www.thelancet.com Vol 368 August 26, 2006
Asthma: defi ning of the persistent adult phenotypes
Sally E Wenzel
The common disease asthma is probably not a single disease, but rather a complex of multiple, separate syndromes
that overlap. Although clinicians have recognised these diff erent phenotypes for many years, they have remained
poorly characterised, with little known about the underlying pathobiology contributing to them. Development of
targeted therapies for asthma, and phenotype-specifi c clinical trials have raised interest in these phenotypes. Improved
understanding of these phenotypes in complex diseases such as asthma will also improve our ability to link specifi c
genotypes to their associated disease, which should help development of biomarkers. However, there is no standardised
method to defi ne asthma phenotypes. This Review analyses some of the methods that have been used to defi ne
asthma phenotypes and proposes an integrated method of classifi cation to improve our understanding of these
“Phenotype” is defi ned as “the visible characteristics of
an organism resulting from the interaction between its
genetic makeup and the environment”.1 The common
disorder asthma is probably a collection of diff erent
phenotypes, rather than a single disease. These
phenotypes are all generally categorised under the broad
umbrella of “asthma” because they meet the simple
criteria for clinical diagnosis of this disease. Traditionally,
asthma has been diagnosed on presentation of
appropriate symptoms (ie, wheeze, chest tightness, or
shortness of breath) accompanied by airway obstruction
and reversible airfl ow restriction. Although clinicians
have recognised certain phenotypes of asthma for some
time, biomarkers for these various phenotypes have not
yet been identifi ed. Therefore, the absence of better
discrimination and comprehension of these phenotypes
is not surprising. Studies now suggest that identifi cation
of the phenotype of a patient’s asthma can assist in
management. Thus, we need better ways to identify
these phenotypes than we have now. Improved
identifi cation of asthma phenotypes should lead to
increased understanding of the underlying pathobiology
that contributes to a particular phenotype. Identifi cation
of a patient’s asthma phenotype will also enhance our
ability to link genetics to specifi c pathobiological features
in this complex disorder.
Many categories have been used to defi ne asthma
phenotypes, mostly with general or clinical criteria.
Although allergic and non-allergic asthma are probably
the most commonly discussed phenotypes, the
determination of additional phenotypes, is possible. This
Review proposes to analyse the broad categories of
phenotypes and classify them in three categories:
phenotypes defi ned by clinical or physiological criteria;
phenotypes related to environmental triggers; and
phenotypes defi ned by their pathobiology (panel 1). This
categorisation is not intended to imply that overlap does
not exist within these groups: there is probably
substantial interaction among the groups. Additionally,
a specifi c phenotype is unlikely to be permanently fi xed.
As the defi nition implies, a phenotype can vary
dependent on interactions with the environment.
Clinical or physiological phenotypes relevant to asthma
include those defi ned by level of severity (from mild to
severe), the frequency of exacerbations, the presence of
chronic airfl ow restriction, and the age of asthma onset.
Phenotypes defi ned by response to treatment, such as
resistance to steroids, can also be put in this category.
Phenotypes can also be defi ned on the basis of their
relation to specifi c triggers including exercise,
Lancet 2006; 368: 804–13
Department of Medicine,
National Jewish Medical and
Research Center, 1400 Jackson
Street, Denver, CO 80206, USA
(S E Wenzel MD)
Search strategy and selection criteria
We searched PubMed for articles containing the keyword, “asthma” in combination with
“phenotypes”, “biomarkers”, “eosinophil”, “neutrophil”, “aspirin sensitive”, “allergic”,
“corticosteroid resistance”, “exercise”, ”extrinsic”, “intrinsic”, “severe exacerbation“. We
made an eff ort to include only peer-reviewed publications. Selection for inclusion was on
the basis of results that were reproducible or had support from other studies. No limit was
placed on date or language of publication, although most references that were used were
from the past 20 years. Abstracts from scientifi c conferences were included if they
supported peer reviewed publications.
