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Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Mini-symposium: Biomarkers and Phenotype

Biomarkers for pediatric pulmonary arterial hypertension:

challenges and recommendations
Ozus Lohani 1,2, Kelley L. Colvin 1,2,3,4, Michael E. Yeager 1,2,3,4,*
1
Department of Bioengineering, University of Colorado Denver
2
Department of Pediatrics-Critical Care
3
Cardiovascular Pulmonary Research, University of Colorado Denver
4
Linda Crnic Institute for Down Syndrome, Denver, Colorado

EDUCATIONAL AIMS

THE READER WILL COME TO APPRECIATE THAT:

 Pediatric pulmonary artery hypertension (PAH) is rarer than adult PAH and in both cases the diagnosis is often delayed (with the
exception of PAH associated with congenital diseases).
 The resulting right ventricle (RV) hypertrophy and eventual right heart failure from PAH is a cause of high mortality in both the
adult and pediatric demographic.
 Biomarkers are a necessity as a diagnostic/prognostic adjunct in children with PAH given limitations with echocardiography and
the risks associated with right heart catheterization.

A R T I C L E I N F O S U M M A R Y

Keywords: Pediatric pulmonary arterial hypertension (PAH) is an uncommon disease that can occur in neonates,
Pediatric pulmonary arterial hypertension
infants, and children, and is associated with high morbidity and mortality. Despite advances in treatment
biomarkers
strategies over the last two decades, the underlying structural and functional changes to the pulmonary
arterial circulation are progressive and lead eventually to right heart failure. The management of PAH in
children is complex due not only to the developmental aspects but also because most evidence-based
practices derive from adult PAH studies. As such, the pediatric clinician would be greatly aided by specific
characteristics (biomarkers) objectively measured in children with PAH to determine appropriate clinical
management. This review highlights the current state of biomarkers in pediatric PAH and looks forward to
potential biomarkers, and makes several recommendations for their use and interpretation.
ß 2015 Published by Elsevier Ltd.

INTRODUCTION pathogenic processes, or pharmacologic response to therapeutic

Biomarker Definition
A biomarker is defined as ‘‘a characteristic that is objectively
measured and evaluated as an indicator of normal biologic processes,
* Corresponding author. Department of Bioengineering, University of Colorado
Denver, Department of Pediatrics-Critical Care, Cardiovascular Pulmonary Re-
search, University of Colorado Denver, Linda Crnic Institute for Down Syndrome,
Denver, Colorado, 12700 E. 19th Ave. Box B131, Aurora CO, USA 80045.
Tel.: +303 724 4193; fax: +303 724 4198.
E-mail address: michael.yeager@ucdenver.edu (M.E. Yeager).
Abbreviations: PH, pulmonary hypertension; PAH, pulmonary arterial hyperten-
sion; IPAH, Idiopathic pulmonary arterial Hypertension; CHD, congenital heart
disease; PVR, pulmonary vascular remodeling; ANP, atrial natriuretic peptide; BNP,
brain natriuretic peptide; RDW, red cell Distribution width; IL, interleukin.
intervention’’ [1]. Biomarkers are increasingly used in clinical
research and practice as a diagnostic and/or prognostic adjunct.
There is however, a constant need for evaluation of biomarkers to
ensure accuracy and reproducibility of such outcomes. This review
will consider the use of biomarkers in the pediatric demographic
with pulmonary arterial hypertension (PAH) focusing on the
biomarkers currently classified for PAH, their potential to ameliorate
the disorder, and recommendations on how some challenges
involving the application of biomarkers could be tackled.
Pulmonary Arterial Hypertension
PAH, a condition characterized by increased pulmonary arterial
blood pressure and resistance in the arterial vasculature of the lung

http://dx.doi.org/10.1016/j.prrv.2015.05.003
1526-0542/ß 2015 Published by Elsevier Ltd.

