An overview of poxviruses

CONTINUING

MEDICAL EDUCATION

An overview of poxviruses Dayna G. Diven, MD* Galveston, Texas The poxvirus family is a diverse and interesting group of viruses that affect both humans and animals. Poxviruses are epitheliotropic and therefore are of interest to the dermatologist. The genera of poxviruses known to affect humans are Orthopoxvirus, Parapoxvirus, Molluscipoxvirus, and Yatapoxvirus. The different poxviruses are reviewed, including their history, incidence, clinical presentation, and treatment. (J Am Acad Dermatol 2001;44:1-14.)

Learning objective: At the conclusion of this learning activity, participants should be able to recognize the members of the family of poxviruses that affect humans and their cutaneous manifestations. Readers will become familiar with the history, epidemiology, and future considerations regarding poxviruses.

T

he poxvirus family is an interesting group of viruses that affect both humans and animals. The poxviruses are the largest of all animal viruses; they can be visualized with light microscopy. By electron microscopy the poxviruses are brickshaped or oval structures, measuring 200 to 400 nm (Fig 1). The nucleosome contains double-stranded DNA, which is surrounded by a membrane. The outer surface of the lipoprotein bilayer has surface tubules that are randomly arranged and give the virion its characteristic textured appearance (Fig 2). The lipid composition of the membrane is different from that of the host cell membrane.1 The nucleoprotein core, lateral bodies, and membrane are infectious as a unit, but the virus also often acquires an envelope. Poxviruses are epitheliotropic and therefore are of interest to dermatologists. The large number of poxvirus species are outlined in Table I. The poxviruses replicate autonomously in the cytoplasm of cells. After uncoating, the virion produces early enzymes and early virion proteins and late enzymes and late virion proteins.1 These replication “factories” are independent of the host nucleus and are discernible on light microscopy as basophilic-staining B-type inclusion bodies. The genome undergoes spontaneous recombination. Poxviruses cause toxic effects on cells, which result in cell rounding and clumping, degeneration of cell architecture, and production of cytoplasmic From the Department of Dermatology, University of Texas Medical Branch. Reprints not available from author. *Dr Diven is currently in Boise, Idaho. Copyright © 2001 by the American Academy of Dermatology, Inc. 0190-9622/2001/$35.00 + 0 16/2/109302 doi:10.1067/mjd.2001.109302

vacuoles. Different poxviruses are capable of producing a localized, self-limited infection by inoculation to the skin (ie, orf) or a fulminant systemic disease (ie, variola). The same virus can affect different species in different ways. Other poxviruses cause localized cell proliferation (ie, molluscum contagiosum virus). Poxviruses that are not known to infect humans (such as camelpox and sheep and goat lumpy skin disease complex) are nevertheless capable of producing great hardship indirectly on communities that are dependent on the host species.2 This review, however, includes only those poxviruses that infect humans.

ORTHOPOXVIRUSES Smallpox Organism. The variola virus is an orthopoxvirus that infects only humans. History. The history of the rise and fall of the smallpox virus is unique and fascinating. The saga includes centuries of horror, scientific triumph, and an undecided future for the fate of the virus. Smallpox affected humankind for generations with unparalleled persistence and diffusion.3 The origin of smallpox is not known. It is thought to have originated in Africa, then spread to India and China thousands of years before Christ. The first recorded smallpox epidemic was in 1350 BC during the EgyptianHittite war.3 It was introduced into Europe between the 5th and 7th centuries. Smallpox occurred in the West Indies in 1507 and followed the Spanish conquest into the New World.4 The Spanish troops were therefore immune while the peoples of Mexico and Peru were not, which is speculated to have been a factor in the outcome of that conquest. By the 18th 1

2 Diven

J AM ACAD DERMATOL JANUARY 2001

Fig 1. Poxvirus (orf): Brick-shaped to oval virus particles are seen in the vacuolated keratinocyte cytoplasm. (Original magnification ×20,160.) (Courtesy of R. L. Sanchez, MD, Galveston, Tex.)

Fig 2. Viral particles with electron-dense DNA core and visible outer membrane. (Original magnification ×93,128.) (Courtesy of R. L. Sanchez, MD, Galveston, Tex.)

Table I. Poxvirus species* Genus

Species

Host

Portal of entry

Orthopoxvirus

Vaccinia Cowpox Variola Monkeypox Orf Bovine papular stomatitis Pseudocowpox Parapoxvirus of red deer in New Zealand Fowlpox, etc. Sheep pox, etc. Myxoma, etc. Swinepox virus

Humans Humans, cats, cattle, rodents Humans Humans, monkeys, rodents Goats, sheep, humans Cows, humans Cows, humans Red deer Birds Sheep, goats, cows Squirrels, rodents, rabbits Swine

Skin Skin Respiratory tract — Skin Skin Skin — Skin

Molluscum contagiosum virus Tanapox virus, etc.

Humans (chimpanzees) Humans, monkeys

Skin

Parapoxvirus

Avipoxvirus Capripoxvirus Leporipoxvirus Suipoxvirus Unclassified Molluscipoxvirus Yatapoxvirus

*Adapted from Tables 1 ( p 82) and 3 (p 98) in Buller RML, Palumbo GJ. Microbiol Rev 1991;55:80-122.

century smallpox was present in major European cities. The 17th and 18th centuries witnessed epidemics in North American colonies.4 At one time smallpox was endemic throughout the world except in Australia and on certain isolated islands.4 During large-scale epidemics, literally millions of people died in Europe and Mexico.3 In the latter half of this century, other countries, especially in Africa and India, continued to suffer major disease while most of North America and Western Europe, Australia, and New Zealand were free of disease. The World Health Organization (WHO) in 1967 set forth with a worldwide campaign to eradicate smallpox, and in 1976 only Ethiopia and surrounding areas were affected by

smallpox. On May 8, 1980, the World Health Assembly declared the world free from smallpox.5 The emergence of smallpox evolved over thousands of years, the global spread occurred over hundreds of years, but the eradication was sealed only 13 years after the WHO program was begun. The history of smallpox during this century is inextricably linked with that of the smallpox vaccine (see “Vaccinia”). With the knowledge that survivors of smallpox were immune, immunization by “variolation” was practiced in China, India, and Turkey in the 1700s.3 Lady Mary Wortley Montague, herself disfigured by smallpox, is credited with advancing the technique of variolation in England in an attempt to control the

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

spread of smallpox.6 Late in the 18th century, Edward Jenner, who had been variolated at the age of 8 years, acted on reports from milkmaids that those who had developed cowpox were protected from smallpox; subsequently he developed the smallpox vaccine that would be used for nearly 200 years (see “Vaccinia”).3 Interestingly, Jenner’s original article delineating his successful experiments was rejected by the Council of the Royal Society because it was “in variance with established knowledge” and “incredible.” He therefore financed the publication himself.3 Incidence. The last outbreak of smallpox in the United States occurred in Texas in 1949 (8 cases, 1 death).7 The last endemic case of smallpox occurred in Somalia in October 1977,8 but a laboratory-associated outbreak occurred at a university in England in 1978.8,9 The person who was infected worked on a floor above the laboratory and died 1 month after infection.9 By 1984, all countries had ceased vaccinating the general population and did not require travelers to certify vaccination.10 In the United States routine vaccination continued until 1971, but the vaccine was given sporadically after this until 1983 when vaccine producers were urged to reserve the vaccine for military personnel only.7 In 1986, it was recommended that the vaccination of military personnel be terminated.11 This was officially discontinued in US military recruits (except for special units) in 1990 (personal communication, Centers for Disease Control and Prevention [CDC]). At the time of this writing, the unvaccinated population consists almost exclusively of persons younger than 30 years. The WHO has monitored and investigated rumors of smallpox, but all cases have been misdiagnosed varicella or other skin diseases. Two known high-security laboratories in Atlanta and Moscow contain the virus; however, some authorities believe that whole virus is no longer needed because the variola virus gene pool has been cloned in bacterial plasmids.10-12 After 1986, global reserves of smallpox vaccine were considered no longer necessary and were destroyed, but it still remains a possibility that unsanctioned laboratories store variola viruses. Therefore physicians would do well to be familiar with the signs and symptoms of this infection (see “Future considerations”). Pathogenesis/epidemiology. Spread of smallpox generally occurs through intimate contact; the portal of entry is the respiratory tract, so population density as well as immunity affects the extent of spread.1 No significant subclinical carrier state exists.4 There are no known animal reservoirs for smallpox, which helped make eradication possible. Infected people are contagious from the onset of illness until the last crusts are gone. The smallpox virus is relatively resistant to environmental conditions.

