Journal of Infection (2013) 66, 18e26

www.elsevierhealth.com/journals/jinf

Plague: History and contemporary analysis

Didier Raoult a,*, Nadjet Mouffok b, Idir Bitam c, Renaud Piarroux d,
Michel Drancourt a

a
Aix Marseille Université, Unité des Rickettsies, UMR CNRS 7278, IRD 198, INSERM 1095, IHU Méditerranée Infection, 27
Boulevard Jean Moulin, 13385 Marseille, Cedex 05, France
b
Service des Maladies Infectieuses, Centre hospitalo-universitaire d’Oran, 72 Boulevard Docteur Benzerdjeb,
31 000 Oran, Algeria
c
Laboratoire d’Ecologie des Syste
mes Vectoriels, Institut Pasteur d’Algérie, 1 Rue du Docteur Laveran, Hamma, Alger
16000, Algeria
d
Laboratoire de Parasitologie et Mycologie, LaTimone Academic Hospital, Marseille, France et Aix Marseille University,
UMR-MD3, Marseille, France

Accepted 26 September 2012

Available online 3 October 2012

KEYWORDS Summary Plague has caused ravaging outbreaks, including the Justinian plague and the
Plague; “black death” in the Middle Ages. The causative agents of these outbreaks have been con-
Yersinia pestis; firmed using modern molecular tests. The vector of plague during pandemics remains the sub-
Black death; ject of controversy. Nowadays, plague must be suspected in all areas where plague is endemic
Louse; in rodents when patients present with adenitis or with pneumonia with a bloody expectorate.
Reemergence Diagnosis is more difficult in the situation of the reemergence of plague, as in Algeria for ex-
ample, told by the first physician involved in that outbreak (NM). When in doubt, it is prefer-
able to prescribe treatment with doxycycline while waiting for the test results because of the
risk of fatality in individuals with plague. The typical bubo is a type of adenitis that is painful,
red and nonfluctuating. The diagnosis is simple when microbiological analysis is conducted.
Plague is a likely diagnosis when one sees gram-negative bacilli in lymph node aspirate or bi-
opsy samples. Yersinia pestis grows very easily in blood cultures and is easy to identify by bio-
chemical tests and MALDI-TOF mass spectrometry. Pneumonic plague and septicemic plague
without adenitis are difficult to diagnose, and these diagnoses are often made by chance or
retrospectively when cases are not part of an epidemic or related to another specific epidemi-
ologic context. The treatment of plague must be based on gentamicin or doxycycline. Treat-
ment with one of these antibiotics must be started as soon as plague is suspected. Analysis
of past plague epidemics by using modern laboratory tools illustrated the value of epidemic
buboes for the clinical diagnosis of plague; and brought new concepts regarding its transmis-
sion by human ectoparasites.
ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.

* Corresponding author. Tel.: þ33 4 91 32 43 75; fax: þ33 4 91 38 77 72.

E-mail address: didier.raoult@gmail.com (D. Raoult).

