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REVIEW
published: 16 April 2020
doi: 10.3389/fped.2020.00095
Frontiers in Pediatrics | www.frontiersin.org 1April 2020 | Volume 8 | Article 95
Edited by:
Ting Fan Leung,
The Chinese University of
Hong Kong, China
Reviewed by:
Kelvin D. MacDonald,
Oregon Health and Science University,
United States
Gary James Connett,
University Hospital Southampton NHS
Foundation Trust, United Kingdom
*Correspondence:
Mark L. Everard
mark.everard@uwa.edu.au
Specialty section:
This article was submitted to
Pediatric Pulmonology,
a section of the journal
Frontiers in Pediatrics
Received: 17 September 2019
Accepted: 24 February 2020
Published: 16 April 2020
Citation:
Anthracopoulos MB and Everard ML
(2020) Asthma: A Loss of Post-natal
Homeostatic Control of Airways
Smooth Muscle With Regression
Toward a Pre-natal State.
Front. Pediatr. 8:95.
doi: 10.3389/fped.2020.00095
Asthma: A Loss of Post-natal
Homeostatic Control of Airways
Smooth Muscle With Regression
Toward a Pre-natal State
Michael B. Anthracopoulos 1and Mark L. Everard 2
*
1Respiratory Unit, Department of Paediatrics, University of Patras, Patras, Greece, 2Division of Paediatrics & Child Health,
Perth Children’s Hospital, University of Western Australia, Perth, WA, Australia
The defining feature of asthma is loss of normal post-natal homeostatic control of
airways smooth muscle (ASM). This is the key feature that distinguishes asthma from
all other forms of respiratory disease. Failure to focus on impaired ASM homeostasis
largely explains our failure to find a cure and contributes to the widespread excessive
morbidity associated with the condition despite the presence of effective therapies. The
mechanisms responsible for destabilizing the normal tight control of ASM and hence
airways caliber in post-natal life are unknown but it is clear that atopic inflammation
is neither necessary nor sufficient. Loss of homeostasis results in excessive ASM
contraction which, in those with poor control, is manifest by variations in airflow
resistance over short periods of time. During viral exacerbations, the ability to respond
to bronchodilators is partially or almost completely lost, resulting in ASM being “locked
down” in a contracted state. Corticosteroids appear to restore normal or near normal
homeostasis in those with poor control and restore bronchodilator responsiveness
during exacerbations. The mechanism of action of corticosteroids is unknown and
the assumption that their action is solely due to “anti-inflammatory” effects needs
to be challenged. ASM, in evolutionary terms, dates to the earliest land dwelling
creatures that required muscle to empty primitive lungs. ASM appears very early in
embryonic development and active peristalsis is essential for the formation of the
lungs. However, in post-natal life its only role appears to be to maintain airways
in a configuration that minimizes resistance to airflow and dead space. In health,
significant constriction is actively prevented, presumably through classic negative
feedback loops. Disruption of this robust homeostatic control can develop at any
age and results in asthma. In order to develop a cure, we need to move from our
current focus on immunology and inflammatory pathways to work that will lead to an
understanding of the mechanisms that contribute to ASM stability in health and how
this is disrupted to cause asthma. This requires a radical change in the focus of most
of “asthma research.”
Keywords: Asthma, airways smooth muscle, homeostasis, poor control, exacerbations, evolution, research
direction
Anthracopoulos and Everard Asthma—What Is IT?
“When I use a word,” Humpty Dumpty said in a rather scornful
tone, “it means just what I choose it to mean – neither more
nor less.”
Through the Looking Glass Lewis Carroll 1871
No disease was less understood by medical men, than asthma.
Every difficulty of breathing, if fixed and continuous, was
designated asthmatic; and the same indefinite application of the
term still remains in vulgar use. This general application of the
word caused it to be employed to denote a variety of morbid states
of the lung, very different from one another.
A practical treatise on the principal diseases of
the lungs, GH Weatherhead. 1837
Homeostasis is the property of a system within an organism
in which a variable is actively regulated to remain very
nearly constant.
INTRODUCTION
It is now 145 years since Dr. Theodore Williams wrote
about the pathology and treatment of spasmodic asthma (1).
The contents of his article (summarized in Table 1) probably
reflects the understanding of most doctors in the twenty-
first century (and indeed demonstrates greater insight than
most current medical practitioners) with the only notable
omission being the dramatic impact of corticosteroids and the
recognition that selective β2-agonists can provide rapid and
symptomatic relief. He noted the hereditary predisposition;
the importance of muscle spasm; the tenacious secretions and
thickened airways walls; the importance of catarrhal infection
in producing “spasmodic” asthma [viral exacerbations]; the
role of environmental factors especially pollens, dust, and
changes in weather; the value of avoiding precipitating factors,
the presence of inflammation, the reversible hyperinflation,
the refractory period, the patient’s experience of greater
difficulty breathing in than breathing out (2) and the value
of bronchodilators.
A search on PubMed indicates that more than 185,000 articles,
at a current rate of more than 21 papers a day, have been
published on the topic of asthma since Dr. Williams’ article.
Despite the billions of dollars and countless hours expended
in generating this body of work, we still cannot define the key
component that underlies this condition and appear no nearer to
finding a cure.
This inability to define the condition is associated with a
depressingly high on-going prevalence of mis-diagnosis (both
over and under) (3–5), morbidity and mortality in most
countries. The introduction of inhaled corticosteroids (ICS) in
the early 1970s (6,7) was the one great step forward in the
intervening 140 years; yet despite having safe and effective
therapy, levels of morbidity and mortality remain unacceptably
high, particularly in countries such as the U.K. and Australia1
(8). This is largely because doctors do not appear to do the
1https://www.nationalasthma.org.au/living-with- asthma/resources/health-
professionals/reports-and- statistics/the-hidden- cost-of- asthma-2015
simple things well. The failure to correctly identify the key
component of the condition probably plays a central role in
the respiratory fraternity’s failure to impact on care throughout
the community.
FASHIONS IN THE DEFINITION OF
ASTHMA
Dr. Whitehead’s observation 182 years ago that “No disease
was less understood by medical men, than asthma” (9) still
resonates today. The on-going struggle to develop an agreed
definition was recently reviewed in part by Hargreaves and
Nair (10). The potentially central role for airways smooth
muscle (ASM) in the causation of asthma was first established
during the C19th starting with the great Rene Laennec who
noted “It is well understood that the spasmodic contraction of
these fibers may be far enough to control the air ducts and to
prevent the penetration of air into a large part of the lungs”
(11). Williams noted that “Laennec’s theory of asthma, was
that the attack depended on spasm of the bronchial muscles”
which had recently been described by Reisseisen and observed
by Laennec (1,11). The functional activity of the ASM was
confirmed by the middle of the century by Dr. Williams ’s
father (12) and others. In the USA, William Osler was echoing
these views noting that excessive ASM contraction is the key
feature that characterizes asthma (13). These pioneers recognized
that the disease was generally associated with inflammation but
emphasized the central, fundamental role played by excessive
ASM constriction.
TABLE 1 | Summary of Williams, 1874 (1).
Hereditary predisposition plays a part
Muscle spasm is a central component of the disease
Tenacious secretions and thickened walls
Catarrhal attacks commonly cause “spasmodic” asthma
[viral induced exacerbations-respond poorly to bronchodilators]
Environmental precipitants
pollens, dust, chemicals, cold air etc.
May also be triggered by emotion, indigestion
Infection may be one of the causes
[“but be careful as almost everything in this country is attributed to a cold”]
Different patterns in different subjects
Typically causes cough, wheeze & difficulty breathing
Pts find it more difficult to breath in than out during an episode
Reversible emphysema (hyperinflation)
Describes the refractory period and effect of a deep breath
Commonly co-exists with eczema
Avoidance of triggers such as hay is helpful
Smoky cities are good for asthma for people from country areas
Bronchodilators are helpful
Patients often know as much about treating their disease as doctors
“it is, happily, not a fatal disease, yet it is one which gives rise to a large amount
of suffering”
Can be associated with hysteria
[dysfunctional breathing]
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Anthracopoulos and Everard Asthma—What Is IT?
At around the turn of the century, the description of
“anaphylaxis” and “allergic” responses propagated a belief
that asthma was an “allergic” disease often being linked
to other conditions then believed to be a consequence of
“hypersensitivity” such as epilepsy and migraines. In its original
sense, “allergy” referred to a change in the host in response to
exposure to an environmental agent(s) (infective or otherwise),
which could be both protective, as in limiting the impact of being
re-exposed to an infectious agent (immunity) and detrimental,
should the response elicited cause harm (hypersensitivity) (14).
The idea that asthma was primarily a “neurological condition”
arose in the C19th from the studies of Dr. Williams Sr. and others
who demonstrated that ASM contracted in response to electrical
stimulation. These ideas were often merged into a model in
which a “sensitivity” or “allergy” to certain stimuli (infectious and
non-infectious) drove a neurological response mediated via the
vagus and parasympathetic system that caused ASM to constrict
(15,16). Hence, for much of the C20th asthma was viewed as
a condition caused by ASM constriction driven by neurological
stimuli as part of a “hypersensitivity reaction.”
In the early 1960s Scadding and others proposed that asthma
is a “disease characterised by wide variation over short periods
of time in resistance to flow in intrapulmonary airways.” This
was widely accepted and adopted by the ATS (17). This placed
bronchial “reactivity” at the core of the definition; that is the
pathognomonic feature of asthma is excessive narrowing of
airways due to contraction of ASM. It should be remembered that
this was a decade before the advent of inhaled corticosteroids (6)
and the majority of asthmatics at that time would have exhibited
the characteristics of “poor control,” i.e., their lung function
varies widely over short periods of time (6,18). The adrenalin
pressurized metered dose inhaler (pMDI) giving “25% more FVC
right now!” as claimed in the adverts of the time2(Figure 1)
had been brought to the market just a few years before and
this convenient, portable, and apparently safe medication, that
could rapidly alleviate symptoms attributable to poor control,
presumably influenced current thinking at the time. In this model
the basic underlying abnormality lies in defective control of ASM
tone and stimuli, such as an allergic response or viral infection
triggering the excessive ASM shortening. This is analogous to
the acquisition of a bacterial bronchitis in a well, cough free
child with cystic fibrosis (CF)—the bacterial bronchitis does not
define the condition but is both a consequence of the underlying
condition and a driver of disease (symptoms and structural
damage). The bacterial bronchitis with associated inflammation,
if untreated, causes disease characterized by a chronic cough
which may on occasions be accompanied by reduced energy
levels leading to progressive damage of the airway wall that
will eventually be manifest by the radiological appearance of
bronchiectasis (which is not a disease but a radiological sign or
pathological feature).
By the end of the 1970’s the focus again moved away
from the ASM such that many still referred to asthma as an
“inflammatory” disease. This was largely attributable to the
identification of IgE and its role in type 1 allergic reactions in the
2http://vintageadsandbooks.com/images/x/x088.jpg
FIGURE 1 | Advert for Medihaler (1956) http://museum.aarc.org/gallery/
asthma-management/.
late 1960s and the demonstration by Dr. Harry Morrow-Brown
in the early 1970’s that an ICS (beclomethasone) could transform
the quality of life of well-characterized “allergic” asthmatics
(based on sputum eosinophilia) (6). For some time it was known
that systemic steroids could have a dramatic effect on the disease,
albeit with significant associated side effects, but the availability of
an apparently safe, effective “anti-inflammatory” agent reinforced
the notion that this almost magical effect was entirely mediated
by its “anti-inflammatory” effects. By the early 1990’s the British
Thoracic Society guidelines (19) noted that “Asthma is a common
and chronic inflammatory condition of the airways. Its cause is not
completely understood. As a result of inflammation, the airways
are hyper responsive.. . ” As with subsequent GINA guidelines
(20), inflammation was elevated to be the cause of asthma rather
than a component and/or trigger factor.
Despite the intense investment of time, expertise and
money this focus on asthma as an “inflammatory disease” has
conspicuously failed to “solve” the origins and fundamental
nature of asthma (though there is no shortage of hypotheses).
This lack of clarity regarding the fundamental nature of the
condition and the associated difficulties in agreeing upon
a definition led to the British Thoracic Society guidelines
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Anthracopoulos and Everard Asthma—What Is IT?
abandoning all attempts at defining the condition and in essence
defaulting to the position that asthma is something that gets
better with asthma therapy3.
Does this matter? Unfortunately it does. The failure to define
the condition leads to fashions, driven by “opinion leaders”
keen to promote their latest “asthma paradigm,” which in turn
contributes to the huge burden of over and under diagnosis
experienced by patients (3–5,21–23). Failure to apply clear
diagnostic criteria means that findings of epidemiological studies
are probably of little value and at worst can be very misleading
(24). Much of the reported “asthma epidemic” of the late
C20th appears to be attributable to diagnostic transfer. This
is particularly true in the pre-school age group (24–26) with
wheezy bronchitis (wheezing associated with a viral bronchitis—
the wheeze being generated by airflow limitation as a result
of accumulated airways secretions and to a degree, mucosal
oedema rather than contraction of ASM) being mislabelled
as asthma due to changes in diagnostic fashions (diagnostic
transfer). As, with many unfortunate erroneous medical ideas
of the past, this was driven by laudable intentions, which
in this case, was an attempt to address the prevalent under
diagnosis and treatment of asthma in school age children in the
1980s (26).
Attempts to hide our confusion has given rise to the
suggestion that there are many forms of asthma with different
“phenotypes” [the observable properties of an organism that are
produced by the interaction of the genotype and the environment].
Pediatricians often have applied the term “phenotypes” to
patterns of “asthma” and/or wheeze over time (27,28),
when in reality these “phenotypes” are not phenotypes at
all, but merely retrospective arbitrary descriptions of temporal
patterns of symptoms generally unrelated to underlying cause
or other observable properties. Giving a condition a new
name because we are having trouble understanding the
underlying process is a game doctors have been playing
for centuries.
If we had not identified the unifying, underlying defect in
CF we would presumably have a similar growth industry with
the various phenotypes such as typical CF characterized by
malabsorption and lung disease, CF with diabetes, CF with liver
disease etc. and we would be applying all kinds of powerful tools
to study biopsies and pathways in and around the affected cells.
At the same time we would have missed the diagnosis in the 15%
or so who are pancreatic sufficient and indeed those turning up
in adult infertility clinics who carry a mutation in the same gene.
WHY SHOULD WE FOCUS ON THE
INSTABILITY OF ASM?
Understanding that loss of postnatal control of ASM homeostasis
is the key component of asthma forms the cornerstone of accurate
diagnosis and good clinical care. The idea that a key component
of “asthma” is excessive narrowing of airways due to contraction
of ASM and that this can vary significantly over short periods
3http://www.sign.ac.uk/pdf/sign101.pdf
of time goes back several centuries. It is the one feature that
distinguishes the condition from all others. Salter recognized this
in 1859 (29), reflecting the consensus of those at the forefront of
studying pulmonary disease at the time. He also recognized the
importance of neurological control of the ASM tone.
COMPONENTS OF THE “BRONCHIAL
HYPERRESPONSIVENESS” THAT
CHARACTERIZES ASTHMA
Asthmatics generally exhibit “bronchial hyperresponsiveness”
(BHR), which critically is composed of two components
(Figure 2); increased bronchial sensitivity (BSen) characterized
by a shift to the left on the dose response curve hence
narrowing at lower levels of stimulation than non-asthmatic
subjects’ and increased bronchial reactivity (BRea) with
asthmatic ASM shortening to a significantly greater extent than
observed “healthy” subjects [(30–43); Figure 2]. “Bronchial
responsiveness” (a term often used for BSens) varies in
response to factors such as viral respiratory infections (39)
and/or treatment with agents such as steroids (40–43). Indeed
“sensitivity” appears to be increased following viral infections
even in apparently healthy individuals (44,45). In the absence
of these factors bronchial “hyper-responsiveness” appears to
be relatively stable over time (46,47). Importantly, there does
not appear to be a discrete, bimodal distribution separating
asthmatics from healthy individuals (33,34). While sensitivity
appears to vary with viral infections and treatment with
medication such as corticosteroids much less is known about
whether bronchial reactivity changes in a similar manner
not indeed whether it differs significantly between asthmatics
and healthy individuals. Healthy individuals demonstrate a
plateau effect when exposed to a bronchoconstriction stimulus
which may be due to reaching maximal shortening but, more
likely, this is due to homeostatic mechanisms preventing
excessive shortening.
It is widely accepted that bronchodilator responsiveness as
demonstrated by an increase in FEV1 of 12% or greater4,5
Main report: p19, will identify pediatric asthmatic subjects. The
diagnosis can also be supported by a “positive” response to one of
the numerous forms of challenge testing. The utility of placing
ASM “hyperresponsiveness” at the core of the condition was
clearly demonstrated in Finland where the introduction of a
clear unified approach to diagnosis and management resulted
in huge reductions in presentations to emergency departments
(EDs), hospitalisations and apparently the virtual elimination
of death due to asthma (48–50). They demonstrated that
simple, consistent, and coherent adjustments to delivery of care
transforms outcomes. In contrast, little or no progress has been
made in countries such as the UK, USA, and Australia, which
have devoted huge efforts to producing “guidelines but have
not addressed failures in the delivery of healthcare.” Crucially,
4https://www.sign.ac.uk/sign-158- british-guideline- on-the- management-of-
asthma.html
5https://ginasthma.org/reports/
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Anthracopoulos and Everard Asthma—What Is IT?
FIGURE 2 | Bronchial hyper-responsiveness consists of two components; how sensitive the airways are to agonists driving shortening of ASM and how much the
ASM shorten when the normal homeostatic mechanisms fail. The impact of shortening can be amplified in presence of significant airways secretions and plugging.
The sensitivity and reactivity of vary between asthmatics and probably accounts for different patterns of symptoms from mild frequent to infrequent severe. Steroids
have significant effects on sensitivity but may have little or no effect on reactivity once destabilization is triggered.
the Finnish “asthma programme” requires objective evidence
that confirms the diagnosis before patients qualify for financial
assistance with medication costs. Establishing a robust diagnosis
with spirometry with bronchodilator responsiveness (or rarely a
positive “challenge” test) is one of the central components of their
enviable and very effective “asthma programme.”
