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\begin{document}

\title{INITIAL REPORT ON SPANISH PEDIATRIC ONCOLOGIC, HEMATOLOGIC AND POST STEM
CELL TRANSPLANTATION PATIENTS DURING SARS-COV-2 PANDEMIC}



\author[1]{Anna Faura Morros}%
\author[2]{Susana  Rives Solà}%
\author[3]{ALVARO LASSALETTA}%
\author[4]{Elena Sebastián}%
\author[3]{Luis Madero}%
\author[5]{Jorge Huerta Aragonés}%
\author[6]{Marina García-Morin}%
\author[7]{Antonio Perez Martinez}%
\author[7]{Luisa Sisinni}%
\author[8]{Itziar Astigarraga}%
\author[9]{Pablo Velasco}%
\author[9]{Luis Gros}%
\author[10]{Lucas Moreno}%
\author[11]{Ana Carboné}%
\author[11]{Carmen Rodriguez-Vigil}%
\author[12]{Susana Riesco}%
\author[12]{Maria del Carmen Mendoza Sanchez}%
\author[13]{Elena Garcia Macias}%
\author[14]{Maria Trabazo}%
\author[14]{Montserrat Torrent}%
\author[14]{Isabel Badell}%
\author[15]{José Luis Fuster Soler}%
\author[16]{Nerea Domínguez-Pinilla}%
\author[17]{Antonio Juan Ribelles}%
\author[18]{Vanesa Pérez-Alonso}%
\author[19]{Manuel Fernández Sanmartin}%
\author[20]{Marta Baragaño}%
\author[2]{Maite Gorostegui}%
\author[2]{Sara Perez-Jaume}%
\author[21]{Ana Fernández-Teijeiro}%
\author[1]{Andres Morales La Madrid}%
\author[1]{Jose Luis Dapena}%
\affil[1]{Hospital Sant Joan de Déu}%
\affil[2]{Hospital Sant Joan de Deu}%
\affil[3]{Hospital Infantil Universitario Niño Jesús}%
\affil[4]{Hospital Infantil Universitario Nino Jesus}%
\affil[5]{Hospital General Universitario Gregorio Marañón}%
\affil[6]{Hospital General Universitario Gregorio Maranon}%
\affil[7]{Hospital Universitario La Paz}%
\affil[8]{Hospital Universitario Cruces, Biocruces Bizkaia Health Research Institute, UPV/EHU}%
\affil[9]{Hospital Universitari Vall d'Hebron}%
\affil[10]{Vall d'Hebron Hospital}%
\affil[11]{Hospital Universitario Miguel Servet}%
\affil[12]{Hospital Clínico de Salamanca}%
\affil[13]{Hospital Universitario Son Espases}%
\affil[14]{Hospital de la Santa Creu i Sant Pau}%
\affil[15]{Hospital Clinico Universitario Virgen de la Arrixaca}%
\affil[16]{Hospital Virgen de la Salud }%
\affil[17]{Hospital La Fe}%
\affil[18]{Hospital Universitario 12 de Octubre}%
\affil[19]{Hospital Clinico Universitario de Santiago de Compostela}%
\affil[20]{Hospital Quirón Madrid}%
\affil[21]{Complejo Hospitalario Virgen de la Macarena}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background: Since the beginning of SARS-CoV-2 pandemic, it has been
widely recognized that children and adolescents seem to have milder
clinical courses as compared to adult counterparts. However, there is
concern that vulnerable collectives including pediatric patients treated
for cancer or under immunosuppression may be at higher risk. Methods: We
retrospectively collected Spanish COVID-19 cases in children and
adolescents with solid and hematological malignancies, non-malignant
chronic hematologic conditions, and post allogeneic-stem cell
transplantation, from the beginning of the pandemic on January 31 to
April 24, 2020. Results: We included 47 cases with RT-PCR positive
COVID-19 from 41 centers in Spain, where 97.6\% of pediatric patients
are treated for cancer. In most cases (76.6\%), infection was
asymptomatic, or symptoms were mild. Severe illness was observed in
14.9\% of cases with respiratory distress and/or hypoxemia, and 8.5\%
required admission to the PICU. Symptomatic patients received supportive
care associated with antiviral and immunomodulatory agents depending
upon severity. Anticancer therapy was withhold in the majority of cases
during the infection course. Most patients recovered from COVID-19. Two
deaths were reported. Conclusion: In our cohort, most children receiving
anticancer chemotherapy presented a mild clinical course and had a good
outcome. Highly immunosuppressed patients with major comorbidities were
at higher risk of severe infections. Among this fragile collective,
individualized expert discussion is critical for anti-infectious therapy
and appropriate anticancer treatment.%
\end{abstract}%



