Progressive Human Orf Virus Infection in a Kidney Transplant Recipient Successfully Treated with Cryotherapy Without Modification of Immunosuppression: A Case Report

Abstract

Human orf is a zoonotic parapoxvirus infection that is typically self-limiting with resolution in 3–6 weeks but may cause severe disease in immunocompromised patients. We report a kidney transplant recipient who developed a rapidly progressive fingertip lesion following contact with raw meat during Eid al-Adha. Initial misdiagnosis and surgical excision were followed by marked lesion progression, mimicking a vascular tumor. Histopathology confirmed orf virus infection. However, PCR testing was not done as the test was not available. Topical imiquimod was not initiated due to an active wound. Weekly liquid nitrogen cryotherapy as monotherapy resulted in complete resolution after nine sessions without recurrence. Further modifications/reduction in immunosuppressive medication was not needed. This case highlights cryotherapy as a potential treatment option for orf infection in transplant recipients.

Introduction

Human orf, also known as ecthyma contagiosum, is a zoonotic infection caused by a parapoxvirus, typically transmitted through direct contact with infected sheep or goats. Infection occurs through breaks in the skin and results in characteristic cutaneous lesions that progress through several stages before spontaneous resolution in immunocompetent individuals.1

Orf virus is endemic in livestock populations worldwide and is frequently encountered in individuals with occupational exposure such as farmers, butchers, and veterinarians. Human infection may also occur following contact with recently vaccinated animals or via contaminated fomites, as the virus can persist in the environment for prolonged periods.2 Human-to-human transmission is rare but has been reported.3 In many regions, cases have been increasingly associated with cultural and religious practices involving animal handling, particularly during the Muslim festival of Eid al-Adha.4–6

In immunocompetent individuals, orf is typically self-limiting and resolves within 3–6 weeks without specific therapy, but can extend upto 8 weeks.1 However, in immunocompromised hosts, including solid-organ transplant recipients, infection may follow an atypical course characterized by rapid lesion progression, exaggerated inflammatory response, tumor-like growth, secondary infection, or prolonged disease duration.7 Such presentations may mimic bacterial infections, herpetic lesions, pyogenic granuloma, or cutaneous malignancies, often leading to delayed diagnosis and unnecessary or potentially harmful interventions.1,8

Given the unreliable nature of clinical presentation alone, other modalities, primarily histopathology and molecular testing, are used in combination with clinical presentation. Histopathology may show supportive features such as epidermal necrosis, ballooning degeneration, and intracytoplasmic inclusions, but these findings are not pathognomonic. Electron microscopy can demonstrate parapoxvirus-like ovoid virions but cannot reliably distinguish orf virus from other parapoxviruses, and serologic testing has similar specificity limitations. Polymerase chain reaction (PCR), particularly real-time PCR performed on lesion material, vesicle fluid, scab debris, or tissue, is considered the most definitive diagnostic method because it can identify orf virus at the species level; however, availability may be limited, and diagnostic yield depends on appropriate specimen collection and handling.9

Orf virus infection is typically self-limiting and requires only supportive care in immunocompetent individuals. Treatment is generally reserved for complicated cases, including large, persistent, or progressive lesions, particularly in immunocompromised patients. Topical immunomodulators such as imiquimod and antivirals such as cidofovir have been used with reported success in refractory disease; however, these therapies are not standardized and are supported mainly by case reports. Surgical interventions may be considered in selected cases but are generally avoided due to the risk of autoinoculation and unnecessary morbidity. Overall, management remains largely conservative, with targeted therapy reserved for severe or atypical presentations.10

Orf virus infection in kidney transplant recipients appears to be rare, with the literature limited mainly to isolated case reports and small descriptive reports; robust frequency or incident data are not available.

We report a case of progressive orf virus infection in a kidney transplant recipient with marked lesion worsening following surgical excision, successfully treated with cryotherapy alone without interruption of immunosuppressive therapy.

Case Report

A 50-year-old man presented with a lesion on the tip of his left index finger that had developed one week prior. The lesion initially appeared as a small papule and progressed to a painless yellowish vesicle without purulent discharge. He denied fever, chills, night sweats, weight loss, or prior similar lesions.