The objective confirmation of ASM reactivity helped ensure
that those with alternative diagnoses were not mis-diagnosed as
asthma, thus denying them the appropriate intervention for their
condition, whilst providing confidence in the diagnosis. Perhaps
unsurprisingly there is evidence that a firm diagnosis is associated
with improved adherence (51). It was also noted that the number
of “milder” asthmatics increased suggesting that the programme
also addressed, in part, the issue of under diagnosis (50). The one
group in whom the “asthma” programme had little or no effect
was in children under 5-years, in whom it is difficult to apply
objective tests other than a dramatic and unequivocal response
to asthma medication. Moreover, the number of “asthmatics” in
early pre-school years represent only a small proportion of those
who develop wheezing with a respiratory virus, with the majority
having “wheezy bronchitis” (24,52).
“THE SAME INDEFINITE APPLICATION OF
THE TERM STILL REMAINS IN VULGAR
USE” (10)
Depressingly, over- and under-diagnosis of asthma remains
common (3–5,21–23). The lack of focus on objectively
documenting the presence of the key component of asthma is one
of the principle reasons for over diagnosis. Conversely a failure
to recognize that the degree of bronchial reactivity (and hence
bronchoconstriction) follows a bell shaped distributed amongst
asthmatics, with many having relatively mild constriction when
triggered, results in under diagnosis at the milder end of the
spectrum. Children with relatively mild asthma may not wheeze
with intercurrent viral illnesses and present with coughing that
takes many days or weeks to regress to the mean. Hence
their symptoms are all too often dismissed as “just another
viral infection.” Additionally, the ability of subjects to adjust to
impaired lung function and thus minimize symptom reporting
results in ongoing under-diagnosis. It is not rare to see an
adolescent with an FEV1 of 54 and 40% reversibility who show
no overt evidence of respiratory distress, are free of wheeze and
who state they are fine and don’t know what the fuss is about.
The lungs have a very limited repertoire of responses which
contributes to the high prevalence of over diagnosis in many
countries. Symptoms and signs commonly associated with
asthma such as shortness of breath, chest tightness, coughing, and
“wheezing” are also manifest in patients with a variety of other
conditions. These include “wheezy bronchitis,” most common
in the early preschool years (24,52,53); persistent bacterial
bronchitis (PBB), again most common in the early years of life but
occurring at all ages (54,55); dysfunctional breathing common
amongst competitive teenagers but also common in adolescents
and adults with and without asthma; paroxysmal vocal cord
dysfunction (pVCD) and related conditions such as exercise
induced laryngomalacia (56–59); reaching ones physiological
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limit during exercise (58–60) (reported by individuals across the
spectrum from unfit obese individuals through to elite athletes);
airways structural problems, particularly in infants and young
children, including malacic airways, vocal cord palsy, subglottic
stenosis, and cardiac anomalies amongst others. Unfortunately
prescribing an inhaler and applying the label “asthmatic” is only
too easy, particularly if the clinician is not aware of conditions
such as a PBB or dysfunctional breathing.
In those with “difficult asthma” mis-diagnosis is commonly
identified. The insistence on objective evidence such as a positive
bronchodilator response or significant constriction during a
challenge before the label applied to a patient moves from
possible or probable asthma to definite asthma would greatly
reduce the very high levels of over diagnosis. De-diagnosing
asthma is one of the principle roles of many tertiary care clinics.
In those with objective evidence of asthma, “difficult” asthma
(at least in childhood) is almost always attributable to either
(1) failure to deliver the ICS to the lungs (poor regimen and/or
device compliance, i.e., they do not adhere >80% of the time
or they have an ineffective inhaler technique (61–63) or
(2) having asthma and a co-morbidity such as those outlined
above with symptoms caused by the co-morbidity being
managed with ever escalating doses of medication (64).
CAVEATS TO SCADDING’S DEFINITION OF
ASTHMA
a) Scadding and the American Thoracic Society (17) noted that
asthma is a “disease characterised by wide variation over short
periods of time in resistance to flow in intrapulmonary airways.”
Wide variation in resistance to airflow per se is not sufficient,
in that significant variations can be observed over relatively
short periods in other conditions. For instance, a patient with
moderately severe CF may experience a relatively rapid fall
in FEV1 with an “infective” exacerbation. Conversely, poorly
compliant adolescent CF patients with deteriorating lung
function may have a rapid improvement in FEV1 over the first
24-h after admission with the institution of physiotherapy.
b) Equally important is the failure of many clinicians to recognize
that one of the key characteristics of asthma is that there
is a fundamental difference between poor control and a
viral induced exacerbation (or “spasmodic” asthma associated
with catarrhal as Dr. Williams described it (1) or commonly
referred to as an “attack”). This difference was highlighted
in early papers reporting the effect of an inhaled steroid and
was later highlighted by Reddel et al. (18) (see Figure 3).
Patients with poor control often exhibit highly variable lung
function changing rapidly over time reflected in diurnal peak
flow measurements or rapid onset and relief from symptoms
brought on by exercise (65) or allergen exposure. Generally,
such patients are not on ICS or (more commonly these days)
are poorly compliant.
In contrast during a “viral” “exacerbation” the infection of the
airways appears to result in both a destabilization of bronchial
ASM homeostasis resulting in bronchial ASM narrowing and,
crucially, a tendency for those airways to become “locked down”
such that they respond very poorly to β-agonist (18). Patients
often describe an viral exacerbation of asthma as an “asthma
attack” analogous to the use of the term “heart attack” to describe
a myocardial infarct.
If the bronchodilator responsiveness were maintained patients
would not require increased inhaled or systemic steroids even
if the virus initiated bronchoconstriction. In those with the
most severe “exacerbations,” heroic amounts of β-agonists at
best produce small reductions in airways resistance (as well
as significant side effects such as tremor tachycardia anxiety,
hypokalaemia etc.). In a study assessing systemic salbutamol
levels in patients dying of asthma in hospital it was demonstrated
that lack of a β-agonists was not the cause of death, rather the
patients died despite massive doses of β-agonists (66,67). Of
course the impact of viruses on the ASM function represents
a spectrum from a mild but discernible increase in BHR in
many “normal” individuals to the severe locked down life
threatening attack experienced by a minority of asthmatics who
have very significant reactivity. Other milder asthmatics do not
experience such sever falls in FEV1 and often retain a degree
β-agonist responsiveness.
In severe exacerbations systemic corticosteroids are required
to “unlock” the ASM and restore the β-agonist responsiveness.
The mechanism of action is unclear as corticosteroids have
little impact on the neutrophilic inflammation typical of viral
respiratory infections (52,68) and have no intrinsic “anti-viral”
effect. It should also be noted they appear to work equally well for
both atopic and non-atopic asthmatics, suggesting that they are
not working on “allergic inflammation.” Their impact on ASM
can be detected within an hour, far too quickly to work through
translational pathways. One group has suggested that the loss
of bronchodilator responsiveness is due to loss of β-receptors
resulting from viral RNA inducing prostaglandin synthesis via
Toll receptors (69–71) (though these patients also fail to respond
dramatically to anti-cholinergic drugs).
Inevitably, this is not an “all or nothing” effect. Clinical
observation would suggest that asthmatics at the mildest
end of the spectrum have mild increase in symptoms with
viral respiratory infections and never experience a severe
exacerbation. Others cope well with most viruses but have
an occasional severe exacerbation and others have significant
exacerbations with each respiratory virus. Along with this it
will be observed that many, usually at the milder end of the
spectrum, report reasonable if not compete relief when inhaling
aβ-agonist during a viral respiratory tract infection and others,
generally those labeled severe, rarely deriving much benefit for
their bronchodilators once an exacerbation has been established.
Primary care data suggest that perhaps only 14% of
“asthmatics” have an exacerbation requiring oral steroids during
a given year (at least in countries such as the UK) with the
best predictor of a significant exacerbation being a previous
such episode (72–74). The “severe” exacerbation presumably
requires both significant reactivity (a tendency to large falls
in airflow) together with a significant loss in bronchodilator
responsiveness—small falls in airflow are unlikely to be life
threatening and even large falls can be managed if bronchodilator
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Anthracopoulos and Everard Asthma—What Is IT?
FIGURE 3 | Impact of inhaled corticosteroids on lung function and bronchial responsiveness (sensitivity). Impact on sensitivity is relatively slow when commencing ICS
but rapidly fades on discontinuing treatment. This largely explains the need for high levels of compliance (>80% of twice daily doses). Study by Reddell et al. (middle
panels) indicates that even when asthma appears well controlled, ASM homeostasis can be severely disrupted during viral infections. The ability to induce/facilitate
bronchoconstriction and the associated impaired bronchodilator responsiveness after the airways constrict might explain why the Finnish/Scandinavian approach of
aggressive bronchodilator and ICS therapy early at first sign of increasing symptoms is successful at minimizing severe exacerbations and why combination products
used intermittently appear to be helpful in mild to moderate asthmatics (65).
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Anthracopoulos and Everard Asthma—What Is IT?
responsiveness is largely preserved. The Finnish programme
advocates aggressive use of β-agonists and ICSs as soon as a
patient experiences increasing symptoms, an approach which
they believe has made a major contribution to both the dramatic
reduction of ED presentations and the very low use of oral
steroids. It is reported that only 2% of asthmatics receive oral
steroids in a year.
OBJECTIVE CONFIRMATION OF ASTHMA
In the absence of having identified the central component of
asthma that leads to loss of ASM homeostasis and hence excess
constriction, we are left with using physiological makers. We
can measure blood glucose to diagnose diabetes, which provides
a marker of disturbed glucose homeostasis resulting from an
absence of insulin in type-1 diabetes or insulin resistance in type-
2 diabetes. In type-1 diabetes we can measure insulin levels but
in type-2 diabetes we need the physiological read out of elevated
blood sugar levels. For those with CF the physiological read out
of elevated sweat chloride (the “sweat test,” which replaced licking
the infant) has long been the test of choice. However, with the
recognition that CF is caused by mutations in a particular gene we
have much greater insight into the spectrum of disease severity
and manifestation.
The physiological read out for asthma is excessive lability
of airways caliber attributable to loss of homeostatic control of
ASM. Home peak flow measurements have been to help identify
this lability though the high variability in peak flow amongst
normal children makes this approach unreliable. As noted above
more robust diagnosis can be based on an increase in FEV1
of >12% following inhaled short acting β-agonist Occasionally
bronchial challenge testing is required to confirm bronchial
hyper-responsiveness as for example, when high level athletes are
seeking permission to use certain medications.
The recent NICE guidelines in the UK recognized the problem
of over-diagnosis and the need for more objective criteria before
confirming a presumptive diagnosis of asthma but curiously,
they proposed the measurement of exhaled nitric oxide FeNO6,
despite the lack of robust evidence that would support its role
as a tool that reliably identifies asthma (75). FeNo appears to
be a good marker of atopy (76,77) but does not appear to
be a marker of asthma or airways “hyper-reactivity.” Induced
sputum eosinophil and FeNO levels do not appear to correlate
with each other and neither correlates with BHR or lung function
(78). FeNO has yet to find a role in the routine management
of asthmatic patients (79,80). The usefulness of the more time
consuming process of evaluating eosinophils in induced sputum
is also questionable, with no evidence of its utility in children
(81,82) and no impact on symptoms or lung function in
adults, although a trend toward reduced exacerbations has been
reported. One group tried to apply the NICE criteria to a cohort
of children and found that the NICE criteria failed to identify the
“asthmatic” children though it should be noted that the definition
6https://pathways.nice.org.uk/pathways/asthma#path=view%3A/pathways/
asthma/asthma-overview.xml&content=view- node%3Anodes-diagnosis-and-
monitoring
of asthma was based on a physician diagnosis and prescription
of a short acting β-agonist, a notoriously inaccurate means of
establishing the prevalence of the condition (83).
The reason NICE failed to learn from the successful Finnish
national asthma programme, in which objective confirmation of
diagnosis using lung function testing was the key component, is
unclear. It is a curiosity that in most specialties, the fundamental
tests supporting their practice are readily available. It is easy to
obtain a full blood count, blood glucose, CXR, or ECG, yet health
care systems are yet to embrace the need for widely available,
high quality lung function testing (LFT). Indeed, for many, it
is much easier to get a CT scan or upper GI endoscopy than
high quality LFTs, which should be as readily available as a CXR.
The fact that this is not the case and the majority of children
with asthma in primary care are neither diagnoses or monitored
using spirometry (3,84) is another example of the failure of
the respiratory world to advocate for their patients and should
be source of embarrassment. The study from the Netherlands
(3) noted that only 15% of school aged children with “asthma”
had spirometry prior to the study. They went on to show
that the majority of “asthmatics” did not have asthma. A very
recent study from the U.K. (84) highlighted the improvement
in outcomes when routine spirometry was introduced into the
routine assessment of asthmatic children in primary care.
“ALLERGIC” INFLAMMATION IS NEITHER
NECESSARY NOR SUFFICIENT FOR
DEVELOPMENT OF ASTHMA
“Atopic” inflammation does not appear necessary for the
development of asthma, with estimates of the prevalence of
atopy amongst asthmatic populations ranging from <5% to 94%
across countries and regions (85–97). In Westernized countries
atopy is generally reported in around 40–60% or more of
asthmatics while in developing countries much lower percentages
are reported. Many countries in South America report a high
prevalence of asthma despite few of these individuals manifesting
atopic markers such as skin prick test positivity. Several studies
have shown that despite increasing atopy within populations
accompanied by increases in eczema and allergic rhinitis, over
recent years the prevalence of asthma has fallen or remained
static. The disparate changes in the prevalence of atopy, asthma
and related “atopic” conditions again questions the central role
of atopy in the generation of asthma (85–96). The explicit
recognition of atopic and non-atopic asthma (97) reinforces the
concept, that while atopy may be an exacerbating co-morbidity,
it is not central to the manifestation of asthma. Association does
not imply causality. One possible confounder is the weakness of
questionnaires that rely on reported wheeze to help estimate the
incidence/prevalence of asthma. To ask whether your child has
had a wheeze or whistling sound in the past year is to invite
a positive response if the child has had any noisy breathing
even if it is not a “whistling” sound (98). As a result, the
prevalence of asthma is probably greatly over-estimated (24)
making assessment of trends over time almost meaningless.
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Conversely, allergic inflammation does not appear sufficient
for the development of asthma, in that the majority of
those with evidence of “atopy” do not manifest the bronchial
hyper-responsiveness central to manifesting asthma. Indeed the
majority of those with an allergic rhinitis or eczema do not
manifest asthma. It appears very likely that many individuals
with a seasonal rhinitis due to grass pollen or perennial rhinitis
due to an allergen such as house dust mite will have airways
inflammation due to an allergic bronchitis. In the absence of
significant bronchoconstriction these individuals may experience
cough and some increase in airways secretions. Examination of
the airways will reveal inflammation similar to that reported
in “allergic asthmatics.” These individuals have an “allergic” or
“eosinophilic” bronchitis but the stability of the airways is not
significantly compromised and they do not bronchoconstrict
(99–102). Some refer to these patients as having “cough
variant asthma”. These subjects with an allergic bronchitis will
respond to ICSs if their cough is troublesome (99–102). Despite
corticosteroid responsiveness and some asthma like symptoms
they do not have asthma in that they do not exhibit significant
bronchoconstriction due to ASM activity.
It is also increasingly recognized that eosinophilic bronchitis
is absent in many asthmatics (103–106) arguing against the
eosinophil having an essential role in the development of asthma
(thought they may well-contribute to symptoms). Conversely,
in those who out-grow their asthma there is evidence that the
inflammatory profile persists in most subjects studied suggesting
that the AHR has altered and homeostasis has been restored
despite persistence of ongoing inflammation (107–112). A study
in asymptomatic subjects previously diagnosed with asthma
found evidence that FeNO fell after introduction of inhaled
steroids but, importantly, there was no change in clinical status
(111), again questioning the link between FeNO and asthma per
se. While several studies suggested this ongoing inflammation
may predispose to relapse, there is no evidence to support
or refute this suggestion. However, the discrepancy between
re-established airways homeostasis and ongoing inflammation
suggests the inflammation per se is not the critical factor.
The central role of the eosinophil has also been questioned
through observations that early studies with anti-IL-5 agents
in asthmatic subjects significantly reduced eosinophilia but had
little or no clinical impact (113,114). Eosinophilic asthma is
variously defined as having >2 or 3% eosinophils in a BAL or
induced sputum. Even in this minority of asthmatic patients
there is debate as to whether driving therapeutic decisions on the
basis of eosinophil numbers is any better than making changes
on the basis of symptoms. More recent studies with anti-IL-
5 agents have been shown to have an impact on the rate of
exacerbations in highly selective populations of “severe” “steroid
resistant” eosinophilic asthmatics but they certainly do not “cure”
asthma and indeed appear to have very little effect on quality of
life or lung function (113,114).
Importantly there is no data to suggest that atopic
status significantly impacts on the response to inhaled
corticosteroids. The most effective therapy for those with
asthma irrespective of atopic status are ICS suggesting that
their action is not fundamentally through suppression of
“atopic” inflammation.
In order to address the problem that atopy does not seem
to be either necessary or sufficient for the development of
asthma, those committed to the idea that “TH2 inflammation”
causes asthma have proposed that in those without atopy the
inflammation underlying the condition is commonly driven by
type 2 innate lymphoid cells (ILC2s) that generate TH2 type
cytokines (115,116). However, the same considerations relating
to the paradigm that asthma is a TH2 “allergic” disease pertain
to the role of ILC2 cells. Moreover, should they prove to have
a role, it is unclear why some individuals should develop ASM
hyper-responsiveness as a consequence of the activity of this type
of cells when they are present in all individuals.
Given that inflammation per se does not define asthma,
those who believe atopic inflammation or certain infections in
early life or dysbiosis of gut and/or lung microbiome causes
asthma (rather than being a exacerbating factors) need to
move from studying inflammatory/immunological pathways and
concentrate on how they might disrupt the normally robust
ASM homeostasis.
