Goodrich J. Smallpox. J Burns [serial online] 2003;2(1):5. Available from: URL: http://www.journalofburns.com

Published February 1, 2003

There has been resurgence in interest in smallpox due to its possible use as a biowarfare agent. This review addresses some clinical issues with special focus on the rash as a prognosticating tool in smallpox patients. Information about vaccine residual immunity and antivirals are included.

Introduction

World events have increased interest in biological agents as possible terrorist weapons. Smallpox has been mentioned as a possible agent for use in a terrorist attack. The last naturally occurring smallpox case was seen in Somalia in October 1977. Since that time there has been one unintentional release of smallpox virus that occurred in a laboratory accident in Birmingham England in 1978. In May 1980, the World Health Organization certified the world free of naturally occurring smallpox. In the United States, recommendations for routine smallpox vaccination ended in 1971. In 1976 routine smallpox vaccinations of health-care workers were discontinued. In 1982, the only licensed producer of vaccinia virus in the United States discontinued production and distribution to the civilian population. All military personnel continued to be vaccinated until 1990. Since that time, only a select population has been vaccinated. Those include people working with vaccinia, monkeypox, and health-care workers involved in clinical trials using recombinant vaccinia vectors. More recently, vaccinia trials have taken place to determine the viability of the vaccine and effective dose for restoring immunity.

Virology

Figure 1. Vaccinia virus



There are eight recognized genera of vertebrate poxviruses. Several of these orthopoxviruses infect humans including variola, monkeypox, cowpox, and vaccinia sub species buffalopox virus. In addition, humans may become infected with pseudocowpox, Orf, Seal parapoxvirus Tanapox, Yabapox, and molluscum contagiosum virus. The disease caused by these viruses may vary from single or multiple localized skin lesions after contact with infected animals, insects, or exposure to fomites to systemic disease after respiratory tract infection. The poxviruses are brick shaped and enveloped. The virions are larger than those of other animal viruses. Poxviruses are the only animal viruses that can be seen by light microscopy. They carry double-stranded DNA and replicate in the cytoplasm of cells. These viruses also have the largest DNA genome that very from 130 to 230 kbp. Complete genome sequences have been reported for vaccinia, variola, and molluscum contagiosum virus.¹

History

Smallpox was a disease that caused epidemics throughout human history and is well described due to its characteristic clinical presentation. It is possible smallpox was present in ancient Egypt dating from 1200 to 1100 BC. Mummies with dome shaped vesicles in the epidermis similar to smallpox suggest the disease was present. Definitive

Fig. 2. Pan-Chen, the god prayed to for black smallpox. Note pox on face.



descriptions of smallpox were recorded in 4th and 7th century China and India, respectively. Smallpox may have been introduced into France and Italy as early as 580 AD. Intranasal variolation in China was described in 910 AD. Most regions of the world described smallpox epidemics. The initial introduction of smallpox into a non-immune population resulted in high mortality rates. For example, an epidemic occurred in the village of Mine, a small island near Japan in 1795. There were 1200 cases of smallpox out of a population of 1400 people with a case mortality rate of 38.3 %. The first epidemic in Iceland in 1241 killed 20,000 of the total population of 70,000 and was followed by other epidemics in 1257 and 1291. By the 15th century, smallpox had become endemic in much of Europe. The first occurrence of smallpox in the Western Hemisphere occurred in 1507 after being imported from Spain. Smallpox spread to islands in the Caribbean including Cuba and Puerto Rico where much of the native population died. Settlers from France, the Netherlands, and Great Britain later imported smallpox into North America. The first epidemic occurred in 1617 to 1619 and killed many of the Indians. This epidemic pattern was seen across North America. It was reported in 1738 that smallpox killed half of the Cherokee tribe. Some of the 18th-century epidemics among the Native Americans appeared to been initiated by deliberate action. Sir Jeffrey Amherst, the Commander-in-Chief of British forces in North America wrote to an officer in 1763 during the Pontiac rebellion and wondered if smallpox could be used to reduce the number of Indians. The plan was to inoculate blankets with smallpox and trade with the Indians.

