Review

The mechanisms, diagnosis, and management of severe

asthma in adults
Stephen T Holgate, Riccardo Polosa

Lancet 2006; 368: 780–93
AIR Division, Level D Centre
Block, Southampton General
Hospital, Southampton, UK
(Prof S T Holgate DSc); and
Dipartimento di Medicina
Interna e Specialistica,
University of Catania, Catania,
Italy (Prof R Polosa MD)
Correspondence to:
Prof S T Holgate,
AIR Division, MP810, F Level,
South Block, Southampton
General Hospital, Southampton
SO16 6YD, UK
sth@soton.ac.uk
There has been a recent increase in the prevalence of asthma worldwide; however, the 5–10% of patients with severe
disease account for a substantial proportion of the health costs. Although most asthma cases can be satisfactorily
managed with a combination of anti-inflammatory drugs and bronchodilators, patients who remain symptomatic
despite maximum combination treatment represent a heterogeneous group consisting of those who are under-treated
or non-adherent with their prescribed medication. After excluding under-treatment and poor compliance, corticosteroid
refractory asthma can be identified as a subphenotype characterised by a heightened neutrophilic airway inflammatory
response in the presence or absence of eosinophils, with evidence of increased tissue injury and remodelling.
Although a wide range of environmental factors such as allergens, smoking, air pollution, infection, hormones, and
specific drugs can contribute to this phenotype, other features associated with changes in the airway inflammatory
response should be taken into account. Aberrant communication between an injured airway epithelium and
underlying mesenchyme contributes to disease chronicity and refractoriness to corticosteroids. The importance of
identifying underlying causative factors and the recent introduction of novel therapeutic approaches, including the
targeting of immunoglobulin E and tumour necrosis factor α with biological agents, emphasise the need for careful
phenotyping of patients with severe disease to target improved management of the individual patient’s needs.

Since there have been several recent overviews of severe
asthma1,2 this review will focus on the underlying
mechanisms, risk factors, diagnosis, and natural history,
with comments on management where there are
mechanistic implications. Most patients with asthma have
mild to moderate disease, which is well controlled by a
combination of anti-inflammatory drugs, especially
corticosteroids and β2-adrenoceptor agonists. However, in
about 10% of patients, asthma remains symptomatic
despite treatment with high-dose inhaled corticosteroids
and long-acting β2 agonists. Patients with refractory
asthma have the greatest impairment of their lifestyles and
account for a disproportionate use of health-care resources
through hospital admissions, unscheduled doctors visits,
and use of emergency services.3,4 In 2000, the American
Thoracic Society reported on an expert workshop on severe
asthma including the development of a consensus
asthma mortality by tenfold.7 A proportion of patients with
severe asthma have a disease that is eminently treatable
but that remains misdiagnosed, under-diagnosed, or
under-treated. Asthma severity can also result from poor
adherence to treatment, most frequently because of fears
over side-effects of inhaled corticosteroids or difficulties
with using inhaler devices.8 These factors should be
checked before diagnosis of refractory disease. A trial of
oral corticosteroids and careful supervision by a specialist
clinic are usually sufficient to establish suboptimum
treatment and correct this problem.
Panel: American Thoracic Society workshop consensus for
definition of severe/refractory asthma*
Major characteristics
● Treatment with continuous or near continuous (≥50% of

definition based on various major and minor criteria.5 year) oral corticosteroids
However, as noted by Moore and Peters in their review,6 ● Need for treatment with high-dose inhaled corticosteroids

this definition has not yet been subject to prospective
assessment (panel). The incorporation of health-care use
would strengthen the definition by identifying patients
with the greatest morbidity.6 Indeed, a previous hospital
admission for asthma is reported to increase the risk of
Search strategy and selection criteria
Our search included a detailed appraisal of the published peer-
reviewed research using the NCBI PubMed website as well as
source literature that the authors have accumulated because
of a major ongoing interest in severe asthma. Keywords used
in the search were “severe asthma”, “classification”,
“pathophysiology”, “remodelling”, “treatment”, “diagnosis”,
and “natural history”. We only reviewed articles published
within the past 10 years in English.
Minor characteristics
● Need for additional daily treatment with a controller
medication (eg, long-acting β agonist, theophylline, or
leukotriene antagonist)
● Asthma symptoms needing short-acting β agonist use on
a daily or near-daily basis
● Persistent airway obstruction (FEV1 <80% predicted,
diurnal peak expiratory flow variability >20%)
● One or more urgent care visits for asthma per year
● Three or more oral steroid bursts per year
● Prompt deterioration with ≤25% reduction in oral or
intravenous corticosteroid dose
● Near-fatal asthma event in the past
*Definition requires that at least one major criterion and two minor criteria are met,
other disorders have been excluded, exacerbating factors have been treated, and
patient is generally compliant.

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 Review

Subphenotypes
Most mild-moderate asthma is associated with atopy, but
in the most severe and chronic phenotype other
characteristics emerge. Refractory asthma is a
heterogeneous disorder that can be subdivided on the
basis of different clinical aetiological, physiological, or
pathophysiological characteristics.9 Although most cases
of severe asthma begin in early childhood as persistent
wheezing associated with atopy,10 adult-onset asthma is
commonly non-allergic and often misdiagnosed because
it possesses some characteristics of chronic obstructive
pulmonary disease.5,11 The pathology of late-onset asthma
is similar to that of the classic allergic form with evidence
of T-helper-2 (Th2) inflammation and tissue remodelling
in both forms of the disease (figure 1).12 These features
are also present in childhood asthma from its onset,
which suggests that from its inception the disease is
more than simple airway inflammation.13,14 Tobacco
smoking is also an important factor that contributes to
asthma severity15 by enhancing resistance to
corticosteroids16 and by eliciting an intense neutrophilic
response.17 The main purpose of attempting to classify
subphenotypes of severe asthma is to guide treatment
and indicate prognosis.18

Contributing factors to asthma severity

In most cases, multiple factors are responsible for
difficult-to-treat asthma. Many of the risk factors that
contribute to disease chronicity are also triggers of
worsening asthma and exacerbations, indicating complex
interactions with the environment.

