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Plague
Richard W Titball and Sophie E C Leary
Defence Evaluation and Research Agency, CBD Porton Down, Salisbury, UK
Yersinia pestis, the aetiological agent of plague, has in the past caused social
devastation on a scale unmatched by other infectious diseases. There is still a
public health problem from plague, with at least 2000 cases reported annually.
Most of these cases are of the bubonic form. Occasionally bubonic plague
develops into pneumonic plague, and this form of the disease can spread
rapidly between susceptible individuals. The recent outbreak of plague in India
highlighted the potential for plague to explosively re-appear, and modern mass
transport systems mean that there is the potential for the rapid spread of
disease. Against this background, there is a need to ensure that vaccines and
antibiotics are available to prevent and treat the disease. Progress has been
made in devising a sub-unit vaccine, effective against bubonic and pneumonic
plague. Antibiotics must be given in the early stages of disease to effect a cure.
Correspondence toDr Richard W Titball,
Defence Evaluation and
Research Agency, CBD
Porton Down, Salisbury,
Wilts SP4 OJQ, UK
The aetiological agent of plague is the Gram-negative bacterium Yersinia
pestts. Nowadays, most cases of the disease in man are of the bubonic
form, which arises following a bite from an infective flea which has
previously fed on an infected rodent1. From the initial focus of infection,
the bacterium becomes disseminated into the lymph nodes (often the
inguinal or femoral lymph nodes) which drain the site of infection.
These lymph nodes become swollen and tender and the classical feature
of bubonic plague is the bubo which may reach the size of a hen's egg.
Often the patient develops a bacteraemia with blood culture counts in
the range < 10 to 4 x 107 cfu/rnl2. A second form of the disease,
septicaemic plague, occurs when there is a bacteraemia without the
development of buboes. This form of the disease is characterised by an
elevated temperature, chills, headache, malaise and gastrointestinal
disturbances1. Due to the absence of buboes, a diagnosis of plague is
often delayed and, even with medical intervention, 50% of patients die,
probably as a result of the induction of the systemic inflammatory
response syndrome2. The most feared form of plague arises when there
is colonisation of the alveolar spaces leading to a suppurative
pneumonia1. Pneumonic plague results in the production of a highly
infectious, watery, and bloody sputum which contains viable bacteria.
Coughing results in the production of airborne droplets containing
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bacteria, which can be inhaled by susceptible individuals13. The
pneumonic form of the disease is feared because of the rapidity with
which the disease develops (1-3 days), the high mortality rate in infected
individuals (approaching 100%) and the rapid spread of disease from
man to man1.
Incidence of disease
Past epidemics of plague
During the last 2000 years, Y. pestis has caused social and economic
devastation on a scale unmatched by other infectious diseases or by armed
conflicts. It is generally considered that there have been three world
pandemics of plague and credible estimates indicate that together these
resulted in 200 million deaths2. During these pandemics, the disease
occurred in both the bubonic and pneumonic forms. The first of these, the
Justinian plague, occurred during the period AD 542 to AD 750. This
pandemic is thought to have originated in Central Africa and then spread
throughout the Mediterranean basin2. The second pandemic started on
the Eurasian border in the mid-14th century. It is this pandemic which
resulted in 25 million deaths in Europe and which is often referred to as
the 'black death'2. This pandemic lasted for several centuries, culminating
in the Great Plague of London in 1665. The third pandemic started in
China in the mid-19th century, spread East and West, and caused 12.5
million deaths in India alone between 1889 and 19504.
Current incidence of plague
World Health Organization (WHO) figures5 indicate that there is still a
public health problem from plague, especially in Africa, Asia and South
America5 and plague, cholera and yellow fever are the only
internationally quarantinable infectious disease. As a class 1 notifiable
disease, all suspected cases must be reported to, and investigated by,
public health authorities and confirmed cases must be reported to the
WHO in Geneva, Switzerland6. During the period 1967-1993, the
average worldwide incidence of plague was 1,666 cases2. Although the
incidence trend was downwards until 1981, there has been an apparent
increase in the incidence of disease over the last decade2"5, possibly
because of more efficient diagnosis and reporting of cases (Fig. 1). Even
today, many cases of plague are not diagnosed and it is likely that the
true incidence of disease is several times the WHO figures.
