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Astma bij volwassenen: diagnose en monitoring in de eerste lijnPublished by: Werkgroep Ontwikkeling Richtlijnen Eerste Lijn (Worel)Last published: 2020Asthme chez l’adulte : diagnostic et surveillance en soins de santé primairesPublished by: Groupe de Travail Développement de recommmandations de première ligneLast published: 2020

​The information on management in this topic is based on the Global Initiative for Asthma (GINA) guideline for the treatment of patients with asthma ages 12 years and older.[3]

Asthma management should be twofold, targeting symptom control and reducing the risk for asthma exacerbations:[3]

  • 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).

Aim to achieve maximum symptom control with the fewest drugs and lowest therapeutic burden. Treatment that uses combination inhalers is preferred, and once control is achieved, attempts should be made to reduce the dose while maintaining control and minimizing adverse effects. Consider confirming the diagnosis if symptoms do not resolve despite good compliance.

All patients with asthma should also receive guided self-management education, including a written personalized asthma action plan, with the following elements:[3][141]

  • General information about asthma

  • How to monitor symptoms and/or lung function

  • How to recognize and respond to worsening symptoms

  • Training on the correct use of prescribed inhaler devices

  • Advice about environmental control and nonpharmacologic elements of treatment (e.g., reducing exposure to indoor and outdoor air pollution, tobacco smoke, and occupational and domestic allergens)

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

Treatment terminology

Therapeutic options are classified as follows:[3]

  • Maintenance: describes drugs used continuously, even when asymptomatic (i.e., frequency of administration, not drug class). Includes ICS-containing drugs, leukotriene receptor antagonists (LTRAs), and biologics. ICS-containing drugs can be prescribed as an ICS alone or combined with a long-acting beta agonist (LABA) and/or long-acting muscarinic antagonist (LAMA).

  • Controller: describes any drug 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 short-acting beta agonists (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 albuterol/budesonide. Used in GINA steps 1-2.

  • 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 GINA steps 3-5.

Stepwise therapy for long-term management

Guidelines recommend that asthma therapy be viewed as a ladder in which drug can be stepped up or stepped down based on disease severity or control (e.g., using the Asthma Control Test).[1][3][142] [ Cochrane Clinical Answers logo ] ​ This 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 based on their presentation. The criteria for each step are then 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).

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.[3]

  • Track 1: reliever drug is as-needed low-dose ICS-formoterol as AIR therapy; steps 1 and 2 are the same. Subsequent steps are treated with MART.

  • Track 2: reliever drug is either as-needed SABA taken with a low-dose ICS for symptom relief (step 1) or as-needed SABA with concurrent maintenance ICS-containing treatment (steps 2-4).

Track 2 options tend to increase treatment complexity by requiring more inhalers. Therefore, consider the likelihood of adherence to maintenance therapy before prescribing a SABA as a reliever. Note that GINA does not recommend SABA monotherapy for the treatment of asthma in adults or adolescents.[3]

Treatment can be stepped up or down in either track, using the same reliever at each step. Treatment can also be switched between tracks, depending on patient preference and need.[3]

In chronic management, aim to change only one drug at a time so that it is clear what drug has 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.[3] [ Cochrane Clinical Answers logo ] ​​ Increasing reliever use generally indicates inadequate control and the need to step up treatment (e.g., use >2 days a week, excluding use to prevent exercise-induced bronchoconstriction).[3]

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.[3]

Initial asthma control

All patients should receive an ICS as part of their treatment.

Step 1

Patients with asthma symptoms 1-2 days per week or less and no risk factors for exacerbations.[3]

  • Track 1 (preferred): start on as-needed low-dose 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.[3]

  • 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.[3]

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.[3]

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

  • Track 2 (alternative): daily low-dose 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.[3]

  • 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, refer to guidance specific to for management of exacerbation. See 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).

Overarching principles

High-dose ICS are only recommended for short-term use (e.g., 3-6 months).[3]​ Additionally, potency is not equivalent between ICS drugs labeled "low dose," "medium dose," and "high dose"; a switch between brands may, therefore, represent a clinically significant dose change.[3]

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.[3]

GINA has released a separate pocket guide on difficult-to-treat and severe asthma. These patients should be referred for expert assessment, phenotyping, and add-on therapy.

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

All patients with asthma should receive an ICS as part of their treatment. Long-term therapy with a low- to medium-dose ICS is safe and associated with only mild local adverse effects.[143][144]​ See Complications.

For step 1, there are two main treatment options, typically given as AIR:[143]

  • 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 taken as needed (track 2).

ICS-formoterol as AIR

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.[143]

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, hospital admissions, and death associated with SABA overuse.[145][146][147][148]​ Although formoterol is a LABA, it has a fast onset of action suitable for reliever treatment.[147][149]​​​​ 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.[150] [ Cochrane Clinical Answers logo ]

As-needed treatment with SABA alone remains an option for patients with infrequent and short-lived wheeze in the National Heart, Lung, and Blood Institute (NHLBI) and National Asthma Education and Prevention Program Coordinating Committee (NAEPPCC) 2020 guideline.[3][111]

ICS-SABA as AIR

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.[151][152][153][154][155]​ 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 (adherence is higher).[3]

Modest overuse of SABA increases the risk of severe exacerbations and asthma-related death, and adding any ICS significantly reduces this risk.[3][147][156]​​ High SABA use is associated with a significant increase in exacerbations and asthma-related healthcare utilization.[157][158]​​ Patient populations most at risk for SABA over-reliance include older adults, smokers, and patients with lower socioeconomic status.[158]​ SABA use history should be obtained at every patient visit to identify usage patterns over time, which in turn, will guide treatment decisions; patient reassessment for possible overuse is suitable if ≥3 SABA inhalers are used in 1 year.[159][160]

GINA step 2: asthma not controlled on step 1 treatment

All patients with asthma should receive an ICS as part of their treatment. Long-term therapy with a low- to medium-dose ICS is safe and associated with only mild local adverse effects.[143][144]​ See Complications.

