Ongoing monitoring and titration of asthma therapies in adolescents and adults

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

For patients using pharmacologic therapy for asthma, treatment should be adjusted based on symptom control, future risk of exacerbations, adverse effects of therapy, and patient preference. Ongoing monitoring of asthma control and subsequent management of pharmacologic therapy for adolescents and adults will be covered here. Our approach is generally consistent with the "2020 Focused Updates to the Asthma Management Guidelines: A Report from the National Asthma Education and Prevention Program (NAEPP) Coordinating Committee Expert Panel Working Group" [1,2] and guidelines published by the Global Initiative for Asthma (GINA) [3].

An overview of asthma management, initiation of asthma therapy, the management of poorly controlled asthma, and the management of asthma exacerbations are covered elsewhere.

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

●(See "Initiating asthma therapy and monitoring 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 touched on in this discussion, nonpharmacological and allergy-based interventions for 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".)

●(See "Sublingual immunotherapy for allergic rhinitis and conjunctivitis: SLIT-tablets", section on 'Impact on asthma'.)

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".)

ASSESSMENT OF ASTHMA CONTROL, EXACERBATION RISK, AND SEVERITY — The patient's level of asthma control should be assessed at every visit [1,3]. Symptom control should be based on interim clinical history for which validated questionnaires such as the Asthma Control Test (form 1) and Asthma Control Questionnaire are available [4]. Appropriate titration of therapy also requires an evaluation of the risk for future asthma exacerbations and adverse effects of therapy. Asthma severity is defined (retrospectively, after titrating therapy) by the minimum effective regimen needed to achieve good control.

Asthma symptom control — Good asthma symptom control is generally defined using patient retrospective assessment over the past four weeks and includes (table 1 and form 1):

●Daytime asthma symptoms less than two days a week

●Two or fewer nocturnal awakenings per month

●Use of short-acting beta-agonists (SABAs) relievers less than two days a week

●No interference with normal activities

Direct questioning is important for assessment of symptom control since many patients may not volunteer less severe symptoms without being prompted. For patients on anti-inflammatory reliever (AIR) therapy containing an inhaled glucocorticoid (aka, inhaled corticosteroid [ICS]) in addition to a fast-acting beta agonist, daytime symptoms and reliever use more than two days a week (but less than daily) may be acceptable if the disease is otherwise well controlled (ie, the patient is undertaking normal activity without nocturnal awakenings or exacerbations).

Risk factors for exacerbations and adverse effects — Exacerbation risk should be evaluated separately, even in patients who otherwise have good asthma control (table 1) [1,3]. 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]. In addition to poor symptom control, independent risk factors for exacerbations include (table 2):

●A history of ≥1 exacerbations in the previous year

●A history of intubation or intensive care unit management of asthma exacerbation

●High SABA use (especially >200-doses per month or three 200-dose canisters per year)

●Poor adherence to controller therapies

●Incorrect inhaler technique

●Smoking

●Comorbidities, including obesity, chronic rhinosinusitis, gastroesophageal reflux disease (GERD), or confirmed food allergies

●Exposures to allergens, air pollution, or other known triggers

●Persistently low lung function, particularly if there is high reversibility

●High type 2 inflammatory markers (blood or sputum eosinophils, fraction of exhaled nitric oxide [FE_NO])

Additional discussion regarding risk factors for severe disease can be found elsewhere. (See "Identifying patients at risk for fatal asthma", section on 'Identifying high-risk patients'.)

Use of type 2 inflammatory markers to adjust therapy in nonsevere asthma is controversial. Systematic reviews have found mixed evidence regarding the use of FE_NO to guide asthma therapy [7-11], and routine monitoring is not recommended by national and international guidelines [2,3]. In our experience, some individuals have highly elevated type 2 markers prior to treatment as well as when their asthma is poorly controlled. In such patients, low levels of type 2 markers may suggest an alternative explanation for new symptoms, whereas high markers may suggest poor adherence to therapy or worsening airway inflammation. We incorporate this data into our patient assessment when it is available. In other patients, type 2 inflammation is not a prominent feature and does not correlate well with disease control. (See "Exhaled nitric oxide analysis and applications".)

We often repeat measurements of spirometry (and type 2 inflammatory markers, if monitored) three to six months after changes in therapy and otherwise every one to two years. These objective studies are particularly helpful in those with poor or worsening asthma control in order to assess the severity of disease and to evaluate for comorbidities (such as allergic bronchopulmonary aspergillosis) and alternative diagnoses (such as chronic obstructive pulmonary disease [COPD]). (See "Overview of pulmonary function testing in adults", section on 'Clinical use of pulmonary function tests' and "Exhaled nitric oxide analysis and applications", section on 'Use in other respiratory diseases'.)

Improvement or normalization of lung function is a secondary goal of asthma treatment. Although it is an objective measure that often correlates with symptom control, it is not a patient-based outcome, and normalization may not always be possible.

In addition to assessment of exacerbation risk, we assess the risks associated with treatment by evaluating adverse medication effects of beta-agonists as well as the degree of ongoing glucocorticoid exposure. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Adverse effects' and "Antileukotriene agents in the management of asthma", section on 'Adverse effects' and "Major side effects of inhaled glucocorticoids".)

Classification of asthma severity — Guideline-based classification of asthma severity uses retrospective definitions that may be confusing to patients and clinicians. The Global Initiative for Asthma (GINA) and an American Thoracic Society (ATS) research committee have questioned the distinction previously made between "intermittent" and "persistent" asthma as lacking in biologic basis and evidence [3,12]. This dichotomy may have provided false reassurance that patients with infrequent symptoms were at low risk of exacerbations. These issues, among others, have led to the following recommended definitions of asthma severity [3,12-14]:

●Mild asthma – Defined by minimal symptoms and minimal risk of exacerbations (table 1) in patients not on therapy, using reliever therapy alone, or using low-dose inhaled glucocorticoids With reliever therapy [12]. GINA advises avoiding the term "mild asthma" altogether to avoid giving the impression that mild symptoms equates with low risk [3].

●Moderate asthma – Defined by good asthma control (table 1) with medium-dose inhaled glucocorticoids or low-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 1) or uncontrolled asthma despite these therapies.

By these retrospective definitions, 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). These definitions are helpful in assessing populations used in asthma investigations, but they tend not to be useful during patient interactions.

DEFINING THERAPEUTIC TIERS (“STEPS”) — After initiation of pharmacotherapy for asthma, regimens are adjusted in a stepwise fashion, increasing medication until asthma is controlled and then decreasing medication as much as possible to minimize adverse effects. Therapeutic tiers, or "steps," are described in both the National Asthma Education and Prevention Program (NAEPP) and Global Initiative for Asthma (GINA) guidelines with some small differences in approach (table 3); we provide a simplified version for ease of use (table 4).

●Step 1 – Step 1 therapies provide reliever medication alone without maintenance therapy. Use of an as-needed short-acting beta-agonist (SABA) alone has been the traditional Step 1 therapy. As risk of exacerbations can be hard to predict, more recent guidelines recommend anti-inflammatory reliever therapy for Step 1 (table 5).

Anti-inflammatory reliever therapy (AIR) refers to the as-needed use of a fast-acting beta-agonist medication in combination with inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) for acute asthma symptoms, allowing for treatment of both bronchoconstriction and underlying airway inflammation. 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 improved exacerbation rates across many different levels of asthma severity [2,3]. We suggest using a form of AIR to replace SABA alone as reliever therapy for any patient with seasonal or otherwise variable symptoms, as well as for those with frequent exacerbations, except for those with very high or very low symptom perception. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Anti-inflammatory reliever (AIR) therapy, in higher risk patients'.)

