DISCUSSION
Orf virus is a member of the Parapoxvirus family, and generally causes highly contagious zoonotic infections [6]. The virus causes sore mouth disease in sheep and goats [6]. In healthy individuals, especially in people who are handling sheep and goats, this virus may cause orf nodules in hands named as contagious ecthyma or contagious pustular dermatitis [6,13]. Orf virus causes skin lesions via direct contact of damaged skin with infected animals or fomites indirectly [6]. The disease course is usually self-limited, and it is not expected to cause disseminated disease, but there are very rare cases of disseminated exanthems, fever and lymphadenopathies [11]. It may, however, cause systemic disease or unexpected giant lesions in primary immunodeficiency patients [12]. Although there is susceptibility to mostly fungal infections in patients with STAT1 gain of function (GOF) defects, there has been a case of a STAT1 GOF mutation who had developed an orf virus infection [12]. Orf virus was reported to be associated with lobular capillary hemangioma in burn patients [13-15]. This may be attributed to the local immunosupression related to burn. It has been shown that the VEGF-E protein produced by orf infections causes epithelial growth in mice models [14]. It may be suggested that virally expressed VEGF-E protein may responsible for proliferative skin lessions. The presented patient had multiple giant lobular capillary hemangiomas which are infected with orf virus.
Epidermodysplasia verruciformis is a rare, autosomal recessive skin disorder, reported a total 501 patients in literature [16]. It is characterized by high susceptibility to certain types of human papillomaviruses. Patients develops flat-topped, wart-like papular lesions similar to verrucae planae on the extremities [17]. Patients have an increased risk of developing non-melanoma skin cancers [17]. The pathogenesis is not completely understood but it is thought to be related to agent selective immunodeficiency [16]. Our patient’s skin biopsy showed epidermodysplasia verruciformis. The presented patient had extensive orf virus infected giant lobular capillary hemangiomas and epidermodysplasia verruciformis lessions.
DOCK8 deficiency is a combined immunodeficiency characterized by recurrent infections, atopy, autoimmunity and cancer [3,4]. It is most commonly seen in Arabic and Turkish populations [3]. Severe cutaneous and invasive viral infections such as varicella zoster, molluscum contagiosum, HSV and HPV are seen [3,4,5]. Viral infections may be systemic or involves deep tissues [3]. DOCK8 deficiency may cause virally-driven malignencies such as HPV-related squamous cell carcinoma, EBV-related smooth muscle tumors or lymphomas [3]. This unusual occurance of orf virus infected giant lessions and epidermodysplasia verruciformis raised our suspicion towards an underlying combined or agent spesific immunodeficiency. Our patient also had eosinophilia and elevated IgE levels. Further investigations revealed DOCK8 deficiency in our patient. The presented case is first case to with DOCK8 deficiency, epidermodysplasia verruciformis and orf virus infection.
Castleman disease is a disease of unknown etiology and seen very rare in childhood [1]. The literature is mainly focused on adult population and small case series have been reported. Clinical and pathologic abnormalities are heterogeneous and overlap with a wide range of other immunologic disorders [2]. Whether autoimmune, autoinflammatory, neoplastic or infectious mechanism make the most contribution is not certain [2]. Our patient hyaline vasculary type CD and clinically had iMCD-NOS. Although the role of HHV8 in HHV8-MCD is relatively well understood, the pathogenesis of iMCD-NOS is unclear [2]. It has been showed that IL-6 overexpression may play a role in disease [18]. Interestingly, VEGF expression is also elevated in iMCD patients [19]. No certain relationship between a virus other that HIV or HHV-8 was shown to date [20]. The presented patient had multiple thoracic, cervical and abdominal lymphadenopathies. Lymph node biopsy of the conglomerated abdominal lymph nodes were performed and revealed hyaline vascular variant of multicentric Castleman disease. Our patient met the inclusion criteria for iMCD-NOS.
This patient is the first case with iMCD-NOS and DOCK8 deficiency. Drolet et al. reported a case of CD in a child with common variable immunodeficiency (CVID) [8]. Castleman disease has also been reported to occur in patients with HIV, which is an acquired T-cell deficiency. Guihot et al. documented polyfunctional effector memory HHV-8 specific CD8+ T cells in MCD and suggested that HHV-8 specific T cell responses may play a role in the pathogenesis of MCD [9]. Elevated effector memory (CD4+CCR7-CD45RA-) in our patient supports this hypothesis. Leroy et al reported a child born to consanguineous parents with proven HHV-8 associated MCD in the absence of an immunodeficiency. He suggested that MCD in childhood may be related to rare inborn errors of immunity against HHV-8 infection [10].
There are no definitive guidelines for treatment of CD and regimens vary among different institutions. The options include steroids, rituximab, anakinra, siltuximab, tocilizumab, conventional cytotoxic chemotherapy, R-CHOP (cyclophosphamide, vincristine, doxorubicin and prednisone) and radiotherapy [2]. The presented patient responded to R-CHOP treatment very well. Our patient also had underlying DOCK8 deficiency. Hematopoietic stem cell transplantation (HSCT) is curative for DOCK8 deficiency. IFN-α treatment may also be beneficial [4]. After remission induction, we planned HSCT to our patient but unfortunatelly, our patient died because of neutropenic sepsis.
In conclusion, our case is the first case with DOCK8 deficiency, iMCD-NOS and orf virus infection. Each of these diseases are rarely seen in childhood. Our findings suggest that inborn errors of immunity may play a role in the occurrence of iMCD-NOS, and orf virus may trigger CD in the presence of an underlying immunodeficiency. Further investigations are required for understanding the immunologic basis of the disease.
Aknowledgements: We are thankful to our staff who contributed to this patient’s care.
Ethical approval : Informed consent was obtained from the patient’s family to publish the details and images of this case.
Conflict of Interest Disclosures: None reported.