CBRNE - Plague

Background

The plague has caused more fear and terror than perhaps any other infectious disease in the history of humankind. It has laid claim to nearly 200 million lives and has brought about monumental changes such as the end of the Dark Ages and the advancement of clinical research in medicine.^[1]

Although still debated by historians, the plague has been responsible for at least 3 great pandemics and multiple epidemics in history. The first spread occurred from the Middle East to the Mediterranean basin during the fifth and sixth centuries CE, killing approximately 50% of the population in these areas. The second pandemic afflicted Europe between the 8th and 14th centuries, destroying nearly 40% of the population. The third pandemic started in approximately 1855 in China, and, although it has been mostly controlled, it is still ongoing.

Alexandre Yersin isolated the plague bacillus, developed an antiserum to combat the disease, and postulated its connection with fleas and rats during the epidemic of 1894. The plague bacillus was named Yersinia pestis in his memory.^{[2, 3]}

Pandemics have succeeded in entrenching the plague in every major continent, with the possible exception of Australia. Unlike smallpox, the plague never will be eradicated. It lives in millions of animals and on billions of fleas that reside on them. It is a disease of the desert, the steppes, the mountains, and the forest.^[4]

Although plague has been considered a disease of the Middle Ages, multiple outbreaks in India and Africa during the last 20 years have stoked fears of another global pandemic. Since the number of human cases has been rising and outbreaks are reappearing in a variety of countries after years of quiescence, the plague is considered a reemerging disease.^{[5, 6, 2]}

One reason for plague's reemergence may be global warming, which is ideal for increasing the prevalence of Ypestis in the host population. One study has estimated a more than 50% increase in the plague host prevalence with an increase of 1º C of the temperature in spring.^[7] Another reason may be the human population explosion worldwide, which is bringing humans into ever-increasing contact with wildlife. Lastly, the dramatic population increase will contribute to conditions of overcrowding and poor sanitation—conditions ripe for plague hosts and vectors to flourish in.

Additionally, there has been significant concern over the return of plague as a potential biological weapon.^{[8, 9, 10, 11, 12]} In 1347, the Tartars catapulted bodies of plague victims over the city walls during the siege of Kaffa, and, in World War II, the Japanese dropped bombs containing fleas inoculated with Y pestis to infect their enemies with the deadly illness.

During the Cold War, the Soviets succeeded in aerosolizing the bacteria and in creating strains of multidrug-resistant Yersinia.^{[13, 14]} Aerosolized Y pestis, causing primary pneumonic plague, has been recognized by bioterrorism experts as having one of the highest potentials as a bioterrorism agent due to its extremely high mortality, its high uptake into enzootic and epizootic animals as well as humans, and its ability to be spread over a large area. It has been classified as a Category A, or high priority, bioterroism agent by the Centers for Disease Control and Prevention (CDC). Biosafety level 3 precautions must be observed for any cultured specimens.^[1]

• References

Pathophysiology

The etiologic agent of the plague is Y pestis, a facultative anaerobic, intracellular, gram-negative bacillus. Significant genomic similarity and conservation of DNA sequences suggest Y pestis evolved from the less virulent Yersinia pseudotuberculosis.^[15]

The organism can be transmitted from a host to a human via the bite of a vector (usually a flea), via close contact with infected tissue or body fluids, and via direct inhalation of aerosolized bacteria. Currently, the most common form of transmission involves the bite of an infected flea. More than 200 different rodents and species can serve as hosts.

The vector is usually the rat flea, Xenopsylla cheopis. Thirty different flea species have been identified as able to carry the plague bacillus. Other carriers of plague include ticks and human lice. A flea is shown in the image below.

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Here a flea is shown with a blocked proventriculus, equivalent to the gastroesophageal region in man. In nature, this flea would develop a ravenous hu....

Rodents resistant to the infection, such as wood rats, kangaroo roots, deer mice, grasshopper mice, and voles, form an enzootic stage that ensures the long-term survival of the bacillus. Occasionally, fleas transfer the bacteria to animals that are susceptible to plague such as ground squirrels (an infected squirrel is shown in the image below), prairie dogs, and chipmunks. In the event of large numbers of host animals dying off, hungry fleas search out new food sources. This is known as an epizootic stage and ensures the spread of the organism to new territory. A sylvatic stage occurs when humans are infected from wild animals. Carnivores with the exception of cats^[16] and black-footed ferrets have a fairly strong resistance profile, but they can be transfer vectors. Birds and hoofed animals are seldom infected, and reptiles and fish are resistant to plague.^[4]

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Rock squirrel in extremis coughing blood-streaked sputum of pneumonic plague. Courtesy of Ken Gage, PhD, CDC, Fort Collins, CO.

