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PLAGUE

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Classification   |    Detailed evidence-based information

Substances Included Synonyms

Therapeutic Toxic Class

    A) Plague, a zoonotic disease, is a flea-transmitted (and rarely airborne-transmitted) bacterial illness caused by Yersinia pestis. It normally exists as a three-way interaction between Y pestis, animal carriers (usually wild rodents or domestic cats), and fleas parasitic on the animals. Infection of Y pestis in humans is unintentional and almost always leads to disease. Y pestis is maintained in nature by rodent-flea-rodent transmission.
    B) Yersinia pestis is a gram-negative coccobacillus (family Enterobacteriaceae) that is aerobic or facultatively anaerobic, nonmotile, non-spore forming, and non-lactose fermenting.
    C) Three principal forms of human plague are: bubonic (infection of the lymph nodes), septicemic (infection of the blood), and pneumonic (infection of the lungs). Of the three, bubonic is most common form, affecting about 84% of United States cases. Septicemic plague affects about 14% of cases, while pneumonic plague affects about 3% of cases.

Specific Substances

    1) Black death
    2) Bubonic plague
    3) Pneumonic plague
    4) Septicemic plague
    5) Y pestis
    6) Yersinia pestis
    7) Plague, bubonic
    8) Plague, pneumonic
    9) Plague, septicemic

Available Forms Sources

    A) FORMS
    1) BUBONIC PLAGUE: Characterized by sudden onset of fever, headache, abdominal distress, chills, myalgias. Painful lymphadenopathy (bubo) occurs in 95% of patients; involves lymph nodes draining site of initial infection, most commonly groin, neck, or axilla (Connor et al, 1978; CDC, 1990a; Butler, 1995; Crook & Tempest, 1992; Morris & McAllister, 1992).
    2) SEPTICEMIC PLAGUE: Characterized by an acute febrile illness, with or without detectable lymphadenopathy, that may progress to septic shock (Hull et al, 1987; Butler, 1995; RR-14:1-15). Sporadic cases of primary septicemic plague are difficult to diagnose because there are no specific findings. Signs and symptoms (fever, headache, GI symptoms, tachycardia, tachypnea, hypotension) are similar to those of other forms of gram-negative septicemia (Hull et al, 1987). Lymphadenopathy is absent (Hull et al, 1987; Welty et al, 1985).
    3) PNEUMONIC PLAGUE: Primary pneumonic plague is difficult to diagnose on clinical grounds alone as it may present as any other overwhelming bacterial pneumonia (Butler, 1995). In over 95% of cases of secondary pneumonic plague, buboes (acute lymphadenopathy) are present somewhere on the body (Connor et al, 1978).
    B) SOURCES
    1) Plague is caused by Yersinia pestis, a gram-negative nonmotile and nonspore-forming bacillus that grows in both anaerobic and aerobic conditions. It produces three toxins: exotoxin, with little human significance, lipopolysaccharide endotoxin that is responsible for several of the clinical manifestations, and W and V antigens that makes the organism resistant to phagocytic killing in vivo (Butler, 1995).
    C) USES
    1) BIOLOGIC WARFARE: A risk exists for use as a biologic warfare agent against military forces in combat or as a tool of terrorists against civilians (Franz et al, 1997).

Overview

Life Support

    A) This overview assumes that basic life support measures have been instituted.

Clinical Effects

    0.2.1) SUMMARY OF EXPOSURE
    A) DESCRIPTION: Plague is an infectious disease of wild rodents (eg, prairie dogs, squirrels) that is naturally transmitted to humans by the bites of infected fleas. It is caused by Yersinia pestis, a gram-negative nonmotile and nonspore-forming bacillus, that grows in both anaerobic and aerobic conditions. Exposure in humans is always almost unintentional but can lead to disease. There is a theoretical risk of using plague for biological warfare. Person-to-person transmission of plague occurs only with pneumonic plague.
    B) TOXICOLOGY: When an infected flea bites a human, Yersinia pestis is carried to regional lymphatics, where it replicates intracellularly. It produces three toxins, an exotoxin that is of little significance to humans, a lipopolysaccharide endotoxin, and W and V antigens that give it protection from phagocytic killing. The lipopolysaccharide endotoxin is responsible for various clinical manifestations. Plague can occur in several different forms, including bubonic plague (majority of cases), septicemic plague (which can be primary or secondary to bubonic plague), and pneumonic plague (very rare but the most lethal form).
    C) EPIDEMIOLOGY: Plague in the United States is very rare, with approximately a dozen reported cases a year over the last 50 years, though with Native Americans (specifically Navajo) disproportionally represented. Worldwide, there have been thousands of cases in the past century, though it is likely underreported. Countries with the highest prevalence of plague include Tanzania, Vietnam and Zaire.
    D) WITH POISONING/EXPOSURE
    1) The site of flea bite(s) may be marked by papule or vesicle and is most commonly located on legs (present in only 10% to 15%). Tissue necrosis of skin and appendages may occur. Necrosis and cyanosis, resulting in a blackened skin explains the terminology, "black death". An acute inflammatory response occurs in the lymph node in 2 to 6 days. The lymph nodes become hemorrhagic, and organisms are released into the bloodstream. Secondary sites like the lungs and meninges may then become infected. Rarely, primary pneumonia may occur from inhalation of aerosolized bacteria. Clinical characteristics depend on the type of plague involved, but diagnostic clues include sudden onset of high fever, nausea, vomiting, diarrhea, malaise, myalgias, severe headache, prostration, and axillary or inguinal lymphadenitis (buboes) following a history of exposure to rodents in endemic areas. An aerosolized plague weapon may cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days following exposure. After symptom onset, rapid progression of disease could occur 2 to 4 days later and could lead to septic shock with high mortality without early treatment. Mortality ranges from 50% to 60% for untreated bubonic plague and up to 100% for untreated septicemic or pneumonic plague. Other reported complications include ARDS (in 5% with 50% mortality), DIC, and bacterial meningitis, and skin necrosis (black plague).

Laboratory Monitoring

    A) Diagnose bubonic plague with Gram stain and culture of aspirated specimen from suppurative lymph nodes and blood cultures. Suspected plague should be considered if small Gram-negative and/or bipolar-staining coccobacilli ("safety pin" appearance) are seen on a smear taken from affected tissues, for example, bubo (bubonic plague), blood (septicemic plague), or tracheal/lung aspirate (pneumonic plague). Cultures may not be positive for 48 hours.
    B) Monitor CBC with differential. Leukocytosis (12,000 to 20,000 WBC/mm(3)) may occur. WBC count may be decreased to 900/mm(3) in patients with severe septicemic or pneumonic plague.
    C) Urinalysis may show hematuria and proteinuria. Cultures and Gram stain can be high yield in pneumonic and septicemic plague.
    D) To confirm the diagnosis of plague, the following must be met: an isolated culture is lysed by specific bacteriophage; 2 serum specimens demonstrate a 4-fold anti-F1 antigen difference by agglutination testing; or a single serum specimen tested by agglutination has a titer greater than 1:128 and the patient has no known previous plague exposure or vaccination history. Hemagglutinating antibody titer rises in 8 to 14 days.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms. Chest x-ray may show pneumonic infiltrates or hilar adenopathy.
    F) Monitor vital signs and mental status. Patients with symptoms of meningitis may require a head CT and/or a lumbar puncture.
    G) Obtain an ECG, and institute continuous cardiac monitoring.

