Approach

Asthma management should target symptom control and reducing the risk for asthma exacerbations.[52] Control-based management relies on a continual cycle of assessing, adjusting, and reviewing response to pharmacologic and nonpharmacologic treatment. Risk reduction is essential because patients (even those with well-controlled symptoms) may continue to be at risk for moderate to severe exacerbations, have ongoing symptoms, or develop adverse effects associated with increasing inhaled corticosteroid (ICS) doses (e.g., impacting growth in adolescents). Exacerbation history is less useful because of the continued risk of severe exacerbations in patients with otherwise good symptom control.[52]

Asthma treatment should aim to achieve maximum symptom control with the fewest medications and lowest therapeutic burden. Therefore, treatment that uses combination inhalers is preferred, and once a state of control is achieved, attempts should be made to reduce the doses of medications while maintaining optimal control and minimizing adverse effects.

This topic covers the treatment of patients ages 12 years and older.

In an urgent care setting or where a patient presents with an acute exacerbation, please refer to guidance for managing Acute asthma exacerbation in adults.

Approach to treatment

The management information in this topic is primarily based on the Global Initiative for Asthma (GINA) guideline.[52] GINA divides its recommendations into five treatment “steps” with preferred and alternative treatment options in each step listed as “track 1” and “track 2,” respectively.

In track 1, the reliever medication is as-needed low-dose ICS-formoterol as an anti-inflammatory reliever (AIR); steps 1 and 2 are the same and termed step 1-2. In track 2, the reliever medication is either an as-needed SABA (taken together with a low-dose ICS for symptom relief in step 1) or as-needed SABA with concurrent maintenance ICS-containing treatment in steps 2-4. For safety reasons, GINA does not recommend SABA monotherapy for asthma in adults or adolescents.[52]

Track 2 options tend to increase treatment complexity, requiring more inhalers. Consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever.

Treatment can be stepped up or down along a particular track, using the same reliever at each step. Treatment can also be switched between tracks, depending on the patient’s preferences and needs.[52]

Treatment terminology

Therapeutic options are classified as follows:[52]

  • Maintenance: describes medications used continuously, even when asymptomatic (i.e., frequency of administration, not drug class). Includes ICS-containing medications (ICS, ICS-LABA, ICS-LABA-LAMA), leukotriene receptor antagonists (LTRA), and biologics.

  • Controller: describes any medication that targets both symptom control and future risk. The introduction of reliever inhalers that contain an anti-inflammatory means that this class is no longer synonymous with ICS-containing or maintenance treatment.

  • Reliever: refers to as-needed inhalers used for rapid symptom relief or before exercise. Includes SABAs and as needed ICS-formoterol and ICS-SABA combinations.

  • Anti-inflammatory reliever (AIR): refers to inhalers that contain a low-dose ICS and rapid-acting bronchodilator. Includes budesonide/formoterol, and any ICS-albuterol combination. AIR-only therapy can be used in steps 1-2 for ages 12 years and older.

  • Maintenance and reliever therapy (MART): refers to the use of combination ICS-formoterol inhalers every day for both maintenance and symptom relief. Includes budesonide/formoterol, but excludes ICS with other LABAs or SABAs. Used in steps 3-5.

Self-management, education, and environmental control

All patients with asthma at all steps of therapy should receive guided self-management education. This should include how to monitor symptoms and/or lung function plus a written personalized asthma action plan explaining how to recognize and respond to worsening symptoms.[52][80] Patient education should also include general information about asthma, training on the correct use of prescribed inhaler devices, and encouragement to take medications as prescribed and to attend all appointments. Advise patients to take environmental control measures, as appropriate (e.g., reduce exposure to indoor and outdoor air pollution, tobacco smoke, and occupational and domestic allergens).

Patients with asthma should have regular professional review by a healthcare professional.

