FOR THE CLINICAL MANAGEMENT OF PLAGUE AND BIOTERRORISM-RELATED PLAGUE

Yersinia. pestis appears to be a good candidate agent for a bioterrorist attack. The use of an aerosolised form of this agent could cause an explosive outbreak of primary plague pneumonia. The bacteria could be used also to infect the rodent population and then spread to humans. Most of the therapeutic guidelines suggest using gentamicin or streptomycin as first line therapy with ciprofloxacin as optional treatment. Persons who come in contact with patients with pneumonic plague should receive antibiotic prophylaxis with doxycycline or ciprofloxacin for 7 days. Prevention of human-to-human transmission via patients with plague pneumonia can be achieved by implementing standard isolation procedures until at least 4 days of antibiotic treatment have been administered. For the other clinical types of the disease, patients should be isolated for the first 48 hours after the initiation of treatment.


Introduction
Plague is an acute bacterial infection caused by the organism Yersinia pestis.Historically, three plague pandemics have killed more than 200 million people, including the Black Death epidemic in 14 th century Europe [1].This disease, primarily the bubonic form, is still reported from several countries in Africa, Asia, South America and rural south-western parts of the United States (US) [2][3][4][5][6].There is currently no plague in Europe: the last reported cases occurred after the second world war.Worldwide, it is estimated that 1000 to 6000 cases occur each year (mean: 1500 cases/year) [7].The total number of human plague cases reported to the World Health Organization by 14 countries in 1997 was 5 419, of which 274 were fatal [8].It remains an enzootic infection of rats and other rodents.Plague occurs in sylvatic rats, which may then spread among more domestic rat species and finally among humans.Bacteria are usually passed to humans through the bite of a flea that has previously fed on an infected rat.In nature, at least 200 species of mammals and 80 species of fleas serve as reservoirs [9].Infection may also occur through direct contact with infected tissues or fluids from sick or dead plague-infected animals, by exposure of humans to respiratory droplets from infected animals, especially cats with plague pneumonia, or by laboratory exposure to plague bacteria.Human-to-human transmission can occur through infectious respiratory droplets from pneumonic cases of plague [10][11][12][13].Primary pneumonia appears as a consequence of this transmission.Bubonic and other forms of plague in humans, without secondary pneumonia, are not considered to be infectious.It has been reported that inhalation from contaminated clothes could be also a route of transmission [10].Propagation of a human plague outbreak depends upon the number and susceptibility of rodent populations, the fleacarrying capacity of the rodent species, the number and infectivity of the flea species, the degree of contact of people with infected rat fleas, climatic conditions, and the number and living conditions of susceptible people [13].

Plague and bioterrorism
Y. pestis appears to be a good candidate agent for a bioterrorist attack.The use of an aerosolised form of this agent could cause with an explosive outbreak of primary plague pneumonia in the exposed population, or alternatively the bacteria could be used to infect the rodent population and precipitate a secondary outbreak in humans living in poor conditions [12,13].Intentional aerosol release should be suspected in patients presenting with plague pneumonia in non-endemic areas or in patients without risk factors.Y. pestis is a relatively fragile organism that remains viable only an hour after an aerosol release.Nevertheless, as few as 1 to 10 bacteria are sufficient to infect rodents via the oral, intradermal, subcutaneous or intravenous routes [14].Estimates of human infectivity by the respiratory route vary from 100 to 20 000 organisms [4,6,7].The Tatars were the first to use plague as a biological weapon, in 1347, during the siege of the Genoesecontrolled Black Sea port of Caffa: they hurled the bodies of their plague victims over the city walls [7,15].It has been reported that the Japanese army dropped plague-infected fleas in China during the second world war [1,7].In 1970, it was reported that if 50 kg of Y. pestis were released over a city of 5 million, plague pneumonia could occur in as many as 150 000 persons, including 36 000 deaths [16].In May 2000, during the virtual exercise TOPOFF in the US (for 'top officials'), simulation of a deliberate release of an aerosol of Y. pestis at a performing arts centre estimated that 3 700-4 000 cases of plague pneumonia and between 950 to over 2 000 deaths might have resulted [12].

