Asthma

Introduction:
Asthma may be a chronic inflammatory disease of the conducting airways in which many cells of the
innate and adaptive immune systems act together with epithelial cells to cause bronchial hyper-
reactivity (BHR) (the tendency of smooth muscle cells in people with asthma to react to nonspecific
stimuli such as cold air and exercise), mucus overproduction, airway wall remodeling, and airway
narrowing. In susceptible patients, this results in repeated periods of shortness of breath, wheezing,
and chest tightness. The disease is extremely common in affluent societies, during which almost 1
in 10 children and 1 in 12 adults is affected, which ends up in substantial morbidity and annual
healthcare expenditure.
Asthma may be a common chronic respiratory condition that can present with acute exacerbations.
It afflicts children also as adults and is highly variable in severity, response to treatment, and clinical
presentation. it's a form of obstructive airway disease characterized by an acute and reversible
increase in airway resistance. Recent evidence suggests that asthma does produce changes within
the respiratory epithelium. The prevalence of asthma is 5% within the adult and 10% in the
pediatric population. there's evidence that this is increasing in the United States, especially in urban
pediatric populations. the varied types of asthma are categorized according to the underlying
etiology of the exacerbation. These may include atopic or IgE-mediated, exercise-induced,
occupational, infectious, or aspirin-induced. Although the mediators that produce an acute asthmatic
attack vary, the resulting physiological responses are similar for all kinds of asthma. Because
airway resistance is inversely associated with the diameter of the bronchial lumen, pediatric
patients are predisposed to rapid decompensation during bronchospasm.
Worldwide, up to 300 million people are affected. the entire cost of the disease, both in direct
medical costs and indirect costs caused by loss of productivity, is estimated to exceed $18 billion
annually within the USA. In many patients, the disease are often controlled by a combination of an
inhaled corticosteroid (which acts to suppress the inflammation) and a short- or long-acting β2-
adrenergic agonist (which acts to open the constricting bronchial smooth muscle), but in some 5–
10% of patients, the disease is refractory to corticosteroid treatment and sometimes leads to
hospital admissions caused by respiratory viral infection with rhinovirus.

Traditionally, two sorts of asthma have been defined in the clinic. most youngsters and roughly
50% of adults have allergic asthma, during which the disease coincides with allergic sensitization
defined by the presence of serum immunoglobulin E (IgE) antibodies and/or a positive skin-prick test
to the (lipo)proteins of common inhaled or ingested allergens such as house dust mite (HDM),
animal dander, fungal spores, plant or tree pollen, or peanuts. In children, the disease starts with
allergic sensitization, often amid eczema in the first year of life. These children later
develop rhinitis and can progress to asthma. This stepwise increase of symptoms has been called
the ‘atopic march. particularly , children with multiple allergies at a young age are likely to develop
asthma, and enormous studies have found that up to half of patients with atopic eczema developed

asthma later in life.(Spergel and Paller 2003)

In up to 80% of cases, patients with allergic asthma have concurrent rhinitis . The ‘united airways
disease’ hypothesis proposes that rhinitis and asthma are manifestations of the same underlying
disease process and that each influences the severity of the other. Asthma may be a disorder of
oxygen insufficiency for global metabolism expressed at the level of the bronchi. The bronchi
modulate the speed of oxygen entry and also the degree of airway resistance to exhalation. it's this
latter function that is activated in asthma-critical terrain. It serves to stent alveoli open and prolongs
the time of oxygen exchange during exhalation. There are two phenotypes of asthma: allergic
(extrinsic) and nonallergic (intrinsic). consistent with the theory of Endobiogeny, there are
phenotypic subtypes based not on clinical severity but on autonomic function within the precritical
terrain.
The Endobiogenic approach to asthma allows for the support of severe asthma together
with standard treatments. It allows for interventions for mild dyspnea which will reduce the
frequency of beta-agonist and glucocorticoid interventions. Finally, it allows for treatment of the
precritical terrain to bring patients out of an asthmatic tendency. Unlike chronic lung disease where
the lung is permanently damaged, asthma is chiefly characterized by its reversibility. regardless
of how dangerously severe the symptoms are, altogether cases, prompt and effective treatment
can open the airways again normal breathing can resume.
Nonallergic (intrinsic) asthma often develops later in life and, per its definition, has neither IgE
reactivity to allergens within the serum nor any obvious involvement of the adaptive immune system
such as type 2 helper T cells (TH2 cells).

This form of the disease is more common in women, is usually associated with chronic
rhinosinusitis and nasal polyps, also as obesity, and is difficult to treat, often requiring long-term
treatment with systemic steroids. the sector of clinical asthma diagnosis and treatment has
undergone great conceptual shifts through the advent of genome-wide expression studies and the
first clinical trials using targeted therapies with biological agents.
As with many chronic inflammatory diseases, clinicians now realize that the division of asthma into
only two clinical forms has been an oversimplification. Different asthma phenotypes, each with
distinct pathophysiology, are now being defined as asthma endotypes. The endotypes differ in terms

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of genetic susceptibility, environmental risk factors, age of onset, clinical presentation, prognosis,

and response to plain and new therapies.(Anderson 2008)

Intraoperative management of asthmatic patients should place emphasis on adequate oxygenation,

and avoiding excessive airway stimulation through the utilization of throat packs and suctioning. A
pretracheal stethoscope are often recommended for auscultation monitoring. In patients who are
intubated, decreased tidal volumes and increased end-tidal CO2 may indicate bronchospasm.
During extubation, minimal stimulation of the airway is suggested . “Deep” extubation could also
be prudent to avoid excessive excitement from the emerging patient because it may generate
enormous negative pressure, leading to acute pulmonary edema. Administration of a dose of
intravenous lidocaine before extubation also will decrease airway stimulation. Despite these
precautions, some patients with asthma will experience bronchospasm during their surgical course.
Management of an acute asthmatic exacerbation should contains early detection and intervention.
Bronchospasm may be a potentially life-threatening emergency that must be treated. Treatment
should contains an assessment of vital signs, supplemental oxygen, inhaled β2-agonists, injectable
sympathomimetics, corticosteroids, and ventilatory support if indicated.

