Review
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
►► Additional material is
published online only. To view
please visit the journal online
(http://d​ x.​doi.​org/​10.​1136/​
archdischild-​2019-​316896).
Department of Paediatrics, Poole
Hospital NHS Foundation Trust,
Poole, UK
Correspondence to
Dr Keir Dan Edwards, Poole
Hospital, Poole BH15 2JB, UK; ​
keir.​edwards93@​gmail.​com
Received 27 January 2019
Revised 18 September 2019
Accepted 30 September 2019
© Author(s) (or their
employer(s)) 2019. No
commercial re-use. See rights
and permissions. Published
by BMJ.
To cite: Edwards KD,
Tighe MP. Arch Dis Child
Educ Pract Ed Epub ahead
of print: [please include Day
Month Year]. doi:10.1136/
edpract-2019-316896
Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
How to use N-terminal pro-brain
natriuretic peptide (NT-proBNP) in
assessing disease severity
in bronchiolitis
Keir Dan Edwards, Mark Peter Tighe
Abstract
Bronchiolitis is a common viral illness which
can lead to severe respiratory compromise
and can coexist with or mask cardiac failure.
Brain natriuretic peptide (BNP) and the inactive
portion of its pro-hormone: N-terminal pro-
BNP (NT-proBNP) are excreted in response to
cardiomyocyte stretching and are established
biomarkers in cardiac failure. Here, we discuss
the technicalities of NT-proBNP testing and
review available evidence regarding NT-proBNP
testing in bronchiolitis. We identified and
appraised seven studies assessing the role of
BNP or NT-proBNP as biomarkers of bronchiolitis
severity, in children with and without underlying
congenital cardiac disease. One study of 76
children with dyspnoea showed that the median
NT-proBNP level in children with cardiac failure
was 7321 pg/mL vs 241 pg/mL in children with
a respiratory cause of dyspnoea vs 87.21 pg/
mL in healthy controls (p<0.05). A cut-off of
726 pg/mL could aid differentiation between
cardiac and respiratory causes of respiratory
distress. Other evidence showed a positive
correlation between BNP levels and bronchiolitis
severity, and that raised BNP can predict acute
heart failure in children with congenital cardiac
disease presenting with bronchiolitis. However,
most studies consisted of small cohorts with
conflicting evidence between them. Furthermore,
several studies assessed BNP rather than NT-
proBNP directly. BNP has a shorter half-life, which
may affect analysis. In conclusion, NT-proBNP is
a rapid and inexpensive test with the potential
to be a useful biomarker in severe bronchiolitis
and cases complicated by acute cardiac failure.
However, studies with larger cohorts are required
to better establish this role.
Introduction
Bronchiolitis is a viral respiratory illness
leading to inflammation of the bron-
chioles and respiratory compromise. It
remains the most common cause of admis-
sion to hospital in infants and in 2015–
2016 accounted for 39 122 admissions
in the UK.1 Diagnosis and assessment of
severity of bronchiolitis is largely clinical,
with limited scope for investigations. The
clinical syndrome ranges from mild illness
to severe respiratory distress and apnoeas.
While many cases are self-limiting and can
be managed in the community, a minority
Consortia. Protected by copyright.
require hospital admission. A propor-
tion require intensive respiratory support
such as high flow nasal oxygen, contin-
uous positive airway pressure (CPAP)
and ventilation. The ability to predict
respiratory deterioration severity early in
the disease course would allow clinicians
to make available appropriate intensive
treatments2 and may reduce admissions
to regional paediatric intensive care
units with early interventions. Clinical
features such as low oxygen saturations,
grunting, apnoeas, chest recession, dehy-
dration, rising CO2 and poor feeding
can be predictive of a need for hospital-
isation and more intensive respiratory
support.3 However, a reliable biomarker
would remove interobserver variation and
may identify these patients earlier in the
disease course.
Physiological background
Brain natriuretic peptide (BNP) and the
inactive portion of its pro-hormone,
N-terminal pro-BNP (NT-proBNP) are
excreted by the ventricles in response to
cardiomyocyte stretching. BNP acts on
the natriuretic peptide (NP) receptor with
effects including inducing natriuresis,
vasoconstriction, thirst suppression
and inhibition of aldosterone synthesis.