\sloppy


\textbf{INITIAL REPORT ON SPANISH PEDIATRIC ONCOLOGIC, HEMATOLOGIC AND
POST STEM CELL TRANSPLANTATION PATIENTS DURING SARS-COV-2 PANDEMIC}

\textbf{A short running title:} Spanish immunosuppressed children and
SARS-COV-2

Faura A\textsuperscript{1}. Rives S\textsuperscript{1}. Lassaletta
A\textsuperscript{2}. Sebasti\selectlanguage{ngerman}án E\textsuperscript{2}. Madero
L\textsuperscript{2}. Huerta J\textsuperscript{3}. García-Morín
M\textsuperscript{3}. Pérez A\textsuperscript{4}.~Sisinni
L\textsuperscript{4}.~Astigarraga I\textsuperscript{5}. Velasco
P\textsuperscript{6}.~Gros L\textsuperscript{6}. Moreno
L\textsuperscript{6} Carboné A\textsuperscript{7}.~Rodríguez-Vigil
C\textsuperscript{7}. Riesco S\textsuperscript{8}. Mendoza
MC\textsuperscript{8}. García E\textsuperscript{9}. Trabazo
M\textsuperscript{10}.~Torrent M\textsuperscript{10}. Badell
I\textsuperscript{10}.~ Fuster JL\textsuperscript{11}. Dominguez
N\textsuperscript{12}. Juan Ribelles A\textsuperscript{13}. Pérez
V\textsuperscript{14}. Fernández Sanmartín
M\textsuperscript{15.}Baragaño M\textsuperscript{16}. Gorostegui
M\textsuperscript{1}. Perez-Jaume S\textsuperscript{1,18}.
Fernández-Teijeiro A\textsuperscript{16}. Morales La Madrid
A\textsuperscript{1*}. Dapena JL\textsuperscript{1}.

\begin{enumerate}
\tightlist
\item
  Pediatric Oncology and Hematology Department. Hospital Sant Joan de
  Deu, Spain.
\item
  Pediatric Hematology-Oncology Department. Hospital Universitario Niño
  Jesús. Madrid. Spain
\item
  Pediatric Hematology-Oncology Department. Hospital Materno-Infantil
  Gregorio Marañón. Madrid. Spain
\item
  Pediatric Hemato-Oncology~Department. Hospital Universitario La Paz.
  Madrid. Spain
\item
  Department of Pediatrics, BioCruces Bizkaia Health Research Institute,
  Hospital Universitario Cruces, University of the Basque Country
  UPV/EHU, Barakaldo, Spain.
\item
  Pediatric Oncology and Hematology. Vall~d'Hebron Barcelona Hospital
  Campus. Spain
\item
  Pediatric Hemato-Oncology~Department. Hospital Universitario Miguel
  Servet. Zaragoza. Spain
\item
  Pediatric Hemato-Oncology~Department. Hospital Clínico Universitario.
  Salamanca. Spain
\item
  Pediatric Hemato-Oncology~Department. Hospital Universitario Son
  Espases. Mallorca. Spain
\item
  Pediatric Oncology and Hematology Department. Hospital de la Santa
  Creu i Sant Pau. Barcelona. Spain.
\item
  Pediatric Oncology and Hematology Department. Hospital Clínico
  Universitario Virgen de la Arrixaca, Instituto Murciano de
  Investigación Biosanitaria (IMIB). Murcia. Spain
\item
  Pediatric Oncology and Hematology Department.~Hospital Virgen de la
  Salud. Toledo. Spain.
\item
  Pediatric Oncology and Hematology Unit. Hospital Universitario La Fe.
  La Valencia, Spain
\item
  Pediatric Oncology and Hematology Department. Hospital Universitario
  12 de Octubre. Madrid. Spain.
\item
  Pediatric Oncology and Hematology Department. Hospital Clinico
  Universitario de Santiago de Compostela. Spain
\item
  Pediatric Oncology and Hematology Department. Hospital Universitario
  Quiron Salud. Madrid. Spain
\item
  Pediatric Oncology Unit, Hospitales Universitarios Virgen Macarena y
  Virgen del Rocio, Sevilla, Spain.
\item
  Developmental Tumor Biology Laboratory, Institut de Recerca Sant Joan
  de Déu, Esplugues de Llobregat, Spain
\end{enumerate}

*Corresponding author:

Andres Morales La Madrid, MD MHM

Pediatric Neuro-Oncology, Department of Pediatric Hematology and
Oncology

Hospital Sant Joan de Deu

Passeig Sant Joan de Deu 2, 08950. Barcelona, Spain

Email: amorales@sjdhospitalbarcelona.org

\textbf{Text word count:} 2493

\textbf{Abstract word count:} 224

\textbf{Brief running title:} COVID-19 in oncologic children with
immunosuppression