Asthma is therefore increasingly seen as a syndrome instead of a single disease. In people with
asthma who smoke, there's also considerable clinical overlap with chronic obstructive pulmonary

disease, whose immunological basis has been reviewed(Simpson, Tan et al. 2010). In this
Review, we'll focus on the underlying immunological basis of the various asthma endotypes,
integrating results from humans targeting particular pathways with results from animal

studies during which a great deal of molecular detail has been gathered. (Brusselle, Joos et al.
2011)

Symptoms and their frequency:

The main symptoms taken into account to characterize asthmatic disease are
dyspnoea, sometimes associated with ‘respiratory discomfort’, cough and
wheezing(Green, Brightling et al. 2006). These symptoms are sometimes
quantified by using a qualitative score (absent, mild, moderate, severe) or a visual
analogue scale (VAS) (Green, Brightling et al. 2002).

Other symptoms such as chest tightness, sputum and specific exercise-related

symptoms (Rytila, Metso et al. 2000) are analysed more inconsistently. Composite
scores are usually proposed including the incidence of symptoms, their day and/or
nighttime occurrence and sometimes their repercussions on daily life. However,
there is considerable heterogeneity in these different evaluations, and few studies
have made it possible to validate these symptomatic scores (Santanello, Barber et
al. 1997). Moreover, in many studies, the evaluation of symptoms is integrated in a
more global analysis of control, which takes into account drug consumption, the
occurrence of exacerbations and changes in respiratory function.

The most relevant symptoms identified in both the adult and adolescent
populations included chest tightness, wheezing, coughing, and shortness of breath.
These symptoms, identified in the qualitative research, are consistent with the core
asthma symptoms identified in the literature (Stein and Martinez 2004) . Among
impacts that are considered to be markers of symptom severity, limitations in
physical activities and sleep disruption were identified in this qualitative research
study as being most difficult for patients to cope with. The decision to include
these two markers of symptom severity in the ASD was supported by both the
qualitative research (patient spontaneous self-report) as well as the literature
(Moore, Meyers et al. 2010), which indicates that physical activity and sleep
problems feature prominently in asthma. Although activity limitations and sleep
disturbances might also be considered as assessing impact, the study team,
influenced by the weight of the evidence in the literature, theorized that, in the case
of asthma, symptom severity may be expressed in terms of their impact.

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The study team conceptualized that one or more markers of symptom severity
could be so interrelated to symptoms that they might scale together with
symptoms. A well-established indicator of asthma symptom severity is interference
with sleep and activity limitation.

Although these could be considered impacts rather than symptoms per se, they
were included as well-established markers of symptom severity, and were endorsed
during the qualitative phase and confirmed during the quantitative phase.

The frequency of respiratory symptoms is significantly associated with disease

severity and usage of anti-asthma treatment(Calciano, Corsico et al. 2017). The
results also highlight the importance of various combinations of symptoms
reported in patients with asthma, and further research is warranted on the treatment
aspect of asthma, including therapy initiation based on different symptom
combinations. Thus, the correct evaluation of signs and symptoms of asthma at an
early stage might have a clinical importance in application of effective treatment
strategies and potentially better prognosis in subjects with asthma (Kaplan, Balter
et al. 2009). Further, accurate diagnosis will also reduce concerns about
overdiagnosis and underdiagnosis.99 We believe that the early diagnostic and
clinical improvement in patients with asthma will translate into a reduction in
economic burden, as demonstrated by Nunes et al.

From the perspective of clinicians, we believe support in accurate and early

diagnosis will help standardize the practices followed for asthma diagnosis. In the
studies it was reported asthma symptoms categorized as occurring during the day
in 7 studies (38.81% of subjects) and occurring at night in 11 studies (32.26% of
subjects). This might not be a correct representation of the timing of the symptoms
because some studies did not report the frequency of symptoms based on time of
day. However, evidence from the literature suggests that subjects with asthma
experience symptoms throughout the day, with the frequency and severity of
symptoms worsening with disease progression (D'Alonzo and Ciccolella 1996).

Pathophysiology and Etiology:

Asthma is characterized by airway hyper-responsiveness, chronic inflammation, mucus production,

and structural airway remodeling that's largely allergic in nature. it's a complex syndrome and not a
singular disease. Clinical and scientific evidence indicates that multiple sub-types of asthma exist in
adulthood, though this is often less true in early childhood. Asthma usually develops at a young
age, and it remains difficult to diagnose before age 3. Upper respiratory viral illnesses, particularly
rhinovirus and respiratory syncytial virus, and environmental allergens combine to trigger an upper
and lower airway inflammatory response in susceptible individuals.
Several theories attempt to describe this phenomenon, like the ‘atopic march’ that states that
allergic inflammation of the airways naturally follows eczema or atopic dermatitis in young children.
The ‘hygiene hypothesis’ suggests that allergic inflammation results from changes within
the patterns of exposure – fewer infections, and more contact with indoor allergens like house dust
mites that children experience at a really young age.
Asthma is related to T helper cell type-2 (Th2) immune responses, which are typical of other atopic
conditions. Asthma triggers may include allergic (e.g., house dust mites, cockroach residue, animal
dander, mold, and pollens) and non-allergic (e.g., viral infections, exposure to tobacco smoke, cold
air, exercise) stimuli, which produce a cascade of events resulting in chronic airway inflammation.
Elevated levels of Th2 cells within the airways release specific cytokines, including interleukin (IL)-
4, IL-5, IL-9, and IL-13, and promote eosinophilic inflammation and immunoglobulin E (IgE)
production. IgE production, in turn, triggers the discharge of inflammatory mediators, like histamine
and cysteinyl leukotrienes, that cause bronchospasm (contraction of the graceful muscle in the

airways), edema, and increased mucus , which cause the characteristic symptoms of asthma

(Lemanske Jr and Busse 2010).

The mediators and cytokines released during the early phase of an immune
response to an inciting trigger further propagate the inflammatory response (late-
phase asthmatic response) that leads to progressive airway inflammation and
bronchial hyperreactivity (Gershon, Guan et al. 2010). Over time, the airway
remodeling that occurs with frequent asthma exacerbations leads to greater lung

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function decline and more severe airway obstruction (Bai, Vonk et al. 2007). This
highlights the importance of frequent assessment of asthma control and the
prevention of exacerbations.

