Initiating asthma therapy and monitoring in adolescents and adults

INTRODUCTION — The goals of asthma therapy are to achieve good symptom control, prevent asthma exacerbations, and improve quality of life. A basic tenet of asthma therapy is that treatment intensity should be individualized to match the frequency and severity of asthmatic symptoms as well as the risk of exacerbations. For all persons with asthma, effective communication, ongoing patient education, and regular reassessment of asthma control are crucial for long-term success.

The initiation of pharmacologic therapy for the treatment of adolescents and adults and the establishment of plans for follow-up monitoring will be covered here. The approach outlined in this topic can also be used for initiating anti-inflammatory therapies for patients who have only been using short-acting beta-agonists (SABAs). In general, these recommendations are consistent with guidelines from the National Asthma Education and Prevention Program (NAEPP), including the "2020 Focused Updates to the Asthma Management Guidelines," and the Global Initiative for Asthma (GINA) [1-3].

An overview of asthma management, follow-up monitoring and titration of asthma therapies, the management of difficult-to-control asthma, and the management of asthma exacerbations are covered elsewhere.

●(See "An overview of asthma management".)

●(See "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

●(See "Treatment of severe asthma in adolescents and adults".)

●(See "Acute exacerbations of asthma in adults: Home and office management".)

●(See "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)

Although briefly summarized in this discussion, nonpharmacologic aspects of initial asthma management are also covered in more detail elsewhere.

●(See "Asthma education and self-management".)

●(See "Trigger control to enhance asthma management".)

●(See "Allergen avoidance in the treatment of asthma and allergic rhinitis".)

●(See "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy".)

In some patient populations or diagnostic groups, the management strategies for asthma differ slightly from those recommended here. These differences are covered in separate topics.

●(See "Management of asthma during pregnancy".)

●(See "Asthma and COPD overlap (ACO)".)

●(See "Diagnosis and management of asthma in older adults".)

●(See "Exercise-induced bronchoconstriction".)

●(See "Irritant-induced asthma".)

●(See "Occupational asthma: Management, prognosis, and prevention".)

ASSESSING SYMPTOM SEVERITY AND EXACERBATION RISK — For patients initiating therapy for asthma, the choice of pharmacotherapy depends on a clinical assessment of symptom severity and the risk of future severe exacerbations. Key data to guide this assessment include:

●Reported daytime and nighttime symptoms, and activity limitation over the previous two to four weeks

●Current airflow obstruction, based on either peak expiratory flow (PEF) or forced expiratory volume in one second (FEV₁) and FEV₁/forced vital capacity (FVC) (see "Peak expiratory flow monitoring in asthma" and "Office spirometry")

●Exacerbations requiring oral glucocorticoids in the previous year

●Clinical and available laboratory assessment of eosinophilic inflammation (eg, nasal polyposis, aspirin-exacerbated respiratory symptoms, peripheral blood eosinophil count, fraction of exhaled nitric oxide)

●Other medical and exposure history that may increase risk for future exacerbations (table 1)

Guideline-based classification of asthma severity uses retrospective definitions that may conflict with patient and clinical intuition. The Global Initiative for Asthma (GINA) and an American Thoracic Society research committee have questioned the distinction previously made between "intermittent" and "persistent" asthma as lacking in biologic basis and evidence [3,4]. This dichotomy may have led to false reassurance that patients with infrequent symptoms were at low enough risk for exacerbations that anti-inflammatory therapy was not necessary. However, observational studies have shown that 30 to 40 percent of acute asthma episodes, 15 percent of near-fatal asthma episodes, and 15 to 30 percent of fatal asthma attacks occur in patients reporting symptoms less than weekly or only with exertion in the preceding three months [5,6]. These issues, among others, have led to the following recommended definitions of asthma severity [3,4,7,8]:

●Mild asthma – Defined by minimal symptoms and minimal risk of exacerbations (table 2) in patients not receiving therapy, using reliever therapy alone, or using low-dose inhaled glucocorticoids with reliever therapy (step 1 or step 2 treatments) [4]. GINA advises avoiding the term "mild asthma" altogether to avoid giving the impression that mild symptoms equate with low risk [3].

●Moderate asthma – Defined by good asthma control (table 2) with medium-dose inhaled glucocorticoids or low- or medium-dose inhaled glucocorticoids with additional controller therapies.

●Severe asthma – Defined by asthma requiring high-dose inhaled glucocorticoids with additional controller agents to maintain good control (table 2), or uncontrolled asthma despite these therapies.

By the retrospective definitions listed above, asthma severity can only be assessed after achieving good control and stepping down to find the minimum effective controller therapy (or unless asthma remains uncontrolled despite maximized therapy). This process typically takes at least several months.

Rather than using these retrospective definitions, both the National Asthma Education and Prevention Program (NAEPP) and GINA practically recognize four or more different levels of symptoms and exacerbation risk to titrate initial therapy (table 3) [1-3]. For patients who are initiating therapy or have only used short-acting beta-agonists (SABAs), we divide treatment groups largely in accordance with NAEPP guidelines (table 4). These criteria for judging asthma severity are appropriately applied to persons who, at the time of assessment, take no medications (other than as-needed SABAs) for control of their asthma. They are not applicable to persons with asthma already using anti-inflammatory medications. For persons already using controller therapies, asthma assessment is best made in terms of asthma control. (See "An overview of asthma management", section on 'Adjusting controller medication' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

We have eschewed controversial descriptors in favor of group definitions based on symptom assessment, representing the primary driver of the initial approach:

●Infrequent symptoms (step 1) – Patients eligible for step 1 therapy have infrequent symptoms without interference in daily activities, accompanied by minimal exacerbation history. Step 1 patients should meet all of the following criteria (table 4):

•Daytime asthma symptoms (with or without SABA use) occurring two or fewer days per week

•One or fewer nocturnal awakenings per month

•No interference with normal activities between exacerbations

•Normal PEF, postbronchodilator FEV₁, and FEV₁/FVC ratio when asymptomatic

•At most one exacerbation requiring oral glucocorticoids in the preceding year

If the patient has impairment that is greater than that described in any domain above, the severity of asthma should be categorized as more severe. However, a person using an inhaled bronchodilator preventively prior to exercise to avoid exercise-induced bronchoconstriction may also be considered part of this group, even if exercising more than two days per week. (See "Exercise-induced bronchoconstriction".)

Others in whom periods of increased asthma symptoms arise only under certain infrequently occurring circumstances (eg, upon encountering a cat or during a viral respiratory tract infection) may be placed in this group, even if they experience intense symptoms, provided that oral glucocorticoids are not required more than once per year [1]. However, the increased risk of exacerbations under these circumstances may suggest benefit to anti-inflammatory reliever (AIR) therapy over SABA alone. (See 'Anti-inflammatory reliever (AIR) therapy, in higher risk patients' below.)

Patients without frequent exacerbations but with multiple risk factors for severe exacerbations or fatal asthma (table 1) should receive AIR (table 5) despite their infrequent symptoms. (See "Identifying patients at risk for fatal asthma" and 'Anti-inflammatory reliever (AIR) therapy, in higher risk patients' below.)

●Frequent but not daily symptoms (step 2): – Patients eligible for step 2 therapy have either more frequent symptoms or significantly higher risk of exacerbations than step 1 patients, but do not have daily asthma symptoms. Patients qualify for step 2 based on any of the following (table 4):

•Daytime symptoms (with or without SABA use) more than two days a week (although less than daily)

•Two to four nocturnal awakenings per month due to asthma (but not more than once weekly)

•Minimal interference with normal activities

•Two or more exacerbations requiring oral glucocorticoids per year

Inclusion of the criterion "two or more glucocorticoid-requiring exacerbations in the past year" is based on the observations that patients who have experienced multiple asthma attacks have an increased risk of future exacerbations and that anti-inflammatory therapy reduces this risk. Thus, guidelines advise use of medication strategies to reduce exacerbation risk, even in the absence of frequent asthma symptoms, nighttime awakenings, or impairment of normal activity level. Most patients with multiple exacerbations will not require a new initiation of therapy, but some may be using SABA alone and require the addition of inhaled glucocorticoids as reliever or maintenance therapy. (See 'Patients with frequent but not daily symptoms (Step 2)' below.)

●Daily asthma symptoms (step 3) – This group is typically characterized by daily asthma symptoms with or without increased exacerbation risk, including any of the following (table 4):

•Daily symptoms of asthma

•Nocturnal awakenings more than once per week

•Occasional limitation in normal activity

•Evidence of airway obstruction outside of an exacerbation (eg, FEV₁ between 60 and 80 percent of predicted with an abnormally low FEV₁/FVC ratio)

Patients with this degree of asthma severity require scheduled controller therapy in addition to reliever medications [1,3]. (See 'Patients with daily symptoms (Step 3)' below.)