Virulent plague bacteria can survive dormant in soil, animal carcasses, grains, flea feces, buried bodies, and dried sputum.^{[17, 4]}

Three forms of the plague exist: bubonic plague, pneumonic plague, and septicemic plague. The bubonic form makes up approximately 80-95% of cases worldwide^[2] and is caused by deposition of the bacillus in the skin by the bite of an infected vector. If the vector is a flea, bacillus proliferates in the flea's esophagus, preventing food entry into the stomach. To overcome starvation, the flea begins a blood-sucking rampage. Between its attempts to swallow, the distended bacillus-packed esophagus recoils, depositing the bacillus into the victim's skin.

The bacillus invades nearby lymphoid tissue, producing the famous bubo, an inflamed, necrotic, and hemorrhagic lymph node. Spread occurs along the lymphatic channels toward the thoracic duct, with eventual seeding of the vasculature. Bacteremia and septicemia ensue. The bacillus potentially seeds every organ, including the lungs, liver, spleen, kidneys, and rarely even the meninges.

The most virulent form, pneumonic plague, results from direct inhalation of the bacillus, which occurs from close contact of infected hosts or from aerosolized bacteria such as may occur if used as a biological weapon. A severe and rapidly progressive multilobar bronchopneumonia ensues with subsequent bacteremia and septicemia. Secondary pneumonic plague is caused when an infected patient seeds his or her lungs and airways.

The third type of plague is a primary septicemic plague. This is hypothesized to occur when the bacillus is deposited in the vasculature, bypassing the lymphatics. Early dissemination with sepsis occurs but without the formation of a bubo. This usually is observed in bites to the oral, tonsillar, and pharyngeal area and is believed to occur because of the vascularity of the tissue and short lymphatic distance to the thoracic duct.

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Epidemiology

Frequency

United States

An average of seven (range, 1-17) human plague cases have been reported each year in the United States in recent decades.^[18] One of the largest animal foci of the plague worldwide is found west of the 100th parallel, in states such as New Mexico, Arizona, Colorado, Utah, and California. Only one case of imported plague has been reported since 1926. Most cases occur during the wet, warmer months of the year.^[19]

International

Worldwide, plague occurs within a broad belt in tropical, subtropical, and warmer temperate climates (see the image below). Its geographical distribution coincides with that of the rodents it infects, which are found on all continents except Australia. Plague epidemics have occurred in Africa, Asia, and South America but since the 1990s, most human cases have occurred in Africa. The three most endemic countries are Madagascar, the Democratic Republic of Congo and Peru.

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World distribution of plague cases, 2000-2009. From the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

According to the World Health Organization (WHO), 3248 cases of plague with 584 deaths were reported worldwide from 2010 to 2015.^[20] The actual number of cases is likely much higher, however. Almost all of the cases reported in the last 2 decades have been in inhabitants of small towns and villages or agricultural areas rather than in larger towns and cities.^[18]

Mortality/Morbidity

Mortality from plague varies by type and treatment, as follows:

• Bubonic plague has a 1-15% mortality rate in treated cases and a 40-60% mortality rate in untreated cases.
• Septicemic plague (primary or secondary) has a 40% mortality rate in treated cases and 100% mortality rate in untreated cases.
• Pneumonic plague (primary or secondary) has 100% mortality rate if not treated within the first 24 hours of infection.

Sex- and Age-related Demographics

More than 50% of cases of plague occur in males, probably because of greater participation in outdoor activities. Approximately 50% of cases occur in persons younger than 20 years.

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History

In general, after an incubation period of 1-6 days, the history suggests a severe and rapidly progressive sepsis.

Recent travel in the Southwestern and Pacific Coast regions of the United States, particularly in New Mexico, Arizona, California, and Utah, should raise suspicion of a fleabite. Although imported plague is rare, similar suspicion should exist for any recent travel to endemic areas outside the United States. Fewer than 10% of patients recall a prior fleabite.