Panel 1: Potential phenotypic categories of asthma by
Clinical or physiological phenotypes
Defi ned by chronic restriction
Defi ned by age at onset
Phenotypes related to the following triggers
Aspirin or on-steroidal anti-infl ammatory drugs
Occupational allergens or irritants
Infl ammatory phenotypes
www.thelancet.com Vol 368 August 26, 2006 805
environmental allergens, occupational allergens and
irritants, drugs (such as aspirin), and menses. Phenotypes
are also categorised by their immunopathology on the
basis of patterns of infl ammation, specifi cally the
presence or absence of particular infl ammatory cell
types—eg, eosinophils or neutrophils.2–4 Features of one
phenotype have generally not been integrated into
another category. Therefore, although clinicians might
understand that exacerbation-prone asthma presents
diff erent signs from asthma in patients with stable
chronic airfl ow obstruction, the immunological and
pathological factors that underlie these two phenotypes
are poorly understood. However, many reports support
the idea that substantial overlap exists among the
phenotypes. For example, aspirin-sensitive asthma has
long been recognised as an asthma phenotype, which in
this Review, is categorised under “phenotypes related to
triggers”. However, aspirin-sensitive asthma is also
associated with at least two clinical subclasses (severe
disease and adult onset) and one pathobiological subclass
(high eosinophil numbers in blood and respiratory tract
tissue).5 Integration of these phenotypic categories
should enhance biomarker development, improve
genetic assessment of phenotypes, and improve therapy
for individual patients with asthma.
Severity-defi ned asthma
Clinicians have identifi ed many diff erent asthma,
phenotypes including those based on severity, liability
(or not) of airfl ow restriction, response to therapy, and
age at onset.6–8 National and international guidelines are
the biggest proponents of phenotyping by severity with
fairly stringent criteria to defi ne four categories of
asthma severity.6,9 However, several publications have
suggested that these defi nitions, which were developed
on the basis of lung function, symptoms, and use of
medication, are not adequate to predict the course of the
disease, control of the disease, or the response to
therapy.10,11 For these reasons, guidelines have started to
move away from the concept of severity and focus on
monitoring and treatment by level of control. Networks
from Europe and the USA have suggested that specifi c
features such as less atopy, lower lung function and a
history of pneumonia might exist in severe asthma but
not milder asthma.12,13 Although a female predominance
for severe asthma was seen in the European cohort, this
fi nding was not replicated in the US study. Many genetic
and lung-specifi c biomarkers have also been proposed to
distinguish mild asthma from severe asthma, but few
have been proven by multiple studies. Possible
biomarkers include transforming growth factor β
(TGFβ), interleukin 11, tumour necrosis factor α, and
interleukin 8.14–19 Validated biomarkers that can be
detected by non-invasive tests to distinguish mild asthma
from severe asthma, or that can predict disease
progression have not been identifi ed.
Almost all patients with asthma will have at least one
moderate-to-severe exacerbation, but some patients with
asthma seem predisposed to frequent exacerbations,
which can be very severe. These patients might have
relatively normal lung function, low lung function, or
show great fl uctuation of lung function between
exacerbations.7,20 This exacerbation-prone
phenotype accounts for more than 40% of the patients
with severe asthma in the severe asthma research
programme (SARP) database sponsored by the US
National Heart, Lung, and Blood Institute.13 In fact,
frequent and severe exacerbations of asthma seems to be
the main distinguishing clinical characteristic of a
subphenotype of severe asthma.13 Since exacerbation-prone
asthma is a hallmark of severe disease and poor outcomes,
determination of immunopathological factors that
distinguish this phenotype is important.
In studies from SARP, logistic regression analysis
suggested that several factors independently contribute to
the severe exacerbating phenotype, including low forced
expiratory volume in 1 second (FEV1), African race, early
age at onset, history of exacerbation in response to aspirin
or non-steroidal anti-infl ammatory drugs, or before
menses.21 Additionally, other researchers have suggested
that psychological disorders, including depression and
anxiety, aff ect exacerbations.22 These psychological
systems might contribute to non-compliance and even
more exacerbations. Patients with exacerbation-prone
asthma seem to have a blunted dyspnoea response to
worsening airway obstruction, which can cause delayed
recognition of symptoms.23,24 This blunted dyspnoea
response has been associated with an increase in
eosinophilic infl ammation.25 In opposition, other studies
suggest that chronically high numbers of eosinophils in
the airways are associated with increased susceptibility to
exacerbations and with greater dyspnoea.2,8
Asthma defi ned by chronic airfl ow restriction.
