PLAGUE JUNE 2008

Immediately report any suspected or

Outline Introduction confirmed cases of plague to:
Epidemiology SFDPH Communicable Disease Control
Clinical Features (24/7 Tel: 415-554-2830)
Differential Diagnosis - By law, health care providers must report
suspected or confirmed cases of plague to their
Laboratory Diagnosis
local health department immediately [within 1 hr].
Treatment and Prophylaxis - SFDPH Communicable Disease Control can
Complications and Admission Criteria facilitate specialized testing and will initiate the
public health response as needed.
Infection Control
Pearls and Pitfalls
Also notify your:
References
• Infection Control Professional
• Clinical Laboratory

INTRODUCTION

Plague is an acute bacterial infection caused by Yersinia pestis, a member of the family
Enterobacteriaceae. Y. pestis is a pleomorphic, nonmotile, nonsporulating, intracellular, Gram-
negative bacillus that has a characteristic bipolar appearance on Wright, Giemsa, and Wayson’s
stains. There are three virulent biovars: antiqua, medievalis, and orientalis and a fourth avirulent
biovar, microtu.1, 2 The orientalis biovar is thought to have originated in southern China and caused
the most recent pandemic.3

The Working Group for Civilian Biodefense considers plague to be a potential biological weapon
because of the pathogen’s availability “around the world, capacity for its mass production and
aerosol dissemination, difficulty in preventing such activities, high fatality rate of pneumonic
plague, and potential for secondary spread of cases during an epidemic.” Of the potential ways
that Y. pestis could be used as a biological weapon, aerosol release would be most likely. This
4
method has been successfully demonstrated to cause disease in Rhesus macaques.

EPIDEMIOLOGY

Plague as a Biological Weapon

In the 20th century, countries including the United States, the former Soviet Union, and Japan
developed ways for using Y. pestis as a weapon.5-7 Creating aerosolized plague is technically
challenging; however, if an intentional release of aerosolized plague were to take place, an
outbreak of pneumonic plague would be likely. This would be of serious concern because of the
high case-fatality rate and the potential for person-to-person transmission.4, 7, 8

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 An outbreak of disease caused by an intentional release of Y. pestis would have the following
characteristics:
• Clustering in time: multiple similarly presenting cases of severe, progressive multilobar
pneumonia, generally 2-4 days after release (range of 1 to 6 days)
• Atypical host characteristics: unexpected, unexplained cases of acute illness in previously
healthy persons who rapidly develop severe, progressive multilobar pneumonia with
hemoptysis and gastrointestinal symptoms
• Unusual geographic clustering: multiple cases in an urban area where naturally occurring
plague is not endemic
• Absence of risk factors: patients lack plague exposure risk factors (e.g., recent flea bite;
exposure to rodents, especially rabbits, squirrels, wood rat, chipmunk, or prairie dogs;
scratches or bites from infected domestic cats)

Intentionally-released Y. pestis strains may be altered to have enhanced virulence, antimicrobial

resistance, or increased ability to evade vaccines and diagnostic tests.4, 7

Naturally Occurring Plague

Reservoirs
The natural reservoir for Y. pestis is primarily wild rodents. Around the world, the domestic rat has
been associated with the most human cases; however in the western United States, burrowing
rodents (e.g., ground squirrels, rock squirrels, and prairie dogs) are the most important reservoir.9
A recent study has found soil to be a potential reservoir, with Y. pestis persisting from months to
several years n association with wild rodents.10, 11
Other mammals that act as hosts include cats,
10, 12-17
goats, sheep, camels, and humans. Human plague cases often follow epizootics in local
10, 18, 19
rodent populations.

Mode of Transmission
Humans can become infected in a number of ways:4, 13, 14, 16, 17, 20
• Bite of infected rat flea
• Direct contact with infected draining buboes
• Direct contact (including bites or scratches) with infected animals
• Inhalation of respiratory droplets from pneumonic plague-infected humans or animals
(within 2 meters)
• Ingestion of bacteria (e.g., eating infected meat)

Human plague cases in nature are most commonly acquired from animal reservoirs via bites of the
Oriental rat flea.9, 21

