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\begin{document}

\title{COVID 19 Prevalence And Survival Outcome In Pediatric Cancer Patients
Undergoing Chemotherapy: A Study From Tertiary Cancer Center Of
North-East India}



\author[1]{MUNLIMA  HAZARIKA}%
\author[1]{raghavender reddy}%
\author[1]{avdhesh rai}%
\author[1]{PARTHA ROY}%
\author[1]{ASIF IqBAL}%
\author[1]{SUHANI BARBHUIYAN}%
\author[1]{NITHIN DANIEL}%
\author[1]{SREYA MALLIK}%
\author[1]{SATYA SARANGI}%
\affil[1]{Dr Bhubaneswar Borooah Cancer Institute}%


\vspace{-1em}



  
  \date{May 19, 2024}


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\selectlanguage{english}
\begin{abstract}
BACKGROUND: Pediatric cancer patients are considered one of vulnerable
group for covid-19 infections and its associated complication. We
assessed in this study, covid-19 prevalence and implications in
pediatric cancer patients of North-East India METHODS: A total of sixty
three pediatric cancer patients were tested for covid-19 by RT-PCR
between July 2020 to September 2020. All the patients received
chemotherapy as per their cancer types. Patients within age group one
year to eighteen years were included. Retrospectively medical records of
pediatric cancer patients were analyzed for clinical outcome between
COVID positive and negative group. RESULTS: Among sixty three patient,
19(30\%) were found positive for COVID-19. Among COVID-19 positive
patients, fourteen patients have hematological malignancies. Fever was
the main presenting symptom along with cough and sore throat there were
no statistically significant association observed between COVID-19
positive and negative group for gender, cancer type, total WBC count and
absolute neutrophil count. Survival outcome has shown statistically
significant association (p=0.0065) between COVID-19 positive and
negative pediatric cancer patients. Four deaths occurred in COVID-19
positive patients but there was no death in COVID-19 negative patients.
Statistically significant association was also observed between COVID-19
positivity in patients being symptomatic (p=0.0001). CONCLUSION: We
conclude from our present study that among pediatric cancer patients of
North-East India, COVID-19 positivity was significantly high in
symptomatic patients compared to asymptomatic. Among COVID-19 positive
pediatric cancer patients risk of death was significantly higher
compared to COVID-19 negative patients.%
\end{abstract}%



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\textbf{INTRODUCTION}

World health organization led initiative in low and middle income
countries towards improvement of survival among childhood cancer
patients\textsuperscript{1.} SIOP-PODC (Pediatric Oncology in Developing
Countries) has been instrumental in developing resource adapted
treatment protocol for LMIC for six common childhood cancers {[}Burkitt
lymphoma , acute lymphoblastic leukemia (ALL), retinoblastoma, low grade
gliomas , Hodgkin lymphoma and Wilms tumor\textsuperscript{2}. World is
in the middle of a pandemic which is posing as the biggest challenge to
public healthcare in many countries. Severe acute respiratory syndrome
coronavirus 2 (SARS-CoV-2) is the causative agent of coronavirus disease
2019 (COVID-19)\textsuperscript{2.} Since its emergence in Dec 2019, it
has resulted in 63.7 million infections and 1.4 million deaths
worldwide. India accounts for 15\% of the total COVID-19 positive cases
as of November 30, 2020. The COVID-19 pandemic has created an
unprecedented global challenge in maintenance and continuity of
established treatment regimen implementation for children with cancer in
both developed as well as developing countries
settings\textsuperscript{3}.