Evidence suggests that there may be a genetic predisposition for the development
of asthma. Several chromosomal regions associated with asthma susceptibility
have been identified, such as those related to the production of IgE antibodies,
expression of airway hyperresponsiveness, and the production of inflammatory
mediators. However, further study is required to determine specific genes involved
in asthma as well as the gene-environment interactions that may lead to expression
of the disease (Yang, To et al. 2011).

Asthma is characterized by airway hyper-responsiveness, chronic inflammation, mucus production,

and structural airway remodeling that's largely allergic in nature. it's a complex syndrome and not a
singular disease. Clinical and scientific evidence indicates that multiple sub-types of asthma exist in
adulthood, though this is often less true in early childhood. Asthma usually develops at a young
age, and it remains difficult to diagnose before age 3. Upper respiratory viral illnesses, particularly
rhinovirus and respiratory syncytial virus, and environmental allergens combine to trigger an upper
and lower airway inflammatory response in susceptible individuals.
Several theories attempt to describe this phenomenon, like the ‘atopic march’ that states that
allergic inflammation of the airways naturally follows eczema or atopic dermatitis in young children.
The ‘hygiene hypothesis’ suggests that allergic inflammation results from changes within
the patterns of exposure – fewer infections, and more contact with indoor allergens like house dust
mites that children experience at a really young age.
Asthma is related to T helper cell type-2 (Th2) immune responses, which are typical of other atopic
conditions. Asthma triggers may include allergic (e.g., house dust mites, cockroach residue, animal
dander, mold, and pollens) and non-allergic (e.g., viral infections, exposure to tobacco smoke, cold
air, exercise) stimuli, which produce a cascade of events resulting in chronic airway inflammation.
Elevated levels of Th2 cells within the airways release specific cytokines, including interleukin (IL)-
4, IL-5, IL-9, and IL-13, and promote eosinophilic inflammation and immunoglobulin E (IgE)
production. IgE production, in turn, triggers the discharge of inflammatory mediators, like histamine
and cysteinyl leukotrienes, that cause bronchospasm (contraction of the graceful muscle in the
airways), edema, and increased mucus , which cause the characteristic symptoms of asthma

(Subbarao, Mandhane et al. 2009). Prenatal risk factors linked to early asthma
development include: maternal smoking, use of antibiotics and delivery by
caesarean section. With respect to prenatal diet and nutrition, a higher intake of
fish or fish oil during pregnancy, and higher prenatal vitamin E and zinc levels
have been associated with a lower risk of development of wheeze in young
children.

Later in childhood, risk factors for asthma development include: allergic

sensitization (particularly house dust mite, cat and cockroach allergens), exposure
to environmental tobacco smoke, breastfeeding (which may initially protect and
then increase the risk of sensitization), decreased lung function in infancy,
antibiotic use and infections, and gender. Future results from CHILD may help
further elucidate risk factors for asthma development.

Diagnosis

There is a huge economic burden associated with asthma in developing countries,

(Nunes, Pereira et al. 2017) which tends to increase with a greater severity and
inadequate control of the disease. The evolution of asthma pathophysiology,
treatments, treatment recommendations, and the adoption of a patient-centered
approach makes possible early diagnosis for effective asthma management (Al-
Zahrani, Ahmad et al. 2015).

Therefore, early identification of asthma symptoms is key to early asthma

diagnosis, its control, and saving the patient (and society) from high treatment
costs. However, despite asthma management guidelines focusing on improving
asthma diagnosis, multiple studies have reported misdiagnosis or overdiagnosis of
asthma (Aaron, Vandemheen et al. 2008).

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Asthma is overdiagnosed in developed countries, and obesity is one of the potential
causes of overdiagnosis. In obesity, there is reduced chest wall compliance,
thereby leading to reduced lung volumes and increased breathlessness, and thus
patients with obesity are more likely to be misdiagnosed as having asthma.8
Misdiagnosis is the major reason for undertreatment or unwanted treatment of
asthma symptoms, which may result in aggravation of symptoms or unwanted
exposure to drugs, respectively, and may lead to adverse consequences (Gillman
and Douglass 2012).

The first step in managing asthma is to make the correct diagnosis. Asthma may
mimic other common conditions and may be either overdiagnosed (Aaron,
Vandemheen et al. 2008) or underdiagnosed. After an appropriate history has been
obtained and a physical examination performed, the recommended diagnostic
testing methods include spirometry (preferred), serial peak flow measurements and
provocational challenges.

Asthma is the most common chronic respiratory disease in Canada, affecting about
2.2 million adults and 0.8 million children. Poor asthma control imposes a
significant burden on the health care system (FitzGerald, Boulet et al. 2006), with
the annual direct and in -direct costs estimated at between $504 million and $648
million in Canada(Krahn, Berka et al. 1996). However, despite the significant
expenditure of health care resources on people with asthma, as well as decades of
improvements in diagnosis and treatment and regular updates of evidence-based
clinical practice guidelines, asthma control at the population level remains
suboptimal.
Canadian guidelines for the diagnosis and treatment of asthma have existed since
1989 and were most recently updated in 2003. In this series, we are using case-
based examples to highlight recent changes in recommendations for asthma
management and to highlight practical aspects of diagnosis and treatment. The case
used here focuses on the diagnosis of asthma in adults.

The presence of certain key symptoms may suggest the presence of asthma, but
can also result from airway inflammation alone, from chronic rather than reversible
airflow limitation, or from other respiratory and nonrespiratory conditions.
Moreover, asthma symptoms correlate poorly with abnormalities of lung function
(Cowie, Underwood et al. 2007) and airway inflammation and thus in isolation
may suggest a less severe form of the disease than is actually present. Although
many clinicians diagnose asthma on the basis of a trial of therapy, objective
measurements are necessary to confirm the clinical diagnosis.

