Acyclovir-Resistant Cutaneous Herpes Simplex Virus in DOCK8 Deficiency
Patients with dedicator of cytokinesis 8 (DOCK8 ) deficiency are susceptible to development of severe viral cutaneous infections, including herpes simplex virus (HSV). We report a 32-month-old girl with homozygous DOCK8 deficiency who developed a posterior auricular cutaneous lesion that was culture positive for HSV despite acyclovir prophylaxis. Resolution of this lesion was only observed after addition of foscarnet to the treatment regimen. Prophylactic acyclovir may be insufficient for suppression of cutaneous HSV in patients with DOCK8 deficiency, and a high index of suspicion for viral resistance is necessary for prompt initiation of appropriate antiviral treatment in these patients.
Practice Points
- Patients with dedicator of cytokinesis 8 ( DOCK 8 ) deficiency are susceptible to development of severe recalcitrant viral cutaneous infections, including herpes simplex virus (HSV).
- Dermatologists should be aware that prophylactic acyclovir may not be sufficient for HSV suppression in the setting of severe immunodeficiency.
- Acyclovir-resistant cutaneous HSV lesions require escalation of therapy, which may include addition of foscarnet, cidofovir, or subcutaneous pegylated interferon alfa-2b to the therapeutic regimen.
- Viral culture should be performed on suspicious lesions in DOCK 8 -deficient patients despite acyclovir prophylaxis, and the threshold for HSV resistance testing should be low.
Treatment Alternatives—Acyclovir competitively inhibits viral DNA polymerase by incorporating into elongating viral DNA strands and halting chain synthesis. Acyclovir requires triphosphorylation for activation, and viral thymidine kinase is responsible for the first phosphorylation event. Ninety-five percent of cases of acyclovir resistance are secondary to mutations in viral thymidine kinase. Foscarnet also inhibits viral DNA polymerase but does so directly without the need to be phosphorylated first.6 For this reason, foscarnet often is the drug of choice in the treatment of acyclovir-resistant HSV, as evidenced in our patient. However, foscarnet-resistant HSV strains may develop from mutations in the DNA polymerase gene.
Cidofovir is a nucleotide analogue that requires phosphorylation by host, as opposed to viral, kinases for antiviral activity. Intravenous and topical formulations of cidofovir have proven effective in the treatment of acyclovir- and foscarnet-resistant HSV lesions.6 Cidofovir also can be applied intralesionally, a method that provides targeted therapy and minimizes cidofovir-associated nephrotoxicity.12 Reports of systemic interferon alfa therapy for acyclovir-resistant HSV also exist. A study found IFN-⍺ production by peripheral blood mononuclear cells in DOCK8-deficient individuals to be significantly reduced relative to controls (P<.05).7 There has been complete resolution of acyclovir-resistant HSV lesions with subcutaneous pegylated interferon alfa-2b injections in several DOCK8-deficient patients.7-9
The need for escalating therapy in DOCK8-deficient individuals with acyclovir-resistant HSV infection underscores the essential role of DOCK8 in dermatologic immunity. Our case demonstrates that a high degree of suspicion for cutaneous HSV infection should be adopted in DOCK8-deficient patients of any age, regardless of acyclovir prophylaxis. Viral culture in addition to bacterial cultures should be performed early in patients with cutaneous erosions, and the threshold for HSV resistance testing should be low to minimize morbidity associated with these infections. Early resistance testing in our case could have prevented prolongation of infection and likely eliminated the need for a biopsy.
Conclusion
DOCK8 deficiency presents a unique challenge to dermatologists and other health care providers given the susceptibility of affected individuals to developing a reservoir of severe and potentially resistant viral cutaneous infections. Prophylactic acyclovir may not be sufficient for HSV suppression, even in the youngest of patients, and suspicion for resistance should be high to avoid delays in adequate treatment.
