater liver, when any bird even a
chicken or animal
liver would have suffice, or insisting upon the precise collection/preparation of
gentian + river crabs) in
herbal remedies; in cauterisation and in treatment. Later medical writers, in large
quantities, by and large
adopted a pick and mix approach which persisted well into the mediaeval period
and beyond.
Claims of success in curing the disease muste have been at best economical with
the truth or more likely
faulty in the diagnosis of rabies.
The history of rabies in Europe and the Mediterranean Basin clearly reminds us of
the extent to which this
disease posed a threat in these regions in ancient times. In continental Europe, dogs
and wolves were
initially the greatest rabies threat, and in the 20th Century fox rabies became the
most important challenge,
before it was eradicated by oral vaccination. In the Mediterranean Basin, dog rabies
is still prevalent in
many places, and, unfortunately, 120 years after Pasteur develpped the rabies
vaccine, the number of

human deaths in some countries of this region is not very different from ancient
times. This is partly
because proper post-exposure treatment is not available to all, but mainly due to
the fact that there is no
effective control of the reservoir of dog rabies virus in these countries.

Introduction
Rabies is a fatal central nervous system (CNS) disease responsible for
approximately 60,000 annual deaths worldwide, making it the tenth most common
lethal infectious disease (Dietzschold et al. 2005). The causative agent is a
neurotropic virus consisting of nonsegmented, negative-stranded RNA contained
within a bullet-shaped envelope. Rabies virus (RV) is 1 of 7 serotypes belonging to
the genus Lyssavirus and the family Rhabdoviridae (Plotkin 2000). The most
common site of RV entry in humans is the skin or mucous membrane, where the
virus is delivered into the muscle and subcutaneous tissue through biting, licking or
scratching by an RV-infected animal (Warrell et al. 2004). Disease can present with
one of two clinical forms. In the majority of rabies cases, the pathologic
manifestation in the CNS is acute encephalomyelitis. This form is known as classic
or encephalitic (furious) rabies and comprises 80-85% of rabies cases. It is
distinguished by neurotropism, neuroinvasiveness and impaired neuronal functions
(Jackson 2002). The ssymptoms of classic rabies include hydrophobia, pharyngeal
spasms, and hyperactivity leading to paralysis, coma and death (Hankins et al.
2004). Paralytic rabies is a less common clinical form characterized by the
development of prominent and flaccid muscle weakness (Jackson 2002). Death in
both clinical and paralytic rabies ultimately results from neuronal dysfunction due to
the dramatically inhibited synthesis of proteins required for maintaining neuronal
functions (Dietzschold et al. 2005).

Rabies progresses through 5 clinical stages that can vary depending on the extent
of the bites, the amount of secretion, and the proximity to the CNS, with disease
transmitted through bites close to the brain progressing more rapidly than disease
transmitted through bites on the lower extremities (Hankins et al. 2004). The
incubation stage ranges from 10 days to 1 year, with the average lying somewhere
between 20-60 days. The prodrome stage occurs 2 to 10 days after exposure and
can last from 1 day to 2 weeks. This stage is characterized by nonspecific flu-like
symptoms such as fever, malaise, headache and nausea (Jackson 2002). Acute
neurologic syndrome occurs 7-10 days after the onset of prodrome and includes
dysarthia, dysphagia, excessive salivation, vertigo, agitation, visual and auditory
hallucinations, hydrophobia secondary to painful contractions of pharyngeal
muscles, and polyneuritis. Coma occurs 7-10 days after the onset of acute
neurologic syndrome. This stage includes hydrophobia, prolonged apnea,
generalized flaccid paralysis, seizures and coma with acute respiratory collapse.
Death may follow 2-3 days after the onset of paralysis (Hankins et al. 2004).

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Pathogenesis
The viral particle is comprised of a membrane made of host lipids and two
proteins, G and M, surrounding a helical nucleocapsid (Thoulouse et al. 1998). As
shown in figure 1, the helical coil of the ribonucleoprotein(RNP) complex core is
formed by the rabies genome, a single non-segmented strand of negative-sense
RNA, a nucleoprotein, a phosphoprotein, and an RNA-dependent RNA polymerase.
The RNP core is covered by a layer of matrix protein, which is in turn covered by a
host-derived lipoprotein envelope studded with rabies glycoprotein (Warrell et al.
2004). The trimeric G protein exposed on the surface of the virion is responsible for
the attachment to the target cell by interaction with several cell membrane
components. In particular, the nicotinic acetylcholine receptor (nAChR) acts as a
receptor for RV. Binding of RV to nAChRs localizes and concentrates the virus on
postsynaptic cells, which in turn facilitates subsequent uptake and transfer of the
virus to peripheral motor nerves (Jackson 2002). In neurons that do not express
nAChRs, it has been shown that other molecules such as phospholipids,
gangliosides, neuronal cell adhesion molecule and the nerve growth factor receptor
can serve as an RV receptors (Dietzschold et al. 2005). Following attachment to the
G protein to the cell membrane, RV enters the cell by endocytosis and then resides
in an early endosomal compartment. The acidic environment of the endosome
causes fusion of the viral membrane with the endosomal membrane (Jackson 2002).
This allows for the nucleocapsid to escape into the cytosol, where transcription and
replication occur (Thoulouse et al. 1998).

