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.