\documentclass[10pt]{article}

\usepackage{fullpage}
\usepackage{setspace}
\usepackage{parskip}
\usepackage{titlesec}
\usepackage[section]{placeins}
\usepackage{xcolor}
\usepackage{breakcites}
\usepackage{lineno}
\usepackage{hyphenat}





\PassOptionsToPackage{hyphens}{url}
\usepackage[colorlinks = true,
            linkcolor = blue,
            urlcolor  = blue,
            citecolor = blue,
            anchorcolor = blue]{hyperref}
\usepackage{etoolbox}
\makeatletter
\patchcmd\@combinedblfloats{\box\@outputbox}{\unvbox\@outputbox}{}{%
  \errmessage{\noexpand\@combinedblfloats could not be patched}%
}%
\makeatother


\usepackage{natbib}




\renewenvironment{abstract}
  {{\bfseries\noindent{\abstractname}\par\nobreak}\footnotesize}
  {\bigskip}

\titlespacing{\section}{0pt}{*3}{*1}
\titlespacing{\subsection}{0pt}{*2}{*0.5}
\titlespacing{\subsubsection}{0pt}{*1.5}{0pt}


\usepackage{authblk}


\usepackage{graphicx}
\usepackage[space]{grffile}
\usepackage{latexsym}
\usepackage{textcomp}
\usepackage{longtable}
\usepackage{tabulary}
\usepackage{booktabs,array,multirow}
\usepackage{amsfonts,amsmath,amssymb}
\providecommand\citet{\cite}
\providecommand\citep{\cite}
\providecommand\citealt{\cite}
% You can conditionalize code for latexml or normal latex using this.
\newif\iflatexml\latexmlfalse
\providecommand{\tightlist}{\setlength{\itemsep}{0pt}\setlength{\parskip}{0pt}}%

\AtBeginDocument{\DeclareGraphicsExtensions{.pdf,.PDF,.eps,.EPS,.png,.PNG,.tif,.TIF,.jpg,.JPG,.jpeg,.JPEG}}

\usepackage[utf8]{inputenc}
\usepackage[T2A]{fontenc}
\usepackage[greek,ngerman,polish,english]{babel}



\usepackage{float}








\begin{document}

\title{Thrombocytosis - a Marker of Disease Severity in Children with Viral
Respiratory Tract Infections}



\author[1]{Sergei Elber-Dorozko}%
\author[1]{Liya Kerem}%
\author[2]{Dana Wolf}%
\author[1]{Shlomit Brodie}%
\author[1]{Yaacov Berkun}%
\author[1]{Rebecca Brooks}%
\author[1]{Oded Breuer}%
\affil[1]{Hadassah Mount Scopus University Hospital}%
\affil[2]{Hadassah University Medical Center}%


\vspace{-1em}



  
  \date{May 17, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
\textbf{Background}: Reactive thrombocytosis (Platelets
\textgreater{}500K/\selectlanguage{greek}μ\selectlanguage{english}l) is estimated between 3-13\% in hospitalized
children and has been associated with RSV infection and younger age. We
aimed to examine the clinical significance of thrombocytosis in children
admitted to the hospital with an influenza-like illness (ILI).
\textbf{Methods}: We performed an analysis of a database of patients
evaluated at our Medical Centers with an ILI between 2009 and 2013. We
included pediatric patients and examined the association between
platelet count, respiratory viral infections, and admission outcomes
(hospital length of stay (LOS) and admission to the pediatric intensive
care unit (PICU() using regression models adjusting for laboratory,
clinical and demographic parameters. \textbf{Results}: Of 19,192 adults
and children in the database, 5,171 children met inclusion criteria
(median age 0.8 years (Interquartile range, 0.2-1.8), 58\% male, median
LOS of 3 days (Interquartile range, 2-5)). Younger age and not the type
of viral infection was associated with a high platelet count
(p\textless{}0.001). Elevated platelet count independently predicted
admission outcomes, adjusted for multiple covariates (p[?]0.006).
Furthermore, the presence of thrombocytosis was associated with an
increased risk for a prolonged LOS (odds ratio=1.2 (95\% Confidence
interval=1.1-1.4, p=0.003)) and admission to the PICU (odds ratio=1.5
(95\% Confidence interval =1.1-2.0, p=0.002)). \textbf{Conclusions:} In
children admitted with an ILI, a high platelet count is associated with
younger age and is an independent predictor of hospital LOS and
admission to the PICU. Our results show that platelet count may be used
to improve risk assessment and management decisions in these pediatric
patients.%
\end{abstract}%



