Cardiology in the Young Pulmonary hypertension during respiratory
cambridge.org/cty
Original Article
Cite this article: Kimura D, McNamara IF,
Wang J, Fowke JH, West AN, and Philip R (2019)
Pulmonary hypertension during respiratory
syncytial virus bronchiolitis: a risk factor for
severity of illness. Cardiology in the Young 29:
615–619. doi: 10.1017/S1047951119000313
Received: 28 March 2018
Revised: 24 January 2019
Accepted: 2 February 2019
First published online: 20 May 2019
Key words:
Pulmonary hypertension; respiratory syncytial
virus; congenital heart disease; chronic lung
disease of infancy; echocardiography
Author for correspondence:
Professor Dai Kimura, MD, FAAP, Division of
Critical Care Medicine, Department of
Pediatrics, University of Tennessee Health
Science Center, Le Bonheur Children’s Hospital,
Children’s Foundation Research Center, 50 N.
Dunlap St 3rd Floor, Memphis TN 38103, USA.
Tel: 901-287-6303; Fax: 901-287-6336; E-mail:
dkimura@uthsc.edu
© Cambridge University Press 2019
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https://doi.org/10.1017/S1047951119000313
syncytial virus bronchiolitis: a risk factor for
severity of illness
Dai Kimura1 , Isabella F. McNamara2, Jiajing Wang3, Jay H. Fowke3, Alina N. West1
and Ranjit Philip4
1
Division of Critical Care Medicine, Department of Pediatrics, University of Tennessee Health Science Center/Le
Bonheur Children’s Hospital, Memphis, TN, USA; 2Department of Health Research Methods, Evidence, and
Impact, McMaster University, Hamilton, ON, Canada; 3Division of Epidemiology, Department of Preventive
Medicine, University of Tennessee Health Science Center, Memphis, TN, USA and 4Division of Cardiology,
Department of Pediatrics, University of Tennessee Health Science Center/Le Bonheur Children’s Hospital,
Memphis, TN, USA
Abstract
Background: Respiratory syncytial virus infection is the most frequent cause of acute lower res-
piratory tract disease in infants. A few reports have suggested that pulmonary hypertension is
associated with increased severity of respiratory syncytial virus infection. We sought to deter-
mine the association between the pulmonary hypertension detected by echocardiography dur-
ing respiratory syncytial virus bronchiolitis and clinical outcomes. Methods: We retrospectively
reviewed 154 children admitted with respiratory syncytial virus bronchiolitis who had an echo-
cardiography performed during the admission. The association between pulmonary hyperten-
sion and clinical outcomes including mortality, intensive care unit (ICU) admission, prolonged
ICU stay (>10 days), tracheal intubation, and need of high frequency oscillator ventilation was
evaluated. Results: Echocardiography detected pulmonary hypertension in 29 patients (18.7%).
Pulmonary hypertension was observed more frequently in patients with congenital heart dis-
ease (CHD) (n = 11/33, 33%), chronic lung disease of infancy (n = 12/25, 48%), prematurity
(<37 weeks gestational age, n = 17/59, 29%), and Down syndrome (n = 4/10, 40%). The pres-
ence of pulmonary hypertension was associated with morbidity (p < 0.001) and mortality
(p = 0.02). However, in patients without these risk factors (n = 68), pulmonary hypertension
was detected in five patients who presented with shock or poor perfusion. Chronic lung disease
was associated with pulmonary hypertension (OR = 5.9, 95% CI 2.2–16.3, p = 0.0005).
Multivariate logistic analysis demonstrated that pulmonary hypertension is associated with ICU
admission (OR = 6.4, 95% CI 2.2–18.8, p = 0.0007), intubation (OR = 4.7, 95% CI 1.8–12.3,
p = 0.002), high frequency oscillator ventilation (OR = 8.4, 95% CI 2.95–23.98, p < 0.0001), and
prolonged ICU stay (OR = 4.9, 95% CI 2.0–11.7, p = 0.0004). Conclusions: Pulmonary hypertension
detected by echocardiography during respiratory syncytial virus infection was associated with
increased morbidity and mortality. Chronic lung disease was associated with pulmonary hyperten-
sion detected during respiratory syncytial virus bronchiolitis. Routine echocardiography is not war-
ranted for previously healthy, haemodynamically stable patients with respiratory syncytial virus
bronchiolitis.
