PLAGUE

PLAGUE

Current Diagnosis

• Plague should be suspected when a person develops abrupt onset of fever, lymphadenopathy or sepsis and there is history of a flea bite or possible exposure to an infected animal or person.

• Yersinia pestis is an aerobic gram-negative coccobacilli that exhibits bipolar staining with Giemsa, Wright’s, and Wayson stains.

• Automated diagnostic systems may misidentify Y. pestis as other organism.

Current Therapy

• Timely and appropriate management is imperative for a good outcome.

• Despite their toxicities, aminoglycosides are the treatment agents of choice.

• Respiratory droplet precautions should be instituted when pneumonic plague is suspected.

•   Postexposure prophylaxis is indicated for close contacts.

Historical descriptions indicate that Yersinia pestis probably caused Justinian’s Plague (ad 541), which led into the first plague pandemic. The second plague pandemic, also known as the Black Death, began in Central Asia in 1347 and then spread to Europe, Asia, and Africa. It killed an estimated 50 million persons. The current (third) plague pandemic began in China and then spread worldwide along shipping routes in 1899–1900. Y. pestis is a gram-negative, nonmotile, facultatively anaerobic, non-spore-forming coccobacillus that is approximately 0.5 to 0.8 µm in diameter and 1 to 3 µm in length.

Genomic sequencing shows that Y. pestis is a recently emerged clone of Y. pseudotuberculosis.

Epidemiology

Plague is a zoonosis for which urban and sylvatic rodents (e.g., rats, prairie dogs, and marmots) are the most important enzootic reservoirs. Additionally, domestic cats and dogs have been linked to human disease. Human plague occurs in North and South America, Asia, and Africa. Recent outbreaks reported to the World Health Organization (WHO) have occurred in the Democratic Republic of Congo (2005, 2006), China (2009), and Peru (2010). Plague is endemic in Madagascar, and between 2004 and 2009, 30% of all human cases worldwide were reported from this country. A new epidemic was identified December 6, 2016 and as of December 27, 62 cases with a case fatality rate of 42% have been reported. From 2000 to 2009, a total of 21,725 cases of plague with a 7.4% fatality rate were reported worldwide. Between 2010 and 2015 another 3248 cases of plague were reported to the WHO. In North America most human cases occur in New Mexico, Arizona, California, Colorado, and Texas. Between 1900 and 2012, 1006 confirmed or probable cases have occurred in the U.S. with over 80% of these attributable to bubonic plague.

Modes of Transmission

Most human infections are transmitted from rodent to humans via the bite of an infected flea. Infection also can be acquired by contact with body fluids from infected animals, such as during field dressing of game or by inhalation of respiratory droplets from animals, particularly cats, or humans with pneumonic plague.

Bioterrorism Threat

Plague was used as an agent of biowarfare by the Japanese in World War II and was a focus of intensive research and development in the former Soviet Union during the Cold War. Primary pneumonic plague is the most likely form of exposure because of biowarfare or bioterrorism. Recent increases in terrorism worldwide have increased the focus of public health management groups to develop comprehensive statements regarding plague as a biological weapon.

Pathogenesis and Clinical Syndromes

Transdermal inoculation of bacilli from the bite of an infected flea ultimately leads to infection of the regional lymph nodes in which massive replication of bacteria creates the bubo (derived from the Greek bubon or “groin”), a swollen, erythematous, and painful lymph node in the groin, axilla, or cervical region. Bacteremia and septicemia frequently develop and lead to secondary infection of other organs including the lungs, spleen, and central nervous system. Primary pneumonic plague is a rare natural occurrence and results from the inhalation of respiratory droplets containing Y. pestis bacilli from another case of pneumonic plague, usually in humans or in cats.

Although plague in dogs is rare, human outbreaks have been traced to sick dogs with wildlife exposure. Secondary pneumonic plague results from seeding of the lungs by blood-borne bacteria in the setting of either bubonic or septicemic plague. Septicemic plague also begins with transdermal exposure but manifests as primary bacteremia/septicemia without the bubo. Less common manifestations include meningitis, pharyngitis, and gastroenteritis.

