TREATMENT Asthma
The treatment of asthma is straightforward, with the majority of patients now managed by internists and family doctors with effective and safe therapies. There are several aims of therapy (Table 281-2). Most of the emphasis has been placed on drug therapy, but several non-pharmacologic approaches have also been used. The main drugs for asthma can be divided into bronchodilators, which give rapid relief of symptoms mainly through relaxation of airway smooth muscle, and controllers, which inhibit the underlying inflammatory process.
BRONCHODILATOR THERAPIES Bronchodilators act primarily on airway smooth muscle to reverse the bronchoconstriction of asthma. This gives rapid relief of symptoms but has little or no effect on the underlying inflammatory process. Thus, bronchodilators are not sufficient to control asthma in patients with persistent symptoms. There are three classes of bronchodilator in current use: β2-adrenergic agonists, anticholinergics, and theophylline; of these, β2-agonists are by far the most effective.
β2-Agonists β2-Agonists activate β2-adrenergic receptors, which are widely expressed in the airways. β2-Receptors are coupled through a stimulatory G protein to adenylyl cyclase, resulting in increased intracellular cyclic adenosine monophosphate (AMP), which relaxes smooth muscle cells and inhibits certain inflammatory cells, particularly mast cells.
Mode of Action The primary action of β2-agonists is to relax airway smooth-muscle cells of all airways, where they act as functional antagonists, reversing and preventing contraction of airway smooth-muscle cells by all known bronchoconstrictors. This generalized action is likely to account for their great efficacy as bronchodilators in asthma. There are also additional non-bronchodilator effects that may be clinically useful, including inhibition of mast cell mediator release, reduction in plasma exudation, and inhibition of sensory nerve activation. Inflammatory cells express small numbers of β2-receptors, but these are rapidly down-regulated with β2-agonist activation so that, in contrast to corticosteroids, there are no effects on inflammatory cells in the airways and there is no reduction in AHR.
Clinical Use β2-Agonists are usually given by inhalation to reduce side effects. SABA, such as albuterol and terbutaline, have a duration of action of 3–6 h. They have a rapid onset of bronchodilatation and are, therefore, used as needed for symptom relief (relievers). Increased use of SABA indicates that asthma is not controlled. They are also useful in preventing EIA if taken prior to exercise. SABA are used in high doses by nebulizer or via a metered-dose inhaler (MDI) with a spacer. Long-acting β2-agonists (LABA) include salmeterol and formoterol, both of which have a duration of action over 12 h and are given twice daily by inhalation; and indacaterol, olodaterol, and vilanterol, which are given once daily. LABA have replaced the regular use of SABA, but LABA should not be given in the absence of ICS therapy as they do not control the underlying inflammation. They do, however, improve asthma control and reduce exacerbations when added to ICS, which allows asthma to be managed with lower doses of corticosteroids. This observation has led to the widespread use of fixed combination inhalers that contain a corticosteroid and a LABA, which have proved to be highly effective in the control of asthma and prevention of exacerbations.
Side Effects Adverse effects are not usually a problem with β2-agonists when given by inhalation. The most common side effects are muscle tremor and palpitations, which are seen more commonly in elderly patients. There is a small fall in plasma potassium due to increased uptake by skeletal muscle cells, but this effect does not usually cause any clinical problem.
Tolerance Tolerance is a potential problem with any agonist given chronically, but while there is down-regulation of β2-receptors, this does not reduce the bronchodilator response as there is a large receptor reserve in airway smooth-muscle cells. By contrast, mast cells become rapidly tolerant, but their tolerance may be prevented by concomitant administration of ICS.
Safety The safety of β2-agonists has been an important issue. There is an association between asthma mortality and the amount of SABA used, but careful analysis demonstrates that the increased use of rescue SABA reflects poor asthma control, which is a risk factor for asthma death. The slight excess in mortality that has been associated with the use of LABA is related to the lack of use of concomitant ICS, as the LABA therapy fails to suppress the underlying inflammation. This highlights the importance of always using an ICS when LABAs are given, which is most conveniently achieved by using a combination inhaler. Recent large safety studies have shown no adverse effects of LABA in adults or children.
Anticholinergics Muscarinic receptor antagonists, such as ipratropium bromide, prevent cholinergic nerve-induced bronchoconstriction and mucus secretion. They are less effective than β2-agonists in asthma therapy as they inhibit only the cholinergic reflex component of bronchoconstriction, whereas β2-agonists prevent all bronchoconstrictor mechanisms. Long-acting muscarinic antagonists (LAMA), including tiotropium bromide or glycopyrronium bromide, may be used as an additional bronchodilator in patients with asthma that is not controlled by maximal doses of ICS-LABA combinations, and improve lung function and further reduce exacerbations. High doses of short-acting anticholinergics may be given by nebulizer in treating acute severe asthma but should only be given following β2-agonists, as they have a slower onset of bronchodilation.
