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\begin{document}

\title{Hematopoietic stem cell transplantation for chronic active Epstein-Barr
virus and hydroa vacciniforme-like lymphoproliferative disorder
complicated by fatal ruptured cerebral artery aneurysm.}



\author[1]{Troy  Yi}%
\author[1]{Jeffrey  Steinberg}%
\author[1]{Scott  Olson}%
\author[1]{Howaida El-Said}%
\author[1]{Jun  Mo}%
\author[1]{Eric Anderson}%
\author[1]{Nicholas  Gloude}%
\author[1]{Deborah Schiff}%
\affil[1]{University of California San Diego School of Medicine}%


\vspace{-1em}



  
  \date{May 22, 2024}


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\selectlanguage{english}
\begin{abstract}
Hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD) is a rare
cutaneous form of Chronic active Epstein-Barr virus (CAEBV) that
presents with vesicular lesions induced by sun-exposure. We describe a
patient with CAEBV and HV-LPD whose course following hematopoietic stem
cell transplantation was complicated by fatal ruptured cerebral artery
aneurysm.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Epstein-Barr Virus (EBV) is a common human herpesvirus with a typically
benign clinical course, most commonly infecting children with an
estimated worldwide prevalence of more than
90\%.\textsuperscript{1}Chronic active Epstein-Barr virus (CAEBV) is a
rare T- and NK-cell lymphoproliferative disorder of EBV origin affecting
children mostly in Asia and the Americas.\textsuperscript{2} CAEBV can
manifest in a broad spectrum of diseases including a cutaneous disorder
known as hydroa vacciniforme-like lymphoproliferative disorder (HV-LPD)
and a systemic form with persistent or recurrent infectious
mononucleosis-like symptoms following primary EBV
infection.\textsuperscript{3} HV-LPD presents with vesicular lesions
induced by sun-exposure. Systemic CAEBV can be associated with a variety
of symptoms including viral hepatitis, hemophagocytic syndrome, coronary
artery aneurysms (CAA), basal ganglia calcification, oral ulcers,
lymphoma, interstitial pneumonia, central nervous system (CNS) disease,
pulmonary arterial hypertension (PAH), enteritis, and gastrointestinal
perforations.\textsuperscript{4,5,6,7,8}Here we present a case of a
pediatric patient diagnosed with T-cell associated CAEBV and HV-LPD
treated with reduced intensity conditioning (RIC) hematopoietic stem
cell transplantation (HSCT) and complicated by transient delirium, CAA,
PAH, and fatal ruptured cerebral artery aneurysm. This case was
previously reported in two case series.\textsuperscript{9,10}

\textbf{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.\textbf{~} 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.\textsuperscript{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 disorders\textsuperscript{12} 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 \textless{}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 \textgreater{}95\%. Six months
post-HSCT, blood and CSF EBV DNA were \textless{}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.

