Sudden onset of high fever with malaise, prostration, headache and backache.
A macular rash develops 1 to 3 days later, firstly on the oral and pharyngeal mucosa, spreading to the face and forearms, trunk and legs.
The macular rash becomes papular after 1 to 2 days and then vesicular after a further 1 to 2 days. The vesicular rash is typically more prominent on the face and extremities than on the trunk (centrifugal distribution).
The vesicular rash becomes pustular after a further 2 to 3 days. Pustules are round, tense and deep in the dermis. They may affect the palms of the hands and soles of the feet.
Vesicles and pustules are typically at the same stage of development in any area of skin.
The pustules form scabs after 5 to 8 days.
The scabs gradually separate leaving characteristic pitted scarring. The scars are most evident on the face.
Full blood count shows a lymphocytosis or a predominance of lymphocytes, with many atypical and activated mononuclear cells. Haemorrhagic disease is preceded by a fall in the platelet count.
Differential diagnosis
Experience from the global eradication campaign was that atypical cases of
chickenpox (varicella-zoster virus (VZV)) and disseminated
herpes simplex virus (HSV) infection presented the greatest difficulties in the differential diagnosis.
Chickenpox can be distinguished from smallpox by its much more superficial lesions, their presence on the trunk rather than on the face and extremities (centripedal distribution), and by the development of successive crops of lesions in the same area (ie. lesions at different stages of development). The WHO has produced training materials to help health staff recognise smallpox, distinguish it from chickenpox, and avoid diagnostic errors. These materials are available electronically:
http://www.who.int/emc/diseases/smallpox/smallpox-english.ppt
Disseminated HSV infection may also present a problem for differential diagnosis. However, VZV and HSV are both herpes viruses, and should be readily distinguished from orthopox virus particles by EM of vesicular fluid preparations.
Other causes of rash such as measles, enterovirus, parvovirus B19 or rubella may also cause uncertainty but should be distinguishable clinically, as well as in the laboratory. Molluscum contagiosum is also an orthopox virus, but is usually distinguishable from smallpox on clinical grounds (lesions are umbilicated from an early stage and the patient is well) and in the laboratory.
The final diagnosis in consultations for suspected smallpox with a single UK smallpox panellist are listed in table 1. These were made over a 20 year period in an immunised population, during which there was one outbreak of variola major and one of variola minor
Table 1: final diagnosis in consultations for smallpox
Diagnosis | Number of cases |
Smallpox | 4 |
No diagnosis, but proved not smallpox (3 cases required isolation) | 15 |
Chickenpox | 113 |
Papular vesicular urticaria | 34 |
Generalised vaccinia and other reactions to vaccination | 23 |
Staphylococcal folliculitis | 9 |
Erythema multiforme | 9 |
Scabies | 6 |
Bacterial septicaemias | 4 |
Herpes simplex | 3 |
Secondary syphilis | 2 |
Others included measles, coxsackie, acute leukaemia, anaphylactoid purpura, fungal infections, septic spots, insect bites, pityriasis rosea, sweat rash | 18 |
Mortality
Estimates of mortality are complicated by the fact that documented epidemics were modified by the presence of some immune individuals in the population or by interventional vaccination. Importation into smallpox naïve and unvaccinated populations caused the highest mortality.
Some clinical forms of smallpox were highly virulent (variola major) and others much less so (variola minor). The highest mortality was seen in children aged less than 1 year, in the elderly, in pregnant women who were more susceptible to haemorrhagic disease, and in people immunocompromised due to medical disorders or treatments. There are now many more vulnerable individuals in the elderly and immunocompromised groups than in the past.
Atypical presentations
Along with the typical presentation of smallpox, two other rare forms are described: haemorrhagic and malignant smallpox.
Cases of
haemorrhagic smallpox were uniformly fatal. They occurred among all ages and in both sexes, with pregnant women particularly susceptible. Haemorrhage into the mucous membranes and the skin accompanied the rash. Haemorrhagic smallpox was most commonly misdiagnosed as haemorrhagic chickenpox, meningococcal septicaemia or acute leukaemia.
Cases of
malignant smallpox were characterised by lesions that did not develop to the pustular stage but remained soft and flat.
Modified smallpox
Vaccinated individuals may develop a mild disease, with similar prodromal features, but only a few atypical lesions, and a mortality of well under 1%.
Note however that they are still infectious.