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Although smallpox was eradicated some decades ago, this disease has again assumed importance since the events of 11 September 2001 and the following weeks of bioterrorism. It is not impossible that clinicians will face questions about this problem.
Smallpox was eradicated, because:
Variola (Lat: "spotted") major has been a scourge of humans since antiquity. The earliest evidence of the disease has been found on the skin lesions of Egyptian mummies from the 18th and 20th dynasties (1570-1085 BC). The first description of an epidemic is from a war between Egypt and the Hittite Kingdom (1350 BC). Smallpox has played an important role in the course of history. We need only think here of the dramatic role of the disease in the fall of Central American cultures after Cortez’s landing. Until the Spaniards arrived in 1518, there were 25 million inhabitants in Mexico. In 1620 this figure had fallen to 1.6 million. The native population was thus literally decimated.
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That people could contract smallpox only once has been known from ancient times. This knowledge encouraged people to inoculate healthy subjects with material from mild forms of smallpox. The material from a pustule or crust was introduced intradermally. This technique was known as variolation and it was encouraged in Europe in 1717 by Lady Mary Wortley Montague, wife of the English ambassador to the Ottoman Court in Istanbul. She had lost her younger brother to the disease in 1713. Two years later, when she was 26 years old, she contracted smallpox herself. She survived, but suffered permanent scarring to her face. She was impressed by the good results achieved by the Turks in fighting this disease. In 1718 she had her five-year old son successfully inoculated. Three months later the family returned to England. In 1721 she had her daughter inoculated in England. Afterwards they visited sick people, yet her child remained uninfected. The story quickly spread, reaching the ear of Princess Caroline, wife of the future King George II, who wished to have her children protected in this way as well. After six prisoners and eleven orphans were successfully inoculated, she allowed her two daughters to be variolated.
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The main side-effect of this technique was the occurrence of smallpox itself. However, the case-fatality in variolated persons was considerably lower than in people who contracted the natural infection. In the course of the 18th century, several doctors noted that milkmaids who had contracted cowpox never developed smallpox. This idea was used to infect people deliberately with cowpox in the hope of making them immune. Both Benjamin Jesty (1774) and Peter Plett (1791) used the technique ("vaccination"). The word vaccinae refers to the Latin "vacca": cow. Jesty and Plett were confronted with serious side-effects such as severe local inflammation of the hand and arm. The technique was therefore viewed with suspicion. Edward Jenner (1749-1823) was an apprentice of the renowned John Hunter in London. Jenner himself was variolated when he was eight years old. He later followed the same hypothesis. On 14 May 1796 he took matter from a cowpox lesion on the hand of the milkmaid Sarah Nelmes and injected the healthy 8-year-old boy James Phipps with it through two small incisions in the arm. Six weeks later he variolated the child (i.e. deliberately infected him with smallpox). The child did not become ill. After the Royal Society refused to publish the article about his findings, he financed the publication from his own pocket.
"An inquiry into the causes and effects of the variolae vaccinae, a disease discovered in some of the western counties of England, particularly Gloucestershire, and known by the name cowpox" was to be one of the most important scientific publications ever. In the text, he described 10 people who were vaccinated (i.e. inoculated with material from cowpox lesions) and 13 others who had had cowpox and in whom variolation was not successful. Jenner was attacked, not least by Woodville, a professional varioleur. Complications of vaccination sometimes occurred, probably from the use of unsterilised lancets (infected with smallpox in the variolation clinics). However, the idea of vaccination spread rapidly. In 1803 King Charles IV of Spain sent the vaccine to the New World and Asia by having 22 orphans taken on board a ship, two of whom in turn were vaccinated with material from two previous children. In this way they formed a transmission chain up to their arrival. In the course of the 20th century, the WHO adopted the plan to eradicate smallpox, initially by routine vaccination and subsequently by ring vaccination. The last case in Asia was in 1975 in Bangladesh. The last case in Europe occurred in 1972 in a Yugoslav in Germany. On 26th October 1977, Ali Maow Maalin, a man in the small Somalian village of Merka, was the last person on earth to develop smallpox following natural infection. There was a laboratory accident in 1978 in Birmingham in which the medical photographer Janet Parker died, but natural infections no longer occurred. In 1980, the WHO approved the ending of routine vaccination against smallpox, although some countries had already discontinued it (e.g. the USA in 1972). Since (1) no cases have been seen in humans for many years, (2) humans are the only host of variola virus and (3) the virus cannot survive for more than two days under natural conditions, smallpox is considered to be eradicated. Because immunity against smallpox decreases over time, it is assumed that at present almost everyone is susceptible to smallpox, certainly those born after 1980.*
Note: Biological weapons and Rebirth Island
Vozrozhdeniye Island, or "Rebirth Island" in English, is located in the Aral Sea, which divides the Central Asian countries of Uzbekistan and Kazakhstan. During the Soviet era, the island was an open-air testing site for the Soviet biological weapons program. From 1936 to 1991, field tests carried out on the island involved the release of "weaponized" pathogens: microorganisms specially developed by military scientists to be virulent, hardy, and antibiotic-resistant.
