INVITED REVIEW SERIES:

SEEKING INNOVATIVE SOLUTIONS IN SEVERE ASTHMA

SERIES EDITORS: VANESSA M. MCDONALD, PETER G. GIBSON AND STEVEN MALTBY

Pathophysiology of severe asthma: We’ve only just started

GREGORY G. KING,1,2,3 ALAN JAMES,1,4,5 LOUISE HARKNESS1,3 AND PETER A.B. WARK1,6,7

1
NHMRC Centre for Excellence in Severe Asthma, , Newcastle, NSW; 2Department of Respiratory Medicine, Royal North Shore
Hospital, Sydney, NSW; 3The Woolcock Institute of Medical Research, The University of Sydney, Sydney, NSW; 4Department
of Pulmonary Physiology and Sleep Medicine, Sir Charles Gairdner Hospital, Perth, WA; 5School of Medicine and
Pharmacology, University of Western Australia, Perth, WA; 6Priority Research Centre for Healthy Lungs, Hunter Medical
Research Institute, University of Newcastle, Newcastle, NSW; 7Department of Respiratory Medicine, John Hunter Hospital,
Newcastle, NSW, Australia

ABSTRACT the marked thickening of the airway wall and wide-

Severe asthma is defined by the high treatment require-
ments to partly or fully control the clinical manifesta-
tions of disease. It remains a problem worldwide with a
large burden for individuals and health services. The
key to improving targeted treatments, reducing disease
burden and improving patient outcomes is a better
understanding of the pathophysiology and mechanisms
of severe disease. The heterogeneity, complexity and
difficulties in undertaking clinical studies in severe
asthma remain challenges to achieving better under-
standing and better outcomes. In this review, we focus
on the structural, mechanical and inflammatory abnor-
malities that are relevant in severe asthma.
Key words: airway inflammation, airway remodelling, patho-
physiology, severe asthma.
Abbreviations: AHR, airway hyperresponsiveness; ASM,
airway smooth muscle; BAL, bronchoalveolar lavage; ECM,
extracellular matrix; FEV1, forced expiratory volume in 1 s; IFN,
interferon; ILC, innate lymphoid cell; NK, natural killer; RBM,
reticular basement membrane; SARP, Severe Asthma Research
Programme; TSLP, thymic stromal lymphopoietin.
INTRODUCTION
Severe asthma remains a worldwide problem with
incomplete understanding of its pathophysiology. It is
characterized by high requirements for treatment to
partly or completely control severe and frequent symp-
toms with disproportionate use of medical resources.
Asthma is a complex interplay between airway inflam-
mation and airway remodelling which results in airway
hyperresponsiveness (AHR)—variable and excessive air-
way narrowing. Severe asthma is also often associated
with some degree of fixed airflow limitation. In Figure 1,
Correspondence: Gregory G. King, Department of Respiratory
Medicine, Royal North Shore Hospital, Pacific Highway, St
Leonards NSW 2065, Australia. Email: ggk@woolcock.org.au
Received 12 July 2017; invited to revise 4 August 2017;
revised 14 November 2017; accepted 7 December 2017.
© 2018 Asian Pacific Society of Respirology
spread inflammatory infiltrate in severe asthma are con-
trasted with a similar-sized normal airway. These
pathological changes result in reduced baseline lung
function (in some cases) and severe, excessive airway
narrowing when the smooth muscle is stimulated to
contract, compared with normal airways or mild asthma
(Fig. 2) where narrowing of the airways is limited.
The aim of investigating asthma pathophysiology is
to understand the basis of AHR as well as incompletely
reversible airflow obstruction. The current pathophysi-
ological paradigm invokes remodelling, the sum of
structural changes to the airway wall and lung paren-
chyma, to explain AHR and fixed airflow obstruction.
The current research challenge is to sort out how and
what structural changes cause AHR and fixed or vari-
able airway narrowing, and how remodelling links with
airway inflammation (Table 1).
AIRWAY REMODELLING: THE SIMPLE
AIRWAY TUBE MODEL
The airway can be conceptualized as a simple elastic
‘tube’ embedded within an elastic lung parenchyma.
The elastic airways stretch (dilate) as the lung stretches,
due to parenchymal tethering to the airway adventitia.
In health, the elastic properties (compliance) of the
lung parenchyma and airways are well matched (rela-
tive hysteresis), which underlies the relationship
between lung volume and airway calibre. Therefore,
changes in both the mechanical properties of the lung
parenchyma and its attachments to the airway wall
may contribute to AHR and fixed airflow obstruction.
The airway walls are clearly thickened in asthma, as
demonstrated in many imaging and pathological stud-
ies. Increased airway wall thickness contributes to air-
way narrowing during airway smooth muscle (ASM)
contraction via geometric effects.1,2 Thickening of the
mucosal layer and the ASM potentiates the increase in
airway resistance for any given amount of ASM short-
ening, because airway resistance is a function of radius
(of the lumen) to the fourth power. Thickening of the
Respirology (2018)
doi: 10.1111/resp.13251
2 GG King et al.