0163-4453/$36 ª 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.jinf.2012.09.010
History and contemporary analysis of plague
Introduction
Plague is primarily a murine zoonosis. Humans are in-
cidental hosts that do not contribute to the natural cycle
of the disease outside of epidemics. The Yersinia pestis
bacterium is the causative agent of plague and can be
transmitted by fleas, bites, scratches, aerosols, or contam-
inated food.1 Plague is one of the most important diseases
shaping the history of humanity because few microbes have
killed as many as a third of the whole population during
a pandemic or have changed the course of history.1 The
transmission of Y. pestis during a pandemic is not com-
pletely understood. Y. pestis is primarily transmitted be-
tween wild animals by ectoparasites, fleas in particular.
Sporadic cases in humans can be the result of various modes
of transmission, but it is difficult to explain historical
plague pandemics by transmission solely by rat fleas. The
mode of plague transmission during pandemics has been
the subject of a very heated debate.
It should be noted that the description of the buboes
associated with an epidemic provided a clue leading to
plague. A precise historical description by Procopus in-
dicated that the Justinian plague was caused by Y. pestis.
The second pandemic plague, which started in the 14th
century (the “Black Death”), was well described by Guy
de Chauliac as an epidemic associated with adenitis
(bubo) and high mortality.2 Currently, we do not know of
any other epidemic diseases of this nature, and it is clear
that this disease was also plague.
History
The analysis of plague corpses in Marseilles was instrumen-
tal in developing the field of paleomicrobiology. In these
studies, modern diagnostic tools were used to analyze the
dental pulp of people thought to have died of plague.3e6
This analysis allowed the role of Y. pestis to be confirmed
and the genotype of the causative agent to be identified.
The origin of the first historical epidemics of plague is
unclear, as the name “plague” refers to nonspecific diseases.
In contrast, the word “bubo” (defined as adenitis in the groin)
is specific to plague. The plague in Athens does not seem to be
related to Y. pestis but instead to Salmonella typhi.5 The
plague that prevailed at the beginning of the Roman Empire
under the Antonine emperors has not been explained. The
Justinian plague (starting in 541) is the first confirmed plague
pandemic. This pandemic stopped the re-conquest of the Ro-
man Empire and has been formally identified retrospectively
as being caused by Y. pestis based on the analysis of the teeth
of people buried at that time.6 The medieval plague (starting
in 1347) is the second pandemic. This pandemic devastated
Europe and may have killed 30% of the population. This pan-
demic was also formally determined to be caused by Y. pestis
in Northern and Southern Europe.7 The last pandemic, which
started in the 19th century (1894), has had a lesser effect on
the demography of the human population but is ongoing in
Africa and America.8
The telluric reservoir of Y. pestis has been the subject of
many debates. It has been demonstrated that Y. pestis can
19
remain alive in a dormant form in soil for a period of several
months or years.9 This finding was recently confirmed in
laboratory experiments10 and in the field following a small
epidemic in the USA.11
Epidemiology
Overall, the epidemiology of plague must be seen in a much
less diagrammatic manner than in the past. However,
outbreaks of either bubonic or pneumonic plague, some
causing dozens of deaths, have recently been reported in
northeastern Democratic Republic of Congo. Many rodents
are susceptible to plague, as many other animals are.1,12
Sporadic cases of this zoonosis in humans can be due to
transmission by rodent fleas or to the consumption of in-
fected food, to wounds or to exposure to aerosolized bacte-
ria. The consumption of infected camels is considered
a source of Y. pestis infection1 (Fig. 1).
In all cases, the ability of Y. pestis to survive in the soil
makes it possible to explain the persistence of this bacte-
rium in environments in which it has been established,
even when no cases are observed among animals (Fig. 1).
Transmission during pandemics is difficult to explain
based only on rat fleas, which are responsible for multiple
sporadic cases. The inability of fleas to explain plague
transmission is particularly clear during the winter, when
flea activities are low. During the winter, inter-human
transmission appears to be prevalent. Transmission via
aerosols can cause plague pneumonia. However, it was
recently shown that this mode of transmission was far from
effective during an epidemic in Uganda, where only the
premortem forms presented a direct risk of inter-human
transmission by cough, and only with very close contacts.13
