AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

The history of smallpox is remarkable both because of the spectacular devastation it wreaked upon civilization since the dawn of humankind and for the astounding achievement of modern medicine, which eradicated this plague through the concerted efforts of global vaccination.

The earliest evidence of smallpox comes from ancient Egypt circa 1157 BCE, where the mummified remains of a pockmarked Ramses V were uncovered. International traders spread smallpox throughout the Old World during the 4th-15th centuries CE, while European explorers and conquerors brought the disease to the Western Hemisphere in the early 16th century.

Smallpox directly and profoundly influenced the course of human history. Its tremendous morbidity and mortality led to indiscriminate killing of kings and warlords and tipped the balance of power with regularity in Europe and elsewhere. Whole civilizations, including the Incas and the Aztecs, were destroyed in a single generation, and efforts to ward off the disease indelibly affected the practice of religion and medicine.

Smallpox is the result of infection by the variola virus, which belongs to the genus Orthopoxvirus in the family Poxviridae. The variola virus is a large brick-shaped, double-stranded DNA virus that serologically cross-reacts with other members of the poxvirus family, including ectromelia, cowpox, monkeypox, vaccinia, and camelpox. Unlike other DNA viruses, the variola virus multiplies in the cytoplasm of parasitized host cells. Smallpox infects only humans and does not exist in a carrier state. The virus can survive in the environment for a short period, and it is most stable at low temperatures and low humidity. Variola is spread most efficiently by means of inhalation and less efficiently by means of direct contact with scabs or pustular material from skin lesions.

The 2 predominant variants of variola, major and minor, differ greatly in their mortality rates (30% vs 1%, respectively). Variola major was the predominant endemic strain throughout the world, and, by the end of the 18th century, it was responsible for approximately 400,000 deaths a year in Europe. In patients who recovered from the disease, blindness was common and disfiguring scars were nearly universal.

Intentional inoculation with subvirulent strains of variola to protect against variola major (variolation) began in India sometime before the first millennium CE. This practice spread throughout the Old World and eventually reached Europe in the early 18th century. Although variolation was capable of inducing lifelong immunity in vaccinated individuals, the practice was a risky procedure, and those inoculated had a mortality rate of approximately one tenth that of individuals with naturally occurring disease. Furthermore, treated individuals were capable of transmitting disease to untreated individuals for some time after variolation.

In one of the major accomplishments in modern medicine, Edward Jenner demonstrated in 1796 that an individual could be protected against disease. The skin could be inoculated with pustular material containing the cowpox virus, an orthopoxvirus closely related to variola. Although the heterologous immunity induced by vaccination (from the Latin word vacca, meaning cow) was not lifelong, this approach was significantly safer than variolation, and vaccination quickly spread throughout the world. In subsequent decades, the strain of virus used was sustained by means of arm-to-arm inoculation or maintained as dried material on threads. Over time, the virus mysteriously changed from its original cowpox form to the strain of vaccinia used in current vaccines. In the latter half of the 19th century, the practice of growing virus for vaccines on the flank of calves was adopted to lessen the risk of transmitting other human diseases (eg, syphilis) during vaccination.

In the late 1940s, large-scale production of freeze-dried vaccine enabled mass vaccination campaigns and, eventually, the global eradication of smallpox. In the latter half of the 1960s, the World Health Assembly intensified its efforts in eradicating the disease by using highly potent and stable vaccine, by rapidly identifying outbreaks, and by performing ring vaccination in all contacts of a person who was infected.

The last case of endemic smallpox occurred in Somalia in 1977, and the last recorded case in humans occurred in England in 1978; this case was due to an accidental laboratory infection. In 1980, the World Health Organization officially declared that smallpox had been eradicated. Currently, the only remaining known variola virus isolates are frozen in closely guarded repositories at the US Centers for Disease Control and Prevention (CDC) in the United States and at the Vektor Institute in Russia.

Pathophysiology

Smallpox is most efficiently spread via the respiratory system, although contact with infected skin or fomites also may transmit the disease. The variola virus multiplies in the reticuloendothelial system, and it is clinically silent for approximately 12 days (range, 7-17 d). Viremia then proceeds to the prodromal phase (range, 2-4 d), which is characterized by the sudden onset of fever, severe headache, pharyngitis, nausea, backache, and malaise. During the later part of the prodromal phase, an enanthem may be appreciated on the palate, the tongue, and the pharynx. The virus then enters the skin; this event marks the beginning of the rash phase of the disease.

The skin findings begin on the face and spread centrifugally. Most lesions are in the same stage of development at any given time. Characteristic lesions start as macules and then develop into papules, pustules, and crusts over a period of approximately 17 days. The virus is readily found on the skin, in the oropharynx, and in the reticuloendothelial system throughout the rash phase (a highly infectious period from the appearance of enanthema until day 10 of the rash). Overwhelming toxemia has been the usual cause of death, and typical cases of smallpox had a mortality rate of 30%. The rarer hemorrhagic and flat-type forms of the disease were nearly universally fatal.

