REVIEW

URRENT
C
OPINION

Comorbidities of asthma: current knowledge and

future research needs
Mario Cazzola a,b, Andrea Segreti a, Luigino Calzetta b, and Paola Rogliani a

Purpose of review
Asthma is often associated with different comorbidities, mainly gastro-oesophageal reflux disease and
allergic rhinitis, but also obesity, depression, diabetes mellitus and cardiovascular disease, which may
affect its clinical intensity and severity. The prevalence of these comorbidities varies tremendously between
studies. Nevertheless, it imposes a significant reflection on the need to explore the phenomenon in depth.
Recent findings
Both clinical and basic studies have established that inflammation plays a vital role in the initiation and
progression of several comorbidities. However, the role of systemic inflammation in asthma is still unclear.
Understanding mechanism(s) that link(s) asthma and its comorbid diseases is essential to design an effective
therapeutic approach.
Summary
In the future, researchers must identify the weight of any comorbidity in patients with asthma, find the true
mechanism(s) that link(s) it to asthma and act on these mechanisms that probably create a vicious circle.
Conversely, we do not think it reasonable that the generalization of treatment with a holistic approach
might affect the link(s) between asthma and its comorbidities.
Keywords
asthma, comorbidities, obesity, systemic inflammation

INTRODUCTION
Asthma is often associated with different comorbidities, which may affect its clinical intensity and
severity, and with which it may share a common
pathophysiological mechanism [1]. However, how
comorbidities interact with asthma is still unclear [2].

EPIDEMIOLOGICAL STUDIES
Several population-based retrospective studies,
which used health administrative data, have shown
that asthmatic patients have significantly higher
rates of many different types of comorbidity
[3,4 ,5,6 ].
The analysis of the health services administrative data for British Columbia showed that asthmatic adults were significantly more likely to have
a variety of comorbidities, including respiratory
infections and allergic rhinitis. One in four adults
with asthma had depression [3]. One in five adult
asthma patients also had chronic obstructive
pulmonary disease, compared with 1.6% in the
adult service user population. Among asthma
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patients at least 56 years old, the proportion

increased to 38% for men and 28% for women.
Asthmatic children had a lower comorbidity burden
than adults, but 12.6% had a chronic medical condition, with depression as the most prevalent
comorbidity. Adults with asthma had a strong and
complex comorbidity burden, particularly in terms
of multiple chronic conditions.
A study that used information obtained from the
Health Search Database owned by the Italian College
of General Practitioners suggested that asthma is
weakly associated with cardiovascular disease,
depression, diabetes mellitus, dyslipidaemia, osteoporosis and rhinosinusitis [4 ]. In contrast, it is
&

Department of System Medicine, University of Rome Tor Vergata and

Department of Pulmonary Rehabilitation, San Raffaele Pisana Hospital,
IRCCS, Rome, Italy
b

Correspondence to Mario Cazzola, Dipartimento di Medicina dei Sistemi,

Universita` di Roma Tor Vergata, Via Montpellier 1, Rome 00133, Italy. Tel:
+39 0620900633; e-mail: mario.cazzola@uniroma2.it
Curr Opin Pulm Med 2013, 19:3641
DOI:10.1097/MCP.0b013e32835b113a
Volume 19  Number 1  January 2013

Comorbidities of asthma Cazzola et al.

affect asthma and the implications for asthma

therapy.

KEY POINTS
 The prevalence of comorbidities in asthma is extremely
high.
 It is essential to understand their origin, real impact on
the natural history and severity of asthma and
implications for asthma therapy, and also the
mechanisms by which they could affect asthma.
 We do not think that it will be possible to oversimplify
mechanism(s) that link(s) asthma and each comorbidity
and, consequently, we do not believe that the
generalization of treatment with a holistic approach
might actually affect the link between asthma and
its comorbidities.