Therefore, direct transmission by aerosols may not explain
pandemics. Regarding inter-human transmission, at the be-
ginning of 20th century, Balthazard hypothesized that the
human body louse can be a vector of Y. pestis during pan-
demics, a hypothesis that we confirmed. Y. pestis can be
found in lice during epidemics.14 In experimental models,
it is possible to transmit plague to rabbits via lice.15 Indeed,
louse-transmitted diseases have caused the worst pan-
demics (typhus, trench fever, louse borne relapsing fever).
The recent discovery of concomitant outbreaks of Barto-
nella quintana and Y. pestis using human remains supports
this hypothesis.16,17 Finally, the role of the “human” flea
Pulex irritans may have been important (Figs. 2 and 3).
Geographical distribution
In recent years, 90% of reported cases of plague occurred
Africa, specifically eastern Africa, central Africa and
Madagascar, with small outbreaks occurring in North Africa.
Currently, only the Orientalis biovar is distributed world-
wide and is thus the only pandemic biovar. From 1958 to
2008, 17,000 cases were reported in Madagascar, 9000 in
Tanzania, 13,000 in Congo, 4800 in India, 3,500 in Vietnam,
5500 in Myanmar, 3693 in Brazil, 4091 in Peru and 438 in the
United States (Fig. 4). Recently, cases were discovered in
North Africa in countries including Algeria and Libya
20
Figure 1 Transmission of sporadic cases of plague to humans from infected animals.
(Fig. 5).18,19 The current mortality rate is 7%. In the United
States, the reported cases occur primarily in the southwest,
including the states of New Mexico, Colorado, California
and Texas.20
Routes of transmission
Sporadic cases of human plague are acquired from animals
by various routes. Plague, being a zoonosis, can be
contracted by contact with animals or their parasites12
and is most often acquired through flea bites, but this dis-
ease can also be transmitted by animal scratches or by the
inhalation of infected particles from animals having a respi-
ratory infection or during the autopsy of infected ani-
mals.1,21,22 Plague can also be contracted in laboratories
in which Y. pestis is handled.23 Recently, an infection by
a non-pathogenic Y. pestis strain in a laboratory was re-
ported.23 Although in most patients with sporadic infec-
tions, a flea bite is suspected to have occurred, actual
clinical evidence of flea bite is rarely observed. Cats and
dogs play a part in human infections, either by bringing in
infected fleas or by producing aerosols, particularly by
cats with plague pneumonia.24,25 Finally, some cases have
been reported after the ingestion of infected meat, partic-
ularly camel meat7 (Fig. 1).
Animals play an important role in the spread of plague,
which is now present worldwide following the last pan-
demics.20 Most mammals can be infected by Y. pestis, but
rodents are the most common hosts. Many species of fleas
are likely to be vectors of plague, but the most effective
vector is Xenopsylla cheopis, the oriental rat flea (Table 1).
During outbreaks, human-to-human transmission can
result from aerosols or, perhaps, parasites such as lice.9
D. Raoult et al.
The rate of transmission via aerosols following pneu-
monia is generally low but was found to reach 8% in a study
in Madagascar,26 with most infected individuals being
asymptomatic.
Microbiology and pathogens
Y. pestis is a Gram-negative bacterium belonging to the en-
terobacteria family. This bacterium can be cultured easily
on ordinary media, and exhibits common characteristic of
enterobacteria in addition to a specific biochemical profile
which can be used for its phenotypic identification. Com-
parative genetic studies have demonstrated that Y. pestis
likely evolved by reductive evolution from Yersinia pseudo-
tuberculosis.27 Several biovars have been described, but
their classification is currently controversial because the
Antigua biovar is not homophyletic.19,27,28 A very popular
theory linking biotypes and pandemics26 led to the naming
of biotypes according to their putative role in each of the
3 pandemics: Y. pestis Antigua (Justinian Plague), Y. pestis
medievalis (“Black Death”) and Y. pestis orientalis (the
current pandemic). We demonstrated that this theory is in-
correct using genomic analysis of Y. pestis in teeth from the
remains of plague victims,28 and we showed for the first
time that the Antigua biovar was comprised of two distinct
branches using single-nucleotide polymorphism-based
trees. This finding was controversial but has been con-
firmed.28e30 The 3 causative agents of the pandemics are
related to Y. pestis orientalis. In all the cases, Y. pestis me-
dievalis has never been associated with pandemics, nor was
Y. pestis antigua associated with the Justinian plague.
Arthropods (fleas, lice) become infected when taking
a blood meal. The inoculation of Y. pestis through the skin
History and contemporary analysis of plague 21

