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Pathogenesis and Prevention Strategies of

Severe Asthma Exacerbations in Children
James Cook; Sejal Saglani
Curr Opin Pulm Med. 2016;22(1):25-31.

Abstract and Introduction

Abstract

Purpose of review Exacerbations of asthma in children are most frequently precipitated by respiratory infections with a seasonal
pattern. However, management takes little account of the underlying infective or other precipitant abnormality.
Recent findings Interactions between environmental triggers, the airway microbiome and innate immune responses are key
determinants of exacerbations. Elevated innate cytokines interleukin (IL)-33 and IL-25, and abnormal molecular responses in the
interferon pathway are associated with rhinoviral infections. Exacerbations caused by fungal allergens also induce IL-33,
highlighting this as an attractive therapeutic target. An equal contribution of bacterial and viral infection during exacerbations,
particularly in preschool children, has become increasingly apparent, but some organisms may be protective. Investigation of
mechanisms underlying infection-related exacerbations especially in preschool children is needed.
Progressive loss of lung function from exacerbations is most pronounced in children aged 611 years, and low FEV 1 is now
recognized as a key predictor for the development of chronic obstructive pulmonary disease and premature death. Although
prevention of exacerbations is critical, suboptimal patient education, prescription and adherence to maintenance therapy, and a
lack of predictive biomarkers, remain key unaddressed issues in children.
Summary Precipitants and predictors of exacerbations, together with the child's age and clinical phenotype, need to be used to
achieve individualized management in preference to the current uniform approach for all.
Introduction

Although asthma exacerbations can be defined in different ways, any increase in asthma symptoms that requires escalation of
treatment, unscheduled medical assessment and an associated deterioration in lung function may be considered an
exacerbation.[1] The ERS/ATS severe asthma guidelines define a severe exacerbation in patients over 6 years of age as a
deterioration requiring the administration of systemic corticosteroids for 3 or more days, whereas a serious exacerbation is defined
as the requirement of hospital admission.[2]
Asthma exacerbations represent a substantial challenge with associated morbidity and mortality, in addition to being expensive to
treat and contributing significantly to the overall cost of asthma care.[3] Less well appreciated is their long-term influence on lung
health. The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) study is a large
prospective cohort study examining associations between asthma exacerbations and lung function. A total of 2429 participants
with severe or difficult to treat asthma aged 6 years and above were observed prospectively for 3 years to determine associations
between exacerbations and annual change in lung function. Exacerbations were associated with progressive loss of lung function,
with the most pronounced effect in children aged between 6 and 11 years (net 12-month change in post bronchodilator percentage
predicted FEV1 by exacerbation history was 3%).[4] A consequent lower peak FEV1 in early adulthood is now known to be an
important predictor for the development of chronic obstructive pulmonary disease (COPD) and premature death.[5,6]
Preventing asthma exacerbations in order to conserve lung function and to prevent morbidity and mortality are essential goals of
paediatric asthma management. This can only be achieved if the basics of asthma management and education are addressed.
The National Review of Asthma Deaths (NRAD) in the United Kingdom has recently shown fatal exacerbations in children were
predominantly caused by low utility of maintenance treatment and unavailable asthma management plans with clear guidance on
recognition and initial management of an exacerbation.[7] Addressing the basics of asthma care is therefore the cornerstone to
prevent exacerbations.
The aim of this review is to consider the importance of mechanisms underlying asthma exacerbations and to propose the potential
utility of exacerbation phenotype-specific management in the future. Also, to consider factors essential to prevent exacerbations,
with a specific focus on the basics of asthma education and management to prevent severe exacerbations and the associated

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decline in lung function.

Pathogenesis of Severe Asthma Exacerbations in Children

Exacerbations in School-aged Children

In a similar manner to adult patients, asthma exacerbations in school-aged children are commonly associated with abnormal
immune responses to environmental exposures such as infections, allergens, and atmospheric pollution. Mechanisms that induce
abnormal molecular responses to these individual or combined influences in older children with asthma have become apparent
recently.