Exercise-induced bronchoconstriction

Exercise-induced symptoms may occur in up to 90% of people with asthma.[2] Shortness of breath or wheezing induced by exercise may also relate to obesity or a lack of fitness, or to conditions such as inducible laryngeal obstruction, which may be comorbid.[52] Exercise-induced bronchoconstriction in athletes should be managed in the same way as in nonathletic individuals.[54]

Breakthrough exercise-induced bronchoconstriction may indicate poorly controlled asthma that requires stepping up of long-term treatment, after checking inhaler technique and adherence.[52] [ Cochrane Clinical Answers logo ]

Pharmacologic therapy

  • The American Thoracic Society recommends as-needed short-acting beta agonist (SABA) administered 5-20 minutes before exercise for the treatment of exercise-induced bronchoconstriction. For patients with uncontrolled symptoms on SABA, addition of as-needed inhaled anticholinergics (ipratropium) before exercise is recommended. For these patients, stepping up regular controller therapy may be required if as-needed treatments are not working. Maintenance regimens include daily ICS with or without LABA, and/or leukotriene receptor antagonist (LTRA), and antihistamines if allergic.[59]

  • Regular treatment with ICS has been shown to significantly reduce the severity of exercise-induced bronchoconstriction.[59]

  • There is evidence to suggest that patients with mild asthma who take ICS-formoterol as needed to control symptoms and prevent exacerbations can use the same medication before exercise to reduce exercise-induced bronchoconstriction, and do not need to be prescribed a SABA for use before exercise.[81] More studies are needed.[52]

  • LTRAs and inhaled anticholinergic agents (ipratropium) are also used to control exercise-induced bronchoconstriction.[59] Antihistamines may also be used as add-on treatment in patients with allergies.[59] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast. These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]​​​ Monitor for neuropsychiatric symptoms during treatment, and discontinue immediately if symptoms occur.[71]

Nonpharmacologic therapy

  • Nonpharmacologic interventions also reduce the incidence and severity of exercise-induced bronchoconstriction. These interventions include training, sufficient warm-up exercise, breathing through a face mask or scarf to pre-warm and humidify air, and dietary modification.[52][59] 

Initial therapy for asthma control

Step 1. Patients with asthma symptoms 1-2 days per week or less and no risk factors for exacerbations.[52]

  • Track 1 (preferred): start on as-needed low-dose ICS plus formoterol (ICS-formoterol).

  • Track 2 (alternative): low-dose ICS whenever a SABA is taken, either as separate or as combined inhalers.

Step 2. Patients with asthma symptoms less than 3-5 days per week and normal (or mildly reduced) lung function.[52]

  • Track 1 (preferred): start on as-needed low-dose ICS-formoterol.

  • Track 2 (alternative): daily low-dose ICS with either as-needed SABA (provided adherence to the ICS is likely) or as-needed ICS-SABA.

In GINA track 1, steps 1-2 are the same (i.e., as-needed low-dose ICS-formoterol). The decision to start step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the presence of specific clinical factors: daily symptoms, current smoking, low lung function, a recent severe exacerbation or a history of life-threatening exacerbation, impaired perception of bronchoconstriction (e.g., low initial lung function but few symptoms), severe airway hyperresponsiveness, or current exposure to a seasonal allergic trigger.[52]

Step 3. Patients with asthma symptoms most days (e.g., 4-5 days per week or more), or waking due to asthma once a week or more, low lung function, and risk factors for exacerbations.[52]

  • Track 1 (preferred): start on low-dose ICS-formoterol as MART.

  • Track 2 (alternative): daily low-dose ICS plus a LABA (ICS-LABA) with either as-needed SABA or as-needed ICS-SABA.

  • Track 2 (alternative): daily medium-dose ICS with either as-needed SABA or as-needed ICS-SABA.

Step 4. Patients with daily asthma symptoms, waking at night once a week or more, and with low lung function.[52]

  • Track 1 (preferred): start on medium-dose ICS-formoterol as MART (the same inhaler should be used for both maintenance and reliever doses. The maintenance dose is increased by increasing the number of inhalations (e.g., 2 inhalations twice daily), but the reliever is still low-dose ICS-formoterol (e.g., 1 inhalation).

  • Track 2 (alternative): daily medium- or high-dose ICS-LABA with either as-needed SABA or as-needed ICS-SABA.

  • Track 2 (alternative): some patients may also be treated with high-dose ICS plus as-needed SABA (consider likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever).

Patients whose initial presentation is with an acute exacerbation.

  • In an urgent care setting or where a patient presents with an acute exacerbation, please refer to the guidance for managing Acute asthma exacerbation in adults.

  • A short course of oral corticosteroids may be needed for patients presenting with severely uncontrolled asthma (track 1 or 2).

