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Key Diagnostic Tests.

• Leukocytosis
• Identification of bacteria in body fluids by characteristic bipolar ("safety pin") staining with Giemsa, Wayson, or Wright stains.
• Isolation of microorganism from body fluids
• 4-fold or more increase in antibody titer to Y. pestis.
• Identification of F₁ capsular antigen in cultures.

Symptoms and effects.

In the case of a biological weapons attack, the most likely manifestation of the disease will be as an outbreak of pneumonic plague rather than the better-known bubonic plague. The pneumonic form of plague is extremely rare with only seven cases recorded in the US since World War II and four of those were fatal.

The first symptoms of pneumonic plague are a fever with a cough (with sputum that may be clear, bloody, or purulent) and difficulty breathing (dypsnea) without the characteristic appearance of buboes. Buboes on the neck are rare but are a sign of pneumonic plague. The disease rapidly engulfs the lungs and hemorrhages develop, filling them with fluid (a hemorrhagic pneumonia). Nausea, diarrhea, vomiting and abdominal pain can accompany the pneumonic form of the disease. The incubation period is short (3-4 days) and pneumonic plague is almost always fatal if not treated.

In general, plague is characterized by the rapid progression of the disease with a high fever, extreme weakness, swelling of the glands, and pneumonia. There may be hemorrhaging in the skin or mucous membranes. The disease can kill within 1-2 days if not diagnosed and treated promptly and can become endemic (a persistent and repeatedly occurring disease). Diagnosis can take 2-5 days to confirm.

It is the hemorrhaging into the skin that gives rise to the name Black Death. The hemorrhaging leads to a loss of blood to the affected area because of damage to blood vessels. As the blood breaks down it turns black and the affected tissue dies because of a lack of blood. The result is the formation of patches of dead black skin.

Bubonic plague is transmitted from rats by the bite of an infected flea. Rats form a reservoir for the disease once it enters an area. The microorganism spreads rapidly through the body via the lymphatic system, causing the lymph nodes, typically in the groin and armpits, to swell forming "buboes". From the lymph nodes, Y. pestis can spread into the bloodstream and produce a generalized infection in which the spleen, lungs and meninges (the protective covering around the brain) can be infected. The incubation period can be 2-19 days and mortality can reach 50-60%.

	Buboes in the inguinal lymph nodes (those in or near the groin.) (Photograph: CDC Public Health Image Library)
	The blotches on the skin are the cutaneous hemorrhages seen in plague. They are the source of the nursery rhyme "Ring-a-ring of roses." (Photograph: CDC Public Health Image Library)

Medical and Physical Countermeasures.

Vaccination (Immunoprophylaxis)

A vaccine, the Greer inactivated vaccine made from killed Y. pestis, was available until 1999 but inoculations are needed every three months to maintain the protective effect. Vaccines based on live avirulent (not disease-causing) strains of the bacterium are effective for six months and re-immunization is needed every six months. These vaccines protect against bubonic plague but not against infection by inhalation of an aerosol, that is, pneumonic plague. Plague survivors develop complete, prolonged immunity.

Manufacture of the killed vaccine was suspended in 1999 and limited quantities are available only for those at high risk of infection.

The British Defence Evaluation Research Agency announce in August 1999 that is was about to begin human testing on a vaccine that has been developed using purified antigens of the bacterium manufactured by genetic engineering.

Antibiotics

Pneumonic plague responds well to antibiotics and antibiotic regimes for treatment of plague have been recommended by the American Medical Association in a consensus statement on plague as a biological weapon (Journal of the American Medical Association, vol 283, No. 17, pp2281-2290 (May 3 2000)). In the case of small outbreaks the preferred treatment for adults (including non-pregnant women) is streptomycin injected intramuscularly (1 gram, twice a day) or gentamicin at 5 mg/kg by intramuscular injection once a day. For mass casualty events, i.e. weapons use, oral antibiotics are preferred. Doxycycline at 100 mg twice a day for seven days is recommended. This dosage can also be prophylactic (prevent infection) if people are at risk of exposure. Ciprofloxacin can also be used (500 mg twice a day) and is prophylactically effective. Doxycycline and ciprofloxacin are also preferred for pregnant women.

Supportive care

• Treat complications promptly.
• Do not drain buboes.
• Protect necrotic tissue from injury.

