Smallpox is a disease caused by the Variola virus. This virus belongs to the orthopoxvirus family. When smallpox was circulating in the environment, there were several forms of the disease, some more severe and life-threatening than others.⁽¹⁾ The various forms included Variola Major, modified smallpox, hemorrhagic smallpox, malignant smallpox (flat type), and Variola Minor. Variola Major was the most common form of the disease when smallpox was circulating in the environment.⁽²⁾

Variola Major

According to the U.S. Centers for Disease Control (CDC), Variola Major was the most common form of the disease when smallpox was around. The incubation period for Variola Major ranged from seven to 19 days, but most often lasted 10 to 14 days. People infected with the virus were not contagious and did not show symptoms of disease during this period.

The first symptoms of the disease appear in the prodrome period, which begins immediately after the incubation period and lasts about four days. Symptoms included anorexia, vomiting, malaise, high fever, chills, headache, back pain, severe abdominal pain, pharyngitis, extreme fatigue, and a rash that occurs mostly in fair-skinned individuals.

As the fever resolves, rashes begin to develop and appear at the back of the mouth, behind the oral cavity (oropharynx), followed by the face, arms, legs, and then spread to the trunk, palms, and soles. The rashes develop uniformly throughout the illness and progress from macules (distinct, flat, discolored skin) to papules (raised, itchy red or pink bumps) to vesicles (fluid-filled blisters) within four to five days. Within a day or two, the vesicles progress to round, firm pustules located deep in the dermis. Crusting and scaling of the lesions usually began on the ninth day, and the crusts began to fall off about 2 weeks after the rash appeared.⁽³⁾

Complications of smallpox include serious bacterial infections of the skin and organs, sepsis, pneumonia, encephalitis, and keratitis.⁽⁴⁾

The most common long-term consequence of smallpox is scarring, which occurs all over the body, but most often on the face. Additional sequelae include stillbirths and miscarriages, infertility in males, osteomyelitis, encephalitis, and blindness. People who recover from smallpox disease develop long-term immunity.⁽⁵⁾

Historically, Variola Major was fatal in about 30% of cases.⁽⁶⁾

Modified type smallpox

When the vaccine failed to prevent the disease, previously vaccinated individuals developed a condition known as modified smallpox. Symptoms of the disease are usually the same as those of people who developed Variola Major; however, the rash usually resolves within 10 days, rather than 2 weeks, and fever is not always present. The lesions are usually fewer and often superficial.⁽⁷⁾ Modified-type smallpox infections are rarely fatal.⁽⁸⁾

Hemorrhagic smallpox

Hemorrhagic smallpox usually occurs in adults, but it can occur in children. Additionally, pregnant women were at greater risk of developing this particular form of the disease. Symptoms of hemorrhagic smallpox were similar to those of Variola major, except that the incubation period was shorter and the prodromal symptoms were usually more severe. Additionally, after the onset of the disease, there was a reddening of the skin that progressed to a petechial rash (small red or purple rash) and hemorrhage of the skin and mucous membranes. Hemorrhagic smallpox is usually fatal within the fifth or sixth day of the appearance of the rash, often due to multisystem organ failure due to toxemia. Vaccination is ineffective against hemorrhagic smallpox.⁽⁹⁾

Malignant smallpox (flat type)

More common among children, flatpox was rare and was characterized by skin lesions that developed slowly, fused together, and became soft and flat. Most cases of flatpox were fatal due to toxemia; however, if the patient survived, the rash healed without crusting.⁽¹⁰⁾ This type of smallpox was fatal in about 97% of cases.⁽¹¹⁾

Variola Minor (Alastrim)

Variola Minor was a less severe and rarely fatal form of the disease. Death occurred in less than 1% of cases.⁽¹²⁾ This form was most common in the United States in the early 20th century.⁽¹³⁾ By the 30s and until the elimination of smallpox from the United States, variola minor, the mildest form of smallpox, had emerged as the predominant strain.⁽¹⁴⁾

The last known case of smallpox occurred in Somalia in October 1977. Smallpox was declared extinct in May 1980 by the World Health Organization (WHO). However, there are two known repositories of the smallpox virus. One is in the United States, at the Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the other in a laboratory outside Moscow, Russia. Some government health officials believe there are secret caches of smallpox that could one day be used for bioterrorism.⁽¹⁵⁾

Other Orthopoxvirus Diseases

Monkeypox (Mpox)

Monkeypox (Mpox) is an infection caused by the mpox virus and, like smallpox, is a member of the Orthopoxvirus family.⁽¹⁶⁾ The incubation period for mpox is usually between 7 and 14 days.⁽¹⁷⁾ Symptoms of mpox are similar to those of smallpox, but are usually milder. Those infected with mpox usually have headache, backache, fever, chills, muscle aches, extreme tiredness, and fatigue. Swollen lymph nodes also occur, a symptom not present in smallpox infection.⁽¹⁸⁾

The rash, which usually appears on the face, begins within one to three days of the fever and spreads over the body. The rash lesions progress from macules to papules to vesicles before breaking out as pustules and crusts. Most people recover from mpox within two to four weeks.⁽¹⁹⁾

Mpox is rare and is usually found in Africa, although cases and outbreaks have occurred worldwide. The virus was first identified in research monkeys in 1958. Although the primary host species for the virus remains unknown, health officials believe that African rodents, monkeys, and other primates can host and transmit the virus. The first known case of human infection was documented in the Democratic Republic of the Congo (DRC) in 1970.⁽²⁰⁾ Transmission of the mpox virus is believed to occur through the respiratory tract, skin cracks, or mucous membranes.⁽²¹⁾

Complications of mpox disease include sepsis, encephalitis, eye infections that can lead to blindness, bronchopneumonia, myocarditis, and other secondary infections that can lead to death.⁽²²⁾

Three clades (types) of mpox have been identified: Clade I, Clade IIa and Clade IIb.⁽²³⁾ Clade I is found in the Congo Basin in Africa and has a mortality rate of 10%. It is also more easily transmissible and associated with higher mortality rates. Historically, those most at risk are individuals who hunt, kill, and eat bushmeat.⁽²⁴⁾

Clade IIa is typically found in West Africa and is rarely fatal, with a case fatality rate of less than 1%. Clade IIb is the strain associated with the 2022 global outbreak and is rarely fatal in immunocompetent individuals. Unlike Clade I and Clade IIa, which typically spread from animals to humans, Clade IIb is transmitted from human to human.⁽²⁵⁾

Monkeypox virus is considered to be closely related to smallpox virus.⁽²⁶⁾ and is contagious. The virus can be transmitted from animals to humans through scratches or bites, through direct contact with rash lesions or other body fluids, or through the meat of contaminated animals. Infected humans can spread the virus to others through respiratory secretions or other body fluids. Direct contact with lesions or contact with objects contaminated by lesions, such as clothing or bedding, can also transmit the infection.⁽²⁷⁾ The virus can also be transmitted sexually, although sexual transmission occurs mainly between men who have sex with men.⁽²⁸⁾