Environmental exposures
Although atopy is less common in severe asthma, according
to the European Network for Understanding Mechanisms
of Severe Asthma (ENFUMOSA) survey in Europe,19 it was
present in about 60% of patients in whom perennial
allergens, including those derived from house dust mite,
cockroaches, and fungi (especially Aspergillus and Alternaria
species), contribute to ongoing disease. Broncho-
pulmonary allergic aspergillosis is a rare but important
asthma subtype because if left untreated it can lead to
bronchiectasis.20 However, even in the presence of atopy,
severe asthma becomes less dependent on aeroallergen
exposure,21 with other environmental factors, such as
infection and exposure to air pollutants, assuming greater
importance. The exception is occupational sensitisers,22
which may be classified as immunoglobulin E dependent—
eg, acid anhydrides, bakers asthma—or non-immuno-
globulin E dependent—eg, di-isocyanates. Late-onset
asthma should raise awareness of occupational exposures
and, if suspected, appropriate steps should be taken to
confirm this diagnosis, such as peak expiratory flow
monitoring in and out of the workplace. Cigarette smoking
also leads to deteriorating asthma, causing more symptoms,
more severe and frequent exacerbations, and an accelerated
decline in baseline lung function over time.23–25
Figure 1: Pathology of asthma
A small airway of a patient with severe asthma showing a combination of inflammation and remodelling.
Inset: submucosal fibrosis and increase in smooth muscle. Courtesy of Dr Marina Saetta.
Adverse drug effects
Asthmatic airways are highly dependent on continued
β2-adrenoceptor stimulation and as a result
administration of β blockers can lead to severe asthma
that is refractory to β2-adrenoceptor agonists. Asthma is,
therefore, a contraindication for this drug class.
Inhibitors of angiotensin converting enzyme and
adenosine for cardiovascular diseases are also associated
with deterioration of asthma. However, aspirin and
non-steroidal anti-inflammatory drugs (NSAIDs) present
the most common and difficult problems. Aspirin
intolerance has emerged as a prominent risk factor of
severe asthma in both the ENFUMOSA19 and TENOR
(The Epidemiology and Natural History of Asthma:
Outcomes and Treatment Regimens)26 studies. In a
further detailed study of 500 patients with