(A) (B) Figure 1 Pathology of severe

asthma. Micrographs of large
airways with prominent carti-
lage plates (C) from a healthy
subject without asthma (A) and
from a case of fatal asthma (B).
The latter is characterized by
prominent airway smooth mus-
cle (ASM), enlarged submucosal
mucous glands (SMG) and
inflammation in the lamina pro-
pria (LP). The airway lumen is
narrowed by shortening of the
ASM (increased folding of the
basement membrane and the
presence of mucus (M)). In these
examples, there is considerable
artefactual loss of the epithe-
lium (Ep). Reproduced from
Araujo et al., with permission.35

airway wall outside of the ASM decreases the elastic
pull of the attached lung (the springs are slackened),
thereby reducing the force against which the ASM has
to shorten.3 ASM cell hypertrophy and hyperplasia4,5
potentially increase force generation even if the con-
tractile properties remain normal.6,7 However, ASM is
highly plastic, that is, it can change its contractile phe-
notype when exposed to inflammatory mediators,
persistent contraction and altered length.8–10 Thus,
increased ASM bulk, combined with increased contrac-
tility that is optimized for any given ASM length
(i.e. airway diameter) will contribute to AHR.
Increased tissue mass and altered composition of the
airway wall, particularly of the extracellular matrix
(ECM), may alter the airway wall mechanics and con-
tribute to AHR and non-reversible airway narrowing.11
Some studies suggest that airways from asthmatic

1.0 Severe asthma Table 1 Summary of the main points of

pathophysiology in severe asthma

Airway inflammation
1 .5
1. Highly heterogeneous and complex in type; impacts
clinical manifestation of asthma and treatment responses
Mild asthma
FEV1 (L)

2. Both innate and adaptive immunities may be involved to

2.0
2.5 Normal
3.0
0.001 0.01 0.1 1.0 10 100
Histamine dose (μmol)
Figure 2 Airway responsiveness in non-asthmatic (normal)
subjects and in those with mild and severe asthma. Normal air-
way responsiveness is characterized by a flat dose–response
curves or those with limited maximal narrowing. Usually, dose–
response curves are displayed with the response expressed as
percent change from the baseline value of lung function (most
often forced expiratory volume in 1 s (FEV1)). In this example,
the response is expressed as change in absolute terms (L). In
mild asthma, maximal response is still detectable but it is
increased compared with non-asthmatic subjects. There is also a
small decrement in baseline lung function. In severe asthma, the
decrement in baseline lung function is greater and a maximal
response cannot be detected within the limits of safety of the
test. In other words, the limit of inducible airway narrowing that
is seen in normal subjects is increased in asthma, in relation to
severity. These functional changes can be explained by the
degree of remodelling observed in mild and severe asthma.
explain steroid resistance
3. Eosinophilic (type 2) inflammation accounts for only
approximately 50% of severe asthma
4. The complex interactions between inflammation and
remodelling likely explain abnormal lung mechanics, but
the mechanisms are poorly understood
Airway remodelling
1. Airway remodelling is more severe in severe asthma
2. Its distribution is heterogeneous and associated with
eosinophils
3. Inflammation could cause or drive airway remodelling but
the reverse could also be easily true—the interaction
remains unclear
Airway and lung mechanics
1. Severe asthma is characterized by greater ventilation
heterogeneity and airway closure, which involves both
small and large airways
2. Abnormal lung parenchyma and adventitial attachments
may worsen AHR and partly explain irreversible airway
obstruction
3. There are complex mechanical interactions between small
and large airways, which in turn interact with airway
inflammation that may be important in explaining
symptoms and AHR in severe asthma
4. There are likely strong influences in early life, with ageing
and with co-morbidities such as obesity
AHR, airway hyperresponsiveness.