Close contact with any potentially infected host or rural environment should raise suspicion for the plague. Historically, the rat has been believed to be the main plague host; however, currently in the United States, the ground and rock squirrels are the most common hosts. In recent years, the domestic cat has emerged as a prominent host that transmits the plague to veterinarians.^[20]

A sudden increase in the incidence of severe pneumonia in previously healthy individuals should raise concern for pneumonic plague possibly deployed as a bioterrorism weapon.

Symptoms include the following:^{[21, 2]}

• Fever
• Chills
• Myalgias
• Sore throat
• Headache
• Weakness
• Malaise
• Enlarged, painful, swollen lymph node
• Abdominal pain - Only presenting symptom more common in a patient presenting with septicemic plague (primary blood-borne plague) versus one presenting with bubonic plague
• Nausea, vomiting (bloody at times)
• Constipation, diarrhea, and black or tarry stools
• Gastrointestinal complaints (may precede a bubo)
• Cough, which may be productive of bloody sputum
• Shortness of breath
• Stiff neck (if meningitic infiltration by plague bacillus has occurred)

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Physical

In general, after an incubation period of 1-6 days, the plague presents with the physical findings of severe and rapidly progressive sepsis with or without features of pneumonia. Multiple organ involvement occurs. Pneumonic plague may present only as a severe pneumonia.

• Temperature of 37-40.9°C, tachycardia, tachypnea, and hypotension, if in late septic shock
• Inguinal bubo (60%), axillary (30%), cervical (10%), or epitrochlear (10%) (Bubo is usually no greater than 5 cm, extremely tender, erythematous, and surrounded by a boggy hemorrhagic area; patient often flexes, abducts, and externally rotates the hip near an involved inguinal node to reduce pain at the site.) Children are more likely to have a cervical or submandibular bubo.^[2] Images below show a bubo and a necrotic ulcer.

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  A suppurative bubo of the femoral lymph node is shown here. This is the most common site of erythematous, tender, swollen, nodes in a plague victim. T....

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  The child in this photo has an erythematous, eroded, crusting, necrotic ulcer on the left upper quadrant of the abdomen, which is presumably the prim....

   

  

   

Dermatologic findings

A maculopapular lesion may be found at the site of the fleabite; however, such lesions commonly are found at autopsy implying that, in the United States, the diagnosis often is not determined until it is too late.

Acral cyanosis, ecchymosis (shown in the image below), petechiae, and digital gangrene are seen with Y pestis septicemia (from disseminated intravascular coagulation [DIC]).

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Ecchymoses at the neck base of a girl with plague. Bandage is over the site of a prior bubo aspirate. These lesions probably gave rise to the title li....

The medieval epithet "Black Death" is thought to have originated from the deeply cyanotic skin, ecchymoses, and/or acral necrosis associated with terminal septicemic and pneumonic plague.

The initially rose-colored purpuric lesions most likely gave rise to the child's nursery rhyme "Ring Around the Rosy."

• "Ring around the rosy" - Rose-colored purpuric macules (may be caused by the Y pestis enzyme that acts alternately as a plasminogen activator or coagulase at various temperatures or may be due to DIC)
• "Pocket full of posies" - Sweet-smelling flowers that those tending the sick would carry to ward off the stench of disease
• "Ashes, ashes" - Impending mortality or "A-choo, a-choo" - The sneezing and coughing of pneumonic plague
• "All fall down" - Death

Rare cases of ecthyma gangrenosum–like lesions and carbuncles due to blood-borne Y pestis have been described.

Other findings

See the list below:

• Diffuse crackles, diffuse areas of dullness to percussion (secondary to patchy consolidation of pneumonic plague), and hemoptysis
• Diffuse abdominal tenderness, with or without guarding, splenomegaly, hematochezia, or heme-positive stools
• Nuchal rigidity and diffuse muscle and joint tenderness
• Various degrees of mental status changes, ranging from mild confusion or agitation to delirium and coma
• Seizures
• Bleeding from any body site or cavity (eg, hematemesis, hematochezia, hemoptysis)
• Gangrene and necrosis (shown in the images below) of areas such as the digits, penis, and nares (ascribed to peripheral thrombosis secondary to DIC)

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  Acral necrosis of nose, lips, fingers (shown here) and toes (image below) and residual ecchymoses over both forearms in a patient recovering from bubo....

