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\begin{document}

\title{COVID-19 in Children with Cancer: A single Low-Middle income center
experience}



\author[1]{Fatma Ebeid}%
\author[1]{iman ragab}%
\author[1]{nayera Elsherif}%
\author[1]{Sara Makkeyah}%
\author[1]{Salwa Mostafa}%
\author[1]{Khadiga Eltonbary}%
\author[1]{Safa Sayed}%
\author[1]{Aya Mostafa }%
\author[1]{Heba   AbdelRaheem}%
\author[1]{Sara Agwa}%
\author[1]{Hala Hafez}%
\author[1]{Samia girgis}%
\author[1]{Yasmin El Gendy }%
\author[1]{Manal El-Sayed}%
\affil[1]{Ain Shams University Faculty of Medicine}%


\vspace{-1em}



  
  \date{June 14, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Coronavirus disease-2019 (COVID-19) could be associated with
morbidity and mortality in immunocompromised children. Objective: To
measure the frequency of SARS-COV-2 infection among hospitalized
children with cancer and detect the associated clinical manifestations
and outcomes. Methodology: A prospective non-interventional study
including all hospitalized children with cancer conducted between
mid-April and mid-June 2020 in Ain Shams University hospital, Egypt.
Clinical, laboratory and radiological data were collected. SARS-CoV2
infection was diagnosed by RT-PCR tests in nasopharyngeal swabs.
Results: Fifteen of 61 hospitalized children with cancer were diagnosed
with SARS-COV-2. Their mean age was 8.3\selectlanguage{ngerman}±3.5 years. Initially, 10(66.7\%)
were asymptomatic and 5(33.3\%) were symptomatic with fever and/or
cough. Baseline laboratory tests other than SARS-COV-2 RT-PCR were not
diagnostic; the mean absolute lymphocyte count was 8.7±2.4 x109/L,
C-reactive protein was mildly elevated in most of patients. Imaging was
performed in 10(66.7\%) patients with significant radiological findings
detected in 4(40\%) patients. Treatment was mainly supportive with
antibiotics as per the febrile neutropenia protocol and local Children
Hospital guidance for management of COVID-19 in children. Conclusion:
Pediatric cancer patients with COVID-19 were mainly asymptomatic or with
mild symptoms. A high index of suspicion and regular screening with
nasopharyngeal swab in asymptomatic hospitalized cancer patients is
recommended.~%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Introduction:}

Coronavirus disease 2019 (COVID-19) is a viral respiratory illness
caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2),
the first case was detected in December 2019. (1) The COVID-19 pandemic
has rapidly escalated into a global crisis. (2) The first case
registered in Egypt was in February 2020 and since that date, the
numbers have been increasing and by mid-June 2020, 47,856 cases of
SARS-CoV-2 and 1766 deaths have been reported by the Ministry of Health
(3).

Children are usually develops mild disease (4), a Chinese analysis of
2135 confirmed or suspected cases of COVID-19 among children revealed
that 55.4\% developed mild symptoms or were asymptomatic and only 5.4\%
had severe illness compared with 18.5\% of adult cases. (5)

Viral infections in general are associated with increased morbidity and
mortality in immunocompromised children. (6) Data on the clinical
features and outcomes of immunocompromised children with cancer who are
infected with SARS-CoV-2 are scarce. Knowledge from previous influenza A
H1N1 pandemics suggests that those vulnerable immunosuppressed children
are likely to be infected and to develop manifestation as an increased
number of cases are described with time. (7,8)

Although isolation as an inpatient is common practice for children who
are receiving intensive chemotherapy or stem cell transplant, most
children with cancer are treated in the outpatient setting, and hospital
visits or intermittent hospital admission are unavoidable for
appropriate delivery of therapy. Risk of exposure to SARS-CoV-2, either
in the hospital or the community setting, has resulted in widespread
anxiety among families of children with cancer. (9)

The primary objective of this study was to measure the frequency of
SARS-COV-2 infection among hospitalized children with cancer, while the
secondary objective was to identify the associated clinical
manifestations and outcomes in those with confirmed SARS-COV2 infection.

\textbf{Methodology}

\textbf{Study design}

A prospective non-interventional study was carried out at the Hematology
Oncology Department, Children's hospital, Ain-Shams University, Cairo,
Egypt. The study sample was obtained using a non-probability convenience
sample including all hospitalized children with cancer with confirmed
SARS-COV-2 between mid-April and mid-June 2020. The study was approved
by the Research Ethics Committee, Faculty of Medicine, Ain Shams
University {[}FMASU P25a /2020{]} in accordance with the Code of Ethics
of the World Medical Association (Declaration of Helsinki) for
experiments in humans, 2013 and was registered on clinicaltrials.gov
{[}NCT04404244{]}.