\sloppy


\textbf{Thrombocytosis - a Marker of Disease Severity in Children with
Viral Respiratory Tract Infections}

Sergei Elber-Dorozko\textsuperscript{a*} M.D, Liya
Kerem\textsuperscript{a,b*} M.D, Dana Wolf\textsuperscript{c} M.D,
Shlomit Brodie\textsuperscript{a} M.D, Yackov
Berkun\textsuperscript{a}M.D, Rebecca Brooks\textsuperscript{a} M.D,
Oded Breuer\textsuperscript{a,d} M.D

\textbf{Affiliations:} \textsuperscript{a}Department of Pediatrics,
Hadassah Medical Center, and Faculty of Medicine, Hebrew University of
Jerusalem, Israel. \textsuperscript{b}Division of Pediatric
Endocrinology, Hadassah Hebrew University Medical Center, Jerusalem,
Israel. \textsuperscript{c}Clinical Virology Unit, Hadassah Medical
Center, and Faculty of Medicine, Hebrew University of Jerusalem,
Israel.\textsuperscript{d}Pediatric Pulmonology and CF Unit, Department
of Pediatrics, Hadassah Medical Center, and Faculty of Medicine, Hebrew
University of Jerusalem, Israel. (*\emph{Contributed equally as co-first
authors} )

\textbf{Corresponding Author:} Oded Breuer, Pediatric Pulmonology,
Hadassah-Hebrew University Medical Center, 91120 Jerusalem, Israel, Tel:
972-2-5845026, Fax: 972-2-6435897, e-mail: odedbr@hadassah.org.il

\textbf{Co-Authors email address:}

Sergei Elber Dorozko -- sergi@hadassah.org.il

Liya Kerem -- liya.em@gmail.com

Dana Wolf -- danaw@ekmd.huji.ac.il

Shlomit Brodie -- Shlomit@brodienet.com

Yackov Berkun -- berkun@hadassah.org.il

Rebecca Brooks -- RebeccaB@hadassah.org.il

\textbf{Conflict of interest statement:} No conflicts of interest or
competing interests exist for the specified authors.

\textbf{Funding information:} The project was supported by internal
departmental funds.

\textbf{Ethical statement:} The planning, conduct, and reporting of
human research reported in this manuscript are in accordance with the
Helsinki Declaration as revised in 2013. Institutional review board
approved the study (HMO-16-0323).

\textbf{Prior presentation of data:} An abstract of this paper was
presented as a poster in the European Respiratory Society international
conference of August 2022. There are no other publications or
submissions with any overlapping information, including studies and
patients.

\textbf{Author Contributions:}

Dr. Sergei Elber-Dorozko -- Conceptualization, formal analysis, writing
-- original draft preparation and reviewing and editing and
visualization.

Dr. Liya Kerem -- Conceptualization, investigation, formal analysis, and
writing -- reviewing and editing.

Prof. Dana Wolf -- Investigation, and writing -- reviewing and editing.

Dr. Shlomit Brodie -- Conceptualization.

Prof. Yackov Berkun and Dr. Rebecca Brooks -- Supervision, and writing
-- reviewing and editing.

Dr. Oded Breuer -- Conceptualization, formal analysis, data curation,
supervision, and writing -- reviewing and editing.

\textbf{Key words:} Admission outcomes; Influenza Like Illness;
Platelets; Respiratory Syncytial Virus;

\textbf{Short title:} Thrombocytosis in influenza like illness

\textbf{Abbreviations:}

CI -- confidence interval

HMPV -- Human metapneumovirus

ILI -- Influenza like illness

IQR -- Interquartile range

LOS -- Length of stay

PICU -- Pediatric intensive care unit

RSV -Respiratory syncytial virus

RT-PCR -- Reverse transcription polymerase chain
reaction\textbf{ABSTRACT}

\textbf{Background} : Reactive thrombocytosis (Platelets
\textgreater{}500K/\selectlanguage{greek}μ\selectlanguage{english}l) is estimated between 3-13\% in hospitalized
children and has been associated with RSV infection and younger age. We
aimed to examine the clinical significance of thrombocytosis in children
admitted to the hospital with an influenza-like illness (ILI).