Given the potential expense of AIR therapy, we still use SABA in those with very infrequent symptoms at very low risk of exacerbations, but we provide education on the need for increased therapy should their symptom frequency change. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Short-acting beta-agonists (SABAs) for quick relief, in low-risk patients'.)

●Step 2 – To assist in symptom control, Step 2 therapies use anti-inflammatory medication either as needed (via AIR) (table 5) or as scheduled controller regimens. For controller regimens, low-dose inhaled glucocorticoids are preferred, but leukotriene receptor antagonists are an alternative option.

●Step 3 – Step 3 therapies generally use low doses of two controller therapies in addition to reliever medications. One preferred strategy involves low-dose ICS-formoterol combination therapy twice daily as well as when needed (ie, maintenance and reliever therapy [MART]) (table 6). The most common alternative involves other long-acting beta-agonists (LABAs) and low-dose inhaled glucocorticoid combinations (ie, ICS-LABA) (table 7) with a separate reliever. Medium-dose inhaled glucocorticoids with a separate reliever is another alternative regimen. For regimens with separate relievers, using AIR (via ICS-SABA or ICS plus SABA as needed) has been shown to reduce exacerbation risk.

●Step 4 – Preferred Step 4 regimens include medium-dose ICS-LABA (table 7) either via MART (table 6) or through using an alternative reliever strategy.

●Step 5 – Step 5 regimens maximize standard controller therapies. They involve medium-dose or high-dose ICS-LABA (either via MART (table 6) or as controller therapy with an alternative reliever) (table 7) in combination with an additional controller. Long-acting muscarinic antagonists (LAMAs) are preferred, but antileukotriene agents are reasonable alternatives. Patients requiring step 5 therapy should undergo severe asthma phenotyping and assessment for potential treatment using biologic therapies. (See "Severe asthma phenotypes" and "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)

In general, patients with poor control or exacerbations on a given regimen should undergo evaluation for titration of therapy ("stepping up"), while those whose asthma is well controlled for several months may be able to decrease the intensity of their regimen ("step down"). Additional considerations are discussed below.

PATIENTS WITH POOR SYMPTOM CONTROL — Patients who have had poor symptom control over the previous four weeks (form 1) should be evaluated for trigger exposure, medication adherence and technique, and modifiable comorbidities. Frequently, addressing these factors obviates the need for changes in pharmacotherapy, or it can allow for a temporary escalation alone. If such contributing factors are not identified, or if addressing them does not improve asthma control, stepping up to the next tier of therapy is warranted.

Assessing and mitigating contributing factors

Controlling asthma triggers — Ongoing exposure to asthma triggers is an important cause of poor asthma control. Patients with uncontrolled symptoms should undergo careful assessment for potential triggers of worsening asthma, including exposure to allergens, irritants, and medications (eg, beta-blockers, angiotensin-converting enzyme [ACE] inhibitors, and nonsteroidal antiinflammatory drugs [NSAIDs]) (table 8) [2,3]. Pets, dust mites, smoking, respiratory viruses, and workplace exposures are among the most frequently encountered triggers.

Multiple strategies may be used to mitigate asthma triggers, depending on the nature of the trigger. These may include hand hygiene and vaccinations (for viral triggers), avoidance (for irritants and allergens), and medication changes (for medication triggers). In those with indoor allergens triggering their asthma, a multicomponent allergen-specific mitigation strategy may be helpful. (See "Trigger control to enhance asthma management".)

Allergy testing (ie, skin testing or in vitro allergen-specific immunoglobulin E [IgE] immunoassays) can help confirm or exclude individual suspected allergic triggers. However, a positive skin test or allergen-specific IgE immunoassay indicates only that the patient is sensitized to that allergen and has the potential to develop symptoms. The diagnosis of an allergy also requires a history consistent with symptoms following that exposure. Allergen avoidance is a recommended initial strategy for most patients with allergic triggers (table 9); if this is not possible or is unsuccessful, subcutaneous or sublingual immunotherapy may be appropriate in those with reasonably well-controlled asthma (poorly controlled asthma is a contraindication for immunotherapy). (See "Allergen avoidance in the treatment of asthma and allergic rhinitis" and "Subcutaneous immunotherapy (SCIT) for allergic rhinoconjunctivitis and asthma: Indications and efficacy" and "Sublingual immunotherapy for allergic rhinitis and conjunctivitis: SLIT-tablets", section on 'Impact on asthma'.)

Medication adherence — Adherence to regularly dosed inhaled asthma medication regimens tends to be very poor, with reported rates of nonadherence ranging from 30 to 70 percent [3,15,16]. This is likely the reason that anti-inflammatory reliever therapy (AIR) is efficacious compared to regular controller therapy: patients often only take their medication when they have symptoms, and if they are using a short-acting beta-agonist (SABA) for reliever, they are not treating the inflammation driving their poor control. Simplifying the medical regimen through prescription of AIR is likely particularly important in nonadherent patients. However, AIR alone is not sufficient to achieve asthma control in those requiring Step 3 therapy or above.

Poor adherence can be identified and managed in partnership with the patient through empathetic questioning and acknowledgement of potential barriers to optimal medication use [17]. Understanding the patient's attitudes and goals regarding their asthma treatment is a core practice in asthma follow-up and can often provide useful insight (table 10).

Patients should bring their inhalers to each appointment and explain how they are using them (both technique and dosing). Inhaler technique should be demonstrated for the patient and reviewed at every visit. Suboptimal inhaler use may be associated with individual medicines or devices (eg, device technique, complexity of the regimen, adverse effects, expense) but may also arise from patient behavior or misunderstanding (eg, fear/anxiety about medication, confusion about appropriate use of medications, forgetfulness, unrealistic expectations). After identifying barriers to adherence, the clinician can engage the patient collaboratively on finding solutions, which may include adopting behavioral techniques (table 11), simplifying or altering regimens, and providing clear written instructions for medication use. (See "Enhancing patient adherence to asthma therapy".)

Comorbidities — Comorbidities may influence asthma control in some cases, so it is reasonable to monitor and manage these conditions (table 12). However, evidence that improvement in these comorbidities alters the course of a patient's asthma is generally limited, and addressing these comorbidities can be a months- or years-long process, so other management strategies should not await response to therapy.

●For patients with obesity, counseling regarding nutrition and physical activity may assist with weight loss, which has been shown to improve asthma control, lung function, and quality of life in several studies. Referral for specialized weight loss management might be appropriate. (See "Obesity and asthma".)

●Patients who smoke should be counseled that this is a risk factor for fatal asthma and that cessation is imperative. Cigarette smoke exposure can also reduce responsiveness to inhaled and systemic corticosteroids, necessitating higher steps in therapy to gain asthma control [18,19]. Smoking cessation classes, counseling, and pharmacologic aids may be helpful [20]. (See "Overview of smoking cessation management in adults" and "Identifying patients at risk for fatal asthma".)

●Treatment of obstructive sleep apnea may improve nocturnal symptoms of dyspnea and choking [21-23]. (See "Clinical presentation and diagnosis of obstructive sleep apnea in adults".)

●Allergic rhinitis, which is common in patients with asthma, should be treated with allergen avoidance and intranasal glucocorticoids [24,25].

●Chronic sinusitis, which is also common in patients with asthma, should be treated medically with intranasal glucocorticoids and antimicrobial agents. If surgically amenable naso-sinus disease is identified (eg, chronic rhinosinusitis in a patient with nasal polyposis), then referral to an otolaryngologist may be appropriate. (See "Chronic rhinosinusitis without nasal polyposis: Management and prognosis" and "Chronic rhinosinusitis with nasal polyposis: Management and prognosis" and "Relationships between rhinosinusitis and asthma".)