Please cite this article in press as: Lohani O, et al. Biomarkers for pediatric pulmonary arterial hypertension: challenges and
recommendations. Paediatr. Respir. Rev. (2015), http://dx.doi.org/10.1016/j.prrv.2015.05.003
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[2], may arise as an idiopathic disorder, or is often associated
with secondary disorders [3]. PAH is a disease of many etiologies
where the right heart and the lungs are adversely affected directly
or indirectly through pathologies of other organs. The ensuing
right ventricular (RV) hypertrophy and eventual right heart failure
leads to high mortality [4]. The current accepted classification
for pulmonary hypertension (PH) is provided in Table 1 [3].
The current clinical classification system categorizes PH into five
groups with the most common form of pediatric PH falling in the
category of Group I (PAH). This group accounts for approximately
90% of the incidence [5]. As in adults, the diagnosis of PAH in
children is often delayed with the exception of PAH associated with
congenital disorders [2]. Thus, the utilization of biomarkers that
are sensitive, accurate, and reproducible has the potential to
greatly improve early diagnosis, relevant prognosis, and more
effective treatment in pediatric PAH.
PH Classification
For children with PH, the Netherlands data registry reported an
incidence of 63.7 cases per million, with a majority of those cases
belonging to PAH diagnosis (57.9 cases per million children)
[6]. Although PAH in children is more rare than in adults, the
incidence reported is comparable to the adult demographic with
a reported incidence of 7.6 cases per million annually and a
prevalence of 52 cases per million [7]. There is very limited data
available on the registries with respect to pediatric PAH because of
the smaller sample size of children with PAH and because of the
lack of standardized assessment in early registries [8]. To overcome
this, studies have been conducted to further our understanding
of pediatric disease epidemiology data [9], and survival rates for
Table 1
Current Classification for Pulmonary Hypertension [3]
1. Pulmonary Arterial Hypertension (PAH)
1.1. Idiopathic (IPAH)
1.2. Heritable/familial (FPAH) 1.2.1. BMPR2
1.2.2. ALK1, Endoglin
1.2.3. Unknown 1.3. Drug and toxin-induced
1.4. Associated with (APAH)
1.4.1. Connective tissue disorders
1.4.2. HIV infection
1.4.3. Portal hypertension
1.4.4. Congenital heart diseases
1.4.5. Schistosomiasis
1.4.6. Chronic hemolytic anemia
1.5. Persistent pulmonary hypertension of the newborn (PPHN)
1’. Pulmonary veno-occlusive disease (PVOD) and pulmonary capillary
hemangiomatosis (PCH)
2. Pulmonary hypertension with left heart disease
2.1. Systolic dysfunction
2.2. Diastolic dysfunction
2.3. Valvular disease
3. Pulmonary hypertension due to lung diseases and/or hypoxia
3.1. Chronic obstructive pulmonary disease (COPD)
3.2. Interstitial lung disease
3.3. Other pulmonary diseases with mixed restrictive and
obstructive pattern
3.4. Sleep disordered breathing
3.5. Alveolar hyperventilation disorders
3.6. Chronic exposure of high altitude
3.7. Developmental abnormalities
4. Chronic thromboembolic pulmonary hypertension (CTEPH)
5. Pulmonary hypertension with indistinct, multi-factorial mechanisms
5.1. Hematological disorders (e.g. myeloproliferative disorders,
splenectomy, hemoglobinopathies)
5.2. Systemic disorders (e.g. sarcoidosis, pulmonary Langerhans cell
histocytosis, lymphangiomatosis)
5.3. Metabolic disorders (e.g. glycogen storage disease, Gaucher’s disease,
thyroid disorders)
5.4. Others (e.g. tumoral obstruction, fibrosing mediastinitis, chronic renal
failure and dialysis)
Please cite this article in press as: Lohani O, et al. Biomarkers for pediatric pulmonary arterial hypertension: challenges and
recommendations. Paediatr. Respir. Rev. (2015), http://dx.doi.org/10.1016/j.prrv.2015.05.003
children diagnosed with PAH have been reported in several studies
[6,10]. Children are treated with either mono- or combination
therapy, drug-specific therapy, treatment with calcium channel
blockers, and bosentan [11]. A study conducted by the UK
Pulmonary Hypertension Service for children [12] reports survival
rates of approximately 90.5, 82.8 and 64.2% at 1, 3, and 5 years,
respectively. Survival rates of 96, 84, and 74% for 1, 3, and 5 years
respectively have recently been reported for children with IPAH/
FPAH (familial) and APAH-CHD (associative) [13]. Similar studies
further support these data [6,10,14]. There are data, however, that
show differences in survival rates between children with IPAH
compared with APAH [6,12,13]. Gender difference is an important
factor for PAH in children, with higher occurrence observed in
females than in males (2:1 ratio) [15].
