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ACI 180206

REVIEW

CURRENT
OPINION Asthma exacerbation prediction: recent insights
Louise Fleming

Purpose of review
Asthma attacks are frequent in children with asthma and can lead to significant adverse outcomes including
time off school, hospital admission and death. Identifying children at risk of an asthma attack affords the
opportunity to prevent attacks and improve outcomes.
Recent findings
Clinical features, patient behaviours and characteristics, physiological factors, environmental data and
biomarkers are all associated with asthma attacks and can be used in asthma exacerbation prediction
models. Recent studies have better characterized children at risk of an attack: history of a severe
exacerbation in the previous 12 months, poor adherence and current poor control are important features
which should alert healthcare professionals to the need for remedial action. There is increasing interest in
the use of biomarkers. A number of novel biomarkers, including patterns of volatile organic compounds in
exhaled breath, show promise. Biomarkers are likely to be of greatest utility if measured frequently and
combined with other measures. To date, most prediction models are based on epidemiological data and
population-based risk. The use of digital technology affords the opportunity to collect large amounts of real-
time data, including clinical and physiological measurements and combine these with environmental data
to develop personal risk scores. These developments need to be matched by changes in clinical guidelines
away from a focus on current asthma control and stepwise escalation in drug therapy towards inclusion of
personal risk scores and tailored management strategies including nonpharmacological approaches.
Summary
There have been significant steps towards personalized prediction models of asthma attacks. The utility of
such models needs to be tested in the ability not only to predict attacks but also to reduce them.

Keywords
adherence, asthma, children, exacerbations

INTRODUCTION an asthma attack over a 12-month period [8].

Asthma exacerbations are characterized by an acute Asthma attacks lead to significant morbidity for
worsening of asthma symptoms caused by broncho- children including time off school, hospital admis-
spasm, airway inflammation and increase in mucus sions, adverse treatment effects, decline in lung
&&

production in response to a trigger such as allergen
exposure, viral infection, environmental irritants
(including pollution and cigarette smoke) or a com-
bination of these. Although current asthma control
is an indicator for future exacerbations [1], they can
occur on the background of seemingly good control
&&
and normal lung function [2,3 ]. Concepts of acute
exacerbations and baseline control, although over-
lapping, are not a continuum [4,5]. Indeed, the
terms ‘exacerbation’ or ‘flare up’ do not accurately
reflect the suddenness and severity of these episodes
and instead ‘asthma attack’ or ‘acute lung attack’
&&
have been proposed as more appropriate [6 ]. It is
estimated that in the United States over 50% of
children with asthma have an asthma attack per
year [7] and in a European study over one-third of
children had an unscheduled healthcare visit due to
function [3 ,9] and in some cases, death. The recent
National Review of Asthma Deaths [10] highlighted
that poor recognition of adverse outcomes in chil-
dren and young people was found to be an impor-
tant avoidable factor. Recognition of these
potentially adverse outcomes, identifying children
at risk of an attack and improved prediction models
affords an opportunity to prevent asthma attacks
and their associated morbidity and mortality.
National Heart and Lung Institute, Imperial College, London, UK
Correspondence to Dr Louise Fleming, MB ChB, MD, Clinical Senior
Lecturer, Paediatric Respiratory Consultant, Department of Respiratory
Paediatrics, Royal Brompton Hospital, Sydney Street, London SW3
6NP. Tel: +02073528121; e-mail: l.fleming@rbht.nhs.uk
Curr Opin Allergy Clin Immunol 2018, 18:000–000
DOI:10.1097/ACI.0000000000000428

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ACI 180206
Pediatric asthma and development of atopy
KEY POINTS
 Asthma exacerbations occur frequently in children with
asthma and contribute significantly to the personal and
societal burden of asthma.
 Patient characteristics, clinical features and
environmental influences are all associated with
increased risk of asthma attacks, the relative
contribution of which varies between individuals.
 Combining data from a variety of sources, including
patient risk factors, biomarkers and real-time
physiological and environmental data has the potential
to improve the prediction of asthma attacks in
the individual.
 Integrating Individual risk scores into targeted
personalized management strategies affords the
opportunity to reduce the frequency and severity of
asthma exacerbations.