Biological characteristics
Y. pestis is a Gram negative, non-motile, non-sporulating rod, which presents bipolar staining with Wayson stain and is a facultative anaerobic bacillus of the family Enterobacteriaceae.It grows aerobically on most culture media [6].

Clinical features
The most usual clinical presentations of plague are bubonic, primary septicaemic and pneumonic disease [4,6,7,11].In a biological attack, the most likely clinical presentation would be primary pneumonic plague, as dispensed by aerosol is considered the most likely way of dispersing the agent [7,12] (TABLE I).
Pneumonic plague may occur by primary respiratory infection, or as a complication of the bubonic and septicaemic forms of the disease (secondary pneumonia).In this case, the incubation period is 1-6 days.It begins abruptly with intense headache and malaise, high fever, vomiting, abdominal pain, diarrhoea and marked prostration.Chest pain, cough, dyspnoea and haemoptysis develop thereafter [6].Chest radiographs show evidence of multilobar consolidation, cavities or bronchopneumonia [6].Laboratory findings are consistent with a bacterial infection with disseminated intravascular coagulation.Respiratory failure develops quickly with septic shock, and mortality is high.Without antibiotics, the disease is fatal in almost all patients within two or three days.Plague pneumonia is highly contagious to other humans by droplet transmission and in practice, patients are still contagious up to 3 days after starting appropriate antibiotic treatment.With the prompt use of antibiotics, the fatality rate decreases below 10% but the treatment should be started as soon as possible.
Bubonic plague is the most common clinical form of naturally occurring plague (75-97% of all cases).After an incubation period of 2 to 8 days, there is sudden onset of fever (38.5°C to 40°C), chills, headache, nausea, vomiting, malaise or prostration and weakness; 6 to 8 hours after the onset of symptoms a bubo develops [4,6,7].The bubo is characterised by severe pain, swelling and marked tenderness.It develops in the area of an infected bite: groin (with femoral more frequent than inguinal lymphnodes affected), axillary and cervical nodes are most commonly affected.It becomes visible after 24 hours, and its size varies from 1 to 10 cm in diameter.There is surrounding oedema and the overlying skin is warm, erythematous and adherent.Pustules, vesicles, eschars, papules or skin ulcerations may occur at the site of the flea bite, which is usually in the lower extremities [7].Rarely, the bubo may become fluctuant and suppurate.Other manifestations include apathy, confusion, fright, anxiety, oliguria or anuria, tachycardia, and hypotension [7].Without specific treatment, complications are common and include primary (without discernible bubo) or secondary septicaemia, secondary pneumonia and meningitis.The mortality rate or case fatality rate for untreated bubonic plague is 60%, which becomes less than 5% with appropriate antibiotic treatment [11].This form is unlikely to occur in a bioterrorist attack, except if fleas were used as a vector [7].
Septicaemic plague may occur as a complication of untreated bubonic plague or pneumonic plague (secondary septicaemic plague) and can develop in the absence of obvious signs of primary disease (primary septicaemic plague).Symptoms and signs are indistinguishable from other Gram negative septicaemias, and include septic shock and disseminated intravascular coagulation with vasculitis, livid cyanotic petechiae, purpura and large ecchymoses that can mimic meningococcaemia [7,11].Gangrene of acral regions, like the tip of the nose or the fingers and toes, due to small artery thrombosis may appear in advanced stages of the disease (Black Death).Left untreated, the mortality approaches 100%.
Plague meningitis is rare but may occur as a complication of inadequately treated infection elsewhere.There appears to be an association between the formation of a bubo and meningitis.
Pharyngeal plague is very rare and possibly a result of ingestion or inhalation of the organism.The tonsils are swollen and inflammed with anterior cervical lymphadenopathy and swelling of the parotid area.