Validated questionnaires may be an option in settings where objective testing is

unavailable (Kaplan, Balter et al. 2009).Asthma is an inflammatory disease
associated with symptoms resulting from abnormalities of airway function, in
particular wide, short-term variations in airflow resistance in the intrapulmonary
airways. Thus, a conclusive diagnosis of asthma is based on tests designed to
detect rapid changes in the forced expiratory volume in 1 second (FEV 1) or peak
expiratory flow. Although this review focuses particularly on diagnosis, these tests
can also be used to assess asthma control and as an aid in optimizing chronic
therapy.

The chronic inflammation of asthma is associated with airway hyperresponsiveness

that leads to recurrent symptoms, yet lung function may nevertheless remain
normal. Identification of airway hyperresponsiveness thus has clinical value,
particularly in the diagnosis of asthma in people with normal spirometry results or

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with symptoms uncharacteristic of asthma. Airway hyperresponsiveness is usually
measured using direct stimuli, such as methacholine or histamine, that act by
stimulating specific receptors on the bronchial smooth muscle to cause contraction
and narrowing of the airways.

The inflammation associated with asthma is characteristically eosinophilic.

Measurement of sputum eosinophilia has been proposed for clinical use in the
diagnosis of asthma. However, some patients with this condition have neutrophilic
inflammation, whereas, conversely, some patients without asthma have
eosinophilic inflammation.

At present, diagnostic investigations recommended in national asthma guidelines

predominantly interpret large airway pathophysiology and fail to take into account
the small airways. This is likely due to the ease of access and also minimal
invasiveness of large airway tests. Small airways are defined as airways without
cartilage and < 2 mm in diameter (Ranga and Kleinerman 1978). Between the
trachea and the alveoli there are 23 generations of branching tubes comprising
large and small airways . Historically, the small airways have been viewed as a
“silent zone” because they account for less than 10% of total airway resistance, and
until recently, commonly used imaging and physiological tests have not been able
to detect abnormalities in these airways. Accurate investigation of the small
airways was only possible by invasive procedures such as transbronchial biopsy
and post-mortem examination.

Non-invasive investigations that can reflect small airways such as forced

expiratory flow at 25–75% of pulmonary volume (FEF 25–75) have been accessible,
but the results are highly variable due to its dependence upon the forced vital
capacity (FVC) (Barreiro and Perillo 2004). It has now been accepted that the
small airways in patients with asthma are a significant contributor to airflow
limitation. Involvement of these airways is not detected by routine spirometry and
peak flow monitoring . Using these large airway tests alone may result in missed
diagnosis of asthma in patients that have early disease with preserved large
airways. It has been demonstrated that pathology can occur in the small airways of
patients before changes are detected in spirometry and even before onset of asthma
symptoms (McNulty and Usmani 2014). Recent advances in non-invasive tests that
are able to assess small airway function and composition could potentially enable
the detection of asthma at an earlier stage.

Novel tests of small airways include functional tests assessing airway physiology
and tests that detect underlying pathology and inflammation. Some promising tests
providing information on airway physiology include impulse oscillometry (IOS)
and multiple-breath washout (MBW) (Kjellberg, Viklund et al. 2018). In addition,
various experimental non-invasive breath analysis tests are emerging and may also
have a role in detecting small airway pathology in asthma. Experimental tests
include breath composition analysis such as that seen in volatile organic
compounds (VOCs) and particles in exhaled air (PExA) (Almstrand, Josefson et al.
2012).

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It is likely that we will start to see some of these novel tests incorporated into asthma diagnostic
algorithms over time. Given the complexity of asthma, it's likely that in the future, a hybrid approach
utilizing both established and novel tests are going to be required in the optimal diagnostic
pathway. the last word goal is to develop a diagnostic pathway that is able to discriminate between
both phenotypes and endotypes. However, at this point , underlying endotypes are still being
defined, and whilst research continues during this area, it's important to take a more pragmatic
approach to diagnose and treating asthma in the present. there's an urgent clinical need to establish
an evidenced-based diagnostic pathway that can identify different subgroups of asthma and identify
patients with treatable traits. the longer term is likely to see the development of personalized
medicine, further enabling the simplest treatment for each individual patient.

Objective measurements to confirm variable expiratory airflow limitation:

In a patient with typical respiratory symptoms, obtaining objective evidence of

excessive variability in expiratory airflow limitation is essential to confirming the
diagnosis of asthma. The greater the variations in lung function, or the more times
excess variation is seen, the more likely the diagnosis is to be asthma. Spirometry
is the preferred objective measure to assess for airflow limitation and excessive
variability in lung function. It is recommended for all patients over 6 years of age
who are able to undergo lung function testing (Lougheed, Lemiere et al. 2012).

Spirometry measures airflow parameters such as the forced vital capacity (FVC,
the maximum volume of air that can be exhaled) and the forced expiratory volume
in 1 s (FEV1). Lung volumes are not measured with spirometry, and instead require
full pulmonary function testing. The ratio of FEV 1 to FVC provides a measure of
airflow obstruction. In the general population, the FEV 1/FVC ratio is usually
greater than 0.75–0.80 in adults, and 0.90 in children. Any values less than these
suggest airflow limitation and support a diagnosis of asthma. Because of the
variability of asthma symptoms, patients will not exhibit reversible airway
obstruction at every visit and a negative spirometry result does not rule out a
diagnosis of asthma.
This is particularly true for children who experience symptoms predominantly with
viral infections, or who are well controlled on asthma medications. Therefore, to
increase sensitivity, spirometry should be repeated, particularly when patients are
symptomatic (Kaplan, Balter et al. 2009).

Once airflow obstruction has been confirmed, obtaining evidence of excessive

variability in expiratory lung function is an essential component of the diagnosis of
asthma. In general, an increase in FEV 1 of > 12% and, in adults, a change of >
200 mL from baseline after administration of a rapid-acting bronchodilator is
accepted as being consistent with asthma.

Peak expiratory flow (PEF) monitoring is an acceptable alternative when

spirometry is not available, and can also be useful for diagnosing occupational
asthma and/or monitoring response to asthma treatments. However, PEF is not
recommended for diagnosing asthma in children. PEF is usually measured in the
morning and in the evening. A diurnal variation in PEF of more than 20% or an
improvement of at least 60 L/min or at least 20% after inhalation of a rapid-acting
bronchodilator suggests asthma (Lougheed, Lemière et al. 2010).

