Variola virus infection is initiated when the virus comes into contact with the oropharyngeal or respiratory mucosa of a susceptible person.

Smallpox | causes, symptoms and management

Smallpox is caused by variola viruses, which are large, enveloped, single-stranded DNA viruses of the Poxvirus family and the Orthopoxvirus genus.  Variola major strains cause three forms of disease (ordinary, flat type, and hemorrhagic), whereas variola minor strains cause a less severe form of smallpox. Vaccination with vaccinia virus, another member of the Orthopoxvirus genus, protects humans against smallpox because of the high antibody cross-neutralization between orthopoxviruses

Smallpox is caused by variola viruses, which are large, enveloped, single-stranded DNA viruses of the Poxvirus family and the Orthopoxvirus genus.
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Smallpox as a Biological Weapon 

Smallpox is considered one of the most serious bioterrorist threats. It was used as a biological weapon during the French and Indian Wars, (1754 to 1767) when British soldiers distributed smallpox-infected blankets to American Indians. In the 1980s, the Soviet Union developed variola as an aerosol biological weapon and produced tons of virus-laden material annually intended for intercontinental ballistic missiles.

Several factors contribute to the concern about the use of smallpox as a biological weapon:
• Variola can spread from person to person.
• There is no widely available or licensed treatment for the disease.
• It has a high fatality rate.
• Most of the world’s population has never been vaccinated or was vaccinated so long ago that immunity to smallpox has waned.
• Variola is relatively stable as an aerosol.
• The infectious dose is small. 

Because there are no symptoms at the time of exposure, a covert release of variola may not be detected until sick people begin showing up at doctor’s offices and hospitals


Variola virus infection is initiated when the virus comes into contact with the oropharyngeal or respiratory mucosa of a susceptible person. The virus then multiplies in regional lymph nodes. An asymptomatic viremia develops 3 or 4 days after infection, which is followed by further virus replication, probably in the bone marrow, spleen, and lymphatics. 

A second viremia begins about 8–10 days after infection and is followed by the first symptoms of illness (prodromal stage), fever and toxemia. The virus localizes in small blood vessels of the dermis and in the oral and pharyngeal mucosa. In the skin, this results in the characteristic maculopapular rash, which evolves into vesicles, then pustules.


Differential diagnosis

Although there are other causes of generalized rash illness which present as vesicles and pustules, the severe prodrome along with the nature of the rash and its evolution distinguishes smallpox from other diseases. The diseases, which can look similar to smallpox, include: varicella, disseminated herpes simplex, disseminated herpes zoster, impetigo, drug eruptions, contact dermatitis, erythema multiforme, enterovirus, scabies, molluscum contagiosum, and monkeypox.


The clinical case definition for smallpox is: an illness with an acute onset of fever of 101°F or higher followed by a rash characterized by firm, deep seated vesicles or pustules in the same stage of development on any body part, without other apparent cause. Laboratory diagnosis is aided by a negative result on one of the rapid diagnostic tests for varicella (i.e., DFA, electron microscopy, and PCR). 

Laboratory diagnosis of smallpox can be made by PCR, culture of vesicular or pustular fluid, or culture of the scab; it should only be performed by the LAC Public Health Laboratory, California Viral and Rickettsial Diseases Laboratory, and Centers for Disease Control and Prevention (CDC). (After appropriate consultation to ensure safe packaging and handling, specimens can be sent to the local public health laboratory for forwarding to the state laboratory and then to CDC.)

Electron microscopy of vesicular or pustular fluid, or of the scab, as well as acute and convalescent serologic testing through CDC, can also be performed for diagnosis.


Usually 10-14 days (range 7-19 days). 


Officially, only in designated laboratory repositories in USA and Russia. Humans are the only natural host. Naturally occurring smallpox no longer exists, although the threat of smallpox release remains due to concerns that variola virus might exist outside the two official repositories.

Macules, papules, vesicles, pustules, and scabs of the skin and lesions in mouth and pharynx.