Diven 3

Clinical manifestations. The incubation period is 12 to 13 days. The illness begins with fever, malaise, and backache. The exanthem appears within 2 to 4 days and evolves from macules to papules to vesicles to pustules and finally crusts. All the lesions are in a similar stage at any one time. The initial lesions occur on the palms and soles and feel firm, like “BB shots,” when palpated.4 The distribution is centrifugal and on extensor surfaces. The lesions are deep with firm multiloculated vesicles. Scarring may be severe. Four recognizable clinical types of smallpox exist: ordinary, modified (by previous vaccination), flat, and hemorrhagic. The latter two have the highest fatality rate.5 Variola major, the severe form of infection, is often fatal because of pulmonary edema from heart failure, but variola minor (“alastrim”) results in few fatalities. No identifiable difference in the virus causing these variants has been found,4 but the pattern of epidemics suggests there were subspecies of the virus that produced either variola minor or variola major depending on the type to which one was exposed. The case fatality rate in adults varied between 20% and 60%, and survivors often had disfiguring scars. Corneal infection frequently resulted in blindness. Dermatopathology. Ballooning degeneration and inclusion bodies are seen within keratinocytes. Reticular degeneration and dermal hemorrhage ensue with massive polymorphonuclear cell infiltrates. This is followed by crust and new epithelial formation.13 Laboratory findings. If the diagnosis of smallpox is considered, immediate isolation is in order, and the CDC should be contacted. All patient contacts should be identified as well. Laboratory confirmation may be obtained from silver impregnation or fluorescent antibody staining of smears taken from skin lesions.4 Electron microscopy can also be used to identify the virus. A negative smear does not exclude the disease. A laboratory prepared to deal with the virus can identify it in chick embryo or in tissue culture. A fourfold or greater rise in antibody titer is also diagnostic. Differential diagnosis. The main disease that might be confused with smallpox is varicella or chickenpox, but in this case small delicate vesicles appear in crops that are concentrated on the trunk, face, and flexor surfaces of the extremities. Syphilis can resemble early smallpox, as can monkeypox, which is endemic in Africa. Treatment/prophylaxis. No treatment for smallpox exists. Supportive care and treatment of complicating bacterial infections are necessary. Smallpox vaccination with vaccinia virus protects against infection from smallpox and monkeypox and

4 Diven

J AM ACAD DERMATOL JANUARY 2001

Fig 3. Vaccinia vesicopustule: A sign of successful vaccination. (Courtesy of Harvey Blank, MD.)

Fig 4. Typical pitted scar after smallpox vaccination with vaccinia. (Courtesy of Harvey Blank, MD.)

therefore may be indicated for the following groups: laboratory persons who handle variola or monkeypox viruses or for staff of surveillance teams who study monkeypox virus in Africa.10 Whether or not laboratory workers who handle other orthopoxviruses infectious to humans (cowpox and vaccinia viruses) should undergo vaccination is subject to opinion. Future considerations. There is a debate regarding whether all stocks of the variola virus should be destroyed. Opponents of destruction argue that more scientific inquiry, requiring the whole virus, could be done (eg, identifying the virulence segment of the genome14-17) and that variola’s unique host specificity also makes it potentially a valuable entity for scientific exploration. In addition, specimens that were collected long ago during epidemics could still be in existence in unauthorized laboratories. Some fear that similar viruses such as monkeypox could mutate.14-17 Proponents of destruction argue that the genomes of reference strains have been cloned and sequenced. In addition, monkeypox virus DNA is similar to variola, has an animal host, and requires less stringent laboratory precautions.12 The fact that a large proportion of the world’s population is not immune to smallpox, that no effective treatment exists, and that the secondary attack rate is 25% to 40%, with a case fatality rate of 25%, makes the smallpox virus a potentially dangerous agent of biologic terrorism.12 Certain authors propose that plans to protect against biologic warfare, including the large-scale production of vaccine, should be initiated now.12 Conclusion. For centuries smallpox brought terror to the civilized world and affected millions of people causing death or disfigurement.3 Worldwide eradication of this virus is a unique event in the history of mankind. The WHO’s efforts and strategies in

this matter are outlined in other publications.7,18 Controversy exists regarding the fate of the remaining stores of virus. Vaccinia Organism. Vaccinia is an orthopoxvirus affecting a wide range of vertebrate hosts. History. Vaccinia virus is the most thoroughly studied poxvirus. Edward Jenner first used vaccinia in 1796 as prophylaxis against smallpox, and it was then used for nearly 200 years for this purpose2 (see “Smallpox”). The virus is thought to have been isolated from infected cows and later horses, but, interestingly, it is now considered to be a laboratory virus with no natural reservoir.2 “Buffalopox” in India may be similar.19 Some favor the idea of vaccinia being a mutant of cowpox20 or derived from a horse.21 Incidence. Infection with vaccinia virus does not occur except in laboratory workers. The vaccine strain is considered to be a relatively safe virus with which to work because it does not cause serious disease in immunocompetent humans or animals.22 Clinical manifestations. After vaccination with a bifurcated needle multiple puncture technique, a papule appears within 2 to 3 days. Then a loculated and umbilicated “Jennerian vesicle” develops, which soon becomes a pustule with surrounding erythema and induration (Fig 3). The erythema is maximal at 10 days, at which time lymphadenopathy, fever, and malaise are common. A scab ensues, which falls off at 21 days leaving the typical pitted scar (Fig 4). Observing a pustule at day 7 confirms successful vaccination. Vaccination scars were used with considerable accuracy to assess the vaccination status of the individual or of populations.23 More severe reactions to vaccination did occasionally occur (Figs 5-7). Complications of vaccination. Generalized vaccinia as a result of viremia can occur at 6 to 9 days after

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

Fig 5. Vaccination site with satellite lesion. (Courtesy of Harvey Blank, MD.)

vaccination. Recovery is expected.20 Autoinoculation or inoculation of another person from the vaccination site is possible. Because the vaccinia virus was not attenuated, it did occasionally cause serious complications. “Eczema vaccinatum,” extensive lesions in eczematous patients or eczematous family contacts of vaccinees, was a real concern because the mortality rate was about 5%.20 Encephalopathy in infants and postvaccinial encephalitis in elderly persons was another rare complication. Persons with impairment in cell-mediated immunity including thymic aplasia, thymic dysplasia, and acquired immune defects developed progressive vaccinia, which is a very serious disease. In some instances vaccinia immune globulin helped those with partial immune deficiencies recover.23 A 1997 report describes an immunocompromised patient inadvertently given a vaccinia melanoma oncolysate vaccination, which led to progressive vaccinia.24 Baxby2 summarizes opinions regarding vaccination and AIDS. Because vaccinia virus is handled by laboratory personnel, a practical guide for such personnel was published in 1993.25 Future applications. Genetically engineered recombinant viruses for use as immunogenic vectors is a much-studied area at present, and vaccinia virus has shown the most promise in this regard since the large genome allows for large or multiple foreign gene insertion to create recombinant vaccinia virus. Its broad host range including humans, laboratory animals, and common tissue culture cells allows for many potential applications.26,27 Because vaccinia virus replicates in the cytoplasm, problems with host cell DNA integration and nuclear transcription errors do not occur.22 Recombinant vaccinia virus strains have been isolated that express influenza hemagglutinin, hepatitis B surface antigen, and antigen from Plasmodium falciparum.22 An oral wild-life rabies vaccine has been

Diven 5

Fig 6. Vaccination reaction from vaccinia. (Courtesy of Harvey Blank, MD.)