Furthermore, in vitro models have
demonstrated relaxant effects on tracheal
    1
Review
smooth muscle cells and protection against bronchial
hyper-responsiveness.4
BNP and NT-proBNP are established in the assess-
ment of cardiac failure in both adults and children,
correlating with disease severity.5 However, more
recently their application as a marker of respiratory
disease severity has been of interest. For example,
elevated NT-proBNP levels have been shown to
correlate with increased length of hospital stay and
need for intensive care support in adults with acute
exacerbations of chronic obstructive pulmonary disease
(COPD), even in the absence of cardiac dysfunction.6
We assess the application of NT-proBNP to several
distinct clinical situations relating to bronchiolitis.
Primarily, we examine the role of NT-proBNP as a
biomarker in predicting the severity of isolated bron-
chiolitis. Second, we address its role in children with
congenital cardiac disease and bronchiolitis; specif-
ically whether NT-proBNP can help identify acute
cardiac failure—a possible complication of bron-
chiolitis in these patients. Finally, we assess whether
NT-proBNP levels are significantly different in cardiac
failure versus pulmonary disease such as bronchiolitis.
This is an important clinical consideration in infants
presenting with acute dyspnoea.
Technical background
BNP begins as a pre-prohormone which is cleaved to
form proBNP. This in turn is cleaved into two parts:
the inactive N-terminal portion (NT-proBNP) and BNP
itself.4 It is preferable to test NT-proBNP levels rather
than BNP for a number of reasons. First, NT-proBNP
has a longer half-life than BNP (1–2 hours vs 20 min).
Furthermore, it reaches higher serum concentrations and
is more stable at room temperature, making testing more
reliable. Finally, antibodies used in laboratory assays
for NT-proBNP are standardised, making comparisons
between different reference laboratories simpler.4
NT-proBNP is measured using an immunofluores-
cence assay. Heparinised or EDTA blood containers
should be used when collecting samples, as it is
measured in serum or plasma. However point-of-care
testing devices are also available which can sample
whole blood. The normal range of NT-proBNP varies
with age. Among children age 1–3 years, the 75th
centile of normal values is approximately 231 pg/mL
and the 97.5th centile 320 pg/mL.7
Sample turnaround is relatively rapid, approxi-
mately 14–20  min (Siemens, Biomerieux). Testing
requires a minimum of 0.2 mL serum. The unit cost
for a NT-proBNP assay is approximately £26.8 Exer-
cise, female sex, diabetes, endocrine disorders (such as
hyperaldosteronism and hyperthyroidism), renal failure,
cardiovascular disease and increased dietary sodium may
all increase levels of NT-proBNP. Levels are lower in
obesity and with the use of drugs such as ACE inhibitors,
diuretics, aldosterone antagonists and nitrates.7
2 Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
Search methodology
The Medline Database was searched via PubMed. Arti-
cles up to and including November 2018 were included
in the search. An advanced search was carried out
including the following search terms: ‘Bronchiolitis’,
‘Respiratory distress’, ‘Respiratory syncytial Virus’,
‘Bronchiolitis severity’, ‘bronchiolitis biomarker’,
‘brain natriuretic peptide’, ‘BNP’, ‘N-terminal
Pro-brain Natriuretic Peptide’, ‘NT-proBNP’, ‘cardiac
failure’ and ‘congenital cardiac disease’. Search results
were sorted via the ‘most relevant’ ranking mechanism.
Articles were included based on their relevance to the
specific clinical questions discussed in the ‘Application
to clinical practice’ section (see figure 1). Searches
yielded 128 results in total, consisting of 86 unique
returns. Seven abstracts were original research deemed
relevant to the clinical questions of our review. Results
were excluded for several reasons, including papers
not assessing BNP or NT-proBNP, or assessing BNP
or NT-proBNP in diseases or patient groups (eg, in
adults) beyond the scope of this article.
Indications and limitations (clinical
scenarios)
Consortia. Protected by copyright.
Among infants presenting to hospital with isolated bron-
chiolitis who require hospitalisation and/or intensive
care support, is NT-proBNP significantly raised com-
pared with those who do not require such measures?
Limited work has been done on the application of
NT-proBNP in children with bronchiolitis and the
quality of evidence is low. One prospective study has
been carried out assessing use of BNP as a marker of
severity in bronchiolitis. Anil et al enrolled 232 chil-
dren presenting with bronchiolitis to an emergency
department.9 32 age and gender matched controls were
selected from children attending with non-respiratory
symptoms. Those with underlying chronic disease or
clinical evidence of heart failure were excluded.