Figure 2 Transmission of plague in focal epidemics.

causes a primary skin lesion (commonly neglected as a phys-
ical symptom in human plague cases15). The gene pla, har-
bored by a plasmid in Y. pestis, encodes for a protein that
blocks the ingestion of blood by the flea. As a consequence,
the fleas eat much more aggressively and regurgitate the
bacteria while biting their hosts.15 However, fleas that do
not exhibit this behavior can also serve as vectors. The
major clinical element of plague is the existence of a tender
area of adenitis, referred to by the name “bubo” where
Y. pestis is able to survive and multiply in macrophages.
The buboes may evolve to suppuration of the adenitis.
After lymph node invasion, the plague bacillus can cause
bacteriemia. Then, ectoparasites, either fleas or lice,
taking their blood meal from the infected patient can be

Figure 3 Putative transmission of plague during pandemics.

22
Figure 4 Geographical distribution of plague over the past 20 years.
infected and can transmit the bacterium. Severe forms of
pneumonia can occur without buboes. These forms can lead
to either a respiratory infection or a vectorized infection
reaching the trunk, without superficial palpable adenitis.
The virulence of Y. pestis15 has been suggested to be based
on several plasmid- and chromosome-encoded factors. Re-
cently, it was found that toxin-antitoxin modules are highly
expressed in Y. pestis.31 Moreover, toxin-antitoxin modules
Figure 5 In July 2008, three patients came to Laghouat Univer-
sity Hospital with signs of severe infection and painful, inflamed,
enlarged lymph nodes evoc of buboes. One additional patient
became ill with pneumonia and coma after a bubo appeared.
The patients were nomads living in a 24 people camp in Thait in
the Laghouat area, 550 km of Algiers.
D. Raoult et al.
have been proposed to be key factors in the pathogenicity
of bacteria associated with pandemics.32
It has been suggested that plague outbreaks positively
selected for a human gene (CCR5) encoding a chemokine and
that this gene is now responsible for resistance to HIV
infection. People with these mutations may be resistant to
the disease, and this resistance may explain the higher
prevalence of this mutation in Europe (where the pandemics
developed) than in Africa. Field work in rats in Madagascar
supports this theory,33 but the recent paleomicrobiological
studies do not support this theory (unpublished).
The fact that as few as 10 bacteria can be sufficient to
cause a human infection and that it has been speculated
that there is a high level of transmission via aerosols led to
the classification of Y. pestis as a possible bioterrorism
agent. This classification was based on deductive analysis,
and there is no documented example of the efficient use
of Y. pestis as a biological weapon.12
Clinical manifestations
Inoculation via a flea bite can cause a skin lesion that is not
usually reported. Depending on the site of inoculation,
infection of the regional lymph node that drains the
inoculation site may be observable (bubo) when the bite
is on the trunk. Inoculation through the skin after handling
a plague-infected animal also results in bubonic fever.
Inhalation results primary in pneumonia, and ingestion
(mostly camel meat or liver)1 results in pharyngitis with
cervical buboes. The buboes due to plague are different
from those due to other causes of lymphadenitis because
plague-related buboes are associated with systemic symp-
toms (hypotension, very high fever) and rapid clinical deg-
radation. A cluster of patients with buboes is also a very
good clue indicating plague.
The clinical presentation of plague depends on the mode
of infection and on reports.1,34e36 Patients typically exhibit
high fever, low blood pressure, chills and fatigue, and in
 History and contemporary analysis of plague
Table 1 Table showing the recorded cases in chronological order. Clinical and biological signs of plague in Oran epidemic 2003.
Age/sex Date Sudden Delay T Altered Bubo Bubo Microadpathy Leuco Intersticiel Bubo aspirate Ponction Blood Treatment Evolution Clinical WHO
onset (d) > 40 health abcsess cytosis pneumopathy du bubon form
Synd Direct Culture AgF1
intertitiel exam
M11 04/06  16 þ þ þ Hemorragy/ Septicemic S
died
M19 09/06  20 þ þ þ þ þ   þ  Ciprofloxacin Coma/ Septicemic C
survive
F27 14/06  10 þ  þ þ þ  þ þ  Ciprofloxacin Favorable Bubonic C
M71 14/06 þ 05   þ     þ  Ciprofloxacin Favorable Bubonic C
M26 15/06 þ 07   þ þ þ   þ  Ciprofloxacin Favorable Bubonic C
M20 16/06 þ 02   þ    Ciprofloxacin Favorable Bubonic S
M21 17/06 þ 04   þ  þ  Ciprofloxacin Favorable Bubonic S
F54 17/06  10   þ    Doxl Favorable Bubonic S
F25 19/06  09 þ þ þ þ   þ þ 
Ciprofloxacin Favorable Ulceration C
þ Dox
M27 21/06 þ 02   þ       Dox Favorable Bubonic S
M55 26/06  07   þ  þ   þ  Dox Favorable Bubonic C
M58 28/06 þ 09   þ þ    þ  Dox Favorable Bubonic C
F55 28/06  05   þ  þ þ Dox Favorable Bubonic C
F02 30/06  06   þ þ þ   þ  Thio þ gent Favorable Bubonic C
F04 30/06  05 þ  þ þ   þ þ  Thio þ gent Favorable Bubonic C
M07 01/07  07   þ     þ  Thio þ gent Favorable Bubonic S
F20  05   þ     þ  Dox Favorable Bubonic P
M28 22/07  04   þ     þ  Dox Favorable Bubonic P
M34 26/07  05   þ     þ  Dox Favorable Bubonic P

