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\begin{document}

\title{Fatal Disseminated Adenovirus Disease in a Patient who Received
Chemotherapy for Mantle Cell Lymphoma: A Case Report}



\author[1]{Bo Yu}%
\author[2]{Lakshmi  Saravanan }%
\author[3]{Dena Tran}%
\author[4]{Alexander  Davies}%
\author[5]{Harpreet Kaur}%
\author[5]{Shivakumar Narayanan}%
\author[5]{Avelino Verceles}%
\author[5]{Hyeong Kim}%
\affil[1]{University of Maryland Medical Center Midtown Campus}%
\affil[2]{American University of Antigua College of Medicine}%
\affil[3]{University of Maryland Medical Center}%
\affil[4]{University of Maryland School of Medicine}%
\affil[5]{UMMC Midtown Campus}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Disseminated adenovirus infections in patients who received chemotherapy
alone for lymphoma are extremely rare, however, should be included in
differential diagnosis for those who received T cell suppressive agents.
We report a fatal case of disseminated adenovirus disease in a patient
who had received chemotherapy and presented with hypoxia%
\end{abstract}%



\sloppy


\textbf{Fatal Disseminated Adenovirus Disease in a Patient who Received
Chemotherapy for Mantle Cell Lymphoma: A Case Report}

Bo Yu, MD\textsuperscript{1}, Lakshmi Saravanan, BSc\textsuperscript{2},
Dena H. Tran, MD\textsuperscript{1}, Alexander J. Davies,
MD\textsuperscript{3}, Harpreet Kaur, MD\textsuperscript{4}, Shivakumar
Naraynanan, MBBS\textsuperscript{4}, Avelino C. Verceles, MD,
MS\textsuperscript{3}, Hyeong J. Kim, MD\textsuperscript{3}

\textsuperscript{1}Department of Medicine, University of Maryland
Medical Center Midtown Campus, 827 Linden Avenue, Baltimore, MD 21201,
USA.

\textsuperscript{2}American University of Antigua College of Medicine,
Jabberwock Road, Osbourn, Antigua and Barbuda.

\textsuperscript{3}Division of Pulmonary and Critical Care Medicine, 22
S Greene Street, Baltimore, MD 21201, USA.

\textsuperscript{4}Department of Infectious Diseases, University of
Maryland Medical Center Midtown Campus, 827 Linden Avenue, Baltimore, MD
21201, USA.

\textbf{Corresponding Author:}

Bo Yu, MD

Department of Medicine

University of Maryland Medical Center Midtown Campus

827 Linden Avenue

Baltimore, MD 21201, USA

Email: mailto:mdyu321@hotmail.com

\textbf{Abstract}

\textbf{Background:} Adenovirus (ADV) may cause severe complications in
hematopoietic stem cell transplant recipients, but disseminated ADV
infections in patients who received chemotherapy alone for hematological
malignancies are poorly understood due to the rarity of cases. Despite
being diagnostically challenging, a more specific workup needs to be
initiated with a low threshold in patients who are exposed to agents
with the potential to suppress T cells. We report a fatal case of
disseminated ADV disease in a patient with mantle cell lymphoma who had
received combination chemotherapy and presented with hypoxia.

\textbf{Case Description:} A 75-year-old man who was diagnosed with
Mantle cell lymphoma 10 months prior was admitted for mild hypoxic
respiratory failure. Bendamustine, Rituximab, Cytarabine regimen had
resulted in complete remission, with the last cycle of chemotherapy
being 3 months prior to admission. CT of the chest revealed ground-glass
opacities concerning pneumonia. Initial laboratory tests were remarkable
for mild leukopenia. The Respiratory Viral Panel was only positive for
ADV. He did not respond to empiric antibiotics for community- acquired
pneumonia and Trimethoprim / Sulfamethoxazole later on in light of
positive Beta D Glucan concerning for Pneumocystis pneumonia. Then, he
developed hemorrhagic cystitis, followed by liver and renal function
derangement which prompted checking serum ADV Polymerase Chain Reaction
(PCR). This test took 1 week to return, showing a viral load of 50, 000
copies/ml, suggesting disseminated ADV infection. Despite treatment with
Cidofovir, the multi-organ failure progressed, and the follow-up viral
load had doubled on day 20. The patient passed away the same day.