strongly associated with gastro-oesophageal reflux

disease (GORD) and, particularly, allergic rhinitis.
Apparently, age does not affect the association of
asthma with comorbidities, whereas sex has a different impact according to the comorbidity.
The evaluation of the Norwegian Prescription
Database documented that 59% of the asthmatic
population 829 years old had at least one of nine
chronic diseases examined, compared with 18% in
the general population [5]. Few individuals with
asthma had more than one additional chronic disease (6% of male individuals and 8% of female
individuals). Standardized morbidity ratios were
increased for all diseases except diabetes. This pattern was observed in both age groups (819 and
2029 years) and sexes. Allergy and GORD had
highest standardized morbidity ratios (range 3.2
4.8), whereas the other diseases were in the range
1.22.5.
The study of the health administrative data on
all individuals living in Ontario, Canada, revealed
that compared with people without asthma, asthmatic individuals had at least 50% or more comorbidity, as indicated by health services utilization,
for respiratory disease (other than asthma) in all
age groups, psychiatric disorders in individuals
age 4 years and under and age 1844 years, perinatal
disorders in individuals 17 years and under and
metabolic and immunity and hematologic disorders
in children 4 years and under [6 ].
The prevalence of comorbidities in asthmatic
patients varies between studies, probably because
we still do not know whether the comorbidities
are directly or indirectly related to asthma, but it is
extremely high in severe asthma [2]. These data
impose the need to investigate the problem
more carefully in order to understand its origin,
the real impact on the natural history and severity
of asthma, the mechanisms by which it could
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POSSIBLE MECHANISMS OF ASTHMA

COMORBIDITIES ASSOCIATION
Inflammation plays a vital role in the initiation and
progression of several comorbidities [7]. Togias [8]
suggested that although the initial manifestations of
a mucosal allergic reaction are localized, a systemic
component develops. This systemic component
could feed back into and perpetuate the original
local reaction and lead to the development of distant local reactions [8]. In asthmatic patients,
systemic dissemination of local lung inflammation
may occur, leading to an overspill effect [9].
Actually, systemic inflammation occurs in asthma,
with an increase in circulating proinflammatory
cytokines, such as interleukin (IL)-6 and tumor
necrosis factor-a [10] and also in high-sensibility
C-reactive protein [11].
However, the role of systemic inflammation in
asthmatic patients is still unclear and, consequently,
debated. Airway inflammation in asthma is heterogeneous in nature and may involve an allergenspecific acquired immune response with IL-5-mediated eosinophilic inflammation or a dysregulation
of innate immune responses involving IL-8-induced
neutrophilic airway inflammation [12]. Apparently,
systemic inflammation is increased in asthmatic
patients with neutrophilic airway inflammation
[13 ].
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Allergic rhinitis
Many patients with asthma suffer from symptoms
of allergic rhinitis [4 ]. A systemic pathway linking
the upper and lower airways, involving both bloodstream and bone marrow has been suggested [14].
Serum IL-5, blood eosinophils, and adhesion molecule expression are increased after local allergen
challenge in individuals with allergic rhinitis.
Moreover, mucosal inflammation extends from
the challenged organ throughout the whole airways. It has been suggested there is a central mechanism behind the link, with eosinophil precursors
emanating from the bone marrow in response to
triggers migrating not only to the site of stimulation, such as the nasal mucosa, but also to other
sites within the airway, including the lower respiratory tract [15]. There are other suggested mechanisms of noselung interaction such as autonomic
imbalance via changes in neural tone to effector
tissues, release of neuropeptides and interplay with
cellular recruitment [16], increased lower airway
exposure to airborne contaminants from mouth

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Asthma

breathing and increased demand for conditioning

the inspired air [17].

Obesity
Numerous studies have demonstrated a strong association between obesity and asthma, but the direction
of causality is unclear [18]. Because obesity is a component of the metabolic syndrome, which is also a
form of systemic inflammation, it is to be expected
that there is a relationship between metabolic syndrome and asthma [19]. In fact, systemic markers of
inflammation are elevated in obesity [20], and
adipokines, correlate, albeit weakly, with asthma
symptoms [21]. Proinflammatory adipokines in the
circulation could induce airway inflammation or
increase its severity, and thus contribute to airway
hyperresponsiveness or asthma [22]. Obesity may
modulate airway inflammation through pathways
other than traditional immunoglobulin (Ig)E-mediated allergic mechanisms [22]. However, also the
pressure of the increased tissue mass in the chest wall
and abdomen, which has direct mechanical effects
on the lungs, could modify airway hyperresponsiveness or increase symptoms directly [22]. Besides, the
association between obesity and asthma symptoms
could be merely an epiphenomenon, and the true
association is due to comorbidities or lifestyle factors
associated with obesity [22].