\textbf{Study Procedures:}

A written signed and dated informed consent and assent were obtained
from each caregiver and patient if applicable before inclusion in the
study. Patient clinical report forms included demographic data, full
medical history, concurrent medications and epidemiological data
(history of contact to a COVID-19 case, history of travel), as well as
the underlying oncological disorders and cause of admission. In
addition, physical examination, vital signs (blood pressure, heart rate
and temperature) and blood oxygen saturation were assessed and recorded.

Baseline Laboratory investigations included complete blood count (CBC)
using Sysmex XT-1800i (Sysmex, Kobe, Japan), examination of Leishman
stained smears for differential white blood cell (WBC) count, liver
(alanine amino transferase (ALT), total and direct bilirubin) and kidney
function tests (serum creatinine), CRP using Cobas Integra 800 (Roche
Diagnostics, Mannheim, Germany), serum ferritin using Immulite 1000
Analyzer, Siemens Healthcare Diagnostics, Marburg, Germany), lactate
dehydrogenase (LDH) and coagulation test (D-dimer, prothrombin time and
INR). COVID-19 was confirmed by SARS-CoV-2 reverse Transcription
Polymerase Chain Reaction (RT-PCR) test by nasopharyngeal (NP) swab.
Chest X-ray and/or computed tomography (CT) scan of the chest was
performed.

During admission, whenever unexplained fever and/or respiratory symptoms
developed or COVID-19 was suspected, chemotherapy during admission was
revised and individualized decisions were taken, NP swab (in patients
with platelet count at least 30x10\textsuperscript{9}/L) was repeated,
and chest X-ray and/or CT chest were performed. In addition, CBC with
differential counts, CRP and serum ferritin level, coagulation test and
routine bacteriological study, blood culture and other
symptoms/signs-based cultures were performed.

On discharge, a thorough physical examination was performed, date of
discharge, period of admission and the outcome were recorded.

\textbf{Results}

Over the study period between mid-April and mid-June 2020, sixty-one
children with cancer were admitted to the Pediatric Hematology Oncology
department, Children's hospital, Ain Shams University. They were 38
(62.2\%) males and 23 (37.7\%) females. The underlying diagnosis was
mainly acute lymphoblastic leukemia (ALL) (n=42, 68.9\%), bone tumor
(n=4, 6.5\%), lymphoma (n=4, 6.5\%), neuroblastoma (n=2, 3.3\%), central
nervous system (CNS) tumors (n=3, 4.9\%), hemophagocytic
lymphohistiocytosis (HLH) 2 (n=2, 3.2\%), retinoblastoma (n=1, 1.6\%),
Wilms tumor (n=1, 1.6\%), germ cell tumor (n=1, 1.6\%) and
rhabdomyosarcoma (n=1, 1.6\%). All patients were admitted either for
their due chemotherapy cycle (n=29, 45.7\%) or for a concurrent illness
that required supportive care (n=33, 54.3\%). Forty-six (75\%) patients
were discharged safely and 4 (6.5\%) died during the admission.

\textbf{Children with cancer diagnosed with SARS-COV-2}

Fifteen patients were diagnosed with SARS-COV-2 by NP swab during the
study period; 9 (60\%) boys and 6 (40\%) girls. Their mean age was 8.3 \selectlanguage{ngerman}±
3.5 years. Their residence mainly in the catchment area of the hospital
(8 (53.3\%) from Cairo, 2 (13.4\%) from Qalyubia, 1 (7\%) from El-Fayoum
and four were from other governates (1 Suez Canal, 3 Beni-Sweif). Five
(33.3\%) patients had a positive history of exposure to confirmed
SARS-CoV2 positive cases. NP Swab was performed for 3 out of 13
care-givers and it returned positive. The underlying diagnosis of those
15 patients was mainly hematological malignancies; ten (76.9\%) were
diagnosed with ALL (n=8, 61.5\% had Pre B and n=2, 15.3\% had T-cell), 1
(6.7\%) had acute myeloid leukemia, 1 (6.7\%) had lymphoblastic
lymphoma, and 1 (6.7\%) had post-transplant Hodgkin Lymphoma. Two
(13.4\%) of these 15 patients had other malignancies; 1 (6.7\%) had high
risk medulloblastoma and 1 (6.7\%) had Ewing's sarcoma.

\emph{Clinical picture}

Regarding the clinical picture, 10 (66.7\%) were asymptomatic (six
patients were newly diagnosed with cancer and three were admitted for
chemotherapy and one was screened preoperatively for excisional lymph
node biopsy for suspicion of relapse). One of the ten asymptomatic cases
who presented at his initial diagnosis found to have a mediastinal mass
and malignant pleural effusion on the initial diagnostic work-up. The
other five (38.4\%) symptomatic patients were admitted for supportive
care; 4 presented with fever and 1 presented with cough and dyspnea as
illustrated in Figure1. During admission, out of ten asymptomatic
children, five remained asymptomatic and the other 5 developed mild
symptoms, mainly fever (n=5), cough (n=3), headaches (n=2), myalgia
(n=1), fatigue (n=1), and pruritis (n=1).