However, the settlers were not spared. Smallpox was usually imported on ships from Great Britain or later, African slave ships. There were numerous epidemics along the Eastern seaboard. Quarantine and isolation were practiced. In 1721, variolation was introduced into the colonies followed by the introduction of vaccination sometime after 1799. Of note, in 1863 Abraham Lincoln was diagnosed with smallpox when the characteristic rash appeared 2 days after giving his Gettysburg address.²

Clinical features

In India and China, it was noted there were different types of smallpox. Smallpox (variola major) was considered a disease with a high mortality rate. In 1904, a mild smallpox-like disease was described in South Africa. This was consequently termed variola minor. It was distinguished from variola major by a mortality rate of around 1 percent. Variola minor will not be discussed further as it would be unlikely to be used in a bioterrorist attack. Variola major could be distinguished also by differences in prognosis and transmissibility. The most important clinical prognostic sign in unvaccinated subjects was the rash. The mortality rate from ordinary smallpox depended on the confluence and the type of the rash (Table 1). Mortality rates could vary from 9 to 100%.^2,3

Incubation period.

The incubation period, as defined from infection to fever onset ranged from 7 to 19 days. The majority of cases became clinically apparent between 10 to 14 days with a median of 12 days.

Pre-eruptive stage.

Figure 3. Smallpox enanthem


There was sudden onset of fever and malaise with temperatures between 38.5 ⁰C to 40.5 ⁰C. Patients complained of a severe headache and backache (Table 2). Vomiting and abdominal colic occurred sometimes and was mistaken for appendicitis. During this time the patient appeared toxic. The fever would decrease by the 2nd, 3rd or 4th day and the patient would feel better. This would herald the onset of the eruptive stage.

Eruptive stage.

Lesions on mucous membranes were the first to appear (enanthem). These were tiny red lesions found on the oropharynx that evolved rapidly from macules followed by papules and then vesicles. The lesions were most prominent on the hard palate, tips and edges of the tongue, and the tonsillar pillars. These lesions would appear about 24 hours prior to the onset of skin rash. They would break down and discharge virus into the oropharynx.
The rash appeared usually 2 to 4 days after the onset of fever as a few macules on the face with a predilection for the forehead (herald spots). Lesions would appear on the proximal extremities followed by the trunk and lastly, the distal portions of the extremities. This is termed centrifugal spread and would evolve rapidly.

Figure 4. Herald spots on the forehead.


In a certain portion of the body, all lesions would be at the same stage although this was not absolute. By day 2, the macules had evolved into what appeared to be papules. Histopathology showed these were early vesicles. By the fourth or fifth day after the appearance of rash, most lesions were vesicular. All the skin lesions were pustular by about the 7th day after appearance of the rash, the lesions would reach their maximum size by day 10. This would be followed by resolution with formation of a scab or a crust. The scab would heal leaving a hypopigmented area after 22 to 27 days. Lesions would persist on the palms of the hands and the soles of the feet after scabbing had occurred elsewhere.

Smallpox rash could be divided into ordinary, modified, variola sine eruptione, flat, and hemorrhagic type. As mentioned previously, the severity of ordinary type smallpox depended on the confluence of the rash. The closer together the lesions more likely death would result. (Table 1). Discrete ordinary smallpox had a mortality rate of 9.3 percent while semiconfluent and confluent smallpox rash (Figure 6) had a mortality rate of 37 and 62 percent, respectively.

Modified type rashes were seen in patients with partial immunity from previous vaccination. The course was rapid but relatively benign. In these patients, little toxemia was seen.

Variola sine eruptione was an interesting phenomenon in which patients would have fever but not rash. Serological confirmation was required to make this diagnosis.
Unlike ordinary smallpox with its vesicles, flat type smallpox was named because the lesions remained flat to the skin. Flat type rash represented approximately 7 percent of smallpox cases and was predominantly seen in children with immune defects. Most cases were fatal (Table 1, Figure 7).