Right Heart Catheterization (RHC) is the gold standard for
diagnosis of PH [16], which is defined (in part) as a mean
pulmonary artery pressure of greater than or equal to 25 mm Hg.
Typically, echocardiography (echo) is used as an initial screening
tool, followed by RHC when pulmonary artery pressures are
estimated to be elevated by echo [17]. Unfortunately in many
cases, RHC fails to confirm a finding of PAH suspected by echo
[18]. Biomarkers that would help inform the clinical decision to go/
not go for RHC in the child with elevated pulmonary artery
pressure as assessed by echo would greatly obviate unnecessary
and expensive RHC (and the associated risks) for children who did
not need it.
With therapy options more standardized for the adult PAH
demographic, the therapeutic approaches to children with PAH can
vary significantly depending on the experience of the clinical
center and the medical team [19]. Although there are similarities in
adults and children in terms of PAH pathobiology and patient
response to therapeutic interventions [20–22], children are not
small adults. Thus, the use of biomarkers in pediatric PAH should
preferably be based on objective data in a systemized manner that
incorporates etiology, developmental age, and gender differences
with regard to prognostication, treatment, and evaluation of
treatment efficacy. For this review, we have arbitrarily divided
biomarkers for pediatric PAH into two classes: biochemical and
imaging.
BIOCHEMICAL BIOMARKERS OF PULMONARY HYPERTENSION
Over the past several years excellent reviews on biomarkers and
their application in PAH have been published [23–25]. However,
these reviews have focused on adult PAH. The ideal biomarker for
any disease would involve a measurement that is convenient,
simple to perform, painless, and affordable, while offering high
specificity and low incidences of false negatives and positives [2]. A
superior biomarker (or set of biomarkers) would possess the
aforementioned qualities while accommodating patient compli-
ance when applied to the pediatric population.
PH is multifactorial with regard to pathobiology; as such, a
single biomarker will not likely be 100% informative for the
accurate diagnosis, relevant outcome and prognosis, and aspects of
the underlying disease process. Thus, a combination of several
biomarkers would be optimal for diagnostic and prognostic
purposes. Current recommended guidelines apply the use of brain
natriuretic peptide (BNP) and the N-terminal pro-BNP fragment as
biomarkers for cardiac function [26] and mortality risk stratifica-
tion [27]. Since natriuretic peptides were the early biomarkers
used in PH, elevated levels of atrial natriuretic peptide (ANP) would
serve as an important prognostic marker [26–29]. In addition, red
cell distribution width (RDW), an emerging prognostic marker in
PH, has been associated with poor survival [30]. Another lab
parameter obtained is c-reactive protein (CRP), where it has been
determined that elevated levels are associated with poor outcome
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in cardiovascular disease, including PH [31]. RDW and CRP are
just a few of many parameters that can aid in the prediction of
PH outcome. They may be an indicator of pulmonary vessel
intimal obliteration and inflammation [31], suggesting that
there is some distress to the organs and that the inflammation is
systemic.
Non-invasive markers that accurately predict the relevant
clinical outcome are sought after because of the convenience,
repeatability and most importantly because they provide an
alternative to invasive measures. Exhaled breath biomarkers (EBB)
falls into this category and here we briefly discuss nitric oxide (NO)
and volatile organic compounds (VOC) as potential markers in
pediatric PH. Inhaled NO as a therapy is US Food and Drug
Administration (FDA) and European Medicine Evaluation Agency
approved for the treatment of infants with persistent PH
[32]. Fractional exhaled nitric oxide (FENO) is lower in patients
with PH and it is shown to rise in concentration in response to
therapy [33]. VOCs in exhaled breath were identified four decades
ago by Linus Pauling using gas chromatography [34]. More
recently, several VOCs were identified using mass spectrometry
that identified individuals with PH vs. healthy controls [35]. The
study found that ammonia levels were elevated in the breaths of
PH patients and correlated with the severity of the disease. There
are additional studies present that show different levels of N-
Terminal pro BNP, endothelin-1, and 6-keto PGF in PH patients vs.
controls. A recent review provides additional summaries of
exhaled breath biomarkers and the adversity in utilizing them
for diagnostic purposes [2]. Despite the complications that arise in
trying to firmly establish the use of exhaled breath biomarkers in
PH, they show promise of high prognostic value with respect to PH.