Both cellular immunity and humoral immunity are elicited in response to variola infection. Neutralizing antibodies can be detected during the first week of clinical illness, whereas hemagglutination-inhibition and complement-fixation antibodies are found in the second to third weeks. Neutralizing antibodies persist for many years or decades after infection, whereas levels of hemagglutination-inhibition and complement-fixation antibodies generally decrease within a year. Cell-mediated immunity likely plays an important role in controlling disease; virus-specific cytotoxic T cells are detectable in lymphoid organs as early as 4 days after infection. These cytotoxic T cells are believed to limit viral spread by causing lysis of infected cells in the reticuloendothelial system and the skin.

The relative importance of the cellular immune response against smallpox has been demonstrated in animals. Studies show that mice with defective T cells are able to generate normal humoral responses to a viral challenge, yet they die when exposed to orthopoxvirus concentrations that are sublethal in healthy mice. Studies in rodents and sheep have demonstrated memory in the form of virus-specific, cytotoxic lymphocyte immune responses that occur long after the initial variola infection.

Currently, nearly half the US population has not been vaccinated and has no immunity to vaccinia or variola. The remainder of the population was vaccinated 30 or more years ago and may retain partial protection from the disease.

Frequency

International

Since 1978, no cases of smallpox have been reported in the world.

Mortality/Morbidity

Morbidity was commonly associated with smallpox (see Complications).

• Typical variola major smallpox in individuals who were not immune was associated with a mortality rate of 30%. A minority of cases were the hemorrhagic and flat-type forms of smallpox (3% and 7%, respectively); each had a mortality rate of close to 100% in individuals who were not immune.
• Variola minor had an associated case-fatality rate of 0.1-2%. In all cases, higher mortality rates occurred in individuals who were immunocompromised, young children, elderly individuals, or pregnant women.
• Congenital infection resulted in a stillbirth rate of 35%, and 50% of neonates died within their first few days of life.

Race

No racial predilection is known.

Sex

Pregnant women were at risk for severe disease.

Age

Young or old individuals were more susceptible to severe disease.

CLINICAL

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History

For additional information, see Evaluating Patients for Smallpox.

• The incubation period of smallpox is 7-17 days.
• The prodromal phase lasts 2-4 days and is characterized by the following:
• • Fever (temperature >40°C)
  • Severe headache
  • Backache
  • Pharyngitis
  • Nausea
  • Vomiting
  • Prostration
  • Enanthema on the mucous membranes of the tongue and the oropharynx
• As many as 10% of fair-skinned individuals may also present with a fine, erythematous, macular rash during the prodromal phase.
• Virus shedding and subsequent infectivity are maximal at the beginning of the enanthema, and they last until scab separation of the skin lesions.
• For a few days, the virus can be found in respiratory secretions, skin lesions, and contaminated objects.
• Respiratory infectivity occurs with face-to-face contact, although reports of infection due to viral spread through ventilation systems are well documented.

Physical

• The characteristic rash of smallpox begins after the prodromal phase.
• • Small, red macules first appear on the face and then spread to the extremities and the trunk.
  • Over 1-2 days, the macules develop into 2- to 3-mm, firm papules.
  • Within 1-2 more days, the papules evolve into 2- to 5-mm vesicles.
  • By days 4-7 after the appearance of the rash, the lesions develop into 4- to 6-mm pustules, many of which become confluent, particularly on the face.
  • The pustules reach their maximal size by day 10.
  • By day 17, the pustules become pitted and are covered with a scab.
• All skin lesions tend to be in the same stage of development at any given time in the course of the infection.
• Compared with unvaccinated persons, vaccinated individuals who contract smallpox tend to have less severe toxemia; fewer constitutional symptoms; and smaller and fewer numbers of lesions, which tend to be more superficial and mimic those of chickenpox.
• The rash of chickenpox was frequently mistaken for that of smallpox during the days of natural infection.
• • Both conditions could result in pustular scarring lesions that involved the face.
  • Varicella typically does not have a prodromal phase, and the evolution of the rash from its appearance to scab separation takes approximately 7 days in varicella.
  • Often, individuals who were previously vaccinated had only a mild prodrome without any rash.
• Hemorrhagic smallpox develops fulminantly and was most often confused with meningococcemia or severe acute leukemia.
• Contact dermatitis, although often vesicular, would be distinguishable from smallpox lesions because contact dermatitis is pruritic and is not accompanied by fever or constitutional symptoms.
• Flat-type smallpox was slower to evolve, but it resulted in confluent velvety macular lesions and was associated with severe prostration.
• Variola minor was characterized by constitutional symptoms, with fewer and smaller skin lesions than variola major.
• The fever and vesicular rash of chickenpox, herpes zoster, and erythema multiforme were often confused with those of variola major.