© 2018 Asian Pacific Society of Respirology Respirology (2018)

Pathophysiology of severe asthma 3

patients are stiffer than those from non-asthmatic
patients.12,13 This would prevent deep inspirations from
dilating airways, but paradoxically it could also resist
airway narrowing. Other studies suggest that airway
stiffness is not greater in asthma7 and the role of
altered airway compliance remains uncertain. Compli-
ance is not related to the severity of AHR14 but is
related to asthma symptoms.13 In any event, an in vitro
study of intact bronchial segments has shown that the
increased thickness of the ASM layer is associated with
increased maximal airway narrowing in asthma.7
AIRWAY REMODELLING: THE
COMPLEX BRANCHING SYSTEM
Airway segments do not act in isolation but are inte-
grated into the moving, branching system of airways
acting in parallel and in series. Remodelling and
inflammation of airways is likely distributed unevenly
over this branching system in patients with severe
asthma.15
Computational models treating the lungs as an inte-
grated complex unit of thousands of airway parenchy-
mal units were used to explore small versus large
airway function, airway closure and ventilation hetero-
geneity. Results suggest that both the large and periph-
eral airway compartments are relevant in severe
asthma.16 The role of the peripheral airways in AHR
and fixed airway narrowing in severe asthma remains
poorly understood. This is because the peripheral air-
ways are the ‘silent zone’, contributing only about 10%
of the total airway resistance.17 Currently, they cannot
be visualized by imaging and biopsy of the lung
periphery is inherently confined to a tiny sample of the
small airways and associated with significant risk
(bleeding and pneumothorax).
Small airway function can be measured by ventila-
tion heterogeneity (synonymous with inhomogeneity),
which is the variability of ‘specific ventilation’ (ventila-
tion per unit lung volume). Healthy lungs ventilate
somewhat heterogeneously but in a highly spatially
organized pattern along the gravitational gradient. Spe-
cific ventilation is greatest in the dependent zones,
unless there is airway closure present, which can be
thought of as the extreme end of the distribution of
ventilation within a lung.18 In asthma, ventilation is
more heterogeneous compared with health, and with
more widespread and patchy airway closure.19–22
Abnormalities of small airway function as measured
by ventilation heterogeneity using the single-breath
nitrogen washout (SBNW) and multiple-breath nitro-
gen washout (MBNW) are associated with asthma
symptoms, severe asthma exacerbations,23,24 loss of
control on withdrawal of treatment,25 airway inflamma-
tion26 and AHR.26,27 The relationship between small air-
way function and remodelling remains unknown. It has
been proposed that peripheral airways influence symp-
toms, AHR and exacerbations due to airway inflamma-
tion and remodelling causing them to be unstable and
prone to sudden closure.28 The mechanism of this
computational instability is that small airways are
highly interconnected via parenchymal tissue (see
Fig. 3); bronchoconstriction and closure in one airway
affect its neighbours with the net result of small airways
‘self-organizing’ into zones of closure or severe hypo-
ventilation.18,22 In severe asthma, these mechanisms
may be exaggerated; however, this needs to be
explored in future studies.
REMODELLING IN SEVERE ASTHMA
In severe asthma, airway walls are thicker on HRCT,29
have more fibroblasts, larger mucous glands and
increased ASM,30–32 greater epithelial fragility33 and
increased blood vessels in the lamina propria.34 There
is ASM hyperplasia in severe asthma compared with

Medium airways Small airways

1. Uneven calibre/remodelling
2. Responsive small airways

3. Interconnected
airways

5. Localized 4. Widespread ASM

regions of contraction
closure

Figure 3 Schema of how heterogeneity in inflammation and remodelling alters the mechanical function of small and large airways to
cause excessive airway narrowing and airway closure. Excessive airway narrowing and closure is increased in severe asthma, and is
based on greater heterogeneity of ventilation across the airway tree. Airway remodelling and inflammation, both distributed heteroge-
neously across the airway tree, lead to an inherent instability because airways are linked to each other by the alveolar elastic tissues.
When bronchoconstriction occurs, some airways contract excessively, which then induces more airway narrowing and closure in its
neighbours, creating a feed-forward loop. This leads to excessive and widespread narrowing and closure that occurs within zones or
regions in the lungs that are easily detected by imaging. ASM, airway smooth muscle.