High-dose ICS are only recommended for short-term use (e.g., 3-6 months).[52]

Patient response should be reviewed 2-3 months after starting treatment, or earlier if clinically indicated, and should include checks of both treatment adherence and inhaler technique. Decisions made about further treatment changes should then follow the stepwise approach to ongoing management. Stepping down treatment can be considered once good control has been maintained for 3 months.[52]

GINA has released a separate pocket guide on difficult-to-treat and severe asthma. GINA: diagnosis and management of difficult-to-treat and severe asthma Opens in new window These patients should be referred for expert assessment, phenotyping, and add-on therapy.

Stepwise therapy for long-term management

Guidelines recommend that asthma severity and control be viewed as a ladder in which medication can be stepped up or stepped down based on the severity of the disease and adequacy of the control, for example, as determined by the Asthma Control Test.[1][52][82] [ Cochrane Clinical Answers logo ] ​​ The stepwise approach is meant to assist, not replace, the clinical decision-making required to meet individual patient needs. 

Patients may start at any step of the ladder, and medications can be added (stepped up) if needed.

Stepping up of treatment may be needed at any time in a patient with poor symptom control and/or exacerbations despite taking asthma treatment. Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. Before stepping up treatment, the patient should have their inhaler technique and adherence to treatment checked, their diagnosis of asthma confirmed, any risk factors or persistent allergen exposure removed (e.g., smoking), and any comorbidities addressed.[52] [ Cochrane Clinical Answers logo ]

If prescribed, increasing use of a reliever or use >2 days a week for symptom relief (not prevention of exercise-induced bronchoconstriction) generally indicates inadequate control and the need to step up treatment.[52]

Regular assessment of a patient's asthma control should be carried out with the aim of stepping down the ladder if disease has been well controlled for at least 3 months.[52]​ The criteria for each GINA step is considered whether stepping up therapy (inadequately controlled on their current step) or stepping down therapy (adequately controlled on the current step and meets the criteria for a lower step).

All patients should receive an ICS as part of their treatment. Potency is not equivalent between ICS medications labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[52]

GINA step 1: Initial treatment for patients using SABA alone or with newly diagnosed asthma, if normal (or mildly reduced) lung function

For step 1, there are two main options:[52]

  • Low-dose ICS-formoterol on an as-needed basis for relief of symptoms and before exercise, if needed (preferred track 1 option - combined as steps 1-2).

  • Low-dose ICS taken whenever a SABA is taken or an ICS-SABA (i.e., anti-inflammatory reliever [AIR]) taken as needed (track 2).

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52]

GINA no longer recommends as-needed SABA monotherapy at step 1; evidence shows that as-needed low-dose ICS-formoterol is superior for preventing asthma exacerbations.[83][84][85][86][87]​ Although formoterol is a LABA, it has a fast onset of action suitable for reliever treatment.[88]

The evidence for using an ICS and SABA at step 1 is indirect, being taken from small studies with separate or combination ICS and SABA inhalers in patients eligible for step 2 treatment.[89][90][91][92]​ When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose (compliance is higher).[52]

Modest over-use of SABA increases the risk of severe exacerbations and asthma-related death, and adding any ICS significantly reduces this risk.[52][88][93]​​​ High SABA use is associated with a significant increase in exacerbations and asthma-related healthcare utilization.[94][95]​​​ Patient populations most at risk for SABA over-reliance include older adults, smokers, and patients with lower socioeconomic status.[95] The Global Policy Steering Group on Improving Asthma Outcomes recommends a patient reassessment if ≥3 SABA inhalers are used in 1 year.[96]

The recommended maximum daily usage of as-needed budesonide/formoterol corresponds to a total of 72 micrograms of formoterol. However, in randomized controlled trials in mild asthma, such high usage was rarely seen, with average use around 3-4 doses per week.[52][83][84][97]​​​ 

Although GINA does not recommend SABA alone for the treatment of asthma in adults or adolescents, as-needed treatment with SABA alone remains an option in other guidelines, including US guidelines, for patients with infrequent and short-lived wheeze.[52][62]​​​​[96]

One Cochrane review of serious adverse events when taking ICS with and without regular formoterol found no difference in risk of death in adults taking ICS-formoterol versus ICS alone.[98] [ Cochrane Clinical Answers logo ]

GINA step 2: asthma not controlled on step 1 treatment

For step 2, there are three main options:

  • Low-dose ICS-formoterol on an as-needed basis for relief of symptoms and before exercise, if needed (preferred track 1 option - combined as steps 1-2)

  • Daily low-dose ICS plus as-needed SABA or ICS-SABA (track 2)

  • Low-dose ICS to be taken whenever a SABA is taken (track 2)

In GINA track 1, the decision to start steps 1-2 (i.e., as-needed low-dose ICS-formoterol) instead of step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the absence of risk factors for exacerbation. These include daily symptoms, current smoking, low lung function, a recent severe exacerbation or history of life-threatening exacerbation, impaired perception of severity, severe airway hyperresponsiveness, or current exposure to an allergic trigger.[52]

Low-dose ICS-formoterol on an as-needed basis decreases glucocorticoid exposure at the expense of some degree of symptom control but is noninferior to low-dose ICS maintenance therapy in terms of preventing exacerbations (track 1).[52][97]

Daily low-dose ICS plus as-needed SABA or ICS-SABA is an alternative option at step 2 (track 2).[1][52]​​​​ Adherence with maintenance ICS is very low in patients with mild asthma.[52]

Another option at step 2 is for low-dose ICS to be taken whenever SABA is taken (track 2).[52][62][89][90][91][92]​ When choosing between steps 1 and 2 (track 2), taking an ICS whenever a SABA is taken is preferred over daily ICS plus as-needed SABA (track 2, step 2) to ensure that patients with infrequent symptoms receive an ICS dose.[52]

LTRAs are less effective than ICS.[99] However, daily LTRA may be appropriate as an alternative initial controller treatment in patients who are unable or unwilling to use ICS, patients who experience adverse effects from ICS, or patients with concomitant allergic rhinitis.[52] Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

For adults or adolescents with asthma who have not previously been using controller treatment, regular daily low-dose ICS-LABA reduces symptoms and improves lung function compared with low-dose ICS alone.[100] However, it is more expensive and does not further reduce the risk of exacerbations compared with ICS alone.​[52][100]​​​ One Cochrane review comparing regular ICS-formoterol with ICS-salmeterol, an alternative LABA, found both combinations to have a similar safety profile in patients with chronic asthma.[101]

GINA step 3: asthma not controlled on steps 1-2 treatment (track 1) or step 2 treatment (track 2), with risk factors for exacerbation

For step 3, there are two main options:

  • Low-dose ICS-formoterol as maintenance therapy plus low-dose ICS-formoterol as reliever therapy (preferred by GINA - track 1)

  • Low-dose ICS plus LABA (ICS-LABA) as maintenance treatment with either as-needed SABA or as-needed ICS-SABA as reliever therapy (track 2).

In maintenance and reliever therapy (MART), the patient takes a regular fixed dose and uses the same inhaler as an as-needed reliever.[52]​​​​ ICS-formoterol as MART reduces exacerbations and provides similar levels of asthma control at relatively low doses of ICS compared with either regular, fixed-dose ICS-LABA plus SABA as needed or higher-dose ICS SABA as needed.[102][103][104][105][106][107][108][109]​​​​ MART is the preferred option at steps 3 and 4 in the 2020 US National Asthma Education and Prevention Program guidelines.​

In GINA track 1, steps 1-2 are the same (i.e., as-needed low-dose ICS-formoterol). The decision to start step 3 (i.e., low-dose ICS-formoterol as MART) is determined by the presence of specific clinical factors:[52]

  • Daily symptoms

  • Current smoking

  • Low lung function

  • A recent severe exacerbation or a history of life-threatening exacerbation

  • Impaired perception of bronchoconstriction (e.g. low initial lung function but few symptoms)

  • Severe airway hyperresponsiveness

  • Current exposure to a seasonal allergic trigger

At GINA steps 3-5, low-dose ICS-formoterol is the preferred reliever only for patients who are prescribed MART with ICS-formoterol. GINA does not recommend use of ICS-formoterol as a reliever for patients taking combination ICS-LABA medications with a different LABA. For these patients, their as-needed reliever inhaler should be a SABA or ICS-SABA.[52]

For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52] 

The alternative to ICS-formoterol as MART in GINA guidance is low-dose ICS plus LABA as regular treatment with as-needed SABA or ICS-SABA as a reliever (track 2). Adding a LABA to ICS in a combination inhaler leads to improved symptoms and lung function, and a reduced risk of exacerbations.[52]​ LABAs should not be used without ICS for asthma.[52]

Another option for track 2 is medium-dose ICS, but this is less efficacious than adding a LABA to low-dose ICS.[52] As-needed SABA or ICS-SABA should also be prescribed.