By contrast with exacerbation-prone asthma, some
patients with asthma present with marked airfl ow
restriction but have only moderately symptomatic or
exacerbation-prone disease. Studies from the US National
Heart, Lung, and Blood Institute Children’s Asthma
Management Program (CAMP) suggest that only a
fraction of patients with childhood-onset asthma develops
progressive loss of lung function over a 5-year period.26
These children can be less allergic, are more likely to be
boys, and are less predisposed to exacerbations than the
children with asthma who have no loss of lung function.
Similar outcomes have been seen in The Epidemiology
and Natural History of Asthma: Outcomes and Treatment
Regimens (TENOR) study of more than 4000 patients
with severe or diffi cult to treat asthma.27
Both CAMP and TENOR suggest that allergic features of
asthma are more likely to be associated with
exacerbation-prone or diffi cult to control asthma, than
www.thelancet.com Vol 368 August 26, 2006
with the phenotype associated with persistent severe
airfl ow restriction. Whether or not allergic processes
protect against profound loss of lung function is not
known. No reported studies have diff erentiated patients
with progressive loss of FEV1 from those without in terms
of lung pathology, partly because of the few longitudinal
studies of asthma. Genetic studies have identifi ed single
nucleotide polymorphisms in ADAM33, IL4, IL4R, and
TGFβ1 that are associated with lower than normal lung
function, and IL4 single nucleotide polymorphisms have
also been associated with near-fatal exacerbations of
Asthma that is resistant to treatment, generally with
corticosteroids, is most commonly seen in patients with
severe disease.31,32 This phenotype of asthma was believed
to be due to a defect in the patient’s response to
corticosteroids that restricts the anti-infl ammatory eff ects
of this class of drugs. However, studies have now shown
that there are many diff erent reasons for steroid resistance.
Additionally, corticosteroid-resistant or poorly-responsive
asthma can be seen in all levels of asthma severity.33 A
proportion of patients with asthma who have persistent
infl ammation despite corticosteroid therapy could have
abnormalities in histone
overexpression of the alternative,
glucocorticoid receptor β,
interference with corticosteroid binding to the functional
glucocorticoid receptor α. However other patients with
asthma probably do not respond either because they do
not have infl ammation or they have a diff erent type of
infl ammation.34–36 Studies suggest that the absence of
sputum eosinophils, which are indicators of infl ammation,
is a predictor of reduced response to corticosteroids.37,38
Other studies have reported that high numbers of sputum
neutrophils, a cell type that shows little response to
corticosteroids, is also a predictor of poor response to
these drugs.3,39 These studies could also explain the poor
response of people with asthma who also smoke to
corticosteroid therapy, since smokers are likely to have
higher sputum neutrophil counts.40
Asthma defi ned by age at onset
The age at which a patient develops asthma also
diff erentiates phenotypes. This diff erentiation might in
be the easiest to discern by simply asking when a patient
developed symptoms of asthma, which could identify
features specifi c to their disease. Patients with early-onset
asthma (arbitrarily defi ned as onset before 12 years of
age) were shown to have a signifi cantly greater likelihood
of allergic sensitisation and clinical response to triggers
than patients with late-onset disease (fi gure 1).8
Additionally, patients with early-onset asthma are
much more likely to have a history of eczema and a
family history of asthma, which could be useful
information for large genetic databases. Generally,
early-onset asthma seems to be a more homogeneous
disease than late-onset asthma, which is contributed to
by a mix of allergic, infectious, and other factors. These
fi ndings have been replicated in the large cohort
involved with the SARP database.13,41 Despite a longer
duration of disease, people with early-onset asthma
were shown to have marginally better lung function
than those with late-onset disease. This outcome was
also reported in studies done in Netherlands.42 These
fi nding are similar to those of previous longitudinal
studies of intrinsic asthma, which is probably a
population with a great number of patients with
late-onset disease.43,44 Although recall bias might
contribute to the report of late-onset disease, the distinct
relation between early-onset disease and allergic
patterns makes recall bias unlikely to be the sole reason
for the existence of these two phenotypes.
