A CASE OF SEVERE ASTHMA WITH ADVERSE EFFECTS

RESULTING FROM ORAL CORTICOSTEROID OVERUSE

LITERATURE REVIEW

Cases of Severe Asthma With Adverse Effects Resulting From Oral CS Overuse and
Difficult-to-Manage Asthma in Primary Care

Asthma is a common, chronic respiratory disease affecting an estimated 235 million individuals
worldwide.1 Asthma represents 1.8% of the total global disease burden and causes an estimated 346,000
deaths worldwide each year.2, 3

ASTHMA DEFINITION AND PHENOTYPES

In the Global Strategy for Asthma Management and Prevention report provided by the Global Initiative
for Asthma (GINA), asthma is defined as follows: "Asthma is a heterogeneous disease, usually
characterized by chronic airway inflammation. It is defined by the history of respiratory symptoms such
as wheeze, shortness of breath, chest tightness, and cough that vary over time and in intensity, together
with variable expiratory airflow limitation."4

Symptoms and airflow limitation, which may resolve spontaneously or in response to medication,
characteristically vary over time and in intensity in relation to many factors including exercise, allergen
exposure, changes in weather, and pollution. Episodic flare-ups (exacerbations) of asthma are triggered
primarily by viral respiratory infections. Asthma is usually associated with airway hyperresponsiveness
to direct or indirect stimuli and with chronic airway inflammation, features that usually persist even
when symptoms are absent or lung function is normal, but which may normalise with treatment.
Importantly, exacerbations may be life-threatening and, at the very least, negatively impact quality of
life. Comorbidities present in patients with asthma include rhinitis, rhinosinusitis, nasal polyps, food
allergy, gastro-oesophageal reflux, obesity, and obstructive sleep apnoea.4

Phenotypes

Asthma is a heterogeneous disease with different demographic, clinical, and/or pathophysiological

characteristics that may be distinguished as "phenotypes."4 Phenotyping integrates biological and
clinical features, ranging from molecular, cellular, morphological, and functional to patient-oriented
characteristics.5 However, the clinical utility of these phenotypes is not fully defined, as no strong
relationship has been found between specific pathologic features and clinical patterns or treatment
responses. Common asthma phenotypes include4:

● Allergic asthma: the most easily recognized phenotype; often commences in childhood; associated
with past and/or familial history of allergic disease (eg, eczema, allergic rhinitis, or food or drug
allergy); examination of the induced sputum often reveals eosinophilic airway inflammation;
patients usually respond well to inhaled corticosteroid (ICS) treatment

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 ● Non-allergic asthma: occurs in adults; not associated with allergy; cellular profile of the sputum
may be neutrophilic, eosinophilic, or paucigranulocytic (few inflammatory cells); patients often
respond less well to ICS treatment
● Late-onset asthma: presents first in adult life, particularly in women; often not associated with
allergy; patients often require higher doses of an ICS or are relatively refractory to ICS treatment
● Asthma with fixed airflow limitation: some patients with long-standing asthma develop fixed
airflow limitation that is thought to be due to airway wall remodelling
● Asthma with obesity: some patients with obesity and asthma have prominent respiratory symptoms
and little eosinophilic airway inflammation

Severity

Asthma severity is assessed retrospectively from the level of treatment required to control symptoms
and exacerbations after an interval of several months of treatment, potentially with treatment step-down
to find a patient's minimum level of effective treatment. Mild asthma is asthma that is well controlled
with Step 1 or Step 2 treatment (described below); moderate asthma is well controlled with Step 3
treatment; and severe asthma requires Step 4 or Step 5 treatment.4

GINA provides other definitions that are pertinent for this program:

● Uncontrolled asthma is characterized by poor symptom control and/or frequent exacerbations (at
least twice a year) requiring oral corticosteroids [OCS] or serious exacerbations (at least once a
year) requiring hospitalisation.6
● Difficult-to-treat asthma is asthma that is uncontrolled despite GINA Step 4 or 5 treatment (eg,
medium- or high-dose ICS with a second controller; maintenance OCS) or that requires such
treatment to maintain good symptom control and reduce the rate of exacerbations.6
● Severe asthma, a subset of difficult-to-treat asthma, is disease that is uncontrolled despite
adherence to maximal optimised therapy and treatment of contributory factors or that worsens
when high-dose treatment is decreased.6 The European Respiratory Society (ERS)/American
Thoracic Society (ATS) Task Force on severe asthma defines severe asthma as "asthma which
requires treatment with high-dose ICS plus a second controller (and/or systemic corticosteroids) to
prevent it from becoming 'uncontrolled' or which remains 'uncontrolled' despite this therapy."5

Difficult-to-treat asthma accounts for roughly 17% of asthma cases in adults, and severe asthma for
roughly 3.7%. Severe asthma is associated with greater morbidity and higher associated healthcare
costs. Patients with severe asthma are also susceptible to side effects caused by medications for their
condition (see below).6, 7 Long-term follow-up data from over 10 years from the TENOR I and
TENOR II observational studies indicate that a prior asthma exacerbation is associated with 2.5-fold
increased odds of a future severe exacerbation. Future severe exacerbations were seen more often in
female patients and were associated with history of chronic obstructive pulmonary disease (COPD),
lower lung function, and use of combined ICS/long-acting β2-agonist (LABA) medication and systemic
corticosteroids.8