23
24
some cases, they exhibit cough, chest pain and dyspnea.
Most cases reported recently involved a bubo that was an
exquisitely tender lymphadenopathy, making the clinical
diagnosis relatively easy. The bubo can be located in the
groin, in the axilla, and more rarely on the neck or the
head. On examination, it is possible to find skin lesions
such as eschars or pustules as well as necrotic lesions and
Ecthyma gangrenosum infections.36 Some patients exhibit
severe septicemia and pneumonia and may have a bloody
expectorate.26 In a series of patients in India, some pa-
tients presented with symptoms similar to those of gastro-
intestinal or urinary tract infections.37
Pneumonia may be primary or secondary following
septicemia and can occur with or without buboes. When
primary, pneumonia may result from an infection acquired
via an aerosol from patients with pneumonia or from
infected animal materials (such as those from cats and
dogs)24,25 handled in laboratories studying Y. pestis.23 In-
fection via an aerosol can also occur following an autopsy
(a case of mountain Lion).21 The occurrence of interhuman
transmission via aerosols during pneumonic plague out-
breaks is a source of controversy. In work performed in Ma-
dagascar,26 it was reported that 8% of pneumonia cases
were contracted via the respiratory tract. In work conduct-
ed in Uganda,13 transmission was only observed in very
close contacts (caregivers) and during the patients’ last
days of life.13 Typically, patients with plague pneumonia
present with chest pain, cough and bloody sputum.
Cases without buboes are difficult to diagnose because the
patients present with a nonspecific disease that may be
associated with multiple organ dysfunction syndrome
(MODS). Patients with MODS account for 10e20% of cases,
with 1/3 of patients dying from this form of disease, three
times more than died during the bubonic plague. This high level
or mortality may be caused by the absence of a diagnosis, the
rapidity of the evolution, and the absence of early treatment.1
Mortality after untreated plague pneumonia is higher than
50%. The risk of pulmonary interhuman transmission (even
though very low) has led to the suggestion to strictly isolate pa-
tients with plague pneumonia under negative pressure.38
Routine clinical studies
Routine chest radiographs do not reveal specific ele-
ments.39 Blood analysis may be very informative. Most pa-
tients have hyperleucocytosis, and 50% have a white
blood cell count over 20,000/mm3. In contrast, half of pa-
tients have thrombocytopenia. The association of hyperleu-
cocytosis with thrombocytopenia is relatively rare and may
be a good indicator of plague.34 Interestingly, in many pa-
tients, eosinophilia is observed during convalescence.34
Diagnosis
Three diagnostic clues can make it possible to reach
a diagnosis quickly and to start specific treatment.26
1. The existence of fever after contact with dead rodents
in a zone where this zoonosis exists.
2. The existence of unexplained adenitis with fever and
hypotension.
D. Raoult et al.
3. Pneumonia with bloody expectoration and gram-
negative bacilli in the sputum.
These characteristics indicate a diagnosis of plague,
even in zones where plague is thought to have disappeared
(such as in Algeria).18,19 The examination of smears of the
material obtained by the puncture and aspiration of
a bubo allows the observation of gram-negative bacteria us-
ing bipolar staining and Giemsa staining. The existence of
gram-negative bacilli in a lymph node sample must immedi-
ately lead the prescription of treatment for plague because
there are extremely few types of adenitis caused by gram-
negative bacteria.40 The finding of gram-negative bacteria
in the bloody sputum from patients with community-
acquired pneumonia should also be considered as diagnos-
tic in endemic areas,26 especially if blood analysis reveals
both hyperleucocytosis and thrombocytopenia.
As far as diagnosis is evokated, it becomes straightfor-
ward. Y. pestis does not require special culture conditions
(although this bacterium grows faster at 28  C than
37  C). Samples suspected of containing Y. pestis should
be handled in a BL3 laboratory. Real-time PCR may be use-
ful because the sample can be easily decontaminated and
tested in a standard laboratory.41 The bacterium is easily
identified by standard microbiological methods, but
MALDI-TOF analysis is faster.42 The diagnosis can also be
made by the systematic analysis of the 16S rDNA in lymph
node biopsies, which lead to a diagnosis of plague even
when not suspected.40 In an epidemic situation, specific
tests can be developed that will have little use in other cir-
cumstances, but in Madagascar or in the Democratic Repub-
