Section 15 Pulmonology Chapter 103 Therapeutic Options for Uncontrolled Asthma

Agam Vora

and appropriate medical therapy.3 However, many factors in-between ABSTRACT may precipitate suboptimal asthma control, for instance, suboptimal treatment adherence, persistently high treatment cost, limited access Asthma is globally relevant and globally prevalent. Uncontrolled asthma to care-diagnosis-medicines, psychosocial and comorbid factors, etc. is a serious challenge wherein one-third patients currently may not obtain desired degree of asthma control. The objective of this paper is It is, therefore, important to identify all such factors in-entirety, and to review the significance of various factors (i.e. barriers) that may affect evaluate the degree of their role in optimizing better control of asthma the control of asthma and putative solutions. Many factors related to and its symptoms. The objective of this paper is to review the role of patients (e.g. adherence, environmental and lack of optimal education), various factors (barriers) that may affect the control of asthma and practitioners (lack of following guidelines, lack of educating patients, putative solutions. In clinical practice this might improve day-to-day lack of proactive approach in management, suboptimal interpretation patient management. 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 DEFINITION equally applied in practice set-ups of developed and resource-poor The control of asthma is said to be achieved if, aspects related (REP) countries, promoting one-size-fits-all approach etc.) are noted. to impairment and risk are reduced or optimally controlled. For This indicates that a collaborative composite approach is necessary instance, firstly asthma symptoms, exacerbations, unscheduled involving all stakeholders for achieving optimal asthma control. hospital visits and hospitalizations are optimally prevented and Particularly practitioners need to partner with the patients in defining personalized therapy goals and empower them to negotiate their own secondly normal (or near-normal) pulmonary function is maintained. care by self-monitoring and self-management. Practitioners should also This should be achieved with minimal burden from treatment side think to go beyond their personal beliefs (preferences, choices) and be effects. The treatment decisions (nature, type and degree) should proactive in the asthma management (management of comorbidities, ideally be based on these parameters. Patients may have their own barriers, etc.). These factors in fact indicate that the control is not solely interpretation about asthma control and should be correlated to related to severity of the underlying disease but how it is managed. clinical parameters (Table 1). Uncontrolled asthma characterizes Hence, it is likely that solving these barriers can help good proportion of that the asthma does not respond optimally to maximum guideline- those who are currently suboptimally controlled. Evaluation of asthma control in practice set-ups needs to be objectively and comprehensively directed management (Table 2). defined. BURDEN FROM POOR CONTROL The gaining optimal asthma control (GOAL) study showed that, after BACKGROUND 1 year high frequency of asthma control was achieved both with Asthma is globally prevalent and globally relevant. Prevalence is not just high and persistently rising in developed countries; but is also high TABLE 1 │ Perspectives of asthma control in REP countries, although for different reasons. For instance, changing patterns of air, occupational, and indoor pollution, unplanned No exacerbations No need for steroids urbanization, packed cohabitation, etc. are important factors for No fear of getting a cold or forgetting 1 Oral steroids ≤ 1 time/year REP-specific settings. Achieving optimal control is the central aim of inhaler therapy yet there are considerable proportions of patients who fail to respond optimally to treatment.2 This remains the case despite ever- No exercise limitations I can exercise increasing knowledge on asthma and its management. The number of No nocturnal awakening I can sleep through the night treatment options has increased to which patients generally respond No school/work absences I can go to school/work every day well. Its diagnosis does not require any sophisticated tools as well. No unscheduled hospital visits Despite this uncontrolled asthma continues to increase both in Can meet friends or hospitalization severity and prevalence. When poorly controlled, asthma can impair No uncontrolled upper airway all aspects of daily functioning and can be fatal. Ideally, optimal asthma No problem with sinus care needs systematic management plan, self-management support symptoms Section 15 Chapter 103 Therapeutic Options for Uncontrolled Asthma