Fig 7. “Vaccinial roseola”: a transient erythematous eruption occurring after vaccination. (Courtesy of Harvey Blank, MD.)

developed.28 Although possible laboratory applications include the insertion of virtually any coding sequence for a protein into vaccinia virus genome, its clinical use depends on improving the safety of live vaccines and achieving high immune responses to recombinant protein.28,29 Some scientists are proponents of programs to mass produce vaccinia for use as a vaccine in the event that the smallpox virus is unleashed on the predominantly unimmunized world population in an act of terrorism or warfare.12 Monkeypox Organism. Monkeypox is an orthopoxvirus that occasionally infects humans. History. The first case of human monkeypox infection was identified in 1970. The virus is found in western and central Africa, mostly in Zaire, which is now referred to as the Democratic Republic of the Congo. The infection is enzootic among squirrels and monkeys in the rain forests of Africa. Monkeypox pro-

6 Diven

duces an illness similar to but much less serious than smallpox except for the greater tendency to produce both lymphadenopathy and skin lesions, which occur in crops (“cropping”). Smallpox vaccination protects against monkeypox. Unvaccinated children are mostly affected and deaths have occurred.2,5 In 1986, the committee on orthopoxvirus infections believed that human monkeypox did not pose a significant worldwide health problem because of its low incidence and evidence that the virus does not sustain itself through interhuman transmission.10 However, person-toperson transmission accounted for most of the cases in 1996 and 1997.30 Preliminary DNA studies indicate only minor genetic variation compared with animal strains collected in 1970 through 1979.30 The WHO in collaboration with the CDC investigated an outbreak of 92 and 419 suspected cases that occurred during an 18-month period in 1996 and 1997. This is the largest recorded human outbreak.31 The secondary attack rate of 9% was lower than that of smallpox and case fatality rates were also much lower.12 Cowpox Organism. Cowpox is an orthopoxvirus that infects cows, cats, possibly rodents, and occasionally humans. History. The original isolate used by Edward Jenner in the 18th century that began the age of vaccination is thought to have been cowpox.32 Incidence. Despite its name, cowpox is not a common infection in cattle and “catpox” is thought to be the same virus as cowpox.32 Small rodents, such as voles and mice, not cows, are thought to be the major reservoir for the virus in nature. The most commonly detected source for human infection is the domestic cat.2,33,34 The origin for outbreaks in cattle is still unknown. Cat-to-cat spread is apparently rare.32 Cowpox now appears to occur only in Europe and the former Soviet Union.20,35 Infection in humans is relatively rare but fairly severe. Clinical manifestations. Pustular lesions on the teats of cows are seen in infected cattle. In cats, vesicobullous lesions occur at sites of bites or scratches, usually on the forelimbs or head, but they may go unnoticed.32 Severe infections can be fatal in immunocompromised cats. Infected humans, after a week-long incubation period, have a painful papule or papules, which quickly become vesicles that progress to umbilicated pustules, which may become hemorrhagic with surrounding edema and erythema. These progress to a crust, eschar, or an ulcer. Multiple lesions are usually present on hands or face.20,33 Lymphadenopathy is common and fever or influenzalike illness is not unusual. The cutaneous lesions heal in 3 to 4 weeks, although they may take more than 12

J AM ACAD DERMATOL JANUARY 2001

weeks to heal and scarring is common. Severe and rarely fatal infection has been reported in atopic patients. One fatality involved an 18-year-old patient with eczema receiving corticosteroids for asthma.33,36 This patient presented with a smallpox-like eruption. Recently a boy was infected with a cowpox virus after being bitten by what was thought to be a rat.37 Dermatopathology. The histologic appearance is similar to vaccinia, but there is less necrosis and more hemorrhage.20 The cytoplasmic inclusions, if seen, are larger than the Guarnieri’s bodies of vaccinia and smallpox.38 Laboratory findings. Skin lesions may be used as a source for the isolation of cowpox in tissue culture or for electron microscopy to visualize the virion. Epidemiologic links can be made with DNA restriction endonuclease analysis from virus isolates.32 Orthopoxvirus antibodies in paired sera may be used but are not definitive.39 Differential diagnosis. The disease in cows can be confused with bovine herpes mammillitis and pseudocowpox, which is much more common in cows than is cowpox.40 Human infections resemble parapoxvirus infections (orf, milker’s nodules), herpesvirus infection, or anthrax. Diagnosis. Painful orflike lesions in a human with a history of exposure to cats should raise the possibility of cowpox infection. Infections are more common from July through October.33 Electron microscopy of vesicle fluid or the crust of lesions is useful.35,41 Tissue culture of the virus is possible and serum samples for antibody detection are useful later in the course of the disease.33 Treatment/prophylaxis. No known treatment exists. In a severe case, homologous vaccinia antiserum was given.36 It has been assumed that orthopoxvirus infections (variola and vaccinia), being antigenically similar, would give protection against cowpox infection32; however, infection has occurred in a recently vaccinated adult.33 Conclusion. Cowpox infection affects humans usually by contact with an infected cat. The infection is often localized but can be severe. Infections have only occurred in Europe and the former Soviet Union. Some authors believed that, with discontinuance of the smallpox vaccine and an increase in the number of immunocompromised persons, the incidence of cowpox would increase, but this has not been the case and suggests that the virus is of low infectivity for humans.35 “Cowpox-like” viruses Such viruses have been isolated in elephants and rodents. Care should be taken to differentiate them from cowpox.2

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

Diven 7

Fig 8. Target stage in orf infection. (Courtesy of Stephen K. Tyring, MD.)

Fig 10. Orf lesion of posterior auricle.

Fig 9. Acute weeping nodules stage in orf.

Fig 11. Early regenerative dry stage of orf.

PARAPOXVIRUS INFECTIONS Orf Organism. Orf is a parapoxvirus that infects sheep, goats, and humans, also referred to as ecthyma contagiosum, scabby mouth, sore mouth, contagious pustular dermatosis, and infectious pustular dermatitis (see “Pseudocowpox/milker’s nodules”). History. Infection transmitted to humans from animals was reported in the scientific literature in the 1930s,42 and in 1937 George Peterkin reported the occurrence of orf in humans from contagious pustular dermatitis of sheep.43 The word “orf ” is derived from the Anglo-Saxon name for cattle,44 and the infection was apparently sufficiently well known for Pope Leo X in 1520 to write, regarding Martin Luther, “We cannot suffer the scabby sheep longer to infect the flock.”45 Incidence. This parapoxvirus is of economic importance, particularly in sheep. Infected lambs may fail to grow properly and lesions can become

secondarily infected.44 In contrast, the infection in humans is relatively trivial. There is a worldwide distribution, but one author has stated that apparently only “whites” are infected.46 Pathogenesis. Transmission to humans is from infected lesions in animals or from fomites including fences, barn doors, feeding troughs, and shears.44 Person-to-person transmission under natural conditions has not been documented, although a nurse who changed the bandage of an infected patient contracted the disease.47 Clinical manifestations. In animals the virus produces a vesicopapular eruption on the gums, lips, nose, or groin.44,48,49 In humans the infection usually presents with 1 to 4 papules on the hands, which progress through 6 stages, each of which lasts approximately 6 days: maculopapular, target lesion, acute weeping nodule, regenerative dry stage with black dots, papillomatous, and, finally, regression with a dry crust48 (Figs 8-13). The typical case of orf

8 Diven

J AM ACAD DERMATOL JANUARY 2001

Fig 12. Papillomatous stage of orf.

