Used in Management 6

Contents 6.1 Introduction 176 6.2 Principles of Use 178 6.3 Available Medications: Broad Categories of Use 179 6.4 Quick-Relief Medications (“Rescue Medications”) 180 6.4.1 Short-Acting Beta-Agonist (SABA) 180 6.4.2 Short-Acting Anti-cholinergic Bronchodilators 181 6.4.3 Systemic 181 6.4.3.1 Side Effects of Systemic Corticosteroids: Some Comments 182 6.4.3.2 Use of Systemic Corticosteroids in Severe Acute Asthma 183 6.5 Long-Term Asthma Control Medications 183 6.5.1 Inhaled Corticosteroids (ICS) 183 6.5.2 Long-Acting Beta-Agonists (LABA) 185 6.5.3 Long-Acting Muscarinic Antagonists (LAMA) 185 6.5.4 Combination Products 186 6.5.5  Antagonists (LTRA) 186 6.5.6 Immunomodulators and “Precision Health” 188 6.5.7 Long-Term Systemic Corticosteroids 193 6.5.8  194 6.5.9 Cromolyn and 196 6.6 Other Medications Used in Asthma 197 6.7 Immunotherapy in Asthma (“ Shots”) 197 6.8 Low Evidence-Based Medications as Treatment Options 206 6.8.1 Approach to the Use of These Medications 206 6.9 Role of Bronchial Thermoplasty in Treatment 206 6.10 Concern About Side Effects: General Approach 207 6.11 Classifcation of Severity After Treatment 209 6.12 Step Approach to Asthma Management 211 6.13 Goals of Therapy 214 6.14 Quality-of-Life Scores 215

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2021 175 I. Mitchell, G. Govias, Asthma Education, https://doi.org/10.1007/978-3-030-77896-5_6 176 6 Medications Used in Asthma Management

6.15 Conclusion 217 6.16 Application 217 References 217

Key Points • Those with asthma should always be • Asthma medications are available in dif- partners with the educator in: ferent therapeutic groups: –– Developing goals of care –– They can be broadly described as for –– Completing quality-of-life scores immediate relief or long-term prophy- –– Planning the details of therapy and laxis, although there is some overlap. its adjustment –– Specifc medications and specifc dosages are required with different degrees of severity. –– Medication type and dose must be Chapter Objectives adjusted according to clinical After reading this chapter, you should be condition. able to: –– Use of a step-wise approach is helpful. • Describe the different medications used • Asthma medications are generally safe, in the treatment of asthma and their ben- but there are specifc potential side efts and drawbacks, including potential effects requiring monitoring. side effects • Some older medications (theophylline, • Understand the importance of initial and nedocromil, and cromolyn)—now no regular reassessment of severity in longer in common use and often diff- determining type and dose of medica- cult to obtain—are listed although tion use asthma can be well managed with many • Develop goals of care jointly with the newer medications. person with asthma (or their caregiver) • Medications not specifcally studied for and understand their relationship to a asthma—such as troleandomycin and step approach to asthma treatment gold—used in the past as -­ • Understand the importance of quality-­ sparing agents, are included. They may of-life scores and be able to incorporate be used by only very few of those with them into all assessments asthma, and strategies are suggested for replacing them with proven medications. • Newer medications (biologics) are an 6.1 Introduction extremely important addition for those with more severe asthma. Successful asthma self-management involves: –– These medications have led to reeval- uation of the underlying nature of • Medications for the prevention and treatment asthma. of symptoms, along with • Good environmental control 6.1 Introduction 177

To be effective, asthma medications must be was rarely explicitly stated, it was implied that carefully chosen. So too must be their dosage and minimal treatment should be used frst, followed route of administration. Many effective medica- by an increase in medication dosage, or substitu- tions are currently available, and most can be deliv- tion of more potent medications, if the initial ered to the lungs through different (and effective) approach proved unsuccessful or only partly suc- delivery devices. As a general rule, the medications cessful, and then accepting full asthma control as a in common use have few signifcant side effects. legitimate objective, by a multi-pronged approach Thus, the medications are safe for most people with that included high doses of potent medications. asthma, though troublesome side effects can some- The logic behind this is fallacious: the false time occur even when they are used appropriately. assumption is that there is a progression from non- And, as with other medications, signifcant side existing asthma, through mild to very severe, in effects may be experienced when other medical people with asthma. In reality, most individuals conditions exist in addition to asthma or when are remarkably consistent over time, within limits, users are also taking other medications or herbal in terms of disease severity. Hence, in most cases, remedies. Detailed advice on the individual’s cur- it is probably better to frst achieve control and rent health situation should always be sought from then reduce treatment, rather than vice versa. a physician or healthcare provider. In any treatment plan, disease severity is an important consideration. The intensity of the effort to control asthma should depend on the severity of Points to Ponder the disease. Severity should also be re-estimated at Principles of Treatment each contact. Overall (“long-­term”) severity is also important, although there is no easy method to • Recognition of the chronic nature of determine this. Nevertheless, both background asthma history and current history can be used to obtain a • Recognition that deterioration can be preliminary determination. Some items that can be prevented used to assess severity over time are: • Dose and delivery systems must be individualized • The age of onset • Frequency of admission to hospital • Any ICU admission Once an assessment of severity has been com- pleted, the intensity of treatment can be deter- Features in the current history that are helpful mined. “Intensity” here refers to the type, dose, in estimating severity at a specifc point in time and strength of drug therapy to be used and also include: to the rigor with which asthma triggers are to be avoided [1]. For example, the recent guideline • Daytime symptoms/limitation of activity update [2] lists six treatment steps; for a person • Night-time symptoms (nocturnal asthma) with moderately severe symptoms, treatment • FEV1 or PEF should start at Step 3. In such a situation, starting • Variability in airfow obstruction (FEV1 or at Step 1 would lead to unnecessary prolongation PEF) of symptoms and erode confdence in the health- care provider. Refer to Chapter 4 for a more detailed discus- Conversely, if treatment intensity is tracked over sion on assessing severity. a longer period, it can be used to estimate severity. An assessment of severity is a good guide to For example, the amount of relieving treatment the intensity of treatment that needs to be offered. () used on a daily basis will indicate Step-wise management has been part of the the frequency of symptoms. This is often a good approach to asthma for many years. Although it guide to a need for change in treatment. 178 6 Medications Used in Asthma Management

Severity must also be gauged through objec- regular medication required to control persistent tive measurements. These have been discussed asthma. Deterioration can be predicted by using a earlier and include both variability in daily peak peak fow meter to monitor lung function, follow- fow readings and formal pulmonary function ing a symptom score sheet, and keeping a record testing. While the “intensity of treatment” of the frequency of bronchodilator use. This approach is used here, an alternative is the “step-­ allows early deterioration to be identifed, and wise” approach. However, the resulting treatment action taken that, hopefully, will prevent further is not likely to be very different when either of progress of the exacerbation. the two approaches is used. A more complete description of severity is similar to the concept 3. Recognition that doses and delivery systems that asthma does show a continuum. must be tailored for each person with asthma While it is generally true that inhaled cortico- steroids and bronchodilators are required for 6.2 Principles of Medication Use most individuals with asthma, the optimum dose will vary considerably from one person to The following principles underlie any program of another. Time should be taken to determine and successful treatment: adjust the dose. There are many ways of delivering medication 1. Recognition that asthma is a chronic disease, to the respiratory tract, and those methods are with acute exacerbations described in detail in Chap. 7. A detailed knowl- This is very important. In the past, asthma was edge of the various medication devices, together often considered only as an acute disease. Thus, with individual preferences, is necessary to deter- both the person who had asthma and the health- mine the fnal selection of a delivery system. This care provider felt comfortable in assuming, when brief overview has the limited objective of intro- recovery seemed to occur after acute asthma, that ducing the topic and making some of the com- the problem had been resolved. Environmental ments on medications understandable. exposures that may have led to deterioration were The three major types of delivery system are: neither identifed nor avoided rigorously, and the long-term approach of using prophylactic drug • Metered dose inhalers (MDIs) therapy was not emphasized. • Dry powder inhalers (DPIs) Once asthma is accepted as a chronic disease, • Nebulizers then other factors—such as environment, the role of long-term treatment, and other issues including per- sonality, coping styles, and family relationships— MDIs can be addressed in detail. Persons with asthma, and The metered dose inhaler (MDI) is probably the their families, need to understand the disease fully single most effective way of delivering the drug; if and must have a written plan for dealing with exac- a spacer or holding chamber is used, the device’s erbations and episodes of deterioration. effciency and effectiveness is further improved. Not all medications are available in this prepara- 2. Recognition that deterioration in asthma can tion. Current MDIs contain “carrier” substances often be prevented or predicted and a propellant to allow the drug itself to be If the concept of preventable and predictable expelled in droplet form. Nowadays, hydrofuoro- deterioration is accepted by persons with asthma, alkane (HFA) is the most likely propellant. then a proactive approach can be recommended and implemented. They should identify their trig- DPIs gers and attempt to avoid them. If they do this Many dry powder devices are available. Examples conscientiously, they may reduce the amount of include the Turbuhaler, Diskus, Ellipta, and medication, especially “rescue” medication, that Aerolizer, each of which varies in its ability to is needed, but avoidance will not eliminate the successfully deliver medication to the lungs. 6.3 Available Medications: Broad Categories of Use 179

Under some situations, DPIs are as effective as, The current wide range of other potent or more effective than, MDIs. They generally medications, often used in combination, has contain lactose, and they vary in the degree of meant better quality of life in those with systemic absorption of the medications. asthma, without possible side effects from corticosteroids. The use of the medications Nebulizers listed in Sect. 6.8 (“Low Evidence-Based Nebulizers are a popular delivery system but Medications as Treatment Options”) was ineffcient in terms of dosages delivered. The explored in the past, in entirely laudable large doses used lead to a perception, among attempts to avoid systemic corticosteroids. individuals with asthma, that they are highly They are probably not needed now, but are effective. It is unlikely that nebulizers are required included as some people may have found them for any more than a minority of individuals, even useful and wish to continue rather than change in infancy and childhood. to a newer medication. Lastly, precautions in Medications for nebulizers come in a variety the use of theophylline are given in detail. of preparations—some contain preservatives that Theophylline was once the mainstay of long-­ may cause some irritation to the airway; others term asthma management in the USA, the last require dilution with saline to give an appropriate western country to realize the value of inhaled volume; or, they may be available in ready-to-use corticosteroids and beta-2 agonists. People nebules. with asthma today can be symptom-free by Individuals with asthma should participate in choosing from a wide range of safe and effec- the selection of the delivery system with the edu- tive medications. Theophylline is not needed cator and the healthcare provider. If they feel they in asthma, but a few devotees remain, and have had a say in the choice of delivery system, asthma educators must still be knowledgeable they will be much more likely to take the medica- about this group of medications. tion as scheduled. They should also have the physical dexterity and strength to be able to use the chosen device. 6.3 Available Medications: On each occasion that a healthcare provider or Broad Categories of Use an educator sees someone with asthma, device technique and the use of the drug should be The standard asthma arsenal consists of medica- reviewed. Studies indicate that deterioration in tions in the following categories [1–5]: usage technique occurs within 3 weeks of the initial teaching. Hence, constant review of technique is 1. Quick-relief medications (“rescue essential for continued successful use of the device. medications”) The medications are arranged in broad catego- • Bronchodilators—short-acting beta- ries. The order in which they are listed corre- agonists sponds, roughly, to their utility. Note that the • Bronchodilators—anti-cholinergic length of individual descriptions and discussions • Systemic corticosteroids is most assuredly not a refection of the value of 2. Long-term asthma control medications the medication to someone who has asthma. • Inhaled corticosteroids Systemic corticosteroids are dealt with in detail, • Bronchodilators—long-acting as this is a group in which side effects do occur. beta-agonists In the past, they were needed often in the treat- • Combination products ment of asthma. Now they remain essential in • Leukotriene inhibitors severe acute asthma and are given over a few • Systemic corticosteroids days only. Their long-term use in severe chronic • Long-acting anti-cholinergic (muscarinic) asthma is required much less frequently these agents days. • Theophylline 180 6 Medications Used in Asthma Management

3. Immunomodulators/biologics increasing airway reactivity [7]. These medica- 4. Other innovative and quasi-experimental tions should be used only for short-term relief. therapies For example, a recent study of 145 persons with Each group is briefy reviewed here. asthma who were allergic to house dust mite