randomized trials have addressed this although only one study has TABLE 2 │ Features defining uncontrolled asthma shown improvement in peak expiratory flow (PEF)16 while other studies have shown reduction in asthma exacerbations and the use Daily daytime symptoms of rescue beta-2 agonists. Improvement in quality of life (QOL)17 and • Limitation in performing day-to-day activities a trend towards improvement of symptom score is also reported.18 • Weekly nocturnal symptoms and awakening Thus, exercises may have some relevance in asthma management especially since it allows patients to take charge of management • More need for rescue medications (self-management) of their asthma to some extent. • Lung function (FEV1) < 80% • Three or more exacerbations per year Difficult Devices 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 inhaled corticosteroid and polytherapy of inhaled corticosteroid crucial for optimal drug delivery, compliance, treatment efficacy and and long-acting beta-2 agonist. However, about one-third of cases resultantly optimal control. Pressurized metered-dose inhalers are remained devoid of this control.2 Subsequent studies such as, most commonly used inhalation device. Many studies report their Asthma Insights and Reality in Europe (AIRE)4 and Asthma Insights inappropriate use in 14–90% of cases.19 This reduces drug delivery and Reality (AIR)5 also showed underwhelming results. For instance, by 13%20 and 30% reduction in 1-second forced expiratory volume AIRE study had 48% cases with regular day-time and 30% with (FEV).21 These results indicate that suboptimal use leads to asthma nocturnal symptoms, and only 50% of those with severe persistent instability from reduced availability and clinical efficacy of drug asthma had well control over their asthma. High frequency of which in turn ends up into impaired asthma control. Inappropriate unscheduled hospital visits and hospitalization was reported.4 AIR use is more important for old-age patients due to higher chances of study also reported low frequency (< 45%) of those who had good coordination error. Other factors such as suboptimal knowledge and control of their asthma.5 The epidemiology and natural history of teaching about inhalation technique22 are also pertinent. Suboptimal asthma: outcomes and treatment regimens (TENOR) study6 showed use of other devices such as dry powder inhalers is reported to be less that 83% cases with severe asthma were consistently uncontrolled on than metered-dose and is also low cost, equally efficacious,23 easier the usual asthma therapy. High burden from off-days, unscheduled to handle and have lesser side-effects from its use such as discomfort, hospitalization and hospital visits, use of steroids and twofold high vocal performance, shimmer score, etc.24 Patient-partnership is cost was observed. 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 RELEVANT FACTORS FOR MODIFICATION might be difficult to achieve an optimal use of that device and thus OF CONTROL optimal asthma control in the same manner.

Adherence Environmental Asthma is a dynamic disorder with on-and-off exacerbations and Exposure to environmental irritants not only increases the risk high variability, thus maintaining optimal adherence is important. for development of asthma but also increase its morbidity for This is more so in children who need support from their peers. instance severity,25 exacerbations, unscheduled hospital visits and Not maintaining this increases the risk for morbidity, mortality hospitalization.26 For these cases positive parental perceptions might and treatment cost.7,8 Despite this the adherence is suboptimally also play an important role in achieving an optimal asthma control.27 achieved for minority of asthma cases, for example, from less than Pollutants produce strong inflammatory responses that in turn 30 to 70%. Less than 50% of children remain adherent to prescribed worsen the asthma symptoms, lung function, respiratory distress, medications.9 Underwhelming situation is observed in this regard increased medication use that all end up into asthma instability.28 in five large states of India.10 Those who are nonadherent are at an These factors may also pose risk by inducing genetic variation in increased risk for asthma instability and long-term poor outcome oxidative stress pathway. Living in traffic dense surroundings, near including unscheduled hospital visits, hospitalization, use of rescue construction sites, having unclean ducts in air-conditioners, house steroids, etc.7,11 Delay in treatment onset is also an important factor dust mites may play a role in poor control and worsening of asthma. for persistent symptoms, deterioration of lung functions, reduced In desert-prominent populations, aeroallergens can also worsen treatment response and frequent exacerbations.12 Simplification asthma, cause unscheduled hospital visits and hospitalization.29 of regimens, better patient education and communication, use of This is also true for those working in construction sites, sudden heavy telecommunication techniques, lack of physician knowledge, lack exposure to dust, and sand-storms among uncontrolled asthma of following treatment guidelines by practitioners, etc. are important patients.30 for improved adherence and are given in Table 2. Gastroesophageal Reflux Disease Breathing Exercise The epidemiological association between asthma and Patients with asthma experience increased airway resistance and gastroesophageal reflux disease (GERD) has long been explored hyperinflation which puts respiratory muscles at a mechanical and the relation is two-way where one worsens another. A higher disadvantage. As with chronic obstructive pulmonary disease prevalence of GERD among asthma population is noted although (COPD), those with asthma also show decreased respiratory muscle that varies widely (up to 82% of those with asthma). 