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Key Diagnostic Tests.

Preliminary symptoms are flu-like (malaise, fevers, rigors, vomiting, headache, backache). They may have been preceded by a short-lived rash. A rash begins to develop 2-3 days after this. Key features are that the rash is centered on the head and face and the development of the lesions is synchronous on all regions of the skin. The trunk or lower abdomen is relatively free of lesions.

• Detection of antigens or antibody to the agent in the blood (serology)
• ELISA
• PCR

Symptoms and effects.

Preliminary symptoms are a brief rash on the upper body, followed by general malaise, fever, muscle stiffness, vomiting, headache, backache with delirium occurring in about 15% of cases.

Two to three days after this, rashes develop on the mucous membranes (enanthema) and on the skin (exanthema) affecting the face, hands, and forearms. Secretions from the enanthema include infectious virus and play a key role in secondary transmission of the virus. However, the most infective period appears to be before the development of the rash. The rash spreads across the body and the lesions enlarge and fuse to form pustular (pus-filled) vesicles. The development of the lesions is remarkably synchronized throughout the course of the disease. The pustules eventually scab about two weeks after the onset of symptoms. Patients remain infective throughout convalescence.

In typical cases of smallpox (variola major) mortality is about 3% in vaccinated populations and 30% in unvaccinated ones. The disease can take on several other forms including black or hemorrhagic smallpox that have higher mortality rates.

	A photograph of the trunk of a young smallpox victim taken in Bangladesh in 1973. The photograph shows several important features: The size and shape of the pocks; the pocks all show about the same stage of development, synchronous development is a key feature; The relative lack of pocks on the trunk and lower abdomen.
Photograph courtesy of the CDC.

Medical and Physical Countermeasures.

Vaccination (Immunoprophylaxis)

A vaccine that can supply effective protection, the Wyeth calf lymph vaccinia vaccine, that gives protection for about 10 years is available. It can still provide protection after exposure to the virus. Stocks had been allowed to run down with the eradication of the virus with only about 10-20 million effective doses left in the United States at the end of 2001. Previously lost stocks had been found and new vaccine had been ordered by many countries by the end of 2002. Most countries expect to be able to control an outbreak by vaccination within a few years.

 Specific Therapy

A number of drugs, most notably the cytosine analog cidofovir, are in an advanced stage of testing. The older drug methisazone is no longer considered safe or effective.

Supportive care

• antibiotics may be needed to deal with secondary infection;
• maintain electrolytes with fluids.

The virus is relatively hardy and is resistant to common phenolic disinfectants. It can be killed with polar, lipophilic solvents such as chloroform or by treating with steam or autoclaving of smaller objects.

Agent Properties and Potential Uses

The virus is relatively hardy and can withstand drying, meaning that it remains infective for several days after being shed by an infected individual. The aerosol behavior of the virus is well-characterized. Viability drops as the ambient temperature and the humidity rise. This would help to explain why outbreaks of the disease have been commoner in the colder seasons than in the summer.

When smallpox was an acute public health problem in the 1960's and 1970's, it was not considered a particularly effective biological weapon. Doctors were trained to recognize the disease and effective vaccine was plentiful and vaccination was widespread. Since the eradication of the disease in the 1970's, it has actually become a greater threat. Doctors are no longer taught about the disease, will probably never see it and may fail to diagnose a case and react swiftly to it. To make matters worse, a provisional diagnosis of smallpox is likely to induce panic.

Very few people have been vaccinated against the disease in the last 10 years, so only a limited number of people would be able to operate safely in a contaminated environment. In addition, vaccine stocks have been run down, making it difficult to achieve effective protection if an attack is threatened or occurs. Modern textbooks, written since the 1980's, have little or no information on the disease and any information is often little more than a historical footnote.

Only two stocks of the virus are believed to remain in existence, one in the United States and one in Russia. However, there are rumors and reports that samples have been obtained by rogue nations.

Terrorist Acquisition and Attempted Use.

• An effort to drive Amazonian Indians from their homes by companies wishing to log the area is believed to have involved the use of several pathogens. Smallpox virus was one of them.

The smallpox virus (variola virus) is one of the largest and structurally most complex of viruses. It does not appear to have an animal host other than man and it does not survive for more than a few days outside of the host. These properties have on the one hand helped to make it possible to eradicate the disease solely by vaccination of humans in infected areas. On the other hand, they identify it as a disease that flourishes in crowded conditions such as modern cities. The possibility of a smallpox attack on a major metropolis now full of people unprotected against the disease evokes images of the charnel house.

The earliest recorded outbreak of a disease though to be smallpox may well have been the great plague of Athens of 430 B.C. reported by the Greek historian Thucydides in The Peloponnesian War. In that case, the disease appears to have come in from northern Africa (Ethiopia) and smallpox-like markings have been found on some Egyptian mummies from about 1100 B.C. The disease may have been known in Asia for centuries before that, but was first described in a manner that we now understand in about the 9th. Century.