\emph{Laboratory results}

Regarding the laboratory results, there was a wide range of lymphocyte
count which is attributed to the presence of three newly diagnosed
patients with acute leukemia within the study and the detected
lymphocytopenia present in 50\% of patients. D-dimer was performed in
seven patients and was elevated in all of them. LDH was also elevated in
all the examined cases. The mean serum creatinine was 0.7 mg/dl, which
was elevated only in one newly diagnosed patient with high TLC count and
picture of tumor lysis. C-reactive protein (CRP) was mildly elevated in
all, except in three patients with a mean of 24.3 mg/dl. Laboratory data
of the 15 patients with confirmed SARS-CoV2 infection are summarized in
Table 1. Creatine kinase was done for 2 patients; 36 and 41 U/l
(reference range 20-200). One patient was isolated at home, whose
parents refused doing further laboratory tests, except for a CBC before
biopsy.

\emph{Radiological data}

Among the 15 patients with confirmed SARS-CoV2 infection, 10 (66.7\%)
performed radiological assessment with significant radiological findings
detected in four (40\%) patients. One patient had only a plain chest
x-ray, which showed bilateral pulmonary infiltrates. Three had an
initial plain chest x-ray followed by high resolution CT-scan (HRCT),
which was abnormal in one of them revealing bilateral mosaic appearance
and left lobar consolidation. Six patients had HRCT from the start and
showed abnormal finding in two patients.as illustrated in Figure 2.

\emph{Treatment}

Treatment was mainly supportive with antibiotic according to the febrile
neutropenia protocol and the local Children Hospital, Ain shams
University guidance for management of COVID-19. Supportive treatment was
mainly in the form of maintaining adequate hydration and nutrition,
ensuring adequate sleeping hours, antipyretics (paracetamol), vitamin C
(50 mg 1-3 year and 100 mg over 3year), zinc 5-10 mg for young children
and 10-15 mg for older children, vitamin D 3 (400-600 IU) below 1 year,
and (600-800 IU) for older children in addition to lactoferrin sachet
once daily.

Treatment of COVID-19 as per the local children's hospital guidance
includes the following medications: 1) azithromycin 10 mg/kg once on day
one max dose 500mg /dose followed by 5 mg/kg (max 250 mg/dose) once
daily for 5 days, 2) hydroxychloroquine 6.5 mg/kg orally every 12 hours
(max: 600 mg/dose) for two doses, followed by 3 mg/kg orally every 12
hours (max: 200 mg/dose) for a total of 5-10 days, 3) ceftriaxone 100
mg/kg/dose once daily for 5 days max daily dose 2 gm, and 4)
anticoagulation prophylaxis (Enoxaparin) \textless{}2 months: 0.75 mg/kg
SC q12h , \selectlanguage{english}[?]2 months: 0.5 mg/kg SC q12hr if D dimer between 500-1000
ng/ml.

\emph{Outcome}

Out of the 15 patients with confirmed SARS-CoV2 infection, eight (53.3
\%) were discharged after their RT-PCR test results became negative,
four (26.6 \%) are still admitted in isolation, one (6.7 \%) patient was
isolated at home and managed through the hospital on-call services. The
duration of hospital stay ranged from 1-24 days (mean 10.2+-8.1) as
illustrated in Figure 1.

\emph{Mortality}

During the study period two death were reported, one of them was 13
years old female who presented on May 16, 2020 with pancytopenia and
severe menorrhagia for which she started hormonal therapy with GnRH
agonist and platelet transfusion with good initial response, eventually
she was diagnosed with ALL pre B. NP swab was performed on the following
day and she was confirmed with SARS-CoV-2 and her CT scan was normal.
She was transferred to Elobour isolation hospital and treated with
supportive treatment, azithromycin, oseltamivir, and hydroxychloroquine.
No anticoagulation was started due to persistent thrombocytopenia. After
12 days of her first presentation to hospital she was deceased due to
the underlying cancer before commencing anti-leukemic therapy because
SARS-CoV-2 RT-PCR was still positive.

