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\begin{document}

\title{Investigation of Chest X-Ray Use in the Emergency Department in
Pediatric Patients with Sickle Cell Disease}



\author[1]{Urania Dagalakis}%
\author[1]{Henna1 Butt}%
\author[1]{Natalie Davis}%
\author[2]{Regina Macatangay}%
\affil[1]{University of Maryland Medical Center}%
\affil[2]{University of Maryland School of Medicine}%


\vspace{-1em}



  
  \date{May 23, 2024}


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\selectlanguage{english}
\begin{abstract}
Determining which patients are at highest risk of acute chest syndrome
(ACS) is challenging for pediatric emergency department (PED) providers,
resulting in more chest x-rays (CXR), increased radiation exposure, and
higher healthcare costs. The objective of this study was to identify
significant clinical predictors of ACS to better guide care. In this
retrospective review, we included patients diagnosed with sickle cell
disease (SCD), aged 2-12 years, who presented to the PED between
2016-2018. We compared patients who were febrile vs. afebrile on
presentation, and those diagnosed with ACS vs. those who were not. A
total of 424 patients met inclusion criteria, 25\% presenting with
fever. For febrile patients, 69\% received a CXR on presentation vs.
42\% of afebrile subjects (p=\textless{}0.0001). Overall, 10\% of
patients were diagnosed with ACS: 13\% of febrile presentations vs. 9\%
of afebrile presentations. Patients diagnosed with ACS were
significantly more likely to present with chest pain (p=0.003),
tachypnea (p=0.001), hypoxia (p\textless{}0.0001), and a history of
asthma (p=0.0085). Upon multivariable modeling the only significant
predictors were chest pain (OR 3.3, CI 1.5-7.4) and hypoxia (OR 8.4, CI
4-17.9). Current guidelines recommend empiric treatment and a CXR for
SCD patients presenting with fever, hypoxia, tachypnea, tachycardia or
abnormal respiratory exam. Our data demonstrate that hypoxia and chest
pain are significant predictors of ACS. Additionally, data indicated
that CXRs were likely performed in excess in febrile patients. Further
research is needed, but chest pain and hypoxia may focus the use of CXR
on the appropriate patients.%
\end{abstract}%



\sloppy


\textbf{Introduction}

In sickle cell disease (SCD), acute chest syndrome (ACS) is a major
cause of significant mortality and morbidity. It is responsible for an
estimated 25\% of sickle cell disease-related deaths, and is associated
with prolonged hospitalization, increased risk of respiratory failure,
future lung disease and 25\% mortality in hospitalized
patients\textsuperscript{1,2}. ACS has a 40\% incidence in the SCD
population and is most commonly caused by infection and pulmonary
infarction. Pediatric patients with SCD frequently present to the
pediatric emergency department (PED) with complaints of fever, chest
pain, and cough, all of which may or may not be associated with ACS.

Other studies have been conducted to evaluate the differences between
adult and pediatric sickle cell patients in their presentation of ACS.
Findings include a lower prominence of extrapulmonary findings in
pediatric patients as compared to adult patients. Factors such as low
hemoglobin (Hb) and oxygen tension fraction were predictors of ACS in
pediatric patients\textsuperscript{3}. Madhi et. al., also noted that
oxygen saturation (SpO\textsubscript{2}) level was significantly lower
at admission for children with ACS when compared to
adults.\textsuperscript{4} Certain co-morbidities, such as asthma, have
been shown to increase risk of ACS in pediatric
patients.\textsuperscript{5} Boyd et al. found that children with both
asthma and SCD experienced almost twice as many ACS episodes vs.
children with SCD without asthma.\textsuperscript{6} Other risk factors
for ACS include young age, severe SCD genotypes, low fetal Hb levels,
high steady-state Hb levels, high steady-state leukocyte count, history
of asthma, and a previous history of ACS\textsuperscript{1}.

Despite growing research in the field, it remains challenging for PED
providers to determine which patients are at highest risk of ACS. In
fact, a national hospital ambulatory medical care survey evaluated
almost two-hundred thousand yearly emergency department (ED) visits by
SCD patients from 1999-2007 and found that 37\% of those aged 0-19 years
ended up hospitalized\textsuperscript{7}. This high frequency of ED
visits and hospitalizations increased pediatric SCD patient exposure to
nosocomial infections, radiation, and was associated with higher
mortality.

