You are on page 1of 7

Paediatric Respiratory Reviews 16 (2015) 167173

Contents lists available at ScienceDirect

Paediatric Respiratory Reviews

Review

New insights into the treatment of severe asthma in children


Lisa Giovannini-Chami 1,2,*, Marc Albertini 1,2, Pierre Scheinmann 3,4, Jacques de Blic 3,4
1

Paediatric Pulmonology and Allergology Department, Hopitaux pediatriques de Nice CHU-Lenval, Nice, F-06200, France
Universite de Nice Sophia Antipolis, Nice, F-06000, France
3
Paediatric Pulmonology and Allergology Department, AP-HP, Hopital Necker Enfants Malades, Paris, F-75015, France
4
Universite Paris Descartes-Paris 5, Paris, F-75005, France
2

EDUCATIONAL AIMS





THE ARTICLE WILL ASSIST THE READER TO:

Be aware of the denition of severe, therapy-resistant asthma and the need to distinguish this from difcult-to-treat asthma
Be aware of the intensive development in new classes of inhaled corticosteroids and bronchodilators
Increase their knowledge of biological therapies targeting inammation and impaired immunity
Discuss the fact that the majority of studies have been conducted in adults and be critical concerning extrapolation to paediatric
populations.

A R T I C L E I N F O

S U M M A R Y

Keywords:
Innovative therapies
Inhaled corticosteroids
Bronchodilators
Anti-cytokine
Omalizumab
Antiviral drugs

Severe asthma accounts for 0.5% of the general paediatric population and 4.5% of children with asthma,
representing the major burden of asthma-health-care-associated costs. After ensuring a diagnosis of
asthma and excluding difcult-to-treat patients with co-morbidities and non-adherence proles, there
remains children with real therapy-resistant asthma for whom the recommendations are to treat beyond
guidelines. We describe new insights into the treatment of severe asthma in children, regarding both
classic drugs (corticosteroids, bronchodilators) and innovative biological therapies targeting airway
inammation and impaired innate immunity. All of these new avenues remain to be studied and
validated in children and will require ne clinical and biological phenotyping.
2014 Elsevier Ltd. All rights reserved.

* Corresponding author. Paediatric Pneumology and Allergology Department,


Hopitaux pediatriques de Nice CHU-Lenval, 57 avenue de la Californie, 06200 NICE,
France. Tel.: +33492030531; fax: +33492030529.
E-mail address: giovannini-chami.l@pediatrie-chulenval-nice.fr (L. GiovanniniChami).
Abbreviations: ATS, American Thoracic Society; ERS, European Respiratory Society;
GINA, Global Initiative for Asthma; ACT, asthma control test; FEV1, forced
expiratory volume in one second; FeNO, fraction of exhaled nitric oxide; BMPRII,
bone morphogenetic protein receptor type II; GLCCI1, glucocorticoid-induced
transcript 1; GRa, glucocorticoid receptor a; GRb, glucocorticoid receptor a; GRE,
glucocorticoid-responsive elements; HDAC2, histone deacetylase 2; IL-, interleukin; ADRB2, adrenoceptor beta 2; LABA, long-acting beta-agonist; LTRA, leukotriene
receptor antagonist; ICS, inhaled corticosteroid; HFA, hydrouoroalkane; MMAD,
mass median aerodynamic diameter; CIC, ciclesonide; BUD, budesonide; FLUT,
uticasone propionate; PEF, peak expiratory ow; MAPK, mitogen-activated
protein kinases; Nrf2, nuclear erythroid 2-related factor 2; COPD, chronic
obstructive pulmonary disease; SAL, salmeterol; ICAM-1, intercellular adhesion
molecule 1; FDA, Food and Drug Administration; EMA, European Medicines Agency;
TSLP, thymic stromal lymphopoeitin; NEJM, New England Journal of Medicine;
AQLQ, Asthma Quality of Life Questionnaire; DREAM study, Mepolizumab for severe
eosinophilic asthma; IFN-, interferon; AZISAST study, Azithromycin for prevention
of exacerbations in severe asthma; RSV, respiratory syncitial virus; AIR study,
Asthma Intervention Research; HRQL, health-related quality of life.
http://dx.doi.org/10.1016/j.prrv.2014.07.006
1526-0542/ 2014 Elsevier Ltd. All rights reserved.

INTRODUCTION
Severe asthma accounts for 0.5% of the general paediatric
population and 4.5% of children with asthma [1]. Unlike in adults
[2], severe asthma in childhood is strongly associated with atopy
[3], with up to 93.5% of children in the TENOR study showing atopy
[4]. Severe asthma represents the major source of asthma-healthcare-associated costs [5]. We sought to review new insights, both
in traditional asthma treatments (corticosteroids, bronchodilators)
and in new avenues which have been studied primarily in adults,
such as biological, antiviral therapies and thermoplasty, and their
potential transfer to severe, therapy-resistant paediatric asthma.

DEFINITION, PHYSIOPATHOLOGY
The ATS/ERS denition of severe asthma for patients 6 years
old is asthma which, during the previous year, required treatment
with medications according to GINA guidelines steps 4-5, or with