The use of as-needed ICS-SABA is supported by evidence from a multinational, phase 3, double-blind, randomized trial showing that, at step 3, the risk of severe asthma exacerbations was significantly lower using a fixed-dose albuterol/budesonide combination than with as-needed albuterol alone.[110] 

Add-on LTRA is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

GINA step 4: asthma not controlled on step 3 treatment

For step 4, there are two main options:

  • Medium-dose ICS-formoterol as maintenance therapy and low-dose ICS-formoterol as reliever therapy (preferred by GINA - track 1)

  • Medium- or high-dose ICS plus LABA as maintenance treatment with either as-needed SABA or as-needed ICS-SABA as a reliever (track 2)

For adults and adolescents with asthma, combination ICS-formoterol as MART is better at reducing exacerbations than the same dose of maintenance ICS-LABA or high doses of ICS.[106] For MART, the same inhaler is used for both maintenance and reliever doses. The maintenance dose can be increased by increasing the number of inhalations, but the reliever is still low-dose ICS-formoterol.[52]

Low-dose ICS-formoterol is the preferred reliever only for patients who are prescribed MART with ICS-formoterol. GINA does not recommend use of ICS-formoterol as the reliever for patients taking combination ICS-LABA medications with a different LABA. For these patients, their as-needed reliever inhaler should be a SABA or ICS-SABA.[52]

The use of as-needed ICS-SABA comes from a multinational, phase 3, double-blind, randomized trial showing that, at step 4 therapy, there was no significant increase in time to first severe exacerbation with as-needed ICS-SABA compared with as-needed SABA.[110]

For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52]

For patients taking daily low-dose ICS plus LABA with as-needed SABA or ICS-SABA at step 3, then a step-up option is an increase to daily medium-dose ICS plus LABA with as-needed SABA or ICS-SABA at step 4 (track 2).[52][111]​​​ Increasing to high-dose ICS-LABA is another option at step 4, but clinicians and patients should consider the potential increase in adverse effects relating to ICS.[52] The increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and the risk of adverse effects is increased. Systemic adverse effects relating to long-term, high-dose ICS include easy bruising, an increased risk of osteoporosis, cataracts, glaucoma, and adrenal suppression. Local adverse effects of ICS include oropharyngeal candidiasis (oral thrush) and dysphonia.[52]​ High-dose ICS are only recommended for short-term use (e.g., 3-6 months).[52]

Another option for track 2 is switching to high-dose ICS, but this is less efficacious than adding a LABA to medium-dose ICS.[52] As-needed SABA or ICS-SABA should also be prescribed.

Add-on LTRA is an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]​​

LAMAs, such as tiotropium, glycopyrrolate, or umeclidinium, may be used as an add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose ICS-LABA (track 1 or track 2).[52] At step 4, there is insufficient evidence to support ICS plus LAMA over ICS plus LABA.[62][112]​​​​ Adding LAMAs to medium- or high-dose ICS-LABA modestly improves lung function and time to severe exacerbations requiring an oral corticosteroid.[112][113][114][115][116][117]​​​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared with ICS-LABA, but no significant differences in quality of life or mortality.[115] Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]​ LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contains ICS, LABA, and LAMA. Inhaler availability varies by country.[52]

GINA step 5: asthma not controlled on step 4 treatment (specialist referral)

If a patient with asthma has persistent symptoms or exacerbations despite taking step 4 treatment with good adherence and correct inhaler technique, and despite considering other controller options, then they should be referred to a specialist in severe asthma (track 1 or track 2).[52] GINA has released a separate pocket guide on difficult-to-treat and severe asthma. GINA: diagnosis and management of difficult-to-treat and severe asthma Opens in new window

Following specialist assessment and optimization of existing treatment, options at step 5 include the following.[52]