Chest x-rays (CXR) are frequently ordered, increasing radiation exposure
and healthcare costs. A Dallas Newborn cohort from 1996-2009 found that
SCD patients had greater than 25 radiographic tests before age 18, and
5\% of these patients had greater than 100 tests.\textsuperscript{8}This
is concerning since one CXR has an average effective radiation dose of
0.01-0.02 millisievert (mSv), comparable to 10 days of natural radiation
exposure\textsuperscript{9,10}. While there is currently no set limit on
an acceptable radiation dose for pediatric patients, providers should
make every effort possible to reduce unnecessary radiation exposure
based on the principle of ``as low as reasonably achievable'' (ALARA).

Therefore, the objectives of this study were: 1) to identify incidence
of CXR performance and ACS diagnosis in SCD patients, both with and
without fever, presenting to our PED, and 2) to identify significant
clinical and demographic predictors of ACS in this population in order
to implement a diagnostic algorithm for PED providers with the goal of
minimizing unnecessary CXR performance in this population.

\textbf{Methods}

This was an IRB-approved retrospective medical record review of subjects
diagnosed with SCD. Individuals were initially identified from
International Classification of Diseases, Tenth Revision, Clinical
Modification 10 (ICD10) codes for PED visits in SCD patients from 2014
to 2019. Retrospective chart review was performed using PED and
inpatient medical record documentation. Inclusion criteria were SCD
patients aged 2-12 years who presented to the University of Maryland
Medical Center (UMMC) PED between 2016-2018. Exclusion criteria included
non-SCD patients, patients less than 2 years of age, or greater than 12
years of age, and patients evaluated at hospitals other than UMMC. Each
PED encounter was counted as a separate data point.

We performed bivariate analyses comparing clinical and demographic
variables between subjects who were febrile vs. afebrile on presentation
to the PED, as well as those who were ultimately diagnosed with ACS
compared to those who were not. Analysis of categorical variables was
performed using Chi-square or Fischer exact test as appropriate. We
performed multivariable logistic regression modelling to identify
significant predictors of an ACS diagnosis. Analyses were performed
using SAS 9.4 (Cary, NC).

\textbf{Results}

We identified 424 SCD subjects who presented to our PED meeting
inclusion and exclusion criteria, with 25\% (n=108) presenting with
fever. Within the febrile group, 69\% (n=74) of subjects received a CXR
on presentation compared to 42\% (n=133) of afebrile group
(p\textless{}0.0001). Of the febrile subjects, 21\% (n=23) had more than
2 febrile episodes of whom 100\% received CXRs. Of the subjects who were
ultimately hospitalized, 46\% (n=50) within the febrile group received
at least one inpatient CXR compared to 26\% (n=82) of the afebrile group
(p\textless{}0.001). Additional radiation exposure via x-ray imaging and
CT scans during their hospitalization occurred in 26\% (n=28) of the
febrile group compared to 28\% (n=90) in the afebrile group.

There were no significant differences between the febrile and afebrile
subjects when it came to sex, asthma diagnosis/comorbidity, hydroxyurea
use, folic acid supplementation, or pneumococcal prophylaxis (Tables 1
\& 2). Overall, 10\% of patients presenting to the PED were diagnosed
with ACS (n=42), 13\% (n=14) of those presenting with fever compared to
9\% (n=28) of those presenting without fever. Those subjects diagnosed
with ACS were significantly more likely to present with chest pain
(p=0.003), tachypnea (p=0.001), and hypoxia (p\textless{}0.0001), and
were more likely to have a history of asthma (p=0.0085). Sickle cell
genotype, home medications, and history of splenectomy were not
significantly associated with ACS diagnosis.

Upon multivariable modeling, when adjusting for known significant
predictors of fever and pre-existing asthma diagnosis, the only
significant predictors of ACS diagnosis were chest pain and hypoxia.
Patients without chest pain had an odds ratio (OR) =0.3 of ACS diagnosis
{[}95\% Confidence Interval, CI 0.14-0.67{]}, indicating they had 70\%
lower odds of ACS compared to patients with chest pain (Table 3).
Patients without hypoxia had OR=0.12 of ACS compared to those with
hypoxia {[}CI 0.06-0.25{]}, indicating 88\% reduced odds of ACS
diagnosis (Table 3). Conversely, those with chest pain had 3.3-fold
increased odds of ACS diagnosis {[}CI 1.5-7.4{]} and those with hypoxia
had 8.4 times the odds of ACS diagnosis {[}CI 4-17.9{]} compared to
those without these symptoms.

