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Medical Professionals

Professional Reference articles are designed for health professionals to use. They are written by UK doctors and based on research evidence, UK and European Guidelines. You may find one of our health articles more useful.

This disease is notifiable in the UK - see the separate NOIDsarticle.

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What is smallpox?

Smallpox has now been eradicated but ongoing interest in this disease lies both in the success of the eradication programme, its potential as a biological weapon and its similarity to monkeypox.

Smallpox used to be a common cause of morbidity and mortality worldwide and is a viral haemorrhagic fever caused by the variola virus which belongs to the same genus as cowpox, monkeypox, orf and molluscum contagiosum.

See also the separate article Smallpox Vaccination.

When was smallpox eradicated?

There have been no known cases of smallpox since 1979.1 There are currently three laboratories in the world which stock the virus: the Centers for Disease Control and Prevention in Atlanta (USA), at the Institute of Viral Preparations in Moscow (Russia) and the Russian State Research Centre of Virology and Biotechnology in Koltsovo.2

There is a theoretical risk from bioterrorism.3 The effects on the population by a release of this virus would be potentiated by:

  • The low population immunity.

  • Difficulty in diagnosis as health professionals have no experience of cases.

  • Density and mobility of today's populations.

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There is no natural animal or insect reservoir. Infection starts in the respiratory tract before disseminating to form infective foci within the skin, respiratory and gastrointestinal tracts, the kidneys and brain. There are subsequently two clinical forms of the disease depending on the sub-strain of variola:

  • Variola major - this is the more severe and most common form of the disease accounting for >90% of cases. These patients present with fevers, and extensive rashes, and there is a 30% mortality rate.4 There are four subtypes of the variola major picture:

    • Ordinary: most frequent type.

    • Modified: occurs in previously vaccinated patients.

    • Flat and haemorrhagic: both rare, very severe and usually fatal (>95% cases).

  • Variola minor - this is a much less severe form of the disease which is less common and associated with a mortality rate of <1%.


  • The virus is acquired from inhalation, although it can remain viable in fomites for about a week and may be transmitted directly via saliva, respiratory secretions and vesicular fluid.

  • There is an asymptomatic incubation period lasting about 14 days (ranging from 9 to17 days) following inoculation.

  • Infectiousness peaks at about the second or third day of the fever but is ongoing until the scabs dry over following recovery, or until death.

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Smallpox symptoms6 7 8

Cardinal signs have been described. The rash is vesicular, most dense on the face and extremities, beginning on days 3-4 of illness. Enlarging vesicles coalesce to form soft, flaccid bullae covered by skin, which easily rubs off, leaving painful exposed areas.

Variola major

  • Incubation (9-17 days): not contagious and usually asymptomatic.

  • Prodrome (2-4 days): usually contagious with abrupt onset of fever (usually ≤39°C), malaise, headache, intense, ill-defined body ache (back, chest, loins), vomiting, and anxiety.

  • Early rash (~4 days): highly contagious and the rash emerges as small red spots on the tongue and in the mouth. These develop into sores that beak open and shed the viral load into the mouth and pharynx. The rash spreads centrifugally to the face, arms and legs and, over 24 hours, to the whole body.

  • Pustular rash (~5 days): contagious and lesions become firm, rounded pustules.

  • Pustules and scabs (~5 to 6 days): contagious still and pustules begin to form a scab and crust over. There are resolving scabs from about 6 days, leaving pitted scars. The patient is no longer contagious once all the scabs have dropped off.

Variola minor

This is more common in previously vaccinated populations or those who have had exposure to the disease. These patients are contagious and may even confer the fulminant variety of smallpox on to unprotected individuals.

  • Prodrome is similar but the temperature tends to be higher (39.5-40.5°C).

  • Early rash is less marked.