Hemorrhagic type smallpox was divided into early and late. Early hemorrhagic type smallpox presented with hemorrhages into the skin and mucous membranes. Subconjunctival hemorrhages were common and could be accompanied by bleeding from the gums, hematemesis, hemoptysis, hematuria, and epistaxis. Vaginal bleeding would also be present. Hemorrhagic type smallpox occurred in adults and was found in both vaccinated and unvaccinated populations. Pregnant women were especially susceptible. Most cases of hemorrhagic type smallpox were fatal (Table 1, Figure 8).

After the fever had decreased on day 2 or 3, it usually rose again by the 7th or eighth day until scabs had formed. Pyogenic infections of the skin were common. Respiratory complications developed seven-day days after onset of fever and were viral or bacterial. In ordinary type smallpox, death occurred between the 10th and 16 days after onset of the rash.

Complications.

Many different organ systems were affected by smallpox. Most complications were due to either direct viral invasion or secondary bacterial infection (Table 3).

Differential diagnosis.

Early in the disease, accurate diagnosis of smallpox on clinical grounds may be difficult. The clinical diagnosis is based on the characteristic fever, appearance of rash, evolution of the lesions, and lesions on the same part of the body at the same stage. However, the differential diagnosis of smallpox is the same as those diseases causing fever and rash (Table 4). They include monkeypox, chickenpox, measles, syphilis, erythema multiforme, drug eruptions, and Coxsackievirus. Hemorrhagic type smallpox was usually misdiagnosed as meningococcal bacteremia or acute leukemia. By far the most common misdiagnosis is chickenpox (Table 5, Figure 9,10).^2,4

Laboratory Diagnosis.

Laboratory confirmation of smallpox is important. Someone who has been vaccinated should collect all specimens. It may be necessary to open lesions with the point edge of the scalpel. The fluid can be harvested on a cotton swab or scabs can be picked off with forceps. Specimens should be deposited in a sealed container (vacutainer, screw top tube, etc) and taped shut. The tube should be put in another watertight container and sent to the appropriate state or federal laboratory.⁵ Laboratory examination requires a BL-4 facility. Smallpox can be confirmed by electron microscopy. Definitive identification requires growth in tissue culture, chorioallantoic egg membranes, or PCR. However, a pustular lesion could be tested for VZV and HSV using direct fluorescent antibody tests. Both of these tests have high sensitivity and specificity for their respective viruses. A lesion that is negative for both viruses in the appropriate clinical setting should further raise the suspicion for smallpox.

Postexposure infection control.

As soon as the diagnosis of smallpox is made, all suspected patients, household contacts, and other face-to-face contacts should be vaccinated. If possible, patients and contacts should be isolated in the home. Vaccination appears to be effective within the first three to 4 days after exposure. It provides some protection against infection and provides significant protection against death. People should be vaccinated regardless of previous vaccination history.

Hospital transmission of smallpox has been recognized for several hundred years. It has been recommended that all hospital workers be vaccinated during an outbreak. For those who cannot receive the vaccine, vaccine immunoglobulin can be given. Transmission occurs by droplets and by aerosol. In a small outbreak, patients admitted to the hospital should be confined to negative pressure rooms equipped with high-efficiency particulate air filtration. All laundry and waste should be placed in biohazard bags and autoclaved.⁵

Vaccination and Immunity.

Vaccination has proven to be an effective means of protection from smallpox. In the United States, Dryvax , a live virus preparation of vaccinia virus is licensed for use.⁶ Vaccine trials have shown the viability of the vaccinia virus.^7,8 The vaccine preparation could be diluted as much as 1 to 10 and still retain a high rate of conversion. Current plans would be not to dilute the vaccine more than 1 to 5. Recently, the pharmaceutical company Aventis-Pasteur, has donated to the U.S. government 70 to 90 million doses of vaccine. Human trials have shown the preparation to be effective. Recently, the Advisory Committee on Immunization Practices (ACIP) has decided not to recommend a mass vaccination of U.S. citizens. However, it has been recommended to vaccinate first responders. In the case of a terrorist attack, the recommendation has been a ring vaccination strategy. Controversy exists on whether this would provide adequate protection for the US population and centers around projections about what the secondary attack rate may be in a planned biological attack. Some factors influencing the secondary attack rate could include the amount of residual vaccine immunity in the population, climate, population infected, and transmissibility and virulence of the smallpox strain. A weaponized smallpox strain would be selected presumably for its ability to be transmitted more readily in an at risk population making models using secondary attack rates based on natural infection data problematic.