Outbreaks and epidemics occurred many times in Eurasia over the centuries, often coming close to destroying cities and perhaps influencing great events such as the rise of Islam. The disease exercised the minds of some of the greatest physicians and alchemists of the early Middle Ages, including Avicenna and Rhazes who approached the disease rationally in a manner not seen again until the time of Thomas Sydenham in the second half of the 17th Century. This was the time when the disease reached its peak in Europe, counting Queen Mary II, the wife of William of Orange, and Louis XV of France among its royal victims. Mary died of the hemorrhagic form of the disease and her doctors were misled about the severity of the disease by the lack of pustules.

The disease was unknown in the Americas. When the Spanish under Cortez assaulted the Incan empire, smallpox rode apocalyptically with him as bubonic plague had ridden across Europe with the Mongols. Smallpox killed almost 90% of the native Incans and allowing large tracts of Central and South America to be conquered a few years later by Pizarro and a handful of men with guns.

Smallpox also spread to North America where it was almost as effective. It may have been in the Northwestern Territories of colonial America (now including parts of Ohio and Pennsylvania) where the disease may first have been deliberately used as a weapon. In 1763, Captain Ecuyer of Fort Pitt gave "two blankets and a handkerchief out of the Small Pox hospital" as peace offerings to fractious local chiefs. This resulted in the deaths of hundreds of Mingo, Delaware, and Shawnee.

A form of vaccination called "variolation", a deliberate infection with smallpox, that had been developed in Asia was practiced in Europe at this time. Those who survived the treatment were resistant to any further outbreak of the disease, but far too many did not survive and those that did had to spend a long time preparing for the treatment and often months recovering. There was also a piece of folk wisdom amongst farmers that infection with cowpox protected against smallpox. Edward Jenner, a country physician in Gloucestershire who had had an unpleasant time undergoing variolation as a child, spent many years tracking down this story and eventually recognized that only one of many diseases called cowpox actually conferred resistance. In 1798 he undertook the first human experiment in what is now called vaccination and successfully protected several children against the disease. Jenner coined the term vaccination as a derivative of the latin Vacca (cow) as cowpox virus was being used to grant protection.

This was the beginning of the end for smallpox as a human scourge, although serious and severe outbreaks continued until well into 20th Century. Jenners studies, although incomplete and small-scale, were accepted surprisingly quickly. There was opposition to the idea of vaccination as being against the will of God, and Jenner was accused of stealing old ideas. However, vaccination also gained powerful allies, such as Thomas Jefferson in the nascent United States. There were also missteps such as identifying the right strain of the cowpox virus and propagating it safely. As vaccination was made more effective and the vaccines became safer, it became widespread and the disease was first held in check and then counterattacked. As more was learned about the biology of the virus, a strategy to isolate and eliminate it was developed. Smallpox was declared extinct in the wild in May 1980.

In theory, that should have been the end of the story. Only two samples remained in highly secure storage and they were eventually to be destroyed. However, there were always doubts about having eliminated all stocks. Preventing cheating in biological weapons research is much harder than it sounds. Did some rogue nation have undisclosed samples? Rumors persist that some counties have sought or maintain samples. The real shock came when scientists began defecting from the massive biological weapons program in the Soviet Union Russia. The real cause for concern had really been the willingness of the Soviet Union to consider any weapon as a component of its arsenal. It had cheated continuously on the Biological and Toxin Weapons Convention of 1972 and had not only weaponized smallpox, it had sought to create newer extremely lethal variants by genetic engineering. In 1986, a doctrine for the use of smallpox as a follow-up to an all-out nuclear attack on the United States was signed by Soviet President Mikhail Gorbachev. Strangely enough, it was the Soviet Union that first demonstrated elimination of the disease on a large geographic scale and it had been one of the prime movers in the early days of the global eradication campaign.

When the Soviet Union collapsed, so did its otherwise sound security practices. Nuclear, biological, and chemical weapons storage sites were now guarded by soldiers who were not paid for months at a time and even doors and padlocks were not well maintained. A number of countries have tried to hire experienced Russian researchers in all of these fields and there is a real fear that emigrés may have taken samples of the virus with them.

Nightmare scenarios for the use of smallpox in terror attacks now abound. Every book and article on biological warfare seems to have its own as an indicator of its legitimacy. Whether it is used by a state actor, a terrorist group, or should spring from some unknown natural hiding place, it became the most devastating pathogen that we were not ready to combat. These scenarios, coupled with the changed world after the terrorist attcks on 11 September 2001, seem to have had a major effect. Many major countries are now acquiring smallpox vaccine and preparing plans for emergency vaccination in the vent of an attack. Such plans are more complicated than they were in the 1960's and 1970's. The vaccine, although not as dangerous as some claim, is not entirely safe. Some people may see complications and there are now a lot more people likely to adverse or lethal reactions. The immune compromised, notably AIDS victims, but also including transplant and chemotherapy patients, are much more likely to show adverse reactions. The debate on how to deal with a vaccination program in such a background is complex and continuing.

White Pox

"Whitepox virus" was the name given to four isolates alleged to derive from kidney tissues of animals captured in Africa in the early 1970s. The viruses were called "whitepox" because of the characteristic pocks formed on chorioallantoic membrane of embryonated chick eggs -- and were otherwise indistinguishable from variola virus, the cause of smallpox.

The isolates were determined to be laboratory contaminants.