As with exhaled breath, urine is a potential source of
noninvasive biomarkers. Urinary F2-isoprostance was indepen-
dently associated with mortality in patients with PAH [36]. Since
the levels of F2-isoprostance are elevated in the cohort of
individuals predisposed to PAH, the measurement of this particular
marker could suggest the potential of being an early indicator.
Partial pressure of carbon dioxide (pCO2) is decreased in patients
with PH and correlates with a poor prognosis in patients with PAH
[37]. Conversely, pO2 proved of no prognostic value. The
speculation is that heart failure elicits a ventilation response
and this could lead to breathing patterns, either hypo- or
hyperventilation being a marker for diagnosis of PAH. Decreased
pCO2 could suggest both left and right heart failure [25], however,
but its utility will see it likely to continue as a combinatorial
marker with other non-invasive tools to improve the understand-
ing of pediatric PAH.
As markers emerge that show promise in defining and
distinguishing pathobiology of specific diseases, peripheral blood
will continue to be a rich source for potential biomarkers. The
presence of various markers present in the blood stream provides
information regarding inflammation, distress to the organs, and
potential remodeling among others [25,38]. The following sub-
sections focus on blood biomarkers and studies assessing their
potential prognostic role in pediatric PAH.
Microparticles and Circulating Endothelial Cells
Membrane fragments from platelets, leukocytes, and damaged
endothelial cells contribute to the population of circulating
microparticles. Microparticles can be considered important blood
biomarkers because changes in their levels aid in distinguishing
the PH cohort from the controls [39–42]. Studies that have
measured circulating microparticles derived from leukocytes:
CD11b+, endothelial: CD62e+, and platelet: CD31+ CD61+, using
flow cytometry reported elevated levels in patients with PH
rather than in controls [39,40]. Another study investigating
Please cite this article in press as: Lohani O, et al. Biomarkers for pediatric pulmonary arterial hypertension: challenges and
recommendations. Paediatr. Respir. Rev. (2015), http://dx.doi.org/10.1016/j.prrv.2015.05.003
3
microparticles reported elevated levels of vascular cell adhesion
molecule-1, monocyte chemo attractant protein-1-CRP, and
CD105+- associated with PH patients [41]. In addition to
microparticles, circulating endothelial cells (CECs) and endothelial
progenitor cells (EPCs) are present in the blood of individuals with
PH [43,44]. CECs have been prospectively measured in IPAH
pediatric demographic as well as PAH secondary to CHD, prior to
and after therapeutic treatment [45]. Furthermore, increased levels
of CECs are associated with irreversible PAH due to congenital
heart defects [42]. This suggests that CECs are important markers
for predicting the prognostic pathway of children with PAH.
Comparatively, the levels of EPCs have indicated neither reversible
nor irreversible PH [46] and studies to date have not been able to
firmly establish a correlation between EPCs and PH [47]. Perhaps
due to the presence of different phenotypes of CECs and EPCs in the
bloodstream, the results among different laboratories vary [42,46].
The lack of standardized assessment further complicates interpre-
tation. Future studies looking into specific phenotypes will likely
provide more insight as to whether CPCs and EPCs are able to
accurately predict the difference between reversible and irrevers-
ible PAH for individuals initiated on therapy.
Plasma Peptides
Plasma and its contents have been looked into for specific
markers with respect to PAH for both adult and pediatric
populations [31,48,49]. It is speculated that the markers sourced
in the plasma will likely represent the aspects that drive the
fundamental disease processes of inflammation [50] and ventric-
ular damage [28].