Respirology (2018) © 2018 Asian Pacific Society of Respirology

4 GG King et al.
controls4,5 and with less severe asthma.5 There is also
ASM hypertrophy in both severe and less severe
asthma compared with controls.5 ECM is increased in
the ASM although this is in proportion to the increase
in ASM.5 Specific ECM proteins are also increased in
asthma, although these may vary across the airway
wall.11,35
Although structural changes in postmortem lungs
following fatal asthma attacks may not necessarily be
generalizable to severe asthma, there are similar
changes in postmortem and biopsy tissue of non-fatal
but clinically severe asthma, relative to mild cases and
non-asthmatic individuals.5,31,36 There are clear-cut dif-
ferences in wall thickness in large airways between
severe and mild-moderate asthma cases. The differ-
ences are less pronounced in the small airways,5,31 pos-
sibly due to the small absolute size of the airways and
variation in airway number and size. However, the
small airways are more susceptible to severe narrowing
and closure due to the greater wall area relative to the
airway lumen area.
The peripheral airways are tethered to the surround-
ing lung parenchyma which maintains airway calibre
and prevents excessive narrowing and closure. Post-
mortem, lung resection and transbronchial biopsy
studies in severe asthma show neutrophilic, eosino-
philic and lymphocytic inflammation and remodelling
in the peripheral airways extending to the adventitia
and lung,33,37–39 closely resembling that seen in the
large airways. Remodelling of the ASM in the small air-
ways32,37 also resembles ASM remodelling in the large
airways.15 Inflammation in the small airways could
break adjacent adventitial attachments, described in
fatal asthma,40 and reduce elastic recoil pressure,
described in long-standing asthma12,41,42 and during
asthma exacerbations.43 Reduced lung elastic recoil
pressure also explains the reduced lung density on
computed tomography (CT) scans, increased small air-
way collapse and gas trapping during expiration and
fixed airway narrowing, all of which are well described
in severe asthma.44 Recently, increased contractile ele-
ments have been documented in the lung parenchyma
in asthma.45
FIXED AIRFLOW OBSTRUCTION IN
SEVERE ASTHMA
Fixed reduction in lung function is highly variable
between asthmatic individuals.46 An increased rate of
forced expiratory volume in 1 s (FEV1) loss is found in
some47,48 but not all studies,49 even in severe asthma.50
Reduced lung function, related to asthma severity,
tracks from infancy and childhood into adult life.51–53 In
severe asthma, risk factors for loss of FEV1 are
exacerbations,54 sputum eosinophilia, adult-onset dis-
ease, longer duration of asthma,55 AHR,56 mucus
hypersecretion,48 blood eosinophilia and bronchial wall
thickening57 and sputum neutrophilia.58 In a longitudi-
nal study, the age-adjusted FEV1 decline was increased
in up to 15% of severe asthmatic individuals,59 com-
pared with around 2% in the general asthmatic
population.
© 2018 Asian Pacific Society of Respirology
Airflow obstruction has a developmental origin that
likely starts in utero, as reticular basement membrane
(RBM) thickening and inflammation are present in
wheezy infants60,61 and ASM remodelling has been
observed in preschool children who later develop
asthma.62 A number of birth cohorts have shown
abnormal lung function in infants who later develop
asthma.53,63,64 These changes are observed before the
onset of allergic sensitization,65 the greatest risk factor
for childhood-onset asthma.66 Thus, remodelling and
inflammation may be parallel processes that may inde-
pendently contribute to asthma. Persistence or acceler-
ation of both inflammation and remodelling in early
childhood, which are then modified by childhood
exposures such as viruses and diet, could underlie the
development of severe asthma and its persistence into
adulthood. Adequate control of symptoms is not a
guarantee of protection against loss of lung
function.67,68
THE NATURE OF THE RELATIONSHIP
BETWEEN INFLAMMATION AND
REMODELLING
How airway inflammation and remodelling relate to
each other is uncertain. The traditional paradigm that
airway inflammation drives airway remodelling leading
to AHR and fixed airflow obstruction derives from the
relation of persistent eosinophilic inflammation and
decreased FEV156,57 and from cross-sectional studies.69
Sputum neutrophilia is also an independent risk factor
for reduced lung function. Eosinophilic, but not neu-
trophilic, inflammation is strongly regionally associated
with increased ASM within the bronchial tree.15 The
drivers of inflammation could be IgE- or IgG-mediated
sensitization to aeroallergens or small molecules,
abnormal epithelial repair70 and/or epithelial mesen-
chymal transformation.71 Alternately, inflammation and
remodelling may be complementary processes, rather
than being cause and effect. The relationships between
ASM remodelling and reduced FEV1, to clinical severity
but not duration, suggests an early and perhaps preex-
isting abnormality of airway structure that strongly
influences severity but which requires inflammation to
manifest clinically. This may explain the ability of anti-
inflammatory treatments to reverse asthma symptoms
and variable airflow limitation without reversing fixed
airflow limitation or altering the rate of decline of lung
function.
Altered airway structure may itself stimulate inflam-
mation.35 Remodelling involves degradation and repair
of ECM and proliferation of fibroblasts and myofibro-
blasts. The action of matrix metalloproteinases on ECM
releases bioactive fragments that are pro-inflammatory
and increase neo-vascularization. For example, elastin
fragments have a wide range of effects and are pro-
proliferative and pro-inflammatory and further stimu-
late matrix degradation via stimulating matrix metallo-
proteinase release.72 Decreased collagen IV in
asthmatic airways reduces the level of one of its bioac-
tive fragments, tumstatin, in airway fluid and airway
biopsies.73 Tumstatin inhibits vascularization and pre-
vents angiogenesis, AHR, inflammatory cell infiltrate
Respirology (2018)
Pathophysiology of severe asthma
and mucus secretion in a mouse model of asthma.73