Figure 1. The internal ribonucleoprotein (RNP) core of the rabies virion consists of a
negative-sense genome RNA encapsidated by nucleoprotein, polymerase cofactor
phosphoprotein, and the virion-associated RNA polymerase. The RNP core is
covered in matrix protein and surrounded by a lipid-bilayer envelope (Warrell et al.
2004). Permission to use figure pending.

Although RV can infect a variety of cell types, it primarily targets neurons. The
cycle of viral infection is depicted in figure 2. The virus spreads by retrograde axonal
transport from the peripheral nerves to the neuronal cell body, possibly by
cytoplasmic dynein (Wang et al. 2005). After replication in the cell body of the
primary neuron, infection proceeds via retrograde axonal transport and
transsynaptic spread through several neurons, as illustrated by figure 3.
Transsynaptic spread is the ability of the virus to use synaptic junctions to
propagate within the CNS (Dietzschold et al. 2005). Neuronal infection by RV causes
abnormalities in the function of neurotransmitters affecting serotonin, GABA and
muscarinic acetylcholine transmission (Warrell et al. 2004). Acinar cells are infected
next, which in turn shed the virus into the oral cavity. This accounts for the presence
of the virus in saliva (Dietzschold et al. 2005).

Figure 2. The cycle of rabies infection begins with viral entry at a peripheral site and
proceeds through retrograde axonal transport. Viral replication occurs in the cell
body of the primary neuron. Infection proceeds by transsynaptic spread through
several neurons before spreading to the acinar cells, which then shed the virus into
the saliva (Dietzschold et al. 2005). Permission to use figure pending.

Figure 3. The neuroinvasiveness of the virus results from its ability to migrate to the
central nervous system (CNS) through retrograde axonal transport and transynaptic
spread. Rabies virus spreads from the postsynaptic site to the presynaptic site via
receptor-mediated endocytosis. In retrograde axonal transport, the
ribonucleoprotein complexes of the virus are carried by direct attachment to a
dynein motor or by encapsulation in vessicles attached to a dynein motor
(Dietzschold et al. 2005). Permission to use figure pending.

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Epidemiology

Because animal bite is the primary route of RV transmission to humans, the

epidemiology of human rabies is a direct reflection of the regional animal reservoir
for rabies virus and the opportunity for human-animal interaction (Childs 2002).
Worldwide, canid species are the main vector in the transmission of rabies to
humans, particularly in developing countries where canine rabies is endemic (Krebs
1995). In countries where canine rabies persists, the age and sex distribution of
human rabies deaths generally mirrors the distribution of dog bit victims. The Indian
subcontinent, Southeast Asia and most of Africa are the major foci of rabies today,
with more than 30,000 cases each year in India alone (Plotkin 2000). Crowded
urban centers with inadequate public health infrastructures are prone to
transmission of rabies virus. In developed countries where canine rabies has
retreated, the transmission of rabies by wild mammals accounts for 90% of human
exposures (Hankins et al. 2004). Rabid bats, especially silver-haired bats, are the
most prevalent source of human rabies in the United States. Between 25,000 and
40,000 people in the US are treated annually for exposure to rabid or potentially
rabid animals (Hankins et al. 2004). Other rare routes of rabies transmission include
handling of infected carcasses, consumption of raw, infected meat and inhalation of
aerosolized rabies in caves inhabited by millions of bats. At least eight cases of
human-to-human transmission of rabies have resulted from the transplantation of
infected corneas (Jackson 2002).
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Diagnosis/Treatment

Diagnosing rabies can be difficult if no history of exposure reported, and it is often

misdiagnosed as Guillain-Barre syndrome, poliomyelitis and other viral
encephalitides, or laryngeal disorder (Plotkin 2000). A conclusive rabies diagnosis
can be made in humans before death by observing virus-specific fluorescent
material in skin biopsy specimens, isolating the virus from patient saliva, or
detecting the presence of antirabies antibodies in the serum or cerebrospinal fluid
of patients who have not been immunized (Hankins et al. 2004). The basic
principles behind rabies prophylaxis are the removal of free virus from the body by
both washing and neutralization, followed by the induction of a rabies virus-specific
immune response in the exposed individual before rabies virus can replicate in the
CNS. This requires the administration of both passive and active vaccination. In
passive vaccination, rabies immune globulin (RIG) from adults who have been
immunized with rabies vaccine is administered to previously unimmunized people
so as to passively impart antibodies. There are three primary types of active rabies
vaccinations currently administered to humans throughout the world: nerve tissuederived vaccines (NTVs), high-quality cell culture vaccines produced under stringent
quality control and lower-quality cell culture vaccines that do not adhere to FDA
regulations of national pharmacopeia standards in industrialized countries (Briggs et
al. 2002). NTVs are produced from brain tissue of animals infected with a fixed
strain of rabies virus. After the brain tissue is harvested, the virus is inactivated and
then diluted to a concentration of 2-5% of brain tissue. NTVs are extremely painful,
however, and can cause severe neurologic adverse reactions due to the presence of
myelinated tissue in the vaccine (Briggs et al. 2002). Unfortunately, nerve tissue
vaccines are still the most widely used prophylaxis for rabies. The optimal rabies
vaccine today is human diploid cell vaccine (HDCV), which is a type of cell-culture
vaccine produced in human fibroblasts. Unfortunately, treatment is generally
unsuccessful when administered after the patient becomes symptomatic. Therefore,
efforts must be focused on disease-preventing measures (Vanniasinkam et al.
2004).