168

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173

systemic corticosteroids for 50% of the time, to prevent it from


becoming uncontrolled, or which remains uncontrolled
despite these interventions [6]. Severe asthma actually comprises
two sub-groups: difcult-to-treat (but treatable) patients in whom
control can be achieved by ensuring adherence, the avoidance of
adverse psycho-social or environmental exposures and comorbidities; and severe, therapy-resistant asthma in which
treatment above and beyond standard guidelines may be
considered [79].
In the difcult-to-treat group, it would be difcult to justify highcost therapies such as omalizumab unless the primary goals of
environmental control (exposure to smoke, allergens...) and
adherence have been achieved. Indeed, after strict management
of co-factors during nurse-led home visits in a group of 71 children
with problematic asthma, potentially modiable factors were
identied in 79% and the interventions recommended led to control
without further escalation of treatment in 55% [10]. The frequency of
treatable, difcult-to-treat asthma is probably underestimated. In
an ancillary study of the Childhood Asthma Management Program,
adherence < 80% was proven for 75% of 140 children when measured
objectively, but was self-reported for only 6% [11].
In the severe, therapy-resistant-asthma, or refractory-asthma,
group, we can identify several avenues for treatment failure.
Corticosteroid resistance is evaluated, after a directly observed
parenteral or oral steroid trial, by ACT, FEV1, sputum eosinophil
count, or FeNO improvement or normalization, with no consensual
paediatric denition in terms of dose, route, length and degree of
response [12]. Congenital corticosteroid resistance linked to
mutations in the glucocorticoid receptor remains exceptional
[13], and to date no mutations in glucorticoid receptors nor single
nucleotide polymorphisms have been associated with corticosteroid resistance in airways diseases. Genetic susceptibility within
asthmatic families has been studied through microarray and
genome-wide association studies, indicating two genes, BMPRII
and GLCCI1, associated with steroid responsiveness. Acquired
steroid resistance in asthma is mainly due to Th2 pro-inammatory cytokines and oxidative stress [14]. This resistance can, in
theory, be overcome with high doses of corticosteroids at the
expense of a major risk of side effects. IL-4 and IL-2 over-expressed
in the airways of corticosteroid-resistant asthma, combined with
IL-13, reduce glucocorticoid-receptor-a (GRa) function through
phosphorylation, altering its nuclear translocation and binding to
Glucocorticosteroid Responsive Elements (GRE). Nitrosylation
through NO donors can also alter GRa binding afnity for
corticosteroids. A second mechanism of acquired resistance, also
induced by pro-inammatory cytokines and microbial superantigens, is the increased expression of a negative inhibitor (GRb).
A third mechanism, induced by oxidative and nitrative stress, is
insufcient histone deacetylation (by HDAC2 inactivation and
degradation), which is normally involved in inammatory gene
repression by corticosteroids.
Resistance to bronchodilators has also been studied. Genetic
variation in the b-2 adrenergic receptor gene [15] and the IL-6 and
IL-6R genes [16] has been associated with modication of the acute
bronchodilator response to short-acting b-agonists, but these
effects have not been demonstrated with long-acting beta-agonists
[17]. Moreover, the ADRB2 genotype does not predict the pattern
of response in step-up therapy when comparing LABA step-up with
LTRA step-up, or to ICS step-up in children with uncontrolled
asthma, despite using low-dose inhaled corticosteroids [18].
Another pitfall is to consider severe, therapy-resistant asthma
as one disease [9,19]. Refractory asthma includes several clinical,
biological, and probably molecular, phenotypes. The exacerbating
child, obstructive or brittle asthma, fungal sensitization, eosinophilia, neutrophilia, cortico-resistance, or cortico-sensitivity, are
not likely to respond equally to treatment. The second-line

management of severe asthma, after conrming that a child is


therapy resistant, is to explore the phenotype in order to tailor the
treatment properly. Few new drugs are yet available, but many
phase II/III studies are ongoing.
NEW CORTICOSTEROIDS
Inhaled corticosteroid (ICS) remains the gold-standard therapy,
even for severe asthma. However, side effects linked to the high
doses needed in this group of patients increase the risk of adrenal
suppression and growth retardation [20].
Three pathways of development aim at providing safer inhaled
corticosteroids, with the highest activity and lowest side effects.
First, a pro-drug such as ciclesonide that is only converted to its
active form, C21-des-methylpropionyl-ciclesonide, in the lungs,
leads to the lowest oro-pharyngeal absorption. Once-daily administration, available with ciclesonide, uticasone furoate and
mometasone furoate [21] due to their high afnity to GR and slow
efux rates, may improve adherence. The development of drugs such
as beclometasone HFA-134a with low MMAD might favour a
maximal distal bronchial deposition of the drug [22]. Ciclesonide
combines these three features and is available for children of 12
years in Europe. In the recent Cochrane review, an improvement in
asthma symptoms, exacerbations and side effects of ciclesonide
(CIC) versus budesonide (BUD) and uticasone propionate (FLUT)
was neither demonstrated nor refuted in children, but the studies
were short (three months) and the maximal ciclesonide dose was
320 mg q.d. [23]. In studies focused on severe asthma in patients
aged 12-75 years, 320 mg b.i.d. CIC had lower side effects than
500 mg b.i.d. FLUT in a 24-week trial [24]. In the same age group,
320 mg b.i.d. for 12 weeks was superior to 160 mg q.d. for timeto-rst-exacerbation, % predicted FEV1, morning PEF, asthmasymptom score and rescue-medication use [25].
A second approach would be to add a second drug in order to
overcome cortico-resistance and to reduce doses. Several drugs
decrease GR phosphorylation, notably long-acting b-agonists
(LABA) but also new molecules currently in clinical development,
such as inhaled p38-MAPK inhibitors. Others have been demonstrated in vitro, in mice, and in adult COPD patients, to improve
HDAC2 activity, notably theophylline which can act as an
epigenetic modulator [26]. Antioxidants such as Nrf2 activators
are also in development [14].
The last approach is the development of dissociated corticosteroids which are, in vitro and in mouse models, more effective in the
trans-repression than the trans-activation of inammatory genes
[27]. Trans-activation causes the expression of anti-inammatory
genes, but also concurrently that of genes responsible for side
effects (e.g., osteocalcin).
NEW BRONCHODILATORS
Long-acting bronchodilators, such as the long-acting anticholinergic (tiotropium) and ultra-LABAs (indacaterol, vilanterol),
have recently been authorized in adult COPD. They can be
administered once daily.
Studies have been conducted with tiotropium, available with
the Handihaler1 and Respimat1 devices, in adults with severe
asthma of xed, obstructive phenotype. Despite an increase in
cardiovascular disease and mortality in adults with the Respimat 5
and 10 mg device in COPD [28,29], studies in asthma have been
conducted with both devices. A phase III clinical trial using 5 mg
Respimat1 for 48 weeks demonstrated better bronchodilation
(pre- and post-dose FEV1) and delay-to-rst-exacerbation when
added to the usual treatment [30]. After a run-in period with 80 mg
b.i.d. beclometasone-HFA, in a triple-crossover study with 14week periods, the pre-dose FEV1 was higher when adding 18 mg