Fig 13. Resolving orf infection. Note minimal skin changes at lateral aspect of finger. This typical case will leave no scar.

leaves no scar. Secondary bacterial infection is rare but can occur, as can lymphadenopathy and lymphangitis.46 One in a series of 19 patients experienced fever of short duration.44 Erythema multiforme and vesicular eruptions have occurred after orf infection.50,51 A child with active atopic dermatitis had secondary spread of lesions to the face and hands.52 A “giant orf ” lesion measuring 6 cm that failed to regress occurred in a patient with chronic lymphocytic leukemia.53 Orf virus contracted during late pregnancy showed no effects in the infant and did not appear to involve the placenta.54 Dermatopathology. The cells in the upper one third of the epidermis are vacuolated and have intracytoplasmic eosinophilic inclusions during the first 2 stages (Fig 14). During the third stage, multilocular vesicles are seen.44 Intranuclear inclusions are occasionally seen as well, usually in the target stage.48 Reticular degeneration of the epidermis, dilated hair follicles filled with debris (producing the black dots clinically), and a lymphohistiocytic dermal infiltrate

Fig 14. Vacuolated keratinocytes in orf. Eosinophilic intranuclear inclusions are seen in upper epidermis. (Hematoxylin-eosin stain; original magnification ×400.)

with plasma cells are seen in the acute or third stage. The epidermis is often necrotic. Fingerlike downward projections occur in the 5th and 6th stages, producing acanthosis and papillomatosis. The histologic features of lymph node reactions in lambs have been described by Leavell et al.44 Laboratory findings. Electron microscopy of lesional skin shows characteristic brick-shaped viral particles 200 to 380 nm in length (Fig 2). No underlying predisposition for infection has been found. The immune response of humans to the orf virus has been studied.55 Differential diagnosis. Ecthyma contagiosum (orf) and milker’s nodules are clinically identical. It is the source of infection: sheep and goats versus cows, which distinguish the two. The lesions are characteristic. Early lesions may resemble a herpetic whitlow or cowpox. Also to be considered is anthrax, tularemia, primary inoculation tuberculosis, atypical mycobacteria infection, syphilitic chancre, sporotrichosis, and pyogenic granuloma.46 Diagnosis. The diagnosis can be made by history and physical examination. This may be confirmed by using cell culture, complement fixation, fluorescent antibody, or by biopsy of a lesion for examination by hematoxylin-eosin staining or electron microscopy, or both.48 The virus survives heating and drying but is sensitive to ether.44 Treatment. There is no specific antiviral treatment for orf. A live vaccine is available for animals.56 Antibiotics are warranted only if secondary infection is present. Isolation of infected animals will inhibit spread of disease. In humans, lasting immunity is conferred by infection. Conclusion. A self-limited infection of humans results from this parapoxvirus. Cross-immunity for

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

Diven 9

variola or other orthopoxviruses (vaccinia or cowpox) does not result from infection.55,57

is transmitted to humans, a self-limited disease clinically identical to orf results.

Pseudocowpox/bovine papular stomatitis virus/ milker’s nodules Organism. The causative organism is a parapoxvirus that infects the teats of cattle referred to as paravaccinia and, when transmitted to humans, is called milker’s nodules, milker’s node, or paravaccinia. History. Jenner apparently grouped milker’s nodules or pseudocowpox under the heading of “spurious cowpox” because it did not immunize against smallpox.61 Wheeler and Cawley61 discussed the etiology of milker’s nodules and its relationship to vaccinia in 1957. They suspected a viral origin at that time. Friedman-Kien, Rowe, and Banfield62 isolated a poxvirus from a case of milker’s nodule in 1963. Gassman, Wyler, and Witter58 in 1985 as well as Paoletti59 in 1990 analyzed the DNA of ovine (orf) and bovine (pseudocowpox, paravaccinia) and papular stomatitis strains and found them to be distinct. Others,2 however, consider these differences to be slight and not enough to separate orf and milker’s nodules into different species. Infection in the bovine mouth is designated bovine papular stomatitis. The viruses responsible for pseudocowpox and bovine papular stomatitis are designated by most investigators as separate species58,59; however, some contend that only one virus may be involved.60 Incidence. A worldwide distribution is seen infecting (usually) new milkers (young people, vacation milkers, or persons who have switched jobs).61 Bovine papular stomatitis usually affects veterinary students who have contact with the mouth of cows, especially while placing feeding or endotracheal tubes.63 Clinical manifestations. Pseudocowpox infection of cattle occurring on the teats usually produces lesions that are similar to the lesions produced in humans. Bovine papular stomatitis, a mild disease, is characterized by papules in the oral cavity and muzzle area that can be difficult to see. When humans are infected with either virus, the lesions are identical with those of orf (see “Orf ”). Milker’s nodules occurring in burn wounds have been reported. The source of inoculation was presumed to be contaminated water or grass.64 Dermatopathology. Dermatopathologic characteristics are similar to those of orf (see “Orf ”). Laboratory findings/differential diagnosis/ treatment. As noted above for dermatopathologic features, laboratory findings, differential diagnosis, and treatment are similar to those for orf (see “Orf ”). Conclusion. Paravaccinia viruses affecting cattle cause oral or cutaneous teat infections. When either

Other parapoxvirus infections Falk65 reported cutaneous infections in humans from reindeer and a musk ox with a parapoxvirus infection. Mercer,58a in 1997, stated that the parapoxvirus of red deer in New Zealand had yet to be recorded as infecting humans. Tentative members of the genus are camel contagious ecthyma, chamois contagious ecthyma, and seal poxviruses.59 TANAPOX Organism. The causative organism is a poxvirus considered to be unclassified66 or in the genus Yatapoxvirus,1,67 which affects humans and monkeys. History. The virus was first isolated in 1962. It was known to cause epidemics in 1957 and 1962 near the Tana River Valley in Kenya66,68 and now affects Central Africa, including Zaire.41 Incidence. All age groups and both sexes are affected, apparently only in Africa (Zaire and Kenya).66,69 The investigation of 357 cases during a 5-year period was reported in 1985.66 Pathogenesis. The mode of transmission is not known, but it is postulated to be transmitted to humans by mosquitos that have fed on infected monkeys.41,66,68 Clinical manifestations. Tanapox infection results in a short febrile illness followed by 1 to 10 skin lesions.66 The lesions consist of pruritic, indurated, and sometimes umbilicated papules that become necrotic and are surrounded by edematous skin. They are 11⁄2 cm in size, usually occur on exposed body parts, and last for weeks. They ulcerate and then heal with a scar. Lymphadenopathy is common.66 Differential diagnosis. The differential diagnosis includes human monkeypox infection and tropical ulcers. Treatment/prophylaxis. Tanapox infection is usually a benign illness that heals within 6 weeks. Lifelong immunity appears to be the rule.66 Smallpox vaccination does not protect an individual from tanapox infection. MOLLUSCUM CONTAGIOSUM Organism. Molluscum contagiosum is a virus of the Molluscipox genus, which produces characteristic skin lesions. Only humans are known to be affected except for one report each of molluscum contagiosum occurring in chimpanzees and a horse.70,71 History. In 1817, Bateman72 described the lesions characteristic for this infection and assigned its name. In 1841, Henderson and Paterson described the intracytoplasmic inclusion bodies now

10 Diven

J AM ACAD DERMATOL JANUARY 2001

Fig 15. Umbilicated shiny papules of molluscum contagiosum. Note molluscum dermatitis surrounding one lesion.

