Plague

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Background

Plague is an acute, contagious, febrile illness transmitted to humans by the bite of an infected rat flea. Human-to-human transmission is rare except during epidemics of pneumonic plague. The disease is caused by the plague bacillus, rod-shaped bacteria referred to as Yersinia pestis. Yersinia is named in honor of Alexander Yersin, who successfully isolated the bacteria in 1894 during the pandemic that began in China in the 1860s.

Plague is worldwide in distribution, with most of the human cases reported from developing countries.

Three studies have shown that this bacterium emerged from the gut pathogen Yersinia pseudotuberculosis shortly after the first epidemic.[1] Three biovars (with minor genetic variations) have been identified within the Y pestis clone—Antiqua, Medievalis, and Orientalis.[1] One theory is that these biovars emerged before any of the plague epidemics. In fact, as reported by Drancourt et al (2004), genotyping performed on bacteria derived from the remains of plague victims of the first two epidemics revealed sequences similar to that of Orientalis.[2]

The virulence of this bacterium results from the 32 Y pestis chromosomal genes and two Y pestis –specific plasmids, constituting the only new genetic material acquired since its evolution from its predecessor.[3] These acquired genetic changes have allowed the pathogen to colonize fleas and to use them as vectors for transmission.[4]

Plague is a zoonotic disease that primarily affects rodents; humans are incidental hosts. Dog-to-human transmission was reported in a 2014 outbreak in Colorado.[5] Survival of the bacillus in nature depends on flea-rodent interaction, and human infection does not contribute to the bacteria's persistence in nature. Of the 1500 flea species identified, only 30 of them have been shown to act as vectors of plague.[6] The most prominent of these vectors is Xenopsylla cheopis (oriental rat flea); however, Oropsylla montana has been incriminated as the primary vector for this disease in North America.[7]



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Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Preventio....

Host fatality has been known to be the harbinger of an epidemic.[6] Whether susceptibility and fatality are related is unknown. However, ground squirrels and prairie dogs have been known to be highly susceptible to plague, whereas others have been known to be either moderately susceptible or absolutely resistant to infection.



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The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of ....



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Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Preve....

Plague was first described in the Old Testament and has persisted into the modern era. Plague has caused large-scale epidemics, thereby changing the course of history in many nations. The first pandemic was believed to have started in Africa and killed 100 million people over a span of 60 years. In the Middle Ages, plague killed approximately one fourth of Europe's population. The pandemic that began in China in the 1860s spread to Hong Kong in the 1890s and was subsequently spread by rats transported on ships to Africa, Asia, California, and port cities of South America. In the early twentieth century, plague epidemics accounted for about 10 million deaths in India. As reported in National Geographic, mass graves of plague victims were recently discovered in an area of Venice called "Quarantine Island."

Pathophysiology

Pathophysiology

Y pestis is a nonmotile, pleomorphic, gram-negative coccobacillus that is nonsporulating. The bacteria elaborate a lipopolysaccharide endotoxin, coagulase, and a fibrinolysin, which are the principal factors in the pathogenesis of plague. The pathophysiology of plague basically involves two phases—a cycle within the fleas and a cycle within humans.

The key to the organism’s virulence is the phenomenon of "blockage," which aids the transmission of bacteria by fleas. After ingestion of infected blood, the bacteria survive in the midgut of the flea owing to a plasmid-encoded phospholipase D that protects them from digestive juices.[8] The bacteria multiply uninhibited in the midgut to form a mass that extends from the stomach proximally into the esophagus through a sphincterlike structure with sharp teeth called the proventriculus.



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Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ....