Treatment Overview

    0.4.3) INHALATION EXPOSURE
    A) People in contact with patients infected with Y. pestis should wear protective masks and use barrier isolation techniques. All patients should be strictly isolated for a minimum of 48 hours following the institution of therapy. Isolation should continue as long as drainage continues, but it may be discontinued after the patient has been treated for at least 48 hours and there is no more drainage or respiratory symptoms. Respiratory isolation of patients with pneumonic plague should continue for at least 72 hours after institution of antibiotic therapy. Primary pneumonic plague may occur from intentional aerosol dispersion or intimate contact (via respiratory droplets) with patients or pets (usually cats) with pneumonic plague.
    B) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.
    0.4.4) EYE EXPOSURE
    A) Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected plague infections should be immediately rinsed with copious amounts of water or eyewash solution.
    0.4.5) DERMAL EXPOSURE
    A) OVERVIEW
    1) Dermal sites, particularly where breaks in skin integrity occur, exposed to blood, body fluids, secretions, or excretions from patients with suspected plague should be immediately washed with soap and water. Cats may transmit bubonic plague via scratches or bites. Direct contact with infected material from a bubo may also cause infection. Masks, gowns, and gloves should be worn while examining wounds or changing dressings. Exudates or discharge should be handled with rubber gloves. All contaminated material should be autoclaved or incinerated.
    2) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.
    0.4.7) BITES/STINGS
    A) MANAGEMENT OF MILD TO MODERATE TOXICITY
    1) For mild to moderate toxicity, antibiotics and supportive care are the mainstay of treatment. Medical personnel working with known Yersinia pestis infected patients should wear protective masks and utilize barrier isolation techniques. Isolation of patients with bubonic plague should occur for 48 hours after initiation of antibiotics or until all purulent drainage is gone. All suspected or confirmed cases of plague should be reported to the local health department, though misdiagnosis may occur. Manage mild hypotension with IV fluids. Antibiotics effective against plague include streptomycin, gentamicin, doxycycline, ciprofloxacin, chloramphenicol, and moxifloxacin (see below for further information). Post-exposure prophylaxis treatment for pneumonic plague includes doxycycline, ciprofloxacin, and moxifloxacin.
    B) MANAGEMENT OF SEVERE TOXICITY
    1) Patients with septicemic or pneumonic plague can be critically ill. In cases of airway compromise, endotracheal intubation and mechanical ventilation may be needed. Correct any significant fluid and/or electrolyte abnormalities in patients with severe diarrhea and/or vomiting. Treat severe hypotension with IV 0.9% NaCl at 10 to 20 mL/kg. Add dopamine or norepinephrine if unresponsive to fluids. Treat seizures with IV benzodiazepines; barbiturates or propofol may be needed if seizures persist or recur. Acute lung injury may require close monitoring with pulse oximetry and/or arterial blood gases, with early use of PEEP. Patients with renal failure may require hemodialysis.
    C) DECONTAMINATION
    1) PREHOSPITAL: There is no utility for the use of prehospital activated charcoal. Following dermal exposure, remove contaminated clothing and wash exposed area extremely thoroughly with soap and water. Following eye exposure, remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. Prehospital personnel working with known Yersinia pestis infected patients should wear protective masks and utilize barrier isolation techniques.
    2) HOSPITAL: There is no role for activated charcoal, gastric lavage or whole bowel irrigation for plague. INHALATIONAL EXPOSURE: People in contact with patients infected with Y. pestis should wear protective masks and use barrier isolation techniques. All patients should be strictly isolated for a minimum of 48 hours following the institution of therapy. Isolation should continue as long as drainage continues, but it may be discontinued after the patient has been treated for at least 48 hours and there is no more drainage or respiratory symptoms. Respiratory isolation of patients with pneumonic plague should continue for at least 72 hours after institution of antibiotic therapy. Primary pneumonic plague may occur from intentional aerosol dispersion or intimate contact (via respiratory droplets) with patients or pets (usually cats) with pneumonic plague. DERMAL EXPOSURE: Dermal sites, particularly where breaks in skin integrity occur, exposed to blood, body fluids, secretions, or excretions from patients with suspected plague should be immediately washed with soap and water. Cats may transmit bubonic plague via scratches or bites. Direct contact with infected material from a bubo may also cause infection. Masks, gowns, and gloves should be worn while examining wounds or changing dressings. Exudates or discharge should be handled with rubber gloves. All contaminated material should be autoclaved or incinerated. EYE EXPOSURE: Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected plague infections should be immediately rinsed with copious amounts of water or eyewash solution.
    D) AIRWAY MANAGEMENT
    1) Critically ill patients, especially those with pneumonic plague, may require aggressive airway management including early intubation due to rapid progression of disease. .
    E) ANTIDOTE
    1) There is no specific antidote. Patients should be treated with antibiotics.
    F) ANTIBIOTIC THERAPY
    1) Treatment approach depends on whether plague is a naturally occurring infection or following the use of a biological weapon. Initial parenteral therapy is usually indicated for either cause but oral antibiotics may be given as monotherapy in mild to moderate cases of naturally occurring plague. Oral agents are recommended in a mass casualty setting (biological weapon use) and for postexposure prophylaxis. Antibiotics effective against plague include streptomycin, gentamicin, doxycycline, ciprofloxacin, or chloramphenicol. Streptomycin is the preferred choice for parenteral therapy; gentamicin may be considered, but experience is limited. Babies delivered during a potential bacteremic phase of maternal plague should receive gentamicin rather than streptomycin. Doxycycline is the preferred oral agent. Tetracycline and chloramphenicol are also considered appropriate therapy for plague. Fluoroquinolones may be another option. Moxifloxacin may be used to prevent or treat adult patients with plague, including pneumonic and septicemic plague, caused by susceptible isolates of Yersinia pestis. In the event of a bioterrorist attack, ciprofloxacin may be given for prophylaxis and treatment of plague, although efficacy evidence is lacking. Chloramphenicol is recommended for treatment of plague meningitis. Post-exposure prophylaxis treatment for pneumonic plague includes doxycycline and ciprofloxacin.
    2) DOSING
    a) STREPTOMYCIN: ADULT: 15 mg/kg IM every 12 hours for 10 to 14 days. An alternate dose of 1 g IM twice daily for 10 days has also been recommended. PEDIATRIC: 15 mg/kg IM twice daily for 10 days to prevent relapses (maximum 2 g/day).
    b) GENTAMICIN: ADULT: 5 mg/kg IV or IM once daily OR 2 mg/kg loading dose IV or IM followed by 1.7 mg/kg 3 times daily. Patients may be switched to oral therapy when warranted by clinical improvement, for a total course of 10 days. PEDIATRIC: 2.5 mg/kg IV or IM 3 times daily. Patients may be switched to oral therapy when warranted by clinical improvement, for a total course of 10 days. NEONATES (younger than 1 week): 2.5 mg/kg IV or IM twice daily. Patients may be switched to oral therapy when warranted by clinical improvement, for a total course of 10 days.
    c) DOXYCYCLINE: ADULT: 100 mg orally twice daily for 10 to 14 days. PEDIATRIC (greater than 45 kg): 100 mg IV twice daily OR 200 mg IV once daily OR 100 mg orally twice daily for a total course of 10 days. PEDIATRIC (less than 45 kg): 2.2 mg/kg orally or IV twice daily for a total course of 10 days (maximum 200 mg/day).
    d) CHLORAMPHENICOL: ADULT: 25 mg/kg IV or orally 4 times daily for a total course of 10 days. PEDIATRIC (older than 2 years): 25 mg/kg IV or orally 4 times daily for a total course of 10 days.
    e) CIPROFLOXACIN: ADULT: 400 mg IV twice daily OR 500 mg orally twice daily for a total course of 10 days. PEDIATRIC: 15 mg/kg IV twice daily OR 20 mg/kg orally twice daily for a total course of 10 days (maximum 1 g/day).
    f) MOXIFLOXACIN: ADULT: 400 mg orally or as an IV infusion once every 24 hours for 10 to 14 days. PEDIATRIC: Safety and efficacy of moxifloxacin in children (less than 18 years of age) have not be established.
    g) PRIMARY PREVENTION: DOXYCYCLINE: Naturally occurring plague: ADULT: 50 to 100 mg orally twice daily for 7 days. Biological weapon: ADULT: 100 mg orally twice daily for 7 days. Naturally occurring plague: PEDIATRIC (greater than 9 years): 1 to 2 mg/kg orally twice daily for 7 days. Biological weapon: PEDIATRIC (less than 45 kg): 2.2 mg/kg orally twice daily for 7 days. Biological weapon: PEDIATRIC (greater than 45 kg): 100 mg orally twice daily for 7 days. CIPROFLOXACIN: ADULT: 500 mg orally twice daily for 7 days. PEDIATRIC: 20 mg/kg orally twice daily for 7 days. MOXIFLOXACIN: ADULT: 400 mg orally or as an IV infusion once every 24 hours for 10 to 14 days. PEDIATRIC: Safety and efficacy of moxifloxacin in children (less than 18 years of age) have not be established.
    G) ENHANCED ELIMINATION PROCEDURE
    1) There is no role for hemoperfusion, urinary alkalinization, or multiple dose charcoal. Consider hemodialysis in patients with acute renal failure.
    H) PATIENT DISPOSITION
    1) OBSERVATION CRITERIA: All patients with known or suspected plague should be sent to a healthcare facility for observation. In addition, strict protective measures should be taken for those in contact with these patients. Patients should only be discharged home if they are clearly improving, under treatment, and arrangements made to prevent transmission of disease. All patients with plague should receive follow-up examinations after discharge, since plague meningitis may develop as long as 14 days after antibiotic therapy has been initiated.
    2) ADMISSION CRITERIA: Patients who are getting worse or at risk of transmitting disease should be admitted to the hospital for further observation and treatment. Depending on the severity of their disease, they may require ICU treatment. They should not be discharged until they are clearly improving, on antibiotic treatment, and arrangements made to avoid further spread of disease.
    3) CONSULT CRITERIA: Depending on the severity of disease, other consultants that may be involved include infectious disease specialists and intensivist. All confirmed and suspected cases should be reported immediately through local and state health departments to the Centers for Disease Control (CDC). Health department personnel will work with the CDC and the attending physician in the treatment of plague. Help for suspected or proved cases can be obtained from the Center for Disease Control and Prevention Bacterial Diseases Branch, Foothills Campus, Fort Collins, CO 80521; 800-CDC-INFO or 800-232-4636; TTY 888-232-6348.
    4) PATIENT-TRANSFER CRITERIA: Whenever possible, patients with suspected cases of plague should not be transferred as it will cause greater exposure of this highly infectious disease. If a patient must be transferred, strict isolation procedures should be observed by all personnel involved in the transfer.
    I) PITFALLS
    1) The most common pitfalls in managing plague include not protecting oneself properly from infected patients and not suspecting or missing the diagnosis.
    J) PREDISPOSING CONDITIONS
    1) Predisposing conditions to contract plague include being a non-urban resident of the Southwestern United States, human crowding in rodent-infested habitats, recent contact with a sick or dead animal, recent camping or sleeping on the ground, being a resident or visitor to an area where plague is endemic, being near domestic dogs or cats in contact with wild animals, or being in contact with family or a community with known plague.
    K) DIFFERENTIAL DIAGNOSIS
    1) The differential diagnosis of plague can be quite broad, as it can appear like many other viral or bacterial illnesses in its various manifestations. Bubonic plague can mimic other forms of infectious lymphangitis, including Streptococcal lymphangitis, Staphylococcal lymphangitis, granuloma inguinale, lymphopathia venereum, Cat-scratch disease, pasteurella multocida infection, melioidosis, mycobacteriosis, tularemia.