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Among the biological warfare agents tested on the island were special strains of Bacillus anthracis (the causative agent of anthrax), Yersinia pestis (plague), and Francisella tularensis (tularemia) that had been rendered resistant to multiple antibiotics and environmental stresses. It is likely that viral agents, including the smallpox virus, were also tested on the island. It is possible that a smallpox outbreak in 1971 has been caused by bioweapons tests in the Aral sea. This would be chilling evidence that smallpox could be succesfully aerosolized and transported by wind for several kilometers.
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The Red Army's Fifteenth Directorate, which ran the test site, operated a year-round command post in Aralsk, on the Kazakh mainland. All of the key facilities on the island, however, were located south of the Uzbek border. At the barracks and headquarters area, up to 800 scientists and troops were deployed at the peak testing periods from April to August.
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The Aral Sea was once the world's fourth largest inland body of water. During the Soviet testing program, deadly germs released experimentally were unable to escape from the island because a large expanse of open water separated it from the mainland. Beginning in the 1960s, however, the Soviet authorities diverted the sea's feeder-rivers into concrete irrigation canals, with the aim of growing large amounts of cotton. After a few successful harvests, the desert soil became exhausted, the rivers silted over, and desiccation and pesticide contamination turned the area into an environmental wasteland, with serious health consequences for the local populations. The diversion of the rivers has also caused the Aral Sea to shrink dramatically and ended the former isolation of Vozrozhdeniye Island. A land bridge has now formed from the Uzbek mainland, transforming the island into a peninsula.
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In 1988, after the Soviet BW program was supposedly shut down. Large quantities of anthrax spores had been produced at the military microbiology facility in Sverdlovsk and then stockpiled near Irkutsk. Because the volume of the anthrax material was too large to autoclave, it was shipped to Vozrozhdeniye Island for decontamination and burial. The anthrax spores were mixed with bleach in 250-liter stainless steel containers and then buried in 11 pits within a total area of less than a football field. Because the spores tended to clump together, some were protected from the bleach and remained viable in the soil.
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In 1992, Kanatjan Alibekov, a senior Soviet bioweapons scientist, defected to the United States and revealed that weaponized anthrax had been buried on Vozrozhdeniye Island. The U.S. intelligence community was able to determine the locations of the burial sites from historical satellite images taken while the pits were being dug. A Department of Defense team then traveled to the island and took soil samples, which revealed the presence of viable spores of weaponized anthrax.
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In the aftermath of the September 11 attacks, the U.S. government recognized the urgency of decontaminating the anthrax burial sites to eliminate the threat of terrorist access. Moreover, because oil companies are interested in drilling on the island for petroleum and natural gas, these activities could stir up contaminated dust that could blow across to the mainland. The current plan is to use a special decontamination solution to soak the anthrax-contaminated soil in situ. The soil will then be dug up and run through the solution again to make sure that all of the spores have been killed. The anthrax pits should have been be decontaminated by the end of 2002.