●Daily limitations in activity (step 4) – This group is characterized by daily limitations in activity due to asthma or severely impaired lung function, including any of the following (table 4):

•Frequent limitation in normal activity due to asthma symptoms

•Nightly awakenings

•Evidence of moderate to severe airway obstruction (FEV₁<60 percent predicted with an abnormally low FEV₁/FVC ratio)

Most patients in this group require initiation of short-term oral glucocorticoids followed by scheduled medium-dose inhaled glucocorticoids and long-acting beta-agonists (LABAs) (table 6). (See 'Patients with daily activity limitations (Step 4)' below.)

ASTHMA EDUCATION FOR PATIENTS INITIATING THERAPY — Asthma education and self-management are essential components of successful care of patients with asthma. Based on extensive research, the core elements of patient education to improve outcomes include: understanding the pathophysiology of asthma, issues in the prevention and treatment of symptoms, and the function and appropriate use of asthma medications. A focused approach is helpful for the initial visit (table 7). Asthma education is discussed in greater depth elsewhere. UpToDate also provides several patient-level topics to assist in patient education. (See "Asthma education and self-management" and 'Information for patients' below.)

●Understanding asthma – Patients should understand that asthma is a chronic lung disease that can be well-controlled with treatment. Asthma causes the airways to become sensitive to triggers, causing them to narrow and make breathing difficult. Asthma is accompanied by ongoing inflammation in the airways that persists even when there are not active asthma symptoms.

●Trigger avoidance – Elimination or avoidance of irritant or allergic triggers may be a useful strategy to help reduce asthma attacks and (in some cases) the underlying inflammation. History-taking is crucial in determining exposure to environmental allergens (such as animal dander, mold, and indoor pests) and irritants (such as cigarette smoke, wood or gas burning stoves, and air pollution) in the home, school, and/or workplace. In those with indoor allergens triggering their asthma, a multi-component allergen-specific mitigation strategy may be helpful. This topic is reviewed in detail separately. (See "Trigger control to enhance asthma management" and "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Occupational asthma: Definitions, epidemiology, causes, and risk factors".)

●Asthma medications and their purpose:

•Reliever versus controller therapies – Asthma medicines may be used for acute relief of symptoms via acute bronchodilation (relievers) or as maintenance therapy to chronically suppress the underlying inflammation and prevent symptoms (controllers). Reliever medications are used to treat acute symptoms, whereas controllers are used regularly to prevent future symptoms.

•Anti-inflammatory reliever (AIR) therapy – Some reliever medications or medication combinations provide anti-inflammatory therapy in addition to acute bronchodilation (table 5). With this approach, patients requiring more rescue inhaler use will achieve a greater dose of glucocorticoids delivered to the airways to suppress the inflammation. AIR has been promoted by national and international guidelines based on decreased exacerbation rates across many different levels of asthma severity [2,3]. It is particularly helpful for patients with seasonal or otherwise variable symptoms, as well as those with frequent exacerbations.

•Maintenance and reliever therapy (MART) – Combination inhalers containing inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) and the fast-acting (and long-acting) beta-agonist formoterol can be used for both controller and reliever therapy, also called MART (table 8). This regimen allows the patient to use one inhaler for both daily therapy and as-needed relief, an approach that reduces inhaler confusion and improves adherence. Using ICS-formoterol as reliever therapy also offers all the advantages of AIR in decreasing asthma exacerbations.

●Use of inhaler devices – Inhaler devices are the major method for delivery of medications for asthma, but their effectiveness depends on proper inhaler technique, which can be challenging for many patients. Each time a new device is introduced, proper use of the device needs should be reviewed in detail. Categories of devices include metered-dose inhalers (MDIs), breath-actuated MDIs, dry powder inhalers, and soft mist inhalers. It is often helpful for patients to watch a video demonstrating use of the particular type of inhaler (eg, MDI with spacer, Diskus, Ellipta, HandiHaler, Respimat). Patients should be shown the device dose counter so that they will know when the inhaler is approaching empty. Besides coaching in proper technique and repeated reinforcement, use of a valved holding chamber or "spacer" can help to optimize medication delivery from compatible MDIs (table 9) and reduce adverse effects from oropharyngeal deposition and systemic absorption. The proper use of inhaler devices is reviewed in detail separately. (See "The use of inhaler devices in adults".)

●Asthma action plan – Every patient with asthma should have a personalized asthma action plan that gives detailed instructions about how to self-administer medications at baseline and during exacerbations. An accessible printed or digital copy of the personalized action plan should be available for the patient's reference. One printable version is available here (form 1). Patients should understand signs of deterioration such as increased intensity or frequency of symptoms, nocturnal awakenings, decreased activity tolerance, and increasing reliever use. It is important for all patients with asthma, even those with infrequent symptoms, to understand that they are at risk for severe, potentially life-threatening asthma attacks. Clinicians should stress the need to seek medical attention without delay if reliever medications fail to control their symptoms during an acute attack. (See "Asthma education and self-management".)

PATIENTS WITH INFREQUENT SYMPTOMS (STEP 1) — Patients with infrequent symptoms (table 4) should receive as-needed reliever therapy rather than daily controller medicines. Reliever therapies contain an inhaled bronchodilator with a rapid onset of action for prompt relief of asthma symptoms (eg, albuterol, levalbuterol) (table 10) and may sometimes contain an inhaled bronchodilator in combination with an inhaled glucocorticoid (ie, anti-inflammatory reliever [AIR] therapy; eg, budesonide-formoterol) (table 5). The choice among reliever options depends upon individual patient characteristics, drug availability, and patient preference.

Short-acting beta-agonists (SABAs) for quick relief, in low-risk patients — For patients with infrequent symptoms and without risk factors for serious exacerbations (table 1), the use of as-needed SABAs is reasonable. SABAs have been used for several decades as the traditional strategy for relieving symptoms of cough, chest tightness, shortness of breath, or wheeze in patients with infrequent symptoms of asthma (table 10) [1,2]. These agents are relatively inexpensive, widely available, and have few side effects.

The use of SABAs alone without anti-inflammatory therapy is most appropriate for patients who are not at risk for serious attacks due to prior history of severe exacerbations or ongoing allergic/irritant triggers. Candidates for this approach also require reliable follow-up so that worsening asthma control can be recognized, and anti-inflammatory therapy initiated. Patients with infrequent symptoms who do not meet these conditions should receive AIR (table 5) instead.

When in doubt about whether a patient fits into a low-risk category, we use AIR. Patients with poor asthma symptom control who use large amounts of SABAs alone have significantly worse asthma outcomes, including exacerbations and mortality [9-12]. (See 'Anti-inflammatory reliever (AIR) therapy, in higher risk patients' below.)

●Pharmacology and dosing – The inhaled SABAs (eg, albuterol and levalbuterol in the United States; aka, salbutamol and levosalbutamol in other parts of the world) have a rapid onset of action (within five minutes), an intermediate duration of effect (approximately four to six hours), and relative beta-2 receptor selectivity (table 10). Although sometimes referred to as a "rescue inhaler," it should be made clear that patients do not need to wait for severe symptoms or a medical emergency to use their reliever.

SABAs can also be used to prevent bronchoconstriction in response to an individual's known asthma triggers. We typically suggest use of SABA therapy 5 to 20 minutes prior to exposure to a predictable trigger, such as exercise or exertion in cold air. Patients require teaching and coaching in proper inhaler technique. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Prevention of asthma symptoms' and "Delivery of inhaled medication in adults".)

Levalbuterol (or levosalbutamol) is the R-enantiomer of albuterol (or salbutamol), purified from the racemic mixture of R- and S-enantiomers that constitute the drug. It is available as a liquid for nebulization and as a metered-dose inhaler (MDI). Each MDI actuation contains 45 mcg of levalbuterol (compared with 90 mcg per actuation of racemic albuterol). The onset, duration of action, and side-effect profile are comparable to albuterol. Although the development of R-enantiomer drugs was based on the possibility that they might cause fewer stimulatory side effects, this difference has not been demonstrated with certainty in clinical practice.

●Adverse effects – Side effects of SABAs are generally mild and reflect sympathomimetic stimulation, including a "racy" feeling, jitteriness, and tachycardia. In those who are particularly sensitive to these side effects, we advise using half the usual dose (one inhalation of medication rather than two), mouth rinsing and spitting after dosing to minimize oral systemic absorption, or (on rare occasion) using a short-acting muscarinic antagonist (eg, ipratropium) rather than a SABA. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Adverse effects'.)

