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.