ASM cells from asthmatic individuals have pro-
proliferative activity74 and increased chemotactic activ-
ity for mast cells.75
INFLAMMATION HETEROGENEITY IN
SEVERE ASTHMA
Heterogeneity of inflammation in asthma was recog-
nized even in 1922 by Huber and Koessler30 in airway
tissue from fatal asthma. They described the associa-
tion between allergy and eosinophilic airway inflamma-
tion, but also mixed infiltrates of eosinophils and
neutrophils. This heterogeneity is clinically relevant in
relation to the variable responses to inhaled corticoste-
roids and to potential effects on remodelling and AHR.
A cluster analysis based on symptom control and
sputum eosinophilia to group statistically similar indi-
viduals together was applied to a UK asthmatic cohort
with a wide range of disease severity and age of onset.76
One cluster had childhood-onset asthma associated
with atopy and active airway eosinophilia whose symp-
toms and sputum eosinophilia were concordant. In the
other three clusters, symptoms and sputum eosino-
philia were discordant. One cluster had eosinophilia
and late-onset asthma, but with few symptoms. The
other two clusters were non-eosinophilic; one charac-
terized by obesity, late-onset disease and female gen-
der, while the other was characterized by early-onset
disease and atopy.76
Another cluster analysis of 378 adult asthmatic
patients enriched with severe disease from the Severe
Asthma Research Programme (SARP)77 identified
112 variables including those from bronchial lavage
and biopsy. Six clusters were identified, three contain-
ing severe asthmatic patients; early-onset allergic
asthma with low lung function and eosinophilic inflam-
mation; later-onset, mostly severe asthma with nasal
polyps and eosinophilia; and those with persistent
inflammation in blood and bronchoalveolar lavage
(BAL) fluid and exacerbations despite high systemic
corticosteroid use. The fact that the clusters could be
identified by using only FEV1 and age of onset of
asthma reinforces the importance and clinical utility of
lung function in severe asthma.
However, the clusters identified by these analyses
are still subject to bias as they are dependent on the
variables that are used for the analyses. In a non-
selected general population in which a wide range of
measures of respiratory symptoms and illness were
used, clusters were dependent on the input variables.
While these studies neither inform on effects of treat-
ment nor specifically address severe asthma, they do
show that the label of ‘asthma’ is non-specific and
occurs in a high percentage of clusters identified with
widely varying characteristics.78,79 Interestingly, both
the cluster analysis of severe asthma77 and general pop-
ulation cluster analyses identified a subgroup of over-
weight females likely to have severe asthma or be
labelled as having asthma.78 These studies confirm that
the clinical diagnosis of asthma, long known to be vari-
able in its presentation and expression, encompasses
different pathological mechanisms that drive the
Respirology (2018)
5
disease throughout life and highlights the importance
of thorough physiological characterization of patients
in routine clinical practice.
ALLERGIC AIRWAY INFLAMMATION
IN SEVERE ASTHMA
Endobronchial biopsy of proximal airways in severe
asthma has shown persistent type 2 inflammation char-
acterized by airway eosinophils, lymphocytes, mast
cells and associated thickening of the RBM despite reg-
ular use of oral corticosteroids.80 Interestingly, eosino-
philia in severe asthma was similar to that in steroid-
naïve, mild asthma with a tendency to increased airway
neutrophils and half had no eosinophilic inflamma-
tion.80 In a study of 80 subjects with severe asthma,
asthma onset before 12 years of age was associated
with atopy (98% vs 76%), higher serum IgE and
increased eosinophils, lymphocytes and mast cells in
the airway wall81 compared with onset after 12 years.
In those with later-onset asthma, half had no airway
eosinophilia and tended to have lower lung function
and a history of near-fatal attacks.81 These findings
were recently replicated in the larger SARP severe
asthma cohort where approximately half had persistent
type 2 inflammation (increased sputum eosinophils,
exhaled nitric oxide, blood eosinophils, IgE and serum
periostin with more atopy and AHR).77 Activation of
type 2 airway inflammation in the context of severe
asthma is summarized in Figure 4.
The persistence of eosinophilia despite corticosteroid
treatment in severe asthma is unexplained. Eotaxin, a
chemokine that recruits eosinophils and TH-2 cells, is
elevated in severe asthma and greater expression in
airway epithelial cells82 and fibroblasts83 may drive
eosinophilia despite steroid treatment. Type 2 innate
lymphoid cells (ILC2) and innate immune activation of
structural cells, such as airway epithelium, also drive
type 2 immune responses in asthma in the absence of
atopy and sputum eosinophilia, and may contribute to
disease severity and steroid resistance. ILC2 cells
release more IL-5, -4 and -13 compared with CD4 TH-2
cells. ILC2 cells are increased in blood but there are
twice as many ILC2 cells in the sputum in subjects with
severe asthma.84 Similarly, children with severe asthma
have 10-fold more ILC2 in the BAL than in the blood.85
Mechanisms to switch off type 2 immune responses
in severe asthma may be impaired. Natural killer
(NK) cells have innate immune functions similar to
CD8 cells, in that they express perforin and granzyme
and may play an important role in switching off acti-
vated immune cells by inducing apoptosis in granulo-
cytes.86 They also induce apoptosis in eosinophils and
are reduced in the blood of subjects with severe
asthma compared with mild asthma and controls.87
Lipoxin A4, an anti-inflammatory cytokine which
enhances NK cell-induced eosinophil apoptosis, is
reduced in the BAL of subjects with severe asthma.88
Such mechanisms may contribute to treatment resis-
tance in severe asthma.
Mast cells are activated when the IgE antibodies bind
with allergen via the FcεR1 high affinity receptors.89 In
severe asthma, mast cells express more chymase and
© 2018 Asian Pacific Society of Respirology
6 GG King et al.