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173

tiotropium Handihaler1 than with 50 mg b.i.d. salmeterol (SAL),


proving a sustained bronchodilation [31]. As compared with
doubling the dose of ICS (Q-var1), adding tiotropium increased
symptom-free days and days with control [31]. Phase II clinical
trials in severe asthma in adolescents and children are ongoing
(available at https://clinicaltrials.gov/ identiers: NCT01277523
and NCT01634152). The antiviral properties of tiotropium, notably
in association with its capacity to decrease expression of the
receptor, ICAM-1, of the major group of rhinoviruses, give hope for
a stronger effect in delay-to-rst-exacerbation, especially in
children [32].
Phase II clinical studies with indacaterol are ongoing in adults
(available at https://clinicaltrials.gov/ identiers: NCT01609478
and NCT01959412). Only one study has been published, using
three different doses (150, 300 and 600 mg) compared with
salmeterol in persistent asthma in adults receiving 200-800 mg
FLUT or equivalent [33]. Bronchodilation speed was faster with
indacaterol and a higher level was achieved with the 300 and
600 mg doses than with salmeterol. The FDA has recently
prohibited the 150 and 300 mg doses of indacaterol (keeping only
the 75 mg dose available) because of the potential increased risk of
severe exacerbation with no signicant increase in efcacy [34].
NEW ASSOCIATIONS
A new association, Breo Ellipta1, combining the ultra-LABA,
vilanterol, and the novel inhaled corticosteroid, uticasone
furoate, was approved by the FDA in May 2013 for COPD. Breo
Ellipta1 offers the advantage of once-daily administration. Two
phase III studies have recently been conducted, in adolescents aged
12 years and in adult asthma. The safety prole has been
established for 100/25 and 200/25 mg q.d. as compared with
500 mg b.i.d. FLUT, over 52 weeks [35]. The efcacy of 100/25 q.d.
Breo Ellipta1 was similar to 250/50 b.i.d. FLUT/SAL in improving
lung function in patients with persistent asthma not controlled
with medium dose ICS after 24 weeks of treatment [36]. A reduced
risk of severe asthma exacerbations compared with uticasone
furoate treatment only has been demonstrated in a variableduration (24-78 weeks) study in 2019 patients aged 12 years
[37]. Specic paediatric studies need to be conducted.
A combination of mometasone furoate and formoterol fumarate
(100/5 and 200/5 mg b.i.d. Dulera1) was approved by the FDA in
2010 for adolescent and adult asthma. A 100/10 mg q.d. combination has been evaluated recently in children aged 5-11 years,
showing a good safety prole and signicant bronchodilation
during the 12-hour post-dosing period [38]. Only a few clinical
studies showing non-inferiority to other equivalent treatments are
available, even in adults, and more studies are needed, especially
regarding comparisons with other associations.
A new combination of extra-ne beclometasone plus formoterol propionate (F) was authorized for adults ve years ago in
Europe. Studies have shown its equivalence to BUD/F and FLUT/SAL
in terms of efcacy and tolerability prole [39,40].
BIOLOGICAL THERAPIES
Numerous biological therapies have been developed targeting
the different biological steps implied in this inammatory disease.
Some well-known steps belonging to traditional Th2 and
eosinophilic inammation pathways (IgE, IL-5, IL-13, IL-4, IL-9)
are targeted by numerous drugs. IL-5 is implied in growth,
activation and maturation of eosinophils. IL-13 is a key target in
children with severe asthma. Enhanced up-regulation of IL-13responsive genes is observed in children with uncontrolled asthma
[41]. IL-13 is a central trait of allergic respiratory disease and
recapitulates most of the characteristics of asthma in several

169

experimental models, including remodelling, mucus production,


IgE synthesis and eosinophil and basophil recruitment [42]. IL-4 is
involved in Th2-cell differentiation, expansion, isotype switching
to IgE synthesis and eosinophil and mast-cell recruitment. IL-9 is
overexpressed in the airways of asthmatic subjects and stimulates
mast cell proliferation. In parallel, inhibitors of new potentiators of
Th2 inammation are also being developed. Thymic stromal
lymphopoietin (TSLP) is a key factor expressed by epithelial cells
after a viral or allergenic trigger and is able to modulate the
activation of dendritic cells so that they induce Th2 differentiation.
Some molecules that target IL-17 have also been developed to
specically inhibit neutrophil inammation, which can be
involved in some severe asthma phenotypes. All of these molecules
are in ongoing phase II trials. Only anti-IgE (omalizumab) is
currently available and approved by the FDA and EMA.
Omalizulab
Xolair1 (omalizumab) is a recombinant, DNA-derived, humanized IgG1k monoclonal antibody that selectively binds to human
immunoglobulin E (IgE). Xolair1 has been indicated by the EMA
since 2005 as add-on therapy to improve asthma control in
patients with severe, persistent allergic asthma. In 2009, a
paediatric indication in children from 6 to <12 years was added
by the EMA (but not the FDA) and the total maximal IgE threshold
broadened to 1500 kU/L. A phase III clinical study was published in
2011, including 419 children aged 6-20 years presenting moderate-to-severe asthma [43]. As compared with placebo, add-on
therapy with omalizumab resulted in a reduction of 0.48 days/2
weeks with symptoms (p<0.001), an 18.5% reduction in exacerbations and a 109 mg reduction in corticosteroids inhaled over a
60-week period. A one-year real-life survey was conducted in
France, including 104 children aged 6-18 years at omalizumab
onset, evaluated for one year [44]. Asthma control levels, dened as
good, partial or poor in 0, 18 and 82% of the population at baseline,
respectively, improved to good (67%), partial (25%) and poor (8%) at
week 52. There was a 72% and 88.5% reduction in exacerbation and
hospitalization rates, respectively, FEV1 improved by 4.9% and ICS
decreased by 30% in the same time-frame. The children studied had
severe refractory asthma which was less well controlled, and were
more frequently atopic than those in previous clinical trials,
suggesting a specic clinical prole targeted by omalizumab.
Anti-IL-5
Initial results with mepolizumab, an anti-IL-5 antibody, were
disappointing in patients with asthma experiencing persistent
symptoms despite inhaled corticosteroids [45]. Further studies
focusing on refractory eosinophilic asthma have been more
convincing. The rst studies, published in the same issue of NEJM
in 2009 [46,47], included a limited number of adults and
demonstrated a reduction in exacerbations and an improvement
in AQLQ score over a one-year period with monthly mepolizumab
infusions [46] and a reduction in exacerbation and a sparing of
daily prednisone dose over a 16-week period [47]. The phase III
international DREAM study later included 621 patients aged 12-74
years with recurrent, severe asthma exacerbations and signs of
eosinophilic inammation [48]. This showed a 52% reduction of
exacerbation per year in the 750 mg group over a one-year period.
Anti-IL-13
A novel serum asthma biomarker, periostin, has been used to
prole patients in studies using anti-IL-13. Periostin is a
component of the extracellular matrix produced by airway epithelial
cells in response to IL-13 and IL-4, and downregulated by