Allergic sensitisation that triggers asthma might be the
largest overall phenotype, especially in childhood asthma,
but probably also in a high proportion of adults with
asthma.45 As noted above, this phenotype can present at
any age, but it commonly begins in early childhood. The
acute pathobiology of this group has been studied
extensively with allergen-challenge protocols. In some
studies a relation to T helper type 2 (Th2) infl ammatory
reactions has been reported, although the evidence to
support Th2 processes is stronger in murine models.46–48
Family history of asthma and early exposure to allergens
are probably important in the initiation of allergic
asthma, but the mechanisms by which some children
develop asthma, whereas others have non-respiratory
allergic manifestations are not understood.49 The presence
Proportion of patients (%)
Figure 1: Diff erentiation of asthma by age of onset defi nes early onset
asthma as a highly allergic phenotype compared with later onset disease
Reproduced from reference 8, with permission.
www.thelancet.com Vol 368 August 26, 2006 807
of allergic characteristics could be associated with better
overall lung function, but with more exacerbations than
Several years ago, pathological studies suggested that
the infl ammatory processes in atopic asthma were the
same as those of non-atopic asthma, with the presence of
pulmonary Th2 cytokines or IgE, in both.50–52 These studies
questioned the idea of heterogeneity and phenotypes in
asthma, because the pathological features seemed to be
similar, but other studies have seen diff erences in
pathology.8,53,54 Further studies to examine in detail the
pathological distinctions between allergic and non-allergic
asthma are needed, but these studies will rely on careful
defi nitions of allergic asthma. Such defi nitions should
include evidence for both specifi c IgE, in the form of a
positive skin-prick test or radioallergosorbent test, and a
history of allergic symptoms in response to that trigger.
Many large-scale epidemiological studies have not
collected suffi cient information on allergic symptoms to
accurately identify an allergic phenotype.
Targeted therapies, such as immunotherapy or
monoclonal antibodies, are available for the treatment of
asthma. In studies of the IgE antibody, omalizumab, an
allergic phenotype was defi ned only by the presence of
allergen-specifi c IgE as measured by skin-prick or serum
testing.55,56 Analysis of these and other trials as well as
clinical experience suggests that not all people with
allergic asthma diagnosed by these tests respond to
anti-IgE therapy. Whether a better defi nition of allergic
asthma, or its biomarkers, could enhance the ability to
identify patients who will respond to this treatment is
The occupational asthma phenotype might account for up
to 15% of adult-onset asthma.57 Occupational asthma has
several subphenotypes, which result from : (1) development
of an immunologically-mediated sensitisation to the causal
agent, usually of high molecular weight, which has
similarities to allergic asthma through development of
IgE antibodies; (2) development of an immunologically
mediated response to low–molecular-weight triggers, in
which an IgE response is not consistently seen; and (3)
development of a non-immunological, rapid-onset
response after exposure to high concentrations of
workplace irritant chemicals.57 The airway infl ammation
is postulated to be similar in both immunological
phenotypes of occupational asthma and characterised by
the presence of eosinophils, lymphocytes, mast cells, and
of thickening of the reticular basement membrane.58,59 By
contrast, in occupational asthma caused by irritant
chemicals, pathological changes consist of fi brosis of the
bronchial wall and epithelial
fi brinohaemorrhagic exudates in the submucosa, without
eosinophilic infl ammation.60 Although occupational
asthma can recede if the patient promptly discontinues
exposure to the off ending agent, once the process is
established, both immunological phenotypes can continue
independent of exposure.57
Aspirin and other non-steroidal anti-infl ammatory drugs
(NSAIDs) have long been recognised as triggers for
perhaps the best defi ned asthma phenotype (panel 2).