Viruses

Allergens

INOS, periostin, eotaxin, mucus hypersecretion

Mast cell
TSLP IL33, IL25 ILC-2
IL-5, 4, IL-13
IL-4, IL-13 Chymase,
PGD2
tryptase
IL-5
APC

TH-2 IL-5 Reduced

Eosinophil
Lipoxin A4

IL-4
B cell
isotype NK cells
switch IgE

Figure 4 Type 2 airway inflammation in severe asthma. CD4 T cells with a TH-2 phenotype produce IL-4, IL-13 and IL-5. IL-13 upregu-
lates airway epithelial genes such as periostin and induces mucus production. Epithelial cells exposed to pro-inflammatory and aller-
gic stimuli release mediators such as thymic stromal lymphopoietin (TSLP), which activate dendritic cells and promote the
development of TH-2 lymphocytes. Epithelial cell damage causes release of IL-33 which can activate the inflammasome and exacer-
bate allergic inflammation. Elevated levels of IL-5 are associated airway eosinophilia and epithelial changes associated with increased
expression of eotaxin and inducible nitric oxide (iNOS). Release of IL-4 is crucial and promotes the plasma/B cell isotype switch to pro-
duce IgE. This is associated with increased intraepithelial mast cell expression of IgE making them prone to degranulation following
IgE crosslinking. Innate lymphoid cells (ILCs) are a particular feature of severe asthma and help explain eosinophilic/type 2 inflamma-
tion that occurs independent of allergic sensitization. Increased intraepithelial mast cells in severe asthma demonstrate an altered phe-
notype with increased expression of chymase and tryptase. Mast cell-derived prostaglandin D2 (PGD2) is increased, which activates
both mast cells themselves as well as ILC2 cells. The ability to switch off inflammation may be impaired. Reduced levels of lipoxin A4
reduce activation of natural killer (NK) cells that play a crucial role in the induction of apoptosis in eosinophils and neutrophils. APC,
antigen presenting cells.

