TRANSATLANTIC AIRWAY CONFERENCE

The Role of Type 2 Inflammation in the Pathogenesis of

Asthma Exacerbations
Eleanor M. Dunican1,2 and John V. Fahy1,2
1
Division of Pulmonary and Critical Care Medicine, Department of Medicine, and 2Cardiovascular Research Institute, University of
California, San Francisco, San Francisco, California

Abstract inhibitors of Type 2 inflammation in asthma. These trials include

Asthma exacerbations are an important cause of asthma morbidity.
Although viral infection of the upper airway is a common cause of
asthma exacerbations, the reasons why some patients with asthma are
exacerbation prone and others are exacerbation resistant are not fully
understood. In this review, we examine whether Type 2 inflammation
modifies airway function to make patients more susceptible to
asthma exacerbations. The best data supporting a role for Type 2
inflammation in asthma exacerbations come from clinical trials of
studies with omalizumab (an inhibitor of IgE) and others with
inhibitors of Type 2 cytokines (IL-4, IL-5, and IL-13). All of these
trials consistently show that inhibiting the Type 2 pathway causes
a clinically significant reduction in asthma exacerbations. Thus, it is
now clear that Type 2 inflammation is an important mechanism of
susceptibility to asthma exacerbation.
Keywords: asthma; exacerbation; IgE; IL-13; Type 2
inflammation

(Received in original form June 22, 2015; accepted in final form August 18, 2015 )
Supported by National Institutes of Health Grants HL080414, HL107202, and HL109146.
Correspondence and requests for reprints should be addressed to John V. Fahy, M.D., M.Sc., Division of Pulmonary and Critical Care Medicine, Department of
Medicine, University of California, San Francisco, Room 1307, Health Sciences East, 513 Parnassus Ave, San Francisco, CA 94143. E-mail: john.fahy@ucsf.edu
Ann Am Thorac Soc Vol 12, Supplement 2, pp S144–S149, Nov 2015
Copyright © 2015 by the American Thoracic Society
DOI: 10.1513/AnnalsATS.201506-377AW
Internet address: www.atsjournals.org

Asthma affects 235 million people
worldwide and represents a growing public
health problem (1). In the United States,
1 in 12 people (approximately 25 million)
had asthma in 2009, compared with 1 in
14 (approximately 20 million) in 2001 (2).
A significant proportion of morbidity and
public health expenditure related to asthma
results from acute exacerbations of asthma.
For example, although only 20% of patients
with asthma experience an asthma
exacerbation annually, the cost of treating
exacerbations accounts for more than 80%
of the total direct costs of asthma (3).
Type 2 immune responses in the airway
involve accumulation of eosinophils, mast
cells, basophils, Th2 cells, Type 2 innate
lymphoid cells (ILC2s) and IgE-producing
B cells (4), and Type 2 mediators and
cytokines (IL-4, IL-5, and IL-13) have been
implicated in the pathogenesis of asthma
exacerbations (5). The purpose of this
review is to describe the epidemiology of
exacerbation-prone asthma, summarize our
understanding of the biology of Type 2
inflammation in asthma, and explore the
role of Type 2 inflammation in mediating
susceptibility to asthma exacerbations.
Asthma Exacerbations
Overview
Asthma exacerbations describe acute or
subacute episodes of progressively
worsening shortness of breath, cough,
wheeze, and chest tightness or some
combination of these symptoms, along with
decreases in expiratory airflow as measured
with a peak flow meter or spirometry (6).
Rates of exacerbations are comparable
across the seasons in adults (7, 8), whereas
children tend to display a seasonal pattern
of exacerbation, with rates lowest in the
summer and highest in the fall (9). This
seasonal variation in children has been
attributed to increased frequency of
rhinovirus (RV) infection coinciding with
return to school. Some strains of human
rhinovirus (HRV) are more associated with
exacerbation than others, with HRV-C and
HRV-A strains detected most frequently in
children experiencing an exacerbation (10).
Exacerbations of asthma impact quality
of life (11) and long-term decline in lung
function (12) and can cause death in rare
instances (8). The effect of exacerbations on
health care costs arising from health care
use, medication use, loss of productivity,
and premature death are substantial.
Compared with patients without
exacerbations, patients with one or more
exacerbation per year have higher annual
total health care costs ($9,223 versus
$5,011) and more asthma-related health
care use ($1,740 versus $847) (13). The

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total economic effects of exacerbation are
even higher when work loss and lost
productivity costs are taken into account.
