1. health and fitness
2. disease
3. asthma

Section 15 Pulmonology
Chapter
103
Therapeutic Options
for Uncontrolled Asthma
Agam Vora
ABSTRACT
Asthma is globally relevant and globally prevalent. Uncontrolled asthma
is a serious challenge wherein one-third patients currently may not
obtain desired degree of asthma control. The objective of this paper is
to review the significance of various factors (i.e. barriers) that may affect
the control of asthma and putative solutions. Many factors related to
patients (e.g. adherence, environmental and lack of optimal education),
practitioners (lack of following guidelines, lack of educating patients,
lack of proactive approach in management, suboptimal interpretation
of severity and control, etc.), public agencies (inability to make
available inexpensive, affordable and guideline-required medications),
researchers (lack of more objective composite approach that can be
equally applied in practice set-ups of developed and resource-poor
(REP) countries, promoting one-size-fits-all approach etc.) are noted.
This indicates that a collaborative composite approach is necessary
involving all stakeholders for achieving optimal asthma control.
Particularly practitioners need to partner with the patients in defining
personalized therapy goals and empower them to negotiate their own
care by self-monitoring and self-management. Practitioners should also
think to go beyond their personal beliefs (preferences, choices) and be
proactive in the asthma management (management of comorbidities,
barriers, etc.). These factors in fact indicate that the control is not solely
related to severity of the underlying disease but how it is managed.
Hence, it is likely that solving these barriers can help good proportion of
those who are currently suboptimally controlled. Evaluation of asthma
control in practice set-ups needs to be objectively and comprehensively
defined.
BACKGROUND
Asthma is globally prevalent and globally relevant. Prevalence is not
just high and persistently rising in developed countries; but is also high
in REP countries, although for different reasons. For instance, changing
patterns of air, occupational, and indoor pollution, unplanned
urbanization, packed cohabitation, etc. are important factors for
REP-specific settings.1 Achieving optimal control is the central aim of
therapy yet there are considerable proportions of patients who fail to
respond optimally to treatment.2 This remains the case despite everincreasing knowledge on asthma and its management. The number of
treatment options has increased to which patients generally respond
well. Its diagnosis does not require any sophisticated tools as well.
Despite this uncontrolled asthma continues to increase both in
severity and prevalence. When poorly controlled, asthma can impair
all aspects of daily functioning and can be fatal. Ideally, optimal asthma
care needs systematic management plan, self-management support
and appropriate medical therapy.3 However, many factors in-between
may precipitate suboptimal asthma control, for instance, suboptimal
treatment adherence, persistently high treatment cost, limited access
to care-diagnosis-medicines, psychosocial and comorbid factors, etc.
It is, therefore, important to identify all such factors in-entirety, and
evaluate the degree of their role in optimizing better control of asthma
and its symptoms. The objective of this paper is to review the role of
various factors (barriers) that may affect the control of asthma and
putative solutions. In clinical practice this might improve day-to-day
patient management.
DEFINITION
The control of asthma is said to be achieved if, aspects related
to impairment and risk are reduced or optimally controlled. For
instance, firstly asthma symptoms, exacerbations, unscheduled
hospital visits and hospitalizations are optimally prevented and
secondly normal (or near-normal) pulmonary function is maintained.
This should be achieved with minimal burden from treatment side
effects. The treatment decisions (nature, type and degree) should
ideally be based on these parameters. Patients may have their own
interpretation about asthma control and should be correlated to
clinical parameters (Table 1). Uncontrolled asthma characterizes
that the asthma does not respond optimally to maximum guidelinedirected management (Table 2).