●Symptomatic gastroesophageal reflux disease (GERD) should be treated with proton pump inhibitors (PPIs), although data suggesting that this therapy improves asthma (as opposed to GERD) are limited. Therapy with PPIs does not improve asthma-related outcomes in patients who do not have symptoms of GERD. (See "Medical management of gastroesophageal reflux disease in adults" and "Gastroesophageal reflux and asthma", section on 'Management of patients without symptoms of GERD'.)

●Inducible laryngeal obstruction (also known as vocal cord dysfunction or paradoxical vocal fold motion), when present, should be treated by a knowledgeable speech therapist. Underlying causes (eg, postnasal drip, GERD, and anxiety) should be addressed. (See "Inducible laryngeal obstruction (paradoxical vocal fold motion)".)

●Anxiety and depression (and other psychiatric issues) may complicate asthma and warrant further evaluation [26].

Reconsideration of the diagnosis — Asthma is the most common respiratory disorder to cause cough, wheezing, shortness of breath, and chest tightness, especially in adolescents and young adults. Because of its prevalence, empiric diagnoses of asthma are often made and treatment initiated without establishing objective evidence of reversible airway obstruction or airway hyperresponsiveness. However, physical deconditioning, bronchiolitis, bronchiectasis, paradoxical vocal fold motion, pulmonary embolism, GERD, panic disorder, and sarcoidosis may all demonstrate similar symptoms, as well as (in some cases) nonreversible airway obstruction on spirometry. In older adults, chronic obstructive pulmonary disease (COPD), heart failure, interstitial lung diseases, central airway tumors, and recurrent aspiration are additional diagnostic considerations. Entertaining other diagnostic possibilities and/or verifying reversible airway obstruction is prudent in those who fail to improve or clinically worsen despite appropriate therapy for asthma. (See "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Diagnosis' and "Asthma in adolescents and adults: Evaluation and diagnosis", section on 'Differential diagnosis'.)

Increasing (stepping up) therapy, for persistent poor symptom control — For patients with poor symptom control despite attempts to address adherence, mitigate triggers, and control contributing comorbidities, an escalation to the next tier ("step") of asthma therapy is warranted. Additional considerations and evidence based on current therapy are addressed further below.

Patients on short-acting bronchodilators alone (Step 1) — Patients with poor symptom control on SABAs alone should be evaluated based on symptom burden and initiated on Step 2, Step 3, or Step 4 therapy based on the criteria used for patients with a new asthma diagnosis. (See "Initiating asthma therapy and monitoring in adolescents and adults".)

Patients using anti-inflammatory relievers alone (Step 1 or 2) — Patients who have poor symptom control or exacerbations despite appropriate use of anti-inflammatory relievers (AIR) (table 5) require initiation of maintenance therapy. We preferably use a long-acting beta-agonist (LABA) combined with low-dose or moderate-dose inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]), depending on the frequency of AIR administration (table 3 and table 4).

Because ICS-formoterol combination inhalers contain both an antiinflammatory medication and a fast-acting bronchodilator, they can be used for both reliever therapy and long-term control. This approach is called maintenance and reliever therapy (MART) (table 6). (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Low-dose maintenance and reliever therapy (MART)'.)

For those using combination albuterol-ICS or albuterol with inhaled glucocorticoids in separate inhalers, we prefer switching to low-dose MART (Step 3) (table 6) if this option is available (table 4).

For those using ICS-formoterol therapy as AIR, we also suggest initiation of MART. The strength of the inhaled glucocorticoid for MART depends in part on the average use of ICS-formoterol AIR over the past several weeks. Patients who have higher average use of inhaled glucocorticoids due to AIR (eg, more than four puffs of budesonide-formoterol 80 mcg-4.5 mcg per day) can be transitioned directly to medium-dose (Step 4) MART (table 6). Otherwise, we begin with low-dose MART (Step 3).

There are several different ICS-formoterol inhalers available worldwide. Typical dosing for MART includes low-dose ICS-formoterol (Step 3) or medium-dose ICS-formoterol (Step 4) maintenance therapy one to two inhalations twice daily, with additional ICS-formoterol used as needed for acute symptom relief (table 6) [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 most preparations of ICS-formoterol is 12 inhalations.

By consolidating maintenance therapy and reliever therapy into one inhaler, the regimen is simpler for patients to use and can also be escalated (to higher-dose maintenance) and de-escalated (to AIR alone (table 5)) more easily than other regimens. However, this approach is not approved by all regulatory agencies and the cost of these combination therapies varies widely worldwide, which may limit their use. For example, insurers in the United States may set a limit of one canister dispensed per month, limiting the number of doses available for as-needed use. Typical dosing and side effects are discussed in the table (table 6) and below.

The use of a single ICS-formoterol combination inhaler as MART has been compared with a low-dose ICS-LABA inhaler as maintenance and a separate SABA as rescue in a number of studies [27-32]. 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. A meta-analysis of 21 trials concluded that MART reduced the risk of severe exacerbation by 27 to 50 percent compared with other controller-reliever strategies [33].

For patients using AIR who are unable to obtain MART, the preferred alternative approach is switching to maintenance, preventive low-dose ICS-LABA therapy with continued AIR as reliever therapy (table 3 and table 4). The combination of inhaled glucocorticoids plus LABA is more effective than higher doses of inhaled glucocorticoids as maintenance in most patients [34-39]. AIR is a reliever approach they are already using that will decrease exacerbation risk. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Low-dose ICS-LABA, with a reliever' and 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations' below.)

Oral candidiasis and dysphonia (hoarse voice) may occur with maintenance use of inhaled glucocorticoids; however, 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".)

Patients using low-dose ICS with a SABA (Step 2) — For patients requiring escalation from traditional Step 2 therapy with low-dose inhaled glucocorticoids and a SABA reliever, we agree with national and international guidelines in preferring initiation of maintenance and reliever therapy (MART) with ICS-formoterol (table 6), as described above (table 3 and table 4) [2,3]. (See 'Patients using anti-inflammatory relievers alone (Step 1 or 2)' above.)

For patients requiring Step 3 therapy or higher, MART has demonstrated reduced risk of severe exacerbations with similar symptomatic control. For those who cannot use MART, low-dose ICS-LABA as controller (table 7) combined with SABA is a reasonable alternative (table 4). The combination of inhaled glucocorticoids plus LABA is more effective than higher doses of inhaled glucocorticoids as maintenance in most patients [34-39]. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'Low-dose ICS-LABA, with a reliever'.)

For patients not receiving MART, adding additional anti-inflammatory therapy whenever SABA is used (either through a separate inhaled glucocorticoid inhaler, or through an inhaler containing both ICS-SABA, if available) will reduce exacerbations and may also lead to improved symptom control (table 4) [40,41]. (See 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations' below.)

Patients using low-dose ICS-LABA or medium-dose ICS maintenance (Step 3) — For patients whose asthma is not well controlled on Step 3 therapy (low-dose ICS-LABA or a medium dose of inhaled glucocorticoids with a reliever), we agree with national and international guidelines in preferring a combination medium-dose ICS-formoterol as maintenance and reliever therapy (eg, budesonide 160 mcg-formoterol or mometasone 100 mcg-formoterol, two inhalations twice daily with one inhalation as needed (table 6)) (table 4) [2,3]. Alternatively, a non-formoterol medium-dose ICS-LABA (table 7) can be used for maintenance along with a separate reliever as Step 4 therapy.