As mentioned above, the natriuretic proteins were the first
blood biomarkers investigated with respect to PH [28]. Just as in
the adult PH population, N-Terminal pro-BNP possesses prognostic
value in the pediatric PH demographic [51,52]. Several studies
have reported low levels of N-Terminal pro-BNP in children with
PH compared to adults [53,54]. A study reported BNP levels of
>150 pg/mL at baseline and increased plasma level of >180 pg/mL
after therapy, suggesting a worse prognosis [48]. The members of
this research group were the first to show the prognostic value of
plasma BNP in PH patients. Proteomics studies conducted recently
have shown that it is convenient to obtain certain plasma
parameters such as interleukins, acute phase proteins and growth
factors [49,55]. These peptides could very well represent systemic
inflammation but could also be associated with control of
inflammatory cell phenotype [31]. As another example, proteomic
studies have reinvigorated the investigation of mast cells and their
involvement in adult PH [56]. Simply put, a broad range of plasma
biomarkers could be assessed in the pediatric PAH demographic.
As we have suggested [2,55], a multiplex platform could be
adopted where protein targets are tailored to a ‘‘PH plasma
proteome signature’’. The customization could be geared towards
promising biomarkers such as IL-6, GDF-15 (growth differentiation
factor) [57], endothelins [58], CRPs [59], and serum amyloid A
among others. The data for pediatric PAH biomarkers is limited due
to a small sample size in the studies conducted. Perhaps
implementing a strategy whereby a panel of biomarkers are
chosen, and with the help of multi-center participation, we can
accumulate data to further our understanding of the roles of these
plasma peptide biomarkers in pediatric PAH.
Plasma Non-Peptides
MicroRNAs (miRNAs) are defined as the non-coding single
stranded RNAs whose purpose is to regulate gene expression by
influencing the stability of mRNA and subsequent translation into
protein. [60]. Circulating miRNAs are known to be involved in lung
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diseases [61] and have presented themselves as a ‘go to’ biomarker
due to their stability and accessibility. Although studies have
shown correlation of miRNA levels to the severity of PAH in adults
[62], there are no studies conducted to mirror that in children.
Furthermore, studies have been conducted where additional
miRNAs were identified and alterations of mir-204 [63] and
mir-21 [64] showed therapeutic potential. With the possibility of
introducing an additional therapeutic option to those already
present, it cannot be stressed that miRNA in the plasma and buffy
coats of the children should be investigated. There is limited data
with respect to miRNA even for adults with PAH. Since miRNA
levels correlate to the severity and progression of PAH, we suggest
that follow up with patients post therapy include collection of
blood and plasma isolation to observe the levels of miRNAs. It
should be kept in mind, however that correlation between miRNAs
and developmental state are at best indeterminate in adults or in
children. Although their exact biological functions are largely
unknown, miRNAs will probably become important biomarkers in
pediatric PAH.
IMAGING BIOMARKERS FOR PULMONARY HYPERTENSION
As mentioned above the gold standard for diagnosing PH is RHC,
yet its invasiveness renders it unsuitable as a ‘‘screening’’ test for
PH. We have also mentioned some non-invasive tools that could be
placed in the arsenal of potential biomarkers for diagnostic and
prognostic purposes.
Echocardiography
Echocardiography is the non-invasive imaging modality used
in diagnosis of PAH as well as the standard of care for monitoring
PH progression [65]. Echocardiography is an essential screening
tool as it is able to estimate hemodynamic functions correlating
closely with those obtained from RHC [66]. Echo based measure-
ment of the acceleration time of pulmonary flow has become an
important measurement recently along with tricuspid annular
plane systolic excursion (TAPSE) [67]. The workup of patients
with PAH almost universally include echo tests. Decreased
TAPSE <1.8 cm is associated with poor prognosis [68] in patients
with dilated cardio-myopathy (DCM) and may correlate to
arterial pressure (pa) and pulmonary vascular remodeling
(PVR) [69]. Additionally, tissue Doppler imaging (TDI) is used to
predict unfavorable clinical outcome in children with IPAH
[70]. Fifty-one children with IPAH were prospectively compared
to controls and the study reported tricuspid early diastolic
myocardial relaxation velocity to possess greater correlation
(when combined with plasma BNP levels and hemodynamics)
than did systolic myocardial velocity [70]. The findings differ
from the measurement obtained from adults as detailed in other
studies [71–73].