In 2010, there were 14.2 million
physician office visits, 1.8 million emergency
department visits, and 439,400
hospitalizations for management of asthma
exacerbations the United States (14).
Among children under the age of 15 years,
asthma represented the third leading cause
of hospitalization (15). The annual direct
health care cost of asthma in the United
States is estimated to be $50.1 billion, with
indirect costs (e.g., lost productivity) adding
another $5.9 billion (14). Hospitalizations
for acute asthma constitute one-third of the
annual health care costs in the United
States, and the treatment of exacerbations
accounts for more than 80% of the total
direct costs of asthma (3).
Exacerbation-prone
Asthma Phenotype
Because exacerbations of asthma requiring
acute medical intervention occur mostly in
response to a specific environmental
exposure (e.g., a respiratory virus), all
patients with asthma would be expected to
be equally susceptible to exacerbation. It is
clear, however, that not all patients with
asthma are equally susceptible to
exacerbation; some patients with asthma
experience exacerbations frequently,
whereas others rarely if ever experience an
exacerbation (16). For example, 73% of
3,151 patients presenting to 83 U.S.
emergency departments with acute asthma
gave a history of at least one visit for
asthma within the previous year, and 21%
reported six or more visits (17). Risk factors
for frequent exacerbations included
nonwhite race, type of medical insurance,
and markers of asthma severity. Data
derived from the National Heart, Lung, and
Blood Institute’s Severe Asthma Research
Program show that the proportion of
patients with asthma with three or more
exacerbations per year increases as disease
severity worsens. Specifically, the Severe
Asthma Research Program investigators
have shown that 5% of patients with mild
asthma have experienced three or more
exacerbations within the past year,
compared with 13% of patients with
moderate asthma and 54% of patients with
severe asthma (18). Consistent with this
finding are data showing that only 5–10%
of the 25 million patients with asthma in
the United States have severe disease but
Dunican and Fahy: Role of Type 2 Inflammation in Pathogenesis of Asthma Exacerbations
that this subgroup represents over half the
annual costs of asthma (19).
Recognition that some patients with
asthma are exacerbation prone but others
remain relatively exacerbation resistant (5)
has resulted in increased efforts to
understand in a systematic way the biology
underlying heterogeneity in asthma.
Epidemiologically, the factors that are
important predictors of future exacerbation
include an exacerbation within the
past year, degree of asthma control,
asthma severity, and Type 2 inflammation
(18, 20–22).
Type 2 Inflammation
Overview
Type 2 inflammation describes an
inflammatory pathway involving a
subpopulation of CD41 T cells known as
Th2 cells that secrete IL-4, IL-5, and IL-13
and stimulate Type 2 immunity, which is
characterized by high IgE antibody titers
and eosinophilia (23). Type 2 immune
responses in the airway are mediated
mainly by eosinophils, mast cells, basophils,
Th2 cells, ILC2s, and IgE-producing B cells
(24). Upstream events in the airway
epithelium involving master regulators such
as IL-33, IL-25, or thymic stromal
lymphopoietin regulate maturation of
CD41 T cells into Th2 cells and
overproduction of Type 2 cytokines (IL-4,
IL-5, and IL-13). Type 2 cytokines drive
a cascade of downstream events, including
activation of airway epithelial cells,
chemoattraction of effector cells (mast cells,
eosinophils, and basophils), and
remodeling of the epithelium and
subepithelial matrix. Together, these
inflammatory and pathologic changes in
the airway predispose an individual to
exaggerated responses to inhaled
exacerbants (23). The characteristics
associated with an exaggerated response to
an exacerbation are airway eosinophilia
and airway remodeling. The relevant
remodeling changes are smooth muscle cell
changes (hyperplasia and hypertrophy),
mucus cell changes (hyperplasia,
metaplasia), and vascular remodeling (more
vessels and more leaky vessels) that
together predispose the airway mucosa to
an exaggerated response to inhaled
allergens or inhaled environmental stimuli
such as viruses and oxidizing stimuli
(cigarette smoke and other air pollutants).