The virus was identified in 1907 by Paschen. It is a large, complex, double-stranded DNA virus (300 x 250 x 200 nm), sometimes described as brick-like or ovoid. There are at least two natural strains of variola virus. The most virulent strain causes variola major and the less virulent strain variola minor (= alastrim). The virus is transmitted from person to person by direct contact or the respiratory route. Contact with infected clothing, sheets, etc, can also result in infection. The infectious dose is very low. Only a few virus particles are sufficient to start an infection. The virus enters the oropharyngal and respiratory mucosa and proliferates in the regional lymph nodes, multiplying in particular in the reticulo-endothelial system. Ultimately it becomes localised in the small blood vessels of the skin and the mouth. Other organs are rarely involved (the brain sometimes). The skin lesions may become secondarily infected with pyogenic organisms. The pharynx and oral mucosa are infected before the rash appears. The virus is also found in tears and urine. Patients become highly contagious following the appearance of the rash and remain infectious for 7 to 10 days. Once crusting occurs, the contagiousness declines. Transmission mostly occurs to those in the patient’s immediate environment. One patient can cause 10 to 20 secondary cases in an immunologically naive population, although in the past, secondary cases were much less than these numbers. In view of the fact that the virus is sensitive to heat and moisture, natural epidemics tended to occur in winter and early spring.
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Infection of a non-immune individual results in very severe generalised disease with a typical pustular rash . In English-speaking countries, smallpox is the name commonly given to variola major. The "pox" was an earlier term referring to syphilis. The word "pox" comes from pock, a small pocket, referring to the pustules.
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The incubation period for smallpox is 12 to 14 days (range 7 to 17 days). This is followed by prodroma for 2 to 4 days. During this phase, the virus can be isolated from the blood. The patient develops a sudden fever (increasing up to 40°), severe headache, dorsolumbar pain and extreme malaise during the prodromal phase. Sometimes there is severe stomach pain, vomiting and delirium. Enanthema of the tongue, mouth and oropharynx precedes the skin rash (24 hours). Approximately two to three days after the beginning of the prodroma, a skin eruption appears. Typically, a centrifugal maculopapular rash occurs on the oropharynx, face and arms, and subsequently on the arms and legs. The lesions in the mouth ulcerate rapidly. There is often chemosis. The skin rash consists of atypical red spots (1-2 days), subsequently becoming vesicular (1-2 days) and then pustular (from day 3-7). The pustules persist for 5-8 days. The blisters have a diameter of 3 to 5 mm. They are round, taut and have a deep base. The density of the pustules is greater on the face than elsewhere. Hard papules can also occur on the palms of the hands and soles of the feet, but they do not become pustular. The skin lesions of smallpox are all at the same stage, in contrast to varicella. Crusts form after 8 to 9 days. Following recovery, there are permanent, somewhat sunken, crater-shaped scars ("pock-marked face") in 65-80% of survivors. Blindness occurs in 1% of smallpox infections. Cough is not predominant in smallpox, but the chance of respiratory complications such as pneumonia is increased in severe disease. Mortality from smallpox is 30%. Death occurs typically in the course of the second week. Variola minor (alastrim, "kaffir pox") follows a similar, but much milder clinical course. Mortality in alastrim is less than 1%.
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Approximately 3-10% of persons with smallpox develop a haemorrhagic or malignant variant. The haemorrhagic variant (purpura variolosa, black pox) is more common in women and has shorter, more intense prodromata, followed by generalised erythema and cutaneous and mucosal bleeding. It is almost uniformly fatal, with death occurring on day 5 or 6. The malignant form of smallpox has confluent, flat, non-pustular skin lesions, as a result of which the diagnosis is not immediately obvious. There can be evolution towards a generalised desquamation of the skin. Few people survive this form.
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Varioloid involves a benign, modified form of smallpox in people with partial protection from vaccination. Smallpox without eruption can occur in previously vaccinated contact persons or in children who still have maternal antibodies. Once smallpox has been contracted, there is immunity for life.
The clinical presentation of smallpox was usually typical. In view of the fact that smallpox is now eradicated, other diagnoses must be considered in the event of pox-like lesions, such as cowpox atypical herpes, varicella and monkeypox, but also measles, drug rash such as erythema multiforme exsudativum, generalised molluscum contagiosum in HIV patients and secondary syphilis. With black pox, various viral haemorrhagic fevers must be considered in the differential diagnosis.