\textbf{Keywords:} COVID-19, SARS-CoV-2, pandemic, children, cancer and
immunosuppression

\textbf{Tables:} 1

\textbf{Figures:} 0

\textbf{Legends:} 1\selectlanguage{english}
\begin{longtable}[]{@{}ll@{}}
\toprule
\textbf{Abbreviations} &\tabularnewline
\midrule
\endhead
B-ALL & Precursor B-cell acute lymphoblastic leukemia\tabularnewline
CAR-T & Chimeric Antigen Receptor T-Cell\tabularnewline
COVID-19 & Coronavirus disease 2019\tabularnewline
CT & Computerized tomography\tabularnewline
HCoV & Human coronavirus\tabularnewline
HLH & Hemophagocytic lymphohistiocytosis\tabularnewline
ICU & Intensive Care Unit\tabularnewline
PICU & Pediatric Intensive Care Unit\tabularnewline
GVHD & Graft-versus-host disease\tabularnewline
MAS & Macrophage activation syndrome\tabularnewline
NR & Normal range\tabularnewline
PHO & Pediatric hemato-oncology\tabularnewline
RETI-SEHOP & Registro Espa\selectlanguage{ngerman}ñol de Tumores Infantiles- Sociedad Española
de Hematología y Oncología\tabularnewline
RT-PCR & Reverse transcription polymerase chain reaction\tabularnewline
SARS-CoV-2 & Severe acute respiratory syndrome coronavirus
2\tabularnewline
SCT & Stem-cell transplantation\tabularnewline
SEHOP & Sociedad Espa\selectlanguage{ngerman}ñola de Hematología y Oncologia\tabularnewline
ECMO & ExtraCorporeal Membrane Oxygenation\tabularnewline
\bottomrule
\end{longtable}

\textbf{Background} : Since the beginning of SARS-CoV-2 pandemic, it has
been widely recognized that children and adolescents seem to have milder
clinical courses as compared to adult counterparts. However, there is
concern that vulnerable collectives including pediatric patients treated
for cancer or under immunosuppression may be at higher risk.

\textbf{Methods} : We retrospectively collected Spanish COVID-19 cases
in children and adolescents with solid and hematological malignancies,
non-malignant chronic hematologic conditions, and post allogeneic-stem
cell transplantation, from the beginning of the pandemic on January 31
to April 24, 2020.

\textbf{Results} : We included 47 cases with RT-PCR positive COVID-19
from 41 centers in Spain, where 97.6\% of pediatric patients are treated
for cancer. In most cases (76.6\%), infection was asymptomatic, or
symptoms were mild. Severe illness was observed in 14.9\% of cases with
respiratory distress and/or hypoxemia, and 8.5\% required admission to
the PICU. Symptomatic patients received supportive care associated with
antiviral and immunomodulatory agents depending upon severity.
Anticancer therapy was withhold in the majority of cases during the
infection course. Most patients recovered from COVID-19. Two deaths were
reported.

\textbf{Conclusion} : In our cohort, most children receiving anticancer
chemotherapy presented a mild clinical course and had a good outcome.
Highly immunosuppressed patients with major comorbidities were at higher
risk of severe infections. Among this fragile collective, individualized
expert discussion is critical for anti-infectious therapy and
appropriate anticancer treatment.

\textbf{Background}

In December 2019, the new coronavirus SARS-CoV-2 outbreak started in
Wuhan, China and rapidly progressed into a pandemic\textsuperscript{1}.
Europe was its next stop and Spain (first case reported on January 31,
2020) was one of the first countries registering alarming increasing
numbers of both confirmed cases and deaths. As of April 24, 2020, while
our health care system was struggling to expand fully, mostly with adult
wards and intensive care unit (ICU) beds, 202 990 cases had been tested
positive and 22 524 deaths were reported in the country due to COVID-19.

