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Orf Viral Infection
Introduction
Orf viral infection, also known as contagious pustular dermatitis or ecthyma contagiosum, is a zoonotic and occupational infection acquired from infected sheep and goats. Orf is caused by the parapoxvirus Orfviridae.[1] The orf virus plagues young sheep and goats, which are their natural host range.[2] The virus induces vesicular, papular, and nodular lesions, prominently appearing in the lips and mouth of affected animals, where observers may perceive it as a mouth sore.[3] In humans, however, it usually presents on the dorsal hands or fingers at areas of contact with the infected animals.[4] Orfviridae is notorious for jumping hosts to human populations after close contact with a zoonotic source with active lesions or via fomites.[5]
Orf passes through 6 clinical stages and is usually diagnosed with a clinical history of handling sheep, goats, or other associated animals during one of the 6 clinical stages in a classic area.[6] Testing through a skin biopsy or a polymerase chain reaction test may be used to aid in the diagnosis of suspicious lesions for which there is no specific clinical history of vague clinical symptoms.[7] Additional testing, such as cell culture or electron microscopy, may be needed when considering other causes of nodules on the hands (eg, Milker nodule, cutaneous anthrax). Histopathologically, Orfviridae appears similar to other viruses with eosinophilic intracytoplasmic inclusions and ballooning degeneration.[8] Treatment may not be necessary for immunocompetent patients, as the disease usually resolves in 6 to 8 weeks. However, multiple treatments can be implemented to prevent the worsening of the disease in patients with immunosuppression.[4]
Etiology
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Etiology
The orf virus is an epitheliotropic virus detected by isothermal amplification in multiple organisms, notably sheep and goats.[2] The parapoxvirus that causes orf is a linear, double-stranded DNA virus; because of this, reinfection of hosts (primarily sheep and goats) is common.[9]
Orf virus has a variety of virulence and immunomodulatory factors, including granulocyte/macrophage colony-stimulating inhibitor factor, nuclear factor-kappa beta inhibitors, vascular endothelial growth factor-E, a chemokine binding protein, and a viral version of interleukin-10.[9][10][11] Further research findings have demonstrated that the orf virus uses macroautophagy in mammals, possibly contributing to the viral infection and pathogenesis in human hosts.[9] The orf virus demonstrates immunomodulatory and antiviral activity, including antifibrotic activity, as observed in hepatic samples from rats infected with hepatitis B virus and hepatitis C virus.[12]
Epidemiology
Orf virus is frequently present in animals, notably sheep and goats. However, this virus may also be in muskoxen or camels.[13][14]. Multiple epidemiologic studies have been performed to understand the presence of orf virus in animals. One study in Nigeria found the prevalence of animals across 2 years to be just under 70%.[15] Reports of mortality in livestock range from 0% to 8%, and it has been demonstrated through polymerase chain reaction and molecular characterization that there is a wide diversity of orf viruses found in animals.[16][17]
Worldwide, orf is rare but more likely in specific populations. Results from a study in France identified 44 infections over 3 years, most of whom had contact with sheep.[18] Orf viral infection is an occupational hazard, and the incidence is higher in at-risk professions such as farmers, veterinarians, employees of slaughterhouses, sheepherders, and butchers.[19] However, this condition may also be found in patients who have other exposures to sheep or goats; for example, those who participate in religious or other rituals where they may have contact with the animals or may have contact with other animals associated with minor trauma to allow entry of the virus.[18][20][21][22]
Pathophysiology
The infection caused by the orf virus is endemic to sheep and goats. Direct contact with active lesions from affected animals or contact with fomites can infect humans.[4] At-risk populations include farmers, butchers, or people who participate in rituals related to sheep and goats; these populations that maintain animals may have minor trauma through which infection passes. The virus uses various immunomodulatory effects to evade the immune system and infect keratinocytes.[23] After approximately one week of the virus’s incubation period, clinicians may clinically observe the initial lesions.[24] Orf virus is rarely, if ever, transmitted from humans to other humans.