“Non-atopic” Asthma in Pre-term and
Small for Gestational Age Infants
Pre-term individuals are an interesting group, in whom there is
a significantly higher rate of asthma (as defined by demonstrable
bronchodilator responsiveness) than the general population and
in whom atopy appears not to be a significant risk factor
(117–121). Around 20% of such individuals may demonstrate
significant bronchodilator responsiveness. There is evidence of
on-going neutrophilic (but not eosinophilic) inflammation in the
majority of these patients (117,122–127) well into childhood, but
the relevance of this, if any, to the development of asthma in a
minority, is unclear. In one study reporting increased sensitivity
to exercise, the fall in FEV1 in those born preterm was <7% in
the vast majority, which may be related to structural changes
and effects of gas trapping rather than bronchoconstriction (126).
Interestingly, the impact on airways responsiveness appears to be
greatest in those born small for gestational age and not related to
“BPD” status (125).
Asthma in those born pre-term has not been studied in detail
and while inhaled steroids and ICS+LABA are widely used
(127) there is no published evidence to support their use in this
group. Older patients often report no significant benefit when
started on ICSs which may imply that in many the BHR may
not improve with steroid or that years of adaptation to low lung
function has resulted in physiological adaptation as with severe
poorly controlled asthmatic or may reflect the impact of the CLD
structural changes as a co-morbidity. There are a number of
on-going studies addressing therapeutic approaches which may
provide valuable information.
LOSS OF EFFECTIVE AIRWAYS SMOOTH
MUSCLE HOMOEOSTASIS—THE KEY TO
UNDERSTANDING ASTHMA
As will be argued in more detail below, the fundamental defect
leading to asthma appears to be a loss of the normal post-natal
homeostatic control. Antenatally, ASM contracts vigorously and
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frequently with regular peristaltic waves moving distally from
even in the earliest stages of lung development. This is vital for
lung development but toward term these peristaltic waves cease.
In contrast to it its marked physical contractions prenatally,
post-natal ASM maintains a relatively constant length with
relatively minor and non-coordinated oscillations around an
optimal length, probably controlled by classic negative feedback
loops. To date no clear role for ASM in a healthy individual after
birth has been identified. The most likely role, if any, is likely
to be helping to maintain an optimal luminal diameter in the
conducting airways in order to minimize resistance to airflow
while at the same time minimizing the dead space within the
conducting airways.
Airways Smooth Muscles Cells Are Not a
Unidimensional
Airways smooth muscle cells are generally considered to be as
highly specialized cell whose function is essentially confined to
shortening or lengthening with little or no other contribution
to the function of the lungs. However, there is a robust body of
work suggesting that ASM have other functions and capabilities
including the ability to produce a range of cytokines, including
IL-13, IL-5, and IL-8 and a range of proliferative cytokines in
respond to a variety stimuli such IL-1, IL-13, TNFα, IgE mediated
activation and LTB4 (128–144). Hence it would not be a surprise
that an inflammatory response could be generated by unstable
or activated ASM which may be independent of/or additive
to other inflammatory processes such as an atopic bronchitis.
Moreover, bronchoconstriction and the resultant stress on cells
such as epithelial cells and fibroblasts may also result in release of
inflammatory cytokines secondary to the constriction.
Cytokine release by ASM and/or associated stressed cells may
be the key link between excessive constriction secondary to
loss of homeostatic control and the evidence of inflammatory
response in the “asthmatic airway” and would explain the
inflammation frequently observed in “non-atopic” individuals
with poorly controlled asthma. The “airways inflammation” may
of course be augmented by “allergic” responses to allergens or
neutrophilic responses to viral and/or bacterial infections (PBB
or perturbation of the “healthy microbiome” occurring in some
poorly controlled asthmatics presumably due to the associated
impaired mucociliary clearance and plugging) (54,55).
A super-added inflammatory processes such as an “allergic
bronchitis” may, in those in whom homeostatic control of
airways caliber is impaired, contribute to symptoms by driving
constriction through the release of mediators such as histamine
and cysteinyl leukotrienes (cLT). It is also possible, but
not proven, that this pattern of inflammation can, in some
individuals, contribute to the development of loss of homeostatic
control of ASM. Despite the enormous financial and intellectual
investment in trying to “prove” the postulated link between an
“allergic” Th2 type inflammatory response and the causation of
asthma (as opposed to inducing symptoms) direct mechanism
linking the two have not been established.
While the natural assumption is that local mediators
predominantly drive the constriction observed during “allergic
asthmatic reactions” highly selective vagotomy appears to
prevent bronchoconstriction and asthma in a dog model of
allergic asthma (145) while a significant proportion of the
constriction due to methacholine appears to be mediated by
a parasympathetic reflex activity that maybe important in
humans (146).
Asthma does not appear to be analogous to type-1 diabetes, in
which a key component of normal homeostasis is permanently
lost. Rather it seems more similar to the development of type-
2 diabetes, which may or may not be evident in individuals of
the same BMI. The same relative obesity does not lead to the
manifestation of a condition in all individuals with a number of
factors influencing whether homeostasis is maintained. In subject
of the same sex age and BMI some will have no identifiable
problem with glucose homeostasis, others only when stressed and
some will have very poor glycaemic control. Similarly removal
of stimuli can result in greatly improved homeostasis (improved
diet or allergen avoidance, respectively), while control can be
fully restored by life style changes in case of type-2 diabetes and
by taking ICSs or growing out of asthma through mechanisms
unknown. As already noted, ASM has been shown to respond
directly to corticosteroids with reduced cytokine production and
changes in bronchial responsiveness, raising the possibility that
a major effect of ICSs is on ASM (147–153). This is potentially
most evident during exacerbation when they can positively
influence ASM responses to bronchodilators when the ASM is
exposed to viral RNA in the absence of any other cell type.
The onset of discernible effects in asthmatics occurring within
minutes would again suggest that there may direct effects on ASM
cells, since the transcriptional changes influencing the “allergic
inflammation” would be expected to take much longer (though
clinically significant changes take longer).
What Is the Role of ASM, If Any, in Healthy
Airways?
Some have argued that ASM is simply a vestigial tissue with no
significant function in highly evolved mammals (154,155). This
argument was one of a number used to promote the concept
of thermoplasty and muscle destruction as a potentially safe
approach to the treatment of asthma (156–158).
Smooth muscle is distributed extensively in the primitive
lungs of lung-fish and amphibians as well as the swim bladders
of fish. In the earliest air-breathing fish and amphibians, the
primitive lung’s airways smooth muscle contributed significantly
to emptying the lung sacs. Air is actively forced into the primitive
lungs by muscles in the upper airways while emptying is also an
active process driven by largely the smooth muscle of the lower
airway (159–164). Of note, much of the control mechanisms via
the vagus nerve appears to have been established at the very
earliest stages in the evolution of the lung and air breathing, while
surfactants also date back to the earliest lungs and swim bladders
(165–171). The evolution of the diaphragm, present only in
mammals, and a separate relatively rigid thoracic cavity, together
with robust elastic recoil provided for a much more efficient
means of filling and emptying the lungs (dinosaurs, birds, and
reptiles developed completely different mechanisms for filling
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and emptying their lungs). Consequently, the need for active
contraction of muscle intimately associated with the lung in order
to exhale air was negated. In diving mammals, ASM appears
to act with cartilage to stabilize the airways while air is forced
out of alveoli into more central and upper airways structures
due to the increase external pressure at depth. Emptying alveoli
helps to both protect these fragile structures from barotrauma
and prevent nitrogen narcosis. Surfactants appear to help unstick
the closed alveoli, a role they probably served in the earliest
rudimentary lungs (165,166).
This led some to suggest that persistence of ASM may
represent an evolutionary curiosity with no contemporary
function but retaining the potential to cause harm analogous to
the appendix (154,155). However, antenatal ASM plays a critical
role in lung development grounded in millennia of evolution
(154–163) and post-natally it probably plays a central role in
the highly efficient process of inhalation and exhalation through
maintaining an optimal configuration of the airways.
Function of ASM in utero
Airways smooth muscle appears very early in fetal development
and exhibits spontaneous rhythmic contraction and relaxation
as well as having functional cholinergic innervation (172–191).
Of note, in utero, the peristalsis is proximal (larynx) to distal,
as is the case in the gastrointestinal (GI) tract from which the
lungs develop. The pressure generated at the tip of the lung buds
by this peristalsis acting on intraluminal fluid appears critical to
lung growth and its absence results in hypoplastic architecture.
Indeed complete inhibition of ASM prenatally is not compatible
with life due to severe lung hypoplasia. The branching structure
of the conducting airways is complete before term with post-
natal growth being largely in relation to the size of conducting
airways and number and size of alveoli and associated respiratory
structures (192). In utero, a proximal pacemaker appears to be
operating, co-ordinating peristalsis in a distal direction (181,
182). There also appears to be differential control of new and
relatively newly formed ASM and that in more established
central airways. As the fetus approaches term the phasic activity
progressively declines starting in the more central airways and
essentially disappearing even in the most distal airway by term.
In primitive amphibians, SM played a role in both developing
the primitive lung and emptying the lung. In mammals, the
evolution of the thoracic cage with a powerful diaphragm to
drive inhalation and use of elastic recoil of the chest to exhale
fundamentally changed the means of inflating and deflating
the lungs. Consequently, in contrast to the gut smooth muscle,
ASM normally ceases to constrict in a coordinated manner
shortly before term. This suggest that a fundamental change
in control has occurred in which homeokinetic control is
established in order to maintain a stable airway that minimizes
the work of breathing air through minimizing resistance to
airflow, while minimizing the anatomical dead-space of the
conducting airways. An example of the post-natal resistance to
significant narrowing (presumably through negative feedback
mechanisms) is the very small change in airways resistance
noted in most normal individuals even when inhaling very high
doses of agonists such as methacholine. One would predict
that establishing stability of mammalian airways in post-natal
life would be the norm, as there would not appear to be any
evolutionary advantage in having the airways contract sufficiently
to impair potentially life-saving activities such as running away
from a predator!
Post-natal Function
Birth brings about major changes with the fetus transitioning
from a submerged life to an air breathing terrestrial existence.
The surges in catecholamines associated with birth are one
of factors driving the physiological and functional changes.
Fluid is rapidly removed from the airways, oxygen is obtained
from the lungs and there are major changes in vascular
resistance and circulation. The epithelium of the conducting
airways undergoes significant changes from the relatively
primitive squamous epithelium to a complex post-natal
epithelium and it is very likely that their functional activity
changes—changes probably paralleled when taking submerged
bronchial epithelial cell cultures and exposing them to an
air-liquid interface.
Post-natally, airways caliber is tightly controlled. There is
evidence of relatively slow phasic contractions (164,193–204),
presumably due to ASM length oscillating around an optimal
mean. These oscillations appear to be relatively small with
little or no impact on total airflow resistance. In order to
maintain an optimal airways caliber the ASM is presumably
under some form of classic negative feedback control. There
is little or no evidence that the acute lower respiratory
illnesses so common in the first year of life evoke significant
bronchoconstriction further strengthening the suggestion that
asthma is an acquired dysfunction of ASM. This is despite clear
evidence that infants have functional ASM which respond to
agents such as histamine and effective β-agonist responses which
can block constriction in response to these agents (205,206).
Indeed infants, soon after birth, may have relatively greater ASM
in their airways than older subjects based on comparative animal
studies (192).
It is unclear whether there is co-ordinated contraction
and relaxation of ASM around or whether units operate
independently. One possibility is that stability is achieved
by ASM cells contracting randomly and independently with
the lack of coordinated constriction producing stability of the
airways (193). Of note, selective vagotomy abolishes both the
baseline tone and the oscillation, indicating that centrally derived
cholinergic innervation plays an important role in one arm of the
homeostatic control of airways caliber.
While the lungs have evolved over millennia to operate as
efficiently as possible it is argued that this optimal design places
the airways at risk of significant functional limitation if the
normal geometry is perturbed (207). The conducting airways take
up as little space as possible and the configuration represents
the least space consistent with minimizing resistance. However,
relatively small decreases in caliber can have significant impact
due to the resistance being related to the fourth power of the
radius. This vulnerability will vary from individual to individual
based on their airway morphology. This potentially contributes to
differences in the impact of similar degrees of airways shortening
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on lung function in different individuals. One mechanism that
may be important in limiting the potential harm that can arise
from excessive constriction lies in the partial helical orientation
of ASM which results in shortening as well as narrowing of the
bronchi which appears to limit transverse narrowing (208).
“Deep breaths” can “reset” the system and reduce the
propensity to bronchoconstriction (30,209,210) though the
effect is less in asthmatics and indeed in more severe asthmatics
frequently induces bronchoconstriction (211,212). This may be
mediated centrally with anticholinergic therapy being reported
to abolish the increase in BHR observed in asthmatics following
breath holding.
The transition from the submerged environment in utero
to air breathing independent existence parallels, in many
aspects, the evolutionary transition from a wholly aquatic
existence to land dwelling creatures. Understanding how this
profound developmental change is established, perhaps through
comparing pre-natal and post-natal function; epigenetics or
gene expression, may finally give us the answer to what is
the fundamental defect underlying the development of asthma
in post-natal life.
FACTORS INFLUENCING ASM STABILITY
Amongst those with asthma the loss of homeostatic control
can be largely restored by treatment with corticosteroids while
for many children and adolescents with asthma the excess
ASM constriction can resolve spontaneously and are often
said to have “grown out” of their asthma (213,214). This
would suggest that cure might be possible if we genuinely
understood the homeostatic mechanisms in healthy airways.
In some of these individuals, asthmatic symptoms will reoccur
at a later date. As has been recognized for centuries there is
a hereditary predisposition to the disease, but environmental
factors are clearly essential for initiating and perpetuating the
condition. While there is intense interest in perinatal/early
life effects asthma can develop at any age, with a very
large proportion (probably the majority) of adult asthmatics
apparently developing the condition after childhood (19,215,
216). The onset of occupational asthma in previously well-
adult individuals3further emphasizes the potential for loss of
homeostasis at any age.
It is of note that the key benefit derived from regular, effective
ICS therapy is to re-establish normal ASM homeostasis—
the significant variations in airways caliber over short
periods resolving over a number of weeks with ASM
“hyperresponsiveness” also being restored to or near “normal”
values (6,18,40–43,217–227). As part of this some appear to
re-establish a “plateau” in the dose response curve when inhaling
an agent such as methacholine (222) though the greatest effect
is on sensitivity. This results in less day to day “bother” (diurnal
night-time symptoms, exercise induced symptoms etc.) and
at least partial protection from exacerbations (72,220,221).
To achieve this it would appear that patients with significant
symptoms need to take at least 80% of doses (that is at least 11
of 14 doses a week for a twice daily regime) (223) something
that is achieved by <80% of the population in most studies.
Below this figure the treatment effects are often completely
lost. It is an indictment of our lack of progress that we still do
not know whether 100% adherence would eliminate symptoms
and prevent all significant exacerbation in the vast majority of
asthmatics subjects.
Studies indicate that lung function variability improves more
quickly than BHR [(40–42); Figure 2]. The greatest impact on
lung function is on the daily trough (Figure 3). The large falls
from one’s best being eliminated in those with good control. In
many the maximum flows also increase after introduction of ICS,
this effect being seen in most in those with the more troublesome
asthma. Much, but not all, of the benefit from commencing ICS,
in terms of reduced BHR, is achieved within the first 4–8 weeks.
This is somewhat slower than would be expected should the
effects be attributable in large part to their “anti-inflammatory”
effects again suggesting a disconnect between “inflammation”
and BHR. Evidence suggests that BHR may continue to improve
over a year and if ICS are stopped at this point lung function
and BHR may return to previous values though this may be a
little slower than after a shorter course (218,224). In contrast to
the relatively slow onset of action, the effect of ICS in restoring
homeostasis and preventing the day to day variation in caliber
attributable to ASM activity is, intriguingly lost within days of
discontinuing them after short term treatment.
Critically, these agents appear to work just as well in non-
atopic “asthmatics” as in atopic subjects which again strongly
suggests that they have a direct impact on ASM function
independent of any “anti-inflammatory effect”.
Is Loss of Homeostasis and Hence
Development of Asthma Reflected in
Bronchial Sensitivity and the Magnitude of
Airflow Obstruction, and Hence “Severity”,
a Function of the “Reactivity”?
Bronchial Sensitivity [BSen]
The observations that asthma can develop at any age and
that many children “outgrow” their asthma, again suggests that
“sensitivity” is not an absolute value and that it can be influenced
by environmental factors, possibly via interactions with the
host immune system and/ or epigenetic changes. Bronchial
sensitivity appears to have two components; inherent baseline
sensitivity and a more labile variable component. As with all
physical and physiological traits there is likely to be a normal
innate distribution of inherent sensitivity to constrictor stimuli.
However, there is ample evidence that an individual’s bronchial
“sensitivity” can vary over short periods of time, exemplified
by the changes in sensitivity following the commencement and
cessation of steroid therapy or the development of an inter-
current respiratory viral illness. As noted above, this can affect
“bronchial sensitivity” even in healthy individuals, though the
effects are generally not marked. In those with an “allergy,” it
can also be observed following a laboratory allergen challenge
or during seasonal exposure to an allergen such as grass pollen.
Conversely allergen avoidance such as moving to high altitude
for house dust mite sensitive individuals appears to be associated
with a reduction in sensitivity (228).
The speed of onset and offset observed in carefully controlled
studies of ICS use suggests they do not simply act through
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their “anti-inflammatory” actions but may have direct effects
of ASM and their “sensitivity.” In a detailed double-blind
placebo controlled study (41), an improvement in PC20 of 1-
doubling dose was noted within 6-h of the first dose of inhaled
corticosteroid [ICS]. This was accompanied by a 0.2 L increase
in FEV1. In a similar study a significant improvement in PC20
was observed at 12-h when compared with placebo (219). By
42-days the PC20 had increased by mean of 3.4-fold (with
a 0.53 L increase in FEV1). Within a week of discontinuing
therapy, the PC20 had returned to placebo values (40). Much
of the improvement in FEV1 occurred in the first week while
BHR was still improving significantly at 42-days—long after the
“anti-inflammatory” effects of ICSs should have had their effect.