  • Maculopapular rash starts earlier (days 3-4) and has characteristic areas of distribution:

    • Scalp and face: particularly on the nose

    • Neck: particularly over the trachea and sternocleidomastoid muscles

    • Arms: particularly over heads of radius and ulna and in wrist folds

    • Legs: particularly over the heads of the malleoli

  • Vesicles appear earlier (~day 5) and are similar to those of variola major in most ways but are not hot or tender to touch.

  • Most crusts are shed by about day 15, when large pitted scars are left behind.

In fulminant cases, death usually occurs during the prodromal or early rash phases. In less fulminant cases, death may occur between day 8 and 15.

Differential diagnosis8 9

  • Atypical chickenpox.

  • Disseminated herpes simplex.

  • Other causes of rash - eg, measles virus, enterovirus, parvovirus B19, rubella.

  • Other infective causes - eg, impetigo, scabies, molluscum contagiosum.

  • Severe adverse reaction to medication/vaccination.

  • Erythema multiforme.

Diagnosis and investigations

Diagnosis is made on the clinical appearance and progression of the disease as outlined above. Diagnostic algorithms will be distributed in the event of an outbreak.

The following are generally agreed to be diagnostic: an illness with acute onset of fever of more than 38°C, which is persistent, followed by a rash without other apparent cause, characterised by vesicles or firm pustules at the same stage of development and with a predominantly centrifugal distribution.

As in symptoms section above, the smallpox risk evaluation algorithm taken from the US CDC checklist provides a tickbox-style question sheet to guide the practitioner.

Smallpox can be confirmed with a viral swab of the pharynx and sent series of rapid tests can then be performed (electron microscopy which takes ~2 hours or real-time polymerase chain reaction (PCR) testing which takes ~6 hours) to confirm suspicions. These tests can only be carried out in specialised laboratories. Full blood count shows a lymphocytosis or a predominance of lymphocytes, and many atypical and activated mononuclear cells. Haemorrhagic disease is preceded by a fall in the platelet count.

Smallpox treatment and management7

General measures of a suspected case include:

  • Call the duty public health specialist/consultant who will then call the Smallpox Diagnostic Expert (SDE) to come and assess the patient. While you are waiting:

    • Isolate the patient as best as possible

    • Try to ensure that close contacts remain at the scene

    • Record details of close contacts who have left the scene

  • There will be management protocols to which you can refer for algorithms.

  • Liaise with the on-call public health specialist.

  • Two specific antiviral treatments have been approved: tecovirimat and brincidofovir.10 11

Outbreak management

There are several issues relating to the management of an outbreak:

  • Care of the patient.

  • Tracing of contacts.

  • Dissemination of information to healthcare professionals and to the public.

  • Vaccination strategy.

This is carried out through the combined work of local specialised clinicians in Smallpox Care Centres and the regional Smallpox Diagnosis and Response Groups. The SDE is the trigger to activating local, regional and national strategies. An alert level will be advised by the Chief Medical Officer and all suspected cases are investigated by the World Health Organization (WHO).

Categorisation of contacts

Contacts can be categorised and there are specific identification, monitoring and vaccination programmes for each of several categories of contact. These would be put into action by the regional Smallpox Diagnosis and Response Group.


In the current climate of global unrest and terrorist threats, smallpox has been highlighted as a potential biological weapon. As it has been eradicated, the most likely outbreak is from such an attack. The threat lies in the fact that it has an airborne route of spread, it is a severe illness with a high fatality rate and those who do survive are left with disfiguring scars and a risk of blindness (see Complications, below).There are clear instructions for Directors of Public Health and Consultants in Communicable Disease, which outline a cascade of urgent management steps; however, the onus is on all healthcare practitioners to have at least an awareness of the disease, its diagnosis and the management contingencies.


  • During the illness: dehydration, bronchopneumonia, osteomyelitis, secondary skin and conjunctival/corneal infections, and death.

  • Following the illness: severe skin scars, particularly round the face, blindness secondary to corneal scarring, and arthritis.