tryptase compared with normal subjects and increased
numbers of intraepithelial mast cells have been found
at endobronchial biopsy in the airways in severe asthma
compared with mild asthma.90 Mast cell activation is
enhanced in severe asthma, with elevated levels of mast
cell-derived prostaglandin D2 in BAL,91 which is able to
activate both mast cells themselves as well as ILC2 cells
via the chemoattractant receptor-homologous molecule
expressed on T helper type 2 cells.91
Inflammation can also affect the airway epithelium.
Exposure to IL-13 induces mucus metaplasia contribut-
ing to mucus hypersecretion and impaired mucus
clearance.92 Mucus hypersecretion is an important
symptom in severe asthma which contributes to
increased luminal narrowing and is associated with
FEV1 decline.93
The importance of the type 2 inflammation in
severe asthma is clearly shown by the clinical and
anti-inflammatory efficacy of monoclonal antibodies
that specifically target these pathways. Omalizumab
binds IgE in the blood94 and reduces exacerbation fre-
quency without improving lung function in subjects
with severe allergic asthma with persistent allergic
inflammation, not controlled by inhaled corticoste-
roids.95 Blocking the actions of the cytokine IL-5 with
mepolizumab in severe asthma markedly reduces
blood eosinophils and, to a lesser extent, tissue eosin-
ophilia and reduces acute exacerbations by approxi-
mately 50%.96,97 Dupilumab is a monoclonal antibody
that blocks the IL-4/IL-13 receptor. It has a poten-
tially larger effect on exacerbation frequency and lung
function in moderate and severe asthma that is inde-
pendent of eosinophilia.98 Most recently, the results
of a phase 2 trial of a monoclonal antibody against
thymic stromal lymphopoietin (TSLP), Tezepelumab,
was published.99 TSLP is released by the airway epi-
thelium not only in response to allergen exposure,
but also in response to viral infection and diesel parti-
cle exposure. In moderate-to-severe symptomatic
asthma, Tezepelumab reduced exacerbations by
60–70% and resulted in a small increase in lung func-
tion.99 These treatments are very promising for those
with severe asthma and persistent allergic airway
inflammation. However, other mechanisms also need
to be considered in non-allergic inflammation and
severe asthma.

© 2018 Asian Pacific Society of Respirology Respirology (2018)