His medical history was significant for end-stage renal disease secondary to bilateral ureteric strictures of unknown etiology, status post deceased donor kidney transplantation 2 months prior to the development of the skin lesion. Pre-transplant immunologic assessment demonstrated high immunologic risk with cPRA 98%, HLA mismatch 4/6, and donor specific antibodies against C6 (2000 MFI) and DR32 (1000 MFI). Upon transplant, induction of immunosuppression was achieved using ATG (anti-thymocyte globulin) and maintenance was with mycophenolate mofetil 1g twice daily, tacrolimus 4.5 mg twice daily and prednisolone 30 mg with weekly tapering. Following transplantation (denoted point A on Figure 1), the patient maintained residual renal function with urine output of approximately 1.2–1.5L/day while on high-dose furosemide. Two months following transplant, the patient had attained a baseline serum creatinine of 150–200 μmol/L (seen between points A and B on Figure 1), when he presented with the skin lesion on his left index finger. At that time, the immunosuppressive doses were mycophenolate mofetil 1g BID, tacrolimus 3 mg morning and 2 mg evening, and prednisolone 20 mg daily. He was also on antimicrobial prophylaxis with atovaquone and valganciclovir, and on entecavir for chronic hepatitis B infection.

Figure 1.

Creatinine trend following kidney transplantation until complete resolution of orf virus lesion.

Initial Evaluation and Diagnostic Course

Given his immunocompromised status, the initial differential diagnosis included herpetic whitlow. Valganciclovir 450 mg daily was continued and HSV IgM testing was performed, which later returned negative. Despite antiviral therapy, the lesion enlarged and became painful. Dermatology consultation was obtained, and serosanguinous fluid was cultured. Topical potassium permanganate soaks and fusidic acid were initiated without clinical improvement. The lesion evolved into a solitary, well-defined plaque with an erythematous border and central dry crust.

A more detailed exposure history revealed that approximately one month earlier, during Eid al-Adha, the patient had handled raw meat, although he denied slaughtering the animal himself and was unaware of visible lesions on the animal. He denied livestock ownership, recent travel, or occupational hand trauma. Based on the clinical presentation and exposure history, a diagnosis of suspected orf virus infection was made. However, PCR test was not done to confirm the diagnosis as it was not available in our center due to the rare nature of the disease. Given the typically self-limiting nature of the disease, conservative management and observation were initially recommended.

Clinical Progression and Surgical Intervention

One month later (denoted by point B on Figure 1), the patient was admitted with worsening kidney function with serum creatinine reaching 300 μmol/L, with proteinuria of 1300 mg/mmol, hence kidney biopsy was performed, revealing focal segmental glomerulosclerosis (FSGS), for which he underwent plasma exchange therapy, resulting in renal function returning back to baseline. During this admission, the finger lesion had significantly worsened, forming a large lobulated nodular mass protruding from the fingertip with hemorrhagic appearance and peripheral sloughing. Given concern for alternative diagnosis including bacillary angiomatosis, Kaposi sarcoma, and amelanotic melanoma, biopsy was recommended. Due to the highly vascular nature of the lesion, bedside biopsy was not feasible.

Plastic surgery was consulted, and an X-ray of the left index finger demonstrated a large soft tissue lesion measuring approximately 3.6 × 3 cm overlying the ulnar aspect of the distal phalanx without bony involvement (Figure 2). Hence, an excisional biopsy of the soft tissue mass was planned by plastic surgery. However, intra-operatively, extension of the mass to the distal phalanx was noted and so the distal phalanx was amputated to ensure the entire lesion is removed and any sinister pathology such as malignancy involving the bone is ruled out. Histopathology confirmed the diagnosis, with the patient’s histopathology images shown in Figures 3 and 4. Following surgical excision, which was done to exclude more sinister causes rather than to manage the orf infection, histopathology confirmed orf virus infection, which is self-limiting and the decision was not to proceed with any further surgical interventions and continue conservative management.

Figure 2.

Left index finger X-ray done on initial presentation showing soft tissue lesion without involvement of underlying bone.

Figure 3.

Pseudoepitheliomatous epidermal hyperplasia with marked reticular degeneration and ballooning change of keratinocytes beneath compact hyperkeratosis (H&E, x40).

Figure 4.

Higher magnification of the lesion demonstrating extensive ballooning degeneration and vacuolization of keratinocytes with viral cytopathic effect characteristic of parapoxvirus (orf) infection (H&E, x200).

Worsening After Excision and Definitive Treatment

Despite excision, the lesion continued to worsen, the patient reported increasing pain, and examination revealed a pyogenic granuloma-like mass with granulation tissue, scattered white papules and an active wound at the biopsy site. Repeat X-ray demonstrated amputation at the level of the distal interphalangeal joint with surrounding soft tissue swelling (Figure 5).

Figure 5.

