Discussion
Classic HV-LPD is described as the most indolent subset of HV-LPD. It was first mentioned by Bazin in 1862 and subsequently described as a rare photosensitivity disorder with a self-limited clinical course, often lacking systemic symptoms, and frequently resolving by young adulthood.13 Classic HV-LPD lesions are located on sun-exposed areas of the face and hands initially appearing as erythematous clustered macules transforming into vesicular or hemorrhagic bullae, healing as crusted lesions, and forming varioliform scars.14 Severe HV-LPD presents primarily in South and Central American and Asian populations with lesions similar to those seen with classic HV-LPD, but may involve non-sun-exposed areas of the skin and mucosa and include systemic symptoms such as weight loss, persistent fever, lymphadenopathy, facial edema, hepatosplenomegaly, hepatitis, and leukopenia.15 Reports have supported the belief that HV-LPD in Western populations is an EBV-associated lymphoproliferative disorder of T/NK-cells with a more indolent clinical course and decreased likelihood to need HSCT compared to HV-LPD in South and Central American and Asian populations.9,16
Treatment of CAEBV has yet to be standardized due to the highly variable clinical outcomes of the disease.17 The mainstay of treatment for patients with classic HV-LPD has been strict photoprotection.14 The only curative treatment for severe HV-LPD and the broader category of disease, CAEBV, has been HSCT.18,19 Unfortunately, death as a result of relapse or sequela of CAEBV may occur post-HSCT.10 Therapies that have demonstrated some benefit or temporary remission include multi-agent chemotherapy, radiotherapy, immunomodulators, anti-inflammatory agents including corticosteroids, antiviral agents, and allogeneic EBV-specific cytotoxic T-lymphocytes.10,20-25 Of note, chronic immunosuppression with dexamethasone provided interim improvement of symptoms for our patient prior to HSCT, and IT/IO MTX/HC was associated with a resolution of CSF pleocytosis and decreased CSF EBV viral load (Figure 3). Placement of an Ommaya tunneled ventricular catheter greatly facilitated CSF administration of MTX/HC. Our patient did not receive rituximab therapy due to T-cell origin of her disease. She had little clinical improvement with oral valganciclovir alone but demonstrated marked improvement with combined bortezomib and ganciclovir (or oral valganciclovir) (Figure 3). The presumed mechanism of action of combined bortezomib/(val)ganciclovir therapy involves multiple steps. When bortezomib is administered with ganciclovir (or oral valganciclovir), bortezomib induces virus replication and expression of the EBV protein kinase (PK), the EBV PK then phosphorylates (val)ganciclovir, and then phosphorylated (val)ganciclovir inhibits EBV replication.11
RIC HSCT with fludarabine, melphalan and cytarabine for patients with CAEBV has shown improved rates in overall survival compared to myeloablative conditioning HSCT with decreased risk of post-transplant complications.26 Our patient received a RIC HSCT (irradiation-free; serotherapy-free conditioning per NIH Primary Immunodeficiency protocol12) with pentostatin, low-dose cyclophosphamide and pharmacokinetically-dosed busulfan with successful engraftment and sustained improvement in EBV viral load (Figure 3). She had minimal transplant associated toxicity—grade II steroid responsive chronic GVHD.
Arterial aneurysm is a rare but reported complication of CAEBV.27-29 This case highlights the risk of arterial aneurysms in patients with CAEBV and HV-LPD. This patient’s giant RCA aneurysm and multiple aneurysms of the LAD and circumflex artery were detected by routine pre-HSCT echocardiogram. CTA of the head, chest, abdomen, and pelvis were performed pre-HSCT to screen for additional arterial aneurysms, but none were seen at that time. However, 12 months after the initial screening head CTA and 7 months after HSCT, a cerebral aneurysm was confirmed by head CTA after the aneurysm ruptured and caused a subarachnoid hemorrhage. Screening guidelines for aneurysms in patients with CAEBV have yet to be developed. This case report suggests that screening these patients for arterial aneurysms with CTA of the head, chest, abdomen, and pelvis prior to HSCT is prudent, and subsequent screening for progression of known arterial aneurysms and the development of new arterial aneurysms with CTA after HSCT may be beneficial.
A previous case report described a 4-year-old girl with CAEBV and CAAs who underwent HSCT; her CAAs remained stable at 3 years post-HSCT.27 A retrospective study of outcomes of 57 patients with CAEBV outside of Asia showed that patients who underwent HSCT had significantly better survival than those who did not (55% vs 25%).10 However, there was still a high rate of death in the HSCT group, and 75% of patients with CAEBV who died after HSCT died due to relapsed disease. Only 2 of 57 patients in this cohort—which included this patient—had vascular involvement; both died. Similarly, 2 patients in this cohort with HV-LPD—which included this patient—did not survive. Early referral for curative therapy with HSCT may potentially lead to improved outcomes for patients with CAEBV and HV-LPD. However, the rarity of patients with CAEBV and HV-LPD currently precludes our ability to confirm this hypothesis. This case report illustrates that additional effective therapy is still needed to decrease post-HSCT mortality due to sequela of CAEBV.