Eosinophilic Asthma

Eosinophilic asthma generally refers to the clinical inflammatory phenotype of asthma wherein a
significant number of sputum, airway, and/or blood eosinophils are present. In contrast to a phenotype,

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which refers to the observable characteristics of a disease in an individual, eosinophilic asthma is an
endotype, meaning that a specific biological mechanism is responsible for the properties of the
phenotype. About half of individuals with asthma fall into this category.9 Eosinophils have long been
recognized as playing a critical role in the pathogenesis and severity of asthma. An increased eosinophil
count is associated with increased asthma severity, frequency of exacerbations, and mortality; one
report determined the mortality risk of asthma to be 7.4-fold greater for patients with eosinophilia than
without eosinophilia.10

Among patients with severe asthma, eosinophilia in either sputum (≥ 2%) or blood (≥ 300 cells/μL) can
be detected in 32% to 40% of individuals. In many asthmatic patients, airway eosinophilia develops as a
consequence of the biological activity of both T helper 2 (Th2) lymphocytes and group 2 innate
lymphoid cells (ILC2), which are implicated in the pathogenesis of type 2 inflammation underlying
eosinophilic allergic and nonallergic asthma.11 Type 2 inflammation is characterized by cytokines such
as interleukin-4 (IL-4), IL-5, and IL-13, which are often produced by the adaptive immune system upon
recognition of allergens.6 Unlike neutrophilic asthma, type 2 eosinophilic asthma is generally well
controlled by corticosteroids. However, some patients with eosinophilic airway inflammation are
refractory to corticosteroids, exhibiting a severe, uncontrolled asthma with recurrent exacerbations. It is
likely that in these subjects with difficult-to-treat eosinophilic asthma there is an intense activation of
type 2 inflammatory pathways, leading to an exaggerated overexpression of IL-5, which decreases
eosinophil sensitivity to corticosteroids.11

DIAGNOSIS

Respiratory Symptoms

A diagnosis of asthma begins with identifying a characteristic pattern of respiratory symptoms.

Wheeze, shortness of breath, cough, and chest tightness are the predominant symptoms of asthma, and
patients generally present with more than one symptom. The symptoms vary over time and in intensity;
are often worse at night or on waking; and are often triggered by viral respiratory infections; exercise;
allergen exposure; changes in weather; cold air; laughter; or irritants such as car exhaust fumes, smoke,
or strong smells. Commencement of respiratory symptoms in childhood, a history of allergic rhinitis or
eczema, or a family history of asthma or allergy increases the probability of all asthma phenotypes.4

Physical Examination

Physical examination of patients with asthma is often normal, but expiratory wheezing (rhonchi) on
auscultation may be found. Wheezing may only be heard on forced expiration or may be absent and is
not a reliable sign, even during severe asthma exacerbations, due to severely reduced airflow ("silent
chest"), though other physical signs of respiratory failure are usually present at the time. During a
severe exacerbation, a silent chest is a sign of impending respiratory arrest and needs to be addressed
urgently. Furthermore, wheezing is not always indicative of asthma and may occur instead with upper
airway dysfunction, COPD, respiratory infections, tracheomalacia, inhaled foreign body, or on forced
expiration in anyone. Crackles (crepitations) and inspiratory wheezing are not features of asthma. There
may be clinical signs of allergic rhinitis or nasal polyposis may occur (eg, nasal polyps, transverse nasal
crease, hypertrophy of inferior nasal turbinates).4

Lung Function Testing

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For patients with signs and symptoms of asthma, lung function testing is performed to document
variable expiratory airflow limitation, meaning expiratory lung function varies over time and in
magnitude to a greater extent than in healthy populations. The greater the variability, or the more
occasions excess variation is seen, the more confident the diagnosis of asthma. Lung function testing
may use either forced expiratory volume in 1 second (FEV1) from spirometry or peak expiratory flow
(PEF; using the same meter each time). To document true airflow limitation, a reduced ratio of FEV1 to
forced vital capacity (values less than normal: > 0.75-0.80 in adults and > 0.90 in children) should be
confirmed at least once in the diagnostic process.4 Despite its centrality to the proper workup of
asthma, only about 40% to 50% of patients receive spirometry of reasonable quality.12

Variability—the improvement and/or deterioration in symptoms and lung function—may be identified

over the course of 1 day, from day to day, from visit to visit, seasonally, or from a reversibility test,
which refers to either rapid improvements in FEV1 of 12%, measured within minutes after inhalation
of a rapid-acting bronchodilator (eg, 200–400 μg of salbutamol), or more sustained improvement over
days or weeks after the introduction of an effective controller treatment such as an ICS. Other testing
options include measuring a decrease in lung function after exercise or during a bronchial provocation
test or excessive variation in lung function between visits, though the latter is less reliable. If possible,
evidence of variable airflow limitation should be documented before treatment is started.4 Generally, in
adults with respiratory symptoms typical of asthma, an increase or decrease in FEV1 of ≥ 12% or ≥ 200
mL from baseline, or a change in PEF of ≥ 20%, is consistent with asthma.4, 13

In essence, performing lung function testing in a patient who is asymptomatic will only give an estimate
of best lung function at best. To be of value, tests need to be performed when the patient is unstable or
symptomatic.

