What Is Smallpox Virus( Variola):Diagnosis,Treatment And Prevention

Smallpox virus is readily visible with any microscope equipped with dark-field illumination or by phase contrast microscopy. With electron microscopy, the smallpox virus resembles – elementary bodies of vaccinia virus. The elementary bodies are small, brick-shaped structures with a diameter of about 20Q m/x. They can be demonstrated by direct examination of smears of early skin lesions. The virus is very resistant to drying,, and living virus can be demonstrated from scabs kept at room temperature for over three years. Virulent virus has survived on clothing of patients and on bedclothes of hospitalized patients, and has caused the disease in laundry workers who were  not protected.


Approximately 75,000 cases of smallpox were reported to the World Health Organization in 1966, principally from Asia and Africa. The last major importation of smallpox into western Europe occured in 1963, when the four original cases resulted in 141 secondary cases and 11 deaths. The United States of America has not had an importation since 1949. The control of smallpox by mass vaccination campaigns sup­ported by the World Health Organization is cur­rently under way in many parts of the world where endemic smallpox persists.


The principal natural reser­voir of smallpox is thought to be the patient suffering from the disease. It is true that smallpox affects monkeys and that there may be other animal reservoirs, but they have not been demon­strated to date as an important source of virus in the absence of human cases. Spread may be direct or, quite often, indirect through clothing or utensils infected by the patient. The patient is not infective until the third day of the clinical disease, that is, one day before the macular-papu­lar phase of the skin eruption is noted. Contacts may be allowed at large until they actually become ill because they are not infective during the early pre-eruptive febrile disease.

Pathology and Pathogenesis.

It is likely that the site of entry of the smallpox virus is the upper respiratory tract. In the 12-day incubation period the virus probably multiplies in the regional lymphoid tissues. The fact that no patient is infectious during the incubation period suggests that in this interval an open lesion does not exist in the respiratory mucous. In the unmodified case, a massive viremia occurs at the onset of the fever, and remains during the first two or three days of the pre-eruptive phase. In this way the virus localizes in the mucous membranes and in the skin as well as in the internal tissues. After the virus disappears from the blood and the skin eruption appears, the patient feels better, and the temperature tends to decrease. Antibodies are noted in the blood as early as the fourth day of the disease. The virus multiplies in the epithelial cells of the skin while being relatively protected from the action of circulating antibody so that cell destruction continues for some time.

When pustulation occurs, the temperature tends to rise again, probably because of the absorption of the toxic products of cell necrosis. It is of interest that patients become infectious on the third day of the disease, probably because saliva has been contaminated through the early mucosal lesions noted in the pharynx and mouth. Skin lesions be­come infective after the superficial corneal layer has been severely damaged. Scabs remain infec­tious throughout the illness and until their separa­tion during the third to fourth week of illness. Thesevere cases, and is due to destruction of sebaceous glands followed by organization and subsequent shrinking of granulation tissue and fibrosis. In cases of hemorrhagic smallpox numerous blood cells are present in the corium. Cytoplasmic inclusions are characteristic of infection with the vaccinia-variola group of viruses. Inclusion bodies can be shown best in epithelial cells, particularly of the involved skin and mucous membranes.

Skin scrapings stained with hematoxylin and eosin show the inclusion to be round or oval homo­geneous masses, either basophilic or acidophilic, located in the cytoplasm fairly close to the nucleus. The appearance of the inclusion bodies varies with the stage of infection but also with the method of fixation and staining, and this suggests that they consist of masses of elementary bodies. Intra­nuclear inclusions have also been described but these are not invariably seen. With antimicrobial therapy, pathologic changes from bacterial com­plications are not found, and bacterial cultures, in this situation, are usually sterile.

Clinical Manifestations.

The incubation period of smallpox is generally 12 days. The illness begins with intense malaise and high fever lasting for four to six days. There is intense prostration, and the clinical impression is often that of dengue. Severe headache, photophobia, and, occasionally, vomiting are noted. A small number of patients show a prodromal or “toxemic” rash, most easily noted in the groins, the axillae, and the flanks. On the fourth day the focal rash occurs, the fever diminishes slightly, and the patient feels much better, just at a time when the first macular skin lesions begin to form. The focal rash usually occurs first on the mucosa of the mouth and pharynx, the face, or the forearms, and it then spreads to the trunk and legs. A feature of variola is the fact that lesions in any one area are all at the same stage of development, whereas in varicel­la they are in all stages.

