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\begin{document}

\title{Sars-CoV-2 Infection in a Neutropenic Pediatric Patient with Leukemia:
Addressing the need for universal guidelines for treatment of Sars-CoV-2
positive, immunocompromised patients}



\author[1]{Anastasia Schied}%
\author[1]{Erin Trovillion}%
\author[1]{Amaran Moodley}%
\affil[1]{University of California San Diego}%


\vspace{-1em}



  
  \date{June 08, 2024}


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\selectlanguage{english}
\begin{abstract}
In December 2019, a novel coronavirus (Sars-CoV-2 ) emerged from Wuhan,
Hubei province, China, and has spread worldwide, with more than 4
million confirmed cases{[}1,2,3{]}. Available literature on the clinical
characteristics and natural history of pediatric patients infected with
Sars-CoV-2 is limited and less has been established regarding guidelines
for the treatment of immunocompromised pediatric patients. This is a
case report on the clinical course and management of a 6 year old female
with acute lymphoblastic lymphoma with Sars-CoV-2. The goal is to
highlight the need for management guidelines in the care of pediatric
cancer patients with Sars-CoV-2.%
\end{abstract}%



\sloppy


\emph{INTRODUCTION:}

\textbf{Patient Presentation:~}

The patient is a 6 year old female with B-lymphoblastic lymphoma who is
in the maintenance phase of treatment, as per Children's Oncology Group
(COG) study AALL1131 High Risk Arm.~ Her family reported a fever of
101.8 Fahrenheit so she was directed to the emergency room for
evaluation of fever in an immunocompromised patient with a central
line.~ She was found to have cytopenias secondary to chemotherapy, with
a white blood cell count (WBC) of 1.4 TH/uL, hemoglobin of 7.7 g/dL,
platelet of 229 TH/uL, and absolute neutrophil count (ANC) of 140/uL.~
Given the severe neutropenia she was started on empiric broad spectrum
antibiotics and was admitted per hospital standard of care.

History was significant for multiple symptomatic family household
members who had tested positive for Sars-CoV-2. The index cases were her
grandmother and grandfather who had exposure to Sars-CoV-2 positive
patients at an adult hospice where they were employed.~ The patient had
a history of 1 day of cough, but was asymptomatic on admission and
remained afebrile throughout her hospitalization. She denied symptoms of
cough, shortness of breath, fatigue, abdominal pain, or diarrhea during
her 10 day admission.

\textbf{Diagnostic/Therapeutic Focus and Assessment:~}

While in the Emergency Department, the patient underwent diagnostic
testing that included a naso-pharyngeal (NP) swab for detection of
SARS-CoV-2 and other respiratory pathogens by polymerase chain reaction
(PCR), blood culture and urine culture. She received a normal saline
bolus, was started on intravenous (IV) cefepime, and admitted to a
single-patient, negative pressure room in the Special Infectious Disease
Unit (SIDU). Infectious disease testing was positive for SARS-CoV-2 by
NP PCR, negative for other respiratory virus co-infections, and negative
blood and urine cultures.

The patient was transfused for a hemoglobin of 7.7, particularly in the
context of SARS-CoV-2 infection. Infectious Disease specialists and
Infection Control were consulted and recommended a baseline chest X-ray
(CXR) and inflammatory markers which were monitored as her clinical
condition evolved during her hospitalization. Table 1 highlights
important lab values. In particular, D-Dimer, lactate dehydrogenase
(LDH), and interleukin 6 (IL-6) were not elevated, and trended down
during admission. Her ferritin was slightly elevated at 1,098, and down
trended to 983 on repeat testing. Her CXR was normal, and as her
clinical status remained stable without shortness of breath, cough,
hypoxia, or increased work of breathing, imaging was not repeated prior
to discharge. Her oral chemotherapy was held while neutropenic as per
COG AALL1131 protocol guidelines and while actively infected with the
virus.

\textbf{Follow up and Outcome:~}

The patient was discharged home after 10 days of hospitalization. Her
blood cultures were negative, she was asymptomatic and remained afebrile
after antibiotics were discontinued, and her ANC was 162/uL at
discharge. She had repeat Sars-CoV-2 PCR testing of a naso-pharyngeal
swab 3 weeks after her diagnosis and it was negative. Her cytopenias had
resolved and her oncology team proceeded with Vincristine therapy,
prednisone pulse dosing, and restarted her oral mercaptopurine and
methotrexate. Serum Sars-CoV-2 IgG testing at 6 weeks after diagnosis
was positive; demonstrating that she did mount an antibody response
while immunocompromised. From the patient and patient's family
perspective, the extended hospital stay was appreciated as necessary to
keep the patient safe. They were receptive to holding chemotherapy while
she was actively infected, and agreed with conservative management in
the context of possible increased risk for severe course in
immunocompromised patients.