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  Acral necrosis of nose, lips, fingers (image above) and toes (shown here) and residual ecchymoses over both forearms in a patient recovering from bubo....

   

  

   
• Pharyngitis culture positive for Y pestis has been seen in endemic areas in household contacts of those with bubonic plague. These patients also have associated cervical lymphadenopathy.

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Causes

The etiologic agent is Y pestis, a facultative anaerobic, intracellular, gram-negative bacillus. The following are some epidemiologic factors that suggest an increased likelihood of infection with the plague:^[4]

• Rural or nonurban residency, especially in geographic areas with known plague foci
• Contact with sick animals, small rodents, or other possible hosts
• Wilderness activities (eg, camping, hiking, sleeping on ground, hunting)
• Fleabite
• Recent plague in the community
• Occupation as a veterinarian
• Summer months
• Sudden influx of previously healthy patients with severe pneumonia, especially if geographically clustered

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Laboratory Studies

Complete blood count

The white blood cell (WBC) count may be markedly elevated to levels of 20,000/μL or greater. Usually, a shift to the left is noted. In late septic shock, the WBC count may be low.

Urinalysis

Urinalysis may demonstrate gross hematuria, red blood cell casts, and proteinuria. Rapid urine dipstick tests have been developed to screen for Yersiniapestis antigen and can be used in the field for rapid identification during outbreak situations.

Arterial blood gas

Arterial blood gas level may reveal hypoxia and/or acidosis.

Peripheral blood smear

Y pestis coccobacillus may be identified on peripheral blood smears in up to 20% of patients, according to some studies

Gram stain

Gram stain may identify the gram-negative, pleomorphic coccobacillus. Gram stain can be performed on bubo aspirate, sputum, and blood.

In 70% of patients, the gram-negative, bipolar-stained coccobacillus is visualized if present. When stained with Wayson or Giemsa stain, a bipolar safety pin structure may be identified. While Wright stain often demonstrates this characteristic appearance, shown in the image below, Giemsa and Wayson stains most consistently highlight this pattern.

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Wright stain peripheral blood smear of patient with septicemic plague demonstrating bipolar, safety pin staining of Yersinia pestis. While Wright stai....

Cultures of blood, sputum and bubo aspirate

The plague bacillus grows readily on most culture media. Features of culture are as follows:

• Growth is slow and may require more than 48 hours before identification of colonies is possible
• Optimal growth occurs at 28°C
• Blood culture results are positive in 85-96% of patients
• Bubo aspirate culture results are positive in 80-85% of patients
• Sputum culture results are positive only if lung involvement is present

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Imaging Studies

Chest radiography

In patients with pneumonic plague, chest radiographs typically show alveolar infiltrates, with or without hilar lymphadenopathy. Bilateral consolidation may be evidenced. The radiograph below shows a patient with plague pneumonia.

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Right-side middle and lower lobe involvement in a patient with plague pneumonia. No chest radiograph pattern is characteristic of plague, but bilatera....

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Other Tests

Specialized diagnostic testing is available at some laboratories, such as state health departments or the Centers for Disease Control and Prevention (CDC).

An F1 antigen rapid diagnostic test using monoclonal antibodies has shown promise in the early detection of the plague.^[22]

Y pestis fluorescent antibody stain

This stain is performed on blood, sputum, or bubo aspirate samples. It may provide rapid diagnosis if available. If unavailable, send specimens to the CDC, Plague Branch, PO Box 2087, Fort Collins, CO 80522.

Y pestis fluorescent antibody titer

Acute and convalescent passive hemagglutination (PHA) titers should be taken 10 days apart. A 4-fold difference or a single convalescent PHA titer of 1:16 is evidence of infection.

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Procedures

Needle aspiration of a bubo

The diagnosis may be made by Gram stain and culture of the aspirate. One may attempt aspiration even if the lymph node is hard and nonfluctuant. Infusion of 1-3 mL of normal saline in the aspiration site prior to aspiration may prove beneficial. Strict contact and respiratory precautions must be practiced to avoid spreading this highly contagious agent.

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Prehospital Care

Provide supportive care. Crystalloid infusion to maintain normal vital signs and clinical hydration state may be necessary. Administer oxygen via nasal cannula, nonrebreather mask, or intubation as determined by the respiratory distress of the patient. Use pulse oximetry to monitor the degree of respiratory compromise.