Aspirin-sensitive asthma is more commonly seen in the
severe asthma population and is associated with little
evidence of atopy, raised airway leukotrienes, and high
numbers of eosinophils in both tissue and blood.5 The
most clinically distinctive patterns associated with aspirin
sensitivity are severe rhinosinusitis and nasal polyps, and
adult onset. This asthma phenotype is frequently poorly
responsive to steroids, and is therefore present most
often in patients with severe asthma.12 The association
with raised leukotrienes predicts a good response to
drugs that modify leukotriene pathways,61,62 but not all
Genetic studies have shown that mutations in the
leukotriene synthesis pathway aff ect this phenotype. Yet
these distinctions alone are not suffi cient to explain the
adult onset of the disease, which suggests an
pathogenesis.63,64 Additional studies have reported that
the enzymes for leukotriene synthesis are upregulated in
patients with aspirin-sensitive asthma, whereas others
have reported an increase in interleukin 5, a potent
eosinophilic chemoattractant, in bronchial biopsies from
aspirin-sensitive patients.65–67 Although this phenotype is
very distinct clinically and pathologically, the underlying
pathogenesis remains poorly understood.5
viral) element to its
Menses-related asthma is the least well characterised of
the trigger-induced subtypes. It probably only occurs in a
small proportion of women with asthma, but can be
severe.68 Although a role for sex hormones in asthma
pathogenesis has been assumed for some time, the actual
hormonal mechanisms for these eff ects are not clear.
Dependent on the environment, both oestrogen and
progesterone have the potential to be proinfl ammatory or
anti-infl ammatory hormones.69–71 Studies in rodents have
shown that female animals have a stronger Th2
infl ammatory response to ovalbumin challenge than male
animals, whereas male mice treated with progesterone
Panel 2: Hallmarks of aspirin-sensitive asthma
● Worsening of symptoms in response to non-steroidal
centi-infl ammatory drugs
● Severe chronic rhinosinusitis and nasal polyps
● Adult onset
● Poor response to corticosteroids
● Raised cysteinyl leukotriene concentrations in urine or
www.thelancet.com Vol 368 August 26, 2006
have increased eosinophillic infl ammation.72,73 Studies in
human beings are few, but some small studies have
suggested an increase
menstruation in susceptible women.74
in infl ammation before
Exercise-induced (or cold-dry-air-induced) asthma is often
cited as a phenotype of asthma, but whether this
represents the development of bronchoconstriction in
response to exercise in all patients with asthma, or is a
pathophysiological response seen only in some people
with asthma is not clear. One study showed that
exercise-induced asthma might or might not be present
in individuals with asthma who were grouped by severity,
and other studies showed that exercise-induced asthma
can be seen in isolation in some people, particularly elite
athletes.75–77 These studies suggest that in previously
healthy individuals (including competitive athletes),
exercise-induced asthma could be a forme fruste of the
disease. The likelihood of progression to more generalised
symptoms of asthma, or the factors that contribute to
progression are not known. The mechanisms that trigger
exercise-induced bronchoconstriction seem to involve
acute infl ammatory (mainly mast cell), epithelial, and
vasoactive responses, but the pathogenesis of the
development of these responses in certain people, or how
they overlap with other aspects of asthma pathology, is
Infl ammatory phenotypes
Perhaps the most important advance in the treatment of
asthma has been the realisation that asthma pathology
has an infl ammatory component, which led to the
widespread use of inhaled corticosteroids, and their rank
as the gold-standard for asthma treatment. Early
pathological studies of patients with mild asthma who
were not treated with corticosteroids, recorded high
numbers of eosinophils and lymphocytes in the large
airway mucosa. The number of these cells decreased
signifi cantly in response to high doses of inhaled
corticosteroids and overall lung function improved.80,81
Although a retrospective look at those early studies
confi rms a wide range of infl ammatory cells in airway
biopsies and lavage, lymphocytic or eosinophilic
infl ammation was assumed to be a hallmark of all forms
of asthma. With that notion in mind, attempts were made
to identify biomarkers, preferably in peripheral blood,
that were relevant to monitoring asthma control, but
little progress was made because correlations were not
done to determine the state of the lung.82,83
Infl ammation is still a hallmark of asthma, but we
now accept that phenotypes of asthma can exist where