lic of Congo, the rapid tests based on immunodetection
allow a diagnosis to be made in a few minutes.43
Treatment and prevention
The early start of antibiotic treatment is an essential compo-
nent of a good prognosis in patients with plague.44,45 The stan-
dard treatment is streptomycin, and this antibiotic has been
used in most studies. Streptomycin can be replaced by genta-
micin at 3 mg per kg per day or with doxycycline at 200 mg per
day, with a first dose of 200 mg followed by 100 mg every
12 h12,46 Fluoroquinolones (such as ciprofloxacin) have an
in vitro effectiveness and have been demonstrated to be ef-
fective in animal models47 but have not been thoroughly eval-
uated in humans.48 Trimethoprim-sulfamethoxazole has been
used but yields less satisfactory results.49
In areas where Y. pestis circulates, gene recombination
and conjugation with other enterobacteria are possible,
and these processes can lead to the acquisition of antibiotic
resistance.44,50 In 1995, an isolate from a patient in Mada-
gascar was reported to harbor a plasmid conferring resis-
tance to aminoglycosides and tetracyclines,50 but this
isolate remained sensitive to cephalosporins, gentamicin,
quinolones and trimethoprim.
Prevention
Reducing exposure to the rodent fleas is the best pre-
ventative measure. In particular, it is necessary to avoid
collecting dead rodents because the fleas on dead animals
History and contemporary analysis of plague
are likely to bite humans after their hosts die. In addition,
animal corpses in zoonotic areas for plague must be
handled with caution due to the risk of infection. It was
recently found in in vitro experiments and in an experi-
mental model that lovastatin (a statin prescribed for the
long-term prevention of arteriopathy) has a protective
effect against plague.8 No human studies have been per-
formed. Post-exposure prophylaxis using doxycycline at
200 mg/day for seven days has been proposed.38
Box 1.History of the re-emergence of
plague in Oran in 2003.
We would like to describe the recent reemergence of
plague in Algeria. Plague had been forgotten for de-
cades before it reemerged in 2003.18 On the 9th of
June, 2003, a 20-year-old shepherd, a resident of Ke-
ha€ılia (Tafraoui, a rural area near Oran) without a re-
markable history was hospitalized for a severe
infectious syndrome that had been developing for 15
days. This syndrome began with fever and left inguinal
pain and evolved to tumefaction. The shepherd was
treated as an outpatient using antibiotics (oxacillin,
cefacidal, etc.), but his condition worsened. After in-
terviewing his neighboring uncle, we learned that 5
days earlier, his 11-year-old cousin had died. The in-
fant had presented with similar symptoms (fever, in-
flammatory adenopathy and left inguinal pain) and
had been treated as an outpatient with antibiotics.
His condition became severe, and his general condi-
tion deteriorated. A large left inguinal abscess was
noted, followed by rectorragy and death on the 4th
of June, 2003.
Para-clinical and clinical examinations of our 20-year-
References
old patient conducted on the 9th of June, 2003, iden-
tified purulent comatose meningitis (purulent C.S.F.,
negative bacteriological findings) and severe mitral in-
sufficiency. This case was reported to the Health Au-
thorities as suffering from purulent bacterial
meningitis on the 10th of June, 2003. A thorough phys-
ical examination revealed several cutaneous lesions
apparently due to mosquito or arthropods bites. The
patient slowly improved during treatment with antibi-
otics (cefotaxime and gentamicin, later used in combi-
nation with ciprofloxacin).
On the 14th of June, 2003, 5 days after the initial hos-
pitalization, 2 other patients were hospitalized for
painful left inguinal adenopathies, one of which par-
ticularly inflamed. These 2 patients lived in the same
town, and an interview revealed similar cases in the
vicinity. This clustering of cases led the medical
team to suspect a vectorial origin for the disease after
having eliminated other causes of inflammatory aden-
opathy. We encouraged these patients’ visitors to tell
people exhibiting the same symptomatology in their
vicinity to come to the hospital as soon as possible.
A biopsy of an adenopathy on the 15th of June re-
vealed pus, which was negative for bacteria by direct
10. Ayyadurai S, Houhamdi L, Lepidi H, Nappez C, Raoult D,
examination. Between the 15th and the 17th of June,
25
4 other patients from Keha€ılia came to the hospital.
On the 16th and on the 17th, epidemiologists and the
Health Authorities were informed of this unusual phe-
nomenon, and the possibility of a vectorial disease was
suggested. On the 17th of June, late in the evening,
