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\begin{document}

\title{Antiviral Therapy Defiant Polyviral Retinitis Post Hematopoietic
Allogeneic Stem Cell Transplant}



\author[1]{Nadia Gabarin}%
\author[2]{Mili Roy}%
\author[2]{Alexander J. Kaplan}%
\author[1]{Shariq Haider}%
\author[1]{Dina Khalaf}%
\affil[1]{McMaster University Department of Medicine}%
\affil[2]{Department of Ophthalmology and Visual Sciences University of Toronto Toronto Ontario Canada}%


\vspace{-1em}



  
  \date{June 13, 2024}


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\selectlanguage{english}
\begin{abstract}
Cytomegalovirus (CMV) retinitis is an uncommon presentation post
allogeneic transplant and can be vision-threatening. This case
demonstrates the occurrence of mixed viral retinitis (CMV and varicella
zoster virus) post allogeneic stem cell transplant despite multiple
prophylactic antiviral therapies, and features CMV retinitis in the
absence of CMV DNAemia.%
\end{abstract}%



\sloppy


\textbf{Title: Antiviral Therapy Defiant Polyviral Retinitis Post
Hematopoietic Allogeneic Stem Cell Transplant}

\textbf{Authors:}

Nadia Gabarin\textsuperscript{1}, Mili Roy\textsuperscript{2}, Alexander
J. Kaplan\textsuperscript{2}, Shariq Haider\textsuperscript{1,3}, Dina
Khalaf\textsuperscript{1,3}

\begin{enumerate}
\tightlist
\item
  Department of Medicine, Michael G. DeGroote School of Medicine,
  McMaster University, Hamilton, Ontario, Canada
\item
  Department of Ophthalmology and Visual Sciences, University of
  Toronto, Toronto, Ontario, Canada
\item
  Juravinski Hospital and Cancer Center, McMaster University, Hamilton,
  ON, Canada
\end{enumerate}

\textbf{Corresponding Author:}

Dr. Nadia Gabarin

McMaster University, Department of Medicine

699 Concession St

Hamilton ON L8V 5C2

nadia.gabarin@medportal.ca

\textbf{Running Title:} Polyviral Retinitis Post Allogeneic Stem Cell
Transplant

\textbf{Keywords}

Cytomegalovirus, varicella zoster virus, allogeneic transplant, acute
myeloid leukemia

\textbf{Word Count:} 1,245

\textbf{Funding:} None

\textbf{Consent:} Written consent for the publication of this case
report has been provided by the patient.

\textbf{ABSTRACT}

\textbf{Background:} Cytomegalovirus (CMV) retinitis is an uncommon
presentation post allogeneic transplant and can be vision-threatening.
Our case demonstrates the occurrence of polymerase chain reaction proven
mixed viral retinitis (cytomegalovirus and varicella zoster virus) post
allogeneic stem cell transplant despite multiple prophylactic antiviral
therapies, and features CMV retinitis in the absence of CMV DNAemia.
This case highlights the emerging challenge of late CMV disease
occurring during secondary prophylaxis with Letermovir.

\textbf{Case presentation:} A 21-year-old female with acute myeloid
leukemia presented with mixed viral retinitis (cytomegalovirus and
varicella zoster virus) post allogenic transplant. This presentation
occurred despite ongoing prophylaxis for both of these viruses, as well
as following two courses of treatment for CMV viremia, with a documented
negative CMV PCR in the blood prior to the presentation with retinitis.
The patient was treated with intravenous Ganciclovir and subsequently
transitioned to oral Valganciclovir with resolution of the retinitis.

\textbf{Conclusions:} We report a rare case of polyviral retinitis in a
post-allogeneic stem cell transplant patient, with polymerase chain
reaction of the aqueous fluid demonstrating two viral populations. With
very little existing literature on either mixed viral retinitis or CMV
retinitis during Letermovir prophylaxis, this case expands the
literature on both topics.