Mechanisms Underlying Infectious Exacerbations

Viral-induced Episodes

Childhood exacerbations remain most strongly linked with viral respiratory tract infections, most commonly human rhinovirus
(HRV).[8,9] Altered innate immune responses to HRV are important in contributing to exacerbations. Impaired interferon responses
(IFN, IFN and IFN) have previously been demonstrated in response to rhinovirus infection in airway cells from asthmatic
children including bronchial epithelial cells and alveolar macrophages.[1012] However, the pathophysiological mechanism
underlying these findings was until recently unknown. New evidence implicates a pathway involving a suppressor of cytokine
signalling (SOCS1) protein. SOCS1 protein has previously been shown to suppress the innate immune response to influenza A
infection, via inhibition of a signalling pathway involving the IFN receptor in human respiratory epithelial cells. [13] It is apparent that
in vitro infection of primary bronchial epithelial cells from children with severe asthma with HRV results in the induction of
SOCS1,[14] which is related to the suppression of IFN and IFN1 promotor activation and associated with increased viral load.
The interferon deficiency seen in patients with asthma during HRV exacerbations may therefore be explained by increased
SOCS1, suggesting this molecule may be a therapeutic target specifically for HRV-induced exacerbations, especially relevant for
those with severe disease.[14]
Evidence supporting a defective antiviral response to rhinovirus in inducing severe asthma exacerbations, specifically in those with
more severe disease, has been demonstrated in a recent randomized, double-blind placebo controlled study of inhaled interferon
beta in asthmatic adults presenting with an acute infective exacerbation.[15] There was evidence of enhanced antiviral activity in
the treatment group, and in a subgroup analysis of 54 participants with moderate to severe asthma (stages 45 on BTS
guidelines) symptoms scores were significantly better in the treatment group.
Innate Cytokines Mediating Severe Exacerbations

Sensitization to fungal allergens is associated with increased asthma severity in children [16] and adults[17] and is known to result in
more severe asthma exacerbations.[18,19] However, clinical trials of antifungals have been disappointing,[20] perhaps because the
mechanisms underlying asthma with fungal sensitisation, and specifically, fungal-associated exacerbations, were unexplored. The
importance of serine protease activity of Alternaria alternata in inducing inflammation in pulmonary epithelial cells is now
apparent.[21] Moreover, a mouse model of chronic house dust mite exposure followed by a single inhalation of Alternaria to mimic
an asthma exacerbation resulted in increased serine protease activity leading to release of the innate epithelial cytokine interleukin
(IL)-33 and significantly increased airways inflammation and hyperresponsiveness.[22]
The triad of innate epithelial cytokines, IL-33, IL-25 and thymic stromal lymphopoeitin (TSLP), have all recently been shown to be
important in mediating asthma exacerbations.[23] HRV-induced exacerbations have specifically been associated with an increase
in IL-25 and IL-33[24,25] in a combination of in-vivo viral-induced human and mouse models. These data, together with the
evidence for IL-33-mediating fungal-induced exacerbations, suggest the innate cytokines are promising novel therapeutic targets
for severe asthma exacerbations. Interestingly, data from children suggest IL-33 is a corticosteroid resistant mediator of severe
asthma.[26] This corticosteroid insensitivity may explain why viral-induced exacerbations do not always respond to systemic
corticosteroids. Specifically, in the case of viral-induced wheezing episodes in preschool children, which have been shown to
respond poorly to systemic corticosteroids, it could be hypothesized that the episodes are mediated by the innate cytokines,
specifically IL-33.
Pollution as a Precipitant of IL-17A-mediated Exacerbations

There is increasing evidence linking road traffic emissions to both the development of asthma in children and subsequent severity
of asthma. The acute negative effect of diesel exhaust particles on asthma symptoms has been demonstrated,[27] although the

