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\begin{document}

\title{Outpatient Inhaled Corticosteroid Use in Bronchopulmonary Dysplasia}



\author[1]{Sharon McGrath-Morrow}%
\author[1]{Cynara Leon}%
\author[1]{Amanda Martin}%
\author[1]{Lisa Young}%
\author[2]{Brianna C. Aoyama}%
\author[1]{Jessica  Rice}%
\author[1]{Jelte Kelchtermans}%
\author[2]{Joseph Collaco}%
\affil[1]{The Children's Hospital of Philadelphia}%
\affil[2]{The Johns Hopkins University School of Medicine}%


\vspace{-1em}



  
  \date{May 16, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
\textbf{Rationale:} In the outpatient setting, inhaled corticosteroids
(ICS) are frequently given to children with bronchopulmonary dysplasia
(BPD) for treatment of respiratory and asthma associated symptoms. In
this study we sought to determine if correlations existed between ICS
use and ICS initiation and patient characteristics and outpatient
respiratory outcomes. \textbf{Methods:} This study included children
with the diagnosis of BPD (n=661) who were seen in outpatient pulmonary
clinics at the Children's Hospital of Philadelphia between 2016-2021.
Chart review was used to determine patient demographics, use and timing
of ICS initiation, asthma diagnosis and acute care usage following
initial hospital discharge. \textbf{Results}: At the first pulmonary
visit, 9.2\% of children had been prescribed an ICS at NICU discharge,
13.9\% had been prescribed an ICS after NICU discharge but before their
first pulmonary appointment, and 6.9\% were prescribed an ICS at
completion of initial pulmonary visit. Children started on an ICS as
outpatients, had a higher likelihood of ER visits (adjusted OR: 2.68
\selectlanguage{ngerman}±0.7), hospitalizations (4.81 ± 1.16) and a diagnosis of asthma (3.58 ±
0.84), compared to children never on an ICS. Of those diagnosed with
asthma, children prescribed an ICS in the outpatient setting received
the diagnosis at an earlier age. No associations between NICU BPD
severity scores and ICS use were found. \textbf{Conclusions}: This study
identifies an outpatient BPD phenotype associated with ICS use and ICS
initiation independent of NICU severity score. Additionally, outpatient
ICS initiation correlates with a subsequent diagnosis of asthma and
acute care usage in children with BPD.%
\end{abstract}\selectlanguage{ngerman}%



\sloppy


\textbf{Outpatient Inhaled Corticosteroid Use in Bronchopulmonary
Dysplasia}

Cynara Leon, MD, MPH\textsuperscript{1}, Amanda Martin,
BA\textsuperscript{1}, Lisa R. Young, MD\textsuperscript{1}, Brianna C.
Aoyama, MD, MHS\textsuperscript{2}, Jessica L. Rice, MD,
MHS\textsuperscript{1}, Jelte Kelchtermans, MD\textsuperscript{1},
Joseph M. Collaco, MD, PhD \textsuperscript{2}, Sharon A.
McGrath-Morrow, MD, MBA\textsuperscript{1}*

\textsuperscript{1}Division of Pulmonary and Sleep Medicine, Children's
Hospital of Philadelphia and University of Pennsylvania, Philadelphia,
PA

\textsuperscript{2}Eudowood Division of Pediatric Respiratory Sciences,
Johns Hopkins University, Baltimore, MD

\textbf{*Corresponding Author:} Sharon A. McGrath-Morrow, MD, MBA,
Division of Pulmonary and Sleep Medicine, Children's Hospital of
Philadelphia, Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, PA, USA. Email: mcgrathmos@chop.edu

\textbf{Funding/Support} : This work was supported by a R03HD109442
(JMC, SAM), T32-HL160493-01 (CL, JK), RFA-ES-18-003 (SAM), Parker B
Francis Foundation (JK) and K24HL143281 (LRY).

The funding sources had no involvement in the writing of the manuscript
or the decision to submit.