Due to their immunocompromised status, Pediatric patients constitute one
of the most vulnerable group of individuals for COVID-19 infection and
its associated morbidity \& mortality as compared to general
population\textsuperscript{4}. Memorial Sloan Kettering Cancer Center
and New York Presbyterian Hospital have reported 7\% and 20\% COVID-19
positivity among pediatric cancer patients\textsuperscript{5.} In
Madrid, Incidence of COVID-19 infection in childhood cancer patients was
found to be 1.3\% higher compared to the general pediatric
population\textsuperscript{6}. In Turkish patients with hematological
malignancy, it was reported that case fatality rate was 13.8\% compared
to 6.8\% in the patients without cancer\textsuperscript{7}. It was also
reported that pediatric patients with cancer may not be more vulnerable
to SARS-CoV-2 infection and resulting morbidity compared to other
children\textsuperscript{8}. A multi centric and multi country survey
showed Covid-19 incidence and severity among children on anticancer
treatment might have a mild or asymptomatic
COVID-19\textsuperscript{9.}However, in a substantial proportion of
pediatric patients with SARS-CoV2, respiratory illness may progress to
severe stage requiring hospital care\textsuperscript{10}. In pediatric
patients with severe COVID-19 symptoms progression to critical illness
with hypoxemic respiratory failure can lead to prolonged ventilatory
support\textsuperscript{11}.

Contradicting outcome of studies from different geographical regions of
the world about COVID-19 and its associated complications in childhood
cancer patients may be a reflection of clinical as well resource setting
disparities. In view of scant availability of data from India and more
specifically from North --East India, current study was undertaken to
assess COVID-19 status and its clinical implications in the cancer
patients in children of North --East India. All the cancer patients of
children were treated at Dr. Bhubaneswar Borooah Cancer Institute,
Guwahati, Assam from July 2020 till September 2020

\textbf{MATERIALS AND METHODS}

Retrospective study was conducted between July 2020 to September 2020 at
Dr B Borooah Cancer Institute (BBCI), Guwahati, Assam, India. Medical
records of the childhood cancer patients were analyzed. All patients who
were tested for SARS-CoV-2 were collected. All childhood cancer patients
with age group between one year to eighteen years were included and
patients with cancer below one year and above eighteen years of age were
excluded from study. All cancer patients undergoing chemotherapy cancer
treatment were only included in the study.

Following set of variables / information were assessed such as age,
gender, diagnosis, cancer treatment undergoing before covid-19,
indication of testing, laboratory parameters, treatment details
(regarding antibiotics, antifungals and steroids), patient status.
Routine hematological and biochemistry test required for childhood
cancer patients were performed.

The study protocol was approved by institutional ethical committee.

RT-PCR COVID-19 Testing

Nasopharyngeal, Oropharyngeal swab specimens were collected in Viral
transport medium. Total viral RNA extraction was done using Viral RNA
mini kit (Qiagen, USA) as per manufacturer instruction. SARS-CoV2 RNA
detection in patient specimen was performed on CFX96 Real Time PCR
system (Bio-Rad, USA) in one tube RT-PCR protocol as per manufacturer's
instruction (Meril Life Sciences, India). Target confirmatory genes for
SARS-CoV2 were ORF1ab gene, Nucleoprotein N gene. RNaseP gene was used
an internal control for RNA quality. Specimen with Ct value [?]35 for both
ORF1ab gene, Nucleoprotein N gene were only considered positive. All
specimen had RNaseP amplification with Ct value [?]35.

Statistical Analysis

Statistical analysis of data was done in Graphpad prism software ver
9.0. The prevalence of SARS-CoV2 infection in test groups were tested
using a Fisher's exact test. Statistical significance was considered for
P-value of [?]0.05.

\textbf{RESULTS}

A total sixty three childhood cancer patients were tested for SARS-CoV2
between July 2020 till September 2020. All cancer patients had undergone
active chemotherapy. Only symptomatic patients and patients due for
hospitalization for chemotherapy were screened for SARS-CoV2 infection
at our institute due to limited resources during the specific time
period

Nineteen out of sixty three (30\%) cancer patients in children were
found to be positive for SARS-CoV2 by RT-PCR testing. Among COVID-19
positive patients, the median age was eight years whereas COVID-19
negative patients, the median age was five years. In COVID-19 positive
patients, sixteen (84\%) were admitted and treated at hospital whereas
three patients were treated in home isolation under the supervision of
local health authority with support from our pediatric oncology expert.
Among COVID1-9 positive group, Twelve (63.2\%) were male and seven
(36.8\%) were female whereas in COVID-19 negative group thirty one
(70.4\%) were male and thirteen (29.6\%) were female (p=0.7724). In
COVID-19 positive group, Fourteen (73.6 \%) were suffering from
hematological malignancy and Five have (26.4\%) solid malignancy but in
COVID-19 negative group, twenty seven have hematological malignancy and
seventeen have solid malignancy (p=0.5654). There were no statistically
significant association observed with gender, cancer type, total WBC
count and absolute neutrophil count (Table1). In COVID-19 positive
group, Among the hematological malignancies; acute lymphoblastic
leukemia (ALL) comprises 57\%, acute myeloid leukemia (AML) 21.5\% and
non-hodgkins lymphoma accounting for 21.5\% (Table1).