Indeed, in long term studies the improvement in BHR is most
marked during the first 4–8 weeks but it continues to improve,
albeit much more slowly, over many months. Short term studies
suggest the improvement in “BHR” are lost over a matter of days
following cessation of the ICS (41,219). For those who have been
prescribed ICS for a number of years the rate of reversion to the
mean appears to be slower but still occurs.
Evidence that the underlying BSen can be altered for
prolonged periods or indeed permanently comes from work
in the field of occupational asthma with subjects who
develop symptoms and who are then removed promptly
from the precipitating allergen may lose both symptoms and
“BHR,” while those exposed for a period of time appear to
exhibit both persistent asthmatic symptoms and “BHR” despite
allergen avoidance and ICS use (228–230). The increased BHR
[sensitivity] and asthmatic symptoms can persist even if the
specific IgE and bronchial response to challenge with a particular
agent resolves. The resolution of the acquired increase in BSen
with early removal of the occupational allergen and the increasing
likelihood of permanent changes with more prolonged exposure
suggests that a component of the persistent/recurrent exposure
induces significant changes that result in a persistent alteration in
the BSen. This observation does not however determine whether
there has been a permanent change in ASM sensitivity per se
or whether the effect is mediated through other changes in
the host, such as ongoing inflammation in the absence of the
initial driver.
Bronchial Reactivity [BRea]
In comparison with BSen far less work has been undertaken
regarding the nature of reactivity and how it is influenced by
factors such as inhaled corticosteroids and allergen exposure.
Importantly we do not know whether changes in BSen are
paralleled in changes in BRea.
It appears that the “normal” human airway has the ability to
respond to non-specific stimuli such as histamine but individuals
rapidly reach a plateau beyond which further constriction
does not occur. Any reduction in lung function is generally
minimal. Very high doses of histamine, for example, can induce
systemic side effects such as flushing and marked tachycardia
in the absence of further constriction suggesting the driver
to constriction is substantial but the normally homeostatic
mechanism are very effective at resisting bronchoconstriction.
Amongst asthmatic subjects there appears to be a spectrum of
responsiveness with many exhibiting a plateau in their maximal
constriction such that while symptomatic further doses do not
lead to death (Figure 2). The concept that an individual’s BRea
in large part determines the severity (rather than frequency)
of symptoms would be consistent with the observation that
the best guide to future significant exacerbations is previous
exacerbations—those who have had severe episodes before are
likely to have them again. While this may reflect factors such
as adherence to therapy it is also likely to reflect the reactivity
of the airways, the impact of a virus being much greater in
someone whose airways are able to constrict sufficiently to
reduce FEV1 by 70% than in someone whose maximal fall is
18%. What determines “reactivity” is unclear but is likely to be
related to muscle mass and other components of the complex
pulmonary structures.
Some have suggested that the “plateau” is an illusion that
reflects a failure to deliver sufficient concentration to the
mucosal surface with nebulised therapy. In support of this,
Brown et al. demonstrated, in an animal model, complete
local occlusion of a bronchus with local topical application
suggesting that all airways can be closed even those with
significant quantities of cartilage (231,232). It should be
noted the closure was limited to the area of application. In
support of this suggestion is the observation that a significant
number of asthmatic deaths and near death episodes appear
to be acute asphyxiating episodes often following exposure
to a particular allergen. An individual who is cyanosed
and unconscious may be walking and free of significant
respiratory distress a short time after an injection of adrenalin,
suggesting the homeostatic mechanisms are overwhelmed but
the ASM is not locked down, as occurs in those with
viral exacerbations.
Although ICSs influence “bronchial responsiveness” primarily
through changing sensitivity to agonists, there is relatively
little information regarding their impact on reactivity and
maximal changes in airway geometry once the homeostatic
mechanisms are overcome. While ICS therapy does tend to
increase the maximum PEF, it has a much greater impact on the
minimum PEF, largely abolishing the significant diurnal variation
characteristic of many with asthma (Figure 3). When the ICS
are discontinued the minimum morning PEF generally returns
to approximately pre-treatment levels suggesting that there is no
fundamental change in reactivity.
Similarly, it is noteworthy in the examples shown in the
Reddell study (18) that during a period of apparent “good
control” the minimum PEF observed during acute exacerbations
were similar to that observed during the period of poor control.
For one subject this equated to a severe life threatening viral
induced exacerbation, but prior to introduction of ICS a similar
degree of airways obstruction as assessed by PEF was merely
a nuisance rapidly responding to an inhaled β-agonist. This
suggests that once the tipping point required to destabilize the
ASM is reached, it will constrict to a similar degree to that seen in
periods of poor control. Airflow limitation that is a nuisance for
the poorly controlled asthmatic, becomes severe and potentially
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Anthracopoulos and Everard Asthma—What Is IT?
life threatening due to the loss of β-agonist responsiveness
with the amplifying effect of secretions accumulating in
the airway.
IMPLICATIONS FOR MANAGING
EXACERBATIONS AND PREVENTING
DEATHS
Asthmatics deaths have been categorized into short or long
interval death, that is death within 2 h of onset of significant
symptoms and those in whom symptoms have been present
for longer, usually >5–8 h. There are clearly confounders
such as failure to perceive deterioration in poorly controlled
subjects. Despite these, post-mortem studies suggest that there
are differences, with short duration deaths being characterized
by greater mast cell degranulation and neutrophils with fewer
eosinophils and less mucus (233–236). As noted above, this
suggests that many rapid deaths are predominantly due to acute
constriction, which may or may not occur on top of signs of poor
control. In those who die after a longer duration, difficult to clear
mucus accumulates in narrowed, severely inflamed airways that
have lost their β-agonist responsiveness and in which mucociliary
clearance is grossly impaired with patients effectively drowning
in secretions.
One clear finding from the Finnish experience4,5(49,237)
is that escalating therapy, usually with increased ICS doses as
well as β-agonists, at the first sign of increased symptoms at
the onset of an exacerbation, usually prevents progression to
significant constriction and severe symptoms. The Finnish action
plans are far more robust than those promulgated in other
countries, with patients advised to take action at the first sign
of deteriorating symptoms and/or a viral infection. Not only
does this reduce presentations to ED, it said to have virtually
eliminate asthma deaths and greatly reduces the use of oral
steroids for exacerbations [2–4% of asthmatics receiving oral
steroids in a year (49,237) compared with 14% or more in the
U.K]. This suggests that being aggressive before lung function
starts to fall significantly with a viral exacerbation is effective in
stabilizing the airways, through combining bronchodilation and
increased steroid exposure. Combination ICS/LABA inhalers are
generally more effective than high dose ICS alone in preventing
significant exacerbation and this may be due to the dual action
of both inhibiting constriction and helping to maintaining
responsiveness. Two very recent, large randomized studies in
adults and adolescents with mild to moderate asthma have found
that using combination therapy with a rapid onset β-agonist with
symptoms was as good or better than maintenance therapy with
a short acting b-agonist for increased symptoms (238,239) This
may be due to the LABA helping to maintain airways caliber with
the high dose ICS helping to maintain β-agonist responsiveness
thus preventing the potentially large and difficult to treat falls
in lung function that characterize severe exacerbation. Given
the very low levels of adherence to maintenance therapy this
is probably is what is happening in real life and is likely to
have driven the popularity of combination ICS/LABA therapy in
primary care.
DOES ASM MASS (WITH OR WITHOUT
HYPERPLASIA OR HYPERTROPHY) PLAY
A ROLE IN SEVERITY?
Assessment of ASM mass in post mortem specimens, resected
lungs, and imaging suggests that asthmatics appear to have more
smooth muscle than non-asthmatics (67,240–249). However, as
with BHR there is no evidence of a clear bimodal distribution in
ASM mass, with values overlapping with the normal population
and hence ASM mass alone will not “cause” asthma. Rather
relatively greater ASM mass may, with other factors such
as airways size, influence the magnitude of narrowing if
the homeostatic state is destabilized. It may also explain in part
the differences in severity of airflow obstruction noted across the
spectrum of asthma severity.
It is likely that, as with other biological variables, the amount
of ASM is normally distributed amongst healthy individuals. One
prospective study suggested that ASM mass in early childhood is
the best predictor of asthma later in childhood (250), suggesting
that ASM mass maybe a risk factor for the manifestation of
asthma, though this was not replicated in a second study (251).
The limited available data from adults suggests that the ASM
bulk in asthmatics is related to severity and not duration of
asthma (244). If this is the case, it suggests that the more severe
asthmatics have a pre-existing relative increase in ASM though it
is also possible there may be an early increase in muscle mass but
the ability to increase in size is limited and hence not progressive.
If there is an increase in ASM mass, is this due to hyperplasia
rather than hypertrophy? Some studies have suggested that ASM
cells increase in number, but to date there has not been any
evidence of increased proliferation in situ (252). For skeletal and
cardiac muscle, the response to increased load appears to be
hypertrophy rather than hyperplasia.
Animal experiments do not suggest significant changes in
muscle mass, lung function, or ability to change the force
generated with repeated ASM constriction, even though other
“remodeling” changes such as increases in goblet cells and
“basement membrane” are observed (253,254). These findings
are similar to observations in a short-term human study
(255), though it should be noted that even after the repeated
stimuli, the values in those who had repeated constriction were
similar to those of the controls. Of note, they did not assess
the effect on ASM. A subsequent study involving repeated
bronchoconstriction in adult asthmatics was unable to identify
any impact on lung function (256).
In studies reviewing the impact of thermoplasty (257,258) it is
clear that ASM mass in larger airways is reduced post procedure,
though it appears that the improvement in control does not
correlate with the reduction of mass (258) and hence maybe in
part due to other effects including those on ASM innervation.
The greatest impact appears to be on the frequency of events
associated with significant contraction (reflecting reactivity) such
as reduced oral steroids use, ED presentation and hospitalization.
Pre and post bronchodilator lung function was largely unchanged
(257). One study, which looked at “equine asthma,” found that
allergen avoidance and inhaled steroids did lead to a small
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Anthracopoulos and Everard Asthma—What Is IT?
reduction in ASM (259). Interestingly, they found avoidance was
better at dealing with the inflammatory component, while ICS
had a greater impact on the ASM mass, again suggesting a degree
of disconnect between inflammation and ASM activity and that
ICS may well act directly on ASM.
ASM may be altered in other ways; resting tone and length
may be re-set or its function may be altered with more rapid
recycling of contractile units producing a greater effect for a
given stimulus. Evidence suggests that ASM show a significant
degree of plasticity and do not have a force-response curve
typical of skeletal muscle. Asthmatic ASM does not appear to
generate greater forces for a given stimulus than that from non-
asthmatics (260,261). Krishnan et al. suggested that asthma
represents “freezing” of smooth muscle (262), but “freezing”
only appears to occur during viral infections when airways
obstruction is relatively fixed. During poorly controlled asthma,
the variability in caliber is greatly enhanced by specific and non-
specific constrictor stimuli, quite the reverse of being “frozen.”
AUTONOMIC INNERVATION OF THE
AIRWAYS
It is well-established that in the GI tract there is parasympathetic
innervation which exerts both excitatory and inhibitory control
on the tone of the smooth muscle as well as sympathetic
innervation that has a predominantly inhibitory effect during
extra-uterine life (263). However, in the case of the human
respiratory tract, sympathetic innervation is sparse and
predominantly supplies blood vessels and submucosal glands.
In contrast to humans, spinal adrenergic sympathetic nerves
supply ASM in some mammals such as guinea pigs, cats and
dogs (165,264,265). In humans it is the cranial parasympathetic
nervous system that predominantly controls the ASM through
extensive plexuses. The vagus nerve carries both cholinergic and
non-adrenergic non-cholinergic (NANC) nerves, activation of
the former leading to constriction and the later to relaxation.
Selective vagotomy results in loss of the normal rhythmic
contraction of ASM and bronchodilation. Given the position
of parasympathetic ganglia which are predominantly located
along the trachea and large bronchi, it is possible the effect of
thermoplasty may be on neuronal control of ASM.
Nitric oxide [NO] and vasoactive intestinal peptide (VIP)
act as the principle transmitters in the mammalian NANC
parasympathetic bronchodilating system with the former
predominating in humans (though to date there is no direct
evidence that NO gas is released during these responses).
It appears that parasympathetic mediated relaxations of
ASM requires higher frequency of stimulation than those
needed to evoke parasympathetic cholinergic contractions
(165,264,265).
The lack of spinal adrenergic innervation capable of
contributing to control of ASM tone may place humans
at particular risk of loss of homeostatic control particular
given the potent potential constricting effects of cholinergic
innervation. Impaired NANC negative feedback in the absence of
adrenergic support would result in destabilization of the normal
negative feedback homeostatic controls. A further constrictor
effect such as release of histamine and other constrictors
would place the system under strain and lead to symptoms
in those whose negative feedback homeostatic controls are
relatively impaired.
The physiological role of the abundant β-adrenergic receptors
in airways smooth muscle remains unclear but may relate
to a fight or flight response. Certainly, bronchodilation is
observed in the first few minutes of moderately intense
exercise in both asthmatics (266) and, to a lesser extent,
healthy subjects with bronchoconstriction in asthmatics typically
not occurring until around 6–8 min of continuous exercise
(65). This exercise related bronchodilation maybe related
to the release of adrenaline or diminished vagal mediated
parasympathetic tone (266). Their presence, despite the absence
of a spinal adrenergic innervation, is fortuitous in that it
permits the use of β-agonist therapy for the management
of bronchoconstriction (with the caveat that tachyphalaxis in
the absence of steroids occurs rapidly, perhaps due to the
lack of neuronal innervation). If novel approach to preventing
tachphylaxis were identified this may provide an effective
alternative treatment. Interestingly the anticholinergic drug
ipratropium bromide appears to produce greater dilatation
in healthy individuals than the selective β-agonist salbutamol
but in those with asthma the β-agonist is significantly more
potent (267).
OTHER POTENTIAL FACTORS
Amongst many suggestions as to factors that contribute to
asthma is the possible contribution of changes in lung mechanics
due factors such as “inflammation” or changes in blood flow. It is
beyond the scope of this review to review these issues though it is
worth reflecting again that inflammation per se as in CF, COPD
etc. is not associated with significant changes in BHR, while
pulmonary diseases such as obliterative bronchiolitis and cardiac
defects such as a large VSD which result in high pulmonary blood
volumes and flow are not typically associated with significant
increases in BHR.
For many years, investigators have been seeking an
epithelium-derived relaxing factor akin to the role played
by nitric oxide in control of endothelial control but despite
intense activity no such factor has been identified (268,269).
Others have suggested that the epithelium acts as an effective
barrier to stimuli and that disruption of the epithelium is a key
factor in the “hyper-reactivity” of asthma, a concept apparently
supported by reports of characteristic epithelial damage in
bronchial biopsies from asthmatic subjects. Larger, more detailed
studies were unable to demonstrate significant differences in
epithelial integrity when biopsies of asthmatics were compared
with those from healthy individuals, though there was goblet cell
hyperplasia (270–272).
WHAT IS THE MECHANISM LEADING TO
LOSS OF HOMEOSTATIC CONTROL?
This article proposes that asthma represents a loss of
homeokinetic/homeostatic control in which a much greater
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Anthracopoulos and Everard Asthma—What Is IT?
variation in ASM length occurs than is consistent with normal
function. In those with more severe asthma as can be seen
in Figure 3 the baseline is also reduced (as reflected in a
fall in maximal lung FEV1). This suggests a failure of the
airways as whole to return to homeostatic point even for
short periods. The manifestations of the underlying defect
are variable, with sensitivity (which clearly is influenced
by corticosteroids) influencing the likelihood of significant
constriction, while reactivity determines the severity of airflow
obstruction when constriction has been initiated, which may be
attributable to greater shortening of the ASM units activated,
or increased recruitment of ASM units producing more
diffuse narrowing. The latter is probably largely determined
at birth.
As noted above, it has long been debated whether there
are fundamental changes in the function of ASM in asthmatic
subjects in terms of contractility, such as an ability to generate
more force, or greater shortening. Despite considerable efforts,
there has been no convincing evidence for this. The reversible
behavior of the ASM in response to corticosteroids over relatively
short periods and over long periods when individuals “grow out”
of their asthma suggests there is no intrinsic difference in ASM
function per se.
Given that ASM changes its behavior toward the end of
pregnancy from regular peristaltic waves sufficient to occlude
the lumen moving distally (i.e., similar to gut from which it is
derived), to one in which there is no significant constriction, it
would appear that the ASM acquire a homeostatic mechanism
that is aimed at preventing excessive constriction which could
severely harm the organism in post-natal life. Perturbation
of this acquired state of homeostasis seems the most likely
cause of asthma. That this is a classical negative feedback
control form of maintaining homeostasis is suggested by the
observation that in healthy individuals there is a small but
regular oscillation of airways caliber around a given mean
value. One potential key observation is that ASM appear to
oscillate about their mean largely independently of the other
millions of cells within the airway and are not normally
acting in a co-ordinated function such that the billions of
potential combinations of narrowing and relaxing units result
in a very small but clinically indiscernible small variations in
overall airways caliber (205). These oscillations are likely to
be controlled by ionic fluxes (193–196,206,273). In those
with bronchoconstriction, this random oscillation appears to
be perturbed with a net increase in units shortening with the
random nature contributing to the inhomogeneity observed
during asthma “attacks” (narrowing due to poor control or
an exacerbation).
Quite how ASM tone is regulated to prevent excessive
narrowing is unknown (274,275). Possible mechanisms include
(most likely first):
a) Airways smooth muscle itself generates one or more autocrine
negative feedback signals triggered by shortening (and
lengthening) thus ensures ASM does not generate significant
airways obstruction.
b) The normal negative feedback homeostatic neural
mechanisms is controlled centrally and ASM activity is
driven by the parasympathetic cholinergic and NANC
innervation in response to airways derived efferent signals.
c) Non-ASM cells such as epithelial cells generate one or
more negative feedback signals in response to compression,
resulting from the mechanical stress generated during
airways narrowing.
d) Smooth muscle has an innate structural mechanism that
limits significant shortening which becomes dysfunctional in
asthmatic subjects.
e) Post-natally ASM phasic contractions are random, non-co-
ordinated. Given the vast number of ASM this ensures
that there is no effective impact on lumen diameter.
