Smallpox

Smallpox is a highly contagious and often fatal variola viral infection that has been completely eradicated by immunization.

Malignant smallpox

Pathophysiology

Prior to its eradication, smallpox was a severe infectious disease caused by the variola virus. It was infectious, meaning it spread from person to person. Smallpox was characterized by a fever and a distinct, progressive rash.

About one-third of those infected with smallpox perished, while the majority recovered. Numerous smallpox survivors have extensive, permanent scarring, especially on their faces. Some are left blind.

Since 1977, there have been no naturally occurring cases of smallpox due to the success of vaccination programs. 1949 marked the last natural outbreak of smallpox in the United States.

Smallpox versus chickenpox

Origin of Varicella

It is unknown where smallpox came from. The discovery of smallpox-like rashes on Egyptian mummies indicates that the disease has existed for at least three thousand years. China produced the earliest written description of a disease similar to smallpox in the fourth century BCE (Common Era). In the seventh century, written descriptions appeared in India and the tenth century in Asia Minor.

Transmission of Smallpox

The global spread of smallpox is attributed by historians to the expansion of civilizations and exploration. Over the centuries, expanding trade routes contributed to the spread of the disease.

Highlights of historical events

• Increased trade with China and Korea spreads smallpox to Japan in the sixth century.
• The Arab expansion of the seventh century spreads smallpox to northern Africa, Spain, and Portugal.
• The Crusades further spread smallpox throughout Europe in the eleventh century.
• Portugal occupies a portion of western Africa in the 15th century and introduces smallpox.
• European colonists and the African slave trade introduce smallpox to:
• The Antilles
• South and Central America
• European settlers introduce smallpox to North America in the 17th century.
• In the 18th century, British explorers introduced smallpox to Australia.

Smallpox

Global Smallpox Eradication Program

The World Health Organization (WHO) initiated a plan to eradicate smallpox in 1959. This global eradication campaign was hampered by a lack of funds, personnel, and country commitment, as well as a shortage of vaccine donations. Smallpox was still widespread in 1966, causing regular outbreaks in South America, Africa, and Asia despite their best efforts.

In 1967, the Intensified Eradication Program was launched with the promise of increased efforts. Numerous countries where smallpox was endemic were able to produce more and of higher quality freeze-dried vaccine. The development of the bifurcated needle, the establishment of a case surveillance system, and the implementation of mass vaccination campaigns also contributed significantly to the success of the intensified efforts.

Prior to the start of the Intensified Eradication Program in 1967, smallpox had already been eradicated from North America (1952) and Europe (1953). Instances persisted in South America, Asia, and Africa (smallpox was never widespread in Australia). Smallpox was eradicated from South America in 1971, followed by Asia in 1975, and then Africa in 1980, as a result of the Program's consistent efforts to eradicate the disease (1977).

Transmission

Human-to-human transmission of variola virus occurs through inhalation of large, airborne salivary droplets containing the virus from an infected individual. Through the shedding of oropharyngeal lesions, infectious virus particles are released. Patients with smallpox are infectious from the time the first oropharyngeal lesions appear until the last scab falls off the body.

After prolonged, close contact with a smallpox patient, a person is considered to be at risk for contracting the disease. Prior to the eradication of smallpox, unvaccinated individuals had a secondary household or close contact attack rate of approximately 60%.

Transmission can also occur through contact with pustules or crusted scabs from a person with smallpox. Scabs are significantly less infectious than respiratory secretions, presumably because the virions are bound to the fibrin matrix of the scab.

There have been reports of airborne transmission in hospitals and laboratories, albeit infrequently. This risk can be mitigated by following infection control protocols. There are no known reservoirs of smallpox in animals or insects.

Clinical presentation

There are four major clinical manifestations of smallpox, each with distinct characteristics. During the era of smallpox, the case-fatality rate varied for the various clinical forms, but was roughly 30% for unvaccinated individuals overall.

Toxaemic rash of smallpox Wellcome

Common Smallpox (Variola Major)

During the smallpox era, ordinary smallpox accounted for more than 85 percent of all cases.

Incubation Interval

The incubation period for variola virus infection typically lasts between 10 and 14 days (range 7 to 19 days). During this time, the infected individual has no symptoms, is not contagious, and may feel completely normal.