Histopathology
After a shave or punch biopsy, histopathology of orf viral infection usually shows epidermal necrosis that may be present with surface erosions and crust or acanthosis but less likely acantholysis; other changes in the epidermis may include viral inclusion bodies, which have cytoplasmic vacuolization of the upper epidermis and eosinophilic intracytoplasmic inclusions.[25] Another common finding is ballooning reticular degeneration due to cellular edema, though the stratum corneum is usually intact.[26] Dermal changes can include a heavy lymphohistiocytic infiltrative change, and further stains like methenamine silver, Ziehl-Neelsen (acid-fast), and periodic acid-Schiff are usually negative.[25] A spongiform degeneration in follicular structures and polymorphic infiltrate can be present in the lower dermis.[27]
History and Physical
A relevant history, especially one targeting occupational hazards (eg, sheep and goat handlers, farmers, butchers, religious leaders who handle sheep or goats) and recent travel emphasizing animal contact, is paramount. Associated orf virus skin lesions are distinctive, polymorphous, asymptomatic, and diagnosed clinically.[28] Hand and digital involvement comprise the majority of affected sites (> 90%).[29] However, involvement of the face, scalp, and even genital regions has been described.[25][30][31] In immunocompromised hosts, the lesion may attain a large size (colloquially known as giant orf) and can lead to some morbidity.[32]
After a week of incubation, the lesions of orf can develop, progressing through 6 stages, each about a week in duration, as below:[4]
- Maculopapular stage: Erythematous macules/papules
- Target stage: Targetoid nodules surrounded by a red halo and necrotic center
- Acute stage: Nodules begin to weep
- Regenerative stage: Nodule becomes dry
- Papilloma stage: Nodule has a dry crust and becomes papillomatous
- Regression stage: Lesion begins to regress
Lesions can be associated with lymphadenopathy, fever, malaise, or occasionally an erythema multiforme-like or bullous pemphigoid-like presentation.[4]
Evaluation
A positive exposure history and a suggestive physical exam are often enough to diagnose orf virus infection in most affected individuals. However, a punch/shave biopsy is diagnostic and the gold standard.[29] Although not always readily available, a PCR assay for orf viral infection is highly sensitive in humans. This assay can be the noninvasive investigation of choice if the diagnosis is in doubt.[33] Other diagnostic tools used include cell culture, electron microscopy, virus neutralization, immunohistochemistry, immunofluorescence, enzyme-linked immunosorbent assay, loop-mediated isothermal amplification, and recombinase polymerase amplification.[34]
Treatment / Management
Orf viral infection, as a zoonotic host-switch illness, generally has a favorable prognosis. The lesions are self-limiting, and in immunocompetent patients, symptoms typically resolve spontaneously within a 4- to 6-week period.[4] Most cases rarely require anything more than reassurance and expectant care. However, in immunocompromised hosts, Orf can grow to several centimeters, and the resultant morphology may mimic those of tumors and pyogenic granuloma, which may require further management. Avoid surgical debridement, as this can prolong recovery.[4]
Because Orfviridae utilizes a novel viral form of DNA-dependent RNA polymerase, topical cidofovir (a potent blocker of this enzyme) has found almost ubiquitous use as first-line antiviral therapy, along with mechanical eradication (eg, cryotherapy, imiquimod) if needed.[35][36][37]
Clinicians have employed systemic interferon-α to treat immunocompromised patients.[38] Additionally, proposed effective treatments include antiviral agents that inhibit nucleoside.[37] Vaccination is particularly effective because of the highly conserved and complex antigenicity of the orf virus.[39] Many domesticated sheep and goat populations are routinely vaccinated, with varying levels of success. In humans, recurrence is rare but with diminished severity per incident.[40][41][42](B3)
A review of therapeutic options for orf virus, among other poxviruses, found multiple medications that may be considered treatment options for the infection.[35]
- Brincidofovir has been studied in ecthyma contagiosum and other orthopoxviruses and has been effective, including in vitro studies of rabbits.
- Cidofovir has demonstrated activity against multiple orthopox and parapox viruses. Animal models revealed its effectiveness in reducing the development of Orf lesions in lambs and rescuing mice with orf lesions. This agent has been used in humans for recalcitrant cases, primarily in immunocompromised patients.
Differential Diagnosis
The 2 most important differential diagnoses to rule out include those that share zoonotic-exposure history with farm animals and exhibit cutaneous lesions.
Paravaccinia (Milker nodules) is a similar parapoxvirus infection from cows rather than goats or sheep, as in orf. Clinically, the lesions of orf and Milker nodules are indistinguishable and typically resolve spontaneously within 6 weeks.[43]
Cutaneous anthrax is a bacterial infection from Bacillus anthracis. An eventual “black eschar” evolution is pathognomonic for this lesion. The more infamous pulmonary symptoms can develop in the systemic spread and can be life-threatening. Spores are transmittable from infected animals, wool, and even meat. Gram stain, culture, and even PCR are all available to aid in diagnosis.[44]
Other differential diagnoses include deep fungal infection, squamous cell carcinoma (especially keratoacanthoma-type), pyogenic granuloma, atypical mycobacterial infection, and neutrophilic dermatoses.[4]
Prognosis
As a zoonotic infection, orf viral infection follows a relatively benign course. It typically resolves spontaneously within 6 to 12 weeks and has a very low rate of human-to-human spread. A more aggressive course with increased size (giant orf) may appear in immunocompromised hosts, especially those with cell-mediated immune deficiency.[45][46] Recurrence is possible but produces a progressively blunted infection.
Complications
Secondary bacterial infections are possible complications of orf infection.[47] Other complications can include lymphangitis, lymphadenopathy, and erysipelas.[47]
Sporadic immunologic reactions can occur fortuitously with zoonotic infections, especially with an immunomodulatory virus such as orf. Erythema multiforme, Stevens-Johnson syndrome, and bullous pemphigoid cases have all been described. For blistering lesions, results from a study of 5 patients showed the presence of IgG1 and IgG3 autoantibodies targeting laminin-332, which is common in mucous membrane pemphigoid.[48][49] A blistering condition should be expected and handled carefully, as orf-related pemphigoid may be a unique clinical entity.[50][51][48]
Deterrence and Patient Education
Educating farmers, herders, and other at-risk occupations on proper glove-wearing and hand-washing techniques is essential. Seminars or other educational tools for recognizing and diagnosing infected livestock and using proper vaccination protocol or inducing herd immunity are appropriate avenues to address and reduce the spread of this infection.
Pearls and Other Issues
A vaccination has been developed for the orf virus, though this represents an attenuated vaccine, which may have some effectiveness in eliciting a specific response to orf virus. Yet, there is a risk of virulence reversal or poor antigenicity.[39] Using adenovirus as a vaccine candidate, a study in mice showed that a prime-protein boost created a more robust humoral and cellular immune response than the adenovirus strategy.[39]
Enhancing Healthcare Team Outcomes
Efficient cost management could be achieved by ensuring healthcare providers in rural areas are knowledgeable in recognizing and treating orf viral infection. Surveillance and infection control measures play a pivotal role in preventing infection. Education of patients on hand hygiene when handling sheep or goats is of the utmost importance.
References
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