Anti-inflammatory reliever (AIR) therapy, in higher risk patients — For patients with infrequent symptoms but risk factors for serious exacerbations (table 1), we suggest the use of AIR (table 5) rather than SABA alone. Use of an inhaled glucocorticoid (aka, inhaled corticosteroid [ICS]) along with a rapid-acting bronchodilator treats both airway smooth muscle constriction and underlying airway inflammation; the more symptomatic the patient and the more frequent the use of the combination inhaler, the greater the dose of glucocorticoids delivered to the airways to suppress the inflammation. In addition to use for traditional asthma symptoms, AIR is also effective in prevention of exercise-induced bronchoconstriction [13]. (See "Exercise-induced bronchoconstriction", section on 'Pre-exercise treatments for EIB'.)

●Potential advantages – The primary advantage of treating patients with infrequent symptoms using AIR is its proven efficacy in reducing the frequency of asthma attacks, including severe attacks leading to a need for oral glucocorticoids, emergency department visits, and hospitalizations. (See 'As-needed low-dose ICS-formoterol (step 1)' below and 'As-needed low-dose ICS and SABA (step 1)' below.)

Although individual patient risk is small, patients with symptoms less than once a month or only with exertion contribute to an estimated 15 percent of near-fatal asthma episodes and 15 to 25 percent of fatal attacks [4,5]. Use of AIR may also help new patients understand anti-inflammatory treatment as essential to asthma control, reducing reliance on albuterol and nonadherence to scheduled controller medicines if their asthma worsens.

●Potential disadvantages – Potential disadvantages of AIR include: the reliance on specific branded inhalers (potentially not available to many patients because of cost and health insurance policies); the aversion of some patients to using any medication containing a glucocorticoid; and potential for inhaled glucocorticoid-associated side effects (although uncommon in clinical trials of AIR).

Based on these advantages and disadvantages, we believe AIR is most appropriate for patients with intermittent asthma who are thought to be at increased risk for severe attacks (table 1), those with irregular medical follow-up to assess changes in asthma severity, or those with predictable periods of worsened asthma control (such as during intermittent high-intensity allergen exposures). The Global Initiative for Asthma (GINA) prefers AIR (using a combination low-dose glucocorticoid-formoterol inhaler) in all patients with infrequent asthma symptoms [3].

As-needed low-dose ICS-formoterol (step 1) — Formoterol has a rapid onset of action comparable to albuterol (within three to five minutes), in addition to being long-acting (up to 12 hours of bronchodilation). Although traditionally used as maintenance therapy for asthma (together with an inhaled glucocorticoid), its rapid onset of action makes it appropriate for quick symptom relief.

●Dosing and adverse effects – There are several different inhaled glucocorticoid-formoterol inhalers available worldwide. When used for AIR, low- or medium-dose inhaled glucocorticoid doses are preferable, and the dose is taken as one to two inhalations, when needed for symptom relief (eg, two puffs of budesonide-formoterol 80 mcg/4.5 mcg, as needed, off-label in the United States) (table 5) [3]. For a severe flare of symptoms, two inhalations can be given every 20 minutes up to a total of six inhalations. The maximum recommended daily dose of the metered-dose inhaler (MDI) preparations is 12 inhalations, which is the equivalent of two inhalations every four hours. Patients require teaching on the appropriate inhaler technique to maximize effectiveness and minimize side effects. (See "The use of inhaler devices in adults".)

Most clinical trials in patients with mild asthma did not use rinsing to avoid dysphonia or oral candidiasis due to inconvenience and did not demonstrate significant incidence of these side effects. Other adverse effects are covered elsewhere but are likely to be uncommon with as-needed use. (See "Major side effects of inhaled glucocorticoids".)

Potential, generally minor side effects of formoterol include headache, muscle cramps, and sympathomimetic stimulation (including tremor and a low risk of tachyarrhythmias).

●Efficacy of AIR compared with as-needed SABA – The strongest evidence in support of ICS-formoterol for patients with infrequent asthma symptoms comes from randomized trials comparing low-dose budesonide plus formoterol taken as needed versus a SABA taken as needed (with or without scheduled inhaled glucocorticoid), although these studies were performed with a patient population that included those with more frequent symptoms (eligible for step 2 treatment).

•In the open-label Novel Symbicort Turbuhaler Asthma Reliever Therapy (START) trial, 668 adults with intermittent or mild persistent asthma were randomly assigned to one of three groups: albuterol as needed; budesonide (200 mcg) one inhalation twice daily plus albuterol as needed; or combination budesonide-formoterol (200 mcg/6 mcg) one inhalation as needed [14]. After 52 weeks, the annualized exacerbation rate among subjects who received budesonide-formoterol was lower than that of the albuterol group (0.2 versus 0.4 exacerbations per patient per year; relative rate [RR] 0.49, 95% CI 0.33-0.72). Severe exacerbations requiring systemic glucocorticoids, emergency department visits, or hospitalization also occurred less often with budesonide-formoterol compared with albuterol (4.1 versus 10 percent of patients; RR 0.40, 95% CI 0.18 to 0.86). The RR was similar, but not statistically significant, for the 25 percent of patients with baseline SABA use once per week or less (RR 0.39, 95% CI 0.13 to 1.14). There were no major differences in symptom scores or lung function between the groups.

•The open-label PeRsonalised Asthma Combination Therapy: with Inhaled Corticosteroid And fast-onset Long-acting beta agonist (PRACTICAL) study randomized 885 adult patients with mild asthma (qualifying for step 1 or step 2 therapy) to either budesonide-formoterol (200 mcg/6 mcg) AIR or maintenance budesonide (200 mcg) plus terbutaline (250 mcg) as reliever for one year (traditional step 2 therapy) [15]. Despite the use of standing anti-inflammatory therapy in the nonAIR arm, severe exacerbations were reduced in patients using AIR (0.12 versus 0.17 severe exacerbations per patient per year; RR 0.69, 95% CI 0.48-1.0), with a similar relative effect in those with baseline SABA use once per week or less (RR 0.73, 95% CI 0.48-1.11).

Because the relative impact of budesonide-formoterol AIR compared with SABA on exacerbations in these studies was similar for patients with fewer and more symptoms (based on SABA use), data from placebo-controlled randomized trials for patients with mild asthma and more frequent symptoms (step 2) therapy may also be relevant. One trial (Symbicort Given as Needed in Mild Asthma [SYGMA-1]) that included 2554 step 2 patients randomized to SABA (terbutaline 0.5 mg) or AIR (budesonide-formoterol 200 mcg/6 mcg) as needed found a robust decrease in severe exacerbations in the AIR group (0.07 versus 0.20 exacerbations per patient per year, RR 0.36, 95% CI 0.27-0.49).

Given the primary impact on exacerbation rates, budesonide-formoterol may be particularly beneficial for persons with intermittent asthma who have experienced or are at risk for repeated or severe asthma attacks (table 1). Use of other inhaled glucocorticoids (eg, beclomethasone, mometasone) with formoterol is likely to be similar, but the evidence is less robust.

As-needed low-dose ICS and SABA (step 1) — An alternative AIR therapy that likely performs similarly to ICS-formoterol is the as-needed use of a low-dose glucocorticoid plus a SABA, such as albuterol [2,3] (table 5). However, additional clinical trial data and real-world experience in patients with infrequent symptoms would be helpful.

Use of as-needed inhaled glucocorticoid and SABA has proven effective in reducing asthma exacerbations and improving asthma quality of life compared with as-needed albuterol alone in persons with moderate to severe asthma also receiving maintenance inhaled glucocorticoids [16]. Data for its use in patients with infrequent asthma symptoms are more limited than for combination glucocorticoid-formoterol inhalers, and combination glucocorticoid-albuterol inhalers are not yet widely available in many parts of the world. The limited trials in patients with mild asthma and more frequent (step 2) symptoms are reviewed below. (See 'As-needed low-dose ICS and SABA (step 2)' below.)

Where combination inhalers are not available, this strategy involves carrying two separate rescue inhalers, which may be impractical and lead to decreased patient compliance. A combination albuterol-budesonide inhaler was approved for patients age >18 years in the United States in January, 2023.

PATIENTS WITH FREQUENT BUT NOT DAILY SYMPTOMS (STEP 2) — Patients with more frequent but not daily asthma symptoms, infrequent symptoms with frequent exacerbations (>1 in the last year), or other evidence of ongoing bronchial inflammation (see 'Assessing symptom severity and exacerbation risk' above) have a burden of disease activity and risk of asthma exacerbations for which as-needed bronchodilator therapy alone is inadequate [1-3]. By adding regular (or appropriately timed intermittent) anti-inflammatory therapy, the frequency of symptoms generally decreases, airway hyperresponsiveness lessens, lung function improves, and the risk of asthmatic attacks decreases.

Inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]), which target the underlying airway inflammation of asthma, are part of the first-line treatment for ongoing asthma inflammation. The most appropriate strategy for effectively administering anti-inflammatory therapy to patients with this symptom burden is controversial, with differing approaches recommended in various asthma guidelines (table 3) [1-3]. Patient education and shared decision-making play a crucial role in choice of therapy, as adherence to an anti-inflammatory regimen is a particular challenge due to large fluctuations in symptom intensity.

Common approaches — For patients with frequent but not daily asthma symptoms, we recommend using a regimen that includes low-dose inhaled glucocorticoids to relieve bronchial inflammation, preferably via anti-inflammatory reliever (AIR) therapy (table 4 and table 5). National and international guidelines similarly advise use of inhaled glucocorticoids as the preferred therapy in patients with mild persistent asthma, but they differ in the specific medication choices and dosing strategies (table 3) [1-3]. The differences in approach are at least in part related to local regulatory approval and availability of medications, but patient factors may contribute.

Daily use of a low-dose inhaled glucocorticoid has been recommended for treatment of mild asthma for approximately 30 years [1]. A major shortcoming of this approach is poor patient adherence, with fewer than 50 percent of patients renewing their prescribed inhaled glucocorticoid on a regular basis. Among the barriers to regular use are the cost, patient fear of medication dependence and long-term side effects, common adverse effects (including thrush and dysphonia), and lack of any immediate symptomatic improvement after each dose. Poor adherence is likely the primary reason that AIR (table 5) is efficacious compared with regular controller therapy — patients frequently only take their medication when they have symptoms, and short-acting beta-agonist (SABA) reliever therapy alone does not treat the inflammation driving poor asthma control.

Based on these concerns, we agree with the Global Initiative for Asthma (GINA) [3], which prefers symptom-guided ("as needed") use of a combination low-dose glucocorticoid and a fast-acting beta-agonist inhaler for this patient group (table 4). For medication-adherent patients without variable symptoms and at low risk for exacerbation (table 1), scheduled low-dose inhaled glucocorticoids with a SABA reliever is also reasonable.

Anti-inflammatory reliever (AIR) therapy (preferred) — In patients with frequent but not daily asthma who are poorly compliant with daily medication use, at high risk of severe exacerbations (table 1), or whose asthma severity tends to vary significantly throughout the year, we suggest as-needed AIR rather than scheduled inhaled glucocorticoids or other alternative options. In general, these therapies have been shown to provide similar relief of symptoms and exacerbations compared with scheduled inhaled low-dose glucocorticoids and a lower mean daily ICS dose; ICS-formoterol further improved severe exacerbation rates in some trials [14,15,17-19].

As-needed low-dose ICS-formoterol (step 2) — The strongest evidence in support of as-needed combination inhaled glucocorticoid-formoterol (off-label in the United States) is based on four randomized trials that found this strategy to be as effective as daily inhaled glucocorticoid (plus a SABA as needed) in preventing severe attacks requiring systemic steroids, while at the same time reducing the annualized dose of inhaled glucocorticoids [14,15,17,18].

Additional advantages to this approach include avoidance of scheduled medication use in the absence of symptoms and ability to use only one inhaler rather than two devices.

However, in these studies, daily inhaled glucocorticoids were equally effective in preventing asthma attacks in general (when including attacks not considered severe) and mildly more effective than combination budesonide-formoterol taken as needed in improving patient-reported symptoms. Importantly, it is possible that patients who are "under-perceivers" and do not recognize worsening airflow obstruction based on their symptoms will underutilize anti-inflammatory glucocorticoids when utilizing this as-needed approach to medication administration. On the other end of the spectrum, "high-perceivers" may be highly sensitive to airway stimuli and overuse their reliever, putting them at risk of inhaled glucocorticoid side effects if using AIR. It is essential to tailor the approach to treatment based on individual patient characteristics.

●Dosing and adverse effects – The pivotal trials of AIR used budesonide-formoterol 200 mcg/6 mcg per inhalation, taken one inhalation as needed. Comparable dosing can be achieved with combined budesonide-formoterol by MDI, 160 mcg/4.5 mcg per inhalation, taken one inhalation as needed; or combined budesonide-formoterol by MDI, 80 mcg/4.5 mcg per inhalation, taken two inhalations as needed (table 5). While this dosing is off-label in the United States, it is supported by international guidelines and clinical trials [3].

Other inhaled glucocorticoids, including mometasone, fluticasone, and beclomethasone, have also been paired with formoterol, and can likely be used in equipotent doses with comparable results.

ICS-long-acting beta-agonist (LABA) combination inhalers containing LABAs other than formoterol (eg, fluticasone-salmeterol) cannot be used as anti-inflammatory relievers because they do not result in bronchodilation rapidly enough to give immediate symptomatic relief.

Adverse effects of AIR are similar to those seen in step 1 patients. (See 'As-needed low-dose ICS-formoterol (step 1)' above.)

●Efficacy compared with scheduled inhaled glucocorticoid plus SABA reliever – Several trials and systematic reviews have examined whether patients with frequent but not daily symptoms can be managed with as-needed ICS-formoterol rather than scheduled inhaled glucocorticoids and as-needed SABA [14,15,17-23]. In general, these trials have shown equivalent or improved exacerbation rates with slightly inferior daily symptoms scores with the as-needed regimen.

•One meta-analysis of four studies and more than 8000 patients with mild asthma demonstrated that ICS-formoterol compared favorably with scheduled low-dose glucocorticoid plus SABA therapy in terms of exacerbation rate (65 versus 81 per 1000 patients per year, odds ratio [OR] 0.79, 95% CI 0.59-1.1), although the result may be consistent with no difference [19]. Severe exacerbations leading to hospital admission, emergency department, or urgent care visits were rare but less frequent in the ICS-formoterol group (12 versus 19 per 1000 patients per year, OR 0.63, 95% CI 0.44 to 0.91). Inhaled glucocorticoid exposure was 20 to 60 percent lower in the ICS-formoterol group; asthma symptom scores were slightly higher with as-needed therapy, but not by a clinically significant amount.

•One trial (SYGMA 1) randomly assigned 2559 participants ages 12 years and older with mild (GINA step 2) asthma to twice-daily placebo plus budesonide-formoterol (200 mcg /6 mcg ) as needed; or budesonide 200 mcg twice daily plus terbutaline as needed [17]. After 52 weeks, the mean percentage of weeks with well-controlled asthma per patient with as-needed budesonide-formoterol was inferior to budesonide maintenance (44 percent versus 24 percent, OR 0.64, 95% CI 0.57-0.73). The annual rate of severe exacerbations (requiring systemic glucocorticoids) was similar between the two budesonide treatment groups (6 percent for budesonide-formoterol versus 6.9 percent for budesonide alone; relative rate [RR] 0.83, 95% CI 0.59-1.16). The median daily dose of inhaled glucocorticoid in the budesonide-formoterol group was 17 percent of the dose in the scheduled twice-daily budesonide group.

•A separate randomized trial (SYGMA 2) compared budesonide-formoterol (200 mcg/6 mcg) as needed, with scheduled budesonide 200 mcg twice daily and a SABA reliever in 4176 participants with mild (GINA step 2) asthma who were 12 years of age or older [18]. After 52 weeks, budesonide-formoterol was noninferior to daily budesonide for severe exacerbations (0.11 versus 0.12 exacerbations/year, annualized RR 0.97, with upper side of 95% confidence limit of 1.16). The time to first exacerbation was also equivalent between the groups, but symptom control (Asthma Control Questionnaire-5) slightly favored budesonide maintenance (by 0.1 units).

As-needed low-dose ICS and SABA (step 2) — This approach mimics the as-needed use of ICS-formoterol, described above, substituting a more conventional SABA, such as albuterol, for the long-acting formoterol [20,24-26]. The 2020 Focused Updates of the National Asthma Education and Prevention Program (NAEPP) embraced the as-needed use of an inhaled glucocorticoid and SABA as a therapy for mild persistent asthma [2], but the practicality of this approach has been hampered until recently by the lack of widespread availability of combination ICS-SABA inhalers. To employ this approach without a combination inhaler, two separate inhalers need to be available to be used one after the other when symptoms occur. Such a strategy poses considerable concern regarding patient adherence.

●Dosing and availability – Combination glucocorticoid-albuterol inhalers are increasingly available in many parts of the world. Albuterol-budesonide (90 mcg/80 mcg) has been approved in the United States for patients aged 18 years and older [27]. Alternatively, patients may be instructed to use low-dose inhaled glucocorticoids (table 11) concomitantly whenever albuterol is needed for asthma symptom relief.