Introduction
Respiratory syncytial virus infection is the most common cause of acute lower respiratory tract
disease in infants worldwide.1 Congenital heart disease (CHD), chronic lung disease of infancy/
bronchopulmonary dysplasia, male gender, premature birth, Down syndrome, immune defi-
ciency, and neuromuscular disease are described as risk factors for increased severity of respi-
ratory syncytial virus infection.2–5 Of these risk factors, CHD and chronic lung disease are
associated with the development of pulmonary hypertension.6,7 Recent studies have shown that
a history of pulmonary hypertension is associated with increased severity of illness during acute
lower respiratory tract infection.8 Worsening pulmonary hypertension secondary to respiratory
syncytial virus infection in infants with CHD is a challenging issue for paediatric cardiologists,
cardiac surgeons, and intensivists, and in severe cases can result in mortality.9–12
Pulmonary hypertension during acute bronchiolitis is observed by echocardiography in 29–
67% of infants and associated with prolonged hospitalisation.13–15 The pathophysiology of pul-
monary hypertension secondary to respiratory syncytial virus infection could be multiple factors
including lung volume changes either with atelectasis or hyperinflation, hypoxic vasoconstric-
tion, endothelin pathway, and Th2-skewed immune response.16–19 Treatment for pulmonary
hypertension during acute lung disease with pulmonary vasodilators is controversial because
 616
it is usually transient and could cause further hypoxia due to wors-
ening ventilation-perfusion mismatch.
In infants with CHD, the presence of pulmonary hypertension
during severe bronchiolitis could be a risk factor for worse clinical
outcomes as indicated by these small studies.11,12,20,21 However, the
clinical significance of pulmonary hypertension during respiratory
syncytial virus bronchiolitis is still undetermined, especially in
infants without CHD. We sought to review echocardiography dur-
ing respiratory syncytial virus infection and assess the association
between the presence of pulmonary hypertension and clinical out-
comes in respiratory syncytial virus infected infants. The primary
outcome measured in this study was mortality, and the secondary
outcomes were the severity of the disease measured by intensive
care unit (ICU) admission, prolonged ICU stay (>10 days), tra-
cheal intubation, and use of high frequency oscillator ventilation.
Methods
Retrospective cohort screening
The UTHSC Institutional Review Board approved this study. We
retrospectively reviewed the records of 154 children hospitalised,
documented with the diagnosis of respiratory syncytial virus bron-
chiolitis who underwent echocardiography at Le Bonheur
Children’s Hospital from December 2007 to December 2014.
International Classification of Diseases (ICD) code was used for
screening patients with respiratory syncytial virus bronchiolitis,
and patients who received echocardiography were identified with
the support of biomedical informatics core team in Le Bonheur
Children’s Hospital. Diagnosis of respiratory syncytial virus was
made with either rapid antigen test (enzyme immunoassay) or pol-
ymerase chain reaction using nasal or tracheal aspirate samples.
Patients without positive respiratory syncytial virus test results
were excluded from this study.
Pulmonary hypertension detection by echocardiography
Indirect measures of pulmonary hypertension were used to catego-
rise subjects with pulmonary hypertension, including peak tricus-
pid regurgitation gradient (TR), interventricular septal curvature
geometry, early and end diastolic pulmonary insufficiency gra-
dients, and the left ventricle to right ventricular ratio in systole
in short axis.22,23 The pressure gradient between the right ventricle
pressure and the right atrium pressure was estimated using the
modified Bernoulli equation (4 × TR2) if TR was measurable.