ASTHMA ATTACKS: DEFINITION
Definitions of asthma attacks vary and those termed
‘mild’ exacerbations are often synonymous with a
loss of baseline control and tend to be responsive to
short-acting bronchodilators (SABA). Attacks which
do not respond to SABAs and require corticosteroids
suggest a different pathogenesis, characterized by
airway inflammation and loss of bronchodilator
responsiveness [5] and are usually termed ‘severe’.
Definitions of severe attacks are more robust and
based on objective criteria. The American Thoracic
Society/European Respiratory Society taskforce [11]
defined a severe attack as one requiring high-dose
oral corticosteroids for 3 or more days, increase in
maintenance oral corticosteroid dose, emergency
department (ED) visit or hospitalization. This review
will focus on the prediction of these severe asthma
attacks in children.
LESSONS FROM CONFIDENTIAL REVIEWS
OF ASTHMA DEATHS
Despite the increasing amounts of money spent on
asthma care there has been little progress in reduc-
ing asthma deaths in the past 10 years [12 ]. Fur-
&
thermore, there is substantial variation globally in
paediatric asthma-related mortality rates, even
between high-income countries [13,14]. Although
asthma deaths are rare in children, those that do
occur are almost always avoidable. The lessons that
can be learnt from analysing these tragic events and
the identification of risk factors leading to the fatal
asthma attack can be extrapolated to other measures
of asthma morbidity including severe attacks and
hospital admissions. In the United Kingdom alone
2 www.co-allergy.com
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there have been five such reviews in the past 20 years
which have included children and young people
[10,15–18]. The lessons from each are depressingly
consistent: poor adherence, overuse of reliever med-
ication, adverse psychosocial factors, inadequate
monitoring and lack of personal asthma actions
plans were all found to be significant, and poten-
tially correctable, factors contributing to asthma
death. Most striking is the fact that 32–50% of those
that died had been classified as having ‘mild-mod-
erate’ asthma. Asthma leading to death cannot by
any standard be considered ‘mild-moderate’ and yet
key risk factors and predictors of a severe, ultimately
fatal, attack had not been recognized.
PREDICTING ASTHMA ATTACKS:
CLINICAL AND PHYSIOLOGICAL FACTORS
Asthma control
Although asthma attacks can occur in the context of
apparently good control, a number of studies have
demonstrated that poor asthma control is an indi-
cator for future control and asthma attacks [4,19]
and an exacerbation is often preceded by a period of
decreased asthma control [20]. Thus, there may be a
window of opportunity to prevent the progression
to an asthma attack. However, this loss of control is
frequently not recognized by either the patient or
their doctor [21,22]. The strongest independent pre-
dictor of an asthma attack is a history of one or more
courses of oral corticosteroids, ED visit or hospitali-
&
zation in the previous 12 months [1,23 ,24,25].
These studies highlight that we cannot be compla-
cent about asthma attacks and need to ensure that a
single asthma attacks triggers a thorough review of
asthma management.
Lung function
There are conflicting data on whether measure-
ments of lung function can be used to predict those
at risk of an asthma attack. Some studies have found
only a weak association and poor positive predictive
value [2,24,26]. Others that have found an associa-
tion have used a very loose definition of an asthma
attack [27,28]. Loss of control and acute attacks are
characterized by different peak expiratory flow rate
patterns [5]. Loss of baseline control is characterized
by wide diurnal peak expiratory flow variation,
whereas acute exacerbation is shown by a steep
decline in peak flow, with no increased variability.
More complex techniques to characterize fluctua-
tions in airway function using peak expiratory flow
data have been shown to be a useful tool for risk
prediction in adults [29]. Preliminary data suggest
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these techniques may also be useful in children and
can distinguish different asthma severities [30].
PREDICTING ASTHMA ATTACKS:
PATIENT-RELATED FACTORS
Adherence
Poor adherence to asthma treatments is associated
with an increased risk of attacks, hospital admis-
sions and asthma-related deaths [31,32]. Further-
more, good adherence is associated with a
decreased risk of exacerbations [33]. Those children
who experience poor control and asthma exacerba-
tions despite documented good adherence to
inhaled corticosteroids are candidates for a step
up in treatment, whereas for those with poor adher-
ence this is the key issue which needs to be
&
addressed [34 ]. However, studies have largely failed
to show an impact of adherence interventions on
asthma control and reduction in exacerbations [35],
although that is more likely due to a failure to
identify those children in need of an intervention
and select the appropriate intervention for the indi-
vidual. The increasing use of electronic monitoring
devices and improved understanding of poor adher-
ence in children can help to address these issues in
&
future studies [34 ].