Eosinophilic Asthma

The optimal workup for patients with severe asthma should also include testing for eosinophilic asthma
through fractional concentration of exhaled nitric oxide (FENO), total eosinophil counts in peripheral
blood, and (if available) induced-sputum eosinophil counts. FENO and eosinophilia are higher in
asthma that is characterized by type 2 inflammation (blood eosinophils (≥ 150 cells/μL, sputum
eosinophils ≥ 2%, and/or FENO ≥ 20 ppb). However, significant eosinophilic inflammation is only
likely if FENO is above 40 ppb (UK guidelines) or 50 ppb (ATS guidelines). Atopic status should also
be evaluated with skin prick testing or measurement of specific immunoglobulin E (IgE) levels in the
blood, as some patients with severe asthma and atopy may particularly benefit from anti-IgE
immunomodulatory therapy.4, 6

ASSESSMENT OF ASTHMA

Assessment of asthma involves the 2 domains of asthma control: symptom control (or impairment) and
future risk of adverse outcomes. The clinician must also consider treatment issues such as inhaler
technique and adherence, medication side effects, and comorbidities.4

Assessing Symptom Control

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Symptom control is determined from the frequency of daytime and night-time asthma symptoms and
reliever use, and from activity limitation. Notably, poor symptom control is a risk factor for future
exacerbations. Simple screening tools are available, such as the consensus-based GINA symptom
control tool, which provides the level of asthma control based on patient responses to several questions
(covering the past 4 weeks).4 The Asthma Control Test (ACT) is an alternative, self-administered tool
to determine control and identify patients with poorly controlled asthma. This 5-item tool assesses the
impact of a patient's asthma on daily functioning based on rating symptoms over the past 4 weeks using
a 5-point scale that ranges from 1 (poor control of asthma) to 5 (complete control of asthma; a total
score > 19 indicates well-controlled asthma).14

Assessing Future Risk of Adverse Outcomes

Asthma control also involves identifying a patient's risk of adverse outcomes, including exacerbations,
fixed airflow limitations, and medication side effects. This assessment is important because asthma
symptoms may not be perceived, leaving airway inflammation untreated. Additionally, other conditions
or comorbidities may contribute to respiratory symptoms or symptom reporting, and some patients have
few symptoms despite poor lung function. A thorough description of risk factors for exacerbations (eg,
frequency of reliever use, higher bronchodilator reversibility, pregnancy), for developing fixed airflow
limitation (eg, lack of ICS treatment, exposure to environmental triggers), and for medication side
effects (eg, high-dose and/or potent ICS) are listed in the GINA report.4

Role of Lung Function in Assessing Asthma Control

Lung function should be assessed at diagnosis or at the start of treatment. Most patients exhibit
approximately 90% of achievable response to ICS after 2 weeks, so this should be rechecked and
reviewed after 2 to 3 weeks or after a change in medication to assess the patient's personal best FEV1
(which provides a more useful comparison in clinical practice than FEV1 percent predicted), and
periodically thereafter. More frequent assessment should be made in patients with exacerbations, in
those at risk of decline in lung function, and in children.4

A low FEV1 predicted identifies patients at greater risk of asthma exacerbations independent of
symptom levels, especially if FEV1 is < 60% predicted. A low FEV1 predicted is a risk factor for lung
function decline independent of symptom levels and suggests limitation of lifestyle or poor perception
of airflow limitation. In patients with frequent respiratory symptoms, a normal or high FEV1 may
suggest alternative causes for the symptoms (eg, cardiac disease). Persistent bronchodilator reversibility
in a patient taking controller treatment suggests uncontrolled asthma.4

Short-term PEF monitoring is also an option for most patients, though long-term PEF monitoring is
reserved for patients with severe asthma or for those with impaired perception of airflow limitation.
Excessive variation in PEF suggests suboptimal asthma control and increases the risk of exacerbations.4

TREATMENT

The long-term goals of asthma management are to achieve good symptom control and to minimize
future risk of exacerbations, fixed airflow limitation, and side effects of treatment. The patient's own
goals regarding asthma and its treatment should also be identified, as effective management requires

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cooperation between the patient and healthcare provider. Treating asthma involves control-based
management and the adjustment of treatment (pharmacologic and nonpharmacologic) in a continuous
cycle of assessment, treatment, and review of the patient's response in terms of both symptom control
and reduction of the risk for adverse outcomes.4

Categories of Asthma Medications

Pharmacologic options for treating asthma belong to the following categories4:

● Controller medications: used for regular maintenance treatment and to reduce airway
inflammation, control symptoms, and reduce future risks (ie, exacerbations and decline in lung
function)
● Reliever (rescue) medications: used for as-needed relief of breakthrough symptoms (ie, during
worsening asthma or exacerbations) or for short-term prevention of exercise-induced
bronchoconstriction; goal is to reduce or eliminate their use in successful asthma control
● Add-on therapies for patients with severe asthma: used in patients with persistent symptoms and/or
exacerbations despite optimized treatment with high-dose controller medications and treatment of
modifiable risks

