Table of contents :
Epidemiology
: > 2,000 years ago, a plague gripped the Greek city of Athens. Ultimately,
as much as a third of the population succumbed and the devastation, which
helped Sparta gain the upper hand in the nearly 30-year-long war between
the city-states. That much Thucydides--an ancient historian, general in
the war and plague victim who recovered--conveys in his History of the
Peloponnesian War. But he did not leave a precise enough description
to decide definitively whether the disease was bubonic plague, smallpox
or a host of other ailments. Now DNA collected from teeth in an ancient
burial pit points to typhoid fever. In 1994 researchers discovered a mass
grave containing at least 150 bodies, including those of infants, deep
beneath the Kerameikos cemetery in Athens. Contrary to Greek custom, the
arrangement of the interred bodies grew progressively more haphazard as
they were piled on top of one another and few burial offerings, which included
a small number of vases, were left with the hastily buried corpses. Scientists
dated the vases to roughly 430 B.C., which is coincident with Thucydides'
report of when the plague broke out in the city. 3 random teeth samples
were picked from the plague victims and extracted the dental pulp. This
soft core under the hard tooth covering can store pathogens and other information
about the body for centuries. The researchers also tested 2 modern teeth
to make sure that no false results were indicated. Proceeding randomly
through a list of possible causes, Papagrigorakis' team tested the pulp
for the bacteria responsible for the bubonic plague, typhus, anthrax, tuberculosis,
cowpox and catscratch disease before finding a match in Salmonella
enterica serovar Typhi
--the
bacteria responsible for typhoid fever.
Typhoid fever--transmitted by contaminated food or water--causes fever,
rash and diarrhea, all closely matching Thucydides' account of the terrible
plague. The only thing that does not match up is the quick onset of the
disease, because modern cases of typhoid fever typically take longer to
gestate. This inconsistency may be explained by a possible evolution of
typhoid fever over time. Considering the overcrowding and unsanitary conditions
especially regarding the water supply within the walls of the besieged
Athens, a typhoid epidemic would have been likely to break outref.
In the 14th century plague killed one third of Europe's population
: around 1348, the population of England was estimated to be about 4 million,
and within 2.5 years about 1/3 had died from plague, sometimes called The
Great Dying. One third of the residents of Florence died in the first 6
months of the epidemic and as much as 75 percent died in a single year.
Venice lost 60 percent of its population over 18 months that the epidemic
raged. The last pandemics started in 19th century in China and
killed 12 millions people. Plague is still present in ... :
-
Africa (where some people live in rat-infested villages, the death toll
is the highest in the world) : Uganda and the Democratic Republic of the
Congo. Pneumonic plague affected 130 suspect cases, including 57 deaths,
in Zobia (a town that was home to at least 7000 diamond miners, some 300
km (186 miles) north of the provincial capital Kisangani), Bas-Uele district,
Oriental province in eastern Congo, since 15 Dec 2004 to Mar 2005. The
disease might have spread when 4000 of the miners left Zobia and disappeared
into the bush 2 weeks ago, fleeing the disease and clashes involving various
factions of the security forces guarding the mining arearef.
As of 19 Jun 2006, WHO has received reports of 144 cases of suspected pneumonic
plague, including 22 deaths in Ituri district, Oriental province. Suspected
cases of bubonic plague have also been reported, but the total number is
not known at this time. Ituri is known to be the most active focus of human
plague worldwide, reporting around 1000 cases a year. The 1st cases in
this outbreak occurred in a rural area, in the Zone de Sante of Linga,
in mid-May 2006. There are now 12 zones in Ituri -- with total population
of almost 100 000 -- affected by the plague outbreak. Bubonic plague, a
less contagious form of the disease, is endemic to Ituri.ref1,
ref2,
ref3.
