(lighthearted music)
- Welcome to part one of CDC's training
on plague response for health care providers.
Today we will provide an overview of plague,
including microbiological characteristics, epidemiology,
the most common clinical forms of plague,
and a summary of plague diagnostics.
Each section will include special considerations
in the event of an intentional release of Yersinia pestis,
the causative agent of plague.
First, we will review the microbiologic characteristics
and epidemiology of plague.
Plague is caused by Yersinia pestis,
a gram-negative bacillus
and facultative intracellular pathogen.
Y. pestis has a safety pin appearance
with bipolar staining on microscopy
shown here using a Wright-Giemsa stain.
The bacteria initially infects macrophages,
then in later stages of infection,
fulminant extracellular growth
can result in local spread of infection and bacteremia.
Plague is endemic in parts of Africa, South America,
and Central Asia as well as the western United States.
Scientists believe that plague evolved
on the high plains of Eurasia.
It has since become endemic in many areas worldwide.
The natural host in the United States are ground rodents,
primarily prairie dogs and certain squirrels.
Fleas serve as the vector and transmit Y. pestis
in an enzootic cycle among rodents in the wild.
Other mammals, including humans, can become infected
after being bitten by an infected flea
or handling the carcasses of animals that died of plague.
Domestic pets can be infected with Y. pestis
either from infected fleas
or direct contact with infected wildlife.
While both dogs and cats can develop plague,
cats tend to develop more severe illness.
Both cats and dogs
can transmit the infection to their owners
indirectly through flea bites or directly by coughing,
in cases where the pet has pneumonic plague.
This map shows reported cases of plague in the United States
by county of residence.
Each dot represents a single case
and is randomly placed within the county.
Note that the dot in Illinois was in a laboratory worker
and does not represent natural exposure.
In recent decades, there have been an average
of seven human plague cases reported
each year in the United States,
with a range of 1 to 17 cases per year.
There are three primary ways
that people become infected with Y. pestis.
The first is from the bite of an infected flea,
which is the most common method of transmission.
Second, people become infected
by directly handling the tissues or carcasses
of infected animals.
Finally, Y. pestis can be transmitted
through direct inhalation of infectious droplets.
This usually results in pneumonic plague.
Direct inhalation of Y. pestis can occur
when a person or animal with pneumonic plague coughs
and generates droplets that are then inhaled
by another person.
Aerosolizing procedures such as necropsy
can also spread Y. pestis to people
if adequate personal protective equipment is not worn.
Yersinia pestis has bioterrorism potential
and is classified as a Tier one select agent,
the highest risk category
because it can be transmitted from person to person,
has a high case fatality rate if untreated,
and can be aerosolized.
Plague was used as a bioterrorism agent
during World War II,
when the Japanese army dropped plague infected fleas
over cities in China.
Additionally, both the United States and the Soviet Union
had active bioweapons programs during the Cold War.
More recently, domestic extremists
and people with links to terrorist organizations
have considered the use of plague bioweapons
in terrorist attacks.
The three most common clinical forms of plague
are bubonic, septicemic, and pneumonic.
Bubonic plague accounts for approximately
75% of plague cases.
It most commonly occurs after the bite of an infected flea.
The incubation period is 2 to 8 days.
The case fatality rate is approximately 66%
for patients who do not receive treatment
and 13% for patients who are treated with antimicrobials.
As with other forms of plague,
illness begins with a fever, headache, chills, myalgias,
arthralgias and weakness.
Patients with plague typically
have white blood cell counts of 12,000
to 25,000 cells per cubic milliliter
with a predominance
of immature polymorphonuclear leukocytes.
Leukemoid reactions with white blood cell counts
as high as 50,000 cells per cubic milliliter or more
can occur, especially in children.
The characteristic bubo forms in a lymph node
near the inoculation site.
Patients typically have tenderness and pain
in one or more regional lymph nodes.
Femoral and inguinal lymph nodes are most commonly involved,
followed by the axillary and cervical nodes.
The surrounding tissue of the infected nodes
may become edematous,
and the overlying skin may be erythematous.
Buboes are exquisitely tender and often remain enlarged
and painful for a week or more after treatment has begun.
Buboes can occasionally become fluctuant.
In about 5 to 10% of cases,
inspection of the skin surrounding
or distal to the bubo reveals the site of a flea bite
marked by a small papule, pustule, scab or ulcer,
which in some instances may be confused with
lesions caused by tularemia or anthrax.