\textbf{Methods} : We performed an analysis of a database of patients
evaluated at our Medical Centers with an ILI between 2009 and 2013. We
included pediatric patients and examined the association between
platelet count, respiratory viral infections, and admission outcomes
(hospital length of stay (LOS) and admission to the pediatric intensive
care unit (PICU() using regression models adjusting for laboratory,
clinical and demographic parameters.

\textbf{Results} : Of 19,192 adults and children in the database, 5,171
children met inclusion criteria (median age 0.8 years (Interquartile
range, 0.2-1.8), 58\% male, median LOS of 3 days (Interquartile range,
2-5)). Younger age and not the type of viral infection was associated
with a high platelet count (p\textless{}0.001). Elevated platelet count
independently predicted admission outcomes, adjusted for multiple
covariates (p[?]0.006). Furthermore, the presence of thrombocytosis was
associated with an increased risk for a prolonged LOS (odds ratio=1.2
(95\% Confidence interval=1.1-1.4, p=0.003)) and admission to the PICU
(odds ratio=1.5 (95\% Confidence interval =1.1-2.0,
p=0.002)).\textbf{Conclusions:} In children admitted with an ILI, a high
platelet count is associated with younger age and is an independent
predictor of hospital LOS and admission to the PICU. Our results show
that platelet count may be used to improve risk assessment and
management decisions in these pediatric patients.

\textbf{INTRODUCTION}

Influenza-like illnesses (ILIs) cause substantial morbidity worldwide
with most cases occurring from December-March in the northern
hemisphere\textsuperscript{1--3}. In the pediatric population, rates of
hospitalization due to ILI vary with age and are up to tenfold higher in
children younger than two years of age\textsuperscript{4--6} with
significant healthcare and economic burden\textsuperscript{7--9}. The
most common viral etiologies for ILI are influenza viruses, respiratory
syncytial virus (RSV) and rhinovirus\textsuperscript{10,11}.

In children admitted due to ILI, previously reported risk factors for a
more severe disease course, include prematurity, young age, low birth
weight, tachypnea, or apnea\textsuperscript{12--16}.

Reactive thrombocytosis, (a platelet count above 500K/\selectlanguage{greek}μ\selectlanguage{english}l), is common in
hospitalized pediatric patients with a prevalence of 3-13\%, is more
pronounced in infants, and declines with age\textsuperscript{17,18}.
Prior studies evaluating thrombocytosis in pediatric patients with ILI
have found an association with RSV and Rhino virus infections but
inconclusive results regarding the association with disease severity and
complications\textsuperscript{19--22}.

The aim of this study was to assess the clinical significance of a high
platelet counts in hospitalized pediatric patients with ILI, evaluating
an association with admission outcomes and viral respiratory tract
infections. \emph{}

\textbf{METHODS}

\textbf{Study design}

We conducted an analysis of a database of patients. This database
includes records of all respiratory viral-panel testing performed on
nasopharyngeal samples in the clinical virology laboratory of our
Medical Centers between May 2009 through July 2013 (inpatient and
outpatient). The nasopharyngeal samples included in this database were
obtained from patients presenting with ``influenza like illness''
(displaying symptoms such as cough, rhinorrhea, fever or sore throat).
These samples were tested using reverse transcription polymerase chain
reaction (RT-PCR) for Influenza A virus (types H3N2, H1N1), Influenza B
virus, Adenovirus, RSV, Parainfluenza 1, 2 and 3 viruses and Human
metapneumovirus (HMPV).

Additional information available in the database included patient
demographics, laboratory blood test results, hospital length of stay
(LOS) (if admitted) and the occurrence of an admission to the pediatric
intensive care unit (PICU).

From this database, we included in the study all children under 16 years
of age who were admitted due to an ILI to the pediatric departments at
our Medical Centers. When more than one nasopharyngeal sample was
collected during a single hospitalization, only the results of the first
sample was included in the analysis.

To reduce the possibility of including hospital-acquired infections in
the study, we excluded all children in whom the nasopharyngeal samples
were collected after more than 5 days of their admission. Furthermore,
to reduce chance for disproportionate effects of uncharacteristic
admissions on the study outcomes, we further excluded from the study all
children in whom the hospital LOS was greater than 14 days (figure 1).
The study was approved by the institutional review board (HMO-16-0323)
and consent was waived due to the retrospective nature of the study.