Pathophysiology of severe asthma
NON-ALLERGIC AIRWAY
INFLAMMATION IN SEVERE ASTHMA
The importance of non-allergic airway inflammation in
severe asthma is increasingly recognized but is much
less well characterized. Non-allergic inflammation is
enhanced in severe asthma, with a mixed inflammatory
infiltrate of eosinophils and neutrophils, increased
CXCL-8 and interferon (IFN)-γ-positive CD4 (TH-1)100
and CD4 TH-17 cells and IL-13.101 Messenger RNA for
a suppressor of type 1 inflammation, secretory leuko-
cyte protease inhibitor, is reduced in epithelial brush-
ings in severe asthma.101 High nitro-oxidative stress is
also increased in BAL in severe asthma compared with
mild/moderate asthma and controls, and is associated
with airway inflammation.102 It is increased by IL-13
(a TH-2 cytokine) and IFN-γ, which also correlate with
airflow obstruction.103
The innate immune response likely plays an impor-
tant role in non-allergic asthma. It involves the airway
epithelium, fibroblasts, smooth muscle cells and innate
immune cells, particularly dendritic cells and ILC.89 ILC
are non-T, non-B lineage negative lymphocytes that
migrate to the airways in response to environmental
triggers86 (see Fig. 4). They are quite plastic cells in
their responses to stimuli, which is modified by their
immune environment.
Increased sputum neutrophils may be the result of
increased innate immune activation as suggested by
the correlations between sputum neutrophil number or
CXCL-8 (IL-8) and innate immune activation markers
toll-like receptor (TLR)-2/4 and CD-14 in sputum.104
The innate immune system may be activated by
chronic airway ‘infection’. Potentially pathogenic bacte-
ria such as Haemophilus, Moraxella and Streptococcus
in sputum in severe asthma correlate with sputum
CXCL-8 and neutrophils.105 ILC are increased in the
BAL of obese patients with severe asthma106 and pro-
duce IL-17 which drives airway neutrophilia and may
cause smooth muscle contraction.107 The precise role
of these mechanisms in severe asthma is yet to be
determined.
Obesity is an independent risk factor for severe
asthma and is associated with non-type 2 inflammation.
Obese asthmatic patients have later-onset disease, cor-
ticosteroid refractoriness,108 less atopy, more severe
symptoms and increased medication use.109 Obesity
alone may worsen nitro-oxidative stress in asthma and
therefore non-type 2 inflammation.110 In asthma, ele-
vated serum IL-6 is associated with increased body
weight, with lower lung function and greater exacerba-
tion risk independent of obesity.111
CONCLUSIONS
The pathophysiology of severe asthma, characterized
by severe AHR, abnormal fixed lung function, high
treatment requirements and persisting symptoms, is
due to a complex interaction between inflammation,
airway remodelling and altered lung mechanics. Airway
inflammation in severe asthma is highly complex,
involving both adaptive and innate systems, and
greater understanding of inflammation has helped
Respirology (2018)
7
clinicians to better understand clinical disease (pheno-
types) and to better treat severe asthma patients. More
importantly, however, there is a great need to deter-
mine how inflammation and airway remodelling inter-
act, which results in the abnormal physiology of AHR
in severe asthma. The magnitude of the structural
changes to the airway wall is increased, and more het-
erogeneously distributed in severe asthma. Further-
more, the mechanical properties of the lung
parenchyma and the interaction between airways and
peribronchial structures are more abnormal in severe
asthma and amplify the mechanical consequences of
airway remodelling. These processes result in airway
narrowing that is excessive, easily triggered and often
irreversible, the complex mechanics of which are
increasingly better understood.
There are many important unanswered questions
regarding the pathophysiology of severe asthma. As the
authors of the Lancet Commission on asthma
suggest,112 we need to think differently and consider
different paradigms to make significant progress in
treatment and finding cures in severe asthma. The
long-standing paradigm of eosinophilic inflammation
leading to remodelling, which then leads to AHR, is
clearly inadequate. We need to know what the relation-
ships between type 1 and type 2 inflammation and
remodelling are, and what roles inflammation and
remodelling play in AHR and the clinical expression of
severe asthma. There are too few clinical studies to
address mechanistic questions. We still do not know
what the mechanisms of irreversible airway narrowing
are, if remodelling (particularly of the ASM) is revers-
ible, how the pathology of asthma is distributed across
the airway tree and how best to treat remodelling or its
progression. Finally, we need to know what the early
life influences and ageing effects on severe asthma
pathophysiology are, if we are to have a chance of pre-
venting asthma, particularly severe asthma, and irre-
versible airflow obstruction.
The Authors
G.G.K. is Staff Specialist, Department of Respiratory
Medicine, Royal North Shore Hospital; Research
Leader, the Woolcock Institute of Medical Research;
Conjoint Professor of Respiratory Medicine, Sydney
University; and Investigator, Centre for Research Excel-
lence of Severe Asthma. A.J. is Chair, Busselton Popula-
tion Medical Research Institute; Clinical Professor,
School of Medicine, University Western Australia and
Department of Pulmonary Physiology and Sleep Medi-
cine, Sir Charles Gairdner Hospital. His clinical inter-
ests are on general respiratory disease, airway disease
and respiratory sleep medicine. His research interests
include airway disease, ASM, airway remodelling, epi-
demiology of respiratory disease and Busselton Health
Study. L.H. is a Post-Doctoral Researcher with the Air-
way Physiology and Imaging Group at the Woolcock
Institute of Medical Research, and a Funded Research
Fellow with the Centre of Excellence in Severe Asthma,
NHMRC. Her clinical interests lie in asthma and COPD.
P.A.B.W. is a Senior Staff Specialist in Respiratory and
Sleep Medicine at John Hunter Hospital, Newcastle,
and a Conjoint Professor with the University of
© 2018 Asian Pacific Society of Respirology
8 GG King et al.
Newcastle at the Hunter Medical Research Institute.
His research interests are in asthma, COPD, cystic
fibrosis and viral respiratory infections.
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Respirology (2018)