Worldwide occurrence
The first recorded plague pandemic was the Justinian plague (541-767 AD) which caused ~100
million deaths and is thought to have contributed to the demise of the Roman Empire. The second
pandemic, also known as the Black Death, lasted from the 14th to the 19th centuries and was
estimated to have killed between a third and a half of Europe's population. The third and most
recent pandemic began in 1894 in China and caused an estimated 12 million deaths.14, 19, 22, 23

Recent outbreaks in humans have included India (1994), Zambia (1996), Indonesia (1997), Algeria

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 (2003), Uganda (2004), and the Congo (2005).24-28 Approximately 1,800 worldwide cases of
plague are reported annually to the WHO, from all continents except Europe and Australia.10

Occurrence in the United States

Ships carrying infected rats introduced plague to the Americas via the ports on the Pacific Ocean
and Gulf of Mexico in the early 1900s. In San Francisco, urban rats passed along the disease to
native rodent populations. Eventually, plague spread across the western half of the United States
and has been found in the native rodent population, their fleas, and their predators. Naturally
occurring human plague generally occurs during the summer months in persons exposed to the
reservoir.27, 29 The last urban plague outbreak in the US occurred in Los Angeles in 1925.25-27, 30

From 1990 to 2005, a median of 7 cases of plague per year were reported in the US.26 Based on
provisional data, in 2006, there were 17 cases, and in 2007, 7 cases.31

Occurrence in California and San Francisco

From 1994 to 2007, 9 cases of plague were reported in California, and none of these occurred in
San Francisco.32-35

CLINICAL FEATURES

Human plague occurs in many forms, determined primarily by the route of infection. The most
common forms of plague in humans are bubonic plague, septicemic plague, and pneumonic plague.
These are presented in detail below.

Plague infection is a severe clinical illness that can be life-threatening. Case fatality rates vary
based on the route of infection. Mortality was historically much higher with nearly 100% mortality
for untreated septicemic and pneumonic plague and 50-60% mortality for untreated bubonic
plague cases. Administration of appropriate antibiotic treatment within the first 18 to 24 hours has
decreased mortality rates to 30-50% for septicemic plague, 5-15% for pneumonic plague, and less
than 5% for bubonic plague.4 Thus, early administration of appropriate antibiotic treatment is
critical, as poor outcomes occur with delays in seeking care and/or instituting effective
antimicrobial treatment.

Pneumonic Plague
Primary pneumonic plague occurs when the organism is inhaled in respiratory droplets from
infected humans or animals or in infectious aerosols accidentally or intentionally produced (e.g.,
spilled lab specimen or bioterrorism related release). Secondary pneumonic plague occurs when
there is hematogenous spread of the organism to the lung. Primary pneumonic plague causes a
more acute and fulminant disease. Pneumonic plague is not highly contagious but transmission
can occur with prolonged close contact (within 2 meters) with a coughing patient in the end stage
of illness. In a recent outbreak in Uganda, 1.3 pneumonic plague transmissions per pneumonic
plague case were reported.24 If untreated, pneumonic plague can spread and progress to
septicemic plague.

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PNEUMONIC PLAGUE

Incubation period • 1-4 days, with a maximum of 6 days

Transmission • Inhalation of contaminated aerosol
• Inhalation of respiratory droplets from pneumonic plague-infected humans or animals
(within 2 meters)
• Secondary hematogenous spread to the lung
Signs and symptoms • Acute fever, chills, malaise, myalgia, headache
• Productive cough, with sputum becoming more and more bloody
• Chest pain, dyspnea, cyanosis
• Tachypnea in children
• Gastrointestinal symptoms
Progression and • Refractory pulmonary syndrome
complications • Adult respiratory distress syndrome
• Septicemia
Laboratory and • Leukocytosis with left shift
Radiographic Findings • Gram-negative bipolar bacilli on sputum smear
• Elevated creatinine and abnormally high liver enzymes
• CXR findings include alveolar infiltrates progressing to lobar consolidation, pleural
effusion
• Rarely, mediastinal widening on CXR due to adenopathy

Bubonic Plague

Yersinia pestis can cause bubonic plague in humans via the bite of an infected rodent flea. Y.
pestis survives in the flea midgut after a blood meal from an infected host. The organism is
transmitted to a new host when the flea regurgitates during its next feeding. Y. pestis migrates to
regional lymph nodes where it causes hemorrhagic lymphadenitis, creating the swollen, painful
buboes that are characteristic of bubonic plague. The organisms often enter the bloodstream,
causing hemorrhagic lesions in distant lymph nodes and organs. If untreated, bubonic plague can
spread and progress to pneumonic or septicemic plague. Approximately, 80% of cases develop
bacteremia, 25% develop clinical septicemia and 10% develop pneumonia as a complication.