170

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173

corticosteroids [49,50]. Periostin, in turn, increases the production


by airway epithelial cells of TSLP [51], a pro-Th2 cytokine. Periostin
seems to belong to a vicious circle of Th2 inammation [51]. Its
expression in brushed airway epithelial cells allows the distinction
between patients with a high Th2 phenotype and a low Th2
phenotype, in adults and children [41,52]. The rst specic anti-IL13 antibody developed was lebrikizumab, given subcutaneously
once a month. Lebrikizumab add-on therapy in adult patients with
asthma inadequately controlled with ICS was associated with
improved lung function over a 32-week treatment period [53]. In
this randomized, multi-centre study, including 219 patients, the
improvement in lung function was signicantly higher in patients
with the highest pre-treatment blood periostin level (8.2% compared
to placebo group) than in the low periostin group (1.6%). This implies
that periostin could be a biomarker relevant for the selection of
specic biologic therapies.
Other anti-IL-13 antibodies studied in adults are: tralokinumab,
which also showed an increase in FEV1 at 13 weeks of treatment
and a sustained effect 12 weeks after the nal dose [54]; and
anrukinzumab, which signicantly inhibited early- and lateallergen-induced asthmatic responses within 14 days in mild
atopic asthma [55]. Larger studies are needed to assess the efcacy
of these two molecules and to obtain more reliable information
about potential adverse events. Recently, GSK679586, an antibody
binding both IL-13 R alpha1 and alpha 2, was evaluated in adult
patients with severe asthma refractory to maximally indicated
doses of inhaled corticosteroids. This antibody did not show
clinically meaningful improvements, leading to questioning of the
composition of the study population, a key difference between this
and previous studies, and the absence of residual Th2 inammation in maximally treated patients [56].
Anti-IL-4
Studies with anti-IL-4 antibodies in humans have yielded
conicting results. Altrakincept is a soluble recombinant human
IL-4R which is unable to activate intracellular signalling pathways
because it lacks transmembrane and cytoplasmic domains [57]. A
single inhalation of this drug in adults with moderate asthma
improved lung function and reduced FeNO levels [57]. These results
were conrmed using repeated doses for 12 weeks [58] but later
clinical trials did not show any improvement in respiratory function
nor in asthma symptoms [59]. Pitrakinra is an antagonist of the
heterodimeric receptor complex IL-4RIL13-R-a developed to
overcome the biological redundancy between Il-4 and IL-13, which
is probably responsible for the failure of strategies targeting IL-4
only [60]. Pitrakinra inhibited allergen-induced early- and late
allergic responses and exacerbations in adults with eosinophilic
asthma [61]. Moreover, it signicantly lowered asthma exacerbation
frequency in subjects with SNPs in the gene encoding Il-4R [62].
AMG 317 is an IL-4R-a-targeted monoclonal antibody which blocks
the binding of IL-4 to its receptor and also inhibits IL-13 signal
transduction. In adults with moderate-to-severe asthma, AMG 317
produced signicant clinical improvement only in the sub-group
with higher baseline ACQ scores [63]. Dupilumab, the most recent
anti-IL-4 therapy targeting the alpha subunit of the IL-4 R, was
associated with a signicant reduction of exacerbation and
improvements of lung function in adults with persistent moderate-to-severe asthma during a course including discontinuation of
LABA and progressive tapering and discontinuation of inhaled
corticosteroid [64].
Other Th2-targeted therapies
An anti-IL-9 antibody, MEDI-528, induced a trend towards
improvement in AQLQ scores and in exacerbation rates in adults

with mild-to-moderate asthma, plus a protective effect against


bronchoconstriction [65].
TSLP, IL-25 and IL-33 are expressed by airway epithelial cells in
response to an allergenic or viral trigger, and drive Th2
differentiation [51]. These seem to be interesting novel targets
for severe asthma therapies. AMG 157, an anti-TSLP antibody,
supports a key role for TSLP in allergen-induced airway response,
with a reduced allergen-induced bronchoconstriction and indices
of airway inammation before and after allergen challenge [66].
Neutrophilic inammation-targeted therapies
IL-17 and Il-23 are implied in neutrophil recruitment in
neutrophilic asthma. Ongoing phase II studies are evaluating an
anti-IL-17 antibody, secukinumab. The safety prole of this
cytokine, implied in immune protection against infectious and
carcinogenic agents, needs to be established.

ANTIBIOTICS AND ANTIVIRAL THERAPIES


About ten years ago, Sebastian Johnstons team demonstrated
that asthmatic airway epithelial cells display impaired IFN-b and
IFN-l production in response to rhinovirus infection [67,68]. This
impaired interferon production has subsequently been demonstrated in severe, therapy-resistant atopic asthma in children [69],
but not in well-controlled asthma [70]. Impaired innate immunity
could be a specic feature of severe asthma, implied moreover in
frequent exacerbations. A synergism between viral infection and
allergen exposure has been revealed as increasing the risk of severe
asthma exacerbation requiring hospitalization [9].
Azithromicyn is widely used in respiratory care due to the antineutrophilic, antiviral properties associated with its capacity to
improve surfactant production. The AZISTAT trial in adult
refractory asthma studied the impact of azithromycin three times
a week versus placebo in terms of severe exacerbations or LTRI
requiring antibiotics [71]. Patients with non-eosinophilic asthma
experienced a signicant decrease in asthma exacerbations. A side
effect was the increase in macrolide-resistant streptococcus
carriage in the oropharynx.
New treatments focusing on innate immunity are currently
being developed. A randomized, multicentre, placebo-controlled
study has been completed, including 134 atopic adults with
uncontrolled asthma experiencing a natural upper airway viral
infection, in order to test the effect of concomitant inhaled IFN-b
therapy (available at https://clinicaltrials.gov/ identier:
NCT01126177). In the sub-group of difcult-to-treat asthma
there was a 65% decrease in moderate exacerbation onset, a
decrease in short-acting b-agonist use, and an increase of
asthma control in the rst week. These data are currently only
available on the Synairgen1 website. The whole population
experienced an increase in blood and sputum antiviral transcript
levels.
Viral inhibitors targeting invasion or replication were initially
discontinued because of adverse effects. A new antibody directed
against ICAM1, the receptor of the major rhinovirus group, has
recently been tested in mice with convincing results, with
diminished viral load and Th2 inammation [72]. Monthly
palivizumab injections in healthy, pre-term infants born between
33-35 weeks gestation during the RSV season resulted in a relative
reduction (-61%) in the total number of wheezing days during the
rst year of life and also a reduction in the proportion of infants
with recurrent wheeze (three or more episodes during the rst
year) (11% vs. 21% with placebo) [73]. These results support the
role of virus, notably RSV, in the pathogenesis of wheezing, and the
need for targeted antiviral therapies [74].