A blinded clinical severity score (CSS), carried
out prior to supportive interventions, stratified the
patients as having mild, moderate or severe bronchiol-
itis. Serum BNP levels were taken following treatment
initiation. All physicians making clinical decisions
were not authors of the study and were blinded to
BNP levels.
The study demonstrated significantly (p<0.001)
different BNP levels between the control group and
each clinical severity group. Furthermore, the CSS as
well as the BNP level were significant predictors of
hospitalisation (p<0.001). A significant correlation
was also demonstrated between BNP levels and length
of hospital stay. These findings provide evidence that
BNP may be a useful biomarker in bronchiolitis inde-
pendent of cardiac pathology. The ability to predict
severity as well as likelihood of hospitalisation supports
its use in clinical decision making in bronchiolitis. This
may be of significant benefit, considering the lack of
useful laboratory tests currently available.

Figure 1  CONSORT flow diagram.
Interestingly, similar findings are coming to
light in adult medicine with evidence suggesting
BNP may predict severity of pneumonia in adults
without underlying cardiac pathology. 10 Unfor-
tunately, as BNP levels rather than NT-proBNP
levels were assessed, useful NT-proBNP level
cut-offs to stratify bronchiolitis severity cannot be
drawn. Furthermore, given the short half-life of
BNP, it is unclear what effect treatment had on the
levels, considering they were taken after treatment
had begun. NT-proBNP levels may not correlate
directly with BNP levels in this scenario, given its
longer half-life. A cut-off could be extrapolated
for NT-proBNP levels based on the relationship
between BNP and NT-proBNP levels in cardiac
disease, where both are well established. However,
this may be too simplistic an approach. Jensen et
al 11 found that the NT-proBNP/BNP ratio increased
in the presence of increased inflammatory markers.
Therefore, NT-proBNP levels may be inflated
compared with BNP in respiratory infections.
It should be noted that a study by Sahingozlu et
al did not replicate these results.12 They assessed
the relationship between bronchiolitis and BNP
levels among 68 children with and without congen-
ital cardiac disease, the former of which we will
return to below. In the context of isolated bronchi-
olitis, although BNP levels were significantly higher
than healthy controls, they found no correlation
between BNP levels and increasing severity of
disease. Other evidence in more heterogeneous
populations regarding elevated NT-pro BNP is
considered below.
Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
Review
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
Consortia. Protected by copyright.
Among infants with known congenital cardiac anoma-
lies and bronchiolitis who require hospitalisation and/
or intensive care support, is NT-proBNP significantly
raised compared with those who do not require such
measures and does NT-pro-BNP help identify those in
cardiac failure?
There is unfortunately little evidence among this
cohort for the use of NT-proBNP as a predictor of
bronchiolitis severity. However, studies have investi-
gated whether BNP is significantly elevated in acute
heart failure in infants with congenital heart disease
(CHD) presenting with bronchiolitis. This is relevant
as bronchiolitis can precipitate acute heart failure in
this patient group and is indicative of severe disease
likely requiring hospitalisation.
Samuel et al performed a prospective cohort study
on 18 children with previously diagnosed CHD
presenting with bronchiolitis.13 Only those with PCR
confirmed RSV infection were included. BNP level
and clinical features were recorded on initial recruit-
ment. A paediatric cardiologist examined the patients
and performed echocardiography within 12 hours to
confirm the presence of CHD and evaluate for the
presence of acute heart failure. The cardiologist was
blinded to patient BNP level. Seven patients (39%)
were diagnosed with heart failure and 11 (61%) were
not. Among the heart failure subgroup, median BNP
was 783 pg/mL compared with 59 pg/mL among the
non-heart failure patients. A BNP level above 95 pg/
mL was suggested as predictive of acute heart failure
(table 1).
As discussed earlier, Sahingozlu et al assessed BNP
levels in 68 children presenting with bronchiolitis.12
3
Review

Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
Table 1  Summary of specificity and sensitivity of NT-proBNP and BNP in differentiating cardiac and respiratory causes of acute
dyspnoea, and in identifying acute heart failure in bronchiolitis on a background of cardiac disease
Positive
Negative predictive predictive value
Cut-off Sensitivity (%) Specificity (%) value (%) (%)
Scenario Variable Paper (pg/mL) (95% CI) (95% CI) (95% CI) (95% CI)
Differentiating cardiac versus NT-proBNP Evim et al 726.8 100 94.3 100 95
Respiratory causes of acute NT-proBNP Cohen et al 2940 Not supplied Not supplied Not supplied Not supplied
dyspnoea
BNP Kolouri et al 40 91 (72 to 99) 77 (56 to 91) 91 (71 to 99) 78 (58 to 91)
Identifying heart failure in those BNP Samuel et al 95 71(29 to 96) 91(58 to 99) 83 (26 to 93) 83 (28 to 95)
with bronchiolitis and underlying
cardiac disease
BNP, brain natriuretic peptide; NT-proBNP, N-terminal pro-BNP.

