Poxviruses (members of the Poxviridae family) can infect both humans and animals. The orthopoxviruses include smallpox (variola), monkeypox, vaccinia, cowpox, buffalopox, cantagalo, and aracatuba viruses. The 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 contagiosum are specific to humans. The other viruses cause rare zoonotic infections in humans. Vaccinia virus, which has been used for vaccination, can also infect humans.
Infections due to poxviruses have dated back to 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 eighth century. The introduction of smallpox to the New World in the 15th and 16th centuries decimated Native American populations. The British used smallpox as a biological weapon during 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, conferred smallpox immunity. This observation 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 orthopoxviruses, cantagalo, and aracatuba viruses. Vaccination was standardized in the mid-20th century. An aggressive program of vaccination eradicated smallpox worldwide. In 1977, the last outbreak of smallpox occurred in Somalia, and the World Health Organization (WHO) certified eradication in 1980. Recently, concern has been raised over the potential of smallpox as an agent in bioterrorism. For an excellent discussion of the subject, refer to the article by Richard Preston, "The Demon in the Freezer."[1]
Following the WHO certification of smallpox eradication 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 is also a poxvirus unique to humans. This virus is spread via close contact, often through sexual contact.
Other human poxvirus infections result from either zoonotic exposure to animal poxviruses or planned or accidental vaccinia administration. Notable examples of zoonotic spread to humans have recently been 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.[2]
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 numerous infections due to transfer to contacts.
For additional information, see Medscape’s Emerging and Reemerging Infectious Diseases Resource Center.
Poxviruses are the largest and most complex viruses. They are linear double-stranded DNA viruses of 130-300 kilobase pair.[3] The 200-400 nm virion is oval or brick-shaped and can be visualized on light microscopy. The extracellular virion possesses 2 envelopes, while the intracellular virus has only one envelope. The virion contains a large number of proteins, at least 10 of which possess enzymatic activity needed for genomic replication.
The replication of poxviruses is equally complex.[4] Infection is initiated by attachment of the poxvirus to one of several cellular receptors. The virus can then enter the cell via numerous 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.
Smallpox infections are initiated by inhalational exposure of nasal, oral, or pharyngeal droplets. The incubation period is 10-14 days. Smallpox viruses replicate locally and spread 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. The characteristic rash of smallpox then develops.
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 develop simultaneously. In addition, smallpox causes a significantly worse fever and toxicity prior to the rash than 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, forming 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 is often 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 10 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.
The last reported cases of wild-type smallpox occurred in 1977 in Somalia. No reporting system exists for molluscum contagiosum, 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 related to the importation of exotic animals from Africa and subsequent spread to prairie dogs that were purchased as pets.[2, 5]
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 carries a mortality rate of 25-30%, while the fatality rate associated with variola minor is less than 1%. Morbidity and mortality due to vaccinia infections are uncommon, but infection can be spread by autoinoculation or by close contact with someone who is infected. Poxvirus infections tend to be more severe in persons with eczema and/or immunodeficiency (eg, leukemia). Molluscum contagiosum rarely causes morbidity, although persons with immunodeficiency who develop molluscum contagiosum tend to develop multiple skin lesions.[6] Other poxvirus infections are rare and generally cause only localized scarring. The exception is monkeypox infection. Mortality rates in African monkeypox outbreaks have been as high as 17%. No deaths were reported in the 81 cases in the United States.
Among poxvirus infections, variola and molluscum contagiosum 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 with smallpox initially present with nonspecific symptoms, including fever and a toxic appearance. These symptoms are followed by a slow developing maculopapular rash, which generally develops on the face and extremities and spreads to the trunk. The rash evolves rapidly into vesicles, followed by pustules, scabs, and healing.
Some 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 is invariably fatal.
Molluscum contagiosum
Patients infected with molluscum contagiosum develop small pearly epidermal nodules (1-2 mm in diameter) that have a characteristic central pit known as an umbilication.
This condition generally resolves over time. However, persons with immunodeficiency (eg, HIV infection) who develop molluscum contagiosum may develop 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 with vaccinia infections may have 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 immunodeficient patients, 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. See the images below.
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Poxviruses. Following vaccination for smallpox, this patient with chronic lymphocytic leukemia developed vaccinia gangrenosum.
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Poxviruses. Following vaccination for smallpox, a patient with chronic lymphocytic leukemia developed vaccinia gangrenosum. The lesion was on the left....
Monkeypox
Monkeypox infection can produce a disease similar to variola minor characterized by a disseminated rash or relatively localized lesions. Clinically, disseminated monkeypox infection cannot be distinguished from smallpox. Monkeypox infections generally occur in villages in tropical regions of western and central Africa. Most of the monkeypox infections that occurred during the US outbreak in 2003 were characterized by localized lesions (Marshfield Clinic Monkeypox Virus Information).
Other human poxvirus infections
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 that are caused by cutaneous inoculation due to the close proximity of humans to animals. Cowpox causes a localized pustular skin lesion that follows a course similar to that of uncomplicated vaccinia infection. The remainder of the infections produce a localized nodular lesion that resolves over time.
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.
Most poxvirus infections can be recognized clinically. The virions can be recognized with 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 vaccinia cases, the HI, CF, and antibody titers decline over time.