Stepwise Treatment of Asthma

Treatment of asthma should follow these stepwise recommendations15:

● Step 1 – as-needed low-dose ICS-formoterol (off-label; based on data only for

budesonide-formoterol) (preferred controller) or low-dose ICS taken whenever short-acting
β2-agonist (SABA) is taken; for quick relief of asthma symptoms, as-needed low-dose
ICS-formoterol (preferred reliever) or as-needed SABA
● Step 2 – daily low-dose ICS or as-needed low-dose ICS-formoterol (preferred controller), or
leukotriene receptor antagonist (LTRA) or low-dose ICS taken whenever SABA taken; reliever
recommendations identical to those in step 1
● Step 3 – low-dose ICS-LABA (preferred controller) or medium-dose ICS or low-dose ICS +
LTRA in addition to reliever therapy with as-needed low-dose ICS-formoterol (preferred) or
as-needed SABA
● Step 4 – medium-dose ICS-LABA (preferred controller) or high-dose ICS, add-on tiotropium or
add-on LTRA in addition to reliever therapy with as-needed low-dose ICS-formoterol (preferred)
or as-needed SABA
● Step 5 – high-dose ICS-LABA (preferred controller) with option to add low-dose OCS, with
consideration of side effects, in addition to reliever therapy with as-needed low-dose
ICS-formoterol (preferred) or as needed SABA; patients at Step 5 should also be referred for
phenotypic assessment for add-on therapy with tiotropium, anti-IgE, anti-IL-5, or anti-IL-4
therapy

2019 GINA Update for Preferred Initial Treatment

Though outside the primary scope of this program, a major change in the preferred initial treatment for
all patients with asthma has been reported in the 2019 GINA guidelines. The guidelines state, "From
2019, for safety, GINA no longer recommends starting with SABA-only treatment. GINA recommends

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that all adults and adolescents with asthma should receive ICS-containing controller treatment, to reduce
their risk of serious exacerbations and to control symptoms." The new ICS-containing controller options
are15:

● For mild asthma: as-needed low-dose ICS-formoterol (off-label; based on data only for
budesonide-formoterol) (preferred option) as both a controller and reliever, or if not available,
low-dose ICS taken whenever SABA is taken (off-label)
● Regular ICS or ICS-LABA every day, plus as-needed SABA
● Maintenance and reliever treatment with ICS-formoterol, with the reliever being low-dose
budesonide-formoterol or beclomethasone dipropionate (BDP)-formoterol

These recommendations are the culmination of a 12-year campaign by the GINA committee to obtain
new evidence about strategies for treating patients with mild asthma, with the aims of reducing the risk
of asthma-related exacerbations and death, including in patients with mild asthma; providing consistent
messaging about the aims of asthma treatment (eg, reduce SABA reliance), including prevention of
exacerbations; and avoiding the establishment of patient reliance on SABA use early in the course of
disease. Detailed rationales for each recommendation are available, but the crux of this paradigm shift
in the initial care of patients with asthma lies in the accumulation of evidence demonstrating the
negative outcomes associated with reliance on SABA reliever use. For example, there is an increased
risk of exacerbations and lower lung function with SABA-only use and severe exacerbations or even
death with SABA overuse.15

Recommendations for Severe Asthma

GINA provides specific guidelines for patients with difficult-to-treat and severe asthma in its
Difficult-to-Treat & Severe Asthma report, updated in April 2019. For the former, it recommends
determining if there are any factors contributing to the disease state, such as incorrect inhaler
technique, suboptimal adherence, comorbidities, modifiable risk factors, and overuse of SABAs.
Management should then be optimized with asthma education, optimisation of treatment, treatment of
comorbidities, non-biologic add-on therapy (eg, LABA, tiotropium, or LTRA, if not used),
nonpharmacologic interventions, and/or a trial of high-dose ICS. If asthma is controlled at this point,
treatment may be stepped down; if it is still uncontrolled or is uncontrolled upon step-down, a diagnosis
of severe asthma is made, and the patient should be referred to a specialist if possible.6

For severe asthma, the GINA recommendations call for assessment of the phenotype during high-dose
ICS treatment (or lowest possible dose of OCS) and investigating for comorbidities and differential
diagnoses. If there is evidence of type 2 inflammation, the clinician may consider increasing the ICS
dose, if the patient is not already on maximal doses, for 3 to 6 months before considering biologic
therapy. Add-on biologic therapy targeting type 2 inflammation should also be considered for patients
with exacerbations and allergic/eosinophilic biomarkers on high-dose ICS/LABA, with or without daily
OCS. Biologics targeting IL-5 should be selected for severe eosinophilic asthma (exacerbations in the
last year, blood eosinophils ≥ 300/μL), and anti-IgE biologics for those with severe allergic asthma. An
anti-IL-4 biologic (dupilumab) is also appropriate for severe eosinophilic/type 2 asthma (exacerbations
in the last year, blood eosinophils ≥ 150/μL, or FENO ≥ 25 ppb). Factors predictive of a good response
to IL-5-directed biologics include higher blood eosinophils, more exacerbations in the previous year,
adult onset of asthma, and nasal polyposis. Factors predictive of a good response to IL-4-directed
biologics include higher blood eosinophils and higher FENO; these agents may also be used to treat
moderate to severe atopic dermatitis and nasal polyposis. Factors that may predict a good response to
anti-IgE therapies are blood eosinophils ≥ 260/μL, FENO ≥ 20 ppb, allergen-driven symptoms, and