\textbf{BACKGROUND}

Cytomegalovirus virus (CMV) infection predominantly affects
immunocompromised individuals.\textsuperscript{1} CMV infection can lead
to CMV disease and has been associated with non-relapse mortality
following allogeneic hematopoietic stem cell
transplant.\textsuperscript{2} CMV disease post allogeneic transplant
commonly affects the lungs or gastrointestinal
tract.\textsuperscript{1,2} CMV retinitis remains an uncommon
presentation post allogeneic transplant and can be
vision-threatening.\textsuperscript{3-6} Implementation of prophylaxis
and preemptive strategies have reduced the incidence of CMV disease to
10\% in the first year post allogeneic
transplant.\textsuperscript{2,7}Our case demonstrates the occurrence of
polymerase chain reaction (PCR) proven mixed viral retinitis (CMV and
varicella zoster virus VZV) post allogeneic stem cell transplant despite
multiple prophylactic antiviral therapies, and features CMV retinitis in
the absence of CMV DNAemia. This case also highlights the emerging
challenge of late CMV disease occurring during secondary prophylaxis
with Letermovir. To our knowledge this represents the first reported
case of polyviral retinitis in this clinical context.

\textbf{CASE REPORT}

We report the case of a previously healthy 21-year-old female diagnosed
with acute myeloid leukemia (AML) February 2020 after presenting with a
two week history of shortness of breath, decreased exercise tolerance,
and lightheadedness. Her karyotyping results confirmed complex
cytogenetics, with monosomy X and double minute chromosomes indicating
MYC locus. With regards to her molecular studies, she had undetectable
FLT3 and NPM1 mutation, undetectable RUNX1, undetectable CBF/MYH11,
undetectable BCR-ABL, and undetectable PML-RARA. Next generation
sequencing (NGS) did not demonstrate any clinically significant
variants. Her baseline viral serologies demonstrated that she was
nonreactive for Hepatitis B, Hepatitis C, and HIV.

The patient was started on induction therapy with 3 + 7 Daunorubicin and
Cytarabine on February 22, 2020, with a view to proceed with a stem cell
transplant consolidation after achieving remission. Her post-induction
course was complicated by culture-negative febrile neutropenia and a
right middle lobe pneumonia for which she was treated with
Piperacillin-Tazobactam, and subsequently stepped down to Ciprofloxacin
and Amoxicillin-Clavulin once she clinically improved. She remained on
prophylaxis with Acyclovir and Fluconazole during this time period.
Following induction chemotherapy, she was treated with high dose
Cytarabine for consolidation therapy starting March 31, 2020, as a
bridge to stem cell transplant.

Pre-transplant screening revealed CMV IgG positive, CMV IgM negative,
Varicella Zoster Virus (VZV) IgG positive, and Herpes Simplex Virus
(HSV) indeterminate.

She subsequently underwent an allogeneic unrelated donor mismatched 8/10
myeloablative stem cell transplant, day zero was July 10, 2020. There
was minor ABO incompatibility, with the donor O positive and recipient B
positive. The donor was CMV seronegative. A hybrid conditioning regimen
was used due to the 8/10 mismatch from an unrelated donor, with
Fludarabine/Busulfan 4 (Flu/Bu 4) plus antithymocyte globulin (ATG),
with post-transplant cyclophosphamide, and omission of methotrexate.
Post-transplant, on July 28, she was found to have early CMV
reactivation, with a serum CMV level of 10,980 units per mL plasma (4.04
log units per mL plasma). She was leukopenic at that time, with a
recovered neutrophil count of 0.7. She was started on intravenous (IV)
Ganciclovir 5mg/kg twice daily. Unfortunately, following three weeks of
treatment with Ganciclovir, the patient's CMV level remained elevated,
with a level of 91,025 units per mL plasma (4.96 log units per mL
plasma) on week 2 of treatment, and a level of 14,520 units per mL of
plasma on week 3 (4.16 log units per mL plasma). At that time,
Ganciclovir was discontinued, and she was initiated on Foscarnet 90
mg/kg twice daily on August 28. Resistance testing was performed and did
not demonstrate any evidence of resistance to Ganciclovir or Foscarnet.
Following treatment with Foscarnet, her CMV PCR became negative on
September 14. She was subsequently started on Letermovir 240 mg daily as
secondary prophylaxis. Throughout this period of time she also remained
on oral prophylaxis with Acyclovir 800 mg bid, Fluconazole 400 mg daily,
and Septra double strength 1 tablet on Monday, Wednesday, and Friday.

Unfortunately, on September 21, follow up CMV PCR was positive, with
3.75 log units per mL plasma, and at that time, a decision was made to
resume Foscarnet, with an induction dose for three weeks, and then
subsequently a maintenance dose initiated, which she completed on
November 3.