Diabetes mellitus
Several studies have found significant correlations
between asthma and type 2 diabetes, [23,24], at least
in women [4 ], with a risk of asthma that is almost
doubled in individuals with type 2 diabetes [23].
Chronic airway inflammation in asthma may be
involved in the pathogenesis of both type 2
[25,26] and type 1 diabetes [27]. However, part of
the effect of the presence of asthma as comorbidity
may be associated with the use of corticosteroids,
which, in turn, may result in the unmasking of
diabetes [24]. Recently, we documented that high
glucose concentrations leads to hyperresponsiveness of human isolated bronchi and enhanced intracellular calcium release in cultured airway smooth
muscle cells via a Rho/Rho-associated kinase
(ROCK) and myosin phosphatase targeting subunit
1 (pMYPT1)-dependent pathway, suggesting that
these crucial pathways, but not systemic inflammation, may contribute to the reduced lung function that is observed in diabetic patients [28 ].
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Gastro-oesophageal reflux
Patients with asthma are also at a significantly
increased risk of developing GORD [4 ,29]. The
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altered respiratory physiology in asthma patients

may predispose them towards GORD [30]. Respiratory obstruction can result in negative pleural pressures, increasing the pressure gradient between the
thorax and abdominal cavity, thus, promoting
reflux [30]. However, GORD may induce asthma
symptoms either by direct effects on airway hyperresponsiveness or via aspiration-induced inflammation. In fact, microaspiration of gastric acid
can directly result in airway constriction stimulating
a vagal response promoting bronchoconstriction or
indirectly through induction of chronic inflammatory changes, which eventually can lead to increased
airways reactivity [31]. Interestingly, acid provocation has been shown to lead to a dose-dependent
increase in lung resistance that is mediated by
release of tachykinins from peripheral nerves [31].
In any case, b-agonist and methylxanthine
bronchodilators may decrease lower oesophageal
sphincter tone, which potentially could promote
acid reflux [32].

Cardiovascular disease
Some epidemiological studies reported a significant
association of asthma with cardiovascular disease
[33,34], but there is a conflict in the literature surrounding the asthma-related risk of cardiovascular
disease identified in large, longitudinal epidemiologic studies. For example, Schanen et al. [35]
reported an increased risk of stroke, but not coronary heart disease, associated with asthma. In any
case, adult-onset asthma is associated with increased
carotid atherosclerosis in women [36], and patients
with bronchial hyperresponsiveness to methacholine demonstrated increased carotid intimamedia
thickness [37]. Apparently, relationships of asthma
and cardiovascular disease in women are stronger
than those observed in men [34,36,38 ]. Asthma and
atherosclerosis occur on a background of inflammation. Animal studies have shown increased myocardial vulnerability in rabbits with systemic allergy
and asthma [39]. A fascinating report revealed that
airway allergen exposure results in impaired vasodilatory response of the aorta in a murine model of
pulmonary allergic response [40]. This finding
suggests that systemic inflammation associated with
asthma may adversely affect cardiovascular function. However, the documentation of sequence
variants affecting eosinophil numbers associated
with asthma and myocardial infarction is an even
more intriguing discovery [41].
Nevertheless, cardiovascular complications in
asthmatic patients have largely been attributed to
asthma treatment [42,43]. Interestingly, Zhang et al.
[44] documented that patterns of risks of myocardial
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Comorbidities of asthma Cazzola et al.

infarction were similar between inhaled short-acting b2-agonists, long-acting b2-agonists and inhaled
corticosteroids. For each of these therapies, hazard
rates for myocardial infarction were increased soon
after the initiation of treatment and reduced thereafter. Hazard rates were also increased in heavy,
long-term users (13 prescriptions of the same
asthma therapy in the year prior). In patients prescribed asthma medication, the risk of myocardial
infarction was powerfully associated with the Framingham myocardial infarction risk score. These
findings suggest that the initial presentation with
symptoms evoking asthma (dyspnoea presumably)
is, in a large proportion of cases, the appearance of
ischaemic heart disease [45]. However, it is noteworthy that we were unable to register concrete
association of asthma with acute or previous myocardial infarction [4 ].
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Anxiety and depression

There is a significant overlap between anxiety,
depression and asthma, with a higher prevalence
of psychological problems [3,4 ] and a higher
mortality rate [46 ] in patients with asthma and
depression. This latter finding can be explained
because concurrent depression leads to poor adherence with asthma treatments and, thus, to poorer
outcomes [47]. IgE-mediated mechanisms do not
explain the relationship between asthma and
depression. Increasingly, evidence supports the
possibility that one or more independent factors,
either environmental or genetic, may affect the risk
of both asthma and anxiety disorders [48]. Systemic
inflammation may also play a role [49]. Frequent
and high doses of systemic corticosteroid therapy
used for severe asthmatic patients may cause neurotoxicity and lead to cognitive impairments [50], but
it has been documented that oral corticosteroid use
is unlikely to be the cause of the increased rate of
depression in patients with asthma [46 ].
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FUTURE RESEARCH NEEDS