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173

THERMOPLASTY
Thermoplasty is a new technique approved in 2010 by the FDA
for the treatment of severe, adult asthma, which aims to reduce the
airway smooth muscle mass to decrease bronchial constriction
potency [75]. High cost and the restriction of this technique to
interventional pulmonologists with advanced skills are the
principal limitations to the dissemination of this technique in
adults. In children, the technique is probably unsuitable due not
only to short-term adverse events (worsening of symptoms,
atelectasia and haemoptysis) but mainly because of the limited
calibre of the bronchi and the lack of knowledge regarding the
potential impact on lung growth [75].
HOW TO STRATIFY TREATMENT AND MANAGEMENT?
Phenotyping severe asthma in children is one of the current
great challenges. Initial phenotyping of severe asthma in the 2000s
relied on expert opinions and included clinical and functional
characteristics as well as the type of inammation and response to
corticosteroid testing [19]. Initially identied were the exacerbating child, the child with chronic symptoms, with xed obstruction,
with eosinophilic or with neutrophilic inammation, and those
responding or not to systemic corticosteroids. More recently,
unsupervised phenotyping relying on clustering analysis applied
to many clinical, physiologic and inammatory variables has
identied more-complex phenotypes. These phenotypes are
variable between the different studies, reecting the high
heterogeneity of severe asthma, but the main criteria of
classication remain quite traditional: atopy, age of onset and
obstruction level [76,77]. New, targeted biotherapies, such as
omalizumab, have been developed in line with these clinical
stratications. Nevertheless, the stability and reproducibility of
these phenotypes, and their potential relationships with endotypes, still need to be established. The discovery of molecular
biomarkers specic to each sub-group will be necessary to dene
specic endotypes with distinct pathogenetic mechanisms. This
will be the rst step towards personalized medicine.
This is why present and future phenotypic studies will rely on
molecular- and genetic-based approaches in order to dene
endotypes. The advent of high-throughput technologies, and the
application of systems biology to dening new markers of disease
and response to therapy, will in addition help the development of
strategies for molecular-phenotype-driven treatment. Only these
multi-dimensional approaches, combining unbiased evaluation of
host cells and their responses to surrounding pathogens, will lead
to the discovery of properly dened asthma endotypes. In adults,
Th2-driven and eosinophilic-inammation endotypes, in linkage
with newly identied biomarkers, have been isolated by molecular
phenotyping, with no clear relation with atopy [52]. These
endotypes appear to be responsive to IL-5, IL-4 and IL-13 therapies,
and periostin levels can help in selecting patients and monitoring
therapy [53]. Mepolizumab, moreover, also seems to be efcient in
non-atopic patients with persistent eosinophilia, showing the
absence of a relationship between atopy and the Th2-high
endotype [78]. Genetic stratication of treatment responsiveness
was performed in the WAIT study, adjusting ALOX 5 genotypes to
montelukast response (available at https://clinicaltrials.gov/ identier: NCT01142505). This type of approach could be of particular
interest in non-Th2 severe asthma, in which no denite intrinsic
biomarkers have been identied, and where new LABA, tiotropium,
theophylline, azithromycin and inhaled IFN- beta use could be of
interest.
Data obtained in adults on Th2-high endotypes constitute only
some clues for the future, and a huge scientic effort for the
endotyping of severe asthma in children has to be instigated before

171

any potential management of these high-cost drugs can be


stratied.
CONCLUSIONS
The critical point in severe asthma remains the evaluation and
improvement of adherence [9]. A key point of cortico-resistance is
persistent Th2 inammation and thus non-adherence. Adherence
reports through SD cards included in the device, such as those
available in nocturnal non-invasive ventilation, would certainly
help clinicians.
Once-daily administration seems to be the major development
axis of the pharmaceutical industry, with ICS, ultra-LABA,
tiotropium and xed combinations. This should improve adherence but will never guarantee total compliance. Nevertheless,
these new drugs do seem to have many advantages in terms of side
effects, diffusion for ICS and viral protection for tiotropium.
Many developments are promising, but few drugs are yet
available despite current intensive work in phase II/III. Paediatric
studies are lacking and data from adult studies can only be
extrapolated to children with great caution. Antiviral drugs may be
helpful in the exacerbating child and very young children, but
consistent results still need to be published in adults. Research is,
moreover, needed on drugs targeting airway remodelling, which
seems to be an early event in paediatric asthma. New pathogenetic
pathways highlighted recently in allergic inammation will help in
the optimization of therapeutic strategies [79]. The use of
biotherapies implies a necessary ne biological phenotyping of
patients. Genome-wide association studies have recently identied genetic determinants of severe asthma [80]. Clear endotypephenotype innovative drug relations still need to be established in
the paediatric population. Cohorts of children with severe asthma,
with the collection of molecular data on blood and epithelial cells,
need to be established.
FUTURE RESEARCH DIRECTIONS
 Large, randomized studies of tiotropium add-on therapy in
children with severe asthma are needed
 Validation of results obtained with mepolizumab and lebrikizumab in selected adult patients should be obtained in children
 Pilot studies of inhaled interferon beta therapies should be
conducted in severe asthma in infants and children
 Drugs specically targeting the epithelium and remodelling
should be developed
 Drugs targeting rhinovirus infections should be developed
Acknowledgements
Thanks to Kate Vassaux PhD for medical editing. Kate Vassaux
has no conict of interest and the funding source for her assistance
was ADPHUN (Association pour le Developpement de la Pediatrie
Hospitalo-Universitaire Nicoise).
References
[1] Lang A, Carlsen KH, Haaland G, Devulapalli CS, Munthe-Kaas M, Mowinckel P,
et al. Severe asthma in childhood: assessed in 10 year olds in a birth cohort
study. Allergy 2008 Aug;63(8):105460.
[2] Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT, Bacharier
L, et al. Characterization of the severe asthma phenotype by the National Heart.
Lung and Blood Institutes Severe Asthma Research Program J Allergy Clin Immunol
2007 Feb;119(2):40513.
[3] Fitzpatrick AM, Gaston BM, Erzurum SC, Teague WG. Features of severe asthma
in school-age children: Atopy and increased exhaled nitric oxide. J Allergy Clin
Immunol 2006 Dec;118(6):121825.
[4] Haselkorn T, Borish L, Miller DP, Weiss ST, Wong DA. High prevalence of skin
test positivity in severe or difcult-to-treat asthma. J Asthma 2006
Dec;43(10):74552.