\textbf{Keywords:} inhaled corticosteroids, bronchopulmonary dysplasia,
outpatient, symptoms, acute care use

\textbf{Running Head:} Inhaled corticosteroids and BPD

\textbf{Abstract}

\textbf{Rationale:} In the outpatient setting, inhaled corticosteroids
(ICS) are frequently given to children with bronchopulmonary dysplasia
(BPD) for treatment of respiratory and asthma associated symptoms. In
this study we sought to determine if correlations existed between ICS
use and ICS initiation and patient characteristics and outpatient
respiratory outcomes.

\textbf{Methods:} This study included children with the diagnosis of BPD
(n=661) who were seen in outpatient pulmonary clinics at the Children's
Hospital of Philadelphia between 2016-2021. Chart review was used to
determine patient demographics, use and timing of ICS initiation, asthma
diagnosis and acute care usage following initial hospital discharge.

\textbf{Results} : At the first pulmonary visit, 9.2\% of children had
been prescribed an ICS at NICU discharge, 13.9\% had been prescribed an
ICS after NICU discharge but before their first pulmonary appointment,
and 6.9\% were prescribed an ICS at completion of initial pulmonary
visit. Children started on an ICS as outpatients, had a higher
likelihood of ER visits (adjusted OR: 2.68 \selectlanguage{ngerman}±0.7), hospitalizations (4.81
± 1.16) and a diagnosis of asthma (3.58 ± 0.84), compared to children
never on an ICS. Of those diagnosed with asthma, children prescribed an
ICS in the outpatient setting received the diagnosis at an earlier age.
No associations between NICU BPD severity scores and ICS use were found.

\textbf{Conclusions} : This study identifies an outpatient BPD phenotype
associated with ICS use and ICS initiation independent of NICU severity
score. Additionally, outpatient ICS initiation correlates with a
subsequent diagnosis of asthma and acute care usage in children with
BPD.



\textbf{Introduction}

Bronchopulmonary dysplasia (BPD) is the most common cause of chronic
lung disease of infancy, occurring primarily in extremely low birth
weight (ELBW) newborns. (1, 2) Extreme preterm birth disrupts alveolar
growth, frequently resulting in poor gas exchange due to alveolar
hypoplasia. (3) As such, many ELBW infants require supplemental oxygen
and/or positive pressure support during their initial hospitalization.
Nevertheless, many ELBW survivors with BPD will undergo alveolar
catch-up growth and be weaned off respiratory support, prior to initial
hospital discharge or during their preschool years. (4, 5)

It has been recognized that children with BPD are commonly diagnosed
with small airflow obstruction, and that abnormalities in airway flow
can persist into adolescent and adult life. (4, 6) The development of
small airflow obstruction in early life, can adversely influence lung
function trajectories in later life (7) and can be a risk factor for the
development of chronic obstructive lung disease (COPD) in adults. (8)
The traditional marker of small airway disease is evidence of airflow
obstruction on spirometry. However, since spirometry is difficult to
perform reliably prior to 6 years of age, a non-invasive method for
identifying young children with BPD who are at risk for a small airway
phenotype is needed. Earlier identification of those at risk for a small
airway phenotype may allow for more timely interventions that may
improve lung function trajectories.

Although BPD severity is formally diagnosed based on respiratory support
needs at 36 weeks post menstrual age (PMA), recent studies indicate that
BPD severity scores assigned in the neonatal intensive care unit (NICU)
may not predict respiratory outcomes in the outpatient setting. (9, 10)
This lack of predictive value of outpatient respiratory outcomes based
on inpatient BPD severity scores suggests the importance of establishing
new criteria for assessing outpatient phenotypes in children with BPD.
Currently, there are no established phenotypes or framework for
classification of respiratory diseases associated with prematurity after
NICU discharge.

Inhaled corticosteroids (ICSs) are commonly used to treat and
control~symptoms of small airflow obstruction in children with asthma.
Children with BPD are also frequently prescribed ICSs, however their use
and effectiveness in the outpatient setting is less well described.(11,
12). In this study we hypothesized that young children with BPD
prescribed an ICS in the outpatient setting, will have different
clinical characteristics and a greater likelihood of adverse respiratory
outcomes when compared to children who are not prescribed an ICS.
Furthermore, we sought to determine if ICS use correlated with the
timing and likelihood of an asthma diagnosis.

Understanding the use and timing of ICS initiation in the outpatient
setting may be a proxy for identifying young children with BPD who have
clinical features of small airway obstruction. Identifying these
children earlier in life may allow for interventions that could improve
respiratory outcomes. This study was preformed using electronic patient
medical records from children with BPD seen in outpatient pulmonary
clinics over a six-year period.

\textbf{Methods}

\textbf{Study Population:} Children with the diagnosis of BPD and seen
in the Children's Hospital of Philadelphia outpatient pulmonary clinics
between 2016-2021 were identified using electronic medical records
(EMR). Inclusion criteria included birth prior to 34 weeks gestational
age, a diagnosis of BPD by the 2001 National Heart, Lung, and Blood
Institute (NHLBI) consensus statement, (13) and being 8 years of age or
less at their first pulmonary clinic visit. Those who had tracheostomies
and/or were ventilator-dependent were excluded.~Inhaled corticosteroid
(ICS) use and timing of initiation were determined by chart review.
History of pulmonary hypertension was determined by chart review.
Outcomes included asthma diagnosis and acute care usage before and after
their first pulmonary visit. This study was approved by the Children's
Hospital of Philadelphia Institutional Review Board (IRB\# 20-017614)
under exempt research. ICD-10 codes were used to identify children with
the diagnosis of BPD with or without the diagnosis of asthma. These ICD
codes were: P27.1, P27.1 + J45, P27.9~and P27.9 + J45.

\textbf{Statistics:} Descriptive means and frequencies were compared
using \emph{t} tests and chi square tests, respectively (Tables 1 and 3
and Supplemental Tables 1-3). Odds ratios for admissions and visits were
derived from logistic regressions adjusted for potential confounders
that were selected \emph{a priori} , including gestational age, birth
weight, supplemental oxygen use at NICU discharge, and duration of
follow-up time (i.e., either time between NICU discharge and first
pulmonary visit or time between first pulmonary visit and time of chart
review) (Table 4). The odds ratio for a diagnosis of asthma was derived
similarly, except age at last follow-up was substituted for duration of
follow-up time. Kaplan-Meier analyses were used to assess differences
between groups for time until the diagnosis of asthma (Figure 1). Stata
IC 15 (StataCorp, LLC; College Station, TX) was used for all analyses. P
values of less than 0.05 were defined as significant.



\textbf{Results}

\emph{Study Population}

The study population included 661 subjects with the diagnosis of BPD.
The majority of children were male (59.8\%), with non-white children
making up 43\% of the study population. The mean gestational age was
26.3 ± 2.4 (mean ± SD) weeks and the mean birthweight was 884 ± 376
grams (\textbf{Table 1} ). Most children (61.5\%) had severe BPD and
12.6\% had a history of pulmonary hypertension. Approximately half
(50.9\%) of the children were discharged from the NICU to home on
supplemental oxygen.

Of the 661 subjects in the study population, 61 (9.2\%) were discharged
from the NICU on an ICS, 138 (20.9\%) were initiated on an ICS as an
outpatient, and 462 (69.9\%) had not received any ICS therapy as an
outpatient, at the conclusion of their first pediatric pulmonary
outpatient visit (\textbf{Table 2} ). Of note, for the 138 subjects who
were initiated on ICS therapy as outpatients, 92 (66.7\%) were initiated
by a non-pulmonologist provider prior to the first pulmonary clinic
visit, whereas 46 (33.3\%) were initiated by a pulmonologist at
completion of the first pulmonary clinic visit.

\emph{ICS Therapy Prescribed at NICU Discharge}

Infants discharged from the NICU on ICS therapy (n=61) were born earlier
(25.5 ± 1.9 versus 26.3 ± 2.4 weeks gestation; \emph{p} \textless{}0.01)
and weighed less at birth (761 ± 263 versus 896 ± 383 grams;\emph{p}
\textless{}0.008) than their counterparts who were not discharged on ICS
therapy (n=600) (\textbf{Table 1} ). Although ICS therapy at NICU
discharge was not associated with BPD severity (\emph{p} =0.07) or
pulmonary hypertension (\emph{p} =0.08), infants on ICS therapy at
discharge were more likely to be discharged on supplemental oxygen
(78.7\% versus 48.1\%; p\textless{}0.001) and to have experienced a
longer NICU length of stay (184 ± 88 versus 133 ± 68 days;
p\textless{}0.001) compared to their counterparts. Interestingly,
infants with a positive family history of asthma were less likely to be
prescribed ICS at NICU discharge than those who were not (36.7\%
compared to 51.4\%; p\textless{}0.029). These findings indicate that BPD
infants prescribed ICSs at NICU discharge likely represent a distinct
clinical BPD phenotype, compared to those who were not prescribed an ICS
at NICU discharge.

\emph{Outpatient Use of ICS Therapy}

Infants and children who were on ICS therapy as outpatients (n=192) did
not differ by clinical characteristics, such as BPD severity or
gestational age, compared to their counterparts who were not on
outpatient ICS therapy (n=469) (\textbf{Table 3} ). However, we observed
that children on an ICS, at completion of their first pulmonary visit
were more likely to have a family history of asthma (\emph{p} =0.021)
and to be on public insurance (\emph{p} =0.031) compared to those who
were not.

To determine if there were subgroup differences related to being started
on ICS therapy at NICU discharge, we compared those started on ICS
therapy as outpatients (n =138) to those never on outpatient ICS therapy
(n=462, \textbf{Supplemental Table 1} ). Similar to before, those
initiated on ICS therapy as outpatients were more likely to have a
family history of asthma (64.9\% versus 47.5\%;\emph{p}
\textless{}0.001) and to be on public insurance (68.6\% versus 58.1\%;
\emph{p} =0.028) than those who were not. Although the groups did not
differ by BPD severity (\emph{p} =0.27), those initiated on ICS therapy
as outpatients were less likely to require home supplemental oxygen
(33.3\% versus 52.5\%; \emph{p} \textless{}0.001) and have shorter NICU
lengths of stay (119 ± 63 versus 137 ± 68 days; \emph{p} =0.005).
Complete comparisons of all three subgroups for analysis can be found
in\textbf{Supplemental Table 2} .

\emph{Respiratory Outcomes Stratified by ICS Therapy}

Respiratory outcomes that were assessed, included having a diagnosis of
asthma as well as acute care use before and after the first pulmonary
clinic visit under the assumption that subjects receiving ICS therapy
were all prescribed it by the conclusion of their pulmonary visit. In
terms of acute care usage prior to the first pulmonary visit, subjects
initiated on ICS therapy as outpatients had more absolute numbers of
emergency department (ED) visits (\emph{p} \textless{}0.001) and
hospital admissions (\emph{p} \textless{}0.001) than those on ICS
therapy at NICU discharge or not started at all (\textbf{Supplemental
Table 3} ). There were no differences in acute care usage after first
pulmonary clinic visit between the three groups.

The frequency of asthma diagnosis (73.4\%) in those initiated on ICS
therapy as outpatients was much higher than in those on ICS therapy at
NICU discharge (51.9\%) or not initiated at all (36.4\%;\emph{p}
\textless{}0.001). However, given that differences in the age at the
time of first pulmonary clinic visit existed (\emph{p}
\textless{}0.001), as well as duration of follow-up time (\emph{p}
=0.001) between the three groups, we also performed adjusted logistic
regression to account for these differences and to adjust for potential
confounders related to prematurity. Adjusted logistic regression
revealed that children started on an ICS at any point as an outpatient
had a higher likelihood of an ED visit (2.68±0.70;\emph{p}
\textless{}0.001) and/or rehospitalization (4.81±1.16;\emph{p}
\textless{}0.001) prior to their first outpatient pulmonary visit
compared to children never on an ICS (\textbf{Table 4} ). After any time
following the first pulmonary visit, the likelihood of ED visits and
re-hospitalizations for those started on ICS therapy as an outpatient,
dropped to 1.73±0.35 (\emph{p} =0.007) and 1.78±0.37 (\emph{p} =0.006),
respectively, when compared to children never on an ICS. There were no
differences in the likelihood of ED visits or rehospitalizations between
those on ICS therapy at NICU discharge versus those never on an ICS.

The likelihood of a diagnosis of asthma was higher in both children
started on an ICS as an outpatient (3.58±0.84; \emph{p}
\textless{}0.001) and those prescribed an ICS continuously since NICU
discharge (1.97±0.65; \emph{p} =0.040) compared to those never on an
ICS. Additionally, of those diagnosed with asthma in the outpatient
setting, the time until asthma diagnosis was earliest in the children
started on an ICS as an outpatient (\emph{p} \textless{}0.001)
(\textbf{Figure 1} ).



\textbf{Discussion}

In this study, we used electronic patient medical records to determine
if ICS use and ICS initiation correlated with patient characteristics
and respiratory outcomes in infants and children with BPD in the
outpatient setting. We found that by completion of the first pulmonary
visit, 29\% of children with BPD were on an ICS while 71\% were not. The
infants and children prescribed an ICS in the outpatient setting were
found to have patient characteristics different from those who were not
prescribed an ICS at all or those prescribed at NICU discharge. These
findings suggest that there exist several distinct outpatient BPD
phenotypes based on ICS use and initiation. For instance, the children
prescribed an ICS as outpatients had a greater likelihood of acute care
usage and were more likely to be diagnosed with asthma compared to those
not on an ICS. Interestingly we found that ICS initiation in the
outpatient setting was driven primarily by healthcare providers that
were not pulmonologists. Another interesting observation was that we
found no associations between BPD severity scores in the NICU and
outpatient ICS phenotypes. In brief, our data indicates a correlation
between a decision to initiate and the timing of ICS initiation (i.e.,
NICU discharge versus outpatient management) with patient demographics
and outpatient respiratory outcomes; suggesting an emergence of several
different outpatient BPD phenotypes defined in part, by ICS use.

Our study revealed that factors related to the prescription of ICS
therapy at the time of NICU discharge were related to the degree of
prematurity and respiratory disease. Notably, gestational age, birth
weight, need for supplemental oxygen at discharge, length of NICU stay,
and BPD severity, (which trended towards significance), were associated
with ICS therapy prescribed at discharge. In contrast, children
initiated on ICS therapy as outpatients were less likely to be on home
supplemental oxygen and more likely to have shorter NICU lengths of
stay, implying that a different set of factors may be contributing to
decision-making for prescribing an ICS in the outpatient setting. Our
outcome data, suggests that the more frequent ED visits and
rehospitalizations observed between NICU discharge and the first
outpatient pulmonary clinic visit, for a select group of infants and
children, may be driving non-pulmonary providers to initiate outpatient
ICS therapy.

After the first pulmonary visit, we found a decrease in the magnitude of
the adjusted odds ratios for ED visits and rehospitalizations, in
subjects prescribed outpatient ICS therapy prior to their first visit.
Nevertheless, it should be noted, that the odds ratio for these outcomes
still remained significantly above 1, when compared to subjects not on
an ICS. This association implies that ICS therapy may only partially
ameliorate the likelihood of adverse outpatient outcomes. Other factors,
such as social determinants of health, neutrophilic-driven small airway
inflammation or small airway dysanapsis may be greater drivers of
outpatient respiratory outcomes once children are discharged from the
NICU. Further studies are needed to examine these relationships.