The smallpox virus must be continuously transmitted from human to human to survive; humans do not become long–term carriers and animal reservoirs do not exist. Virus is spread by direct contact or inhalation of aerosols; infectious virus is present in oronasal secretions and in scabs from the skin. (The virus in scabs may be tightly bound and spread by this method may be less efficient.) Close contact is usually required for efficient virus transmission; therefore, smallpox mainly spreads to household members and others in close contact. Variola viruses can also be transmitted by individuals who maintain the virus in the throat without clinical signs. 

The potential for long–distance aerosol spread is controversial but has been demonstrated under certain conditions such as in hospitals. Transmission on fomites such as contaminated clothing or bedclothes is possible for short periods of time; however, variola does not remain viable for more than 2 days outside a human host. It is sensitive to heat and humidity; most natural epidemics occurred in the winter and spring.


Most significantly, the rash of smallpox is preceded by a prodrome consisting of 1 to 4 days of high fever, malaise, head and body aches, prostration; sometimes nausea, vomiting, abdominal pain, and backache. In 90% of cases, smallpox (variola major) presents as an acute infectious disease characterized by a maculopapular rash (usually starts as small red spots on the tongue and in the mouth), which becomes vesicular on day 3 or 4, then slowly evolves into pustular lesions, deeply embedded into the dermis, by day 6. 

Fourteen days after the initial appearance of the rash, most of the lesions have developed scabs. The rash in smallpox usually appears as a single crop with all lesions progressing from the macular to the pustular stage at about the same time.

The mortality rate for smallpox may be as high as 30% in unvaccinated persons and 3% in those with a history of vaccination sometime in the past. (Patients with variola minor have similar signs and symptoms but the disease is less severe and the mortality rate is only about 1%.)
 In a minority of instances, smallpox can present as “flat type” smallpox where lesions remain flush with the skin, never becoming elevated even during the pustular stage. This type of presentation is seen in 5% to 10% of cases and results in very severe disease. 

Another severe form of smallpox is “hemorrhagic smallpox” which involves extensive bleeding into the skin and almost always results in death. This form of disease, which can be seen in less than 3% of cases, can easily be mistaken for meningococcal sepsis.
Milder disease with a less severe prodrome and a more rapid evolution of lesions can be seen in previously vaccinated individuals.


The management of confirmed or suspected cases of smallpox consists of supportive care, with careful attention to electrolyte and volume status, and ventilatory and hemodynamic support.  General supportive measures include ensuring adequate fluid intake (difficult because of the enanthem), alleviation of pain and fever, and keeping skin lesions clean to prevent bacterial superinfection. Currently there are no FDA approved antiviral agents with proven activity against smallpox in humans. 

Antiviral agents that have shown some activity in vitro against poxviruses may be available from the CDC under an investigational protocol. ST-246 is a novel agent that is currently undergoing safety and efficacy testing. Additionally, cidofovir, a nucleoside analogue DNA polymerase inhibitor, might be useful if administered within 1-2 days after exposure; however, there is no evidence that it would be more effective than vaccination, and it has to be administered intravenously and causes renal toxicity.


Postexposure prophylaxis 

Postexposure prophylaxis for smallpox is the administration of vaccinia vaccine after suspected exposure to smallpox has occurred but before symptoms are present. Immunity generally develops within 8 to 11 days after vaccination with vaccinia virus.  Because the incubation period for smallpox averages about 12 days, vaccination within 4 days may confer some immunity to exposed persons and reduce the likelihood of a fatal outcome.  

Postexposure vaccination may be particularly important for those vaccinated in the past, provided that revaccination is able to boost the anamnestic immune response.  In addition to vaccination, exposed persons should be monitored for symptoms. Temperature should be checked once a day, preferably in evening, for 17 days after exposure for fever (over 38°C).

If a case or cases of smallpox occur, public health authorities will conduct surveillance and implement containment strategies. Ring vaccination will be important and includes identification of contacts of cases and provision of prophylaxis and guidance on monitoring for symptoms.  Large-scale voluntary vaccination may be offered to low-risk populations to supplement and address public concerns.


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