\textbf{Conclusions:}

Disseminated ADV infection in patients who only received chemotherapy is
a very rare phenomenon. T cell suppression seems to be a risk factor for
disseminated disease. Clinicians may need to maintain a low threshold to
send serum quantitative ADV PCR when symptoms are not improved by
anti-microbial treatment for more conventional infections in patients
who received agents that are known to suppress T cells, such as
Bendamustine.

\textbf{Keywords:} adenovirus infection, chemotherapy, Bendamustine,
Cidifovir, Case Report

\textbf{Background}

Human adenovirus infection can cause a wide spectrum of diseases in the
immunocompetent host that is generally mild and self-limiting. However,
in immunocompromised hosts, adenovirus infection can be severe with
progression to multisystem organ failure resulting in mortality as high
as 55\% {[}1{]}. Disseminated Adenovirus infection(DAI) can involve the
respiratory tract, gastrointestinal genitourinary systems, myocardium,
central nervous system, and eyes {[}2{]}. There is a wide estimate for
the incidence of adenovirus infection following hematopoietic stem cell
transplants, ranging from 5-20\% {[}3,4{]}. The immune response to
adenovirus is T-cell mediated and allogeneic transplant recipients are
at the highest risk of severe disease, however, disseminated disease in
adult patients with underlying hematologic malignancy who have not
received stem cell transplant seems rare. We report a fatal case of
disseminated Adenovirus infection in an immunocompromised patient with
mantle cell lymphoma who had received combination chemotherapy and
Rituximab but had not undergone stem-cell transplantation.

\textbf{Case Presentation}

A 75-year-old man presented to our emergency room with cough and
worsening dyspnea on exertion for the previous four days. His medical
history was significant for mantle cell lymphoma diagnosed 10 months
prior to admission, for which he received six cycles of Bendamustine,
Rituximab, Cytarabine (BRCA) followed by maintenance Rituximab. He
completed chemotherapy 3 months before this admission, and his last dose
of Rituximab was 6 weeks prior. He had achieved a complete metabolic
response based on recent PET(Positive Electron Tomogtaphy) imaging and
blood work. On arrival to the emergency room, he was hypoxic requiring
supplemental oxygen via nasal cannula, but otherwise appeared well.
Heart and lung auscultation normal. Computed Tomography Angiography
(CTA) chest revealed widespread patchy ground-glass opacities
bilaterally compatible with multifocal pneumonia (Figure 1). Laboratory
results revealed white blood cell count 3.2 K/mcL with 60\% neutrophils,
20\% bands, and 6\% lymphocytes. Lactate dehydrogenase was elevated 1959
units/L(normal range 313-618 u/L), ferritin 1622 ng/ml(normal range
17.9-464.0 ng/ml), D-Dimer 1670 ng/ml(normal range \textless{}749ng/ml).
Nasopharyngeal swab for SARS-COV2 polymerase chain reaction (PCR) was
negative.

Figure 1. Representative slices of CT chest obtained on hospital day 1
showed patchy ground-glass opacity with areas of increased
consolidation, especially in the left lower lobe.

Urine antigen assay for \emph{Streptococcus pneumoniae}
and\emph{Legionella pneumophila} were negative. Given his
immunocompromised state, opportunistic pathogens
including\emph{Pneumocystis jirovecii}(PJP), and other fungal causes of
infectious pneumonia were considered, and beta-d-glucan testing was
sent. Drug-related hypersensitivity pneumonitis or lung injury due to
Rituximab were also considered but felt less likely given the timing of
presentation. The nasopharyngeal swab was positive for Adenovirus by
multiplex polymerase chain reaction by multiplex respiratory virus PCR
panel. He was started on empiric antibiotic therapy with ceftriaxone and
azithromycin for possible superimposed community-acquired pneumonia and
admitted to the medical ward for ongoing care.

