AUTHOR AND EDITOR INFORMATION

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• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Infections due to the poxviruses (members of the Poxviridae family) occur in humans and animals. The orthopoxviruses include smallpox (variola), monkeypox, vaccinia, cowpox, buffalopox, cantagalo, and aracatuba viruses. Parapoxviruses include orf virus, bovine papular stomatitis virus, pseudocowpox virus, deerpox virus, and sealpox virus. Yatapoxviruses include tanapox virus and yabapoxviruses, which are found primarily in Africa. Molluscipoxviruses include the human poxvirus, molluscum contagiosum virus. Smallpox and molluscum are specific to humans. The other viruses cause rare zoonotic infections in humans. Vaccinia virus, which has been used for vaccination, also can infect humans.

Infections due to poxviruses were present in antiquity. The first evidence of smallpox was found in Egyptian mummies of the 18th Dynasty (1580-1350 BC). Variola became endemic in India in the first millennium BC and spread to Asia and, ultimately, to Europe in the 8th century. The introduction of smallpox to the New World in the 15th and 16th centuries decimated the Native American populations. The British used smallpox as a biological weapon in the French-Indian wars. Smallpox continued to be a major worldwide problem well into the 20th century, accounting for up to a half million deaths per year in Europe. In the 20th century, through an intense program of vaccination, naturally occurring smallpox was eradicated.

The origins of immunization are grounded in the history of smallpox. The recognition that cutaneous exposure to the dried material of smallpox lesions caused a milder infection and induced permanent immunity led to the practice of variolization. Unfortunately, this practice frequently induced severe smallpox and death. In the 19th century, Jenner observed that inoculation with cowpox virus, a close relative of smallpox, led to smallpox immunity. This observation about immunity established the practice of vaccination, although variolization continued into the 20th century.

The practice of vaccination with vaccinia virus began in the early 20th century. The origins of vaccinia virus remain unknown, but this virus is distinct from both variola and cowpox. Vaccinia virus has recently been shown to be closely related to the New World orthopox viruses, cantagalo, and aracatuba viruses. Vaccination was standardized in the mid-20th century. An aggressive program of vaccination led to the worldwide eradication of smallpox. In 1977, the last outbreak of smallpox occurred in Somalia, and the World Health Organization certified eradication in 1980. Recently, concern has been raised over the potential of smallpox as an agent in bioterrorism. For an excellent review of smallpox as a potential agent of bioterrorism, refer to the article by Richard Preston, "The Demon in the Freezer."

Following the World Health Organization (WHO) certification of the eradication of smallpox in 1980, only 2 known stocks of variola virus were permitted to exist. One is kept at the US Centers for Disease Control and Prevention (CDC) in Atlanta, Georgia, and the other is kept in the former USSR. Evidence suggests that the former USSR expanded their stocks of variola and experimented with it for use as a biological weapon. Concern also exists that samples of these virus stocks have been transferred to other countries.

Molluscum contagiosum also is a poxvirus unique to humans. This virus is spread by close contact, often through sexual contact.

Other human pox infections are the result of either zoonotic exposure to animal poxviruses or planned or accidental vaccinia administration. Notable examples of zoonotic spread to humans have been recently reported. In 2003, the first outbreak of monkeypox in North America occurred in the Midwest, with 81 cases. These infections were linked to skin exposure to pets, notably prairie dogs. The origin of the infection was ultimately traced to exotic rodents imported from Africa.

Laboratory exposures that have led to infection with vaccinia and tanapox viruses, which are commonly used as vectors for experimental vaccines, have recently been documented. The smallpox vaccination program of civilian and military personnel resulted in a number of infections due to transfer to contacts.

Pathophysiology

Poxviruses are the largest and most complex viruses. They are linear double-stranded DNA viruses of 130-300 kilobase pair. The 200-400 nm virion is oval or brick-shaped and can be visualized by light microscopy. The extracellular virion possesses 2 envelopes, while the intracellular virus has only 1 envelope. The virion contains a large number of proteins, at least 10 of which possess enzymatic activity needed for genomic replication.

Virus replication is equally complex. Infection is initiated by attachment of the virus to one of several cellular receptors. The virus then can enter the cell by a number of mechanisms. Unlike other DNA viruses, poxviruses replicate in the cytoplasm. The virus contains all the elements for genomic replication, but cellular functions appear necessary for complete viral maturation.