Bronchoconstriction occurs once a degree of co-ordination
is re-established.
f) The pacemaker driving peristaltic constriction in utero
“switches off” toward the end of pregnancy but is “switched”
back on to cause asthma and the pacemaker destabilizes the
homeostatic control.
g) ASM lose the ability to respond to an airways pacemaker but
this response is restored in asthmatic subjects.
h) ASM is a passive player and non-ASM structures within
and/or surrounding the airways limit shortening and are
altered by disease.
CONCLUSION
Given that asthma appears to be a manifestation of a failure of
post-natal homeostatic control of ASM there should be a shift
in focus in asthma research toward understanding how stability
is maintained in healthy airways and how, when this control
is disrupted, it may be re-established. The focus may identify a
single key missing feedback signal such as the loss of insulin in
type 1 diabetes or, more likely, may be a result from a number of
factors as observed in type 2 diabetes.
The observation that corticosteroids can largely or completely
restore homeostasis and the recognition that natural resolution
is relatively common, at least amongst those with relatively mild
childhood asthma, would suggest that the aim should be to
understand how normal homeostasis is maintained. As a result,
we should finally be able to define the basic unifying underlying
defect and ultimately be able to offer a cure.
AUTHOR CONTRIBUTIONS
ME and MA conceived and wrote the article collaboratively.
REFERENCES
1. Williams CT. The pathology and treatment of spasmodic asthma. Br Med J.
(1874) 1:769–7. doi: 10.1136/bmj.1.702.769
2. Morris MJ. Asthma–expiratory dyspnoea? Br Med J. (1981) 283:838–
9. doi: 10.1136/bmj.283.6295.838
3. Looijmans-van den Akker I, van Luijn K, Verheij T. Overdiagnosis
of asthma in children in primary care: a retrospective analysis.
Frontiers in Pediatrics | www.frontiersin.org 16 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
Br J Gen Pract. (2016) 66:e152–7. doi: 10.3399/bjgp16X6
83965
4. Yang CL, Simons E, Foty RG, Subbarao P, To T, Dell SD.
Misdiagnosis of asthma in schoolchildren. Pediatr Pulmonol. (2017)
52:293–302. doi: 10.1002/ppul.23541
5. MacNeil J, Loves RH, Aaron SD. Addressing the misdiagnosis of asthma in
adults: where does it go wrong? Expert Rev Respir Med. (2016) 10:1187–
98. doi: 10.1080/17476348.2016.1242415
6. Morrow-Brown H, Storey G, George WHS. Beclomethasone diproprionate:
a new steroid aerosol for the treatment of allergic asthma. Brit Med J. (1972)
2:585–9. doi: 10.1136/bmj.1.5800.585
7. Brown HM, Storey G. Beclomethasone dipropionate steriod aerosol in
treatment of perennial allergic asthma in children. Br Med J. (1973) 3:161–
4. doi: 10.1136/bmj.3.5872.161
8. Mukherjee M, Stoddart A, Gupta RP, Nwaru BI, Farr A, Heaven M, et al.
The epidemiology, healthcare and societal burden and costs of asthma
in the UK and its member nations: analyses of standalone and linked
national databases. BMC Med. (2016) 14:113. doi: 10.1186/s12916-016-
0657-8
9. Weatherhead GH. A Practical Treatise on the Principal Disease of the Lungs,
Considered Especially in Relation to the Particular Tissues Affect, Illustrating
the Different Kinds of Cough. London: John Churchill (1837).
10. Hargreave FE, Nair P. The definition and diagnosis of asthma.
Clin Exp Allergy. (2009) 39:1652–8. doi: 10.1111/j.1365-2222.2009.
03321.x
11. Laënnec RTH. De l’ausculatation médiate, un Traité du diagnostic des
maladies des poumons et du coeur, fonde, principalement sur ce naveau
moyen d’exploration. (A Treatise on the Diseases of the Chest and on Mediate
Auscultation) Paris: Brosson et Chande (1819).
12. Lötvall J. Contractility of lungs and air-tubes: experiments
performed in 1840 by Charles J.B. Williams. Eur Respir J. (1994)
7:592–5. doi: 10.1183/09031936.94.07030592
13. Holgate ST. Asthma: a simple concept but in reality a complex disease.
Eur J Clin Invest. (2011) 41:1339–52. doi: 10.1111/j.1365-2362.2011.
02534.x
14. Igea JM. The history of the idea of allergy. Allergy. (2013) 68:966–
73. doi: 10.1111/all.12174
15. Stolkind E. The history of bronchial asthma and allergy. Proc R Soc Med.
(1933) 26:1120–6. doi: 10.1177/003591573302600903
16. Blumstein GI. The etiologic diagnosis of asthma in childhood. AMA
J Dis Child. (1957) 93:237–41. doi: 10.1001/archpedi.1957.0206004023
9006
17. American Thoracic Society. Definitions and classifications of chronic
bronchitis, asthma and pulmonary emphysema and related conditions. Am
Rev Respir Dis. (1962) 85:762–8.
18. Reddel H, Ware S, Marks G, Salome C, Jenkins C, Woolcock A. Differences
between asthma exacerbations and poor asthma control. Lancet. (1999)
353:64–9. doi: 10.1016/S0140-6736(98)06128-5
19. British Thoracic Society and others. Guidelines on the management of
asthma. Thorax. (1993) 48(2Suppl):S1–24. doi: 10.1136/thx.48.2_Suppl.S1
20. Global Initiative for Asthma. Global strategy for asthma management and
prevention. Available online at: http://www.ginasthma.org
21. Aaron SD, Vandemheen KL, FitzGerald JM, Ainslie M, Gupta S, Lemière
C, et al. Canadian respiratory research network. reevaluation of diagnosis
in adults with physician-diagnosed asthma. JAMA. (2017) 317:269–
79. doi: 10.1001/jama.2016.19627
22. Gillis RME, van Litsenburg W, van Balkom RH, Muris JW, Smeenk
FW. The contribution of an asthma diagnostic consultation service
in obtaining an accurate asthma diagnosis for primary care patients:
results of a real-life study. NPJ Prim Care Respir Med. (2017)
27:35. doi: 10.1038/s41533-017-0027-9
23. McGrath KW, Fahy JV. Negative methacholine challenge tests in subjects
who report physician-diagnosed asthma. Clin Exp Allergy. (2011) 41:46–
51. doi: 10.1111/j.1365-2222.2010.03627.x
24. Everard ML. ‘Recurrent lower respiratory tract infections’ - going around
in circles, respiratory medicine style. Paediatr Respir Rev. (2012) 13:139–
43. doi: 10.1016/j.prrv.2012.03.003
25. Carman PG, Landau LI. Increased paediatric admissions with asthma in
Western Australia–a problem of diagnosis? Med J Aust. (1990) 152:23–
6. doi: 10.5694/j.1326-5377.1990.tb124423.x
26. Speight AN, Lee DA, Hey EN. Under diagnosis and under
treatment of asthma in childhood. Br Med J. (1983) 286:1253–
6. doi: 10.1136/bmj.286.6373.1253
27. Stein RT, Martinez FD. Asthma phenotypes in childhood: lessons
from an epidemiological approach. Paediatr Respir Rev. (2004) 5:155–
61. doi: 10.1016/j.prrv.2004.01.007
28. Henderson J, Granell R, Heron J, Sherriff A, Simpson A, Woodcock, A et al.
Associations of wheezing phenotypes in the first 6 years of life with atopy,
lung function and airway responsiveness in mid-childhood. Thorax. (2008)
63:974–80. doi: 10.1136/thx.2007.093187
29. Salter H. On the varieties of asthma. Edinb Med J. (1859) 4:965–
73. doi: 10.1136/bmj.s4-1.132.538-b
30. Curry JJ. The effect of antihist amine substances and other drugs on histamine
bronchoconstriction in asthmatic subjects. J Clin Invest. (1946) 25:792–
9. doi: 10.1172/JCI101765
31. An SS, Bai TR, Bates JH, Black JL, Brown RH, Brusasco V, et al. Airway
smooth muscle dynamics: a common pathway of airway obstruction in
asthma. Eur Respir J. (2007) 29:834–60. doi: 10.1183/09031936.00112606
32. Woolcock AJ, Salome CM, Yan K. The shape of the dose-response curve
to histamine in asthmatic and normal subjects. Am Rev Respir Dis.
(1984) 130:71–5.
33. Cockcroft DW, Berscheid BA, Murdock KY. Unimodal distribution of
bronchial responsiveness to inhaled histamine in a random human
population. Chest. (1983) 83:751–4. doi: 10.1378/chest.83.5.751
34. Cockcroft DW, Murdock KY, Berscheid BA, Gore BP. Sensitivity and
specificity of histamine PC20 determination in a random selection
of young college students. J Allergy Clin Immunol. (1992) 89:23–
30. doi: 10.1016/S0091-6749(05)80037-5
35. Sterk PJ, Bel EH. Bronchial hyperresponsiveness: the need for a distinction
between hypersensitivity and excessive airway narrowing. Eur Respir J.
(1989) 2:267–74.
36. Lötvall J, Inman M, O’Byrne P. Measurement of airway hyperresponsiveness:
new considerations. Thorax. (1998) 53:419–24. doi: 10.1136/thx.53.5.419
37. Fredberg JJ. Bronchospasm and its biophysical basis in airway smooth
muscle. Respir Res. (2004) 5:2. doi: 10.1186/1465-9921-5-2
38. James A, Lougheed D, Pearce-Pinto G, Ryan G, Musk B. Maximal airway
narrowing in a general population. Am Rev Respir Dis. (1992) 146:895–
9. doi: 10.1164/ajrccm/146.4.895
39. Xepapadaki P, Papadopoulos NG, Bossios A, Manoussakis E, Manousakas
T, Saxoni-Papageorgiou P. Duration of postviral airway hyperresponsiveness
in children with asthma: effect of atopy. J Allergy Clin Immunol. (2005)
116:299–304. doi: 10.1016/j.jaci.2005.04.007
40. Kraan J, Koëter GH, van der Mark TW, Boorsma M, Kukler J, Sluiter HJ, et al.
Dosage and time effects of inhaled budesonide on bronchial hyperreactivity.
Am Rev Respir Dis. (1988) 137:44–8. doi: 10.1164/ajrccm/137.1.44
41. Vathenen AS, Knox AJ, Wisniewski A, Tattersfield AE. Time course
of change in bronchial reactivity with an inhaled corticosteroid in
asthma. Am Rev Respir Dis. (1991) 143:1317–21. doi: 10.1164/ajrccm/143.6.
1317
42. Phillips K, Oborne J, Lewis S, Harrison TW, Tattersfield AE. Time
course of action of two inhaled corticosteroids, fluticasone propionate
and budesonide. Thorax. (2004) 59:26–30. doi: 10.1136/thx.2003.0
15297
43. Bel EH, Timmers MC, Hermans J, Dijkman JH, Sterk PJ. The long-
term effects of nedocromil sodium and beclomethasone dipropionate on
bronchial responsiveness to methacholine in nonatopic asthmatic subjects.
Am Rev Respir Dis. (1990) 141:21–8. doi: 10.1164/ajrccm/141.1.21
44. Empey DW, Laitinen LA, Jacobs L, Gold WM, Nadel JA. Mechanisms of
bronchial hyperreactivity in normal subjects after upper respiratory tract
infection. Am Rev Respir Dis. (1976) 113:131–9.
45. Laitinen LA, Elkin RB, Empey DW, Jacobs L, Mills J, Nadel
JA. Bronchial hyperresponsiveness in normal subjects during
attenuated influenza virus infection. Am Rev Respir Dis. (1991)
143:358–61. doi: 10.1164/ajrccm/143.2.358
Frontiers in Pediatrics | www.frontiersin.org 17 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
46. Juniper EF, Frith PA, Hargreave FE. Long-term stability of
bronchial responsiveness to histamine. Thorax. (1982) 37:288–
91. doi: 10.1136/thx.37.4.288
47. Udesen PB, Westergaard CG, Porsbjerg C, Backer V. Stability of FeNO and
airway hyperresponsiveness to mannitol in untreated asthmatics. J Asthma.
(2017) 54:530–6. doi: 10.1080/02770903.2016.1238928
48. Haahtela T, Tuomisto LE, Pietinalho A, Klaukka T, Erhola M, Kaila M, et al. A
10 year asthma programme in Finland: major change for the better. Thorax.
(2006) 61:663–70. doi: 10.1136/thx.2005.055699
49. Kauppi P, Linna M, Martikainen J, Mäkelä MJ, Haahtela T. Follow-
up of the Finnish asthma programme 2000-2010: reduction of
hospital burden needs risk group rethinking. Thorax. (2013)
68:292–3. doi: 10.1136/thoraxjnl-2011-201028
50. Kainu A, Pallasaho P, Piirilä P, Lindqvist A, Sovijär vi A, Pietinalho A.
Increase in prevalence of physician-diagnosed asthma in Helsinki during
the Finnish asthma programme: improved recognition of asthma in primary
care? a cross-sectional cohort study. Prim Care Respir J. (2013) 22:64–
71. doi: 10.4104/pcrj.2013.00002
51. Backer V, Stensen L, Sverrild A, Wedge E, Porsbjerg C. Objective
confirmation of asthma diagnosis improves medication adherence. J Asthma.
(2017) 55:1262–8. doi: 10.1080/02770903.2017.1410830
52. Duros K, Everard ML. Time to say goodbye to bronchiolitis, viral wheeze,
reactive airways disease, wheeze bronchitis and all that. Front Pediatr
Pulmonol. (2020) In Press.
53. Reynolds EO, Cook CD. The treatment of bronchiolitis. J Pediatr. (1963)
63:1205–7. doi: 10.1016/S0022-3476(63)80215-2
54. Craven V, Everard ML. Protracted bacterial bronchitis:
reinventing an old disease. Arch Dis Child. (2013) 98:72–
6. doi: 10.1136/archdischild-2012-302760
55. Ishak A, Everard ML. Persistent and recurrent bacterial bronchitis - a
paradigm shift in our understanding of chronic respiratory disease. Front
Pediatr. (2017) 5:19. doi: 10.3389/fped.2017.00019
56. Barker NJ, Everard ML. Getting to grips with ‘dysfunctional breathing’.
Pediatr Respir Rev. (2015) 16:53–61. doi: 10.1016/j.prrv.2014.10.001
57. Barker N, Elphick H, Everard ML. The impact of a dedicated
physiotherapist clinic on quality of life and symptoms of
children with dysfunctional breathing. ERJ Open Res. (2016)
2:00103–2015. doi: 10.1183/23120541.00103-2015
58. Depiazzi J, Everard ML. Dysfunctional breathing and reaching one’s
physiological limit as significant causes of exercised induced dyspnoea
- the importance of accurate assessment. Breathe. (2016) 12:120–
9. doi: 10.1183/20734735.007216
59. Abu-Hasan M, Tannous B, Weinberger M. Exercise-induced dyspnea in
children and adolescents: if not asthma then what? Ann Allergy Asthma
Immunol. (2005) 94:366–71. doi: 10.1016/S1081-1206(10)60989-1
60. Weinberger M, Abu-Hasan M. Perceptions and pathophysiology of
dyspnea and exercise intolerance. Pediatr Clin North Am. (2009) 56:33–
48. doi: 10.1016/j.pcl.2008.10.015
61. Everard, ML. Clinical consequences of inhaler non-adherence in asthma and
COPD. In: Dalby RN, Byron, PR, Peart J, Farr SJ, Suman JD Young PM.
editors. Respiratory Drug Delivery. Vol. 1. River Grove, IL: DHI Publishing
(2012). p. 251–60.
62. Everard ML. Aerosol delivery to children. Pediatr Ann. (2006) 35:630–
6. doi: 10.3928/0090-4481-20060901-06
63. Everard ML. Regimen and device compliance – key factors in therapeutic
outcomes. J Aerosol Med. (2006) 19:67–73. doi: 10.1089/jam.2006.19.67
64. Everard ML. The art and science of paediatric ‘asthma’. Clin Exp Allergy.
(2007) 37:1581–5. doi: 10.1111/j.1365-2222.2007.02840.x
65. Silverman M, Anderson SD. Standardization of exercise tests in
asthmatic children. Arch Dis Child. (1972) 47:882–9. doi: 10.1136/adc.47.
256.882
66. James AL, Elliot JG, Abramson MJ, Walters EH. Time to death, airway
wall inflammation and remodelling in fatal asthma. Eur Respir J. (2005)
26:429–34. doi: 10.1183/09031936.05.00146404
67. Elliot JG, Abramson MJ, Drummer OH, Walters EH, James AL. Time
to death and mast cell degranulation in fatal asthma. Respirology. (2009)
14:808–13. doi: 10.1111/j.1440-1843.2009.01551.x
68. Everard ML, Swarbrick A, Wrightham M, McIntyre J, Dunkley C, James
PD, et al. Analysis of cells obtained by bronchial lavage of infants
with respiratory syncytial virus infection. Arch Dis Child. (1994) 71:428–
32. doi: 10.1136/adc.71.5.428
69. Trian T, Moir LM, Ge Q, Burgess JK, Kuo C, King NJ, et al.
Rhinovirus-induced exacerbations of asthma: how is the b2-
adrenoceptor implicated? Am J Respir Cell Mol Biol. (2010)
43:227–33. doi: 10.1165/rcmb.2009-0126OC
70. Van Ly D, Faiz A, Jenkins C, Crossett B, Black JL, McParland B, et al.
Characterising the mechanism of airway smooth muscle β2 adrenoceptor
desensitization by rhinovirus infected bronchial epithelial cells. PLoS ONE.
(2013) 8:e56058. doi: 10.1371/journal.pone.0056058
71. Oliver BG, Robinson P, Peters M, Black J. Viral infections and
asthma: an inflammatory interface? Eur Respir J. (2014) 44:1666–
81. doi: 10.1183/09031936.00047714
72. Julious SA, Campbell MJ, Bianchi SM, Murray-Thomas T. Seasonality of
medical contacts in school-aged children with asthma: association with
school holidays. Public Health. (2011) 125:769–76. doi: 10.1016/j.puhe.2011.
