1. Asthma Control

Level of control is assessed by evaluating symptoms. Patients are asked about their past 4 weeks including frequency of symptoms (days per week), awakening from sleep, and use of reliever therapy (short-acting beta-agonist (SABA), inhaled corticosteroid (ICS)-formoterol, or ICS-SABA) for symptom relief (Table 9-1. Assessing Asthma Control). Patients should also be asked about activity limitation.

2. Risk Factors for Exacerbations

Poor symptom control increases risk of exacerbations. Other risk factors include more than one exacerbation in the previous year; inadequate inhaled corticosteroid (ICS) use (due to under-treatment, poor adherence, or incorrect inhaler technique); and other comorbidities, such as chronic sinusitis, GERD, obesity, and smoking.

3. Asthma Severity

Severity is evaluated retrospectively from the level of treatment needed to control symptoms and exacerbations. Table 9-2. Step Therapy in Personalized Asthma Management Plan describes the step therapy in a personalized asthma management plan. Typically, mild asthma responds to Step 1 or 2 treatments, moderate asthma to Step 3 treatment, and severe asthma to Step 4 or 5 treatments. It is important to distinguish between uncontrolled and severe asthma in patients who are using Step 4 or Step 5 treatments. The clinician must assess inhaler technique, medication adherence, comorbidities such as obstructive sleep apnea or GERD, and ongoing exposure to allergens as causes of poor asthma control (“uncontrolled” asthma). If the patient still requires Step 4 or 5 therapy after these issues have been addressed, then the patient has “severe” asthma and should be referred to a pulmonary or asthma specialist. Serial lung function testing is beneficial at time of diagnosis, 3-6 months after treatment initiation, and periodically thereafter but is not necessarily needed at every visit.

4. Treatment Adjustment

The goals of asthma therapy are to minimize chronic symptoms that interfere with normal activity (including exercise), prevent recurrent exacerbations, reduce or eliminate the need for emergency department visits or hospitalizations, and maintain normal or near-normal pulmonary function. A multidisciplinary approach using pharmacologic and nonpharmacologic strategies is best to address disease pathogenesis and modifiable risk factors. Pharmacologic agents that satisfy the patient's expectations of asthma care with the fewest adverse events should be prescribed. Management should include stepping up therapy if asthma remains uncontrolled despite adherence and good inhaler technique and stepping down if asthma is well controlled to find the minimum effective therapeutic dose. Nonpharmacologic interventions include increasing physical activity and breathing exercises. Significant reduction in exposure to nonspecific airway irritants in all patients or to inhaled allergens in atopic patients may reduce symptoms and medication needs. Comorbid conditions that impair asthma management, such as smoking, rhinosinusitis, GERD, obesity, and obstructive sleep apnea, should be identified and treated. The asthma plan of care, level of symptom control, and patient satisfaction should be reviewed on a periodic basis and facilitated by guided patient self-management education and skills training. Self-management includes self-monitoring of symptoms or peak flow; a written action plan; and regular review of asthma control, treatment, and skills with a health care professional.

5. Periodic Lung Function Testing

Serial spirometry is beneficial at time of diagnosis, 3-6 months after treatment initiation, and periodically thereafter to monitor the disease trajectory and response to therapy.

1. Inhaled Corticosteroids

Inhaled corticosteroids (ICS) are essential controller medications (Tables 9-4. Reliever Medications for Asthma and 9-5. Estimated Clinically Comparable Daily Dosages for Inhaled Corticosteroids for Adults with Asthma). Once the diagnosis of asthma is made, early initiation of ICS therapy leads to a greater improvement in lung function than delayed therapy. Prescribing as-needed or daily controller ICS at the start of asthma therapy conveys a message to patients that both symptom control and risk reduction are the mainstays of asthma treatment. The most important determinants of medication choice, device, and dose are a patient's symptoms and risk factors, along with practical issues (such as cost and delivery mechanism). ICS dosages are classified as low-, medium-, and high-dose strengths, but low-dose ICS provides clinical benefit and is sufficient for most patients with asthma. Dosages for ICS vary depending on the specific agent and delivery device (Table 9-5. Estimated Clinically Comparable Daily Dosages for Inhaled Corticosteroids for Adults with Asthma). For patients who require high-dose ICS to achieve adequate symptom control, the dose of inhaled corticosteroid should be decreased after 3 months of good control to the lowest dose that preserves symptom control and minimizes exacerbation risk.

Concomitant use of an MDI and an inhalation chamber coupled with mouth washing after ICS use decreases systemic absorption and local side effects (cough, dysphonia, oropharyngeal candidiasis). Dry powder inhalers (DPIs) are not used with an inhalation chamber. Systemic effects (adrenal suppression, osteoporosis, skin thinning, easy bruising, and cataracts) may occur with high-dose ICS therapy. Combination inhalers with an ICS and a long-acting beta-2-agonist (LABA) offer convenient treatment of asthma. The GINA report recommends low-dose inhaled corticosteroid/formoterol as its preferred agent due to clinical evidence but notes that its cost and availability in different countries must be taken into consideration. Budesonide/formoterol is listed as a WHO essential medication.