We uniformly estimated right atrium pressure as 5 mmHg and cal-
culated systolic pulmonary artery pressure as 4 × TR2 + 5 mmHg.22
If patients had intracardiac or extracardiac shunt without measur-
able TR, the gradient across the shunt was used for calculating esti-
mated systolic pulmonary artery pressure.22 Systemic blood
pressure measured by a cuff or arterial line was used to compare
with estimated systolic pulmonary artery pressure. For this study,
pulmonary hypertension was defined as an estimated pulmonary
artery pressure of at least one-third systemic arterial blood pressure
as assessed by echocardiography. If patients had multiple echocar-
diograms, the presence of pulmonary hypertension was deter-
mined by the echocardiogram with the most severe pulmonary
hypertension. Echocardiographic images were reviewed by a
paediatric cardiologist, who was blinded to the clinical outcomes.
In the subjects that had echocardiography done after recovery from
their acute illness, follow-up echocardiograms were reviewed for
the presence of pulmonary hypertension.
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https://doi.org/10.1017/S1047951119000313
D. Kimura et al.
Data collection
In addition to demographic data and indications for echocardiog-
raphy, the presence of risk factors for severe respiratory syncytial
virus bronchiolitis (CHD, chronic lung disease, premature birth
(<37 weeks gestational age (wGA)), Down syndrome, and neuro-
muscular disease), and clinical outcomes such as ICU admission,
prolonged ICU stay (>10 days), tracheal intubation for mechanical
ventilatory support, use of high frequency oscillator ventilation,
and mortality during the admission were collected for these
patients from the electronic health record. In this study, prolonged
ICU stay was defined as >10 days according to the median ICU
stay in patients with comorbidities and it includes 25 percentile
of patients reported by others.24,25
Statistical analyses
Demographic data between patients with and without pulmonary
hypertension, indications for echocardiography, and clinical out-
comes were compared with Mann–Whitney U-test or Fisher’s
exact test, according to the data type. Continuous variables are
reported as median (25th, 75th percentile) unless otherwise speci-
fied. Subgroup analysis was conducted to evaluate the effect of pul-
monary hypertension on clinical outcomes within the patients who
required ICU admission using Fisher’s exact test. A multivariate
logistic analysis was conducted to evaluate the association between
pulmonary hypertension and clinical outcomes using variables
including age, gender, CHD, chronic lung disease, Down syn-
drome, and neuromuscular disorders to predict clinical outcomes
including ICU admission, prolonged ICU stay (>10 days), tracheal
intubation for mechanical ventilation, and necessity of high fre-
quency oscillator ventilation. We chose these variables described
as risk factors by other groups for increased severity of respiratory
syncytial virus bronchiolitis.2–5 Statistical analyses were conducted
with JMP and SAS 9.4 software (SAS, Cary, North Carolina, United
States of America), and p < 0.05 was considered statistically
significant.
Results
The summary of demographic data for the 154 patients included in
this study is shown in Table 1. Indications for echocardiography
are summarised in Table 2. Most patients with pulmonary hyper-
tension had echocardiography for either past medical history of
CHD, chronic lung disease, shock, or poor perfusion.
Conversely, one-third of the patients without pulmonary hyper-
tension underwent echocardiography for a heart murmur.
Echocardiography detected evidence of pulmonary hypertension
in 29 patients (19%) and suspected right ventricle pressures were
1/3–1/2 of systemic blood pressure in these patients. The patients
with pulmonary hypertension (median 7 months of age; 25–75
percentile, 2–13 months) are significantly older than the patients
without pulmonary hypertension (2, 1–5-month-old) (p < 0.01).
Approximately one-fourth (n = 40) of the patients in this study
had CHD, and 11 of these 40 patients (28%) with CHD had pul-
monary hypertension. In these patients with CHD, there were no
patients with unrestrictive communication at the ventricular or
great artery level. Pulmonary hypertension was observed more fre-
quently in patients with chronic lung disease (n = 12/29, 41%,
p = 0.0002), and those who were born prematurely (<37 wGA,
n = 17/29, 59%, p = 0.03). Few patients without any risk factors
developed pulmonary hypertension (n = 5/29, 17%, p = 0.0009).