The cohort included children with underlying congen- Are there other studies assessing the role of pro-BNP in
ital cardiac abnormalities, children with isolated bron- respiratory or cardiac failure?
chiolitis and a control group. Children with congenital
Evim et al analysed NT-proBNP levels in a cohort of
cardiac abnormalities with bronchiolitis had BNP
76 children presenting with dyspnoea.14 Ages ranged
levels significantly higher than the isolated bronchi-
from 1 month to 17.5 years, with a median age of 8
olitis subgroup or controls (mean BNP levels were
841.2 pg/mL, 118.9 pg/mL and 11.6 pg/mL, respec- months. 25 were suffering from acute cardiac failure
tively). Furthermore, patients with isolated bronchi- due to underlying cardiac pathology, 16 from acute
olitis still had a raised BNP compared with controls. cardiac failure due to acute pulmonary disease and 35
The study also assessed for acute cardiac failure, which from acute pulmonary disease alone. A control group

Consortia. Protected by copyright.

was again shown to be associated with BNP levels far of non-dyspnoeic children was used. They demon-
higher than in patients without (mean BNP 1122.1 pg/ strated significantly higher levels of NT-proBNP
mL vs 112.9 pg/mL, respectively). among the cardiac failure groups than controls (median

Table 2  Table of evidence

Citation Study group Study type Outcome Key result Comments
9
Anil et al Isolated bronchiolitis Prospective BNP level, CSS, Higher BNP levels correlated with BNP level may be predictive of severe
n=232 vs controls n=32 cohort hospitalisation increased CSS, hospitalisation and bronchiolitis requiring hospitalisation.
increased length of hospital stay.
Samuel n=18 bronchiolitis, Prospective BNP level acute heart Higher BNP levels correlated with Very small study supporting role for BNP in
et al13 background of congenital cohort—single failure length of stay in presence of acute heart failure and identifying acute heart failure in bronchiolitis
heart disease group hospital increased hospital stay. with underlying cardiac disease.
Evim et al14 n=76 with dyspnoea, Prospective NT-proBNP level acute Significantly higher NT-proBNP levels Suggests NT-proBNP may be used to
due to cardiac failure or cohort heart failure with breathlessness due to cardiac failure differentiate cardiac failure and pulmonary
pulmonary disease compared with pulmonary disease and disease as a cause of dyspnoea as well as
n=32 non-dyspnoeic controls. identifying causes of pulmonary disease
controls. Also significantly higher levels in complicated by heart failure. A NT-proBNP level
pulmonary disease versus controls. of 726.8 pg/mL is suggested as a cut-off.
Sahingozlu n=68 bronchiolitis, Prospective BNP level acute heart Significantly higher BNP levels with Although significantly different BNP levels
et al12 including patients with cohort failure congenital cardiac disease and acute between cardiac failure, isolated bronchiolitis
and without congenital heart failure versus controls and isolated and controls were demonstrated, no correlation
cardiac disease bronchiolitis. between BNP level and severity of bronchiolitis
n=30 controls Also significantly higher levels in isolated was found.
bronchiolitis versus controls.
Markovic- n=60 neonates with RD, Prospective NT-proBNP level Significantly higher BNP levels in RD Suggests NT-proBNP cannot differentiate
Sovtic et al16 n=3 controls cohort neonates versus controls. between cardiac and pulmonary causes of
No difference in NT-proBNP levels RD; however, more severe RD correlated with
between pulmonary and cardiac causes higher NT-proBNP, supporting a possible role
of RD. for prediction of severity of bronchiolitis.
Cohen et al17 n=35 infants with RD Prospective NT-proBNP acute cardiac Significantly higher NT-proBNP levels in Small cohort size, however, results refute role
n=13 controls cohort failure RD due to acute cardiac failure versus for NT-proBNP in assessment of bronchiolitis
controls. severity.