Survival outcome between COVID-19 positive and negative group has also
shown statistically significant association (p=0.0065). Statistically
significant association was observed between COVID-19 positivity and
patients being symptomatic (p=0.0001) (Table1).

Among COVID-19 positive patients, fourteen had fever as presenting
symptom. Cough and sore throat were seen in four patients, two patients
experienced headache. Sudden onset of breathlessness, vomiting and
diarrhea were observed in one patient each. Five patients were
asymptomatic of which four were screened before admission and one
patient was tested in view of close contact with the COVID positive
cancer child. In COVID-19 negative patients, thirty six patients were
asymptomatic and eight patients were symptomatic where fever was most
common symptom followed by cough, sore throat, diarrhea, headache.

Three patients had preexisting signs of infection and were started on
antibiotics prior to covid 19 infection. They were continued on
antibiotics during the course of covid 19 hospitalization. Demographics
and clinical characteristics have been detailed in TABLE 1.

Routine blood count done in our covid-19 positive patients showed three
patients with white blood cell (WBC) and absolute neutrophil count (ANC)
less than 1500 and 500 per microliter respectively. Two patients had ANC
20 per microliter and both of these patients had platelet less than
10,000. They also had multiple fever spikes and were on first induction
of acute myeloid leukemia (AML) receiving chemotherapy with daunorubicin
and cytosine arabinoside on day 10 and 14 respectively. Both of them
required oxygenation supplement and ultimately succumbed to death (TABLE
1).

COVID-19 Treatment:

Majority of COVID-19 positive patients received azithromycin,
dexamethasone, vitamin C, vitamin D and B complex, steroids etc. as per
institutional and prevailing national \& international consensus
guidelines for childhood cancer patients. Few COVID-19 positive patients
with AML and ALL on induction chemotherapy were started on systemic
antibiotics along with anti-fungal according to the protocol in
suspicion of systemic infection and prophylactically in view of fever
spike (TABLE 2).

Four patients out of 19 expired of which three patients experienced
death during treatment for COVID 19. One patient expired after he had
been cured of COVID 19 due to complication of chemotherapy. Out of the
three expired patients two were suffering from AML and both were on
induction daunorubicin and cytosine arabinoside chemotherapy and
developed multiple systemic bacterial infection along with other
comorbidities. One osteosarcoma patient on week 3 MAP protocol (high
dose methotrexate, doxorubicin and cisplatin) tested positive for
covid-19 and was started on antivirals, antibiotics and supplement
oxygen. This patient developed sudden onset of breathlessness and
patient needed urgent ventilator support and succumbed to death. One
patient suffering from ALL on induction chemotherapy expired after
patient has been cured from covid-19 and induction chemotherapy had been
restarted. Patient expired due to systemic bacterial infection and not
due to covid-19

\textbf{DISCUSSION}

In our study, death among COVID-19 positive patients was (4/19) 21.0 \%
but in COVID-19 negative cancer patients we had not observed any death
during the study period. In pooled meta-analysis of 3377 hematological
malignancy patients of Asia, Europe and North Americans which also
included five studies with 102 childhood hematological malignancy
patients, pooled risk of death for childhood hematological malignancy
was computed at 4\% (95\% CI)\textsuperscript{12} . Hamdy et al. (2021)
in 24 febrile neutropenia pediatric hematology patients seven were found
positive for COVID-19 among them three (43\%) had
died\textsuperscript{13}. Childhood cancer status, early SARS-COV2
infection detection, treatment protocol, resource settings, geographical
region may have impact on the varying degree of survival outcome in
COVID-19 positive childhood cancer patients.