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pathogenesis of this effect was unknown. Exposure to emission particulates increases IL-17 production in the lungs of mice,[28]
and IL-17 has also been associated with severe asthma in adults.[29] In a mouse model, IL-17A neutralization prevented diesel
exhaust particle-mediated airway hyperresponsiveness.[30] Furthermore, diesel exhaust particle exposure estimated at the primary
residential address of 235 children with atopic asthma was associated with more frequent symptoms (used as a marker of
exacerbation) in the high exposure group. Highly exposed children also had approximately six times higher serum IL-17A levels
than the low exposure group.[30] The role of IL-17A in mediating diesel exhaust particle-induced exacerbations is therefore
highlighted. However, this was an association, and cannot be extrapolated to imply IL-17A should be blocked to treat pollutionassociated exacerbations, because it has been shown that corticosteroids induce IL-17A in paediatric severe asthma, [31] making
its role as pathologic or protective uncertain.[32]
Susceptibility to Severe Exacerbations

Genetic factors appear important as predictors of asthma severity and exacerbation, and genome wide association studies have
resulted in a number of candidate genes, specifically in children. Utilizing data from two paediatric asthma cohorts (The Childhood
Asthma Management Program[33] and The Childhood Asthma Research and Education Network[34]), two novel loci have been
associated with asthma exacerbation; catenin alpha 3 (CTNNA3) and semaphorin class 3D (SEMA3D).[35] SEMA3D is a signalling
protein responsible for endothelial cell migration and lies adjacent to SEMA3A and SEMA3E which are involved in immune
signalling and recruitment of T cells. CTNNA3 binds to CCAT enhancer binding protein, a transcription factor which influences
inflammatory processes and has been shown to be induced by steroids in rat bronchial epithelial cells.[36] CTNNA3 was
associated with a protective effect on exacerbations in both cohorts.
Combined Exposures Resulting in Severe Exacerbations

Up to 90% of children with asthma are infected with rhinovirus during the peak season, but there is a wide variation in
symptomatology, ranging from asymptomatic to severe exacerbation,[37] suggesting other factors modify the risk of a rhinovirus
infection eliciting an exacerbation. Aeroallergen exposure during rhinovirus infection has been previously postulated to modify
clinical symptoms but not conclusively proved.[38] In a large prospective case-crossover study, the Melbourne Air Pollen Children
and Adolescent Health study, 644 participants aged 217 years were assessed following admission with an exacerbation caused
by respiratory viral infection. In boys there was an increased risk of exacerbation requiring hospitalization when rhinoviral infection
occurred on days with high concentrations of grass pollen. However, this association was not demonstrated in girls.[39] In another
prospective study (part of the Childhood Origins of Asthma Study) 102 children with asthma were monitored between 6 and 11
years for symptoms of exacerbation and nasal samples analysed for viral infection. In addition, serum allergen-specific
immunoglobulin E (IgE) levels were measured at 6 and 11 years. Exacerbations, both viral and nonviral, were positively associated
with indicators of atopy including total IgE levels at 6 and 11 years, and with aeroallergen sensitization at 11 years. [40]
A further interactive effect, which can either be additive and increase exacerbation severity, or may be protective, is related to
changes in the airway bacterial or microbiome profile during virus infection. It has been hypothesized that coinfection of selected
bacteria would be increased in children with rhinovirus infection and asthma compared with children without asthma, and that
detection of airway bacteria in patients with asthma would be associated with increased symptoms. Samples of nasal mucus
obtained during peak rhinovirus season from 308 children aged between 4 and 12 years with and without asthma showed no
significant difference in the rates of rhinovirus infection or rates of bacterial co-infection between the asthmatic and nonasthmatic
group.[41] However, children with asthma with both rhinovirus and Streptococcus pneumoniae, or rhinovirus and Moraxella
catarrhalis had a significantly increased risk of a more severe asthma exacerbation. Interestingly, Haemophilus influenzae did not
influence symptom severity, regardless of rhinovirus status.[41] Although the mechanisms underlying coinfection of rhinovirus with
respiratory bacteria were unexplored, these data imply molecular pathways are different depending on the infecting organism, and
may explain why antibiotics are not uniformly beneficial during asthma exacerbations, even though a bacterial organism may be
detected.
Exacerbations in Preschool Children With Wheeze