Although many of the MART trials used lower doses, MART therapy with medium-dose ICS-formoterol likely reduces exacerbations (by approximately 20 to 50 percent) compared with medium-dose ICS-LABA plus a SABA reliever [31,33]. A meta-analysis of trials comparing ICS-formoterol MART to equivalent ICS-LABA dosing with SABA also strongly favored MART for reducing the number of patients suffering severe exacerbations (14 percent with MART versus 20 percent on ICS-LABA plus SABA, RR 0.68 [95% CI 0.58-0.80]) [42].

For patients not receiving MART, adding additional anti-inflammatory therapy whenever SABA is used (either through a separate inhaled glucocorticoid inhaler, or through an inhaler containing both ICS-SABA if available) will reduce exacerbations and may also lead to improved symptom control (table 4) [40,41]. (See 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations' below.)

Alternative agents for escalation from Steps 2 or 3 — Long-acting muscarinic antagonists (LAMAs) or antileukotrienes may also be used in some patients as alternative add-on therapies to inhaled glucocorticoid maintenance therapy (Step 3 and 4 therapy) (table 3 and table 4) [1-3].

●Long-acting muscarinic antagonists (LAMAs) – Tiotropium bromide (Spiriva Respimat) is approved by the US Food and Drug Administration (FDA) for the treatment of asthma at a dose of 1.25 mcg/inhalation, two inhalations once daily. Data from randomized trials suggest that the addition of LAMA to low- and medium-dose inhaled glucocorticoids has a similar effect to the addition of LABA in terms of reduction in exacerbations and improvements in asthma control and quality of life [43-45]. Occasional patients are highly susceptible to adverse effects of LABAs, including palpitations, tremor, anxiety, and insomnia. In these patients, we frequently substitute the LAMA tiotropium bromide for a LABA in Step 3 and Step 4 therapy (table 3 and table 4). The onset of action of tiotropium is too long for use as reliever therapy, so LAMAs cannot be used as part of a MART strategy.

One trial raised concern about increased asthma hospitalizations in those treated with ICS-LAMA compared with ICS-LABA [46], although the exact risk of LAMA compared with LABA was uncertain and other trials have supported safety relative to placebo [47,48].

●Antileukotrienes – Antileukotrienes are oral medications which may be easier to use than inhaled therapies but have less efficacy than LABAs as add-on therapy for asthma symptom and exacerbation control. In our experience, those most likely to benefit from these agents as part of Step 3 or Step 4 therapy include those currently smoking (which may decrease sensitivity to inhaled glucocorticoids [18]) or those with concomitant allergic rhinitis, aspirin-exacerbated respiratory disease (AERD), difficulty with inhaler technique or adherence, or prominent exercise-induced bronchoconstriction. Poor control after a one-month trial on antileukotrienes and inhaled glucocorticoids should prompt an alternative strategy.

Antileukotrienes include the leukotriene receptor antagonists, zafirlukast (Accolate) and montelukast (Singulair), as well as the 5-lipoxygenase inhibitor zileuton (Zyflo) (table 13). Montelukast has a boxed warning from the FDA listing its potential for severe neuropsychiatric effects including suicidal ideation and action, so it should be used with caution in patients with mental health comorbidities, especially preexisting depression. Although these side effects are rare, we recommend informing patients of these risks and stopping the medication if they note any mood changes. Zileuton requires additional monitoring for hepatic impairment. The mechanisms of action, efficacy, and safety of these agents are discussed in further detail separately. (See "Antileukotriene agents in the management of asthma".)

A systematic review (18 trials with 7208 participants) found that adding a LABA to inhaled glucocorticoids, compared with adding a leukotriene receptor antagonist, reduced the risk of exacerbations requiring systemic glucocorticoids from 13 to 11 percent (relative risk [RR] 0.87, 95% CI 0.76-0.99) [49]. Addition of a LABA was also associated with improved pulmonary function and (to a lesser extent) reduced symptoms and rescue medication use. Thus, addition of a leukotriene-modifying agent to inhaled low-dose glucocorticoids is considered a second-line alternative option. 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 when SABA alone is used as reliever therapy [50]. There are minimal data comparing leukotrienes to AIR.

Patients using medium-dose ICS-LABA (Step 4) — For patients with poor symptom control despite mitigation of triggers and adherence to medium-dose ICS-LABA therapy, we suggest the addition of a maintenance medication in a separate class, typically a long-acting muscarinic antagonist (LAMA), rather than use of high-dose ICS-LABA or other options (table 3 and table 4). The addition of an antileukotriene agent is a reasonable alternative.

●Tiotropium – Tiotropium, a once daily inhaled LAMA, is approved by the FDA for long-term maintenance treatment in asthma at a dose of 2.5 mcg/day (two inhalations of 1.25 mcg by soft mist inhaler) [51]. We typically add tiotropium for patients with uncontrolled symptoms using ICS-LABA maintenance or MART given the relative simplicity of this regimen (table 4).

Evidence in favor of using a LAMA as add-on therapy for difficult-to-control asthma is modest and based on a proportion of participants experiencing improvements in asthma control and asthma-related quality of life [52-54].

•Two trials have shown that the proportion of participants who experience a clinically significant improvement in asthma control and asthma quality of life is increased in adults treated with LAMA added to ICS-LABA compared to placebo added to ICS-LABA [52]. In 392 adolescents aged 12 to 17 years, the addition of tiotropium to inhaled glucocorticoids plus other controller therapies showed minor improvement in lung function compared with placebo [53].

•A systematic review found that adding a LAMA to an ICS-LABA regimen did not reduce exacerbation risk significantly compared with adding placebo (RR 0.84, 95% CI 0.57-1.22), but lung function was slightly improved (mean difference in forced expiratory volume in one second [FEV₁] of 70 mL [95% CI 10-140 mL]) [54].

The main adverse effect of tiotropium in these asthma trials was dry mouth. Although increased cardiac events have been seen with use of tiotropium in some observational chronic obstructive pulmonary disease (COPD) cohorts, data from trials of combination therapies including inhaled glucocorticoids have been reassuring. (See "Management of the patient with COPD and cardiovascular disease", section on 'Combination inhaled bronchodilators plus glucocorticoid'.)

●Combination ICS-LAMA-LABA therapy – Clinical trials using three agent inhalers (ICS-LABA-LAMA) show similar effects of adding a single LAMA inhaler to ICS-LABA treatment; no effect on exacerbations, modest effects on asthma control and quality of life, and significant improvements in lung function [55,56]. The once-daily three-agent dry powder inhaler, fluticasone furoate-umeclidinium-vilanterol (FF-UM-VI), has been approved by the FDA and other regulatory bodies for use in moderate or severe asthma based primarily on improvements in lung function [55]. It is available in two strengths: a moderate-dose inhaled glucocorticoid (FF 100 mcg-UM 62.5 mcg-VI 25 mcg); or a high-dose inhaled glucocorticoid (FF 200 mcg-UM 62.5 mcg-VI 25 mcg); the use of the higher inhaled glucocorticoid dose appears to reduce risk of exacerbations in those with high blood eosinophils [56]. Use of this agent is appealing for patients who do not use MART because it often leads to simplification of their regimen (one inhaler once a day for maintenance with a reliever) (table 4). We typically use the higher dose when transitioning from Step 4 to Step 5 therapy unless there are individual patient factors increasing concern for inhaled glucocorticoid adverse effects.

Other combination ICS-LAMA-LABA agents (twice daily beclomethasone-glycopyrronium-formoterol 200-10-6 mcg and once-daily mometasone-glycopyrrolate-indacaterol 160-50-150 mcg), which have not yet undergone regulatory approval in the United States for asthma treatment, likely have similar efficacy as FF-UM-VI.

