Recent Patents on Biomarkers 2012, 2, 54-59

54

Biomarkers of Asthma: Recent Patents from 2009-2011

Ma. Henrietta Olmos-Dela Cruz1, Rene Angelo S. Macahig2, Mailyn M. Terrado2, Henson L.
LeeYu2, Armando M. Guidote, Jr.2 and Joselito P. Quirino2,3*
1

Ateneo School of Medicine and Public Health, Ateneo de Manila University, Don Eugenio Lopez Sr. Medical Complex,
Pasig City 1604, Philippines; 2Department of Chemistry, School of Science and Engineering, Loyola Schools, Ateneo de
Manila University, Quezon City 1108, Philippines; 3Australian Centre for Research on Separation Science (ACROSS),
University of Tasmania, Private Bag 75, Hobart, Tasmania 7001, Australia
Received: August 7, 2011; Accepted: September 26, 2011; Revised: December 5, 2011

Abstract: This review informs on current literature on patents for biomarkers for asthma from 2009 to 2011. Variable airflow obstruction in asthma is generally triggered by gene-environment interactions that can lead to key symptoms of
cough, shortness of breath, chest tightness, and wheezing. The episodic and variable degrees of airway hyperresponsiveness arise from a variety of inflammatory pathways that can make diagnosis and management difficult. Standard pulmonary function tests used for the diagnosis of asthma may fail to predict individual responses to the standard
bronchodilator and corticosteroid therapies. Phenotypic predispositions can alter the severity of the asthmatic condition
and treatment response. Biomarkers from sputum, exhaled gases, exhaled breath condensates, urine, serum, and broncheolaveolar fluid lavage proteins are currently explored to provide objective metrics for identifying individuals at risk, provide therapy guidance, monitor disease progression and evaluate response to therapy, as a supplement to standard pulmonary function tests. Updates on the refinement of technologies, inherent limitations and benefits of these biomarkers are
discussed to provide insights on how current understanding of pathologic mechanisms has been applied to provide information for addressing gaps in the diagnosis and management of asthma.

Keywords: Asthma, biomarkers, diagnosis, metabolites, proteins, small molecules.

INTRODUCTION
Asthma, a chronic disorder of the airways, affects an estimated 300 million people worldwide [1], with significant
patient morbidity. It is a significant public health concern
because of the growing number of cases, high healthcare and
societal costs [2]. There is wide variability in the spectrum of
clinical presentations and underlying mechanisms suggesting
an interaction of changing environmental exposure and genetic factors in inducing the hallmark changes of airway inflammation, airway hyperresponsiveness and variable airway
obstruction. Genetic, protein and metabolite profiling approaches in the form of a concentration change that correlate
with the disease when compared to a control, have led to the
identification of asthma biomarkers. This can provide objective parameters for supplementing traditional spirometric
testing and bronchial biopsies in identifying risk in individuals, measuring response to treatment, and monitoring disease
progression. This review summarizes the recent patents on
asthma biomarkers from 2009-2011, analyzing key strengths
and limitations, of each approach.
Biomarkers have traditionally been reserved for chemical
or molecular analytes coming from various sources such as
bodily fluids, e.g., blood, urine, sputum, and other tissues.
These sampes provide a surrogate measure that can be
*Address correspondence to this author at the Australian Centre for Research on Separation Science (ACROSS), University of Tasmania, Private
Bag 75, Hobart, Tasmania 7001, Australia; Tel: +61362262529;
Fax: +61362262858; E-mail: jquirino@utas.edu.au
2210-3104/12 $100.00+.00