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childhood onset of asthma. If biologic therapy is not available or affordable for the patient, higher-dose
ICS (if not previously used), non-biologic add-on therapy (eg, LABA, tiotropium, or leukotriene
receptor antagonist), or add-on low-dose OCS may be considered.6

ASTHMA PHARMACOTHERAPY

Controller Medications

Inhaled Corticosteroids

ICS treatment is the most effective anti-inflammatory therapy for the treatment of persistent asthma.
ICS treatment, which is available at low, medium, or high doses, depending on patient need, includes
beclometasone dipropionate (HFA [hydrofluoroalkane propellant]), budesonide (DPI [dry powder
inhaler]), budesonide (nebulizer), ciclesonide (HFA), fluticasone furoate (DPI), fluticasone propionate
(DPI), fluticasone propionate (HFA), mometasone furoate, and triamcinolone acetonide. Most of the
benefit from an ICS is achieved in adults at relatively low doses, therefore, add-on therapy with another
class of controller such as a LABA is generally recommended as opposed to increasing the dose of an
ICS. However, some patients may benefit from long-term therapy with higher doses of an ICS.16

Local adverse effects from ICS treatment include oropharyngeal candidiasis, dysphonia, and
(occasionally) coughing from upper airway irritation, all of which may be reduced by using a spacer
device. Systemic effects differ for each type of ICS but are unlikely among adults treated with ≤ 400
μg budesonide or equivalent daily. However, long-term treatment adverse effects with high doses of an
ICS include easy bruising, adrenal suppression, and decreased bone mineral density. Lastly, exposure to
high doses of an ICS may increase the risk of tuberculosis in endemic regions, though ICS treatment is
not contraindicated in patients with active tuberculosis.16

ICS/LABA Combinations

Addition of a LABA to ICS treatment in the form of a combination ICS/LABA inhaler can improve
clinical asthma outcomes and reduce the number of exacerbations. ICS/LABA inhalers for maintenance
treatment include beclomethasone/formoterol, budesonide/formoterol, fluticasone furoate/vilanterol
trifenoate (once daily), fluticasone propionate/formoterol, fluticasone propionate/salmeterol, and
mometasone/formoterol. Also, low-dose combination inhalers containing the rapid-acting β2-agonist
formoterol with either budesonide or beclomethasone may be used for both maintenance and reliever
treatment.16 Formoterol has a more rapid onset of action than salmeterol17; thus it may be suitable for
symptom relief as well as symptom prevention.16

Adverse effects from inhaled LABAs include headache and cramps. Systemic adverse effects such as
cardiovascular stimulation, skeletal muscle tremor, and hypokalaemia are less common than with oral
treatment. Due to a possible risk of exacerbations or asthma-related death with LABA monotherapy,
LABAs should never be used as a substitute for ICS or OCS and should only be used in combination
with an appropriate dose of an ICS as determined by a physician.16

Leukotriene Modifiers

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Leukotriene modifiers include leukotriene receptor antagonists (LTRAs) (eg, montelukast,
investigational pranlukast, and zafirlukast) and a 5-lipoxygenase inhibitor (zileuton). They have a small
and variable bronchodilator effect; improve lung function; and reduce symptoms, airway inflammation,
and asthma exacerbations. They can be used as add-on therapy with an ICS in patients with moderate to
severe asthma to reduce exacerbations, improve asthma control, and potentially reduce the dose of the
ICS. However, leukotriene modifiers are less effective than LABAs as add-on therapy. Few, if any,
class-related effects have been recognized with leukotriene modifiers, except for zileuton, which is
associated with liver toxicity. Monitoring liver function is recommended during treatment with zileuton.
16

Chromones

Sodium cromoglicate and nedocromil sodium have a favourable safety profile (ie, uncommon side
effects of cough upon inhalation and pharyngeal discomfort) but low anti-inflammatory efficacy and a
requirement for meticulous daily cleaning. Therefore, chromones are not recommended for routine use.
16

Systemic Corticosteroids

Long-term treatment (ie, > 2 weeks) with OCS may be required for severe, uncontrolled asthma, but
long-term use of OCS is limited by the risk of significant adverse effects. Long-term OCS use is
associated with such adverse events as obesity, diabetes, osteoporosis, cataracts, hypertension, and
adrenal suppression, and short-term OCS use is associated with sleep disturbance and elevated risk of
infection, fracture, and thromboembolism.6, 7 A longitudinal, observational study that followed 3648
patients with severe asthma found that those with medium and high exposure to systemic
corticosteroids had significantly higher risks of corticosteroid-related complications and more
emergency department and inpatient visits than those with low exposure.18 Furthermore, long-term ICS
treatment has a more favourable outcome in terms of therapeutic index (effect/side effect) than
systemic corticosteroids, of which oral are preferred over intramuscular or intravenous.16 Clinicians
should employ OCS-sparing strategies whenever possible by making use of other medication classes
and/or treatment strategies.