BURDEN FROM POOR CONTROL
The gaining optimal asthma control (GOAL) study showed that, after
1 year high frequency of asthma control was achieved both with
TABLE 1 │ Perspectives of asthma control
No exacerbations
No need for steroids
Oral steroids ≤ 1 time/year
No fear of getting a cold or forgetting
inhaler
No exercise limitations
I can exercise
No nocturnal awakening
I can sleep through the night
No school/work absences
I can go to school/work every day
No unscheduled hospital visits
or hospitalization
Can meet friends
No uncontrolled upper airway
symptoms
No problem with sinus
Section 15
Chapter 103 Therapeutic Options for Uncontrolled Asthma
TABLE 2 │ Features defining uncontrolled asthma
Daily daytime symptoms
• Limitation in performing day-to-day activities
• Weekly nocturnal symptoms and awakening
• More need for rescue medications
• Lung function (FEV1) < 80%
• Three or more exacerbations per year
randomized trials have addressed this although only one study has
shown improvement in peak expiratory flow (PEF)16 while other
studies have shown reduction in asthma exacerbations and the use
of rescue beta-2 agonists. Improvement in quality of life (QOL)17 and
a trend towards improvement of symptom score is also reported.18
Thus, exercises may have some relevance in asthma management
especially since it allows patients to take charge of management
(self-management) of their asthma to some extent.
Difficult Devices
RELEVANT FACTORS FOR MODIFICATION
OF CONTROL
Inhalation is the mainstay of treatment since it facilitates high
bronchial concentration of drug without high systemic bioavailability
but with reduced side effects. Optimal use of device is extremely
crucial for optimal drug delivery, compliance, treatment efficacy and
resultantly optimal control. Pressurized metered-dose inhalers are
most commonly used inhalation device. Many studies report their
inappropriate use in 14–90% of cases.19 This reduces drug delivery
by 13%20 and 30% reduction in 1-second forced expiratory volume
(FEV).21 These results indicate that suboptimal use leads to asthma
instability from reduced availability and clinical efficacy of drug
which in turn ends up into impaired asthma control. Inappropriate
use is more important for old-age patients due to higher chances of
coordination error. Other factors such as suboptimal knowledge and
teaching about inhalation technique22 are also pertinent. Suboptimal
use of other devices such as dry powder inhalers is reported to be less
than metered-dose and is also low cost, equally efficacious,23 easier
to handle and have lesser side-effects from its use such as discomfort,
vocal performance, shimmer score, etc.24 Patient-partnership is
of paramount importance in choosing the right device. One may
choose the best possible device, but if it is not liked by the patient, it
might be difficult to achieve an optimal use of that device and thus
optimal asthma control in the same manner.
Adherence
Environmental
Asthma is a dynamic disorder with on-and-off exacerbations and
high variability, thus maintaining optimal adherence is important.
This is more so in children who need support from their peers.
Not maintaining this increases the risk for morbidity, mortality
and treatment cost.7,8 Despite this the adherence is suboptimally
achieved for minority of asthma cases, for example, from less than
30 to 70%. Less than 50% of children remain adherent to prescribed
medications.9 Underwhelming situation is observed in this regard
in five large states of India.10 Those who are nonadherent are at an
increased risk for asthma instability and long-term poor outcome
including unscheduled hospital visits, hospitalization, use of rescue
steroids, etc.7,11 Delay in treatment onset is also an important factor
for persistent symptoms, deterioration of lung functions, reduced
treatment response and frequent exacerbations.12 Simplification
of regimens, better patient education and communication, use of
telecommunication techniques, lack of physician knowledge, lack
of following treatment guidelines by practitioners, etc. are important
for improved adherence and are given in Table 2.
Exposure to environmental irritants not only increases the risk
for development of asthma but also increase its morbidity for
instance severity,25 exacerbations, unscheduled hospital visits and
hospitalization.26 For these cases positive parental perceptions might
also play an important role in achieving an optimal asthma control.27
Pollutants produce strong inflammatory responses that in turn
worsen the asthma symptoms, lung function, respiratory distress,
increased medication use that all end up into asthma instability.28
These factors may also pose risk by inducing genetic variation in
oxidative stress pathway. Living in traffic dense surroundings, near
construction sites, having unclean ducts in air-conditioners, house
dust mites may play a role in poor control and worsening of asthma.