observed and confrmed a small decline in FEV1 in those on short-acting, but not in those on long-­ 6.4 Quick-Relief Medications acting, beta-2 agonists [8]. When asthma is under (“Rescue Medications”) good control, inhaled beta-2 agonists are only infrequently required, on an as-needed (prn) These are bronchodilators used to relieve symp- basis. This should be twice a week or less; more toms or to obtain rapid improvement in severe frequent use should lead to re-evaluation of the acute asthma where systemic corticosteroids are severity of the asthma. Some educators and pre- used. Systemic corticosteroids are not usually scribers may include pre-treatment for exercise-­ mentioned in the context of quick relief, but their induced asthma more than twice/week as a reason placement here is appropriate. However, while for re-evaluation, while others may not. bronchodilators are almost always required to Beta-agonists may be given orally or by inha- provide relief, systemic corticosteroids, with lation. Oral administration is rare in asthma their major potential side effects, are reserved for because it causes an increase in side effects; for the most severe exacerbations. this reason, the inhalation preparations [nebuliz- This section really deals with symptomatic ers, metered dose inhalers (MDI), and dry pow- treatment, of which the most widely used are der inhalers (DPI)] are all more widely used. beta-2 agonists (bronchodilators). Any of the Onset of action occurs within a few minutes, with available medications may be employed, and a peak within 30 minutes and a total duration of 2 their main use is to abort episodes of asthma or as to 4 hours. Side effects can include a slight a preventive treatment before exercise. As men- increase in heart rate and mild muscle tremor. tioned earlier, the frequency of inhaled broncho- Tolerance, a decrease in bronchodilator effect, dilator use is a good guide to asthma severity. and shortened duration of action when the drugs are used on a regular basis are intrinsic parts of beta-2 agonist use. This is a sharp reminder of one 6.4.1 Short-Acting Beta-Agonist of the reasons why SABA medicines should not (SABA) Bronchodilators be used on a regular basis. Tolerance also applies to side effects of SABA such as tremor. While the Short-acting beta-2 agonists (SABA) act as bron- absence of tremor may be welcome, if someone chodilators directly on the of the with asthma has no side effects when being tested airway and provide immediate relief. The most for reversibility, then the educator must explore widely used relievers are albuterol and terbuta- the possibility of regular SABA use. line. They act on the beta-receptors. Beta-1 It is worth noting that resistance (i.e., loss of response occurs on the cardiovascular system and effectiveness) to the beta-agonists: beta-2 response on the smooth muscle. SABAs are generally safe. Obvious side effects include • Is different skeletal muscle tremor, tachycardia and palpita- • Occurs late in an asthma episode tions, and central nervous system (CNS) stimula- • Is ominous tion (especially hyperactivity) [6], but these are • Demands a high dose of systemic corticoste- short-lived. roids urgently Of more importance is the long-term regular use of these medications. There has been some Thus, most healthcare providers would sug- concern in the past that regular long-term use of gest that their regular use be limited to two or beta-2 agonists might increase asthma severity by three times per week. However, as noted, more 6.4 Quick-Relief Medications (“Rescue Medications”) 181 frequent use is permitted (as in the prevention of both the number of circulating and exercise-induced asthma) and may be essential mucosal mast cells. They also appear to decrease during acute exacerbations. mucus secretion and appear also to restore dis- While the side effects of beta-agonists, such as rupted epithelium. tremor and tachycardia, may be transient, they Corticosteroids should not be confused with can cause great distress in some individuals. the androgenic steroids often used illegally by Hence, if they cause unpleasant side effects to athletes to increase muscle bulk. This dangerous occur when used to prevent exercise-induced use of one type of steroid, with its attendant neg- asthma, ipratropium (Atrovent™) is an appropri- ative publicity, has caused much confusion, and ate bronchodilator choice. many patients tend to be wary of any medica- tions with similar-sounding names. They will have to be reassured on this point, and it will 6.4.2 Short-Acting Anti-cholinergic generally be helpful to be proactive and to Bronchodilators explain that the steroids used in asthma are glu- cocorticoids and not androgenic or anabolic ste- Anti-cholinergic medications are much less com- roids. ( are similar to the natural monly employed in asthma than in other lung dis- hormone cortisone produced by the adrenal orders, such as COPD. Ipratropium (Atrovent) is gland, while the androgenic steroids are similar the only short-acting medication that acts on the to natural male sex hormones.) It might also help cholinergic receptors. When given by inhalation, to remind them that estrogens—the female sex it starts working within 30 minutes and is there- hormone in birth control pills—are also fore used as an adjunct to beta-2 agonists in the steroids. emergency department (ED) and in-patient set- It is of interest, and of importance, that after tings, particularly with children. Its effect lasts many years of use there is no evidence that the from 3 to 6 hours. This medication is particularly basement membrane of the airways is thinned by effective in children and elderly people. If deliv- corticosteroids. ered through a nebulizer, eye protection should Adrenal hormones are controlled in a manner be worn to prevent dilation of the pupils, eye irri- similar to that of a servo loop. This is an engi- tation, and the possible development of neering phrase and best understood by glaucoma. ­considering a domestic room heater whose ther- While SABAs help the respiratory muscles to mostat is set at a particular temperature level. relax, the anti-cholinergic bronchodilators work When the temperature falls below the set level, to prevent the muscles from tightening. Thus, the thermostat causes the heater to switch on and there are two different approaches to the room to be heated until the pre-set tempera- . ture is reached. Then, the thermostat switches off the room heater. A similar mechanism occurs with many hormones. There is a pre-determined 6.4.3 Systemic Corticosteroids level associated with health. When the hormone level (in this case cortisol) falls below that level, Systemic corticosteroids are included here then the tropic hormone which is produced by the because of their role in severe, life-threatening pituitary gland (in this case adrenocorticotrophic asthma. Much of the information below is also hormone or ACTH) and which stimulates the relevant to their use in long-term diffcult-to-­ production of the hormone in the adrenal gland is control asthma and will not be repeated later. increased. Once the cortisol level in the blood- Corticosteroids are effective in asthma for a stream has increased, release of ACTH from the number of different reasons. For example, they pituitary is lessened as there is no longer a need decrease the release of mediators from the alveo- to stimulate the adrenal gland to produce more lar cells, reduce cytokine release, and decrease cortisol. 182 6 Medications Used in Asthma Management

In other words, adrenocorticotrophic hormone • Moon face (ACTH), the hormone in the pituitary gland that • Hirsutism stimulates the adrenal gland to produce cortisol, is • Insomnia released. When the body requires corticosteroids, ACTH levels increase and stimulate the adrenal 6.4.3.1 Side Efects of Systemic glands to produce more cortisol. As more cortisol Corticosteroids: Some is produced by the adrenal gland, following the Comments servo loop principle, the action of the pituitary While severe untreated asthma, by itself, may gland is suppressed, and therefore less ACTH is lead to growth suppression, growth suppression produced. Corticosteroids given in asthma imitate is also known to occur in children on long-term the action of cortisol, “fool the pituitary gland,” systemic corticosteroids. In the past, oral or sys- and thus less ACTH is released into the blood- temic corticosteroids (OCS) were used for the stream. The net result is that anyone taking oral most severe cases. It is likely that in many cases corticosteroids (OCS) on a daily basis, including there was no reduction in fnal adult height, those with asthma, will suppress the production though there was some delay, during puberty, of and release of ACTH and the adrenal glands will growth spurts, resulting in apparent short stature have no stimulus to produce their own cortisol. As at specifc moments in time. Growth suppression a result, the adrenal gland may atrophy with the may occur because of a number of mechanisms, long-term use of OCS. This has important impli- some unknown, but what is known is that produc- cations. At a time of major stress, the person will tion of growth hormone will be impaired particu- be unable to produce the extra cortisol needed. larly if the corticosteroid is given daily. Growth This atrophy will affect not just the adrenal gland suppression will occur if the asthma is left but also the hypothalamus and pituitary, the so- untreated. called hypothalamic-pituitary-adrenal­ (HPA) axis. Bone metabolism and calcium metabolism are OCS are powerful hormones, related to the also affected. Osteomalacia and osteoporosis hormones produced in the body, and with a num- may occur, and bones will fracture with minimal ber of well-recognized side effects. They can also force [11]. be affected by other medications that increase or Cataracts may occur, and adults on long-term decrease their effectiveness. They have many systemic corticosteroids should have regular eye potential side effects, some of which are very examinations to test for this condition. serious. The major side effects [9, 10] include: Diabetes may result from a change in glucose metabolism caused by the corticosteroids. If dia- • Adrenal suppression betes symptoms exist, appropriate testing and • Impaired bone metabolism management will be required. • Linear growth delay in children OCS may impair the immune response; with • Cataracts high doses, this impairment may lead to unusual • Diabetes infections. However, this side effect, though theo- • Infection retically possible, is rare. In children, the impair- • Myopathy ment of the immune response may mean that a • Hypertension common illness such as chicken pox may be more severe when it occurs in children with asthma on Less medically important side effects, but often OCS than in other children not on OCS. very important to those with asthma, include: Myopathy, or muscle weakness, may occur with OCS use. It is characterized by weakness, • Bruising wasting, and changes within muscle cells. • Weight gain Blood pressure may rise with regular use and • Mood change should therefore be monitored. Other OCS side • Acne effects include weight gain, bruising, and swell- 6.5 Long-Term Asthma Control Medications 183 ing of the face, known as moon face. Moods may situation, control over the asthma can usually be change quickly from depression to euphoria to regained within 24 hours. At the same time, aggression (emotional lability). Excess hair effective prophylactic treatment can be started. growth on the face and body may be present. In summary, OCS remain important in the OCS also increase the incidence of acne and treatment of severe asthma. Their use is best min- insomnia. Some children become hyperactive imized, not by arbitrarily reducing the dose, but when put on systemic corticosteroids. by careful attention to all of the details of asthma Thus, the side effects of OCS are a major issue management, including environmental control, in the treatment of asthma. At the same time, it is correct use of a prophylactic drug, and detailed important to recognize that they are life savers in teaching of a delivery system, all described in the many situations. Hence, they should only be con- next section. sidered when other options have been explored and rejected. It is also important to realize that the metabo- 6.5 Long-Term Asthma Control lism, and therefore the actions, of corticosteroids Medications may be affected by many other medications, pre- scribed and over-the-counter alike. The interaction There are boundaries between the various classes will vary from one preparation to another, and in of medications, but these are sometimes blurred. some cases, the benefts of the OCS will be at least For example, an individual with asthma may partly lost, while in other cases, the action will be manage very well without regular medication. more marked. Obviously, the reverse is also true, That same person may use inhaled corticoste- and the benefts of a medication used long term for roids, designed for long-term prophylaxis, for a another condition may be lost. When OCS are pre- week or so during a viral-induced exacerbation. scribed, a full medication history is essential. The combination product / Direct questions must be asked, as OTC prepara- may be taken twice daily as prophylactic therapy tions such as Pepsin, Rolaids, and Tums are rele- and also be used occasionally to provide immedi- vant. Many birth controls pills and antibiotics ate relief from breakthrough symptoms [2]. affect OCS actions. In addition to asking the per- son with asthma about concurrent treatments, a pharmacist should be asked to check any potential 6.5.1 Inhaled Corticosteroids (ICS) effects on any medication in use. Inhaled corticosteroids [12, 13] suppress airway 6.4.3.2 Use of Systemic Corticosteroids infammation and are used almost exclusively in in Severe Acute Asthma the long-term prophylaxis of asthma. ICS were the OCS continue to be essential in crisis interven- mainstay of asthma management in previous tion. When developing an asthma management guidelines, and if asthma control was incomplete plan with an individual who has moderate or while on ICS, poor adherence was commonly con- severe asthma, OCS (prednisone 40 to 60 mg/ sidered, and if adherence was assured, an increase day) may be used when peak fow falls to 50% of in ICS dose was often the option of choice. The its usual value. In children, a rough guide to pred- new NHLBI Guidelines [2] suggest changes to the nisone dose is 1–2 mg/kg/day, to a maximum of paradigm of focusing almost exclusively on ICS at 60 mg/day. Dexamethasone may also be used in both ends of the severity spectrum. children, 0.6 mg/kg given at onset and repeated For those with severe asthma, an important 24 hours later. The use of OCS should be limited, development is that there are now a number of but not to the detriment of asthma control. effective and safe immunomodulators, which In severe attacks, when prophylaxis has not will be discussed later. At the other end of the been attempted or has not proved effective, or the spectrum, there are also changes in the approach exacerbation is severe, OCS are essential. In this to those with mild asthma who have only 184 6 Medications Used in Asthma Management

­occasional exacerbations. Such individuals the minimum dose is found that controls would have been treated with daily ICS even symptoms. when well, with SABA and OCS added in exac- ICS may be used for extended periods. Many erbations and perhaps with an increase in ICS individuals with asthma do not agree with (or do dose. Now a new option is to avoid regular, not understand the need for) long-term use and everyday therapy. Instead, at the early stages of will stop taking them after a few months of treat- an exacerbation, ICS can be started with or with- ment. If symptoms do not recur, they will not out SABA and continued for a week or so. The restart the drug; if symptoms recur, then they implications of these two changes will be dealt have a stimulus to continue. with in detail later. While side effects are uncommon, they vary ICS are extremely effective. They decrease from mild to potentially severe, the latter being airway infammation and airway hyperrespon- related to systemic absorption. With high-dose siveness, improve lung function, decrease symp- ICS, there may be a systemic effect, and some of toms, and reduce mortality [14–21]. They may the side effects associated with systemic cortico- also interfere with metabolism steroids may be seen. Some growth suppression and with synthesis of and prosta- has been shown in children on very high doses of glandins and prevent the migration of infamma- ICS. Most clinicians believe that when the ICS is tory cells. In addition, ICS may increase the stopped, the growth rate will increase. The issue responsiveness of beta-receptors in the airway of growth is very complex, as children with smooth muscle. Because they also help by reduc- asthma may have growth retardation if treatment ing the number of infammatory cells, individuals is inadequate. Studies [22–24] have shown that with asthma should be started on ICS when newly there is decreased velocity in growth during the diagnosed, either every day or in exacerbations frst year of treatment in children. However, when [2, 21]. followed through to adulthood, there was no ICS may be given by MDI, by nebulizer, or by ­signifcant difference in height between children DPI, and it can take up to 2 weeks before signif- who had used inhaled corticosteroids and those cant effects on symptoms are noticeable, although who did not have asthma. Growth and develop- some effect is commonly seen sooner. Their ment should be monitored, and if growth delay is action subsides a few days after the medication noted, a full medical evaluation is indicated. In has been discontinued. The starting dose of ICS the elderly, high-dose ICS may increase the risk should be suffcient to control symptoms, and of cataracts [25] and slightly increase the risk of therefore the assessment of severity is important glaucoma. In all groups, there is concern about to determine what that dose should be. It is often adrenal suppression and inadequate response to higher than the intended maintenance dose—for stress. example, while a person might stabilize eventu- ICS are not all the same in terms of systemic ally on 100 micrograms per day, the usual start- side effects. Lipworth examined available studies ing dose will be between 400 and 1,000 of systemic adverse effects of ICS and wrote that micrograms, depending on the potency of the “Marked adrenal suppression occurs with high ICS. If the medication is taken correctly, as noted, doses of inhaled corticosteroid above 1.5 mg/d there will be improvement in 1 to 2 weeks. (0.75 mg/d for futicasone propionate), although Once good control has been achieved, the there is a considerable degree of inter-individual dose should be reduced slowly. The time interval susceptibility” [26]. There was greater “dose-­ at which reductions are made varies considerably related adrenal suppression with futicasone com- from person to person. If there is severe life-­ pared with beclomethasone dipropionate, threatening asthma, reduction should be made at budesonide, or acetonide.” In intervals of 2 or 3 months or perhaps even longer. terms of adrenal crisis, Todd et al. noted that this If the asthma is very mild, reductions may be occurred most commonly with futicasone and made quickly over a period of 2 or 3 weeks until suggested caution in the use of high doses of this 6.5 Long-Term Asthma Control Medications 185 medication in children [27]. On the other hand, formoterol MDI or DPI, and long-acting alb- when was compared with futicasone, uterol as an extended-release tablet. Side effects the former “achieves greater pulmonary deposi- become less with time as tolerance develops to tion, causes fewer adverse oropharyngeal effects, beta-2 adverse effects, a phenomenon described deposits less biologically active drug in the sys- earlier, and are typical of this class of temic circulation, and has less potential for adre- medications. nal suppression” [28]. The safety of ciclesonide Long-acting beta-agonists (LABAs) should has been confrmed in adults [29]. not be used as monotherapy in asthma [34] but as The more common side effects seen with ICS add-on therapy [35] in both moderate and severe are oral thrush and dysphonia (hoarseness). Oral persistent asthma when the asthma is not con- thrush can usually be prevented by using a spacer trolled despite the use of ICS and adherence to and rinsing the mouth after inhalation. Hoarseness environmental measures. Combination products, can be prevented by reducing the dosage of ICS, described in Sect. 6.5.4, are available that conve- if this is considered safe, or spreading the dose niently contain both an ICS and a LABA. throughout the day in smaller individual amounts. When there is a perception of poor control with a particular dose of ICS, many prescribers 6.5.3 Long-Acting Muscarinic will respond by increasing the dose. To a certain Antagonists (LAMA) level, this will be successful. The dose-response curve rises steeply with an increase from low to The use of the shorter-acting anti-cholinergic was moderate doses of ICS. However, it then starts to described earlier. There has been interest recently fatten, and further increases in ICS dosage may in the role of the neurotransmitter acetylcholine not only be relatively unsuccessful, but also raise in asthma. Acetylcholine is released from para- the risk of side effects. In the case of the ICS sympathetic nerves and interacts with M3 futicasone, a recent meta-analysis showed that ­muscarinic receptors in the lung, airway ganglia, most of the therapeutic beneft was obtained with nerves, smooth muscle, mucous glands, and total daily doses of 100–250 micrograms, with a endothelium of pulmonary blood vessels. The maximum beneft at a dose of around 500 micro- effect is to increase airway tone, contract bron- gram/day. As noted, while there may be modest chial smooth muscle, and reduce mucus secretion beneft at doses above this level, it has been and vasodilation. Acetylcholine also plays a role shown that it is better to add another drug (e.g., a in infammation, by inducing the release of pro- long-acting beta-2 agonist or leukotriene antago- infammatory mediators. Hence, medications that nist) and re-emphasize environmental control, can block these actions for an extended period rather than prescribe even more inhaled cortico- may have an add-on role when the asthma is dif- steroids [30–32]. fcult to control with low to moderate doses of ICS along with LABA. Such a medication will also be helpful when side effects of a LABA are 6.5.2 Long-Acting Beta-Agonists troublesome. (LABA) The muscarinic antagonists induce broncho- dilatation and perhaps reduce infammation by Long-acting beta-agonists are related chemically competing with acetylcholine at the muscarinic to the short-acting beta-agonists. They relax the receptors. The use of these medications has been smooth muscle, with an onset of 30 minutes or studied in people with COPD, and the fve cur- less for and 2–3 minutes for for- rently licensed for use in this condition are moterol and a duration of action that is 12 hours ipratropium, aclidinium, glycopyrronium (also or longer [33]. Because of its speedy action, for- known as glycopyrrolate), umeclidinium, and moterol can also be used for quick relief. Three tiotropium. For asthma, only two anti-­ medications are currently available—salmeterol, cholinergics have been approved: ipratropium 186 6 Medications Used in Asthma Management and tiotropium [36]. The short-acting ipratro- Various studies have raised concerns that the pium has been described above. As of the end of use of LABA as monotherapy increases the risk 2020, only tiotropium has been approved for use of acute hospital admissions due to asthma and in the treatment of asthma in adults as add-on perhaps an increase in asthma mortality. The lit- therapy to ICS and a LABA in a number of coun- erature is certainly contradictory, and an FDA tries worldwide, including the European Union, meta-analysis did not settle the issue [39]. Japan, and the USA [37]. Tiotropium is the only Nevertheless, given the concerns, the use of the long-acting anti-cholinergic approved for use in combination product means that those with asthma. asthma cannot take a LABA by itself and that it Available evidence was further reviewed in must always be combined with an ICS. the recent guidelines update [38]. The studies A more general concern about treating asthma covered people more than 12 years old. The real-­ without an ICS (or alternative long-term control- world impact of LAMA on asthma is not yet ler), i.e., using beta-agonists as monotherapy, clear as “the majority of LAMA studies used a extends backs to the 1960s [40]. This legitimate comparative effcacy design, and not an effective- anxiety is alleviated by the availability of these ness design, but the key questions were about combination products. effectiveness.” In the situation when asthma is The use of an ICS in one inhaler, and a LABA not controlled on ICS alone, the recommendation in another inhaler, might have the same beneft as was to add a LABA rather than a LAMA. Having a combination inhaler. It is intuitively obvious that said that, a LAMA can still be used as an add-on adherence is likely to be enhanced with a combi- to ICS in individuals aged 12 years and older nation product, and this has been confrmed [41]. with uncontrolled asthma. It should be explained More recently, a new approach has been sug- to them that add-on LABA therapy has a more gested—that of using one combination inhaler on favorable beneft-harm profle. And as a precau- a regular basis and using the same inhaler as a res- tion, it should be noted that “individuals at risk of cue inhaler [42]. Using the combination inhaler in urinary retention and those who have glaucoma this way is another strategy to improve adher- should not receive LAMA therapy.” However, as ence. Obviously, this strategy can only be used in most newer preparations, the role of LAMA when the LABA in the combination product has will evolve as more robust real-life evidence immediate onset, as in formoterol in Symbicort. becomes available.