Bubonic plague is an acute febrile lymphadenitis that develops 2 to 8 days after inoculation. Inflamed lymph nodes are usually 1 to 6 cm in diameter and painful. Abrupt onset of fever is an almost universal finding and occurs simultaneously with, or up to 24 hours before, the appearance of the bubo. Headache, malaise, and chills are frequent, along with nausea, vomiting, and diarrhea. Most patients are tachycardic, hypotensive, and appear prostrate and lethargic with episodic restlessness. Leukocytosis with a left shift is typical.

Complications include pneumonia, shock, disseminated intravascular coagulation, purpuric skin lesions, acral cyanosis, and gangrene. The differential diagnosis of bubonic plague includes tularemia and Group A β-hemolytic streptococcal adenitis with bacteremia.

Symptoms of septicemic plague are similar to those caused by other gram-negative bacteria, and are very similar to those of bubonic plague except that abdominal pain is more common in septicemic plague. Septicemic plague must be differentiated from fulminating septicemia caused by other gram-negative bacteria. Primary pneumonic plague has an abrupt onset of fever and influenza-like symptoms 1 to 5 days after inhalation exposure. Symptoms include shortness of breath, cough, chest pain, and bloody sputum with rapid progression to fulminating pneumonia and respiratory failure.

Patients with secondary pneumonic infection show respiratory symptoms in addition to those attributed to the bubo or sepsis. Radiographic findings include patchy bronchopneumonia, multilobar consolidations, cavitations, and alveolar hemorrhage and are not pathognomonic of Y. pestis. Plague pneumonia must be differentiated from severe influenza, inhalation anthrax, and overwhelming community-acquired pneumonia.

Diagnosis

Plague is diagnosed by demonstrating Y. pestis in blood or body fluids such as a lymph node aspirate, sputum, or cerebrospinal fluid. A tentative diagnosis of bubonic plague can be made rapidly with fluid aspirated from a bubo showing gram-negative coccobacilli with bipolar staining. It is important to remember that automated diagnostic systems might misidentify Y. pestis. In an outbreak in Colorado, the misidentification of Y. pestis as Pseudomonas luteola delayed the recognition of the outbreak. Serology showing a fourfold rise in antibody titers to F1 antigen or a single titer of more than 1:128 is also diagnostic. Rapid tests using monoclonal antibodies to detect Y. pestis F1 antigen in bubo aspirates and sputum have been developed and field tested. The use of mass spectrometry as a more rapid and cost-effective diagnostic tool has also been studied.

Treatment

The aminoglycosides (gentamicin and streptomycin), doxycycline (Vibramycin), and the fluoroquinolones ciprofloxacin (Cipro) moxifloxacin (Avelox) and levofloxacin (Levaquin) and doxycycline (Vibramycin) are the first-, second-, and third-line classes of antibiotics, respectively. Typical minimal inhibitory concentrations for 90% (MIC90) of tested strains for the fluoroquinolones are less than 0.03 to 0.25 µg/mL compared with less than 1.0 µg/mL and less than 1.1 µg/mL to 4.0 µg/mL for gentamicin and streptomycin, respectively, and less than 1.0 µg/mL for doxycycline. Streptomycin (15 mg/kg up to 1 g intramuscularly [IM] every 12 hours) and gentamicin (5 to 7 mg/kg/day intravenously [IV]/IM in one or two doses daily) are the drugs of choice for severe infection. Standard fluoroquinolone dosing includes ciprofloxacin 400 mg IV/500 mg orally every 12 hours; levofloxacin 500–750 mg IV/orally daily; and moxifloxacin 400 mg IV/orally daily. Doxycycline is administered at 100 mg IV/orally every 12 hours. Chloramphenicol (25 mg/kg IV/orally every 6 hours) can be used in select Antibiotic therapy should be continued for a total of 10 days.