Fig 16. Large molluscum contagiosum lesions in patient with AIDS.

known by their names or by “molluscum bodies.”73 In 1905, Juliusberg74 showed transmissibility by a filterable agent. In 1911, Lipshutz granules within the molluscum bodies were described.75 Inoculation experiments, however, have not been reliable.76 Incidence. Molluscum contagiosum virus (MCV) occurs worldwide but is more prevalent in tropical areas. It mainly affects children, sexually active adults, and persons with impaired cellular immunity. The incidence in the United States has been increasing since the 1960s, mainly as a sexually transmitted disease.77 It occurs most commonly in persons 15 to 29 years of age.77 The two main subtypes of MCV, I and II, occur in both genital and nongenital lesions. Patients usually have either MCV I or MCV II, not both. In one study, patients younger than 15 years had only MCV I.78 MCV I is more prevalent than MCV II except in HIV-infected persons.79 The incidence of molluscum contagiosum was found to be twice as high in children who were exposed to swimming pools than children who were not.80 Some authors refer to the type II variants as MCV III,81 whereas others have found a rare type IV.82 Pathogenesis. Skin-to-skin transmission is presumed to be the method of spread, including autoinoculation (the Koebner phenomenon), as well as contact with fomites.83 The incubation period may be 1 week to several months.73 The virus, like human papillomavirus, differs from other poxviruses in that it cannot be grown reproducibly in cell cultures, which has hindered scientific study as to how it causes disease and escapes immune detection. The pathogenesis of the lesions has been postulated to be due to hyperplasia and hypertrophy of the keratinocytes.83 Free virus cores have been found in all layers of the epidermis. “Viral factories” are found in the malpighian and granular cell layers,83 and the

molluscum bodies contain large numbers of maturing virions. These are sealed off intracellularly by a collagen and lipid-rich saclike structure, which is thought to protect the virus from immunologic recognition by the host.84 Rupture and discharge of the infectious virus-packed cells occur in the crater of the lesion. It is interesting that MCV induces a benign tumor instead of the usual necrotic “pox” lesion induced by other poxviruses. Clinical manifestations. The typical molluscum contagiosum lesion is a small firm umbilicated papule with a smooth, waxy, or pearly surface. The base may or may not be erythematous. The lesions vary in size from less than 1 mm to 1 cm or more. An average patient has between 10 and 20 lesions (Fig 15), which are typically present for months before they spontaneously resolve. Individual papules last 2 months or more.85 Solitary lesions can last for years,86 but the average case clears in 2 years or less; however, after a period of remission, lesions can appear again. Any cutaneous surface may be involved but sites of predilection include the axillae, antecubital and popliteal fossae, and the crural folds. Rarely, molluscum contagiosum lesions occur in the mouth87 or conjunctivae.88,89 The lesions produced by MCV I and II are clinically indistinguishable. Molluscum contagiosum in adults is often acquired as a sexually transmitted disease affecting the groin, genital area, thighs, and lower abdomen. Children usually acquire molluscum contagiosum nonsexually but may have genital lesions in addition to lesions in extragenital areas. Patients with atopic dermatitis can have a profuse disseminated eruption. A widespread eruption, especially on the face, without a tendency to regress is seen in immunocompromised hosts,90 particularly those with AIDS (Fig 16).91,92 These are very resistant to treatment.

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

Fig 17. Molluscum contagiosum. Intraepidermal lobule containing cellular and viral debris. (Hematoxylin-eosin stain; original magnification ×25.)

“Molluscum dermatitis” or an eczematous reaction around a molluscum papule is occasionally seen (Fig 15). This papule usually resolves after such a reaction occurs and is presumably due to the host immune response to viral antigen.93,94 Occasionally molluscum lesions can become quite inflamed and resemble a pyoderma.95 Molluscum contagiosum sometimes infects the conjunctiva88,89 and can be the cause of unilateral chronic conjunctivitis when the eyelid is involved.96 Dermatopathology. The histology of molluscum contagiosum shows intraepidermal lobules with central cellular and viral debris (Fig 17) with enlarged basophilic nuclei and mitotic figures in the basal layer. Progressing upward, the cells show cytoplasmic vacuolization and eosinophilic globules, and the nucleus becomes compressed at the periphery of the cell. In the granular cell layer, the molluscum bodies lose their internal structural markings (Fig 18). Typically undisrupted lesions show an absence of inflammation, but dermal changes can include an infiltrate that is lymphohis-

Diven 11

Fig 18. Large eosinopilic globules within keratinocytes are termed “molluscum bodies.” (Hematoxylin-eosin stain; original magnification ×100.)

tiocytic, neutrophilic, or granulomatous, particularly in solitary lesions.86 Laboratory findings. Antibody to molluscum lesions by indirect immunofluorescence has been found in 69% of patients with visible lesions.97 Detection of MCV in skin lesions has been accomplished with the polymerase chain reaction.98,99 There is currently no in vitro or animal model for MCV. MCV can undergo an abortive infection in some cell lines, which can cause confusion with herpes simplex virus in laboratories.100 Two groups of investigators have grafted infected human skin onto athymic mice; however, continued viral replication did not occur.101,102 Differential diagnosis. Molluscum contagiosum lesions may be mistaken for verruca vulgaris, syringoma or other adnexal tumors, pyoderma, papular granular annulare, or condyloma acuminatum. Cutaneous cryptococcosis and histoplasmosis can masquerade as molluscum contagiosum in immunocompromised hosts. The solitary giant molluscum contagiosum can be confused with keratoacanthoma, epidermal inclu-

12 Diven

sion cyst, basal cell carcinoma, or a neurilemmoma. An inflamed solitary lesion can resemble a furuncle or a pyogenic granuloma. Diagnosis. The diagnosis of molluscum contagiosum is made clinically. When necessary, histologic examination is diagnostic. Microscopic examination of a curetted lesion crushed on a slide and left unstained or stained with Wright’s, Giemsa, Gram’s or Papanicolaou stains demonstrates the inclusion bodies. Electron microscopy shows characteristic poxvirus structures. Penneys, Matsuo, and Mogollon103 generated a polyclonal antibody that recognized molluscum contagiosum in fixed tissue by means of standard immunohistochemical methods. In situ hybridization for MCV DNA has been used as well.104 Treatment/prophylaxis. Molluscum contagiosum may be left untreated because most lesions will eventually resolve; however, most patients seek medical attention to rid themselves of the papules in which case many destructive methods have been employed. Such methods include curettage, liquid nitrogen, cantharidin, podophyllin, podophyllotoxin, salicylic acid/lactic acid, phenol, tincture of iodine, tretinoin cream or gel, silver nitrate, trichloroacetic acid, oral cimetidine, repeated application and removal of tape (“tape stripping”), squeezing with blunt forceps, or diathermy. Recently reported treatments include use of the carbon dioxide or pulsed-dye laser or topical photodynamic therapy.105,106 The first 4 of these are the methods used most commonly. Lesions, which were clinically undetectable at the time of examination, may appear after treatment, which necessitates multiple treatments. Treatment of the facial molluscum lesions affecting those with AIDS poses a great challenge. At least partial success has been accomplished with the use of combined antiretroviral therapy,107 cidofovir given intravenously or by mouth,108 ritonavir,109 or photodynamic therapy with 5-aminolevulinic acid.105 Conclusion. MCV causes a benign cutaneous infection in humans, which differs from other poxviruses in that it does not cause a “poxlike” vesicular lesion but instead causes tumors of the skin that spontaneously regress. Many local treatments are at least temporarily effective except in the immunocompromised host whose infection may be difficult to eradicate.

