Dedicator of cytokinesis 8 (DOCK8 ) deficiency is the major cause of autosomal-recessive hyper-IgEsyndrome. 1 Characteristic clinical features including eosinophilia, eczema, and recurrent Staphylococcus aureus cutaneous and respiratory tract infections are common in DOCK8 deficiency, similar to the autosomal-dominant form of hyper-IgE syndrome that is due to defi c iency of signal transducer and activation of transcription 3 (STAT-3 ). 1 In addition, patients with DOCK8 deficiency are particularly susceptible to asthma; food allergies; lymphomas; and severe cutaneous viral infections, including herpes simplex virus (HSV), molluscum contagiosum, varicella-zoster virus, and human papillomavirus. Since the discovery of the DOCK8 gene in 2009, various studies have sought to elucidate the mechanistic contribution of DOCK8 to the dermatologic immune environment. 2 Although cutaneous viral infections such as those caused by HSV typically are short lived and self-limiting in immunocompetent hosts, they have proven to be severe and recalcitrant in the setting of DOCK8 deficiency. 1 Herein, we report the case of a 32-month-old girl with homozygous DOCK8 deficiency who developed acyclovir-resistant cutaneous HSV.
A 32-month-old girl presented with an approximately 2-cm linear erosion along the left posterior auricular sulcus at month 9 of a hospital stay for recurrent infections. Her medical history was notable for multiple upper respiratory tract infections, diffuse eczema, and food allergies. She had presented to an outside hospital at 14 months of age with herpetic gingivostomatitis and eczema herpeticum that was successfully treated with acyclovir. She was readmitted at 20 months of age due to Pneumocystis jiroveci pneumonia, pancytopenia, and disseminated histoplasmosis. Prophylactic oral acyclovir (20 mg/kg twice daily) was started, given her history of HSV infection. Because of recurrent infections, she underwent an immunodeficiency workup. Whole exome sequencing analysis revealed a homozygous deletion c.(528+1_529−1)_(1516+1_1517−1)del in DOCK8 gene–affecting exons 5 to 13. The patient was transferred to our hospital for continued care and as a potential candidate for bone marrow transplant following resolution of the disseminated histoplasmosis infection.
During her hospitalization at the current presentation, she was noted to have a 2-cm linear erosion along the left posterior auricular sulcus. Initial wound care with bacitracin ointment was applied to the area while specimens were obtained and empiric oral acyclovir therapy was initiated (20 mg/kg 4 times daily [QID]), given a clinical impression consistent with cutaneous HSV infection despite acyclovir prophylaxis. Direct immunofluorescence and viral cultures were positive for HSV-1, while bacterial cultures grew methicillin-susceptible S aureus. Cephalexin and mupirocin ointment were started, and acyclovir was continued. After 2 weeks of therapy, there was no visible change in the wound; cultures were repeated, again showing the wound contained HSV. Bacterial cultures this time grew Pseudomonas putida, and the antibiotic regimen was transitioned to cefepime.
After no response to the continued course of therapeutic acyclovir, HSV cultures were sent to the Centers for Disease Control and Prevention for resistance testing, and biopsy of the lesion was performed by the otolaryngology service to rule out malignancy and potential alternative diagnoses. Histopathology showed only reactive inflammation without visible microorganisms on tissue HSV-1/HSV-2 immunostain; however, tissue viral culture was positive for HSV-1. The patient was transitioned back to acyclovir (intravenous [IV] 20 mg/kg QID) with the addition of empiric foscarnet (IV 40 mg/kg 3 times daily) given the worsening appearance of the lesion. The HSV acyclovir resistance test results from the Centers for Disease Control and Prevention returned soon after and were positive for resistance (median infectious dose, 3.29 µg/L [reference interval, sensitive <2.00 µg/L; resistant >1.90 µg/L]). The patient completed a 21-day course of combination foscarnet and acyclovir therapy, during which time the lesion showed notable improvement and healing. The patient was continued on prophylactic acyclovir (IV 20 mg/kg QID). Unfortunately, the patient eventually died due to complications related to pneumonia.
Infection in Patients With DOCK8 Deficiency—The gene DOCK8 has emerged as playing a central role in both innate and adaptive immunity, as it is expressed primarily in immune cells and serves as a mediator of numerous processes, including immune synapse formation, cell signaling and trafficking, antibody and cytokine production, and lymphocyte memory.3 Cells that are critical for combating cutaneous viral infections, including skin-resident memory T cells and natural killer cells, are defective, which leads to a severely immunocompromised state in DOCK8-deficient patients with a particular susceptibility to infectious and inflammatory dermatologic disease.4
Herpes simplex virus infection commonly is seen in DOCK8 deficiency, with retrospective analysis of a DOCK8-deficient cohort revealing HSV infection in approximately 38% of patients.5 Prophylactic acyclovir is essential for DOCK8-deficient individuals with a history of HSV infection given the tendency of the virus to reactivate.6 However, despite prophylaxis, our patient developed an HSV-positive posterior auricular erosion that continued to progress even after increase of the acyclovir dose. Acyclovir resistance testing of the HSV isolated from the wound was positive, confirming the clinical suspicion of the presence of acyclovir-resistant HSV infection.
Acyclovir-Resistant HSV—Acyclovir-resistant HSV in immunosuppressed individuals was first noted in 1982, and most cases since then have occurred in the setting of AIDS and in organ transplant recipients.6 Few reports of acyclovir-resistant HSV in DOCK8 deficiency exist, and to our knowledge, our patient is the youngest DOCK8-deficient individual to be documented with acyclovir-resistant HSV infection.1,7-15 We identified relevant cases from the PubMed and EMBASE databases using the search terms DOCK8 deficiency and acyclovir and DOCK8 deficiency and herpes. The eTable lists other reported cases of acyclovir-resistant HSV in DOCK8-deficient patients. The majority of cases involved school-aged females. Lesion types varied and included herpes labialis, eczema herpeticum, and blepharoconjunctivitis. Escalation of therapy and resolution of the lesion was seen in some cases with administration of subcutaneous pegylated interferon alfa-2b.