Diagnosis
Case definitions of suspected or confirmed cases and cases due to deliberate release are summarised in Tables 2 and 3.

Vaccines
A killed whole cell plague vaccine that was efficacious against bubonic disease was available until 1999 in the US [4].This vaccine was associated with a poor protection against pneumonic disease [9].It was recommended for persons working with Y. pestis in a laboratory, for those working in plague-affected areas or with potentially infected animals [18].
A live attenuated vaccine is also available in the US, but it retains some virulence and is therefore not considered suitable for human use in most countries [9].Recent vaccine research in Europe is focused on the development of a sub-unit vaccine containing F1 antigens and recombinant V antigens, which proved to be efficacious against pneumonic plague in mice [9,19].

Conclusion
In conclusion, Y. pestis is one of the major agents that could be as a biological weapon.The main clinical manifestations would be plague pneumonia if aerosolised bacteria were used, and bubonic and/or septicaemic plague if fleas were used as infected vectors. 17

Second line treatment; first line prophylaxis
-Ciprofloxacin: 400 mg IV bid followed by 500 mg per os bid or -Ofloxacin: 400 mg IV bid followed by 400 mg per os bid or -Levofloxacin: 500 mg IV once a day, followed by 500 mg per os once a day

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Ciprofloxacin: 500 mg per os bid or -Ofloxacin: 400 mg per os bid or -Levofloxacin: 500 mg per os once a day Third line treatment; second line prophylaxis -Doxycycline: 100 mg IV bid followed by 100 mg bid per os -Doxycycline: 100 mg bid per os Children First line treatment -Gentamicin: 2.5 mg/kg IV in 3 doses daily or -Streptomycin: 15 mg/kg IM twice daily (max, 2g) Second line treatment; first line prophylaxis -Ciprofloxacin: 10-15 mg/kg IV bid followed by 10-15 mg/kg per os bid -Ciprofloxacin: 10-15 mg/kg per os bid Third line treatment; second line prophylaxis -Doxycycline: .>8 years and > 45 kg: adult dose .>8 years and < 45 kg or < 8 years: 2.2 mg/kg IV bid followed by 2.2 mg/kg per os bid (max 200 mg/d) -Doxycycline: .>8 years and > 45 kg: adult dose .>8 years and < 45 kg or < 8 years: 2.2 mg/kg per os bid (max 200 mg/d) Source: [17] . The European Agency for the Evaluation of Medicinal Products/CPMP guidance document on use of medicinal products for treatment and prophylaxis of biological agents that might be used as weapons of bioterrorism.July 2002; www.emea.eu.int 18. Jefferson T, Demicheli V, Pratt M. Vaccines for preventing plague.Cochrane Database Syst Rev 2000; 2: CD000976 19.Du Y, Rosqvist R, Forsberg A. Role of fraction 1 antigen of Yersinia pestis in inhibition of phagocytosis.BICHAT, the European Commission's Task Force on Biological and Chemical Agent Threats, has developed this set of guidelines that may be the basis of national authorities' guidance, and may also be used directly by clinicians, general practitioners and specialists when confronted with patients infected by agents that may be due to deliberate release of biological agents.Ref. Bossi P, Van Loock F, Tegnell A, Gouvras G. Bichat clinical guidelines for bioterrorist agents.Euro Surveill.2004; 9(12) http://www.eurosurveillance.org/em/v09n12/0912-230.asp Editorial note: These clinical guidelines were reviewed by the Task Force and by two experts designated by each Member State of the European Union.This review was completed at the end of February 2003.The revised guidelines were submitted to the Health Security Committee which approved them in April 2003 and agreed their publication in a widely disseminated journal so as to allow access to as large an audience as possible.The editorial process of Eurosurveillance also introduced modifications that improved the contents of these guidelines.