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 Review
aspirin-intolerant asthma,27 51% needed oral cortico-
steroids and 24% had received inhaled corticosteroids in
the previous 2 months. In the TENOR study, aspirin
intolerance predicted an increased level of persistent
airflow obstruction.26 Aspirin-intolerance can occur as a
triad of rhinitis, flushing, and asthma and is associated
with excess cysteinyl leukotriene formation.
Aspirin-intolerant asthma is four-times less common in
children than in adults, although in part it could have a
genetic basis with polymorphic variation in the cysteinyl
leukotriene synthetic enzymes and their receptors.28
Although a wide range of NSAIDs can trigger worsening
asthma in patients with aspirin-intolerant asthma, these
drugs are restricted to the non-selective cyclo-oxygenase
inhibitors (eg, indometacin, ibuprofen) because
cyclooxygenase-2 inhibitors (eg, celecoxib, refecoxib) do
not elicit this adverse effect.29 There is increasing
evidence that by inhibiting cyclooxygenase-1, the
protective effect exerted by endogenous prostaglandin E2
on leukotriene generation by mast cells, eosinophils,
and macrophages in the airways is removed. As might
be predicted, patients with aspirin-intolerant asthma
usually respond well to treatment with cysteinyl
leukotriene receptor antagonists such as montelukast.30
Other factors that have been associated with severe
asthma are obstructive sleep apnoea and vocal-cord
dysfunction, both of which need a high level of suspicion
and special physiological tests to confirm their
presence.31,32
Psychopathology
Severe asthma has long been associated with
psychological and psychiatric disorders, which are
particularly strong risk factors for frequent emergency
room visits and asthma mortality with depression,
anxiety, panic or fear, and behavioural problems that
adversely affect disease control.8,33–35 Asthma and this
psychopathology can mutually potentiate each other
through direct psychophysiological pathways, non-
adherence with treatment, exposure to asthma triggers,
and reduced perception of asthma symptoms.
Endocrine factors
Severe asthma is two to three times more common in
women than in men, as shown in the ENFUMOSA19 and
TENOR26 studies. At its inception in childhood, asthma is
more common in boys, but during the early teenage
years severe asthma becomes more common in girls
than in boys and this pattern persists into adulthood.36
The higher prevalence of adult-onset asthma and severe
asthma in women than in men is probably the result of
endocrine factors since strong associations have been
reported with the menstrual cycle,37 whereas in pregnancy
asthma commonly improves, especially in the mid and
late trimesters.38 However, the discovery of a genetic
polymorphism of the oestrogen receptor affecting disease
severity also provides a genetic basis for some of these
782
endocrine effects.39 Thyrotoxicosis is a recognised
endocrine factor leading to loss of asthma control.40
Obesity is a newly recognised risk factor for both asthma
and its severity, especially in women,19,41 with weight loss
being accompanied by improved asthma control.42 In
addition to the link with obesity, endocrine factors, such
as leptin and other adipokines such as adiponectin and
resistin, also have actions on immune and inflammatory
cells.43
Comorbidity
The coexistence of chronic rhinitis, nasal polyposis, and
sinusitis contribute to asthma severity.15,44 There is
ample evidence to show that adequate treatment of these
upper airway diseases is beneficial to asthma by
mechanisms not clearly understood. The “one airway”
concept developed by the WHO ARIA Group45 has drawn
attention to the importance of treating the whole of the
respiratory tract when managing asthma. Gastro-
oesophageal reflux is also commonly associated with
chronic asthma both in adults and children,46 possibly
related to the proximity of the organs and neural
connections. However, whereas evidence that treatment
of reflux is reported to have little overall effect on asthma
control,47 two studies48,49 indicate that proton-pump
inhibitors in patients with symptomatic reflux improve
asthma control in severe disease.
Mechanisms of severe asthma
Until relatively recently, all asthma cases were regarded
as being similar, differing only in severity and therefore
requiring treatment that differed only in the dose, route,
or frequency of corticosteroid and β2-adrenoceptor
agonist required to control the disease. However, with
the identification of asthma subphenotypes this view is
being challenged.50 Research over the past two decades
has identified allergic pathways as being fundamental to
asthma with a prominent part played by a subset of
T cells (designated Th2-like) that produce cytokines and
chemokines implicated in the regulation of immuno-
globulin E and the maturation, recruitment, priming,
and activation of mast cells, basophils, and eosinophils.
Allergic pathways that contribute to airway dysfunction
in mild-moderate asthma are largely sensitive to
corticosteroids. However, in more severe asthma the
inflammatory profile commonly changes with greater
involvement of neutrophils and evidence of tissue
destruction and airway remodelling (figure 2).51,52 The
airways in severe asthma exhibit characteristics of a
chronic wound with evidence of ongoing epithelial
injury and repair.53 As in any wound, responses to injury
create the necessary stimuli to recruit the underlying
mesenchyme to participate in the repair process through
the release of a range of growth factors such as epidermal
growth factor (EGF), transforming growth factor α
(TGFα), amphiregulin, heparin-binding like growth
factor (HB-EGF), keratinocyte growth factor (KGF),
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Th-2/Th-1
Environmental agents
cytokines — eg
IL-13, TNFα
Dendritic cell
B lymphocyte T lymphocyte
lgE
IL-3, IL-4, IL-3, IL-5,
Inflammation
IL-13, IL-9 GM-CSF
TNFα
Mast cell Eosinophil
Neutrophil
The epithelial-mesenchymal trophic unit
in asthma
Proinflammatory mediators
Figure 2: Inflammatory and remodelling responses in asthma with activation of the epithelial mesenchymal trophic unit
Epithelial damage alters the set point for communication between bronchial epithelium and underlying mesenchymal cells, leading to myofibroblast activation, an
increase in mesenchymal volume, and induction of structural changes throughout airway wall. Adapted from J Allergy Clin Immunol 2003; 111: 215–25, with
permission of Elsevier.
fibroblast growth factors (FGFs), insulin-like growth
factors (IGFs), vascular endothelial growth factors
(VEGFs), and transforming growth factor-β (TGFβ),
which together promote remodelling and vasculo-
genesis.54 The airway epithelium displays characteristics
of injury and stress with over expression of EGF
receptors and reduced anti-oxidant defences.55,56
Disordered epithelial function and augmentation of
mesenchymal responses emphasise the potential role of
the epithelial-mesenchymal trophic unit (EMTU), which
is associated with lung development and disease
chronicity and remodelling (figure 2).57,58 This process
includes increased matrix deposition in the subepithelial
lamina reticularis of the basement membrane, disruption
of elastin filaments, and the deposition of types 1, 3, 5,
and 6 repair collagens and proteoglycans throughout the
airway wall (including the smooth muscle) leading to
thickened and stiffer airways.59,60 The relation between
thickened and stiffer airways to hyper-responsiveness is
not clear, although changes to airway smooth muscle are
likely to be important. In severe asthma the spiral
bundles of smooth muscle increase both in number and
size and spread upwards to affect the large airways
(including the tracheae) and peripherally to affect the
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Review
Environmental agents
Inflammatory cell products
Mucus
Initiation
Airway microenvironment
(mvo) fibroblasts
Amplification
Propagation
Smooth muscle
Blood vessels
respiratory bronchioles and alveolar ducts.61 Within this
new microenvironment the ability to recruit, retain, and
activate selective inflammatory cells such a monocytes,
mast cells, and neutrophils changes. Thus, despite
high-dose inhaled and oral corticosteroids, mast cells
persist or even increase, especially those within and
close to the airway smooth-muscle bundles with many
of these cells containing high concentrations of TNFα.62
In patients on high doses of inhaled corticosteroids
TNFα is also raised in bronchoalveolar lavage fluid and
in airway biopsies at mRNA level.63 Mast cells are also an
important source of interleukin 13, a cytokine with
potential for driving both inflammatory and remodelling
processes. Factors that maintain activation of the EMTU
might include allergens—especially those with biological
activities (eg, those derived from house dust mites,
fungi, and cockroaches)—repeated virus infections
linked to exacerbations, and air pollutants (eg, outdoor,
indoor including environmental tobacco smoke).