Range Of Toxicity

    A) TOXICITY: There is no known specific toxic dose of plague, but exposures can be lethal. Mortality rates range from 50% to 60% for untreated bubonic plague; up to 100% for untreated septicemic or pneumonic plague.

Clinical Effects

Vital Signs

    3.3.2) RESPIRATIONS
    A) WITH POISONING/EXPOSURE
    1) Tachypnea be seen with the pneumonic form of plague (Connor et al, 1978).
    3.3.3) TEMPERATURE
    A) WITH POISONING/EXPOSURE
    1) TEMPERATURE, INCREASED: Temperature of 37 to 40.9 degrees C (mean 39.4 degrees C) occurs and is caused by the bacterial toxin. This is evident in all forms of the disease, but the greatest increase in temperature occurs in pneumonic plague (Connor et al, 1978; Butler, 1995; Barnes & Quam, 1992; Welty et al, 1985a).
    a) Patients may present with a nonspecific febrile syndrome, characterized by fever, myalgias, and malaise (Crook & Tempest, 1992). Some patients may present with an acute febrile illness with no bubo or lymph node involvement, which is typical of septicemic plague (Goddard, 1999).
    3.3.5) PULSE
    A) WITH POISONING/EXPOSURE
    1) Tachycardia is a usual finding and is caused by bacterial toxin (Connor et al, 1978).

Heent

    3.4.2) HEAD
    A) WITH POISONING/EXPOSURE
    1) NUCHAL RIGIDITY: In plague complicated by infection of the meninges, nuchal rigidity will be seen. The meningitic aspect is usually evident 2 to 3 days after initial onset of the disease in the untreated patient (Butler, 1995; Crook & Tempest, 1992).
    3.4.3) EYES
    A) WITH POISONING/EXPOSURE
    1) Clinical presentation of human plague includes conjunctival injection of the eyes (Goddard, 1999).
    3.4.5) NOSE
    A) WITH POISONING/EXPOSURE
    1) EPISTAXIS may occur in septicemic plague secondary to hemorrhage caused by the effect of plague toxin producing DIC.
    3.4.6) THROAT
    A) WITH POISONING/EXPOSURE
    1) PHARYNGITIS: Patients may present with fever, sore throat, and headache, mimicking pharyngitis or sinusitis (Crook & Tempest, 1992).

Cardiovascular

    3.5.2) CLINICAL EFFECTS
    A) HYPOTENSIVE EPISODE
    1) Hypotension may occur, similarly to that occurring with other forms of gram-negative septicemia. Nearly every organ and tissue of the body may become infected with Y pestis, resulting in pyogenic, necrotic, infarctive, inflammatory, hemorrhagic, or edematous lesions. Circulatory collapse may occur in 5% to 10% of cases (Hull et al, 1987).
    B) TACHYARRHYTHMIA
    1) Tachycardia is a usual finding and is caused by bacterial toxin (Connor et al, 1978).

Respiratory

    3.6.2) CLINICAL EFFECTS
    A) PNEUMONIA
    1) PRIMARY PNEUMONIC PLAGUE
    a) Least common (2%) but most dangerous form of plague (57% of plague deaths); may be a primary pneumonia when the organism is transmitted from human to human, or it may be a complication of bubonic or septicemic plague. In US, primary pneumonia has been reported in laboratory workers and in persons acquiring disease from a cat with plague pneumonia. Incubation period is 1 to 3 days (Hull et al, 1987; Welty et al, 1985a; RR-14:1-15; CDC, 1997).
    2) SECONDARY PNEUMONIC PLAGUE
    a) Approximately 10% to 25% of all plague patients develop pulmonary symptoms (either pneumonia or ARDS), with a death rate of about 50%. Secondary pneumonia may serve as a source of cough-generated aerosols for developing primary plague pneumonia and causing interpersonal spread. Associated with a 100% mortality if not treated within the first 18 to 24 hours (Werner et al, 1984; Butler, 1995; CDC, 1992; RR-14:1-15).
    3) PRESENTATION
    a) Primary pneumonic plague is difficult to diagnose on clinical grounds alone as it may present as any other overwhelming bacterial pneumonia. In over 95% of secondary pneumonic plague cases, buboes (acute lymphadenopathy) are present somewhere on the body (Connor et al, 1978; Butler, 1995).
    B) DYSPNEA
    1) Dyspnea may occur in the pneumonic form of plague as a direct result of the pulmonary infiltrate and resembles the dyspnea occurring in any other form of fulminant bacterial pneumonia (Connor et al, 1978; Butler, 1995).
    C) COUGH
    1) A productive, often bloody, cough is a symptom of pneumonic plague (Barnes & Quam, 1992; Butler, 1995).
    D) HEMOPTYSIS
    1) Patients with pneumonic plague will frequently produce blood-streaked sputum, but it is not rust-colored as in other bacterial pneumonias (Connor et al, 1978).
    E) DISORDER OF RESPIRATORY SYSTEM
    1) Scattered rales may be heard on auscultation in patients with primary or secondary pneumonic form of plague. Areas of dullness to percussion may be noted in patients with pneumonic plague and are an indication of the patchy consolidation found in the lungs (Hoffman, 1980).