Although simpler to perform than spirometry, PEF is more effort-dependent and

much less reliable. Therefore, as mentioned earlier, spirometry is the preferred
method of documenting variable expiratory airflow limitation and confirming the
diagnosis of asthma.

Tests of bronchial hyperactivity

When spirometry is normal, but symptoms and therefore the clinical history are suggestive of
asthma, measurement of airway responsiveness using direct airway challenges to inhaled
bronchoconstrictor stimuli (e.g., methacholine or histamine) or indirect challenges (e.g., with

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mannitol or exercise) may help confirm a diagnosis of asthma.
Tests of bronchial hyperreactivity should be conducted during a ccordance with standardized
protocols in a pulmonary function laboratory or other facility equipped to manage acute
bronchospasm. Bronchopovocation testing involves the patient inhaling increasing doses or
concentrations of an inert stimulus until a given level of bronchoconstriction is achieved, typically a
20% fall in FEV1.
An inhaled rapid-acting bronchodilator is then provided to reverse the obstruction. Test results are
usually expressed because the provocative dose (PD) or provocative concentration (PC) of the
provoking agent that causes the FEV1 to drop by 20% (the PD20 or PC20, respectively). For
methacholine, most pulmonary function laboratories use a PC20 value of but 4-8 mg/mL as the
threshold for a positive result indicative of airway hyperreactivity, supporting a diagnosis of asthma.
However, positive challenge tests aren't specific to asthma and may occur with other conditions
such as allergic rhinitis and chronic obstructive pulmonary disease (COPD). Therefore, tests of
bronchial hyperreactivity could also be most useful for ruling out asthma among individuals who are
symptomatic.
A negative test end in a symptomatic patient not receiving anti-inflammatory therapy is highly

sensitive (Kaplan, Balter et al. 2009).

In order to properly assess lung function, patients who have been prescribed a
combination of an ICS and a LABA must discontinue these long-acting
medications 24 h prior to tests of airway hyperreactivity or testing with spirometry.
Tests of bronchial hyperreactivity are contraindicated in patients with FEV 1 values
less than 60–70% of the normal predicted value (since bronchoprovocation could
cause significant bronchospasm), in patients with uncontrolled hypertension or in
those who recently experienced a stroke or myocardial infarction (Crapo 2000).

Non-invasive markers of airway inflammation

The measurement of inflammatory markers such as sputum eosinophilia

(proportion of eosinophils in the cell analysis of sputum) or levels of exhaled nitric
oxide (a gaseous molecule produced by some cells during an inflammatory
response) can also be useful for diagnosing asthma. Evidence suggests that exhaled
nitric oxide levels can be supportive of the diagnosis of asthma, and may also be
useful for monitoring patient response to asthma therapy (Wenzel 2012).

It is still not accepted as a standard test for the diagnosis of asthma. Although these
tests have been studied in the diagnosis and monitoring of asthma, they are not yet
widely available in Canada.

Allergy skin testing

Allergy skin prick (epicutaneous) testing is suggested to identify possible environmental allergic
triggers of asthma and is helpful in identifying the asthma phenotype of the patient. Testing is
usually performed using the allergens relevant to the patient’s geographic region. Although allergen-
specific IgE tests that provide an in vitro measure of a patient’s specific IgE levels for specific
allergens are suggested as an alternative to skin tests, these tests are less sensitive, more invasive
(requires venipuncture), and costlier than skin prick tests. there's no minimum age at which skin
prick testing can be performed

Differential diagnosis

Conditions that should be considered in the differential diagnosis of adults with

suspected asthma may include: COPD, bronchitis, gastrointestinal reflux disease,
recurrent respiratory infections, heart disease, and vocal cord dysfunction.
Distinguishing asthma from COPD can be particularly difficult as some patients
have features of both disorders. The term asthma-COPD overlap syndrome
(ACOS), though not a single disease entity, has been adopted to describe these
patients. A recent population-based cohort study conducted in Ontario suggests
that the prevalence of concurrent asthma and COPD is increasing, particularly in
women and young adults (Kendzerska, Sadatsafavi et al. 2017).

Types of Asthma:

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Asthma occurs in different patterns. Different types of asthma are classified by
their temporal pattern, or the time when attacks occur and the following forms
have been identified.

Intermittent asthma

In some people episodes of asthma occur between intervening symptom-free periods. In most
cases, the asthmatic symptoms resolve spontaneously. The symptom-free periods are usually quite
long. In such patients, viral infections of the tract such as those which cause the common cold are a
common trigger of asthma symptoms. this is often especially true in small children between 2-5
years of age who may get 8-12 viral colds and coughs a year. In other cases, strenuous exercise or
physical activity, exposure to cold air, or certain environmental agents are found to act as asthma
triggers.
Seasonal allergic asthma
Seasonal allergic asthma has been observed in response to the seasonal release of
allergens like pollens that occur in the environment. Mold spores are another common explanation
for seasonal asthma. it's important to understand how your local climate and air allergen level vary
from season to season to determine whether you have this type of asthma is, and to stop it by
appropriate measures.
Non-seasonal allergic asthma
Everyone with allergies doesn't necessarily develop asthma, and neither do all asthmatics have
allergies. However, allergies do intensify asthma in some cases. Thus, exposure to cold or dry air,
dust, pet hair, or pollen may depart an acute attack of asthma. additionally , there's another type of
allergic asthma in which the asthma triggers are not related to season, but could also be due to a
hyper-reaction of the airway mucosa to things that are not typically allergenic. These include viruses,
air pollutants or irritants like tobacco smoke or paint fumes, heavy exercise, certain chemicals in
food or drugs, and changes within the weather.

Exercise-induced bronchoconstriction (EIB)

This term is employed when a bout of exercise is followed by a narrowing of the airways. it's
going to be found in up to 80% of people with asthma. However, not all cases of EIB are found
in asthma patients. it's thought to be caused by the dehydration and/or heating up that occurs
with strenuous physical activity in a dry climate. In children with asthma, it's often the first
symptom to develop. Certain irritants which are encountered during the course of
varied sports activities include chlorine in swimming pools, air pollutants while jogging,
running, or cycling cold dry air during winter sports, and powerful smells due to chemicals or
perfumes in a gym environment. The transient and treatable nature of EIB means patients
with this condition should not be prevented from physical activity at any level whatsoever,
provided it's properly managed.