J AM ACAD DERMATOL JANUARY 2001

4. 5.

6. 7. 8.

9.

10.

11.

12.

13. 14.

15.

16. 17.

18. 19.

20.

21. 22. 23. 24.

25. 26.

REFERENCES 1. Buller RML, Palumbo GJ. Poxvirus pathogenesis. Microbiol Rev 1991;55:80-122. 2. Baxby D. Human poxvirus infection after the eradication of smallpox. Epidemiol Infect 1988;100:321-34. 3. Barquet N, Domingo P. Smallpox: the triumph over the most

27.

terrible of the ministers of death. Ann Intern Med 1997;127: 635-42. Klainer AS. Smallpox. Clin Dermatol 1989;7:19-22. World Health Organization. The global eradication of smallpox: final report of the Global Commission for the Certification of Smallpox Eradication. Geneva: World Health Organization; 1980. Rathbone J. Lady Mary Wortley Montague’s contribution to the eradication of smallpox. Lancet 1996;347:1566. Fenner F, Henderson DA, Arita I, Jezek Z, Ladnyi ID. Smallpox and its eradication. Geneva: World Health Organization; 1988. Deria A, Jezek Z, Markvart K, Carrasco P, Weisfeld J. The world’s last endemic case of smallpox: surveillance and containment measures. Bull World Health Organ 1980;58:279-83. Centers for Disease Control. Laboratory-associated smallpox—England: smallpox follow-up. MMWR 1978;27:319-20, 346. Jezek Z, Khodakevich LN, Wickett JF. Smallpox and its posteradication surveillance. Bull World Health Organ 1987; 65:425-34. Committee on Orthopoxvirus Infections. Report of the fourth meeting: weekly epidemiological record. MMWR Morb Mortal Wkly Rep 1986;61:289-93. Breman JG, Henderson DA. Poxvirus dilemmas: monkeypox, smallpox, and biologic terrorism. N Engl J Med 1998;339:5569. Fenner F, Wittek R, Dumbell KR. The orthopoxviruses. San Diego: Academic Press; 1989. p. 107. Joklik WK, Moss B, Fields BN, Bishop DH, Sandakhchiev LS.Why the smallpox virus stocks should not be destroyed. Science 1993;262:1225-6. Roizman B, Joklik W, Fields B, Moss B. The destruction of smallpox virus stocks in national repositories: a grave mistake and a bad precedent. Infect Agents Dis 1994;3:215-7. Joklik W.The remaining smallpox virus stocks are too valuable to be destroyed. Scientist 1996;10:11. Mahy BW, Almond JW, Berns KI, Chanock RM, Lvov DK, Pettersson RF, et al. The remaining stocks of smallpox virus should be destroyed. Science 1994;263:13. Henderson DA. Principles and lessons from the smallpox eradication programme. Bull World Health Organ 1987;65:535-46. Baxby D, Gaskell RM, Gaskell CJ, Bennett M. Ecology of orthopox viruses and use of recombinant vaccinia vaccines. Lancet 1986;2:850-1. Highet AS, Kurst J. Viral infections. In: Champion RH, Burton JL, Edling FJG, editors. Textbook of dermatology. 5th ed. London: Blackwell Scientific Publications; 1992. p. 872-3. Taylor CE. Did vaccinia virus come from a horse? Equine Vet J 1993;25:8-10. Hruby DE. Present and future applications of vaccinia virus as a vector. Vet Parasitol 1988;29:281-92. Fenner F, Wittek R, Dumbell KR. The orthopoxviruses. San Diego: Academic Press; 1989. p. 152. Kesson AM, Ferguson JK, Rawlinson WD, Cunningham AL. Progressive vaccinia treated with ribavirin and vaccinia immune globulin. Clin Infect Dis 1997;25:911-4. Williams NR, Cooper BM. Counseling of workers handling vaccinia virus. Occup Med 1993;43:125-7. Chung CS, Hsiao JC, Chang YS, Chang YS. A27L protein mediates vaccinia virus interaction with cell surface heparan sulfate. J Virol 1998;72:1577-85. Minich WB, Behr M, Loos U. Expression of a functional tagged human thyrotropin receptor in HeLa cells using recombinant vaccinia virus. Exp Clin Endocrinol Diabetes 1997;105:282-90.

J AM ACAD DERMATOL VOLUME 44, NUMBER 1

28. Moss B. Genetically engineered poxviruses for recombinant gene expression, vaccination, and safety. Proc Natl Acad Sci U S A 1996;93:11341-8. 29. Moss B. Vaccinia virus: a tool for research and vaccine development. Science 1991;252:1662-7. 30. MMWR 1997;46(April 11):304-7. 31. MMWR 1997;46(Dec 12):1168-71. 32. Westey JP, Yirrel, Norval M. What is human catpox/cowpox infection? Int J Dermatol 1991;30:696-8. 33. Baxby D, Bennett M, Getty B. Human cowpox 1969-93: a review based on 54 cases. Br J Dermatol 1994;131:598-607. 34. Willemse E, Egberink HF. Transmission of cowpox virus infection from domestic cat to man. Lancet 1985;1:1515. 35. Baxby D, Bennett M. Cowpox: a reevaluation of the risks of human cowpox based on new epidemiological information. Arch Virol 1997;13:1-12. 36. Eis-Hubinger AM, Gerritzen A, Schneweis KE, et al. Fatal cowpox-like virus infection transmitted by cat. Lancet 1990;2:880. 37. Postma BH, Diepersloot RJA, Niessen GJCM, Droog RP. Cowpox-virus-like infection associated with rat bite. Lancet 1991;337:733-4. 38. Nagington J, Rook A, Highet AS.Virus and related infections. In: Rook A, Wilkinson DS, Ebling FJG, editors. Textbook of dermatology. 4th ed. Oxford: Blackwell Scientific Publications; 1986. p. 694. 39. Vestey JP, Yirrel DL, Aldridge RD. Cowpox/catpox infection. Br J Dermatol 1991;124:74-8. 40. Fenner F, Wittek R, Dumbell KR. The orthopoxviruses. San Diego: Academic Press; 1989. p. 186. 41. Baxby D, Bennett M. Poxvirus zoonoses. J Med Microbiol 1997;46:17-20, 28-3. 42. Newsom IE, Cross F. Sore mouth in sheep transmissible to man. J Am Vet Med Assoc 1934;84:790-802. 43. Peterkin AG. Occurrence in humans of contagious pustular dermatitis of sheep (“orf”). Br J Dermatol 1937;49:492-7. 44. Leavell UW, McNamara MJ, Muelling R, Talbert WM, Rucker RC, Dalton AJ. Orf: report of 19 human cases with clinical and pathological observations. JAMA 1968;204:109-16. 45. Bainton RH. Here I stand: the life of Martin Luther. New York: Abingdon-Cokesbury Press; 1950. 46. Leavell UW JR. Orf in eermatology. In: Fitzpatrick TB, Eisen AZ, Wolff K, Freedberg IM, Austen KF, editors. Dermatology in general medicine. 3rd ed. New York: McGraw-Hill; 1987. p. 2347. 47. Wespahl HO. Human to human transmission of orf. Cutis 1973;11:202-5. 48. Mendez B, Burnett JW. Orf. Cutis 1989;44:286-7. 49. Allworth MB, Hughes KL, Studdert MJ. Contagious pustular dermatitis (orf ) of sheep affecting the ear following ear tagging. Am Vet J 1987;64:61-2. 50. Ferrando MF, Leaute-LaBreze C, Fleury H, Taieb A. Orf and erythema multiforme in a child. Pediatr Dermatol 1997;14:154-5. 51. Bassioukas K, Orfanidou A, Stergiopoulou CH, Hatzis J. Orf: clinical and epidemiologic study. Australas J Dermatol 1993;34: 119-23. 52. Dupre A, Christol B, Bonafe JL, Lassere J. Orf and atopic dermatitis. Br J Dermatol 1981;105:103-4. 53. Hunskaar S. Giant orf in a patient with chronic lymphocytic leukaemia. Br J Dermatol 1986;114:631-4. 54. Watson WJ, Meyer MW, Madison DL. Orf virus infection in pregnancy. S D J Med 1993;46:423-4. 55. Yirrell DL, Vestey JP, Norval M. Immune responses of patients to orf virus infection. Br J Dermatol 19994;130:438-43. 56. Fox RA. Orf vaccine supplies. Vet Rec 1987;120:624. 57. Robinson AJ, Mercer AA. Orf virus and vaccinia virus do not cross-protect sheep. Arch Virol 1988;101:255-9.