Corticosteroid responsiveness
If dependency on glucocorticoids is essential for
maintaining asthma control, then any defects in this
pathway will be problematic. Corticosteroid treatment is
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 Review
effective in only about 70% of the general population with
asthma.64 In severe asthma the proportion of patients with
reduced responsiveness to inhaled and oral corticosteroids
is higher than in mild-moderate disease. A wide range of
mechanisms have been proposed for corticosteroid
refractoriness,65,66 including proinflammatory cytokine
activation of p38 mitogen-activated protein kinase (which
interferes with the nuclear translocation of corticosteroid
receptors), reduced acetylation of a lysine residue in
histone-4 of the nuclear chromatin leading to reduced
activation of anti-inflammatory genes, and increased
expression of the corticosteroid receptors alternatively
spliced β variant that serves as a dominant negative
inhibitor by competing with the fully functional variant
GRα. Th-2 cytokines have also been proposed to play a
part in severe corticosteroid refractory asthma with CD4+
T-cells from refractory asthmatics being less able to
produce the anti-inflammatory cytokine interleukin 10 in
response to dexamethasone than cells from patients
sensitive to corticosteroids.67 Genetics could also have a
role in reducing corticosteroid sensitivity. Weiss and
colleagues68 examined 31 single nucleotide polymorphisms
in 14 candidate genes in the corticosteroid pathway in
patients with asthma undergoing a steroid intervention
trial and have identified one gene, corticotrophin-releasing
hormone receptor-1 (CRHR-1), which contained a poly-
morphism associated with corticosteroid responsiveness
in three different asthmatic populations.
Airway remodelling
All studies of chronic severe asthma have identified a
degree of fixed airflow obstruction as a distinctive
characteristic.18,19,26 However, there is a subgroup of severe
asthma with highly unstable airways and marked
bronchial hyper-responsiveness detected even after
inhalation of isotonic saline, which has been described as
brittle asthma.69 These patients are at great risk of
unexpected severe bronchoconstriction, which may be
catastrophic. Patients are often young, female, and highly
atopic. By contrast, most difficult-to-treat chronic asthma
is accompanied by reduced baseline lung function, which
is only partly reversible with a β2 agonist and is
accompanied by increased lung volumes, reduced vital
capacity, and a degree of hypoxaemia. High resolution CT
reveals thickened airways that increase in proportion to
disease severity and are inversely proportional to the level
of bronchial hyper-responsiveness, possibly suggesting
that remodelling of the airways is a mechanism for
protecting them against repeated bronchoconstriction.70,71
Although the significance of airway remodelling in
asthma is controversial, factors that predispose to an
accelerated decline in lung function over time include
tobacco smoking, male sex, concurrent rhinosinusitis,
and persistent sputum eosinophilia.72 In a systematic
analysis of bronchial biopsies in patients with differing
severity of asthma, Pepe and co-workers73 reported that
the airway smooth muscle both increases in amount and
784
also becomes more superficial. Such changes in smooth
muscle could be relevant to the function of an asthma
susceptibility gene encoding A disintegrin and metallo-
proteinase 33 (ADAM33). This is a novel asthma
susceptibility gene identified by positional cloning, whose
polymorphism is associated not only with asthma and
bronchial hyper-responsiveness74 but also with an
accelerated decline in lung function over time at a
population level, in asthma, and in chronic obstructive
pulmonary disease,75,76 suggesting a role for ADAM33 in
chronic airway injury and repair. Other abnormalities
associated with disease severity include loss of elastic
recoil and increased lung compliance, both of which are
risk factors for near fatal asthma. Airway remodelling of
the most peripheral airways and loss of alveolar-airway
attachments can contribute to these abnormalities.77 As
asthma becomes more severe, another important
characteristic is a diminished perception of dyspnoea, of
which the underlying mechanism is unknown.78 Such
patients are clearly at heightened risk of a life-threatening
attack.
Increased mucus production is another characteristic
of asthma, which is especially problematic in severe
disease. Goblet-cell metaplasia is partly driven by neutro-
phil-dependent EGF receptor signalling,79 and interactions
with specific cytokines, especially TNFα80 and interleukin
1381 indicate that this neglected component of asthma is
tractable with new therapeutic approaches. Not only does
the amount and viscoelastic properties of mucus increase
in severe asthma, but also the production of mucus
spreads to the small airways where its effect on lung
function is likely to be substantial.82
Asthma exacerbations
Asthma exacerbations are acute worsening of the disease
with durations of 3 days or more and a need for
unscheduled health-care intervention with an increase in
treatment and a suspension of normal activities. Severe
asthma is characterised by two or more exacerbations per
year. Until recently, there has been little attempt to
understand the underlying causes of these events, other
than attributing them to allergen exposure or under-
treatment. With the availability of gene-based detection
methods most exacerbations of asthma seem to be virus-
related, with common cold viruses being especially
important.83,84 Virus-induced exacerbations occur at
particular times of the year and are accompanied by
lower-airway neutrophilia,85 are relatively refractory to
corticosteroids,86 and have been linked to increased
asthma mortality.87 Patients with severe asthma do not
have more virus episodes than non-asthmatics or mild
asthmatics, but when infected the effect on lower airway
function in asthma is substantial.88 In non-asthmatics,
infection of epithelial cells with rhinovirus initiates a
cascade of events that leads to inhibition of viral
replication, programmed cell death, and, as a con-
sequence, effective viral elimination. However, in asthma,
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irrespective of severity, these processes are defective
because of a deficiency of interferon-β production.89 This
finding raises the possibility of restoring this innate
immune response through use of exogenous interferon β
by inhalation or by induction of its increased production
by asthmatic airway epithelial cells as a novel therapeutic
intervention to prevent severe exacerbations in those at
greatest risk. Detection of rhinovirus up to 6 months after
an exacerbation90 and evidence for rhinovirus infection in
infancy as a strong predictor of subsequent persistent
wheezing suggest that respiratory viruses might also be
important in the origins and persistence of asthma.91
Certain bacteria are also associated with exacerbations of
asthma, especially Chlamydia pneumoniae and Mycoplasma
pneumoniae.92,93 In the study by Wark and colleagues,85
more than a third of patients with acute severe asthma
showed a rise in C pneumoniae-specific antibodies and
these patients had a more intense inflammatory response
with marked sputum neutrophilia and raised serum
concentrations of eosinophil cationic protein compared
with people with acute asthma in whom C pneumoniae
antibodies were not detected. The presence of these
micro-organisms in sputum and lung biopsies is also
associated with disease severity and a poor clinical
outcome. In this respect, the strong association found
between the number of airway CD8+ T cells, which are
an important line of defence against infection and
long-term decline in lung function, is of particular
interest.94
Outdoor air pollutants also aggravate asthmatic airways;
ozone, particulates, sulphur dioxide, and oxides of
nitrogen are all associated with increased hospital
admissions and unscheduled use of health-care resources
during air-pollution episodes.95 As referred to earlier, an
important cause of exacerbations is suboptimum
controller therapy and breakthrough airway
inflammation.96 Under these circumstances the level of
sputum eosinophilia is particularly useful as shown by
Green and co-workers97 in a 12-month study of
moderate-severe asthma showing that a treatment strategy
directed at normalising sputum eosinophilia reduced
exacerbations and hospital admissions without the need
for additional anti-inflammatory therapy. Measurement
of exhaled nitric oxide is also reported to be a good marker
in severe refractory asthma with persistent eosinophilia.98
Chronic airway inflammation
Although chronic asthma is associated with airway
eosinophilia, when the disease adopts a severe phenotype
the inflammatory profile commonly changes to the
presence of neutrophils alone or in combination with
eosinophils. Initially this process was thought to be a