●Efficacy compared with scheduled inhaled glucocorticoid plus SABA reliever – Two randomized trials have examined the use of as-needed low-dose ICS combined with a SABA reliever compared with scheduled low-dose ICS and as-needed SABA; one used a combination inhaler and the other two separate inhalers. Although much smaller than studies of ICS-formoterol, these trials suggest roughly similar efficacy for this intervention.

•In one trial, 455 patients with NAEPP-defined step 2 symptoms (table 3) were randomized to receive AIR (as-needed high-dose beclomethasone [250 mcg] and albuterol 100 mcg in a single inhaler) compared with as-needed albuterol reliever alone, scheduled twice-daily high-dose beclomethasone with as-needed albuterol reliever, or scheduled twice-daily high-dose beclomethasone and albuterol with as-needed albuterol reliever [24]. Compared with the scheduled beclomethasone plus SABA reliever group, patients who received AIR had a similar number of exacerbations (as determined by fall in peak flow or increased rescue inhaler use) with a decreased cumulative inhaled glucocorticoid dose. However, AIR led to fewer symptom-free days and less improvement in asthma symptoms after six months.

•Another trial of 342 patients compared AIR (beclomethasone 80 mcg and albuterol 180 mcg) with a separate SABA reliever plus regular low-dose inhaled glucocorticoid therapy (beclomethasone 80 mcg), adjusted by physician or biomarker assessment [26]. There was no difference in the rate of clinical asthma worsening (treatment failure) between the different groups, but the AIR group used approximately half the cumulative dose of glucocorticoids. Exacerbations were relatively uncommon and statistically similar between the groups (0.12 exacerbations/year [97.5% CI 0.03-0.21] for AIR versus 0.21 exacerbations/year [97.5% CI 0.10-0.32] for the physician-adjusted low-dose inhaled glucocorticoids).

Scheduled low-dose inhaled glucocorticoids with a reliever — For patients who cannot receive AIR or who are at very low risk for exacerbations (table 1), scheduled low-dose inhaled glucocorticoids with a separate reliever (table 11) is a reasonable alternative to AIR (table 4). (See "An overview of asthma management".)

●Patient education – When using daily inhaled glucocorticoid and a separate SABA reliever, patient education is crucial to convey an understanding of the distinct roles of the two different inhalers: the inhaled glucocorticoid is to be taken every day but has no immediate symptomatic benefit; the SABA reliever provides immediate symptom relief and should be kept on-hand at all times, but it is to be used only as needed when symptoms develop (or prior to exercise). In particular, patients need to know that frequent use of the SABA reliever (eg, needing it every four hours) is a sign of worsening asthma control that requires additional steps to prevent exacerbations and further symptomatic deterioration. This should be part of each patient's asthma action plan, but also needs to be emphasized during in-person discussions. (See 'Asthma education for patients initiating therapy' above.)

●Dosing and adverse effects – The initial dose of inhaled glucocorticoids for mild persistent asthma should be in the low-dose range [1,2]. The usual starting dose and the different types of inhaled glucocorticoids are shown in the low-dose column in the table (table 11). Among the low-dose inhaled glucocorticoids, mometasone and fluticasone furoate are approved for once-daily dosing. The other inhaled glucocorticoids have traditionally been administered twice daily, although it is likely that they can be used once daily in many patients with mild asthma, which might improve compliance [28,29]. Inhaled glucocorticoids are available via metered-dose inhaler (MDI), breath-actuated MDI, dry powder inhaler, and as a solution (budesonide) for nebulization (table 11). (See "Delivery of inhaled medication in adults" and "The use of inhaler devices in adults".)

Oral candidiasis and dysphonia (hoarse voice) may occur with inhaled glucocorticoids, but long-term adverse effects are rare. We recommend rinsing of the mouth after scheduled doses of inhaled glucocorticoids. In patients with a history of recurrent thrush, ciclesonide, if available and affordable, may be an appealing option since it is not converted to the active form until it reaches the airway epithelium, minimizing the risk of thrush and other systemic effects. Additional local and systemic side effects of inhaled glucocorticoids, as well as strategies for minimizing them, are discussed in detail separately. (See "Major side effects of inhaled glucocorticoids" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

●Efficacy compared with SABA alone – Regular treatment with inhaled glucocorticoids reduces the frequency of symptoms (and the need for inhaled bronchodilators), improves overall quality of life, and decreases the risk of serious exacerbations for patients with asthma [30-37]. In addition, by reducing airway inflammation, this therapy reduces bronchial hyperresponsiveness, thereby ameliorating the exaggerated sensitivity to triggers of asthma [30]. Representative studies demonstrating the efficacy of inhaled glucocorticoids include the following [30-36,38]:

•A multicenter, double-blind trial randomly assigned over 7000 patients with mild persistent asthma to treatment with low-dose inhaled budesonide (400 mcg once daily) or placebo for three years [31]. Early initiation of budesonide was associated with a lower risk of a severe asthma exacerbation during the study period compared with placebo (3.2 versus 5.5 percent; hazard ratio 0.56, 95% CI 0.45-0.71). Patients who were treated with budesonide demonstrated better pulmonary function and experienced fewer days with symptoms [31,39].

•A second trial randomly assigned 103 patients with recent-onset mild asthma to either high-dose budesonide (600 mcg twice daily) or terbutaline (375 mcg twice daily); both groups used terbutaline (250 mcg/puff) as needed [32]. At one- and two-year follow-up, budesonide therapy was associated with a greater increase in morning peak expiratory flow (PEF; 32.8 versus 4.8 L/min with terbutaline), fewer asthma symptoms, and decreased need for supplemental dosing of SABA.

Not all patients with step 2 asthma are responsive to inhaled glucocorticoid therapy. Studies suggest that up to 35 to 40 percent of patients may not experience improvements in asthma control, forced expiratory volume in one second (FEV₁), or bronchial responsiveness [40-42]. In some studies, patients with mild asthma who smoke cigarettes appear relatively resistant to the effects of low-dose inhaled glucocorticoids, although this has not been confirmed in all studies [43-46]. The optimal choice of medications for treating asthma in patients who continue to smoke has not been determined. Additional study of response to asthma pharmacotherapy based on asthma phenotype may provide useful alternative approaches for this patient group.

Alternative approach: leukotriene receptor antagonists (LTRAs) plus SABA — LTRAs are considered alternative treatment choices for mild persistent asthma (table 4 and table 12) [1,3]. Despite the convenience of these agents (orally administered and once- or twice-daily dosing), inhaled glucocorticoids remain the preferred option when initiating long-term controller therapy in mild persistent asthma because of their greater and more consistent efficacy [1-3]. (See "Antileukotriene agents in the management of asthma".)

Clinical trials in patients with mild to moderate asthma have demonstrated that zafirlukast and montelukast induce persistent bronchodilation and improve symptoms [47,48]. In addition, these drugs decrease the need for rescue use of SABA inhalers and, in some studies, protect against acute asthmatic exacerbations requiring oral glucocorticoids. Relative to inhaled medications, adherence is high with oral medications administered only once or twice daily [49].

The leukotriene-modifying agents, however, are generally less effective than inhaled glucocorticoids [41,50,51]. As an example, one randomized trial of 451 patients found that those treated with low-dose inhaled fluticasone had significantly greater improvements in lung function, more symptom-free days, and less use of rescue medications than patients treated with zafirlukast [50]. On the other hand, when the greater efficacy of inhaled glucocorticoids is balanced against the greater compliance with oral medication, the two types of medications appear to achieve similar outcomes in "real-world" practice [52]. However, AIR has not been compared to LTRAs directly in clinical trials.

It appears that some people with asthma respond well to the leukotriene-blocking drugs, whereas others do not. These differences likely relate to variability among patients in the relative contribution of leukotriene overexpression to the pathogenesis of their asthma, possibly due to genetic polymorphisms in leukotriene synthesis pathways [53]. There is no evidence to suggest that the presence of atopic asthma (ie, asthma with clear allergic sensitivities) responds more favorably to LTRAs than nonatopic asthma.

●Patient selection – In our experience, a one-month therapeutic trial of LTRAs is most helpful for step 2 patients in the following settings:

•Among patients with step 2 asthma and allergic rhinitis, use of an LTRA may simultaneously treat both processes. LTRAs are effective in the treatment of seasonal and perennial allergic rhinitis, with an efficacy comparable to second-generation antihistamines, but substantially inferior to intranasal glucocorticoids. (See "Pharmacotherapy of allergic rhinitis", section on 'Therapies requiring caution'.)

•When exercise-induced bronchospasm is a prominent feature, an LTRA can be used to prevent exercise-induced symptoms. Chronic use of LTRAs for prevention of exercise-induced bronchoconstriction can be helpful in those with frequent exercise to help prevent loss of SABA bronchoprotective effects over time (tachyphylaxis) due to overuse [54]. (See "Exercise-induced bronchoconstriction", section on 'Prolonged or recurrent exercise'.)