Adverse effects with combination therapy include the typical effects of beta agonists and inhaled glucocorticoids with the addition of dry mouth from the muscarinic antagonist. Data on cardiac risks in patients with COPD on combination therapies have been largely reassuring. (See "Management of the patient with COPD and cardiovascular disease", section on 'Combination inhaled bronchodilators plus glucocorticoid'.)

●Antileukotrienes – Evidence for the efficacy of leukotriene modifying agents (LTMAs) as add-on therapy in moderate to severe asthma is limited [57-59]. Although older trials showed efficacy of LTMAs as add-on therapy to high-dose corticosteroids alone [57,58], one study that evaluated montelukast in patients whose asthma was not controlled with ICS-LABA did not find a benefit after a limited trial (two weeks) [59]. On the other hand, LTMAs have been shown to be variably helpful in certain subsets of patients, including those with aspirin-exacerbated respiratory disease (AERD), and can help treat allergic rhinitis or other manifestations of seasonal allergies [60].

Common leukotriene receptor antagonists (LTRAs) are zafirlukast, typically dosed at 20mg once daily, and montelukast, typically dosed at 10 mg once daily (table 13). When we add an LTMA at this step, we usually try an LTRA first. If an LTRA does not improve asthma control, switching to zileuton can be considered [61,62]. However, due to zileuton's potential adverse effects and its monitoring requirements, our authors only rarely use this therapy. Additional discussion of dosing, adverse effects, and efficacy of antileukotrienes may be found above and elsewhere. (See 'Alternative agents for escalation from Steps 2 or 3' above and "Antileukotriene agents in the management of asthma".)

Poor control despite three maintenance agents (Step 5) — Patients with asthma that is poorly controlled despite good inhaler technique and adherence to three maintenance therapies should be referred to a center that specializes in the treatment of severe asthma. For patients with difficult to control asthma, referral to specialist centers has been shown to improve asthma control, reduce exacerbations, and decrease oral corticosteroid use [63-66]. These benefits are likely increasing with the expansion of biologic treatment options. Additional evaluation of patients with severe asthma is discussed in detail separately. (See "Evaluation of severe asthma in adolescents and adults" and "Severe asthma phenotypes".)

If necessary while awaiting specialist evaluation, it is reasonable to transition patients to a high-dose ICS-LABA (or ICS-LAMA-LABA) (table 7) if they are using a medium-dose inhaled glucocorticoid in their current combination therapy. An additional pharmacologic management option is adding on a fourth controller agent (typically either a LAMA or antileukotriene agent, depending on the current regimen).

Where biologic agents for severe asthma are available, patients should receive prompt evaluation for these therapies rather than initiation of maintenance systemic glucocorticoids [3].

Further management of patients with persistently uncontrolled asthma is discussed separately. (See "Treatment of severe asthma in adolescents and adults".)

PATIENTS WITH GOOD DAILY CONTROL BUT FREQUENT EXACERBATIONS — Many patients with asthma typically maintain good symptom control but also have intermittent periods of poor control or asthma exacerbations. For such patients, we prioritize avoiding asthma triggers, establishing effective asthma action plans, and utilizing anti-inflammatory reliever approaches before escalating maintenance therapies.

Risk factor reduction — Beyond poor asthma symptom control, a number of additional risk factors for frequent asthma exacerbations have been identified, including a history of frequent or severe exacerbations, high short-acting beta-agonist (SABA) usage, and poor adherence to controller therapies (table 2). (See 'Risk factors for exacerbations and adverse effects' above.)

Avoidance of asthma triggers, weight loss in those with obesity, smoking cessation, and improving inhaler adherence and technique are the most high-yield nonpharmacologic mitigating measures. (See 'Controlling asthma triggers' above and 'Medication adherence' above.)

Patient education — Patients with variable symptoms and/or frequent exacerbations require extra attention to symptom monitoring, understanding the proper use of their medications (eg, "long-term control" versus "symptom relief") and a clear approach to asthma worsening.

An "asthma action plan" is a written document that provides instructions for the patient to follow at home, which includes directions about daily self-assessment and baseline medications as well as a plan for managing exacerbations (form 2). (See "Asthma education and self-management", section on 'Asthma action plans'.)

As part of this planning, clinicians should stress the importance of recognizing and immediately treating early warning signs and symptoms. These include an increase in asthma symptoms, awakening at night or early in the morning with asthma symptoms, or other individual patterns related to shortness of breath or tightness in the chest. Plans should include instructions about when to take extra doses of reliever medications, when to initiate a course of oral glucocorticoids, and when to seek immediate medical attention (form 2) [1,3].

For patients willing and able to monitor their asthma using a peak flow meter, the concept of personal best peak flow rate and how this measurement is used should be discussed. (See "Peak expiratory flow monitoring in asthma".)

For motivated patients, keeping diaries of medication use, peak flow rates, environmental exposures, symptoms, and actions taken can provide valuable insight into asthma triggers and effective control measures to aid in exacerbation prevention and overall asthma management.

Anti-inflammatory reliever therapy (AIR) to reduce exacerbations — As discussed above, AIR describes use of a fast-acting beta agonist medication in combination with inhaled glucocorticoids to treat both bronchoconstriction and underlying airway inflammation when used as needed for acute asthma symptoms; patients requiring more rescue inhaler use will achieve a greater dose of glucocorticoids delivered to the airways to suppress the inflammation (table 5). AIR has been promoted by national and international guidelines based on improved exacerbation rates across many different levels of asthma severity [2,3].

ICS-formoterol — The usual dose of ICS-formoterol (eg, budesonide-formoterol, mometasone-formoterol) for acute symptom relief is one to two puffs (4.5, 5, or 6 mcg formoterol per puff) as needed every four hours up to 12 inhalations total per day (table 5) [2]. We typically use the lower dose of inhaled glucocorticoids for reliever therapy unless the patient is on a higher dose of ICS-formoterol as part of their maintenance regimen.

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 as-needed SABA with or without inhaled glucocorticoids [67-75]. In general, these trials have shown improved exacerbation rates compared to albuterol alone and equivalent or improved exacerbation rates with slightly inferior daily symptoms scores compared with maintenance inhaled glucocorticoids. For example, in one study of nearly 700 patients eligible for Step 1 or Step 2 therapy, 10 percent of patients using albuterol alone developed an exacerbation requiring systemic glucocorticoids or emergency care compared to 4.1 percent of patients using budesonide-formoterol as needed [69].

Because ICS-formoterol combination inhalers contain both an anti-inflammatory medication and a bronchodilator, they can be used for both reliever therapy and long-term control. This approach, called maintenance and reliever therapy (MART) (table 6), is a preferred single-inhaler management strategy for patients requiring Step 3 or Step 4 therapy (table 3 and table 4). However, cost and insurance coverage may limit the availability of this option.

ICS-formoterol has been compared with formoterol alone and SABA alone as reliever therapies in patients using baseline ICS-formoterol for controller therapy. In one large trial, 3394 patients with persistent asthma and a history of severe exacerbation despite inhaled glucocorticoid maintenance therapy were assigned to budesonide-formoterol maintenance plus as-needed budesonide-formoterol MART, formoterol alone, or SABA alone (terbutaline) and followed for 12 months [28]. The percentage of patients with severe exacerbations in each group was as follows:

●Terbutaline – 22 percent

●Formoterol – 17 percent

●MART – 13 percent (hazard ratio [HR] for severe exacerbations 0.52, 95% CI 0.44-0.62 versus terbutaline; HR 0.67, 95% CI 0.56-0.80 versus formoterol)

Subsequent trials have found comparable improvements in exacerbation risk with the use of ICS-formoterol reliever therapy in patients with poorly controlled (HR 0.64) [30] or stable asthma (HR 0.70) [29], although evidence regarding assessment of asthma symptoms and percentage of asthma control days was mixed.