Allergen
Airway epithelium

Goblet cell

Fibroblast Myofibroblast
Subepithelial fibrosis

TGFβ
Macrophage
Airway remodelling

MAPK Mast cell

Eosinophil
TNFα
IL-8
Autocrine loop
Neutrophil
TNFα
Leucocyte ICAM-1, VCAM-1
recruitment Airway hyper-responsiveness
Microvasculature

Airway smooth muscle

Figure 3: Possible cellular targets for TNFα in severe corticosteroid refractory asthma
ICAM=interstitial cell adhesion molecule. VCAM=vascular cell adhesion molecule. MAPK=mitogen-activated protein kinase. TNFα is stored in granules and is released
in large amounts from mast cells and macrophages as a result of immunological stimulation. In the airways, TNFα elicits a general inflammatory response mainly
through enhanced release of pro-inflammatory and chemotactic mediators and upregulation of adhesion molecules. These series of events will ultimately lead to
chronic eosinophilic and neutrophilic infiltration and irreversible airway remodelling. TNFα also has a potent direct effect on the airway smooth muscles leading to an
increase in airway hyper-responsiveness. Adapted from Clin Sci 2005; 109: 135–42 with permission of Portland Press.

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 Review
response to increasing inhaled corticosteroids because, by
contrast with their proapoptotic effect on eosinophils,
these drugs enhance neutrophil survival.99 However, in
severe asthma the neutrophils also seem to be in an
activated state100 with their numbers correlating with
indices of airway damage52,101 and reduced corticosteroid
responsiveness.102 These changes can be explained by a
change in the inflammatory pattern away from Th2
towards a Th-1-like pattern with increased expression of
TNFα62 and interferon-γ.103 The importance of TNFα as a
multifunctional cytokine in severe refractory asthma has
been strengthened by showing up to 30-fold increases in
gene expression in the airways and enhanced circulating
mononuclear cell expression of membrane precursor TNF,
TNFα-cleaving enzyme (TACE, ADAM17) and its receptors,
p75 and p55,104 as well as increased secretion of soluble
TNFα even in the presence of high-dose inhaled or oral
corticosteroids.105 The mechanisms responsible for this
change in inflammatory phenotype are not known,
although TNFα has been shown to increase the level of the
β-isoform of the corticosteroid receptor106 and it has
multiple effects on inflammatory and structural cells in
the airways (figure 3).
There exists a group of patients with severe asthma in
whom there is scant evidence of inflammation but where
there occurs an increase in airway smooth muscle
(pauci-inflammatory asthma).9,107 Although this finding
could represent the irreversible consequence of chronic
inflammation that resolves with corticosteroids, it might
represent yet another phenotype of severe asthma in which
inflammation is not a major feature. An increase in airways
smooth muscle is a characteristic feature of chronic asthma
and yet its relation with concurrent inflammation is
unknown.73,107,108 There is evidence that smooth muscle in
asthma is highly abnormal in exhibiting a secretory and
remodelling phenotype, but at the same time behaving
differently from normal in its response to both contractile
and relaxant agonists.109 A defect in the ability of
corticosteroids to inhibit airway smooth muscle cells
obtained from patients with severe asthma from
proliferation has been shown to involve increased
expression of ineffective splice variants of the CCAAT/
enhancer binding protein-α (C/EBPα) pathway.110 The
importance of airway smooth muscle in severe asthma
warrants further attention to its role in the pathobiology
and its association with the inflammatory components of
the disease.
Role of small airways
Pathology studies in patients who have died from asthma
reveal extensive involvement of the peripheral airways with
inflammatory, smooth muscle, and remodelling responses
(figure 1).111 Transbronchial biopsies have confirmed
peripheral airway involvement in severe asthma including
the alveoli.112 Additionally, the distribution of inflammatory
cells also changes with greater infiltration of the adventitial
region with a range of inflammatory cells including
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chymase-positive (connective tissue-type) mast cells.113
Since a similar mast-cell phenotype is also present in
increased numbers within the smooth-muscle bundles of
large airways,114 the mast cell is emerging as an important
inflammatory cell in chronic asthma. Extensive
small-airway involvement in severe disease has important
implications for inhaled drug delivery and might explain
the increased efficacy of the hydrofluoroalkane
formulations of inhaled corticosteroids and systemically
available drugs.
Diagnosis and assessment of severe asthma
Although new algorithm-based approaches are being tested
for diagnosis and subphenotyping of severe asthma,115 none
has yet been validated in a clinic setting. However, a series
of key steps might include establishing asthma as the
diagnosis, assessing underlying factors (including
under-treatment and poor adherence), and providing an
asthma phenotype. Although the diagnosis of asthma
according to established guidelines should be relatively
straightforward, the presence of phenotypes where there is
a substantial degree of fixed airflow obstruction, reduced
diurnal variability, and extensive small-airway disease could
be problematic.116,117 In such cases, detailed lung function,
including measurement of lung volumes and assessment
of small airway function, chest radiograph, CT, and, if the
baseline FEV1 is more than 60% of predicted, methacholine
bronchial provocation, is helpful. Of particular value is
sputum cytology with a focus on eosinophils and