For these five patients without risk factors, echocardiography
 618
Table 5. (A) Multivariate logistic analysis for the association between
pulmonary hypertension and CLD or CHD. (B) Multivariate logistic analysis to
determine the association between pulmonary hypertension and clinical
outcomes. Adjusted for age and CLD
A virus infection.11 In our subgroup analysis, the presence of pulmo-
Independent variable Odds ratio 95% CI
CLD 5.97 (2.19–6.27)
CHD 2.56 (1.00–6.57)
B with CHD than in patients without CHD, and these patients with
ICU admission 6.17 (2.09–18.20)
Intubation 4.46 (1.68–11.82)
HFOV 11.15 (3.59–34.58)
Prolonged ICU stay 4.90 (2.02–11.88)
CHD = congenital heart disease; CI = confidence interval; CLD = chronic lung disease;
HFOV = high frequency oscillatory ventilation; ICU = intensive care unit
In multiple variate analysis adjusted for age, pulmonary hyper-
tension was associated with chronic lung disease, but was not asso-
ciated with CHD (Table 5A). A multivariate logistic regression
modelling was also conducted to evaluate the association between
pulmonary hypertension and clinical outcomes. The number of
mortality cases in this study was so small that we removed mortal-
ity from the logistic regression model. Since pulmonary hyperten-
sion remained associated with chronic lung disease (Table 5A), we
calculated odds ratio between pulmonary hypertension and clinical
outcomes adjusted for age and chronic lung disease. Pulmonary
hypertension detected by echocardiography was associated with
ICU admission, intubation, use of high frequency oscillator
ventilation, and prolonged ICU stay even after adjusted for age
and chronic lung disease (Table 5B).
Discussion
In this study, pulmonary hypertension was detected in 29 out of
154 patients (19%) by echocardiography during acute bronchiolitis
from respiratory syncytial virus infection. To the best of our knowl-
edge, this study includes the largest cohort of patients to undergo
echocardiography during acute bronchiolitis from respiratory syn-
cytial virus infection.13–15 When compared with prior investiga-
tions, this study included a larger number of critically ill
patients who were admitted to the ICU, received mechanical ven-
tilation, and were treated with high frequency oscillatory ventila-
tion. However, pulmonary hypertension was detected less
frequently than previous studies,13–15 probably due to the inclusion
of many patients who had echocardiography for murmur and a
milder clinical course. Furthermore, significant associations
between pulmonary hypertension and clinical outcomes, including
ICU admission, endotracheal intubation, high frequency oscillator
ventilation, prolonged ICU stay, and mortality, were also demon-
strated as previously described by others.8,13 After intubation, more
than half of the patients with pulmonary hypertension were treated
with high frequency oscillator ventilation. We only observed a
mild-to-moderate form of pulmonary hypertension which is sim-
ilar to the report by Fitzgerald.15 We also observed pulmonary
hypertension in several patients with shock or poor perfusion.
The follow-up echocardiography showed improvement in pulmo-
nary hypertension, and it indicates a transient or worsening
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D. Kimura et al.
pulmonary hypertension by respiratory syncytial virus infection
as previously described.14
In patients with CHD, pulmonary hypertension has been asso-
ciated with morbidity and mortality during respiratory syncytial
p value nary hypertension in patients with CHD was not associated with
worse clinical outcomes, and this finding differs from the previ-
<0.01
ously reported studies.11,26 In this study, the prevalence of
0.05 obtaining an echocardiography might have been higher in patients
CHD had only mild pulmonary hypertension and tolerated respi-
<0.01
ratory syncytial virus infection without complications. However,
<0.01 many patients in the comparison group of CHD/no-pulmonary
<0.01 hypertension were also critically ill in this study, indicated by
the 67% of patients who received mechanical ventilation. This
<0.01
study is a small-single centre study, and our sample size may be
too small to prove the association between pulmonary hyperten-
sion and clinical outcomes in patients with CHD. These may have
contributed to the unexpected results. Recent advances in ICU
management and therapies for pulmonary hypertension might
also have contributed to our observed clinical outcomes.