Neurologic

    3.7.2) CLINICAL EFFECTS
    A) HEADACHE
    1) Headache is a result of the fulminant bacterial infection (Connor et al, 1978).
    2) Patients may present with fever, sore throat, and headache, mimicking pharyngitis or sinusitis (Crook & Tempest, 1992).
    B) SEIZURE
    1) Seizures are noted occasionally and, when present, are an ominous sign (Butler, 1995; Barnes & Quam, 1992).
    C) ALTERED MENTAL STATUS
    1) NERVOUSNESS
    a) Disease severity is indicated by the degree of mental status change that is exhibited; may include restlessness (Butler, 1995; Barnes & Quam, 1992).
    b) Bacterial toxin is responsible for changes in personality and mental status (Connor et al, 1978).
    2) DELIRIUM
    a) Delirium may occur, and is a sign of disease severity
    b) (Barnes & Quam, 1992; Butler, 1995).
    c) Bacterial toxin is responsible for changes in personality and mental status (Connor et al, 1978).
    3) COMA
    a) Coma may occur in the end stages of the disease (Butler, 1995; Barnes & Quam, 1992).
    b) Bacterial toxin of plague is responsible for changes in personality and mental status (Connor et al, 1978).
    D) MENINGITIS
    1) Plague may affect the meninges and result in meningitis (0.2% to 7% of cases) (Becker et al, 1987; Crook & Tempest, 1992).
    a) Meningitis developed in 6 of the 105 patients (6%) with plague reported to the CDC from 1970 to 1979; five of the six cases occurred in children aged 10 to 15 years. All six patients received antibiotic therapy before meningitis developed, which appeared between the ninth and fourteenth days after the onset of acute illness in five patients. There were no neurologic sequelae (Becker et al, 1987).
    b) Patients with cervical or axillary buboes appear to be at increased risk of developing meningitis (Becker et al, 1987).
    2) Cerebrospinal fluid examination findings include gram-negative organisms, leukocytosis, decreased glucose level, and an increased protein level (Butler, 1995; Becker et al, 1987).
    3) The most likely explanation for plague meningitis is that ineffective antibiotic therapy for the acute stage of plague infection allows the development of meningitis later in the course of the illness.
    4) The combination of the type of drug used, the rapidity with which it is administered following the onset of illness, and the length of time it is administered may be important factors in successful treatment.
    5) All patients with plague should receive follow-up examinations after discharge, since plague meningitis may develop as long as 14 days after antibiotic therapy for the acute plague infection has been initiated (Becker et al, 1987).

Gastrointestinal

    3.8.2) CLINICAL EFFECTS
    A) GASTROINTESTINAL COMPLICATION
    1) Gastrointestinal symptoms occur in about 60%; may be a general response to serious illness and stress rather than from a specific gastrointestinal process (Hull et al, 1986).
    2) Onset may be early in the course, sometimes preceding the appearance of lymphadenopathy. May occur more frequently in septicemic plague (Hull et al, 1986).
    B) NAUSEA
    1) Nausea is a toxic manifestation of the bacterial infection and is nonspecific (Connor et al, 1978). It was noted in 24 of 71 plague cases (34%) in one review (Hull et al, 1986).
    2) Patients may present with fever, nausea, vomiting, diarrhea, and myalgias, mimicking a gastrointestinal infection (Crook & Tempest, 1992).
    C) VOMITING
    1) Patients with plague may experience vomiting as a toxic manifestation of the bacterial infection; the vomiting is nonspecific (Connor et al, 1978).
    2) In one review, vomiting was the most frequent symptom, found in 28 of 71 cases (39%) (Hull et al, 1986). Patients may present with fever, nausea, vomiting, diarrhea, and myalgias, mimicking a GI infection (Crook & Tempest, 1992).
    D) DIARRHEA
    1) Nonspecific diarrhea, often bloody, may occur in the bubonic and septicemic forms of plague. It occurred in 20 of 71 plague cases (28%) in one review (Hull et al, 1986).
    E) ABDOMINAL PAIN
    1) Abdominal pain occurred in 12 of 71 plague cases (17%) in one review (Hull et al, 1986); it might be caused by intra-abdominal buboes or hepatic or splenic enlargement.
    2) Septicemic plague often presents as an acute abdominal process mimicking appendicitis or Yersinia enterocolitica or Campylobacter infection (Humphrey et al, 1988; Hull et al, 1987).
    F) HEMATEMESIS
    1) Hematemesis may occur secondary to hemorrhage caused by the effect of plague toxin producing disseminated intravascular coagulation (DIC).
    G) MELENA
    1) Bloody or black stools may possibly be due to hemorrhage caused by DIC.
    H) CONSTIPATION
    1) Diarrhea may be preceded by constipation, but this is a nonspecific symptom.
    I) SPLENOMEGALY
    1) The spleen is at times palpable.

Hematologic

    3.13.2) CLINICAL EFFECTS
    A) DISSEMINATED INTRAVASCULAR COAGULATION
    1) Subclinical disseminated intravascular coagulation (DIC) was noted in 86% of cases of septicemic plague. These patients may develop gangrenous involvement of the distal digits, penis, and nose (Butler, 1974).
    2) Bruises may be present secondary to plague toxin producing DIC. Bleeding from all parts of the body may occur secondary to DIC. Purpura, associated with vasculitis and thrombosis, may be seen (Morris, 1996).
    B) LEUKOCYTOSIS
    1) As the disease progresses, elevated white blood cell count persists (Morris, 1996).

Dermatologic

    3.14.2) CLINICAL EFFECTS
    A) SKIN NECROSIS
    1) Tissue necrosis of skin and appendages may occur rarely in neglected cases of plague (Hull et al, 1987; Butler, 1995; Crook & Tempest, 1992; RR-14:1-15).
    2) A peripheral thrombotic phenomenon secondary to DIC may complicate a Y pestis infection, resulting in severe peripheral tissue necrosis of skin and appendages in patients with the septicemic and pneumonic forms of the plague. The nature and degree of blackened skin over the entire body caused by a combination of this necrosis and cyanosis may explain the medieval epithet applied to the disease - the "black death". The blackened skin is more profound and qualitatively different from simple cyanosis (Barnes & Quam, 1992; Butler, 1995).
    B) BITE - WOUND
    1) History of travel to or residence in the western third of the United States, particularly New Mexico, Arizona, or California, and possibly Colorado and Oregon, should arouse suspicion of the possibility of a flea bite.
    2) Although the actual site of the flea bite is rarely seen, a visible bite will be marked by a papule or vesicle that ultimately becomes papular. Flea bites most commonly involve the lower extremities.
    C) LYMPHADENOPATHY
    1) BUBOES: INCIDENCE: 5% of patients with bubonic plague have two or more swollen lymph nodes. Cervical buboes are more common in children (Butler, 1995). The swollen nodes are the hallmark of bubonic plague, which is the most common form of plague, accounting for 80% to 90% of all plague cases in the United States (Levy & Gage, 1999).
    2) LOCATION: Buboes are firm, painful, swollen (up to 5 cm) lymph nodes, often surrounded by a boggy, erythematous area - may be found in the femoral-inguinal (60%), axillary (30%), cervical (10%), and epitrochlear regions.
    a) Buboes in the femoral area occur in 60% to 70% of patients because of the large number of flea bites in the lower extremities (Butler, 1995; Levy & Gage, 1999).
    3) TIMING: Two thirds of persons develop lymphadenopathy within 2 days of exposure; 20% to 30% of persons with buboes experience pain in the node before swelling occurs (Butler, 1995).
    4) PRESENTATION: Buboes are so tender that, when in the groin area, the leg will usually be flexed to avoid touch and movement (Barnes & Quam, 1992; Butler, 1995).
    a) Usually continue to enlarge even though other clinical signs remit, and they may remain tender for weeks after recovery. May become secondarily infected (usually with S aureus) late in the course (Butler, 1995; Barnes & Quam, 1992).
    D) BULLOUS ERUPTION
    1) Rarely, vesicles may occur (Butler, 1995; Barnes & Quam, 1992), especially in highly immunogenic individuals (Barnes & Quam, 1992; Butler, 1995).
    E) PUSTULE
    1) Rarely, pustular lesions may be noted (Butler, 1995; Barnes & Quam, 1992).
    F) DISCOLORATION OF SKIN
    1) The skin may become mottled if circulatory collapse occurs (Connor et al, 1978).
    G) PURPURA
    1) Petechiae are caused by plague toxin affecting the blood vessels, resulting from disseminated intravascular coagulation, a rare complication of septicemic plague (Butler, 1995; Barnes & Quam, 1992).