cheaper, less invasive, technically simpler and more available, with an acceptable sensitivity and specificity, compared
with standard pulmonary function tests for the assessment of
airway inflammation [3, 4]. Molecular biomarkers may be
correlated with the biochemistry of disease states, often
traceable to the enzymatic proteins involved in pathophysiologic and metabolic processes as well as the genes that encode for these proteins [5-7].
EXHALED BIOMARKERS
Exhaled breath is a complex mixture of low molecular
weight organic and inorganic compounds. Fluctuations in the
relative concentrations of these molecular components may
be clinically monitored. These can also be potentially used as
indices for diagnosis and therapeutic monitoring, particularly
for lung and airway diseases. Some of the analytical approaches that have been applied to exhaled breath include
direct measurement of expired gases, analysis of volatile
organic compounds (VOC) from exhaled breath as well as
analysis of volatile and non-volatile compounds in exhaled
breath condensate (EBC). Exhaled breath analysis is noninvasive and thus has a distinct clinical advantage in terms of
ease and convenience in sample collection [8, 9].
FeNO
The fraction of exhaled nitric oxide (FeNO) is a widely
studied, non-invasive biomarker that evaluates airway inflammation in asthma. FeNO levels have been shown to correlate well with sputum eosinophil count, airway hyperre 2012 Bentham Science Publishers

Biomarkers of Asthma

sponsiveness, bronchodilator response, serum IgE levels,

allergen skin prick testing, asthma symptoms and lung function [10-13]. New sensing systems for gaseous biomarkers
have been developed and recent patents describe instrumentation improvements. These include a photometric device
using a mid-range infra-red laser as a discriminating light
source for photoacoustic sensors, conversion of NO to NO 2
using an oxidizer unit coupled to a gas sensor, an inline
preconcentrator unit with a detector array for detection of
multiple gaseous analytes as well as the use of carbon nanotubes as sensor components [14-17]. These innovations address, but do not entirely eliminate, the significant interactions of the exhaled breath condensate with contaminants in
the mouth (e.g. saliva, pH and bacterial elements) [4]. FeNO
may have the potential to identify individuals who are likely
to respond to airway inflammation [18]. While studies have
pointed out differences in FeNO findings with bronchial biopsies, the Global Initiative for Asthma guideline has recognized the value of FeNO in monitoring dose adjustments of
corticosteroids for the treatment of asthma. This is with the
qualification that the use of FeNO has not, however, improved control nor reduced dosing of inhaled glucocorticoid
treatment [19].
CARBON MONOXIDE
A recent patent by Choi et al. describes the use of carbon
monoxide (CO) as a biomarker for various inflammatory
pulmonary conditions related to oxidative stress, including
asthma. Carbon monoxide is produced in minute but detectable amounts in the breath and is detected by a CO analyzer.
An increase in CO concentration may indicate risk or a current state of oxidative stress and may be useful in the detection of the early stages of the condition [20]. The principal
source of endogenous CO is heme metabolism catalyzed by
hemeoxygenase (HO) enzymes, which occur as constitutive
(HO-2) and inducible (HO-1) isozymes. Expression of HO-1
is highly induced by oxidative stress in inflammatory and
lung cells. A limitation of analyzers, however, is that exhaled
CO (eCO) may come from endogenous metabolic sources as
well as airway contamination from environmental exposure.
High background contamination principally from smoking
presents a significant challenge for the application of eCO as
a diagnostic tool [21, 22]. The marker is generally considered non-specific for asthma although its predictive value as
a diagnostic marker is unclear [22].