Other than measles and influenza, variola remains one of the most readily communicable infectious diseases. Mortality is significant with an overall rate of about 30% (up to 90% in non-immune populations).The highest mortality is seen in children aged less than 1 year, in the elderly, in pregnant women and in immunocompromised patients.

Prevention of smallpox13

In the event of an outbreak, healthcare workers involved in the primary management of these patients (primarily Smallpox Diagnostic Experts (SDEs) and Diagnosis and Response Teams) will be vaccinated on a voluntary basis. Their families will not be vaccinated but, following a confirmed case, contacts may be vaccinated according to predetermined protocols. The side-effects preclude mass vaccination.

This is a live vaccine made from the related Vaccinia virus (therefore you cannot get smallpox from the vaccine). It produces a high level of immunity for 3-5 years and gradually decreasing immunity thereafter (it lasts no longer than 10 years). A further vaccination confers longer immunity.

Historical background - when was smallpox discovered?2

Cases of smallpox have been documented in the 4th century A.D. in China and there is less reliable evidence suggesting that it has been recognised as far back as 1200 B.C. Pandemics have since affected Europe and Asia and the disease was introduced into the Americas in the 1600s via infected blankets, where it caused massive fatalities among the indigenous peoples. In 1796, Edward Jenner developed the basis for vaccination (starting with the related cowpox virus) and, by the early 1900s, smallpox vaccination had become mandatory in developed countries. The last documented natural case was that of an unvaccinated Somali cook on the 26th October 1977 and a further accidental case involving a laboratory worker in Birmingham occurred a year later. The World Health Organization officially declared it eradicated in 1979.

Further reading and references

  1. Smallpox and Monkeypox; The Green Book Chapter 29, GOV.UK, Sept 2022
  2. Meyer H, Ehmann R, Smith GL; Smallpox in the Post-Eradication Era. Viruses. 2020 Jan 24;12(2). pii: v12020138. doi: 10.3390/v12020138.
  3. Delaune D, Iseni F; Drug Development against Smallpox: Present and Future. Antimicrob Agents Chemother. 2020 Mar 24;64(4). pii: AAC.01683-19. doi: 10.1128/AAC.01683-19. Print 2020 Mar 24.
  4. Theves C, Biagini P, Crubezy E; The rediscovery of smallpox. Clin Microbiol Infect. 2014 Mar;20(3):210-8. doi: 10.1111/1469-0691.12536.
  5. Simonsen KA, Snowden J; Smallpox
  6. CDC Smallpox risk evaluation; Algorithm to evaluate a rash suspicious of smallpox, Centers for Disease Control and Prevention - this is an American website.
  7. Simonsen KA, Snowden J; Smallpox
  8. Smallpox, DermNet - last updated 2006
  9. Breman JG; Smallpox. J Infect Dis. 2021 Sep 30;224(12 Suppl 2):S379-S386. doi: 10.1093/infdis/jiaa588.
  10. Merchlinsky M, Albright A, Olson V, et al; The development and approval of tecoviromat (TPOXX((R))), the first antiviral against smallpox. Antiviral Res. 2019 Aug;168:168-174. doi: 10.1016/j.antiviral.2019.06.005. Epub 2019 Jun 7.
  11. Hutson CL, Kondas AV, Mauldin MR, et al; Pharmacokinetics and Efficacy of a Potential Smallpox Therapeutic, Brincidofovir, in a Lethal Monkeypox Virus Animal Model. mSphere. 2021 Feb 3;6(1). pii: 6/1/e00927-20. doi: 10.1128/mSphere.00927-20.
  12. Hayoun MA, King KC; Biologic Warfare Agent Toxicity
  13. Smallpox; Centers for Disease Control and Prevention, National Center for Emerging and Zoonotic Infectious Diseases (NCEZID), Division of High-Consequence Pathogens and Pathology (DHCPP), July 2017

Article history

The information on this page is written and peer reviewed by qualified clinicians.

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