Musculoskeletal

    3.15.2) CLINICAL EFFECTS
    A) MUSCLE PAIN
    1) Muscle aches are a toxic manifestation of the bacterial infectious process (Connor et al, 1978).
    2) Patients may present with a nonspecific febrile syndrome, characterized by fever, myalgias, and malaise; or with fever, nausea, vomiting, diarrhea, and myalgias mimicking a gastrointestinal infection (Crook & Tempest, 1992).
    B) BACKACHE
    1) Diffuse muscle tenderness in the back may occur.

Immunologic

    3.19.2) CLINICAL EFFECTS
    A) SYSTEMIC INFECTION
    1) SEPTICEMIC PLAGUE
    a) INCIDENCE/MORTALITY (Humphrey et al, 1988; Hull et al, 1987; Butler, 1995; Crook & Tempest, 1992; RR-14:1-15; CDC, 1997):
    1) 5% to 15% of patients with a Y pestis infection develop septicemic plague. This occurs when the organism multiplies in the bloodstream; may be secondary to bubonic plague or develop without lymphadenopathy (primary septicemic plague).
    2) Accounts for about 13% of US cases and 22% of plague deaths. Mortality is almost 40%, and in untreated cases, approaches 100%.
    3) Patients presenting with septicemic plague are likely to be middle-aged or elderly adults, although cases have been reported in all age groups.
    b) PRESENTATION: Characterized by an acute febrile illness, with or without detectable lymphadenopathy, that may progress to septic shock (Hull et al, 1987; Butler, 1995; RR-14:1-15). Sporadic cases of primary septicemic plague are difficult to diagnose because there are no specific findings.
    1) Signs and symptoms (fever, headache, GI symptoms, tachycardia, tachypnea, hypotension) are similar to those of other forms of gram-negative or gram-positive septicemia (Hull et al, 1987). Lymphadenopathy is absent (Hull et al, 1987; Welty et al, 1985a).
    2) Often presents as an acute abdominal process mimicking gastroenteritis or appendicitis (Humphrey et al, 1988).
    c) COMPLICATIONS: Septic shock, meningitis, coma, and consumptive coagulopathy. Tissue necrosis of skin and appendages may occur rarely in neglected cases of plague. The necrosis and cyanosis may explain the medieval epithet applied to the disease -- the "black death."
    B) BACTERIAL INFECTIOUS DISEASE
    1) Patient may complain of chills caused by the bacterial toxin (Connor et al, 1978). The complaint of weakness is nonspecific and is similar to the malaise found in other fulminant bacterial infections (Butler, 1995; Barnes & Quam, 1992).
    C) LYMPHADENOPATHY
    1) INCIDENCE: 15% of patients with bubonic plague have two or more swollen lymph nodes. Cervical buboes are more common in children (Butler, 1995).
    2) LOCATION: Buboes - firm, painful, swollen (up to 5 cm) lymph nodes, often surrounded by a boggy, hemorrhagic area, may be found (in order of decreasing frequency) in the femoral-inguinal, axillary, cervical, and epitrochlear regions (Butler, 1995).
    a) Buboes in the femoral area occur in 60% to 70% of patients because of the large number of flea bites in the lower extremities (Butler, 1995).
    3) TIMING: Two thirds of persons develop lymphadenopathy within 2 days of exposure; 20% to 30% of persons with buboes experience pain in the node before swelling occurs (Butler, 1995). Patients from plague-endemic areas who present with lymphadenopathy should have increased suspicion of plague with facilitated early diagnosis and treatment (Levy & Gage, 1999).
    4) PRESENTATION: Buboes are so tender that, when in the groin area, the leg will usually be flexed to avoid touch and movement (Barnes & Quam, 1992); (Butler, 1995). They usually continue to enlarge even though other clinical signs remit, and they may remain tender for weeks after recovery (Butler, 1995; Barnes & Quam, 1992).
    D) MALAISE
    1) Patients may present with a nonspecific febrile syndrome, characterized by myalgias and malaise (Crook & Tempest, 1992).

Summary Of Exposure

    A) DESCRIPTION: Plague is an infectious disease of wild rodents (eg, prairie dogs, squirrels) that is naturally transmitted to humans by the bites of infected fleas. It is caused by Yersinia pestis, a gram-negative nonmotile and nonspore-forming bacillus, that grows in both anaerobic and aerobic conditions. Exposure in humans is always almost unintentional but can lead to disease. There is a theoretical risk of using plague for biological warfare. Person-to-person transmission of plague occurs only with pneumonic plague.
    B) TOXICOLOGY: When an infected flea bites a human, Yersinia pestis is carried to regional lymphatics, where it replicates intracellularly. It produces three toxins, an exotoxin that is of little significance to humans, a lipopolysaccharide endotoxin, and W and V antigens that give it protection from phagocytic killing. The lipopolysaccharide endotoxin is responsible for various clinical manifestations. Plague can occur in several different forms, including bubonic plague (majority of cases), septicemic plague (which can be primary or secondary to bubonic plague), and pneumonic plague (very rare but the most lethal form).
    C) EPIDEMIOLOGY: Plague in the United States is very rare, with approximately a dozen reported cases a year over the last 50 years, though with Native Americans (specifically Navajo) disproportionally represented. Worldwide, there have been thousands of cases in the past century, though it is likely underreported. Countries with the highest prevalence of plague include Tanzania, Vietnam and Zaire.
    D) WITH POISONING/EXPOSURE
    1) The site of flea bite(s) may be marked by papule or vesicle and is most commonly located on legs (present in only 10% to 15%). Tissue necrosis of skin and appendages may occur. Necrosis and cyanosis, resulting in a blackened skin explains the terminology, "black death". An acute inflammatory response occurs in the lymph node in 2 to 6 days. The lymph nodes become hemorrhagic, and organisms are released into the bloodstream. Secondary sites like the lungs and meninges may then become infected. Rarely, primary pneumonia may occur from inhalation of aerosolized bacteria. Clinical characteristics depend on the type of plague involved, but diagnostic clues include sudden onset of high fever, nausea, vomiting, diarrhea, malaise, myalgias, severe headache, prostration, and axillary or inguinal lymphadenitis (buboes) following a history of exposure to rodents in endemic areas. An aerosolized plague weapon may cause fever, cough, chest pain, and hemoptysis with signs consistent with severe pneumonia 1 to 6 days following exposure. After symptom onset, rapid progression of disease could occur 2 to 4 days later and could lead to septic shock with high mortality without early treatment. Mortality ranges from 50% to 60% for untreated bubonic plague and up to 100% for untreated septicemic or pneumonic plague. Other reported complications include ARDS (in 5% with 50% mortality), DIC, and bacterial meningitis, and skin necrosis (black plague).