Side effects are not usually a problem as there is little or no systemic absorption. The most common side effect is dry mouth; in elderly patients, urinary retention and glaucoma may also be observed.
Theophylline Theophylline was widely prescribed as an oral bronchodilator several years ago, especially as it was inexpensive. It has now fallen out of favor as side effects are common, and inhaled β2-agonists are much more effective as bronchodilators. The bronchodilator effect is due to inhibition of phosphodiesterases in airway smooth-muscle cells, which increases cyclic AMP, but doses required for bronchodilatation commonly cause side effects that are mediated mainly by phosphodiesterase inhibition. There is increasing evidence that theophylline at lower doses has anti-inflammatory effects, and these are likely to be mediated through different molecular mechanisms. Theophylline activates the key nuclear enzyme histone deacetylase-2 (HDAC2), which is a critical mechanism for switching off activated inflammatory genes and may therefore reduce corticosteroid insensitivity in severe asthma.
Clinical Use Oral theophylline is usually given as a slow-release preparation once or twice daily as this gives more stable plasma concentrations than normal theophylline tablets. It may be used as an additional bronchodilator in patients with severe asthma when plasma concentrations of 10–20 mg/L are required, although these concentrations are often associated with side effects. Low doses of theophylline, giving plasma concentrations of 5–10 mg/L, have additive effects to ICS and are particularly useful in patients with severe asthma. Indeed, withdrawal of theophylline from these patients may result in marked deterioration in asthma control. At low doses, the drug is well tolerated. IV aminophylline (a soluble salt of theophylline) was used for the treatment of severe asthma but has now been largely replaced by high doses of inhaled SABA, which are more effective and have fewer side effects. Aminophylline is occasionally used (via slow IV infusion) in patients with severe exacerbations that are refractory to SABA.
Side Effects Oral theophylline is well absorbed and is largely inactivated in the liver. Side effects are related to plasma concentrations; measurement of plasma theophylline may be useful in determining the correct dose. The most common side effects are nausea, vomiting, and headaches and are due to phosphodiesterase inhibition. Diuresis and palpitations may also occur, and at high concentrations cardiac arrhythmias, epileptic seizures, and death may occur due to adenosine A1-receptor antagonism. Theophylline side effects are related to plasma concentration and are rarely observed at plasma concentrations <10 mg/L. Theophylline is metabolized by CYP450 (CYP1A2) in the liver, and, thus, plasma concentrations may be elevated by drugs that block CYP450 such as erythromycin and allopurinol. Other drugs may also reduce clearance by other mechanisms leading to increased plasma concentrations (Table 281-3).
CONTROLLER THERAPIES Inhaled Corticosteroids ICS are by far the most effective controllers for asthma, and their early use has revolutionized asthma therapy.
Mode of Action ICS are the most effective anti-inflammatory agents used in asthma therapy, reducing inflammatory cell numbers and their activation in the airways. ICS reduce eosinophils in the airways and sputum, and numbers of activated T lymphocytes and surface mast cells in the airway mucosa. These effects may account for the reduction in AHR that is seen with chronic ICS therapy.
The molecular mechanism of action of corticosteroids involves several effects on the inflammatory process. The major effect of corticosteroids is to switch off the transcription of multiple activated genes that encode inflammatory proteins such as cytokines, chemokines, adhesion molecules, and inflammatory enzymes. This effect involves several mechanisms, including inhibition of the transcription factors NF-κB, but an important mechanism is recruitment of HDAC2 to the inflammatory gene complex, which reverses the histone acetylation associated with increased gene transcription. Corticosteroids also activate anti-inflammatory genes such as mitogen-activated protein (MAP) kinase phosphatase-1, and increase the expression of β2-receptors. Most of the metabolic and endocrine side effects of corticosteroids are also mediated through transcriptional activation.