\textbf{Evaluated outcomes}

The main outcomes evaluated in this study were hospital LOS and
admission to the PICU, as measures of disease severity. In addition, we
evaluated the association between platelet count and respiratory viral
panel results.

\textbf{Statistical analysis}

Data were summarized by standard descriptive statistics. Differences
between different viral infections (viral pathogen not detected, RSV,
influenza A and B, adenovirus, HMPV and parainfluenza) were evaluated
using chi square test for categorical variables and Kruskal-Wallis test
for continuous variables, with the Mann--Whitney U test for multiple
pairwise comparisons. A linear regression model correcting for age and
sex was used to evaluate the association between different respiratory
viral infections and platelet count. Linear and logistic regression
models were used to evaluate the association between platelet count and
the primary study outcomes (hospital LOS and admission to the PICU),
correcting for demographic variables, laboratory blood test results and
respiratory viral panel results. The statistical analysis was performed
using STATA 15.1 (StataCorp LLC, Texas USA). For the primary outcomes,
p-values of less than 0.05 were considered significant. For multiple
pairwise comparisons, nominal p-values are reported and p-values of less
than 0.008 were considered significant, as per the Bonferroni
correction.

\textbf{RESULTS}

\textbf{Study population}

The database included 19,192, inpatient and outpatient, adults and
children with an ILI who underwent a respiratory viral panel RT-PCR
test. Of these patients, 5,171 children were included in the study
(figure 1) (median age = 0.8 years (interquartile range (IQR)=0.2-1.8),
58\% male, median LOS = 3 days (IQR=2-5)). Nasopharyngeal swab results
were positive in 2595 children (58\%), the most commonly detected viral
pathogen was RSV (57\%) followed by adenovirus (19\%). The prevalence of
thrombocytosis in our cohort was 22\%. This decreased to 9\% and 6\% in
children above 2 years and 5 years of age, respectively, and varied
significantly with the type of viral infection (see below). Additional
clinical characteristics are presented in table 1.

\textbf{The association of platelet count and other clinical variables
with the type of viral infection}

We found significant differences in most evaluated clinical and
laboratory parameters when assessing admissions according to different
respiratory viruses (table 1).

The platelet count was found to be significantly higher in children in
whom an RSV infection was detected (P-value \textless{} 0.008, for
multiple pairwise comparisons) when compared to children in whom a
respiratory virus panel was negative or other respiratory viruses were
detected. Furthermore, the presence of thrombocytosis had an odds ratio
of 1.3 (95\% confidence interval (CI), 1.1-1.5 (P\textless{}0.001)) for
the detection of an RSV infection in the respiratory viral panel
analysis. However, children with an RSV infection were also found to be
significantly younger (P-value \textless{} 0.001, for multiple pairwise
comparisons) when compared to children in whom a respiratory virus panel
was negative or other respiratory viruses were detected (table 1).

When performing a multivariate analysis, evaluating factors associated
with platelet count, a younger age was independently associated with an
increased platelet count (difference per year of age = -14.4; 95\% CI,
-16--12; P\textless{}0.001), however the detection of an RSV infection
was not (difference = -2.6; 95\%CI, -5.7-14.1; P=0.648) (E-Table 1 --
Online supporting information). Figure 2A presents the association
between platelet count and age in children with and without an RSV
infection.

E-Table 1 shows additional results of multivariate models looking at the
association between laboratory evaluation results and the type of viral
infection corrected for demographic variables. Of note is a strong
positive association between an adenoviral infection and increased
inflammatory indices and a strong negative association between influenza
B infection and increased inflammatory indices.

\textbf{The association between platelet count and disease severity
outcomes}

Figure 2 (Panels B and C) shows a highly significant association between
disease severity outcomes (hospital LOS and admission to the PICU) and
platelet count.

A multivariate regression analysis, corrected for demographic variables,
laboratory results and the type of viral respiratory infections,
similarly showed that platelet count is independently associated with
the disease severity outcomes evaluated in our study. Specifically,
platelet count was found to be positively associated with hospital LOS
(difference in LOS of = 0.11 days, 95\%CI (0.1-0.2) for every 100 K/\selectlanguage{greek}μ\selectlanguage{english}l
increase in platelet count, p\textless{}0.001) and increased risk for
admission to the PICU (odds ratio = 1.1 95\%CI (1.03-1.25) for every
100K/\selectlanguage{greek}μ\selectlanguage{english}l increase in platelet count, p=0.006). These findings remained
significant also when evaluating young children, under 2 or 3 years of
age (Table 2).