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Plague
2500
Fig. 1 WHO figures
for the incidence of
plague worldwide
during the period
1967-1994. The solid
line indicates the
total number of cases
of plague whilst the
number of deaths due
to plague are
indicated by the
dashed line
1976
1696
The Indian outbreak of plague in 1994. Despite the high incidence of
plague in India during the first half of this century, the number of cases
had declined since 1950, and the last recorded case occurred in 19667.
However, between August and October 1994 two outbreaks of suspected
plague occurred, one of bubonic plague in the Beed District of
Maharashtra State, and the other of pneumonic plague in the city of Surat
in Gujarat State (Fig. 2). The Surat epidemic caused panic throughout
India, resulting in a mass exodus of up to half a million people from the
city, and attracted international media attention.
At the peak of the epidemic, over 6300 suspected cases were recorded8.
However, official figures released later indicated that only 876 presumptive cases of plague were identified (by serological testing for antibodies to Fl antigen of Y. pestts) and there were 54 fatalities8 (Fig. 2). The
cases were confined to six states m central and western India; none of the
suspected cases in other states, such as Bihar, Punjab, Rajasthan and West
Bengal, had positive serological markers for presumptive plague.
During the outbreaks, one of the major problems was the failure to
collect systematically clinical samples for analysis. Routine tests to
confirm a diagnosis of plague were not carried out and pure isolates of Y
pestis were not cultured from blood, sputum or autopsy samples. As a
result, the exact nature of the outbreaks in Maharashtra and Surat has
provoked controversy and alternative causative agents have been
proposed9. To address concerns, a team of experts from the WHO visited
India in October 1994. Although the WHO team was unable to isolate Y
pestis from clinical samples, it established that there was clinical,
epidemiological and serological evidence of an outbreak of plague8.
In response to the crisis, the Indian government constituted a Technical
Advisory Committee (TAC) on 9 October, 19949 'to elucidate the factors
responsible for the current outbreak of plague and its spread'. In clinical
and environmental studies co-ordinated by the TAC, pure Y pestis was
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Fig. 2 Map of India
and its States, where
relevant the numbers
of presumptive cases
of plague and
fatalities (in brackets)
are shown for the
States
isolated from the sputum of 11 pneumonic plague cases in Surat, and the
tissues of 6 rodents trapped in Beed and 1 rodent trapped in Surat9. The
biochemical, genetic and immunological similarity of the Surat and Beed
isolates suggested that they arose from the same Y. pestis strain and, for the
first time, provided evidence that the outbreaks were linked9.
The TAC also conducted studies to identify the events leading up to the
epidemics. In the Beed District of the Maharashtra State, the seeds of the
outbreak were laid in October 1993 when the residents of Mamla village
abandoned their homes in fear of tremors associated with a major
earthquake in the neighboring districts of Latur and Osmanabad. Large
quantities of grain remained in the homes, which provided a source of
food for domestic rats leading to a population explosion and a rodent
epizootic of plague9. The initial source of human infection was the wild
rodent population located in habitats surrounding the village. During
August 1994, a heavy flea nuisance and 'rat fall' was reported in the village
and, shortly afterwards, the first cases of bubonic plague occurred9.
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The origin of the pneumonic plague outbreak in Surat is less well
understood. Monsoon flooding occurred in the city in the first week of
September 1994 causing people to leave their homes. Although such
disruptions to the local ecological balance are known to contribute to
plague outbreaks, there is no evidence that this occurred in Surat. The
index case locality of the pneumonic plague outbreak was traced to
Laxminagar colony in the north of the city and, although the origin of
the disease remains obscure, the most likely scenario is that an
individual with pneumonic plague who travelled from the Beed district
to Surat was the source of the epidemic7*9.
