Smallpox Treatment & Management

No known treatment is effective for smallpox. Medical management of smallpox is mainly supportive. Supportive care in patients with symptomatic smallpox consists of the following:

• The patient should be isolated until all scabs have fallen off (about 3-4 wk after rash onset) to prevent transmission of the variola virus to nonimmune persons.
• The fluid and electrolyte balance should be monitored and maintained to avoid dehydration.
• Oral antiviral agents (ie, tecovirimat, cidofovir) are available from the US government’s Strategic National Stockpile (SNS).
• Medications should be given for fever and pain.
• Good nutritional support should be maintained.
• Skin care should be instituted.
• Complications should be monitored for and treated.
• Unless the diagnosis of smallpox is confirmed in a laboratory, patients should receive smallpox vaccination if they will be isolated with other patients with confirmed or suspected smallpox, to prevent accidental transmission.
• Corneal lesions may be treated with topical idoxuridine.

Whenever possible, patients should be cared for at home in the event of a large smallpox outbreak. However, in the event of an outbreak with only a few cases or when patients cannot be cared for at home, hospital admission is advisable. The CDC recommends that authorities consider designating specific hospitals for smallpox care.

Treatment of patients with possible or known exposure to smallpox

The smallpox vaccine is the only known way to prevent smallpox in an exposed person. If given within 4 days of viral exposure, the vaccine can prevent or significantly lessen the severity of smallpox symptoms. Vaccination 4-7 days after exposure may offer some protection from the disease and may lessen its severity.

Isolate patients possibly infected with smallpox virus in negative-pressure rooms under airborne precautions ^[15] and vaccinate them within the first 4 days after exposure. Supportive and symptomatic treatment (eg, hydration, nutrition) should be provided.

In July 2018, the US Food and Drug Administration approved tecovirimat (TPOXX), the first drug indicated for the treatment of smallpox, should smallpox ever be used as a bioweapon. Tecovirimat is an antiviral that inhibits the activity of the orthopoxvirus VP37 protein. The effectiveness of tecovirimat against smallpox was established by studies in animals infected with viruses closely related to variola virus, which demonstrated higher survival rates compared with those of placebo. The safety of tecovirimat was demonstrated in 359 healthy human volunteers in whom the most frequently reported adverse effects included headache, nausea, and abdominal pain. ^[16]

The FDA approved a second antiviral according to the animal rule, brincidofovir, for treatment of smallpox in June 2021. Brincidofovir is a prodrug of cidofovir. Brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis by incorporation of cidofovir into the growing viral DNA chain. This results in reductions in the rate of viral DNA synthesis. It is indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates. ^[45]

To obtain tecovirimat, clinicians should contact the Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100, which will coordinate shipment with the SNS.

Vaccinia immunoglobulin (VIG) does not appear to offer a survival benefit when given to patients during the incubation or active-disease stages of smallpox. However, new drugs are under investigation. For example, cidofovir may be beneficial if given in the early stages of illness, although the effectiveness of this treatment has not been proven in humans. ^{[17, 18, 19, 20]}

Transfer

Smallpox patients should be transferred as necessary, with appropriate respiratory and contact isolation.

Consultations

Infectious disease specialists and public health officials should be consulted in cases of smallpox. CDC officials and state health authorities should be notified immediately.

Outpatient care

Further outpatient care for smallpox patients includes cosmetic management of scars and corrective vision care.

One of the best ways to prevent smallpox is through vaccination. Vaccine given to individuals before exposure to smallpox can completely protect them. Vaccination within 3 days after exposure prevents or greatly lessens the severity of smallpox in most people. Vaccination 4-7 days after exposure likely offers some protection from disease or may decrease the severity of disease. Vaccination does not protect patients with smallpox who have already developed a rash. ^{[21, 22, 23, 24, 25]}