31 GERD is one mass or strength. Also, dyspnea in part results from inappropriate of the exacerbating factors for those with poorly controlled asthma.32 respiratory muscle efforts in these cases.13 It is seen that inspiratory Mechanistically also the acid may get into the airways and cause muscles of those with COPD and asthma after training led to increased airway reactivity, bronchoconstriction or chronic airway decrease of dyspnea and use of beta-2 agonists.14 On the other inflammation.33 Esophagitis and persistent cough also ensue with hand, anecdotal reports indicate improvement or sometimes chronic acid reflux. Individual clinical trials show treatment of GERD alleviation of asthma symptoms with yoga-derived exercises.15 Few improves asthma control34 whereas a large review of all such trials 465 Pulmonology Section 15

shows underwhelming results for both adults35 and children.36 These psychopathological states may negatively affect treatment adherence differences are most likely due to the biases from sample size or the and the chances of following the self-management plan diligently. incoherent parameters used in individual trials. Larger trials have These factors are crucial for achieving optimal asthma control. shown mild improvement in PEF especially for those taking long- acting beta-2 agonists.37 Many factors such as localization of GERD, Rhinitis non-acid reflux such as bile, and neurogenically mediated airway Both asthma and rhinitis are similar systemic airway inflammatory inflammation are yet to be evaluated comprehensively. GERD may processes. Epidemiologically up to 38% of rhinitis patients have manifest poor lung function and respiratory symptoms through asthma51 while prevalence of rhinitis among those with asthma its intricate relation with obstructive sleep apnea (OSA) as well. can be beyond 50%.52,53 Both allergic and nonallergic rhinitis have Persistent cough and OSA occurring through GERD is well known.38 been associated with increased prevalence of asthma. For instance, those with allergic rhinitis there is a higher prevalence of asthma, Guidelines food sensitivity, eosinophilia, increased total IgE, bronchial hyper- Lack of following treatment guidelines by practitioners is not responsiveness while those with nonallergic rhinitis show higher uncommon.39 Multitude of reasons may partially explain this prevalence of asthma alone.53 This suggests different endotypes of practice for instance degree of specialization, lack of awareness of asthma with allergic and nonallergic rhinitis. Rhinitis often precedes existing or updated guidelines especially of nonspecialists, priority asthma and can therefore present as a risk factor for asthma.54 Among by individual practitioners to their own personal preferences, children, however, asthma often precedes rhinitis.53 Studies indicate location of patient or practice, underestimated severity and severity that optimal treatment of rhinitis reduces odds ratio for uncontrolled misclassification of asthma etc. Health-system differences may asthma55 as well as reduction in unscheduled hospital visits, missed partially have a role for instance infrequent discussion of asthma work days, nocturnal awakening by about 50%.56 Similar results are management among colleagues for instance. Taboo with the use of obtained in asthma children among whom rhinitis is an important steroids is another major hindrance in optimal control.40 Guidelines disorder.55 Asthma in rhinitis patients often triggers worse nasal recommend steroids as gold-standard yet they are insufficiently symptoms and an improved control of these nasal symptoms prescribed; preference for use of beta agonists as monotherapy frequently results in improved asthma symptom scores.55 Thus, although not useful; or preference for combination therapies at the the influence of untreated rhinitis is rather detrimental on asthma start of the therapy, etc. are another hindrances.40 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 Continuous monitoring is essential to achieve treatment goals or to 41 asthma and causes frequent exacerbations. Continuous positive tailor the asthma therapy. Currently, many asthma cases fail to attend airway pressure (CPAP) therapy for OSA in patients with nocturnal checkups or visit their physicians regularly58 thus paving way for the self- asthma improves