As widely reported, the clinical presentation of COVID-19 is
heterogeneous, ranging from asymptomatic or pauci-symptomatic cases to
severe forms, with an overall small percentage of patients developing
respiratory insufficiency and requiring admission in the ICU. The severe
forms were observed more frequently in male adults older than 65 years
with certain comorbidities like diabetes, hypertension, cardiac and
pulmonary conditions, and obesity\textsuperscript{2}. In contrast, a
number of reported series show that pediatric patients rarely develop
critical illness\textsuperscript{3,4}. The reasons underlying this
significant disparity in clinical presentation and outcome is still a
matter of debate. In Spain, from all SARS-CoV-2 confirmed positive
cases, the pediatric population (cases under the age of 19) represented
only 0.9\%. Furthermore, only 2.8\% of these cases required pediatric
intensive care unit (PICU) admission with a mortality rate of around
0.3\%\textsuperscript{5}. Children diagnosed with cancer receiving
immunosuppressive chemotherapy and cellular therapies have typically
significant abnormalities in immune function. Additionally, these
abnormalities may persist for months or years and puts them at a higher
risk for opportunistic viral --\emph{among other} - infections. To this
date, reports describing the clinical and epidemiological
characteristics as well as outcomes in pediatric patients with cancer
and/or under immunosuppression secondary to allogeneic-stem cell
transplantation, or CART cell therapy acquiring the COVID-19 are scarce.
A flash survey performed on March 16, 2020 on SARS secondary to
SARS-CoV-2 infections in pediatric patients with anticancer treatment
was recently published, identifying only 9 patients (among 10,000
patients at risk) from several countries in Europe who presented a mild
or asymptomatic course\textsuperscript{6}. Understandably, a reasonable
fear exists that SARS-CoV-2, like other
coronaviruses\textsuperscript{7}, could cause more severe infections in
immunocompromised children, as has been observed in
adults\textsuperscript{8}, especially in patients with hematological
cancer were the highest severity index and death rate have been
published\textsuperscript{9}.

In this report, we present the initial Spanish experience with COVID-19
in pediatric patients affected with cancer, hematologic conditions, and
post allogeneic stem cell transplantation since the beginning of this
pandemic.

\textbf{Patients and methods}

We surveyed all 43 Spanish institutions treating pediatric cases (1
month - 18 years of age), with solid and hematologic malignancies,
non-malignant hematologic conditions (those receiving immunosuppressive
treatment or bone marrow failure syndrome) and after allogeneic-stem
cell transplantation, or CAR-T cell therapy who were diagnosed with
COVID-19 from the start of the SARS-CoV-2 pandemic on January 31 to
April 24, 2020. This is a collaborative SEHOP initiative. Demographic
and clinical data were collected from medical records.

This study was approved by the Hospital Sant Joan de D\selectlanguage{ngerman}éu Research
Ethical Committee.

Definitions: Symptoms severity was classified using the WHO
criteria\textsuperscript{10}: Asymptomatic infection, mild-moderate
(presence of fever, symptoms of upper respiratory tract infection,
pneumonia without the need for respiratory support), severe (dyspnea,
tachypnea, blood oxygen saturation \selectlanguage{english}[?]93\%), critical (respiratory
failure, septic shock, and / or multiple organ dysfunction / failure).
Pneumonia was diagnosed in those cases with lung field infiltrates
identified in chest imaging and was considered bilateral when
\textgreater{} 1 lobe on each lung were affected.

Statistical Analysis : Qualitative variables were described using
absolute frequencies and percentages. Quantitative variables that can be
assumed to be normally distributed were described using mean and
standard deviation, whereas non-normal quantitative variables were
described using the median. To compare quantitative variables among
groups we used the Mann-Whitney test. All the analyses were performed
using R version 3.6.2.

\textbf{Results}

Information of SARS-CoV-2 positive cases was received from 41 hospitals.
According to the Spanish Pediatric Cancer Registry (RETI-SEHOP), these
centers are responsible for the treatment of 97.6\% of pediatric cancer
patients in Spain. As to non-malignant hematological cases, no global
database is available due to the heterogeneity of the different
diseases, but the sample seems to be representative because these
chronic diseases are treated in the same Pediatric and Oncology Units.

Demographic data, underlying diagnosis, clinical features, therapy
received and outcome related to RT-PCR confirmed SARS-CoV-2
(nasopharyngeal swab) infection of 47 patients are summarized
in\textbf{Table 1} . The median age of our cohort was 8.2 years, with
male predominance (72.3\%). The majority of cases had leukemia or
lymphoma (51.5\%), followed by patients with solid tumors (29.8\%) as
underlying condition. Seventeen percent of the patients (n=8) had
undergone an allo-stem-cell transplantation (SCT); five of these
secondary to hematological diseases and the rest of them due to severe
primary immunodeficiencies. Six patients with severe non-oncologic
hematologic conditions under immunosuppressive therapy were included in
the study. Three of 47 patients had received CAR T-cell therapy as
salvage regimen for relapsed B-ALL. Regarding clinical impact, the
majority of patients were asymptomatic (25.5\%) or had only mild
symptoms (51.1\%). Fever was the most frequent symptom at presentation
(51.1\%), followed by cough and rhinorrhea (40.4\%). A minority of cases
presented diarrhea (4.2\%) and only two patients presented some type of
cutaneous manifestation (1 case with rash, 1 case with purpuric
lesions). Radiologic abnormalities (mostly by chest-X-ray, 3 CT scans
performed in critical patients) consisting in pneumonia were observed in
32.4\% of the patients. The percentage of children who required
hospitalization was 76.6\% (n=32). However, 12 of them were already
admitted when COVID-19 diagnosis was made: One due to febrile
neutropenia, five for cancer treatment, 2 post-SCT, 4 not reported).
Severe illness with respiratory distress and/or hypoxemia was identified
in 11 patients. Four of them, all males, evolved to critical illness
with progressive respiratory failure requiring admission to the PICU
(8.5\% of all patients).