there is little evidence of eosinophilic infl ammation in
the lung.2,4 At least three pathological phenotypes of
asthma have been proposed on the basis of the
predominant cell type
neutrophilic, and paucigranulocytic.4 These phenotypes
are becoming increasingly associated with distinct
clinical and physiological infl ammatory and repair
Eosinophilic asthma is the best studied pathological
phenotype. Eosinophils have been reported, in various
numbers, in sputum, lavage and endobronchial biopsies
of many people with asthma. Although some people argue
that the variability in eosinophil concentration is because
of the single time-point studied and the small sample
obtained, several lines of evidence suggest otherwise. First,
presence of eosinophils is usually consistent throughout
the lung, such that if they are not in one compartment,
they are unlikely to be in another.85–87 Second, other
pathological processes seem closely linked to the presence
or absence of eosinophils. Such processes include greater
subepithelial basement membrane thickening, presence
of cells that express TGFβ, activated metalloproteinases,
15 lipoxygenase, and its product, 15 hydroxyeicosaetetranoic
acid.2,4,16,84 Third, studies that have defi ned an eosinophilic
phenotype by sputum or biopsy testing in patients with
varying severities of asthma consistently show that around
50% of patients have eosinophilic involvement.2,88 Finally, a
study presented at the annual meeting of the American
Thoracic Society in 2005 suggested that the eosinophil
phenotype in severe asthma is persistent over a 5-year
period.25 A persistently eosinophilic phenotype in mild or
moderate asthma has not been reported, probably because
eosinophils in milder asthma are more responsive to
corticosteroids than in severe asthma.80 Hence, the overall
response to corticosteroid
infl ammatory phenotype.
Some studies have suggested that eosinophilic
infl ammation increases with severity of disease, but other
infl ammation in severe asthma is often associated with
adult-onset disease, and with aspirin sensitivity.8 Patients
with eosinophilic infl ammation
heightened symptoms, worse disease control, and a
greater risk of exacerbations than patients with asthma of
other pathological phenotypes.11,25,91,92 The mechanisms of
eosinophilic infl ammation are not well defi ned. Although
both interleukin 5 and the chemokine eotaxin have been
reported to be increased in asthma, studies that aimed to
inhibit these pro-eosinophilic mediators were not
accompanied by clinical effi cacy.93 Studies of targeted
therapy have not been done specifi cally in a cohort with
eosinophilic asthma, which might have caused the
absence of effi cacy.
Identifi cation of an eosinophilic phenotype has
traditionally been done with sputum analysis or endo-
bronchial biopsy. Additionally, exhaled nitric oxide
concentration has been proposed as a tool to identify
patients with persistent eosinophilic infl ammation.94,95
Generally, exhaled nitric oxide concentrations correlate
with the number of eosinophils in sputum or biopsy
treatment can aff ect
www.thelancet.com Vol 368 August 26, 2006 809
samples, even in patients on high doses of corticosteroids.95
However, treatment strategies that use exhaled nitric
oxide to control steroid dose have been disappointing.96
Despite the evidence for a persistent eosinophilic
phenotype in a proportion of patients with moderate-to-
severe asthma, two studies97,98 suggest that eosinophilic
infl ammation might be present in a greater proportion of
asthmatic patients than previously believed, since this
infl ammation could be present in a distal portion of the
lung that is not assessed by standard methods. In one
study, about 50% of patients with severe asthma that had
previously been identifi ed as non-eosinophilic had
eosinophilic infl ammation in the distal lung.97 These
fi ndings support the results of another study, in which the
concentration of alveolar nitric oxide was measured and
compared with standard measures of exhaled nitric oxide
in patients with corticosteroid-refractory asthma. Although
the proximal measures of exhaled nitric oxide were not
increased, assessments of nitric oxide at high fl ow rates,
which are believed to measure distal nitric oxide
concentrations, were found to be signifi cantly higher in
these patients. These alveolar nitric oxide concentrations
correlated with the number of lavage eosinophils, but not
with eosinophil numbers in sputum or bronchial wash
fl uid, which supports a distal source of these eosinophils.98
Too few patients have been assessed in this manner for us
to be able to determine whether these patients with
presumed distal lung eosinophils defi ne a distinct
phenotype or sub-phenotype.