08.005
73. Price D, Haughney J, Sims E, Ali M, von Ziegenweidt J, Hillyer EV,
et al. Effectiveness of inhaler types for real-world asthma management:
retrospective observational study using the GPRD. J Asthma Allergy. (2011)
4:37–47. doi: 10.2147/JAA.S17709
74. Covar RA, Szefler SJ, Zeiger RS, Sorkness CA, Moss M, Mauger DT et al.
Factors associated with asthma exacerbations during a long-term clinical
trial of controller medications in children. J Allergy Clin Immunol. (2008)
122:741–7. doi: 10.1016/j.jaci.2008.08.021
75. Harnan SE, Essat M, Gomersall T, Tappenden P, Pavord I, Everard
M, et al. Exhaled nitric oxide in the diagnosis of asthma in adults: a
systematic review. Clin Exp Allergy. (2017) 47:410–29. doi: 10.1111/cea.
12867
76. Scott M, Raza A, Karmaus W, Mitchell F, Grundy J, Kurukulaaratchy RJ,
et al. Influence of atopy and asthma on exhaled nitric oxide in an unselected
birth cohort study. Thorax. (2010) 65:258–62. doi: 10.1136/thx.200
9.125443
77. Mikalsen IB, Halvorsen T, Øymar K. Exhaled nitric oxide is related
to atopy, but not asthma in adolescents with bronchiolitis in
infancy. BMC Pulm Med. (2013) 13:66. doi: 10.1186/1471-2466-
13-66
78. Fleming L, Tsartsali L, Wilson N, Regamey N, Bush A. Longitudinal
relationship between sputum eosinophils and exhaled nitric oxide in
children with asthma. Am J Respir Crit Care Med. (2013) 188:400–
2. doi: 10.1164/rccm.201212-2156LE
79. Essat M, Harnan S, Gomersall T, Tappenden P, Wong R, Pavord
I, et al. Fractional exhaled nitric oxide for the management
of asthma in adults: a systematic review. Eur Respir J. (2016)
47:751–68. doi: 10.1183/13993003.01882-2015
80. Gomersall T, Harnan S, Essat M, Tappenden P, Wong R, Lawson R,
et al. A systematic review of fractional exhaled nitric oxide in the
routine management of childhood asthma. Ped Pulmonol. (2016) 51:316–
28. doi: 10.1002/ppul.23371
81. Petsky HL, Cates CJ, Kew KM, Chang AB. Tailoring asthma treatment
on eosinophilic markers (exhaled nitric oxide or sputum eosinophils):
a systematic review and meta-analysis. Thorax. (2018) 73:1110–9.
doi: 10.1136/thoraxjnl-2018-211540
82. Fleming L, Wilson N, Regamey N, Bush A. Use of sputum eosinophil
counts to guide management in children with severe asthma. Thorax. (2012)
67:193–8. doi: 10.1136/thx.2010.156836
83. Murray C, Foden P, Lowe L, Durrington H, Custovic A, Simpson
A. Diagnosis of asthma in symptomatic children based on
measures of lung function: an analysis of data from a population-
based birth cohort study. Lancet Child Adolesc Health. (2017)
1:114–123. doi: 10.1016/S2352-4642(17)30008-1
84. Lo DK, Beardsmore CS, Roland D, Richardson M, Yang Y, Danvers
L, et al. Lung function and asthma control in school-age children
managed in UK primary care: a cohort study. Thorax. (2019) 75:101–
107. doi: 10.1136/thoraxjnl-2019-213068
Frontiers in Pediatrics | www.frontiersin.org 18 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
85. Pearce N, Pekkanen J, Beasley R. How much asthma is really
attributable to atopy? Thorax. (1999) 54:268–72. doi: 10.1136/thx.54.
3.268
86. Asher MI. Recent perspectives on global epidemiology of
asthma in childhood. Allergol Immunopathol (Madr). (2010)
38:83–7. doi: 10.1016/j.aller.2009.11.002
87. Weinmayr G, Weiland SK, Björkstén B, Brunekreef B, Büchele G, Cookson
WO, et al. ISAAC phase two study group. atopic sensitization and the
international variation of asthma symptom prevalence in children. Am J
Respir Crit Care Med. (2007) 176:565–74. doi: 10.1164/rccm.200607-994OC
88. Ronchetti R, Jesenak M, Ronchetti F, Rennerova Z. Is asthma
caused by atopy (positive skin prick tests)? Epidemiologic evidence
suggests a negative answer. Inflamm Allergy Drug Targets. (2010)
9:91–6. doi: 10.2174/187152810791292791
89. Moustaki M, Loukou I, Tsabouri S, Douros K. The role of sensitization
to allergen in asthma prediction and prevention. Front Pediatr. (2017)
5:166. doi: 10.3389/fped.2017.00166
90. de Marco R, Cappa V, Accordini S, Rava M, Antonicelli L, Bortolami O, et al.
Trends in the prevalence of asthma and allergic rhinitis in Italy between 1991
and 2010. Eur Respir J. (2012) 39:883–92. doi: 10.1183/09031936.00061611
91. Penny ME, Murad S, Madrid SS, Herrera TS, Piñeiro A, Caceres DE,
et al. Respiratory symptoms, asthma, exercise test spirometry, and atopy
in schoolchildren from a Lima shanty town. Thorax. (2001) 56:607–
12. doi: 10.1136/thorax.56.8.607
92. Mallol J. Asthma in Latin America: where the asthma
causative/protective hypotheses fail. Allergol Immunopathol. (2008)
36:150–3. doi: 10.1157/13124721
93. McNeill G, Tagiyeva N, Aucott L, Russell G, Helms PJ. Changes
in the prevalence of asthma, eczema and hay fever in pre-pubertal
children: a 40-year perspective. Paediatr Perinat Epidemiol. (2009) 23:506–
12. doi: 10.1111/j.1365-3016.2009.01057.x
94. Moncayo AL, Vaca M, Oviedo G, Erazo S, Quinzo I, Fiaccone RL,
et al. Risk factors for atopic and non-atopic asthma in a rural
area of Ecuador. Thorax. (2010) 65:409–16. doi: 10.1136/thx.2009.
126490
95. Leynaert B, Sunyer J, Garcia-Esteban R, Svanes C, Jarvis D,
Cerveri I, et al. Gender differences in prevalence, diagnosis and
incidence of allergic and non-allergic asthma: a population-based
cohort. Thorax. (2012) 67:625–31. doi: 10.1136/thoraxjnl-2011-
201249
96. Pesce G, Locatelli F, Cerveri I, Bugiani M, Pirina P, Johannessen
A, et al. Seventy years of asthma in italy: age, period and cohort
effects on incidence and remission of self-reported asthma from 1940
to 2010. PLoS ONE. (2015) 10:e0138570. doi: 10.1371/journal.pone.013
8570
97. Johansson SG, Bieber T, Dahl R, Friedmann PS, Lanier BQ, Lockey RF, et al.
Revised nomenclature for allergy for global use: report of the nomenclature
review committee of the world allergy organization, october 2003. J Allergy
Clin Immunol. (2004) 113:832–6. doi: 10.1016/j.jaci.2003.12.591
98. Elphick H, Everard ML. Noisy breathing in children. In: David T,
editors. Recent Advances in Paediatrics. London: The Royal Society of
Medicine (2002).
99. Gibson PG, Dolovich J, Denburg J, Ramsdale EH, Hargreave FE. Chronic
cough: eosinophilic bronchitis without asthma. Lancet. (1989) 1:1346–
8. doi: 10.1016/S0140-6736(89)92801-8
100. Brightling CE, Ward R, Wardlaw AJ, Pavord ID. Airway inflammation,
airway responsiveness and cough before and after inhaled budesonide
in patients with eosinophilic bronchitis. Eur Respir J. (2000) 15:682–
6. doi: 10.1034/j.1399-3003.2000.15d10.x
101. Brightling CE, Ward R, Woltmann G, Bradding P, Sheller JR, Dworski R,
et al. Induced sputum inflammatory mediator concentrations in eosinophilic
bronchitis and asthma. Am J Respir Crit Care Med. (2000) 162(3 Pt 1):878–
82. doi: 10.1164/ajrccm.162.3.9909064
102. Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis:
clinical manifestations and implications for treatment. Thorax.
57:178–82. doi: 10.1136/thorax.57.2.178
103. McGrath KW, Icitovic N, Boushey HA, Lazarus SC, Sutherland ER,
Chinchilli VM, et al. A large subgroup of mild-to-moderate asthma is
persistently non eosinophilic. Am J Respir Crit Care Med. (2012) 185:612–
9. doi: 10.1164/rccm.201109-1640OC
104. Vizmanos-Lamotte G, Moreno-Galdó A, Muñoz X, Gómez-Ollés S, Gartner
S, Cruz MJ. Induced sputum cell count and cytokine profile in atopic
and non-atopic children with asthma. Pediatr Pulmonol. (2013) 48:1062–
9. doi: 10.1002/ppul.22769
105. Boulay ME, Boulet LP. Discordance between asthma control clinical,
physiological and inflammatory parameters in mild asthma. Respir Med.
(2013) 107:511–8. doi: 10.1016/j.rmed.2012.12.015
106. Fleming L, Tsartsali L, Wilson N, Regamey N, Bush A. Sputum inflammatory
phenotypes are not stable in children with asthma. Thorax. (2012) 67:675–
81. doi: 10.1136/thoraxjnl-2011-201064
107. van den Toorn LM, Overbeek SE, de Jongste JC, Leman K, Hoogsteden
HC, Prins JB. Airway inflammation is present during clinical remission
of atopic asthma. Am J Respir Crit Care Med. (2001) 164:2107–
13. doi: 10.1164/ajrccm.164.11.2006165
108. Boulet LP, Turcott H, Plante S, Chakir J. Airway function, inflammation
and regulatory T cell function in subjects in asthma remission. Can Respir
J. (2012) 19:19–25. doi: 10.1155/2012/347989
109. Arshad SH, Raza A, Lau L, Bawakid K, Karmaus W, Zhang H,
et al. Pathophysiological characterization of asth-ma transitions across
adolescence. Respir Res. (2014) 15:153. doi: 10.1186/s12931-014-0153-7
110. Komatsu Y, Fujimoto K, Yasuo M, Urushihata K, Hanaoka M, Koizumi
T, et al. Airway hyper-responsiveness in young adults with asthma that
remitted either during or before adolescence. Respirology. (2009) 14:217–
23. doi: 10.1111/j.1440-1843.2008.01413.x
111. van den Toorn LM, Prins JB, de Jongste JC, Leman K, Mulder
PG, Hoogsteden HC, et al. Benefit from anti-inflammatory treatment
during clinical remission of atopic asthma. Respir Med. (2005) 99:779–
87. doi: 10.1016/j.rmed.2004.11.011
112. Volbeda F, ten Hacken NHT, Lodewijk ME, Dijkstra A, Hylkema
MN, Broekema M, et al. Can AMP induce sputum eosinophils,
even in subjects with complete asthma remission? Respir Res. (2010)
11:106. doi: 10.1186/1465-9921-11-106
113. Corren J. Inhibition of interleukin-5 for the treatment of eosinophilic
diseases. Discov Med. (2012) 13:305–12. doi: 10.1007/s11882-013-
0373-9
114. Farne HA, Wilson A, Powell C, Bax L, Milan SJ. Anti-IL5
therapies for asthma. Cochrane Database Syst Rev. (2017)
9:CD010834. doi: 10.1002/14651858.CD010834.pub3
115. Karta MR, Broide DH, Doherty TA. Insights into group 2 innate
lymphoid cells in human airway disease. Curr Allergy Asthma Rep. (2016)
16:8. doi: 10.1007/s11882-015-0581-6
116. Mjösberg J, Spits H. Human innate lymphoid cells. J Allergy Clin Immunol.
(2016) 138:1265–76. doi: 10.1016/j.jaci.2016.09.009
117. Halvorsen T, Skadberg BT, Eide GE, Røksund O, Aksnes
L, Øymar K. Characteristics of asthma and airway hyper-
responsiveness after premature birth. Pediatr Allergy Immunol. (2005)
16:487–94. doi: 10.1111/j.1399-3038.2005.00314.x
118. Landry JS, Tremblay GM, Li PZ, Wong C, Benedetti A, Taivassalo
T. Lung function and bronchial hyperresponsiveness in adults born
prematurely. A cohort study. Ann Am Thorac Soc. (2016) 13:17–
24. doi: 10.1513/AnnalsATS.201508-553OC
119. Nordlund B, James A, Ebersjö C, Hedlin G, Broström EB.
Differences and similarities between bronchopulmonary dysplasia
and asthma in schoolchildren. Pediatr Pulmonol. (2017)
52:1179–86. doi: 10.1002/ppul.23741
120. Clemm HH, Engeseth M, Vollsæter M, Kotecha S, Halvorsen T. Bronchial
hyper-responsiveness after preterm birth. Paediatr Respir Rev. (2018) 26:34–
40. doi: 10.1016/j.prrv.2017.06.010
121. Malleske DT, Chorna O, Maitre NL. Pulmonary sequelae and
functional limitations in children and adults with bronchopulmonary
dysplasia. Paediatr Respir Rev. (2018) 26:55–9. doi: 10.1016/j.prrv.201
7.07.002
122. Teig N, Allali M, Rieger C, Hamelmann E. Inflammatory markers in
induced sputum of school children born before 32 completed weeks
of gestation. J Pediatr. (2012) 161:1085–90. doi: 10.1016/j.jpeds.2012.
06.007
Frontiers in Pediatrics | www.frontiersin.org 19 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
123. Filippone M, Bonetto G, Corradi M, Frigo AC, Baraldi E. Evidence of
unexpected oxidative stress in airways of adolescents born very pre-term. Eur
Respir J. (2012) 40:1253–9. doi: 10.1183/09031936.00185511
124. Urs R, Kotecha S, Hall GL, Simpson SJ. Persistent and progressive long-
term lung disease in survivors of preterm birth. Paediatr Respir Rev. (2018)
28:87–94. doi: 10.1016/j.prrv.2018.04.001
125. Bjørke-Monsen AL, Vollsæter M, Ueland PM, Markestad T, Øymar
K, Halvorsen T. Increased bronchial hyperresponsiveness and higher
asymmetric dimethylarginine levels after fetal growth restriction. Am J Respir
Cell Mol Biol. (2017) 56:83–9. doi: 10.1165/rcmb.2016-0210OC
126. Hamon I, Varechova S, Vieux R, Ioan I, Bonabel C, Schweitzer
C, et al. Exercise-induced bronchoconstriction in school-age
children born extremely preterm. Pediatr Res. (2013) 73(4 Pt
1):464–8. doi: 10.1038/pr.2012.202
127. Simpson SJ, Logie KM, O’Dea CA, Banton GL, Murray C,
Wilson AC, et al. Altered lung structure and function in mid-
childhood survivors of very preterm birth. Thorax. (2017)
72:702–11. doi: 10.1136/thoraxjnl-2016-208985
128. McKay S, de Jongste JC, Saxena PR, Sharma HS. Angiotensin II
induces hypertrophy of human airway smooth muscle cells: expression of
transcription factors and transforming growth factor-beta1. Am J Respir Cell
Mol Biol. (1998) 18:823–33. doi: 10.1165/ajrcmb.18.6.2924
129. Grunstein MM, Hakonarson H, Leiter J, Chen M, Whelan R, Grunstein JS,
et al. IL-13-dependent autocrine signaling mediates altered responsiveness
of IgE-sensitized airway smooth muscle. Am J Physiol Lung Cell Mol Physiol.
(2002) 282:L520–8. doi: 10.1152/ajplung.00343.2001
130. McKay S, Sharma HS. Autocrine regulation of asthmatic airway
inflammation: role of airway smooth muscle. Respir Res. (2002)
3:11. doi: 10.1186/rr160
131. Tliba O, Deshpande D, Chen H, Van Besien C, Kannan M, Panettieri RA
Jr, et al. IL-13 enhances agonist-evoked calcium signals and contractile
responses in airway smooth muscle. Br J Pharmacol. (2003) 140:1159–
62. doi: 10.1038/sj.bjp.0705558
132. Hakonarson H, Grunstein MM. Autocrine regulation of airway
smooth muscle responsiveness. Respir Physiol Neurobiol. (2003)
137:263–76. doi: 10.1016/S1569-9048(03)00152-6
133. Alagappan VK, McKay S, Widyastuti A, Garrelds IM, Bogers AJ,
Hoogsteden HC, et al. Proinflammatory cytokines upregulate mRNA
expression and secretion of vascular endothelial growth factor in cultured
human airway smooth muscle cells. Cell Biochem Biophys. (2005) 43:119–
29. doi: 10.1385/CBB:43:1:119
134. Macklem PT. Bronchial thermoplasty. N Engl J Med. (2007) 356:2744–
5. doi: 10.1056/NEJMc071166
135. Joubert P, Lajoie-Kadoch S, Welman M, Dragon S, Létuvée S, Tolloczko
B, et al. Expression and regulation of CCR1 by airway smooth muscle
cells in asthma. J Immunol. (2008) 180:1268–75. doi: 10.4049/jimmunol.180.
2.1268
136. Bansal G, Wong CM, Liu L, Suzuki YJ. Oxidant signaling for interleukin-13
gene expression in lung smooth muscle cells. Free Radic Biol Med. (2012)
52:1552–9. doi: 10.1016/j.freeradbiomed.2012.02.023
137. Abcejo AJ, Sathish V, Smelter DF, Aravamudan B, Thompson MA,
Hartman WR, et al. Brain-derived neurotrophic factor enhances calcium
regulatory mechanisms in human airway smooth muscle. PLoS ONE. (2012)
7:e44343. doi: 10.1371/journal.pone.0044343
138. Wright DB, Trian T, Siddiqui S, Pascoe CD, Johnson JR, Dekkers BG, et al.
Phenotype modulation of airway smooth muscle in asthma. Pulm Pharmacol
Ther. (2013) 26:42–9. doi: 10.1016/j.pupt.2012.08.005
139. Calvén J, Yudina Y, Uller L. Rhinovirus and dsRNA induce RIG-I-like
receptors and expression of interferon βand λ1 in human bronchial smooth
muscle cells. PLoS ONE. (2013) 8:e62718. doi: 10.1371/journal.pone.0062718
140. Elias JA, Wu Y, Zheng T, Panettieri R. Cytokine- and virus-stimulated
airway smooth muscle cells produce IL-11 and other IL-6-type cytokines.