In desert-prominent populations, aeroallergens can also worsen
asthma, cause unscheduled hospital visits and hospitalization.29
This is also true for those working in construction sites, sudden heavy
exposure to dust, and sand-storms among uncontrolled asthma
patients.30
inhaled corticosteroid and polytherapy of inhaled corticosteroid
and long-acting beta-2 agonist. However, about one-third of cases
remained devoid of this control.2 Subsequent studies such as,
Asthma Insights and Reality in Europe (AIRE)4 and Asthma Insights
and Reality (AIR)5 also showed underwhelming results. For instance,
AIRE study had 48% cases with regular day-time and 30% with
nocturnal symptoms, and only 50% of those with severe persistent
asthma had well control over their asthma. High frequency of
unscheduled hospital visits and hospitalization was reported.4 AIR
study also reported low frequency (< 45%) of those who had good
control of their asthma.5 The epidemiology and natural history of
asthma: outcomes and treatment regimens (TENOR) study6 showed
that 83% cases with severe asthma were consistently uncontrolled on
the usual asthma therapy. High burden from off-days, unscheduled
hospitalization and hospital visits, use of steroids and twofold high
cost was observed.
Breathing Exercise
Patients with asthma experience increased airway resistance and
hyperinflation which puts respiratory muscles at a mechanical
disadvantage. As with chronic obstructive pulmonary disease
(COPD), those with asthma also show decreased respiratory muscle
mass or strength. Also, dyspnea in part results from inappropriate
respiratory muscle efforts in these cases.13 It is seen that inspiratory
muscles of those with COPD and asthma after training led to
decrease of dyspnea and use of beta-2 agonists.14 On the other
hand, anecdotal reports indicate improvement or sometimes
alleviation of asthma symptoms with yoga-derived exercises.15 Few
Gastroesophageal Reflux Disease
The epidemiological association between asthma and
gastroesophageal reflux disease (GERD) has long been explored
and the relation is two-way where one worsens another. A higher
prevalence of GERD among asthma population is noted although
that varies widely (up to 82% of those with asthma). 31 GERD is one
of the exacerbating factors for those with poorly controlled asthma.32
Mechanistically also the acid may get into the airways and cause
increased airway reactivity, bronchoconstriction or chronic airway
inflammation.33 Esophagitis and persistent cough also ensue with
chronic acid reflux. Individual clinical trials show treatment of GERD
improves asthma control34 whereas a large review of all such trials
465
Pulmonology
shows underwhelming results for both adults35 and children.36 These
differences are most likely due to the biases from sample size or the
incoherent parameters used in individual trials. Larger trials have
shown mild improvement in PEF especially for those taking longacting beta-2 agonists.37 Many factors such as localization of GERD,
non-acid reflux such as bile, and neurogenically mediated airway
inflammation are yet to be evaluated comprehensively. GERD may
manifest poor lung function and respiratory symptoms through
its intricate relation with obstructive sleep apnea (OSA) as well.
Persistent cough and OSA occurring through GERD is well known.38
psychopathological states may negatively affect treatment adherence
and the chances of following the self-management plan diligently.
These factors are crucial for achieving optimal asthma control.
Rhinitis
Lack of following treatment guidelines by practitioners is not
uncommon.39 Multitude of reasons may partially explain this
practice for instance degree of specialization, lack of awareness of
existing or updated guidelines especially of nonspecialists, priority
by individual practitioners to their own personal preferences,
location of patient or practice, underestimated severity and severity
misclassification of asthma etc. Health-system differences may
partially have a role for instance infrequent discussion of asthma
management among colleagues for instance. Taboo with the use of
steroids is another major hindrance in optimal control.40 Guidelines
recommend steroids as gold-standard yet they are insufficiently
prescribed; preference for use of beta agonists as monotherapy
although not useful; or preference for combination therapies at the
start of the therapy, etc. are another hindrances.40
Both asthma and rhinitis are similar systemic airway inflammatory
processes. Epidemiologically up to 38% of rhinitis patients have
asthma51 while prevalence of rhinitis among those with asthma
can be beyond 50%.52,53 Both allergic and nonallergic rhinitis have
been associated with increased prevalence of asthma. For instance,
those with allergic rhinitis there is a higher prevalence of asthma,
food sensitivity, eosinophilia, increased total IgE, bronchial hyperresponsiveness while those with nonallergic rhinitis show higher
prevalence of asthma alone.53 This suggests different endotypes of
asthma with allergic and nonallergic rhinitis. Rhinitis often precedes
asthma and can therefore present as a risk factor for asthma.54 Among
children, however, asthma often precedes rhinitis.53 Studies indicate
that optimal treatment of rhinitis reduces odds ratio for uncontrolled
asthma55 as well as reduction in unscheduled hospital visits, missed
work days, nocturnal awakening by about 50%.56 Similar results are
obtained in asthma children among whom rhinitis is an important
disorder.55 Asthma in rhinitis patients often triggers worse nasal
symptoms and an improved control of these nasal symptoms
frequently results in improved asthma symptom scores.55 Thus,
the influence of untreated rhinitis is rather detrimental on asthma
control.57 Despite this it is still not part of recommendations.