Recent Patents on Biomarkers 2012, Vol. 2, No. 1

55

artificial sensor system consisting of an array of chemical

sensors for VOC detection and an algorithm for pattern recognition. Findings from VOC analysis increased the predictive value of FeNO in discriminating healthy subjects from
asthmatic patients for the diagnosis of asthma [25].
SERUM INFLAMMATORY BIOMARKERS
Allergens and other environmental stimuli elicit varying
degrees of immune responses among individuals. Once the
antigen or irritant passes and escapes the mucociliary barrier
of the respiratory tract, the humoral (antibodies) and cellmediated defense systems of the host come into action, recruiting mast cells, eosinophils, and other lymphocytes. This
in turn results to the production of inflammatory mediator
molecules Fig. (1) [26]. Non-specific biomarkers currently
explored for asthma include detectable traces of genomic and
protein markers of inflammation including eosinophil cationic proteins (ECP), eosinophil peroxidases (EPO), neutrophil elastases (NE), myeloperoxidases (MPO), matrix metalloproteinases (MMP) and monocyte chemotactic proteins
(MCP) [3].
Cross-linking of the receptors initiate signaling cascades
that will result in exocytosis of preformed mediators (histamine, tryptase) and production of cytokines and eicosanoids
(prostaglandins, leukotrienes).
Various inflammatory mediators are known to cause constriction of bronchial smooth muscle cells. The release of
histamines, leukotrienes and eosinophil granule proteins,
which bind to specific receptors in the muscle cells, open
calcium channels and may recruit other contractile agonists
[26]. Other immunological markers are mainly cytokines
such as interleukins (IL), tumor necrosis factors (TNF-) and
eotaxins [3]. Small signaling molecules including increased
levels of cysteinyl leukotrienes (cys-LK) have been detected
and measured from various bodily fluids of asthmatic subjects [3, 5-7]. A small signaling molecule found both in serum and bronchoalveolar lavage fluid, 8-isopros-tane, has
been noted to be a marker for oxidative stress and antioxidant deficiency. DP2 receptors bind prostaglandin D2 molecules, released by mast cells to recruit eosinophils, basophils,
and TH2 cells [27]. These molecules are currently being explored not only as biomarkers in the inflammatory cascade
but as potential targets for therapy [3, 5-7].
YKL-40

SMALL MOLECULAR BIOMARKERS

In another patent, Van Schooten et al.empirically correlated a set of small molecular biomarkers in exhaled breath
with asthma. Carbon disulfide, 1-penten-2-on, butanoic acid,
benzoic acid, 3-(1-methylethyl)-benzene and C13H28/C11H24
hydrocarbons are detected by Gas Chromatography-Time of
Flight-Mass Spectrometry [23]. Also, 8-isoprostane in exhaled air has been associated with small airway dysfunction
in mild asthma. An increase in the concentration of these
compounds among asthma patients who were not in exacerbation suggests their role as disease markers [24]. Detection
of these volatile organic compounds (VOCs) was reported
using a variety of methods including an electronic nose, an

YKL-40, a chitinase-like protein, mediates airway inflammation in mouse models. YKL-40 levels in the serum
correlate with a single nucleotide polymorphism (SNP) in
the chitinase-3-like 1 gene (CHI3L1) known to increase in
asthma. The rise in YKL-40 protein levels has been associated with asthma severity and thickness of the subepithelial
basement membrane. Elevations of YKL-40 have been
shown to correlate with blood eosinophils but not with clinical severity, control or IgE levels in a study comparing
asthmatics with healthy controls (r = - 0.05, p = 0.05) [28].
These studies have pointed out a potential for YKL-40 as a
biomarker for asthma and other lung disorders with bronchial hyperresponsivity or reduced lung function [29, 30].

56 Recent Patents on Biomarkers 2012, Vol. 2, No. 1

antigen

Cruz et al.

IgE

LAT

PLC

FcRI

Lyn
v

P
P

Fyn
v

PIP

Syk
DA

P
Gab2

IP3
PI3K

PLA2

arachidonic acid

Ca

2+

cytokine

PKC

granule

SNARE

histamine,
tryptase

production of prostaglandins,
leukotrienes

release of IL-4, IL-5,

IL-13, TNF

Fig. (1). Activation of mast cells.

IL-18 and Mast Cell Stability (Chymases)

Interleukin-18 is another biomarker used to monitor
treatment response against chymase activity. Alpha-chymase
is a chymotrypsin-like protease expressed by mast cells. This
protein degrades the extracellular matrix of the respiratory
tract promoting further inflammation. Moreover, studies
have shown that chymase also cleaves interleukin-18. If the
chymase mechanism of action is inhibited, there should be
detectable levels of IL-18 in the biological sample [31]. Significantly higher interleukin-18 levels were found in poorly
controlled rather than well controlled asthma [32].
Periostin as an Anti-IL13 Surrogate Marker
Another interleukin, IL-13, is also strongly correlated
with inflammatory responses in asthma [33]. The detection
of IL-13 in blood and airway samples require highlysensitive assays. IL-13 induces bronchial epithelial cells to
secrete periostin, a matricellular protein which can be used
as a biomarker substitute for IL-13. An anti-IL13 drug
Lebrikizumab was monitored by its effect on periostin lev-