Am J Physiol. 273(3 Pt 1):L648–55. doi: 10.1152/ajplung.1997.273.3.
L648
141. Keglowich L, Roth M, Philippova M, Resink T, Tjin G, Oliver B, et al.
Bronchial smooth muscle cells of asthmatics promote angiogenesis through
elevated secretion of CXC-chemokines (ENA-78, GRO-α, and IL-8) PLoS
ONE. (2013) 8:e81494. doi: 10.1371/journal.pone.0081494
142. Yick CY, Zwinderman AH, Kunst PW, Grünberg K, Mauad T, Chowdhury
S, et al. Gene expression profiling of laser microdissected airway
smooth muscle tissue in asthma and atopy. Allergy. (2014) 69:1233–
40. doi: 10.1111/all.12452
143. Pearson H, Britt RD Jr, Pabelick CM, Prakash YS, Amrani Y, Pandya
HC. Fetal human airway smooth muscle cell production of leukocyte
chemoattractants is differentially regulated by fluticasone. Pediatr Res. (2015)
78:650–6. doi: 10.1038/pr.2015.168
144. Faksh A, Britt RD Jr, Vogel ER, Thompson MA, Pandya HC, Martin
RJ, et al. TLR3 activation increases chemokine expression in human fetal
airway smooth muscle cells. Am J Physiol Lung Cell Mol Physiol. (2016)
310: L202–11. doi: 10.1152/ajplung.00151.2015
145. Liu R , Song J, Li H, Wu Z, Chen H, Wu W, et al. Treatment of canine asthma
by high selective vagotomy. J Thorac Cardiovasc Surg. (2014) 148:683–
9. doi: 10.1016/j.jtcvs.2013.12.041
146. Wagner EM, Jacoby DB. Methacholine causes reflex bronchoconstriction. J
Appl Physiol. (1999) 86:294–7. doi: 10.1152/jappl.1999.86.1.294
147. Lakser OJ, Dowell ML, Hoyte FL, Chen B, Lavoie TL, Ferreira C, et al.
Steroids augment relengthening of contracted airway smooth muscle:
potential additional mechanism of benefit in asthma. Eur Respir J. (2008)
32:1224–30. doi: 10.1183/09031936.00092908
148. Banerjee A, Damera G, Bhandare R, Gu S, Lopez-Boado Y, Panettieri R
Jr, et al. Vitamin D and glucocorticoids differentially modulate chemokine
expression in human airway smooth muscle cells. Br J Pharmacol. (2008)
155:84–92. doi: 10.1038/bjp.2008.232
149. Sun HW, Miao CY, Liu L, Zhou J, Su DF, Wang YX, et al. Rapid inhibitory
effect of glucocorticoids on airway smooth muscle contractions in guinea
pigs. Steroids. (2006) 71:154–9. doi: 10.1016/j.steroids.2005.09.019
150. Goldsmith AM, Hershenson MB, Wolbert MP, Bentley JK.
Regulation of airway smooth muscle alpha-actin expression by
glucocorticoids. Am J Physiol Lung Cell Mol Physiol. (2007)
292:L99–106. doi: 10.1152/ajplung.00269.2006
151. Holden NS, Bell MJ, Rider CF, King EM, Gaunt DD, Leigh R, et al. β2-
Adrenoceptor agonist-induced RGS2 expression is a genomic mechanism of
bronchoprotection that is enhanced by glucocorticoids. Proc Natl Acad Sci
USA. (2011) 108:19713–8. doi: 10.1073/pnas.1110226108
152. Boivin R, Vargas A, Lefebvre-Lavoie J, Lauzon AM, Lavoie JP.
Inhaled corticosteroids modulate the (+)insert smooth muscle
myosin heavy chain in the equine asthmatic airways. Thorax. (2014)
69:1113–9. doi: 10.1136/thoraxjnl-2014-205572
153. Espinoza J, Montano LM, Perusquia M. Nongenomic bronchodilating
action elicited by dehydroepiandrosterone (DHEA) in a
guinea pig asthma model. J Steroid Biochem Mol Biol. (2013)
138:174–182. doi: 10.1016/j.jsbmb.2013.05.009
154. Seow CY, Fredberg JJ. Historical perspective on airway smooth
muscle: the saga of a frustrated cell. J Appl Physiol. (2001)
91:938–52. doi: 10.1152/jappl.2001.91.2.938
155. Mitzner W. Airway smooth muscle: the appendix of the lung. Am J Respir
Crit Care Med. (2004) 169:787–90. doi: 10.1164/rccm.200312-1636PP
156. Cox PG, Miller J, Mitzner W, Leff AR. Radiofrequency
ablation of airway smooth muscle for sustained treatment
of asthma: preliminary investigations. Eur Respir J. (2004)
24:659–63. doi: 10.1183/09031936.04.00054604
157. Thomson NC, Chanez P. How effective is bronchial thermoplasty
for severe asthma in clinical practice? Eur Respir J. (2017)
50:1701140. doi: 10.1183/13993003.01140-2017
158. d’Hooghe JNS, Ten Hacken NHT, Weersink EJM, Sterk PJ, Annema
JT, Bonta PI. Emerging understanding of the mechanism of action
of bronchial thermoplasty in asthma. Pharmacol Ther. (2017) 181:101–
7. doi: 10.1016/j.pharmthera.2017.07.015
159. Grigg GC. Studies on the Queensland lung fish. I anatomy,
histology and functioning of the lung. Aust J Zool. (1965)
13:243–53. doi: 10.1071/ZO9650243
160. Bell PB Jr, Stark-Vancs VI. Scanning electron microscopic study of
the microarchitecture of the lung of the giant salamander Amphiuma
tridactylum. Scan Electron Microsc. (1983) (Pt 1):449–56.
161. Johansen K, Reite OB. Influence of acetylcholine and biogenic amines
on branchial, pulmonary and systemic vascular resistance in the African
Frontiers in Pediatrics | www.frontiersin.org 20 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
lungfish, Protopterus aethiopicus. Acta Physiol Scand. (1968) 74:465–
71. doi: 10.1111/j.1365-201X.1968.tb10939.x
162. Pack AI, Galante RJ, Fishman AP. Role of lung inflation in control
of air breath duration in African lungfish (Protopterus annectens). Am
J Physiol. (1992) 262(5 Pt 2):R879–84. doi: 10.1152/ajpregu.1992.262.5.
R879
163. Torday JS, Rehan VK. Deconvoluting lung evolution using
functional/comparative genomics. Am J Resp Cell Mol Biol. (2004)
31:8–12. doi: 10.1165/rcmb.2004-0019TR
164. Brainerd EL, Owerkowicz T. Functional morphology and evolution of
aspiration breathing in tetrapods. Respir Physiol Neurobiol. (2006) 154:73–
88. doi: 10.1016/j.resp.2006.06.003
165. Cieri RL. Pulmonary smooth muscle in vertebrates: a comparative
review of structure and function. Integr Comp Biol. (2019) 59:10–
28. doi: 10.1093/icb/icz002
166. Orgeig S, Daniels CB. The evolutionary significance of pulmonary
surfactant in lungfish (Dipnoi). Am J Respir Cell Mol Biol. (1995) 13:161–
6. doi: 10.1165/ajrcmb.13.2.7626285
167. Robertson GN, McGee CA, Dumbarton TC, Croll RP, Smith FM.
Development of the swimbladder and its innervation in the zebrafish,
Danio rerio. J Morphol. (2007) 268:967–85. doi: 10.1002/jmor.
10558
168. Torday JS, Rehan VK. Cell-cell signaling drives the evolution of complex
traits: introduction-lung evo-devo. Integr Comp Biol. (2009) 49:142–
54. doi: 10.1093/icb/icp017
169. Torday JS, Powell FL, Farmer CG, Orgeig S, Nielsen HC, Hall AJ. Leptin
integrates vertebrate evolution: from oxygen to the blood-gas barrier.
Respir Physiol Neurobiol. (2010) 173(Suppl.):S37–4. doi: 10.1016/j.resp.2010.
01.007
170. Torday JS, Rehan VK. The evolutionary continuum from lung development
to homeostasis and repair. Am J Physiol Lung Cell Mol Physiol. (2007)
292:L608–11. doi: 10.1152/ajplung.00379.2006
171. Zheng W, Wang Z, Collins JE, Andrews RM, Stemple D, Gong
Z. Comparative transcriptome analyses indicate molecular homology
of zebrafish swimbladder and mammalian lung. PLoS ONE. (2011)
6:e24019. doi: 10.1371/journal.pone.0024019
172. Lewis MR. Spontaneous rhymical contrations of the muscles of the bronchial
tubes and air sacs of the chick embryo. Am J Physiol. (1924) 68:385–
88. doi: 10.1152/ajplegacy.1924.68.2.385
173. Sollman T, Gilbert AJ. Microscopic observations of bronchiolar reactions. J
Pharmacol Exptl Therap. (1937) 61:272–85.
174. McCray PB Jr. Spontaneous contractility of human fetal
airway smooth muscle. Am J Respir Cell Mol Biol. (1993)
8:573–80. doi: 10.1165/ajrcmb/8.5.573
175. Sparrow MP, Warwick SP, Mitchell HW. Foetal airway motor tone in
prenatal lung development of the pig. Eur Respir J. (1994) 7:1416–
24. doi: 10.1183/09031936.94.07081416
176. Sparrow MP, Warwick SP, Everett AW. Innervation and function of
the distal airways in the developing bronchial tree of fetal pig lung.
Am J Respir Cell Mol Biol. (1995) 13:518–25. doi: 10.1165/ajrcmb.13.5.
7576686
177. Sward-Comunelli SL, Mabry SM, Truog WE, Thibeault DW. Airway muscle
in preterm infants: changes during development. Pediatrics. (1997) 130:570–
6. doi: 10.1016/S0022-3476(97)70241-5
178. Sparrow MP, Weichselbaum M, McCray PB. Development of the
innervation and airway smooth muscle in human fetal lung. Am
J Respir Cell Mol Biol. (1999) 20:550–60. doi: 10.1165/ajrcmb.20.4.
3385
179. Nakamura KT, McCray PB Jr. Fetal airway smooth-muscle contractility and
lung development. A player in the band or just someone in the audience? Am
J Respir Cell Mol Biol. (2000) 23:3–6. doi: 10.1165/ajrcmb.23.1.f188
180. Yang Y, Beqaj S, Kemp P, Ariel I, Schuger L. Stretch-induced
alternative splicing of serum response factor promotes bronchial
myogenesis and is defective in lung hypoplasia. J Clin Invest. (2000)
106:1321–30. doi: 10.1172/JCI8893
181. Jesudason EC, Smith NP, Connell MG, Spiller DG, White MR, Fernig
DG, et al. Developing rat lung has a sided pacemaker region for
morphogenesis-related airway peristalsis. Am J Respir Cell Mol Biol. (2005)
32:118–27. doi: 10.1165/rcmb.2004-0304OC
182. Featherstone NC, Jesudason EC, Connell MG, Fernig DG, Wray S,
Losty PD, et al. Spontaneous propagating calcium waves underpin airway
peristalsis in embryonic rat lung. Am J Respir Cell Mol Biol. (2005) 33:153–
60. doi: 10.1165/rcmb.2005-0137OC
183. Jesudason EC, Smith NP, Connell MG, Spiller DG, White MR, Fernig
DG, et al. Peristalsis of airway smooth muscle is developmentally
regulated and uncoupled from hypoplastic lung growth. Am J Physiol
Lung Cell Mol Physiol. (2006) 291:L559–65. doi: 10.1152/ajplung.004
98.2005
184. Jesudason EC. Airway smooth muscle: an architect of the lung? Thorax.
(2009) 64:541–5. doi: 10.1136/thx.2008.107094
185. Warburton D, El-Hashash A, Carraro G, Tiozzo C,
Sala F, Rogers O, et al. Lung organogenesis. Curr Top
Dev Biol. (2010) 90:73–158. doi: 10.1016/S0070-2153(10)
90003-3
186. Shinkai T, Shinkai M, Pirker MA, Montedonico S, Puri P. Spatial and
temporal patterns of c-kit positive cells in embryonic lungs. Pediatr Surg Int.
(2011) 27:181–5. doi: 10.1007/s00383-010-2797-9
187. Kim HY, Varner VD, Nelson CM. Apical constriction initiates new bud
formation during monopodial branching of the embryonic chicken lung.
Development. (2013) 140:3146–55. doi: 10.1242/dev.093682
188. Kim HY, Pang MF, Varner VD, Kojima L, Miller E, Radisky DC, et al.
Localized smooth muscle differentiation is essential for epithelial bifurcation
during branching morphogenesis of the mammalian lung. Dev Cell. (2015)
34:719–26. doi: 10.1016/j.devcel.2015.08.012
189. Bower DV, Lee HK, Lansford R, Zinn K, Warburton D, Fraser
SE, et al. Airway branching has conserved needs for local
parasympathetic innervation but not neurotransmission. BMC Biol.
(2014) 12:92. doi: 10.1186/s12915-014-0092-2
190. Bokka KK, Jesudason EC, Lozoya OA, Guilak F, Warburton D, Lubkin SR.
Morphogenetic implications of peristalsis-driven fluid flow in the embryonic
lung. PLoS ONE. (2015) 10:e0132015. doi: 10.1371/journal.pone.0132015
191. Bokka KK, Jesudason EC, Warburton D, Lubkin SR. Quantifying
cellular and subcellular stretches in embryonic lung epithelia under
peristalsis: where to look for mechanosensing. Interface Focus. (2016)
6:20160031. doi: 10.1098/rsfs.2016.0031
192. Stocks J, Hislop A, Sonnappa S. Early lung development: lifelong effect
on respiratory health and disease. Lancet Respir Med. (2013) 1:728–
42. doi: 10.1016/S2213-2600(13)70118-8
193. Que CL, Kenyon CM, Olivenstein R, Macklem PT, Maksym GN.
Homeokinesis and short-term variability of human airway caliber.
J Appl Physiol. (2001) 91:1131–41. doi: 10.1152/jappl.2001.91.
3.1131
194. Davis C, Kannan MS, Jones TR, Daniel EE. Control of human airway smoot h
muscle: in vitro studies. J Appl Physiol Respir Environ Exerc Physiol. (1982)
53:1080–7. doi: 10.1152/jappl.1982.53.5.1080
195. Chideckel EW, Frost JL, Mike P, Fedan JS. The effect of ouabain on tension
in isolated respiratory tract smooth muscle of humans and other species. Br
J Pharmacol. (1987) 92:609–14. doi: 10.1111/j.1476-5381.1987.tb11363.x
196. Ito Y, Suzuki H, Aizawa H, Hakoda H, Hirose T. The spontaneous
electrical and mechanical activity of human bronchial smooth
muscle: its modulation by drugs. Br J Pharmacol. (1989)
98:1249–60. doi: 10.1111/j.1476-5381.1989.tb12671.x
197. Gobbi A, Pellegrino R, Gulotta C, Antonelli A, Pompilio P, Crimi
C, et al. Short-term variability in respiratory impedance and effect of
deep breath in asthmatic and healthy subjects with airway smooth
muscle activation and unloading. J Appl Physiol. (2013) 115:708–
15. doi: 10.1152/japplphysiol.00013.2013
198. Kuo KH, Dai J, Seow CY, Lee CH, van Breemen C. Relationship
between asynchronous Ca2+waves and force development in intact
smooth muscle bundles of the porcine trachea. Am J Physiol Lung
Cell Mol Physiol. (2003) 285:L1345-53. doi: 10.1152/ajplung.00043.
2003
199. Ressmeyer AR, Bai Y, Delmotte P, Uy KF, Thistlethwaite P, Fraire A, et al.
Human airway contraction and formoterol-induced relaxation is determined
Frontiers in Pediatrics | www.frontiersin.org 21 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
by Ca2+oscillations and Ca2+sensitivity. Am J Respir Cell Mol Biol. (2010)
43:179–91. doi: 10.1165/rcmb.2009-0222OC
200. Sommer B, Flores-Soto E, Gonzalez-Avila G. Cellular Na+handling
mechanisms involved in airway smooth muscle contraction. Int J Mol Med.
(2017) 40:3–9. doi: 10.3892/ijmm.2017.2993
201. Boie S, Chen J, Sanderson MJ, Sneyd J. The relative contributions
of store-operated and voltage-gated Ca2+channels to the control of
Ca2+oscillations in airway smooth muscle. J Physiol. (2017) 595:3129–
41. doi: 10.1113/JP272996
202. Brown RH, Zerhouni EA, Mitzner W. Variability in the size of individual
airways over the course of one year. Am J Respir Crit Care Med. (1995)
151:1159–64. doi: 10.1164/ajrccm.151.4.7697246
203. LaPrad AS, Lutchen KR, Suki B. A mechanical design principle for tissue
structure and function in the airway tree. PLoS Comput Biol. (2013)
9:e1003083. doi: 10.1371/journal.pcbi.1003083
204. Wang KCW, Chang AY, Pillow J, Suki B, Noble PB. Transition from phasic to
tonic contractility in airway smooth muscle after birth: an experimental and
computational modelling study phasic to tonic activity of the airway smooth
muscle. J Eng Sci Med Diagn Ther. (2019) 2. doi: 10.1115/1.4042312
205. Prendiville A, Green S, Silverman M. Airway responsiveness in wheezy
infants: evidence for functional beta adrenergic receptors. Thorax. (1987)
42:100–4. doi: 10.1136/thx.42.2.100
206. Tepper RS. Airway reactivity in infants: a positive
response to methacholine and metaproterenol. J Appl
Physiol. (1987) 62:1155–9. doi: 10.1152/jappl.1987.62.3.
