Are You Confident of the Diagnosis?

What you should be alert for in the history

Parapoxviruses (such as orf virus [goats and sheep], pseudocowpox virus [dairy cattle], sealpox virus [grey seals], and deer-associated parapoxviruses) all produce clinically indistinguishable vesiculopustular lesions in humans. Infections occur at the site of contact with the infected animal (or fomite like a harness), so the hand and upper extremity are by far the most common sites involved.

Characteristic findings on physical examination

Orf lesions (and other parapoxvirus lesions) begin as a small papule, and then enlarge into a pustulovesicular lesion, which will range from erythematous to violaceous in color and from 5mm to up to several centimeters in diameter, until they involute and scab (Figure 1).Unless superinfected or excoriated, they do not scar, as the infection is limited to to the epidermis. Lesions may be painful or painless (50/50), and regional lymphadenopathy is variable. Systemic symptoms (fever, chills) are uncommon unless the lesion has become superinfected with bacteria.

Figure 1.

An otherwise asymptomatic orf lesion in a goat handler (2-3 weeks into infection).

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Expected results of diagnostic studies

A clinical diagnosis may be made with a classic lesion and good exposure history; often patients will not present for health care and definitive diagnosis because they (or their vet) recognize the infection and know it is self-limited. If patients do present for evaluation by a physician, swabs of the lesion can be sent for polymerase chain reaction (PCR) confirmation (CDC or research labs); culture of parapoxviruses is difficult and not routinely performed.

Serology for parapoxviruses is also challenging, but has been developed by the California State Department of Health Services Laboratory and may be performed at special request. Unfortunately, levels of antibodies may remain high for years after infection, so serology may not provide a definitive diagnosis.

Punch biopsy with standard hematoxylin and eosin (H&E) staining (Figure 2) will reveal viral cytopathic changes in keratinocytes (ballooning degeneration and eosinophilic viral inclusions); immunohistochemistry (IHC) staining at the CDC may be performed for parapoxviruses, but at this time it is not species-specific.

Figure 2.

Orf. Histology (H&E) , showing viral changes in the keratinocytes. (Courtesy of Bryan Anderson, MD)

Diagnosis confirmation

Since patients will inevitably have a history of contact with animals, and since the lesion often has a violaceous hue and an eschar, the most critical entity to exclude in the differential diagnosis is cutaneous anthrax. The simplest way to exclude anthrax is to inquire about the health of the animals; animals infected with anthrax are visibly ill and often die within 48 hours. Animals with parapoxviruses are generally well-appearing, but may have visible eschars on their lips, face, and/or udders; they may also have gingival/oral granulomatous lesions, which cause them to feed poorly or appear uncomfortable.

Other diagnoses to consider are: molluscum contagiosum (usually smaller, no animal exposures identified, and more common in children), erythema multiforme (may be bullous and violaceous, but usually multiple lesions and associated with drug exposure or herpes simplex or Mycoplasma), herpetic whitlow (occupational exposures such as dentistry and very painful), orthopoxvirus infections such as cowpox (not endemic to North America), tanapox virus infection (travel to sub-Saharan Africa), and contact vaccinia (close contact with a smallpox vaccinee or a lab accident).

Who is at Risk for Developing this Disease?

Patients will describe some degree of close contact with sheep, goats, or their equipment (harness). Contact may involve feeding and medicating young animals, shearing sheep, hand milking, or sustaining a bite. Lambs and kids that are infected may be abandonded by their mothers, which leads to bottle/tube feeding and increased direct human exposure.

What is the Cause of the Disease?

The infectious agent is orf virus (genus Parapoxvirus, species orf), a common infection of sheep and goats. Infection of an immunocompetent human leads to a localized, self-limited infection.


Parapoxviruses are not able to penetrate intact skin, so the portal of entry may be created when an individual removes brambles from an animal’s wool, has a pre-existing break in the cuticle or skin, or sustains a bite. Since the time from infection to presentation to a health care provider may be as long as several weeks, the injury (usually minor) is not easily recalled.