6.5.5 Leukotriene Receptor 6.5.4 Combination Products Antagonists (LTRA)

Fixed-dose combination products, i.e., an ICS + Leukotrienes [43, 44] are important mediators in LABA in one inhaler, have been available for the pathogenesis of asthma. They have a potent almost two decades. /salmeterol bronchoconstrictive effect that is 1000 times (Advair™) was introduced in the UK in 1999 and more powerful than histamine [45–47]. They the USA in 2000; budesonide/formoterol have been shown to increase white blood cells in (Symbicort™) in Sweden in 2000 and the USA lung tissue and facilitate the leakage of fuids into in 2006; and /formoterol (Dulera™) tissue. This adds to infammation and swelling in the USA in 2010. There is a difference in the and also gives irritants in the fuids access to the onset of action of the LABAs used. Salmeterol tissues and muscles around the airway. Evidence has a delay of about 30 minutes before the onset also suggests that leukotrienes increase mucus of its bronchodilation. By contrast, formoterol production. Thus, attempts have been made to starts working almost immediately and, as identify substances which would block their already discussed, can be used for symptomatic action and which can be taken with safety. These relief. substances are called leukotriene inhibitors or 6.5 Long-Term Asthma Control Medications 187 leukotriene receptor antagonists (LTRA). They dence of adverse events and discontinuations are active in preventing both the early and late from therapy were similar in the and asthmatic response [48, 49]. placebo groups.” Similarly, in 698 children with There are currently three leukotriene receptor asthma aged 2–5 years in a double-blind study antagonists (LTRA) in use: with placebo, breakthrough asthma “occurred signifcantly more frequently in the placebo • , which inhibits one of the early steps group” [51]. As in the previous study, “there were in the formation of leukotrienes no clinically meaningful differences between • Montelukast, which binds to leukotriene treatment groups in overall frequency of adverse receptors effects or of individual adverse effects.” • Zafrlukast, which binds to leukotriene receptors Pregnant women with asthma, and their health- care providers, are concerned about the use of any The NHLBI Expert Panel Update classifes medication. As always, the risk of inadequate treat- leukotriene inhibitors as an addition to, but not a ment of asthma, and consequent risk to the fetus of replacement for, inhaled corticosteroids for per- possible hypoxemia, must be balanced against sons with moderate persistent asthma [35]. potential risks of the medication. It is impossible to Despite being available since the 1990s, the pre- be certain that montelukast is absolutely safe dur- cise role of the LTRAs in asthma management ing pregnancy, and given the many alternatives to remains unclear [49]. It is reasonable to use an LTRA, the issue may not be raised very frequently. LTRA in asthma when ICS alone will provide If a woman with asthma on LTRA becomes preg- inadequate control, although use of a combina- nant, some modest reassurance can be given from a tion product (ICS + LABA) will be more effec- Danish study [52], which noted that “pregnant tive and obviously more convenient. women with prescriptions for montelukast had a When there is inadequate control with an ICS/ higher risk of pre-term­ birth and maternal compli- LABA combination, and all the usual provisos, cations.” However, as the authors point out, these such as adherence, ability to use an inhaler, risks are also associated with maternal asthma fnances, comorbidities, and alternative diagnoses without LTRA. There was no increased risk of con- and other conditions, have been dealt with, then genital anomalies. In the same vein, a recent study adding an LTRA is a reasonable step before showed very low levels of montelukast in infants increasing the dose of ICS. Despite the proven breast-fed by mothers receiving LTRA [53]. effectiveness and safety of ICS, there remains a Having noted a low incidence of side effects in small population of people with asthma and par- the original studies, a concern has arisen over the ents of children with asthma, who have a great fear last several years about neuropsychiatric side of corticosteroids (corticophobia). In such a situa- effects. Based on case reports received by the US tion, LTRA might be used in conjunction with Food and Drug Administration (FDA), a “black low-dose ICS in consultation with the person with box” warning has been placed on montelukast. asthma or their family over time to provide reas- This is a warning that appears on the medication surance about the safety of ICS. In those unable to label and is “to call attention to serious or life-­ use an inhaler, LTRA should be used before resort- threatening risks.” In the case of montelukast, ing to OCS. There may also be a role for LTRA this is about serious neuropsychiatric (NP) events when stepping down or reducing the dose of ICS, reported in those with/without a history of psy- with careful monitoring, of course [35]. chiatric disorder during montelukast treatment The most commonly used LTRA is montelu- and after its discontinuation. The events include kast, and it seems safe, with one exception that agitation, aggression, depression, sleep distur- will be discussed later in this section. In a double-­ bances, and suicidal thoughts and behavior blind study of 681 individuals with asthma over (including suicide). There was great variability in the age of 15 years, effcacy was shown [50]. In the NP event types reported, and it is unclear addition, the investigators noted that “the inci- what, if any, are the underlying mechanisms [54]. 188 6 Medications Used in Asthma Management

Concerns were also noted in data from the 6.5.6 Immunomodulators WHO database of 14,670 reports on montelukast and “Precision Health” [55]. The main symptoms were sleep disorders (infants aged less than 2 years), depression/anxi- Immunomodulators are medicines intended to ety (children aged 2–11 years), and suicidal “help regulate or normalize” the behavior and depression/anxiety (adolescents [62]. They are employed in many areas of health- aged 12–17 years). Thus, there are worrying care, but this section will focus on those used as concerns, but an important caveat is that these add-on therapy in asthma. are passive reports, with clear limitations on The immunomodulators currently available being able to attribute causality, rather than asso- for asthma are monoclonal antibodies, an entirely ciation. Formal studies have given varying new class of medication being used across the results, with some showing no NP events [56, spectrum of medicine—in cancer, rheumatoid 57]. In a case-controlled­ study of 898 NP cases arthritis, multiple sclerosis, and other diseases— in children, where each child was matched to 4 and now available specifcally for asthma. They controls, there was a statistically signifcant are an exciting addition to current therapies and increase in NP events in those newly prescribed have a specifc role when asthma is severe enough montelukast [58], but the events were mainly to require very-high-dose inhaled corticosteroids anxiety or sleep disturbance. In a nested cohort or systemic corticosteroids. Their development study, NP events were confrmed, especially in and rational use follow a deeper understanding of the frst few weeks [59]. the pathogenesis and genomics of asthma. The LTRA Zileuton does require that liver Given the novelty of this new class of medica- enzyme testing be done before treatment com- tions, some general background information is mences and every 2 to 3 months while treatment essential. The monoclonal antibodies are part of a is in progress. If theophylline is used, more fre- larger group of new compounds called biologics, quent monitoring of theophylline levels is essen- developed using biotechnology, with an origin tial. Zafrlukast affects the body’s handling of from human or animal tissue or from a microor- warfarin and should not be used in anyone on this ganism. Monoclonal antibodies (mAb or moAb) medication [60]. This effect was not seen with are made by cloning a unique white blood cell, montelukast [61]. which is ultimately the origin for every antibody How should the asthma educator or asthma derived in this way. prescriber respond to this information? Use At a basic level, an antibody is a protein made basic principles that apply to all medications. by the immune system to attack an antigen, which That is, use a medication that is most appropriate is also a protein. Monoclonal antibodies are for the specifc situation in a specifc individual, designed in a laboratory to attack very specifc warn about side effects, and ensure ongoing antigens, and their name suffxes indicate their assessments that include appropriate monitor- primary source: antibodies made from mouse ing. And of course, medications should be protein have names ending in “-omab”; part stopped when no longer required or when there mouse and part human protein, “-ximab”; small is a suspicion of side effects and an alternative is parts of most protein attached to human footing, available. Great care should be taken with initial so-called humanized “-zumab”; and fully human prescriptions and ongoing monitoring of monte- proteins, “-umab.” lukast given the presence of a “black box warn- The starting point in the development of a ing” regarding neuropsychiatric side effects. monoclonal antibody for any health condition is a This medication should be used when there are detailed knowledge and understanding of causal no reasonable alternatives, only after a warning mechanisms. The use of any specifc monoclonal has been given regarding side effects, and ques- antibody in asthma requires knowledge of pheno- tions asked about behavior/psychiatric issues at type and endotype in individuals with asthma, as every visit. described earlier in the book. Specifcally, the 6.5 Long-Term Asthma Control Medications 189 understanding of the role of IgE and of interleu- steroids regularly and then to adjust the dose kins such as IL5 was helpful in the development according to the response. Currently, the use of of the frst two monoclonal antibodies for asthma, monoclonal antibodies in asthma is following the (anti-IgE) and mepolizumab (anti- traditional path: all possible attempts are made to ­IL5). More of the currently available monoclonal control the asthma using current therapeutic antibodies are listed in Table 6.1, and many more agents, avoidance strategies, and control of aller- are in development. gies and other comorbidities. Monoclonal anti- The use of these new compounds is part of body treatment is considered only if the asthma what is called “precision health” or “precision remains problematic after all conventional steps medicine,” in which both treatment and preven- have been tried and discarded. tion are patient-specifc. While the term “preci- In the future, precise classifcation of the indi- sion health” may be new, the underlying principle vidual and the asthma can be expected, and some is not: in the past, knowledge permitting, preci- people will be identifed very early as being sion was used in treatment. Consider blood trans- unlikely to respond to conventional therapy, fusions: originally blood would be withdrawn including the use of ICS and additional medica- from the nearest available donor, but once blood tions such as LABA. Precise classifcation will typing and serology were understood, a donation require continued research into the genetic and was always taken from a matching donor. biochemical basis of asthma and the specifc The “precision health” approach is based on genomics of each individual. In addition, the spe- knowledge of individual variability in genes, cialized discipline of pharmacogenomics, the environment, and lifestyle. Until recently, this study of how genes affect any one person’s was not the case: the general approach was to use response to any one specifc medication, will treatment considered the most appropriate for come to the fore. There are hence many steps to most people; if it proved unsuccessful, then other be taken before a full realization of the benefts of options were tried. That approach led to delays, precision health will be seen in the management complications, and, sometimes, death. of asthma. New privacy safeguards will also be Where precision health is already well-developed,­ required, since precision health will depend on accurate information allows the best treatment to be the sharing of large data sets of confdential determined in advance and used frst. Rather than information. Given that a specifc treatment employing the old trial-and-error­ approach, treat- might be designed for a specifc individual, new ment is aimed very carefully at one target. research designs will be needed, and novel and The contrast between accurate pre-transfusion rigorous ways of oversight by the various drug matching of blood types and what has been done regulatory authorities will be demanded. to date in asthma is clear. Until recently, asthma Successful partnership of scientists from many education was mainly an attempt to persuade disciplines is required and between healthcare people with asthma to take their inhaled cortico- practitioners must also be developed.