The initial rash is macular and quickly becomes papular. Within two days the papules have developed into vesicles and these, within a few hours, become cloudy and pustular. On the eighth or ninth day from the beginning of the rash, drying and crusting begin. From three to four weeks from the onset of the disease, scabs have generally fallen off, leaving pigment-free skin, frequently with some scarring or pitting. The eruption is characteristically more severe on the face and the distal parts of the arms and legs, and least severe over the trurik and abdomen. The groins and axillae may be entirely spared. This centrifugal distribution is distinct from the char­acteristic rash of varicella, which tends to be centripetal. Lesions are generally found on the palms of the hands and the soles of the feet, a situation uncommonly seen in varicella of child­hood, although these parts are often involved in the adult form. Fever generally recurs during the pustular stage, but the temperature returns to normal as the lesions become crusted. The char­acteristic pustular lesions of smallpox are round, raised, and tense with a tendency to central depression as they begin to dry out.

Clinical classifi­cation of disease from the mildest form (variola sine eruptione) to modified, to confluent, to malig­nant confluent, to hemorrhagic indicates degrees of severity of smallpox influenced in part by age, state of immunity, and state of hormonal balance. It is of great interest that women within a short time of term, either before or after delivery, tend to have a much more severe disease than those not pregnant.

In cases modified by vaccination or transpla­cental immunity in the first few months of life, the rash may be scant and the evolution of lesions may be very quick. Regardless of how mild an index case of smallpox may be, the susceptible in­fected contacts suffer unmodified disease, and overlooked early cases are frequently the cause of severe epidemics. Permanent scarring or pitting may result even in the absence of purulent in­fection of lesions with secondary bacterial patho­gens (staphylococci and streptococci) in patients who have deep lesions and serious disease.

In previous years, the bacterial complications were incriminated as the principal cause of death, particularly after the pustular phase had com­menced. It is now known that the mortality rate is chiefly related to the amount of virus present in the blood during the viremic phase that occurs in the first two days of the disease before any erup­tion is noted. It has been shown that if the amount of virus in the blood is so great that the whole blood of the patient in the viremic pre-eruptive phase can be used as the antigen in the comiple- ment-fixation test, the patient will surely die, although death may be delayed for nine or ten days. Patients who do die in the first week of ill­ness often show evidence of heart failure and ter­minal pneumonia.

Even in the absence of any anti­microbial therapy, the lungs are often sterile, indicating that the pneumonia is caused by the smallpox virus itself. The majority of deaths occur, however, in the pustular stage toward the end of the second week of the disease. Occasionally an encephalitis has been described that is indis­tinguishable from that associated with measles, varicella, or smallpox vaccination and tends to occur between the eighth and sixteenth day of disease.


Differential Diagnosis of Smallpox Virus.

Smallpox is easily diagnosed, particularly during an epidemic period. More difficult to diagnose is the first and un­suspected case in those countries where small­pox is not endemic. This is particularly true if the first case is hemorrhagic. In this situation meningococcemia, a bleeding diathesis as a part of a blood dyscrasia, or typhus may be the suspected diagnosis. Very mild smallpox, modified by previous vaccination or alastrim. may be thought to be varicella, a drug eruption, or erythema multiforme. Except after known exposure, the clinical diagnosis cannot be made with certainty during the febrile phase, because the picture is indistinguishable from that of dengue, entero- viral infections and other febrile diseases. In the eruptive phase, the most useful clinical points to remember are (1) the centrifugal distribution of lesions; (2) the fact that in a given area all the lesions are at the same stage of development; (3) the fact that there is a relative progression of eruptions from the face and arms to more recent lesions on the arms or legs; (4) the presence of a severe, febrile, three-day pre-eruptive disease; and, on occasion, (5) a known contact at least 12 days previously.

Laboratory Tests.