asthma symptoms, rescue bronchodilator use, PEF, management. Self-management, excepting exacerbations, improves 42 and QOL and stoppage of treatment cancels these benefits. Other asthma control, lung function and the QOL59 among uncontrolled studies in contrast show development or worsening of bronchial subjects. Similar overwhelming results are noted in a very large hyper-reactivity with CPAP. Putative benefits for those having daytime review of several clinical trials60 that showed that self-management asthma are yet to be evaluated. OSA promotes other asthma triggers reduced hospitalization, unscheduled hospital visits, days-off, 38 such as GERD. Obesity and OSA are other factors that independently nocturnal asthma, asthma symptoms, need for rescue medications lead to increased airways inflammation thus may facilitate poor and improvements of lung function, PEF and QOL.60 Self-management asthma control in this scenario. Contrasting results in terms of airway approach can also be particularly useful for achieving asthma control 43 obstruction and inflammation are however observed. Role of other in subjects, for instances living in remote or rural residence. 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 Vaccination have lower levels of eosinophilic inflammation and noneosinophilic Although 60–80% asthma cases have upper respiratory infections, phenotype is especially noted with poorly controlled asthma.44 particularly influenza, in the background,61 but only few of them get vaccinated against influenza.62 Many times an increased risk Psychiatric of asthma exacerbations after influenza vaccination has been suspected but large reviews have not shown any link between two.63 Factors such as anxiety and depression are reported to be On the other hand, a study did not find any reduction in asthma modulators of poorly controlled asthma.45 These are frequently severity or fatal complications following influenza vaccination.64 observed especially among those with uncontrolled asthma.46 It Thus, in current scenarios vaccination remains the best strategy to is however uncertain whether these factors are consequence of reduce additional disease burden among asthma subjects.65 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 Limited Access and Cost may undermine their own symptomatic perception. This is partial There is a direct relation between severity and control of asthma with explanation that these parameters might not always reflect in the the availability10 and affordability of its treatment.66 Those who may objective measurements of asthma control such as asthma symptoms access can increase their income67 and reduce their asthma-related 48 49 or QOL. To add, stress can cause pro-inflammatory states as seen expenditure (unscheduled visits, hospitalization, etc.) by about with increased cytokine production. There might also be hormonal 40%.68 Currently, this is not the case though.10 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 BRITTLE FORM OF ASTHMA disturbance, anxiety, depression, etc.) when assessing asthma Being one of the variant of severe refractory asthma,69 this occurs in control and QOL.49 This is an important step since these negative approximately 10% of severe asthma cases and 0.5% of all asthma 466 Section 15 Chapter 103 Therapeutic Options for Uncontrolled Asthma

TABLE 3 │ Brittle asthma and its subtypes Parameter Type 1 Type 2 Definition 40% diurnal variation in PEF for > 50% of time over Sudden acute attack without an obvious trigger with apparently at least 150 days normal airway function Risk factors Atopy Exposure to aeroallergens Impaired local immunity Poor perception and interpretation of asthma Increased respiratory infections Psychosocial factors

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 Control of allergen exposure Inhaled bronchodilators Control of triggers Control of allergen exposure Self-management Immunotherapy Management of acute attacks Allied, e.g. adherence

cases.70 It has two clinical subtypes (Table 3). These cases are number of cases, sizeable number of cases remains symptomatic phenotypically different and have particularly high risk of morbidities with its use. Such patients are needed to be treated by: increasing (hospital admission, treatment side effects, and psychosocial effects) ICS dose; or adding long-acting beta-agonist (LABA) or leukotriene- and mortality (acute asthma, disease severity).70,71 These factors are receptor antagonist (LTRA) or theophylline.75 Studies have sufficient to worsen the asthma control or precipitate exacerbations. shown that increasing the ICS dose does not provide sufficient improvement of most lung function and symptom parameters. A THERAPEUTIC APPROACHES fourfold increase in dose however is noted to render improvements in the need of rescue beta-agonists, PEF, or the lung function, etc.76 Conventional approaches are based on relievers (bronchodilators) Its anti-inflammatory activity does not improve with increasing the and controllers (immunomodulators and/or anti-inflammatory dose (4–16 folds).76-78 This suggests that current doses are likely to be agents). Relievers open airways and provide more symptomatic sufficient for suppressing any inflammation in most patients. There short-term relief while controllers are suitable for long-term relief by is no conclusive evidence79,80 on the risk of systemic adverse effects reducing hyper-reactivity and inflammation. Avoidance of exposure with increasing the ICS dose, due to the heterogeneity of studies. to relevant triggers is often the additional gold-step in the asthma Some degree of dose-dependency in the HPA-axis effects of inhaled management. Current therapies pragmatically propose one-size-fits- steroids is noted. A large meta-analysis showed increased risk for all approach consisting of bronchodilators and immunomodulator posterior subcapsular cataracts, and to a much lesser degree, the risk and/or anti-inflammatory agents. These can effectively control for ocular hypertension and glaucoma, and skin bruising, with high- asthma but substantial number of cases fails to optimally respond. dose exposure.80 This is partially because practitioners/patients have been seen Long-acting beta-agonist (long-lasting relaxation of airway the tendency to underestimate their severity but overestimate the smooth muscle) and ICS (potent anti-inflammatory effects) have control of their asthma. complementary effects. ICS can also increase the expression of beta- Several approaches are now available at different stages of their 2 receptors in inflammatory cells to overcome the desensitization development that are based on: reducing airway smooth muscle, in response to chronic beta-2 agonist exposure.81 In addition, reducing airway inflammatory cell number or activity, optimization LABA may prime the glucocorticoid receptor facilitating activation of bronchodilation, etc. by corticosteroids.82 Proinflammatory effects with beta agonists are generally suspected although available studies are not seen Optimization of Bronchodilation to increase the inflammatory indices. This matches with other Inhaled beta-2 agonists are likely to partially become less effective studies that indicate that there is no increase in number and from their chronic use72 although optimal degree of bronchodilation severity of asthma exacerbation with their long-term use.83 Safety is still likely to be maintained.73 Instead of its use with inhaled of this add-on therapy is not unpredictable and only results in slight corticosteroids (ICS), studies have tested its use with long-acting increase in tremor and tachycardia; without any discontinuation muscarinic antagonists (tiotropium) and double dosed ICS in of this therapy.84,85 This add-on has been found to be better than severe refractory asthma. The results showed better lung functions increasing the ICS dose by fourfold in reducing day/night time and asthma control with tiotropium when individually compared symptom score, asthma exacerbations, rescue therapy, etc.76,83,86 to double dosed corticosteroid or beta-2 agonists.73 This treatment Cysteinyl leukotriene receptor-antagonists (LTRA) are a new class in severe refractory asthma showed that addition of tiotropium, to of asthma medication and have a weak anti-inflammatory activity. inhaled corticosteroid and beta-2 agonists, significantly improved Since corticosteroids are not very effective inhibitors of cysteinyl lung function.74 leukotriene pathways87 and thus their combination may offer some benefit. Studies does not show different results that this, and many Add-on Options adult and children studies state that their combination reduce Inhaled corticosteroids are the mainstay of treatment for persistent the number of patients who may need a systemic corticosteroid, asthma. Although significantly effective, at its usual doses, for compared to ICS alone [RR = 0.34; 95% CI 0.13, 0.88].88 This risk of 467 Pulmonology Section 15

reduced exacerbations that may eventually need systemic steroids optimal management of allergic rhinitis. For instance, combined indicate that this may modestly improve asthma control compared treatment with montelukast and budesonide had significant effect with ICS alone but this strategy cannot be recommended as a on reducing airflow obstruction. Other studies also indicate towards substitute for increasing the dose of ICS.89 Other study however improvement in asthma control and QOL following successful showed that addition of LTRA may be equal to doubling the dose treatment for allergic rhinitis. of ICS,90 however, this was stated without including a placebo arm. More data is needed before this combination can be included as a Omalizumab more global practice. Theophyllines have bronchodilator effect, It is a recombinant DNA-derived humanized immunoglobulin immunomodulatory, anti-inflammatory, and broncho­­protective G 1k monoclonal antibody that selectively binds to human effects.91 Studies indicate that there is an improvement in pulmonary immunoglobulin