while recording 7 of these unusual cases, the medical
team held an emergency meeting within the service
and concluded that these patients most likely had bu-
bonic plague. The clinical diagnosis of bubonic plague
was established in the morning of the 18th of June and
was reported to the people in charge of Health Care.
Microbiologists were contacted on the same day.
They looked for Yersinia pestis in the pus of a bubo
taken 3 days earlier, and they identified a small colony
o f Y. p e s t i s i n a d d i t i o n t o t h e c o l o n i e s o f
staphylococci.
In addition to the fatal index case, additional 71 patients
have been hospitalized due to suspicion of plague.
Among these patients, 10 cases of plague have been
confirmed, 3 were considered probable, and 5 were sus-
pected. Clinically, we observed 2 septicemic forms and
one bubonic form in a patient with a large abscess and
an ulcer on the skin. No cases of pneumonic plague
have been observed. All of our patients recovered. At
the beginning of the outbreak, the patients came from
the area of Keha€ılia, and one patient came from Oran.
Later, patients came from the surrounding villages and
then from a farm in a district 50 km from Keka€ılia (Ain Té-
mouchent). The last suspected case was recorded on the
1st of August, 2003.
1. Butler T. Plague into the 21st century. Clin Infect Dis 2009;49:
736e42.
2. Drancourt M, Raoult D. Molecular insights into the history of
plague. Microbes Infect 2002;4:105e9.
3. Drancourt M, Aboudharam G, Signoli M, Dutour O, Raoult D. De-
tection of 400-year-old Yersinia pestis DNA in human dental
pulp: an approach to the diagnosis of ancient septicemia.
Proc Natl Acad Sci USA 1998;95:12637e40.
4. Raoult D, Aboudharam G, Crubezy E, Larrouy G, Ludes B,
Drancourt M. Molecular identification by “suicide PCR” of Yer-
sinia pestis as the agent of medieval black death. Proc Natl
Acad Sci USA 2000;97:12800e3.
5. Tran TN, Aboudharam G, Raoult D, Drancourt M. Beyond an-
cient microbial DNA: nonnucleotidic biomolecules for paleomi-
crobiology. Biotechniques 2011;50:370e80.
6. Drancourt M, Raoult D. Palaeomicrobiology: current issues and
perspectives. Nat Rev Microbiol 2005;3:23e35.
7. Drancourt M, Raoult D. Genotyping Yersinia pestis in historical
plague. Lancet Infect Dis 2011;11:894e5.
8. Ayyadurai S, Lepidi H, Nappez C, Raoult D, Drancourt M. Lova-
statin protects against experimental plague in mice. PLoS ONE
2010;5:e10928.
9. Drancourt M, Houhamdi L, Raoult D. Yersinia pestis as a tellu-
ric, human ectoparasite-borne organism. Lancet Infect Dis
2006;6:234e41.
Drancourt M. Long-term persistence of virulent Yersinia pestis
in soil. Microbiology 2008;154:2865e71.
26
11. Eisen RJ, Petersen JM, Higgins CL, Wong D, Levy CE, Mead PS,
et al. Persistence of Yersinia pestis in soil under natural condi-
tions. Emerg Infect Dis 2008;14:941e3.
12. Prentice MB, Rahalison L. Plague. Lancet 2007;369:1196e207.
13. Begier EM, Asiki G, Anywaine Z, Yockey B, Schriefer ME, Aleti P,
et al. Pneumonic plague cluster, Uganda, 2004. Emerg Infect
Dis 2006;12:460e7.
14. Ayyadurai S, Sebbane F, Raoult D, Drancourt M. Body lice, Yer-
sinia pestis orientalis, and black death. Emerg Infect Dis 2010;
16:892e3.
15. Houhamdi L, Lepidi H, Drancourt M, Raoult D. Experimental
model to evaluate the human body louse as a vector of plague.
J Infect Dis 2006;194:1589e96.
16. Tran TN, Forestier CL, Drancourt M, Raoult D, Aboudharam G.
Brief communication: co-detection of Bartonella quintana and
Yersinia pestis in an 11the15th burial site in Bondy, France. Am
J Phys Anthropol 2011;145:489e94.
17. Raoult D, Roux V. The body louse as a vector of reemerging hu-
man diseases. Clin Infect Dis 1999;29:888e911.
18. Bertherat E, Bekhoucha S, Chougrani S, Razik F, Duchemin JB,
Houti L, et al. Plague reappearance in Algeria after 50 years,
2003. Emerg Infect Dis 2007;13:1459e62.
19. Bitam I, Ayyadurai S, Kernif T, Chetta M, Boulaghman N,
Raoult D, et al. New rural focus of plague, Algeria. Emerg In-
fect Dis 2010;16:1639e40.
20. Human plague e United States, 1993e1994. MMWR Morb Mor-
tal Wkly Rep 1994;43:242e6.
21. Wong D, Wild MA, Walburger MA, Higgins CL, Callahan M,
Czarnecki LA, et al. Primary pneumonic plague contracted
from a mountain lion carcass. Clin Infect Dis 2009;49:e33e8.
22. Wong JD, Barash JR, Sandfort RF, Janda JM. Susceptibilities of
Yersinia pestis strains to 12 antimicrobial agents. Antimicrob
Agents Chemother 2000;44:1995e6.
23. Fatal laboratory-acquired infection with an attenuated Yersi-
nia pestis Strain e Chicago, Illinois, 2009. MMWR Morb Mortal
Wkly Rep 2011;60:201e5.
24. Wang H, Cui Y, Wang Z, Wang X, Guo Z, Yan Y, et al. A dog-
associated primary pneumonic plague in Qinghai Province,
China. Clin Infect Dis 2011;52:185e90.