•Patients with asthma and aspirin-exacerbated respiratory disease overproduce leukotrienes at baseline as well as in response to ingestion of aspirin or any nonsteroidal anti-inflammatory drug (NSAID). Use of a leukotriene modifier in this context makes biologic sense and may improve overall asthma control. It does not make ingestion of aspirin or NSAIDs safe for these patients. (See "Aspirin-exacerbated respiratory disease".)

●Availability and dosing – The LTRAs in use in the United States are zafirlukast, typically dosed at 20 mg once daily, and montelukast, typically dosed at 10 mg once daily (table 12). Montelukast has a boxed warning from the US Food and Drug Administration (FDA) about serious neuropsychiatric effects including suicidal ideation and action, so should be used with particular caution in patients with mental health issues, especially preexisting depression. Although these side effects are rare, we recommend informing patients and stopping the medication if they note any mood changes. In our experience, when patients are educated about the possibility of side effects, montelukast is generally well-tolerated and safe. Zileuton, which inhibits 5-lipoxygenase and thus production of leukotrienes B4, C4, D4, and E4, is generally reserved for more severe asthma due to its greater cost and potential for adverse effects (eg, hepatic inflammation and drug-drug interactions). Dosing and adverse effects of LTRAs are discussed separately. (See "Antileukotriene agents in the management of asthma", section on 'Clinical use of leukotriene-modifying drugs in asthma' and "Antileukotriene agents in the management of asthma", section on 'Adverse effects'.)

PATIENTS WITH DAILY SYMPTOMS (STEP 3) — Maintenance inhaled glucocorticoids, generally in combination with maintenance long-acting beta-agonists (LABAs), are the mainstay of therapy for patients with daily asthma symptoms, impaired baseline lung function, or frequent nocturnal awakenings (table 4).

Preferred options — When initiating step 3 therapy, either of two approaches (ie, low-dose inhaled corticosteroids [ICS]-formoterol as maintenance and reliever therapy [MART] (table 8) or low-dose inhaled glucocorticoids plus LABA with a short-acting beta-agonist [SABA]-containing reliever) is advised by national and international guidelines (table 3) [1,3]; MART is preferred due to both ease of use and evidence of increased efficacy.

Several randomized, prospective studies demonstrate that maintenance inhaled glucocorticoids (aka, ICS) improve lung function, diminish symptoms, decrease need for SABAs, and improve airway responsiveness to methacholine in patients with all levels of asthma severity [30,32,55-57]. Observational data also suggest that inhaled glucocorticoids diminish hospitalizations and mortality from asthma [34,58,59].

Despite historical concern, several safety trials have demonstrated that ICS-LABA combination inhalers do not significantly increase the risk of serious asthma-related side effects compared with inhaled glucocorticoids alone [60]. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Long-term maintenance therapy with LABAs'.)

Given the widespread agreement that LABAs should only be used in combination with inhaled glucocorticoids to treat asthma [61,62], the use of ICS-LABA inhalers (eg, budesonide-formoterol, mometasone-formoterol, fluticasone-salmeterol, fluticasone furoate-vilanterol) is a practical way to ensure that patients do not omit the inhaled glucocorticoids [63-66]. Each combination is available in several strengths that contain a differing amount of inhaled glucocorticoids (table 6). The use of these combination inhalers eliminates the possibility of using LABAs as monotherapy and therefore improves patient safety, although precise titration of the inhaled glucocorticoid dose is somewhat limited with these devices. (See "Delivery of inhaled medication in adults".)

The rapid onset of action of the LABA formoterol allows it to be used as a reliever medication like SABAs. Other LABAs do not have a sufficiently rapid onset to be used in this manner and have not been studied for use as relievers. For step 3 and step 4 patients, ICS-formoterol combination inhalers can be used for MART (table 8), a parsimonious approach that simplifies patient regimens and has been shown to improve outcomes. (See 'Low-dose maintenance and reliever therapy (MART)' below and 'Medium-dose maintenance and reliever therapy (MART), preferred' below.)

Low-dose maintenance and reliever therapy (MART) — The use of a single ICS-formoterol combination inhaler as both controller and reliever therapy (ie, MART) (table 8) has been compared with an ICS-LABA inhaler as controller and a separate SABA as rescue in a number of studies [67-72]. In aggregate, MART reduces the risk of asthma exacerbations by approximately 35 percent (eg, 22 versus 16 percent per year) and may also improve asthma control. Combination low-dose ICS-formoterol as MART is considered preferred step 3 therapy by international guidelines (table 6) [3]. In the United States this approach is not approved by the US Food and Drug Administration (FDA) and insurance coverage varies, which may limit access.

●Dosing and adverse effects – Most trials of MART used low- or medium-dose budesonide-formoterol (eg, 80 mcg/4.5 mcg/inhalation, two inhalations twice daily and as needed). Only formoterol, which has a rapid onset of action compared with other LABAs can be used in combination with glucocorticoids for MART. Although less well-studied, any low-dose ICS-formoterol combination therapy (off-label; eg, beclomethasone-formoterol) is reasonable for step 3 patients (table 8). Oral candidiasis and dysphonia (hoarse voice) may occur with the use of low-dose inhaled glucocorticoids, but long-term adverse effects are rare. We recommend rinsing of the mouth after scheduled doses. Additional local and systemic side effects of inhaled glucocorticoids, as well as strategies for minimizing them, are discussed in detail separately. (See "Major side effects of inhaled glucocorticoids" and "Clinical features and evaluation of glucocorticoid-induced osteoporosis".)

●Efficacy compared with ICS-LABA plus a SABA reliever – A meta-analysis of 21 trials (18 of which included patients with step 3 indications) concluded that MART reduced the risk of severe exacerbation by 27 to 50 percent compared with other controller-reliever strategies [73]. For example, in one study, ICS-formoterol MART led to fewer patients with severe exacerbations compared with maintenance ICS-formoterol and either terbutaline or formoterol alone as reliever therapy (13 percent versus 22 percent or 17 percent, respectively) [68]. Other trials have also demonstrated improvements in exacerbation risk [69,70], but evidence regarding assessment of asthma symptoms and percentage of asthma control days was mixed. Improvements in exacerbations and total glucocorticoid exposure have also been observed in practice outside of the clinical trial setting [74].

Low-dose ICS-LABA, with a reliever — If low-dose MART is not an option, combination inhalers delivering low-dose ICS-LABA (table 6) are more effective than higher doses of inhaled glucocorticoids for asthma control in most patients, as demonstrated in several randomized trials [75-81].

As an example, in a double-blind study, 429 patients who were symptomatic on low-dose inhaled beclomethasone (200 mcg twice daily) were randomly assigned to receive either increased beclomethasone (500 mcg twice daily) or the combination of salmeterol (50 mcg twice daily) plus beclomethasone (200 mcg twice daily) [76]. Although both treatments resulted in improvement over baseline, the addition of salmeterol yielded a greater decrease in symptoms and beta-agonist use, improvement in morning peak flow, and reduction in peak flow variability. Furthermore, the addition of LABAs may allow for lowering of the inhaled glucocorticoid dose.

Reliever options include anti-inflammatory reliever (AIR) therapy (using low-dose ICS and SABA) or a SABA alone. AIR has been demonstrated to improve the rates of severe exacerbations, but AIR may be more difficult to obtain and for patients to use effectively. (See 'Reliever options for those not on MART' below.)

Alternative options — Although there are several alternative approaches to step 3 level treatment (table 3), for patients initiating therapy for daily asthma symptoms, frequent nocturnal awakenings, or impaired lung function, the primary alternative considerations are medium-dose inhaled glucocorticoids or combined low-dose inhaled glucocorticoids plus a leukotriene modifying agent or long-acting muscarinic antagonist (LAMA).

Medium-dose inhaled glucocorticoids with a reliever — Medium-dose inhaled glucocorticoids (table 11) may be an effective therapy for patients with daily asthma symptoms, but we typically use this approach only for patients who have known side effects or other intolerance of beta-agonists given the demonstrated inferiority of medium-dose ICS compared with ICS-LABA at the population level [2,3]. (See 'Low-dose ICS-LABA, with a reliever' above.)

Reliever options include an AIR strategy or a SABA alone. (See 'Reliever options for those not on MART' below.)

Low-dose inhaled glucocorticoid, antileukotriene, and reliever — Although the use of low-dose ICS-LABA is generally better than the use of leukotriene modifying agents, some patients may be more likely to benefit from leukotriene therapy than the general asthma population. In our experience, the most likely to benefit include those with concomitant allergic rhinitis, prominent exercise-induced bronchoconstriction, or aspirin-exacerbated respiratory disease. Poor control after a one-month trial of this combination should prompt an alternative strategy. (See 'Alternative approach: leukotriene receptor antagonists (LTRAs) plus SABA' above.)