Other patient-related factors
Ethnic origin, psychological and socioeconomic fac-
tors have also been associated with an increased risk
of asthma attacks. Ethnic minorities have higher
hospitalizations and urgent care visits related to
asthma [36]. This may in part be related to socieco-
nomic status, an independent risk factor for exac-
erbations [37]. In many health systems free access to
asthma medications for children can be challenging
and impact on adherence. Although both salbuta-
mol and inhaled cortiscosteroids (ICS) appear on the
WHO essential medicines list, they are frequently
missed on essential medicines lists in low-income
and middle-income countries (http://www.globa-
lasthmareport.org/management/medicines.php)
and even in high-income countries social disparities
exist [38,39], However, socioeconomic status does
not entirely explain the increased risk of exacerba-
tions in certain populations and it is likely that there
may also be differences in genetic disposition and
gene–environment interactions [40]. One study
that used intramuscular triamcinolone to assess ste-
roid response (and hence ensure adherence) found
that children of black origin were more likely to
exacerbate in the 4 weeks following triamcinolone
&
than white children [41 ].
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Asthma exacerbation prediction Fleming
Psychological issues, particularly anxiety disor-
ders, are more common in children with asthma
than healthy controls [42,43]. Although associated
with asthma severity and poor control, the relation-
ship is complex [44]. In a prospective study of 60
children with persistent asthma a severely negative
life event increased the risk of an asthma attack
within a short time of the event [45] and this was
magnified if there was a background of chronic
stress [46]. The precise mechanisms underlying
the relationship between stress and asthma exacer-
bations are not known, although an increased TH2
cytokine response has been associated with higher
chronic stress and perceived threat in children [47].
Salbutamol overuse
SABA use is included as a measure of asthma control
in most guidelines [48]. Excessive use is associated
with both asthma attacks and as a risk factor for
asthma death [10]. Both high daily use (>2 actua-
tions per day) and use on 2 or more days in 2 weeks
increase the odds ratio of an asthma attack with
average daily use the strongest predictor [49]. High
salbutamol use may be due to discordance between
preventer and reliever use or loss of baseline control
leading to an asthma attack, both of which have
been discussed in the previous sections. There is also
evidence to suggest that excessive SABA use can
increase the risk of an attack by increasing peak
bronchial hyperreactivity and inducing pro-inflam-
matory pathways, including an interaction with
rhinovirus leading to increased interleukin-6 pro-
duction [50,51]. Polymorphisms in the b2 adreno-
ceptor gene have been associated with reduced
responsiveness to SABAs and an increased risk of
exacerbation, particularly in those prescribed long-
&&
acting beta agonists [52 ]. It has been suggested that
prescription of 12 or more SABA inhalers per year
should alert healthcare professionals to the risk of an
attack and prompt an asthma review [10]. This
equates to more than 6 puffs per day, every day,
and therefore even lower thresholds should trigger
concern.
PREDICTING ASTHMA ATTACKS: USE OF
BIOMARKERS
There has been increasing interest in the use of
biomarkers to predict asthma attacks. Increasing
levels of airway inflammation may precede symp-
toms and offer a window of opportunity for inter-
vention. A key challenge is the frequency of
measurement. Minimally invasive samples such as
breath are particularly attractive in children and
offer the possibility of frequent and repeated
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Pediatric asthma and development of atopy
sampling. A study in children assessed exacerbations
over a 12-month period following a single fraction
of exhaled nitric oxide (FENO) measurements [53].
Although those who exacerbated had higher
median FENO levels at baseline, there was complete
overlap between the groups, limiting the utility of a
single exhaled nitric oxide measurement for predict-
ing exacerbation in the forthcoming year. Even
measurements of FENO 2 weeks before a severe
attack in children with severe asthma had poor
positive predictive value [54]. A recent prospective
study in children again showed low predictive value,
even when FENO measurements were combined
with clinical characteristics [55]. Measurements of
FENO taken at single time points are unlikely to be
useful in predicting an attack, particularly in view of
the variability of FENO levels. Fractal analysis of the
variation in daily FENO measurements in children
with asthma and cross correlation with symptom
scores distinguished those who exacerbated from
those who had no attacks during the period of
monitoring [56]. Although this approach shows
promise for predicting exacerbations, its use is lim-
ited by the cost and availability of daily FENO
measurements.