\textbf{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{9,16}

Treatment of CAEBV has yet to be standardized due to the highly variable
clinical outcomes of the disease.\textsuperscript{17} The mainstay of
treatment for patients with classic HV-LPD has been strict
photoprotection.\textsuperscript{14} The only curative treatment for
severe HV-LPD and the broader category of disease, CAEBV, has been
HSCT.\textsuperscript{18,19} Unfortunately, death as a result of relapse
or sequela of CAEBV may occur post-HSCT.\textsuperscript{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.\textsuperscript{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.\textsuperscript{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.\textsuperscript{26} Our patient received a RIC HSCT
(irradiation-free; serotherapy-free conditioning per NIH Primary
Immunodeficiency protocol\textsuperscript{12}) 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.\textsuperscript{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.\textsuperscript{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\%).\textsuperscript{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.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Smatti MK, Al-Sadeq DW, Ali NH, Pintus G, Abou-Saleh H, and Nasrallah
  GK. Epstein--Barr Virus Epidemiology, Serology, and Genetic
  Variability of LMP-1 Oncogene among Healthy Population: An
  Update.~\emph{Frontiers in Oncology} ~2018;8:211.
\item
  Swerdlow SH, Campo E, Pileri SA, Harris NL, Stein H, Siebert R, Advani
  R, et al. The 2016 Revision of the World Health Organization
  Classification of Lymphoid Neoplasms.~\emph{Blood}
  ~2016;127:2375--2390.
\item
  Fernandez-Pol S, Silva O, and Natkunam Y. Defining the Elusive
  Boundaries of Chronic Active Epstein-Barr Virus
  Infection.~\emph{Haematologica} ~2018;103: 924--927.
\item
  Cohen JI. Optimal Treatment for Chronic Active Epstein-Barr Virus
  Disease.~\emph{Pediatric Transplantation} ~2009;13:393--96.
\item
  Roli\selectlanguage{polish}ń\selectlanguage{english}ski J, Grywalska E, Pyzik A, Dzik M, Opoka-Winiarska V, Surdacka
  A, Maj M, et al. Interferon Alpha as Antiviral Therapy in Chronic
  Active Epstein-Barr Virus Disease with Interstitial Pneumonia - Case
  Report.~\emph{BMC Infectious Diseases} ~2018;18:190.
\item
  Hongjun B, Xu L, Peng H, Lin Y, Li X, Wang H, and Qin Y. Chronic
  Active Epstein-Barr Virus Infection with Systemic Vasculitis and
  Pulmonary Arterial Hypertension in a Child.~\emph{Frontiers in
  Pediatrics} ~2019;7:219.
\item
  Tseng YJ, Ding WQ, Zhong L, Chen J, and Luo ZG. Chronic Active
  Epstein--Barr Virus (CAEBV) Enteritis.~\emph{International Journal of
  Infectious Diseases} ~2019;82:15--17.
\item
  Xiao HJ, Li J, Song HM, Li ZH, Dong M, and Zhou XG. Epstein--Barr
  Virus-Positive T/NK-Cell Lymphoproliferative Disorders Manifested as
  Gastrointestinal Perforations and Skin
  Lesions.~\emph{Medicine}2016;95:e2676.
\item
  Cohen, JI, Manoli I, Dowdell K, Krogmann TA, Tamura D, Radecki P, Bu
  W, et al. Hydroa Vacciniforme--like Lymphoproliferative Disorder: An
  EBV Disease with a Low Risk of Systemic Illness in
  Whites.~\emph{Blood} ~2019;133:2753--2764.
\item
  D\selectlanguage{ngerman}ávila Saldaña BJ,~John T,~Bonifant C,~Buchbinder D,~Chandra
  S,~Chandrakasan S,~Chang W,~Chen L,~et al. High risk of relapsed
  disease in patients with NK/T-cell chronic active Epstein-Barr virus
  disease outside of Asia. \emph{Blood Adv} ~2022;6:452-459.
\item
  Bollard CM and Cohen JI. How I Treat T-Cell Chronic Active
  Epstein-Barr Virus Disease.~\emph{Blood} ~2018;131: 2899--2905.
\item
  Dimitrova D, Gea-Banacloche J, Steinberg SM, Sadler JL, Hicks SN,
  Carroll E, Wilder JS, et al. Prospective Study of a Novel,
  Radiation-Free, Reduced-Intensity Bone Marrow Transplantation Platform
  for Primary Immunodeficiency Diseases.~\emph{Biology of Blood and
  Marrow Transplantation} 2020;26:94--106.
\item
  Gupta G, Man I, and Kemmett D. Hydroa Vacciniforme: A Clinical and
  Follow-up Study of 17 Cases.~\emph{Journal of the American Academy of
  Dermatology} ~2000;42:208--213.
\item
  Nitiyarom R, and Wongpraparut C. Hydroa Vacciniforme and Solar
  Urticaria.~\emph{Dermatologic Clinics} 2014;32:345--53.
\item
  Hirai Y, Yamamoto T, Kimura H, Ito Y, Tsuji K, Miyake T, Morizane S,
  Suzuki D, Fujii K, and Iwatsuki K. Hydroa Vacciniforme Is Associated
  with Increased Numbers of Epstein--Barr Virus--Infected \selectlanguage{greek}γδ \selectlanguage{english}T
  Cells.~\emph{Journal of Investigative Dermatology}
  ~2012;132:1401--1408.
\item
  Quintanilla-Martinez L, and Fend F. Deciphering Hydroa
  Vacciniforme.~\emph{Blood} ~2019;133:2735--2737.
\item
  Kimura H and Fujiwara S. Overview of EBV-Associated T/NK-Cell
  Lymphoproliferative Diseases.~\emph{Frontiers in Pediatrics}
  ~2019;6:417.
\item
  Kawa K, Okamura T, Yasui M, Sato E, and Inoue M. Allogeneic
  Hematopoietic Stem Cell Transplantation for Epstein--Barr
  Virus-Associated T/NK-Cell Lymphoproliferative Disease.~\emph{Critical
  Reviews in Oncology/Hematology} ~2002;44: 251--257.
\item
  Sawada A and Inoue M. Hematopoietic Stem Cell Transplantation for the
  Treatment of Epstein-Barr Virus-Associated T- or NK-Cell
  Lymphoproliferative Diseases and Associated Disorders.~\emph{Frontiers
  in Pediatrics} ~2018;6:334.
\item
  Guo N, Chen Y, Wang Y, Huang Y, Feng Y, Li M, and Rao H.
  Clinicopathological Categorization of Hydroa Vacciniforme-like
  Lymphoproliferative Disorder: An Analysis of Prognostic Implications
  and Treatment Based on 19 Cases.~\emph{Diagnostic Pathology}
  ~2019;14:82.
\item
  Liu Z, Savoldo B, Huls H, Lopez T, Gee A, Wilson J, Brenner MK, Heslop
  HE, and Rooney CM. Epstein-Barr Virus (EBV)-Specific Cytotoxic T
  Lymphocytes for the Prevention and Treatment of EBV-Associated
  Post-Transplant Lymphomas.~\emph{Immunosurveillance,
  Immunodeficiencies and Lymphoproliferations} , 2002;159:123--133.
\item
  Kim YJ, Choi SY, Lee WJ, Won CH, Chang SE, Choi JH, and Lee MW. Two
  Cases of Hydroa Vacciniforme-like Lymphoproliferative Disease
  Controlled by Anti-Inflammatory Agents.~\emph{Photodermatology,
  Photoimmunology \& Photomedicine} ~2017;33:287--290.
\item
  Rodriguez-Pinilla SM, Barrionuevo C, Garcia J, Martinez MT, Pajares R,
  Montes-Moreno S, Casavilca S, et al. EBV-Associated Cutaneous
  NK/T-Cell Lymphoma.~\emph{American Journal of Surgical Pathology}
  ~2010;34:1773--1782.
\item
  Cohen J, Jaffe ES, Dale JK, Pittaluga S, Heslop HE, Rooney CM,
  Gottschalk S, et al. Characterization and Treatment of Chronic Active
  Epstein-Barr Virus Disease: A 28-Year Experience in the United
  States.\emph{Blood} 2011;22:5835-5849.
\item
  Sawada A, Inoue M, and Kawa K. How We Treat Chronic Active
  Epstein--Barr Virus Infection. \emph{International Journal of
  Hematology} 2017;4:406-418.
\item
  Kawa K, Sawada A, Sato M, Okamura T, Sakata N, Kondo O, Kimoto T, et
  al. Excellent Outcome of Allogeneic Hematopoietic SCT with
  Reduced-Intensity Conditioning for the Treatment of Chronic Active EBV
  Infection.~\emph{Bone Marrow Transplantation} ~2010;46:77--83.
\item
  Xiao H, Hu B, Luo R, Hu H, Zhang J, Kuang W, Zhang R, et al. Chronic
  active Epstein--Barr virus infection manifesting as coronary artery
  aneurysm and uveitis. \emph{Virol J} 2020;17:166-175.
\item
  Ba H, Xu L, Peng H, Lin Y, Li X, Wang H, and Qin Y. Chronic Active
  Epstein-Barr Virus Infection with Systemic Vasculitis and Pulmonary
  Arterial Hypertension in a Child.~\emph{Frontiers in Pediatrics}
  ~2019;7:219.
\item
  Murakami K, Ohsawa M, Hu SX, Kanno H, Aozasa K, and Nose M.
  Large-Vessel Arteritis Associated with Chronic Active Epstein-Barr
  Virus Infection.~\emph{Arthritis \& Rheumatism} ~1998;41:369--373.
\end{enumerate}