Prevention and Control

Standard infection control procedures should include a disposable surgical mask, latex gloves, devices to protect mucous membranes, and good hand washing. Hospitalized patients with known or suspected pneumonic plague should be isolated under respiratory droplet precautions for at least 48 hours after appropriate antibiotics are initiated. Patients without respiratory plague can be managed under standard precautions. Postexposure prophylaxis should be given to individuals with close contact (less than 2 meters) with an infectious case or who have had a potential respiratory exposure. The recommended adult antibiotics for prophylaxis are doxycycline or ciprofloxacin in the same doses used for treatment. Postexposure prophylaxis can be given orally and should be continued for 7 days following exposure. Currently, there is no licensed plague vaccine. An encapsulated Y. pseudotuberculosis, strain V674pF1,5 is an efficient live oral vaccine against pneumonic plague in mice. Recently, flea resistance to insecticides such as DDT and Deltamethrin in Madagascar has prompted an immediate need for alternative insecticides to prevent future plague outbreaks.

References

1.     Andrianaivoarimanana V., et al. Understanding the persistence of plague foci in Madagascar. PLoS Negl Trop Dis. 2013;7(11):e2382.

2.    Boulanger L.L., Ettestad P., Fogarty J.D., et al. Gentamicin and tetracyclines for the treatment of human plague: review of 75 cases in New Mexico, 1985–1999. Clin Infect Dis. 2004;38:663– 669.

3.     Boyer S., et al. Xenopsylla cheopis (Siphonaptera: Pulicidae) susceptibility to deltamethrin in Madagascar. PLoS One. 2014;9(11) e111998.

4.    Butler T. A clinical study of bubonic plague. Observations of the 1970 Vietnam epidemic with emphasis on coagulation studies, skin histology and electrocardiograms. Am J Med. 1972;53:268– 276.

5.     Butler T. Plague gives surprises in the first decade of the 21st century in the United States and worldwide. Am J Trop Med Hyg 2013; 89(4):788–93.

6.     CDC. Maps and Statistics. http://www.cdc.gov/plague/maps/index.html.

7.    Cler D.J., Vernaleo J.R., Lombardi L.J., et al. Plague pneumonia disease caused by Yersinia pestis. Semin Respir Infect. 1997;12:12–23.

8.     Derbise A., Cerdà Marín A., et al. An encapsulated Yersinia pseudotuberculosis is a highly efficient vaccine against pneumonic plague. PLoS Negl Trop Dis. 2012;6(2):e1528 Feb.

9.       Gage K.L., Dennis D.T., Orloski K.A., et al. Cases of cat- associated human plague in the Western US, 1977–1998. Clin Infect Dis. 2000;30:893–900.

10.      Inglesby T.V., Dennis D.T., Henderson D.A., et al. Plague as a biological weapon: Medical and public health management. Working Group on Civilian Biodefense. JAMA. 2000;283:2281– 2290.

11.    Perry R.D., Fetherston J.D. Yersinia pestis—etiologic agent of plague. Clin Microbiol Rev. 1997;10:35–66.

12.     Prentice M.B., Rahalison L. Plague. Lancet. 2007;369:1196–1207. Runfola J.K., et al. Outbreak of human pneumonic plague with dog- to-human and possible human-to-human transmission. MMWR Morb Mortal Wkly Rep. 2015;64(16):429–434.

13.   Wang H., et al. A dog-associated primary pneumonic plague in Qinghai Province, China. Clin Infect Dis. 2011 Jan 15;52(2):185– 190.

14.    Wong J.D., Barash J.R., Sandfort R.F., Janda J.M. Susceptibilities of Yersinia pestis strains to 12 antimicrobial agents. Antimicrob Agents Chemother. 2000;44:1995–1996.

15. World Health Organization. Emergencies Preparedness and Response. http://www.who.int/csr/don/09-january-2017- plague-mdg/en/.

5  Investigational drug in the United  States.

KNOWLEDGE BASE
About Genomic Medicine UK

Genomic Medicine UK is the home of comprehensive genomic testing in London. Our consultant medical doctors work tirelessly to provide the highest standards of medical laboratory testing for personalised medical treatments, genomic risk assessments for common diseases and genomic risk assessment for cancers at an affordable cost for everybody. We use state-of-the-art modern technologies of next-generation sequencing and DNA chip microarray to provide all of our patients and partner doctors with a reliable, evidence-based, thorough and valuable medical service.

X