BUBONIC PLAGUE

Incubation period 1-8 days

Transmission • Bite of infected rat flea
• Direct contact with infected draining buboes
• Direct contact (including bites or scratches) with infected animals
Signs and symptoms Major
• Sudden onset of chills, high fever, headache, lethargy
• Buboes - Swollen, red, painful lymph nodes in areas proximal to the inoculation site
(e.g., inguinal, axillary or cervical areas)
• Rapid pulse
• Hypotension
Other
• Gastrointestinal discomfort
• Restlessness, confusion, lack of coordination
• Skin lesion at the site of the flea bite occurs in < 10% of cases
• Buboes may rupture and suppurate in second week

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Progression and • Septicemia
complications • Secondary pneumonic plague
• Meningitis (rare)
Laboratory findings • Leukocytosis with left shift
• Gram-negative bipolar bacilli on bubo aspirate smear
• Elevated creatinine and abnormally high liver enzymes

Septicemic Plague

In primary septicemic plague there is systemic sepsis caused by Y. pestis, but without noticeable,
preceding lymph node or pulmonary involvement. Up to 25% of naturally-occurring plague cases
may present with primary septicemic plague.19 Secondary septicemic plague occurs commonly
with either bubonic or pneumonic plague.

Septicemic plague causes a Gram-negative sepsis syndrome with multi-organ involvement,

disseminated intravascular coagulation (DIC), and shock. In the late stages of infection, high-
grade bacteremia often occurs, with identifiable organisms on peripheral blood smear.18 Meningitis
can occur and is characterized by cerebrospinal fluid (CSF) with many polymorphonuclear
leukocytes.9

SEPTICEMIC PLAGUE

Incubation period 1-4 days

Transmission Site of primary infection may be unknown
Signs and symptoms • Acute fever, chills, weakness, malaise
• Gastrointestinal symptoms
• Purpuric skin lesions and gangrene of the distal digits
Progression and • Disseminated intravascular coagulation (DIC)
complications • Shock
• Multi-organ failure
Laboratory findings • Leukocytosis with left shift and toxic granulation
• Gram-negative bipolar bacilli on blood smear
• Disseminated intravascular coagulation (DIC)
• Elevated creatinine and abnormally high liver enzymes

Other syndromes caused by Y. pestis infection include:

• Plague meningitis. Although it is generally a complication of other forms of plague, it

can be the presenting clinical syndrome. Plague meningitis results from hematogenous
spread of Y. pestis organisms and is characterized by CSF with many polymorphonuclear
leukocytes.9
• Plague pharyngitis. Plague pharyngitis generally results from direct inoculation of the
pharynx. Eating raw infected meat is a risk factor. Clinically, plague pharyngitis presents
as a severe pharyngitis or tonsillitis with cervical adenitis.
• Pestis minor. Pestis minor is a milder form of bubonic plague. Lymph nodes drain and
patients convalesce without treatment.10

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DIFFERENTIAL DIAGNOSIS
The diagnosis of plague during the initial stages requires a high index of suspicion because of the
nonspecific, flu-like picture early in the disease. Early diagnosis is critical because prompt
administration of antibiotics can decrease mortality.

Differential: Pneumonic Plague

Consider pneumonic plague in any case of severe Gram-negative pneumonia.

Key features that may help to distinguish plague pneumonia are:

Primary pneumonic plague:
• Rapid onset and rapid progression
Secondary pneumonic plague:
• Presence of painful adenitis (buboes)
Primary or secondary pneumonic plague:
• No response to typical antibiotic therapy for community-acquired pneumonia
• Hemoptysis in late stages of disease

Other conditions to consider are:

• bacterial pneumonia (Mycoplasma, • Q fever
Legionella, Staphylococcus, • inhalation anthrax
Streptococcus, Haemophilus, Klebsiella, • tularemia
Moraxella) • ricin
• viral pneumonia (influenza, respiratory • rickettsial infections
syncytial virus [RSV], cytomegalovirus • aerosolized exposure to staphylococcal
[CMV], hantavirus, severe acute enterotoxin B
respiratory syndrome [SARS])
• Chlamydia infection