Th2-high and Th2-low
Asthma Endotypes
Although Type 2 inflammation plays an
important role in asthma
pathophysiology, not all patients with
asthma have Type 2 inflammation in their
airways. Gene expression levels of Type 2
cytokines (IL-4, IL-5, and IL-13) and of
epithelial cell genes that are upregulated
by IL-13 (periostin, CLCA1, and
SERPINB2) range from low to high in
airway biospecimens from patients with
asthma (25, 26), and there is a threshold
level of expression in the airway that,
when exceeded, defines a distinct, “Th2-
high” endotype of asthma. Th2-high
asthma is characterized by greater airway
hyperresponsiveness, airway and systemic
eosinophilia, and responsiveness to
glucocorticoids and inhibitors of Type 2
inflammation. Only 50% patients with
asthma have the Th2-high endotype (25,
26), and alternative mechanisms must
operate to drive disease in “Th2-low”
asthma. The pathways operating in Th2-
low asthma have not been elucidated and
are a subject of ongoing research.
Does Type 2 Inflammation Promote
Susceptibility to Asthma
Exacerbation?
Evidence that Type 2 inflammation is a risk
for exacerbation proneness comes from
genetic studies, clinical studies, and studies
of treatment trials targeting Type 2
inflammation. Genetic studies in two
independent cohorts have shown that the
IL-4 receptor gene IL4Ra is associated with
a history of severe asthma exacerbations
and lower lung function (27). The
polymorphisms were more prevalent in
African Americans but conferred similar
risk in both African Americans and whites.
One of the polymorphisms was also
associated with higher tissue mast cells and
higher levels of IgE bound to mast cells.
The most convincing evidence for the
role of Type 2 inflammation in asthma
exacerbation comes from the effects of its
suppression by Type 2–directed therapies.
With growing understanding of the
pathways of Type 2 inflammation, multiple
potential therapeutic targets for Type 2
inhibition have been identified, including
IgE, IL-5, and IL-13.
Inhibiting IgE. For more than 30 years,
IgE has been recognized to play a key role in
asthma. IgE antibodies attach to mast cells,
S145

basophils, and dendritic cells (DCs) through
high-affinity IgE receptors (FceRIa) that
prime these cells for activation during
subsequent allergen exposure (28, 29).
Upon antigen binding, adjacent IgE
receptors on mast cells and basophils
become cross-linked to trigger release of
preformed proinflammatory autacoids that
mediate early- and late-phase responses to
inhaled aeroallergens (30). Omalizumab is
a recombinant, humanized monoclonal
antibody specific to IgE that blocks
interaction between IgE and FceRIa. Its
biologic effects are to deplete IgE, disarm
mast cells and basophils, and block the
effect of IgE on DCs. Clinical trials of
omalizumab have consistently shown a 50%
reduction in the number of asthma
exacerbations (31, 32), and omalizumab has
been shown to nearly eliminate seasonal
peaks in exacerbations when used in
children (31–33). Other benefits seen
include a reduction in maintenance dose
inhaled corticosteroids, lower symptom
scores, lower rescue medication use, and
a modest but statistically significant
increase in FEV1. Multiple postregistration
studies have replicated the finding that
omalizumab reduces exacerbation rates by
approximately 50%, even in patients on
high-dose inhaled corticosteroids, despite
having only a modest effect on lung
function and airway hyperresponsiveness
(31, 32, 34).
Inhibiting IL-5. IL-5 is produced by
CD41T helper cells (Th2 cells), mast cells,
basophils, and ILC2s (35). IL-5 is a major
regulator of eosinophil accumulation in
tissue and eosinophil function at every
stage of maturation. It mediates its response
through interaction with its receptor (IL-
5Ra), which is present on eosinophils and
some basophils. Because levels of sputum
eosinophils are predictive of increased
exacerbation risk, targeting eosinophils is
a rational strategy to reduce exacerbations,
with IL-5 being the logical pathway (36).
Mepolizumab is a humanized monoclonal
antibody that binds to IL-5 and prevents its
interaction with the IL-5Ra (37). By
blocking IL-5, mepolizumab selectively
inhibits eosinophilic inflammation. The
initial multicenter study of the effect
of mepolizumab failed to show an
improvement in asthma control, including
exacerbation rates (38). Subsequent studies
of mepolizumab in selected patients
(subjects with persistent eosinophilia
despite steroid treatment and history of
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TRANSATLANTIC AIRWAY CONFERENCE
exacerbation) showed a 50% reduction in two monoclonal antibodies that inhibit
rate of exacerbation and significant binding of IL-13 to its receptors have been
improvements in asthma control (39–41). studied in phase III clinical trials in asthma.