-
Asia : carriers of plague in central Asia are often Camelidae
getting their feet stuck in gerbil burrows, picking up the disease and
passing it on to their owners
-
endemic in Mongolia
-
the last case of plague was registered in Russia in 1979
-
Kazakhstan was the only former Soviet republic reporting plague : this
is, in part, because the Soviet Union actively suppressed all reports of
plague outbreaks. In fact, in 1949-50, there was a sizeable outbreak of
pneumonic plague, which may have killed upwards of 100 people, according
to Dr. Lev A. Melnikov, who was an eyewitness. Melnikov attributed the
outbreak to the dangerous plague reservoir Rhombomys
optimus
(the great gerbil). The first reports were from 1989. In the 1989-1997
period, 11 cases with 4 deaths were reported from the Guriev and Kzyl-Orda
regionsref
-
Turkmenistan : an epidemic of plague began in May 2004 : > 20 deaths (7
in Mari, Ashgabad ) after 25 years of absence
-
rural Americas (< 1.4% of world cases annually) :
-
North America : southwestern USA. The introduction of plague into the US
via California in 1900Lipson LG, 303-310 led to the spread of
the infection eastward across about halfway across the country, but it
did not reach the east coast (there are about 10-15 cases each year in
humans in the USA) : although endemic in rodent populations the western
USA, plague is most commonly seen in 2 regions:
-
firstly :
-
northern New Mexico : there were no reported cases of human plague in the
state in 2004. 1 case was reported in Torrance County in 2003 and
2 cases were reported in 2002 in Santa Fe County. The last plague
fatality occurred in 1994 in a Rio Arriba County child. There have been
cases of plague in animals reported in 2005 in Rio Arriba, Santa Fe, Taos,
Los Alamos, Colfax and Bernalillo Counties : an adolescent from Santa Fe
County was affected by bubonic plague in July 2005 (rock squirrels collected
in the vicinity of the patient's home were heavily infested with fleas,
and fleas were collected from burrows in the area).
-
northern Arizona
-
southern Colorado : 3 Coloradans contracted plague in 2004 and 1 person
died. In 2005 there were also 3 human cases of plague. 43 positive cases
of plague in animals have been documented in Colorado in 2006ref
-
Utah
-
Texas : the last recorded human case of plague was in 1993 in a Kent County
resident : in 2004 it has been isolated near the Midland-Glasscock counties
border in West Texas and in fleas from wild prairie dogs in Dallam County
in the Texas Panhandle
-
secondly, California, southern Oregon, and western Nevadaref
The last urban plague epidemic in the USA occurred in Los Angeles in 1924-25.
Since then, human plague in the USA has occurred as mostly scattered cases
in rural areas (an average of 10 to 15 persons each year).
The FBI and CDC are investigating the disappearance from a New Jersey
research lab of at least 3 mice carrying a deadly strain of plague. The
rodents have been missing for 2 weeks. Sources say FBI agents and bioterrorism
experts are interviewing and polygraphing employees at the University of
Medicine and Dentistry in Newark, N.J., the location of the lab run by
the Public Health Research Institute, a leading center for research on
infectious diseases. There are no indications of terrorism. The FBI responded
to the matter, and we dedicated a great number of agents as well as a large
number of resources to the investigation, which is still ongoing : we're
satisfied that there is no public safety risk and there doesn't seem to
be any nexus to criminal activity or terrorism. New Jersey officials also
are downplaying the health risk. They believe the infected mice probably
died quickly. However, some government officials are deeply concerned about
what the case says about security of some of the most deadly infectious
disease projects and research labs. One source admitted that while officials
are saying there is minimal health risk, no one can be entirely certain.
There is minimal information provided, but "3 mice" possibly represents
only a single box of such animals in a BSL-3 facility. Occam's razor would
indicate a stupid mistake, but as the loss was noted 2 weeks ago, all probable
explanations will have been investigated and the answer is still being
sought. If the mice had died, been incinerated, and the box emptied, cleaned,
and sterilized, all traces will have been lost, along with any memories
of what had happened. But the card for the box should have been kept along
with any comments. If this were a break-in by Friends of the Earth, there
would have been ancillary damage unless this has been suppressed. They
have the experience to carry out such a "raid" -- if raid it was. Clearly
those involved are assuming that the mice have died, if they were removed.
Odd, but those with experience of such facilities probably have plenty
of pre-Homeland Security war stories.
3 mice infected with the bacteria that cause bubonic plague have gone
missing from a laboratory in Newark, New Jersey. Authorities have launched
a search for the animals and an investigation into how they might have
escaped. But researchers are quick to add that the mice, even if they are
on the loose, pose little risk to the public. At this point we are satisfied
that there is no public-safety risk, but the investigation is ongoing.
The mice, which carried Yersinia pestis, were being studied at the
Public Health Research Institute as part of a vaccine experiment. The institute,
which handles about 10,000 mice a year, had a total of 24 plague mice in
this experiment. Eight of these had not been vaccinated, 8 had been given
the best current vaccine, and 8 had an experimental version: each group
is missing a mouse, and has been for the past two-and-a-half weeks. There
are many potential explanations. The rodents could have been stolen or
accidentally incinerated along with bedding from the cages. It is even
possible that they ate each other, as mice are known to do this when they
have plague. The institute's director, David Perlin, acknowledges the possibility
of theft, but says he thinks it is more likely to be an honest mistake.