els, as a surrogate marker for interleukin-13. A six-month

course of Lebrikizumab resulted in improvements in lung
function compared with a placebo group [34, 35].
BRONCHOALVEOLAR LAVAGE PROTEINS
Bronchoalveolar lavage (BAL) protein biomarkers generally have the advantage of direct sampling from the airways, yielding a variety of cellular and protein products that
often correlate with the degree of inflammation in the airway
[36]. Studies using BAL isolates for the identification of
inflammation in asthma are generally limited by the invasive
nature of the procedure, but they yield significant protein
differences in segmentally challenged airways of asthmatics
compared with controls. Proteins that have been identified
include cytokines such as the high mobility group protein 1
(HMG-1), matrix metalloproteinases such as MMP-9 and
cellular signalling proteins. These proteins have also been
identified in various inlammatory responses, notably relating
to cell adhesion, cell mobility, proliferation, and signal
transduction [37]. Other proteins in broncheoalveolar fluid
are discussed in detail.

Biomarkers of Asthma

Table 1.

Recent Patents on Biomarkers 2012, Vol. 2, No. 1

57

Summary of Current Patents on Asthma Biomarkers (2009-2011).

Source

Exhaled air

Analyte

Serum

Bronchoalveolar
lavage (BAL)

Urine

FENO

CO

VOC

YKL-40

IL-18

Periostin

Patents (Assignee)

US20107704214

(Siemens Aktiengesselschaft)

US20107678390

(Yale University, John Hopkins

University)

US20097606274

(University of Alabama)

WO2010065452

(Tricorntech Corp.)

WO2009144725

(Technion Research and Development Foundation)

WO2011003922

(Universiteit Maastricht)

US20110177963

(Yale University, University of

Chicago)

US20097579147

(Wake Forest University)

WO2009148958

(Janssen Pharmaceutical)

US20110123530

(Arron et al.)

DP2 receptors

US20100173313

(also called CRTH2)

(AMIRA Pharmaceuticals)

TGFb1/ TGFb2

US20107858763

(Council of Scientific & Industrial

Research)

Description

Conversion of exhaled NO to NO2 using an oxidation catalyst, coupled to a

gas sensor unit

Use of CO as a biomarker for oxidative stress or a condition/disease state

to which oxidative stress is secondary

Optical nose for detection of exhaled

gases utilizing a mid-IR range laser

Breath analysis system for diagnosing

asthma among other lung diseases

Use of carbon nanotubes as sensing

elements for biomarkers in breath
samples

Use of GC-TOF-MS to identify VOCs

as biomarkers for asthma

CHI3L1 encoding YKL-40 is associated with elevated YKL-40 levels and

increased risk for developing a lung
disorder, including asthma

MSR1 gene mutation indicates increased risk for asthma among other
diseases

IL-18 as a biomarker to assess response to treatment with drugs that

inhibit chymase activity

Use of periostin as a surrogate marker

for IL-13

Not normally expressed in human

neutrophils, however, neutrophils recruited in site of inflammation expressed DP2 receptors

TGF-b induces structural changes associated with asthma

Vitamin D binding
protein (DBP)

WO2009072749 (Soonchunhyang
University)

Elevated DBP in bronchoalveolar lavage fluid (BALF) signals bronchial

asthma

Surfactant protein D

(SP-D)

WO2008124010 (University of
Pennsylvania)

Presence of pro-inflammatory SP-D

can be used to monitor responsiveness
to corticosteroids treatment

Formate, hippurate,
trigonellin

WO2011082433

(Lineagen, Inc.)