The clinical course of the 4 critically-ill COVID-19 patients is
summarized below:

Case 1: A 16-year-old male undergoing myelosuppressive chemotherapy for
primary mediastinal large B-cell lymphoma admitted initially for severe
neutropenia and pancreatitis. He developed pneumonia requiring cannula
oxygen therapy; recovering soon after. Case 2 was an 8-year-old boy
admitted post-SCT due to a primary immunodeficiency with
graft-versus-host disease (GVHD), who presented with bilateral pneumonia
requiring mechanical ventilation and ECMO. The patient presented a
torpid clinical evolution and deceased. Case 3, 18 year-old male on
therapy for an Ewing-like round cell sarcoma, with initial fever and
cough. Thereafter he developed respiratory worsening with new bilateral
infiltrates and respiratory failure, needing high flow oxygen therapy,
with a favorable clinical outcome. Case 4 was an 11-year-old boy,
diagnosed with relapsed B-ALL in third complete remission after CART
cell therapy followed by unrelated allo-SCT. At the time of COVID-19
diagnosis, 15 months after allo-SCT, he presented an extensive chronic
GVHD and poor engraftment that required several immunosuppressors. He
presented initially with fever, cough, and unilateral pneumonia. Few
days later developed dyspnea and hypoxemia, requiring increasing
respiratory support with non-invasive ventilation and mechanical
ventilation. He also developed secondary HLH, with altered coagulation,
hypertriglyceridemia, hypoalbuminemia, and ferritin levels that raised
up to 124 000 ug/L (NR 10-120ug/L). Moreover, D-Dimer and IL-6 raised up
to 2.02 mg/dL (NR \textless{}0,5mg/dl) and 394 pg/mL (NR \textless{}
5pg/ml), respectively. Finally, the patient died secondary to a
pulmonary hemorrhage and multiorgan failure. Regarding relevant abnormal
laboratory findings, critically ill patients presented in a higher
frequency with severe lymphopenia (medians: 85 vs 1000, p=0.0034) and
higher ferritin levels at the onset of symptoms (medians: 6666.5 ng/ml
vs 1037 ng/ml, p=0.027). The maximum ferritin level was also
significantly superior in critical patients admitted to the PICU in
comparison to the other cases (medians: 23 077 ng/ml vs 1507.5 ng/ml,
p\textless{}0.001). No statistically significant differences were
observed in the absolute number of neutrophils and LDH. The time from
clinical onset to first negative RT-PCR results was not available for
all patients, but in some of them, RT-PCR remained positive after 7
weeks. Asymptomatic/mild cases (44.6\%) did not received any therapy.
Twenty-three patients received hydroxychloroquine (9 patients combined
with azithromycin), followed by antivirals (19.1\%) and corticosteroids
(6.4\%). Six patients received monoclonal antibodies against IL1/IL6.
Anti-cancer therapy was interrupted in 57.9\% of the cases. Prophylactic
anticoagulation was administered to five patients (10.6\%) with no
thromboembolic events diagnosed. Outcome was overall good, with most
symptomatic patients recovering back to baseline clinical situation. Two
deaths were reported in the post allo-SCT subgroup.

\textbf{Discussion}

Respiratory viral infections in immunosuppressed patients usually
present a more severe clinical evolution, longer viral excretion,
several pulmonary complications, and a higher mortality
rate\textsuperscript{11}. In the specific case of HCoV, a study
published by Ogimi et al\textsuperscript{12} observed an association
between the immunocompromised state and an increased risk of serious
virus-related lower respiratory tract disease. During the period of data
collection for this report, Spain was the second most affected country
by the SARS-CoV-2 pandemic. In our country, around 1,300 children and
adolescents are diagnosed with cancer every day (155.5 new cases
annually per million children aged 0-14 years, similarly to other
European countries)\textsuperscript{13}. This report includes almost all
Spanish centers with Pediatric hemato-oncology (PHO) units, providing a
significative representation of the current situation in the country
from the beginning of the pandemic. Thereafter, including only cancer
diagnosis we observed a COVID-19 infection rate of approximately 2.5 \%
among this patient population over the first 3 months of the pandemic.
As expected, most of the reported patients (68\%) were from the States
of Madrid and Catalonia, the two most affected areas in Spain by
SARS-CoV-2\textsuperscript{14}. Fifteen of the patients included in the
present study were previously reported in the Madrid cohort recently
published by de Rojas et al\textsuperscript{15}. Initial experiences
from Italy (Lombardy)\textsuperscript{16}, China
(Wuhan)\textsuperscript{17,18} and Europe suggest a low number and
severity of COVID-19 cases in pediatric patients with oncologic,
hematologic, or post allo-SCT diseases\textsuperscript{6}. However, a
recently published study in France, observed a higher incidence of
critical patients, as 5 out of the 33 included patients were admitted to
the PICU\textsuperscript{19}. In addition, as the pandemic develops, and
with a higher availability for viral testing, our study shows that we
may expect an increasing number of reported cases in the literature. Our
series represents a good initial ``snapshot'' of the Spanish number of
cases and severity in the midst of the peak of SARS-CoV-2 cases within
the country.