An important question about residual immunity in vaccine recipients remains. Some older data suggest that the effects of vaccination may last for several decades (Table 6, 7). In a 1902 outbreak described by Fenner et al., there appeared to be a profound protective effect in subjects vaccinated despite the passage of several decades.² Similar effects were described by Mack et al.⁹ Unfortunately, these data are difficult to interpret secondary to intercurrent smallpox infection in the populations studied.^9,10 Other data have demonstrated in vitro that vaccinia –specific CD8+ CTL may be recovered from vaccine recipients after several decades.¹¹ A recent study looked at residual vaccine immunity in laboratory workers that had been vaccinated at different time periods (Figure 11). The investigators looked for vaccinia specific CD8+ CTL and found measurable responses in workers who had been vaccinated > 35 years ago.¹² Whether workers were exposed to vaccinia in the laboratory was not mentioned.

Antiviral treatment.

Antiviral therapy is limited. Vaccinia immune globulin (VIG) is available through the CDC but is reserved presently for vaccine induced disease. There have been several compounds that have shown promising activity both in vitro and in vivo for inhibiting smallpox virus. Ribavirin has been shown in vitro to inhibit variola major.¹³ More recently, cidofovir has shown both in vitro and in vivo activity against smallpox virus.^13,14 An oral analogue is being developed. Cidofovir has a long intracellular half-life but has been shown to be toxic to the renal tubules. It is necessary to give probenecid and hydrate the patient prior to giving the drug.

Summary

The clinical course of natural smallpox virus infection has been well-characterized.² Much is owed to the previous generation of physicians and scientist who helped eradicate this disease over two decades ago. Whether most of the lessons learned about natural smallpox disease would apply if weaponized smallpox virus were intentionally released into a susceptible population remains unanswered. Hopefully, these questions will never need to be answered.

Table 1
Clinical classification of variola major and mortality based on rash^2,3

 

Excerpted from: Fenner F, Henderson DA, Arita I, Jezek A, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988:1-68. (Accessed August 9, 2002, at http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.)

Figure 5. Ordinary type- discrete smallpox rash. See Table 1 (above).


http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html

Figure 6. Ordinary type –Confluent smallpox

http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html

Figure 7. Flat type smallpox rash.

http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html

Figure 8. Late hemorrhagic smallpox.

http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html

Table 2.
Frequency of symptoms in the pre-eruptive phase of variola major^2,3

 

Excerpted from: Fenner F, Henderson DA, Arita I, Jezek A, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988:1-68. (Accessed August 9, 2002, at http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.)


Table 3.
Complication of smallpox²

 

Excerpted from: Fenner F, Henderson DA, Arita I, Jezek A, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988:1-68. (Accessed August 9, 2002, at http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.)


Table 4.
Differential diagnosis of fever and rash: Causes of papulovesicular and maculovesicular eruptions.⁴

 

Table 5.
Differential diagnosis of chickenpox and smallpox

 

Figure 9. Smallpox                      Figure 10. Chickenpox

Table 6.
Residual vaccine immunity: 1902-1903 Outbreak²

 

Excerpted from: Fenner F, Henderson DA, Arita I, Jezek A, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization, 1988:1-68. (Accessed August 9, 2002, at http://www.who.int/emc/diseases/smallpox/Smallpoxeradication.html.)


Table 7.
Vaccine residual immunity: Secondary attack rates in vaccinated and unvaccinated subjects in West Pakistan⁹

 

Figure 11. Residual vaccine immunity in laboratory workers¹²

References

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2. Fenner F, Henderson D, Arita I, Jezek Z, Ladnyi I. Smallpox and it eradication. Geneva: World Health Organization; 1988.
3. Rao A. Smallpox. Bombay: Kithari; 1972.
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