Clinical Use ICS are by far the most effective controllers in the management of asthma and are beneficial in treating asthma of any severity and age. ICS are usually given twice daily, but some may be effective once daily in mildly symptomatic patients. ICS rapidly improve the symptoms of asthma, and lung function improves over several days. They are effective in preventing asthma symptoms, such as EIA and nocturnal exacerbations, but also prevent severe exacerbations. ICS reduce AHR, but maximal improvement may take several months of therapy. Early treatment with ICS appears to prevent irreversible changes in airway function that occur with chronic asthma. Withdrawal of ICS results in slow deterioration of asthma control, indicating that they suppress inflammation and symptoms, but do not cure the underlying condition. ICS are now given as first-line therapy for patients with persistent asthma, but if they do not control symptoms at low doses, it is usual to add a LABA as the next step.
Side Effects Local side effects include hoarseness (dysphonia) and oral candidiasis, which may be reduced with the use of a large-volume spacer device. There has been concern about systemic side effects from lung absorption, but many studies have demonstrated that ICS have minimal systemic effects (Fig. 281-7). At the highest recommended doses, there may be some suppression of plasma and urinary cortisol concentrations, but there is no convincing evidence that long-term treatment leads to impaired growth in children or to osteoporosis in adults. Indeed effective control of asthma with ICS reduces the number of courses of OCS that are needed and, thus, reduces systemic exposure to ICS.
Systemic Corticosteroids Corticosteroids are used intravenously (hydrocortisone or methylprednisolone) for the treatment of acute severe asthma, although several studies now show that OCS are as effective and easier to administer. A course of OCS (usually prednisone or prednisolone 30–45 mg once daily for 5–10 days) is used to treat acute exacerbations of asthma; no tapering of the dose is needed. Approximately 1% of asthma patients may require maintenance treatment with OCS; the lowest dose necessary to maintain control needs to be determined. Systemic side effects, including truncal obesity, bruising, osteoporosis, diabetes, hypertension, gastric ulceration, proximal myopathy, depression, and cataracts, may be a major problem, and steroid-sparing therapies may be considered if side effects are a significant problem. If patients require maintenance treatment with OCS, it is important to monitor bone density so that preventive treatment with bisphosphonates or estrogen in postmenopausal women may be initiated if bone density is low. Intramuscular triamcinolone acetonide is a depot preparation that is occasionally used in noncompliant patients, but proximal myopathy is a major problem with this therapy.
Antileukotrienes Cysteinyl-leukotrienes are potent bronchoconstrictors; they cause microvascular leakage and increase eosinophilic inflammation through the activation of cys-LT1-receptors. These inflammatory mediators are produced predominantly by mast cells and, to a lesser extent, eosinophils in asthma. Antileukotrienes, such as montelukast and zafirlukast, block cys-LT1-receptors and provide modest clinical benefit in asthma. They are less effective than ICS in controlling asthma and have less effect on airway inflammation, but are useful as an add-on therapy in some patients not controlled with low doses of ICS, although less effective than a LABA. They are given orally once or twice daily and are well tolerated. Some patients show a better response than others to antileukotrienes, but this has not been convincingly linked to any genomic differences in the leukotriene pathway.
Cromones Cromolyn sodium and nedocromil sodium are asthma controller drugs that appear to inhibit mast cell and sensory nerve activation and are, therefore, effective in blocking trigger-induced asthma such as EIA and allergen- and sulfur dioxide-induced symptoms. Cromones have relatively little benefit in the long-term control of asthma due to their short duration of action (at least four times daily by inhalation). They are very safe and were popular in the treatment of childhood asthma, although now low doses of ICS are preferred as they are far more effective and have a proven safety profile.
Steroid-Sparing Therapies Various immunomodulatory treatments have been used to reduce the requirement for OCS in patients with severe asthma, who have serious side effects with this therapy. Methotrexate, cyclosporin A, azathioprine, gold, and IV gamma globulin have all been used as steroid-sparing therapies, but none of these treatments has any long-term benefit and each is associated with a relatively high risk of side effects.
Anti-IgE Omalizumab is a blocking antibody that neutralizes circulating IgE without binding to cell-bound IgE and, thus, inhibits IgE-mediated reactions. This treatment has been shown to reduce the number of exacerbations in patients with severe asthma and may improve asthma control. However, the treatment is very expensive and is only suitable for highly selected patients who are not controlled on maximal doses of inhaler therapy and have a circulating IgE within a specified range. Patients should be given a 3- to 4-month trial of therapy to show objective benefit. Omalizumab is usually given as a subcutaneous injection every 2–4 weeks and appears not to have significant side effects, although anaphylaxis is very occasionally seen.
Anti-IL-5 Antibodies that block IL-5 (mepolizumab, reslizumab) or its receptor (benralizumab) markedly reduce blood and tissue eosinophils and reduce exacerbations in patients who have persistently increased sputum eosinophils despite maximal ICS therapy.
