Henderson DA, Moss B.

Publication Details

Clinical Description

Smallpox had an incubation period of about 12 days, with a range of 7 to 17 days. A 2- to 5-day period of high fever, malaise, and prostration with headache and backache was followed by the development of a maculopapular rash. The rash appeared first on the mucosa of the mouth and pharynx, the face, and the forearms and spread to the trunk and legs. Within 1 to 2 days, the rash became vesicular and then pustular. The pustules were characteristically round, tense, and deeply embedded in the dermis; crusts began to form about the eighth or ninth day. When they separated, they left pigment-free skin and, eventually, pitted scars. The eruption was characteristically more extensive on the face and distal parts of the arms and legs (Fig. 6-2), and lesions were occasionally found on the palms and soles. Death, when it occurred, was usually late in the first week or during the second week of the illness and was commonly due to the effects of an overwhelming viremia. On occasion, a severe and always fatal hemorrhagic form occurred, with extensive bleeding into the skin and gastrointestinal tract followed by death within a few days.

Figure 6-2. A typical case of variola major about 7 days after the onset of rash.

Figure 6-2

A typical case of variola major about 7 days after the onset of rash. (World Health Organization Smallpox Recognition Card.)

Illness caused by variola major was generally more severe, with a more extensive rash, a higher fever, and a greater degree of prostration, than illness caused by variola minor. A milder form of disease was also seen among those who had previously been vaccinated; the rash in such persons tended to be more scant and atypical and the evolution of lesions more rapid.

Cases of smallpox among pregnant women often resulted in spontaneous abortion of the fetus or a stillborn infant with evidence of lesions on the skin.


Variola virus belongs to the genus Orthopoxvirus, family Poxviridae, which includes the agents of vaccinia, monkeypox, cowpox, camelpox, and ectromelia. 46 All species exhibit extensive serological cross-reactivity, both in in vitro tests and in experimental animals. The poxvirus genome, the largest of all virions, is a brick-shaped structure with a diameter of about 200 nm, consisting of a single molecule of a double-stranded DNA. It differs from most other DNA viruses in that it multiplies in the cytoplasm rather than in the nucleus of susceptible cells.

The orthopoxviruses grow and produce a cytoplasmic effect in cultured cells derived from many species, 47, 48 although they generally grow best in cells from humans and other primates. The four that infect humans (variola, vaccinia, cowpox, and monkeypox viruses), however, cannot be differentiated readily from one another in most cell cultures. For diagnostic purposes, therefore, they are customarily grown on the chorioallantoic membrane of 10- to 12-day-old chick embryos on which they produce pocks characteristic of their species. 49


Natural smallpox infection occurred by implantation of variola virus on the oropharyngeal or respiratory mucosa. Virions in droplets expressed from nasal and oropharyngeal secretions were far more infectious than those bound in the fibrin mesh of scabs. After migration to and multiplication in regional lymph nodes, an asymptomatic viremia developed about the third or fourth day, followed by multiplication of virus in the spleen, bone marrow, and lymph nodes. A secondary viremia began about the eighth day, accompanied by fever and toxemia. The virus, contained in leukocytes, then localized in small blood vessels of the dermis beneath the oral and pharyngeal mucosa and subsequently infected adjacent cells. In the skin, this process resulted in the characteristic maculopapular lesions and, later, the vesicular and pustular lesions, which, for reasons unknown, were more extensive on the face and distal extremities. Lesions in the mouth and pharynx ulcerated quickly because of the absence of a stratum corneum, releasing large amounts of virus into the saliva about the time the cutaneous rash first became visible. Virus titers in saliva were highest during the first week of illness, corresponding with the period during which patients were most infectious.

Hemagglutinin-inhibiting (HI) and neutralizing antibodies could be detected beginning about the sixth day of illness, or about 18 days after infection, and complement-fixing (CF) antibodies approximately 2 days later. 50, 51 Neutralizing antibodies were long lasting, whereas HI antibodies declined to low levels within 5 years, and CF antibodies rarely persisted for longer than 6 months. Little is known about the development of cell-mediated immunity.

Vaccinia-induced antibody responses were more rapid. They could be detected as early as the 10th day 52 after primary vaccination and within a week of revaccination. This accelerated response was associated with complete or partial protection of persons vaccinated at or soon after exposure.

Except for the lesions in the skin and mucous membranes and reticulum cell hyperplasia, other organs were seldom involved in variola infection. Secondary bacterial infection was not common, and death, when it occurred, probably resulted from the toxemia associated with circulating immune complexes and soluble variola antigens. 53 Encephalitis sometimes ensued that was indistinguishable from the acute perivascular demyelination observed as a complication of infection due to vaccinia, measles, and varicella.

As the patient recovered, the scabs separated and the characteristic pitted scarring gradually developed (Fig. 6-3). The scars were most evident on the face and resulted from the destruction of sebaceous glands followed by shrinking of granulation tissue and fibrosis.

Figure 6-3. An Afghani boy with characteristic residual facial scars after smallpox.

Figure 6-3

An Afghani boy with characteristic residual facial scars after smallpox. (Courtesy of the World Health Organization, Geneva, Switzerland.)


Most cases of smallpox were able to be diagnosed readily by the appearance of the typical deep-seated rash, the centrifugal distribution of lesions, and the fact that all lesions were at the same stage of development on any given area of the body. The infrequent hemorrhagic cases were often initially misdiagnosed as meningococcemia, acute leukemia, or drug toxicity, but their identity was soon established by examination of other patients who were the source of infection or to whom disease had been transmitted. Varicella was by far the most frequent disease to be confused with smallpox. Smallpox patients who had previously been vaccinated and those with variola minor sometimes exhibited a sparse and sometimes atypical rash with minimal systemic symptoms that resembled varicella; severe cases of varicella in adults with extensive rash were also sometimes mistaken for smallpox. 54

Diagnosis of a poxvirus infection can be rapidly confirmed by electron microscopic identification of virus particles in vesicular or pustular fluid or scabs. Differentiation as to which orthopoxvirus is the responsible agent is usually apparent from its characteristics of growth on the chorioallantoic membrane of chick embryos, although confirmation by other biological tests is sometimes necessary.

Recovered patients exhibit high titers of neutralizing, HI, and CF orthopoxvirus antibodies, but cross-absorption studies are required to identify which of the orthopoxvirus species is the agent responsible for illness. Characteristic residual facial scars are most useful in documenting prior cases of variola major, 55 but such scars were too infrequent to be of value in identifying recovered cases of variola minor. 56