Some estimate that research into plague and plague vaccines has tripled
in the United States following fears of bioterrorism sparked by the 11
September 2001 attacks. This trend means there are more infected animals
scattered about the country that could, potentially, go missing. But experts
have expressed surprise that such mice could actually escape. Research
on plague takes place under tight security, in labs categorized as BSL3
and the entire lab is under video surveillance. The CDC is working with
the FBI and local officials to see what happened. If the mice did actually
escape from the lab, they would have quickly died from the disease. And
the animals' bodies wouldn't be expected to pose a risk after decomposing
for several days. Having plague running wild is not as unusual as some
might think
A Los Angeles woman is being treated for bubonic plague, the 1st case
of the age-old pestilence in the county since 1984, health officials announced
Tue 18 Apr 2006. She may have contracted the disease from fleas in the
area around her Country Club Park neighborhood. Although human cases of
the plague are uncommon, it is endemic to ground squirrels and some rodents
in parts of the Angeles National Forest, Tehachapi, Lake Isabella and Frazier
Park.ref
-
South America :
-
Peru : northern
-
Bolivia : in the Department of La Paz
-
Brazil : several areas in northeastern
-
Ecuador : the Chimborazo Province since 1977ref.
200-350 cases per year were reported from 1961 to 1966. 2 outbreaks of
pneumonic plague occurred in Guamote county/canton, Ecuador in 1998 (160
casesref1,
ref2)
and 2004. Plague has been reported in this general region since first reports
of cases in Chimborazo in 1977. There was a major outbreak in 1998 (approximately
160 cases) and 14 cases reported in 1999ref
..., causing 1,000-4,000 deaths per year. Worldwide, there were nearly
2,700 human cases and 175 deaths from plague in 2001. The following children's'
rhyme (of unclear origin) has elements that can be interpreted as being
related to plague, epidemic in the Middle Ages.
Ring around the rosies,
A pocket full of posies,
Ashes, ashes!
We all fall down
Rosies represent rosary beads, used to (hopefully) provide divine intervention
against the disease. Plague victims may emit a rather strong and objectionable
odor; flowers (posies) could be carried to mask the smell. Ashes
are all that was left of a burnt corpse (in the Middle Ages). "All fall
down" reflects the profound death rate. Alternatively, for the last 2 lines
of the rhyme: The 3rd line can be replaced with "A Tishoo, a tishoo," which
represents the sneezes of the victims of pneumonic plague which are infectious
to others. To be sneezed on by them was a sure death sentence for all.
The death rate for those who acquire pneumonic plague directly is almost
100%.
Genomics : as many
as 13% of Y. pseudotuberculosis
genes no longer function in Y. pestis. The number of insertion sequence
(IS) elements (DNA sequences capable of interfering with gene expression)
has dramatically expanded in Y. pestis, delineating the probable
role of IS expansion in the elimination and modification of preexisting
gene expression pathways
Proteomics :
-
3 biovars :
-
antiqua
-
orientalis
-
medievalis
-
microcapsule, no flagella.
-
PLD is required for survival in the midgut of rat flea.
-
> 19 different antigenic components. Virulence factors (all plasmid-encoded)
:
-
fraction 1 (F1) capsular antigen is the principal antigen involved
with both virulence and immunity. Although some experts consider a titer
of antibody to F1 (determined by PHA) of at least 1:32 to be indicative
of protection, the U.S. ACIP states that the minimum titer of antibody
to F1 capsular antigen (determined by PHA) indicative of adequate protection
against plague infection is 1:128 in animals.
-
V antigen
-
W antigen
-
exotoxin
-
endotoxin
-
pesticin
-
protease
-
coagulase
-
fibrinolysin
Transmission
: a zooanthroponosis :
-
reservoir :
-
Rattus rattus
and Rattus norvegicus
,
great gerbils (Rhombomys
opimus
)
-
less commonly other animals may be exposed to plague infection either by
feeding on infected carcasses or by becoming infested with infected fleas
-
Lynx rufus

-
Felis
catus
(extremely sensitive : when sylvatic outbreaks occur in rodent populations,
domestic cats can be infected by fleas on the rodents or by direct contact
with infected rodent tissues as they chomp on squirrels or other rodents.