Obstructive Sleep Apnea
Self-Management
Obstructive sleep apnea has some role to play in poorly controlled
asthma and causes frequent exacerbations.41 Continuous positive
airway pressure (CPAP) therapy for OSA in patients with nocturnal
asthma improves asthma symptoms, rescue bronchodilator use, PEF,
and QOL42 and stoppage of treatment cancels these benefits. Other
studies in contrast show development or worsening of bronchial
hyper-reactivity with CPAP. Putative benefits for those having daytime
asthma are yet to be evaluated. OSA promotes other asthma triggers
such as GERD.38 Obesity and OSA are other factors that independently
lead to increased airways inflammation thus may facilitate poor
asthma control in this scenario. Contrasting results in terms of airway
obstruction and inflammation are however observed.43 Role of other
factors such as local and systemic mechanisms for bronchial wall
thickness, cough suppression, impaired symptom perception, etc.43
could have some role in pathogenesis. Those with asthma and OSA
have lower levels of eosinophilic inflammation and noneosinophilic
phenotype is especially noted with poorly controlled asthma.44
Continuous monitoring is essential to achieve treatment goals or to
tailor the asthma therapy. Currently, many asthma cases fail to attend
checkups or visit their physicians regularly58 thus paving way for the selfmanagement. Self-management, excepting exacerbations, improves
asthma control, lung function and the QOL59 among uncontrolled
subjects. Similar overwhelming results are noted in a very large
review of several clinical trials60 that showed that self-management
reduced hospitalization, unscheduled hospital visits, days-off,
nocturnal asthma, asthma symptoms, need for rescue medications
and improvements of lung function, PEF and QOL.60 Self-management
approach can also be particularly useful for achieving asthma control
in subjects, for instances living in remote or rural residence.
Guidelines
Psychiatric
466
Section 15
Factors such as anxiety and depression are reported to be
modulators of poorly controlled asthma.45 These are frequently
observed especially among those with uncontrolled asthma.46 It
is however uncertain whether these factors are consequence of
poorly controlled asthma or the cause of it. This is partially because
both asthma and anxiety are contrasting situations wherein anxiety
has exaggerated perception of symptoms47 and in asthma patients
may undermine their own symptomatic perception. This is partial
explanation that these parameters might not always reflect in the
objective measurements of asthma control such as asthma symptoms
or QOL.48 To add, stress can cause pro-inflammatory states49 as seen
with increased cytokine production. There might also be hormonal
significance since anxiety and insomnia are more common among
women with asthma.50 Irrespective of these contrasting observations,
it is crucial to integrate these psychopathological states (fear, mood
disturbance, anxiety, depression, etc.) when assessing asthma
control and QOL.49 This is an important step since these negative
Vaccination
Although 60–80% asthma cases have upper respiratory infections,
particularly influenza, in the background,61 but only few of them
get vaccinated against influenza.62 Many times an increased risk
of asthma exacerbations after influenza vaccination has been
suspected but large reviews have not shown any link between two.63
On the other hand, a study did not find any reduction in asthma
severity or fatal complications following influenza vaccination.64
Thus, in current scenarios vaccination remains the best strategy to
reduce additional disease burden among asthma subjects.65
Limited Access and Cost
There is a direct relation between severity and control of asthma with
the availability10 and affordability of its treatment.66 Those who may
access can increase their income67 and reduce their asthma-related
expenditure (unscheduled visits, hospitalization, etc.) by about
40%.68 Currently, this is not the case though.10
BRITTLE FORM OF ASTHMA
Being one of the variant of severe refractory asthma,69 this occurs in
approximately 10% of severe asthma cases and 0.5% of all asthma
Chapter 103 Therapeutic Options for Uncontrolled Asthma
Section 15
TABLE 3 │ Brittle asthma and its subtypes
Parameter
Type 1
Type 2
Definition
40% diurnal variation in PEF for > 50% of time over
at least 150 days
Sudden acute attack without an obvious trigger with apparently
normal airway function
Risk factors
Atopy
Impaired local immunity
Increased respiratory infections
Psychosocial factors
Exposure to aeroallergens
Poor perception and interpretation of asthma
Gender
Women predominance
Equally prevalent in men and women
Morbidity
High morbidity
No high morbidity
Mortality
No high mortality
High mortality
Management
Inhaled/oral steroids
Inhaled bronchodilators
Control of allergen exposure
Immunotherapy
Allied, e.g. adherence
Control of allergen exposure
Control of triggers
Self-management
Management of acute attacks
cases.70 It has two clinical subtypes (Table 3). These cases are
phenotypically different and have particularly high risk of morbidities
(hospital admission, treatment side effects, and psychosocial effects)
and mortality (acute asthma, disease severity).70,71 These factors are
sufficient to worsen the asthma control or precipitate exacerbations.