When evaluating the presence of thrombocytosis as a dichotomic variable
predicting admission

outcomes, the odds ratios (corrected for age and gender) of a child with
thrombocytosis to have a longer than median hospital LOS or to be
admitted to the PICU were 1.2 (95\%CI 1.1-1.4, p=0.003) and 1.5 (95\%CI
1.1-2.0, p=0.002), respectively.



\textbf{DISCUSSION}

In this observational study, evaluating a large database of patients
with an influenza like illness, we show that in hospitalized children
under 16 years of age, an elevated platelet count is associated with
worse admission outcomes. Our results also show that thrombocytosis in
children with ILI is more prevalent in younger children and not
associated with the type of viral infection. Results from our study
provide information, which may improve risk assessment in children
admitted to the hospital with an ILI, directing attention to children at
higher risk to have a more severe disease course.

To the best of our knowledge our findings of worse disease outcomes in
children with ILI and elevated platelet counts were previously examined
in two retrospective studies with contradictory findings. The first,
evaluating clinical data in 92 hospitalized children, did not find any
association between disease outcomes and
thrombocytosis\textsuperscript{20}. The second, evaluating medical
records of 136 hospitalized infants, using multivariate logistic
regression analysis, found a significant association between
thrombocytosis and both hospital LOS and the duration of oxygen
requirement during admission\textsuperscript{19,23}. Our results,
evaluating a large database of admitted children provide conclusive
findings, which strongly associate elevated platelet count with worse
disease outcomes in children admitted with symptoms of viral lower
respiratory tract infections. Unlike the above-mentioned
studies\textsuperscript{19,23}, we did not evaluate the duration of
oxygen therapy but we similarly found hospital LOS to be associated with
high platelet count. We further show an increased risk of admission to
the PICU in children with an elevated platelet count; with a 10\%
increase in risk in PICU admission for every 100 K/\selectlanguage{greek}μ\selectlanguage{english}l increase in
platelet count.

Reactive or secondary thrombocytosis is a well described phenomenon seen
frequently in hospitalized children\textsuperscript{17,24}. It is
thought to be secondary to stimulation of megakaryocytic progenitor
cells by circulating cytokines and hematopoietic factors, such as
interleukin-3, interleukin-6, interleukin-8, interleukin-11 and
thrombopoietin\textsuperscript{17,18}. Thus, our findings showing that
increased platelet count is associated with worse disease outcome,
suggest that the increased platelet count is related to an increased
inflammatory response, possibly due to increased lower airway
inflammation.

Furthermore, secondary thrombocytosis is thought to be an age dependent
phenomenon. Young children, compared to adults, demonstrate higher
circulating thrombopoietin concentrations and a higher megakaryocyte
progenitor cells sensitivity to thrombopoietin\textsuperscript{25,26}.

Indeed, in our study as well as in numerous previous
studies\textsuperscript{18--20,22,27,28}, the prevalence of reactive
thrombocytosis was found to be higher in younger children. We further
show that when evaluating multiple variables in children with an ILI, a
younger age was the main factor independently associated with increased
platelet count while the type of respiratory viral infection was not.

Previous studies have described an association between thrombocytosis
and respiratory infection with RSV and
rhinovirus\textsuperscript{19--21,29,30}. We also present an association
between thrombocytosis and the detection of an RSV infection, but our
results show, that at least in part, this association reflects a younger
median age of children admitted with an RSV infection, when compared to
children admitted due to other viral respiratory infections.

The main strengths of this study lie in the large number of children
included in the database and the available RT-PCR results for multiple
respiratory viruses, allowing a comprehensive assessment of the study
aims. The main limitations of the study lie in the retrospective nature
of its design, the lack of assessment for rhinovirus infection and the
absence of information which has been previously shown to be associated
with worse admission outcomes (i.e. prematurity, chronic cardiac or
respiratory morbidity etc.). However, while this study is of
retrospective nature, the relatively large cohort allows the
generalization of our findings.

In summary, we show that elevated platelet counts in children with an
influenza like illness are associated with worse admission outcomes.
This finding provides data that may be used to improve emergency
department and inpatient management of these children. We speculate that
the increased platelet count is due to an increased inflammatory
response and that platelet count may serve an indirect marker for lower
airway inflammation in children with an influenza like illness.