Animal reservoirs of plague
Y. pestts is an obligate pathogen which is unable to replicate outside of
an animal host. In parts of the world where plague is endemic, the
bacterium persists in 'foci' of infected rodents1'2'10. The observation that
distinct foci of infection occur at sites throughout the world indicates
that the bacterium can persist for long periods in some relatively
resistant (enzootic) animal hosts and their fleas1*2'10. For this reason it
would be very difficult, if not impossible, to eradicate Y pestts
completely. The bacterium is transferred between animals by fleas and it
is thought that the bacterium persists in the environment as the result of
a stable rodent-flea infection cycle. Mice, voles and gerbils have all been
suggested as enzootic hosts2. The rapid spread of disease occurs when
epizootic hosts such as the rat, prairie dog, squirrels or mice become
infected. In the US, prairie dogs or ground squirrels are often the rodent
reservoir1>2 and a local increase in the number of infected animals is
considered to be an indication of an increased risk of an outbreak of
plague2. In this situation the likelihood of direct infection of man is low,
but domestic pets, which come into contact with prairie dogs, can
become infected and then transmit the disease to man either via infective
fleas even or via the pneumonic route. In the US, there has been an
increase in the number of human cases of primary pneumonic plague,
especially in veterinarians, following exposure to infected cats2.
Changes in the incidence and pattern of disease
Changes in the patterns of contact with animal reservoirs
Where man and rodents are in close proximity, or when the rodent
population is reduced, as a result of the disease or as a consequence of
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rodent control measures, humans and other warm blooded mammals
serve as alternative hosts for the infective fleas. The increase in plague in
Vietnam during the Vietnam war has been attributed to deforestation
which resulted in the movement of animal hosts into areas inhabited by
man1. In the US, a new trend in plague epidemiology appears to be
related to the residential encroachment on former rural areas which
contain enzootic foci of plague2. This can lead to infection of humans as
a result of bites by infected fleas or to infection as the result of close
contact with domestic cats which have become infected2. In summary,
any change which results in man encroaching on areas of plague foci or
which leads to the movement of infective animals hosts into populated
areas brings with it the risk of an outbreak of plague.
Potential for spread by mass transport systems
The spread of plague during the great epidemics can be associated with
the movement of man or infected animal hosts along trading routes. The
spread of plague into South Africa and into San Francisco during the
period 1899 to 1902 is thought to have occurred as a result of the entry
of infected rats on ships from the Far East10. The potential for the rapid
spread of plague by mass transport systems (especially air transport) was
also of concern during the Indian outbreak of plague. This concern is
related especially to the pneumonic form of the disease because
individuals with little evidence of serious disease when boarding a longhaul flight could become infectious during the flight. The spread of
disease by air transport was controlled by two measures. Firstly, crews
on flights which originated from or continued through India were
instructed to pay special attention to passengers with a fever, cough or
chills and to notify the destination airport of such passengers11. In many
countries, investigations also took place when the flight landed and
passengers who displayed symptoms which might indicate pneumonic
plague were placed under the surveillance of the local health
department11. If there was no rise in temperature or the development of
further symptoms in the following 7 days, the individual was considered
to be free from plague11. If plague could not be excluded as a cause of
disease, then the individual might have been placed in an isolation
hospital. There was also concern that an infected individual might have
transmitted the disease to other travellers. However, the air flow on
passenger aircraft is downwards and only individuals within 2 m of the
patient were considered to be at risk of inhaling an infectious dose of the
bacteria11. The possible impact of rapid mass transport systems on the
spread of infectious disease was amply demonstrated during the Indian
outbreak of plague and served to heighten our awareness that suitable
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systems and facilities for the diagnosis and surveillance of individuals
infected with dangerous pathogens must be maintained.
