Variola virus (smallpox)

INTRODUCTION — Variola virus is the causative agent of smallpox, a highly infectious disease characterized by fever, rash, and a high mortality rate. In 1979, the global eradication of smallpox was announced, marking one of the greatest achievements of modern medicine [1]. Several factors facilitated eradication [2]:

●Human beings were the only known reservoir for the virus.

●No asymptomatic carrier state existed.

●An effective vaccine was available.

●Vaccination of contacts resulted in prevention or modification of disease.

Although there have been no reported cases since eradication, continued interest in this virus remains because of the concern regarding smallpox as a potential agent of bioterrorism [3-5]. There are lessons that were learned from smallpox eradication that can be applied to the current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic [6,7]. (See "COVID-19: Epidemiology, virology, and prevention".)

The virology, pathogenesis, epidemiology, clinical manifestations, diagnosis, and treatment of smallpox will be reviewed here. The use of variola virus as a bioterrorism agent and the use of the smallpox vaccine are discussed in detail elsewhere. (See "Identifying and managing casualties of biological terrorism" and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses".)

DEFINITIONS — Smallpox occurred in two forms: variola major, which was a serious illness with a mortality rate of 30 to 50 percent in the unvaccinated individual, and variola minor, which was a milder infection with a mortality rate of less than 1 percent [2]. The two forms are caused by different strains of variola virus. (See 'Virology' below.)

EPIDEMIOLOGY — In the past, smallpox was endemic. The illness was described in Asia during the first century AD, in Europe and Africa around 700 AD, and in Central, South, and North America during the 16^th and 17^th centuries.

In temperate climates, endemic smallpox occurred in winter and spring and was mainly a disease of children and young adults [8]. There was less seasonal variability in tropical climates, where there were fewer fluctuations in temperature and humidity. However, in regions that had distinct hot (high humidity) and cool (low humidity) seasons, the incidence of smallpox was always much higher in the cool, dry season [2].

Endemic variola major was eradicated from the United States in 1926, and variola minor during the 1940s. Eradication was slower in Asia, Africa, and in parts of the Americas. The last naturally occurring smallpox infection occurred in Somalia in October 1977 [2]. The last known case in the world, in September 1978, resulted from a laboratory accident in Birmingham, England.

TRANSMISSION — Smallpox can only be spread through humans. It is mainly spread by respiratory viral shedding (eg, via sneezing or coughing) and requires fairly prolonged direct contact between people [9]. Patients with smallpox become contagious as the first lesions appear in their mouth and throat, and infectivity appears to be the highest at the beginning of the rash. Patients remain contagious until their last scabs fall off.

Transmission can also occur through contact with the fluid found in the patient's sores, since they also contain variola virus [9]. The virus can spread through direct contact with these materials or through the objects contaminated by them, such as bedding or clothing. Rarely, smallpox has spread through the air in enclosed settings, such as a building (airborne route).

Before smallpox was eradicated, transmission was usually confined to unimmunized persons sharing living quarters.

Among unvaccinated family members, approximately 58 percent contracted smallpox compared with 4 percent in vaccinees. The severity of the illness, which usually confined the patient to bed and restricted contact, may have contributed to the relatively low attack rate. Because of long incubation times, transmission intervals were two to three weeks apart; thus, new cases of smallpox would appear in a community over many months.

VIROLOGY — Variola virus is an orthopoxvirus within the Poxviridae family. Other poxviruses that infect humans include molluscum contagiosum, vaccinia (the virus used in smallpox vaccine), and monkeypox [10]. (See "Molluscum contagiosum" and "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses" and "Treatment and prevention of mpox (monkeypox)".)

Variola virus is a large (200 to 400 nm) DNA virus that lacks icosahedral symmetry, unlike most other DNA viruses. The virus has a complex structure with an outer membrane, two lateral bodies, and a dumbbell-shaped core that contains a single molecule of double-stranded DNA [11]. The entire 186,000-base pair genome has been sequenced [12,13]. The majority of the genes are closely related to the genes of vaccinia virus [14]. When viewed by electron microscopy, variola virus appears brick shaped (picture 1).