The incubation period in cats may be short, a day or 2, and marked by a
fever of up to 41.5°C and lymphadenopathy. Typical buboes often occur
in the head and neck, which can be mistaken for cat fight abscesses. Bubonic
plague is of zoonotic concern as individuals may contract disease from
either infected fleas or contact with purulent discharges from ruptured
bubos or blood from the cat. An even greater threat occurs when the disease
in cats progresses to pneumonic plague. This has been documented in cats,
including transmission to veterinarians and owners. Antibiotic treatment
is effective in cats, but the threat of plague is only one of many reasons
that people should keep their pets free of fleas. There are many good flea
control products and methods of eliminating fleas from the animal as well
as the yard. If an animal owner is having trouble with fleas, a visit
to the veterinarian may be in order. If an animal has a swelling, extra
caution should be taken by the animal owner as well as the veterinarian.
The swellings may rupture and expose the owner and/or the veterinarian
to the plague agent. The disease is treatable with antibiotics, so a trip
to the veterinarian may be in order)
-
Canis familiaris
(considered to be less susceptible than cat), ground squirrels (sylvatic
plague in the western United States)
-
marmots
-
Canis latrans

-
Odocoileus
hemionus

-
Cynomys parvidens
(often considered sentinel animals because of their susceptibility to the
organism)
-
Oryctolagus cuniculus
(contact with infected rabbit carcasses has been a significant source of
infection for man during the winter)
-
Sylvilagus audubonii

-
Neotoma spp.

-
of the domestic animals, Bos
taurus
,
Equus
caballus
,
Ovis
aries
and Sus scrofa
are
not known to develop plague
-
Capra hircus
and Camelidae
have reportedly developed clinical illness, and there have been several
human outbreaks of plague attributable to ingestion of camel meat infected
with Yersinia pestis in Middle Eastern and Central Asian countriesref
-
bite of infected vectors : Xenopsylla
cheopis
,
Nosopsylla
fasciatus
,
Leptopsyllaspp.
,
Pulex
irritans
.
Fleas become infected upon feeding on the blood of a rodent suffering from
bacteremic infection. The bacteria are restricted to the alimentary tract
of the flea, where they multiply in the midgut. The
bacteria may form large brown clumps that extend throughout the midgut,
esophagus and proventriculus, a valve-like chamber situated between the
esophagus and the midgut. The clumps increase in mass over a few days until
the proventriculus is blocked. The "blocked" flea then feeds on blood,
but the meal is unable to pass into the stomach. The flea continues to
attempt to feed, but as it futilely sucks blood from the host, the blood
meal, mixed with bacteria from the foregut, is regurgitated into the mammal.
As many as 24 000 bacilli may be transmitted in a single attempted feeding
(Burroughs, AL: Sylvatic plague studies. The vector efficiency of nine
species of plague compared with Xenopsylla cheopis. J Hyg 1947;45:371-96)
-
contact with breath or ingestion of infected reservoirs
-
human-to-human infection usually occurs by inhalation of plague bacilli–laden
droplet aerosols
Pathogenesis :
plague bacteria are thought to inject so called effector Yops via the type
III pathway into host cells. The identity of host cells targeted for injection
during plague infection is unknown. Using Yop
b-lactamase
hybrids and fluorescent staining of live cells from plague infected animals,
it was found that
Y. pestis selected immune cells for injection.
In
vivo, dendritic cells, macrophages and neutrophils were injected most
frequently, whereas B and T lymphocytes were rarely selected. Thus, it
appears that
Y. pestis disable these cell populations to annihilate
host immune responses during plague
ref.
Y.
pestis is able to replicate in macrophages that are activated with
IFN-
g after infection (postactivated). A region
of chromosomal DNA known as the pigmentation (
pgm) locus was required
for replication in postactivated macrophages, and this replication was
associated with reduced nitric oxide (NO) levels but not with reduced iNOS
expression.
Y. pestis pgm replicated in iNOS
-/- macrophages
that were postactivated with IFN-
g, suggesting
that killing of
Dpgm Y. pestis is NO-dependent.
A specific genetic locus within
pgm, which shares similarity to
a pathogenicity island in
Salmonella, was shown to be required for
replication of
Y. pestis and restriction of NO levels in postactivated
macrophages. Intracellular
Y. pestis can evade killing by macrophages
that are exposed to IFN-
g and identify a potential
virulence gene encoded in the pgm locus that is required for this activity
ref.