TGF-1 and TGF-2

Ghosh et al. identified the human transforming growth
factor beta 1 (TGF-1) as an important fibrogenic and immu-

H-NMR to detect urine metabolites

as markers for lung function and disease

nomodulatory factor known to induce structural changes

associated with asthma [38]. TGF- is produced in the airways by inflammatory cells infiltrated in the bronchial mucosa, as well as by structural cells of the airway wall includ-

58 Recent Patents on Biomarkers 2012, Vol. 2, No. 1

ing fibroblasts, epithelial, endothelial and smooth muscle

cells. TGF-1 and TGF-2 have been shown to be increased
in asthmatic airways and cells, together with evidence of
increased TGF- signaling [39, 40]. Levels of TGF-2 have
been shown to supplement the use of eNO determinations as
a potential biomarker for asthma [41]. These studies point
out a role for TGF not only as a potential biomarker but as a
therapeutic target for modulation of airway remodeling in
asthma [40].
Vitamin D and Vitamin D Binding Protein
It has been observed that the vitamin D binding protein
(DBP), a carrier of the vitamin D sterol, is a potential biomarker for the inflammation in asthma [42]. Reduced vitamin D levels were associated with impaired lung function,
increased airway hyperresponsiveness, and reduced glucocorticoid response suggesting a role of vitamin D in proinflammatory or immune regulatory mechanisms [43]. Elevated concentrations of vitamin D binding protein in
broncheoalveolar lavage fluid (BALF) reportedly signal inflammation in bronchial asthma. Further studies have been
suggested to clarify the diagnostic and therapeutic implications of vitamin D in asthma management [42, 43].
SP-D and Steroid Response
Surfactant protein D (SP-D), a member of the collectin
family of lectins, has been used as a biomarker to check response to corticosteroids. SP-D is a 43 kDa glycoprotein
with a structure composed of a globular head and a collagenous tail. Oxidizing agents that can trigger asthma may destroy the disulfide bridges that account for its multimeric
structure, thus exposing its collagenous tail. If this happens,
the tail can bind to receptors of effector cells, leading to opposing effect by encouraging the release of cytokines. Binding to viruses, bacteria, fungi, and allergens alters its multimeric structure and subsequently increases the ingestion of
these proteins by macrophages [44]. SP-D binding to certain
carbohydrate patterns on the surface of some pathogens
helps apoptotic macrophages to recognize the pathogens. SPD is also known to inhibit cytokine release of effector cells
by the binding of its globular head to cell receptors. This
triggers the signaling cascade for cytokine transcription in
mast cells, basophils and eosinophils. A study conducted by
Cheng et al. revealed increased SP-D concentration in alveolar lavage of asthma patients [45]. SP-D presence in asthma
was noted to be a non-specific indicator of lung injury and
inflammation and has potential use in evaluating the response of corticosteroid treatment for asthma [46].

Cruz et al.

and quantified using high resolution proton NMR [48]. Urinary leukotriene E4, in conjunction with exhaled nitric oxide
and sputum eosinophils were noted to have potential value in
monitoring conventional methods for airway control [11].
The use of these markers as potential biomarkers for asthma
has yet to be established in larger studies.
CURRENT & FUTURE DEVELOPMENTS
The complexity of inflammatory pathways in the pathology of asthma limits the identification of suitable biomarkers
for the disease. Although a number of small molecule and
protein biomarkers have been identified in patents found in a
search of the literature from 2009-2011, the development of
metabolite signatures or fingerprints (multiple biomarkers)
from metabolite profiling has yet to be explored and validated with larger studies. In addition, since metabolites are
in a mixture and are often found at very low levels, the discovery of biomarkers will rely on more sensitive and selective analytical tools for the analysis of samples. Since asthma
is related to a number of similar inflammatory diseases, the
discovery of selective biomarkers may at best be adjuncts to
conventional tests in the treatment of children with asthma
and in differentiating the various phenotypes. The use of
biomarkers for diagnosing specific phenotypes, monitoring
and guiding therapy remains a significant challenge.
ACKNOWLEDGEMENTS
JPQ thanks the Australian Research Council for a Future
Fellowship (FT100100213).
CONFLICT OF INTEREST
This invited review was written by the authors within the
scope of their research and academic positions at the Ateneo
de Manila University, Philippines and the University of
Tasmania, Australia. The authors declare that they have no
competing interests.
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