Decontamination

Decontamination can be dealt with by boiling, dry heat, steam, or disinfectants such as lysol or calcium hypochlorite. The organism can be killed by heating at 55°C (130°F) for 15 minutes and by exposure to sunlight for 3-5 hours. Cells released in a biological attack will all have died before the disease is first seen, so area decontamination is not a priority.

Agent Properties and Potential Uses

Plague, especially pneumonic plague, has been considered as biological weapon because it is extremely infective. An aerosol made up of bacteria-containing droplets of the size best suited for absorption in the lungs (1-5 micrometers) dispensed over an unprotected population could kill a very large fraction (90-100%) of those exposed. The LD₅₀ (the dose an individual has to receive to have a 50% chance of dying) for Y. pestis is about 3,000 cells, making it somewhat more effective than anthrax, but less effective than tularemia or Q fever.

The organism can be manufactured by fermentation at relatively low temperatures without affecting its properties as a biological warfare agent. Y. pestis can be stored relatively easily because it can survive at low or freezing temperatures for extended periods as long as there is water available. It can survive for 30 days in water. It can also be freeze-dried and stored for up to ten years without loss of viability, i.e. can be revived and cultured.

A 1970 study by the World Health Organization found that the the organism could remain viable for up to an hour after dispersal as an aerosol. Under poor conditions for dispersal, a rapid loss of viability (up to 70% per minute) depending upon the temperature and humidity of the atmosphere can be seen.

According to former KGB officer Valeri Mitrokhin, the use of pneumonic plague as a weapon of assassination was considered by the Soviet leadership in the 1950's. In the end, the targets (Ukrainian nationalists including Stephan Bandera) were killed with cyanide sprays.

Terrorist Acquisition and Attempted Use.

• In 1978, the city of Tucson, Arizona was threatened with infestation with plague-carrying fleas unless a ransom of $500,000 was paid.
• There has been one case of an individual attempting to obtain Y. pestis from the ATCC under fraudulent conditions. Ostensibly this was to develop a vaccine.
• An extremist group in the Southwestern US is reported to have captured plague-infected animals as part of an attempt to obtain the microorganism for weapons use. This was discovered when several members of the group came down with the disease.

Antibiotic Resistance.

Plasmid-borne antibiotic resistance has been identified in Y. pestis. A 1997 report described a naturally-occurring plasmid conferring resistance to a number of widely-used antibiotics upon Y. pestis.

The History and Natural History of the Plague.

The natural home of Y. pestis appears to be the steppe and the desert. As far as we can tell, its natural home is the Gobi Desert of central Asia, and it has also become established as an endemic problem in the dryer areas of the Western United States. A few cases are still diagnosed every year in the Desert Southwest. The natural hosts of the bacterium are rodents such as the marmot (or tarabagan) in the Gobi and squirrels, ground squirrels, gophers, chipmunks, pack rats and prairie dogs in the US. The nomadic peoples of Mongolia have learned to avoid areas where dead marmots have become common. The bacterium is not really too selective about its host and as long as it can be transported by a flea, the Oriental rat flea Xenopsylla cheopis, it will reside in any mammal that the flea will bite.

One of the great oddities of Y. pestis is that its pathogenicity arises not so much from the acquisition of abilities as from their loss. Unlike other pathogenic members of the species, the plague bacterium lacks the ability to enter cells and kill them. Instead, it circulates in the blood stream and becomes trapped in the lymph nodes. In the lymph nodes, it multiplies rapidly, and the nodes swell to form the buboes that give the disease its name. Cells shed into the blood stream and continue to multiply, blocking fine capillaries and eventually causing them to burst and hemorrhage. Essentially the same thing happens in the fleas that transmit it between animals. The bacterium fends off the phagocytes that would normally engulf and destroy it by secreting an enzyme, a protease, that destroys the cell surface proteins that identify and capture the pathogen. The bacterium has also lost the function of a key enzyme, a component of the Krebs cycle, that makes it dependent upon an animal host.

The effects of this disease upon man may never be fully comprehended. It serves as a paradigm for the most devastating effects of biological warfare. It also has had major cultural effects, one being the use of the disease as a metaphor for corruption in La Peste by the French writer Albert Camus.