In the 1800s, a milder form of smallpox was recognized in the Americas, which was later identified as variola minor. Sequencing of the virus clearly indicated it was a different strain of variola virus [15]. While variola minor strains have high sequence similarity to variola major strains, it is believed that changes in differential gene expression may explain the differences in virulence. Newer diagnostic tests can now differentiate the two strains of virus [16].

PATHOGENESIS AND PATHOLOGY — Spread of upper airway secretions, including secretions from the oropharynx, leads to person-to-person transmission of smallpox virus [2,17]. (See 'Transmission' above.)

Inhaled secretions containing variola virus enter the respiratory tract, where viruses multiply locally and then spread to regional lymph nodes via circulating macrophages [10]. Multiplication within lymph nodes then leads to a primary viremia with dissemination of virus to lymphoid organs, such as the spleen. Viral amplification within lymphoid organs leads to a secondary viremia, which is associated with the onset of symptoms and the characteristic smallpox rash. Virus can be isolated from the oropharynx, skin lesions, bone marrow, spleen, liver, and kidneys.

Virus that localizes within small dermal blood vessels produces endothelial swelling and infection of epidermal cells, resulting in characteristic vesicles in skin and mucous membranes. When stained with hematoxylin and eosin, the cytoplasm of infected cells contains characteristic inclusions, called Guarnieri bodies, which are faintly basophilic or acidophilic (picture 2). Extension of infection into the corium and sebaceous glands produces the "pockmarks" or scars which, upon healing, are hallmarks of prior smallpox infection.

Variola virus infection stimulates specific cytotoxic T cell responses, neutralizing antibodies, and the production of interferons [2]. These immune responses restrict viral replication and induce prolonged immunity in the patients who recover. In one study, survivors had evidence of variola virus-specific CD4+ memory T cell lymphoproliferative responses and neutralizing antibodies greater than 40 years after infection [18,19].

CLINICAL FEATURES — As noted above, smallpox occurred in two forms: variola major, which was a serious illness, and variola minor, which was a milder infection. (See 'Definitions' above.).

However, the two infections cannot be clinically distinguished in an individual patient. Prior to the eradication of smallpox, the distinction became clear only based on the epidemiology of the outbreak; for example, when low mortality was seen, the infection would be attributed to variola minor. Modern molecular diagnostic techniques could likely distinguish between the two strains of variola [16]. (See 'Virology' above.)

Clinical categories — Smallpox is classified into five clinical categories, each associated with a different level of severity of disease:

●Ordinary type

●Modified type

●Flat type

●Hemorrhagic type

●Variola sine eruptione

All of these forms have a characteristic rash, except for variola sine eruptione. The descriptions below refer to observations in the past, before smallpox was eradicated.

In general, smallpox was most severe in infants, older adults, and in the impaired host, particularly those with T cell deficits. Milder forms of infection were observed in patients with a history of smallpox immunization.

Ordinary type — In a typical case of ordinary type smallpox, the incubation period was 10 to 14 days (range 7 to 19 days) [10]. A pre-eruptive phase, lasting two to four days, was characterized by the sudden onset of high fever, severe headache, backache, and malaise. Vomiting occurred in 50 percent and diarrhea in 10 percent of patients [2].

The eruptive phase was characterized by lesions on the mucous membranes (enanthem) followed approximately 24 hours later by the cutaneous rash (exanthem). Intraoral lesions first appeared as papules followed by vesicles on the tongue and palate. The spread of the exanthem was centrifugal, involving initially the face, followed by proximal extremities, the trunk, and the distal extremities [20]. The exanthem began as small macules ("herald spots") on the face. Macules evolved to papules by day 2 of the rash, vesicles by days 4 to 5, and pustules by day 7. Fever occasionally recurred during the pustular phase [8].

The number of lesions ranged from a few to thousands. Classic lesions were described as deep-seated, firm, round, and well-circumscribed vesicles or nodules. Crusts developed by day 14 and healed with residual depigmentation.

More than 70 percent of smallpox cases were of the "ordinary type," which was further subdivided into three categories according to the type of rash (picture 3):

●Confluent rash present on face and forearms

●Semi-confluent rash present on the face with discrete rash elsewhere

●Discrete rash on all involved areas with normal skin between pustules

The clinical outcome for ordinary type smallpox was closely linked to the type of accompanying rash. As an example, in unvaccinated patients, mortality was 62 percent for confluent infection, 37 percent for semi-confluent, and 9 percent for discrete rash [2]. Death from smallpox was secondary to coagulopathy, hypotension, and multiorgan failure [21].