\textbf{References}

1. Taubenberger JK, Morens DM. The pathology of influenza virus
infections. Annu Rev Pathol 2008;3:499--522.

2. Wu P, Presanis AM, Bond HS, Lau EHY, Fang VJ, Cowling BJ. A joint
analysis of influenza-associated hospitalizations and mortality in Hong
Kong, 1998-2013. Sci Rep 2017;7(1):929.

3. Thompson WW, Shay DK, Weintraub E, Brammer L, Cox N, Anderson LJ,
Fukuda K. Mortality associated with influenza and respiratory syncytial
virus in the United States. JAMA 2003;289(2):179--86.

4. Izurieta HS, Thompson WW, Kramarz P, Shay DK, Davis RL, DeStefano F,
Black S, Shinefield H, Fukuda K. Influenza and the rates of
hospitalization for respiratory disease among infants and young
children. N Engl J Med 2000;342(4):232--9.

5. Weigl JAI, Puppe W, Schmitt HJ. The incidence of influenza-associated
hospitalizations in children in Germany. Epidemiol Infect
2002;129(3):525--33.

6. Arriola CS, Kim L, Langley G, Anderson EJ, Openo K, Martin AM,
Lynfield R, Bye E, Como-Sabetti K, Reingold A, et al. Estimated Burden
of Community-Onset Respiratory Syncytial Virus-Associated
Hospitalizations Among Children Aged \textless{}2 Years in the United
States, 2014-15. J Pediatric Infect Dis Soc 2020;9(5):587--595.

7. Ehlken B, Anastassopoulou A, Hain J, Schr\selectlanguage{ngerman}öder C, Wahle K. Cost for
physician-diagnosed influenza and influenza-like illnesses on primary
care level in Germany--results of a database analysis from May 2010 to
April 2012. BMC Public Health 2015;15:578.

8. Li S, Leader S. Economic burden and absenteeism from influenza-like
illness in healthy households with children (5-17 years) in the US.
Respir Med 2007;101(6):1244--50.

9. Wang Y, Chen L, Cheng F, Biggerstaff M, Situ S, Zhou S, Gao J, Liu C,
Zhang J, Millman AJ, et al. Economic burden of influenza illness among
children under 5 years in Suzhou, China: Report from the cost surveys
during 2011/12 to 2016/17 influenza seasons. Vaccine
2021;39(8):1303--1309.

10. Fowlkes A, Giorgi A, Erdman D, Temte J, Goodin K, Di Lonardo S, Sun
Y, Martin K, Feist M, Linz R, et al. Viruses associated with acute
respiratory infections and influenza-like illness among outpatients from
the Influenza Incidence Surveillance Project, 2010-2011. J Infect Dis
2014;209(11):1715--25.

11. Lim FJ, Wake Z V, Levy A, Tempone S, Moore HC, Richmond PC, de Klerk
N, Conway NT, Keil AD, Effler P V, et al. Viral Etiology and the Impact
of Codetection in Young Children Presenting With Influenza-Like Illness.
J Pediatric Infect Dis Soc 2017;6(3):260--266.

12. Wang EE, Law BJ, Stephens D. Pediatric Investigators Collaborative
Network on Infections in Canada (PICNIC) prospective study of risk
factors and outcomes in patients hospitalized with respiratory syncytial
viral lower respiratory tract infection. J Pediatr 1995;126(2):212--9.

13. Mansbach JM, Piedra PA, Stevenson MD, Sullivan AF, Forgey TF, Clark
S, Espinola JA, Camargo CA, MARC-30 Investigators. Prospective
multicenter study of children with bronchiolitis requiring mechanical
ventilation. Pediatrics 2012;130(3):e492-500.

14. Hasegawa K, Pate BM, Mansbach JM, Macias CG, Fisher ES, Piedra PA,
Espinola JA, Sullivan AF, Camargo CA. Risk factors for requiring
intensive care among children admitted to ward with bronchiolitis. Acad
Pediatr 15(1):77--81.

15. Gill PJ, Ashdown HF, Wang K, Heneghan C, Roberts NW, Harnden A,
Mallett S. Identification of children at risk of influenza-related
complications in primary and ambulatory care: a systematic review and
meta-analysis. Lancet Respir Med 2015;3(2):139--149.