There have been two major eruptions of the disease from its home into Europe. The first of these was recorded by the historian Procopius, and although the less well-known, was just as devastating as the later outbreak. It began in 542 A.D. when it invaded Byzantine Empire and brought despair to the emperor Justinian and his subjects. The disease did not spread directly in the European heartland west of the empire because it was at war with the Visigoths who had taken over the remnants of the Western Roman Empire. This blocked the direct spread along trade routes. However, it spread along the Mediterranean littoral and devastated the remnants of the Western Roman Empire and helped bring it to an end.

Within the Empire, the plague killed about 40% of the adult population, destroying rural communities and farms. The capital, Constantinople, was ringed by trenches filled with the dead until there were not enough left to bury the dead and the bodies were floated out to sea on rafts or placed in the turrets of fortifications that were being built to guard the city wall. This gave the city the stench of death when the wind blew over the turrets.

The second was the legendary the Black Death of the Middle Ages, although it was known at the time as the Pestilence or the Great Dying and was only dubbed the Black Death in the 19th Century. Europeans believe that it was solely a European event but it was truly a pandemic (a world-wide epidemic). The outbreak began in China and Mongolia and its arrival in Europe was preceded by reports, first heard in 1346, of a terrible pestilence in China. The disease was carried westward along trade routes, apparently being brought into them by the Mongol Hordes as they broke out of Mongolia, first eastward into China, and then west towards Europe. A key incident in the introduction of the disease into Europe was the introduction of the plague into the Genoese settlement of Kaffa (now called Feodosiya) in the Crimea when it was reduced by the Mongols. Legend has the Mongols catapulting the corpses of plague victims into the fortifications, a siege tactic known in Europe. It was more likely that the plague was brough into the settlement by its preferred carrier, the black rat that picked up infected fleas as it wandered amongst the Mongol plague victims in the encampment. Plague-ridden survivors returning to Italy carried the disease with them when they landed at Messina in Sicily in 1346.

By 1348, the disease reached Marseille and by the end of 1349 it had reached as far north as Iceland and into North Africa with Russia becoming a victim in 1351.

Within two years, a third of the population of Western Europe had been killed by the disease with peasants and kings succumbing alike. Many died with the odor of their own rotting flesh filling their nostrils. Bodies piled up faster than they could be buried, making matters worse. Farms could not be tended and crops and livestock were lost. Husbands abandoned wives and children abandoned parents. Morality vanished and the rending of the fabric of society seemed at hand. However, the spread appears to have been random, with some cities in Italy being missed almost entirely and others being brough close to extinction.

There was essentially no medical response to the disease, and the pandemic ran its course unfettered by human intervention. The plague was seen as the wrath of God and the commonest response was prayer to St. Sebastian. The random nature of the disease was seen as a rain of arrows and St. Sebastian had survived execution by archers. Responses such as sealing a home to prevent the disease entering on the air and the draining of buboes were exactly the wrong things to do and made an entire household vulnerable. Some, notably noblemen with country estates, left the cities and were spared. Such an escape is the premise for the round of story-telling that is The Decameron by Boccaccio. One of the few people to understand the origins of the disease and to correctly ascribe fresh air and personal cleanliness as keys to prevention was Michel de Nôtre Dame (the seer Nostradamus) who was also one of the better scientists of the time. His herbal remedy for the disease, the Rose Pill, was (1 ounce = 28 grams = 16 drams):

• Petals of 400 roses gathered before dawn;
• 16 drams Green Cypress sawdust;
• 96 drams Orris root (dried rhizome of Iris);
• 48 drams fresh ground cloves;
• 48 drams sweet flag (Calamus);
• 48 drams aloe juice.

Livestock also died on the same scale. The one animal that could have helped limit the spread of the disease, the vermin-hunting domestic cat, was seen as part of the problem and was killed by the thousands by a superstitious people for whom it was a witches familiar and a servant of Satan.

In a society that was still dependent on muscle power, the loss was crippling. Eventually, marginal farms were abandoned and farms on fertile land were to prosper. One of the interesting sidelights on this is an explanation for the story of the dissappearance of the children in the story of the Pied Piper of Hamelin. Actually, it was any male son but the first born, who would inherit everything by the rule of primogeniture. Having been freed of rats (by the Pied Piper), the city escaped the worst of the plague and had a relatively healthy, young population that was taken away by labor agents to colonize land recently conquered by Saxony in eastern Europe where they ultimately prospered, although presumed dead by their families. The older sons and those unfit to work remained in Hamelin.