On hospital day 4 his hypoxemia worsened. He was transitioned to high
flow nasal cannula, initiated on dexamethasone based on dosing per
RECOVERY trial {[}5{]} for potential viral induced Acute Respiratory
Distress Syndrome (ARDS), and he was admitted to the intensive care
unit. At the time of upgrading to ICU level of care, the patient's
Beta-D-Glucan test resulted positive, and considering the CT chest
findings and worsening hypoxemic respiratory failure,
Trimethoprim-Sulfamethoxazole was initiated for high suspicion of PJP
pneumonia. Bronchoscopic sampling was not obtained for antigen
confirmation due to tenuous respiratory status.

On hospital day 5 patient developed hematuria, initially mild and
thought to be due to traumatic foley catheter insertion, but gradually
increasing in quantity to the point of requiring continuous bladder
irrigation. Urinalysis with culture and ultrasound of urinary tract were
obtained without evidence of obstruction/calculi, or bacterial urinary
tract infection, raising concern for hemorrhagic cystitis. This first
suggestion of disseminated adenoviral infection prompted serum
adenoviral PCR testing to be sent. On hospital day 7, transaminases were
noted to be elevated with ALT 203 U/L and AST 176 U/L. The patient
concurrently developed declining renal function with creatinine rising
to 1.5 mg/dL (baseline creatinine 0.9mg/dL) in the context of stable
hemodynamics and a negative viral hepatitis panel. The constellation of
findings of interstitial pneumonia, transaminitis, and gross hematuria
with acute kidney injury further supported a diagnosis of disseminated
adenovirus infection. Dexamethasone was therefore held, and the patient
was given intravenous immunoglobulin based on limited data {[}6,7{]}. He
was not given Cidofovir however due to worsening renal injury.

The patient completed a 5-day course of ceftriaxone and vancomycin for
presumed superimposed bacterial pneumonia and was kept on
trimethoprim/sulfamethoxazole for possible PJP pneumonia as this
differential diagnosis could not be safely ruled out during the course
of his hospitalization. Over the next week patient's clinical status
continued to slowly decline, with the need for increasing levels of
supplemental oxygen via high flow system (Figure 2), worsening renal
failure necessitating renal replacement therapy, and increasing
abdominal distension with adynamic ileus on imaging. On hospital day 12,
whole blood adenovirus polymerase chain reaction (PCR) that had been
sent seven days earlier returned positive, yielding a load of 548,000
copies/ml. Diagnosis of disseminated Adenovirus infection was therefore
confirmed. Repeat chest imaging at this time showed progression of
multifocal ground-glass opacities and evidence of organization and early
fibrotic changes (Figure 3). Despite the renal failure, the decision was
made it start the patient on Cidofovir therapy at 3mg/kg, dosing twice
weekly, in conjunction with probenecid. Additionally, given
progressively worsening hypoxemic respiratory failure despite maximum
medical therapy including continuous renal replacement therapy and
escalation to BiPAP patient was resumed on dexamethasone as salvage
therapy.

Unfortunately, over the following days patient's mentation declined
likely due to Central nervous system(CNS) involvement of infection (CNS
imaging was not obtained based on goals of care discussion) and he was
transitioned to full comfort measures, passing away on hospital day 18.
Repeat adenovirus PCR sent shortly before patients died revealed a viral
load further increased to greater than 10,000,000 copies/ml
(\textgreater{}7 log copies).

The timeline of this case is illustrated in figure 4.

Figure 2. Daily progression of supplemental oxygen requirements.

Figure 3. Representative slices of CT chest obtained on hospital day 12
showed more diffuse ground-glass opacities with peripheral clearing and
reticulations consistent with organization and early fibrotic changes.