Laboratory Monitoring

Monitoring Parameters Levels

    4.1.1) SUMMARY
    A) Diagnose bubonic plague with Gram stain and culture of aspirated specimen from suppurative lymph nodes and blood cultures. Suspected plague should be considered if small Gram-negative and/or bipolar-staining coccobacilli ("safety pin" appearance) are seen on a smear taken from affected tissues, for example, bubo (bubonic plague), blood (septicemic plague), or tracheal/lung aspirate (pneumonic plague). Cultures may not be positive for 48 hours.
    B) Monitor CBC with differential. Leukocytosis (12,000 to 20,000 WBC/mm(3)) may occur. WBC count may be decreased to 900/mm(3) in patients with severe septicemic or pneumonic plague.
    C) Urinalysis may show hematuria and proteinuria. Cultures and Gram stain can be high yield in pneumonic and septicemic plague.
    D) To confirm the diagnosis of plague, the following must be met: an isolated culture is lysed by specific bacteriophage; 2 serum specimens demonstrate a 4-fold anti-F1 antigen difference by agglutination testing; or a single serum specimen tested by agglutination has a titer greater than 1:128 and the patient has no known previous plague exposure or vaccination history. Hemagglutinating antibody titer rises in 8 to 14 days.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms. Chest x-ray may show pneumonic infiltrates or hilar adenopathy.
    F) Monitor vital signs and mental status. Patients with symptoms of meningitis may require a head CT and/or a lumbar puncture.
    G) Obtain an ECG, and institute continuous cardiac monitoring.
    4.1.2) SERUM/BLOOD
    A) HEMATOLOGIC
    1) LEUKOCYTOSIS
    a) WBC count is usually strikingly elevated (Leopold, 1986; Hull et al, 1987; Butler, 1995). However, the wide range of WBC counts make it an unreliable diagnostic test (Crook, 1993).
    b) It may be increased to 20,000/mm(3) in both pneumonic and bubonic plague (Werner, 1984).
    c) Mean WBC count in patients with septicemic plague was 18,950/mm(3) (range, 2000 to 68,000/mm(3)) in one study (Hull et al, 1987).
    2) LEUKOPENIA
    a) In severe septicemic or pneumonic plague, the WBC count may be extremely low (to 900/mm(3)) (Werner, 1984; (Hull et al, 1987).
    3) WHITE BLOOD CELLS, DIFFERENTIAL
    a) Patients with septicemic plague typically have leukocytosis with marked left shifts (mean, 69% PMNs and 26% band forms) (Hull et al, 1987) Humphrey, 1988).
    4) PERIPHERAL BLOOD SMEAR
    a) Diagnosis should be suspected when Y pestis organisms are seen on the peripheral blood smear. Thirteen of 71 patients (18%) with septicemic plague in one study were found to have Y pestis on peripheral smears (Hull et al, 1987).
    B) ACID/BASE
    1) ARTERIAL BLOOD GASES: In pneumonic plague, hypoxia will occur as the disease becomes fulminant as a result of the extensive pulmonary involvement. As with other fulminant bacterial pneumonias, there is a severe ventilation-perfusion abnormality present. Measure arterial blood gases.
    4.1.3) URINE
    A) URINALYSIS
    1) HEMATURIA
    a) Gross hematuria may result from the effect of plague toxin on the blood vessels (Werner, 1984).
    2) CASTS, RED CELL, URINE
    a) Red cell casts have been reported in patients with bubonic plague (Hoffman, 1980).
    3) ALBUMINURIA
    a) Proteinuria (4+) has been reported in patients with the plague (Hoffman, 1980) Werner, 1984).
    4.1.4) OTHER
    A) OTHER
    1) Diagnose bubonic plague with Gram stain and culture of aspirated specimen from suppurative lymph nodes and blood cultures (Stevens et al, 2014). Suspected plague should be considered if small Gram-negative and/or bipolar-staining coccobacilli are seen on a smear taken from affected tissues, for example, bubo (bubonic plague), blood (septicemic plague), or tracheal/lung aspirate (pneumonic plague) (CDC, Division of Vector-Borne Infectious Diseases, 2003).
    2) Presumptive evidence of plague would include a positive immunofluorescence stain or smear for Yersinia pestis FI antigen. If only a single serum specimen is tested, the anti-F1 antigen titer by agglutination needs to be greater than 1:10. Agglutination testing must be shown to be specific to Yersinia pestis FI hemagglutination inhibition (CDC, Division of Vector-Borne Infectious Diseases, 2003). Polymerase chain reaction at reference laboratories may be used in diagnosis, and serologic testing can confirm the diagnosis retrospectively (Stevens et al, 2014).
    3) To confirm the diagnosis of plague, the following must be met: an isolated culture is lysed by specific bacteriophage; 2 serum specimens demonstrate a 4-fold anti-F1 antigen difference by agglutination testing; or a single serum specimen tested by agglutination has a titer greater than 1:128 and the patient has no known previous plague exposure or vaccination history (CDC, Division of Vector-Borne Infectious Diseases, 2003).
    4) CULTURES
    a) GENERAL: Characteristics of plague include massive growth of Y pestis in tissues. This organism has a bipolar (safety-pin) appearance in Giemsa, Wright, and Wayson stains and can be visualized on these and Gram staining of infected tissue (Goddard, 1999). Culture isolates are confirmed by lysis with a Y pestis specific bacteriophage. Single positive serologic test by passive hemagglutination assay or enzyme immunoassay in an unvaccinated patient who has not previously had plague provides presumptive evidence of infection.
    b) GRAM STAIN, BUBO ASPIRATE: INDICATIONS: Material for Gram stain should be obtained by aspiration of the involved lymph node in suspected cases of plague (Hoffman, 1980) Crook, 1993).
    1) FINDINGS: Yersinia pestis is a gram-negative, bipolar-staining pleomorphic coccobacilli with a characteristic appearance on Gram stain and will be evident in 70% of cases. When stained with Wayson or Giemsa stain, it shows a bipolar "safety pin" structure (Butler, 1995) Crook, 1993).
    c) GRAM STAIN, SPUTUM: A sputum sample should be obtained for Gram stain in suspected cases of plague. Yersinia pestis is a gram-negative, bipolar-staining pleomorphic coccobacilli with a characteristic appearance on Gram stain and will be evident in 70% of cases. When stained with Wayson or Giemsa stain, it shows a bipolar "safety pin" structure (Butler, 1995).
    d) GRAM STAIN, BLOOD: In severe bacteremia, Y pestis organisms may be noted in peripheral blood smears using Gram, Wayson, or Wright stain. The organisms appear bipolar. Detection of plague organisms in the peripheral smears is usually associated with overwhelming sepsis and death, but survival has been reported (Mann, 1984).
    e) CULTURE, BLOOD: INDICATIONS: Should be obtained in all patients with suspected plague.
    1) FINDINGS - Positive in 80% to 96% of patients with bubonic plague and in 100% of those with septicemic plague (Welty, 1985; Crook, 1993).
    2) Plague bacilli are both aerobic and facultatively anaerobic. The bacilli grow readily on most culture media. Growth is optimal at 28 degrees C but still satisfactory at 35 to 37 degrees C. However, growth is slow, even at optimal temperatures; it takes about 48 hours before colonies can be seen on plain agar. The colonies are small (1 to 3 cm) and grayish.
    f) CULTURE, SPUTUM: Should be obtained in all patients with suspected plague. Plague bacilli are both aerobic and facultatively anaerobic. The bacilli grow readily on most culture media. Growth is optimal at 28 degrees C but still satisfactory at 35 to 37 degrees C. However, growth is slow, even at optimal temperatures; it takes about 48 hours before colonies can be seen on plain agar. The colonies are small (1 to 3 cm) and grayish.
    g) CULTURE, BUBO ASPIRATE: INDICATIONS - Should be obtained in all patients with suspected plague.
    1) FINDINGS - Positive culture results in 80% to 85% of cases (Welty, 1985). Plague bacilli are both aerobic and facultatively anaerobic. The bacilli grow readily on most culture media. Growth is optimal at 28 degrees C but still satisfactory at 35 to 37 degrees C. However, growth is slow, even at optimal temperatures; it takes about 48 hours before colonies can be seen on plain agar. The colonies are small (1 to 3 cm) and grayish.
    h) ASPIRATION, NEEDLE, LYMPH NODE - Suspected plague is one of the few diseases in which aspiration of a hard, nonfluctuant lymph node is indicated. Extreme caution must be exercised during aspiration to avoid accidental spillage of aspirate material on health personnel; all persons in the patient's room must wear masks, caps, gowns, and gloves.
    1) The aspirated specimen should be both cultured and Gram stained.
    2) If no material can be aspirated from the bubo, 1 to 3 mL of normal saline can be taken from a sterile intravenous solution and injected into the hard lymph node prior to aspiration. Bacteriostatic normal saline should NOT be used as it may inhibit culture growth of the infecting organism.