Exacerbations are the predominant clinical presentation of asthma in children under 5 years. However, the response to systemic
steroids in this age group is poor. In particular, viral-induced episodes have little or no benefit from oral steroids, [42,43] implying the
mechanisms underlying preschool exacerbations of wheeze are different to those associated with atopic asthma in school-aged
children. However, disappointingly, mechanistic studies in this age group remain scarce. A likely contributory factor may be the
previously held belief that the majority of preschool wheezers with an 'exacerbation only' or episodic wheezing phenotype[44] grow
out of their symptoms, do not develop asthma and have no long-term impact on lung health. But, it is now apparent that although
symptoms may remit, lung function remains reduced and many preschool wheezers are susceptible to COPD in adulthood. [45,46]

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Furthermore, children under 5 continue to utilize the majority of healthcare resources for acute asthma admissions. [47]
Infectious Causes of Acute Wheezy Episodes in Preschool Children

The role of bacteria in causing acute symptoms in preschool children is becoming increasingly apparent. Indeed, recent data from
the Copenhagen Prospective Study on Asthma in Childhood (COPSAC 2000) have shown that both viruses and bacteria were
detected during 55% of acute episodes of wheeze in children under 3 years old.[48] Bacterial organisms alone were identified in
31% of all episodes, in contrast viruses alone were identified in only 10% of episodes. In total, a bacterial organism was detected
in 86% of episodes making the authors propose the term viral wheeze is now inappropriate.[48] Although it could be argued that
infectious exacerbations of preschool wheeze should now be treated with antibiotics, the mechanisms mediating bacterial, viral or
dual infection-related episodes remain unknown. An unfavourable alteration in the airway bacterial profile using untargeted, broadspectrum antibiotics may render the airway microbiome with a reduced diversity or richness of microbes, making the airways even
more susceptible to aberrant immune responses.[49] However, with the wealth of evidence from cohort studies showing the role of
infectious agents in causing acute episodes of preschool wheeze, and the clear evidence from clinical trials showing
corticosteroids have little benefit, and that this condition cannot be considered an extrapolation of atopic asthma, it is now prudent
to investigate the molecular mechanisms underlying episodic wheezing in young children. Only this will enable improved treatment
of acute exacerbations and limit the reduction in lung function in later life from repeated exacerbations.