Modified type — The modified form of smallpox was similar to ordinary disease, except that the phases of the rash developed more rapidly and pustular lesions were smaller. Modified smallpox was common in vaccinated patients who became infected despite immunization and in those intentionally infected by variolation, a procedure that had been widely used as a method of vaccination prior to vaccinia virus vaccination [2].

Flat type — This type of smallpox infection was characterized by pustules which remained flat and were usually confluent or semi-confluent. Flat-type smallpox occurred mainly in children and was often fatal.

Hemorrhagic type — In this rare form of smallpox, skin lesions and mucous membranes became hemorrhagic. Profound prostration, heart failure, diffuse bleeding, and bone marrow suppression commonly resulted in a fatal outcome within three to four days, earning it the name "sledgehammer smallpox." Pregnant women were predisposed to this type of smallpox. However, hemorrhagic smallpox was difficult to recognize unless the patient had a known exposure to a patient with smallpox [10]. A study in non-human primates has suggested that secondary bacterial infection may contribute to the development of hemorrhagic-type smallpox [22].

Variola sine eruptione — After exposure to variola virus, variola sine eruptione occurred among vaccinated individuals or in partially immune patients who had been previously infected. These patients had fever but no rash. A rise in anti-variola antibody titers at a time after the fever would indicate that such patients had been infected with variola virus but did not develop a rash [2].

Laboratory findings — Nonspecific laboratory findings included granulocytopenia, thrombocytopenia, and lymphocytosis, which were common during the prodromal and early-rash phase. Leukocytosis often occurred when vesicles became pustular. Disseminated intravascular coagulation was often seen in patients with hemorrhagic smallpox [2].

Complications and sequelae — Additional complications of smallpox included [2,17]:

●Secondary bacterial infections of the skin

●Keratitis and corneal ulcerations leading to blindness

●Viral arthritis and osteomyelitis

●Bacterial pneumonia

●Orchitis

●Encephalitis

Residual pockmarks appeared hypopigmented in dark-skinned individuals and hyperpigmented in light-skinned patients.

DIAGNOSIS

Presumptive clinical diagnosis — Since smallpox was eradicated in 1979, most clinicians have not seen a case of smallpox and, therefore, may not recognize the characteristic lesions. (See 'Clinical features' above.)

The United States Centers for Disease Control and Prevention (CDC) has proposed both major and minor clinical diagnostic criteria for smallpox in the event that variola virus could be used as an agent of bioterrorism [23]. These criteria determine the subsequent public health response. A description of these criteria and the approach to evaluating a patient with potential signs and symptoms of smallpox are presented in the algorithm (algorithm 1).

If a presumptive diagnosis of smallpox is being considered, appropriate infection control precautions must be instituted. (See 'Infection control precautions' below.)

Diagnostic testing to confirm the diagnosis should be performed in patients at high risk of having smallpox (febrile prodrome, classic smallpox lesion, and lesions in same stage of development). (See 'Laboratory diagnosis' below.)

Laboratory diagnosis — A definitive diagnosis of smallpox is typically made on the basis of molecular testing [24]. Providers should work with local and state health departments to determine the appropriate handling and processing of specimens. Testing is only performed in specialized laboratories.

Virus isolation — Virus can be isolated from the oropharynx, conjunctiva, and urine, as well as skin lesions prior to scab formation. Viremia precedes the rash and has disappeared in most patients by the time the cutaneous manifestations appear.

Polymerase chain reaction testing — Polymerase chain reaction (PCR) identification of variola DNA in a clinical specimen is needed to confirm the diagnosis [25]. Alternatively, the diagnosis can be confirmed by culturing smallpox virus from a clinical specimen (only done in a World Health Organization [WHO] Smallpox Reference Laboratory) with variola PCR confirmation.

Generic orthopoxvirus PCR and negative-stain electron microscopy identification of a poxvirus in a clinical specimen is suggestive of an orthopoxvirus infection but is not diagnostic for smallpox.