\textbf{Discussion}

In ACS, guidelines from the British Society of Hematology recommend that
patients presenting with fever, hypoxia, tachypnea, tachycardia and
abnormal respiratory exam findings should be treated empirically as well
as receive a CXR\textsuperscript{11}. However, radiological signs can be
delayed compared to physical signs; a normal CXR does not preclude the
diagnosis of ACS if there is clinical suspicion\textsuperscript{11}.
Vichinsky's study of 939 patients found that 35\% had normal lung exams
and 17\% presented with lower extremity pain when they presented with
ACS\textsuperscript{12}. Our data demonstrate that clinical findings
such as chest pain, tachypnea and hypoxia were most likely to correlate
with a diagnosis of ACS. While 69\% of our febrile patients received a
CXR in the PED, only 13\% were ultimately diagnosed with ACS, indicating
that more CXRs and radiation exposure occurred in the febrile population
than may have been necessary. When adjusting for fever and asthma, the
most salient predictors of ACS were hypoxia and chest pain. When
present, these findings were significant predictors of ACS; when absent,
patients had significantly decreased odds of ACS.

While CXR remains a key diagnostic tool in the diagnosis of ACS, many
studies have suggested that lung ultrasound may provide evidence for
diagnosis and evolution of ACS. CXR can be normal in up to approximately
66\% of early cases of ACS, including CXRs obtained in patients who were
hypoxemic on presentation\textsuperscript{13}. Historically, lung
ultrasound diagnostic research had been primarily performed in adult
patients; however, more recently, lung ultrasound has been evaluated in
the pediatric population. Multiple studies in pediatric SCD patients
have demonstrated that lung ultrasounds showed a higher number of ACS
associated lesions than CXR\textsuperscript{13}. In a study by Vetter et
al., lung ultrasound was superior to CXR for diagnosing consolidations
and pleural effusions in these patients.\textsuperscript{13} Future
investigations should evaluate whether lung ultrasound is at least equal
to, if not superior, to CXR to support the broader use of
radiation-sparing bedside alternatives for diagnosing ACS in pediatric
patients.

Strengths of our study include a relatively large sample size; the total
``n'' of 424 was robust enough to allow for significant statistical
analysis and supported a meaningful analysis stratifying by risk
factors. Our study evaluated SCD in an understudied patient population,
with a focus on children aged 2 to 12 years old due to the higher
incidence and severity of ACS in this age group. One limitation is that
our data may not be generalizable to patients under 2 years or older
than 12 years. The retrospective study design can limit results due to
risk of bias in documentation, but we evaluated all PED and inpatient
notes and laboratory values to increase likelihood of capturing
important clinical data. As with any retrospective study, we can only
evaluate for associations and not causation, but we performed
multivariable modelling, in addition to bivariate analysis, in order to
control for confounders and better assess for significant predictors. In
addition, we evaluated subjects presenting to the PED in 2016-2018,
which is a more modern cohort than many studies on pediatric SCD and ACS
diagnosis.

In conclusion, studies have demonstrated that the clinical presentation
of ACS differ based on the age of patients. Prior studies have noted
that children under the age of 10 tend to present with fever, cough and
wheezing, whereas adults typically report chest pain and
dyspnea.\textsuperscript{14} Further research is needed to confirm, but
based on our data, incorporating the presence or absence of chest pain
and hypoxia in pediatric patients may help focus the use of CXR to the
appropriate patient population at risk of developing ACS. By 18 years of
age, most children with SCD will have had on average 26.7 (95\% CI:
24.1-29.3; range 0-492.1) radiographic tests while 5\% of these patients
will have had more than 100 radiographic tests\textsuperscript{15}. A
high cumulative lifetime of radiation exposure is an established risk
factor for serious life-threatening diseases such as
cancer\textsuperscript{16}. With advancements in standards of medical
care for patients with SCD, the life expectancy for SCD patients has
improved to an average of 54 years old\textsuperscript{8}, which makes
it even more important to reduce cumulative exposure to diagnostic
radiation in this vulnerable population. Thus, this study provides
evidence to support a more critical assessment of risk factors and
presenting symptoms to better triage which pediatric patients warrant
further imaging in the PED at initial presentation to investigate for
possible ACS.

\textbf{Conflict-of-interest statements}

The authors have no conflicts of interest to disclose.

\textbf{Acknowledgements}

The authors sincerely thank the University of Maryland Department of
Pediatrics for its support in pursuing this research work.

