Clinical Features

The incubation period of naturally-acquired smallpox averages 12 days, although it could range from 7-19 days after exposure. Clinical manifestations begin acutely with malaise, high fever (to 104 degrees F), rigors, vomiting, headache, backache, and prostration; 15% of patients develop delirium. Approximately 10% of light-skinned patients exhibit an erythematous rash during this phase. Two to three days later, an enanthem consisting of small, painful ulcerations of the tongue and oropharynx appears concomitantly or within 24 hours of a discrete rash about the face, hands, and forearms.

After eruptions on the lower extremities, the rash spreads centrally to the trunk over the next week. The exanthem typically begins as small, erythematous macules which progress to 2-3-mm papules over 2 to 3 days, then to 2-5-mm vesicles within 1 to 2 more days. Four to 7 days after rash onset, the vesicles become 4-6mm umbilicated pustules, often accompanied by a second, smaller fever spike. Lesions are more abundant on the extremities and face, and this centrifugal distribution is an important diagnostic feature. In distinct contrast to varicella, lesions on various segments of the body remain generally synchronous in their stages of development. From 8 to 14 days after onset, the pustules form scabs that leave depressed depigmented scars upon healing. Death, if it occurs, is usually during the second week of clinical disease. The precise cause of death is not entirely understood, but is often attributed to toxemia, with high levels of circulating immune complexes. Although variola concentrations in the throat, conjunctiva, and urine diminish with time, the virus can be readily recovered from scabs throughout convalescence. Therefore, patients should be isolated and considered infectious until all scabs separate.

During the 20th century, two distinct types of smallpox were recognized. Variola minor was distinguished by milder systemic toxicity and more diminutive pox lesions, and caused 1% mortality in unvaccinated victims. However, the prototypical disease caused by Variola major resulted in mortality of 3% and 30% in the vaccinated and unvaccinated, respectively. Mortality rates were higher in certain populations (e.g., Pacific islanders and Native Americans), at extremes of age, during pregnancy (average 65% for ordinary smallpox), and in people with immunodeficiencies. Higher mortality was associated with higher concentrations of lesions, with confluence of lesions portending the worst prognosis. Smallpox during pregnancy resulted in an increased incidence of spontaneous abortions. Acute complications of smallpox included viral keratitis or secondary ocular infection (1%), encephalitis (<1%), and arthritis (up to 2% of children). Bronchopneumonia was common in severely ill patients.

Other clinical forms associated with Variola major - flat-type and hemorrhagic-type smallpox - were notable for severe mortality. Flat-type smallpox occurred in about 6% of all cases and was most common in children. Hemorrhagic smallpox occurred in about 2-3% of all cases, was more common in pregnant women and immunocompromised individuals, and presented with both "early" and "late" forms. Early hemorrhagic disease had a shorter incubation period, often large areas of ecchymosis, and fulminant progression to death, sometimes before lesions had even formed. In the late form, the disease progression was normal, with discrete hemorrhagic areas forming at lesion sites. Mortality was approximately 95% in both flat and hemorrhagic forms.

Partially immune patients, especially those vaccinated more than 3 years before smallpox exposure, could develop less severe forms of disease. Modified smallpox is a clinical form of disease characterized by fewer lesions which are more superficial, associated with a less pronounced fever and a more rapid resolution of disease, often with lesion crusting within 10 days of onset. Some previously immune individuals or infants with maternal antibodies could develop a short-lived febrile syndrome without rash upon exposure to smallpox.

Long-term sequelae in survivors of smallpox include 1-4% blindness from corneal scarring, growth abnormalities in children, and disfiguring or even physically debilitating dermal scarring.

Animal studies suggest that unnaturally large inhaled inoculae of poxviruses may result in a significantly shortened incubation period (even 3-5 days) and fulminant pulmonary disease with or without appearance of rash before death; the implications of these findings for human disease resulting from intentional smallpox aerosolization is unknown at this time.

Historically, smallpox tended to spread slowly through communities. Smallpox could become endemic in densely populated regions even in a population with up to 80% vaccination rates. Increased person to person spread of disease was associated with: 1) exposure to cases with confluent rash or severe enanthem; 2) exposure to cases with severe bronchiolitis and cough; 3) low humidity environment; 4) crowding (as in winter or rainy seasons). The average secondary attack rate of Variola major in unvaccinated household contacts was 58.4% and in vaccinated household contacts 3.8%.

A relative of variola, monkeypox, occurs naturally in equatorial Africa. In 2003, an outbreak of 81 primary human cases occurred in the U.S. due to exposure to exotic pets, some of which had been imported from Africa. Descriptions of human monkeypox in Africa revealed a disease that could be clinically indistinguishable from smallpox with the exception of a generally lower case fatality rate and notable enlargement of cervical and inguinal lymphadenopathy appearing 1-2 days before the rash in 90% of cases. The U.S. cases in 2003 tended to be less severe, with often localized lesions only, no mortality, and no secondary transmission to other humans.