2. Beta-Adrenergic Agonists

Beta-agonists are divided into SABAs and LABAs. SABAs (Table 9-4. Reliever Medications for Asthma), including agents such as albuterol, levalbuterol, bitolterol, pirbuterol, and terbutaline, are mainstays of reliever or rescue therapy for asthma patients. There is no convincing evidence to support the use of one agent over another. All asthmatics should have immediate access to a bronchodilator, preferably SABA, because they are the most effective bronchodilators during exacerbations and provide immediate relief of symptoms. Alternatively, GINA has proposed the combination of low-dose glucocorticoid plus formoterol, a fast-acting LABA, or combination of low dose inhaled corticosteroid plus SABA, as symptom relief on as needed basis instead. Administration before exercise effectively prevents exercise-induced bronchoconstriction.

Inhaled SABA therapy is as effective as oral or parenteral beta-agonist therapy in relaxing airway smooth muscle and improving acute asthma and offers the advantages of rapid onset of action (less than 5 minutes) with fewer systemic side effects. Beta-2-selective agents may produce less cardiac stimulation than those with mixed beta-1 and beta-2 activities, although clinical trials have not consistently demonstrated this finding. Repetitive administration produces incremental bronchodilation. One or two inhalations of a SABA from an MDI are usually sufficient for mild to moderate symptoms. Severe exacerbations frequently require higher doses: 6-12 puffs every 30-60 minutes of albuterol by MDI with an inhalation chamber or 2.5 mg by nebulizer provide equivalent bronchodilation. Administration by nebulization does not offer more effective delivery than MDIs used correctly but does provide higher doses. With most SABAs, the recommended dose by nebulizer for acute asthma (albuterol, 2.5 mg) is 25-30 times that delivered by a single activation of the MDI (albuterol, 0.09 mg). This difference suggests that standard dosing of inhalations from an MDI may be insufficient in the setting of an acute exacerbation. Independent of dose, nebulizer therapy may be more effective in patients who are unable to coordinate inhalation of medication from an MDI because of age, agitation, or severity of the exacerbation.

GINA recommends against SABA-only treatment of asthma in adults or adolescents and does not recommend scheduled daily use of SABAs. Although SABA is effective as a quick relief medication, patients who are treated with SABA alone are at increased risk for asthma-related death and urgent health care even if their symptoms are controlled. Increased use (more than one canister a month) or lack of expected effect indicates diminished asthma control and the need for additional long-term controller therapy.

LABAs provide bronchodilation for up to 12 hours after a single dose. Salmeterol and formoterol are LABAs available for asthma in the United States. Olodaterol, indacaterol, and arformoterol are approved in the United States for COPD but not for asthma. In combination with an ICS, they are indicated for maintenance therapy of asthma. LABAs should not be used as monotherapy because they have no anti-inflammatory effect and because monotherapy has been associated with a small but significant increased risk of severe or fatal asthma attacks in two large studies. Based on clinical trial data in patients with mild asthma, combination inhalers containing formoterol and low-dose budesonide are the preferred option, which have demonstrated a 64% reduction in severe exacerbations compared with SABA-only treatment and noninferiority for severe exacerbations compared to low-dose ICS alone.

3. Systemic Corticosteroids

Systemic corticosteroids (oral prednisone or prednisolone or parenteral methylprednisolone) are most effective in achieving prompt control of asthma during acute exacerbations. Systemic corticosteroids are effective as primary treatments for patients with moderate to severe asthma exacerbations and for patients with exacerbations that do not respond promptly and completely to inhaled SABA therapy. These medications speed the resolution of airflow obstruction and reduce the rate of relapse. Delays in administering corticosteroids may result in progressive impairment. Therefore, patients with moderate to severe asthma should be prescribed oral corticosteroids so they are available for early, at-home administration, when needed. The minimal effective dose of systemic corticosteroids for asthma patients has not been identified. Outpatient prednisone “burst” therapy is 0.5-1 mg/kg/day (typically 40-60 mg) in 1-2 doses for 3-7 days. Severe exacerbations requiring hospitalization typically require 1 mg/kg of prednisone or methylprednisolone every 6-12 hours for 48 hours or until the FEV₁ (or PEF rate) returns to 50% of predicted (or 50% of baseline). The dose is then decreased to 0.5 mg/kg/day until the PEF reaches 70% of predicted or personal best. No clear advantage has been found for higher doses of corticosteroids. It may be prudent to administer corticosteroids intravenously to critically ill patients to avoid concerns about altered GI absorption.