Data from China's nationwide case series of 2135 pediatric patients with
COVID-19 observed that more than 90\% of all patients had asymptomatic,
mild, or moderate cases\textsuperscript{3}. In our series, most of the
cases remained asymptomatic (25\%) or with mild symptoms (51.1\%).
However, severe and critical cases comprised 23.4\%, higher than the
3-10.6\% described in the previously healthy Chinese pediatric
population (according to age range)\textsuperscript{3}. Most of our
patients who presented lower respiratory tract symptoms developed
dyspnea and/or hypoxemia, were managed successfully in the ward with
good clinical outcome. The proportion of infected children requiring
intensive care management was 8.5\%, a higher percentage compared to
that observed in the general pediatric population\textsuperscript{20}.
Of note, all four patients were either receiving intensive chemotherapy
or severely immunosuppressed post allo-SCT. Noteworthy, laboratory
abnormalities accompanying more severe forms of infection and admission
to the PICU identified as surrogate markers low total lymphocyte count
and high ferritin levels at onset of symptoms. One of the deaths in the
post allo-SCT subgroup was probably related to an uncontrolled systemic
inflammatory response that closely resembled that of secondary
hemophagocytic lymphohistiocytosis (sHLH) or macrophage activation
syndrome (MAS), as it has been described in other severe COVID-19
patients\textsuperscript{21}. SARS-CoV-2 infection seems to trigger a
cytokine storm and hyper-activation of the immune response, with
consequent multiple organ damage. In this cohort of patients, no
diagnosis of Kawasaki disease or toxic syndrome were observed as
described elsewhere\textsuperscript{22}.

Regarding therapy, hydroxychloroquine and antivirals
(lopinavir/ritonavir, remdesivir, and oseltamivir) were used mainly in
early stages\textsuperscript{23}. In those with a more aggressive
disease and/or hyperinflammation component, immunomodulatory treatments
similar to those used in the cytokine release syndrome associated with
CART therapy (\emph{i.e} . tocilizumab, siltuximab, anakinra,
corticosteroids) were administered\textsuperscript{24}. Clear
recommendations of anti-viral therapy, immunomodulation, and of an
effective vaccine are not available yet, but hopefully they will be
stablished soon after the ongoing basic and clinical trials
progress\textsuperscript{25}. According to our data, most patients will
have a good outcome with supportive care. However, it may be postulated
that patients receiving intensive chemotherapy, severely
immunosuppressed, or GVHD may be at a higher risk of morbidity and even
mortality secondary to COVID-19.

There is also the concern that during this pandemic, children with
cancer may have an incremented risk of presenting a poor prognosis for
their disease, due to late diagnosis and not appropriate
treatment\textsuperscript{26-27}. In this respect, half of the patients
included in our cohort had interrupted their anticancer directed
treatment for a number of days due to the concomitant infection. Larger
series of cases and longer follow up information will be needed to
understand its real impact. However, it is not infrequent that
chemotherapy regimens have to be stopped during opportunistic infections
in patients undergoing immunosuppression. Recent guidelines published
from SIOP, COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude Global
for children with cancer recommend that the standards of care for the
diagnosis, treatment and supportive care should not be compromised or
electively modified during the pandemic, if at all
possible\textsuperscript{28}. In this line and based on our experience,
we recommend individualized multidisciplinary discussions whenever a
COVID-19 case is identified. A number of variables including the
underlying condition, stage of disease, prognosis and clinical infection
related impact should be taking into consideration for interrupting or
delaying anti-cancer therapy.

Limitations of this report include the small sample size, which limits
the extrapolation of results to the general hemato-oncological pediatric
population. Moreover, the data was collected both retrospectively and
prospectively. Thus, it may be a limitation when reporting disease
evolution and other time-dependent factors. Finally, as the present
study is multicentric and data was collected from different hospitals
around the country, a potential interindividual variability may exist
when reporting the different clinical scenarios. However, since most of
the physicians of the Spanish Units of PHO took part in this initiative,
we believe our report represents an accurate infection prevalence among
children diagnosed with cancer and chronic hematological disorders in
our country.