Differential: Bubonic Plague

A key feature that may help to distinguish bubonic plague is:
• Presence of painful adenitis (buboes) progressing to systemic disease

Other conditions to consider are:

• cat scratch disease (Bartonella) • chancroid
• ulceroglandular tularemia • primary genital herpes
• adenitis due to staphylococcal, • primary or secondary syphilis
streptococcal, or filarial infection • appendicitis
• tuberculosis • strangulated inguinal or femoral hernia
• non-tuberculosis mycobacterial • lymphadenopathy (secondary lymphoma,
infection Kikuchi’s lymphadenitis, systemic lupus
• lymphogranuloma venereum erythematosus, toxoplasmosis, infectious
• Capnocytophaga canimorsus infection mononucleosis)

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 Differential: Septicemic Plague
Key features that may help to distinguish septicemic plague are:
Primary septicemic plague:
• Absence of painful adenitis (buboes) or pulmonary involvement
Secondary septicemic plague:
• Presence of painful adenitis (buboes)

Other conditions to consider are:

• Gram-negative sepsis • malaria
• Gram-positive sepsis (Staphylococcus) • louse-borne relapsing fever
• meningococcemia • appendicitis
• rickettsial infections

LABORATORY DIAGNOSIS

Routine laboratory and radiographic findings for If you are testing or considering testing for
specific clinical presentations of plague are plague, you should:
listed in the clinical features tables. ƒ IMMEDIATELY notify
SFDPH Communicable Disease Control
Initial identification of the organism relies on (24/7 Tel: 415-554-2830).
microscopic evaluation of infected tissue (blood, SFDPH can authorize and facilitate testing, and
sputum, CSF, or fluid aspirated from a bubo or will initiate the public health response as needed.
skin lesion scraping). Staining of the infected
ƒ Inform your lab that plague is under
tissue may reveal Gram-negative bacilli (Gram
suspicion. Some commercial bacterial test
stain) and bipolar staining (Wright, Giemsa, or
systems cannot reliably identify Y. pestis.
Wayson stain).4, 9
Order a Gram stain, culture,
and Giemsa, Wright or Wayson stain of the
material. Store and transport blood at room temperature. Transport other samples at room
temperature, but store under refrigeration if transport time will be > 2 hours.

Although recommended, culture and isolation may be difficult. Blood and site-specific specimens
should be collected prior to antibiotic administration as sterilization can occur rapidly. Y. pestis is
slow-growing in culture and may not demonstrate growth until 48 hours after inoculation. Also,
many commercial bacterial identification systems may misidentify Y. pestis.4 To improve yield and
ensure biosafety precautions, clinicians should notify laboratory personnel when plague is
suspected.

Although rapid diagnostic tests are not widely available, the public health laboratory system may
have access to rapid diagnostic testing on clinical specimens (e.g., polymerase chain reaction [PCR]
or direct fluorescent antibody testing for Y. pestis F1 antigen).

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TREATMENT AND PROPHYLAXIS

These recommendations are current as of this document date. SFDPH will provide periodic updates as needed
and situational guidance in response to events (www.sfcdcp.org).

Treatment
Supportive care and timely administration of antibiotics are the keys to successful management of
plague. Plague pneumonia is often fatal if antibiotics are not begun within 12-24 hours of
symptoms. Many patients will require intensive care with respiratory support because of
complications of Gram-negative sepsis.

Resistant strains may occur either naturally or be engineered. In 1995, 2 distinct strains of
naturally-occurring antibiotic-resistant Y. pestis were isolated from human cases of bubonic plague
in Madagascar. One strain was resistant to all drugs recommended for plague treatment and
prophylaxis and the other had high-level resistance to streptomycin. Both patients recovered with
oral trimethoprim-sulfamethoxazole and intramuscular injections of streptomycin.36, 37
In addition,
10
in vitro resistance to imipenem and rifampin has been seen.

Contained casualty setting: The Working Group recommends parenteral antimicrobial therapy
when individual medical management is available. Antibiotics should be administered to all
patients for 10 days. Therapy may be switched to oral antimicrobials when clinically indicated.

Mass casualty setting: Replacement of parenteral antibiotics with oral antibiotics may be
indicated if the number of patients exceeds the medical care system’s capacity to administer
parenteral antibiotics.