neutrophils.118 Exhaled nitric oxide (eNO) is a useful
non-invasive guide to eosinophilic inflammation,119 but
since many patients are already taking corticosteroids at
initial presentation values may be normal.19 Care must be
taken to exclude bronchiolitis obliterans, bronchopulmonary
allergic aspergillosis, Churg-Strauss syndrome, and
paradoxical vocal-cord closure. Assessment of atopic status,
appraisal of the upper airways for evidence of rhinosinusitis,
and consideration of gastro-oesophageal reflux are part of
the clinical work up.
According to management guidelines, asthma severity
may be classified into steps on the basis of clinical
treatment. When the patient is already receiving treatment,
severity should be based on the clinical characteristics
present and the step of the daily medication regimen being
taken (table). The severity of acute asthma exacerbations is
often underestimated by patients, their relatives, and
health-care professionals and is an important factor
contributing to mortality.120 Specific factors linked to
mortality include a history of life-threatening attacks, a
hospital admission within the past year, previous
intubations for asthma, psychopathology, comorbidities,
recent reductions or cessation of corticosteroids, and poor
adherence with prescribed treatment.
Management of severe asthma
Figure 4 shows an algorithm for the treatment of severe
asthma. In accordance with global guidelines, tertiary
www.thelancet.com Vol 368 August 26, 2006

Patient symptoms and lung function on current therapy
Step 1: Intermittent
Symptoms less than once a week
Brief exacerbations
Nocturnal symptoms not more than twice a month
Normal lung function between episodes
Step 2: Mild persistent
Symptoms more than once a week but less than once a day
Nocturnal symptoms more than twice a month but less than once a week
Normal lung function between episodes
Step 3: Moderate persistent
Symptoms daily
Exacerbations may affect activity and sleep
Nocturnal symptoms at least once a week
60% <FEV1 <80% predicted OR
60% <PEV < 80% of personal best
Step 4: Severe persistent
Symptoms daily
Frequent exacerbations
Frequent nocturnal asthma symptoms
FEV1 ≤60% predicted OR
PEF ≤60% of personal best
Reproduced from The Global Initiative for Asthma (GINA) Global Strategy for Asthma Management and Prevention. NIH Publication No 02-3659:2005.
Table: Classification of asthma severity by daily medication regimen and response to treatment
prevention aims to reduce exposure to known inducers
and triggers to improve asthma control. However, there
is little evidence that treating such factors has much
effect on asthma control; for example, although inhaled
allergens are known to be important in driving asthmatic
inflammation, allergen-avoidance strategies have
generally been disappointing.121 Standard treatment for
severe asthma includes high-dose inhaled corticosteroids
combined with a long-acting β2 agonist as the preferred
add-on therapy, often administered by a single inhaler
device.122 Alternatives are a cysteinyl leukotriene receptor
antagonist123 and sustained release theophylline.124 These
treatments can also be added to the combination therapy.
Because corticosteroids by inhalation begin to lose their
efficacy as the dose increases above 800–1000 μg
beclometasone dipropionate-equivalents per day and
because both local and systemic side-effects (osteo-
porosis, skin thinning, and cataracts) increase, care
should be taken with doses in excess of 2000 μg/day,
especially in patients beyond middle age.125 A new
corticosteroid, ciclesonide, seems to have a greater
therapeutic index but has not yet been approved for
high-dose use in severe asthma.126 If required, long-term
oral corticosteroids should be used at the lowest possible
dose. A recent Cochrane review concluded that use of
long-acting β2 agonists allows up to 57% reduction of
inhaled corticosteroids.127 There is also strong evidence
www.thelancet.com Vol 368 August 26, 2006
Review
Current treatment step*
Step 1: Intermittent Step 2: Mild persistent Step 3: Moderate persistent
Level of severity
Intermittent Mild persistent Moderate persistent
Mild persistent Moderate persistent Severe persistent
Moderate persistent Severe persistent Severe persistent
Severe persistent Severe persistent Severe persistent
that adequate inhaled corticosteroid treatment
substantially reduces asthma mortality128 and hospital
admissions129 for severe asthma. The wider use of
inhaled corticosteroids in asthma is the most likely
explanation for the decline in mortality seen over the
past 3–5 years in various countries that have
implemented asthma guidelines. However, in a large
European survey that involved 14 countries, only 17% of
patients with persistent symptomatic asthma were using
inhaled corticosteroids on a daily basis130 with very wide
inter-country differences in their uptake. The effects of
corticosteroids on airway remodelling and on other
aspects of the natural history of asthma is controversial,
with some aspects responding (eg, accelerated decline
in lung function131 and thickening of the lamina
reticularis132) and others (eg, smooth-muscle hypertrophy
and hyperplasia) not responding. Corticosteroid-sparing
treatments include methotrexate, cyclosporine A, and
oral gold, but in general these treatments have limited
effects and have appreciable side-effects. A Cochrane
review of the benefit of adding fixed doses of
methotrexate to oral corticosteroids in patients with
corticosteroid-dependent asthma has concluded that the
evidence is conflicting.133 However, as in rheumatoid
arthritis, for the best results the dose of methotrexate
should be tailored to the severity of the patient’s
symptoms.
787
 Review