A response to the disease that is still with us is the concept of quarantine. The city-state of Venice, being a port, tried to prevent import of the disease by making any ships wishing to trade with it wait offshore for forty days, a period significantly longer than the disease took to develop. The word "quarantine" is a corruption of the Italian quaranti meaning "forty." The effort failed because the quarantine did not block rats from swimming ashore.

The plague abated when the disease had thinned human and rat populations to a point where they could no longer support its spread. There were a number of recurrences over the next few centuries, but each was less severe than the preceding one. One of the last major outbreaks in Europe was in London in 1665. The outbreak is described in the detailed diary kept by Samuel Pepys. The outbreak was a mass casualty event with Pepys losing friends and family to it and the medical response almost as bad as it had been in the 14th Century, However, life appeared to go on and the city held together and the relatively well-off, such as Pepys, survived by being prudent about avoiding plague-ridden areas. This Great Plague of London also became immortalized in literature (A Journal of the Plague Year by Daniel Defoe) and in a nursery rhyme.

Ring-a-ring o' roses or Ring around the roses

This refers to the rings of hemorrhages appearing on the skins of victims

A pocket full of posies

Physicians and others carried carried scent-bearing flowers to mask the smell of the disease. Until recently, judges in England carried flowers (violets or tussy-mussies) into court for the same reason.

A-tishoo, a-tishoo, or, Ashes, ashes

"A-tishoo" refers to the sneezing and cold-like symptoms that were symptoms of the later stage of the disease. "Ashes" may refer to the cremation of the corpses.

All fall down

Everybody dies.

One of the lasting effects of this outbreak was that it formalized the burial depth at six feet. Before this, it was quite haphazard.

Identification of the causative agent was to be one of the early successes of the new science of bacteriology in the 19th Century. The agent was identified by the Swiss microbiologist Alexandre Yersin and the pioneering Japanese microbiologist Kitasato investigating an outbreak in Hong Kong. Initially, it was placed within a genus named after the legendary French bacteriologist Louis Pasteur (Pasteurella) but in the 1970's it was realized that it belonged in a distinct genus that was named after Yersin (Yersinia.)

Shortly after this, the first large scale outbreaks of pneumonic plague were seen in Manchuria in 1910-11 and 1920-1921 with the two outbreaks claiming over 100,000 lives. This was the last of a number of major outbreaks killing large numbers of people that occurred in Russia and Central Asia between 1771 and 1921. After the Bolshevik Revolution, the Soviet Union established reak stimulated Russia to develop a network of public health stations in Siberia to monitor plague outbreaks and conduct public health operations. Members of the organization made major advances did an outstanding job in public health, but others, and some of its establishments were later co-opted by the Soviet Union's biological warfare program.

The Japanese used the plague during their invasion of China before the outbreak of World War II. The agent was delivered by at least three different methods, including:

• the dropping of contaminated rice for rats to feed on;
• the dropping of contaminated materials such as lint
• an attempt to use bacteria encapsulated in a water-soluble matrix, and
• using infected fleas that were dropped over the target in a cluster bomb-like weapon called Ujithat scattered porcelain bomblets containing infected fleas. The fleas were released when the bomblet shattered.

Several hundred civilians died as a result of these efforts during a campaign in the Chekian region and a Japanese unit that entered the infected area also suffered heavy casualties. Plans were also in place to use the agent in the defense of the island of Saipan and to carry the war to the United States' mainland by attacking San Diego and its naval base. Neither plan came to fruition. The submarine carrying the agent to Saipan was sunk en route and Japan surrendered a monthe before the attack on San Diego was scheduled.

Although never used as an agent during the Vietnam War, plague claimed a number of U.S. victims because of the abundance of the Oriental rat flea.

Y. pestis is probably the only biological warfare organism for which genetic engineering has been acknowledged and published. The British have published a number of papers associated with the genetically engineered vaccine described above. After President Yeltsin made public the continuing Russian biological warfare effort in the 1990's, a number of Russian patents were granted dealing with the genetic manipulation of the microorganism. These included patents on strains of Y. pestis lacking the same key antigens the British were trying to make for vaccine use and that is used in diagnosis of the disease. The Russians also published documents on the manufacture of the antigen.