Prodrome

The first prodrome symptoms appear following the incubation period and include:

• Fever between 101°F and 105°F (38.3°C and 40.5°C).
• Malaise
• Prostration
• Headache
• Backache
• Vomiting
• Extreme abdominal distress
• Chills
• Anorexia
• Pharyngitis

This phase typically lasts four days. Patients with pale skin may exhibit an erythematous rash or, rarely, a petechial rash.

A human hand with smallpox pustules

Eruptive Stage

As the fever subsides, a rash begins to manifest. Lesions typically manifest on the oropharynx, followed by the face and extremities, and then spread in a centrifugal pattern to the trunk, palms, and soles.

Lesions develop uniformly and progress from macules to papules to vesicles over the course of four or five days. In one to two days, the vesicles typically umbilicate and transform into pustules that are round, tight, firm to the touch, and deeply rooted in the dermis. Lesions are typically at the same stage of development in any given region of the body.

Typically, crusting and scab formation commence on the ninth day of exanthema. The crusts fall off approximately 14 days after the rash's onset.

Sequelae

The most common sequelae are pockmarks and scarring, which result from virus-mediated necrosis and destruction of sebaceous glands. Scarring can occur anywhere on the body, but it is most prevalent on the face, which contains the greatest number of sebaceous glands.

Other repercussions include:

• Scarring of the cornea following keratitis or corneal ulcerations is the rare cause of blindness. In most cases, it is caused by malnutrition and/or an opportunistic infection.
• Encephalitis
• Osteomyelitis
• Stillbirths and spontaneous abortions are major public health concerns.
• Male infertility (obstructive azoospermia)

Recovery from smallpox confers long-lasting immunity against reinfection with variola virus. After recovery, the virus does not persist in the body.

Variant of Smallpox

Previously immunized individuals contract a modified form of smallpox. In this form, the prodrome stage may still include severe headache, backache, and fever, and it may last as long as in the common form. However, once lesions appear on the skin, they tend to progress more rapidly, and crusting is typically complete within 10 days as opposed to 14 days with ordinary smallpox. In addition, there may be fewer and more superficial lesions than in typical smallpox. Patients also tend not to develop a fever as the rash progresses.

Malignant Variant of Smallpox

Malignant or flat-type smallpox is extremely rare and is characterized by intense toxemia. It is more prevalent among children. In contrast to ordinary smallpox, this variant's skin lesions develop slowly, merge, and remain flat and soft (often described as "velvety"). They never reach pustular development.

Lesions suggest a deficient cellular immune response to variola virus, and the majority of cases of flat-type smallpox are fatal. The lesions gradually disappear without forming scabs if the patient survives. Prior vaccination appears to protect against smallpox of the flat variety.

Hemorrhagic Varicella

Hemorrhagic-type smallpox affects people of all ages and both sexes, although it is more prevalent in adults. It appears that pregnant women are more susceptible. The biological causes underlying this type are unknown. Prior vaccination does not confer immunity. The following distinguishes this type from ordinary smallpox:

Reduced gestation period More intense prodromal symptoms, including high fever, severe headache, and abdominal pain. After the onset of illness, a dusky erythema develops, followed by petechiae and skin and mucosal hemorrhages. Typically, death occurs on the fifth or sixth day of the rash, frequently before the characteristic smallpox lesions appear. A profound toxemia resulting in multi-organ failure causes death.

Clinical Case Definition for Varicella

A disease characterized by an acute onset of fever 101°F (38.3°C) followed by a rash consisting of firm, deep-seated vesicles or pustules in the same stage of development and no other apparent cause.

Patient Evaluation Methodology

Numerous rash diseases can manifest as vesicles and pustules. Although it is possible, a patient with a rash illness is unlikely to have smallpox. The "Evaluating Patients for Smallpox: Acute, Generalized Vesicular or Pustular Rash Illness Protocol" algorithm provides a standard method for evaluating patients with acute, severe vesicular or pustular rash illness by providing clinical clues for distinguishing smallpox from varicella and other rash illnesses.