Causes

Smallpox is caused by infection with the variola virus.

DIFFERENTIALS

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Other Problems to be Considered

Varicella virus
Varicella-zoster virus
Acne
Atypical measles
Coxsackievirus
Rickettsialpox
Acute leukemia
Secondary syphilis
Rat-bite fever
Infectious mononucleosis
Toxic erythemas
Parvovirus B19
Cytomegalovirus

WORKUP

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Lab Studies

• Any suspected index case of smallpox should be immediately reported to state health officials and the CDC. The 24-hour emergency telephone number of the Emergency Preparedness and Response Branch of the CDC is 770-488-7100 or 404-639-3532. General clinician information regarding smallpox and smallpox vaccine can be obtained from the CDC Web site or by calling 877-554-4625. An excellent algorithm for evaluating generalized vesicular or pustular rash illness is also provided on the CDC Web site; this was compiled jointly by the American Academy of Dermatology Task Force on Bioterrorism and the CDC.
• Major criteria for diagnosing smallpox include the following:
  • Febrile prodrome occurring 1-4 days before rash onset - Fever greater than 102°F and at least one of the following: prostration, headache, backache, chills, vomiting, severe abdominal pain
  • Classic smallpox lesions (deep, firm, round, well-circumscribed; may be umbilicated or confluent)
  • Lesions in same stage of development on any one part of the body
• Minor criteria for diagnosing smallpox include the following:
  • Centrifugal distribution of rash; greatest concentration of lesions on face and distal extremities
  • First lesions on the oral mucosa/palate, face, forearms
  • Patient appears toxic or moribund
  • Slow (several days each stage) evolution of rash from macules to papules to pustules to scabs
  • Lesions on the palms and soles
• Suitably vaccinated and trained personnel should obtain viral swabs of the patient's pharynx and/or open skin lesions (eg, pustule contents, material from the base of the scab).
• • Under biosafety level 4 (BL4) laboratory conditions, these samples can be examined for the presence of virions by using electron microscopy, polymerase chain reaction (PCR), or immunohistochemical analysis or by growing the virus on live cell cultures.
  • Serologic testing can be performed to detect neutralizing antibodies, but the results cannot be used to differentiate orthopoxvirus species.

Procedures

• Depending on the presenting clinical symptoms, other diseases, such as meningococcemia, leukemia, herpes viruses, and drug eruptions, must be ruled out.
• Tests likely to be performed include the following:
• • Tzanck preparations
  • Direct fluorescent antibody testing for herpes viruses
  • Blood tests
  • Skin biopsy
  • Lumbar puncture
• A meticulous drug history should be obtained.

TREATMENT

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Medical Care

• Initial treatment involves strict respiratory and contact isolation.
• • If given early in the incubation period (within 3-4 d), vaccination can significantly attenuate or prevent smallpox disease.
  • If the patient is already ill, he or she should be kept in a negative-pressure room.
  • Diligent supportive care should consist of adequate nutrition and hydration, eye care, and treatment to prevent secondary skin infections.
  • Cidofovir may be beneficial if given in the early stages of illness, although the effectiveness of this treatment has not been proven in humans.
  • Corneal lesions may be treated with topical idoxuridine.
• Vaccinia immune globulin does not appear to offer a survival benefit when given to patients during the incubation or active-disease stages of smallpox.

Consultations

Infectious diseases personnel, CDC officials, and state health authorities should be notified immediately.

MEDICATION

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The goals of pharmacotherapy are to induce active immunity, to reduce morbidity, and to prevent complications.

For additional information, see Smallpox Vaccination: Vaccination Method and Reactions.

Drug Category: Vaccine, live virus

Vaccinia vaccine promotes active immunity against the smallpox virus by inducing specific antibodies. Currently available stocks of vaccinia vaccine were derived from the vaccinia strain maintained at the New York Board of Health. Wyeth Laboratories (Dryvax; Wyeth Laboratories, Marietta, Pa) manufactured the last batches of the vaccine in the early 1980s; these batches were made by using the calf lymph method, and they were lyophilized. Both full concentration and 5- to 10-fold diluted vaccine appear to be immunogenic.

New cell-derived lots of vaccinia appear to have similar adverse effect profiles as the older calf lymph–derived lots.

Several attenuated vaccinia vaccine candidates are undergoing investigation.