Assume universal precautions, including goggles, gloves, and gown, when dealing with any patient with an infectious disease presentation. Masks should be worn if respiratory involvement is possible.

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Emergency Department Care

Depending on the stage of presentation, supportive care varies. Early presentation may require only crystalloid administration with monitoring of vital signs, clinical state, and urine output.^[2]

Septic shock requires invasive hemodynamic monitoring with crystalloid and vasopressor agents. Airway management may require intubation and mechanical ventilation with positive end-expiratory pressure (PEEP).

Any patient with predisposing risk factors and signs and symptoms consistent with plague should receive empiric treatment with antibiotics that cover Yersinia pestis. Empiric antibiotic coverage is discussed in Medication.

Use strict isolation precautions. If respiratory symptoms are present, institute universal precautions with strict respiratory isolation for the first 96 hours of therapy.^[21] If no respiratory symptoms are present, only 48 hours of isolation or isolation until purulent drainage from the bubo ceases is required. Incinerate or autoclave all contaminated material. Inform the laboratory of the possibility of handling plague infected material. Cases of laboratory-acquired plague have occurred.

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Consultations

See the list below:

• Consult an infectious disease specialist.
• Early notification of the CDC allows samples to be sent to the headquarters in Colorado for diagnosis by fluorescent antibody testing. The CDC, in conjunction with the Department of Health, will attempt to identify the source of the plague and implement early epidemiologic measures to control a potential epidemic.
• Consult a medical intensivist as indicated. In most patients with plague, some degree of septic shock is present. Invasive hemodynamic monitoring and close observation of fluid and cardiac status requires admission to a medical intensive care unit.

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Medication Summary

Medical management of plague can involve a myriad of supportive medications, including crystalloids, colloids, medications used for intubation, vasopressor agents, and antiulcer and antipyretic agents. This section describes only antibiotic management of plague. Early administration of antibiotics is essential after samples for diagnostic purposes have been obtained.

For both prophylaxis and treatment, antibiotics shown to be effective against plague include gentamicin and doxycycline. Fluoroquinolones are recommended, despite the lack of studies in humans.^{[23, 24]}

Two cases of mutiple-antibiotic resistant Yersinia pestis were discovered in Madagascar in 1995 and were presumed to be the result of horizontal gene transfer in the flea midgut. This discovery has raised the concern for the possibility of a natural or engineered antibiotic-resistant strain that could be used for biological attacks.^[25]

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Gentamicin

• Dosing, Interactions, etc.

Clinical Context:  Aminoglycoside antibiotic for gram-negative coverage. Drug of choice (DOC) with consideration of use as secondary agent.

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Streptomycin

• Dosing, Interactions, etc.

Clinical Context:  Alternative DOC in combination with consideration of use with a secondary agent. Drug often not commercially available. Treatment usually limited to 5 d due to toxicity concerns. Continuation of secondary agent for full 10 d recommended.

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Chloramphenicol

• Dosing, Interactions, etc.

Clinical Context:  DOC to be used as secondary agent in plague meningitis (better CNS penetration), profound hypotension, and pleural and/or pericardial involvement. May be considered as secondary agent. DOC for pregnant patients. Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth. Effective against gram-negative and gram-positive bacteria.

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Doxycycline (Doryx, Vibramycin, Monodox, Morgidox, Adoxa, Oracea)

• Dosing, Interactions, etc.

Clinical Context:  Inhibits protein synthesis and thus bacterial growth by binding to 30S and possibly 50S ribosomal subunits of susceptible bacteria.

May be considered as secondary agent or for postexposure prophylaxis.

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Levofloxacin (Levaquin)

• Dosing, Interactions, etc.

Clinical Context:  Second-generation quinolone. Acts by interfering with DNA gyrase in bacterial cells. Bactericidal. Fluoroquinolone antibiotic indicated for treatment or prophylaxis following exposure of Yersinia pestis (plague).

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Ciprofloxacin (Cipro)

• Dosing, Interactions, etc.

Clinical Context:  Fluoroquinolone that inhibits bacterial DNA synthesis and, consequently, growth, by inhibiting DNA gyrase and topoisomerases, which are required for replication, transcription, and translation of genetic material. Quinolones have broad activity against gram-positive and gram-negative aerobic organisms. Has no activity against anaerobes.

