Case Presentation
An 11-year-old previously healthy Hispanic female presented with
waxing/waning malar rash exacerbated by sunlight (Figure 1),
submandibular lymphadenopathy, scleritis/keratitis, and oral
ulcers/abscesses. Exam revealed an enlarged submandibular lymph
node, hemorrhagic crusted papules in sun-exposed areas; and conjunctival
injection. She had no hepatosplenomegaly. Complete blood counts,
electrolytes, creatinine, liver enzymes, and lactate dehydrogenase were
normal. Antinuclear antibody was negative. EBV antibody panel was
positive for viral capsid antigen IgG and EBV nuclear antigen IgG, and
plasma EBV DNA was elevated (975 copies/ml). Oral mucosal biopsy
revealed atypical large cells demonstrating marked infiltration and
destruction of several medium- and large-caliber blood vessels within
the tissue. The large atypical cells were positive for CD3, CD5, CD8,
CD30, CD43, TIA1, granzyme, and EBV; and negative for CD1A, CD15, CD20,
and CD56. Bone marrow biopsy showed an infiltrate of EBV positive
lymphocytes (Figure 2) by in situ hybridization. Atypical cells on
biopsies of oral mucosa and bone marrow were T-cell receptor (TCR)-gamma
positive. A diagnosis of T-cell associated CAEBV and HV-LPD was made
based on her clinical course, concordant biopsies, and elevated EBV
antibody titers and plasma EBV DNA levels.
Initially, her ocular disease was treated with corticosteroid drops and
her rash was treated with topical corticosteroids and strict
photoprotection with some improvement. At age 14-years, she started oral
valganciclovir due to right corneal ulcer with vascular changes of her
right retina and recurrent oral ulcers presumed to be secondary to EBV.
After 11 months, valganciclovir was discontinued because the frequency
and severity of her skin, mouth, and eye symptoms were not significantly
improved by valganciclovir treatment. At age 16-years, she developed
systemic symptoms with intermittent fevers and 5 kg weight loss, and CNS
symptoms with intermittent headaches and one episode of transient
delirium lasting several hours with visual hallucinations and amnesia.
Cerebral spinal fluid (CSF) showed a mild lymphocytic pleocytosis and
CSF EBV DNA levels of 313,858 copies/ml (Figure 3). CSF was positive for
TCR-gamma and -beta gene rearrangements. CSF gram stain and culture were
negative. Whole blood EBV DNA levels were over 2 million copies/ml
(Figure 3). The patient’s plasma and whole blood EBV DNA levels were
discordant; the whole blood EBV DNA levels were higher, as expected with
T-cell associated CAEBV.23 Hemophagocytic
lymphohistiocytosis (HLH) screening labs were unremarkable. Whole body
positron emission tomography revealed mild splenomegaly without abnormal
fluorodeoxyglucose activity.
At age 16-years, curative therapy was pursued due to development of
systemic symptoms and involvement of the CNS. She received oral
high-dose dexamethasone and intrathecal (IT) or intra-Ommaya (IO)
methotrexate (MTX) and hydrocortisone (HC) to reduce viral burden with
marked symptomatic improvement and decrease in EBV DNA levels (Figure
3). An Ommaya tunneled ventricular reservoir was placed to facilitate
CSF administration of MTX/HC and monitoring of CSF EBV viral load. She
received 5 cycles of bortezomib and ganciclovir/valganciclovir and 7
doses of IT/IO MTX/HC to reduce total EBV viral burden prior to planned
HSCT. Pre-HSCT screening echocardiogram revealed a giant right coronary
artery (RCA) aneurysm (Figure 4). Cardiac catheterization confirmed
severely dilated RCA, left anterior descending artery with multiple
aneurysms in a beaded appearance, circumflex artery with multiple large
aneurysms, and PAH. She was started on long-term anticoagulation with
apixaban for CAA and endothelin receptor antagonist macitentan for
PAH. Because of the presence of CAA, pre-HSCT CTA of the head, chest,
abdomen, and pelvis were performed prior to HSCT, and were negative for
additional arterial aneurysms.
At age 16-years, she received the National Institute of Health (NIH)
irradiation-free, serotherapy-free RIC regimen for primary
immunodeficiency disorders12 with pentostatin,
cyclophosphamide, and pharmacokinetically-dosed busulfan, followed by
peripheral blood stem cell transplant (PBSCT) from a 9/10 HLA mismatched
unrelated male donor who was EBV seropositive. Post-transplant
cyclophosphamide, sirolimus, and mycophenolate mofetil were used for
graft-versus-host disease (GVHD) prophylaxis. Neutrophil engraftment was
achieved on post-transplant day 16, and bone marrow demonstrated 60%
cellularity and 94% donor chimerism on post-transplant day 30. Whole
blood EBV DNA level was <200 copies/ml and CSF EBV DNA level
was 469 copies/ml on post-transplant day 30. She continued to have
baseline flesh colored papular malar rash but remained asymptomatic for
other CAEBV-associated symptoms. Post-transplant course was complicated
by grade II steroid responsive chronic GI GVHD. She had no
veno-occlusive disease. Bone marrow aspirate and biopsy obtained 6
months post-HSCT showed a hypocellular marrow (10% cellularity), no
evidence of malignancy, negative EBER
expression, 100% donor by cytogenetics (46, XY), no abnormal phenotype
by flow cytometry, and donor chimerism >95%. Six months
post-HSCT, blood and CSF EBV DNA were <200 and 1109 copies/mL,
respectively.
On post-transplant day 212, the patient had an episode of syncope with
closed head injury that resulted in subarachnoid and intraventricular
hemorrhage. Computed tomography demonstrated fusiform aneurysm of distal
right internal carotid artery (ICA) with extension into the anterior and
medial cerebral artery (MCA) (Figure 5). The patient returned to her
neurologic baseline after pipeline flow diverting stent placements from
right MCA to ICA and aneurysm coiling (Figure 6). Unfortunately, 8
months post-transplant, the patient developed a massive spontaneous
subarachnoid hemorrhage (Figure 7) resulting in devastating irreversible
neurologic injury and she expired one day later.