E (IgE) and inhibits interaction of IgE with IgE function and asthma symptoms when theophyllines are added to receptors preventing the release of inflammatory mediators that ICS,92 although all studies have not been able to confirm this result.93 occur in allergic asthma. This has therefore seen to cause significant, This combination may or may not equate to doubling the dose of ICS rapid and sustained reduction in serum free IgE levels at differing in the treatment of uncontrolled asthma. Side effects can be reduced dosing regimens and in a dose-dependent fashion.105 This has by using a concentration slightly below the recommended range. also been seen to reduce airway eosinophilia in the mild asthma Inhaler Devices patients. Better clinical benefits are seen in many trials among those with moderate-severe asthma in terms of number of exacerbations Different devices are reported to have different difficulties, and reduction of use of inhaled corticosteroids when compared advantages and limitations. To what extent these differences affect with control.105,106 Among those with severe asthma Omalizumab clinical outcome in asthma subjects is inconclusive. A large review of led to longer steroid reduction phase and reduction in median different devices reported no significant difference in drug delivery corticosteroid dosage. This also decreases use of rescue medication, and clinical effectiveness.94 In contrast, other studies report that improves asthma symptoms as well as QOL.107 Among those with certain devices (e.g. metered dose) are more difficult than rest95 and inadequately controlled severe persistent asthma despite best considerably affect compliance to treatment and asthma control. available therapy108 Omalizumab has shown improvements in severe Another study reinstates the importance of choosing right inhaler exacerbation rate, unscheduled emergency visit rate, QOL, asthma for optimal asthma control.96 Patient training is another area that symptom score, etc. For instance, reductions in hospitalizations due may improve compliance and asthma control. Many studies have to asthma can be 92% lower,109 total emergency visit rate by 47% highlighted importance of patient training and regular checking lower, and exacerbations by 38% lower versus placebo in patients of patients’ inhalation techniques.97 Guidelines reinforce that an with omalizumab-treated severe persistent asthma.110 Meta analysis inhaler should only be prescribed after confirming that the patient also indicated a 1.6- to 2-fold increase in moderate (≥ 1 point) (P < knows how to use the device.98 Switching to cheaper alternatives, 0.001) and 1.8- to 2.1-fold increase in large (≥ 1.5 point) (P < 0.001) such as metered-dose, has been seen to worsen asthma control improvements in overall QOL scores in Omalizumab-treated patients with greater need for emergency beta-agonists.99 This is more so if compared with placebo during both steroid stabilization and steroid it is done without clinical consultation or training. All this should reduction periods.111 Omalizumab has been extensively evaluated in fact be personalized, and guided by patient’s sociodemographic for adverse events and similar safety profile to that of the control characters such as young or old age, trembling of limbs, affordability, group, with no significant differences between groups112 have been literacy level, etc. found among patients with moderate-to-severe persistent asthma. Similar safety profile is noted among children as well. Asthma Control through Management of Comorbid Diseases Reducing Airway Inflammatory Effect of GERD on asthma is still debatable since improvement in Cell Number/Activity asthma following GERD treatment is variable. Studies however show Studies show that monitoring sputum eosinophil count might help in improvement of asthma symptoms for 69% cases following successful reducing the risk for severe exacerbations in the future.113 However, treatment for GERD.100 In another study, 24-week treatment with this seems to be useful for those with moderate-severe asthma113 only. lansoprazole reduced asthma exacerbations and improved QOL, Further studies have tested mepolizumab114,115 and reslizumab116 especially for those on polytherapy already.101 A recent large review (anti-interleukin-5 monoclonal antibody) among hypereosinophilic confirmed this by stating significant association between GERD patients having had severe refractory asthma. These treatments have and asthma.102 Similar paucity of data is noted for OSA and results shown clinical benefits in terms of corticosteroid sparing, number of are currently more inconclusive than GERD. Mechanical changes future exacerbations, improved expiratory flow and overall asthma from treatment with CPAP could influence airway responsiveness control. These effects are however not observed among those with but other study did not find any such association. Treatment of less severe asthma117 indicating importance of patient-selection. For psychopathologies