Table 6.1 Monoclonal antibodies for asthma Name Binds to Age Route Dosing Administered Xolair IgE > 6 SC Based on IgE level and body weight In clinic or at home (omalizumab) yrs Nucala IL-5 > 6 SC Every 4 weeks At home (mepolizumab) yrs Cinqair IL-5 > 18 IV Every 4 weeks In clinic (reslizumab) yrs Fasenra IL-5R >12 SC Every 4 weeks for frst three doses and At home (benralizumab) yrs then once every 8 weeks Dupixent IL-4Rα, IL-4, >12 SC Every other week At home (dupilumab) IL-13 yrs 190 6 Medications Used in Asthma Management

To return to current concerns: monoclonal were designed to target infammation in the air- antibodies should be considered whenever severe ways. It is administered as a subcutaneous injec- asthma remains uncontrolled despite adherence tion on a monthly basis. It can also be given to an excellent treatment regimen. At this very intravenously [66, 67]. Pre-flled syringes of early stage, statements such as “everyone with omalizumab (XolairTM) are now available. asthma is different” do not come close to describ- Given that omalizumab has been longest in ing the true heterogeneity of the disease. While use, there is a greater body of knowledge about it bronchial obstruction is still the ultimate cause of than about the newer products. The approach to symptoms, and this measurement will remain the its use will be described in detail and will act as a key factor in asthma assessment, other measure- template for the use of the newer monoclonal ments will become more relevant. The focus cur- preparations. rently is on airway infammation, and that Omalizumab’s use is limited, specifc, and very described as Type II seems most likely to be the important. It is for people with moderate to severe target of monoclonal antibodies. Type II shows asthma who are inadequately controlled on inhaled evidence of eosinophilic involvement, associated corticosteroids and on whom all the usual proce- with high IgE and a variety of interleukins [63]. dures in the assessment of control have been car- The monoclonal antibodies will bind to block key ried out. As noted above, it binds to IgE and parts of the infammatory pathways. There will reduces the release of allergic mediators. It is therefore be much less infammation and as a hence reserved for persons with proven consequence improved control of the asthma and and raised serum IgE levels. The dose prescribed future symptoms in the individual [64]. is based on body weight and serum IgE level. Immunomodulators are a new class of “add- Omalizumab is effective in reducing both the ­on” drug available for moderate to severe asthma. number of exacerbations and the dose of inhaled They are biologics, made from living organisms, corticosteroids [68–71]. Studies show an and act on the immune system. The immunomod- improvement in the quality of life in children ulators used for asthma are monoclonal antibod- [72] and adults [73, 74]. It is licensed for those ies that bind to a particular target of the immune aged 6 years and above. It has also been tested in response. The targets affected by these medica- the treatment of perennial and tions include immunoglobulin (IgE) and cyto- found to provide effective control of symptoms, kines. The available immunomodulators and reduced reliance on , and improved their targets are listed in Table 6.1. quality of life [75]. The other biologics have not been used or Immunomodulators for Asthma studied as much, but enough information exists to Most of these new asthma medications are realize they are very promising, but always as approved for IgE (eosinophilic) asthma. High lev- add-ons. It should also be noted that they are all els of IgE are a marker of asthma in most cases. expensive. Blocking IgE might be helpful, although this does not necessarily imply a causal relationship [65]. Side Effects The frst monoclonal antibody to be approved, While the asthma biologics are generally well omalizumab, is produced by recombinant human- tolerated, possible side effects do exist: ized technology, hence the ending ‘zumab.’ It binds to and blocks IgE, neutralizing it and reduc- • Omalizumab (Xolair) may cause arthralgia, ing airway damage. It prevents IgE from attach- generalized pain, leg pain, fatigue, dizziness, ing to receptors, signifcantly reducing fracture, pruritus, dermatitis, and earache. the release of histamine. It interrupts the allergic • Mepolizumab (Nucala) may cause injection reaction earlier than other medications, which site reaction, headache, back pain, and fatigue. 6.5 Long-Term Asthma Control Medications 191

• Benralizumab (Fasenra) may bring on head- (d) Are there risks or triggers that can be ache and pharyngitis negated or minimized both at work and at • Dupilumab (Dupixent) users may experience home, such as: injection site reactions, oropharyngeal pain, (i) Smoking (including second- or eosinophilia, conjunctivitis, blepharitis, oral third-hand smoke) herpes, and keratitis. (ii) Environmental exposures to irritants • Reslizumab (Cinqair) users may have oropha- (iii) Allergen exposure known to cause ryngeal pain. sensitization (iv) Use of medications such as beta-­ Both omalizumab and reslizumab carry “black blockers or ASA box” warnings regarding anaphylaxis. In the case of (e) Is SABA being overused? omalizumab, safety has been evaluated in over 4,000 (f) Are asthma medications leading to dis- individuals with asthma. It has triggered anaphylaxis tressing side effects? in a small number of them, usually within 2 hours of (g) Are there psychosocial issues (anxiety, administration. However, it has been known to cause depression and problems with social rela- anaphylaxis even 2 years after administration. Hence, tionships, social isolation)? anyone prescribed omalizumab (or reslizumab) 3. Ensure that current management is optimal. should also be prescribed an epinephrine injector and Action should refect concerns listed in Step 2 taught how to use it. The other most serious adverse above. reaction is various forms of malignancies. (a) Insist on asthma education, even if done previously. Determining Suitability of Biologics: The (b) Check and correct inhaler technique and Process The GINA Guidelines [1] are helpful in encourage adherence with tips on how to approaching so-called diffcult-to-treat asthma; do this. NHLBI Guidelines are silent. The GINA (c) Switch to ICS-formoterol maintenance Guidelines focus on “adolescents and adults with and reliever combination therapy. symptoms and/or exacerbations despite GINA (d) Treat all identifed comorbidities, and Step 4 treatment or taking maintenance OCS.” ensure risk factors are eliminated or While the process has been outlined several times reduced. already, it is described in more detail here. (e) Consider add-on therapy if not already in use, such as LABA, tiotropium, LAMA, The process to be followed when considering or LTRA. the use of a monoclonal antibody is: (f) Encourage non-pharmacological inter- ventions, including smoking cessation, 1. Confrm that the diagnosis is correct and that weight loss, exercise, mucus clearance, no other another condition could be responsi- and annual infuenza immunization. ble for the symptoms. (g) Consider high-dose ICS if not already in 2. Explore in detail the possibility of specifc use. factors contributing to symptoms and increas- 4. Perform a review in 3–6 months. ing the possibility of exacerbations adversely (a) If asthma remains uncontrolled, then affecting quality of life: severe asthma is confrmed, and proceed (a) Is inhaler technique correct? to “Determining suitability of (b) Is medication actually being taken as biologics – confrmation”. prescribed? (b) If asthma is controlled, consider reduction (c) Are there comorbidities such as obesity, in treatment, with OCS being reduced GERD, chronic rhinosinusitis, and OSA? frst if they are in use: 192 6 Medications Used in Asthma Management

(i) Perform close follow-up, and if deterio- (e) Determine whether there is a registry or ration occurs, return to previous regi- clinical trial that the person may enroll in men, accepting that this is severe at little or no cost. asthma, and proceed to “Determining 6. If severe asthma phenotype is confrmed, and suitability of biologics – confrmation.” all other possibilities are discounted, use (ii) If asthma remains under control, then biologics. monitor closely, reducing therapy Once the decision to prescribe biologics has slowly, ensuring control is maintained. been made, other complications may arise: 5. Determining suitability of biologics – confrmation • The high costs involved, since many drug Having diagnosed severe asthma, the HCP plans may not cover these products should perform a full assessment, but con- • Variations in product availability between tinue with high-dose ICS (or lowest OCS countries dose) during assessment. • Diffculty in choosing the best biologic for the (a) Re-confrm presence of Type 2 infamma- job tion through the presence of one or more • The choice of product will be diffcult. of the following: There are no objective, standard-baseline (i) Blood eosinophils ≥ 150/μl comparisons between the various biologics (ii) FeNO ≥ 20ppb that can be used as an evidence-based guide (iii) Sputum eosinophils ≥ 2% to the choice of medication. In addition, (iv) Clinical features of the asthma based studies done to date have used varying on allergies inclusion/exclusion criteria and outcomes. (v) Need for maintenance OCS, with Nevertheless, a rough guide would be as tests i and ii above repeated on low- follows: est possible OCS dose (a) Anti-IgE if: sensitization (skin tests or (b) Investigate comorbidities and differential specifc IgE), total serum IgE and weight diagnosis by performing: within dosage range, and exacerbations in (i) Complete blood count (CBC), the last year C-reactive protein (CRP)1, IgG, IgM, (b) Anti-IL5/anti-IL5R: exacerbations in the IgE, fungal precipitins, chest x-ray, last year and blood eosinophils ≥ 300/μl high-resolution CT of chest (HRCT), (c) Anti-IL4R: exacerbations in the last year and diffusing capacity of the lungs + blood eosinophils ≥ 150/μl or FeNO ≥ for carbon monoxide (DLCO)2 25ppb (ii) Formal allergy testing, either skin 7. While predictors of success with biologics prick or specifc IgE have been described, they vary in accuracy (iii) ANCA3, CT sinuses, echocardio- and do not replace careful monitoring and grams if required intermittent full reassessment. (c) Ensure social/psychological support. (a) If response is good: if on OCS, these (d) Ensure multidisciplinary team involvement. should be reduced frst. If on inhaled ther- apy, dose may be reduced, but do not stop ICS. In general, medications should be 1 CRP is a protein made in the liver, and raised levels in the reduced slowly based on evidence of pre- blood indicate infammation. vious beneft, potential side effects, cost, 2 DLCO measures how well gases cross into the blood- and of course the preference of the person stream from the alveoli and is low in emphysema and in who is actually receiving the medications. interstitial and fbrotic lung diseases. At the same time, do not forget to ensue 3 ANCA is anti-neutrophil cytoplasmic autoantibody, and management is optimized using the 1–3 raised levels raise the possibility of autoimmune vasculitis. steps above at every visit. 6.5 Long-Term Asthma Control Medications 193

(b) If response is not good: stop biologic ther- tezepelumab with different phenotypes/endotypes apy. Then: of asthma, should be addressed.” Some beneft (i) Review the basics as already was shown in another study, but “tezepelumab was described. unable to signifcantly reduce daily oral corticoste- (ii) Consider HRCT if not already done. roid dose without loss of asthma control” [77]. (iii) Reassess phenotype. Tezepelumab will eventually become avail- (i) Induced sputum. able. Amgen and AstraZeneca, the manufactur- (ii) Consider bronchoscopy for ing partners, intend to seek approval in 2021. alternative diagnoses. Assuming approval is given, a predictable (iv) Consider add-on macrolide. additional challenge to healthcare profession- (v) Consider low-dose OCS, ensuring als that occurs with all medications (at least in strategies in place to minimize the the USA and New Zealand) will be direct-to- side effects. consumer advertising. This is likely to be the (i) Consider bronchial thermoplasty. frst source of information for many with asthma and the start of a dialogue with their Current biologics currently available are com- HCP or asthma educator. There are advantages plex molecules that must be given by IV or SC in this mode of disseminating­ information, but injection. Most persons with asthma considered also some drawbacks. The topic is now so for a biologic will have a long history of asthma, important that it is further discussed in Sect. including IV medication as part of ED treatment of 8.11 along with strategies that educators might exacerbations. As a result, needle phobia may have consider. set in. Hence, whenever these medications are In summary, the biologics are not only new considered, the presence or absence of needle pho- preparations, but part of a new approach, and fur- bia must be explored and if present treated. Some ther experience in a variety of situations will help asthma educators may have the skills to do this, establish their place over time. However, the but often additional professional help is needed. problem the prescriber faces—because of the Over time, more biologics will undoubtedly lack of head-to-head studies—is likely to remain become available. The HCP will nonetheless have not only a reality but also a continuing source of to perform individual assessment and will con- confusion and frustration. tinue to face challenges in assessing the evidence and deciding exactly which medication is likely to prove benefcial in any one individual. An example 6.5.7 Long-Term Systemic of the challenges involved is exemplifed in what is Corticosteroids happening in research and perhaps eventual licens- ing of tezepelumab. This medication is not cur- Given the wide range of other effective and safe rently approved, but may well be in the near future. medications, the use of OCS is no longer a Tezepelumab was reviewed in 2019 [76]. It common strategy. There remain a few people binds to TSLP (thymic stromal lymphopoietin), a with asthma severe enough that this last resort cytokine overexpressed in the airways of those must be used. with severe asthma and responsible for infamma- It is more important when long-term systemic tory responses in asthma. This binding inhibits the corticosteroids are being considered to ensure a action of the TSLP receptor complex and poten- full evaluation. This evaluation, as described ear- tially helps to lessen asthma symptoms. The lier, is so important it must be repeated at inter- reviewers saw tezepelumab as a promising candi- vals in order to: date to be used in asthma. However, there was a caution: “Several unanswered questions concern- 1. Confrm or re-confrm the asthma diagnosis ing basic pathophysiological aspects of TSLP vari- 2. Address factors that might contribute to ants, and the long-term safety and effcacy of uncontrolled asthma: 194 6 Medications Used in Asthma Management