Animal studies have shown effectiveness against the plague. Can be considered as a secondary agent or as an agent for postexposure prophylaxis.

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Tetracycline

• Dosing, Interactions, etc.

Clinical Context:  Treats susceptible bacterial infections of both gram-positive and gram-negative organisms as well as mycoplasmal, chlamydial, and rickettsial infections; inhibits bacterial protein synthesis by binding with 30S and possibly 50S ribosomal subunits of susceptible bacteria; use with either streptomycin or gentamicin. Consider as a secondary agent or for postexposure prophylaxis.

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Trimethoprim/sulfamethoxazole (Bactrim, Bactrim DS, Sulfatrim Pediatric)

• Dosing, Interactions, etc.

Clinical Context:  DOC for prophylaxis of pregnant women and children < 8 y; inhibits bacterial synthesis of dihydrofolic acid by competing with PABA, inhibiting folic acid synthesis and resulting in the inhibition of bacterial growth.

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Moxifloxacin (Avelox)

• Dosing, Interactions, etc.

Clinical Context:  This fluoroquinolone is indicated in adults for the treatment of plague, including pneumonic and septicemic plague, caused by susceptible isolates of Yersinia pestis; it is also indicated for prophylaxis of plague in adults.

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Class Summary

Antibiotics that cover Yersinia pestis should be empirically given to any patient with predisposing risk factors and signs and symptoms of the plague. Treatment duration should be 10 days. In severe cases, a two-drug regimen should be used. Antibiotic regimens for postexposure prophylaxis should be considered for close contacts of infected patients. Agents and dosages are covered below.

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Further Inpatient Care

Take care to isolate all infected individuals.

Hospital laboratories and the public health department should be notified whenever plague is considered.  Any delay in diagnosis may place other health care workers and patients at risk for exposure.

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Transfer

Whenever possible, patients suspected of having plague should not be transferred. When transport is necessary, it must be performed with the patient in strict isolation. All transfers must comply with Consolidated Omnibus Budget Reconciliation Act (COBRA) regulations

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Deterrence/Prevention

Actions to limit the risk of acquiring the plague should be considered and include but are not limited to the following:^[4]

• Limit contact with rodents.
• Treat domesticated animals for fleas.
• Consider use of protective clothing, insect repellants (DEET), insecticides, and/or rodenticides, especially if in an endemic area.
• Improve environmental sanitation, such as proper disposal of trash, which may serve to attract rodents.
• Surface disinfection where appropriate

Use prophylactic antibiotics in close contacts (within 2-5 ft) of patients who are infected. In those who refuse treatment, close observation and isolation is mandated for 7 days.

A plague vaccine exists, but it has not been commercially available in the United States since 1999. Its use is recommended only for health personnel who may come into contact with Y pestis. The vaccine may also be useful for specialized care and for agricultural personnel who work in areas with endemic plague and are unable to minimize contact with wild animals. The amount of protection the vaccine provides is poor, especially for pneumonic plague. As such, it is not currently recommended in outbreak-type situations.

A genetically modified form of a Y pseudotuberculosis strain has been used to develop an oral vaccine that provides protection against both bubonic and pneumonic plague after a single dose. Development of the vaccine involved deleting genes coding for virulence factors and inserting Y pestis genetic material to increase cross-species immunogenicity. The developers propose that the vaccine could be used for mass vaccination in endemic areas and as a response to a bioterrorism incident.^[26]

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Complications

See the list below:

• Meningitis
• Septic shock
• Disseminated intravascular coagulation (DIC)
• Skin necrosis
• Pericarditis
• Death

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Prognosis

See the list below:

• In those treated for bubonic plague, the mortality rate is 1-15%.
• Primary or secondary septicemic plague has a 40% mortality rate, even in treated patients.
• Pneumonic plague has 100% mortality if not treated within the first 24 hours.

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Patient Education

See the list below:

• For excellent patient education resources, visit eMedicineHealth's First Aid and Injuries Center. Also, see eMedicineHealth's patient education articles Biological Warfare, Plague, Personal Protective Equipment, and Ticks.
• For additional information, visit the Centers for Disease Control and Prevention, Plague Information.

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