  • High-dose ICS-formoterol as maintenance therapy plus low-dose ICS-formoterol as reliever therapy may be considered (track 1).[52] For the MART regimen, the same inhaler should be used for both maintenance and reliever doses. The maintenance dose can be increased by increasing the number of inhalations, but the reliever is still low-dose ICS-formoterol.[52] At steps 3-5 of the GINA recommendations for adults and adolescents, low-dose ICS-formoterol is the preferred reliever only for patients who are prescribed MART with ICS-formoterol. GINA does not recommend use of ICS-formoterol as the reliever for patients taking combination ICS-LABA medications with a different LABA. For these patients, their reliever inhaler should be either as-needed SABA or as-needed ICS-SABA (i.e., AIR). For patients taking ICS-formoterol as MART, the maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) for budesonide/formoterol.[52]

  • High-dose ICS plus LABA may be considered (track 2): however, the increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and the risk of adverse effects is increased, including adrenal suppression. A high dose should only be used on a trial basis for 3-6 months while good asthma control is not attained with medium-dose ICS plus LABA and/or a third controller (e.g., LTRA or sustained-release theophylline). The patient must also take a SABA or ICS-SABA as needed.[52]​ High-dose ICS are only recommended for short-term use (e.g., 3-6 months).[52]

  • Add-on LTRA: an option for either track 1 or track 2.[52] Please note that it is preferable to change only one medication at a time in chronic management, in order to see which medication had an effect. Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[71]​ These include new-onset nightmares, behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression, and headache), and suicidal ideation. Healthcare professionals are advised to consider the benefits and risks of montelukast before prescribing, to have an open discussion with patients about potential adverse effects, and to monitor for the emergence of adverse effects during treatment.[52]

  • Add-on LAMA: LAMAs, such as tiotropium, glycopyrrolate, or umeclidinium, may be used as add-on therapy if asthma is persistently uncontrolled despite medium- or high-dose ICS-LABA (track 1 or track 2). Add-on LAMA modestly improves lung function and time to severe exacerbations requiring oral corticosteroids.[112][113][114][115][116][117]​​ A systematic review and meta-analysis found beneficial effects of ICS-LABA-LAMA on exacerbations and asthma control compared with ICS-LABA, but no significant differences in quality of life or mortality.[115] Benefit is seen primarily in patients with a history of exacerbations in the previous year.[118]​ LAMAs may be given as a separate inhaler, or in a combination ("triple") inhaler that contains ICS, LABA, and LAMA. Inhaler availability varies by country.[52]

  • Add-on biologic agent (track 1 or track 2): omalizumab for moderate or severe allergic asthma; mepolizumab, reslizumab, or benralizumab for severe eosinophilic asthma; or dupilumab for severe eosinophilic/type 2 asthma; or tezepelumab for severe asthma.[52] See Biologic agents section.

  • Add-on bronchial thermoplasty (track 1 or track 2): this procedure is a potential option at step 5 in patients ages ≥18 years when the patient's asthma remains uncontrolled despite optimized pharmacologic therapy and referral to a specialist.[52]​​​ See Bronchial thermoplasty section.

  • Add-on azithromycin (track 1 or track 2): azithromycin is included in the GINA guideline as an alternative add-on therapy (off-label) for patients ages 18 years and older with severe asthma (i.e., after referral at step 5).[52][119] A Cochrane review of macrolides (including azithromycin) for the management of chronic asthma found macrolides superior to placebo in reducing severe exacerbations and improving symptoms.[120] However, more robust clinical trial evidence is needed for definite conclusions to be drawn, and concerns remain over the potential for selection of resistant infections and frequency of adverse effects, especially gastrointestinal upset.[120][121] In addition, a cohort study including almost 8 million antibiotic exposures showed an association between outpatient azithromycin use and an increased risk of cardiovascular death and noncardiovascular death.[122] Before starting add-on azithromycin, the patient’s sputum should be checked for atypical mycobacteria, their EKG should be assessed for long QTc interval and re-checked a month after starting treatment, and the risk of antimicrobial resistance should be considered.[52] A baseline audiogram should also be performed to allow monitoring of the effect of azithromycin on hearing function.