●Dosing and adverse effects – Leukotriene-modifying agents include the leukotriene receptor antagonists (LTRAs), zafirlukast (Accolate) and montelukast (Singulair), and the 5-lipoxygenase inhibitor zileuton (Zyflo) (table 12). The usual doses for adolescents and adults are 10 mg once daily for montelukast, 20 mg once daily for zafirlukast, and 225 mg twice daily for zileuton. Montelukast has a boxed warning from the FDA related to serious neuropsychiatric events including suicidal thoughts or actions, so it should be used with caution in patients with mental health issues. The black-box warning should not be taken as an absolute contraindication to montelukast in patients with neuropsychiatric disease. In our experience, when patients are educated about the possibility of side effects, and know to stop it if they experience these, it is generally well-tolerated and safe. The mechanisms of action and safety of these agents and the need for monitoring with the use of zileuton are discussed separately. (See "Antileukotriene agents in the management of asthma".)

●Efficacy as an add-on agent to inhaled glucocorticoids compared with LABA – A systematic review (18 trials with 7208 participants) found that adding a LABA to inhaled glucocorticoids, compared with adding an LTRA, reduced the risk of exacerbations requiring systemic glucocorticoids from 13 to 11 percent (relative risk [RR] 0.87, 95% CI 0.76-0.99) [82]. LABA use was also associated with improved pulmonary function and (to a lesser extent) reduced symptoms and rescue medication use.

Reliever options include an AIR strategy or SABA alone. (See 'Reliever options for those not on MART' below.)

Low-dose ICS plus a long-acting muscarinic antagonist (LAMA) — In patients who are known to be intolerant of beta-agonists, use of a LAMA in addition to low-dose inhaled glucocorticoids likely provides a similar effect as a LABA, although combination inhalers are not available. Due to concerns about a possible increased risk of hospitalization in one trial [83] and the decreased ease of use due to lack of combination inhalers, ICS-LABA is generally preferred to LAMA plus inhaled glucocorticoids.

●Dosing and adverse effects – Although other antimuscarinics may have similar effect (off-label in the United States), tiotropium is the best studied agent and is FDA-approved (as a soft mist inhaler) for the treatment of asthma at a dose of 1.25 mcg/inhalation, two inhalations once daily. Dry mouth was the only adverse effect commonly seen in asthma trials, although there is a small risk of urinary retention as well.

●Efficacy as add-on therapy to ICS compared with LABA – Data from randomized trials suggest that the addition of LAMA to low- and medium-dose inhaled glucocorticoids are generally equivalent to LABA in terms of reduction in exacerbations and improvements in asthma control and quality of life [84-86]. One trial raised concern about increased asthma hospitalizations in those treated with ICS-LAMA compared with ICS-LABA [83], although the exact risk of LAMA compared with LABA was uncertain, and other trials have supported safety relative to placebo [87,88].

Reliever options for those not on MART — Evidence supports the use of AIR for patients with daily asthma symptoms to prevent severe exacerbations. In those for whom MART is not an option (ie, they are unable to obtain an ICS-formoterol inhaler or cannot obtain adequate supply per month for reliever use), AIR can be delivered by either a combination albuterol-ICS reliever or by using low-dose inhaled glucocorticoids whenever an as-needed SABA is used.

Two trials have evaluated albuterol-ICS or albuterol plus inhaled glucocorticoids as-needed in patients with poorly controlled moderate to severe asthma. Compared with usual care, these AIR strategies reduced the annualized relative rate of severe exacerbations by approximately 15 to 25 percent, or 0.15 exacerbations per person per year in the populations studied [16,89]. This primary effect size is robust, but somewhat smaller than that seen in meta-analyses of MART. (See 'Low-dose maintenance and reliever therapy (MART)' above.)

Aside from the possibly smaller effect size, the largest disadvantage relative to formoterol-ICS for rescue therapy is the potential need for multiple rescue inhalers. With increasing availability of combination ICS-SABA inhalers, including FDA approval in the United States [27], AIR is more feasible for patients on maintenance regimens that do not include formoterol.

PATIENTS WITH DAILY ACTIVITY LIMITATIONS (STEP 4) — Patients presenting with daily limitations in activity due to asthma symptoms, daily nocturnal symptoms, or an acute exacerbation of asthma require urgent initiation of controller therapy (table 4). For most of these patients, a course of systemic glucocorticoids is appropriate, along with concomitant initiation of maintenance therapy including medium-dose inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) and long-acting beta-agonists (LABAs).

Achieving the usual goals of asthma treatment (prevention of chronic and troublesome symptoms, normalization of pulmonary function, maintenance of normal activity levels, prevention of exacerbations, improvement in health-related quality of life, and minimization of adverse effects of pharmacotherapy) may not be fully possible in patients with asthma of this severity, particularly if it is longstanding. It may be necessary to accept some degree of reduced activity and persistent airflow limitation, and to focus instead on reducing the frequency and severity of exacerbations and hospitalizations, avoiding further loss of pulmonary function and limiting toxicity from medications.

Oral glucocorticoid pulse with maintenance therapy initiation — Most patients who are not on any controller medication and meet criteria for step 4 therapy will need a brief course of oral glucocorticoid therapy to bring their asthma under control in addition to initiation of maintenance therapy [1-3]. In deciding when to prescribe oral glucocorticoids at therapy initiation, we consider the severity of symptoms, degree of airflow limitation, and whether symptoms have been stable or worsening. In general, we prescribe a brief course of an oral glucocorticoid (eg, equivalent of prednisone 40 to 60 mg/day for five to seven days) to patients with frequent daytime or nocturnal symptoms, recent deterioration, or a forced expiratory volume in one second (FEV₁) less than 60 percent of predicted. The treatment of acute asthma exacerbations is discussed separately. (See "Acute exacerbations of asthma in adults: Home and office management".)

A re-evaluation of symptom control in two weeks is appropriate to assess the response to therapy and determine the need for longer term, low-dose oral glucocorticoid or biologic therapy versus transition to ICS-LABA alone. Reassessing lung function at the end of a course of glucocorticoids may be useful to differentiate obstruction associated with active airway inflammation from fixed obstruction due to long-term airway remodeling. However, longitudinal assessment over a longer period of time is often needed to be more certain of these results. (See "Treatment of severe asthma in adolescents and adults".)

Medium-dose maintenance and reliever therapy (MART), preferred — Although evidence is less direct in this patient group, we agree with international guidelines in preferring MART using medium doses of inhaled glucocorticoids as the initial therapeutic approach [2,3] (table 4 and table 8). In patients with daily asthma symptoms (with or without activity limitation), use of combination ICS-formoterol as both maintenance and reliever treatment appears to be more effective at preventing severe exacerbations than the same dose of ICS-LABA or higher dose ICS with only short-acting beta-agonists (SABAs) as a reliever [67-72]. This approach is off-label in the United States and insurance coverage varies, which may limit access. (See 'Low-dose maintenance and reliever therapy (MART)' above.)

Typical medium-dose MART regimens use two inhalations twice daily of a medium-dose ICS-formoterol combination (eg, budesonide 160 mcg/4.5 mcg, mometasone-formoterol 100 mcg/5 mcg, or beclomethasone-formoterol 100 mcg/6 mcg) for maintenance and one inhalation as needed as a reliever (table 8). A maximum of 12 puffs per day is recommended by regulatory agencies. Patients should be instructed to rinse after maintenance doses, and additional counseling on side effects of inhaled glucocorticoids is appropriate. (See "Major side effects of inhaled glucocorticoids".)

Due to the longer onset of action of LABAs other than formoterol, combinations of these LABAs with inhaled glucocorticoids cannot be used in this manner.

Medium-dose inhaled glucocorticoids plus LABA with a reliever — If medium-dose MART is not an option, we suggest medium-dose ICS-LABA therapy (table 6) with a separate reliever as the best alternative approach (table 4) [1,3,78]. Indirect evidence for this approach comes from studies showing increased effectiveness of adding LABA therapy compared to increasing ICS doses in patients with frequent asthma symptoms and/or frequent exacerbations [75-81].

Reliever options include anti-inflammatory reliever (AIR) therapy (with inhaled glucocorticoids and SABA) or SABA alone. AIR has been demonstrated to decrease the rate of severe exacerbations, but may be more difficult for some patients to obtain. (See 'Reliever options for those not on MART' above.)