It has been shown that this property requires the presence of hemin-producing genes, which are needed for the formation of a biofilm that permits colonization of the proventriculus.[9] In fact, as described by Jarrett et al (2004), this mutation in hemin genes allows colonization in the midgut without extension to the proventriculus. Consequently, the "blockage phenomenon" does not occur, thereby leading to failure of transmission.[9] This blockage causes the flea to die of starvation and dehydration.[10]

As a desperate measure, the flea then repeatedly tries to obtain a meal by biting a host, managing only to regurgitate the infected mass into host's bloodstream. However, the concept that the flea must be engorged before becoming infectious loses support when trying to explain the rapid rate of spread of disease during a plague epidemic. Studies of vectors such as O montana clearly indicate the redundancy of the aforementioned hypothesis, since this vector does not die of blockage and remains infectious for a long period, unlike its counterpart.[11]

Once the flea bites a susceptible host, the bacilli migrate to the regional lymph nodes, are phagocytosed by polymorphonuclear and mononuclear phagocytes, and multiply intracellularly. Survival and replication within macrophages is probably of greatest importance in early stages of the disease.[12] Involved lymph nodes show dense concentrations of plague bacilli, destruction of the normal architecture, and medullary necrosis. With subsequent lysis of the phagocytes, bacteremia can occur and may lead to invasion of distant organs in the absence of specific therapy.

The following are the modes of plague transmission in humans:[13]

  1. Bites by fleas
  2. Exposure to humans with pneumonic plague
  3. Handling of infected carcasses
  4. Scratches or bites from infected domestic cats
  5. Exposure to aerosols containing plague-causing bacilli

Another potential cause of plague transmission in humans is contact with an infected dog. In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924.[5]

Epidemiology

Frequency

United States

Between 2010 and 2015, 39 cases of human plague were reported in the United States, resulting in 5 deaths.[14] About half of human plague cases involve individuals aged 12-45 years, although it can affect people of all ages. The risk is slightly higher in men, probably owing to a higher likelihood of outdoor activities among males, increasing their risk of exposure to vectors.[14]

A few natural plague foci are located in the western United States. From the states of Arizona, California, Colorado, New Mexico, and Utah, 49 cases of plague and 3 attributed deaths were reported from 1994-1999.[15] In 2006, 13 plague cases were reported among residents of New Mexico, Colorado, California, and Texas, two of which resulted in death.[16]

On average, 7 cases of human plague are reported annually in the United States, with a range of 1-17 cases per year.[14] Over time, human cases of plague have moved from crowded cities to the rural West. This has paralleled the observed patterns of introduction of exotic plants and animals.[17] The rate of plague in the United States is low, since most of the endemic areas are rural and largely uninhabited, thereby limiting human exposure. In recent years, and with the potential threat for bioterrorism, the Centers for Disease Control and Prevention (CDC) has specified Y pestis as a Category A bioterrorism agent.

Animal reservoirs in America mostly include squirrels, rabbits, and prairie dogs. However, there has been an established role of domestic cats in the transmission of plague since the late 1970s. From 1977-1998, 23 cases of human plague associated with cats were reported from the western states, representing 8% of all reported plague cases during that time.[7] In this scenario, transmission via inhalation was more common than in any other form of plague.

In a study of cat-related plague, mortality was associated with misdiagnosis or delay in treatment. Of the 23 cases from 1977-1998, 5 of 17 bubonic plague cases resulted in death.[7]

In 2014, the Colorado Department of Public Health and Environment (CDPHE) laboratory isolated Y pestis in a blood specimen from a hospitalized man with pneumonia. Further investigation found that the man’s dog had recently died with hemoptysis and that 3 other persons who came into contact with the dog had respiratory symptoms and fever. Specimens from the dog and the other three persons showed evidence of acute Y pestis infection. One of the transmissions may have been human to human, which would be the first such reported US case since 1924.[5]

International

Most cases of plague reported outside of the United States are from developing countries in Africa and Asia. During 1990-1995, a total of 12,998 cases of plague were reported to the World Health Organization (WHO), particularly from countries such as India, Zaire, Peru, Malawi, and Mozambique. The following countries reported more than 100 cases of plague: China, Congo, India, Madagascar, Mozambique, Myanmar, Peru, Tanzania, Uganda, Vietnam, and Zimbabwe. Several foci are located in the semi-arid regions of northeastern Brazil, and outbreaks have also been reported from Malawi and Zambia. Australia is the only continent that is considered free of plague. The largest enzootic plague area is in North America—the southwestern United States and the Pacific coastal area.