Occupational asthma
In this form, the symptoms are caused or worsened by chemical irritants or dust within the air.
Pre-existing asthma also can become worse with such exposure. Clues to the character of a
patient’s asthma may include the time of earliest symptoms coinciding with a change of
workplace or job, an improvement in symptoms upon leaving the workplace, and therefore
the occurrence of breathing difficulty due to workplace chemicals. There are over 250
occupational asthma triggers or promoters. As always, pre-existing asthma also
increases the danger of this condition, as does smoking and therefore the presence of allergies
in the individual or the family. Some high-risk occupations include bakers, manufacturers of
medicine and detergents, those that measure grain, metal workers and laboratory workers,
plastic workers, and woodworkers.
Chronic asthma
Also called persistent asthma, this condition is defined by daily symptoms or those which
recur several times every week . The intensity of symptoms could also be quite variable, but
there are not any long periods without symptoms. Acute exacerbations may supervene at any
time upon the chronic course of the disease.
These could also be traced in some cases to seasonal increases in air allergens or viral
pathogens that provoke airway inflammation. Chronic asthma must be correctly
identified during a patient to ensure proper intervention strategies.
Adult-onset asthma
Most cases of asthma begin in childhood, but in some patients, the primary symptoms appear
only in adult life. The causes could also be many. Some people were just not exposed to
potential triggers for his or her asthma until they became adults. for instance , they're exposed
to a house pet when their roommate brings one home, or they start to work in an environment
containing chemical fumes, that trigger their latent hypersensitivity. It could even be a virus
infection that sets off an asthmatic reaction for the first time in adulthood.
Difficult-to-control and severe asthma
A 2014 study suggests that around 5–10% of individuals with asthma have severe asthma.
Some individuals have severe symptoms for reasons that don't relate directly to asthma. for

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instance , they'll not yet have learned the correct way to use an inhaler. Others have severe
refractory asthma. In these cases, asthma doesn't respond to treatment, even with high
dosages of medication or the right use of inhalers. this sort of asthma may affect 3.6% of
individuals with the condition. Eosinophilic asthma is another sort of asthma that, in severe
cases, might not respond to the usual medications. Although some people with eosinophilic
asthma manage with standard asthma medications, others may enjoy specific biologic
therapies. One sort of biological medication reduces the number of eosinophils, which are a
kind of blood cell involved in an allergic reaction that can trigger asthma.

Management
The medical diagnosis of asthma is unique for infants and young children and includes
anatomic defects (laryngo- or tracheomalacia, congenital heart defects), physiological
defects (primary ciliary dyskinesia), and genetic conditions like cystic fibrosis and primary
immunodeficiency, to call just a few conditions. A chest X-ray could also be considered in the
workup of a child with suspected asthma, particularly if the diagnosis is unclear or if the kid is
not responding as expected to treatment. the first goal of asthma management is to achieve
and maintain control of the disease in order to prevent exacerbations (abrupt and/or
progressive worsening of asthma symptoms that often require immediate medical attention
and/or the use of oral steroid therapy) and reduce the risk of morbidity and mortality. Other
goals of therapy are to attenuate the frequency and severity of asthma symptoms,
decrease the necessity for reliever medications, normalize physical activity, and improve lung
function also as the overall quality of life. the extent of asthma control should be assessed at
each visit and treatment should be tailored to achieve control. In most asthma patients,
control are often achieved using both trigger avoidance measures and pharmacological
interventions.

The pharmacologic agents commonly used for the treatment of asthma are often classified as
controllers (medications taken daily on a long-term basis that achieve control primarily
through anti-inflammatory effects) and relievers (medications used on an as-needed basis for
quick relief of bronchoconstriction and symptoms). Controller medications include ICSs,
leukotriene receptor antagonists (LTRAs), LABAs together with an ICS, long-acting
muscarinic receptor antagonists (LAMAs), and biologic agents including anti-IgE therapy,
and anti-IL-5 therapy. Reliever medications include rapid-acting inhaled beta2-agonists and
inhaled anticholinergics.

Allergen-specific immunotherapy can also be considered in most patients with allergic

asthma but must be prescribed by physicians who are adequately trained in the treatment of

allergies (see Allergen-specific immunotherapy article in this supplement (Frew 2010).

Systemic corticosteroid therapy may also be required for the management of acute
asthma exacerbations.The goal of asthma therapy is to treat individuals using the
least amount of medications required to control asthma symptoms and maintain
normal daily activities.

When asthma control has been achieved, ongoing monitoring and follow-up are
essential to monitor for side effects, preserve lung function over time, observe for
new triggers, and establish the minimum maintenance doses required to maintain
control. However, because asthma is a variable disease, treatment may need to be
adjusted periodically in response to loss of control .

It is also imperative that all asthma patients be empowered to take an active role in
the management of their disease. This can be accomplished by providing patients
with a personalized written action plan for disease management and by educating
the patient about the nature of the disease, the role of medications, the importance
of adhering to controller therapy, and the appropriate use of inhaler devices.

The goal of asthma therapy is to treat individuals using the least amount of
medications required to control asthma symptoms and maintain normal daily