Similar effects of IL-5 inhibition on asthma Lebrikizumab is an IgG4 humanized
exacerbations have been shown with other monoclonal antibody that binds to IL-13 to
IL-5 inhibitors. For example, treatment block its binding to IL-4Ra. Lebrikizumab
with reslizumab (a humanized monoclonal treatment in asthma is associated with
antibody against IL-5) is associated with improvements in lung function, asthma
a 50% reduction in exacerbation rate (42), control, and exacerbation rates, especially
and a phase IIB dose-ranging study with in the subgroup with high periostin levels
benralizumab (a recombinant IgG1 (47). Dupilumab is a humanized
antibody that binds to IL-5Ra) has shown monoclonal antibody that binds to IL-4Ra
a similar effect on exacerbations in patients to block IL-4 and IL-13 activity. Blockade
with uncontrolled eosinophilic asthma (43). of these pathways in subjects with
Inhibiting IL-13. IL-13 is a central persistent eosinophilia is associated with
mediator of asthma with roles in regulation a large reduction in exacerbations (87%)
of eosinophilic inflammation, airway and improvements in lung function and
hyperresponsiveness, mucus secretion, and asthma control (48).
airway remodeling (44). IL-13 induces Lessons learned from Type 2
bronchial epithelial cells to secrete large inhibition. Although inhibiting Type 2
quantities of periostin, a matricellular inflammation has limited effects on baseline
protein with effects on both epithelial and measures of asthma activity such as airway
fibroblast function (45). IL-13 signals hyperresponsiveness or lung function, it
through two receptors, the first has large effects on exacerbation rate and
a heterodimer composed of IL-13 asthma control. These findings are
receptor a1 and IL-4 receptor a (IL-4Ra) consistent with the conceptualization of
and the second a high-affinity monomeric asthma as a disease with a core abnormality
receptor, IL-13 receptor a2 (46). Currently, in smooth airway muscle function that can
Healthy Airway
- Absence of type 2 inflammation and low circulation lgE
Type 1 inteferons
Rhinovirus
Plasmacytoid
dendritic cell Airway protected
from viral infection
Asthmatic Airway
- Presence of type 2 inflammation
- lgE arming of Plasmacytoid Dendritic Cells
Fewer inteferons
Airway susceptible
to viral infection
Figure 1. Plasmacytoid dendritic cells (pDCs) secrete IFN-a to activate the innate immune response
to virus in the airway. pDCs in healthy airways secrete large amounts of IFN-a in response to viruses.
The presence of Type 2 inflammation in asthmatic airways is associated with increased expression of
high-affinity IgE receptor FceRI on the surface of pDCs, which causes a blunted IFN-a response to
airway viral infection.
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 TRANSATLANTIC AIRWAY CONFERENCE

be modified by Type 2 inflammation to
worsen asthma control and promote
susceptibility to asthma exacerbations. A
major lesson derived from the advent of
specific treatment for Type 2 inflammation
is that treatment of Type 2 inflammation
significantly reduces the frequency of
asthma exacerbations.
Type 2 Inflammation and Susceptibility
to Asthma Exacerbation
Airway remodeling. One possible
explanation for how Type 2 inflammation
promotes susceptibility to asthma
exacerbation is through its remodeling
effects on the airway. When activated, Type
2 inflammatory cells migrate to the airway
epithelium and subepithelial mucosa and
secrete IL-5 and IL-13 to mediate
inflammatory and remodeling changes in
the airway. Pathological changes of
smooth muscle hypertrophy, goblet cell
metaplasia and hyperplasia, and
subepithelial fibrosis combine to narrow
airway caliber at baseline and alter
structural elements of the
airway, predisposing to an exaggerated
response to inhaled antigen (23).
Exacerbations then further activate multiple
pathways that may have cumulative
remodeling effects. In this way, asthma
exacerbation may become a self-
perpetuating cycle, with one exacerbation
causing changes in lung function that
promote a subsequent exacerbation. The
interrelationship between exacerbation and
airway remodeling is a potential explanation
for the susceptibility to exacerbation seen
in the subgroup of exacerbation-prone
patients with asthma (5).