Diven 13

58. Gassman U, Wyler R, Witter R. Analysis of poxvirus genomes. Arch Virol 1985;83:17-31. 59. Paoletti E. Pox virus recombinant vaccines. Ann N Y Acad Sci 1990;590:309-25. 60. Rossi CR, Kiesel GK, Jong MH. A paravaccinia virus isolated from cattle. Cornell Vet 1977;67:72-90. 61. Wheeler CE, Cawley EP. The etiology of milker’s nodules. Arch Dermatol 1957;75:249-59. 62. Friedman-Kien AE, Rowe WP, Banfield WG. Milker’s nodules: isolation of a poxvirus from a human case. Science 1963;140: 1335-6. 63. Bowman KF, Barbery RT, Swango LJ, Schnurrenberger PR. Cutaneous form of bovine papular stomatitis in man. JAMA 1981;246:2813-8. 64. Schuler G, Honigsmann H, Wolff K. The syndrome of milker’s nodules in burn injury. J Am Acad Dermatol 1982;6:334-9. 65. Falk ES. Parapoxvirus infections with reindeer and musk-ox associated with unusual human infections. Br J Dermatol 1978;99:647-54. 66. Jezek Z, Arita I, Szczenowski M, Paluku KM, Ruti K, Nakano JH. Human tanapox in Zaire: clinical and epidemiological observations on cases confirmed by laboratory studies. Bull World Health Organ 1985;63:1027-35. 67. Knight JC, Novembre FJ, Brown DR, Goldsmith CS, Esposito JJ. Studies on tanapox virus. Virology 1989;172:116-24. 68. Downie AW, Taylor-Robinson CH, Caunt AE, Nelson GS, Manson-Bahr PE, Matthews TC.Tanapox: a new disease caused by a pox virus. Br Med J 1971;1:363-8. 69. Axford JS, Downie AW. Tanapox. A serological survey of the lower Tana River Valley. J Hygiene 1979;83:273-6. 70. Douglas JD, Tanner KN, Prine JR, VanRiper DC, Derwelis SK. Molluscum contagiosum in chimpanzees. J Am Vet Med Assoc 1967;151:901-4. 71. Van Resburg IB, Collett MG, Ronen N, Gerdes T. Molluscum contagiosum in a horse. J S Afr Vet Assoc 1991;62:72-4. 72. Bateman F. Molluscum contagiosum. In: Shelley WB, Crissey JT, editors. Classics in dermatology. Springfield (IL): Charles C Thomas; 1953. p. 20. 73. Brown ST, Nalley JF, Kraus SJ. Molluscum contagiosum. Sex Transm Dis 1981;8:227-34. 74. Juliusberg M. Zur Kenntnis des virus des molluscum contagiosum. Dtsch Med Wochenschr 1905;31:1598-9. 75. Lipshutz B. Weitere beitrage zuenntnis des molluscum contagiosum. Arch Derm Syph 1911;287-396. 76. Goldschmidt H, Kligman AM. Experimental inoculation of humans with ectodermotrophic viruses. J Invest Dermatol 1958;31:175-82. 77. Becker TM, Blount JH, Douglas J, Judson FN. Trends in molluscum contagiosum in the United States, 1966-1983. Sex Transm Dis 1988;13:88-92. 78. Porter CD, Blake NW, Archard LC, Muhlemann MF, Rosedale N, Cream JJ. Molluscum contagiosum virus types in genital and non-genital lesions. Br J Dermatol 1989;120:37-41. 79. Yamashita H, Uemura T, Kawashima M. Molecular epidemiologic analysis of Japanese patients with molluscum contagiosum. Int J Dermatol 1996;35:99-105. 80. Niizeki K, Kano O, Kondo Y. An epidemic study of molluscum contagiosum. Dermatologica 1984;169:197-8. 81. Scholz J, Rosen-Wolff A, Bugert J, Reisner H, White ME, Darai G, et al. Epidemiology of molluscum contagiosum using genetic analysis of the viral DNA. J Med Virol 1989;27:87-90. 82. Nakamura J, Muraki Y, Yamada M, Hatano Y, Nii S. Analysis of MCV genomes isolated in Japan. J Med Virol 1995;46:339-48. 83. Billstein SA, Mattaliana VJ. The “Nuisance” sexually transmitted diseases: molluscum contagiosum, scabies, and crab lice. Med Clin North Am 1990;74:1487-505.

14 Diven

J AM ACAD DERMATOL JANUARY 2001

84. Bugert JJ, Darai G. Recent advances in molluscum contagiosum virus research. Arch Virol 1997;13(Suppl):35-47. 85. Hawley TG. The natural history of molluscum contagiosum in Fijiian children. J Hyg (Camb) 1970;68:631-2. 86. Funt TR. Solitary molluscum contagiosum: clinical histological study of nine cases. Cutis 1967;3:339-44. 87. Whitaker SB, Wiegand SE, Budnick SD. Intraoral molluscum contagiosum. Oral Surg Oral Med Oral Pathol 1991;72:334-6. 88. Vannas S, Lapinleimu K. Molluscum contagiosum of the skin, caruncle, and conjunctiva. Acta Ophthalmol 1967;45:314-21. 89. Ingraham HJ, Schoenleber DB. Epibulbar molluscum contagiosum. Am J Ophthalmol 1998;125:394-6. 90. Cotton DWK, Cooper C, Barrett DF, Leppard BJ. Severe atypical molluscum contagiosum infection in an immunocompromised host. Br J Dermatol 1987;116:871-6. 91. Katzman M, Carey JT, Elmets CA, Jacobs GH, Lederman MM. Molluscum contagiosum and the acquired immunodeficiency syndrome: clinical and immunological details of two cases. Br J Dermatol 1987;116:131-8. 92. Schwartz JJ, Myuskowski PL. Molluscum contagiosum in patients with HIV infection: a review of 27 patients. J Am Acad Dermatol 1992;27:583-8. 93. Kipping HF. Molluscum dermatitis. Arch Dermatol 1971;103: 106-7. 94. Takematsu H, Tagami H. Proinflammatory properties of molluscum bodies. Arch Dermatol Res 1994;287:102-6. 95. Brandrup F, Asschenfeld P. Molluscum contagiosum-induced comedo and secondary abscess formation. Pediatr Dermatol 1989;6:118-21. 96. Curtin BJ, Theodure FH. Ocular molluscum contagiosum. Am J Ophthalmol 1955;39:302-7. 97. Shirodaria PV, Matthews RS. Observations on the antibody responses in molluscum contagiosum. Br J Dermatol 1977;96: 29-34. 98. Nunez A, Funes JM, Agromayor M, Moratilla M,Varas AJ, LopezEstebaranz JL, et al. Detection and typing of molluscum contagiosum virus in skin lesions by using a simple lysis method and polymerase chain reaction. J Med Virol 1996;50:342-9.