Radiographic Studies

    A) CHEST RADIOGRAPH
    1) Evidence of pneumonia indicated by alveolar infiltrates and/or hilar lymphadenopathy may be seen in pneumonic plague on chest X-ray (Welty, 1985; Crook, 1993).

Methods

    A) BIOASSAY
    1) SUMMARY
    a) Positive fluorescent antibody test for the presence of Y pestis in direct smears or cultures of a bubo aspirate, sputum, cerebrospinal fluid, or blood specimen provides presumptive evidence of Y pestis infection.
    b) Single positive serologic test by passive hemagglutination assay or enzyme immunoassay in an unvaccinated patient who has not previously had plague provides presumptive evidence of infection. Seroconversion and/or a fourfold difference in antibody titer between two serum specimens obtained 4 weeks to 3 months apart provides serological confirmation of plague.
    2) ANTIBODY STAIN, FLUORESCENT, YERSINIA PESTIS
    a) Enables diagnosis to be made rapidly; should be done directly on blood and sputum samples, as well as on bubo culture growth (Hull et al, 1986). However, a negative test does not rule out the diagnosis (Crook, 1993).
    b) Ratsitorahina et al (2000) reported the IgG anti-F1 ELISA (or F1-antigen rapid test, Naval Medical Research Institute, Bethesda, MD) on sputum to be a valuable tool for the quick diagnosis of pneumonic plague.
    c) Specimens should be sent to the Centers for Disease Control, Plague Branch, PO Box 2087, Fort Collins, CO 80522, if the test is unavailable in the hospital or a community laboratory.
    d) CAUTION - Rapid microbiologic testing devices may not be programmed to identify Y pestis, which delays initial identification of the organism (CDC, 1992).
    e) A rapid monoclonal antibody test targeted at the Yersinia pestis F1 antigen has been developed and tested in Madagascar. In a study of 691 samples, the F1 ELISA test demonstrated 100% sensitivity and 100% specificity (Chanteau et al, 2003).
    3) BACTERIOPHAGE LYSIS
    a) Highly specific and can be performed rapidly.
    4) ANTIBODY TITER, FLUORESCENT
    a) A four-fold difference between acute and convalescent passive hemagglutination (PHA) titers taken at least 10 days apart, or a single convalescent PHA titer of 1:16 or greater, is presumptive evidence of infection (Leopold, 1986; Hull et al, 1986).
    5) POLYMERASE CHAIN REACTION ASSAY
    a) The polymerase chain reaction assay (PCR) is still in developmental stages. PCR using oligoncleotide primers specific for the plasminogen activator gene of Y pestis appears to be a rapid, sensitive, and specific test (Arya, 1994).

Treatment

Life Support

    A) Support respiratory and cardiovascular function.

Patient Disposition

    6.3.6) DISPOSITION/BITE-STING EXPOSURE
    6.3.6.1) ADMISSION CRITERIA/BITE-STING
    A) SUMMARY: Patients who are getting worse or at risk of transmitting disease should be admitted to the hospital for further observation and treatment. Depending on the severity of their disease, they may require ICU treatment. They should not be discharged until they are clearly improving, on antibiotic treatment, and arrangements made to avoid further spread of disease.
    B) All patients with suspected or known bubonic, septicemic, or pneumonic plague should be admitted with strict isolation precautions. Patients with a cough or other signs of pneumonia should be placed on respiratory droplet isolation in a private room for at least 48 hours after institution of antibiotic therapy and clinical improvement occurs. Care should be taken to avoid aerosolization when handling bubo aspirate and blood (Inglesby et al, 2000a; APIC (Assoc for Professional in Infection Control) Bioterrorism Task Force & CDC Hospital Infection, April 13, 1999).
    6.3.6.3) CONSULT CRITERIA/BITE-STING
    A) Depending on the severity of disease, other consultants that may be involved include infectious disease specialists and intensivist. All confirmed and suspected cases should be reported immediately through local and state health departments to the Centers for Disease Control (CDC). Health department personnel will work with the CDC and the attending physician in the treatment of plague. Help for suspected or proved cases can be obtained from the Center for Disease Control and Prevention Bacterial Diseases Branch, Foothills Campus, Fort Collins, CO 80521; 800-CDC-INFO or 800-232-4636; TTY 888-232-6348.
    6.3.6.4) PATIENT TRANSFER/BITE-STING
    A) Whenever possible, patients with suspected cases of plague should not be transferred as it will cause greater exposure of this highly infectious disease. If a patient must be transferred, strict isolation procedures should be observed by all personnel involved in the transfer.
    6.3.6.5) OBSERVATION CRITERIA/BITE-STING
    A) All patients with known or suspected plague should be sent to a healthcare facility for observation. In addition, strict protective measures should be taken for those in contact with these patients. Patients should only be discharged home if they are clearly improving, under treatment, and arrangements made to prevent transmission of disease. All patients with plague should receive follow-up examinations after discharge, since plague meningitis may develop as long as 14 days after antibiotic therapy has been initiated.

Monitoring

    A) Diagnose bubonic plague with Gram stain and culture of aspirated specimen from suppurative lymph nodes and blood cultures. Suspected plague should be considered if small Gram-negative and/or bipolar-staining coccobacilli ("safety pin" appearance) are seen on a smear taken from affected tissues, for example, bubo (bubonic plague), blood (septicemic plague), or tracheal/lung aspirate (pneumonic plague). Cultures may not be positive for 48 hours.
    B) Monitor CBC with differential. Leukocytosis (12,000 to 20,000 WBC/mm(3)) may occur. WBC count may be decreased to 900/mm(3) in patients with severe septicemic or pneumonic plague.
    C) Urinalysis may show hematuria and proteinuria. Cultures and Gram stain can be high yield in pneumonic and septicemic plague.
    D) To confirm the diagnosis of plague, the following must be met: an isolated culture is lysed by specific bacteriophage; 2 serum specimens demonstrate a 4-fold anti-F1 antigen difference by agglutination testing; or a single serum specimen tested by agglutination has a titer greater than 1:128 and the patient has no known previous plague exposure or vaccination history. Hemagglutinating antibody titer rises in 8 to 14 days.
    E) Monitor arterial blood gases, pulse oximetry, and pulmonary function tests, and obtain a chest x-ray in any patient with respiratory symptoms. Chest x-ray may show pneumonic infiltrates or hilar adenopathy.
    F) Monitor vital signs and mental status. Patients with symptoms of meningitis may require a head CT and/or a lumbar puncture.
    G) Obtain an ECG, and institute continuous cardiac monitoring.

Oral Exposure

    6.5.1) PREVENTION OF ABSORPTION/PREHOSPITAL
    A) There is no utility for the use of prehospital activated charcoal. Prehospital personnel working with known Yersinia pestis infected patients should wear protective masks and utilize barrier isolation techniques.
    B) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    C) DECONTAMINATION: Remove contaminated clothing and wash exposed area thoroughly with soap and water for 10 to 15 minutes. A physician may need to examine the area if irritation or pain persists (Burgess et al, 1999).
    6.5.2) PREVENTION OF ABSORPTION
    A) There is no role for activated charcoal, gastric lavage or whole bowel irrigation for plague. Protective gear should be worn by healthcare providers taking care of those with plague.
    6.5.3) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.