Perhaps the greatest validation of the importance of
defi ning a specifi c phenotype is that phenotypic
assessment improves therapy. Studies that selected an
eosinophilic endpoint in their design support the idea
that identifi cation then modifi cation of the level of
eosinophilic infl ammation can lead to improved
outcomes. Two large-scale, long-term studies have
compared a basic “guidelines” approach to therapy with
an approach in which the number of sputum eosinophils
dictated which intervention was used.11,99 In the fi rst
study, which had a 1-year treatment period, treatment
designed to lower the number of sputum eosinophils to
less than 3% of the total infl ammatory cells led to fewer
severe exacerbations of asthma and no overall change in
corticosteroid dose compared with the “guidelines”
approach (fi gure 2). These fi ndings were replicated in the
second large-scale trial.99
Treatment choices in severe asthma are often diffi cult,
centering around whether corticosteroid doses should be
increased, decreased, or held constant. A small study of
severe asthmatics who were treated with high-dose
inhaled corticosteroids and were pre-selected for sputum
eosinophilia showed that a very large systemic dose of
corticosteroid (triamcinolone 120 mg intramuscular) was
able to reduce eosinophil number and improve symptoms
and lung function.100 In another study, the presence or
absence of eosinophilic infl ammation in children with
refractory asthma was a predictor of the ability to decrease
corticosteroid dose; children with no eosinophilic
infl ammation were able to decrease the corticosteroid
dose the most.101 Considerable evidence exists to support
an eosinophilic phenotype, identifi cation of which can
aff ect treatment decisions. Whether eosinophilia is a
permanent phenotype or one dependent on current
treatment and level of disease control remains to be seen.
The relation of neutrophilic asthma with a clinical
phenotype is less clear than the association of
eosinophils with exacerbation-prone or adult-onset
asthma. Additionally, many patients with neutrophilic
infl ammation (fi gure 3) can have concomitant eosinophilic
infl ammation seen on tissue biopsy, whereas sputum
assessment might show clear predominance of
neutrophils or eosinophils.2,88 Neutrophilic asthma is seen
most commonly in patients with severe disease and has
0123456789 10 1112
Guidelines management group
Sputum management group
Figure 2: Cumulative asthma exacerbations in a group managed according to
standard guidelines, and one managed by identifi cation of eosinophilic
infl ammation in sputum and adjustment of treatment where necessary
Reproduced from reference 10, with permission.
Figure 3: Neutrophilic infl ammation in an endobronchial biopsy from a
patient with severe asthma
Neutrophils were identifi ed with an antibody to neutrophil elastase (original
magnifi cation 100x).
www.thelancet.com Vol 368 August 26, 2006
been reported in autopsies of patients who died soon after
the onset of a severe exacerbation.102–104
The cause of neutrophilic infl ammation in asthma is
unknown. External factors, such as current or previous
tobacco smoke exposure, occupational exposure to
irritants, or viral infections could be involved.105–108
Additionally, the association with severe asthma could be
caused by treatment with high doses of corticosteroids,
which have been shown to decrease the apoptosis of
neutrophils in vitro.39,109
Clinical features of neutrophilic asthma or its long-term
consequences have not been reported. However, in
patients with asthma, neutrophils have been associated
with increases in interleukin 8, neutrophil elastase, and a
high-molecular-weight form of matrix metalloproteinase 9
that shows reduced inhibition by tissue inhibitors of
metalloproteinases (TIMPs).4,18,19,110 Activation of these
enzymes might modify airway structures in certain
asthmatic patients to contribute to the lower FEV1 seen in
patients with evidence of neutrophilic activity.111 Whether
monitoring sputum neutrophils, as opposed to
eosinophils, would have any eff ect on identifi cation of
viral exacerbations of asthma or predict long-term decline
in FEV1 remains unknown.