Short-term treatment with systemic corticosteroids is used in the setting of an acute exacerbation to
prevent progression of the exacerbation, reduce the need for emergency care and hospitalisation,
prevent early relapse after emergency treatment, and reduce overall morbidity. Effects are observed 4
to 6 hours after treatment. A typical short-term course of OCS is 40–50 mg of prednisolone given daily
for 5 to 10 days. Adverse effects of such corticosteroid bursts are uncommon but include certain
reversible abnormalities (eg, glucose metabolism, hypertension, peptic ulcer).16

Anti-IgE Treatment

Anti-IgE treatment includes the monoclonal antibody (mAb) omalizumab, which is used in patients 6
years or older with severe persistent allergic asthma and elevated serum IgE whose asthma is
uncontrolled with treatment with moderate/high-dose ICS and/or OCS and LABAs, or who require high
doses of such treatment to maintain good asthma control. Patients may have a positive skin test or in
vitro reactivity to a perennial aeroallergen. Prior to administering anti-IgE, patients should be screened

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for common causes of uncontrolled asthma (ie, incorrect inhaler technique and poor adherence).
Comorbidities and modifiable risk factors should also be identified and minimized prior to treatment.
Anti-IgE can reduce exacerbations, asthma symptoms, and the need for reliever medications, as well as
permit lower doses of OCS for therapeutic effect. However, anti-IgE is expensive and requires regular
subcutaneous injections every 2 to 4 weeks while under observation.16

In a randomised, double-blind, placebo-controlled, phase 3 study (N = 525) in patients with severe

allergic asthma, omalizumab treatment resulted in fewer patients experiencing 1 or more asthma
exacerbations compared to placebo (14.6% vs 23.3%; P = .009) after 16 weeks of treatment, as well as
reductions in the mean number of exacerbations per patient (0.28 vs 0.54; P = .006) and mean duration
of exacerbations (7.8 vs 12.7 days; P < .001). The frequency of adverse events was virtually equal
between the omalizumab and placebo groups (89.2% vs 89.1%, respectively), and the majority of
events were mild or moderate in severity. Study limitations included a relatively short study duration.19

Adverse effects from anti-IgE treatment are mainly limited to injection-site reactions. However,
clinicians should be aware that withdrawal of corticosteroids facilitated by anti-IgE has led to
unmasking the presence of Churg-Strauss syndrome in a small number of cases.16

Anti-IL-5 Treatment

Anti-IL-5 treatments include the mAbs mepolizumab, reslizumab, and benralizumab. Anti-IL-5
antibodies, directed at either IL-5 itself (mepolizumab, reslizumab) or its receptor (benralizumab),
inhibit eosinophil maturation and survival. Treatment with anti-IL-5 is an option for patients with
severe eosinophilic asthma whose asthma is uncontrolled with treatment with moderate/high-dose ICS
and/or OCS and LABAs (or another controller), or who require high doses of such treatment to
maintain good asthma control. Because these medications are expensive, patients should be screened for
common causes of uncontrolled asthma (ie, incorrect inhaler technique and poor adherence) prior to
receiving anti-IL-5. Comorbidities and modifiable risk factors should also be identified and minimized
prior to treatment. Dosage and age restrictions for anti-IL-5 treatment are as follows16:

● Mepolizumab: patients 12 years or older; administered monthly by subcutaneous injection of 100

mg
● Reslizumab: patients 18 years or older; administered monthly by intravenous infusion of 3 mg/kg
body weight
● Benralizumab: patients 12 years or older; administered by subcutaneous injection of 30 mg, with
the first 3 doses given every 4 weeks, followed by once every 8 weeks thereafter

Anti-IL-5 agents can reduce exacerbations in patients with certain baseline blood eosinophil counts and
a recent history of exacerbations. Modest improvements in lung function and/or symptoms may also
occur. There is debate surrounding the optimal blood eosinophil count required at baseline for patients
who may benefit from anti-IL-5.16

The MENSA study (N = 576), a randomised, double-blind, double-dummy, phase 3 study in patients
with severe eosinophilic asthma, demonstrated a 53% reduction in the rate of exacerbations in the
100-mg subcutaneous mepolizumab treatment group compared to placebo (P < .001). The incidence of
adverse events was similar between the 2 treatment groups (78% in the mepolizumab group and 83% in
the placebo group), and the most frequently reported events were nasopharyngitis and headache. Study

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limitations included the questionable value of statistical adjustments in interpreting secondary
outcomes.20