\textbf{Conflicts of Interest:}

The authors have no conflicts of interest to disclose.

\textbf{Legend:}

Figure 1. HV Skin Lesions in Sun-exposed Areas. Consent to publish
photographs of the patient for the case report was obtained from the
patient's parent.

Figure 2. Bone marrow with lymphocytic infiltrate and scattered
EBV-positive lymphocytes

Figure 3. Whole Blood and CSF EBV Levels by Day of Management with
Interventions. Day 0 represents the initiation of systemic interventions
with oral valganciclovir. Abbreviations: GCV, ganciclovir; DEX,
dexamethasone; IT/IO HC/MTX, intrathecal/Intra-Ommaya hydrocortisone and
methotrexate; BTZ, bortezomib; BSF, busulfan; PBSCs, peripheral blood
stem cells; PTCy, post-transplantation cyclophosphamide.

Figure 4. Angiography~at 6 Months Prior to HSCT shows severely dilated
RCA with low flow in the RCA, left anterior descending artery with
multiple aneurysms with a beaded appearance, and circumflex artery with
multiple large aneurysms.

Figure 5. CTA performed day +213 after HSCT demonstrates Middle Cerebral
Artery Aneurysm

Figure 6. Flow-diverting Stent with Aneurysm Coiling

Figure 7. Head CT day +235 after HSCT demonstrates massive diffuse
subarachnoid hemorrhage with right frontal lobe hemorrhage and
hemorrhage into the ventricular system.

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