Advances in the prevention and treatment of disease
Current vaccines
Two types of plague vaccine have been used in man. One of these, the
killed whole cells vaccine was first produced in 1946 and, over the past
decade, there have been several commercial suppliers of this type of
vaccine6. It is generally considered that antibody against the Fl capsular
antigen is the key protective response induced by these vaccines6. The V
antigen is also known to induce a protective response against Y pestis
but the level of V antigen is low or undetectable in killed whole cells
vaccines12. There is good epidemiological evidence that the killed whole
cell vaccine was at least partially effective against bubonic plague.
During the period 1961-1971, many thousands of Vietnamese civilians
developed plague but the incidence of disease in immunised US troops
based in Vietnam was low during this period6. Furthermore, serological
studies indicated that some immunised individuals were exposed to Y
pestis and some developed sub-clinical infections6. Evidence from studies
in a murine model of disease indicates that the vaccine is less effective
against pneumonic than bubonic plague and cases of pneumonic plague
have been reported in vaccinated individuals6'13. The reason for the
lower efficacy of the vaccine against pneumonic plague is not known,
but the rapidity with which this form of the disease develops may
overwhelm the primed host defence mechanisms.
Improved vaccines
Over the past few years, a wide variety of antigens from Y pestis have
been evaluated as potential components of a sub-unit vaccine14. The Fl
and V antigens show the greatest potential as components of an
improved vaccine14. Immunisation of mice with a mixture of the Fl and
V antigens induced protection against 109 cfu of Y pestis given by the
subcutaneous route and also protected mice against at least 100 LDJ0
doses of Y pestis given by the inhalation route15. Protection appears to
be mainly antibody-mediated. When cultured at 37°C, the bacterium
produces large amounts of the Fl capsule which surrounds bacteria2 and
antibody against the Fl antigen is thought to opsonise these bacteria.
The V antigen has been shown to affect the ability of host phagocytic
cells to produce TNFoc and EFN-y in response to infection2. Antibody
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against the V antigen would allow the host to mount a normal
inflammatory response which would enable the host phagocytes to clear
bacteria opsonised by antibody against Fl antigen. The Fl+V antigen
subunit vaccine shows good promise for development as a replacement
for the killed whole cell vaccines and this vaccine is currently being
developed for use in man.
Antibiotic therapy
A variety of antibiotics are effective against bubonic plague and
antibiotic resistant strains have been reported infrequently2. One notable
exception involves the recent isolation, from a case of bubonic plague in
Madagascar, of Y. pestts which was resistant to ampicillin, chloramphenicol, kanamycin, streptomycin, sulfonamide and tetracycline16.
Even without the complication of antibiotic resistance, the treatment of
septicaemic and pneumonic plague is difficult; in the former case
because diagnosis is often not made at a sufficiently early stage and in
the latter case because the disease develops so rapidly that many patients
are already close to death when treatment commences. Streptomycin is
the drug of choice2 but should be used with care since the ensuing
bacteriolysis can result in the release of large amounts of endotoxin.
Tetracycline is often used prophylactically and chloramphenicol used to
treat plague meningitis2.
Key points for clinical practice
Plague is a disease which most medical practitioners will not encounter
during their working lifetime. However, plague does occur in many
countries throughout the world and the incidence of disease does not
appear to be declining. The epidemic potential of the disease is well
recognised and any suspect case of plague must be reported to the public
health authorities and confirmed cases of plague must be reported to the
WHO. Outbreaks of the disease can occur explosively, especially when
natural disaster strikes an area of the world where endemic plague foci
already exist. Rapid mass transport systems provide the means for the
spread of disease to other countries. Pneumonic plague is especially
feared in this context, since the disease develops rapidly and is readily
transmissible from man to man. Vaccines might well play a role in the
control of disease in areas of the world where the disease is endemic but
antibiotics will continue to play a key role in the control of disease in
infected individuals arriving in the UK. Such a case of plague will
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certainly require hospitalisation in an isolation ward and measures will
need to be taken to identify contacts who might have become infected.
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