Reslizumab was evaluated in 2 identical phase 3 trials in patients aged ≥ 12 years (N = 953) with
inadequately controlled asthma, elevated blood eosinophils (≥ 400 cells/μL), and at least 1 exacerbation
during the previous year. Patients were randomized to receive reslizumab 3 mg/kg or placebo
intravenously every 4 weeks for 1 year. In both studies, patients treated with reslizumab experienced a
significant reduction in clinical asthma exacerbations compared with placebo (50% reduction [95% CI:
0.37, 0.67] in one study; 59% reduction [95% CI: 0.28, 0.59] in the other; both P < .0001). The drug
also produced a significant reduction in blood eosinophil count, which was observed starting at week 4
and sustained for the duration of the studies. There was no significant change in SABA use between
reslizumab and placebo in either study. Worsening asthma symptoms were the most common adverse
event, followed by upper respiratory tract infection, nasopharyngitis, and headache in both the
reslizumab and placebo groups.21 A subcutaneous formulation of reslizumab is also in development, but
a phase 3 registration study did not meet its primary endpoint of significantly reducing the frequency of
clinical asthma exacerbations in patients with uncontrolled asthma and elevated blood eosinophils (>
300 cells/μL). A phase 3 claim-support study evaluating subcutaneous reslizumab in patients with
OCS-dependent asthma also did not meet its primary endpoint of reduction in daily OCS dose.22

Benralizumab was evaluated in the randomised, placebo-controlled, phase 3 SIROCCO trial, which
included 1205 patients who had asthma for at least 1 year and had at least 2 exacerbations while on
high-dose ICS plus LABA in the previous year. Compared with placebo, benralizumab reduced the
annual asthma exacerbation rate over 48 weeks when given every 4 weeks (rate ratio [RR] 0.55, 95%
CI: 0.42, 0.71; P < .0001) or every 8 weeks (RR 0.49, CI: 0.37, 0.64; P < .0001). Both dosing regimens
significantly improved prebronchodilator FEV1 in patients at week 48 compared with placebo
(least-squares mean change from baseline: every-4-weeks group 0.106 L, 95% CI: 0.016, 0.196;
every-8-weeks group 0.159 L, CI: 0.068, 0.249). Compared with placebo, asthma symptoms were
improved by the every-8-week regimen but not the every-4-week regimen. The most common adverse
events were worsening asthma and nasopharyngitis.23 A limitation of this study is that long-term safety
cannot be established in a 1-year study period.

The CALIMA trial set out to determine which patients could benefit the most from benralizumab
therapy. This randomised, placebo-controlled, phase 3 study enrolled 1306 patients with severe asthma
that was uncontrolled with medium- to high-dose ICS plus LABA and who had a history of 2 or more
exacerbations in the past year. These patients were stratified (2:1) by baseline blood eosinophil counts ≥
300 cells/μL and < 300 cells/μL, respectively. Benralizumab produced significantly lower annual
exacerbation rates with the every-4-week regimen (rate 0.60 [95% CI: 0.48, 0.74], RR 0.64 [95% CI:
0.49, 0.85], P = .0018) and every-8-week regimen (rate 0.66 [95% CI: 0.54, 0.82], RR 0.72 [95% CI:
0.54, 0.95], P = .0188) compared with placebo (rate 0.93; 95% CI: 0.77, 1.12). The most common
adverse events were nasopharyngitis and worsening asthma. The study's authors concluded that
benralizumab showed the most benefit in patients with blood eosinophils ≥ 300 cells/μL.24 A limitation
of this study is that only 728 of the 1306 patients who were randomised were included in the primary
analysis.

A pooled analysis of the randomized, double-blind, placebo-controlled, phase 3 SIROCCO and

CALIMA trials (N = 2295) showed that, in comparison with the placebo group, patients with severe,
uncontrolled asthma who received benralizumab every 8 weeks experienced an annual exacerbation RR
of 0.64 (95% CI: 0.55, 0.75; P < .0001). In general, the extent to which exacerbation rates were reduced
increased with increasing baseline blood eosinophil count and with greater exacerbation history in

11
patients in the every-4-week and every-8-week benralizumab arms. Safety was not assessed in this
pooled analysis, which was a study limitation.25

The ZONDA trial enrolled 220 patients to evaluate benralizumab vs placebo on the reduction in the use
of OCS while asthma control was maintained in adult patients with severe asthma. Benralizumab 30 mg
dosed every 4 weeks or every 8 weeks both significantly reduced the median final OCS doses from
baseline by 75%, as compared with a reduction of 25% in the OCS doses in the placebo group (P < .001
for both comparisons). At 28 weeks, there was no significant effect of either dosing regimen on the
FEV1 as compared with placebo. Effects on various measures of asthma symptoms were mixed, with
some showing significant changes in favour of benralizumab and others not showing significant
changes. Adverse events were similar between all arms of the study.26 The study is limited by the small
number of participants and the relatively short duration as compared to other benralizumab trials.