(a). Lack of fnance/inadequate insurance diurnal variation is a common feature in human coverage physiology, and the important one in asthma is (b). Non-adherence the natural diurnal variation in the production of (c). Poor inhaler technique corticosteroids and growth hormone. Larger (d). Unidentifed or poorly or untreated amounts of both substances are produced at night comorbidities such as gastroesophageal than during the day. refux Sudden stoppage of long-term corticosteroid 3. Give advice on the mitigation of occupational therapy can lead to withdrawal symptoms such as and environmental triggers headaches, nausea, low blood sugar, muscle and joint pain, restlessness and hypotension and, in In addition, for the small number of users some cases, death. Corticosteroids should be who continue to require OCS long term, the gradually reduced over a period of weeks. This regimen should be optimized by determining does not apply in cases where treatment is being the minimal effective dose and prescribing it for made with a short burst of oral corticosteroids use in the morning on alternate days (a single (typically lasting less than a week). dose at 7–8 a.m. every other day) where possi- Extra care must be employed for corticosteroid-­ ble. These particular individuals require a much dependent individuals with severe asthma symp- more wide-­ranging assessment—one that toms. These persons have been shown to have a should cover the many aspects of care, includ- higher incidence of psychiatric comorbidity [78]. ing psychosocial aspects. They also require full Cessation of corticosteroid therapy must be done assessment of: under a healthcare provider’s supervision. Slow reduction in the dose of corticosteroid allows the • Pulmonary function hypothalamic-pituitary-adrenal (HPA) axis to • Home and work environment recover, though symptoms such as depression • Psychosocial status may occur. Systemic corticosteroids have been used And of course, frequent evaluation and re-­ extensively as long-term agents in the control of evaluation must be done for side effects and to moderate to severe asthma. Their use has dimin- ensure alternatives are being explored. ished in chronic asthma with greater knowledge Many side effects have already been described, of environmental control and with the availability but one specifc form of immune suppression is of other pharmacological agents, which include of concern in children. Chicken pox is a universal high-potency ICS, LABAs, immunomodulators, infectious disease of childhood, almost always and LTRAs. The newer ICS and LABAs are mild. It may turn severe in a child who is receiv- delivered effectively by modern delivery devices. ing high doses of OCS. If a child on OCS has had Adrenal suppression, in particular, is much less contact with a child with chicken pox, the parents common with ICS than with systemic corticoste- should obtain medical advice immediately. roids, but as noted earlier, it does occur. Hence, Particularly in children, the suppression of care in prescribing and ongoing monitoring is growth hormone production and adrenal cortico- still an essential component of care. steroids can be reduced (but not prevented) by giving prednisone early in the morning—between 7 and 8 a.m. Note this is different from the use of 6.5.8 Theophylline inhaled corticosteroids, which may be more effective when given in the afternoon. References Though their use in the USA is currently very lim- have been made earlier to the changes in asthma ited, the methylxanthine group of bronchodilator that occurs between day and night. This so-called medications was the mainstay of US asthma man- 6.5 Long-Term Asthma Control Medications 195 agement till recently. Usage in other parts of the [81] (that include inattention, hyperactivity, irri- world has always been much less. The theophyl- tability, and behavior that is withdrawn or diff- line group consists of theophylline itself, amino- cult to control) to major cardiac effects and, phylline, , and oxtriphylline, rarely, cerebral hemorrhage. Behavior and learn- and their use has been continuously evaluated over ing problems have also been described in chil- the last several years. The drugs remain low in dren, but these have been overemphasized. cost, which is an obvious advantage. Theophylline Theophylline has a number of other effects in is mentioned in the recent NHLBI Update but with addition to those on the smooth muscle [82]. It an important qualifer that it was “not considered increases diaphragmatic contractibility. It cer- in this update” and has “an increased risk of tainly acts on the heart and circulation and may adverse consequences and need for monitoring stimulate respiration. It can also trigger or worsen that make ... use less desirable” [2]. In other words, gastroesophageal refux (GERD) as it increases the therapeutic window between an effective dose gastric production and reduces the pressure of the and a toxic dose is narrow, and the margin between esophageal sphincter which permits refux of an effective dose and one with side effects is small. gastric acid into the esophagus. Its use has been The authors believe that with the current availabil- shown to increase GERD by 24% and to increase ity of a wide range of more effective products, this the amount of reported heartburn and regurgita- medication is not needed for successful asthma tion by 170% [83, 84]. management. In addition, the newer medications This medication is always administered orally have a much lower risk of side effects, without the or by injection, and the usual theophylline prepa- need for monitoring through frequent blood tests. rations currently available are of the extended-­ Regardless, theophyllines are still in use, and release form. This permits administration just details are provided to help ensure safety of those once or twice a day, with appropriate testing of given this medication. levels to monitor adequacy of dosages. These lev- Theophylline relaxes the smooth muscle and els are an indicator of adherence. inhibits the release of mediators from mast cells. In using theophylline, the healthcare provider It inhibits the late asthmatic response, and there is must: evidence that it has some anti-infammatory action at low (about 5 ug/ml) serum concentra- • Consider the age of the individual tions. There has been some interest in the possible • Proceed much more cautiously for children benefts of this modest anti-infammatory effect in under 5, and the elderly, than for other ages COPD, but even this use seems forlorn [79]. • Determine whether the individual is a smoker The onset of action of theophylline depends (smoking increases theophylline metabolism) on the route and the dose, and the duration • Determine the individual’s level of obesity depends on the dose. Generally, doses producing (whether thin or fat) serum levels in the range of 5 to 15 micrograms/ • Ascertain whether any other ailments are pres- ml [80] are required. Beyond this level, side ent that may affect drug activity, such as liver effects occur, such as nausea, vomiting, head- disease, heart failure, or seizure ache, nervousness, and tachycardia. As the level rises, so does the severity of the side effects, and Theophylline can interact with, and be affected these include all the preceding mild effects plus by, a large number of prescribed medications, seizures leading to status epilepticus, refractory such as Tagamet, erythromycin, and ciprofoxa- cardiac rhythms, severe hypertension, and possi- cin [85]. It may also cause gastroesophageal bly death. refux in the elderly and in children. Tables 6.2 Side effects are common and vary consider- and 6.3 list the medications that can increase and ably, from minor changes in behavior in children decrease theophylline levels. 196 6 Medications Used in Asthma Management

Table 6.2 Medications that INCREASE theophylline levels Use Trade names Alcoholism Antabuse Birth control Brevicon, Enovid, Demulen, Genora, Loestrin, Nelova, Nordette, Ortho-Novum,­ Ovcon, Ovral, Triphasil, and many others Gout Lopurin, Zyloprim Heart disease Adalat, Blocadren, Calan, Cardizem, Cartol, Dilacor, Inderal, Isoptin, Levatol, Mexitil, Procardia, Timoptic, Verelan, Visken Infections Antibiotics such as: Biaxin, Cipro, Comprecin, EES, E-Mycin, Eryc, EryPed, Ery-Tab, Erythrocin, Floxin, Ilosone, Noroxin, Pediazole, Penetrex, TAO Parasites Mintezol Stroke Ticlid Ulcers Tagamet Note: Cigarette smoking and marijuana as well as phenytoin therapy will increase theophylline clearance

Table 6.3 Medications that DECREASE theophylline levels Use Trade names Adrenal disease Cytadren Sleep disorders Alurate, Amytal, Butisol, Lotusate, Mebaral, Seconal Seizures Dilantin, Luminal, Mysoline, Peganone, Solfoton Tuberculosis Rifadin, Rifamate, Rimactane Note: Theophylline clearance will decrease with cirrhosis, cardiac failure, sustained fever, old age, neonates, and viral infection

From an initial reading of the above descrip- ­availability for use in the United States, and/or tion, it would appear that this is one drug to avoid. have an increased risk of adverse consequences However, and despite all these side effects, it has and need for monitoring that make their use less been used successfully over many years, and desirable.” where healthcare providers have confdence in its Cromolyn (cromolyn sodium, IntalTM) and use, they continue to do so with safety. Recently, nedocromil (TiladeTM) are both non-steroidal anti- it has been suggested that in severe asthma, low-­ infammatory medications that prevent mediator dose theophylline may allow reduction in the release. In the case of cromolyn, only histamine amount of ICS taken [86]. release is prevented, while nedocromil blocks the However, every indication is that the decline release of many other mediators as well. The in worldwide usage is likely to continue. medications inhibit the early and late phases of allergen-induced bronchoconstriction and are used in the long-term prophylaxis of asthma. 6.5.9 Cromolyn and Nedocromil Cromolyn may prevent exercise-induced asthma. For such use, the drug needs to be taken 30 These medications are considered together. Both minutes before the exercise starts, and this delay in were once popular, but are of low potency and onset of protection is a major drawback. When therefore have a limited role, and there may be used for long-term prevention of asthma, between problems in availability. They are mentioned in 3 and 6 weeks are required before it can be deter- the most recent update, at the level of Step 2 but mined whether or not the drug is effective. not at any greater level of severity [2, 38]. In Both cromolyn and nedocromil are adminis- addition, there is a footnote, “Cromolyn, tered via inhalation, and both are available in Nedocromil, LTRAs including Zileuton and MDI. Cromolyn is also available in nebulizer Montelukast, and Theophylline were not consid- solution. Both products cause very few serious ered for this update, and/or have limited side effects, mainly minor irritability, especially 6.7 Immunotherapy in Asthma (“Allergy Shots”) 197 with the powder inhaler, and an unpleasant taste ingly, once a diagnosis of asthma has been made with nedocromil [86]. The effcacy of cromolyn and appropriate treatment taken, the “recurrent has recently been reassessed, and it is doubtful if bronchitis” disappears, and the need for antibiot- it has any more than a minimal effect on symp- ics ceases. toms. Neither of these are the primary drug of choice for the treatment of asthma, but may be used in those individuals who are 6.7 Immunotherapy in Asthma steroid-phobic. (“Allergy Shots”) Some healthcare providers choose nedocromil and cromolyn rather than inhaled corticosteroids. Immunotherapy in the form of “allergy shots” These medications are useful when individuals or has been in use for many years, yet remains con- their families are antagonistic to the use of ICS troversial with professionals [87]. In an attempt because of a fear of side effects. Neither is par- to make patients understand immunotherapy in ticularly potent, and some researchers have ques- familiar terms, allergy shots specifcally have tioned whether cromolyn has any beneft at all. been described as vaccinations to desensitize With cromolyn, the major drawback is that it individuals to allergens (Vaccine Weekly, 1998, needs to be taken four times a day; further, it is Dec 21). Currently immunotherapy may still be only after 4 weeks of therapy that the healthcare delivered as subcutaneous injection (SCIT) or provider can determine whether or not it is prov- “shots,” but use of sublingual immunotherapy ing successful. Nedocromil must be taken three (SLIT) with drops is also possible. times a day; while this is better than four times a Many allergists believe that immunotherapy day, it is still a partial barrier to adherence. has been unfairly maligned. They note success Nedocromil also has a very unpleasant taste. when a vaccine, carefully chosen and prepared, Asthma can be safely and effectively managed follows assessment by a well-trained allergist. without these medications. Individuals with asthma often fnd logic in SCIT, The medications used in asthma, their side which offer the possibility of modifying the natu- effects and the time needed before they are effec- ral history of asthma. Strong proponents of tive are shown in Tables 6.4 and 6.5. immunotherapy believe that other treatments . This is a repeat of the sentence that comes may provide control of asthma but do not funda- before the tables. Please delete. mentally change it. In other words, immunother- apy may be disease-modifying. Given the controversy, it was appropriate that 6.6 Other Medications Used the 2020 Focused Updates to the Asthma in Asthma Management Guidelines reviewed in detail the role of subcutaneous and sublingual immuno- Mucolytic medications, which are used to loosen therapy in the treatment of allergic asthma [2]. sputum, are available both over the counter and An essential prerequisite to immunotherapy is by prescription. In general, these medications are demonstration of allergic sensitization by skin not very effective, and conventional asthma treat- testing or by measuring antigen-specifc IgE anti- ment is more benefcial to most individuals. body in the blood. Immunotherapy by SCIT is While acetylcysteine is effective, it irritates the something to be considered in adults and children airways and must be given by nebulizer. over the age of 5 who: Antibiotics are often given for acute asthma exacerbations. While there are some genuine • Have well-controlled allergic asthma and wish indications for their use, such as sinusitis, they to reduce the burden of medication are generally not helpful. Many individuals are • Have a history of worsening symptoms with diagnosed with asthma after years of taking anti- specifc seasons biotics for “recurrent bronchitis.” Not surpris- 198 6 Medications Used in Asthma Management Available without prescription. Available Not recommended due to cardiac stimulation. excessive Comments Rarely used Dose may be given until mild Dose may be given such as tremor are seen. effects of asthma will dictate Severity of administration. frequency Monitor use: use preventer medication if using >3 times a week. Not recommended for long-term treatment. May double usual dose for exacerbations Dosage 0.1 mg/kg via nebulizer Max dose: 5 mg Child: 2 puffs tid-qid prn or 1–2 Child: 2 puffs prior to exercise puffs tid-qid prn or 2 Adult: 2 puffs 5 minutes prior to exercise puffs 2–11 yrs : 0.025 mg/kg (min 0.63 mg to a maximum of 1.25 q 4–8 hrs >12 yrs: 0.63–1.24 mg q 4–8 hrs Adult: 0.63–2.5 mg q 4–8 hrs Child: 1 capsule q 4–6 hrs prn and prior to exercise Adult: 1–2 capsules q 4–6 hrs prn and prior to exercise Child: >4 yr to adult: 2 puffs q Child: >4 yr to adult: 2 puffs 4–6 hrs ≥2 yrs : 0.1 mg/kg bid 6–12 yrs: 2mg tid 6–12 yrs: 2mg tid to qid. Child: 0.05 mg/kg (min 1.25 mg to max 2.5 mg) in 3 cc of saline q 4–6 hrs Adult: 1.25 mg – 5mg in 3cc of saline q 4–6 hrs Strength(s) 0.2 mg 0.25 mg 0.3 mg per dose 0.08% 0.143% 0.167% 0.2% and 1% 90 mcg/dose 0.31 mg/3ml 0.63 mg/3ml 1.25 mg/3ml 200 mcg/dose 59 mcg/dose 2 mg/ml 2, 3 & 8 mg 5mg/ml. (0.5%) 2.5 mg/ml 1.25 mg/3ml 0.63 mg/3ml Packaging MDI or caplets tablets Inhalation solution MDI Inhalation solution DPI MDI Oral syrup oral tablets inhalation solution ** ** Medications used to manage asthma Isotherine hydrochloride Generic Name Bronkaid Primatene AsthmaHaler Asthmanefrin Medihaler-Epi and various Bronkosol manufacturers Beta-agonists (short acting) Albuterol Proventil Proventil-HFA Ventolin ProAir Accuneb Albuterol of Other manufacturers HFA Levalbuterol [R-albuterol] Xopenex Epinephrine Table 6.4 Table 6.7 Immunotherapy in Asthma (“Allergy Shots”) 199 (continued) Comments May cause more irritability than other preparations Tablets rarely used Tablets Monitor use: use prophylactic Monitor use: use prophylactic drug if using >3 times a week Not to be used for symptomatic relief or in place of anti- infammatory therapy Can be used for symptomatic relief Not to be used for symptomatic relief or in place of anti- infammatory therapy Dosage < 2 yrs : 0.4 mg/dose tid to qid 2–6 yrs: 1.3–2.6 mg/kg/day ÷ q 6–8 hrs 6–9 yrs: 10mg/dose tid to qid >9 yrs: 20 mg/dose tid to qid 2–3 puffs q 3–4 hr. Max 12 q 3–4 hr. 2–3 puffs puffs/day 0.01 – 0.02 ml/kg (max: 15 mg/ dose) q 4–6 hours >12 yrs: 1–2 puffs q 4–6 hours to >12 yrs: 1–2 puffs a total of 12 puffs <12 yrs: 0.05 mg/kg/dose tid increase to 0.15mg/kg/dose Max daily dose: 5 mg Max daily dose: 12–15 yr: 7.5mg >15 yr: 15 mg 0.25 mg/dose may be repeated in 15–30 min. Max: 0.5 mg/dose within 4 hr Child: > 6 yrs: 4 mg q 12 hrs >12 yrs: 8 mg q 12 hrs Adult: 8 mg q 12 hrs Child: < 12 yrs: 1 cap q hrs >12 yrs: 1 cap q 12 hrs Adult: 1 cap q 12 hrs Child: < 12 yrs: 1–2 puffs q 12 Child: < 12 yrs: 1–2 puffs hrs q 12 hrs >12 yrs: 2 puffs Child: 1 blister q 12 hrs Adult: 1 blister q 12 hrs Strength(s) 2mg/ml 10mg & 20mg 0.65 mg/ dose 0.4%, 0.5% and 5% 200 mcg 2.5 mg, 5 mg 200 mcg 1 mg/ml 4 mg, 8 mg 12 mcg/cap 21 mcg/puff 50 mcg/blister Packaging Oral syrup or tablet MDI inhalation solution MDI or Breath activated MDI MDI or Breath activated Oral tablets MDI Injectable (SC) Oral tablets Inhalation capsule MDI Diskus Generic Name Metaproterenol sulfate Metaproterenol Alupent Maxair sulfate Terbutaline Brethine and other manufacturers Beta-agonsits (Long-Acting) (LABA) Albuterol Vospire Formoterol fumarate Formoterol Foradil Salmerterol xinafoate Salmerterol Serevent 200 6 Medications Used in Asthma Management Comments Always use with a spacer device Always May replace beclomethasone or at half the MDI dose budesonide Dosage Low daily dose Low Child: 84–336 mcg Adult: 168–504 mcg Medium daily dose Child: 336–672 mcg Adult: 504–840 mcg High daily dose Child: > 672 mcg Adult: > 840 mcg 4–11 yrs: 1–2 puffs bid 4–11 yrs: 1–2 puffs bid of 40 or >12 yrs: 1–2 puffs 80 mcg 1–8 yrs: 0.5 mg to 1 qd doses or in divided Child 6–17 yrs: 180 mcg bid. 360 mcg Max not to exceed bid Adult: ≥18 yrs: 360 mcg bid 720 mcg bid Max not to exceed ≥12 yrs: dose: 80 mcg bid Low High dose: 160 mcg bid 320 mcg bid Max not to exceed ≥5 yrs 50 mcg 1 qd ≥12 yrs 100 or 200 mcg 1 qd Low daily dose Low Child > 4 yrs: 88–176 mcg Adult: 88–264 mcg Medium daily dose Child: 176–440 mcg Adult: 264–600 mcg High daily dose Child: >440 mcg Adult: >660 mcg 1–2 puffs bid 1–2 puffs Strength(s) 43 mcg/dose 84 mcg/dose 42 mcg, 84 mcg 40 mcg 80 mcg 0.25 mg/2ml 0.5 mg/2ml 1 mg/2ml 90 mcg 180 mcg 80 mcg 160 mcg 50 mcg 100 mcg 200 mcg 44 mcg 110 mcg 220 mcg 50, 100 and 250 mcg Packaging MDI DPI MDI Respules DPI MDI DPI MDI DPI Generic Name Anti-infammatory steroid (inhaled) Anti-infammatory steroid Beclomethasone diproprionate and other Beclovent Vanceril, manufactuers Beclomethasone diproprionate Qvar Budesonide and Generic Pulmicort Flexhaler Ciclesonide Alvesco Fluticasone furoate Arnuity Ellipta Flovent Table 6.4 (continued) Table 6.7 Immunotherapy in Asthma (“Allergy Shots”) 201 (continued) Comments Pleasant taste Useful in those who are vomiting Useful in those who are vomiting and in place of oral steroids Also available as a syrup Also available Also use in the treatment of rhinitis. Doses >10 mg will not produce greater response in adults Dosage Child 4–11 yrs 1 qd in the evening ≥12 yrs: 220–880 mcg ≥12 yrs: 2 puffs bid ≥12 yrs: 2 puffs dose: 200 mcg/day Low Medium dose: 400 mcg/day High dose: 400 mcg bid 0.5–2 mg/kg/day divided q 6 h 0.5–2 mg/kg/day divided Child: 0.25–2mg/kg daily in single dose. If needed long term other day and adjust use every other controller therapy : 1–2 mg/kg/day up to Short burst 60 mg/day maximum for 3–10 days Adult: 7.5–60 mg in single dose other day for control or every : 40–60 mg/day as Short burst doses for single or 2 divided 3–10 days Child: 7.5 mg/kg IM once Adult: 240 mg IM once 2–5 yrs: 4 mg/day 6–14 yrs: 5 mg/day >14 yrs: 10 mg/day Adult: 10 mg/day Strength(s) 220 mcg 110 mcg 100 mcg 200 mcg 0.25 mg, 0.5 0.75 1.5 mg, 2 mg & 6 0.1 mg/ml and 1 5 mg/5cc 15 mg/5cc 5 mg 5 mg/cc 5 mg/5cc 1, 2.5, 5, 10, and 50 mg 2, 4, 8, 16, and 32 mg 40 mg/ml 80 mg/ml 4 and 5 mg chew tabs and 10 mg 4 and 5 mg chew tablet 1 mg, 2mg, 4 and 8 mg Packaging DPI MDI Oral tablets Oral solution Oral solution Oral solution Oral tablets Oral tablet Repository injection Oral tablets Oral tablet Generic Name Mometasone Asmanex Twisthaler Mometasone furoate Asmanex Oral Corticostroids Dexamethasone generic Decadron and various manufacturers Prednisolone Prelone, Orapred, and various manufacturers Prednisone Deltasone and various manufacturers Methylprednisolone Medrol and various manufacturers Leukotriene receptor antagonists (LTRA) receptor Leukotriene Montelukast sodium Singulair Triamcinolone Aristocort and various manufacturers 202 6 Medications Used in Asthma Management Comments Take 1 hour before or 2 hours Take after meals Hepatic enzymes must be monitored Protect eyes from exposure when from exposure Protect eyes using inhalation solution 100 mg = 80 mg aminophyline theophylline Serum monitoring required so that 5–15 mcg/ml is maintained Initial sedation common. Can be used prior to exercise May be reduced to Inconvenient. tid or bid Dosage 7–11 yrs: 10 mg bid > 12 yrs: 20 mg bid Adult: 20 mg bid > 12 yrs: 600 mg qid with meals Child > 6 yrs 2 puffs qd Child > 6 yrs 2 puffs qd Adult: 2 puffs 3–12 yrs: 1–2 puffs tid. Max 6 3–12 yrs: 1–2 puffs puff/day qid. Max 12 > 12 yrs: 2 puffs puffs/day Infants or children: 250–500 Infants mcg tid or qid > 12 yrs: 250 mcg 3–4 times daily See theophylline dosing See theophylline (consider mg of theophylline available) Child: start with 10 mg/kg/day Usual maximum < 1 yr: 0.2 × (age in weeks) + 5 = mg/kg/day > 1 yr: 16 mg/kg/day Adult: start with 10 mg/kg/day up to 300 mg max Usual maximum: 800mg/day 6m–3yr: 0.05mg/kg/dose bid >3 yr: 1mg bid hild: 1–2 puffs (2 mg) tid or qid hild: 1–2 puffs tid or qid Adult: 2–4 puffs 20 mg (one ampoule of 2 ml) tid or qid Strength(s) 10 mg and 20 300 mg and 600 1.25 mg 2.5 mg 0.018 mg/dose 200 mcg/ml 100 mg, 200 mg 21 mg/ml 250 mg, 500 mg 5.33 mg/ml 300 mg 100, 200, 300 and 450 mg 100, 200, 300 and 400 mg 400, 600 mg 1 mg 0.2 mg/ml 1 mg/puff 10 mg/ml (2 ml) Packaging Oral tablets Oral tablets MDI MDI Inhalation solution Oral tablets Oral solution Rectal suppositories Oral liquid Oral tablet Oral extended release capsules Oral extended and tablets Oral extended release capsules Oral extended Oral tablets Oral syrup Inhalation solution MDI Generic Name Zafrlukast Accolate Zileuton Zyfo Long-acting muscarinic antagonists (LAMAS) Tiotropium Respimat Spiriva Anti-cholinergics Ipratopium bromide Atrovent (Bronchodilators) Aminophyline manufacturers Various Theophylline Theo-24 Uniphyl agents Anti-allergic Cromolyn manufacturers Intal and various Table 6.4 (continued) Table 6.7 Immunotherapy in Asthma (“Allergy Shots”) 203 Comments Rinse mouth after inhalation ICS after any Rinse mouth after inhalation Pre-flled syringes, pre-flled pen Pre-flled syringes, pre-flled pen Autoinjector Pre-flled syringes, pre-flled pen Intravenous infusion over 20–50 infusion over Intravenous minutes Dosage Child and adult: 1 inhalation bid with dose depending on the of asthma severity ≥ 4 yrs: 1 inhalation bid ≥ 12 yrs: 1 inhalation qd 1 inhalation qd ≥ 18 yrs: 1 inhalation qd ≥ 12 yrs: 1 inhalation qd ≥ 18 yrs: 1 inhalation qd ≥12 yrs: q 4 weeks for frst 3 doses then q 8 weeks ≥12 yrs: q 2 weeks ≥12 yrs: 100 mg q 4 weeks ≥6 yrs: 75–375 mg q 2–4 weeks ≥18 yrs: 3 mg/kg q 4 weeks ed. 2000-2001, Lexi-Comp Inc. Hudson Ohio. 2000. Electronic Orange Book, Approved Drug Products Approved Inc. Hudson Ohio. 2000. Electronic Orange Book, ed. 2000-2001, Lexi-Comp Strength(s) 45 mcg F/21 S 115 mcg F/21 S 230 mcg F/21 S 250 mcg F/50 S 100 mcg F/50 S 250 mcg F/50 S 500 mcg F/50 S 113 mg F/14 mcg S 80 mcg B/4.5 F 160 mcg B/4.5 F 100 mcg F/25 mcg V 100 mcg F/25 V 200 mcg F/25 100 mcg M/5 F 200 mcg M/5 F 100 mcg F/62.5 mcg U/25 mcg V 100 mcg F/62.5 U/25 V 200 mcg F/62.5 U/25 30 mg/ml 200 mg/1.4 ml 300 mg/2ml 100 mg/ml 75 mg/0.5 ml 150/ml 100 mg/10 ml th Packaging MDI 45 mcg 115 mcg 230 mcg Diskus 250 mcg DPI DPI 80 mcg 160 mcg 100 mcg 200 mcg 100 mcg 200 mcg 100 mcg 200 mcg Injection Injection Injection Injection Injection Generic Name Combination products Advair Salmeterol/Fluticasone Wixela Inhub Wixela Salmeterol/Fluticasone AirDuo Digihaler Salmeterol/futicasone Symbicort Budesonide/formoterol Breo Ellipta Breo Fluticasone/ Dulera Mometasone/formoterol Trelegy Ellipta Trelegy Fluticasone/umeclidinium/ vilanterol Immunomodulators Benralizumab Fasenra Dupilumab Dupixent Mepolizumab Nucala Omalizumab Xolair Reslizumab Cinquair with Therapeutic Equivalence, http://www.fda.gov/cder/ob/default.htm. American Hospital Formulary System (AHFS) Drug Information 2001. American Society of Health System (AHFS) Drug Information 2001. American Hospital Formulary http://www.fda.gov/cder/ob/default.htm. Therapeutic Equivalence, with Academy of American The 2000. Asthma & Immunology, Allergy Academy of American 2. Volume Atopic Diatheses, Report. Diseases of the Allergy The System pharmacists. ­ and- treatments/drug- guide Asthma & Immunology website at https://www.aaaai.org/conditions- Allergy dry powder inhaler DPI dry powder MDI metered dose inhaler, Abbreviations Guidelines **Not listed by the NAEPP References Dosage Handbook 7 CK, Hodding JH, Kraus DM. Pediatric Taketamo 204 6 Medications Used in Asthma Management