Strategies to Prevent Severe Exacerbations of Asthma in Children

Addressing the Basics of Asthma Management

Although exacerbations are a feature of asthma in all patients, their prevention or minimization is essential to prevent lung function
decline. Several simple strategies including optimal asthma control,[50] patient/carer education, adherence to maintenance
therapy[51] and minimizing environmental triggers such as allergen and smoke exposure[52] result in fewer exacerbations.
Asthma control at baseline is strongly associated with symptom severity and degree of airway obstruction during an infective
exacerbation. In an in vivo study of rhinovirus exposure in adults with mild to moderate asthma, respiratory symptoms were
significantly worse in those with uncontrolled asthma at baseline,[53] thus uncontrolled asthma resulted in a more severe
exacerbation. Achieving good asthma control at baseline also reduces the risk of exacerbations. A retrospective analysis of
children admitted to intensive care with asthma exacerbations in 14 American centres identified suboptimal outpatient
management which did not comply with guideline recommendations as a key contributory factor.[54] Only 65% of those admitted to
the intensive care unit had prior treatment with an inhaled corticosteroid according to guidelines.
Accurate prediction of asthma exacerbations would allow the use of personalized treatment plans to adjust therapy during periods
of predicted high risk and thus reduce exacerbations. Analysis of two cohorts with 400 patients aged 620 years including
participants in the Asthma Control Evaluation Trial[55] and the Inner City Anti-IgE Therapy for Asthma Trial[56] identified an
exacerbation in the summer as a strong predictor for an exacerbation in the autumn.[57] In addition, five predictors for exacerbation
within 12 months: high GINA treatment step, mean daily number of rescue inhalations, post bronchodilator FEV 1, asthma control
questionnaire score, and body mass index were identified from patients enrolled in three clinical trials that included adolescents
and evaluated budesonide and formoterol maintenance and reliever therapy with fixed dose inhaled corticosteroid and long acting
beta agonist.[58]
Improving adherence to treatment is a priority in improving asthma control and reducing severe exacerbations. However, its
assessment is rarely undertaken thoroughly even in clinical trials. A meta-analysis assessing the association between adherence
to asthma controller treatment and risk of exacerbation in children and adults showed such a high degree of heterogeneity in the
measurement of adherence that a formal analysis was impossible.[59] An audiovisual reminder device in conjunction with an
electronic inhaler monitoring device was used to determine whether adherence influenced asthma outcomes in school aged
children in New Zealand.[60] Two hundred and twenty children were randomized and followed 2 monthly for 6 months. Median
adherence overall in the intervention group was 84% compared with 30% in the control group. However, asthma control only
improved in the intervention group at 2 months with fewer exacerbations (7 vs. 24%), but was not sustained, suggesting
adherence fell in subsequent months in the intervention group. Thus, satisfactory long-term interventions that ensure sustained
adherence are still needed.
Biomarkers to Predict Exacerbations

Exhaled nitric oxide (FeNO) as a simple and noninvasive biomarker to improve control and reduce exacerbations is an attractive
strategy that has proven useful in adults, even in primary care,[61] but its use to monitor asthma control in children has been

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disappointing.[62,63] Recently, the utility of FeNO, adjusted for atopy, in a dual centre randomized control trial resulted in
significantly fewer exacerbations in children in the intervention group, but by the end the FeNO monitored group was also on
significantly higher doses of inhaled corticosteroids.[64]

Conclusion
A critical step in the prevention of exacerbations is to ensure the basics of asthma management have been addressed (Fig. 1).
However, even allowing for this, there remains the risk of exacerbation in all patients. There is, therefore, a need to understand the
mechanisms underlying acute exacerbations, and in children, a specific need to identify predictive biomarkers. Environmental
factors precipitating exacerbations vary markedly, including a combination of allergen exposure, infection and pollution, and have
different effects in children at different ages and with different clinical phenotypes. Increasing evidence suggests the molecular
mechanisms underlying each of these precipitating factors individually, or when combined, are very different. The current uniform
therapeutic approach of systemic steroids and bronchodilators for all patients needs to be reconsidered, especially for severe
exacerbations, if we are to achieve effective treatment and prevention of acute episodes.

Figure 1.

A summary of contributory factors influencing the risk of acute exacerbation.

Sidebar
Key Points

Asthma exacerbations in childhood have a significant long-term impact on lung function and future lung health in adulthood.
Molecular mechanisms underlying exacerbations vary and are determined by the precipitating environmental exposure and
disease severity.

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Innate cytokines are a novel target, recently identified in mediating fungal and viral induced exacerbations.
Individually tailored therapeutic approaches that take account of the precipitant and clinical asthma phenotype need to be
considered for future management strategies.
Basic asthma management is a critical step in preventing exacerbations.
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http://www.medscape.com/viewarticle/855408_print

* First study to demonstrate a reduction in asthma exacerbations utilizing exhaled nitric oxide as a marker of disease
severity.

Acknowledgements
None.
Curr Opin Pulm Med. 2016;22(1):25-31. 2016 Lippincott Williams & Wilkins
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