172

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173

[5] Godard P, Chanez P, Siraudin L, Nicoloyannis N, Duru G. Costs of asthma are


correlated with severity: a 1-yr prospective study. Eur Respir J 2002
Jan;19(1):617.
[6] Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International
ERS/ATS guidelines on denition, evaluation and treatment of severe asthma.
Eur Respir J 2013 Dec 12.
[7] Hedlin G, Bush A, Lodrup Carlsen K, Wennergren G, De Benedictis FM, Melen E,
et al. Problematic severe asthma in children, not one problem but many: a
GA2LEN initiative. Eur Respir J 2010 Jul;36(1):196201.
[8] Bousquet J, Mantzouranis E, Cruz AA, Ait-Khaled N, Baena-Cagnani CE,
Bleecker ER, et al. Uniform denition of asthma severity, control, and exacerbations: document presented for the World Health Organization Consultation
on Severe Asthma. J Allergy Clin Immunol 2010 Nov;126(5):92638.
[9] Custovic A, Johnston SL, Pavord I, Gaga M, Fabbri L, Bel EH, et al. EAACI position
statement on asthma exacerbations and severe asthma. Allergy 2013
Dec;68(12):152031.
[10] Bracken M, Fleming L, Hall P, Van Stiphout N, Bossley C, Biggart E, et al. The
importance of nurse-led home visits in the assessment of children with
problematic asthma. Arch Dis Child 2009 Oct;94(10):7804.
[11] Krishnan JA, Bender BG, Wamboldt FS, Szeer SJ, Adkinson Jr NF, Zeiger RS,
et al. Adherence to inhaled corticosteroids: an ancillary study of the Childhood
Asthma Management Program clinical trial. J Allergy Clin Immunol 2012
Jan;129(1):1128.
[12] Bush A, Saglani S. Management of severe asthma in children. Lancet 2010 Sep
4;376(9743):81425.
[13] Lamberts SW. Hereditary glucocorticoid resistance. Ann Endocrinol (Paris)
2001 Apr;62(2):1647.
[14] Barnes PJ. Corticosteroid resistance in patients with asthma and chronic
obstructive pulmonary disease. J Allergy Clin Immunol 2013 Mar;131(3):
63645.
[15] Martinez FD, Graves PE, Baldini M, Solomon S, Erickson R. Association between
genetic polymorphisms of the beta2-adrenoceptor and response to albuterol
in children with and without a history of wheezing. J Clin Invest 1997 Dec
15;100(12):31848.
[16] Corvol H, De Giacomo A, Eng C, Seibold M, Ziv E, Chapela R, et al. Genetic
ancestry modies pharmacogenetic gene-gene interaction for asthma. Pharmacogenet Genomics 2009 Jul;19(7):48996.
[17] Wechsler ME, Kunselman SJ, Chinchilli VM, Bleecker E, Boushey HA, Calhoun
WJ, et al. Effect of beta2-adrenergic receptor polymorphism on response to
longacting beta2 agonist in asthma (LARGE trial): a genotype-stratied,
randomised, placebo-controlled, crossover trial. Lancet 2009 Nov
21;374(9703):175464.
[18] Lemanske Jr RF, Mauger DT, Sorkness CA, Jackson DJ, Boehmer SJ, Martinez FD,
et al. Step-up therapy for children with uncontrolled asthma receiving inhaled
corticosteroids. N Engl J Med 2010 Mar 18;362(11):97585.
[19] Bush A, Fleming L. Phenotypes of refractory/severe asthma. Paediatr Respir Rev
2011 Sep;12(3):17781.
[20] Buehring B, Viswanathan R, Binkley N, Busse W. Glucocorticoid-induced
osteoporosis: an update on effects and management. J Allergy Clin Immunol
2013 Nov;132(5):101930.
[21] Allen A, Bareille PJ, Rousell VM. Fluticasone furoate, a novel inhaled corticosteroid, demonstrates prolonged lung absorption kinetics in man compared
with inhaled uticasone propionate. Clin Pharmacokinet 2013 Jan;52(1):
3742.
[22] Gentile DA, Skoner DP. New asthma drugs: small molecule inhaled corticosteroids. Curr Opin Pharmacol 2010 Jun;10(3):2605.
[23] Kramer S, Rottier BL, Scholten RJ, Boluyt N. Ciclesonide versus other inhaled
corticosteroids for chronic asthma in children. Cochrane Database Syst Rev
2013;2:CD010352.
[24] van der Molen T, Foster JM, Caeser M, Muller T, Postma DS. Difference between
patient-reported side effects of ciclesonide versus uticasone propionate.
Respir Med 2010 Dec;104(12):182533.
[25] Bateman ED, Cheung D, Lapa e Silva J, Gohring UM, Schafer M, Engelstatter R.
Randomized comparison of ciclesonide 160 and 640 microg/day in severe
asthma. Pulm Pharmacol Ther 2008;21(3):48998.
[26] Barnes PJ. Targeting the epigenome in the treatment of asthma and chronic
obstructive pulmonary disease. Proc Am Thorac Soc 2009 Dec;6(8):6936.
[27] Barnes PJ. Glucocorticosteroids: current and future directions. Br J Pharmacol
2011 May;163(1):2943.
[28] Jenkins CR, Beasley R. Tiotropium Respimat increases the risk of mortality.
Thorax 2013 Jan;68(1):57.
[29] Loke YK, Singh S, Furberg CD. Tiotropium and the risk of death in COPD. N Engl J
Med 2014 Jan 30;370(5):4801.
[30] Kerstjens HA, Engel M, Dahl R, Paggiaro P, Beck E, Vandewalker M, et al.
Tiotropium in asthma poorly controlled with standard combination therapy. N
Engl J Med 2012 Sep 27;367(13):1198207.
[31] Peters SP, Kunselman SJ, Icitovic N, Moore WC, Pascual R, Ameredes BT, et al.
Tiotropium bromide step-up therapy for adults with uncontrolled asthma. N
Engl J Med 2010 Oct 28;363(18):171526.
[32] Yamaya M, Nishimura H, Hatachi Y, Yasuda H, Deng X, Sasaki T, et al. Inhibitory
effects of tiotropium on rhinovirus infection in human airway epithelial cells.
Eur Respir J 2012 Jul;40(1):12232.
[33] Sugihara N, Kanada S, Haida M, Ichinose M, Adachi M, Hosoe M, et al. 24-h
bronchodilator efcacy of single doses of indacaterol in Japanese patients with
asthma: a comparison with placebo and salmeterol. Respir Med 2010
Nov;104(11):162937.