Inflammatory mediators, including a number of
cytokines and chemokines can be measured in
exhaled breath condensate. A prospective study
found that exhaled breath condensate acidity and
interleukin-5 levels were significant predictors of an
asthma exacerbation [20]. However, there were only
six severe exacerbations and a more recent larger
study from the same group found low predictive
capabilities for a range of cytokines including inter-
leukin-5, interleukin-13, interleukin-17 and TNF-a,
even when combined with FENO and symptom
scores [55].
Sputum eosinophils have been shown to predict
failed ICS reduction and loss of control in children
with asthma [57]. Although management strategies
based on sputum eosinophilia have been shown to
reduce exacerbations in adults [58], the same is not
true of children [59]. Sputum eosinophils in chil-
dren measured 2 weeks before a severe asthma
attack showed poor positive predictive value [54].
Elevated blood eosinophils have been associated
with increased morbidity including exacerbations
in children with asthma, particularly when com-
bined with FENO [60,61]. However, the utility of
blood eosinophils to predict exacerbation needs to
be tested in a prospective study. One such study is
currently on-going in adults [62]. The assessing
biomarkers in a real world severe asthma study
(ARIETTA) is an ambitious prospective real-world
trial which aims to recruit 1200 severe asthmatics
and measure biomarkers over a 1-year period. These
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sorts of large, collaborative studies are needed
for children.
Novel biomarkers
Transcriptomic analysis of nasal brushings from
adults with frequent exacerbations identified gene
signatures associated with active viral responses
[63]. Although the data are preliminary, these sug-
gest that nasal brushings could be used to predict
those at risk of a viral induced exacerbation. How-
ever, obtaining nasal brushings in children may be
more challenging. Saliva and urine are potentially
easier to collect. Analysis of inflammatory markers
in saliva showed a strong correlation between symp-
tom control and salivary levels of eotaxin, interleu-
kin-5 and interleukin-8 in children and adults with
asthma [64]. Urine is rich in metabolites and can be
easily obtained from children of any age. Urinary
bromotyrosine, a marker of eosinophil activation
has been shown to track asthma control and predict
future risk of an exacerbation in asthmatic children
[65]. Urinary leukotriene E4 (ULTE4) levels reflect
systemic cysteinyl leukotriene production [66,67].
In a small study, elevated ULTE4 levels were a sig-
nificant predictor of exacerbations in children
exposed to ETS [68]. Measurement of volatile
organic compounds (VOCs) in exhaled breath also
shows promise. Two studies have demonstrated that
patterns of VOCs can be used to predict exacerba-
&
tions in children [69,70 ]. In an initial small study,
six key VOCs were identified which predicted
within-subject exacerbations with a sensitivity of
100% and specificity of 93% [69]. In a more recent
larger study, the sensitivity and specificity were
&
lower at 88 and 75%, respectively [70 ]. The positive
predictive value of VOCs improved the closer the
measurement was made to an exacerbation. The
studies identified different VOCs and further work
is needed to move these measurements into clinical
practice [71].
PREDICTING ASTHMA ATTACKS:
ENVIRONMENTAL EXPOSURES
There is a well established association between viral
respiratory tract infections and asthma attacks in
children [72]. In the individual the greatest risk is in
those with atopic sensitization with high levels of
exposure to the allergen to which they are sensitized
&&
[73]. In the study by Murray et al. [74 ] this combi-
nation increased the odds ratio of an attack to 19.4.
Although little can be done at present to reduce the
risk of a viral infection, allergen exposure is poten-
tially modifiable. A recent study demonstrated that
the use of house dust mite (HDM) bed covers
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ACI 180206
reduced the likelihood of an attack in those identi-
fied to be at risk. Participants were enrolled in the
study if they presented to ED with an exacerbation
(as previously discussed, a strong predictor of a
future attack) and were HDM sensitized.
One of the most reproducible predictors of
asthma attacks is the peak in emergency visits in
children with asthma after schools return from
summer holidays (September in the Northern hemi-
sphere and January in the Southern hemisphere
[75,76]). This observation was first made in the
1980s and a recent study confirmed that ED admis-
sions remain significantly higher in September,
although the magnitude of the peak has decreased
[77]. The most plausible explanation is an increase
in respiratory viral infections in autumn [78]. It is
also likely that change in routine during the school
holidays leads to reduce adherence. The peak also
occurs at the end of the hay fever season. Prolonged
allergen exposure can lead to increased airway
inflammation making the individual more suscep-
tible to the effects of a viral infection. The recent
PROSE study demonstrated an attenuation of the
September peak in children given the IgE monoclo-
nal, omalizumab, 4–6 weeks before the autumn
peak [79]. IgE is thought to play a role in the pro-
motion of rhinovirus infections and therefore
reduction in IgE diminishes this effect.