Left hand X-ray done on subsequent presentation showing invasion and amputation of distal phalanx by the soft tissue lesion.

During this time, patient had another spike in serum creatinine (denoted by point C in Figure 1), hence another kidney biopsy was undertaken to assess for FSGS recurrence and progression, which demonstrated collapsing glomerulopathy with focal acute tubular injury, mild tubular atrophy/interstitial fibrosis, and mild arteriosclerosis. There was no evidence of rejection or of the orf infection involving the kidney. Electron microscopy revealed preserved podocyte foot processes, normal glomerular basement membrane thickness, and absence of electron dense deposits.

Topical imiquimod was deferred due to concerns regarding impaired wound healing. Moreover, antivirals such as cidofovir were not given as they can worsen leukopenia which, with immunosuppression, would increase the risk of more serious infections, and this was also agreed by the infectious disease team. A trial of oral amoxicillin-clavulanate was initiated for presumed secondary infection but resulted in no improvement. Once the wound had healed, the lesion appeared as shown in Figure 6.

Figure 6.

Showing orf skin lesion at advanced stage.

After discussion with the patient regarding potential adverse effects, weekly cryotherapy with liquid nitrogen was initiated. A total of nine sessions were administered, resulting in complete resolution of the lesion with no recurrence (Figure 7).

Figure 7.

Lesion after cryotherapy.

To conclude, immunosuppression was not reduced because the patient was only 2 months post renal transplant and was already having worsening renal parameters with high risk of graft rejection. In such circumstances, reducing immunosuppression would put the patient at the harm of losing the precious transplanted kidney which is greater than the harm from a self-limiting infection. The amputation of distal phalanx was not done as part of treating orf virus, which would be a very last step after all treatment lines are used, but was rather done as a diagnostic step to rule out other sinister underlying pathology. The first line treatments such as imiquimod and antivirals were avoided due to concerns of worsening wound with imiquimod and leukopenia and more severe infections with antivirals.

Discussion

Human orf is an under-recognized zoonotic infection that is likely more prevalent than reported. While orf virus commonly infects livestock in many parts of the world, there is limited data on how often it affects humans.11 Traditionally, people with frequent animal contact—like veterinarians, butchers, and farmers—have been considered at the highest risk. For instance, a study in the UK found that 30% of sheep herders had previously been infected.12 These individuals may not seek medical care because they are familiar with the disease, leading to underreporting.13 In recent years, cases have increased among people without traditional risk factors, such as those who keep livestock as pets, process meat at home, participate in animal slaughter for events, or children who visit petting zoos.14 Therefore, it is important for healthcare providers to recognize orf even in patients without typical risk factors to prevent delays in diagnosis and unnecessary treatments.

Orf virus infection is usually diagnosed through a combination of medical history and physical examination. In more complex cases, confirmation may require additional methods such as biopsy, serologic tests, or molecular diagnostics. If a biopsy is performed, it typically demonstrates pseudoepitheliomatous epidermal hyperplasia with ballooning degeneration of keratinocytes and characteristic eosinophilic intracytoplasmic viral inclusion bodies, accompanied by a dense dermal inflammatory infiltrate and prominent capillary proliferation. However, these findings are non-specific and can be seen in other parapoxvirus infections. Molecular techniques such as real-time polymerase chain reaction (PCR) and conventional PCR are highly sensitive and can confirm diagnosis, however, they are not widely available, as in our center, which limits their utility. Other diagnostic tools include Western blotting, cell culture, virus isolation, and enzyme-linked immunosorbent assay (ELISA).15

Currently, there is no specific treatment for orf in immunocompetent individuals, as the lesions typically resolve on their own within upto 8 weeks. Topical or oral antibiotics are sometimes prescribed to prevent secondary bacterial infections. Clinicians should instead focus on educating patients about preventive strategies, such as wearing gloves and examining animals for lesions before slaughtering. Due to limited awareness of orf among healthcare providers, patients may sometimes undergo unnecessary and potentially harmful treatments or procedures.1 In some cases, surgical removal of the lesion may be considered, especially if the patient is immunocompromised—though this can lead to recurrence at the site of removal.16 Moreover, prescribing antimicrobials without evidence of secondary infection can lead to side effects and contributes to the growing problem of antimicrobial resistance.