The FDA approved an attenuated, live, nonreplicating smallpox and monkeypox vaccine (Jynneos) for immunization of adults at high risk for smallpox or monkeypox infection in September 2019. Approval was determined in a clinical study comparing the immune responses in study participants who received either Jynneos or ACAM2000, an FDA-approved vaccine for the prevention of smallpox. The study included approximately 400 healthy adults aged 18-42 years who had never been vaccinated for smallpox. Half of the study participants received 2 doses of Jynneos administered 28 days apart, and half received 1 dose of ACAM2000. The group vaccinated with Jynneos had an immune response that was not inferior to immune responses to ACAM2000. ^{[26, 27]}

Cross-protective immunity from vaccinia is most effective during the first 10 years after vaccination and slowly wanes thereafter. Persons who have been vaccinated several times are likely to have longer-lasting immunity of unclear duration.

The level of protection in individuals who were vaccinated 30 or more years ago, should they be exposed to smallpox today, is unclear.

Vaccinated persons normally exhibit an accelerated immune response. Thus, whenever possible, assigning those who have previously been vaccinated to duties involving close patient contact is prudent.

Persons with known or possible exposure to smallpox should be vaccinated if the exposure has occurred within 3 days, unless the patient has specific contraindications for which the risks of immunization are considered even greater than the dangers associated with contracting smallpox.

Persons with known cardiac disease (eg, previous myocardial infarction, angina, congestive heart failure, cardiomyopathy) should receive smallpox vaccination. Myocardial infarctions and angina without myocardial infarction have been reported following smallpox vaccinations. The association between smallpox vaccination and these cardiac events is not clear.

The US military ended vaccination in 1990, but vaccination was subsequently reinstituted in December 2002 for potential use against variola virus as bioterrorism agent. Since smallpox vaccination can lead to progressive vaccinia among immunocompromised individuals, HIV-infected individuals are excluded from preemptive vaccination.

Pregnant women who receive the smallpox vaccine are at risk of fetal vaccinia, which usually results in stillbirth or death of the infant. Pregnant women should not receive smallpox vaccination, and women should be advised against becoming pregnant for 4 weeks after smallpox vaccination. ^[28]

Vaccinia immunoglobulin

Vaccinia immunoglobulin (VIG) is indicated when the vaccination is contraindicated.

In a smallpox outbreak, patients with confirmed or suspected smallpox may be isolated in several ways. The goal of isolation is to prevent transmission of smallpox from an infected patient to nonimmune individuals while maintaining an appropriate care and comfort level for the patient. Medical personnel should consult with public health officials to determine the most appropriate method for isolation of patients with smallpox.

Hospital isolation

If a patient with confirmed or suspected smallpox requires hospital care, the steps below must be taken while the patient is hospitalized.

The patient should be kept in strict airborne and contact isolation in a room with negative air pressure (and an individual high-efficiency particulate air [HEPA]–filtered ventilation exhaust, if available). This room should have private shower and bathroom facilities and not share ventilation with any other part of the hospital.

Unvaccinated personnel who enter and leave the isolation room should wear protective clothing, including gowns, masks (properly fitted N95 respirator masks), gloves, protective eyewear, and surgical booties. Recently successfully vaccinated personnel should exercise contact precautions (eg, gowns, gloves) and should wear a surgical mask and eye protection, as indicated, for procedures in which contact with body fluids is possible.

All protective clothing should be removed and placed into biohazard waste disposal containers before leaving the isolation room and reentering other areas of the hospital.

All infectious waste and contaminated protective clothing should be disposed of or sterilized in an appropriate manner (incineration for disposable materials; autoclaving, ethylene oxide decontamination, or laundering in hot water and bleach for reusable equipment or clothing). Public health officials should be consulted for specific waste-disposal and decontamination guidelines.

Personnel entering the isolation room or handling infectious waste or clinical specimens from the patient should be vaccinated or should have had recent, documented, successful smallpox vaccinations (within 3 y). Public health officials should be contacted for vaccination requests.

Steps should be taken to confirm or rule out the diagnosis of smallpox. Public health officials should be consulted for assistance with the laboratory diagnosis.