=> plague / pest / pestis :
-
bubonic or glandular plague / pestis bubonica (85-90% : incidence
: 1,000-3,000 / yr ; lethality : 15-30%, none if treated with antibiotics)
: 2-15 days incubation => abrupt onset of fever, chills, weakness, and
headache, followed by regional lymphadenitis
(malignant buboes => secondary buboes undergo necrolysis => hemorrhages),
most often the femoral > inguinal (90%), axillary, and cervical nodes =>
suppuration, associated with a marked hemorrhagic tendency (hemorrhagic
plague) and the development of DIC
and necrotic purpura and extensive symmetrical gangrene (which may have
led to the epithet “black death”). Local bacterial proliferation
is sometimes evident (4-10% of cases) in the form of an abscess or ulcer
at the site of infection. Usually heralded by very severe pain within 6-8
hours after the onset of constitutional symptoms, the bubo becomes evident
within 24 hours. The bubo may be so tender that semicomatose patients will
posture in a way to attempt to decrease pressure on the swelling. The bubo
may not be evident in the 1st few days of symptoms. Furthermore, involvement
of deeper lymph nodes may not be visible. In these cases, abdominal pain
suggestive of appendicitis, colitis, enteritis or cholecystitis may be
described. In such cases, tenderness upon abdominal palpitation will be
misleading and may result in hazardous exploratory surgery and a potentially
lethal delay in specific antimicrobial therapy (McGovern, T. W. and Friedlander
A. M. Plague. In Zajtchuk R. and Bellamy R.F. (eds.) Textbook of Military
Medicine: Medical Aspects of Chemical and Biological Warfare. Office of
the Surgeon General, Borden Institute, Washington, D.C., pp 479-502)
Therapy :
IM streptomycin
is the first line treatment, though IM or IV gentamicin
is frequently used. IV or po chloramphenicol
,
tetracycline
or doxycycline
are also used over a 7-10 day period, reducing mortality from 60% to less
than
15% => recovery (expecially from pestis minor / ambulatory plague /
parapestis / pestis ambulans : a mild form of bubonic plague, usually
occurring only in endemic areas, with lymphadenitis, fever, headache, prostration,
and a short course) or hematogenous dissemination => suppurative foci throughout
the body =>
-
septicemic plague / pesticemia / pestis siderans / plague septicemia
/ siderating pestis / pestis fulminans / pestis major : acute fulminating,
high-density
bacteraemia
occurring in the acute stage of bubonic plague (within day 6-7), or as
a so-called primary infection that may present and result in death before
the appearance of buboes or of pulmonic manifestations
-
meningeal plague
/ plague meningitis
=> coma vigil / "typhoid
status"
-
secondary plague alveolar
pneumonia
,
which is also the contagion source for ...
-
primary pulmonic or pneumonic plague / plague pneumonia (1% of natural
plague presentations) : a rapidly progressive, highly contagious alveolar
pneumonia
due to inhalation of droplet nuclei expelled during coughing (from infected
animals or other humans with pneumonic plague) in which there is extensive
involvement of the lungs and productive cough
with mucoid, blood-stained (hemoptysis), foamy, plague bacillus–laden sputum,
with incubation period ranging from some hrs up to 5 days => 100% lethality
in < 4 dd due to septic
shock
=> coma
if antibiotics aren't administered within 24 hours. Patients with primary
pneumonic plague generate large quantities of infectious aerosols that
pose a significant risk to close contacts. CDC guidelines identify contacts
within 2 meters as being at greatest risk and do not consider the organism
likely to be carried through air ducts or vents. Persons who have been
in contact with pneumonic plague patients or handling potentially infectious
body fluids or tissues without appropriate protection should receive preventive
antimicrobial therapy with tetracyclines, quinolones, or chloramphenicol
-
pharyngeal plague
/ plague pharyngitis

It is considered by CDC as a category A
biological
weapon
.
Laboratory
examinations : dipstrip rapid detection test (RDT) for
F1 antigen
in blood, bubo pus, or phlegm
Prevention
:
-
local officials could simply assess numbers of great gerbils (Rhombomys
opimus
)
and cull them during an upswing, rather than capturing the animals and
performing expensive lab tests as they now do. As shown in Kazakhstan You
could know about an outbreak 2 years in advance upswing, rather than capturing
the animals and performing expensive lab tests as they now doref.
The disease tends to crop up around 18 months after a heavy winter rainfalls
that could have fed the plants on which rodents nibble
-
killed
vaccine

Web resources
: