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 (p =0.45), it is associated
with being on ICS therapy at the conclusion of the first pulmonary
clinic visit (p <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 <34
weeks-gestation found that the combination of an ICS coupled with a
long-acting β 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.