Inhalation Exposure

    6.7.1) DECONTAMINATION
    A) People in contact with patients infected with Y. pestis should wear protective masks and use barrier isolation techniques. All patients should be strictly isolated for a minimum of 48 hours following the institution of therapy. Isolation should continue as long as drainage continues, but it may be discontinued after the patient has been treated for at least 48 hours and there is no more drainage or respiratory symptoms. Respiratory isolation of patients with pneumonic plague should continue for at least 72 hours after institution of antibiotic therapy. Primary pneumonic plague may occur from intentional aerosol dispersion or intimate contact (via respiratory droplets) with patients or pets (usually cats) with pneumonic plague.
    B) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.
    6.7.2) TREATMENT
    A) SUPPORT
    1) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.
    B) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Eye Exposure

    6.8.1) DECONTAMINATION
    A) EYE IRRIGATION, ROUTINE: Remove contact lenses and irrigate exposed eyes with copious amounts of room temperature 0.9% saline or water for at least 15 minutes. If irritation, pain, swelling, lacrimation, or photophobia persist after 15 minutes of irrigation, an ophthalmologic examination should be performed (Peate, 2007; Naradzay & Barish, 2006).
    B) Mucocutaneous exposures to blood, body fluids, secretions, or excretions from patients with suspected plague infections should be immediately rinsed with copious amounts of water or eyewash solution.

Dermal Exposure

    6.9.1) DECONTAMINATION
    A) Dermal sites, particularly where breaks in skin integrity occur, exposed to blood, body fluids, secretions, or excretions from patients with suspected plague should be immediately washed with soap and water. Cats may transmit bubonic plague via scratches or bites. Direct contact with infected material from a bubo may also cause infection. Masks, gowns, and gloves should be worn while examining wounds or changing dressings. Exudates or discharge should be handled with rubber gloves. All contaminated material should be autoclaved or incinerated.
    6.9.2) TREATMENT
    A) DRAINAGE OF ABSCESS
    1) Drainage of abscesses may be necessary. Barrier precautions should be used since drainage material is potentially highly infectious until effective antibiotic therapy has been given (Anon, 1997).
    B) SUPPORT
    1) Treatment should include recommendations listed in the BITES/STINGS EXPOSURE section when appropriate.
    C) Treatment should include recommendations listed in the ORAL EXPOSURE section when appropriate.

Abstracts

Case Reports

    A) ADULT
    1) BUBONIC PLAGUE
    a) A 33-year-old woman biologist developed chills, fever (102.2 degrees F), headache, nausea, vomiting, fatigue, and right axillary lymphadenopathy (2 x 3 cm bubo). She had been working for many days in northern Arizona conducting research on prairie dogs. Also noted after hospital admission was an elevated white blood cell count (12,400 WBC; 89% neutrophils). An aspirate taken from the affected lymph node was noted to contain gram-negative rods, and a diagnosis of plague was entertained. Immediate treatment with chloramphenicol, gentamicin, and doxycycline was started. A full and rapid recovery occurred. After treatment had been started, a culture was confirmed to be positive for Yersinia pestis (Levy & Gage, 1999).
    2) SEPTICEMIC PLAGUE
    a) A 63-year-old man developed influenza-like illness, with chills and fever persisting for over one week. He collapsed at his home and was taken to a local hospital. A fever of 103 degrees F was recorded at admission as well as cough. Chest radiograph was normal. No detectable lymphadenopathy was present. Blood culture was shown to contain gram-negative rods, which later proved to be Y pestis. Treatment for probable plague infection was started. The patient recovered and was discharged to home (Levy & Gage, 1999).
    3) PNEUMONIC PLAGUE
    a) Three days after the onset of nausea, vomiting, chest pain, and cough, a 22-year-old male was admitted to a hospital with weakness, disorientation, dyspnea, and fever. Chest radiograph revealed a radiodense concentration in the upper right lobe. Because of his symptomatology, chest radiograph results and other evidence, a tentative diagnosis of primary pneumonic plague was suspected. The patients condition declined, and he was placed on life support following the development of coma and respiratory failure. Sputum and blood, collected on admission, were shown to contain gram-negative rods, later confirmed as Y pestis. After life support was stopped, the patient expired. The source of this patient's exposure was never identified following an environmental investigation of his workplace and home (Levy & Gage, 1999).

Range Of Toxicity

Summary

    A) TOXICITY: There is no known specific toxic dose of plague, but exposures can be lethal. Mortality rates range from 50% to 60% for untreated bubonic plague; up to 100% for untreated septicemic or pneumonic plague.

Minimum Lethal Exposure

    A) ROUTE OF EXPOSURE
    1) AEROSOL: If no antibiotic therapy is initiated, the time from respiratory exposure to death in humans has been reported to be 2 to 6 days, with a mean of 2 to 4 days in most epidemics (Inglesby et al, 2000).
    a) Fatality rate is high if antibiotic therapy is delayed more than 24 hours after symptom onset.
    B) MORTALITY
    1) Mortality rates range from 50% to 60% for untreated bubonic plague; up to 100% for untreated septicemic or pneumonic plague (Hull et al, 1987; Welty et al, 1985a; RR-14:1-15; CDC, 1997; Leopold, 1986; Crook & Tempest, 1992; Werner et al, 1984; Butler, 1995).

Maximum Tolerated Exposure

    A) ROUTE OF EXPOSURE
    1) AEROSOL: The epidemiology of plague disseminated as a biological weapon differs substantially from that of naturally occurring infection. The most likely means of dissemination is via an aerosol of Y pestis. Primary pneumonic plague outbreak could follow with symptoms initially resembling those of other severe respiratory illnesses. In contrast to secondary pneumonic plague, buboes are usually absent in cases of primary pneumonic plague (Inglesby et al, 2000).
    a) The size of the outbreak would depend on several factors:
    1) quantity of biological agent used
    2) characteristics of the strain
    3) environmental conditions
    4) methods of aerosolization
    b) Symptoms would occur 1 to 6 days (most often, 2 to 4 days) following exposure, with fatalities occurring quickly following symptom onset. Pathologic examination would show pulmonary disease with areas of profound lobular exudation and bacillary aggregation. Indications that a biologic attack occurred would be:
    1) occurrence of cases in non-endemic locations
    2) infection in persons without known risk factors
    3) absence of prior rodent deaths
    c) Currently, there are no effective environmental warning systems for detection of an aerosol of plague bacilli (Ingelsby et al, 2000).

Pharmacology Toxicology

Toxicologic Mechanism

    A) Plague is caused by Yersinia pestis, a gram-negative nonmotile and nonspore- forming bacillus that grows in both anaerobic and aerobic conditions. It produces three toxins (Butler, 1995): exotoxin, with little human significance, lipopolysaccharide endotoxin that is responsible for several of the clinical manifestations, and W and V antigens that makes the organism resistant to phagocytic killing in vivo.
    B) TRANSMISSION - Yersinia pestis organisms can be introduced into humans by rodent flea bites, contact with domestic dogs and cats, and exposure to infected tissue in wild animals during handling (Becker, 1987; (Leopold, 1986) Eidson, 1988).
    1) Rarely, plague is spread by infected exudates, droplet spread (pneumonic type), or human body lice or ticks (very uncommon, never observed in United States).
    C) When an infected flea bites a human, the organisms are carried to regional lymphatics where they replicate intracellularly (Connor, 1978; (RR-14:1-15; Wilson, 1995).
    1) An acute inflammatory response occurs in the lymph nodes in two to six days. At this point, lymph nodes became hemorrhagic, organisms are released into the blood stream, and the manifestations of bubonic plague become evident.
    D) With bacteremia, secondary sites may become infected (lung, meninges), and secondary pneumonia or meningitis may develop (Connor, 1978; (RR-14:1-15; Wilson, 1995).
    E) Rarely, primary pneumonia may be acquired by inhalation of infected aerosols from another source (Franz, 1997).

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