Clinical Syndromes and Differential Diagnosis

Variola Major

Variola major is the most severe form of smallpox and can be further classified into five clinical types on the basis of differences in rash characteristics and density. The prognosis differs among the types (Fenner 1988). The clinical types are:

  • Ordinary (or classic) smallpox
  • Flat-type (or malignant) smallpox
  • Hemorrhagic smallpox
  • Modified smallpox
  • Variola sine eruptione

In the pre-eradication era, diagnosing smallpox and distinguishing its type took into account clinical illness pattern, epidemiologic considerations, and laboratory findings. Although there is some overlap between ordinary, flat-type, and hemorrhagic smallpox, their clinical and epidemiologic features are sufficiently distinct to warrant separate consideration (see below), particularly to enhance clinicians' awareness of the various clinical manifestations of what should be an extinct disease.

Modified smallpox was like ordinary smallpox but had an accelerated course and was a milder illness with fewer skin lesions and a low case-fatality rate; it was more likely to occur in persons with some immunity from past vaccination. Variola sine eruptione occurred in vaccinated contacts of cases and was characterized by sudden onset of fever, headache, and backache. Illness resolved in 1 to 2 days without development of a rash.

Case-fatality rates in the pre-eradication era for the various types of smallpox were high; however, such rates may be lower with modern medical management and intensive care. Recovery results in prolonged immunity to reinfection (Rotz 2010: Smallpox as an agent of bioterrorism. In: Mandell GL, Bennett JE, Dolin R. Principles and practice of infectious diseases. Ed 7. Philadelphia, PA: Elsevier Churchill Livingstone, 2010;2:3977-81).

Images of smallpox rashes are available from the CDC (CDC: Smallpox disease images).

Ordinary (classic) smallpox

  • Ordinary smallpox was the most common type of variola major infection and accounted for at least 90% of cases in the pre-eradication era.
  • The case-fatality rate was usually about 30% in unvaccinated persons (range, 15% to 45%) (Fenner 1988). Death resulted from hypotension and toxemia (associated with circulating immune complexes).
  • The rash illness of ordinary smallpox is somewhat similar to varicella, although disease severity is greater (Henderson 1999: Smallpox: clinical and epidemiologic features).
  • The rash consists of firm, raised pustules that can be confluent, semiconfluent, or discrete.

Clinical features of ordinary smallpox are shown in the table below. A risk-evaluation algorithm can be found on the CDC Smallpox Web site to help clinicians determine if a patient with rash illness is at low or high risk of having smallpox on the basis of the clinical features of the illness (CDC: Evaluate a rash illness suspicious for smallpox).

Clinical Features of Ordinary Smallpox



Incubation perioda

—10-13 days (usually about 12 days)
—May be as short as 7 days and as long as 19 days


—Lasts 2-4 days
—Frequency of prodromal symptoms in one large case seriesb:
    ~Fever, 100%
    ~Chills, 60%
    ~Headache, 90%
    ~Backache, 90%
    ~Vomiting, 50%
    ~Pharyngitis, 15%
    ~Abdominal pain, 13%
    ~Diarrhea, 10%


—Enanthem on mucosa of mouth and pharynx usually begins about 24 hr before skin lesions appear (initially papular, then vesicular, then ulcerative over several days)
—First few skin lesions often appear on face ("herald spots")
—Lesions spread to trunk and proximal extremities and then to distal extremities
—Lesions prominent on face and distal extremities, including palms and soles, in centrifugal pattern
—Lesions initially maculopapular (days 1-2), then vesicular (days 3-5), then pustular (days 7-14); pustules gradually scab over by end of second week or during third week
—Vesicular lesions often have central umbilication that may persist into pustular stage, but as lesions progress they gradually flatten
—Pustules often described as "shotty" (ie, like hard, round foreign bodies embedded in skin)
—Lesions extend deep into skin, often are painful, and pitted scarring occurs as they heal
—Lesions may be discrete (relatively few in number), semiconfluent, or confluent
—Lesions generally progress at same rate with relatively synchronous onset
—In partially immune persons, clinical course may be much less severe and rash may be atypical with fewer lesions and more rapid healing (ie, "modified smallpox")

Laboratory featuresa

—Relative or absolute increase in lymphocytes may be noted
—Granulocytopenia may occur