[34] Chowdhury BA, Seymour SM, Michele TM, Durmowicz AG, Liu D, Rosebraugh
CJ. The risks and benets of indacaterolthe FDAs review. N Engl J Med 2011
Dec 15;365(24):22479.
[35] Busse WW, OByrne PM, Bleecker ER, Lotvall J, Woodcock A, Andersen L, et al.
Safety and tolerability of the novel inhaled corticosteroid uticasone furoate
in combination with the beta2 agonist vilanterol administered once daily for
52 weeks in patients >=12 years old with asthma: a randomised trial. Thorax
2013 Jun;68(6):51320.
[36] Woodcock A, Bleecker ER, Lotvall J, OByrne PM, Bateman ED, Medley H, et al.
Efcacy and safety of uticasone furoate/vilanterol compared with uticasone
propionate/salmeterol combination in adult and adolescent patients with
persistent asthma: a randomized trial. Chest 2013 Oct;144(4):12229.
[37] Bateman ED, OByrne PM, Busse WW, Lotvall J, Bleecker ER, Andersen L, et al.
Once-daily uticasone furoate (FF)/vilanterol reduces risk of severe exacerbations in asthma versus FF alone. Thorax. 2013 Nov 19.
[38] Berger WE, Bensch GW, Weinstein SF, Skoner DP, Prenner BM, Shekar T, et al.
Bronchodilation with mometasone furoate/formoterol fumarate administered
by metered-dose inhaler with and without a spacer in children with persistent
asthma. Pediatr Pulmonol 2013 Sep 9.
[39] Papi A, Paggiaro PL, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/
formoterol versus budesonide/formoterol combination therapy in asthma.
Eur Respir J 2007 Apr;29(4):6829.
[40] Papi A, Paggiaro P, Nicolini G, Vignola AM, Fabbri LM. Beclomethasone/formoterol vs uticasone/salmeterol inhaled combination in moderate to severe
asthma. Allergy 2007 Oct;62(10):11828.
[41] Giovannini-Chami L, Marcet B, Moreilhon C, Chevalier B, Illie MI, Lebrigand K,
et al. Distinct epithelial gene expression phenotypes in childhood respiratory
allergy. Eur Respir J 2012 May;39(5):1197205.
[42] Grunig G, Warnock M, Wakil AE, Venkayya R, Brombacher F, Rennick DM, et al.
Requirement for IL-13 independently of IL-4 in experimental asthma. Science
1998 Dec 18;282(5397):22613.
[43] Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH, et al.
Randomized trial of omalizumab (anti-IgE) for asthma in inner-city children.
N Engl J Med 2011 Mar 17;364(11):100515.
[44] Deschildre A, Marguet C, Salleron J, Pin I, Rittie JL, Derelle J, et al. Add-on
omalizumab in children with severe allergic asthma: a 1-year real life survey.
Eur Respir J 2013 Nov;42(5):122433.
[45] Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M, Brannick L, et al. A
study to evaluate safety and efcacy of mepolizumab in patients with moderate
persistent asthma. Am J Respir Crit Care Med 2007 Dec 1;176(11):106271.
[46] Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al.
Mepolizumab and exacerbations of refractory eosinophilic asthma. N Engl J
Med 2009 Mar 5;360(10):97384.
[47] Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E,
et al. Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 2009 Mar 5;360(10):98593.
[48] Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe eosinophilic asthma (DREAM): a multicentre, double-blind,
placebo-controlled trial. Lancet 2012 Aug 18;380(9842):6519.
[49] Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, et al. Roles of epithelial
cell-derived periostin in TGF-beta activation, collagen production, and collagen gel elasticity in asthma. Proc Natl Acad Sci U S A 2010 Aug
10;107(32):141705.
[50] Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH, Donnelly S, et al.
Genome-wide proling identies epithelial cell genes associated with asthma
and with treatment response to corticosteroids. Proc Natl Acad Sci U S A 2007
Oct 2;104(40):1585863.
[51] Masuoka M, Shiraishi H, Ohta S, Suzuki S, Arima K, Aoki S, et al. Periostin
promotes chronic allergic inammation in response to Th2 cytokines. J Clin
Invest 2012 Jul 2;122(7):2590600.
[52] Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, et al. T-helper
type 2-driven inammation denes major subphenotypes of asthma. Am J
Respir Crit Care Med 2009 Sep 1;180(5):38895.
[53] Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron JR, et al.
Lebrikizumab treatment in adults with asthma. N Engl J Med 2011 Sep
22;365(12):108898.
[54] Piper E, Brightling C, Niven R, Oh C, Faggioni R, Poon K, et al. A phase II placebocontrolled study of tralokinumab in moderate-to-severe asthma. Eur Respir J
2013 Feb;41(2):3308.
[55] Gauvreau GM, Boulet LP, Cockcroft DW, Fitzgerald JM, Carlsten C, Davis BE,
et al. Effects of interleukin-13 blockade on allergen-induced airway responses
in mild atopic asthma. Am J Respir Crit Care Med 2011 Apr 15;183(8):100714.
[56] De Boever EH, Ashman C, Cahn AP, Locantore NW, Overend P, Pouliquen IJ,
et al. Efcacy and safety of an anti-IL-13 mAb in patients with severe asthma: a
randomized trial. J Allergy Clin Immunol 2014 Apr;133(4):98996.
[57] Borish LC, Nelson HS, Lanz MJ, Claussen L, Whitmore JB, Agosti JM, et al.
Interleukin-4 receptor in moderate atopic asthma. A phase I/II randomized,
placebo-controlled trial. Am J Respir Crit Care Med 1999 Dec;160(6):181623.
[58] Borish LC, Nelson HS, Corren J, Bensch G, Busse WW, Whitmore JB, et al.
Efcacy of soluble IL-4 receptor for the treatment of adults with asthma. J
Allergy Clin Immunol 2001 Jun;107(6):96370.
[59] Steinke JW. Anti-interleukin-4 therapy. Immunol Allergy Clin North Am 2004
Nov;24(4):599614. vi.
[60] Burmeister Getz E, Fisher DM, Fuller R. Human pharmacokinetics/pharmacodynamics of an interleukin-4 and interleukin-13 dual antagonist in asthma. J
Clin Pharmacol 2009 Sep;49(9):102536.