Using the below algorithm and instructions, evaluate a patient with an acute, generalized vesicular or pustular rash for smallpox. The algorithm will provide a risk assessment, which will direct the medical and public health response that is most appropriate. Contact your state or local department of public health for consultation. State and local departments of public health should contact the CDC at 770-488-7100 for consultation on high-risk patients and other complex cases.

Precautions for Infection Prevention

• Transfer the patient to an airborne isolation room (AIIR). If one is not available, a private room should be used. Avoid leaving patients in shared waiting areas.
• Notify the Infection Control Division (if in a healthcare facility).
• Use standard, airborne, and contact precautions as necessary. Staff and visitors should wear N95 respirators, gloves, and gowns that are properly fitted.
• If it is necessary to move the patient, cover the patient's rash with a sheet and cover the patient's mouth and nose with a N95 respirator or surgical mask.
• Histories and a Physical Exam

Ask your patient detailed questions about:

• Any symptoms preceding rash onset, including prodromal symptoms and clinical manifestations 1 to 4 days prior to rash onset
• Contact with any ill persons (especially those with a rash illness)
• Recent travel experience
• Contact with ill or exotic animals is hazardous.
• including a record of medications
• Prior varicella or herpes zoster infection
• The background of varicella vaccination (vaccine available since 1995)

Treatment

Generally, smallpox patients are treated with supportive care. If administered within 2 to 3 days of exposure, vaccination with replication-competent smallpox vaccines (i.e., ACAM2000 and APSV) can prevent or lessen the severity of disease. If administered during the first week of exposure, they may reduce symptoms.

In order to treat smallpox patients in a healthcare setting, isolation and proper infection and environmental controls are required.

Antivirals

In animal and in vitro studies, three antiviral therapies have proven effective against orthopoxviruses, including variola (the virus that causes smallpox). However, there is no treatment for smallpox disease that has been tested and proven effective in this population of ill patients.

Tecovirimat

In July of 2018, U.S. The Food and Drug Administration (FDA) approved tecovirimat (also known as ST-246 or its brand name Tpoxx), the first drug with a smallpox indication. Tecovirimat has been used to treat severe adverse reactions to vaccination with the vaccinia virus; however, human efficacy data are limited. The effectiveness of Tecovirimat against smallpox was established through in vitro studies utilizing related orthopoxviruses and variola. Multiple animal model studies measuring survival in animals infected with either variola virus or other closely related orthopoxviruses have demonstrated the efficacy of tecovirimat treatment. In addition, treatment with tecovirimat reduced signs of morbidity and protected prairie dogs from death when exposed to monkeypox virus. In 359 healthy human volunteers, the safety of tecovirimat was assessed.

Tecovirimat was approved under the FDA's Animal Rule, which permits efficacy findings from adequate and well-controlled animal studies to support FDA approval when conducting efficacy trials in humans is impractical or unethical. The FDA Antimicrobial Drugs Advisory Committee voted unanimously (17-0) that the benefits of treating smallpox with tecovirimat outweigh its risks.

Brincidofovir

The FDA approved brincidofovir (also known as its brand name TEMBEXA) for the treatment of smallpox in June 2021. Brincidofovir's efficacy against smallpox was demonstrated through in vitro tests with related orthopoxviruses and variola. Multiple animal model studies measuring survival in animals infected with either variola virus or other closely related orthopoxviruses have demonstrated the efficacy of brincidofovir therapy. The safety of brincidofovir was evaluated for indications other than smallpox, primarily in individuals who had received bone marrow transplants. The FDA approved brincidofovir under the Animal Rule.

Cidofovir

In laboratory tests, cidofovir has been demonstrated to be effective against the virus that causes smallpox and in treating animals with diseases similar to smallpox. Cidofovir has not been tested on smallpox patients, but it has been tested on healthy individuals and those with other viral diseases. This drug is still being evaluated for efficacy and toxicity. It is not FDA-approved for the treatment of variola virus infections (smallpox), but it could be used during an outbreak if the proper regulatory mechanisms are in place (such as an investigational new drug [IND] protocol or Emergency Use Authorization).

Smallpox Resources
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Classification	ICD-10: B03 ICD-9-CM: 050 DiseasesDB: 12219
External resources	MedlinePlus: 001356 eMedicine: emerg/885 Scholia: Q12214