—Massive amounts of subcutaneous fluid may accumulate during vesicular and pustular stages of rash, leading to severe fluid and electrolyte disturbances, including renal failure
—Massive skin desquamation can occur in cases of confluent disease; patients may clinically and metabolically resemble severe burn victims
—Viral bronchitis/pneumonitis occurs relatively commonly
—Other less common complications:
    ~Corneal ulceration (about 1% of cases) and/or keratitis (about 0.25% of cases) may cause corneal scarring and blindness
    ~Secondary bacterial infections (particularly skin and pulmonary infections)
    ~Encephalitis (0.2% of cases)
    ~Osteomyelitis or arthritis (about 1.7% of cases; usually in children)
    ~Orchitis (rare, 0.1%)

Case-fatality ratesd

—Overall case-fatality rate for ordinary smallpox, 15%-45%a
—Likelihood of death varies by type of disease (ie, confluent, semiconfluent, or discrete)c
—Observed case-fatality rates by type of disease among unvaccinated patients in one large seriesb:
    ~Overall rate, 30%
    ~Confluent disease, 62%
    ~Semiconfluent disease, 37%
    ~Discrete disease, 9%

aFenner 1988.
bRao 1972: Smallpox. Bombay, India: Kothari Book Depot, 1972.
cKoplan 1979: Smallpox: clinical types, causes of death, and treatment. J Infect Dis 1979 Sep;140(3):440-1
dCase-fatality rates are based on historical data from pre-eradication era; such rates may be lower with modern medical management and intensive care.

Flat-type (malignant) smallpox

  • Flat-type smallpox accounted for about 6% of cases in the pre-eradication era and occurred most commonly in children; illness was usually fatal.
  • The rash seen in flat-type smallpox involves flattened, confluent lesions rather than the characteristic firm pustules seen with ordinary smallpox.
  • Flat-type smallpox is thought to be associated with a deficient cellular immune response to the virus, although immunologic data are generally lacking (Henderson 1999: Smallpox as a biological weapon: medical and public health management).

Clinical features are shown in the table below.

Clinical Features of Flat-Type Smallpox



Incubation period

—Similar to ordinary smallpox (mean, 12 days; usual range, 10-14 days)


—Similar to ordinary smallpox (ie, fever, headache, backache, abdominal pain)
—Lasts 2-4 days
—Severe toxemia may occur

Rash illnessa,b

—Lesions develop slowly
—Lesions rarely progress to pustular stage and remain soft and flattened
—Lesions may be "velvety" to touch by 4th or 5th day
—Lesions often confluent
—Lesions and surrounding skin warm to the touch and tender to slight pressure
—If patient survives, lesions gradually disappear without forming scabs and without scarring
—Skin peeling or desquamation may occur as lesions heal

Laboratory features

—Similar to ordinary smallpox
—Relative or absolute increase in lymphocytes may be noted
—Granulocytopenia may occur

Case-fatality ratec

—Case-fatality rate 97% in one series involving 236 patientsd

aFenner 1988.
bDixon 1948.
cCase-fatality rates are based on historical data from the pre-eradication era; such rates may be lower with modern medical management and intensive care.
dRao 1972: Smallpox. Bombay, India: Kothari Book Depot, 1972.

Hemorrhagic smallpox

  • Hemorrhagic smallpox accounted for between 2% and 3% of cases in the pre-eradication era. In one series, 200 cases occurred out of 6,942 hospitalized patients (Rao 1972: Smallpox. Bombay, India: Kothari Book Depot, 1972).
  • Illness was more common in adults, and pregnant women appeared to be at greater risk.
  • Hemorrhagic smallpox involved hemorrhages into the skin and/or mucous membranes. Early-onset and late-onset forms were described (Fenner 1988).
  • The pathologic features of hemorrhagic smallpox are consistent with disseminated intravascular coagulation (Mehta 1967: Hemorrhagic smallpox. A study of 22 cases to determine the cause of bleeding. Indian J Med Sci 1967 Aug;21(8):518-23, Mitra 1976: Some observations on haemorrhagic smallpox (Type I). J Indian Med Assoc 1976 Dec 1;67(11):237-40).
  • As with flat-type smallpox, a defective immune response is suspected as the cause; however, immunologic data generally are lacking (Henderson 1999: Smallpox as a biological weapon: medical and public health management). Several studies have found lower antibody responses among patients with hemorrhagic disease compared with those with ordinary disease (Downie 1969, Sarkar 1967: Antibody response in haemorrhagic smallpox. Indian J Med Res 1967 Nov;55(11):1143-9).

Clinical features are outlined in the table below.