Inhaled glucocorticoids plus SABA — Like ICS-formoterol, the use of inhaled glucocorticoids and a short-acting beta-agonist (SABA) together provides concomitant anti-inflammatory and reliever therapy. For combination albuterol-budesonide metered dose inhaler (MDI; 90 mcg / 80 mcg) the usual dose is two inhalations every four to six hours as needed (table 5). A low-dose inhaled glucocorticoid can also be used separately along with albuterol (aka, salbutamol) by provision of two separate inhalers (table 14 and table 15).

For patients with well-controlled mild asthma, use of inhaled glucocorticoids and SABA as needed showed similar efficacy to maintenance inhaled glucocorticoids and a SABA reliever for prevention of exacerbations. (See "Initiating asthma therapy and monitoring in adolescents and adults", section on 'As-needed low-dose ICS and SABA (step 2)'.)

For patients with poorly controlled asthma or frequent exacerbations, two trials have evaluated ICS-SABA or inhaled glucocorticoid plus SABA as reliever strategies in addition to standard maintenance therapies (typically ICS-LABA). Compared with SABA relievers, ICS-SABA reduced the annualized rate of severe exacerbations by approximately 0.15 exacerbations per year in both studies [40,41]. This primary effect size is robust but somewhat smaller than that seen in meta-analyses of MART.

●In one double-blind trial, 3049 adults and adolescents with poorly controlled asthma were randomly assigned 1:1:1 to high-dose AIR (budesonide 180 mcg/albuterol 180 mcg), low-dose AIR (budesonide 80 mcg/albuterol 180 mcg), or SABA (albuterol 180 mcg) alone as the sole rescue inhaler for use as needed in response to asthma symptoms [41]. The participants had all suffered a severe exacerbation requiring systemic glucocorticoids in the last year and were on stable medium- to high-dose inhaled glucocorticoid or low- to high-dose ICS-LABA for at least three months. Compared with SABA alone, high-dose AIR reduced the annualized rate of severe asthma exacerbation (0.43 versus 0.58 per year; relative risk [RR] 0.75, 95% CI 0.61-0.91). Additionally, more patients in the high-dose AIR group experienced a clinically significant improvement in standardized asthma symptom scores compared with the SABA alone group (absolute difference of 5 percent). The low-dose AIR group showed a similar trend on all measures, but it did not reach statistical significance.

●Similar findings were observed in an open-label trial that enrolled 1201 Black and Latinx patients with poorly controlled moderate to severe asthma on stable maintenance inhaled glucocorticoids or ICS-LABA therapy [40]. Patients were randomly assigned to AIR (beclomethasone 80 mcg and albuterol 90 mcg together whenever rescue therapy was needed) or to usual care [40]. Compared with usual care, AIR reduced the annualized rate of severe asthma exacerbations (0.69 versus 0.82 per year; HR 0.85, 95% CI 0.72-0.999). AIR also decreased the annualized rate of missed days of work or school (13.4 versus 16.8 per year; rate ratio 0.80, 95% CI 0.67-0.95).

Aside from the possibly smaller effect size, the largest disadvantage of ICS-SABA relative to ICS-formoterol for rescue therapy is the potential need for multiple rescue inhalers. With increasing availability of combination ICS-SABA inhalers (table 5), including Food and Drug Administration (FDA) approval in the United States [76], this strategy may be more feasible for patients on maintenance regimens that do not include formoterol (table 4).

Stepping up maintenance therapy — For patients with frequent exacerbations who are unable to use AIR or do not improve after a change to this approach, pharmacotherapy should be escalated to the next therapeutic tier ("step") as in patients with poor control (table 3 and table 4). Those with frequent exacerbations on Step 4 or Step 5 therapy may have severe asthma and should be referred to an asthma specialist for consideration of advanced therapies such as biologics. (See 'Increasing (stepping up) therapy, for persistent poor symptom control' above and "Treatment of severe asthma in adolescents and adults".)

PATIENTS WITH GOOD SYMPTOM CONTROL AND LOW EXACERBATION RISK — Once good asthma control has been achieved and maintained for a clinically significant period of time, many patients are able to decrease the intensity of treatment without loss of asthma control. Determination of good asthma control may be influenced by regional allergen exposures and respiratory viral seasons, and medication changes should account for these potential risk factors for loss of control. This area has been understudied and is not without risk of clinical deterioration, so good communication, close monitoring, and shared decision-making are essential to success.

Patient communication — After achieving good symptom control without exacerbations, many patients question the need for ongoing therapy, while others strongly prefer to avoid stepping down in case their asthma control worsens. Navigating a prudent course often involves tempering expectations and/or alleviating anxiety.

All patients using maintenance therapies should learn about the role of maintenance therapy in calming ongoing airway inflammation and the need for caution in reducing anti-inflammatory medication to avoid exacerbations. For patients who are doing well but anxious about medication changes, education can focus on the waxing-waning course of asthma throughout life and how the disease can be highly responsive to lifestyle changes such as avoidance of asthma triggers. (See "Asthma education and self-management", section on 'Understanding asthma' and "Asthma education and self-management", section on 'Communication'.)

When decreasing therapy, patients should monitor their asthma symptoms closely; peak flow monitoring may also be helpful. In addition to acute reliever therapy, worsening of symptoms while stepping down therapy should prompt resumption of the previous regimen. Clear communication about this course of action is very important; we usually modify the "asthma action plan" (form 2) to include these instructions. (See "Asthma education and self-management", section on 'Asthma action plans' and "Peak expiratory flow monitoring in asthma".)

Decreasing (stepping down) therapy — Patients whose asthma has been well controlled over a period of four to six months on a stable medication regimen can often tolerate a step down in therapy, although careful monitoring is needed to quickly identify any deterioration in control.

Deterioration of asthma control while stepping down therapy is common and is more often associated with discontinuation of controller therapies rather than tapering. Clinical risk factors for deterioration have also been studied. For example, in one study, increased risk of deterioration after decreasing therapy was associated with emergency room visits for asthma in the past 12 months and persistently low FEV₁ but not age of asthma onset or duration of asthma therapy [77]. For patients with these additional risk factors, we wait for a longer period of stability (typically 6 to 12 months) before stepping down therapy.

●General approach – A preferred order for stepping down therapy has not been determined, and therefore individual patient factors and preferences should be taken into account [3,78]. In those on maintenance therapies, complete cessation of either inhaled glucocorticoids (aka, inhaled corticosteroids [ICS]) or long-acting beta-agonists (LABAs) have shown increased risk of clinical deterioration in patients with persistent asthma compared with tapering inhaled glucocorticoids. Tapering has not been well studied in the setting of maintenance and reliever therapy (MART) or maintenance plus other anti-inflammatory reliever (AIR) strategies, but the use of AIR appears to protect against exacerbations compared with short-acting beta-agonist (SABA) alone [67-70].

Tapering choices were examined in a trial with 459 participants whose asthma was well controlled on medium-dose ICS-LABA; participants were assigned to continue the same dose ICS-LABA, reduce the inhaled glucocorticoid dose 50 percent but continue the LABA, or continue the same inhaled glucocorticoid dose but omit the LABA [79]. After 48 weeks, the time to treatment failure did not differ significantly between a reduced-dose inhaled glucocorticoid or stopping the LABA (hazard ratio [HR] 1.07, 95.3% CI 0.69-1.65) or between the two doses of ICS-LABA (HR 1.11, 95% CI 0.70-1.76), although the 10 percent noninferiority margin was exceeded in the latter case. When the LABA was omitted, lung function declined (mean decrease in FEV₁ 70 mL) and the number of hospitalizations was greater, although the total number was small.