Our study showed transient or worsening pulmonary hyperten-
sion during respiratory syncytial virus infection in patients with
chronic lung disease or born prematurely. This phenomenon in
this population is not well described, and further investigation,
including prevalence and effects on clinical outcomes, is needed
to improve care.27 Chronic lung disease of infancy is known to
cause pulmonary hypertension without respiratory syncytial virus
infection6 and is a risk factor for severity of disease with respiratory
syncytial virus infection.2,28
Obtaining an echocardiogram in every patient admitted with
respiratory syncytial virus is a significant cost and resource burden.
For previously healthy infants who developed a mild clinical course
of respiratory syncytial virus, there seem to be no indications for
obtaining echocardiography, except in infants who develop shock
or poor perfusion, i.e., a haemodynamic indication for an
echocardiogram since our data did show an association with pul-
monary hypertension in this cohort. Based on the risk factors and
clinical outcome metrics evaluated in this study, it may be reason-
able to obtain a screening echocardiogram for pulmonary hyper-
tension in patients with a past medical history of CHD, chronic
lung disease/bronchopulmonary dysplasia, or premature birth.
The echocardiogram findings may provide prognostic information
by identifying a risk factor such as pulmonary hypertension for
severe illness, and may also potentially help the clinician alter
the clinical course by taking measures to prevent a pulmonary
hypertensive crisis.
There are several limitations to this study. Due to study design,
we cannot exclude selection bias. We included the patients who
received echocardiography retrospectively. It is difficult to define
the incidence of pulmonary hypertension during respiratory syn-
cytial virus infection due to this study design. During the hospital-
isation for respiratory syncytial virus bronchiolitis, patients with
CHD were more likely to have an echocardiogram when compared
to those patients without risk factors. These with CHD and mild
pulmonary hypertension tolerated respiratory syncytial virus
infection without complications, and these might have an effect
on our results. As our standard of care is not to order echocardi-
ography for every patient with respiratory syncytial virus bron-
chiolitis, this study may have included relatively sicker patients
without CHD who had worse clinical outcomes. Furthermore,
echocardiography was ordered by a primary team, and there
 Cardiology in the Young
was no clear guideline for ordering echocardiography. The direct
measurement of pulmonary hypertension with catheterisation,
which is the gold standard for the diagnosis of pulmonary hyper-
tension, was not performed in these clinically unstable patients.
Some of the patients without pulmonary hypertension were treated
with inhaled nitric oxid (iNO) for hypoxia, which may have modi-
fied the echocardiography findings. The impact of treatment for
pulmonary hypertension on outcomes was not evaluated and war-
rants further. Several patients who had pulmonary hypertension
during respiratory syncytial virus never had echocardiography
before respiratory syncytial virus infection, and it is impossible
to differentiate pulmonary hypertension as a baseline from a
new development of pulmonary hypertension. Paediatric intensive
care unit admission criteria and the decision to place on high fre-
quency oscillator ventilation were not consistent due to variations
in decision making by different primary ICU teams. This study was
conducted in a single centre with a small sample size. Lastly, echo-
cardiography was reviewed by a single paediatric cardiologist.
Conclusions
Echocardiographic signs of pulmonary hypertension in hospital-
ised infants during respiratory syncytial virus infection were asso-
ciated with a higher rate of morbidity and mortality. Patients with a
history of chronic lung disease of infancy are associated with pul-
monary hypertension observed by echocardiography during respi-
ratory syncytial virus infection. During respiratory syncytial virus
bronchiolitis, echocardiography may not be indicated if a patient is
previously healthy and does not have shock or poor perfusion.
Author ORCIDs. Dai Kimura 0000-0001-9360-8506
Acknowledgement. The authors appreciate the support from Biomedical
Informatics core team in Le Bonheur Children’s Hospital led by Dr.
Teeradache Viangteeravat.
Financial Support. This research received no specific grant from any funding
agency, commercial or not-for-profit sectors.
Conflicts of Interest. None.
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