THERAPEUTIC APPROACHES
Conventional approaches are based on relievers (bronchodilators)
and controllers (immunomodulators and/or anti-inflammatory
agents). Relievers open airways and provide more symptomatic
short-term relief while controllers are suitable for long-term relief by
reducing hyper-reactivity and inflammation. Avoidance of exposure
to relevant triggers is often the additional gold-step in the asthma
management. Current therapies pragmatically propose one-size-fitsall approach consisting of bronchodilators and immunomodulator
and/or anti-inflammatory agents. These can effectively control
asthma but substantial number of cases fails to optimally respond.
This is partially because practitioners/patients have been seen
the tendency to underestimate their severity but overestimate the
control of their asthma.
Several approaches are now available at different stages of their
development that are based on: reducing airway smooth muscle,
reducing airway inflammatory cell number or activity, optimization
of bronchodilation, etc.
Optimization of Bronchodilation
Inhaled beta-2 agonists are likely to partially become less effective
from their chronic use72 although optimal degree of bronchodilation
is still likely to be maintained.73 Instead of its use with inhaled
corticosteroids (ICS), studies have tested its use with long-acting
muscarinic antagonists (tiotropium) and double dosed ICS in
severe refractory asthma. The results showed better lung functions
and asthma control with tiotropium when individually compared
to double dosed corticosteroid or beta-2 agonists.73 This treatment
in severe refractory asthma showed that addition of tiotropium, to
inhaled corticosteroid and beta-2 agonists, significantly improved
lung function.74
Add-on Options
Inhaled corticosteroids are the mainstay of treatment for persistent
asthma. Although significantly effective, at its usual doses, for
number of cases, sizeable number of cases remains symptomatic
with its use. Such patients are needed to be treated by: increasing
ICS dose; or adding long-acting beta-agonist (LABA) or leukotrienereceptor antagonist (LTRA) or theophylline.75 Studies have
shown that increasing the ICS dose does not provide sufficient
improvement of most lung function and symptom parameters. A
fourfold increase in dose however is noted to render improvements
in the need of rescue beta-agonists, PEF, or the lung function, etc.76
Its anti-inflammatory activity does not improve with increasing the
dose (4–16 folds).76-78 This suggests that current doses are likely to be
sufficient for suppressing any inflammation in most patients. There
is no conclusive evidence79,80 on the risk of systemic adverse effects
with increasing the ICS dose, due to the heterogeneity of studies.
Some degree of dose-dependency in the HPA-axis effects of inhaled
steroids is noted. A large meta-analysis showed increased risk for
posterior subcapsular cataracts, and to a much lesser degree, the risk
for ocular hypertension and glaucoma, and skin bruising, with highdose exposure.80
Long-acting beta-agonist (long-lasting relaxation of airway
smooth muscle) and ICS (potent anti-inflammatory effects) have
complementary effects. ICS can also increase the expression of beta2 receptors in inflammatory cells to overcome the desensitization
in response to chronic beta-2 agonist exposure.81 In addition,
LABA may prime the glucocorticoid receptor facilitating activation
by corticosteroids.82 Proinflammatory effects with beta agonists
are generally suspected although available studies are not seen
to increase the inflammatory indices. This matches with other
studies that indicate that there is no increase in number and
severity of asthma exacerbation with their long-term use.83 Safety
of this add-on therapy is not unpredictable and only results in slight
increase in tremor and tachycardia; without any discontinuation
of this therapy.84,85 This add-on has been found to be better than
increasing the ICS dose by fourfold in reducing day/night time
symptom score, asthma exacerbations, rescue therapy, etc.76,83,86
Cysteinyl leukotriene receptor-antagonists (LTRA) are a new class
of asthma medication and have a weak anti-inflammatory activity.