The WHO reports that, in 2003, 9 countries reported a total of 2118 plague cases and 182 deaths, 98.7% and 98.9% of which were reported from Africa, respectively.



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1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Mortality/Morbidity

The risk of plague-related death depends on the type of plague and whether the infected individual receives appropriate treatment.[4]

The following are the mortality rates associated with the different types of plague:

Race

In the United States, most cases of plague occur in whites. Native Americans living in endemic areas of Arizona, New Mexico, and Utah have a 10-fold greater risk of acquiring the disease than non–Native Americans.

Humans are exposed in the domestic or outdoor environment. Infections in the wild are usually isolated or sporadic, causing infections in Indians, hunters, miners, and tourists in the United States and Brazil.

Sex

Plague has no sexual predilection.

Age

Most cases of plague occur in persons younger than 20 years.

History

Travel to endemic areas within and outside the United States, history of a flea bite, close contact with a potential host, or exposure to dead rodents or rabbits should raise suspicion for plague.

Bubonic plague

This is the most common presentation of plague.

The incubation period varies but usually ranges 2-6 days.

There is a sudden onset of high fever, chills, and headache.

Patients with this type experience body aches, extreme exhaustion, weakness, abdominal pain, and/or diarrhea.

Painful, swollen lymph glands (buboes) arise, usually in the groin (most common site), axilla, or neck.



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Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atl....

Axillary, cervical, and epitrochlear buboes are almost always seen in cat-associated plague.[18]

Without intervention, this stage may lead to secondary pneumonic plague or meningitis or may disseminate and manifest as a sepsis picture.

Meningeal plague

This is characterized by fever, headache, and nuchal rigidity.

Buboes are common in meningeal plague.

Axillary buboes are associated with an increased incidence of meningeal plague.

Pharyngeal plague

Pharyngeal plague results from ingestion of the plague bacilli.

Patients experience sore throat, fever, and painful cervical lymph nodes.[19]

Marshall et al (1967) has described an asymptomatic pharyngeal carrier state of Y pestis infection in patients with bubonic plague.[20]

Pneumonic plague

Pneumonic plague is highly contagious and transmitted by aerosol droplets.

This is often secondary to bubonic or septicemic plague. However, primary pneumonic plague may be seen in laboratory workers, individuals exposed to an infected person, or those who have been exposed to a cat with pneumonic plague.[21]

There is an abrupt onset of fever and chills, accompanied by cough, chest pain, dyspnea, purulent sputum, or hemoptysis.

Buboes may or may not be associated with pneumonic plague.

The ability for plague to be spread by aerosols makes Y pestis a potential agent of bioterrorism.

Septicemic plague

Septicemic plague is observed in elderly patients and causes a rapid onset of symptoms.

Patients experience nausea, vomiting, abdominal pain, and diarrhea. (Diarrhea may be the predominant symptom.)

Patients exhibit a toxic appearance and soon become moribund.

Buboes are uncommon in septicemic plague, making the diagnosis elusive.

Septicemic plague carries a high mortality rate and is associated with disseminated intravascular coagulation (DIC), multiorgan failure, and profound hypotension.

Plague initially occurred as a flea-borne septicemic disease. However, over its evolutionary course, it acquired the plasminogen activator gene, giving rise to the bubonic form of disease.[22]

Genitourinary/gastrointestinal plague

This was reported as the sole presentation of Y pestis infection in 4 of 27 patients in a case series published in 1992.[13]

Cutaneous plague

This manifests as purpura.[19]

Physical

Bubonic plague

Vesicles may be observed at the site of the infected flea bite. With advanced disease, papules, pustules, carbuncles, or an eschar may be observed in areas of the skin drained by the involved lymph nodes. A generalized papular rash of the hands and feet may be observed.

Buboes are unilateral, oval, extremely tender lymph nodes and can vary from 2-10 cm in size. Femoral lymph nodes are most commonly involved. Patients with an inguinal bubo walk with a limp, and the affected limb may be in a position of flexion, abduction, and external rotation. Patients resist any attempt to examine the involved lymph nodes. Enlargement of the buboes leads to rupture and discharge of malodorous pus.

Hepatomegaly and splenomegaly often occur and may be tender.