  • Add-on low-dose oral corticosteroid (track 1 or track 2): should only be considered if the patient has poor control of symptoms and/or frequent exacerbations despite correct inhaler technique and good adherence with step 5 treatments, and having excluded contributory factors, and having tried other add-on treatments including biologic agents.[52] Results from a systematic review and meta-analysis suggested that patients with increased markers of type 2 inflammation (i.e., high blood eosinophils and fractional exhaled nitric oxide values) are most responsive to oral corticosteroid therapy.[123] As oral corticosteroids often lead to substantial adverse effects, patients need to be counseled on, and monitored for, potential adverse effects.[124][125]​ Some patients may need therapy for prevention of osteoporosis.[52]

  • Sputum-guided treatment (track 1 or track 2): if the patient has symptoms that persist and/or exacerbations despite high-dose ICS or ICS plus LABA, then their treatment may be adjusted based on eosinophilia (>3%) in induced sputum. However, only a limited number of centers have facilities to analyze induced sputum routinely.[52]

Biologic agents

In general, biologics reduce the need for oral corticosteroid treatment in patients with severe asthma.[125]

GINA only recommends biologic therapy for severe asthma and after existing treatment has been optimized, regardless of regulatory approvals.[52] 

Omalizumab can be considered at step 5 in patients with moderate or severe allergic asthma that is uncontrolled on step 4 to 5 treatment.[52][126][127][128]​​ Mepolizumab, reslizumab, or benralizumab can be considered for patients with severe eosinophilic asthma that is uncontrolled on step 4 to 5 treatment.[52][129][130]​​ Dupilumab can be considered for patients with severe eosinophilic/type 2 asthma, or patients requiring treatment with maintenance oral corticosteroids.[52][131]​​ Tezepelumab can be considered for patients with severe asthma as an add-on maintenance treatment.[52][132][133]

Omalizumab

  • Omalizumab is approved for patients with severe allergic asthma, elevated immunoglobulin E (IgE) levels, and positive testing for a perennial aeroallergen. It works by binding to the high-affinity IgE receptor on mast cells and basophils and thus preventing the activation and release of cytokines involved in the response to allergic antigens. Studies have shown that add-on therapy with omalizumab can lead to a significant decrease in asthma exacerbations, as well as allowing for a decrease in dose of oral corticosteroids while maintaining asthma control.[127][134] Real-world data collected since use of omalizumab became widespread confirms the effectiveness of omalizumab as add-on therapy to standard therapy.[135][136][137] Observational trials have shown an increase in long-term quality of life after 48 weeks and 9 years of using omalizumab.[138]

Mepolizumab

  • Interleukin-5 (IL-5) is part of the eosinophilic type 2 inflammatory response, and modulating it likely reduces the inflammation in asthma and target airway remodeling. Phase 3 studies of mepolizumab have shown a role in reducing exacerbations and oral corticosteroid dose in refractory eosinophilic asthma.[139][140][141][142][143] Mepolizumab is approved as add-on maintenance treatment for patients with severe asthma with an eosinophilic phenotype. A post-hoc meta-analysis has shown that a fixed-dose regimen of mepolizumab can be used, regardless of body weight or body mass index.[144] A post-hoc analysis of two randomized controlled trials has shown improvements in morning peak expiratory flow with use of mepolizumab.[145]

Reslizumab

  • Reslizumab is a humanized monoclonal antibody that binds to IL-5. It has been approved as add-on maintenance therapy for patients with severe asthma and eosinophilic phenotype. It is approved for use in adults ages ≥18 years of age only. An indirect comparison meta-analysis of reslizumab and mepolizumab mostly showed no significant differences in efficacy or safety.[146]

Benralizumab

  • Benralizumab is a humanized monoclonal antibody that binds to the IL-5 alpha receptor and is approved as add-on therapy in patients with severe asthma and an eosinophilic phenotype. It has been shown to decrease rates of asthma exacerbations and also has a significant corticosteroid-sparing effect, as well as benefits in patient-reported outcomes, health-related quality of life, lung function, and nasal polyposis symptoms.[147][148][149][150] An open-label study of an individualized corticosteroid-reduction algorithm found that 63% of patients treated with benralizumab eliminated use of oral corticosteroids, and 82% eliminated use or achieved a dosage of ≤5 mg/day if the reduction was stopped due to adrenal insufficiency.[151] During the oral corticosteroid reduction phase (which was of a variable duration depending on starting oral corticosteroid dose, adrenal status, and symptoms), 75% of patients had no asthma exacerbations.[151] About 6% of patients experienced exacerbations requiring urgent medical intervention.[151]