1155
207. Mauroy B, Filoche M, Weibel ER, Sapoval B. An optimal bronchial
tree may be dangerous. Nature. (2004) 427:633–6. doi: 10.1038/nature
02287
208. Smiley-Jewell SM, Tran MU, Weir AJ, Johnson ZA, Van Winkle LS, Plopper
CG. Three-dimensional mapping of smooth muscle in the distal conducting
airways of mouse, rabbit, and monkey. J Appl Physiol. (2002) 93:1506–
14. doi: 10.1152/japplphysiol.01109.2001
209. Salter HH. On Asthma: Its Pathology and Treatment. London: J. Churchill
(1859). p. 24–60.
210. Nadel JA, Tierney DF. Effect of a previous deep inspiration
on airway resistance in man. J Appl Physiol. (1961) 16:717–
9. doi: 10.1152/jappl.1961.16.4.717
211. Ingram RH Jr. Deep breaths and airway obstruction in asthma. Trans Am
Clin Climatol Assoc. (1987) 98:80–5.
212. Pellegrino R, Sterk PJ, Sont JK, Brusasco V. Assessing the effect
of deep inhalation on airway calibre: a novel approach to lung
function in bronchial asthma and COPD. Eur Respir J. (1998) 12:1219–
27. doi: 10.1183/0903.1936.98.12051219
213. Burgess JA, Matheson MC, Gurrin LC, Byrnes GB, Adams KS,
Wharton CL, et al. Factors influencing asthma remission: a
longitudinal study from childhood to middle age. Thorax. (2011)
66:508–13. doi: 10.1136/thx.2010.146845
214. Tai A, Tran H, Roberts M, Clarke N, Gibson AM, Vidmar S, et al. Outcomes
of childhood asthma to the age of 50 years. J Allergy Clin Immunol. (2014)
133:1572–8. doi: 10.1016/j.jaci.2013.12.1033
215. Tuomisto LE, Ilmarinen P, Kankaanranta H. Prognosis
of new-onset asthma diagnosed at adult age. Respir
Med. (2015) 109:944–54. doi: 10.1016/j.rmed.2015.
05.001
216. de Nijs SB, Venekamp LN, Bel EH. Adult-onset asthma: is it really
different? Eur Respir Rev. (2013) 22:44–52. doi: 10.1183/09059180.000
07112
217. van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, Duiverman EJ,
Pocock SJ, Kerrebijn KF. Effects of 22 months of treatment with
inhaled corticosteroids and/or beta-2-agonists on lung function, airway
responsiveness, and symptoms in children with asthma. The Dutch Chronic
Non-specific Lung Disease Study Group. Am Rev Respir Dis. (1992) 146:547–
54. doi: 10.1164/ajrccm/146.3.547
218. Haahtela T, Järvinen M, Kava T, Kiviranta K, Koskinen S, Lehtonen
K, et al. Comparison of a beta 2-agonist, terbutaline, with an inhaled
corticosteroid, budesonide, in newly detected asthma. NEMJ. (1991)
325:388–92. doi: 10.1056/NEJM199108083250603
219. Sovijär vi AR, Haahtela T, Ekroos HJ, Lindqvist A, Saarinen A, Poussa
T, et al. Sustained reduction in bronchial hyperresponsiveness with
inhaled fluticasone propionate within three days in mild asthma: time
course after onset and cessation of treatment. Thorax. (2003) 58:500–
4. doi: 10.1136/thorax.58.6.500
220. Williams LK, Peterson EL, Wells K, Ahmedani BK, Kumar R, Burchard EG
et al. Quantifying the proportion of severe asthma exacerbations attributable
to inhaled corticosteroid non-adherence. J Allergy Clin Immunol. (2011)
128:1185–91. doi: 10.1016/j.jaci.2011.09.011
221. Calpin C, MacArthur C, Stephens D. Effectiveness of prophylactic inhaled
steroids in childhood asthma: a systematic review of the literature. JACI.
(1997) 100:452–457. doi: 10.1016/S0091-6749(97)70134-9
222. Booms P, Cheung D, Timmers MC, Zwinderman AH, Sterk PJ. Protective
effect of inhaled budesonide against unlimited airway narrowing to
methacholine in atopic patients with asthma. J Allergy Clin Immunol. (1997)
99:330–7. doi: 10.1016/S0091-6749(97)70050-2
223. Everard, ML. clinical consequences of inhaler non-adherence in asthma and
COPD. In: Dalby RN, Byron, PR, Peart J, Farr SJ, Suman JD, Young PM
editors. Respiratory Drug Delivery. Vol. 1. DHI Publishing; River Grove: IL
(2012) p. 251–260.
224. Haahtela T, Järvinen M, Kava T, Kiviranta K, Koskinen S,
Lehtonen K, et al. Effects of reducing or discontinuing inhaled
budesonide in patients with mild asthma. N Engl J Med. (1994)
331:700–5. doi: 10.1056/NEJM199409153311103
225. Cheung D, Sont JK, Sterk PJ. Clinical features of bronchial
hyperresponsiveness. Pulm Pharmacol Ther. (1999) 12:91–
6. doi: 10.1006/pupt.1999.0194
226. Katial RK, Covar RA. Bronchoprovocation testing in asthma. Immunol
Allergy Clin North Am. (2012) 32:413–31. doi: 10.1016/j.iac.2012.06.002
227. Nair P, Martin JG, Cockcroft DC, Dolovich M, Lemiere C, Boulet
LP, et al. Airway hyperresponsiveness in asthma: measurement
and clinical relevance. J Allergy Clin Immunol Pract. (2017)
5:649–659. doi: 10.1016/j.jaip.2016.11.030
228. Peroni DG, Boner AL, Vallone G, Antolini I, Warner JO. Effective
allergen avoidance at high altitude reduces allergen-induced bronchial
hyperresponsiveness. Am J Respir Crit Care Med. (1994) 149:1442–
6. doi: 10.1164/ajrccm.149.6.8004296
229. Dao A, Bernstein DI. Occupational exposure and asthma. Ann Allergy
Asthma Immunol. (2018) 120:468–75. doi: 10.1016/j.anai.2018.03.026
230. Fishwick D, Barber CM, Bradshaw LM, Ayres JG, Barraclough R, Burge S,
et al. Standards of care for occupational asthma: an update. Thorax. (2012)
67:278–80. doi: 10.1136/thoraxjnl-2011-200755
231. Brown RH, Mitzner W. The myth of maximal airway responsiveness in vivo.
J Appl Physiol. (1998) 85:2012–7. doi: 10.1152/jappl.1998.85.6.2012
232. Brown RH, Mitzner W. Airway closure with high PEEP in vivo. J Appl
Physiol. (2000) 89:956–60. doi: 10.1152/jappl.2000.89.3.956
233. Reid LM. The presence or absence of bronchial mucus in
fatal asthma. J Allergy Clin Immunol. (1987) 80(3 Pt 2):415–
6. doi: 10.1016/0091-6749(87)90064-9
234. Sur S, Crotty TB, Kephart GM, Hyma BA, Colby TV, Reed CE, et al. Sudden-
onset fatal asthma. a distinct entity with few eosinophils and relatively
more neutrophils in the airway submucosa? Am Rev Respir Dis. (1993)
148:713–9. doi: 10.1164/ajrccm/148.3.713
235. Carroll N, Carello S, Cooke C, James A. Airway structure and
inflammatory cells in fatal attacks of asthma. Eur Respir J. (1996)
9:709–15. doi: 10.1183/09031936.96.09040709
236. Hays SR, Fahy JV. The role of mucus in fatal asthma. Am J Med. (2003)
115:68–9. doi: 10.1016/S0002-9343(03)00260-2
237. Kauppi P, Peura S, Salimäki J, Järvenpää S, Linna M, Haahtela
T. Reduced severity and improved control of self-reported
asthma in Finland during 2001–2010. Asia Pac Allergy. (2015)
5:32–9. doi: 10.5415/apallergy.2015.5.1.32
238. Hardy J, Baggott C, Fingleton J, Reddel HK, Hancox RJ, Harwood
M. Budesonide-formoterol reliever therapy versus maintenance
budesonide plus terbutaline reliever therapy in adults with mild
to moderate asthma (PRACTICAL): a 52-week, open-label,
multicentre, superiority, randomised controlled trial. Lancet. (2019)
394:919–28. doi: 10.1016/S0140-6736(19)31948-8
Frontiers in Pediatrics | www.frontiersin.org 22 April 2020 | Volume 8 | Article 95
Anthracopoulos and Everard Asthma—What Is IT?
239. O’Byrne PM, FitzGerald JM, B ateman ED, Barnes PJ, Zhong N, Keen C, et al.
Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl
J Med. (2018) 378:1865–1876. doi: 10.1056/NEJMoa1715274
240. Dunnill MS, Massarella GR, Anderson JA. A comparison of the quantitative
anatomy of the bronchi in normal subjects, in status asthmaticus,
in chronic bronchitis, and in emphysema. Thorax. (1969) 24:176–
9. doi: 10.1136/thx.24.2.176
241. Kuwano K, Bosken CH, Paré PD, Bai TR, Wiggs BR, Hogg JC. Small airways
dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev
Respir Dis. (1993) 148:1220–5. doi: 10.1164/ajrccm/148.5.1220
242. Carroll N, Elliot J, Morton A, James A. The structure of large and small
airways in 412 nonfatal and fatal asthma. Am Rev Respir Dis. (1993) 147:405–
10.
243. Woodruff PG, Dolganov GM, Ferrando RE, Donnelly S, Hays SR, Solberg
OD, et al. Hyperplasia of smooth muscle in mild to moderate asthma without
changes in cell size or gene expression. Am J Respir Crit Care Med. (2004)
169:1001–6. doi: 10.1164/rccm.200311-1529OC
244. James AL, Bai TR, Mauad T, Abramson MJ, Dolhnikoff M, McKay
KO, et al. Airway smooth muscle thickness in asthma is related to
severity but not duration of asthma. Eur Respir J. (2009) 34:1040–
5. doi: 10.1183/09031936.00181608
245. James AL, Elliot JG, Jones RL, Carroll ML, Mauad T, Bai TR, et al. Airway
smooth muscle hypertrophy and hyperplasia in asthma. Am J Respir Crit
Care Med. (2012) 185:1058–64. doi: 10.1164/rccm.201110-1849OC
246. Lauzon AM, Martin JG. Airway hyperresponsiveness; mooth muscle as the
principal actor. F1000Res. (2016) 5. doi: 10.12688/f1000research.7422.1
247. Ijpma G, Panariti A, Lauzon AM, Martin JG. Directional preference of airway
smooth muscle mass increase in human asthmatic airways. Am J Physiol Lung
Cell Mol Physiol. (2017) 312:L845–54. doi: 10.1152/ajplung.00353.2016
248. Elliot JG, Noble PB, Mauad T, Bai TR, Abramson MJ, McKay KO, et al.
Inflammation-dependent and independent airway remodelling in asthma.
Respirology. (2018) 23:1138–45. doi: 10.1111/resp.13360
249. Lambert RK, Wiggs BR, Kuwano K, Hogg JC, Paré PD. Functional
significance of increased airway smooth muscle in asthma and COPD. J Appl
Physiol. (1993) 74:2771–81. doi: 10.1164/ajrccm/147.2.405
250. O’Reilly R, Ullmann N, Ir ving S, Bossley CJ, Sonnappa S, Zhu J,
et al. Increased airway smooth muscle in preschool wheezers who
have asthma at school age. J Allergy Clin Immunol. (2013) 131:1024–
32. doi: 10.1016/j.jaci.2012.08.044
251. Malmström K, Malmberg LP, O’Reilly R, Lindahl H, Kajosaari M, Saarinen
KM, et al. Lung function, airway remodeling, and inflammation in
infants: outcome at 8 years. Ann Allergy Asthma Immunol. (2015) 114:90–
6. doi: 10.1016/j.anai.2014.09.019
252. James AL, Noble PB, Drew SA, Mauad T, Bai TR, Abramson MJ, et al. Airway
smooth muscle proliferation and inflammation in asthma. J Appl Physiol.
(2018) 125:1090–96. doi: 10.1152/japplphysiol.00342.2018
253. Labonté I, Hassan M, Risse PA, Tsuchiya K, Laviolette M, Lauzon
AM, et al. The effects of repeated allergen challenge on airway
smooth muscle structural and molecular remodeling in a rat model of
allergic asthma. Am J Physiol Lung Cell Mol Physiol. (2009) 297:L698–
705. doi: 10.1152/ajplung.00142.2009
254. Mailhot-Larouche S, Deschênes L, Gazzola M, Lortie K, Henry C, Brook BS,
et al. Repeated airway constrictions in mice do not alter respiratory function.
J Appl Physiol. (2018) 124:1483–90. doi: 10.1152/japplphysiol.01073.2017
255. Grainge CL, Lau LC, Ward JA, Dulay V, Lahiff G, Wilson S, et al. Effect of
bronchoconstriction on airway remodeling in asthma. N Engl J Med. (2011)
364:2006–15. doi: 10.1056/NEJMoa1014350
256. Janssen LJ, Gauvreau GM, Killian KJ, O’Byrne PM. The effects of repeated
bronchoprovocation on fev1 in subjects with asthma. Ann Am Thorac Soc.
(2015) 12:1589–91. doi: 10.1513/AnnalsATS.201506-325LE
257. Pretolani M, Bergqvist A, Thabut G, Dombret MC, Knapp D, Hamidi F, et al.
Effectiveness of bronchial thermoplasty in patients with severe refractory
asthma: clinical and histopathologic correlations. J Allergy Clin Immunol.
(2017) 139:1176–1185. doi: 10.1016/j.jaci.2016.08.009
258. Chernyavsky IL, Russell RJ, Saunders RM, Morris GE, Berair R, Singapuri A,
et al. In vitro,in silico and in vivo study challenges the impact of bronchial
thermoplasty on acute airway smooth muscle mass loss. Eur Respir J. (2018)
51:1701680. doi: 10.1183/13993003.01680-2017
259. Leclere M, Lavoie-Lamoureux A, Joubert P, Relave F, Setlakwe EL,
Beauchamp G, et al. Corticosteroids and antigen avoidance decrease airway
smooth muscle mass in an equine asthma model. Am J Respir Cell Mol Biol.
(2012) 47:589–96. doi: 10.1165/rcmb.2011-0363OC
260. Chin LY, Bossé Y, Pascoe C, Hackett TL, Seow CY, Paré PD. Mechanical
properties of asthmatic airway smooth muscle. Eur Respir J. (2012) 40:45–
54. doi: 10.1183/09031936.00065411
261. Ijpma G, Kachmar L, Matusovsky OS, Bates JH, Benedetti A, Martin
JG, et al. Human trachealis and main bronchi smooth muscle are
normoresponsive in asthma. Am J Respir Crit Care Med. (2015) 191:884–
93. doi: 10.1164/rccm.201407-1296OC
262. Krishnan R, Trepat X, Nguyen TT, Lenormand G, Oliver M, Fredberg JJ.
Airway smooth muscle and bronchospasm: fluctuating, fluidizing, freezing.
Respir Physiol Neurobiol. (2008) 163:17–24. doi: 10.1016/j.resp.2008.04.006
263. Browning KN, Travagli RA. Central nervous system control of
gastrointestinal motility and secretion and modulation of gastrointestinal
functions. Compr Physiol. (2014) 4:1339–1368. doi: 10.1002/cphy.c130055
264. Van der Velden VH, Hulsmann AR. Autonomic innervation of
human airways: structure, function, and pathphysiology of asthma.
Neuroimmunomodulation. (1999) 6:145–59. doi: 10.1159/000026376
265. Undem BJ, Potenzieri C. Autonomic neural control of intrathoracic airways.
Compr Physiol. (2012) 2:1241–67. doi: 10.1002/cphy.c110032
266. Joseph J, Bandler L, Anderson SD. Exercise as a bronchodilator. Aust J
Physiother. (1976) 22:47–50. doi: 10.1016/S0004-9514(14)61000-X
267. Thiessen B, Pedersen OF. Maximal expiratory flows and forced
vital capacity in normal, asthmatic and bronchitic subjects
after salbutamol and ipratropium bromide. Respiration. (1982)
43:304–16. doi: 10.1159/000194499
268. Vanhoutte PM. Airway epithelium-derived relaxing factor:
myth, reality, or naivety? Am J Physiol Cell Physiol. (2013)
304:C813–20. doi: 10.1152/ajpcell.00013.2013
269. Mitchell HW, Willet KE, Sparrow MP. The role of epithelium in the
responsiveness of the bronchi to stimuli. Agents Actions Suppl. (1990)
31:275–8. doi: 10.1007/978-3-0348-7379-6_37
270. Lozewicz S, Wells C, Gomez E, Ferguson H, Richman P, Devalia J, et al.
Morphological integrity of the bronchial epithelium in mild asthma. Thorax.
(1990) 45:12–5. doi: 10.1136/thx.45.1.12
271. Ordoñez C, Ferrando R, Hyde DM, Wong HH, Fahy JV. Epithelial
desquamation in asthma: artifact or pathology? Am J Respir
Crit Care Med. (2000) 162:2324–9. doi: 10.1164/ajrccm.162.6.200
1041
272. Ordoñez CL, Khashayar R, Wong HH, Ferrando R, Wu R, Hyde
DM, et al. Mild and moderate asthma is associated with airway goblet
cell hyperplasia and abnormalities in mucin gene expression. Am J
Respir Crit Care Med. (2001) 163:517–23. doi: 10.1164/ajrccm.163.2.20
04039
273. Tran MU, Weir AJ, Fanucchi MV, Murphy AE, Van Winkle LS, Evans
MJ, et al. Smooth muscle development during postnatal growth of distal
bronchioles in infant rhesus monkeys. J Appl Physiol. (2004) 97:2364–
71. doi: 10.1152/japplphysiol.00476.2004
274. Janssen LJ, Killian K. Airway smooth muscle as a target of
asthma therapy: history and new directions. Respir Res. (2006)
7:123. doi: 10.1186/1465-99217-123
275. Lam M, Lamanna E, Bourke JE. Regulation of Airway Smooth Muscle
Contraction in Health and Disease. Adv Exp Med Biol. (2019) 1124:381–422.
doi: 10.1007/978-981-13-5895-1_16
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