99. Thompson CH. Identification and typing of molluscum contagiosum virus in clinical specimens by polymerase chain reaction. J Med Virol 1997;53:205-11. 100. Hovendue JL, Bushell TEC. Molluscum contagiosum: possible culture misdiagnosis as herpes simplex. Genitourin Med 1991;67:270. 101. Buller RM, Burnett J, Chen W, Kreider J. Replication of molluscum contagiosum virus. Virology 1995;213:655-9. 102. Fife KH, Whitfield M, Faust H, Goheen MP, Bryan J, Brown DR. Growth of a molluscum contagiosum virus in a human foreskin xenograft model. Virology 1996;226:95-101. 103. Penneys NJ, Matsuo S, Mogollon R. The identification of molluscum infection of immunohistochemical means. J Cutan Pathol 1986;13:97-101. 104. Thompson CH, Biggs IM, DeZwart-Steffe RT. Detection of molluscum contagiosum virus DNA by in-situ hybridization. Pathology 1990;22:181-6. 105. Smetana Z, Malik Z, Orenstein A, Mendelson E, Ben-Hur E. Treatment of viral infections with 5-aminolevulinic acid and light. Lasers Surg Med 1997;21:351-8. 106. Hughs PS.Treatment of molluscum contagiosum with the 585 nm pulsed dye laser. Dermatol Surg 1998;24:229-30. 107. Hurni MA, Bohlen L, Furrer H, Braathen LR. Complete regression of giant molluscum contagiosum lesions in an HIVinfected patient following combined antiretroviral therapy with saquinavir, zidovudine and lamivudine. AIDS 1997;11: 1784-5. 108. Meadows KP, Tyring SK, Pavia AT, Rallis TM. Resolution of recalcitrant molluscum contagiosum virus lesions in a human immunodeficiency virus-infected patients treated with cidofovir. Arch Dermatol 1997;133:351-8. 109. Hicks CB, Myers SA, Giner J. Resolution of intractable molluscum contagiosum in a human immunodeficiency virus-infected patient after institution of antiretroviral therapy with ritonovir. Clin Infect Dis 1997;24:1023-5.

Answers to CME examination Identification No. 801-101

January 2001 issue of the Journal of the American Academy of Dermatology

Questions 1-30, Diven DG. J Am Acad Dermatol 2001;44:1-14.

1. 2. 3. 4. 5. 6. 7. 8. 9. 10.

d b a a d c c c a d

11. 12. 13. 14. 15. 16. 17. 18. 19. 20.

a d e b b a b b c d

21. 22. 23. 24. 25. 26. 27. 28. 29. 30.

d c a a c a d b a e

Answer sheets are bound into the Journal for US members. Request additional answer sheets from American Academy of Dermatology, Member Services Department, PO Box 4014, Schaumburg, IL 60168-4014. Phone 847-330-0230; E-mail [email protected]

CME examination Identification No. 801-101

Instructions for Category I CME credit appear in the front advertising section. See last page of Contents for page number.

Questions 1-30, Diven DG. J Am Acad Dermatol 2001;44:1-14.

Directions for questions 1-30: Give single best response. 1. The Poxvirus family is a group of viruses that affects a. only humans b. only animals c. mainly aquatic species d. both humans and animals 2. The nucleosome of poxviruses contains a. single-stranded DNA b. double-stranded DNA c. single-stranded RNA d. double-stranded RNA 3. Poxviruses replicate in the a. host cell cytoplasm b. host cell nucleus c. host cell mitochondria d. outside the host cell 4. Variola was first known to have affected humans a. more than a thousand years before Christ b. between the fifth and seventh centuries AD c. circa 1000 AD d. the 18th century 5. The World Health Organization declared the world free of smallpox in a. 1947 b. 1967 c. 1970 d. 1980 6. Edward Jenner developed a vaccine using the vaccinia virus in the a. 1500s b. 1600s c. 1700s d. 1800s 7. The portal of entry for smallpox during epidemics was the a. gastrointestinal tract b. skin c. respiratory tract d. ocular mucosa

8. The typical skin lesion of smallpox is a a. papule b. pustule c. multiloculated vesicle d. plaque 9. Vaccinia virus a. is still available today b. has a rodent as its natural reservoir c. usually does not leave a scar when used as a vaccine d. is a member of the Parapoxvirus genus 10. Monkeypox virus a. usually does not infect humans who have had smallpox vaccination with vaccinia b. is enzootic among squirrels and monkeys in the rain forests of Africa c. produces an illness in humans that is similar to but much less deadly than smallpox d. all of the above 11. Cowpox virus a. has a natural reservoir in rodents and the domestic cat b. affects humans in Central and South America c. usually produces nonpainful lesions on the trunk d. usually results from human-to-human transmission 12. Orf a. infects cows and humans b. is an orthopoxvirus c. results in a relatively serious infection in humans d. usually takes more than a month to resolve in humans 13. The histopathology of orf may include a. vacuolated cells with intracytoplasmic eosinophilic inclusions b. intranuclear inclusions c. a lymphohistiocytic dermal infiltrate with plasma cells d. acanthosis and papillomatosis e. all of the above

15

16 CME examination

J AM ACAD DERMATOL JANUARY 2001

14. Milker’s nodules (pseudocowpox/bovine papular stomatitis virus) a. immunized infected people against smallpox b. has a worldwide distribution c. can be differentiated from orf on a clinical basis d. is usually acquired from fomites

23. Molluscum contagiosum occurs in what area in the immunocompromised host? a. Face b. Trunk c. Groin d. Extremities

15. Tanapox a. affects humans and monkeys in Europe and the former Soviet Union b. affects all age groups and both sexes in endemic areas c. infects thousands of people per year in India d. usually produces hundreds of delicate vesicles in humans

24. Poxviruses are a. epitheliotropic b. hepatotropic c. nephrotropic d. cardiotropic

16. Molluscum contagiosum virus a. is a virus of the Molluscipox genus b. has a natural reservoir in small rodents c. is easily inoculated experimentally onto humans and laboratory animals d. grows well in cell culture 17. Molluscum contagiosum occurs worldwide but is more prevalent in a. western Africa b. tropical areas c. desert areas d. high mountain areas 18. Henderson-Paterson or “molluscum bodies” are found in the a. nucleus b. cytoplasm c. dermis d. stratum corneum 19. An average patient with molluscum contagiosum has a. fewer than 5 papules b. 5 to 10 papules c. 10 to 20 papules d. more than 30 papules 20. Molluscum lesions a. are sometimes 1 cm or larger b. can involve the conjunctiva c. in immunocompetent adults usually involve the groin d. all of the above 21. Molluscum contagiosum may be mistaken for a. a pyoderma b. an adnexal tumor c. cutaneous cryptococcosis d. all of the above 22. A common treatment for molluscum contagiosum is a. acyclovir b. ganciclovir c. liquid nitrogen d. Nd:YAG laser

25. A disease characterized by high infectivity and high case fatality rate is a. monkeypox b. cowpox c. smallpox d. pseudocowpox 26. A poxvirus that is solely a laboratory virus with no natural host is a. vaccinia b. tanapox c. cowpox d. pseudocowpox 27. A poxvirus that does not have vesicles as its characteristic lesion is a. vaccinia b. tanapox c. cowpox d. molluscum contagiosum 28. A poxvirus with a low human-to-human transmission is a. smallpox b. orf c. molluscum contagiosum d. monkeypox 29. In which poxvirus infection are lesions characteristically all in the same stage at the same time? a. Smallpox b. Monkeypox c. Molluscum contagiosum 30. In humans, the portal of entry is the skin for which of the following viruses? a. Cowpox b. Orf c. Pseudocowpox d. Molluscum contagiosum e. All of the above