Computed Tomography
Computed tomography (CT) is also used frequently to evaluate
cardiovascular changes in PAH patients. The precision of using CT
has improved with the arrival of respiration-timed CT gathering
with echo but the drawback of exposing patients to radiation
remains [74]. There is variability in correlating the measurement of
main pulmonary artery diameter to pa [75–77], albeit CT has been
used to characterize the differential diagnosis of PAH by ruling out
associated disorders, for instance, pulmonary fibrosis. CT imaging
is used routinely in adults but is difficult to implement in infants
with respect to patient compliance. Single photon emission
computed tomography (SPECT), a variation to CT imaging,
deserves a mention as it is able to provide three-dimensionally
Please cite this article in press as: Lohani O, et al. Biomarkers for pediatric pulmonary arterial hypertension: challenges and
recommendations. Paediatr. Respir. Rev. (2015), http://dx.doi.org/10.1016/j.prrv.2015.05.003
reconstructed images and allows for in-depth assessment of tissue
of interest when paired with specifically radio labeled ligands
[78]. As with CT, the gamma rays make this modality unfavorable
for repeated exposure and the image acquisition takes longer
which brings up the concern of patient compliance, especially in
the pediatric population.
Magnetic Resonance Imaging
Magnetic resonance imaging (MRI) has proven itself to be a
very important screening tool. Cardiac MRI is used to assess
morphology of the right ventricle and certain measurements such
as volumes and ejection fractions can be obtained [79–83]. Cardiac
MRI has been used to define the RV stroke volume index, RV
ejection fraction, RV mass, RV iso-volumetric relaxation time, LV
septal bowing, and LV ejection fraction [11]. With minimized
intra-operator variability factor, high prognostic value, true
three-dimensionality, and high specificity towards desired
measurements, MRI is considered the gold standard for RV study
[84]. The prognostic value of MRI was recently assessed where
100 children with PAH were scanned and 60 were diagnosed with
IPAH [85]. The study showed that the measurements attained by
MRI closely correlated to the invasively obtained pulmonary
artery parameters.
There are drawbacks in using the aforementioned imaging
modalities, especially in the pediatric population [5]. To broadly
adopt imaging biomarkers to PAH, the drawbacks have to be
carefully contrasted and weighed with the benefits. Using
powerful non-invasive tools is always favorable to those of
invasive and surgical in nature. With the imaging biomarkers
mentioned we have the potential to: pinpoint and investigate the
tissue of interest, use three-dimensionally reconstructed images
(that takes us out of the 2-D space), eliminate subjectivity with low
variability among operators, and (perhaps most importantly) to
minimize the need for invasive screening tools such as RHC. With
technology improving at a rapid pace, these imaging biomarkers
are being modeled to accurately obtain measurements that would
be only done invasively. Thus, the desirability of using non-
invasive biomarkers to accurately diagnose PAH in pediatrics
makes imaging modalities an important tool for the pediatric
clinician.
SPECIFIC RECOMMENDATIONS AND CHALLENGES FOR
APPLICATION OF BIOMARKERS IN CHILDREN WITH
PULMONARY ARTERIAL HYPERTENSION
The utilization of biomarkers will continue to increase. There is
great potential for specific biomarkers to be able to provide
information that helps in early diagnosis of a diseased state,
response to therapeutic treatments, disease pathophysiology and
relevant outcome of disease progression [2,25,38]. Even though
there are several biomarkers for use in adult PAH, application to
the pediatric demographic is limited both in clinical studies/
research and in clinical practice. PAH in pediatrics differs from PAH
in adults, and the utilization of biomarkers can, and should reflect
such differences. These include, but are not limited to: age and
developmental progression, gender differences, ethnicity, envi-
ronmental factors, degree of physical activity and genetic
predisposition. We suggest the adoption of a panel of biomarkers
that can be developed eventually into a gold standard for
application in pediatric PAH (Table 2). This should be done
separately and in parallel to the growing list of biomarkers for
adult PAH. There are many hurdles present in implementing such a
solution into clinical trials and practices, and arguably the largest
of them is the continued evaluation and re-evaluation process for
the biomarkers. Additional challenges more specific to pediatric
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Table 2
Challenges in using biomarkers in children and how we can overcome the roadblocks
Challenges
1. Account for developmental progression
1.1 Adult PAH vs. Pediatric PAH
1.2 Age difference w/in the pediatric demographic
2. Low incidence of pediatric PAH
2.1 Pediatric PAH rarer than adult PAH
2.2 Avoid unnecessary right heart catheterization
3. Address questions re: responders vs. non-responders
3.1 Identify subgroups and treat in more customized fashion
3.2 Measure effectiveness of therapies
Table 3
List of biomarkers related to Pulmonary Arterial Hypertension
Biomarkers
1. Biochemical biomarkers
1.1 Nitric Oxide (NO) and Volatile Organic
Compounds (VOCs)
1.2 N-terminal pro BNP (Brain natriuretic peptide)
1.3 Red Cell Distribution Width (RCDW)
c-reactive protein
1.4 Microparticles and Circulating Endothelial
Cells (CECs)
1.5 MicroRNAs
2. Imaging biomarkers
2.1 Echocardiography
2.2 Computer Tomography (CT)
2.3 Single Photon Emission CT (SPECT)
2.4 Magnetic Resonance Imaging (MRI)
3. Additional Biomarkers (not discussed here)
3.1 Cardiac MRI
PAH and recommendations to tackle them are outlined in
Table 3. We anticipate that the next 5-10 years will bring forth
a ‘‘renaissance’’ of biomarkers that will facilitate greatly improved
detection, confirmation, selection of treatment, and monitoring of
children with PAH. As with any change, technology will play a large
role in shaping the future (not discussed here), but the single
biggest factor will likely be the design and implementation of a
rational and thoughtful plan for success.
FUTURE RESEARCH DIRECTIONS
 Most of the biomarkers studies in the recent years have focused
mainly on adult PH. Although there is some crossover correlation
between adults and children, future studies should focus on the
pediatric demographic. Age, gender and development progres-
sion (even within the pediatric group) affects how the pathology
presents itself.
 A call to collaborate; since pediatric PAH is rare, prospective
studies with multi-center contribution and evaluation would
increase sample size and thus provide statistically powerful
studies.
 Future studies would benefit by designing experiments that
* prospectively correlates biomarkers to confirm PAH suspected
by screening/diagnostic tools currently used,
* correlates biomarkers to severity and course of the disease, and
* correlates biomarkers to response to therapy.
Please cite this article in press as: Lohani O, et al. Biomarkers for pediatric pulmonary arterial hypertension: challenges and
recommendations. Paediatr. Respir. Rev. (2015), http://dx.doi.org/10.1016/j.prrv.2015.05.003
5
Recommendations
Strong standardized measurements
Prospective studies with multi-center contribution and evaluation;
increase numbers to statistically power studies
Combinations of biomarkers as opposed to single marker; employ multivariate statistical tests
Controls age-matched to the disease demographic
Prospective studies with multi-center contribution and evaluation
Design studies that test correlation of biomarkers to confirm suspected PAH by echo as true PAH
Design studies that test correlation of biomarkers to response to classes of established
therapies (prostacyclins, endothelin receptor antagonists, calcium channel blockers,
phosphodiesterase inhibitors)
Design studies that employ serial analyses of biomarkers to monitor response to therapy and
course of disease
Pros and Cons
+ Readily available through minimally invasive procedures (blood draw)
+ Potential to provide insight into severity, course of disease and response to therapeutic
intervention
Sample size is very low
Mostly identified for the adult demographic; presentation and difference of the disease in
children calls for a focused study within the pediatric demographic
+ Non-invasive measures to obtain information
+ Repetition due to the non-invasive nature
Gamma radiation from CT and SPECT procedures renders this option unfavorable for repeated use
+ Optimized for cardiovascular system CMRI is able to provide 3D and 4D images for morphological
and hemodynamic assessment.
CONFLICTS OF INTEREST
None
Acknowledgements
All authors contributed equally to this review.
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