Table 6.5 Asthma medications, side effects, and time to onset of activity Medications Common side effects and precautions Time to take effect Relievers Albuterol Mild tremor 1 to 15 minutes Slight increase in heart rate Isoetharine Hyperactivity Levalbuterol Occasional leg cramps Metaproterenol No advantage to adding another one from the same group Terbutaline Pirbuterol Ipratropium Dry mouth 30 to 40 minutes Unpleasant taste in mouth Theophylline Hyperactivity, abdominal pain, vomiting, headache, increase 4 to 8 hours products in heart rate Take with food. Blood level must be monitored regularly Long-acting relievers—used as controllers and always with inhaled corticosteroids Salmeterol Headache, tremor, dizziness, nausea, anxiety, vomiting Salmeterol: some effect in Formoterol Increase in heart rate 30 mins; 4 hours for Long-acting bronchodilator maximum effectiveness Maximum use: 2 times a day Formoterol: some effect in Salmeterol cannot be used for symptomatic relief 1–3 mins; 30 mins to maximum effectiveness Albuterol sulfate Nervousness, headache, dizziness, trouble sleeping, nausea, 7 hrs to maximum muscle cramps effectiveness May raise blood pressure Extended-release tablets should not be crushed, chewed, or split. Swallow whole Inhaled corticosteroids Beclomethasone May cause hoarseness or oral thrush 3 to 7 days Budesonide Rinse mouth after inhalation Ciclesonide Very effective in preventing asthma Systemic effects possible at high doses Fluticasone furoate Fluticasone propionate Mometasone furoate Oral corticosteroids Prednisone Few side effects if used for short term 4 to 6 hours Prednisolone May increase appetite Dexamethasone May cause mood changes Methylprednisolone Special precautions required Leukotriene inhibitors Zafrlukast May cause headache, dizziness, infection, nausea, diarrhea, 3 hours Montelukast vomiting. Cannot be used for symptomatic relief Cannot be used for symptomatic relief Zileuton Must be swallowed whole without chewing. Must be taken 1 hour before or 2 hours after meals. Long-acting Tiotropium May cause dry mouth, constipation, stomach pain, vomiting, 3 hours indigestion, muscle pain, nosebleed, runny nose, sneezing, painful white patches in mouth. Do not swallow capsules. Do not get powder from capsules in eyes 6.7 Immunotherapy in Asthma (“Allergy Shots”) 205

• Have relevant confrmatory testing proving conditional recommendation that SCIT be con- sensitization (as above) sidered by individuals who place: • Test positive because of rhinitis, for example, and not asthma • A high value on small improvements in qual- • Are aware of the risks, including that of severe ity of life and symptom control systemic reactions • A high value on reductions in long-term and/ or quick-relief medication use It is important that control be optimized in the • A lower value on the potential for systemic all the ways detailed earlier in this book. Having reactions of wide-ranging severity said that, SCIT should not be used in severe asthma. The SCIT dose should not be changed Additional cautions included the small sample when there are asthma symptoms. Both the pre- size of studies and a lack of reference to race or scriber and the person with asthma must recognize social determinants of the health of those studied. the heterogeneous nature of asthma triggers. There The conclusion was: “Whether to use SCIT may be allergic triggers, but other triggers may be should be a shared decision between the individ- more relevant in many people with asthma, includ- ual and the healthcare provider, and this decision ing viral illness, irritants, and exercise. should consider the individual’s asthma severity SCIT should never be administered at home— and willingness to accept the potential harms “personnel with appropriate training should pre- related to SCIT. Clinicians should administer pare and administer injections for each individual’s SCIT in a clinical setting that has the capacity to dosing schedule, from the build-up to the mainte- monitor and treat reactions.” nance phase.” Reactions “can include a range of In terms of sublingual immunotherapy (SLIT), anaphylactic symptoms involving the skin (urti- the FDA has approved SLIT tablets, but not aque- caria), respiratory tract (rhinitis and asthma), gas- ous preparations, for allergic rhinoconjunctivitis. trointestinal tract (nausea, diarrhea, and vomiting), People with this condition together with asthma and the cardiovascular system (hypotension and may derive beneft. However, the Expert Panel arrhythmias). Although rare, deaths after injec- recommends against the use of SLIT in the treat- tions have been reported.” (See “Anaphylaxis” in ment of asthma. Chap. 9.) Hence, SCIT should be carefully super- Given the many questions, and lack of strong vised, and resuscitative equipment should be evidence, it is not surprising that “the Expert readily available. Some reactions may occur more Panel identifed the following opportunities for than 30 minutes after injection, so the individual additional research: must carry an epinephrine injector and ensure that it has not reached its expiry date. • Investigate the safety and effcacy of immuno- Overall, the evidence reviewed by the panel therapy in individuals with severe asthma, provides only moderate or low certainty of bene- particularly those whose asthma is under con- ft to people with asthma [38]. Studies were trol but who want to reduce their medication mainly of persons with mild and moderate burden asthma. They included people with varying • Include only children ages 5–11 years in stud- degrees of control, and often the degree of con- ies of children, or, if a study includes a broader trol was not stated. There was low certainty of age group, report fndings separately for chil- evidence for critical outcomes such as reduction dren ages 5–11 years and those 12 years and in exacerbations, improvement in quality of life, older and asthma control. • Study more diverse populations to determine SCIT may reduce SABA use and allow doses whether race or ethnicity infuences the eff- of long-term controllers to be reduced. Quality of cacy and safety of immunotherapy life may be improved in those with troublesome • Study the effcacy and safety of multiple-­ rhinitis or conjunctivitis. The Expert Panel gave a allergen SCIT or SLIT regimens to assess 206 6 Medications Used in Asthma Management