Immunotherapy Specific immunotherapy using injected extracts of pollens or house dust mites has not been very effective in controlling asthma and may cause anaphylaxis. Side effects may be reduced by sublingual dosing. It is not recommended in most asthma treatment guidelines because of lack of evidence of clinical efficacy and potential anaphylaxis.
Alternative Therapies Nonpharmacologic treatments, including hypnosis, acupuncture, chiropraxis, breathing control, yoga, and speleotherapy, may be popular with some patients. However, placebo-controlled studies have shown that each of these treatments lacks efficacy and cannot be recommended. However, they are not detrimental and may be used as long as conventional pharmacologic therapy is continued.
Bronchial Thermoplasty Bronchial thermoplasty is a bronchoscopic treatment using thermal energy to ablate airway smooth muscle in accessible bronchi. It may reduce exacerbations and improve asthma control in highly selected patients not controlled on maximal inhaler therapy, particularly when there is no increase in inflammation.
Future Therapies It has proved very difficult to discover novel pharmaceutical therapies, particularly as current therapy with corticosteroids and β2-agonists is so effective in the majority of patients. There is, however, a need for the development of new therapies for patients with refractory asthma who have side effects with systemic corticosteroids. Antagonists of specific mediators have little or no benefit in asthma, apart from antileukotrienes, which have rather weak effects, presumably reflecting the fact that multiple mediators are involved. Anti-TNF-α antibodies are not effective in severe asthma. Anti-IL-13 blocking antibodies have little clinical effect, but an antibody (dupilumab) against the common receptor for IL-4 and IL-13 (IL-4Rα) is more promising in reducing exacerbations and improving asthma control in severe asthma. Novel anti-inflammatory treatments that are in clinical development include inhibitors of phosphodiesterase-4, NF-κB, and p38 MAP kinase. However, these drugs, which act on signal transduction pathways common to many cells, have troublesome side effects, which may necessitate their delivery by inhalation. Safer and more effective immunotherapy using T cell peptide fragments of allergens or DNA vaccination are also being investigated. Bacterial products, such as CpG oligonucleotides that stimulate TH1 immunity or Treg, are also currently under evaluation.
MANAGEMENT OF CHRONIC ASTHMA There are several aims of chronic therapy in asthma (Table 281-2). It is important to establish the diagnosis objectively using spirometry or PEF measurements at home. Triggers that worsen asthma control, such as allergens or occupational agents, should be avoided, whereas triggers, such as exercise and fog, which result in transient symptoms, provide an indication that more controller therapy is needed. It is important to assess asthma control, assessed by symptoms, night awakening, need for reliever inhalers, limitation of activity and lung function (Table 281-4). Avoidance of side effects and expense of medications are also important. There are several validated questionnaires for quantifying asthma control, such as the Asthma Quality of Life Questionnaire (AQLQ) and Asthma Control Test (ACT).
Stepwise Therapy For patients with mild, intermittent asthma, a SABA is all that is required (Fig. 281-8). However, use of a reliever medication more than twice a week indicates the need for regular controller therapy. The treatment of choice for all patients is an ICS given twice daily. It is usual to start with an intermediate dose (e.g., 200 [μg] bid of [beclomethasone dipropionate] BDP) or equivalent and to decrease the dose if symptoms are controlled after three months. If symptoms are not controlled, a LABA should be added, which is most conveniently given by switching to a combination inhaler. The dose of controller should be adjusted accordingly, as judged by the need for a rescue inhaler. Low doses of theophylline or an antileukotriene may also be considered as an add-on therapy, but these are less effective than LABA. In patients with severe asthma, low-dose oral theophylline is also helpful, and when there is irreversible airway narrowing, the long-acting anticholinergic may be tried. If asthma is not controlled despite the maximal recommended dose of inhaled therapy, it is important to check adherence and inhaler technique. In these patients, maintenance treatment with an OCS may be needed and the lowest dose that maintains control should be used. Occasionally omalizumab and anti-IL-5 may be tried in steroid-dependent asthmatics who are not well controlled. Once asthma is controlled, it is important to slowly decrease therapy in order to find the optimal dose to control symptoms.
Education Patients with asthma need to understand how to use their medications and the difference between reliever and controller therapies. Education may improve adherence, particularly with ICS. All patients should be taught how to use their inhalers correctly. In particular, they need to understand how to recognize worsening of asthma and how to step up therapy accordingly. Written action plans have been shown to reduce hospital admissions and morbidity rates in adults and children, and are recommended particularly in patients with unstable disease who have frequent exacerbations.