No significant difference in NT-proBNP
levels between RD due to pulmonary
disease and controls.
Koulouri n=49 children with Prospective BNP acute heart failure Significantly higher BNP level in RD due to Suggests BNP can differentiate between
et al15 acute RD cohort congestive cardiac failure (CHF), compared cardiac and respiratory causes of RD. A cut-
with RD due to pulmonary disease. off of 40 pg/mL is suggested—a higher level
differentiating CHF from respiratory causes
with 84% accuracy.
BNP, brain natriuretic peptide; CHF, cardiac failure; CSS, clinical severity score; NT-proBNP, N-terminal pro-BNP; RD, respiratory distress.

4 Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896


Box 1  Grey case
A 6-week-old boy with Trisomy 21 and a known ventricular-
septal defect presents to the DGH emergency department
at 22:00 hours. His parents report a 2-day history of coryzal
symptoms, with worsening breathlessness and lethargy over
the course of today. On examination, he is tachypnoeic and
lethargic with bilateral crackles through the lung fields. He
has a pan-systolic murmur but no gallop rhythm, and his
liver edge is 2 cm below the costal margin. His observations
are as follows:
­ tion of NT-proBNP to differentiate acute cardiac and
HR: 150
RR: 55
Temperature: 37.7
Oxygen saturation: 95% in 2 L nasal cannulae
Venous blood gas shows pH 7.34 pCO2 6.2 BXS −2. Lac 2.1.
Rapid viral assay confirms RSV.
­
You diagnose bronchiolitis and instigate appropriate
supportive management but are concerned that acute
cardiac failure may be part of the clinical picture.
Echocardiography and paediatric cardiology review is not
routinely available at your district general hospital until
the next day. You take bloods including a NT-proBNP which
comes back at 6600 pg/mL. The NT-proBNP strengthens
your suspicion of acute cardiac failure and you contact the
paediatric cardiology team at the regional hospital to plan
treatment and transfer for echocardiography and review
in the morning. You trial a dose of furosemide (0.5 mg/kg)
which improves the child’s work of breathing and oxygen
requirement overnight and stabilises the child for transfer in
the morning.
7321 pg/mL vs 87.21 pg/mL, p<0.05). Furthermore,
the pulmonary disease alone group had significantly
higher NT-proBNP levels than controls, but signifi-
cantly lower levels than heart failure groups (median
241 pg/mL).
This suggests that although NT-proBNP is raised
in both pulmonary and cardiac pathology, it can be
used in the assessment of each independently. For
example, regarding an infant with respiratory distress,
a NT-proBNP level of several thousand would likely
indicate cardiac failure, whereas a level of several
hundred would suggest acute pulmonary disease such
as isolated bronchiolitis to be the cause of their symp-
toms. A cut-off of 726 pg/mL was suggested in this
study in order to differentiate cardiac failure from
pulmonary disease as the cause of respiratory distress
(table 1).
For the same reason, NT-proBNP levels could be
used to identify cases of bronchiolitis complicated by
heart failure. The subgroup of patients in this study
with cardiac failure secondary to pulmonary disease
had significantly higher NT-proBNP levels than the
isolated pulmonary disease group, which would
support this.
Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
Review
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
Work by Koulouri et al assessing BNP in acute respi-
ratory distress supports these conclusions.15 Of 49
children with respiratory distress, 23 had congestive
cardiac failure, confirmed by echocardiography, and
26 a respiratory cause for their symptoms. Those with
cardiac failure had significantly higher BNP levels, as
tested with rapid immunoassay (693.0±501.6 pg/mL
vs 45.2±64.0 pg/mL). A BNP level of 40 pg/mL was
suggested as a cut-off for the differentiation of cardiac
failure from respiratory disease.
Not all available evidence supports the applica-
pulmonary pathology. For example, Markovic-Sovtic
et al measured NT-proBNP levels in term neonates
admitted with respiratory distress.16 They were divided
into those with respiratory distress due to a pulmonary
Test your knowledge
1. What is NT-proBNP?
A. Biologically inactive protein cleaved from the
pro-hormone during BNP formation.
B. Biologically active protein cleaved from the pro-
Consortia. Protected by copyright.
hormone during BNP formation.
C. The pro-hormone from which BNP is formed.
D. A cardiomyocyte surface receptor.
2. What is a key benefit of NT-proBNP as a biomarker?
A. It has a longer half-life in the circulation than
BNP.
