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SmallpoxClinical FeaturesThe 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 DiagnosisVariola MajorVariola 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:
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
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).
Flat-type (malignant) smallpox
Clinical features are shown in the table below.
Hemorrhagic smallpox
Clinical features are outlined in the table below.
Smallpox in childrenThe 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.
Variola MinorVariola 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.
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