This is one of the largest series of COVID-19 in pediatric cases with
solid and hematological malignancies, benign hematologic conditions, and
post allo-SCT reported during the present pandemic. Recent publications
based on a low number of cases seem to suggest that immunosuppressed
pediatric patients do not present an increased risk of developing severe
SARS-CoV-2 infection\textsuperscript{616} Our results show that the
clinical course of most patients is overall good. However, severe forms
of infection can be seen in highly immunosuppressed patients or in those
with chronic co-morbidities such as GVHD, or patients receiving CART
cell therapy. International collaborative groups' series cases will
surely be published soon in order to better establish the real impact of
this infection in our vulnerable pediatric population.

\textbf{Conflict of Interest}

The authors disclose no conflict of interest.

This research did not receive any specific grant from funding agencies
in the public, commercial, or not-for-profit sectors.

\textbf{Authors' contributions:} AF, JLD, SR and AML were involved in
designing the study. All authors were involved with patient accrual and
data collection. SPJ was the statistician of the study. AF, JLD, SPJ, SR
and AML were involved with data interpretation. All authors contributed
to the manuscript editing and approved the final manuscript.

AML and JLD contributed equally to this work.

\textbf{Acknowledgements}

\selectlanguage{english}\textbf{} We thank all SEHOP contributing members for rapidly sharing
their experience during the SARS-CoV-19 pandemic. We also would like to
acknowledge all healthcare providers fighting this terrible crisis.



\textbf{References}

1. Li Q, Guan X, Wu P, et al. Early transmission dynamics in Wuhan,
China, of novel coronavirus-infected pneumonia. \emph{N Engl J Med} .
2020;382(13):1199-1207. doi:10.1056/NEJMoa2001316

2. Cevik M, Bamford C, Ho A. COVID-19 pandemic -- A focused review for
clinicians. \emph{Clin Microbiol Infect} . 2020.
doi:10.1016/j.cmi.2020.04.023

3. Dong Y, Mo X, Hu Y, et al. Epidemiological Characteristics of 2143
Pediatric Patients With 2019 Coronavirus Disease in
China.\emph{Pediatrics} . 2020;145(6):e20200702.
doi:10.1542/peds.2020-0702

4. Coronavirus Disease 2019 in Children - United States, February
12-April 2, 2020. \emph{MMWR Morb Mortal Wkly Rep} .
2020;69(14):422-426. doi:10.15585/mmwr.mm6914e4

5. Centro de Coordinaci\selectlanguage{ngerman}ón Alertas y Emergencias Sanitarias del Gobierno
de España. Actualización n\textsuperscript{o} 50. Enfermedad por el
coronavirus (COVID-19). 20.03.2020.
https://www.mscbs.gob.es/profesionales/saludPublica/ccayes/alertasActual/nCov-China/documentos/Actualizacion\_50\_COVID-19.pdf.
Published 2020. Accessed April 27, 2020.

6. Hrusak O, Kalina T, Wolf J, et al. Flash survey on severe acute
respiratory syndrome coronavirus-2 infections in paediatric patients on
anticancer treatment. \emph{Eur J Cancer} . 2020;132:11-16.
doi:10.1016/j.ejca.2020.03.021

7. Hirsch HH, Martino R, Ward KN, Boeckh M, Einsele H, Ljungman P.
Fourth European conference on infections in leukaemia (ECIL-4):
Guidelines for diagnosis and treatment of human respiratory syncytial
virus, parainfluenza virus, metapneumovirus, rhinovirus, and
coronavirus. \emph{Clin Infect Dis} . 2013. doi:10.1093/cid/cis844

8. Liang W, Guan W, Chen R, et al. Cancer patients in SARS-CoV-2
infection: a nationwide analysis in China. \emph{Lancet Oncol} .
2020;21(3):335-337. doi:10.1016/S1470-2045(20)30096-6

9. Dai M-Y, Liu D, Liu M, et al. Patients with Cancer Appear More
Vulnerable to SARS-CoV-2: A Multi-Center Study During the COVID-19
Outbreak. \emph{SSRN Electron J} . 2020. doi:10.2139/ssrn.3558017

10. Aylward, Bruce (WHO); Liang W (PRC). \emph{Report of the WHO-China
Joint Mission on Coronavirus Disease 2019 (COVID-19)} .; 2020.

11. von Lilienfeld-Toal M, Berger A, Christopeit M, et al. Community
acquired respiratory virus infections in cancer patients---Guideline on
diagnosis and management by the Infectious Diseases Working Party~of the
German Society for haematology and Medical Oncology. \emph{Eur J Cancer}
. 2016. doi:10.1016/j.ejca.2016.08.015

12. Ogimi C, Englund JA, Bradford MC, Qin X, Boeckh M, Waghmare A.
Characteristics and outcomes of coronavirus infection in children: The
role of viral factors and an immunocompromised state. \emph{J Pediatric
Infect Dis Soc} . 2019;8(1):21-28. doi:10.1093/jpids/pix093

13. Bonet RP, Romaguera EP, Poveda SV. Registro Español de Tumores
Infantiles Estadísticas Cáncer infantil en España cohortes. \emph{Minist
Sanidad, Serv Soc e Igual} . 2019. https://www.uv.es/rnti/informes.html.