\textbf{Discussion}

COVID-19 was declared by World Health Organization as a public health
emergency of international concern (10) and despite the worldwide
spread, clinical patterns of COVID-19 particularly among children remain
largely unclear. (5) The clinical spectrum of COVID-19 could range from
being asymptomatic to developing severe acute respiratory distress. (2)
In the current study, despite of the immunocompromised status of the
hospitalized patients with cancer, 66.7\% were asymptomatic at admission
and 33.3\% had mild symptoms. This is in comparison to 4.4\% and 50.9\%
respectively in large Chinese study in which 731 patients were confirmed
positive by laboratory testing. (2)

While other coronaviruses can produce more severe disease in
immunocompromised children with increased risk with coexisting pulmonary
disease or concurrent lower respiratory tract infection (6,11), the
severity of children's COVID-19 cases was milder than adult. (2) A
systemic review of 110 immunosuppressed patients, mostly presenting with
cancer, along with transplantation and immunodeficiency, they seemed to
have a favorable disease course, as compared to the general population,
72 (65.5\%) recovered (discharged or inpatients) or did not require
intensive care and 6 (5.5\%) needed intensive care or invasive
ventilation and 23 (20.9\%) died. (12) In an Italian pediatric
haemato\selectlanguage{english}-oncology clinic, SARS\selectlanguage{english}-CoV\selectlanguage{english}-2 infection was detected in 4 out 170
patients at the molecular level; three of them were asymptomatic.
(13)The clinical course and outcome of SARS\selectlanguage{english}-CoV\selectlanguage{english}-2 was reported to be
more favorable in children than in adults (1) A possible explanation
that children might have less severe disease was attributed to the lower
expression of ACE2 receptor and present with a different inflammatory
response, with higher numbers of B and T regulator cells, involved in
immune tolerance and leading to a less inflammatory immune response.
(14)

The detrimental impact of COVID-19 pandemic on childhood cancer may be
delay in diagnosis (15), delay in starting treatment, the detrimental
impact of infection on children with cancer, and the uncertainty about
decision for chemotherapy in PCR-positive asymptomatic patients.
Universal testing of asymptomatic cancer patients may help safe
continuation of treatment. (16)

As regards the treatment, all the patients received supportive care in
addition to antivirals or antibiotics guided by radiological findings
and symptom progression (according to Children's hospital and MOH
guidelines). With the large diversity of therapeutic options, (17)
whether a different treatment approaches in children with cancer on
chemotherapy is not adopted. The important decision is the proper time
to start anticoagulation, the main concern is that childhood cancer is
predisposing for thrombosis (18). Whether early start of anticoagulation
for COVID-19 or delay usage as that it might be an immune thrombosis
related to neutrophil extracellular traps (19); yet it is acceptable
that in both cancer (20) and COVID-19 (21), D-dimer level is the most
important laboratory result in decision for anticoagulation.

As for total and differential leucocytic count, there was wide
variability; lymphocytopenia was present in 50\% of patients compared to
3.6\% in a previous study that is evaluating children infected with
SARS-CoV-2 and treated at the Wuhan Children's Hospital. (11) Although
lymphopenia was associated with severe disease (22) which was not
consistent with the clinical manifestations of our patients group, yet
the high frequency of lymphopenia might be attributed to the underlying
cancer, chemotherapy and the wide variation could be due to the
inclusion of three newly diagnosed patients with hematological
malignancy.

The radiological findings in our patients were mainly ground glass
opacities (GGO), not necessarily affecting the periphery, consolidation
(lobar) and interstitial infiltrates. This finding is in agreement with
Chen et al, 2020 who reported that initially, chest radiography findings
can show signs of pneumonia, such as small irregular lung opacities and
interstitial alterations, usually affecting peripheral areas. The
authors also reported that chest computed tomography also exhibits GGO
and segmental consolidation in both lungs while pleural effusion being
uncommon. (23) However, correlation of radiological findings with
COVID-19 severity in the current study may not be applicable due to
small sample size.

\textbf{Conclusion} :

Pediatric oncology patients with SARS-COV-2 infection in this study were
mainly asymptomatic or with mild symptoms. A high index of suspicion
with mild symptoms and regular screening by NP swab in asymptomatic
hospitalized cancer patients admitted for intensive chemotherapy and
initiation of treatment, guided by laboratory data is recommended. More
studies are required to report the incidence, outcomes and therapeutic
decisions of SARS-COV-2 in pediatric patients with cancer.

.

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Figure Legend

\par\null\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.56\columnwidth]{figures/Screen-Shot-2020-08-20-at-9-56-47-PM/Screen-Shot-2020-08-20-at-9-56-47-PM}

\end{center}
\end{figure}

\textbf{Figure 1: Consort Diagram presenting admitted children with
cancer, SARS-COV-2 results and outcome}

\textbf{}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Screen-Shot-2020-08-20-at-9-56-59-PM/Screen-Shot-2020-08-20-at-9-56-59-PM}

\end{center}
\end{figure}

\textbf{Figure2: Consort Diagram showing radiologic findings in children
with cancer and COVID positive by RT-PCR}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/351657/articles/476209-covid-19-in-children-with-cancer-a-single-low-middle-income-center-experience}

\selectlanguage{english}
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\end{document}