The diagnosis can be made clinically while skin lesions are still present. Confirmation can be obtained by electron microscopy, immunohistochemistry or PCR of blood samples. Serology is less useful. Viral particles, known as Guarnieri bodies, can be found in the cytoplasm of infected cells by light microscopy. The virus is found in blood, saliva and serous exudates. Smallpox can be cultured in embryonated chicken eggs. The origin of the virus may be traced by genome analysis of the virus. The so-called India-1 strain of variola major was used to produce large quantities of biological weapons. Tests may only be conducted in specially protected laboratories, known as "Biosafety Level 4" labs (BSL-4). Vaccinia and variola viruses can be distinguished by PCR, monoclonal antibodies, ELISA and RIA.
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Electron microscopic diagnosis is uniquely suited for rapid identification of infectious agents. A specimen can be ready for examination and an experienced virologist or technologist can identify, by electron microscopy, a viral pathogen morphologically within 10 minutes of arrival in the electron microscopy laboratory. The distinct morphology of members of different viral families usually allows an agent to be assigned to a particular family. This morpho-diagnosis, combined with clinical information is, in most cases, sufficient to permit a provisional diagnosis or rule out a more serious infection and to initiate treatment and containment protocols without waiting for other test results. Because electron microscopy is not suitable for screening large numbers of samples, many immunologic and molecular methods have been developed on the basis of nucleic acid amplification techniques. While immunologic tests have almost unlimited throughput, the high specificity of these assays may result in failure to identify etiologic agents with different antigenic determinants. Diagnostic electron microscopy has two advantages over enzyme-linked immunosorbent assay and nucleic acid amplification tests. After a simple and fast negative stain preparation, the undirected, "open view" of electron microscopy allows rapid morphologic identification and differential diagnosis of different agents contained in the specimen. Electron microscopy can be applied to many body samples and can also hasten routine cell culture diagnosis. To exploit the potential of diagnostic electron microscopy fully, it should be quality controlled and be coordinated and run in parallel with other diagnostic techniques.
Isolation of people with smallpox is essential. They are best accommodated in a room under negative pressure equipped with HEPA filters ("high-efficiency particulate filters"). All health workers should be protected against contact and airborne transmission and all should be successfully vaccinated. During epidemics, patients may have to be isolated at home. Treatment in the first place is symptomatic. Bacterial superinfection should be controlled with penicillinase-resistant antibiotics. Eye care, adequate hydration and nutrition are important. It is doubtful whether the use of hyperimmune globulins from vaccinated persons reduces the severity of smallpox. At present no-one has any up-to-date experience with such situations and the number of available doses is very limited. The prophylactic administration of immunoglobulins is of dubious benefit. In vitro, cidofovir (Vistide®) is active against variola virus, but its clinical relevance is unclear. Vistide® must be given IV and has a limited bioavailability. A derivative that can be taken orally is HDP-CDV (hexadecyloxypropyl-cidofovir). Once the cell membrane has been crossed, the fatty portion of the molecule is enzymatically removed within the cell and the cidofovir released can exert its antiviral action. The antiviral activity of HDP-CDV is 100 times greater than that of cidofovir itself. Methisazone is another antiviral agent that has been reported in this context, but experience is lacking.
Prevention of smallpox rests on two pillars: vaccination and isolation. There is a live vaccine based on vaccinia virus. This virus causes cross-immunity against variola. The mean duration of protection provided by vaccination is not known. Some sources estimate it to be about ten years, others think that protection lasts lifelong. Post-exposure vaccination can prevent the disease or limit its severity. The vaccine should be given as rapidly as possible to contact persons. The earlier it is given, the more effective it is. Administration up to 4 days after exposure is still useful. Healthy contact persons are not contagious but should be placed under surveillance. Quarantine for 17 days is imperative. Patients should be securely isolated if they develop fever. Naturally contact persons are vaccinated as rapidly as possible. The vaccine is administered by means of a bifurcated needle that is dipped in the reconstituted vaccine. Fifteen pricks should be made with the needle in the dermis of the deltoid region over an area of 5 mm diameter. A small amount of blood should appear at the vaccination site within 20-25 seconds. After 6-8 days a greyish-white pustule with a diameter of 1 to 2 cm develops if the vaccination is successful. This pustule exhibits central umbilication and is referred to as a "Jennerian pustule" or a "major reaction". Central crusting occurs subsequently, extending to the periphery over the course of 3 to 5 days. Local oedema and a darker crust remain present for up to three weeks after the vaccination. Successful revaccination is seen in the form of a palpable inflammation 6 to 8 days after vaccination. Other local reactions are referred to as "dubious" and require revaccination.
