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.[47]

  • Persistent symptoms (e.g., anorectal or genital issues, fatigue, loss of physical fitness, pain, scarring, mental health issues) have been reported in up to two-thirds of patients 3-20 weeks after the initial infection in the 2022-23 global outbreak, which may significantly affect the patient's quality of life.[275]

  • 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 viremia.[242]

  • The occurrence of a second febrile period when the lesions become pustular has been associated with deterioration of the patient’s general condition.[141]

Severe or complicated disease and death occurs more commonly in younger children and immunocompromised people.

  • Most reported deaths, prior to the 2022-23 global outbreak, occurred in younger children and immunocompromised people (e.g., poorly controlled HIV infection).[47]

  • 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.[4]

  • Patients with fatal disease had higher viral loads of the virus in their blood, maximum skin lesion count, and elevated transaminases.[47]

  • Severe complications and sequelae were more common among unvaccinated patients (74%) compared with vaccinated patients (40%).[141]

Case fatality rates (CFRs) vary according to virus clade, geographic 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%.[47]​ 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).[4]​ The overall CFR was 0% in an outbreak in the US in 2003.[36]

  • Fatalities due to the Clade IIb virus are rare. Overall mortality has decreased in the 2022-23 global outbreak compared with previous outbreaks.[13]​ The overall CFR is 0.16% (as of 9 May 2023).[7] Approximately 1.2 deaths per 1000 cases occurred globally during the outbreak, with 1.3 deaths per 1000 cases in the US.[276]​ Causes of death have included multi-organ failure and encephalitis.[277][278]​ Whether mortality is associated with any specific factors is currently unknown. However, nearly all deaths in the US were in patients who were immunocompromised at the time of diagnosis.[276][279]

Cases of suspected reinfection have been reported.

  • Apparent cases of reinfection have been reported 3-6 months after recovery from initial infection, possibly with different strains of the virus.[280][281][282][283][284]

  • Further research is required on immunity after recovering from infection.​​​

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