The identification of comorbidities must become an
integral part of the core management of asthma. A
systematic evaluation is necessary, not only of their
presence, is necessary, and we must also ensure that
they are adequately treated/controlled so that their
impact on asthma is minimized [1].
Unfortunately, it has not been established yet
whether controlling asthma would reduce comorbidities occurrence, or whether their treatment
improves asthma control, or treatment of asthma
is altered by the presence of comorbidity. There is
suggestive documentation that escalating doses of

b2-adrenoceptor inverse agonists, such as nadolol,

lower airway responsiveness in patients with asthma
[51], and the simultaneous administration of nadolol and a corticosteroid is more effective at reducing
indexes of airway inflammation than either drug
given alone, at least in an asthma model [52 ].
Moreover, emerging evidence suggests beneficial
effects of statins in asthma management [53 ]. Further prospective studies should consider investigating these issues, although this is an empirical
approach failing reliable information about the
link(s) between asthma and its comorbidities.
In fact, it is still unclear what mechanism(s)
link(s) asthma and its comorbidities. Understanding
these links is essential to design an effective treatment to overcome them. However, this will not be
an easy task, mainly because asthma is highly
heterogeneous. At present, we identify many different phenotypes of asthma. Moreover, there is considerable overlap between the various phenotypes,
which often makes it difficult to accept a specific
phenotype [54]. The available data, mainly due to
the extreme heterogeneity of asthma, do not yet let
us determine whether a specific phenotype of
asthma may be related to a specific type of comorbidity, and then the possible link(s) between asthma
and this comorbidity.
In any case, the available information is still
extremely limited to accept the idea that the presence of a specific comorbidity per se may represent a
phenotype of asthma. Although the mechanisms
underlying obesity in asthma require further investigation, it has been suggested that obesity is a
specific phenotype of the disease [55]. This is an
intriguing idea, but it does not tell us anything. In
fact, if this was true, we should speculate that all
obese patients could suffer from asthma, and this is
not the case. Systemic inflammation, oxidative
stress and mechanical events may be more or less
extensively involved in the link between obesity and
asthma, but it is likely that there is a driver, which is
probably genetic in its nature, that allows the obese
patient to become asthmatic. Obviously, this driver
is not available in all obese patients. Currently, we
accept the existence of distinct phenotypes of
obesity depending on compartments for body fat
accumulation, with a significant association
between some candidate gene polymorphisms and
phenotypes [56]. It should be possible to predict
beneficial and detrimental effects of these phenotypes, depending on compartments for body fat
accumulation [56].
In addition, we still do not know whether the
low-grade systemic inflammation has local effects
on the lung parenchyma and causes or enhances the
bronchial inflammation. If inflammation affects the

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Asthma

systemic circulation, anti-inflammatory treatment

might have the potential to reduce the risk of
comorbidities. However, always remaining in the
paradigm of obesity that we are using as the prototype of comorbidities in asthma, obese patients with
difficult-to-treat asthma do not have more airway
inflammation as compared with nonobese patients
[57]. On the contrary, they have higher forced expiratory volume in 1 sec and less airway inflammation.
We totally agree that obese patients with asthma
may reveal more severe asthma symptoms or even
become difficult to treat because of an unfavourable
impact of overweight on lung function, or because
of aggravating comorbid factors including GORD
and obstructive sleep apnoea [58]. The therapeutic
approach of obese patients with difficult-to-treat
asthma should, therefore, not be primarily focused
on intensifying anti-inflammatory treatment but
rather on weight reduction and adequate control
of comorbid factors.

CONCLUSION
The prevalence of comorbidities is extremely high.
Therefore, it is now essential to understand their
origin, real impact on the natural history and
severity of asthma and implications for asthma
therapy, and also identify the mechanisms by which
they could affect asthma. However, we cannot
generalize mechanism(s) that link(s) asthma and
each comorbidity. In the future, researchers must
establish the specific weight of any comorbidity in
patients with asthma, understand the real mechanism(s) that link(s) it to asthma, and act on these
mechanisms that probably create a vicious circle.
Conversely, we do not think it reasonable that the
generalization of treatment with a holistic approach
might affect the link between asthma and its comorbidities.
Acknowledgements
None.
Conflicts of interest
There are no conflicts of interest.

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