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There have been previous proposals to use smallpox as a biological weapon. In a letter in 1763, Sir Jeffrey Amherst, head of the British armed forces in North America, wrote the suggestion to rub crusts of smallpox pustules in blankets and then distribute them among the local Ottawa Indians. There are at present officially only two places on earth where batches of virulent virus are still kept: one at the CDC, USA and one in Russia, since 1994, in the Vector Institute, Novosibirsk. Although there has been repeated international pressure to destroy these batches, their destruction to date has always been put off for various reasons. Whether batches of variola virus resulting from the Russian biological war programme active during the Cold War may have found their way to third parties is unknown. The possibility that smallpox might be used for bioterrorism is now being taken seriously. Until recently it was difficult to obtain vaccine. After 11 September 2001 many countries decided to increase their stocks of strategic smallpox vaccine. If there would be insufficient vaccine, it is possible to vaccinate with diluted vaccine (dilution to 1/10). In one study, this showed comparable success (97%) to the undiluted vaccine. As a vaccination strategy, ring vaccination (vaccinating contact persons) or routine vaccination (mass vaccination) may be used.
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In December 2002, it was decided that 500,000 US military personnel would be vaccinated against smallpox with vaccinia (vaccine: Dryvax). There will be a voluntary campaign to be completed by the summer of 2003, among a similar number of health care workers or first responders (those at the highest risk of coming into contact with the virus in case of a bioterrrism attack). Due to uncertainty and suspicion of side-effects (cardiac and other), only about 30.000 civilian personel was vaccinated by late August 2003. The US government considers offering the vaccine to up to 10 million additional health care workers, police, firefighters and other personnel deemed essential.
The origin of vaccinia virus is unclear. Vaccinia virus can infect a number of species of animals, in contrast to variola virus which only occurs (occurred) in humans. It is assumed that vaccinia virus derived from the virus that causes cowpox and, following repeated transmission from person to person over the course of the last few centuries, developed its own character. Possibly a recombination event with variola virus occurred in earlier times. Vaccinia virus cannot mutate back to variola virus. Vaccinia virus causes cross-protection against smallpox, alastrim and monkeypox. There are at present several different vaccinia strains: the Elstree strain (Lister Institute), the EM63 strain (Moscow Research Institute of Virus Propagation) and an American strain (New York Board of Health). Two new attenuated vaccine strains have been developed and tested: "Modified Vaccinia Ankara" (MVA) and a Japanese strain (LC16m8). Their efficacy is not known. MVA is being studied as a vector for immunisation against other diseases.
The vaccinia "seed virus" can be inoculated in the skin of healthy BSE-free calves. After harvesting of the virus and bacterial decontamination, it is stored in liquid form or freeze-dried. Currently, vaccine virus can be prepared on cell culture. As a WHO standard, the vaccine must produce a marked reaction in 95% of primary vaccinees and in 90% of people vaccinated more than ten years previously. This means that after 6 to 8 days a pustular lesion develops with a central crust or ulcer and surrounding erythema or induration. Vaccination leaves a slight sunken scar. Revaccination results in a local reaction more rapidly and tends to leave no scar. The vaccine must contain at least 108 "pock-forming units" per ml. The vaccination is given in the skin of deltoid region. A forked needle is used, dipped in the vaccine solution. The needle is held perpendicularly to the skin and pricked 5 to 15 times into the skin (15 times for revaccination). A trace of blood should become visible. If a large amount of blood escapes from the vaccination site initially, there is the risk that the vaccine is actually mechanically rinsed away (more chance of failure of the vaccine). Afterwards, the vaccination site is covered with a bandage to prevent dispersion to other parts of the body. Vaccination results in local proliferation of the virus in the skin. No viraemia occurs. Local lymphadenopathy may appear. Protection following vaccination which lead to a pustular reaction is almost 100%. Subjects who do not have a local reaction after vaccination should be revaccinated.
