Most cases are usually mild and self-limiting, and most patients will recover within 2 to 4 weeks without treatment.
Typically, more than 90% of survivors have no complications, regardless of smallpox vaccination status. In survivors who do develop long-term complications, the most common sequelae are disfiguring scarring of the skin (including pitted scars) and blindness.
The acute infectious illness results in immunity following recovery. Relapse of disease is rare, but is possible. One UK patient experienced a mild relapse 6 weeks after hospital discharge in 2019. The relapse was short, and was not associated with detectable viraemia.
The occurrence of a second febrile period when the lesions become pustular has been associated with deterioration of the patient’s general condition.
Severe or complicated disease and death occurs more commonly in younger children and immunocompromised people.
Most reported deaths, prior to the 2022 global outbreak, occurred in younger children and immunocompromised people (e.g., poorly controlled HIV infection).
In the early years of human infection, 100% of deaths were in children <10 years of age. However, between 2000 and 2019, children <10 years of age accounted for only 37.5% of deaths.
Patients with fatal disease had higher viral loads of the virus in their blood, maximum skin lesion count, and elevated transaminases.
Severe complications and sequelae were more common among unvaccinated patients (74%) compared with vaccinated patients (40%).
Case fatality rates (CFRs) vary according to virus clade, geographical location, and availability of medical facilities, and are vulnerable to case ascertainment bias during outbreaks.
Historically, the CFR of the Clade I virus has been estimated to be 1% to 10%, while the CFR of the Clade IIa virus has been estimated to be 1.4% to 3%. The estimated pooled CFR was 8.7% for both clades in one systematic review (10.6% for Clade I and 3.6% for Clade IIa). The overall CFR was 0% in an outbreak in the US in 2003.
Overall mortality has decreased in the 2022 global outbreak compared with previous outbreaks. The overall CFR is 0.09% (as of 20 January 2023). Fatalities due to the Clade IIb virus are rare. Causes of death have included multi-organ failure and encephalitis. Whether mortality is associated with any specific factors is currently unknown.
An apparent case of reinfection has been reported 4 months after recovery from initial infection. Further research is required on immunity after recovering from infection.
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