Nonhospital isolation

Public health officials should be consulted before nonhospital isolation is initiated. Patients with confirmed or suspected smallpox who do not require hospital care may be isolated in nonhospital facilities that do not share ventilation systems with other facilities. These facilities should have appropriate climate-control capabilities (heating and air conditioning), running water, and bathroom facilities.

If patients with suspected or confirmed smallpox are isolated together, all patients should receive smallpox vaccination to prevent accidental transmission due to misdiagnosis. All persons entering these facilities must have had recent, documented, successful smallpox vaccinations (within 3 y).

Avoid transporting the patient through the hospital (eg, use in-room portable radiographic equipment); if transporting the patient is unavoidable, have the patient wear a surgical mask and the health care worker a mask with an N-95 respirator.

If smallpox infection is confirmed, place contacts under fever surveillance for 18 days after their last contact with the infected patient.

Contacts or a supervisor should monitor the patient’s temperature twice daily. If the patient’s temperature is higher than 38.1°C (100.5°F), public health authorities should be notified immediately. (See the graph below.)

Typical temperature chart of a patient with smallpox infection (from Henderson, 1999).

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Isolation and mass and/or ring vaccination can prevent the spread of smallpox. The reemergence of smallpox would constitute an international emergency, and failure to immediately report cases to public health authorities would severely impair their ability to contain the disease. ^{[9, 29]}

An informed public could better comply with vaccination and quarantine procedures if smallpox reemerged. If the disease did reemerge, management strategies would include the following:

• Isolation

• Barrier protection - Gown, mask, gloves

• Cremation of corpses

• Isolation of contacts if fever or rash develops

• Surveillance of all face-to-face contacts

Any suspected index case of smallpox should be immediately reported to state health officials and the CDC. The 24-hour emergency telephone number of the Emergency Preparedness and Response Branch of the CDC is 770-488-7100 or 404-639-3532. General clinician information regarding smallpox and smallpox vaccine can be obtained from the CDC Web site or by calling 877-554-4625.

The first drug for the treatment of smallpox, tecovirimat, was approved in July 2018 should smallpox ever be used as a bioweapon. Tecovirimat is an antiviral that inhibits the activity of the orthopoxvirus VP37 protein. The effectiveness of tecovirimat against smallpox was established by studies in animals infected with viruses closely related to variola virus, which demonstrated higher survival rates compared with those of placebo. The safety of tecovirimat was demonstrated in 359 healthy human volunteers, in whom the most frequently reported adverse effects included headache, nausea, and abdominal pain. ^[16]

The FDA approved a second antiviral according to the animal rule, brincidofovir, for treatment of smallpox in June 2021. Brincidofovir is a prodrug of cidofovir. Brincidofovir effectively penetrates cells via its lipid conjugate, releasing the nucleotide analog cidofovir, which then acts to inhibit viral replication. Cidofovir diphosphate selectively inhibits orthopoxvirus DNA polymerase-mediated viral DNA synthesis by incorporation of cidofovir into the growing viral DNA chain. This results in reductions in the rate of viral DNA synthesis. It is indicated for treatment of human smallpox disease caused by variola virus in adult and pediatric patients, including neonates. ^[45]  

To obtain tecovirimat or brincidofovir, clinicians should contact the Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100, which will coordinate shipment with the US government’s Strategic National Stockpile (SNS).

Brincidofovir is a broad-spectrum and long-acting antiviral therapy that has been used to prevent cytomegalovirus (CMV) and adenovirus infections in hematopoietic cell transplantation recipients. It is an effective treatment for infection with orthopoxviruses (eg, variola virus) and is investigational in the US. It is being developed as an effective therapy for smallpox with a recommended oral dose of 200 mg weekly for 3 consecutive weeks.

The antiviral agent cidofovir is available from the SNS as an investigational agent for the treatment of smallpox. Cidofovir is approved in the United States for CMV retinitis.

The most common complications of smallpox vaccination in the modern era range from mild to severe reactions encompassing localized redness, enlarged lymph nodes, fever, insomnia, cross-contamination, eczema vaccinatum, bullseye (progressive vaccinia), postvaccinal encephalitis, myocarditis, pericarditis, angina, myocardial infarction, and death.