Pharyngeal plague

Pharyngeal plague causes pharyngeal erythema and painful and tender anterior cervical nodes.

Pneumonic plague

Pneumonic plague causes fever, lymphadenopathy, productive sputum, and/or hemoptysis.

Septicemic plague

Because of an overwhelming infection with the plague bacillus, patients with septicemic plague have a toxic appearance and may present with tachycardia, tachypnea, and hypotension. Hypothermia is common.

Generalized purpura may be observed and can progress to necrosis and gangrene of the distal extremities.



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Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that diss....



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Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and t....

No evidence of lymphadenitis or bubo formation is apparent. Patients may die of a high-grade bacteremia.

Causes

Y pestis is the cause of plague.

Risk factors include the following:

Laboratory Studies

The possibility of plague should be strongly considered in febrile patients from endemic areas who have history of exposure to rodents. Rapid recognition of the classic symptoms of this disease and laboratory confirmation are essential to instituting lifesaving therapy.

Expertise in testing for plague bacilli is limited to reference laboratories in plague-endemic states and the CDC.

Leukocytosis with a predominance of neutrophils is observed, and the degree of leukocytosis is proportional to the severity of illness.

Peripheral blood smear shows toxic granulations and Dohle bodies.

Thrombocytopenia is common, and fibrin degradation product levels may be elevated.

Serum transaminases and bilirubin levels may be elevated.

Proteinuria may be present, and abnormalities in renal function have been associated.

Hypoglycemia may be observed.

Twenty-seven percent to 96% of blood cultures are positive for Y pestis in patients with bubonic plague and septicemic plague.[21] Microbiology staff should be informed of the possibility of Y pestis agents in samples so that they can take adequate precautions when handling specimens.

Y pestis may be observed on a peripheral blood smear. Smear stained with Wright-Giemsa reveals rod-shaped bacteria. A Wayson stain demonstrates the typical "safety pin" appearance (bipolar staining) of the bacterium. Gram stain shows small gram-negative coccobacilli.



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Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control....

Lymph node aspirates often demonstrate Y pestis. In patients with pharyngeal plague, Y pestis is cultured from throat swabs.

Cerebrospinal fluid (CSF) analysis in meningeal plague may show pleocytosis with a predominance of polymorphonuclear leukocytes.[23] Gram stain of CSF may show plague bacilli. Limulus test of CSF demonstrates the presence of endotoxin.

Gram stain of sputum often reveals Y pestis.

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[24]

Imaging Studies

Chest radiography reveals patchy infiltrates, consolidation, or a persistent cavity in patients with pneumonic plague.

ECG reveals sinus tachycardia and ST-T changes.

Nuclear imaging may help localize areas of lymphadenitis and meningeal inflammation.

Other Tests

Direct immunofluorescence testing of fluid or cultures may aid in rapid diagnosis. A novel rapid diagnostic test capable of detecting miniscule amounts of Y pestis F1 antigen within 15 minutes has been developed and field tested in Madagascar.[25] This test yields 100% sensitivity and specificity for Y pestis and other Yersinia species.

A passive hemagglutination test (performed on serum from a patient in acute or convalescent stages) with a 16-fold or greater increase in titer (single titer) suggests plague infection.[19]

A 4-fold rise in antibody titers to the F-1 antigen of Y pestis also confirms infection.[16]

A polymerase chain reaction (PCR) using primers derived from Y pestis plasminogen activator gene has been used to detect the pathogen in fleas, but the application of this method in humans is still a matter of speculation.[26]

Procedures

Aspiration of lymph node (bubo)

Inject 1 mL of sterile saline into the bubo with a 20-gauge needle; after withdrawing several times, aspirate the fluid. Gram stain of the aspirate reveals gram-negative coccobacilli and polymorphonuclear leucocytes.

Wayson stain of the aspirate shows plague bacilli as light-blue bacilli with dark-blue polar bodies.

Examination of the aspirate of the fluid from the inguinal lymph nodes shows a characteristic bipolar appearance that resembles a closed safety pin.

Lumbar puncture

Lumbar puncture is strongly recommended when meningeal plague is suspected.