Increased susceptibility to respiratory
viruses. The majority of asthma
exacerbations are associated with upper
respiratory viral infection (7). The
mechanism responsible for increased
susceptibility to developing virus-induced
asthma exacerbations is poorly understood
but likely relates to impairment of
antiviral responses in the asthmatic
airway. DCs are antigen-presenting cells
that have the capacity to bridge innate and
adaptive responses through induction of
both primary immune response and long-
term immune tolerance. Plasmacytoid
dendritic cells (pDCs) are a subset of blood
DCs that are recruited to the airways
during an acute viral infection (49). pDCs
express Toll-like receptor (TLR)7 and
TLR9, which recognize single-stranded
RNA and unmethylated CpG motifs in
DNA, respectively, and initiate signaling to
produce large concentrations of Type I
IFN in response to viral stimulation (50).
They also express FceRIa and have been
implicated in a range of allergic diseases,
including allergic asthma and atopic
dermatitis (29). Patients with allergic
asthma express increased surface FceRIa
on pDCs, which is associated with reduced
IFN-a secretion in response to influenza
viruses. Likewise, cross-linking of FceRIa
in response to IgE is associated with
decreased expression of TLR7 and TLR9
and reduces influenza-induced secretion of
IFN-a by pDCs (51–53). This supports
a biological mechanism for IgE in the
pathogenesis of asthma exacerbations
whereby IgE cross-linking impairs virus
recognition and IFN-a production by
pDCs (Figure 1). On the basis of this
mechanism, the mechanism by which
omalizumab decreases asthma
exacerbations is through disarming pDCs
of IgE and restoration of the antiviral
activity of pDCs.
Other deficiencies in innate immune
response to viral infections have also been
described in asthma. Suboptimal
production of IFN-b in response to RV is
seen in primary bronchial epithelial cells
cultured from patients with asthma, and it
results in greater viral replication and
shedding and impaired apoptosis (54).
Treatment of these infected cells with
exogenous IFN-b restored apoptosis and
reduced virus replication. In a randomized
controlled trial of inhaled IFN-b in
subjects with mild to moderate asthma and
a history of cold-induced exacerbations,
IFN-b resulted in a marked decrease in
asthma symptoms (as measured with the
six-item Juniper Asthma Control
Questionnaire) and improvements in peak
expiratory flow in the subgroup with
more severe disease (55). The authors
concluded that future studies of the utility
of IFN-b should target patients with more
severe asthma. Because total IgE levels
are inversely associated with RV-induced
IFN production (51, 53), it is plausible that
patients with Type 2 inflammation and
moderate to severe disease may benefit
from inhaled IFN-b.
Conclusions
Asthma exacerbations are an important
cause of asthma morbidity and a key driver
of the economic burden associated with
asthma. Not all persons with asthma are
equally susceptible to exacerbations; some
are exacerbation prone, whereas others are
exacerbation resistant. Mechanisms of
susceptibility to exacerbation include Type 2
immune pathways, including arming of
pDCs with IgE and increased accumulation
of eosinophils in the airway. Treatments
that target IgE and Type 2 cytokines are
proving effective in reducing susceptibility
to asthma exacerbations. n
Author disclosures are available with the text
of this article at www.atsjournals.org.

References 5 Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology,

1 World Health Organization. Fact sheet number 307: asthma [updated
2013; accessed 2015 Sep 13]. http://www.who.int/mediacentre/
factsheets/fs307/en/
2 Centers for Disease Control and Prevention (CDC). Vital signs: asthma
prevalence, disease characteristics, and self-management
education: United States, 2001–2009. MMWR Morb Mortal Wkly Rep
2011;60:547–552.
3 Rodrigo GJ, Rodrigo C, Hall JB. Acute asthma in adults: a review.
Chest 2004;125:1081–1102.
4 Oliphant CJ, Barlow JL, McKenzie AN. Insights into the initiation of type
2 immune responses. Immunology 2011;134:378–385.
biology and the exacerbation-prone phenotype. Clin Exp Allergy
2009;39:193–202.
6 National Asthma Education and Prevention Program. Expert Panel
Report 3 (EPR-3): Guidelines for the Diagnosis and Management of
Asthma–Summary Report 2007. J Allergy Clin Immunol 2007; 120(5
Suppl):S94–S138. [Published erratum appears inJ Allergy Clin
Immunol 2008;121:1330.]
7 Johnston NW, Sears MR. Asthma exacerbations. 1: epidemiology.
Thorax 2006;61:722–728.