In the longer term, we observed striking differences in the development
of asthma associated with the timing of prescription of ICS therapy.
While the frequency of a diagnosis of asthma is not associated with ICS
therapy at the time of NICU discharge (\emph{p} =0.45), it is associated
with being on ICS therapy at the conclusion of the first pulmonary
clinic visit (\emph{p} \textless{}0.001). Moreover, over 70\% of those
prescribed ICS therapy after NICU discharge and before the first
pulmonary clinic visit had a diagnosis of asthma, which may suggest the
emergence of a new respiratory phenotype, that presents in the
outpatient setting. Although our study is limited in identifying
potential causes for the emergence of this phenotype, we would speculate
that both genetic and environmental factors may be involved, given the
associations we observed with a family history of asthma and public
insurance coverage for the group of subjects placed on ICS therapy after
NICU discharge.

This study did not address whether ICS use was beneficial in modifying
respiratory outcomes in the BPD patient population prescribed an ICS.
Indeed, a beneficial response to ICS in the BPD population has been
shown to be variable.(11, 12) ICS has been shown to improve small
airflow obstruction caused by eosinophilic inflammation, however their
effectiveness in neutrophilic airway inflammation is less clear. (14)
Several studies have suggested that small airway obstruction in children
with BPD, is likely driven by a non-eosinophilic inflammatory process.
(15-18). One study of ICS use in formerly preterm children between 6 and
12 years of age found that by 12 weeks, ICS use resulted in modest lung
function improvement. (19) Although a modest improvement in lung
function was found in this study, results may have been different if
participants had been enriched for a family history of asthma and asthma
diagnosis. Another smaller study in children born \textless{}34
weeks-gestation found that the combination of an ICS coupled with a
long-acting \selectlanguage{greek}β \selectlanguage{english}agonist was superior to an ICS alone.(20) Larger studies
will be needed to address which phenotypes of BPD children will
potentially benefit from ICS use to mitigate respiratory morbidities and
symptoms.

We also did not address why an ICS was prescribed (at NICU discharge or
in the outpatient setting). Nevertheless, three different phenotypes
emerged that were associated with distinct demographic features and
outpatient respiratory outcomes, independent of BPD severity in the
NICU. These different outpatient BPD phenotypes (as described by ICS use
and initiation of ICS use) may be driven by genetic influences. (21)
however, we cannot rule out a component of caregiver preference in
deciding to initiate an ICS or not. In a single center study, we
previously reported that children with BPD and a family history of
asthma had a greater likelihood of ED visits, and systemic steroid use
in the outpatient setting, suggesting that there may be a genetic
component influencing ICS use. (22) A more precise understanding of
outpatient BPD phenotypes may help with prognosticating respiratory
outcomes and modifying long-term outcomes in children at risk for
lifetime respiratory morbidities.

Limitations of this study include its retrospective nature and the use
of electronic patient records which may contain inaccuracies based on
ICD codes and encounter information. Furthermore, our results reflect a
large urban center which may not be generalizable to other geographic
areas. Furthermore, practice variations in use of ICS therapy in infants
and children with BPD likely exist. Nevertheless, different demographic
characteristics were found among the three groups based on ICS use and
timing of initiation.

In summary, insights gained from this study may improve our
understanding of outpatient clinical phenotypes in preterm children with
BPD, further improving our understanding of their long-term respiratory
outcomes. Furthermore, identifying specific cohorts of children with BPD
who stand to benefit from ICS therapy will allow for more robust,
evidence-based guidelines for outpatient ICS use in this population
moving forward.

\textbf{Figure Legends}

\textbf{Figure 1.} Kaplan Meier curve showing that children with BPD who
were started on ICS as outpatients were more likely to be diagnosed with
asthma and to be diagnosed with asthma at an earlier age.



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\verb`Table 4 2-23-2024.docx`  available at \url{https://authorea.com/users/462418/articles/793448-outpatient-inhaled-corticosteroid-use-in-bronchopulmonary-dysplasia}

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