An 18-year-old female was diagnosed with CVID at age six. As previously described in Chen et al. she, her mother, and younger brother were found to have a heterozygous pathogenic variant in NFKB2 that results in an autosomal dominant form of CVID. She developed autoimmune manifestations, including acquired central adrenal insufficiency, alopecia universalis, vitiligo, and nail dystrophy. Her infectious history was significant for both bacterial and viral respiratory infections, recurrent herpes simplex of the lips and surrounding perioral skin, and chronic candidal onychomycosis. Adrenal insufficiency was treated with maintenance doses of hydrocortisone and stress dose adjustments during times of illness. Early-onset hypogammaglobulinemia required lifelong gammaglobulin replacement to prevent recurrent sinopulmonary infections. Recurrent herpes simplex infection was controlled with chronic suppressive oral valacyclovir therapy. A Luminex-based assay of the patient's plasma [1:100 dilution, as described by Ding et al. ] identified the presence of autoantibodies against interferon-alpha (IFN-alpha) and interferon-omega (IFN-omega) (Figure 1A). Next, patient plasma was incubated with control peripheral blood mononuclear cells and STAT1 phosphorylation was measured by flow cytometry after incubation in unstimulated or stimulated conditions as described by Burbelo et al.. The patient's plasma demonstrated neutralizing anti-IFN-alpha and IFN-omega antibodies which inhibited STAT1-phosphorylation in control cells, whereas control and parental plasma did not lead to inhibition (Figure 1B). The affected sibling's plasma also demonstrated neutralizing anti-IFN-alpha antibodies, and partial blockade of IFN-omega signaling.
At 16 years of age, the patient required intensive care hospitalization for decompensated septic shock of unknown etiology requiring vasopressor support. Prior to the hospitalization she had become non-compliant with medications, including gammaglobulin replacement. She developed acute renal injury, electrolyte disturbances, and adrenal crisis secondary to sepsis of unknown etiology which required stress dosing of steroids and electrolyte replacement. During this time, hypomagnesemia resulted in torsades de pointes and prolonged QT syndrome. Her persistent renal injury required chronic daily oral electrolyte replacement to prevent recurrence of arrhythmias.
Two years later, the patient presented to the emergency department with a month-long history of progressive, painful, vegetative facial lesions. The lesions initially developed periorally, similar to prior herpes simplex outbreaks. Despite increasing valacyclovir to treatment dosing, the lesions became purulent and continued to spread, involving the nose and right cheek. She was treated for presumed bacterial cellulitis with oral cefdinir. When a bacterial culture reportedly grew group B streptococcus, cefdinir was transitioned to oral clindamycin. Valacyclovir was discontinued as the lesions did not improve while on the medication. She reported tactile fevers and chills with continued progression of the vegetative lesions despite antibiotic treatment.
Upon hospitalization, laboratory evaluation identified leukocytosis (neutrophils 7,000 cells/mul; lymphocytes 7,900 cells/mul) and elevated C-reactive protein (11.6 mg/dL; normal range 0-1.5 mg/dL). Natural killer (NK) cell expression of CD107a was reduced, and NK cell functional assays demonstrated reduced cytotoxicity (Cincinnati Children's Diagnostic Immunology Laboratory). Her cutaneous exam revealed exophytic, thick, yellow-brown plaques involving the bilateral nares, right oral commissure, and adjacent medial cheek. The plaques were exudative and distorted the nasal architecture (Figure 2). A wound swab from the medial cheek was positive for HSV by polymerase chain reaction (PCR) assay. Other bacterial or viral infections often seen in immunodeficient patients, including varicella zoster and cytomegalovirus (CMV), were ruled out. The patient's systemic symptoms raised concern for HSV viremia, and a HSV peripheral blood PCR was positive. She did not have any neurological symptoms or meningeal signs; thus, HSV meningitis or encephalitis were not suspected. HSV type-1 was isolated from tissue culture of affected skin on the medial cheek; pathology demonstrated spongiosis and mixed granulomatous dermal infiltration with fat necrosis. Intravenous foscarnet therapy resulted in rapid improvement of her cutaneous eruption, including the associated pain, and systemic symptoms (Figure 3). Slower, continued resolution occurred over several weeks (Figure 4). The patient had recurrence of HSV vegetans and HSV viremia 3 months later. On this second occasion, early identification of HSV as the source of skin infection led to expedited hospitalization and early initiation of antiviral therapy. She had a significantly shorter hospital course with transition to oral valacyclovir at discharge when HSV culture demonstrated susceptibility to acyclovir.