Clinical Features of Hemorrhagic Smallpox



Incubation period

—Similar to ordinary smallpox (mean, 12 days; usual range, 10-14 days)


Early-onset form: illness onset sudden, with high fever, severe headache and backache, and toxemia; hemorrhages often noted by day 2
Late-onset form: illness begins with a typical prodrome, lasting 3-4 days

Rash illnessa,b

Early-onset form: generalized dusky erythema, petechiae, and ecchymoses occur soon after illness onset
Late-onset form: lesions begin as macules and develop into pustules; bleeding at base of skin lesions occurs

Hemorrhagic manifestations

—In both forms, bleeding may occur from mucosal surfaces
—Features in one series of nine patients with early-onset formc:
    ~Subconjunctival hemorrhage, 67%
    ~Hematuria, 56%
    ~Epistaxis, 33%
    ~Hematemesis and/or melena, 33%
    ~Hemoptysis, 33%
    ~Bleeding from gums, 33%

Laboratory featuresc,d

—Relative or absolute increase in lymphocytes may be noted
—Granulocytopenia may occur
—Features consistent with disseminated intravascular coagulation are common:
    ~Clotting-factor deficiency
    ~Prolonged prothrombin time

Case-fatality ratee

—In one series of 85 patients, case-fatality rate was 96%b
—Death usually occurs during the first week of illness

aFenner 1988.
bRao 1972: Smallpox. Bombay, India: Kothari Book Depot, 1972.
cMitra 1976: Some observations on haemorrhagic smallpox (Type I). J Indian Med Assoc 1976 Dec 1;67(11):237-40.
dMehta 1967: Hemorrhagic smallpox. A study of 22 cases to determine the cause of bleeding. Indian J Med Sci 1967 Aug;21(8):518-23.
eCase-fatality rates are based on historical data from pre-eradication era; such rates may be lower with modern medical management and intensive care.

Smallpox in children

The clinical picture of smallpox in children generally is similar to that seen in adults. However, in one series of 100 cases among children in India, the frequency of various signs and symptoms varied somewhat from those classically described (Sheth 1971). For example, headache and backache were less common, whereas vomiting, conjunctivitis, and cough were somewhat more common. Signs, symptoms, and complications identified in that series are shown in the table below. Of the 100 patients, 66 had confluent ordinary smallpox, 25 had discrete ordinary smallpox, 6 had flat-type smallpox, and 3 had hemorrhagic smallpox. Overall, 34 children died (including all of those with flat-type or hemorrhagic smallpox).

The case-fatality rate in infants may be somewhat higher than in older children or adults (ie, >40%) (Fenner 1988). In one case series, the case-fatality rate for infants was 85% (Mazumder 1975).

Infection in pregnant women often leads to premature labor and death of the fetus (Fenner 1988). The overall case-fatality rate for pregnant women estimated from analysis of mid-20th century outbreaks was calculated to be about 34%. The proportion of miscarriage or premature birth was found to be approximately 40%, but no clear pattern was discernable. Premature birth was highest during the last trimester of pregnancy (Nishiura 2006) No clear congenital syndrome has been associated with smallpox infection in utero.

Signs, Symptoms, and Complications of Smallpox in Children


Headache (15%)
Backache (15%)
Retro-orbital pain (15%)
Prostration (75%)


Fever (100%)
Vomiting (83%)
Conjunctivitis (77%)
Hepatosplenomegaly (75%)
Hypotonia (75%)
Cough (71%)
Hoarseness (71%)
Edema (71%)
Delirium (64%)
Convulsions (7%)


Constipation (66%)
Bronchopneumonia (37%)
Alopecia (19%)
Osteomyelitis (4%)
Subcutaneous abscess (3%)
Diarrhea (2%)

Adapted from Sheth 1971.

Variola Minor

Variola minor is a milder form of smallpox that is caused by distinct strains of variola virus. Variola minor was first recognized in the late 1800s; during the early 20th century, it was the most prevalent form of smallpox in the United States and Great Britain. The illness may be difficult to distinguish from variola major infection in partially immune persons.

Distinguishing Features of Variola Major and Variola Minor


Variola Major

Variola Minor*†


—Constitutional symptoms severe

—Constitutional symptoms tend to be mild

Rash illness

—Lesions often confluent or semiconfluent
—Rash evolves over 2-3 wk

—Lesions usually discrete
—Rash evolves over 1-2 wk


—Flat-type or hemorrhagic disease occurs more commonly (6% and 2%, respectively, in one large series‡)

—Hemorrhagic disease rare (<0.5%)

Case-fatality rate

—May be high (15%-45%)

—Fatal outcomes rare (<1%)

aFenner 1988.
bKer 1967: Variola minor: observations and experiences in Staffordshire, England, during 1966. Clin Pediatr 1967 Sep;6(9):533-9, Marsden 1948: Variola minor: a personal analysis of 13,686 cases. Bull Hyg 1948;23:735-46.
cRao 1972: Smallpox. Bombay, India: Kothari Book Depot, 1972.

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