8 Krishnan V, Diette GB, Rand CS, Bilderback AL, Merriman B, Hansel NN,
Krishnan JA. Mortality in patients hospitalized for asthma exacerbations
in the United States. Am J Respir Crit Care Med 2006;174:633–638.

Dunican and Fahy: Role of Type 2 Inflammation in Pathogenesis of Asthma Exacerbations S147

9 Teach SJ, Gergen PJ, Szefler SJ, Mitchell HE, Calatroni A, Wildfire J,
Bloomberg GR, Kercsmar CM, Liu AH, Makhija MM, et al. Seasonal
risk factors for asthma exacerbations among inner-city children.
J Allergy Clin Immunol 2015;135:1465–1473.e5.
10 Khetsuriani N, Lu X, Teague WG, Kazerouni N, Anderson LJ, Erdman
DD. Novel human rhinoviruses and exacerbation of asthma in
children. Emerg Infect Dis 2008;14:1793–1796.
11 Lloyd A, Price D, Brown R. The impact of asthma exacerbations on
health-related quality of life in moderate to severe asthma patients in
the UK. Prim Care Respir J 2007;16:22–27.
12 Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations
predict excess lung function decline in asthma. Eur Respir J 2007;30:
452–456.
13 Ivanova JI, Bergman R, Birnbaum HG, Colice GL, Silverman RA,
McLaurin K. Effect of asthma exacerbations on health care costs
among asthmatic patients with moderate and severe persistent
asthma. J Allergy Clin Immunol 2012;129:1229–1235.
14 Centers for Disease Control and Prevention (CDC). Asthma facts:
CDC’s National Asthma Control Program grantees. Atlanta, GA: U.S.
Department of Health and Human Services, Centers for Disease
Control and Prevention; July 2013 [accessed 2015 Sep 13]. http://
www.cdc.gov/asthma/pdfs/asthma_facts_program_grantees.pdf
15 Centers for Disease Control and Prevention (CDC), National Center for
Health Statistics. National Hospital Discharge Survey, 1995–2010.
Analysis by the American Lung Association Research and Health
Education Division [accessed 2015 Sep 13]. http://www.cdc.gov/
nchs/nhds.htm
16 Innes AL, McGrath KW, Dougherty RH, McCulloch CE, Woodruff PG,
Seibold MA, Okamoto KS, Ingmundson KJ, Solon MC, Carrington
SD, et al. The H antigen at epithelial surfaces is associated with
susceptibility to asthma exacerbation. Am J Respir Crit Care Med
2011;183:189–194.
17 Griswold SK, Nordstrom CR, Clark S, Gaeta TJ, Price ML, Camargo CA
Jr. Asthma exacerbations in North American adults: who are the
“frequent fliers” in the emergency department? Chest 2005;127:
1579–1586.
18 Moore WC, Bleecker ER, Curran-Everett D, Erzurum SC, Ameredes BT,
Bacharier L, Calhoun WJ, Castro M, Chung KF, Clark MP, et al.;
National Heart, Lung, Blood Institute’s Severe Asthma Research
Program. Characterization of the severe asthma phenotype by the
National Heart, Lung, and Blood Institute’s Severe Asthma Research
Program. J Allergy Clin Immunol 2007;119:405–413.
19 Serra-Batlles J, Plaza V, Morejón E, Comella A, Brugués J. Costs of
asthma according to the degree of severity. Eur Respir J 1998;12:
1322–1326.
20 ten Brinke A, Sterk PJ, Masclee AA, Spinhoven P, Schmidt JT,
Zwinderman AH, Rabe KF, Bel EH. Risk factors of frequent
exacerbations in difficult-to-treat asthma. Eur Respir J 2005;26:
812–818.
21 Miller MK, Lee JH, Miller DP, Wenzel SE; TENOR Study Group. Recent
asthma exacerbations: a key predictor of future exacerbations.
Respir Med 2007;101:481–489.
22 Sullivan SD, Wenzel SE, Bresnahan BW, Zheng B, Lee JH, Pritchard M,
Kamath TV, Weiss ST; TENOR Study Group. Association of control
and risk of severe asthma-related events in severe or difficult-to-treat
asthma patients. Allergy 2007;62:655–660.
23 Fahy JV. Type 2 inflammation in asthma—present in most, absent in
many. Nat Rev Immunol 2015;15:57–65.
24 Locksley RM. Asthma and allergic inflammation. Cell 2010;140:
777–783.