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activities. When asthma control has been achieved, ongoing monitoring and
follow-up are essential to monitor for side effects, preserve lung function over
time, observe for new triggers, and establish the minimum maintenance doses
required to maintain control. However, because asthma is a variable disease,
treatment may need to be adjusted periodically in response to loss of control
(Akinbami, Moorman et al. 2009). It is also imperative that all asthma patients be
empowered to take an active role in the management of their disease. this will be accomplished by
providing patients with a personalized written action plan for disease management and by educating
the patient about the nature of the disease, the role of medicines , the importance of adhering to
controller therapy, and therefore the appropriate use of inhaler devices. Once a written action plan
for management is provided, ongoing follow-up should include:
• Reviewing the asthma action plan at each visit to work out if modifications are required based on
the level of asthma control
• Observation of inhaler device technique at each visit
• Counselling patients or caregivers who smoke on smoking cessation;
• Measuring height and weight of youngsters and adolescents to monitor growth velocity and
potential corticosteroid side effects
• Screening for signs and symptoms of adrenal suppression for people requiring moderate- to high-
dose ICS
• Asking about food or venom allergies and ensuring that patients with these allergies are prescribed
an epinephrine autoinjector and given a written anaphylaxis plan. Patients with poorly controlled
asthma and food/venom allergy are at greater risk for anaphylaxis upon accidental exposure to their
known allergen.
Inhaled medication delivery devices:
Inhaled asthma medications are available a variety of forms including pressurized metered-dose
inhalers (pMDIs) and dry powder inhalers (DPIs) (Turbuhaler, Diskus, Twisthaler, Ellipta). Not all
medications are available within the same delivery devices. Also, some devices have dose counters
included, et al. , like pMDIs, do not. the foremost important factor in selecting a medication delivery
device is to ensure that the patient uses it properly.
In children, it's recommended that pMDIs always be used with a spacer device since they are as
effective as nebulizers; a pMDI with a spacer is also preferred over nebulizers. A spacer with
a mask is recommended for children 2–4 years of age, while a spacer with a mouthpiece is
suggested for children 4–6 years of age. To transition to a spacer with a mouthpiece, children must
be ready to form a seal around the mouthpiece and breathe through their mouths. for youngsters 6
years of age or over, a pMDI plus spacer with mouthpiece or DPI is suggested . Since children
must have the sufficient inspiratory force to use a DPI, these devices are generally not
recommended for youngsters under 6 years of age.

Reliever medications

Inhaled rapid-acting beta2-agonists are the preferred reliever medications for the
treatment of acute symptoms, and should be prescribed to all patients with asthma.
In Canada, several short-acting beta2-agonists (SABAs; e.g., salbutamol,
terbutaline) and one LABA (formoterol) are approved for this indication. SABAs
should only be taken on an as needed basis for symptom relief. Use of an as-
needed SABA in the absence of a controller therapy should be reserved for patients
with symptoms less than twice per month, without nocturnal wakening in the past
month, or an exacerbation within the past year. In children with well controlled
asthma, a SABA should be used less than three times per week.

Unlike other LABAs, formoterol has a rapid onset of action and, therefore, can be
used for acute symptom relief. Given that LABA monotherapy has been associated
with an increased risk of asthma-related morbidity and mortality, formoterol

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should only be used as a reliever in patients 12 years of age or older who are on
regular controller therapy with an ICS (Lougheed, Lemiere et al. 2012).

Short-acting anticholinergic bronchodilators, such as ipratropium bromide, may

also be used as reliever therapy. These agents appear to be less effective than
inhaled rapid-acting beta2-agonists and, therefore, should be reserved as second-
line therapy for patients who are unable to use SABAs. They may also be used in
addition to SABAs in patients experiencing moderate to severe asthma
exacerbations. Short-acting anticholinergic bronchodilator therapy is not
recommended for use in children.

Controller medications

Inhaled corticosteroids (ICSs)

ICSs are the most effective anti-inflammatory medications available for the
treatment of asthma and represent the mainstay of therapy for most patients with
the disease. Low-dose ICS monotherapy is recommended as first-line maintenance
therapy for most children and adults with asthma.

Regular ICS use has been shown to reduce symptoms and exacerbations, and
improve lung function and quality of life. ICSs do not, however, “cure” asthma,
and symptoms tend to recur within weeks to months of ICS discontinuation. Most
patients will require long-term, if not life-long, ICS treatment .

Since ICSs are highly effective when used optimally, factors other than treatment
efficacy need to be considered if ICS therapy is unsuccessful in achieving asthma
control. These factors include: misdiagnosis of the disease, poor adherence to ICS
therapy, improper inhaler technique, continued trigger exposure or the presence of
other comorbidities. If, after addressing such factors, patients fail to achieve
control with low-to-moderate ICS doses, then treatment should be modified. For
most children, ICS dose escalation (to a moderate dose) is the preferred approach
to achieve control, while the addition of another class of medications (usually a
LABA) is recommended for patients over 12 years of age (Kaplan, Balter et al.
2009). Low, medium and high doses of ICS therapy varies by age and are
summarized in table given below. Children who fail to achieve control on a
moderate ICS dose should be referred to an asthma specialist, such a respirologist,
an allergist, an immunologist or a pediatrician. It is also recommended that
children receiving daily ICS therapy do not increase their daily ICS dose with the
onset of a viral illness .

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Side effects of ICS:

The most common local adverse events associated with ICS therapy are
oropharyngeal candidiasis (also known as oral thrush) and dysphonia (hoarseness,
difficulty speaking). Rinsing and expectorating (spitting) after each treatment and
the use of a spacer with pMDI devices can help reduce the risk of these side
effects. Systemic adverse effects with ICS therapy are rare, but may occur at high
doses, such as > 500 μg of fluticasone propionate equivalent, and include changes
in bone density, cataracts, glaucoma and growth retardation . Patients using high
ICS doses should also be monitored for adrenal suppression (Issa-El-Khoury, Kim
et al. 2015). It is important to note that the potential for side effects with ICS
therapy needs to be considered in the context of other steroids (i.e., systemic,
intranasal and topical) that may be prescribed for other atopic conditions such as
allergic rhinitis or atopic dermatitis.

Combination ICS/LABA inhalers

LABA monotherapy is not recommended in patients with asthma as it does not

impact airway inflammation and is associated with an increased risk of morbidity
and mortality. LABAs are only recommended when used in combination with ICS
therapy. The combination of a LABA and ICS has been shown to be highly
effective in reducing asthma symptoms and exacerbations, and is the preferred
treatment option in adolescents or adults whose asthma is inadequately controlled
on low-dose ICS therapy, or in children over 6 years of age who are uncontrolled
on moderate ICS doses . Although there is no apparent difference in efficacy
between ICSs and LABAs given in the same or in separate inhalers, combination

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ICS/LABA inhalers are preferred because they preclude use of the LABA without
an ICS, are more convenient and may enhance patient adherence. Four
combination ICS/LABA inhalers are available in Canada: fluticasone
propionate/salmeterol, budesonide/formoterol, mometasone/formoterol and
fluticasone furoate/vilanterol. Combination budesonide/formoterol has been
approved for use as a single inhaler for both daily maintenance (controller) and
reliever therapy in individuals 12 years of age and older. It should only be used in
patients whose asthma is not adequately controlled with low-dose ICS who warrant
treatment with combination therapy (Lougheed, Lemière et al. 2010).