Medical Care

Updated (2014) guidelines on the diagnosis and treatment of bubonic plague have been published by the Infectious Diseases Society of America (IDSA) (see Practice Guidelines for the Diagnosis and Management of Skin and Soft Tissue Infections: 2014 Update by the Infectious Diseases Society of America).[24]

Precautions

All patients with suspected plague and signs of pneumonia should be placed in strict respiratory isolation for 48-72 hours after antibiotic therapy is initiated and kept there until pneumonia has been ruled out or until sputum culture have shown negative findings.

Report patients thought to have plague to the local health department and to the WHO.

Alert laboratory personnel to the possibility of the diagnosis of plague. All fluid specimens must be handled with care to prevent aerosolization of the infected fluids. Gowns, gloves, and masks should be worn at all times, and strict infection control is of utmost importance.

Supportive therapy

Hemodynamic monitoring and ventilatory support are performed as appropriate.

Management of sepsis associated with plague requires aggressive intravenous hydration. Norepinephrine and other vasopressors may be required to manage hypotension and to improve hemodynamic status.

Postexposure prophylaxis

Presumptive therapy consists of a 7-day course of oral doxycycline and ciprofloxacin.

Chloramphenicol may be used as an alternative.

Levofloxacin may be prescribed as a 10-14 day regimen for either treatment or postexposure prophylaxis.

In a community experiencing a pneumonic plague epidemic, individuals with a temperature of 38.5°C or higher or newly onset cough should promptly receive parenteral antimicrobial therapy.[27]

Surgical Care

Enlarging or fluctuant buboes require incision and drainage.

Consultations

The following specialists may be consulted:

Medication Summary

Untreated plague can progress to a fulminant illness with a high risk of mortality. Thus, early and appropriate antibiotic treatment is essential.

Historically, streptomycin (15 mg/kg, up to 1 g intramuscularly every 12 h) has been the drug of choice.[27] However, in the United States, supplies of streptomycin are scarce.

An in vitro comparison[28] and a murine model trial[29] demonstrated that gentamicin (5 mg/kg intravenously or intramuscularly once daily) is comparable to or superior than streptomycin. Gentamicin has been used successfully in the treatment of human plague,[13] is inexpensive, and can be dosed once daily.

Doxycycline (as dosed for anthrax) is a recommended alternative in patients who cannot take aminoglycosides or in the event of a mass casualty scenario, making parenteral therapy unachievable.[27]

Because chloramphenicol attains high CSF concentrations,[27] it has been used to treat meningeal plague, although no studies have been conducted for substantiation.[30]

Studies in murine models have shown that fluoroquinolones demonstrate efficacy similar to that of the aminoglycosides.[29] Fluoroquinolones are a reasonable alternative therapy. However, no clinical trials of fluoroquinolone therapy in human plague have been conducted.[30]

The FDA has approved levofloxacin and moxifloxacin for the treatment of plague. These have also been approved for use as prophylaxis following exposure to Yersinia pestis.

Trimethoprim-sulfamethoxazole has been used to treat bubonic plague; however, it is not considered first-line therapy.

Beta-lactam antibiotics and macrolides should not be used.

Patients with advanced plague have a presentation of typical gram-negative sepsis and need antibiotic treatment for 10-14 days, along with other supportive measures.[30]

Levofloxacin (Levaquin)

Clinical Context:  Levofloxacin is the L-isomer of the racemate, ofloxacin, a quinolone antimicrobial agent. The antibacterial activity of ofloxacin resides primarily in the L-isomer. It inhibits bacterial topoisomerase IV and DNA gyrase (topoisomerases type II), enzymes required for DNA replication, transcription, repair, and recombination. It is indicated for treatment and prophylaxis of plague, including pneumonic and septicemic plague, caused by Yersinia pestis in adults and pediatric patients, aged 6 months or older.

Moxifloxacin (Avelox)

Clinical Context:  Moxifloxacin is a fluoroquinolone antibiotic that inhibits A subunits of DNA gyrase (topoisomerase type II) and topoisomerase IV, resulting in inhibition of bacterial DNA replication and transcription. It is indicated in adults for treatment and prophylaxis of pneumonic or septicemic plague caused by Yersinia pestis.