Epidemiological studies have suggested an asso-
ciation between ambient air pollution and asthma
exacerbations in children [80–82]. A meta-analysis
found levels of nitrogen dioxide (NO2), sulphur
dioxide (SO2) and particulate matter of at least
2.5 mm (PM2.5) were significantly associated with
&
an increased risk of asthma attacks [83 ].
A number of ‘outbreaks’ of asthma attacks have
been associated with thunderstorms during the pol-
len season. It is likely associated with the release of
fungal spores or allergenic material from pollen
which have been concentrated at ground level
due to changes in atmospheric pressure associated
&
with thunderstorms [84 ].
Pollution and meteorological data are readily
available and have been incorporated into predic-
tion models for asthma attacks [85]. Google
searches and twitter data can also be utilized
[86,87]. These models are of use for clinical resource
planning; healthcare facilities can ready themselves
for a potential ‘asthma epidemic’ and from a public
health perspective mass and social media can be
used to warn asthma patients. However, a far more
promising use of these data are to identify individ-
ual patients at risk of an attack and offer an inter-
vention to reduce the risk – for example offering
review appointments or early initiation of oral ste-
roids [87].
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Asthma exacerbation prediction Fleming
PREDICTING ASTHMA ATTACKS:
PERSONAL RISK SCORES
There are clearly many risk factors which can be
used to predict asthma attacks; however, the relative
contributions of each of these will vary between
individuals. Current guidelines focus on current
asthma control and stepwise escalation in drug
therapy to achieve improved control and reduce
the risk of an attack. However, novel approaches
may help to improve prediction of exacerbations
and personalize interventions, including nonphar-
macological interventions such as reduced allergen
exposure, improved adherence and smoking cessa-
tion. Risk scores and measures of asthma control can
be used to determine the most appropriate manage-
ment step [88]. Vast amounts of data are currently
being collected in people with asthma including
daily peak expiratory flow rate, daily FENO, symp-
tom diaries, exhaled breath temperature, respiratory
rate, heart rate and physical activity and adherence
which can be combined with local pollen and pol-
lution data [89]. The MyAirCoach study aims to
combine these physiological, behavioural and envi-
ronmental data with patient characteristics to deter-
mine the extent to which they can be used to predict
asthma attacks. A similar approach is being taken in
children to develop an asthma prediction app using
Biomedical Real-Time Health Evaluation (BREATH)
platform (https://news.usc.edu/90836/usc-ucla-to-
develop-childrens-asthma-prediction-app/). Analy-
sing these data using machine learning algorithms
shows promise and potential utility for developing
individual predictive modelling [90 ].
&&
SUMMARY
Asthma attacks have a considerable impact on the
lives of children with asthma. Identification of risk
factors and improved prediction models can help to
prevent attacks. There is no room for complacency
towards asthma attacks. A single asthma attack is a
predictor for future attacks. Although it is important
that daily control is optimised, it must also be
recognized that current control and future risk are
separate domains which should be assessed individ-
ually and managed appropriately. There are numer-
ous factors that can contribute to an increased risk of
an asthma attack. Biomarker discovery may help to
improve the prediction of an attack in the individ-
ual; however, it is unlikely that a single biomarker
will hold all the answers. Of greater promise are
novel approaches to combining large datasets
including patient factors, physiological and envi-
ronmental measurements and frequently measured
biomarkers, to develop individual risk scores. The
utility of such approaches needs to be measured not
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Pediatric asthma and development of atopy
only in their ability to predict attacks, but ultimately
to prevent them.
Acknowledgements
None.
Financial support and sponsorship
The author is an Asthma UK Senior Clinical Fellow. In
the past 3 years the author has received honoraria to
speak at sponsored meetings from Novartis and Astra
Zeneca and for expert consultation from Novartis, Vec-
tura, Chiesi and Boehringer-Ingelheim.
Conflicts of interest
There are no conflicts of interest
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