Leukotriene receptor antagonists

The LTRAs, montelukast and zafirlukast, are also effective for the treatment of
asthma and are generally considered to be safe and well tolerated. Because these
agents are less effective than ICS treatment when used as monotherapy, they are
usually reserved for patients who are unwilling or unable to use ICSs. LTRAs can
also be used as add-on therapy if asthma is uncontrolled despite the use of low-to-
moderate dose ICS therapy or combination ICS/LABA therapy. It is important to
note, however, that LTRAs are considered to be less effective than LABAs as add-
on therapy in adults . In children, if medium-dose ICS therapy is ineffective,
LTRAs are considered the next-line treatment option (Lougheed, Lemiere et al.
2012). If, however, the child has persistent airway obstruction, the addition of a
LABA may be preferred.

Long-acting muscarinic receptor antagonists

The LAMA, tiotropium, administered by mist inhaler can be used as add-on

therapy for patients with a history of exacerbations despite treatment with
ICS/LABA combination therapy. It is only indicated for patients 12 years of age
and older.

Theophylline

Theophylline is an oral bronchodilator with modest anti-inflammatory effects.

Given its narrow therapeutic window and frequent adverse events (e.g.,
gastrointestinal symptoms, loose stools, seizures, cardiac arrhythmias, nausea and
vomiting), its use is generally reserved for patients over 12 years of age who are
intolerant to or continue to be symptomatic despite other add-on therapies .

Biologic therapies
The anti-IgE antibody , omalizumab, has been shown to scale back the frequency of asthma
exacerbations by approximately 50%. The drug is run subcutaneously once every 2–4 weeks and is
approved in Canada for the treatment of moderate to severe, persistent allergic asthma in patients 6
years old or older. at the present , omalizumab is reserved for patients with difficult-to-control
asthma who have documented allergies, an elevated serum IgE level, and whose asthma symptoms
remain uncontrolled despite ICS therapy together with a second controller medication.

Two monoclonal antibodies to IL-5 are approved in Canada for patients aged 18 years or older with
severe eosinophilia: mepolizumab and reslizumab. These are given every 4 weeks by injection and
intravenous infusion, respectively, and are indicated in patients who are uncontrolled despite
treatment with high-dose ICS therapy and a further controller therapy, like a LABA, and who have
elevated blood eosinophils. Recently, benralizumab, a antibody against the IL-5 receptor has also
been approved in Canada for the treatment of adult patients with severe eosinophilic
asthma. it's important to note that long-term compliance with controller therapy is poor because
patients tend to stop therapy when their symptoms subside. Therefore, regular follow-up visits are
important to assist promote treatment adherence.

Systemic corticosteroids

Systemic corticosteroids, such as oral prednisone, are generally used for the acute
treatment of moderate to severe asthma exacerbations. While chronic systemic

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corticosteroid therapy may also be effective for the management of difficult to
control asthma, prolonged use of oral steroids are associated with well-known and
potentially serious adverse effects and, therefore, their routine or long-term use
should be avoided if at all possible, particularly in children . Adverse events with
short-term, high-dose oral prednisone are uncommon, but may include: reversible
abnormalities in glucose metabolism, increased appetite, edema, weight gain,
rounding of the face, mood alterations, hypertension, peptic ulcers and avascular
necrosis of the hip (Ducharme, Dell et al. 2015).

Bronchial thermoplasty

Bronchial thermoplasty involves the treatment of airways with a series of

radiofrequency pulses. This treatment may be considered for adult patients with
severe asthma despite pharmacotherapy .

Allergen-specific immunotherapy

Allergen-specific immunotherapy involves the subcutaneous or sublingual

administration of gradually increasing quantities of the patient’s relevant allergens
until a dose is reached that is effective in inducing immunologic tolerance to the
allergen. Although it has been widely used to treat allergic asthma, it is not
universally accepted by all clinical practice guideline committees due to the
potential for serious anaphylactic reactions with this form of therapy (Cox, Nelson
et al. 2011).

A Cochrane review of 88 randomized controlled trials examining the use of

allergen-specific immunotherapy in asthma management confirmed its efficacy in
reducing asthma symptoms and the use of asthma medications, and improving
airway hyperresponsiveness . Similar benefits have been noted with sublingual
immunotherapy which is now available for use in Canada for grass and ragweed
allergies, as well as house dust mite-induced allergic rhinitis (see Allergen-specific
immunotherapy article in this supplement). Evidence also suggests that allergen-
specific immunotherapy may prevent the onset of asthma in atopic individuals
(Niggemann, Jacobsen et al. 2006).

At present, allergen-specific immunotherapy should be considered on a case-by-

case basis. Allergen-specific subcutaneous immunotherapy may be considered as
add-on therapy in patients using ICS monotherapy, combination ICS/LABA
inhalers, ICS/LTRAs and/or omalizumab if asthma symptoms are controlled. It
should not be initiated in patients with uncontrolled asthma or an FEV 1 < 70% of
predicted. For subcutaneous immunotherapy, asthma must be controlled at the time
of each injection, and it must be administered in clinics that are equipped to
manage possible life-threatening anaphylaxis where a physician is present. Since
allergen-specific immunotherapy carries the risk of anaphylactic reactions, it
should only be prescribed by physicians who are specialists in allergy .

Indications for referral

In older children, adolescents and adults, referral to a specialist in asthma care (e.g.,
respirologist, allergist) is suggested when:
• Atypical asthma symptoms are present or the diagnosis of asthma is in question;
• The patient has poor asthma control (poor lung function, persistent asthma symptoms) or
severe asthma exacerbations (≥ 1 course of systemic steroids per annum or hospitalization)
despite moderate doses of ICS (with proper technique and good compliance);
• The patient requires an in depth assessment for and management of potential environmental
triggers;
• The patient has been admitted to the medical care unit (ICU) for asthma.

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