Laboratory diagnostic pro­cedures are of great value in firmly establishing the diagnosis of smallpox in the first case that appears in a community. These consist of (1) light microscopic or electron microscopic demonstra­tion of viral particles in stained smears of vesicu­lar fluid, (2) serologic demonstration of viral anti­gen in materials from cutaneous lesions, (3) iso­lation of virus from such materials, and (4) detection of antibodies in the serum early in the eruptive phase. The results of such tests are particularly helpful in differentiating varioloid from varicella and the hemorrhagic forms of the disease from other conditions (see articles on Varicella and Herpes Zoster). A detailed descrip­tion of these procedures may be found in the 1969 article by Downie and Kempe.


No specific treatment for smallpox is currently available, although a nuijiber of promising antiviral drugs are under study. Peni­cillin and broader-spectrum antimicrobials have been used in the prevention and treatment of bacterial complications. There is suggestive clini­cal evidence that secondary late bacterial compli­cations, including pneumonia and staphylococcal involvement of skin and bones, are decreased by the use of antimicrobial therapy. But even with such therapy the mortality rates have not been reduced below 25 per cent in most outbreaks of variola major. Good nursing care and maintenance of fluid and electrolyte balance are essential. Convalescent smallpox serum and vaccinia-im­mune gamma globulin have been used in the treat­ment of severe cases without any evidence of success. It is possible that in the particular trials made such therapy may have been instituted too late.

Prevention of Smallpox.

Management of Re­cently Exposed Persons. The use of vaccinia-im­mune gamma globulin has been successful in the prophylaxis of smallpox and has reduced the incidence after known contact by 75 per cent in controlled trials (Kempe et al., 1956, 1961). Thiosemicarbazone preparations have shown much greater and more practical promise in prophylaxis (Bauer, 1955, 1967). In the initial large-scale trial over 1100 household contacts were given B-isatin-thiosemicarbazone by mouth, and only three mild cases of smallpox occurred. In a comparable group of contacts who did not receive the drug there were 78 cases of smallpox and 12 deaths. The drug was effective even when given more than six days after exposure and was equally effective in either unvaccinated or previously vaccinated patients. Data from Brazil on prophylaxis of variola minor have confirmed the earlier findings of the efficacy of this drug.

Community Control.

The American Public Health Association and the United States Public Health Service have approved steps for the control of smallpox under the following four preventive measures:    (1) routine vaccination in infancy,with revaccination at school entry and/or expo­sure to risk of infection; (2) ensuring available supply of potent vaccine kept below freezing to maintain potency; (3) vaccination with mul­tiple pressure on small area of skin, the deltoid being preferred (no dressing need be applied); and (4) prevention of vaccination of children with eczema, who also should not be allowed to come into contact with recently vaccinated persons.

After revaccination an examination should be made after one week to determine whether the reaction is of a major type (primary or vaccinoid) or equivocal (early or immediate). If the latter, the patient should be revaccinated. If there is no reaction the patient should always be revacci­nated.

Control of Infected Persons, Contacts, and Environment. All cases should be reported to the local health authority and patients should be isolated in a hospital until all crusts have dis­appeared. All oral, nasal, fecal, and urinary dis­charges and. articles associated with patients should be disinfected by burning, high-pressure steam, or boiling. All contacts at home, place of work, or elsewhere should be vaccinated or re­vaccinated with potent lymph and kept under surveillance for 16 days from the time of last contact. Any fever during surveillance calls for- prompt isolation until smallpox can be excluded. The patient’s source case should be sought assidu­ously. Adults with chickenpox or patients with hemorrhagic or pustular lesions of the skin need careful review for possible errors in diagnosis.

Epidemic Measures.

In an epidemic the measures to be taken are as follows: (1) All cases and suspects should be isolated in hospital until they are no longer infectious. (2) All contacts should be carefully listed, vaccinated, and kept under surveillance for 16 days. (3) By all avail­able methods, there should be a public statement of the situation and all possible contacts should be urged to be vaccinated. Potent vaccine should be provided and arrangements made for early vaccination of inner ring and outer ring contacts. (4) Chemoprophylaxis of contacts with N-methy- lisatin B-thiosemicarbazone has specific value in decreasing the number of secondary cases. (5) Mass immunization of the entire population of a community or larger area is an emergency measure to be used only when an outbreak has given evidence of material spread.


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