Drug Name	Cidofovir (Vistide)
Description	Nucleoside DNA polymerase inhibitor analog. Animal studies indicate that if given within first 2 d of exposure to smallpox, may attenuate or prevent disease.
Adult Dose	5 mg/kg IV over 1 h
Pediatric Dose	Not established
Contraindications	Documented hypersensitivity; coadministration with other nephrotoxic agents; serum creatinine level >1.5 mg/dL; CrCl rate <55 mL/min; urine protein level >100 mg/dL
Interactions	Coadministration of aminoglycosides, amphotericin B, IV pentamidine, and foscarnet may increase nephrotoxicity
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Monitor neutrophil counts; renal toxicity is major adverse effect; prehydrate with IV normal saline and coadminister probenecid with each infusion to minimize nephrotoxicity (monitor renal function); monitor serum creatinine and urine protein levels 48 h prior to treatment (adjust dose accordingly); granulocytopenia may occur; additional adverse effects include neutropenia, fever, anemia, headache, hair loss, iritis, uveitis, and abdominal pain

Drug Category: Immune globulins

Indicated for passive immunity. Vaccinia immune globulin (VIG) is the only drug available for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions usually is not necessary. The FDA recently approved intravenous VIG (VIGIV).

FOLLOW-UP

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Further Inpatient Care

• Inpatient care of patients with smallpox should include the following:
• • Respiratory and contact isolation
  • Nutritional support and eye care
  • Antibiotics as needed for secondary infections

Further Outpatient Care

• Further outpatient care includes cosmetic management of scars and corrective vision care.

Transfer

• Patients should be transferred as necessary, with appropriate respiratory and contact isolation.

Deterrence/Prevention

• Isolation and mass and/or ring vaccination can prevent the spread of smallpox.
• Cross-protective immunity from vaccinia is most effective during the first 10 years after vaccination and slowly wanes thereafter. Those vaccinated several times are likely to have longer-lasting immunity of unclear duration.
• The level of protection in individuals who were vaccinated 30 or more years ago, should they be exposed to smallpox today, is unclear.

Complications

• Morbidity was commonly associated with smallpox.
• Most patients (65-80%) recovering from infection had cutaneous scarring, which was made worse if secondary bacterial infections developed during the course of the disease.
• Other complications included the following:
• • Bronchopneumonia
  • Keratitis
  • Corneal ulceration
  • Blindness (1% of cases)
  • Arthritis (2% of cases)
  • Osteomyelitis
  • Orchitis
  • Encephalitis (<1% of cases)

Prognosis

• Smallpox is highly infectious and has a mortality rate of approximately 30% (see Mortality/Morbidity).

Patient Education

• An informed public can better comply with vaccination and quarantine procedures should smallpox reemerge.

MISCELLANEOUS

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Medical/Legal Pitfalls

• The reemergence of smallpox would constitute an international emergency.
• The failure to immediately report cases to public health authorities would severely impair their ability to contain the disease.
• Liable medical practitioners would be subject to severe reprimand.

MULTIMEDIA

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Media file 1:  Characteristic skin lesion of variola on the arms and the legs of an adolescent. Photo used with permission from the World Health Organization.
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Media file 2:  Child with pustular lesions of variola. Photo used with permission from the World Health Organization.
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Media file 3:  Infant with advanced lesions of variola. Photo used with permission from the World Health Organization.
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Media file 4:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 3 after exposure to the ordinary form of the variola major strain of smallpox (same patient as in Images 5-6). Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 5:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 5 after exposure to the ordinary form of the variola major strain of smallpox (same patient as in Images 4 and 6). Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 6:  Unvaccinated infant with centrifugally distributed umbilicated pustules on day 7 after exposure to the ordinary form of the variola major strain of smallpox (same patient as in Images 4-5). Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 7:  Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of the skin lesions. The facial lesions are sparse, and they evolved more rapidly than did the lesions on her extremities. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 8:  Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of the skin lesions (same woman as in Images 7 and 9). Note the lesions on her arm. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 9:  Ordinary form of variola minor strain of smallpox (alastrim) in an unvaccinated woman 12 days after onset of skin lesions (same woman as in Images 7-8). Note the lesions on her feet and legs. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 10:  Adult with variola major infection. Hundreds of pustular lesions are centrifugally distributed. Courtesy of the Fitzsimmons Army Medical Center slide file.
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Media file 11:  Hemorrhagic-type variola major lesions. Death usually ensues before typical pustules develop. Reprinted with permission from Smallpox and Its Eradication. Copyright 1988, World Health Organization.
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Media file 12:  Bioterrorist Agents. Signs and symptoms. Chart courtesy of North Carolina Statewide Program for Infection Control and Epidemiology (SPICE), copyright University of North Carolina at Chapel Hill, www.unc.edu/depts/spice/bioterrorism.html.
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REFERENCES

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Article Last Updated: Feb 1, 2007