Serology — Serology results can indicate an orthopoxvirus infection but are not diagnostic for smallpox. Serum antibodies, which appear by days 6 to 8 of infection, can be detected with hemagglutination inhibition, complement fixation, neutralization, or gel precipitation assays. Paired serum samples, drawn two to three weeks apart, can demonstrate rising antibody titers.

DIFFERENTIAL DIAGNOSIS — A variety of disorders may be considered in the differential diagnosis of smallpox, including varicella, monkeypox, or tanapox infections (table 1). Most can be differentiated clinically from variola virus infection since smallpox usually causes severe disease with high rates of mortality, while the other infections are usually mild. Epidemiologic history is also helpful in distinguishing these entities.

●Varicella – In patients with varicella infection (chickenpox), lesions are in various stages of development, whereas in smallpox, all lesions appear morphologically similar. In addition, patients with varicella infection usually appear less ill. However, distinguishing mild to moderate varicella infection from smallpox was particularly difficult during epidemics of variola minor or when mild smallpox infection developed in patients previously immunized with vaccinia. (See "Clinical features of varicella-zoster virus infection: Chickenpox".)

●Monkeypox – The rash of human monkeypox can be difficult to distinguish from smallpox. Key distinguishing clinical features are that monkeypox is associated with cervical and inguinal lymphadenopathy, and patients appear less ill than patients with smallpox. Patients with monkeypox may also have a history of travel to Africa or exposure to an animal from this geographic region (See "Treatment and prevention of mpox (monkeypox)".)

●Tanapox – Tanapox infection is another poxvirus infection acquired in Africa that might be confused with smallpox. It infects non-human primates and is believed to be transmitted to humans by an arthropod intermediate. However, unlike smallpox, this infection is self-limited, and the rash is usually localized [26].

●Vaccinia – On rare occasion, patients who are immunized with a replication-competent smallpox vaccine like ACAM2000 can develop disseminated vaccinia infection. When this occurred in the past, virus isolation was required to distinguish disseminated vaccinia infection from smallpox the disease. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Complications'.)

TREATMENT

Supportive care — The mainstay of treatment for smallpox was supportive care, which includes maintenance of fluid and electrolyte balance, skin care, and observation for complications of infection.

Antiviral therapy

Tecovirimat — Tecovirimat, the first antiviral indicated for the treatment of smallpox, was approved for use in the United States in July of 2018 [27,28]. Tecovirimat targets a viral envelope protein required for viral maturation and inhibits release of the infectious orthopoxvirus from infected cells. This agent is only available through the United States Government's Strategic National Stockpile.

The recommended dosage of tecovirimat depends upon the patient’s weight, as described in manufacturer labeling and the Lexicomp drug information topic within UpToDate. The duration of treatment is 14 days. The most frequently reported side effects are headache, nausea, and abdominal pain. An intravenous formulation is under development.

The efficacy of this agent could not be tested in humans. However, studies have demonstrated improved survival in animals who received tecovirimat compared with those who received placebo after challenge with a number of orthopoxviruses [28-31]; this benefit was seen even when the drug was administered at later stages of illness. Tecovirimat is the first drug approved by the US Food and Drug Administration (FDA) that was developed under the "Animal Rule." This rule allows approval of drugs based upon well-controlled animal efficacy studies when the agent treats or prevents serious or life-threatening conditions and when human efficacy studies are not ethical and field trials are not feasible. Tecovirimat has also demonstrated efficacy in the treatment of non-human primates challenged with variola virus [32], but these data were not used to gain FDA approval.

Although the efficacy of this agent has only been evaluated in animals, it has been administered to approximately 360 human volunteers in an expanded safety trial, which found an adverse effect profile similar to placebo [28]. It was also given as an Emergency Investigational Drug to patients who developed complications from the smallpox vaccine, including a severely ill child with eczema vaccinatum [33,34] and a military recruit with progressive vaccinia [35]. In both of these cases, tecovirimat was administered in conjunction with vaccinia immune globulin, and both patients survived. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses", section on 'Treatment and prevention of complications'.)

Brincidofovir — Brincidofovir is an analog of cidofovir that can be given orally and does not appear to have renal toxicity [36]. In the United States, this agent was approved for treatment of smallpox in June 2021 [37]. Similar to tecovirimat, this agent will not be available for commercial sale.