such as panic attack, improves asthma outcomes those who have mild allergic asthma, use of antisense approach for although a large meta-analyses does not support this. In any case, reducing the level of messenger RNA and its translation into protein more extreme psychopathologies such as bipolar disorder, etc. has been found to be effective in reducing airway eosinophils by do not occur more frequently among those with asthma.103 The inhibiting the production of cytokine receptors.118 Many subjects effect of intervention for obesity is much clear for improvement in exhibit neutrophilic asthma instead and these subjects with asthma. A large review of 15 studies noted that each of the study neutrophilic severe refractory asthma have been demonstrated to that examined the effect of weight loss on asthma outcomes noted benefit with chemokine receptor antagonist.119 an improvement in at least one of the asthma related outcome.104 Novel therapeutics120 such as with cytokine inhibitors, including This effect stands irrespective of type of intervention, age, gender daclizumab, etanercept, etc. have been tested in relation to refractory and ethnicity. Thus weight loss for improvement of asthma control asthma. These compounds have been shown to improve asthma should be stressed. Similarly cessation of smoking has similar effect control; inhibit, in vitro, expression of inflammatory mediators such on improving asthma outcomes. Although still debatable, there are as interleukins 4, 5, and 13; decline in bronchial hyperresponsiveness, number of reports that report an improvement of asthma following improvements in QOL and postbronchodilator FEV1. Similarly 468 Section 15 Chapter 103 Therapeutic Options for Uncontrolled Asthma lumixilimab, an anti CD23 antibody is shown to reduce IgE more composite yet personalized approach (Table 4 and Figure 1) concentration by 40% and reduced production of proinflammatory should replace the current one size fits all approach. On the other cytokines, in patients with asthma. hand, practitioners should align their personal beliefs (preferences or choices) with recommended guidelines and should be more Reducing Airway Smooth Muscle effectively educated on the complexities of measuring asthma severity and initiate appropriate asthma treatment. These aspects Bronchial thermoplasty is a nonpharmacologic option that involves would make sure that asthma is properly treated, monitored and the delivery of radiofrequency to large airways in order to reduce managed and may result in desired degree of asthma control. Public the volume of smooth muscle and their responsiveness.121 Among agencies especially of REP countries should ensure that the diagnostic patients with relatively better controlled asthma, reduction in mild- gap and treatment gap is reduced and suitable medications are easily severe exacerbations and further improvement in asthma control available in an affordable manner. This would help patients not to has been noted with thermoplasty.122 Among those with severe self-prescribe or take suboptimal medications but help them to take refractory asthma, over a short follow-up period, thermoplasty has regular controller medications and avoid taking treatment only at been found to reduce exacerbations and emergency hospital visits, the time of complication or hospitalization. Researchers should improved morning peak exploratory flow123 and QOL (e.g. days lost adopt a collaborative approach for conducting organized research due to asthma).124 Similar results are observed over a longer follow- on uncontrolled asthma. This might facilitate faster advancement of up period of time such as absent complications and maintenance our understanding about uncontrolled asthma. of stable lung function.125 Side effects among those with mild- moderate 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.

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 Time-based repeated patient review 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 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 Section 15

Learning more about the complexities of asthma pathophysiology­ 15. Manocha R, Marks GB, Kenchington P, et al. Sahaja yoga in the will strengthen our therapeutic armaments for patients who do management of moderate to severe asthma: a randomised controlled not respond well to conventional medications. Some of these have trial. Thorax. 2002;57(2):110-5. already shown promise for those with poorly controlled asthma for 16. Nagarathna R, Nagendra HR. Yoga for bronchial asthma: a controlled study. Br Med J (Clin Res Ed). 1985;291(6502):1077-9. instance omalizumab, muscarinic antagonists, etc. The researchers 17. Bidwell AJ, Yazel B, Davin D, et al. Yoga training improves quality of life should also define how newer treatments are going to be integrated in women with asthma. J Altern Complement Med. 2012;18(8):749-55. into existing therapies. 18. Vedanthan PK, Kesavalu LN, Murthy KC, et al. 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