Figure 4. Timeline of clinical findings, treatment, and course

\textbf{Discussion and Conclusion}

Adenovirus is a common pathogen associated with upper and lower
respiratory tract infections, as well as viral conjunctivitis. The viral
infection is usually self-limiting, although devastating disseminated
infections in immunocompetent individuals have been reported {[}8{]}.
Disseminated Adenovirus infection usually occurs in immunocompromised
hosts, such as those who underwent hematopoietic stem cell transplant
(HSCT), solid organ transplant(SOT), or patients with acquired
immunodeficiency syndrome (AIDS). Disseminated disease can manifest in
the form of interstitial pneumonia, hepatitis, meningoencephalitis, and
tubulointerstitial nephritis.

The incidence of adenovirus infection in patients who underwent HSCT can
be highly variable (3-47\%) {[}9,10{]} and disease is usually limited to
one organ system (gastrointestinal, genitourinary, or respiratory
system), and disseminated disease is considered if involving two organs
or more, but not including adenovirus viremia {[}1,11{]}. Based on
hemagglutination traits, Adenovirus species are divided into A-G groups.
Disseminated diseases in HSCT recipients appeared to be more caused by
Adenovirus C species {[}12,13{]}. In SOT recipients, adenovirus
infection is frequently allograft limited, though disseminated diseases
are not uncommon {[}14{]}.

Conditioning chemotherapy before the HSCT is known to cause long-lasting
effects on the host's immune system due to depletion of host T/B cells
leading to increased risks of opportunistic infections. The
reconstitution of immunity with engraftment is also a complicated and
high-risk process related to the development of severe infections.
T-cell depletion by alemtuzumab or anti-thymocyte globulin is known to
increase the risk of disseminated Adenovirus {[}15{]}.

However, there are limited data about adenovirus infection in
non-HSCT/SOT patients who received only chemotherapy for hematological
malignancies. Bendamustine has the features of both alkylating and
antimetabolite chemotherapy agents. Due to its presumed safe side effect
profiles, Bendamustine is often used off-label to treat indolent
lymphomas, such as follicular lymphoma and chronic lymphocytic leukemia.
More recent data suggest Bendamustine can cause significant and
prolonged CD4+ suppression of 24-26 months in a high percentage of
patients who received it either as 1\textsuperscript{st} line therapy or
advanced treatment line {[}16{]}, leading to increased risk for both
community-acquired and opportunistic infections including adenovirus
infection when compared to other chemotherapy agents for the treatment
of indolent non-Hodgkin Lymphoma in elderly patients {[}17{]}.

Rituximab is associated with increased risks of hepatitis B, Varicella
zoster virus, and Cytomegalovirus infections {[}18{]}. In comparison,
there is only one case of Rituximab-related fulminant adenoviral
hepatitis reported, who received 11200 mg total dose of Rituximab for
his lymphoma {[}19{]}. Our patient's chemotherapy regimen consisted of
Bendamustine, Cytarabine, and Rituximab (total dose of 3700mg) and he
did have lymphocytopenia at presentation though specific T/B cell
subsets were not measured by flow cytometry that would be valuable to
provide more granular measurements of the adaptive immunity.

Of note, multiplex tools have limited sensitivity in general since they
are designed to only detect common Adenovirus serotypes. Though being
questioned about its value in the general patient population, it may
still serve as a quick and convenient diagnostic modality in the
diagnosis of possible opportunistic infections in immunocompromised
patients as in our case. In the context of clinically severe disease,
physicians may favor the management of more common infectious processes
while diagnostic cues are weighted for multiple possibilities. In our
case, the patient had two positive Beta-D-glucan tests and relevant CT
chest findings pointing to the better-recognized PCP pneumonia.