In general, plague buboes are distinguishable
from most other causes of lymphadenitis
by their rapid onset, extreme tenderness,
accompanying signs of toxemia,
and absence of obvious ascending lymphangitis.
Differential diagnosis for bubonic plague
includes streptococcal or staphylococcal adenitis,
tularemia, cat scratch disease, mycobacterial infection,
strangulated inguinal hernia, and chancroid
or other sexually transmitted diseases
that cause regional lymphadenitis.
Septicemic plague accounts for approximately
15% of plague cases.
Septicemic plague most commonly develops
after progressing from other clinical forms,
typically bubonic.
The incubation period for septicemic plague
is poorly defined but likely occurs within days of exposure.
The case fatality rate is 90%, if untreated,
and even with prompt treatment can still be as high
as 30 to 40%.
Septicemic plague is characterized
by dissemination of infection and a rapidly progressive,
overwhelming endotoxemia.
Presenting symptoms include acute fever,
chills and prostration,
often accompanied by gastrointestinal symptoms
such as nausea, vomiting, diarrhea and abdominal pain.
The course of illness is fulminant.
Patients develop disseminated intravascular coagulation
or DIC with petechiae and ecchymoses,
refractory hypotension, renal failure, obtundation,
and other signs of shock.
Acute respiratory distress syndrome, or ARDS,
can occur in septicemic plague
and may be refractory to treatment.
Localizing signs are often absent,
and it can be difficult to distinguish septicemic plague
from other types of sepsis.
Differential diagnosis for septicemic plague
includes any other overwhelming systemic infection
such as meningococcemia, gram-negative sepsis
with other pathogens, and bacterial endocarditis.
As abdominal pain is a common feature,
both appendicitis and diverticulitis
could also be confused with septicemic plague.
Pneumonic plague is the third most common form of plague,
accounting for approximately 10% of cases.
It has a shorter incubation period of just 1 to 3 days.
Pneumonic plague is notable because it is the only form
that can be transmitted from person to person.
Pneumonic plague is almost always fatal without treatment.
Even with prompt treatment, the case fatality rate is high
at nearly 30%.
Patients with pneumonic plague
are likely to have a prolonged hospitalization
and slow recovery.
Pneumonic plague is divided
into primary and secondary disease.
Primary pneumonic plague is caused by direct inhalation
of infective respiratory droplets.
The onset is often sudden with fever, chills, headache,
myalgias, weakness, dizziness and chest discomfort.
Primary pneumonic plague is principally an alveolar process,
and the sputum is most often watery or mucoid,
blood tinged and frothy.
Sputum may become, frankly, bloody in untreated patients.
As illness progresses cough, sputum production, chest pain,
and tachypnea typically predominate.
These may be accompanied by hemoptysis,
increasing respiratory distress, and circulatory collapse.
Secondary pneumonic plague is caused by
hematogenous spread of infection to the lungs
from another anatomic site.
Initially, secondary pneumonic plague manifests
as an interstitial pneumonitis
in which sputum production is often scant.
However, left untreated,
it will also progress to a severe broncho pneumonia
with bloody sputum.
Radiographic findings in patients with pneumonic plague
are variable and include unilateral
or bilateral alveolar infiltrates, pleural effusions,
and mediastinal or hilar adenopathy.
Untreated patients show
rapidly progressive bronchopneumonia,
parenchymal necrosis, and hemorrhage.
Occasionally, patients develop pneumonic abscesses
and resultant cavities.
Management of patients with pneumonic plague
requires intensive medical and nursing support.
Death can occur quickly in patients
who do not receive prompt treatment
with effective antimicrobials.
Bloody sputum, as found in patients
in advanced stages of illness,
contains large numbers of plague bacilli.
A coughing patient can spread infection
to people in close contact,
defined as within six feet through respiratory droplets.
Respiratory droplet precautions should be used
with any suspect case
due to the risk of person to person transmission.
Patients with suspected pneumonic plague
should wear surgical masks for evaluation and transport.
Health care providers should wear a surgical mask
when caring for these patients.
Additionally, there is a theoretical risk of transmission
during aerosol generating procedures.
Consider wearing an N95 respirator during these procedures
for additional protection.
The differential diagnosis of pneumonic plague
includes other bacterial pneumonias
such as pneumococcal pneumonia, tularemia, mycoplasma,
legionnaires disease and Q fever.