compliance, adherence, and the effect of these acquired notoriety in the COVID pandemic factors on asthma management despite a lack of supportive evidence [91]. • Standardize methods to report SCIT and SLIT Their use belongs to a previous era of asthma doses used in studies and use validated out- management, when there were few alternatives to come measurement instruments, such as OCS for severe asthma. HCPs sought desperately asthma symptoms and adverse events.” to identify medications already in use for other conditions that might have an effect in asthma. The evidence for beneft in asthma was always 6.8 Low Evidence-Based tenuous, and where Cochrane reviews were done, Medications as Treatment strong recommendations never emerged. If any- Options one with asthma is still receiving one of these preparations, the educator should provide the The unusual title of this section requires some person with full information on current explanation. Some authors have used the term approaches to asthma and encourage transition to “alternative” to describe the use, in asthma, of a modern regimen. approved medication that was not originally intended for asthma [88, 89]. In this book, “alter- native” has a different but more widespread 6.9 Role of Bronchial meaning—it refers to “complementary/alterna- Thermoplasty in Treatment tive” treatments that are not usually used by con- ventional healthcare practitioners. While Bronchial thermoplasty (BT) is used in some alternative treatments are described in Chap. 12, centers as an adjunct therapy. Smooth muscle is it is worth noting that the evidence in favor of the increased in the airways of those with asthma, add-on treatments described here is weak, some- and this muscle thickening may persist even with thing that they share with the evidence in favor of appropriate conventional therapy. BT is radiofre- many of the treatments described in Chap. 12. quency energy provided with proprietary equip- ment, via probes, to the airway wall. This controlled heating of the airway wall eventually 6.8.1 Approach to the Use of These reduces the muscle mass. Medications Some early studies have been promising. For example, Cox et al. studied 16 subjects, all with These medications include troleandomycin mild to moderate asthma [92]. Before any treat- (a macrolide antibiotic), cyclosporine, metho- ment was given, the subjects were assessed using trexate, gold, intravenous immunoglobulin, dap- spirometry, peak fow diaries, monitoring of sone, hydroxychloroquine, and colchicine. In symptoms, and their use of medication. The same general, they have proved disappointing. They measurements were made at 12 weeks, 1 year, either have no effect, or when they do, the effect and 2 years after the treatment. The treatment is small together with the potential to cause seri- itself was delivered via bronchoscopy with a ous side effects. There is some readily available probe directed toward the airway wall, as far as but limited evidence for the use of intravenous could be reached with the bronchoscope. There gamma globulin. The only medication mentioned was no comparison group nor sham (i.e., pla- in current guidelines is a macrolide antibiotic, but cebo) group. The main conclusion of the study the one used previously, troleandomycin, is listed was that it was well tolerated and that they dem- as discontinued on the FDA’s website [90]. If a onstrated decreased airway hyperresponsiveness macrolide is needed in the very limited way that persisted for the 2 years of the study. described in current guidelines, a number are By contrast, Castro and coworkers used a ran- available including azithromycin. The list domized, double-blind, sham-controlled clinical includes hydroxychloroquine, a medication that trial [93], with 30 trial sites in 6 countries. Those 6.10 Concern About Side Efects: General Approach 207 studied were adults, 18–65 years of age and with Overall, asthma medications are safe, with a a confrmed diagnosis of asthma and high-dose low (but not zero) incidence of side effects. Most ICS, usually with a long-acting beta-2 agonist. recent developments in asthma therapy have been Many of them were on other medications such as directed toward fnding safe alternatives to leukotriene modifers, omalizumab, and oral cor- OCS. Nevertheless, a survey of 1,230 children ticosteroids. 580 individuals were screened, with and 604 adults with asthma found that side effects 297 randomized to the BT group and 101 to the of medications and quality-of-life issues were of sham control group. All subjects underwent three great concern [94]. More than half (56–58%) of bronchoscopy procedures, 3 weeks apart. In the the children or their parents, and 42 to 64% of active group, the radiofrequency treatment was adults, complained of the side effects of broncho- delivered to the airway using commercial equip- dilator therapy. These included tachycardia ment. In the sham group, the catheter for the (64%), jitteriness (60%), shaky hands (43%), and equipment was introduced into the airway, and a restlessness (42%). The study also revealed that sham controller with fashing lights was used. healthcare providers tended to adjust bronchodi- Asthma quality-of-life scores (AQLQ) were used lator therapy for adults more than for children. A to assess the impact of the therapy and were further disturbing statistic was that only 3% of higher with thermoplasty compared to sham those using MDIs (79% of children and 72% of treatment. There was also a reduction in severe adults) viewed their healthcare providers as “car- exacerbations, and in healthcare use, after ing, sympathetic, willing to listen or willing to treatment. discuss the problem.” As a result, in an attempt to The 2020 NHLBI Update [2] is clearly unen- alleviate the side effects, 25 to 30% of them thusiastic about thermoplasty. It describes reduced either the dose or frequency of their “small” harms and “moderate” benefts, with a bronchodilator medications without consulting paucity of information on long-term outcomes. their healthcare providers. Thus, the report strongly encourages research Full information should always be provided using randomization and also long-term regis- about: tries. If thermoplasty is to be used, it should be supervised by a physician experienced in its use • The medication that has been given and following a consent process that is detailed • The reason why it was given and truthful about potential risks and poor evi- • The time it will require before any effect may dence of beneft. be noticed (about a week for ICS) • How and when it should be taken

6.10 Concern About Side Efects: The above list must include a description of General Approach potential side effects and action to be taken when the person with asthma suspects side effects. The Side effects are real, and concern about them is specifc manner in which potential side effects based in reality. Medications used in asthma may are described is very important and will be cause side effects, and most are listed earlier in detailed later. The importance of dealing effec- this chapter. Many people using asthma medica- tively with side effects lies not only on the harm tions will be familiar with the history of other they might cause but also on the harm misattribu- medications and delayed recognition of their side tion of side effects or misunderstanding of bene- effects in such substances as thalidomide, chlor- fts might cause. For example, many people with amphenicol, and cisapride. Similarly, hormone asthma have become used to the immediate replacement therapy for women after menopause effects of bronchodilators and when given ICS was once enthusiastically prescribed, then pro- expect similar immediate relief. They then scribed, and is now used cautiously in some spe- become annoyed and upset when it is not forth- cial situations. coming. This encourages them to reduce or stop 208 6 Medications Used in Asthma Management the medication. Unpleasant symptoms attributed ftes, are known to cause bronchoconstriction and to side effects, whether or not they are side trigger asthma [99]. effects, will also lead to reluctance to medicate. Most pharmaceutical companies offer a toll-free­ Perception of side effects does not necessarily consumer information phone number (available equate to their reality. There is already a “large from any pharmacy or on package inserts). Persons reservoir of bodily symptoms available for misat- with asthma or their caregivers should call these tribution by the patient to the medication” [95]. numbers if they have any concerns and should Also, new symptoms may be the somatic accom- check not only prescription items but also over-the- paniments of anxiety, depression, or stress. Any counter (OTC) products that they purchase. chronic condition, and asthma is no exception, Studies have found that asthma medica- may be accompanied by psychological conse- tions, particularly in children, result in tooth quences. Symptoms of mild infrmities or self-­ erosion [100–102]. Long-term use of asthma limited ailments, such as headaches, cramps, or medication was also associated with tooth extra symptoms, may be attributed to a new, or wear in American adolescents and young even an existing, medication. Perception of nor- adults [103]. Another study by McDerra, mal functioning, such as dizziness when rising Pollard, and Curzon [104] in the UK also too quickly, may also be labeled a medication found a potential dental problem with pow- side effect. It should be remembered that approx- dered asthma medications. Tooth substance imately one quarter of patients taking a placebo begins to dissolve at a pH of 5.5. Since most report adverse side effects [96]! asthma medications have a pH less than 5.5, In addition to the issue discussed above, it is children should be advised to: important to remember that potential adverse reac- tions to inhaled medications may actually be due • Rinse their mouths with water directly after to problems with the non-medicinal compo- taking asthma medications nents—the propellants, preservatives, and surfac- • Use a spacer device tants. Many DPIs use lactose as a fller. MDIs may • Brush their teeth twice a day use ethylenediaminetetraacetic acid (EDTA), metabisulfte, or benzalkonium chloride as preser- The knowledge that misattribution of side vatives. For some people, these compounds induce effects is more likely in those who expect side bronchospasm and bronchoconstriction [97]. effects or have coexistent psychological condi- Many pharmaceutical preparations contain a tions or psychosocial stressors will help suggest variety of excipients. These are generally inac- an approach to the discussion. The precise nature tive, but persons with allergies need to be aware of how information about potential side effects is of their presence. Lactose is a common excipient, given is dependent on one’s personal style. but others that may cause allergic reactions However, in general, consider the following: include sweeteners, favorings, dyes, and preser- vatives. Most package inserts often do not iden- • The medication should be related to disease tify the favorings. In those who are severity: lactose-intolerant, lactose in medications has • Systemic corticosteroids have no place in been known to cause diarrhea, malabsorption, mild asthma, but if they have been found fatulence, and vomiting. Saccharin has been necessary in severe asthma, and there is associated with wheezing, tachycardia, urticaria, concern about side effects, then any pruritus, nausea, and diarrhea. For sorbitol, the planned discontinuation should happen adverse effects include poor absorption of the gradually under professional supervision active drug, fatulence, osmotic diarrhea, and with simultaneous substitution of alterna- abdominal pain. The preservative ethylenedi- tive anti-asthma medications. amine can irritate both skin and mucous mem- • Potential side effects should be discussed, and branes [98]. Dyes such as FD&C Blue 1, information provided about their likely fre- Tartrazine, FD&C 4, and carmine, as well as sul- quency, if known. 6.11 Classifcation of Severity After Treatment 209

• The professional monitoring that will be done may be that appropriate treatment has not been (with respect to side effects) should be prescribed or followed, or that the diagnosis of explained. asthma is wrong, or that the asthma is very severe • Reassurance should be provided that all medi- [1, 105–107]. cations, and their doses, have been well justi- Classifcation of control and severity should fed and will be reviewed at every be done both before and after treatment [108], but assessment. will change after treatment. Classifcation before treatment was described in Chap. 4 (Tables 4.2 When concern about side effects is expressed, and 4.3), while classifcation after treatment is the educator or HCP must take that concern seri- shown in Figs. 6.1, 6.2, and 6.3. ously, and all possibilities explored and an agreed If the asthma is intermittent, use of a short-­ course of action mapped out. acting beta-agonist more than twice a week may be indicative of a need for daily long-term control therapy. People with intermittent asthma may 6.11 Classifcation of Severity require regular low-dose ICS. In effect, their After Treatment asthma can be classifed as mild persistent. Intermittent asthma can be effectively and safely Asthma control and asthma severity should not managed with short courses of ICS during exac- be confused—the two are different concepts, erbations and without them during symptom-free although severe asthma will often prove diffcult intervals. If the asthma can be controlled with a to control. Nevertheless, the perception that low to medium dose of inhaled corticosteroids poorly controlled asthma is synonymous with with or without other controller medications severe persistent asthma is incorrect. Control has (such as long-acting beta-agonists), it is consid- more immediate importance and is normally ered moderate persistent. As soon as high-dose achievable. When good control is not achieved, it ICS with a LABA are required (and even OCS),

Fig. 6.1 Step-wise approach to therapy (0–4 yrs) (© The Asthma Education Clinic Ltd.) 210 6 Medications Used in Asthma Management

Fig. 6.2 Step-wise approach to therapy (5–11 yrs) (© The Asthma Education Clinic Ltd.)

Fig. 6.3 Step-wise approach to therapy (12 yrs and older) (© The Asthma Education Clinic Ltd.) 6.12 Step Approach to Asthma Management 211 the asthma is considered severe persistent. In hand, severe asthma may become moderate or effect, once control of asthma has been estab- even mild with the appropriate treatment. Hence, lished, it is the medication requirement that the healthcare provider or asthma educator should refects the degree of severity [35, 107]. Severity periodically classify (or re-classify) each individ- in that sense is based on the minimum medication ual’s degree of control and asthma severity. needed to maintain control. Asthma control is currently achieved through one of the two approaches: 6.12 Step Approach to Asthma Management • The frst starts the therapy at the level appro- priate to the assessed severity by using the The 2007 guidelines [35] suggest that once a diag- classifcation system to determine the initial nosis has been made, two factors must be taken into amount of medication that should be pre- account when reviewing a person’s asthma—sever- scribed. If control is not achieved, medication ity and control. Control will determine initial ther- is then stepped up to the next higher level apy and whether treatment needs to be stepped up where the dosage of ICS is increased, and add- over time or can be reduced. Control must be evalu- ­on therapy possibly commenced. ated at all visits. Severity may be clear at the initial • The second approach starts one level higher visit. As an example, someone may come for evalu- than indicated by the degree of severity, brings ation having previously been on low-dose ICS and the disease under control, and then reduces the was admitted to an ICU with asthma. This is severe medication to the minimum needed while asthma. Someone else may come for assessment monitoring the asthma to ensure that it remains with a history of 2–3 days’ symptoms with colds, under control. easily relieved with SABA and with normal spirom- etry. This person has mild asthma. The true severity Once the asthma is well controlled, consider- may only become clear over time. Based on symp- ation can be given to stepping down or reducing toms and moderately abnormal spirometry, a mod- the dosage of ICS. Current guidelines [2, 35] sug- erate ICS dose may be prescribed. If there is a poor gest reducing the dose by about 25% every 2 to 3 response, a higher-dose ICS along with LABA will months as long as asthma control is appropriate. be used. If symptoms and abnormal spirometry per- The time period is important, since too rapid a sist, this is severe asthma, and consideration should step-down may lead to sharp deterioration in be given to use of a biologic. As always, as men- symptoms. The step-down approach begins with tioned repeatedly in this book, when there is an an initial reduction in the dose of ICS. If the apparent poor response, a full reassessment is asthma remains under control, then the ICS are needed before reaching a conclusion about severity reduced further, perhaps adding a long-acting or about changing treatment. The assessment as bronchodilator. Again, if asthma control is main- always will include confrmation that: tained for about 3 months, then the dose of ICS may be further reduced. • The diagnosis of asthma is correct The classifcation of severity gives the health- • There are no signifcant comorbidities care provider a starting point for prescribing ICS • There are no fnancial barriers to accessing and add-on therapy until the asthma is well con- therapy trolled. It also provides the basis for written • Inhaler technique is perfect Asthma Action Plans (AAP) and permits the • Adherence to a treatment schedule is reduction of ICS on the premise that the asthma near-perfect remains well controlled. • Triggers are avoided, wherever possible Whatever the classifcation, it should be noted that asthma severity is a continuum. Mild or mod- At all visits, including the initial visit, asthma erate asthma may become severe; on the other severity is ascertained using the domains of cur- 212 6 Medications Used in Asthma Management rent impairment and future risk. Impairment is Predictors of attacks for all ages include: evaluated according to: • Psychosocial factors—depression, increased • Frequency of symptoms stress, socioeconomic factors • Nocturnal awakenings • Familial attitudes and beliefs about taking • Frequency usage of short-acting medications beta-agonists • Demographic characteristics—female, non-­ • Level of interference with normal activities white, current smoking, non-use of ICS • Work/school days missed • A feeling of being fearful or in danger • Quality-of-life assessments • Pulmonary function For children aged 4 and under, the risk factors for persistent asthma also include [35]: Because it is generally diffcult to measure Any one of the following: pulmonary function in children under the age of 5, pulmonary function tests done through spi- • Parental history of asthma rometry are part of both diagnosis and assess- • A diagnosis of atopic dermatitis ment of severity for every one over this age. • Evidence of sensitization to (Peak fow meters, while adequate for monitor- ing asthma, are not suffciently reliable to aid in And any two of the following: the classifcation of severity or degree of control.) • Evidence of food sensitization Measures of lung function to be determined • >4% peripheral blood eosinophils by spirometry include: • Wheezing apart from colds

• FEV1—forced expiratory volume in one Risk in those aged 5 and above is ascertained second by the frequency of attacks. Two or more attacks • FVC—forced vital capacity a year automatically put them into the persistent

• FEV1/FVC—the ratio of the two measures asthma category.