●Tapering maintenance inhaled glucocorticoids – We typically taper the inhaled glucocorticoid portion of the maintenance regimen step-wise by 50 percent at a time, which can usually be managed by altering the strength of the inhaler or the number of puffs used (table 7 and table 15). Once the patient is on low-dose maintenance ICS-LABA (or inhaled glucocorticoids alone), we will typically transition to once-daily dosing of the maintenance therapy.

The ability to reduce inhaled glucocorticoid therapy to a lower dose without losing control of asthma is supported by clinical trial data [77,79-81]. In the trial noted above that compared tapering regimens in 459 participants with well-controlled asthma, the time to treatment failure was not significantly different between higher and lower doses of inhaled glucocorticoids (with continued LABA) [79]. A separate randomized trial of 259 patients with moderate persistent asthma assigned participants to stable-dose inhaled glucocorticoids or a step-down approach to inhaled glucocorticoid dosing based on the patient's clinical condition [80]. Standard measures of asthma control were the same in both groups; however, patients in the dose-reduction group maintained control with a lower cumulative dose of inhaled glucocorticoids over the course of the 12-month trial.

●Discontinuing long-acting beta-agonists (LABAs) – In patients not on MART or AIR, the decision to discontinue a LABA after asthma control is attained should be made on a case-by-case basis, taking into consideration the patient's prior asthma history and estimated risk of deterioration in asthma control. We typically discontinue maintenance LABA therapy only after patients have good control on once-daily low-dose ICS-LABA.

A meta-analysis examined the effect of discontinuing the LABA in patients whose asthma was well controlled on a combination ICS-LABA for at least three months [82]. Five randomized trials with a total of 1352 patients were included. Discontinuation of LABA resulted in loss of asthma control, fewer symptom-free days, and increased rescue bronchodilator use. Increases in emergency or unscheduled visits and use of systemic glucocorticoids did not meet significance. In these studies, SABA was used as reliever therapy.

●Discontinuing long-acting muscarinic antagonists (LAMAs) – For patients using LAMAs in combination with an ICS-LABA (typically Step 5 therapy), we are comfortable discontinuing the LAMA as the first step or after a dose reduction in glucocorticoids, depending on the simplicity of the adjustment to the patient's regimen. For patients who are using a LAMA and inhaled glucocorticoid therapy instead of ICS-LABA, we approach discontinuation of LAMA therapy similarly to discontinuation of a LABA (see above), as it is the only long-acting bronchodilator agent. This typically involves discontinuing LAMA when the patient is stable on daily low-dose inhaled glucocorticoid and LAMA.

●Discontinuing antileukotriene therapy – Patients who benefit clinically from the use of antileukotriene therapy may need to continue their antileukotriene for comorbid allergic conditions (eg, seasonal allergies, allergic rhinitis, aspirin-exacerbated respiratory disease [AERD]). For patients without these comorbidities, we are cautious about discontinuing antileukotrienes if these agents were markedly helpful to achieve initial disease control. In such patients, we discontinue leukotrienes carefully only after patients are otherwise doing well on reliever therapy alone. For patients with good control who did not notice a difference in asthma symptoms with leukotriene initiation, we often attempt earlier monitored discontinuation of this therapy to simplify the asthma regimen.

●Transition to reliever therapy alone – For patients who have previously required maintenance therapy to control their asthma, we prefer to step down to AIR (table 5) when transitioning to reliever therapy alone. Those who have good asthma control for three to six months on low-dose inhaled glucocorticoids or low-dose ICS-LABA can transition to as-needed ICS-formoterol or ICS-SABA to reduce exacerbation risk during de-escalation. (See 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations' above.)

The safety of transition to as-needed ICS-formoterol from maintenance inhaled glucocorticoid therapy comes from four trials that randomized patients on Step 2 therapy to continued maintenance inhaled glucocorticoids or ICS-formoterol [67-70]. In the largest of these (SYGMA 2, n = 4176), as-needed budesonide-formoterol was noninferior to daily budesonide over 52 weeks (0.11 versus 0.12 exacerbations per year) [68]; similar results were seen in the other trials.

●Risk of discontinuing inhaled glucocorticoids – In contrast to careful dose reduction or transition to AIR, complete cessation of inhaled glucocorticoids is more likely to lead to clinical deterioration in patients with persistent asthma. In patients who are unable to conveniently use AIR alone, we carefully transition to SABA alone after more than a year of disease quiescence on low-dose inhaled glucocorticoids. During this transition, we discuss the risks of deterioration with the patient, ensure appropriate symptom monitoring, and plan for close interval follow-up.

In one systematic review and meta-analysis of over 1000 patients, those who discontinued inhaled glucocorticoids had more than twice the risk of exacerbation over the next six months than those who continued them (38 versus 16 percent); however, the risk of severe exacerbations was low [83]. Similarly, in a trial of 154 patients with asthma controlled on inhaled triamcinolone and salmeterol, inhaled glucocorticoid doses were successfully reduced by 50 percent in most patients (90 percent) without a significant loss of asthma control [84]. However, complete elimination of inhaled glucocorticoids resulted in significant deterioration of asthma control in nearly half of the cohort.

MEDICATIONS THAT ARE AVOIDED OR RARELY USED — 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.

Medications to avoid:

●Monotherapy with a long-acting beta-agonist (LABA) – We concur with national and international guidelines and the US Food and Drug Administration (FDA) in recommending against using LABAs as monotherapy for asthma [1,3,85]. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Evidence against LABA monotherapy'.)

●Racemic epinephrine – The FDA has approved the short-acting bronchodilator, inhaled racemic epinephrine, for nonprescription sale. We join a number of professional societies (such as the American Thoracic Society (ATS) and the American Academy of Allergy, Asthma, and Immunology) in discouraging its use. We find anti-inflammatory reliever therapy (AIR) and short-acting selective beta-2 agonists to be more effective, longer acting, and safer.

●Oral beta-agonists – Oral beta-agonists (eg, albuterol in liquid or tablet formulation, terbutaline tablets) generally do not make good alternative bronchodilators for mild asthma. They take longer to begin to work, achieve less bronchodilation, and are associated with more side effects than when the same medication is delivered by inhalation [86,87].

Rarely used medications:

●Ipratropium – Inhaled ipratropium is a muscarinic antagonist that has a slower onset of action (15 to 20 minutes) and achieves significantly less bronchodilation in asthma than inhaled short-acting beta-agonists (SABAs). Its use is not recommended except in very special circumstances (eg, tachyarrhythmias due to inhaled beta-agonists or concomitant use of monoamine oxidase inhibitors). A systematic review concluded that, except in the setting of acute, severe asthmatic attacks, combination therapy with ipratropium and SABAs is not superior to SABAs alone in adults with asthma [88].

●Theophylline – Sustained-release theophylline is a long-acting bronchodilator that was widely used in the past as a controller medication for persistent asthma. It is now rarely used because its anti-inflammatory properties are at best modest, side effects are common, blood levels must be monitored to avoid toxicity, and more effective long-acting bronchodilators are now available. The dosing and proper administration of theophylline in asthma is presented in more detail elsewhere. (See "Theophylline use in asthma".)

●Cromoglycates – Cromolyn and nedocromil are alternative medications for prevention of exercise-induced bronchoconstriction or prevention of asthma symptoms caused by predictable allergic exposures (eg, visiting a home with a cat), but availability is limited (table 16). Neither cromolyn nor nedocromil is available via inhaler device in most of the world. The only remaining formulation for asthma in the United States is the solution of cromolyn for nebulization, although oral therapies are available for other indications.