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Smallpox Vaccine, Dried, Calf Lymph Type (Dryvax®), is a live-virus preparation of vaccinia virus prepared from calf lymph. The calf lymph is purified, concentrated, and dried by lyophilization. During processing, polymyxin B sulfate, dihydrostreptomycin sulfate, chlortetracycline hydrochloride, and neomycin sulfate are added, and trace amounts of these antibiotics may be present in the final product. The reconstituted vaccine, which contains approximately 100 million infectious vaccinia viruses per ml, is intended only for multiple-puncture use, ie, administration of the vaccine into the superficial layers of the skin using a bifurcated needle.
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Introduction of potent smallpox vaccine containing infectious vaccinia viruses into the superficial layers of the skin results in viral multiplication, immunological reaction and cellular hypersensitivity. With the primary vaccination, a papule appears at the site of vaccination on about the 2nd to 5th day. This becomes a vesicle on the 5th or 6th day, which becomes pustular, umbilicated, and surrounded by erythema and induration. The maximal area of erythema is attained between the 8th and 12th day following vaccination (usually the 10th). The erythema and swelling then subside, and a crust forms which comes off about the 14th to 21st day. At the height of the primary reaction known as the Jennerian response, there is usually regional lymphadenopathy and there may be systemic manifestations of fever and malaise.
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Contraindications for Routine Non-Emergency Vaccine Use.
Primary vaccination and revaccination with smallpox vaccine are contraindicated:
(1) Vaccination with vaccinia virus can sometimes cause complications, such as local pain and swelling, regional lymphadenopathy, urticaria and mild fever. Sometimes a generalised vaccinia infection can occur. (2) Vaccinia necrosum can occur in immunodeficient people and takes the form of local skin necrosis, followed by metastatic lesions elsewhere on the skin. There is no lymphadenopathy in this complication. Eczema sufferers are unusually susceptible to two viruses: herpes simplex and vaccinia. Both viruses can cause a similar clinical presentation: (3) Kaposi's varicelliform eruption. (4) Eczema vaccinatum is a rare complication of smallpox vaccination. It develops in patients with a history of eczema who are given the vaccine or who are in close contact with vaccinated subjects. (5) Post-vaccination encephalitis occurs with a frequency of 1/300,000 typically about 8 to 15 days after vaccination. Symptoms include headache, delirium, coma, convulsions and paralysis. Mortality from this complication is 25%. Vaccinia virus cannot be isolated from the brain of these individuals. (6) Transverse myelitis following vaccination is rare. (7) Mortality following primary vaccination is 1/1,000,000 and after revaccination 1/4,000,000. Severe complications occur in approximately 1/100,000 vaccinees. Eczema, neoplasia, immunodepression and pregnancy increase the risk. It is suspected that patients with HIV-AIDS will pose more problems, but no one has any experience here (smallpox officially declared eradicated in 1980, AIDS was only recognised some years later).
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In 1950, the US pediatrician Henry Kempe pioneered what is still the first line of defence for vaccine-induced disease: vaccinia immune globulin (VIG), a product made from the blood plasma of recently vaccinated people, which is high in antibodies against vaccinia. Only 700 doses were available at the end of 2002, but this cache is being supplemented with new VIG, produced by Cangene, a company in Winnipeg, Canada and Dynport, a military contractor in Frederick, Maryland, USA. Severe complications are treated with vaccinia immune globulins, 0.6 ml/kg IM in divided doses, repeated after two to three days if necessary (1 ml = 500 IU). Risk patients who nevertheless have to be vaccinated can receive the vaccine and immune globulins at the same time (20 IU). Hyperimmune globulins, however, are very difficult to obtain (CDC). Administration of immune globulins does not reduce the efficacy of the vaccine. No controlled clinical trials of VIG's efficacy were performed, but previous studies suggested that VIG worked well and reduced the death rate from eczema vaccinatum, an occasionally fatal complication of vaccination in eczema patients, by as much as 70%. It also seemed beneficial in severe cases of generalised vaccinia, a pock-like rash that covers the body. It rarely helped in progressive vaccinia and was useless against vaccinia-related encephalitis. The recommended dose is 0,6 ml of VIG per kilogram of body weight and -absent improvement- ratcheting up to as much as 10 ml per kilogram.