proportion of patients who were taking long-acting

Patients with uncontrolled asthma symptoms with: β2 agonists alone and the greater proportion of deaths
1. Persisting refractory symptoms and poor lung function (reduced FEV1) despite high dose ICS+LABA
2. Frequent use of oral steroids
that occurred in the African American subpopulation in
3. Regular use of health-care resources (doctors’ consultations, emergency services, hospital admissions) which asthma was more severe than in the trial population
as a whole. One factor that could provide an explanation
for the treatment-related increase in asthma mortality
1. Review inhalation technique YES NO
2. Written self-management plan
Poor relates to pharmacogenetics. For the Arg/Arg polymorphic
compliance
3. Reassessment at next visit variant of the β2 adrenoceptor, treatment of asthma with
regular salbutamol results in deterioration in clinical
control rather than improvement as seen with the Gly/Gly
Diagnostic confirmation/verification for variant.140 In two separate trials, a similar effect has been
shown for salmeterol irrespective of whether patients were
taking concomitant inhaled corticosteroids.141 These
Diseases that Conditions associated Unusual
mimic asthma with asthma asthma triggers
findings, along with the reported reduced efficacy of
long-acting β2 agonists in childhood asthma142 warrant
• Bronchiectasis • Chronic • Occupational
further assessment of this drug class, especially since a
• Constrictive rhinosinusitis exposure third generation of even longer acting β2-adrenoceptor
bronchiolitis • Gastro-oesophageal • Domestic irritants
• COPD reflux • Respiratory
agonists are currently in development. With respect to the
• CHF • Anxiety, panic-fear, infections* use of short-acting β2-adrenoceptor agonists, their
• Dysfunctional depression • Drugs (aspirin, NSAIDs, increased use by asthmatic patients should be used as an
breathlessness • Dysfunctional ACE inhibitors,
• Vocal cord breathlessness β blockers) index of worsening asthma control mandating an increase
dysfunction • Vocal cord • Food (eg, sulphite in anti-inflammatory treatment. The use of short-acting
• Upper airway dysfunction sensitivity)
obstruction • Obesity • Smoking β2 adrenoceptpor agonists at high doses by a portable
• ABPA • Obstructive sleep • Inflamed upper inhaler or nebuliser should be reserved for the treatment
• Chung-Strauss apnoea airways
syndrome • Acid reflux
of exacerbations. A Cochrane review concludes that there
• Eosinophilic • Stress is little evidence for the use of anticholinergics as part of
pneumonia add-on therapy for severe exacerbations of asthma.143
• Thyrotoxicosis
High-dose intravenous human immunoglobulin is
Short course NO YES YES YES efficacious in some patients with corticosteroid-dependent
oral steroids severe asthma144,145 with suppressive effects on persistent
inflammation,146 but cost and inconvenience precludes its
Negative 1. Management of 1. Management of 1. Avoid triggers widespread use.
the condition the condition 2. Reassess at next visit
YES response
2. Reassess at next visit 2. Reassess at next visit Assessment and subsequent treatment of rhinosinusitis
NO forms an important part of the management plan for
severe asthma, with substantial clinical improvement in
1. Titrate down oral steroids (administer the lowest amount of oral steroid to control/stabilise symptoms) disease control being reported.147,148 Treatment of
2. Consider adding a steroid sparing drug (eg, azathioprine, methotrexate) gastro-oesophageal reflux with proton-pump inhibitors
3. Add treatment for steroid-induced adverse effects (eg, osteoporosis)
4. If uncontrolled, consider alternative therapeutic options (eg, omalizumab, etanercept, high dose IVIG) such as lansoprazole48 and esomeprazole49 is beneficial but
5. Frequent periodic re-evaluations only in patients in whom both conditions coexist. Attention
to other comorbidities is important including weight loss
Figure 4: Algorithm of possible strategies and recommendations for managing patients with difficult to in severe asthmatics who are overweight, hormonal
control asthma despite maximum combination treatment imbalance in women in whom a strong association is
*Includes C pneumoniae and M pneumoniae. CF=cystic fibrosis. COPD=chronic obstructive pulmonary disease.
CHF=chronic heart failure. ABPA=allergic bronchopulmonary aspergillosis.
established between worsening of disease and the
menstrual cycle, and treatment of fungal infections,
When C pneumoniae is suspected as a contributory factor especially bronchopulmonary allergic aspergillosis.149
in persistent airflow obstruction134 or exacerbations,135 the Persistent eosinophilia and multi-organ involvement such
addition of macrolides can be effective. The complexity of as a mononeuropathy multiplex150 in the presence of severe
multiple daily drugs is an important factor in asthma should arouse suspicion of Churg-Strauss
non-adherence.8,136 In extreme circumstances bilateral syndrome which, in addition to oral corticosteroids,
lung transplantation has also had some success.137 As in requires cytotoxic or immunosuppressive therapy.151
the case of overuse of short-acting β2-adrenoceptor
agonists,138 there has been some concern over the use of New approaches to treatment
long-acting β2 agonists. A large 28-week study of The introduction of the humanised monoclonal immuno-
salmeterol in moderate-severe asthma (SMART)139 was globulin G1 blocking antibody directed to immuno-
stopped prematurely because of a significant 4·4-fold globulin E (omalizumab) represents an advance in the
increase in asthma mortality in the active treatment treatment of severe allergic asthma when symptoms
group.139 Of importance in this study was the high remain despite use of optimum combination treatment