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 PLAGUE - TREATMENT AND POST-EXPOSURE PROPHYLAXIS RECOMMENDATIONSA

Contained Casualty Setting Mass Casualty Post-Exposure

Setting Prophylaxis
Duration of Rx 10 days 10 days 7 days

Streptomycin, 1 gm IM q12 hrs or Doxycycline, 100 mg orally twice daily or

B Ciprofloxacin, 500 mg orally twice daily
Preferred Gentamicin, 5 mg/kg IM or IV q24 hrs, or 2
mg/kg loading dose followed by 1.7 mg/kg IM or IV
q8 hrs
Adult

Doxycycline5,6, 100 mg IV q12 hrs or 200 mg IV ChloramphenicolC, 25 mg/kg orally 4 times

q24 hrs or daily (max 4 g/day)
Alternative H Ciprofloxacin, 400 mg IV q12 hrs or

ChloramphenicolC, 25 mg/kg IV q6 hrs (max 4

g/day)

Streptomycin, 15 mg/kg IM q12 hrs (max 2 DoxycyclineE,F:

g/day) or
>45 kg, give adult dosage

Preferred GentamicinB, 2.5 mg/kg IM or IV q8 hrs <45 kg, give 2.2 mg/kg orally twice daily (max
200 mg/day) or

CiprofloxacinE,G, 20 mg/kg orally twice daily

(max 1 g/day)
Children

DoxycyclineE,F: ChloramphenicolC,D, 25 mg/kg orally 4 times

>45 kg, give adult dosage daily (max 4 g/day)
<45 kg, give 2.2 mg/kg IV q12 hrs (max 200
mg/day) or
Alternative H
CiprofloxacinE,G, 15 mg/kg IV q12 hrs (max 1
g/day) or

ChloramphenicolC,D, 25 mg/kg IV q6 hrs (max 4

g/day)

GentamicinB, 5 mg/kg IM or IV q24 hrs or 2 mg/kg

E,F
Doxycycline , 100 mg orally twice daily or
Pregnant Women

Preferred loading dose followed by 1.7 mg/kg IM or IV q8 hrs

CiprofloxacinE, 500 mg orally twice daily

DoxycyclineE,F, 100 mg IV q12 hrs or 200 mg IV ChloramphenicolC,D, 25 mg/kg orally 4 times

Alternative H q24 hrs or daily

CiprofloxacinE, 400 mg IV q12 hrs

For plague meningitis, pleuritis, or myocarditis: Chloramphenicol should be used for 21 days for conditions when
tissue penetration is important4. Irreversible marrow aplasia is rare (1 in 40,000 patients).
A
Treatment recommendations come from the Working Group of Civilian Biodefense and may not necessarily be
approved by the US Food and Drug Administration. Table adapted from JAMA. 2000;283:2281-2290.
B
Aminoglycoside doses must be further adjusted for newborns, and according to renal function.
C
Therapeutic concentration is 5 - 20 mcg/mL; concentrations >25 mcg/mL can cause reversible bone marrow
suppression.
D
According to the Working Group on Civilian Biodefense, children younger than 2 years of age should not receive
chloramphenicol due to risk of ‘gray baby syndrome’; however, the American Academy of Pediatrics has
recommended chloramphenicol as the drug of choice for plague meningitis in children.
E
Tetracycline and quinolone antibiotics are generally not recommended during pregnancy or childhood; however their
use may be indicated for life-threatening illness.
F
Ciprofloxacin may be preferred in pregnant women and children up to 8 years of age because of the known adverse
event profile of doxycycline (e.g., tooth discoloration).
G
Doxycycline may be preferred in children 8 years and older because of the adverse event profile of ciprofloxacin
(e.g., arthropathies).
H
Trimethoprim-sulfamethoxazole has been successfully used to treat plague; however the Working Group considers
this a second tier choice.