16. Ozsurekci Y, Aykac K, Bal F, Bayhan C, Basaranoglu ST, Alp A, Cengiz
AB, Kara A, Ceyhan M. Outcome predictors of influenza for
hospitalization and mortality in children. J Med Virol
2021;93(11):6148--6154.

17. Dame C, Sutor AH. Primary and secondary thrombocytosis in childhood.
Br J Haematol 2005;129(2):165--77.

18. Sutor AH. Thrombocytosis in childhood. Semin Thromb Hemost
1995;21(3):330--9.

19. Zheng S-Y, Xiao Q-Y, Xie X-H, Deng Y, Ren L, Tian D-Y, Luo Z-X, Luo
J, Fu Z, Huang A-L, et al. Association between secondary thrombocytosis
and viral respiratory tract infections in children. Sci Rep
2016;6:22964.

20. Haidopoulou K, Goutaki M, Lemonaki M, Kavga M, Papa A. Reactive
thrombocytosis in children with viral respiratory tract infections.
Minerva Pediatr 2011;63(4):257--62.

21. Bilavsky E, Yarden-Bilavsky H, Shouval DS, Fisch N, Garty B-Z,
Ashkenazi S, Amir J. Respiratory syncytial virus-positive bronchiolitis
in hospitalized infants is associated with thrombocytosis. Isr Med Assoc
J 2010;12(1):39--41.

22. Al Shibli A, Alkuwaiti N, Hamie M, Abukhater D, Noureddin MB, Amri
A, Al Kaabi S, Al Kaabi A, Harbi M, Narchi H. Significance of platelet
count in children admitted with bronchiolitis. World J Clin Pediatr
2017;6(2):118--123.

23. Pavi\selectlanguage{polish}ć \selectlanguage{english}V, Crnkovi\selectlanguage{polish}ć \selectlanguage{english}HT, Klari\selectlanguage{polish}ć \selectlanguage{english}A\selectlanguage{polish}Š. \selectlanguage{english}421 Association between
thrombocytosis and disease severity in children with bronchiolitis. Arch
Dis Child 2021;106(Suppl 2):A176.

24. Chiarello P, Magnolia M, Rubino M, Liguori SA, Miniero R.
Thrombocytosis in children. Minerva Pediatr 2011;63(6):507--13.

25. Wolber EM, Dame C, Fahnenstich H, Hofmann D, Bartmann P, Jelkmann W,
Fandrey J. Expression of the thrombopoietin gene in human fetal and
neonatal tissues. Blood 1999;94(1):97--105.

26. Dame C. Developmental biology of thrombopoietin in the human fetus
and neonate. Acta Paediatr Suppl 2002;91(438):54--65.

27. Wang J-L, Huang L-T, Wu K-H, Lin H-W, Ho M-Y, Liu HE. Associations
of reactive thrombocytosis with clinical characteristics in pediatric
diseases. Pediatr Neonatol 2011;52(5):261--6.

28. Thom CS, Echevarria E, Osborne AD, Carr L, Rubey KM, Salazar E,
Callaway D, Pawlowski T, Devine M, Kleinman S, et al. Extreme
thrombocytosis is associated with critical illness and young age, but
not increased thrombotic risk, in hospitalized pediatric patients. J
Thromb Haemost 2020;18(12):3352--3358.

29. Mammas I, Koutsaftiki C, Tapaki-Papadopoulou G, Myriokefalitakis N.
Respiratory syncytial virus (RSV) bronchiolitis and excessive
thrombocytosis. Acta Paediatr 2010;99(4):489--90.

30. Kubota M, Maeda H, Yoshimoto J, Kobayashi K, Usami I, Yamaoka K.
Thrombocytosis at an early stage of respiratory tract viral infection.
Acta Paediatr 2005;94(3):364--6.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure1/Figure1}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2/Figure-2}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Image Legends.docx`  available at \url{https://authorea.com/users/579189/articles/620790-thrombocytosis-a-marker-of-disease-severity-in-children-with-viral-respiratory-tract-infections}

\textbf{Hosted file}

\verb`Tables.docx`  available at \url{https://authorea.com/users/579189/articles/620790-thrombocytosis-a-marker-of-disease-severity-in-children-with-viral-respiratory-tract-infections}

\selectlanguage{english}
\FloatBarrier
\end{document}