788 www.thelancet.com Vol 368 August 26, 2006


(figure 5).152 In the GOAL (Gaining Optimal Asthma
Control) study153 of 3421 patients with uncontrolled
asthma in whom combination treatment was increased
until total control had been achieved or 1000 μg
fluticasone reached, 38% remained inadequately
controlled, which fell to 31% only after oral corticosteroids
were added.153 In a series of six phase III clinical trials in
severe adult allergic asthma involving 2548 patients on
omalizumab as add-on therapy, given by subcutaneous
injection two to four times weekly for 28–52 weeks,
benefit was achieved in multiple asthma outcome
measures, including exacerbations, symptoms, lung
function, and asthma-specific quality of life. However,
there were only small changes in baseline spirometry.154
Omalizumab is dosed against the patient’s total serum
concentration of immunoglobulin E (30–700 IU/mL) and
bodyweight. The drug achieves its effects not only by
removing circulating and tissue immunoglobulin E as
small complexes, but also through promoting loss of
high affinity immunoglobulin E receptors on mast cells,
basophils, and dendritic cells, accompanied by reduced
airway inflammation.155 Peak therapeutic response with
omalizumab is achieved 12–16 weeks after starting
treatment.156 Since only about two-thirds of patients
respond to omalizumab, an assessment needs to be made
16 weeks after starting treatment to establish whether to
continue using the physicians overall clinical assessment
to arrive at this decision. As in other diseases there is a
need for greater understanding of the responder and
non-responder status to develop a simple test that could
predict those most likely to benefit from this treatment.
As the disease progresses in severity, blockade of a Th-1
cytokine in clinical asthma might be most beneficial at
the severe end of the disease spectrum.157–159 The failure of
inhaled corticosteroids to reduce TNFα and Th1-derived
cytokines in asthmatic airways could explain why inhaled
corticosteroids have limited effects in the more severe
forms of asthma and it is likely that treatments blocking
TNFα and interfering with Th1-derived cytokines could
represent an advance in the management of those asthma
patients who are particularly resistant to the widely used
treatment modalities.
Based on the increased expression in TNFα in the
airways of severe refractory asthma, an exciting break-
through has been the demonstration of efficacy of the
soluble TNF receptor fusion protein etanercept; in two
small studies particularly impressive results were seen
against bronchial hyper-reactivity and asthma-specific
quality of life with surprisingly little effect on indices of
inflammation.63,160 The main action of etanercept is
probably directed towards airways smooth muscle.161
Large clinical trials with etanercept and anti-TNFα
monoclonal antibodies are now in progress. Other
biological treatments that also look promising in severe
asthma include interferon-α, anti-interleukin-13,162,163
and anti-CD25 (daclizumab)164 monoclonal antibodies.
The potential costs of new targeted treatments will make
www.thelancet.com Vol 368 August 26, 2006
Review
Omalizumab
complexes lgE
Anti-IgE
decreases
Dentritic
free-IgE
cell
Clinical
effects
B cell
Mast cell/basophil
T cell
Clinical
effects
Anti-IgE
decrease
allergen Eosinphil
presentation
Tissue
Anti-IgE reduce Th2 cell mediated
infiltration
production of eosinophils
Figure 5: Cellular molecular targets for anti-immunoglobulin E monoclonal antibody treatment in severe
allergic asthma
Omalizumab decreases free immunoglobulin E levels and reduces FcεRI receptor expression on mast cells and
basophils. This process results in decreased mast-cell activation and sensitivity, leading to a reduction in eosinophil
influx and activation. Anti-immunoglobulin E treatment with omalizumab might result in decreased mast-cell
survival. Omalizumab also reduces dendritic cell FcεRI receptor expression. Reproduced from J Allergy Clin Immunol
2005; 115: 459–65 with permission of Elsevier.
it even more important to subphenotype asthma so that
those most likely to respond to a specific treatment can
be identified.
Conclusions
The recognition that there is a substantial number of
patients whose asthma is not adequately controlled with
conventional treatments reveals an important unmet
clinical need in this disease. With the recent increasing
trends in childhood asthma, the burden of severe asthma
in adults is likely to increase. A combination of early
diagnosis and subphenotyping of asthma taking disease
severity into account will provide the basis for more
accurate diagnosis and targeting of preventative and
therapeutic interventions. The application of genetic,
pharmacogenetic, and proteomic technologies to identify
improved biomarkers relevant to severe asthma will
enable the close tailoring of disease prevention and
management strategies to the individual patient’s needs.
Contributors
STH and RP reviewed the available literature and contributed to the
content of this review.
Conflict of interest statement
S Holgate is a UK Medical Research Council supported
Clinical Professor, is a consultant for Novartis, Synairgen, Merck,
Wyerth, and Centocor, and has received lecture fees from their
companies. R Polosa is a consultant for Cardiovascular Therapeutics,
Duska Therapeutics, and NeuroSearch and has received lecture fees
from Merck and Novartis.
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