Streptomycin

Clinical Context:  Aminoglycoside antibiotic recommended when less potentially hazardous therapeutic agents are ineffective or contraindicated.

Gentamicin (Garamycin)

Clinical Context:  Aminoglycoside antibiotic for gram-negative coverage.

Doxycycline (Bio-Tab, Doryx, Doxy, Vibramycin, Vibra-Tabs

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

Chloramphenicol (Chloromycetin)

Clinical Context:  Binds to 50S bacterial ribosomal subunits and inhibits bacterial growth by inhibiting protein synthesis. Effective against gram-negative and gram-positive bacteria.

Class Summary

Therapy must be comprehensive and cover all likely pathogens in the context of this clinical setting. Antibiotic selection should be guided by blood culture sensitivity whenever feasible.

Transfer

Patients with plague who are critically ill and require transfer to another facility should be transported under strict isolation precautions.

Deterrence/Prevention

Prophylactic antibiotic therapy

The CDC recommends short-term prophylactic antibiotic therapy in people who have been bitten by potentially infected rodent fleas during a plague outbreak.

Prophylactic antibiotic therapy is recommended in persons who have handled an animal known to be infected with the plague bacterium.

Prophylactic antibiotic therapy is recommended in persons who have had close exposure to a person or an animal thought to have pneumonic plague. Sulfadoxine prophylaxis has been effective in outbreaks of pneumonic plague.[31] The infection rate in contacts was 8.4% with this strategy. Recent studies have shown that doxycycline can be used as an alternative for sulfadoxine.[30]

Preferred antibiotics for prophylaxis against plague include doxycycline 100 mg PO q12h for 14-21 days (for patients >8 y) or full-dose ciprofloxacin for 7 days.[32] Chloramphenicol may be used as an alternative. To be effective, chemoprophylaxis must be initiated within 7 days of exposure.

Plague vaccine

Plague vaccination is of limited use[33] and is not mandatory for entry into any country. The vaccine is not effective against the pneumonic form of plague. Plague vaccine is recommended for field workers in endemic areas and for scientists and laboratory personnel who routinely work with the plague bacterium. The vaccine is composed of killed whole cells. It needs to be taken as 2 injections 1-3 months apart followed by the booster every 6 months until the patient is no longer considered to be at risk.[19] Live vaccines are in development.[34]

Animal studies have conclusively established that certain antibodies are protective against plague.[35] Murine antibodies to fraction (FI) protein and/or fraction V antigen have been shown to be protective against bubonic and pneumonic plague in murine models.[36]

The F1-V (fusion protein) vaccine protected mice for a year against an inhalation challenge and is now being tested in primates.[32]

An oral vaccine with an attenuated strain of Y pseudotuberculosis named VTNF1 has been reported to provide highly efficient and long-lasting protection against both bubonic and pneumonic plague after a single oral vaccine dose. It confers full protection against the two forms of plague. This may offer an option for mass vaccination in tropical endemic areas, as well as for populations exposed to bioterrorism.[37]

Environmental sanitation

Efforts to control the animal reservoir and flea population may be effective in reducing transmission of plague bacteria.

Remove food sources used by rodents.

Rodent-proof homes, buildings, and warehouses.

Trained professionals should apply chemicals to kill fleas and rodents.

Trained professionals should fumigate cargo areas of ships and docks.

Complications

Potential complications of plague include the following:

Prognosis

Untreated plague carries a mortality rate of approximately 50%; however, with appropriate therapy, the mortality rate drops to approximately 5%.[38]

Patient Education

Report sick or dead animals to the local health department or law enforcement officials and wear gloves when handling potentially infected animals.

Eliminate food sources and nesting places for rodents around homes, workplaces, and recreation areas and make homes rodent-proof.

Personal protective measures include wearing protective clothing and applying insect repellents to clothing and skin to prevent flea bites.

Restrain pet dogs and cats in areas endemic to plague and regularly treat pets to control fleas.