Individuals with compromised immune systems face a higher risk of orf virus infection, secondary infections, widespread skin involvement, prolonged disease courses, and complications such as large, painful, and atypical lesions that may grow as large as a few centimeters.7 A notable example occurred in 2012, when a burn unit in Turkey documented a hospital-acquired outbreak of generalized orf infection. It originated from a patient who had slaughtered an animal during Eid al-Adha and subsequently infected 12 others.17 Various treatments—including cryotherapy, corticosteroids, surgical removal, electrocautery, imiquimod, and cidofovir—have shown mixed levels of effectiveness in these immunocompromised patients.1

Imiquimod is often used as first line, well-tolerated therapy in treatment of Orf virus lesions.18 However, cases of lesions that fail to improve with imiquimod cream have been reported.8,19,20 Intralesional or systemic subcutaneous Interferon-2a has been reported to be effective as second-line option, but severe pain with intralesional injection might be a concern for patients.20

The positive role of cryotherapy has been observed in several cases with Orf virus lesions. In one patient with kidney transplant, a month-long course of valaciclovir (3g/day) and imiquimod (once a day for 5 days a week) and a two-fold reduction in the dose of immunosuppressive drugs had no effect. A Weekly course of Cryotherapy was started, and complete remission was achieved after 7 courses, with no recurrence at 9 months follow-up.8

Cryotherapy has also been reported to be of benefit with lesions that recur after one or multiple surgical excisions21–23 in combination with Imiquimod cream or topical idoxuridine 40%. However, it represents a non-specific destructive modality rather than a targeted antiviral therapy. Its effect is primarily through local tissue destruction, which may reduce lesion burden but does not directly address the underlying viral infection. In viral lesions, this may reduce infected tissue burden and viral load, with possible secondary immune stimulation, but it does not directly inhibit orf virus replication.24 Consequently, its use is generally limited to selected cases, such as large or persistent lesions, as in our case, or when other modalities have either failed or cannot be safely used, as in our case,1 and is supported mainly by case reports including immunocompromised hosts, and should therefore be considered selectively rather than generalized as first-line monotherapy. Potential adverse effects include procedural pain, blistering, edema, secondary infection, delayed healing, dyspigmentation, scarring, tissue distortion, and nail dystrophy, which are particularly relevant for periungual or digital lesions.24 Caution is warranted in large or deeply invasive lesions and patients with impaired wound healing, where destructive therapy may worsen morbidity. In our patient, cryotherapy was chosen only after histopathologic confirmation, wound healing, inability to use imiquimod safely, and multidisciplinary discussion; therefore, this case supports cryotherapy use in selected refractory or progressive orf lesions, but not as routine first-line monotherapy.

In a case reported by Saeidi V et al,19 cryotherapy once every two weeks, in addition to topical imiquimod 3 times per week, failed to produce results at one month follow-up, for which intralesional interferon-2a was used and resulted in resolution of lesions.

Our case is unique in that we had a progressively worsening lesion in a kidney transplant patient, for whom Imiquimod was deemed inappropriate, and a trial of cryotherapy alone led to complete remission despite initial worsening following surgical excision, without the need of concomitant topical or systemic therapy, or interruption of immunosuppressive therapy for kidney transplant, suggesting that weekly Cryotherapy may be effective as a first-line monotherapy option in carefully selected patients.

In summary, healthcare providers should be well-versed in recognizing the risk factors, symptoms, and appropriate treatment of human orf. Although orf presents with distinctive skin lesions and may spread through lymphatic channels, its tendency to resolve on its own means that awareness of its natural course can prevent unnecessary hospitalizations, medical procedures, or antibiotic use. When evaluating unusual or non-healing cutaneous lesions in immunocompromised individuals, clinicians should obtain a detailed history that includes not only traditional occupational exposures but also cultural and recreational risk factors. In this population, infections such as orf may present atypically, with larger, persistent, or progressively enlarging lesions that can mimic malignancy or other opportunistic infections. Numerous cases of human orf have been reported globally following animal slaughter during the Muslim festival of Eid al-Adha. With increasing global migration and animal exposure in urban settings, clinicians – particularly those unfamiliar with orf or cultural practices involving animal handling – should maintain a high index of suspicion and be prepared to promptly recognize and appropriately manage this infection in immunocompromised patients.

Funding Statement

This research did not receive any external funding.

Data Sharing Statement

Data supporting this case report are available from the corresponding author upon reasonable request. Further inquiries can be directed to the corresponding author.

Ethics Approval and Consent

Ethical approval obtained from Medical Research Council. Permission was also required from Hamad General Hospital to publish this case report and was obtained. The patient has given written informed consent to include his details including pictures, for the case report, and has consented to publish it.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no conflicts of interest related to this work.