25. Weniger BG, Warren AJ, Forseth V, Shipps GW, Creelman T,
Gorton J, et al. Human bubonic plague transmitted by a domes-
tic cat scratch. JAMA 1984;251:927e8.
26. Ratsitorahina M, Chanteau S, Rahalison L, Ratsifasoamanana L,
Boisier P. Epidemiological and diagnostic aspects of the outbreak
of pneumonic plague in Madagascar. Lancet 2000;355:111e3.
27. Morelli G, Song Y, Mazzoni CJ, Eppinger M, Roumagnac P,
Wagner DM, et al. Yersinia pestis genome sequencing identifies
patterns of global phylogenetic diversity. Nat Genet 2010;42:
1140e3.
28. Drancourt M, Roux V, Dang LV, Tran-Hung L, Castex D, Chenal-
Francisque V, et al. Genotyping, Orientalis-like Yersinia pestis,
and plague pandemics. Emerg Infect Dis 2004;10:1585e92.
29. Drancourt M, Signoli M, Dang LV, Bizot B, Roux V, Tzortzis S,
et al. Yersinia pestis Orientalis in remains of ancient plague
patients. Emerg Infect Dis 2007;13:332e3.
30. Bos KI, Schuenemann VJ, Golding GB, Burbano HA,
Waglechner N, Coombes BK, et al. A draft genome of Yersinia
pestis from victims of the Black Death. Nature 2011;10.
31. Goulard C, Langrand S, Carniel E, Chauvaux S. The Yersinia
pestis chromosome encodes active addiction toxins. J Bacter-
iol 2010;192:3669e77.
32. Georgiades K, Raoult D. Genomes of the most dangerous epi-
demic bacteria have a virulence repertoire characterized by
D. Raoult et al.
fewer genes but more toxin-antitoxin modules. PLoS ONE
2011;6:e17962.
33. Tollenaere C, Rahalison L, Ranjalahy M, Rahelinirina S,
Duplantier JM, Brouat C. CCR5 polymorphism and plague resis-
tance in natural populations of the black rat in Madagascar. In-
fect Genet Evol 2008;8:891e7.
34. Butler T, Levin J, Linh NN, Chau DM, Adickman M, Arnold K.
Yersinia pestis infection in Vietnam. II. Quantiative blood cul-
tures and detection of endotoxin in the cerebrospinal fluid of
patients with meningitis. J Infect Dis 1976;133:493e9.
35. Crook LD, Tempest B. Plague. A clinical review of 27 cases.
Arch Intern Med 1992;152:1253e6.
36. Welty TK, Grabman J, Kompare E, Wood G, Welty E, Van DJ,
et al. Nineteen cases of plague in Arizona. A spectrum includ-
ing ecthyma gangrenosum due to plague and plague in preg-
nancy. West J Med 1985;142:641e6.
37. Campbell GL, Hughes JM. Plague in India: a new warning from
an old nemesis. Ann Intern Med 1995;122:151e3.
38. Inglesby TV, Henderson DA, O’Toole T, Dennis DT. Safety pre-
cautions to limit exposure from plague-infected patients.
JAMA 2000;284:1648e9.
39. Alsofrom DJ, Mettler Jr FA, Mann JM. Radiographic manifesta-
tions of plaque in New Mexico, 1975e1980. A review of 42
proved cases. Radiology 1981;139:561e5.
40. Rolain JM, Lepidi H, Zanaret M, Triglia JM, Michel G,
Thomas PA, et al. Lymph node biopsy specimens and diagnosis
of cat-scratch disease. Emerg Infect Dis 2006;12:1338e44.
41. Loiez C, Herwegh S, Wallet F, Armand S, Guinet F, Courcol RJ.
Detection of Yersinia pestis in sputum by real-time PCR. J Clin
Microbiol 2003;41:4873e5.
42. Ayyadurai S, Flaudrops C, Raoult D, Drancourt M. Rapid identi-
fication and typing of Yersinia pestis and other Yersinia species
by matrix-assisted laser desorption/ionization time-of-flight
(MALDI-TOF) mass spectrometry. BMC Microbiol 2010;10:285.
43. Bertherat E, Thullier P, Shako JC, England K, Kone ML,
Arntzen L, et al. Lessons learned about pneumonic plague diag-
nosis from two outbreaks, Democratic Republic of the Congo.
Emerg Infect Dis 2011;17:778e84.
44. Galimand M, Carniel E, Courvalin P. Resistance of Yersinia pes-
tis to antimicrobial agents. Antimicrob Agents Chemother
2006;50:3233e6.
45. Boulanger LL, Ettestad P, Fogarty JD, Dennis DT, Romig D,
Mertz G. Gentamicin and tetracyclines for the treatment of hu-
man plague: review of 75 cases in new Mexico, 1985e1999.
Clin Infect Dis 2004;38:663e9.
46. Mwengee W, Butler T, Mgema S, Mhina G, Almasi Y, Bradley C,
et al. Treatment of plague with gentamicin or doxycycline in
a randomized clinical trial in Tanzania. Clin Infect Dis 2006;
42:614e21.
47. Peterson JW, Moen ST, Healy D, Pawlik JE, Taormina J,
Hardcastle J, et al. Protection afforded by fluoroquinolones
in animal models of respiratory infections with bacillus anthra-
cis, Yersinia pestis, and Francisella tularensis. Open Microbiol
J 2010;4:34e46.
48. Kuberski T, Robinson L, Schurgin A. A case of plague success-
fully treated with ciprofloxacin and sympathetic blockade for
treatment of gangrene. Clin Infect Dis 2003;36:521e3.
49. Nguyen VA, Nguyen DH, Pham VD, Nguyen VL. Letter: co-
trimoxazole in bubonic plague. Br Med J 1973;4:108e9.
50. Galimand M, Guiyoule A, Gerbaud G, Rasoamanana B,
Chanteau S, Carniel E, et al. Multidrug resistance in Yersinia
pestis mediated by a transferable plasmid. N Engl J Med
1997;337:677e80.