Spraying of appropriate chemicals by health authorities may be necessary to kill fleas at selected sites during animal plague outbreaks.

Author

Venkat R Minnaganti, MD, FACP, Consulting Staff, Department of Medicine, Winthrop University Hospital; Clinical Instructor, Department of Internal Medicine, Division of Infectious Disease, SUNY Stony Brook University School of Medicine

Disclosure: Nothing to disclose.

Coauthor(s)

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Rhett L Jackson, MD, FACP, David Ross Boyd Professor and Chief, Section of General Internal Medicine, Department of Medicine, University of Oklahoma College of Medicine; Assistant Chief, Medicine Service, Oklahoma City Veterans Affairs Hospital

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance

Disclosure: Nothing to disclose.

Chief Editor

Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London

Disclosure: Nothing to disclose.

Additional Contributors

Siddharth Wayangankar, MD, MPH, Resident Physician, Department of Internal Medicine, Oklahoma University Health Sciences Center

Disclosure: Nothing to disclose.

Thomas J Marrie, MD, Dean of Faculty of Medicine, Dalhousie University Faculty of Medicine, Canada

Disclosure: Nothing to disclose.

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Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood and bacteria. If this flea were to bite a mammal, the proventriculus would be cleared, and thousands of bacteria would be regurgitated into the bite wound. Courtesy of the United States Army Environmental Hygiene Agency.

1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC, US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

1998 world distribution of plague. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

The prairie dog is a burrowing rodent of the genus Cynomys. It can harbor fleas infected with Yersinia pestis, the plague bacillus. Image courtesy of the Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Oriental rat flea (Xenopsylla cheopis), the primary vector of plague, engorged with blood. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Ulcerated flea bite caused by Yersinia pestis bacteria. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Swollen lymph glands, termed buboes, are a hallmark finding in bubonic plague. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Wayson stain showing the characteristic "safety pin" appearance of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Fluorescence antibody positivity is observed as bright, intense green staining around the cell wall of Yersinia pestis, the plague bacillus. Image courtesy of Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lung in fatal human plague–fibrinopurulent pneumonia. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lung showing pneumonia with many Yersinia pestis organisms (the plague bacillus) on a Giemsa stain. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of spleen in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of lymph node showing medullary necrosis and Yersinia pestis, the plague bacillus. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Histopathology of liver in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Focal hemorrhages in islet of Langerhans in fatal human plague. Image courtesy of Marshall Fox, MD, Centers for Disease Control and Prevention (CDC), Atlanta, Ga.

Pictured is a flea with a blocked proventriculus, which is equivalent to the gastroesophageal region in a human. In nature, this flea would develop a ravenous hunger because of its inability to digest the fibrinoid mass of blood and bacteria. If this flea were to bite a mammal, the proventriculus would be cleared, and thousands of bacteria would be regurgitated into the bite wound. Courtesy of the United States Army Environmental Hygiene Agency.

After the femoral lymph nodes, the next most commonly involved regions in plague are the inguinal, axillary, and cervical areas. This child has an erythematous, eroded, crusting, necrotic ulcer at the presumed primary inoculation site in the left upper quadrant. This type of lesion is uncommon in patients with plague. The location of the bubo is primarily a function of the region of the body in which an infected flea inoculates plague bacilli. Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Ecchymoses at the base of the neck in a girl with plague. The bandage is over the site of a prior bubo aspirate. These lesions are probably the source of the line from the children's nursery rhyme, "ring around the rosy." Courtesy of Jack Poland, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.

Acral necrosis of the nose, the lips, and the fingers and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC, US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Acral necrosis of the toes and residual ecchymoses over both forearms in a patient recovering from bubonic plague that disseminated to the blood and the lungs. At one time, the patient's entire body was ecchymotic. Reprinted from Textbook of Military Medicine. Washington, DC: US Department of the Army, Office of the Surgeon General, and Borden Institute. 1997:493. Government publication, no copyright on photos.

Rock squirrel in extremis coughing blood-streaked sputum related to pneumonic plague. Courtesy of Ken Gage, PhD, Centers for Disease Control and Prevention (CDC), Fort Collins, Colo.