Anti-neutrophilic therapies have not been systematically
studied. Thus no studies have successfully targeted
treatment of this pathological phenotype. However, this
phenotype seems to be less responsive to corticosteroid
therapy than eosinophilic asthma.3 The presence of an
underlying neutrophilic pathology could also explain the
poor response to corticosteroids seen in some patients
with asthma who smoke.105 Notably, smokers who present
with an eosinophilic infl ammatory process seem to have
a similar response to corticosteroids to non-smokers.37
Asthma has been thought of as an infl ammatory disease
for the past 20–30 years, yet studies suggest that asthma
can exist in the absence of an identifi able infl ux of
infl ammatory cells such as eosinophils, neutrophils, or
lymphocytes (fi gure 4).2,4 Unfortunately, we do not know
whether the absence of infi ltrating cells is factual or
whether the samples missed the presence or location of
infl ammation. In some cases, these patients can be on
high doses of corticosteroids but are still symptomatic,
which suggests that other cells or pathologies contribute
to their symptoms.8 Infl ammation might take less
traditional forms, perhaps caused by activation of resident
cells, such as mast, epithelial, or smooth muscle cells.
Unfortunately, no biological markers have been identifi ed
for this phenotype. Some studies have suggested that
these patients do not respond to corticosteroid therapy,
and might benefi t from reductions in their corticosteroid
dose.37,38,101 However the infl ammation might increase
during exacerbations in these patients or in response to
corticosteroid dose reductions, such that these patients
could become granulocytic in phenotype.
Additional pathological phenotypes
The description of pathological phenotypes of asthma is
in its infancy. In the future, more specifi c biomarkers
than we know about now will almost certainly be found
that better discriminate phenotypes. However, only
cysteinyl leukotrienes, and IgE, have been associated
with an identifi able phenotype (aspirin-sensitive and
allergic asthma, respectively) or a response to a targeted
therapy such as anti-leukotriene therapy in children, and
anti-IgE drugs.5,55,56,112 An increased emphasis on the use
of gene and protein arrays to study a wide range of
potential targets, should lead to the discovery and
validation of useful biomarkers.
How does it all fi t together?
Few studies have attempted to link diff erent approaches
to describing phenotypes in asthma. This is probably
because of the insuffi cient pathological or immunological
information available from large studies of asthma
patients. As minimally invasive tests, such as exhaled
nitric oxide and sputum analysis, become more
commonplace, we will be able to link clinical,
immunological and pathological characteristics of various
asthma phenotypes. New approaches to statistical
modeling, such as factor analysis, will also help with the
defi nition of asthma phenotypes. The only published
study of factor analysis supports the idea that airway
obstruction, hyper-responsiveness, and eosinophilic
infl ammation are independent contributors to chronic
asthma.113 How many phenotypes there are remains to be
seen, but it is probable that no more than fi ve or six
defi nite patterns will emerge. However, we currently
have inadequate defi nitions, bias from therapy, and
considerable overlap in phenotypes. Figure 5 outlines a
Figure 4: Paucigranulocytic infl ammation
Haematoxylin and eosin stain showing no granulocytic cells, but an active
epithelial and vascular process with mucus production and submucosal oedema
(original magnifi cation 100x).
www.thelancet.com Vol 368 August 26, 2006 811
possible scenario of how phenotypes discussed in this
Considerable progress has been made in the past few
years to defi ne and understand the pathophysiology of
asthma. As new therapies for asthma, become available,
substantial eff ort is needed to defi ne and understand who
will respond to these therapies. In turn, these targeted
approaches will aid in the identifi cation of better
biomarkers for certain phenotypes. By identifying these
asthma phenotypes, more appropriate, eff ective, and safer
therapies for treatment of each phenotype of asthma will
Confl ict of interest statement
Sally Wenzel has consulted for and served on advisory boards and
speaker’s bureaus for Merck, Critical Therapeutics, Genentech, Novartis,
Centocor, and Wyeth.
I thank Shirley Pearce for her technical support.
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