Since corticosteroids are not very effective inhibitors of cysteinyl
leukotriene pathways87 and thus their combination may offer some
benefit. Studies does not show different results that this, and many
adult and children studies state that their combination reduce
the number of patients who may need a systemic corticosteroid,
compared to ICS alone [RR = 0.34; 95% CI 0.13, 0.88].88 This risk of
467
Pulmonology
reduced exacerbations that may eventually need systemic steroids
indicate that this may modestly improve asthma control compared
with ICS alone but this strategy cannot be recommended as a
substitute for increasing the dose of ICS.89 Other study however
showed that addition of LTRA may be equal to doubling the dose
of ICS,90 however, this was stated without including a placebo arm.
More data is needed before this combination can be included as a
more global practice. Theophyllines have bronchodilator effect,
immunomodulatory, anti-inflammatory, and bronch­
o­
protective
effects.91 Studies indicate that there is an improvement in pulmonary
function and asthma symptoms when theophyllines are added to
ICS,92 although all studies have not been able to confirm this result.93
This combination may or may not equate to doubling the dose of ICS
in the treatment of uncontrolled asthma. Side effects can be reduced
by using a concentration slightly below the recommended range.
Inhaler Devices
Different devices are reported to have different difficulties,
advantages and limitations. To what extent these differences affect
clinical outcome in asthma subjects is inconclusive. A large review of
different devices reported no significant difference in drug delivery
and clinical effectiveness.94 In contrast, other studies report that
certain devices (e.g. metered dose) are more difficult than rest95 and
considerably affect compliance to treatment and asthma control.
Another study reinstates the importance of choosing right inhaler
for optimal asthma control.96 Patient training is another area that
may improve compliance and asthma control. Many studies have
highlighted importance of patient training and regular checking
of patients’ inhalation techniques.97 Guidelines reinforce that an
inhaler should only be prescribed after confirming that the patient
knows how to use the device.98 Switching to cheaper alternatives,
such as metered-dose, has been seen to worsen asthma control
with greater need for emergency beta-agonists.99 This is more so if
it is done without clinical consultation or training. All this should
in fact be personalized, and guided by patient’s sociodemographic
characters such as young or old age, trembling of limbs, affordability,
literacy level, etc.
Asthma Control through Management of
Comorbid Diseases
468
Effect of GERD on asthma is still debatable since improvement in
asthma following GERD treatment is variable. Studies however show
improvement of asthma symptoms for 69% cases following successful
treatment for GERD.100 In another study, 24-week treatment with
lansoprazole reduced asthma exacerbations and improved QOL,
especially for those on polytherapy already.101 A recent large review
confirmed this by stating significant association between GERD
and asthma.102 Similar paucity of data is noted for OSA and results
are currently more inconclusive than GERD. Mechanical changes
from treatment with CPAP could influence airway responsiveness
but other study did not find any such association. Treatment of
psychopathologies such as panic attack, improves asthma outcomes
although a large meta-analyses does not support this. In any case,
more extreme psychopathologies such as bipolar disorder, etc.
do not occur more frequently among those with asthma.103 The
effect of intervention for obesity is much clear for improvement in
asthma. A large review of 15 studies noted that each of the study
that examined the effect of weight loss on asthma outcomes noted
an improvement in at least one of the asthma related outcome.104
This effect stands irrespective of type of intervention, age, gender
and ethnicity. Thus weight loss for improvement of asthma control
should be stressed. Similarly cessation of smoking has similar effect
on improving asthma outcomes. Although still debatable, there are
number of reports that report an improvement of asthma following
Section 15
optimal management of allergic rhinitis. For instance, combined
treatment with montelukast and budesonide had significant effect
on reducing airflow obstruction. Other studies also indicate towards
improvement in asthma control and QOL following successful
treatment for allergic rhinitis.