Dupilumab

  • Dupilumab is a fully human monoclonal antibody to the alpha subunit of the IL-4 receptor. In patients with persistent moderate-to-severe asthma and elevated eosinophil levels who used inhaled glucocorticoids and LABAs, dupilumab therapy, compared with placebo, was associated with fewer asthma exacerbations when LABAs and inhaled glucocorticoids were withdrawn, and with improved lung function and reduced levels of type 2-associated inflammatory markers.[131] Data from a long-term open-label extension study are consistent with findings from earlier clinical studies of dupilumab, with nasopharyngitis, injection-site erythema, and bronchitis representing the most common treatment-related adverse events.[152] The efficacy and safety of dupilumab was sustained for up to 96 weeks in the main patient cohort, and for up to 148 weeks in a subgroup of patients with an eosinophilic/type 2 inflammatory phenotype.[152] Dupilumab is approved as add-on maintenance therapy in patients with moderate-to-severe asthma, patients with an eosinophilic phenotype, or patients with oral corticosteroid-dependent asthma.

  • A Cochrane review found that anti-IL-4 agents (including dupilumab) probably reduce asthma exacerbations requiring urgent medical intervention.[153] However, there was a trade-off with increased adverse events (most commonly upper respiratory tract infection, nasopharyngitis, headache, and injection-site reaction).[153] The authors of the review therefore concluded that anti-IL-4 therapy may be appropriate for adults with moderate-to-severe uncontrolled asthma who have not responded to other treatments.[153]

Tezepelumab

  • Tezepelumab is a human IgG2 monoclonal antibody that blocks thymic stromal lymphopoietin, an upstream epithelial alarmin cytokine believed to be involved in airway inflammation.[154][155] A randomized controlled phase 3 trial of 1061 people with severe, uncontrolled asthma found that those who were treated with tezepelumab had fewer exacerbations and better lung function, asthma control, and health-related quality of life compared with those who received placebo.[132] Tezepelumab is approved as add-on maintenance therapy in patients with severe asthma.

Some biologics are suitable for self-administration at home after appropriate training.[156]

Stepping down therapy

Asthma therapy may be stepped down in patients with severe asthma who show a good response to type 2-targeted therapy.[52] Any step-down in therapy should prioritize reducing and stopping maintenance OCS. One phase 4 study of patients receiving benralizumab showed that it was possible to reduce the maintenance ICS dose slowly while maintaining asthma control.[157]​ Switching to the use of a low-dose MART may be possible at GINA step 5 treatment.[52]

Biologic therapy withdrawal

Limited research has looked at the topic of withdrawing biologic therapy; stepping down therapy requires careful consideration because of the risk of relapse.[158][159][160][161][162] A trial withdrawal of the biologic should not be considered until after at least 12 months of treatment, only if asthma remains well controlled on medium-dose ICS therapy, and only if exposure to a previously well-documented allergic trigger can be avoided.[52] Careful monitoring is needed when a trial withdrawal is attempted.

One double-blind randomized controlled trial reported that patients who stopped mepolizumab experienced more exacerbations and reduced asthma control over the subsequent 12 month period than patients who continued treatment.[160]

Bronchial thermoplasty

Bronchial thermoplasty is a bronchoscopic procedure in which controlled thermal energy is applied to the airway wall to decrease smooth muscle. In people with severe asthma, this procedure improves asthma-specific quality of life, with a reduction in severe exacerbations and healthcare use in the post-treatment period.​[163][164][165]​​ This procedure is a potential option at step 5 in patients ages ≥18 years when the patient's asthma remains uncontrolled despite optimized pharmacologic therapy and referral to a specialist.[52]​​​​ Approval was based on strict criteria including a history of poorly controlled asthma despite high-dose ICS plus LABA treatment, FEV₁ >60% of predicted, no history of life-threatening exacerbations, and fewer than three exacerbations in the past year. Bronchial thermoplasty performed outside these criteria is considered experimental. A follow-up of 45% of patients from three randomized controlled trials found that the efficacy of bronchial thermoplasty, in terms of proportions of severe exacerbations, quality of life, and spirometry, was sustained for 10 years or more, with a small proportion of patients developing mild or moderate bronchiectasis.[166] The 2020 US guidelines on asthma conditionally recommend against bronchial thermoplasty, except where patients place a low value on harms and a high value on potential benefits.[62]

Use of this content is subject to our disclaimer