Currently, there is no U.S. Food and Drug Administration (FDA)-approved
medicine for disseminated Adenovirus disease. Nonetheless, Cidofovir is
the standard treatment for disseminated Adenovirus in many centers, but
dosing regimens are center-specific. There is no current study that
compares the safety and efficacy of the two most frequently used
regimens: 5 mg/kg every 12-2 weeks and 1 mg three times per week.
Although a low-dose regimen was associated with less nephrotoxicity,
this may carry a higher risk of treatment failure and breakthrough
infection {[}20{]}. Besides, Cidofovir has unpredictable effects as some
patients seemed to respond well while others did not. BrinCidofovir is a
lipid ester of Cidofovir with less nephrotoxicity than Cidofovir, which
was reported to have a higher intracellular level important for
virustatic effect. A few case reports showed the success of
BrinCidofovir in the treatment of refractory Adenovirus infection thus
it may be a promising drug of choice in the future, but more data are
needed to confirm its efficacy. At this point, the availability of
BrinCidofovir is also limited by the lack of approval by the FDA or its
counterparts. Adoptive transfer of donor Adenovirus specific T-cells
(ACT) is an experimental therapy with prompt response in HSCT, but this
intervention failed to show the same benefits in solid organ transplant
recipients {[}21{]}. For patients deemed to receive chemotherapy as the
only treatment for hematological malignancies, it is also unrealistic to
routinely isolate and expand Adenovirus specific T-cells from each
patient due to the low incidence of disseminated Adenovirus infections
in general.

To conclude, disseminated adenovirus infections in patients with
hematological malignancies who have not undergone stem cell
transplantation are rarely reported. Diagnosis of disseminated
adenovirus infection(DAI) remains very challenging and given limited
treatment options with unclear efficacy, early identification so that
targeted therapies can be given in a timely manner may be key to
ensuring good outcomes. Suspicion for DAI should be raised when
interstitial pneumonia, hemorrhagic cystitis, acute liver injury, and
other organ specific manifestations are present without an obvious
cause, especially in the setting of a positive nasal PCR test for
adenovirus. DAI should be especially suspected in patients who received
agents that can severely suppress T cell population, such as
Bendamustine, Alemtuzumab, and Antithymocyte immune globulin. Cidofovir
is currently the standard treatment for severe adenovirus infection,
though the ideal regimen is unclear. Its derivative medication,
BrinCidofovir, may offer better efficacy at less risk of nephrotoxicity,
however, more data is required.

\textbf{List of abbreviations}

\textbf{ACT:} Adenovirus specific T-cells

\textbf{ADV:} adenovirus

\textbf{AIDS:} Acquired immunodeficiency syndrome

\textbf{ALT:} alanine aminotransferase

\textbf{ARDS:} Acute Respiratory Distress Syndrome

\textbf{AST:} aspartate aminotransferase

\textbf{BRCA:} bendamustine, rituximab, cytarabine

\textbf{CNS:} Central nervous system

\textbf{CT:} Computed Tomography

\textbf{CTA:} Computed Tomography Angiography

\textbf{FDA:} Food and Drug Administration

\textbf{HSCT:} hematopoietic stem cell transplant

\textbf{PCP:} Pneumocystis jirovecii

\textbf{PCR:} Polymerase Chain Reaction

\textbf{PET:} Positive Electron Tomography

\textbf{SOT:} solid organ transplant

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\textbf{Declarations:}

\textbf{Ethics approval and consent to participate}

Not Applicable

\textbf{Consent for publication}

Written consent to publish this case report and any accompanying images
was obtained from the patient's next of kin.

\textbf{Availability of data and materials}

Any data (suitably anonymized to maintain patient confidentiality) is
available for readers to review if a suitable written request to the
Corresponding author is made.

\textbf{Competing interests}

All authors declare that they have no competing interests.

\textbf{Funding}

University of Maryland Health Sciences and Human Services Library's Open
Access Publishing Fund

\textbf{Authors Contributions}

BY, DT, AV, HK(Hyeong Kim) -- participated in the direct care of the
patient in the ICU. SN and HK(Harpreet Kaur)-- Infectious Disease
consultant, also helped with forming the discussion part of this paper.
BY and LS -- wrote the initial draft, which was edited for style and
accuracy by DT, AV, SN, and AD. All authors critically reviewed the
manuscript for publication. All authors have read and approved the final
version of this manuscript.

\textbf{Acknowledgements}

None\selectlanguage{english}
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