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 Post-Exposure Prophylaxis
Post-exposure prophylaxis is the administration of antibiotics after suspected exposure to plague
has occurred but before symptoms are present. If symptoms are present, see section above on
treatment. Persons thought to have had an infective exposure should receive post-exposure
prophylaxis. Infective exposures include household, hospital, or other close contact (less than 2
meters) with a person suspected or confirmed to have pneumonic plague who has received no
treatment, less than 48 hours of antimicrobial therapy, or more than 48 hours of antimicrobial
therapy without clinical improvement. Post-exposure prophylaxis may be recommended for
persons exposed to intentional aerosol releases. In such an event, public health authorities will
provide guidance. Regardless of whether post-exposure prophylaxis is recommended or taken,
persons potentially exposed should be observed for fever or cough for 7 days after exposure. Any
potentially-exposed person who develops a fever or cough should seek prompt medical attention
and begin treatment. Quarantine is not currently recommended.4, 7, 9

Vaccination

Current killed whole cell vaccines have been in use for military personnel and have been shown to
generate cell-mediated responses lasting at least 15 years; however, they require repeat dosing
with adjuvants, have questionable protection against respiratory infections, and are reactogenic.
Vaccine production has been discontinued in the US. Microencapsulated subunit vaccines (of F1
and V proteins) requiring only single dose administration are under development and show the
most promise against aerosol exposures.4, 38, 39

COMPLICATIONS AND ADMISSION CRITERIA

Whereas primary pneumonic plague results from direct inhalation of plague bacilli, secondary
pneumonic plague can manifest as a complication in patients with bubonic plague. Hematogenous
dissemination of Y. pestis results in plague septicemia, which can be complicated by septic shock,
disseminated intravascular coagulation, necrosis of small vessels, and purpuric skin lesions. Plague
meningitis due to hematogenous seeding of the meninges occurs infrequently.

Patients with suspect or confirmed pneumonic or bubonic plague require hospitalization for
intravenous antibiotics, supportive care, and close monitoring for decompensation and signs of
toxemia.

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INFECTION CONTROL

These recommendations are current as of this document date. SFDPH will provide periodic updates as needed
and situational guidance in response to events (www.sfcdcp.org).

Clinicians should notify local public health authorities, their institution’s infection control
professional and their laboratory of any suspected plague cases. Public health authorities may
conduct epidemiological investigations and implement disease control interventions to protect the
public. Infection control professionals will guide and enforce implementation of infection control
precautions within the healthcare setting. Laboratory personnel will take appropriate biosafety
precautions.

Although not highly contagious, plague can be transmitted person-to person via respiratory
droplets when the disease is end stage.30 Both the Healthcare Infection Control Practices Advisory
Committee of the CDC and the Working Group on Civilian Biodefense recommend Droplet and
Standard precautions for patients with suspected or confirmed pneumonic plague. These
precautions should be maintained until 48 hours of appropriate antibiotics have been administered
AND the patient shows clinical improvement. Close contacts of pneumonic plague patients should
be identified, assessed for prophylaxis and monitored for symptoms. For patients with suspected
or confirmed bubonic plague or other non-pneumonic plague syndromes, Standard precautions
are recommended. Aerosol-generating procedures should be avoided if possible. Routine
laboratory procedures should be carried out under Biosafety level-2 conditions; however,
manipulation of cultures or other activities that may produce aerosol or droplets (e.g., centrifuging,
grinding, vigorous shaking, and animal studies) require Biosafety level -3 conditions.4, 40

Decontamination
In general, environmental decontamination following an aerosol event has not been recommended,
since experts have estimated that an aerosol of Y. pestis organism would be infectious for only
about 1 hour.4, 40
A recent study demonstrated that Y. pestis can survive on selected
environmental surfaces for at least several days; however the potential for re-aerosolization of
these organisms was not addressed.41 Commercially available bleach or 0.5% hypochlorite
solution (1:10 dilution of household bleach) is considered adequate for cleaning and
decontamination. All persons exposed to an aerosol containing Y. pestis should be instructed to
wash body surfaces and clothing with soap and water.

PEARLS AND PITFALLS

• Bubonic plague is not transmitted directly from one human to another in the absence of
lymph node suppuration and drainage. Persons with bubonic plague become more
infectious as Y. pestis organisms reach the lungs via hematogenous spread. Once
pneumonic plague develops, transmission occurs via direct contact with respiratory
secretions or inhalation of respiratory droplets.

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 • Clinical clues pointing toward a diagnosis of primary pneumonic plague are sudden onset of
headache, malaise, and fever, fulminant pneumonitis with rapid progression from dry
cough to tachypnea, dyspnea, and productive cough, and in the late stage of disease,
hemoptysis with copious amounts of bright red sputum.30

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