Severe viral pneumonia, including influenza,
Hantavirus pulmonary syndrome, COVID-19,
and other coronavirus infections
such as Middle East Respiratory Syndrome
could also be confused with plague.
Although rare,
two other presentations of plague deserve mention,
plague pharyngitis and meningitis.
Plague pharyngitis may develop
after respiratory droplet exposure
or from the ingestion of infectious undercooked meat.
Plague pharyngitis is an uncommon condition
and presents with fever, sore throat,
and cervical lymphadenitis.
In its early stages, it may be clinically indistinguishable
from more common causes of pharyngitis.
Cervical or submandibular buboes
usually develop secondary to the pharyngeal involvement.
Meningitis is another uncommon
but serious manifestation of plague.
Meningitis may be part of
the initial presentation of plague,
however, its onset is often delayed
and may result from insufficient antimicrobial treatment
of the primary illness.
Plague meningitis presents
as a typical bacterial meningitis,
with fever, headache, meningismus, altered mental status,
and polymorphonuclear leukocytosis
in the cerebrospinal fluid.
In situations where you suspect plague,
do not wait for diagnostic test results,
begin treatment with antimicrobials immediately.
Plague can be rapidly fatal if not treated promptly.
As with many diseases, a high index of clinical suspicion
and a careful history and physical examination
are required to make a timely diagnosis of plague.
A delayed or misdiagnosis of plague
is associated with a high case fatality rate.
Travelers who become infected in an endemic area
and seek care after returning home are especially at risk.
Laboratory tests for plague are highly reliable
when conducted by people experienced
in working with Y. Pestis,
but such expertise is usually limited
to specialized reference laboratories.
Contact your local public health laboratory for assistance
with diagnostic testing and coordination with CDC.
Guidelines for Y. pestis laboratory testing
from the American Society for Microbiology
can be found at the link here.
If plague is suspected,
laboratory personnel should be notified
when clinical specimens are sent
so they can take appropriate biosafety precautions.
Laboratory specimens should be obtained promptly.
Appropriate diagnostic specimens include blood,
lymph node aspirates from patients with suspected buboes,
sputum samples or tracheal-bronchial aspirates
in patients with suspected pneumonic plague,
and cerebrospinal fluid in those with meningeal signs.
Bacterial culture of blood, CSF, sputum, or bubo aspirates,
and nucleic acid amplification tests such as PCR
are the most accurate tests.
The specific test performed can vary by specimen type.
Blood cultures should be collected from all patients
with suspected plague.
Keep in mind that blood cultures may be negative
in the early stages of primary bubonic and pneumonic plague.
If a lymph node aspirate is obtained for culture,
a small amount of sterile saline
can be injected into the bubo prior to aspiration.
In culture, Y. pestis grows at 28 to 35 degrees Celsius.
The organism can be grown on a variety of different media,
including blood agar.
Small colonies develop after 48 hours.
Laboratory confirmation of plague is based on, one,
a positive Y. pestis phage lysis assay
on a clinical isolate,
or two, a fourfold or greater change in serum antibodies
to Y. pestis F1 antigen
in acute and convalescent paired sera.
Here you can see an image of phage lysis testing.
The top band and three lowest bands are positive,
indicating the presence of Y. pestis,
while the second band from the top is the negative control.
A presumptive laboratory diagnosis of plague can be made
when Y. pestis is detected by PCR from a clinical specimen,
or if there is a positive F1 antigen antibody titer
from a single serum specimen.
Note that plague may be initially misidentified
by automated laboratory systems, particularly MALDI-TOF,
resulting in a delay in accurate diagnosis
and appropriate treatment.
It's important to note that antimicrobial resistance
has never been observed
in a naturally acquired Y. pestis infection
in the United States.
However, if a bioterrorism event is suspected,
antimicrobial susceptibility testing should be performed,
as strains in these events may be modified
to confer antimicrobial resistance.
Because of recent concerns with bioterrorism,
the Laboratory Response Network or LRN,
a system of participating laboratories
across the United States, has been developed.
The LRN can conduct laboratory testing
for specific pathogens when requested by a state
or jurisdictional public health laboratory.
In an emergency, the CDC emergency operation center
can be reached 24 hours a day, seven days a week
at 800-232-4636.
Thank you for watching part one in this series.
Part two will review treatment and prophylaxis of plague.
(lighthearted music)