• FEV6—forced expiratory volume in 6 Once the diagnosis is made and asthma sever- seconds ity classifed, an aggressive approach toward con- trol is taken. The classifcation of severity is

The role of this last measure (FEV6) in assess- connected to the six-step approach recommended ing pulmonary function has recently been by the Expert Panel Report 3 (EPR 3) Guidelines reviewed [109]. It has been suggested that it be [35] for three distinct age groups: 0–4, 5–11, and used instead of the FEV1/FVC ratio as FVC does 12 years and older with: not need to be measured. Risk pertains to the number of asthma exacer- • Intermittent asthma considered a Step 1 bations or wheezing episodes that have occurred. category Frequency and intensity of attacks are also fac- • Mild persistent asthma a Step 2 category tors and would include: • Moderate persistent asthma rated at the Step 3 and Step 4 categories • Two or more emergency visits in the past • Severe persistent asthma rated at the Step 5 year and Step 6 categories • Any history of intubation or ICU admission within the last 5 years The initial treatment corresponds with the • Severe airfow obstruction, as determined by appropriate step therapy and should be such that spirometry the asthma is quickly brought under control. This • Persistent severe airfow obstruction may require oral corticosteroids to reduce the 6.12 Step Approach to Asthma Management 213 infammation in the airways and to remind them LAMA is suggested only for the 12 years and of how well they can be, a feeling too often for- older group, while LTRA are alternate choices gotten if they have adjusted to the symptoms of for both the 5–11 and older age groups. asthma and modifed their lifestyle to handle the Montelukast is a suggested alternate choice only limitations imposed by the asthma. for the 0–4 age group. All groups, of all ages, are Figures 6.1, 6.2, and 6.3 provide the necessary prescribed a SABA. information for both stepping up and stepping It should be noted that immunotherapy may be down with the recommended alternatives accord- considered for the 5–11 age group with allergic ing to the 2020 guidelines. asthma, particularly to house dust mite, animal Note that Steps 1 and 2 are identical for all dander, and pollen. A more detailed review of three age groups—for individuals with intermit- immunotherapy is in Sect. 6.7. tent asthma (Step 1), a short-acting beta-agonist Table 6.6 shows a comparison of Steps 3 to 6 can be taken as required, and for those with mild between the different age groups. persistent asthma (Step 2), a low corticosteroid When assessing control, consider the loss of dose is recommended. The three following tables lung function. Spirometry is recommended not provide a comparison of Steps 3 to 6 (moderate to only at the initial visit to confrm a diagnosis of severe persistent asthma) for different age groups. asthma but also after treatment has been initiated Regular use of oral corticosteroids (OCS) is added and both symptoms and peak fow readings have to the medication regime only at Step 6, indicative stabilized. Spirometry should also be done during of diffcult-to-control severe persistent asthma. periods of progressive or prolonged loss of control. Note that the preferred frst choice of a LABA The EPR 3 Guidelines [35] recommend spirometry for Steps 3, 4, and 5, for the 5–11 and 12 yrs and every 1 to 2 years for everyone who has asthma. older age groups, is formoterol. This is in keep- The following three levels of control, well ing with the SMART (single maintenance and controlled, not well controlled, and very poorly reliever therapy) approach since formoterol, a controlled, can be used in anyone with asthma. LABA which can be used as a reliever, is avail- The guidelines use three age groups—0 to 4 able in combination with the ICS budesonide in a years, 5–11 years, and those 12 and over. single device. Assessment of control is shown in the following

Table 6.6 Age-related comparison of Step 3 to Step 6 0–4 years 5–11 years 12 years and over Step 3 ICS low dose + ICS low dose + formoterol ICS low dose + formoterol LABA or montelukast Or medium-dose ICS Or ICS low dose + LABA/LAMA/ Or medium-dose ICS Or low-dose ICS + LABA/LTRA LTRA Or low-dose ICS + theophylline Or ICS low dose + theophylline Or ICS low dose + zileuton Step 4 ICS medium dose + LABA ICS medium dose + formoterol ICS medium dose + formoterol Or ICS medium dose + Or ICS medium dose + LTRA Or medium-dose ICS + LABA/LAMA montelukast Or ICS medium dose + theophylline Or medium-dose ICS + LTRA Step 5 ICS high dose + LABA ICS high dose + formoterol ICS high dose+ formoterol Or ICS high dose + montelukast Or ICS high dose + LTRA Or medium-dose ICS-LABA Or ICS high dose + theophylline Or high-dose ICS + LTRA Step 6 ICS high dose + LABA + OCS ICS high dose + LABA + OCS ICS high dose+ LABA + OCS Or ICS high dose + montelukast + Or ICS high dose + LTRA + OCS Consider biologics OCS Or ICS high dose + theophylline + OCS ICS inhaled corticosteroid, OCS oral corticosteroid, LABA long-acting bronchodilator, LTRA leukotriene . SABA prn for all categories and all age groups 214 6 Medications Used in Asthma Management

Table 6.7 Level of control for ages 0–4 years Level of control 0–4 years Impairment components Controlled Poor control Very poor control Symptoms ≤ 2 days/week > 2 days/week Throughout the day Night awakenings 1/month > 1/month > 1/week SABA use ≤ 2 days/week > 2 days/week Several times/day Interference with normal activities None Some Extremely limited Risk domain: exacerbations 0–1/year 2–3/year > 3/year

Table 6.8 Level of control for ages 5–11 and for 12 years and older Level of control 5–11 years and ≥ 12 years Impairment components Controlled Poor control Very poor control Symptoms ≤ 2 days/week > 2 days/week Throughout the day Night awakenings < 1/month > 2/month > 2/month ≥ 12 yrs ≤ 2/month 1–3/week > 4/week SABA use ≤ 2 days/week > 2 days/week Several times/day Interference with normal activities None Some Extremely limited

Lung function 5–11 yrs FEV1> 80% FEV1 60–80% FEV1< 60% FEV1/FVC > 80% FEV1/FVC 75–80% FEV1/FVC < 75% ≥ 12 yrs FEV1 or PEFR > 80% FEV1 or PEFR FEV1 or PEFR < 60% 60–80% Risk domain: exacerbations 0–1/year ≥ 2/year ≥ 2/year

Table 6.9 Recommended action for treatment depending on level of control Well controlled Not well controlled Very poorly controlled • Maintain current regimen • Step up one step • Consider burst of OCS • Follow-up regularly every 1–6 months • Re-evaluate in 2–6 weeks • Step up 1–2 steps • If well controlled for 3 months, then step down • Re-evaluate in 2 weeks two tables, where there is considerable common- can be made to reduce the medications by step- ality except where the 5–11 age group differs ping down while ensuring that the asthma from the 12 and older (Tables 6.7 and 6.8). remains under control. As noted earlier, step- The EPR 3 Guidelines [35] recommend step- ping down is best done at infrequent intervals, ping up or down, depending on the level of con- with careful reassessment 2–3 months after each trol. See Table 6.9. change. Again, prior to taking action and stepping up treatment, the educator should confrm the diag- nosis and review: 6.13 Goals of Therapy

• Adherence to medication What is the purpose of assessment and treatment • Inhaler technique of people with asthma? In essence, it is to give • Environmental control them a good life, with minimal restrictions and • Avoidance of allergens and irritants minimal or no symptoms using an acceptable • Comorbid conditions medication regimen without side effects. Such are the “goals of therapy” in broad terms. Specifc It follows that an assessment of control is goals will be developed jointly between the pre- necessary at every visit to ensure that the asthma scriber/educator and the person with asthma is not going out of control. If control is poor, based on individual preferences. then stepping up should be considered. Once the Assessment of severity is the basis in determin- asthma is brought under control, then attempts ing goals of therapy. Severity is assessed on two 6.14 Quality-of-Life Scores 215 items—impairment and risk. Hence, measures to study of children with moderate asthma noted fve reduce both impairment and risk are essential. areas that determined their quality of life [112]: Impairment can be reduced by: • Physical restrictions due to symptoms • Preventing chronic symptoms • Limitations on daily activities • Infrequent symptoms requiring SABA for • Discord in parent-child relationships relief • Restrictions in school social activities • Maintaining normal pulmonary function • Daily inconvenience in managing their asthma • Maintaining normal activity levels • Defning “normal” may be diffcult as low Family members and all caregivers are activity levels may have become a coping affected by the presence of asthma. This is obvi- mechanism. ous but often overlooked. For example, 360 care- • Meeting the expectations of the person who givers of children with uncontrolled asthma and actually has asthma and their families 113 children with controlled asthma were sur- • Satisfying both personal and family require- veyed. Not surprisingly, children with uncon- ments for asthma care trolled asthma had signifcantly lower QOL than those with controlled asthma. The caregivers of Risk can be reduced by: children with uncontrolled asthma also reported a signifcantly increased workload, impaired activ- • Preventing attacks and ED visits ities, and lower QOL. Caregivers of these chil- • Preventing progressive loss of lung function dren lost more work time and had signifcantly • Providing optimal pharmacotherapy with reduced productivity and work impairment. minimal or no adverse effects Asthma had an impact on emotions, time, and family activities [113]. The goal is simple: minimum medication and Poorly controlled or uncontrolled asthma has minimum side effects to achieve asthma control. a deleterious effect on QOL of all parties [114, The “goal” should be an agreed one. The person 115]. Compared with people who do not have with asthma must be a full partner in this assess- asthma, people with asthma have a lower QOL ment process. which is compounded by both asthma severity and lack of control [116]. There is a link between QOL scores and pulmonary function [117]. Thus, 6.14 Quality-of-Life Scores QOL questionnaires used in asthma are similar to those used to determine severity and include Healthcare professionals (HCP) are concerned questions related to symptoms, exercise-related about asthma control and in the past have focused symptoms, night-time awakenings, and use of more on the condition called asthma than on the reliever medication. Some also ask about limita- individual who has asthma. This was wrong then tions to daily activities. and remains wrong. Successful treatment must be a The National Standards of Care require the partnership. The healthcare professional should use of validated QOL scores. While a number of create an environment in which those with asthma QOL questionnaires are available, with some feel free to comment about the treatment in relation intended for specifc age groups, the most com- to its effect on their lives. If the person with asthma monly used ones in practice for asthma are: doesn’t volunteer the information, the healthcare professional should use gentle questioning. • Asthma Control Test (ACT) Quality-of-life (QOL) scores are an essential • Asthma Control Questionnaire (ACQ) objective measure about how the person with • Asthma Therapy Assessment Questionnaire asthma feels about their health and life overall. (ATAQ) Studies have been done on the effect of asthma • Test for Respiratory and Asthma Control in on the lives of people with asthma [110, 111]. A Kids (TRACK) 216 6 Medications Used in Asthma Management

Table 6.10 Validated quality-of-life questionnaires LEVEL OF CONTROL Questionnaire Controlled Poor Very poor ACT /= 1.5 N/A ATAQ 0 1–2 3–4 TRACK >/= 80 70–80 <70 Asthma APGAR 0 1–2 >2

• Asthma Control and Communication nym for the healthcare provider to ask ques- Instrument (ACCI) tions about Activities; Persistence; triGgers; • Asthma APGAR (with PLUS) Asthma medications; and Response to therapy. Levels of control according to each of these After an Asthma APGAR questionnaire is tests are shown in Table 6.10. completed, the provider follows the specifed The ACT, which is most commonly used, has procedure to get to PLUS (Plan, Lung Function, fve questions and is available in two versions— and Inhaler and Steroid Uses). It also reminds for children aged 4 to 11 and for those aged 12 them not to substitute an exacerbation visit with a and above. The ACQ has seven questions includ- management visit. ing one on spirometry (a shortened version has QOL is important because it is correlated to just fve questions). The ATAQ has 20 questions the degree of control of the asthma. It allows per- for adults, has a 7-question version for those aged sons with asthma: 5 to 17, and is often used for research. TRACK has fve questions for parents of children under • To see their progress (or the lack thereof) from the age of 5. A TRACK score change of 10 or one visit to the next more points (out of 100) represents a clinically • Assuming that the prescribed regimen is fol- meaningful change in asthma control. lowed and inhaler technique is optimal, to The ACCI, for those aged 12 and above, was assess the treatment regimen and determine if developed for social and ethnic minorities. It uses it is successful or not a simple scoring system with color-coded boxes. • To let their healthcare provider know how the If all 12 green boxes are selected, asthma is con- asthma is affecting them trolled. If any yellow boxes are selected, then the asthma is partly controlled, and any brown/red It can help validate what they have been told boxes indicate uncontrolled asthma. Nine ques- by the asthma educator and their healthcare pro- tions span four domains that include three ques- vider. Above all, they soon realize that their input tions on risk, one on “bother,” fve on control, and is important and that they are a part of the asthma one on direction of symptoms. There are also one team. question on adherence and an open-ended ques- Thus, at every visit, individuals with asthma tion that states “What would you like your doctor should: to know about your asthma?”. Some clinics use the Asthma APGAR test • Be assessed for asthma control [118]. This was developed to improve imple- • Complete a quality-of-life questionnaire mentation of the guidelines and provides a • Be checked for appropriate medication adher- detailed management and care algorithm. ence and device technique Asthma APGAR4 is a reminder and an acro- • Be asked if there are any side effects from the medications 4 This must not be confused with the Apgar score used at • Be questioned about any concerns delivery to assess newborns, a test named after Virginia • Be given appropriate and timely education Apgar, and introduced in 1952. References 217

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