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.
Variola infections have been eradicated worldwide. However, concern exists about the reintroduction of smallpox through bioterrorism. The reappearance of smallpox would precipitate an international health care emergency. Suspected cases of smallpox should be reported to state and federal public health officials.
No known treatments are presently available for smallpox or vaccinia.
Several nucleoside and nucleotide analogues have demonstrated potent in vitro and in vivo antiviral activity against numerous poxviruses, including variola, vaccinia, monkeypox, cowpox, molluscum contagiosum and orf.[7] Cidofovir and a number of its derivatives have proven to be most efficacious so far.
Alkoxyalkyl esters of cidofovir have good bioavailability, cause reduced renal toxicity, and are currently being studied for treatment of poxvirus infections.
Cidofovir has been used successfully to treat recalcitrant molluscum contagiosum in patients with AIDS.[8, 9] Cidofovir has also been successful in treating orf in an immunocompromised patient.[10]
Vaccinia vaccination confers at least short-term (up to 10 y) protection from smallpox. Vaccination has also been shown to blunt clinical smallpox if administered early after exposure.[11] The current vaccine, Dryvax, was prepared in the late 1970s as lyophilized virus derived from calf lymph. Fresh stocks of vaccinia vaccine prepared using tissue culture methods are now available.
Curettage can be used to treat molluscum contagiosum but is usually ineffective in immunocompromised patients.
Early recognition of poxvirus infection is essential to prevent inadvertent secondary spread.
Patients suspected of having smallpox or monkeypox should be isolated according to CDC protocol, and the CDC and local health officials should be notified.
Patients with other poxvirus infections generally do not require activity modification.
Numerous nucleoside and nucleotide agents have demonstrated potent antiviral activity against poxvirus infection in vitro and in animal models. Cidofovir has been used successfully to treat extensive molluscum contagiosum and orf in patients with AIDS.[8, 10, 9] Vaccination remains a key defense for patients at high risk of infection.
Clinical Context:
This agent is made from vaccinia, which is related to, but different from, the virus that causes smallpox. It contains live vaccinia virus and works by causing a mild infection that stimulates an immune response that effectively protects against smallpox without actually causing disease.
The vaccine contains live vaccinia virus but does not contain variola virus, the virus that causes smallpox. Vaccinia is a member of the Orthopoxvirus genus, which includes smallpox (variola), cowpox, monkeypox, gerbilpox, camelpox, and others. Following inoculation, the vaccine induces an immune reaction that protects against smallpox.
ACAM2000 is derived from Dryvax, which is the only other smallpox vaccine licensed by the FDA. Dryvax, which was approved in 1931, is now in limited supply because it is no longer being manufactured. The US military resumed vaccination of at-risk personnel in 1999 after concluding that the disease posed a potential bioterrorism threat.
Clinical Context:
Vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola or monkeypox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and monkeypox disease in adults who are at high risk for smallpox or monkeypox infection. It is administered as a 2-dose series administered 4 weeks apart.
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 manufactured the last batches of the vaccine (Dryvax) in the early 1980s. These batches were made by using the calf lymph method, and they were lyophilized but are no longer available.
Several attenuated vaccinia vaccine candidates are undergoing investigation, with ACAM2000 receiving FDA approval as a replacement for Dryvax. Another vaccine (smallpox [vaccinia] and monkeypox vaccine, live, nonreplicating [Jynneos]) has also been approved by the FDA for immunization of adults at high risk for smallpox or monkeypox infection.
New cell-derived lots of vaccinia appear to have adverse effect profiles similar to those of the older calf lymph–derived lots.
John D Shanley, MD, MPH, Professor Emeritus, University of Connecticut School of Medicine; Professor of Preventive Medicine, Stony Brook Medical Center
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Charles V Sanders, MD, Edgar Hull Professor and Chairman, Department of Internal Medicine, Professor of Microbiology, Immunology and Parasitology, Louisiana State University School of Medicine at New Orleans; Medical Director, Medicine Hospital Center, Charity Hospital and Medical Center of Louisiana at New Orleans; Consulting Staff, Ochsner Medical Center
Disclosure: Received royalty from Baxter International for other.
Chief Editor
Michael Stuart Bronze, MD, David Ross Boyd Professor and Chairman, Department of Medicine, Stewart G Wolf Endowed Chair in Internal Medicine, Department of Medicine, University of Oklahoma Health Science Center; Master of the American College of Physicians; Fellow, Infectious Diseases Society of America; Fellow of the Royal College of Physicians, London
Disclosure: Nothing to disclose.
Additional Contributors
Larry I Lutwick, MD, FACP, Editor-in-Chief, ID Cases; Moderator, Program for Monitoring Emerging Diseases; Adjunct Professor of Medicine, State University of New York Downstate College of Medicine
Disclosure: Nothing to disclose.
References
Preston R. The Demon in the Freezer. The New Yorker. July 12, 1999. 44-61.
Poxviruses. Following vaccination for smallpox, this patient with chronic lymphocytic leukemia developed vaccinia gangrenosum.
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.
Poxviruses. Following vaccination for smallpox, this patient with chronic lymphocytic leukemia developed vaccinia gangrenosum.
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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