In patients with refractory, poorly controlled asthma, or patients with frequent exacerbations despite optimized inhaler therapy, systemic corticosteroids may be required for the long-term suppression of symptoms. Repeated efforts should be made to reduce the dose to the minimum needed to control symptoms. Concurrent treatment with calcium supplements and vitamin D should be initiated to prevent corticosteroid-induced bone mineral loss with long-term administration. Bone mineral density testing after 3 or more months of cumulative systemic corticosteroid exposure can guide the use of bisphosphonates for treatment of steroid-induced osteoporosis. Rapid discontinuation of systemic corticosteroids after long-term use may precipitate adrenal insufficiency.

4. Anticholinergics

Anticholinergic agents reverse vagally mediated bronchospasm but not allergen- or exercise-induced bronchospasm. They may decrease mucous gland hypersecretion. Both short-acting muscarinic antagonists (SAMAs) and long-acting muscarinic antagonists (LAMAs) are available. Ipratropium bromide, a SAMA, is less effective than SABA for relief of acute bronchospasm but is the inhaled drug of choice for patients with intolerance to SABA or bronchospasm due to beta-blocker medications. Ipratropium bromide reduces the rate of hospital admissions when added to inhaled SABAs in patients with moderate to severe asthma exacerbations. Although LAMAs have long been the cornerstone of therapy for COPD, their role in asthma continues to evolve. Studies have shown that the addition of tiotropium to medium-dose inhaled corticosteroid and salmeterol improves lung function and reduces the frequency of asthma exacerbations.

5. Leukotriene Modifiers

Leukotrienes are potent mediators that contribute to airway obstruction and asthma symptoms by contracting airway smooth muscle, increasing vascular permeability and mucous secretion, and attracting and activating airway inflammatory cells. Zileuton is a 5-lipoxygenase inhibitor that decreases leukotriene production, and zafirlukast and montelukast are cysteinyl leukotriene receptor antagonists. In RCTs, these agents caused modest improvements in lung function and reductions in asthma symptoms and lessened the need for SABA rescue therapy. These agents are less effective than inhaled corticosteroid for exacerbation reduction or as first-line controller therapy but may be considered as alternatives in patients with asthma who are unable to take inhaled corticosteroid or who experience undesirable corticosteroid side effects.

6. Monoclonal Antibody Agents

Asthmatic patients who require monoclonal antibody therapies should be evaluated by either a pulmonologist or allergist experienced in their use. Omalizumab is a recombinant antibody that binds IgE without activating mast cells. Clinical trials in patients with moderate to severe asthma and elevated serum IgE levels have found that omalizumab, when administered subcutaneously every 2-4 weeks, reduced the need for corticosteroids. Three other IL-5 antagonist monoclonal antibodies (anti IL-5/5R) are approved for the treatment of severe asthma with peripheral blood eosinophilia that has not responded to standard treatments: reslizumab (administered intravenously every 4 weeks), mepolizumab (administered subcutaneously every 4 weeks), and benralizumab (administered subcutaneously every 4-8 weeks). Dupilumab is a monoclonal antibody (anti-IL-4Rα) that, when administered subcutaneously every 2 weeks, inhibits overactive signaling of IL-4 and IL-13.

7. Phosphodiesterase Inhibitor

Theophylline provides mild bronchodilation in asthmatic patients. It also has anti-inflammatory and immunomodulatory properties, enhances mucociliary clearance, and strengthens diaphragmatic contractility. Sustained-release theophylline preparations are effective in controlling nocturnal symptoms and as added therapy in patients with moderate or severe persistent asthma whose symptoms are inadequately controlled by inhaled corticosteroids. Low-dose sustained-release theophylline is included as a less effective option in Step 3 treatment. Neither theophylline nor aminophylline is recommended for therapy of acute asthma exacerbations.

Theophylline has a notably narrow therapeutic-toxic range. At therapeutic doses, potential adverse effects include insomnia, aggravation of dyspepsia and gastroesophageal reflux, and urination difficulties in men with prostatic hyperplasia. Dose-related toxicities include nausea, vomiting, tachyarrhythmias, headache, seizures, hyperglycemia, and hypokalemia. Theophylline serum levels are highly variable due to many factors that alter drug absorption, significant individual differences in metabolism, and multiple drug-drug interactions. Therefore, serum concentrations need to be monitored closely.

Theophylline and its intravenous formulation, aminophylline, are not recommended for therapy of asthma exacerbations. Aminophylline has clearly been shown to be less effective than SABAs when used as single-drug therapy for acute asthma; it adds little except toxicity to the acute bronchodilator effects achieved by nebulized metaproterenol alone. Patients with exacerbations who are currently taking theophylline should have its serum concentration measured to exclude theophylline toxicity.

8. Mediator Inhibitors

Cromolyn sodium and nedocromil are long-term control medications that prevent asthma symptoms and improve airway function in patients with mild persistent or exercise-induced asthma. These agents modulate mast cell mediator release and eosinophil recruitment and inhibit both early and late asthmatic responses to allergen challenge and exercise-induced bronchospasm. The clinical response to these agents is less predictable than to inhaled corticosteroids. Both agents have excellent safety profiles.