In the case of smallpox, infections are initiated by inhalational exposure of nasal, oral, or pharyngeal droplets. The incubation period is 10-14 days. The virus replicates locally and spreads to the local lymph nodes. An asymptomatic viremia ensues on day 3-4, with spread to the bone marrow and spleen. A secondary viremia begins on approximately day 8. This secondary viremia is associated with generalized symptoms of fever and a toxic appearance. The virus in leukocytes then becomes localized in the blood vessels of the dermis. Development of the characteristic rash of smallpox follows.

Maculopapular lesions appear on the buccal and pharyngeal mucosa and on the face and extremities and move to the trunk. Over several days, these lesions first form vesicles, which are firm and imbedded in the epidermis. They then slowly form pustules. Approximately 8 days after onset, the pustules umbilicate. Scab formation follows. At this stage, mucosal lesions ulcerate, with the release of infectious virus into secretions. The smallpox rash is characterized by skin lesions that are in the same stage of evolution. These lesions are in contrast to chickenpox, in which lesions appear in successive waves and various forms (ie, vesicles, pustules, scabs) that can be observed simultaneously. In addition, patients with smallpox have significantly more fever and toxicity prior to the rash than those with chickenpox. The smallpox lesions then heal, although they characteristically lead to significant scarring.

Other poxviruses are introduced by cutaneous or ocular inoculation. Vaccinia virus used as a vaccine replicates at the site of inoculation, leading to the formation of local erythematous maculopapules. These maculopapules then vesiculate (ie, jennerian vesicles), scar, and heal over 10-14 days. The virus also spreads to regional lymph nodes, which often is associated with tenderness and fever. Resolution of the lesions involves pustule formation followed by scabbing and healing. This resolution is associated with the development of immunity to variola infection that persists for up to ten years.

Other poxviruses generally follow the same pattern of evolution, with primarily localized disease. An exception is monkeypox infection, which leads to a clinical syndrome similar to variola. Monkeypox infections can range from mild with few lesions, as in the North American outbreak, to severe systemic illness that resembles smallpox. Molluscum contagiosum virus also replicates at the site of inoculation, but the character of the skin lesions is distinct.

Frequency

United States

The last reported cases of wild-type smallpox occurred in 1977 in Somalia. No reporting system exists for molluscum, but its transmission as a sexually transmitted disease is fairly common. Infections involving the other poxviruses are rare. In 2003, a monkeypox outbreak occurred, involving 81 cases.

International

With the exception of molluscum contagiosum, poxvirus infections are uncommon. The last cases of smallpox occurred in the late 1970s. Infections with the other poxviruses are due to animal exposures, laboratory infections, or spread following vaccinia immunization.

Mortality/Morbidity

Variola major is associated with a fatality rate of 25-30%, while the patient fatality rate for variola minor is less than 1%. Morbidity and mortality due to vaccinia infections are uncommon, but infection can be spread by autoinoculation or to closed contacts. The frequency of severe infections increases with eczema or immune-deficiency conditions such as leukemia. Molluscum contagiosum rarely causes morbidity, although infections acquired in the face of immune deficiency often lead to multiple skin lesions. Other poxvirus infections are rare and generally lead only to localized scaring. The exception is monkeypox infection. Mortality rates in African outbreaks have been as high as 17%. No deaths were reported in the 81 cases in the United States.

Race

No racial predilection exists for poxvirus infections.

Sex

No sexual predilection exists for poxvirus infections.

Age

No age predilection exists for poxvirus infections.

CLINICAL

Section 3 of 11  

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History

Variola and molluscum are diseases of humans. Vaccinia results from either vaccination or accidental laboratory exposure. Other poxvirus infections are zoonoses, resulting from close animal exposure.