14. Centro Nacional de Epidemiología. Distribución geográfica de los
casos totales y los casos de las últimas 24h (obtenidos a partir de la
declaración agregada de casos del Ministerio de Sanidad).
https://cnecovid.isciii.es/covid19/. Accessed May 13, 2020.

15. de Rojas T, Pérez-Martínez A, Cela E, et al. COVID-19 infection in
children and adolescents with cancer in Madrid. \emph{Pediatr Blood
Cancer} . 2020;(April):e28397. doi:10.1002/pbc.28397

16. D'Antiga L. Coronaviruses and immunosuppressed patients. The facts
during the third epidemic. \emph{Liver Transpl} . 2020:0-1.
doi:10.1002/lt.25756

17. Lu X, Zhang L, Du H, et al. SARS-CoV-2 Infection in Children.\emph{N
Engl J Med} . 2020. doi:10.1056/NEJMc2005073

18. Chen Z, Xiong H, Li JX, et al. COVID-19 with post-chemotherapy
agranulocytosis in childhood acute leukemia: a case
report.\emph{Zhonghua Xue Ye Xue Za Zhi} . 2020.
doi:10.3760/cma.j.issn.0253-2727.2020.0004

19. André N, Rouger-Gaudichon J, Brethon B, et al. COVID-19 in pediatric
oncology from French pediatric oncology and hematology centers: High
risk of severe forms? \emph{Pediatr Blood Cancer} . 2020;(April):e28392.
doi:10.1002/pbc.28392

20. Ludvigsson JF. Systematic review of COVID-19 in children shows
milder cases and a better prognosis than adults. \emph{Acta Paediatr Int
J Paediatr} . 2020. doi:10.1111/apa.15270

21. Mehta P, McAuley DF, Brown M, Sanchez E, Tattersall RS, Manson JJ.
COVID-19: consider cytokine storm syndromes and
immunosuppression.\emph{Lancet} . 2020;395(10229):1033-1034.
doi:10.1016/S0140-6736(20)30628-0

22. Harahsheh AS, Dahdah N, Newburger JW, et al. Missed or Delayed
Diagnosis of Kawasaki Disease During the 2019 Novel Coronavirus Disease
(COVID-19) Pandemic. \emph{J Pediatr} . April
2020:S0022-3476(20)30556-4. doi:10.1016/j.jpeds.2020.04.052

23. Sankar J, Dhochak N, Kabra SK, Lodha R. COVID-19 in Children:
Clinical Approach and Management. \emph{Indian J Pediatr} . 2020.
doi:10.1007/s12098-020-03292-1

24. Ye Q, Wang B, Mao J. The pathogenesis and treatment of the `Cytokine
Storm'' in COVID-19.' \emph{J Infect} . 2020.
doi:10.1016/j.jinf.2020.03.037

25. Chiotos K, Hayes M, Kimberlin DW, et al. Multicenter initial
guidance on use of antivirals for children with
COVID-19/SARS-CoV-2.\emph{J Pediatric Infect Dis Soc} . 2020.
doi:10.1093/jpids/piaa045

26. Yang C, Li C, Wang S. Clinical strategies for treating pediatric
cancer during the outbreak of 2019 novel coronavirus
infection.\emph{Pediatr Blood Cancer} . 2020;67(5):1-2.
doi:10.1002/pbc.28248

27. Balduzzi A, Brivio E, Rovelli A, et al. Lessons After the Early
Management of the COVID-19 Outbreak in a Pediatric Transplant and
Hemato-Oncology Center Embedded within a COVID-19 Dedicated Hospital in
Lombardia, Italy. \emph{Estote Parati.} (Be Ready.). \emph{SSRN Electron
J} . 2020. doi:10.2139/ssrn.3559560

28. Sullivan M, Bouffet E, Rodriguez-Galindo C, et al. The COVID-19
pandemic: A rapid global response for children with cancer from SIOP,
COG, SIOP-E, SIOP-PODC, IPSO, PROS, CCI, and St Jude
Global.\emph{Pediatr Blood Cancer} . April 2020. doi:10.1002/pbc.28409



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\verb`Table 1 PBC.docx`  available at \url{https://authorea.com/users/330911/articles/457718-initial-report-on-spanish-pediatric-oncologic-hematologic-and-post-stem-cell-transplantation-patients-during-sars-cov-2-pandemic}

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