Alternative maintenance strategies — Long-acting muscarinic antagonists (LAMAs) can likely be substituted for LABAs as add-on agents to medium-dose glucocorticoids for step 4 patients in those who are intolerant of beta-agonists, based on studies of their use as add-on agents in moderate and severe asthma. Tiotropium via soft mist inhaler is the best-studied agent, dosed at 1.25 mcg/inhalation, two inhalations daily. (See 'Low-dose ICS plus a long-acting muscarinic antagonist (LAMA)' above.)

Although previously discussed as an option in some guidelines, high-dose inhaled glucocorticoids alone are no longer recommended or used by UpToDate authors as initial therapy due to lower efficacy compared with dual-controller therapies, as well as the increased risk of adverse effects, including oral candidiasis, dysphonia, pneumonia, and the adverse cumulative dose effects of inhaled glucocorticoids. (See "Major side effects of inhaled glucocorticoids".)

Although leukotriene modifying agents in addition to medium-dose glucocorticoids may be effective in some patients [2], the variability of this response makes these agents a poor initial choice for therapy in patients with severe presenting symptoms.

PATIENTS PRESENTING WITH ACUTE EXACERBATION — Patients commonly present for initiation of asthma therapy due to or immediately following treatment for an acute asthma exacerbation. Management of acute asthma exacerbations are discussed separately. (See "Acute exacerbations of asthma in adults: Home and office management" and "Acute exacerbations of asthma in adults: Emergency department and inpatient management".)

For these patients, it is reasonable to initiate therapy based on the symptoms and pulmonary function (if known) prior to the exacerbation, as described above. All patients with a recent exacerbation should be considered at increased risk for future exacerbations and are therefore likely to benefit from anti-inflammatory reliever (AIR) therapy (table 5). (See 'Assessing symptom severity and exacerbation risk' above.)

We typically schedule interval follow-up within two to four weeks after completion of systemic glucocorticoid tapers to reassess symptoms and lung function and help ensure that the initial choice of therapy is adequate to manage symptoms. Additional aspects of follow-up monitoring are discussed below and separately. (See 'Monitoring disease control on treatment' below and "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

OTHER MEDICATIONS — Several additional therapies are available or have been previously used for asthma control or relief, but generally do not have a role in modern asthma management. (See "Ongoing monitoring and titration of asthma therapies in adolescents and adults", section on 'Medications that are avoided or rarely used'.)

MONITORING DISEASE CONTROL ON TREATMENT — The patient's level of asthma control should be assessed at each medical visit [1,3]. After initiating therapy, we typically schedule a follow-up visit within three months, earlier for those requiring maintenance therapy. Improvements in symptoms on effective therapy are usually evident within three to four weeks, so a brief telemedicine follow-up at this interval can be helpful to ensure clinical improvement.

Assessments of control should be based upon the interim clinical history (for which validated questionnaires such as the Asthma Control Test and Asthma Control Questionnaire are available (form 2)), current pulmonary function, and the patient's level of risk of future asthma exacerbations (table 2). Management of pharmacotherapy based on reassessment of asthma control is discussed in detail separately. Reviewing inhaler technique on a regular basis has also been shown to be effective in reducing exacerbation risk and improving symptom control [90]. (See "An overview of asthma management", section on 'Adjusting controller medication' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Asthma in adolescents and adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles relevant to this topic. We encourage you to print or email these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basic topics (see "Patient education: Medicines for asthma (The Basics)" and "Patient education: Inhaled corticosteroid medicines (The Basics)")

●Beyond the Basics topics (see "Patient education: Asthma treatment in adolescents and adults (Beyond the Basics)" and "Patient education: Trigger avoidance in asthma (Beyond the Basics)" and "Patient education: How to use a peak flow meter (Beyond the Basics)" and "Patient education: Inhaler techniques in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of pharmacotherapy – A basic tenet of asthma therapy is that treatment should be individualized to match the frequency and severity of asthmatic symptoms and the risk of future exacerbations. The primary goals of treatment are relief of symptoms and prevention of acute attacks. Patients can have severe and life-threatening exacerbations even if their symptoms are generally mild and infrequent. (See 'Introduction' above and 'Assessing symptom severity and exacerbation risk' above.)

●Asthma education – For patients initiating therapy, initial education should focus on explaining the role of inflammation and cause of symptoms, the concept of reliever and controller therapy, the identification and avoidance of asthma triggers, and formulation of a simple asthma action plan. (See 'Asthma education for patients initiating therapy' above.)

●Immediate access to reliever therapy – All patients with asthma should have immediate access to an inhaled bronchodilator with a rapid onset of action (eg, albuterol, albuterol-budesonide, or formoterol combined with an inhaled glucocorticoid) (table 4).

●Step 1 therapy (for those with infrequent symptoms)

•Anti-inflammatory reliever (AIR) – For patients with infrequent symptoms but risk factors for serious exacerbations (table 1) or uncertain exacerbation risk (table 4), we suggest the use of AIR (eg, as-needed budesonide-formoterol or albuterol-budesonide) (table 5) rather than short-acting beta-agonists (SABAs) alone (Grade 2B). AIR decreases risk of exacerbation even in patients with infrequent baseline symptoms. (See 'Anti-inflammatory reliever (AIR) therapy, in higher risk patients' above.)

•Short acting beta-agonists (SABA) – For patients with infrequent symptoms (table 4) and without risk factors for serious exacerbations (table 1), use of as-needed SABAs (table 10) rather than other agents is a reasonable alternative. (See 'Short-acting beta-agonists (SABAs) for quick relief, in low-risk patients' above.)

●Step 2 therapy (frequent but not daily symptoms or infrequent symptoms with frequent exacerbations) – For patients with more frequent but not daily asthma symptoms or infrequent symptoms with frequent exacerbations (table 4), we recommend using a regimen that includes a low-dose inhaled glucocorticoid rather than bronchodilator therapy alone (Grade 1B). (See 'Patients with frequent but not daily symptoms (Step 2)' above.)

•For step 2-qualifying patients (table 4) who are poorly adherent with daily medication use, at high risk of severe exacerbations (table 1), or whose asthma severity tends to vary significantly throughout the year, we suggest AIR (table 5) rather than scheduled inhaled glucocorticoid or other alternative options (Grade 2C).

•For the remaining patients, we suggest either AIR or scheduled low-dose inhaled glucocorticoid therapy (table 11) with a reliever rather than higher doses of inhaled glucocorticoids or leukotriene receptor antagonists (LTRAs) plus a SABA reliever (table 4) (Grade 2C). (See 'Scheduled low-dose inhaled glucocorticoids with a reliever' above and 'Anti-inflammatory reliever (AIR) therapy (preferred)' above.)

●Step 3 therapy (patients with daily symptoms) – For patients with daily symptoms, frequent nocturnal awakening, or significant baseline airway obstruction (table 4), we suggest initiating a regimen that includes maintenance inhaled glucocorticoids combined with a long-acting beta-agonist (LABA), rather than inhaled glucocorticoids alone or combined with an antileukotriene (Grade 2B).

•Among ICS-LABA inhalers, we use ICS-formoterol as single-inhaler combination maintenance and reliever therapy (MART) when available, as this simple regimen improves adherence, has been shown to reduce asthma exacerbations and may improve asthma control. Only ICS-formoterol combinations can be used for MART. Other low dose ICS-LABA combination therapies are appropriate in these patients if MART cannot be used. (See 'Preferred options' above.)

•For patients qualifying for initiation of step 3 (or step 4) therapy (table 4), we suggest the use of AIR for reliever therapy (table 5) rather than SABA alone (Grade 2B) to prevent severe exacerbations. For those receiving MART, the ICS-formoterol is an AIR. For the remainder, AIR can be delivered by either combination albuterol-ICS or use of inhaled glucocorticoids whenever a SABA is used. (See 'Reliever options for those not on MART' above.)

●Step 4 therapy (patients with daily activity limitation or severe airway obstruction) – For patients not on controller therapy who present with daily activity limitation or severe airway obstruction, we suggest a five- to seven-day course of oral glucocorticoids (eg, 40 mg of prednisone, daily) (Grade 2C) to more rapidly bring their asthma symptoms under control. For accompanying controller therapy, we suggest medium-dose ICS-LABA (table 6) rather than other controller therapy (Grade 2C), preferably via ICS-formoterol MART (table 8). Medium-dose ICS combined with a different LABA is the most reasonable alternative. (See 'Patients with daily activity limitations (Step 4)' above.)

Reliever therapy should be approached as in step 3 patients. (See 'Reliever options for those not on MART' above.)

●Monitoring asthma and adjusting therapy – The patient's asthma control should be reassessed at each asthma-related medical visit (table 2). Return visits should also allow for ongoing patient/family education. Management of pharmacotherapy based on reassessment of asthma control is discussed in detail separately. (See "An overview of asthma management", section on 'Adjusting controller medication' and "Ongoing monitoring and titration of asthma therapies in adolescents and adults".)