25 Woodruff PG, Boushey HA, Dolganov GM, Barker CS, Yang YH,
Donnelly S, Ellwanger A, Sidhu SS, Dao-Pick TP, Pantoja C, et al.
Genome-wide profiling identifies epithelial cell genes associated with
asthma and with treatment response to corticosteroids. Proc Natl
Acad Sci USA 2007;104:15858–15863.
26 Woodruff PG, Modrek B, Choy DF, Jia G, Abbas AR, Ellwanger A, Koth
LL, Arron JR, Fahy JV. T-helper type 2-driven inflammation defines
major subphenotypes of asthma. Am J Respir Crit Care Med 2009;
180:388–395.
27 Wenzel SE, Balzar S, Ampleford E, Hawkins GA, Busse WW,
Calhoun WJ, Castro M, Chung KF, Erzurum S, Gaston B, et al.
S148
TRANSATLANTIC AIRWAY CONFERENCE
IL4Ra mutations are associated with asthma exacerbations and
mast cell/IgE expression. Am J Respir Crit Care Med 2007;175:
570–576.
28 Presta L, Shields R, O’Connell L, Lahr S, Porter J, Gorman C, Jardieu P.
The binding site on human immunoglobulin E for its high affinity
receptor. J Biol Chem 1994;269:26368–26373.
29 Foster B, Metcalfe DD, Prussin C. Human dendritic cell 1 and dendritic
cell 2 subsets express FceRI: correlation with serum IgE and allergic
asthma. J Allergy Clin Immunol 2003;112:1132–1138.
30 Turner H, Kinet JP. Signalling through the high-affinity IgE receptor
FceRI. Nature 1999; 402(6760 Suppl):B24–B30.
31 Busse W, Corren J, Lanier BQ, McAlary M, Fowler-Taylor A, Cioppa
GD, van As A, Gupta N. Omalizumab, anti-IgE recombinant
humanized monoclonal antibody, for the treatment of severe allergic
asthma. J Allergy Clin Immunol 2001;108:184–190.
32 Solèr M, Matz J, Townley R, Buhl R, O’Brien J, Fox H, Thirlwell J, Gupta
N, Della Cioppa G. The anti-IgE antibody omalizumab reduces
exacerbations and steroid requirement in allergic asthmatics. Eur
Respir J 2001;18:254–261.
33 Busse WW, Morgan WJ, Gergen PJ, Mitchell HE, Gern JE, Liu AH,
Gruchalla RS, Kattan M, Teach SJ, Pongracic JA, et al. Randomized
trial of omalizumab (anti-IgE) for asthma in inner-city children. N Engl
J Med 2011;364:1005–1015.
34 Milgrom H, Fick RB Jr, Su JQ, Reimann JD, Bush RK, Watrous ML,
Metzger WJ; rhuMAb-E25 Study Group. Treatment of allergic asthma
with monoclonal anti-IgE antibody. N Engl J Med 1999;341:
1966–1973.
35 Kouro T, Takatsu K. IL-5- and eosinophil-mediated inflammation: from
discovery to therapy. Int Immunol 2009;21:1303–1309.
36 Belda J, Giner J, Casan P, Sanchis J. Mild exacerbations and
eosinophilic inflammation in patients with stable, well-controlled
asthma after 1 year of follow-up. Chest 2001;119:1011–1017.
37 Abonia JP, Putnam PE. Mepolizumab in eosinophilic disorders. Expert
Rev Clin Immunol 2011;7:411–417.
38 Flood-Page P, Swenson C, Faiferman I, Matthews J, Williams M,
Brannick L, Robinson D, Wenzel S, Busse W, Hansel TT, et al.;
International Mepolizumab Study Group. A study to evaluate safety
and efficacy of mepolizumab in patients with moderate persistent
asthma. Am J Respir Crit Care Med 2007;176:1062–1071.
39 Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A,
Marshall RP, Bradding P, Green RH, Wardlaw AJ, et al. Mepolizumab
and exacerbations of refractory eosinophilic asthma. N Engl J Med
2009;360:973–984.
40 Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey
SW, Ortega HG, Pavord ID; SIRIUS Investigators. Oral
glucocorticoid-sparing effect of mepolizumab in eosinophilic
asthma. N Engl J Med 2014;371:1189–1197.