\emph{DISCUSSION:}

This case report provides an example of an immunocompromised pediatric
patient who had a favorable course and outcome after infection with
Sars-CoV-2. She was treated with supportive care only, and did not
receive any experimental antiviral therapies or intravenous
immunoglobulin. In the pediatric population overall, rate of
hospitalization is lower (5.7\% compared to 20\% in adults), and most
recover within 1-2 weeks of symptom onset.\textsuperscript{{[}4,5{]}} It
is still unclear why younger people are not as severely affected by the
virus, but theories attributing differences in immune system function
prompt additional questions regarding oncology
patients.\textsuperscript{6} The literature available is limited, but
our patient has followed a similarly mild course to 5 case reports from
a childhood cancer center in Lombardy Italy.\textsuperscript{7} Some of
those patients were managed at home, rather than admitted to the
hospital. We do not yet have specific guidelines for admission or
discharge criteria in the United States for pediatric oncology patients
who contract the virus. Our Infectious Diseases team recommended
baseline CXR, as well as trending certain inflammatory markers based on
findings in the adult literature, IL-6 in particular\textsuperscript{8}.
Other possible guidelines suggested in the World Journal of Pediatrics
recommend the following criteria be met prior to discharge: Afebrile for
3 days, absence of respiratory distress, and two negative Sars-CoV-2
tests.

Although a small number of case reports have demonstrated mild clinical
courses for pediatric oncology patients, there is evidence that an
immunocompromised state is associated with higher rates of Lower
Respiratory Tract Disease (LRTD).\textsuperscript{9} In a study
performed by Ogimi C et al. in Seattle, Washington, the characteristics
of coronavirus infection in immunocompromised as well as immunocompetent
pediatric patients were investigated, specifically the prevalence of
LRTD, which is an indicator of more severe disease and worse prognosis
in Sars-CoV-2 cases. The difference in prevalence was not statistically
significant, but in a multivariable model, there was an increased
likelihood of severe LRTD associated with an immunocompromised state
(adjusted odds ratio, 2.5 {[}95\% confidence interval, 1.2-4.9{]}; P =
.01).\textsuperscript{9} Until we have gathered more robust data on the
clinical course of immunocompromised patients, it remains prudent to
observe and monitor these patients conservatively if they contract
Sars-CoV-2.

Current recommendations for pediatric oncology patients are being
published by various specific oncology
organizations.\textsuperscript{{[}7,10,11{]}} A general theme is to
reduce intense chemotherapy and prolong intervals between cycles in
patients with stable disease. For asymptomatic oncology patients,
particularly sarcoma patients, surgery should not be delayed despite the
aerosolizing procedures required for operative management. In
immunocompromised patients who are found positive for Sars-CoV-2, the
French Sarcoma Group recommends delaying treatment for at least 15 days
after symptom onset, similar to how we proceeded in this case
report.\textsuperscript{11}

While caring for this patient, we identified multiple areas where
unified guidelines for patient care would be beneficial.

\begin{enumerate}
\tightlist
\item
  Admission criteria, routine lab monitoring and imaging recommended,
  possible treatment options/protocols, and discharge criteria.
\item
  Specific follow up testing/monitoring in immunocompromised patients.
\item
  Guidelines for adjustments in chemotherapy, radiation, and surgical
  interventions for pediatric oncology patients.
\item
  It will be important to understand which patients may benefit from
  various experimental therapies.\textsuperscript{12}
\end{enumerate}

We have a need as providers to further investigate how immunocompromised
children are responding differently to the virus, and the community of
patient families needs clear recommendations. For example, additional
precautions these families should take as the country begins reopening,
information on how the clinical course may differ in immunocompromised
children, and how treatment protocols may be adjusted during this
pandemic. There has been some epidemiologic investigation into the
perceived risk, and anxiety regarding the pandemic in pediatric oncology
patients. In a survey of young cancer patients in Milan, a large
proportion of them felt ``personally at risk of severe complications''.
The SIOP, St. Jude, the American Society of Hematology, and others are
actively developing a new platform for sharing resources and experiences
in the evolving time of this global
pandemic\textsuperscript{{[}5,13{]}}. It will be important to continue
sharing case information and conducting additional research in the
coming years.

\emph{CONFLICT OF INTEREST STATEMENT:} Authors do not have any conflicts
of interest.

\emph{ACKNOWLEDGEMENTS:} Consent was provided by the patient and her
family to publish information regarding her medical condition and
treatment.

\emph{REFERENCES:}

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\textbf{TABLE 1} Summary of Inflammatory Markers\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& Day 1 & Day 3 & Day 5\tabularnewline
\midrule
\endhead
D-Dimer (Ref: \textless{}250 ng/mL) & - & \textless{}100 &
\textless{}100\tabularnewline
Lactate dehydrogenase (Ref: 470-900 u/L) & 601 & - & 560\tabularnewline
Ferritin (Ref: 6-70 ng/mL) & 1,098 & - & 983\tabularnewline
Interleukin-6 (Ref: \textless{}5.00 pg/mL) & - & 2.77 &
1.81\tabularnewline
\bottomrule
\end{longtable}

\textbf{FIGURE LEGEND:}

Figure 1 Chest X-ray with \emph{``No acute cardiopulmonary
abnormality.''} obtained on Day 3 of hospitalization.\selectlanguage{english}
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