Adverse effects from anti-IL-5 treatment are infrequent but include injection-site reactions with
mepolizumab, myalgia with reslizumab, and headache with benralizumab. Anaphylactic reactions are
rare, and a small number of cases of herpes zoster have been reported in patients receiving
mepolizumab. Patients at risk for parasitic infections should be screened, and treated if found positive,
prior to initiating anti-IL-5.16

Anti-IL-4 Treatment

Anti-IL-4 treatment includes dupilumab, a mAb that inhibits signalling of both IL-4 and IL-13, which
are key drivers of Th2-mediated inflammation. The Liberty Asthma QUEST study, a phase 3,
randomized, double-blind, placebo-controlled, parallel-group trial, enrolled 1902 participants 12 years
of age or older with uncontrolled asthma in a 2:2:1:1 ratio to receive add-on subcutaneous dupilumab at
a dose of 200 or 300 mg (or placebo) every 2 weeks for 52 weeks. The study demonstrated a 47.7%
lower rate of severe asthma exacerbations in the 200-mg dupilumab group compared to placebo (P <
.001). Similar results were seen with the 300-mg dupilumab group. Greater benefits were seen in
participants with higher baseline levels of eosinophils (≥ 300 cells/μL). Injection-site reaction was the
most common adverse event associated with treatment, and eosinophilia occurred in 52 participants
(4.1%) who received dupilumab vs 4 participants (0.6%) who received placebo. Study limitations
included the exclusion of patients without at least a 12-month history of asthma.27

Other Medications

Tiotropium

The long-acting anticholinergic tiotropium has been studied in adolescents and adults with uncontrolled
asthma in a variety of contexts, but given the larger evidence base for adding a LABA to an ICS in
patients whose asthma is not well controlled, substitution of a LABA with tiotropium as add-on therapy
is not advised. However, tiotropium may be an alternative in patients with LABA side effects.16 In a
meta-analysis of 13 clinical trials, tiotropium was noninferior to salmeterol and superior to placebo in
patients with moderate to severe asthma who were not adequately controlled by ICS or ICS/salmeterol.
Major benefits took the form of an increase in lung function and, in patients with severe asthma, a
reduction in exacerbations.28 There are no published long-term data (> 1 year) on tiotropium safety in
asthma. Dry mouth is a characteristic side effect, and the safety of tiotropium mimics that of salmeterol

12
in patients who are also taking an ICS.16

Investigational Agents

Tezepelumab, a human mAb specific for thymic stromal lymphopoietin (TSLP), is in late-stage clinical
development. TSLP, an epithelial-cell-derived cytokine produced in response to environmental and
proinflammatory stimuli, is central to the regulation of type 2 immunity. In PATHWAY, a phase 2b
study in patients whose asthma remained uncontrolled despite treatment with LABAs and medium to
high doses of inhaled glucocorticoids, the mAb was evaluated at a dose of 70 mg every 4 weeks, 210
mg every 4 weeks, or 280 mg every 2 weeks. Exacerbation rates in the respective tezepelumab groups
were lower by 61%, 71%, and 66% than the rate in the placebo group (P < .001 for all comparisons).
Similar results were observed in patients regardless of blood eosinophil counts at enrolment.29 Based on
the PATHWAY results, the US Food and Drug Administration granted Breakthrough Therapy
Designation for tezepelumab in patients with severe asthma, without an eosinophilic phenotype, who
are receiving ICS/LABAs with or without OCS and additional asthma controllers. The drug is currently
in development in the phase 3 PATHFINDER clinical trial program.30

Fevipiprant, an orally dosed prostaglandin D2 receptor antagonist, demonstrated promise in 2 phase 2

trials. In a study in patients with moderate to severe eosinophilic asthma, mean sputum eosinophil
percentage was reduced from baseline to week 12 by 4.5 times in the fevipiprant group and by 1.3
times in the placebo group (P = .0014). Fevipiprant had a favourable safety profile.31 The agent was
also assessed in patients with allergic asthma uncontrolled by low-dose ICS. Fevipiprant produced a
statistically significant improvement in the primary endpoint of change in predose FEV1 at week 12 (P
= .0035).32 Phase 3 trials are in progress.33

NONPHARMACOLOGIC TREATMENTS

Bronchial thermoplasty as an add-on treatment is a consideration at Step 5 in some adult patients with
severe asthma. It involves treatment of the airways during 3 separate bronchoscopies with a localized
radiofrequency pulse. In patients on high-dose ICS/LABA, 3 months of thermoplasty was associated
with an increase in asthma exacerbations during the treatment period and a subsequent decrease in
exacerbations, but it did not produce a benefit in terms of lung function or asthma symptoms compared
with sham control. In some treated patients, extended follow-up demonstrated a sustained reduction in
exacerbations compared with pretreatment. However, longer-term follow-up in higher numbers of
patients is needed to accrue further evidence of the safety and efficacy of the procedure.4

All patients should be brought up to date on immunisations and be counselled about medication
adherence, self-monitoring of symptoms, home use of a PEF meter, and proper use of any prescribed
inhalers.34 It is especially important to make sure inhaler technique is discussed for each inhaler as
some patients may be on both a metered-dose and a dry powder inhaler, for which administration
techniques are not the same.35 Other nonpharmacologic measures include smoking cessation, avoidance
of environmental asthma stimuli, avoidance of medications that may worsen asthma, engagement in
physical activity, weight reduction and healthy diet, and breathing exercises.34 A written asthma action
plan that considers patient preferences and delineates self-care responsibilities has been uniformly
recommended to improve patient outcomes related to asthma.4 For patients with uncontrolled asthma,
SIMPLES (Smoking, Inhaler technique, Monitoring, Pharmacotherapy, Lifestyle, Education, Support)
is a structured primary care approach that encompasses patient education monitoring, lifestyle and

13
pharmacologic management, and addressing support needs that will achieve control in most patients.36

14
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