41 Ortega HG, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A,
Humbert M, Katz LE, Keene ON, Yancey SW, et al.; MENSA
Investigators. Mepolizumab treatment in patients with severe
eosinophilic asthma. N Engl J Med 2014;371:1198–1207.
42 Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin
P, Murphy K, Maspero JF, O’Brien C, Korn S. Reslizumab for
inadequately controlled asthma with elevated blood eosinophil
counts: results from two multicentre, parallel, double-blind,
randomised, placebo-controlled, phase 3 trials. Lancet Respir Med
2015;3:355–366.
43 Castro M, Wenzel SE, Bleecker ER, Pizzichini E, Kuna P, Busse WW,
Gossage DL, Ward CK, Wu Y, Wang B, et al. Benralizumab, an anti-
interleukin 5 receptor a monoclonal antibody, versus placebo for
uncontrolled eosinophilic asthma: a phase 2b randomised dose-
ranging study. Lancet Respir Med 2014;2:879–890.
44 Wills-Karp M, Luyimbazi J, Xu X, Schofield B, Neben TY, Karp CL,
Donaldson DD. Interleukin-13: central mediator of allergic asthma.
Science 1998;282:2258–2261.
45 Sidhu SS, Yuan S, Innes AL, Kerr S, Woodruff PG, Hou L, Muller SJ,
Fahy JV. Roles of epithelial cell-derived periostin in TGF-b activation,
collagen production, and collagen gel elasticity in asthma. Proc Natl
Acad Sci USA 2010;107:14170–14175.
46 Tabata Y, Khurana Hershey GK. IL-13 receptor isoforms: breaking
through the complexity. Curr Allergy Asthma Rep 2007;7:338–345.
AnnalsATS Volume 12 Supplement 2 | November 2015
 TRANSATLANTIC AIRWAY CONFERENCE
47 Corren J, Lemanske RF, Hanania NA, Korenblat PE, Parsey MV, Arron
JR, Harris JM, Scheerens H, Wu LC, Su Z, et al. Lebrikizumab
treatment in adults with asthma. N Engl J Med 2011;365:1088–1098.
48 Wenzel S, Ford L, Pearlman D, Spector S, Sher L, Skobieranda F, Wang
L, Kirkesseli S, Rocklin R, Bock B, et al. Dupilumab in persistent
asthma with elevated eosinophil levels. N Engl J Med 2013;368:
2455–2466.
49 Gill MA, Palucka AK, Barton T, Ghaffar F, Jafri H, Banchereau J, Ramilo
O. Mobilization of plasmacytoid and myeloid dendritic cells to
mucosal sites in children with respiratory syncytial virus and other
viral respiratory infections. J Infect Dis 2005;191:1105–1115.
50 Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in
immunity. Nat Immunol 2004;5:1219–1226.
51 Gill MA, Bajwa G, George TA, Dong CC, Dougherty II, Jiang N, Gan VN,
Gruchalla RS. Counterregulation between the FceRI pathway and
antiviral responses in human plasmacytoid dendritic cells. J Immunol
2010;184:5999–6006.
Dunican and Fahy: Role of Type 2 Inflammation in Pathogenesis of Asthma Exacerbations
52 Schroeder JT, Bieneman AP, Xiao H, Chichester KL, Vasagar K, Saini
S, Liu MC. TLR9- and FceRI-mediated responses oppose one
another in plasmacytoid dendritic cells by down-regulating receptor
expression. J Immunol 2005;175:5724–5731.
53 Durrani SR, Montville DJ, Pratt AS, Sahu S, DeVries MK, Rajamanickam V,
Gangnon RE, Gill MA, Gern JE, Lemanske RF Jr, et al. Innate immune
responses to rhinovirus are reduced by the high-affinity IgE receptor in
allergic asthmatic children. J Allergy Clin Immunol 2012;130:489–495.
54 Wark PA, Johnston SL, Bucchieri F, Powell R, Puddicombe S, Laza-
Stanca V, Holgate ST, Davies DE. Asthmatic bronchial epithelial cells
have a deficient innate immune response to infection with rhinovirus.
J Exp Med 2005;201:937–947.
55 Djukanović R, Harrison T, Johnston SL, Gabbay F, Wark P, Thomson
NC, Niven R, Singh D, Reddel HK, Davies DE, et al.; INTERCIA Study
Group. The effect of inhaled IFN-b on worsening of asthma
symptoms caused by viral infections: a randomized trial. Am J Respir
Crit Care Med 2014;190:145–154.
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