The recommended regimen for those weighing ≥48 kg is 200 mg once weekly for two doses; for those weighing ≥10 kg to less than 48 kg, the dose is 4 mg/kg of the oral suspension once weekly for two doses; for children weighing less than 10 kg, the dose is 6 mg/kg of the oral suspension once weekly for 2 doses [38]. The most common side effects are diarrhea, nausea, vomiting, and abdominal pain.

Brincidofovir has good activity against orthopoxviruses in animal models [39-41] and was administered as an Emergency Investigational Drug to a military recruit with progressive vaccinia [35]. Although it was originally developed to treat orthopoxvirus infections [42], it was also found to have broad activity against some other DNA viruses (eg, adenovirus, BK virus, cytomegalovirus) and has undergone testing in humans against some of these viruses [43,44].

The US FDA approved brincidofovir under the agency’s "Animal Rule," as described above (see 'Tecovirimat' above). Safety information was derived from clinical trials of the drug for non-smallpox indications [37].

PREVENTION

Infection control precautions — For patients who present with an acute generalized vesicular or pustular rash illness, appropriate standard, airborne, and contact precautions should be implemented [25]. (See "Infection prevention: Precautions for preventing transmission of infection".)

Precautions should include properly fitted N95 respirators, gloves, and gowns. If it is necessary to move the patient, a sheet should be used to cover the patient's rash and a surgical mask should be used to cover the patient's mouth and nose.

Vaccination — Vaccination led to the global eradication of smallpox. Although routine vaccination with vaccinia virus is no longer performed, some laboratory researchers, health care workers, first responders, and military personnel are being vaccinated. In addition, in the event of an exposure to smallpox, immediate vaccination may reduce the severity of disease. A detailed discussion of the smallpox vaccine is found elsewhere. (See "Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Orthopoxvirus (smallpox and mpox [monkeypox])".)

SUMMARY AND RECOMMENDATIONS

●Variola virus is the causative agent of smallpox, a contagious disease characterized by fever, a vesicular and pustular eruption, and a high mortality rate in nonimmune patients. The global eradication of smallpox was officially announced in 1979, marking one of the greatest achievements of modern medicine. However, there remains continued interest in this virus because of the concern regarding smallpox as a potential agent of bioterrorism. (See 'Introduction' above and 'Epidemiology' above.)

●Smallpox occurred in two forms: variola major, which was a serious illness with a mortality rate of 30 to 50 percent in the unvaccinated individual, and variola minor, which was a milder infection with a mortality rate of less than 1 percent. (See 'Definitions' above.)

●Inhaled variola virus entered the respiratory tract, where it multiplied locally and then spread to regional lymph nodes via circulating macrophages. Multiplication within lymph nodes then led to a primary viremia with dissemination of virus to lymphoid organs. Viral amplification within lymphoid organs led to a secondary viremia, which was associated with the onset of symptoms and the characteristic smallpox rash. (See 'Pathogenesis and pathology' above.)

●Smallpox was most commonly characterized by the sudden onset of high fever, severe headache, backache, and malaise. These constitutional symptoms were then followed by the onset of lesions on the mucous membranes (enanthem) followed by the onset of rash (exanthem) involving the face, proximal extremities, trunk, and distal extremities. The risk of mortality was closely linked to the severity of the rash. (See 'Clinical features' above.)

●Complications of smallpox infection included secondary bacterial infections of the skin, keratitis of corneal ulcerations, and encephalitis. (See 'Complications and sequelae' above.)

●The United States Centers for Disease Control and Prevention (CDC) has proposed both major and minor clinical diagnostic criteria for smallpox in the event that variola virus could be used as an agent of bioterrorism (algorithm 1). A definitive diagnosis of smallpox is typically made on the basis of molecular testing. (See 'Diagnosis' above.)

●The mainstay of treatment for smallpox had been supportive care. However, two antiviral agents, tecovirimat and brincidofovir, are now approved for the treatment of smallpox in the United States. (See 'Treatment' above.)

●In the setting of a smallpox outbreak, prevention efforts include the use of appropriate infection control precautions and vaccination. (See 'Prevention' above.)