Systemic Implications and Complications

Parapoxviruses such as orf virus do not disseminate through the bloodstream. They may become superinfected with bacteria, and patients may become septic from this complication. Coverage for staphylococcal and streptococcal organisms is indicated if superinfection is suspected.

Treatment Options

Treatment options are summarized in Table I.

Table I.
Medical Surgical Physical
topical imiquimod surgical debridement** n/a
intralesional cidofovir**
CMX001® (oral)**

**only indicated in immunocompromised patients with severe infections

Optimal Therapeutic Approach for this Disease

In otherwise healthy patients, orf infection is self-limiting. No treatment is required; however, recent reports indicate that use of topical imiquimod will reduce the time of healing in relatively immunocompetent patients.

When patients with poor immune function become infected with orf virus, medical intervention will be necessary. As these cases are rare, no clinical trial data is available, and case reports provide our only source of evidence.

Topical imiquimod cured a woman with progressive orf lesions (“giant orf”), even after failure of intralesional cidofovir injections. Topical imiquimod is relatively inexpensive and safe, and should be used as a first-line agent if treatment is desired.

Intralesional cidofovir has been used anecdotally with success, and could be used with or without imiquimod.

In severe cases of orf (immunocompromised hosts), surgical debridement may be indicated. There is no evidence of viremia in parapoxvirus infections, so resection of the lesion should eliminate the infection; however, healing large wounds and superinfection of open wounds may be of concern in patients with significant immunocompromise.

Patient Management

No special management is required in patients with normal immune systems. They should be counseled about using gloves and proper hand hygiene when handling infected animals in the future (patients can get reinfected). Patients should also be advised of the potential for superinfection, and told to keep the lesion clean and dry.

If systemic symptoms (fever, rigors, poor appetite), or a sudden worsening of local symptoms (spreading erythema, pain, lymphadenopathy) develop, suspicion for bacterial superinfection should be heightened and coverage for staphyloccocal and streptococcal pathogens should be initiated.

Contact precautions and isolation are not necessary; parapoxviruses are not spread from person to person.

Unusual Clinical Scenarios to Consider in Patient Management

“Giant orf,” which is progressive in nature and found in patients with poor immune function, requires medical, and possibly surgical, intervention. As described above, the use of imiquimod, intralesional cidofovir, and/or surgical debridement may be necessary. CMX001® has activity against DNA viruses, including parapoxviruses, and could be obtained for compassionate use from the FDA and Chimerix Inc.

What is the Evidence?

Lederman, E, Green, G, DeGroot, H. “Progressive orf virus in a patient with lymphoma: successful treatment using imiquimod”. Clin Infect Dis. vol. 44. 2007. pp. e100-3. (An example of the dramatic effects of topical imiquimod on orf lesions in a significantly immunocompromised patient. Several case reports have been published since, with similar results.)

Lederman, E, Austin, C, Trevino, I. “Orf virus infection in children: clinical characteristics, transmission, diagnostic methods and future therapeutics”. Pediatric Infect Dis J. vol. 26. 2007. pp. 740-4. (This paper reviews the clinical and epidemiologic aspects of orf virus infection in children with goat and sheep exposure)

MacNeil, A, Lederman, E, Reynolds, MG. “Diagnosis of bovine parapoxvirus infections in humans: molecular and epidemiologic evidence”. Zoonoses Public Health. vol. 57. 2010. pp. e161-4. (This paper highlights the clinical presentation of other “barnyard parapoxviruses”—pseudocowpox virus and bovine papular stomatitis virus. These clinical entities are the same in humans; the only difference is the cattle origin versus small ungulates [sheep and goats].)

Erbagci, Z, Erbagci, I, Almila, T. “Rapid improvement of human orf (ecthyma contagiosum) with topical imiquimod cream: report of four complicated cases”. J Dermatolog Treat. vol. 16. 2005. pp. 353-6. (This is the largest case series to date, evaluating relatively healthy patients infected with orf virus and their response to imiquimod.)