B. It is more stable at room temperature than BNP.
C. Assays are standardised allowing easy
comparison of results.
D. All of the above.
3. Which of the following has a raised BNP been shown to
correlate with in children with bronchiolitis?
A. Increased clinical severity.
B. Shorter length of hospital stay.
C. Increased mortality.
D. Presence of acute renal failure.
4. How may NT-proBNP inform decision making in
children presenting with congenital cardiac disease and
bronchiolitis?
A. By identifying children who can be managed in
primary care.
B. By allowing early identification of the presence of
acute heart failure precipitated by bronchiolitis.
C. By predicting length of hospital stay.
D. By predicting need for invasive ventilation.
5. What is the approximate sample processing time for NT-
proBNP testing?
A. 20 min.
B. 30 min–1 hour.
C. 1–2 hours.
D. 4–6 hours.
Answers to the quiz are at the end of the references.
5
Review
aetiology and those with congenital cardiac disease,
with a non-dyspnoeic control group. NT-proBNP was
significantly higher among the respiratory distress
groups compared with controls; however, there was
no significant difference in NT-proBNP levels between
the congenital cardiac disease and pulmonary disease
subgroups. The authors noted that more severe respi-
ratory distress did correlate with higher NT-proBNP
levels. This may support the evidence from Anil et
al discussed above on the use of BNP as a marker of
bronchiolitis severity. Cohen et al carried out a similar
study measuring BNP levels in 35 infants with acute
respiratory distress due to either acute heart failure
or pulmonary disease (predominantly bronchiol-
itis) as well as a control group.17 While they showed
significantly higher BNP levels among the heart failure
group, there was no significant difference between
controls and pulmonary disease groups.
Conclusion and topics for further research
NT-proBNP is a rapid and inexpensive biochemical
marker with applications in both paediatric cardiac and
respiratory disease. Its potential use in the management
of bronchiolitis is twofold, especially where access to
echocardiography may be limited.
First, in isolated bronchiolitis, Anil et al demon-
strated a correlation between BNP and severity of
bronchiolitis, as well as rate of hospitalisation and
length of hospital stay. Early NT-proBNP testing could
inform decisions on the need for hospitalisation in
cases when this is not wholly clear. Equally, it may
highlight cases in which clinical deterioration is likely,
triggering closer clinical monitoring or preparation of
supportive measures such as high-flow oxygen therapy.
Second, to identify cases of bronchiolitis compli-
cated by acute heart failure, often in the context of
CHD. Evidence from Samuel et al suggests that
NT-proBNP has potential as a biomarker that may
influence management. For example, when faced with
Clinical bottom line
►► N-terminal pro-brain natriuretic peptide (NT-proBNP)
is a rapid and inexpensive biochemical marker with
applications in both paediatric cardiac and respiratory
disease.
►► Available evidence suggests that NT-proBNP is a
potential tool for stratification of bronchiolitis severity
and prediction of hospitalisation, but further work
looking at NT-proBNP directly is needed to confirm this
and provide solid cut-off values for use clinically.
►► There is evidence that BNP levels can identify children
with bronchiolitis and congenital cardiac abnormalities
who proceed to develop acute heart failure, although
study cohorts in this area are small.
►► Nt-proBNP may have a role in differentiating cardiac and
pulmonary causes of acute dyspnoea, although evidence
in this area is conflicting.
6 Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
worsening dyspnoea in such a patient, a NT-proBNP of
several thousand could alert clinicians to likely cardiac
failure and support discussion with paediatric cardi-
ology, potentially averting deterioration and PICU
admission. (box 1)
Furthermore, work by Evim et al and Kolouri et al
supports the use of NT-proBNP in the wider differen-
tiation of cardiac and pulmonary causes of respiratory
distress.
However, the majority of current studies involve
small patient cohorts with some conflicting evidence
(table 2), such as the finding by Cohen et al in which
BNP was not significantly raised among children with
bronchiolitis. Furthermore, more studies assessing
NT-proBNP directly are needed in order to provide
clear cut-off values to inform clinical decision making.
Most studies have focused on BNP levels in bronchi-
olitis. While NT-proBNP has clear benefits over BNP
as a biomarker, their differing half-lives and assays
make it important to translate this work into concrete
NT-proBNP levels to use in clinical practice.
Funding  The authors have not declared a specific grant for this research from
any funding agency in the public, commercial or not-for-profit sectors.