L. Giovannini-Chami et al. / Paediatric Respiratory Reviews 16 (2015) 167173


[61] Wenzel S, Wilbraham D, Fuller R, Getz EB, Longphre M. Effect of an interleukin4 variant on late phase asthmatic response to allergen challenge in
asthmatic patients: results of two phase 2a studies. Lancet 2007 Oct 20;
370(9596):142231.
[62] Slager RE, Otulana BA, Hawkins GA, Yen YP, Peters SP, Wenzel SE, et al. IL-4
receptor polymorphisms predict reduction in asthma exacerbations during
response to an anti-IL-4 receptor alpha antagonist. J Allergy Clin Immunol 2012
Aug;130(2). 516-22 e4.
[63] Corren J, Busse W, Meltzer EO, Manseld L, Bensch G, Fahrenholz J, et al. A
randomized, controlled, phase 2 study of AMG 317, an IL-4Ralpha antagonist,
in patients with asthma. Am J Respir Crit Care Med 2010 Apr 15;181(8):78896.
[64] Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, et al. Dupilumab
in persistent asthma with elevated eosinophil levels. N Engl J Med 2013 Jun
27;368(26):245566.
[65] Parker JM, Oh CK, LaForce C, Miller SD, Pearlman DS, Le C, et al. Safety prole
and clinical activity of multiple subcutaneous doses of MEDI-528, a humanized anti-interleukin-9 monoclonal antibody, in two randomized phase 2a
studies in subjects with asthma. BMC Pulm Med 2011;11:14.
[66] Gauvreau GM, OByrne PM, Boulet LP, Wang Y, Cockcroft D, Bigler J, et al.
Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N
Engl J Med 2014 May 29;370(22):210210.
[67] Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-Stanca V, et al.
Asthmatic bronchial epithelial cells have a decient innate immune response
to infection with rhinovirus. J Exp Med 2005 Mar 21;201(6):93747.
[68] Contoli M, Message SD, Laza-Stanca V, Edwards MR, Wark PA, Bartlett NW,
et al. Role of decient type III interferon-lambda production in asthma
exacerbations. Nat Med 2006 Sep;12(9):10236.
[69] Edwards MR, Regamey N, Vareille M, Kieninger E, Gupta A, Shoemark A, et al.
Impaired innate interferon induction in severe therapy resistant atopic asthmatic children. Mucosal Immunol 2013 Jul;6(4):797806.
[70] Sykes A, Macintyre J, Edwards MR, Del Rosario A, Haas J, Gielen V, et al.
Rhinovirus-induced interferon production is not decient in well controlled
asthma. Thorax 2013 Oct 14.

173

[71] Brusselle GG, Vanderstichele C, Jordens P, Deman R, Slabbynck H, Ringoet V,


et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax 2013 Apr;68(4):3229.
[72] Traub S, Nikonova A, Carruthers A, Dunmore R, Vousden KA, Gogsadze L, et al.
An anti-human ICAM-1 antibody inhibits rhinovirus-induced exacerbations of
lung inammation. PLoS Pathog 2013;9(8):e1003520.
[73] Blanken MO, Rovers MM, Molenaar JM, Winkler-Seinstra PL, Meijer A, Kimpen
JL, et al. Respiratory syncytial virus and recurrent wheeze in healthy preterm
infants. N Engl J Med 2013 May 9;368(19):17919.
[74] Yoo JK, Kim TS, Hufford MM, Braciale TJ. Viral infection of the lung: host response
and sequelae. J Allergy Clin Immunol 2013 Dec;132(6):126376. quiz 77.
[75] Wahidi MM, Kraft M. Bronchial thermoplasty for severe asthma. Am J Respir
Crit Care Med 2012 Apr 1;185(7):70914.
[76] Just J, Gouvis-Echraghi R, Rouve S, Wanin S, Moreau D, Annesi-Maesano I. Two
novel, severe asthma phenotypes identied during childhood using a clustering approach. Eur Respir J 2012 Jul;40(1):5560.
[77] Fitzpatrick AM, Teague WG, Meyers DA, Peters SP, Li X, Li H, et al. Heterogeneity of severe asthma in childhood: conrmation by cluster analysis of
children in the National Institutes of Health/National Heart, Lung, and Blood
Institute Severe Asthma Research Program. J Allergy Clin Immunol 2011
Feb;127(2). 382-9 e1-13.
[78] Ortega H, Chupp G, Bardin P, Bourdin A, Garcia G, Hartley B, et al. The role of
mepolizumab in atopic and nonatopic severe asthma with persistent eosinophilia. Eur Respir J 2014 Mar 23.
[79] von Gunten S, Cortinas-Elizondo F, Kollarik M, Beisswenger C, Lepper PM.
Mechanisms and potential therapeutic targets in allergic inammation: recent
insights. Allergy 2013 Dec;68(12):148798.
[80] Wan YI, Shrine NR, Soler Artigas M, Wain LV, Blakey JD, Moffatt MF, et al.
Genome-wide association study to identify genetic determinants of severe
asthma. Thorax 2012 Sep;67(9):7628.