Omalizumab
It is a recombinant DNA-derived humanized immunoglobulin
G 1k monoclonal antibody that selectively binds to human
immunoglobulin E (IgE) and inhibits interaction of IgE with IgE
receptors preventing the release of inflammatory mediators that
occur in allergic asthma. This has therefore seen to cause significant,
rapid and sustained reduction in serum free IgE levels at differing
dosing regimens and in a dose-dependent fashion.105 This has
also been seen to reduce airway eosinophilia in the mild asthma
patients. Better clinical benefits are seen in many trials among those
with moderate-severe asthma in terms of number of exacerbations
and reduction of use of inhaled corticosteroids when compared
with control.105,106 Among those with severe asthma Omalizumab
led to longer steroid reduction phase and reduction in median
corticosteroid dosage. This also decreases use of rescue medication,
improves asthma symptoms as well as QOL.107 Among those with
inadequately controlled severe persistent asthma despite best
available therapy108 Omalizumab has shown improvements in severe
exacerbation rate, unscheduled emergency visit rate, QOL, asthma
symptom score, etc. For instance, reductions in hospitalizations due
to asthma can be 92% lower,109 total emergency visit rate by 47%
lower, and exacerbations by 38% lower versus placebo in patients
with omalizumab-treated severe persistent asthma.110 Meta analysis
also indicated a 1.6- to 2-fold increase in moderate (≥ 1 point) (P <
0.001) and 1.8- to 2.1-fold increase in large (≥ 1.5 point) (P < 0.001)
improvements in overall QOL scores in Omalizumab-treated patients
compared with placebo during both steroid stabilization and steroid
reduction periods.111 Omalizumab has been extensively evaluated
for adverse events and similar safety profile to that of the control
group, with no significant differences between groups112 have been
found among patients with moderate-to-severe persistent asthma.
Similar safety profile is noted among children as well.
Reducing Airway Inflammatory
Cell Number/Activity
Studies show that monitoring sputum eosinophil count might help in
reducing the risk for severe exacerbations in the future.113 However,
this seems to be useful for those with moderate-severe asthma113 only.
Further studies have tested mepolizumab114,115 and reslizumab116
(anti-interleukin-5 monoclonal antibody) among hypereosinophilic
patients having had severe refractory asthma. These treatments have
shown clinical benefits in terms of corticosteroid sparing, number of
future exacerbations, improved expiratory flow and overall asthma
control. These effects are however not observed among those with
less severe asthma117 indicating importance of patient-selection. For
those who have mild allergic asthma, use of antisense approach for
reducing the level of messenger RNA and its translation into protein
has been found to be effective in reducing airway eosinophils by
inhibiting the production of cytokine receptors.118 Many subjects
exhibit neutrophilic asthma instead and these subjects with
neutrophilic severe refractory asthma have been demonstrated to
benefit with chemokine receptor antagonist.119
Novel therapeutics120 such as with cytokine inhibitors, including
daclizumab, etanercept, etc. have been tested in relation to refractory
asthma. These compounds have been shown to improve asthma
control; inhibit, in vitro, expression of inflammatory mediators such
as interleukins 4, 5, and 13; decline in bronchial hyperresponsiveness,
improvements in QOL and postbronchodilator FEV1. Similarly
Chapter 103 Therapeutic Options for Uncontrolled Asthma
Section 15
lumixilimab, an anti CD23 antibody is shown to reduce IgE
concentration by 40% and reduced production of proinflammatory
cytokines, in patients with asthma.
Reducing Airway Smooth Muscle
Bronchial thermoplasty is a nonpharmacologic option that involves
the delivery of radiofrequency to large airways in order to reduce
the volume of smooth muscle and their responsiveness.121 Among
patients with relatively better controlled asthma, reduction in mildsevere exacerbations and further improvement in asthma control
has been noted with thermoplasty.122 Among those with severe
refractory asthma, over a short follow-up period, thermoplasty has
been found to reduce exacerbations and emergency hospital visits,
improved morning peak exploratory flow123 and QOL (e.g. days lost
due to asthma).124 Similar results are observed over a longer followup period of time such as absent complications and maintenance
of stable lung function.125 Side effects among those with mildmoderate asthma are mild and self-limiting and include cough,
dyspnea, wheezing, and bronchospasm.121 However those with
severe asthma, the side effects are reported to be more frequent but
these gradually balance out over time.124,126 Patient’s selection for
this therapy is therefore important.