\textbf{Data Sharing Statement}

The data that support the findings of this study are available from the
corresponding author upon reasonable request.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Jain, S, Bakshi, N, \& Krishnamurti, L. Acute Chest Syndrome in
  Children with Sickle Cell Disease\emph{. Pediatric Allergy,
  Immunology, and Pulmonology} . 2017;\emph{30} (4):191--201.
\item
  Vinchinsky, EP, Styles, LA, Colangelo, LH, Wright, EC, Castro, O,
  Nickerson, B. Acute Chest Syndrome in Sickle Cell Disease: Clinical
  Presentation and Course.~\emph{Blood} . 1997;\emph{89} (5):1787--1792.
\item
  Al-Sharydah AM, Alshahrani M, Aldhaferi B, Al-Muhanna AF, Al-Thani H.
  Radiological Patterns in Sickle Cell Disease Patients with Acute Chest
  Syndrome: Are There Age-Related Differences?~\emph{Saudi J Med Med
  Sci} . 2019;7(2):74-79.
\item
  Madhi F, Kamdem A, Jung C, et al. Identification of Clinical and
  Laboratory Parameters Associated with the Development of Acute Chest
  Syndrome during Vaso-Occlusive Episodes in Children with Sickle Cell
  Disease: A Preliminary Step before Assessing Specific and Early
  Treatment Strategies.~\emph{J Clin Med} . 2019;8(11):1-16.
\item
  Patterson GD, Mashegu H, Rutherford J, et al. Recurrent Acute Chest
  Syndrome in Pediatric Sickle Cell Disease: Clinical Features and Risk
  Factors.~\emph{J Pediatr Hematol Oncol} . 2018;40(1):51-55.
\item
  Boyd JH, Macklin EA, Strunk RC, DeBaun MR. Asthma is associated with
  acute chest syndrome and pain in children with sickle cell
  anemia.~\emph{Blood} . 2006;108(9):2923-2927.
\item
  Yusuf H.R., Atrash H.K., Grosse S.D., Parker C.S., Grant A.M.
  Emergency department visits made by patients with sickle cell disease:
  a descriptive study, 1999--2007.\emph{~Am J Prev Med.} ~2011;38(4
  Suppl):S536-41.
\item
  Lubeck D, Agodoa I, Bhakta N, et al. Estimated life expectancy and
  income of patients with sickle cell disease compared with those
  without sickle cell disease. \emph{JAMA Netw Open} . 2019;2(11):1-14.
\item
  Mettler, FA, Mahesh, M, Bhargavan-Chatfield, M, et al. Patient
  exposure from radiologic and nuclear medicine procedures in the United
  States: Procedure volume and effective dose for the period
  2006-2016.\emph{Radiology} . 2020;295(2):418-427.
\item
  Ait-Ali L, Andreassi MG, Foffa I, Spadoni I, Vano E, Picano E.
  Cumulative patient effective dose and acute radiation-induced
  chromosomal DNA damage in children with congenital heart
  disease.~\emph{Heart} . 2010;96(4):269-274.
\item
  Howard, J, Hart, N, Roberts-Harewood, M, Cummins, M, Awogbade, M,
  Davis, B. Guideline on the management of acute chest syndrome in
  sickle cell disease.~\emph{British Journal of Haematology}
  .~2015;169(4):492--505.
\item
  Vichinsky EP, Neumayr LD, Earles AN, et al. Causes and outcomes of the
  acute chest syndrome in sickle cell disease. National Acute Chest
  Syndrome Study Group. \emph{N Engl J Med} . 2000;342(25):1855-65.
\item
  Bobillo-Perez S, Rodriguez-Fanjul J, Girona-Alarcon M, Cambra FJ,
  Jordan I, Balaguer M. Ultrasound-guided recruitment maneuvers in
  pediatric acute chest syndrome due to sickle cell disease.~\emph{Med
  Intensiva} . 2019;S0210-5691(19):30172-X.
\item
  Vichinsky EP, Styles LA, Colangelo LH, Wright EC, Castro O, Nickerson
  B. Acute chest syndrome in sickle cell disease: clinical presentation
  and course: Cooperative Study of Sickle Cell Disease.~\emph{Blood} .
  1997;89:1787-1792
\item
  Vetter CL, Buchanan GR, Quinn CT. Burden of diagnostic radiation
  exposure in children with sickle cell disease. \emph{Pediatr Blood
  Cancer} . 2014;61(7):1322--1324.
\item
  Gilbert ES. Ionizing radiation and cancer risks: what have we learned
  from epidemiology?.~\emph{Int J Radiat Biol} . 2009;85(6):467-482.
\end{enumerate}

\textbf{Hosted file}

\verb`Table 1.docx`  available at \url{https://authorea.com/users/728122/articles/709453-investigation-of-chest-x-ray-use-in-the-emergency-department-in-pediatric-patients-with-sickle-cell-disease}

\textbf{Hosted file}

\verb`Table 2.docx`  available at \url{https://authorea.com/users/728122/articles/709453-investigation-of-chest-x-ray-use-in-the-emergency-department-in-pediatric-patients-with-sickle-cell-disease}

\textbf{Hosted file}

\verb`Table 3.docx`  available at \url{https://authorea.com/users/728122/articles/709453-investigation-of-chest-x-ray-use-in-the-emergency-department-in-pediatric-patients-with-sickle-cell-disease}

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