Competing interests  None declared.
Consortia. Protected by copyright.
Provenance and peer review  Not commissioned; externally peer reviewed.
References
1 QualtyWatch. Focus on: emergency hospital care for children
and young people, 2017. Available: http://www.​qualitywatch.​
org.​uk/​sites/​files/​qualitywatch/​field/​field_​document/​
QualityWatch%​20CYP%​20report.​pdf [Accessed 20 Nov
2018].
2 Nice Guideline NG9. Bronchiolitis in children: diagnosis and
management, 2015. Available: www.​nice.​org.​uk/​guidance/​ng9
[Accessed 11 Nov 2018].
3 Freire G, Kuppermann N, Zemek R, et al. Predicting
Escalated care in infants with bronchiolitis. Pediatrics
2018;142:e20174253.
4 Calzetta L, Orlandi A, Page C, et al. Brain natriuretic peptide:
much more than a biomarker. Int J Cardiol 2016;221:1031–8.
5 Nir A, Nasser N. Clinical value of NT-proBNP and BNP in
pediatric cardiology. J Card Fail 2005;11:S76–80.
6 Adrish M, Nannaka VB, Cano EJ, et al. Significance of NT-
pro-BNP in acute exacerbation of COPD patients without
underlying left ventricular dysfunction. Int J Chron Obstruct
Pulmon Dis 2017;12:1183–9.
7 Sodhi R. “N-terminal pro B-type natriuretic peptide”
Association for clinical Biochemistry and LaboratoryMedicine
2014.
8 Nice Guideline NG106. Chronic heart failure in adults:
diagnosis and management, 2018. Available: https://www.​
nice.​org.​uk/​guidance/​ng106/​evidence/​full-​guideline-​pdf-​
6538850029 [Accessed 20 Nov 2018].
9 Anıl M, Göç Z, Avcı R, et al. B-Type natriuretic peptide is a
useful biomarker predicting disease severity in children with
isolated bronchiolitis in the emergency department. Turk J
Pediatr 2017;59:561.
10 Usuda D, Sangen R, Hashimoto Y, et al. Validation of
a B-type natriuretic peptide as a prognostic marker in

pneumonia patients: a prospective cohort study. BMJ Open
2016;6:e010440.
11 Jensen J, Ma L-P, Fu MLX, et al. Inflammation increases
NT-proBNP and the NT-proBNP/BNP ratio. Clin Res Cardiol
2010;99:445–52.
12 Sahingozlu T, Karadas U, Eliacik K, et al. Brain natriuretic
peptide: the reason of respiratory distress is heart disease or
lung disease? Am J Emerg Med 2015;33:697–700.
13 Samuel N, Hershkovitz T, Brik R, et al. Diagnosing heart failure
in children with congenital heart disease and respiratory syncytial
virus bronchiolitis. Am J Emerg Med 2014;32:1510–2.
14 Sezgin Evim M, Ucar B, Kilic Z, et al. The value of serum
N-terminal pro-brain natriuretic peptide levels in the
differential diagnosis and follow-up of congestive cardiac
failure and respiratory distress due to pulmonary aetiologies in
infants and children. Cardiol Young 2010;20:495–504.
Edwards KD, Tighe MP. Arch Dis Child Educ Pract Ed 2019;0:1–7. doi:10.1136/edpract-2019-316896
Review
Arch Dis Child Educ Pract Ed: first published as 10.1136/archdischild-2019-316896 on 15 October 2019. Downloaded from http://ep.bmj.com/ on October 15, 2019 at Bournemouth Uni
15 Koulouri S, Acherman RJ, Wong PC, et al. Utility of B-type
natriuretic peptide in differentiating congestive heart failure
from lung disease in pediatric patients with respiratory distress.
Pediatr Cardiol 2004;25:341–6.
16 Markovic-Sovtic G, Kosutic J, Jankovic B, et al. N-Terminal
pro-brain natriuretic peptide in the assessment of respiratory
distress in term neonates. Pediatr Int 2014;56:373–7.
17 Cohen S, Springer C, Avital A, et al. Amino-Terminal pro-
brain-type natriuretic peptide: heart or lung disease in pediatric
respiratory distress? Pediatrics 2005;115:1347–50.
Answers to the multiple choice questions
1 (A); 2 (D); 3 (A); 4 (B); 5 (A).
Consortia. Protected by copyright.
7