more composite yet personalized approach (Table 4 and Figure 1)
should replace the current one size fits all approach. On the other
hand, practitioners should align their personal beliefs (preferences
or choices) with recommended guidelines and should be more
effectively educated on the complexities of measuring asthma
severity and initiate appropriate asthma treatment. These aspects
would make sure that asthma is properly treated, monitored and
managed and may result in desired degree of asthma control. Public
agencies especially of REP countries should ensure that the diagnostic
gap and treatment gap is reduced and suitable medications are easily
available in an affordable manner. This would help patients not to
self-prescribe or take suboptimal medications but help them to take
regular controller medications and avoid taking treatment only at
the time of complication or hospitalization. Researchers should
adopt a collaborative approach for conducting organized research
on uncontrolled asthma. This might facilitate faster advancement of
our understanding about uncontrolled asthma.
FINAL REMARKS AND CONCLUSION
Currently the control of asthma is the recognized central theme in
the asthma management while asthma severity paradoxically has
taken the back-seat for now. Control is less likely to be independent
of the disease severity because severity is closely related to the
treatment response (i.e. degree of control).127 Thus, at first it might
be necessary to integrate both parameters in the future management
recommendations. No doubt, management of asthma needs to be
improved. Much of the poor control of asthma can be attributed to
the factors that are related to both practitioner (following treatment
guidelines as recommended etc.) and patients (optimal adherence
etc.). Thus, a comprehensive approach should be adopted where both
practitioner and patient become partner together and support each
other to achieve personalized predefined therapy goals. The level
of asthma control likely to be achieved in patients reflects behavior
of both patients and their practitioners. Practitioners must identify
barriers at the start of therapy that likely hinder optimal control
including residence in traffic or construction sites, adherence issues,
ease in availability of medications, self-monitoring by the patients,
optimal education of the patient, management of comorbidities
(e.g. obesity, upper respiratory infections), etc. They should also
aim to identify those are at risk of failing to achieve these or those
who may have more severe forms such as brittle asthma. Thus a
Time-based repeated patient review
Figure 1: Management of patients with poor control of the asthma
TABLE 4 │Measures for difficult-to-control asthma
• Educate patient about treatment plan-rationale-goals
• Emphasize written asthma management plan and adherence to it
• Evaluate understanding about asthma and its medications
• Identify patients’ priorities in treatment
• Ask patients to demonstrate the use of technique for instance inhaler
• Ensure regular follow-up and evaluate measures of response
• Assess patient’s desire and commitment to treatment
• Follow treatment guidelines yourself
• Identify barriers to treatment (cost, availability, triggers, etc.)
• Identify and treat comorbidities
• Be proactive in alternative medication choices that are likely to meet patient goals
469
Pulmonology
Learning more about the complexities of asthma patho­physiology
will strengthen our therapeutic armaments for patients who do
not respond well to conventional medications. Some of these have
already shown promise for those with poorly controlled asthma for
instance omalizumab, muscarinic antagonists, etc. The researchers
should also define how newer treatments are going to be integrated
into existing therapies.
To conclude, there are numerous barriers to meeting needs in
asthma control and only a few have been explored here. Nevertheless,
it is evident that a composite approach to asthma control by
involving all stakeholders (patient, practitioner, researchers and
public agencies) is necessary. These factors in fact also indicate that
the asthma control is not solely related to severity of the asthma
but how it is managed by the practitioners, patients and public
agencies. Hence, solving some of these barriers can putatively help
good proportion of those who are currently suboptimally controlled.
Particularly practitioners need to partner with the patients in defining
personalized therapy goals and empower them to negotiate their
own care by self-monitoring and self-management. Practitioners
should also think to go beyond their personal beliefs (preferences,
choices) and be proactive in the asthma management (management
of comorbidities, barriers, etc.). Evaluation of asthma control in
practice set-ups needs to objectively and comprehensively defined.
Needless to mention that better tools for assessment and monitoring
of asthma are needed.
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