In our study, the COVID-19 positivity among childhood cancer patients
tested for SARS COV2 was found to be approximately 30\%. Fourteen
COVID-19 positive patients become negative in RT PCR testing by
11\textsuperscript{th} day. Only two patients turn negative after more
than 16 days. In New York city up to 20\% COVID-19 positivity was
reported in cancer patients in children\textsuperscript{5}. In Madrid
region COVID-19 positivity in cancer patients in children was found to
be 1.3\% only\textsuperscript{14}. Pediatric cancer patients studies
related to COVID-19 very limited compared to adult cancer patients
studies. Our study was performed in cancer patients in children during
the peak period of COVID-19 infection across India therefore the outcome
of our study may be reflection of North-East region scenario.

In our study we found that COVID-19 positivity (73.6\%; 14/19) was
significantly high in cancer patients with suspected covid-19 symptoms
compared to asymptomatic patients (26.4\%; 5/19). There has been studies
which concluded that pediatric cancer patients may have mild or
asymptomatic COVID-19 infection\textsuperscript{8,9}.

The current rapid global spread of COVID-19 infection prioritizes our
intense efforts to identify effective preventive strategies and develop
optimal medical management. There is relatively ample information
available for adult covid-19 patients but our knowledge of clinical
characteristics of childhood covid-19 cancer patients is quite limited.
Many of our patients had fever, cough and sore throat as presenting
symptoms with majority of symptomatic patients having fever as
presenting complaints which is similar to earlier studies
conclusions\textsuperscript{15}. Fever has been presenting
symptom\textbackslash{}souts even in non-cancer pediatric population and
seen in 70-80\% of cases\textsuperscript{16}. In our observation we
found that Childhood cancer patients with COVID-19 had minor
complications and likely to have good prospect of favorable prognosis.
In our study, majority of patients with solid malignancy, lymphoma and
acute lymphoblastic leukemia had minor complications. Only two patient
from this group required oxygen support out of 16 COVID-19 positive
patients. In majority of COVID-19 positive patients (n=15) fever
subsided by day five of COVID positive status and their clinical course
was mild. Total deaths in COVID 19 positive patients in our study was
four comprising about 21\%. A study reported by Jacqueline Montoya et
al. showed similar death rate in childhood cancer patients of 10\%.
However this study included few myeloid cancer patients (4\%) as
compared to our study, which included 15.7\% AML and majority of death
during COVID 19 period in our study were seen in AML patients only,
accounting for 66.7\% of deaths\textsuperscript{17}. In our study,
deaths in COVID 19 positive patients as compared to COVID 19 negative
patients was statistically significant Primarily deaths occurred to AML
patients with COVID-19 positive status and they were treated with
intensive chemotherapy regimen and during course of time after both AML
patients expired all subsequent AML patients regardless of COVID status
were treated with adequate isolation.

Our study may have certain limitations owing to retrospective study
design. Our patient sample size may be not very large but it is very
well comparable with reference to earlier published COVID-19 studies in
childhood cancer patients. We were not able to perform COVID-19 related
inflammatory markers, chest radiography, computed tomography scan for
all COVID-19 positive patients in our setting as ours is not designate
COVID hospital as per government guidelines. All COVID-19 positive
patients with immediate intensive medical requirement were transferred
on priority basis to designate COVID-19 hospital ICU.

\textbf{CONCLUSION}

We would like to conclude from our present study observation that in
pediatric cancer patients of North-East India COVID-19 positivity was
significantly high in symptomatic patients compared to asymptomatic
patients. Among COVID-19 positive childhood cancer patients risk of
death was significantly higher compared to COVID-19 negative patients.
To validate our current observation future studies with larger sample
size need to be done.

\textbf{Conflict of interest} : All the authors declare that there is no
conflict of interest

\textbf{Acknowledgement:} We acknowledge cooperation of the pediatric
cancer patients. We also thank National Health Mission, Government of
assam for providing COVID-19 RT-PCR testing consumables and equipment.

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