• Smallpox
• • Smallpox generally presents in 2 clinical forms, variola major (25-30% fatality rate) and a similar but milder disease known as variola minor ( <1% fatality rate).
  • Patients initially present with nonspecific symptoms, including fever and a toxic appearance. These symptoms are followed by the slow development of a maculopapular rash. The rash generally presents on the face and extremities and spreads to the trunk. The rash evolves rapidly into vesicles, followed by pustules, scabs, and healing.
  • Occasionally, patients present with unusual forms of variola. Flat smallpox is a severe form in which the pustules remain relatively flat. Hemorrhagic variola is a syndrome that appears clinically similar to meningococcemia. This form invariably is fatal.
• Molluscum contagiosum
• • Patients infected with molluscum contagiosum develop small pearly epidermal nodules (1-2 mm) that have a characteristic central pit known as an umbilication.
  • This condition generally resolves over time, but in cases of patient immune deficiency (eg, HIV infection), infection with molluscum contagiosum may cause chronic and extensive skin lesions.
• Vaccinia
• • Vaccinia infections result from iatrogenic or accidental inoculation of the virus.
  • Infections have been described at multiple sites, including the eyes. On the skin, the infection initially appears as localized maculopapular lesions that evolve into vesicles and pustules, which then form a scab. Healing may be associated with significant scarring. The CDC has provided an excellent training program on vaccinia vaccination and adverse events (Smallpox Vaccination and Adverse Events Training Module).
  • Patients may have a fever and regional lymphadenopathy.
  • In patients with eczema (ie, active or inactive), vaccinia can cause eczema vaccinatum. Infection involves the eczematous skin, and areas become intensely inflamed. The infection may disseminate. Constitutional symptoms are severe, with high fever and generalized lymphadenopathy. Death is common.
  • In patients with immune deficiency, vaccinia is known to cause progressive vaccinia. The initial site of inoculation develops a progressive unrelenting lesion known as vaccinia gangrenosum. Dissemination of vaccinia can occur with generalized lesions. Death is common in these patients.
• Monkeypox infection can produce a disease similar to variola minor. Clinically, monkeypox infection cannot be distinguished from smallpox. Cases of monkeypox infection generally occur in villages in tropical regions of western and central Africa.
• Other human poxvirus infections include cowpox, orf (ie, contagious pustular dermatitis), bovine papular stomatitis, pseudocowpox (milker's nodule), sealpox, tanapox, and yabapox. These are rare zoonotic infections resulting from cutaneous inoculation due to the close proximity of humans to animals. Cowpox causes a localized pustular skin lesion that follows a course similar to uncomplicated vaccinia infection. The remainder of the infections produce a localized nodular lesion that resolves over time.

Physical

Poxvirus infections cause either a localized or a generalized vesicular exanthem. The lesions of smallpox, vaccinia, monkeypox, and cowpox evolve from a papule to a vesicle. The vesicles then form pustules, followed by scabbing and healing. The remaining viruses cause localized nodules at the site of inoculation. Individual viruses cause characteristic clinical syndromes. With the exception of smallpox, regional lymphadenopathy is common.

Causes

Exposure to viruses of the Poxviridae family causes these infections.

DIFFERENTIALS

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Other Problems to be Considered

Chickenpox
North American blastomycosis
Varicella

WORKUP

Section 5 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
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Lab Studies

• Most poxvirus infections can be recognized clinically. The virions can be recognized by negative staining and electron microscopy.
• Variola and vaccinia can be cultured in vitro on chorioallantoic membranes of eggs and in tissue culture. In suspected cases of smallpox, the public health authorities should be notified immediately and clinical samples processed in containment facilities.
• Infections with poxviruses induce humoral responses that include hemagglutination inhibition (HI), complement fixing (CF), and neutralizing antibodies. In the case of vaccinia, the HI, CF, and antibody titers decline over time.

Other Tests

• Histological analysis of the nodular skin lesions can be performed.

Histologic Findings

The cutaneous lesions of smallpox begin with vascular congestion of the dermis associated with mononuclear (lymphocytes and monocytes) infiltration. Epidermal cells develop ballooning degeneration, and intraepithelial multiloculated vesicles develop by rupture of cellular membranes in the stratum spinosum. Cells develop cytoplasmic acidophilic inclusions known as Guarnieri bodies. The lesions of vaccinia and monkeypox follow a similar evolution.

The lesion of molluscum contagiosum consists of a localized area of hypertrophic and hyperplastic epidermis that extends down to the dermis and produces a nodule that rises above the skin. Individual epidermal cells are enlarged and contain a characteristic cytoplasmic inclusion of hyaline acidophilic material called a molluscum body. The center of the lesion consists of degenerating epidermal cells and keratin. Very little inflammation is present.

TREATMENT

Section 6 of 11  

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• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• Variola infections have been eradicated worldwide. Concern exists about the reintroduction of smallpox through bioterrorism. The reappearance of smallpox would precipitate an international health care emergency. In suspected cases of smallpox, the state and federal public health officials should be notified immediately.
• • No known treatments exist for smallpox or vaccinia.
  • Some experimental evidence suggests that cidofovir may have clinical utility.
  • Vaccinia vaccination leads to at least short-term (up to 10 years) protection from smallpox. Vaccination also has been shown to blunt clinical smallpox if administered early after exposure. The current vaccine, Dryvax, was prepared in the late 1970s as lyophilized virus derived from calf lymph. Fresh stocks of vaccinia vaccine are being prepared using tissue culture methods and should be available in late 2003.
• Molluscum contagiosum may be treated with curettage, but this treatment usually is ineffective in immunocompromised patients.
• Early recognition of poxvirus infection is essential to prevent inadvertent secondary spread.