These agents prevent bronchospasm through mast-cell stabilizing and other properties, but they do not have acute-bronchodilator activity. A disadvantage to their use as a long-term controller medication is the need for dosing three to four times daily. They are no longer recommended by asthma guidelines for controller therapy.

LONG-TERM MONITORING — After adjusting therapy, we typically schedule a follow-up visit within three months [1,3]. Improvements in symptoms on effective controller 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.

We suggest discontinuing add-on therapies such as leukotriene receptor antagonists (LTRAs) and long-acting muscarinic antagonists (LAMAs) if benefit is not seen within a reasonable follow up time frame of one to three months. This approach reduces the potential for adverse effects and focuses efforts toward compliance on effective therapies.

We perform annual spirometry for patients on maintenance therapies. Spirometry should also be performed when there is a significant change in clinical status and may be considered to confirm that a step down in medication has not caused a clinically silent decline in lung function. Spirometry may have utility in comparing the efficacy of various add-on controller agents.

Asthma control requires regular re-evaluation even in the absence of perceived problems. We typically request that patients with asthma return to the office at least every six months.

Long-term monitoring also includes evaluation of ongoing and progressive side effects of inhaled glucocorticoid (aka, inhaled corticosteroid [ICS]) therapy, including dysphonia, oral candidiasis, adrenal suppression, cataract development, and osteoporosis, although most of the systemic side effects are highly unusual when typical doses of inhaled glucocorticoids are used [89]. (See "Major side effects of inhaled glucocorticoids".)

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 that are 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.)

●Basics topics (see "Patient education: Medicines for asthma (The Basics)" and "Patient education: Inhaled corticosteroid medicines (The Basics)" and "Patient education: Asthma in adults (The Basics)" and "Patient education: How to use your soft mist inhaler (adults) (The Basics)" and "Patient education: How to use your metered dose inhaler (adults) (The Basics)" and "Patient education: How to use your dry powder inhaler (adults) (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

●Assessment of asthma control – Asthma control, defined by both symptom burden and risk for future exacerbations, should be assessed at every visit (table 1). (See 'Assessment of asthma control, exacerbation risk, and severity' above.)

●Treatment of patients with poor symptom control

•Controlling asthma triggers – Patients with poor symptom control should undergo careful assessment for potential triggers of worsening asthma (table 8). (See 'Controlling asthma triggers' above.)

•Medication adherence – Inhaler technique and dosing should be reviewed at every visit. Poor adherence can be managed in partnership with the patient by adopting behavioral techniques (table 11), simplifying or altering regimens, and providing clear written instructions. (See 'Medication adherence' above and "Enhancing patient adherence to asthma therapy" and "The use of inhaler devices in adults", section on 'Teaching inhaler use skills'.)

•Comorbid diseases – Several other medical and social factors can contribute to poor asthma symptom control (table 12); these should be addressed whenever possible. (See 'Comorbidities' above.)

•Stepping up therapy – Therapeutic tiers, or "steps," are described in national and international guidelines (table 3); we provide a simplified version for ease of use (table 4). For patients with poor symptom control despite mitigation of triggers and poor adherence, escalation to the next tier of asthma therapy is warranted. (See 'Defining therapeutic tiers (“steps”)' above and 'Increasing (stepping up) therapy, for persistent poor symptom control' above.)

-Patients on Step 1: Patients with poor symptom control on short-acting beta-agonists (SABAs) alone can be initiated on therapy like patients with a new asthma diagnosis. (See 'Patients on short-acting bronchodilators alone (Step 1)' above and "Initiating asthma therapy and monitoring in adolescents and adults".)

-Step 2 to Step 3: For patients with poor asthma symptom control on Step 2 therapies, we recommend a regimen that includes maintenance inhaled glucocorticoids (aka, inhaled corticosteroid [ICS]) (Grade 1B), preferably a combination low-dose ICS-formoterol as maintenance and reliever therapy (MART) (Grade 2C), rather than other agents. Reasonable alternative strategies include a low dose ICS-LABA, low-dose inhaled glucocorticoids with an antileukotriene agent, low-dose inhaled glucocorticoids with a long acting muscarinic antagonist (LAMA), or medium-dose inhaled glucocorticoids; each of these should be paired with an ICS-SABA or SABA reliever. (See 'Patients using anti-inflammatory relievers alone (Step 1 or 2)' above and 'Patients using low-dose ICS with a SABA (Step 2)' above.)

-Step 3 to Step 4: For patients whose asthma symptoms are not well controlled on Step 3 therapy, we suggest medium-dose ICS-formoterol using a MART strategy rather than other options (Grade 2C); medium dose ICS-LABA with a separate ICS-SABA or SABA reliever is a reasonable alternative. (See 'Patients using low-dose ICS-LABA or medium-dose ICS maintenance (Step 3)' above.)

-Step 4 to Step 5: For patients with poor symptom control despite mitigation of triggers and adherence to medium-dose ICS-LABA therapy, we suggest the addition of a LAMA or antileukotriene agent rather than use of high-dose ICS-LABA or other options (Grade 2C). (See 'Patients using medium-dose ICS-LABA (Step 4)' above.)

-Poor control on Step 5: Patients with asthma that is poorly controlled despite good inhaler technique and adherence to three maintenance therapies should be referred to a specialist center in the treatment of severe asthma and evaluated for biologic treatments. (See 'Poor control despite three maintenance agents (Step 5)' above and "Treatment of severe asthma in adolescents and adults".)

●Patients with good daily control but frequent exacerbations

•Nonpharmacologic approaches – Avoidance of asthma triggers, weight loss (in patients with obesity), smoking cessation, improving medication adherence, and developing an asthma action plan are particularly helpful in this patient group (table 2). (See 'Risk factor reduction' above and 'Patient education' above.)

•Anti-inflammatory reliever therapy (AIR) – For patients with variable symptoms and/or frequent exacerbations, we suggest switching to AIR from SABAs alone as reliever therapy (table 5) (Grade 2B). We prefer as-needed ICS-formoterol due to ease of use and more extensive trial data, but use of low-dose inhaled glucocorticoids in combination with albuterol is a reasonable alternative, particularly if available in a single inhaler. For those on maintenance therapy, MART is a simple and effective option to allow both maintenance and AIR treatment. (See 'Anti-inflammatory reliever therapy (AIR) to reduce exacerbations' above.)

•Stepping-up – Patients with frequent exacerbations who do not improve with other measures should step up to the next therapeutic tier. (See 'Increasing (stepping up) therapy, for persistent poor symptom control' above.)

●Patients with good asthma control – Once good asthma control has been achieved and maintained for four to six months, many patients are able to decrease the intensity of treatment. (See 'Patients with good symptom control and low exacerbation risk' above.)

•Stepping down – In patients on maintenance therapies, we suggest tapering inhaled glucocorticoids to lower doses (table 15) prior to cessation of long-acting bronchodilator controller therapies (ie, LAMA or LABA) (Grade 2C).

For patients who have previously required maintenance therapy, we suggest stepping down to AIR (table 5) rather than as-needed SABAs when initially transitioning to reliever therapy alone (Grade 2B) in order to prevent exacerbations.

Other aspects of stepping down have not been well studied, and therefore individual patient factors and preferences should help guide therapy. (See 'Decreasing (stepping down) therapy' above.)

●Monitoring - After adjusting therapy, we typically schedule a follow-up visit within three months. Asthma control should be reassessed regularly, even in those with minimal symptoms. (See 'Long-term monitoring' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Rodolfo Pascual, MD, and Jennifer McCallister, MD, ATSF, FACP, FCCP, who contributed to earlier versions of this topic review.