At the time of her third CMV reactivation episode on September 21, she
also had evidence of reactivation of EBV for the first time and was
treated for this with a dose of rituximab on September 24, with
subsequent negative EBV levels.

While on treatment with Foscarnet, she developed mild graft versus host
disease of the gut, with apoptotic bodies demonstrated on endoscopy
biopsy. This was treated conservatively with Budesonide 1 mg oral three
times per day and Beclomethasone 3 mg oral four times per day which were
gradually weaned with resolution of her symptoms. On November 3,
following her completion of Foscarnet, repeat CMV testing was negative.
EBV testing was also negative at that time. The patient was restarted on
Letermovir and continued on her other prophylactic agents (Acyclovir,
Septra and Fluconazole).

In late November 2020, the patient experienced new onset blurry vision
in the right eye. She was assessed by Ophthalmology with clinical
findings demonstrating stellate keratic precipitates, peripheral retinal
vascular sheathing and active unilateral hemorrhagic retinitis in two
separate foci in a vascular distribution. One area of retinitis was
encroaching on the macula and threatening vision. In the clinical
context a working diagnosis of viral retinitis was suspected, further
supported by subsequent ocular coherence (OCT) and fundus fluorescein
angiography (Image 1). An urgent anterior chamber paracentesis was
performed and sent for HSV, VZV and CMV PCR testing followed by an
intravitreal injection of Ganciclovir 2 mg. PCR of the aqueous humour
confirmed the presence of both CMV and VZV. Serum CMV PCR performed at
that time was negative. She completed two weeks of intravenous
Ganciclovir induction therapy (5mg/kg), then extended one additional
week at maintenance dosing but unfortunately still had some mild
retinitis activity. She was then transitioned to oral Valganciclovir
therapy (900 mg twice daily). The retinitis resolved fully showing
excellent clinical response after the 3\textsuperscript{rd} week of
Valganciclovir dosing and no further evidence of active viral retinitis
as of her last examination of Mar 10, 2021. Repeat serum CMV PCR
performed March 2021 remained negative.

\textbf{DISCUSSION:}

We report a rare case of polyviral retinitis in a post-allogeneic stem
cell transplant patient, with PCR of the aqueous fluid demonstrating two
viral populations, CMV and VZV, which occurred despite ongoing
prophylaxis for these two viruses, and despite completing two courses of
treatment for CMV viremia, with a documented negative CMV PCR in the
blood prior to the presentation with retinitis. CMV sensitivity testing
performed indicated sensitivity to both agents used for previous
treatment (Ganciclovir and Foscarnet)\textsuperscript{8}. As the CMV
serum PCR was undetectable at the time of the presentation with CMV
retinitis, it is unlikely that this presentation was driven by
resistance to treatment. Presentation of CMV retinitis was likely
multifactorial driven by early CMV reactivation, low CD4 counts and
delayed CD4 lymphocyte recovery in the first 100 days post-transplant
which are all associated with late CMV disease. Other potential
contributing factors are poor CNS and poor retinal penetration of
Letermovir. With very little existing literature on either mixed viral
retinitis or CMV retinitis during Letermovir
prophylaxis\textsuperscript{9}, this case serves to expand the
literature on both topics. The case also highlights the need to expand
efficacy data on secondary prophylaxis with Letermovir to address an
unmet therapeutic need. To our knowledge this represents the first
documented case of mixed viral retinitis in this therapeutic context.

\textbf{Figure 1:}

Fundus image right eye showing hemorrhagic retinitis and retinal
vasculitis, more prominent inferotemporally in the distribution of the
inferotemporal vascular arcade vessels with an additional more subtle
area of involvement superonasally. Areas of retinal whitening (white
arrows), hemorrhage (red arrows) and retinal vascular sheathing (yellow
arrows) indicative of vasculitis could be discerned by clinical
examination

\textbf{Declarations:}

\textbf{Ethics Approval:} Not applicable

\textbf{Consent:} Consent for the publication of this case report has
been provided by the patient.

\textbf{Conflict of Interest Statement:} All authors declare no
conflicts of interest.

\textbf{Funding:} None

\textbf{Authors' contributions:} NG wrote the first draft of the
manuscript. DK, MR, AK, and SH all provided patient care and important
edits to the manuscript. All authors read and approved the final
manuscript.

\textbf{Acknowledgements:} Not applicable

\textbf{References:}

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\end{enumerate}\selectlanguage{english}
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