Surgical Care

• The nodules of molluscum contagiosum infection can be removed by curettage.

Consultations

• Consultation with a dermatologist and infectious disease specialist may be appropriate.
• If smallpox is suspected, the CDC and local public health departments should be notified immediately.

Activity

• Patients suggested to have smallpox should be quarantined, and the CDC and local health officials should be notified.
• Patients with other poxvirus infections generally do not require modification of activity.

MEDICATION

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No antiviral medications are known to effectively treat poxvirus infections. Experimental data suggest that cidofovir may have antiviral activity.

FOLLOW-UP

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• Follow-up
• Miscellaneous
• Multimedia
• References

Deterrence/Prevention

Early recognition of poxvirus infection is essential to prevent inadvertent secondary spread.

Complications

• Vaccinia infections may spread locally (eg, vaccinia gangrenosum) or disseminate in hosts who are immune deficient or in patients with eczema.
• Molluscum contagiosum may be refractory in patients with immune deficiencies (eg, infection with HIV).

Prognosis

• Patients with infection from most poxviruses have excellent prognoses for healing, although localized scarring is common.

Patient Education

• For excellent patient education resources, visit eMedicine's Skin, Hair, and Nails Center. Also, see eMedicine's patient education article Molluscum Contagiosum.

MISCELLANEOUS

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• Miscellaneous
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Medical/Legal Pitfalls

• Very few legal pitfalls are associated with poxvirus infections. Inappropriate administration of vaccinia vaccine to patients with immune deficiencies was one of the most serious errors made in the past. As of December 2002, there is a federal program under way to vaccinate volunteer first responders and medical personnel. The medical/legal implications of vaccination are not clear at this time.

MULTIMEDIA

Section 10 of 11  

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• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Poxviruses. Following vaccination for smallpox, this patient with chronic lymphocytic leukemia developed vaccinia gangrenosum.
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Media type:  Photo

Media file 2:  Poxviruses. Following vaccination for smallpox, a patient with chronic lymphocytic leukemia developed vaccinia gangrenosum. The lesion was on the left shoulder. As the lesion progressed, the patient also developed evidence of dissemination. This image shows a vaccinia pustule on the foot.
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Media type:  Photo

Media file 3:  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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Media type:  PDF

REFERENCES

Section 11 of 11

• Authors and Editors
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• Multimedia
• References

• Baxby D, Bennett M. Poxvirus zoonoses. J Med Microbiol. Jan 1997;46(1):17-20, 28-33. [Medline].
• Di Giulio DB, Eckburg PB. Human monkeypox: an emerging zoonosis. Lancet Infect Dis. Jan 2004;4(1):15-25.
• Fenner F. Adventures with poxviruses of vertebrates. FEMS Microbiol Rev. Apr 2000;24(2):123-33. [Medline].
• Fenner F. Poxviruses. In: Richman D, Whitley RJ, Hayden FG, eds. Clinical Virology. 1st ed. New York, NY: Churchill Livingstone;. 1996:357-74.
• Fenner F, Henderson DH, Arita I, Jezek Z, et al. Smallpox and its eradication. Geneva, Switzerland: World Health Organization. 1988.
• Henderson DA, Inglesby TV, Bartlett JG, et al. Smallpox as a biological weapon: medical and public health management. Working Group on Civilian Biodefense. JAMA. Jun 9 1999;281(22):2127-37. [Medline].
• Henderson DH, Moss B. Smallpox and vaccinia. In: Plotkin S, Orenstein WA, eds. Vaccines. 3rd ed. Philadelphia, Pa: WB Saunders; 1999:. 74-97.
• Lewis-Jones S. Zoonotic poxvirus infections in humans. Curr Opin Infect Dis. Apr 2004;17(2):81-9.
• Perna AG, Tyring SK. A review of the dermatologic manifestations of poxvirus infections. Dermatol Clin. Apr 2002;20(2):343-6.
• Preston R. The Demon in the Freezer. In: The New Yorker. July 12, 1999:44-61. [Full Text].
• Slifka MK, Hanifin JM. Smallpox: the basics. Dermatol Clin. Jul 2004;22(3):263-74, vi.

Article Last Updated: May 26, 2006