For step 2, there are three main treatment 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)

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

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

ICS-formoterol as AIR

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.[3]

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).[3][148]​​[161]​​

Low-dose ICS taken whenever SABA is taken

Low-dose ICS to be taken whenever SABA is taken is an alternative option at step 2 (track 2).[3][111][151][152][153][154]​​​ 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.[3]

Low-dose ICS maintenance plus as-needed SABA or ICS-SABA

Another option at step 2 is daily low-dose ICS plus as-needed SABA or ICS-SABA.[1][3]​ Adherence with maintenance ICS is very low in patients with mild asthma.[3]

For patients new to controller treatment, regular daily low-dose ICS-LABA reduces symptoms and improves lung function compared with low-dose ICS alone, but it is more expensive and does not further reduce the risk of exacerbations compared with ICS alone.[3][162]

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

All patients with asthma should receive an ICS as part of their treatment. Long-term therapy with a low- to medium-dose ICS is safe and associated with only mild local adverse effects.[143][144]​ See Complications.

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

  • 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

Low-dose MART

In MART, the patient takes a regular fixed dose and uses the same inhaler as an as-needed reliever.[3]

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.[149][163][164][165][166][167][168][169]​​​​ MART is the preferred option at steps 3 and 4 in the 2020 US National Asthma Education and Prevention Program guidelines.[111]

At GINA steps 3-5, low-dose ICS-formoterol is the preferred reliever only for patients who are prescribed MART with ICS-formoterol. 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.[3]

Low-dose ICS-LABA maintenance plus as-needed SABA or ICS-SABA

The alternative to ICS-formoterol as MART in the 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.[3]​ LABAs should not be used without ICS for asthma.[3]​ 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.[170]

GINA does not recommend use of ICS-formoterol as a reliever for patients taking combination ICS-LABA drugs with a different LABA. For these patients, their as-needed reliever inhaler should be a SABA or ICS-SABA.[3]

Medium-dose ICS

Another option for track 2 is medium-dose ICS, but this is less efficacious than adding a LABA to low-dose ICS.[3]​ 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.[171]

Switching from track 2 to track 1

In patients with uncontrolled asthma receiving a GINA track 2 treatment (i.e. maintenance ICS-LABA plus reliever SABA), a meta-analysis has shown that switching to GINA track 1 (i.e., MART) is associated with a longer time to first severe asthma exacerbation compared with stepping up or continuation of track 2 options at steps 3-5.[172]

LTRA

Add-on LTRA (e.g., montelukast) is an option for either track 1 or track 2.[3]​ LTRAs are less effective than ICS, but may be considered in combination with ICS-based therapy.[3][173]​​ Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[128]​ These include:

  • new-onset nightmares,

  • headache,

  • 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.[3]

GINA step 4: asthma not controlled on step 3 treatment

All patients with asthma should receive an ICS as part of their treatment. Long-term therapy with a low- to medium-dose ICS is safe and associated with only mild local adverse effects.[143][144]​ See Complications.

For step 4, there are two main treatment 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 (ICS-LABA) as maintenance treatment with either as-needed SABA or as-needed ICS-SABA as a reliever (track 2)

Medium-dose MART maintenance plus as-needed low-dose MART

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.[148][167]​​​ 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.[3]​ MART is the preferred option at steps 3 and 4 in the 2020 US National Asthma Education and Prevention Program guidelines.[111]​ The maximum recommended dose of formoterol in a single day is 72 micrograms metered dose (equivalent to 54 micrograms delivered dose) when budesonide/formoterol is given as MART.[3]

Medium- or high-dose ICS-LABA maintenance plus as-needed SABA or ICS-SABA

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).[3][174]​​ ​​​Long-term therapy with a low- to medium-dose ICS is safe and mainly associated with mild local adverse effects (e.g., oral or oropharyngeal candidiasis and dysphonia/hoarseness); treatment is not associated with increased risks of upper or lower respiratory tract infection (including influenza) or of fractures and changes in bone mineral density.[143][144]

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.[3]​ The increased dose of ICS rarely provides substantial extra benefit compared with a medium dose and increases the risk of adverse effects. Patients exposed to high-dose ICS are more susceptible to osteoporosis, cataracts, glaucoma, and adrenal suppression.[175]​ See Complications. High-dose ICS are only recommended for short-term use (e.g., 3-6 months).[3]

GINA does not recommend ICS-formoterol as the reliever for patients taking combination ICS-LABA drugs with a different LABA. For these patients, their as-needed reliever inhaler should be a SABA or ICS-SABA.[3]​ 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.[171]

High-dose ICS

Another option for track 2 is switching to high-dose ICS, but this is less efficacious than adding a LABA to medium-dose ICS at step 4.[3]​ As-needed SABA or ICS-SABA should also be prescribed. 

The increased dose of ICS rarely provides substantial extra benefit compared with a medium dose, and increases the risk of adverse effects. Patients exposed to high-dose ICS are more susceptible to osteoporosis, cataracts, glaucoma, and adrenal suppression.[175]​ See Complications.

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

LTRA

An LTRA (e.g., montelukast) may be considered if asthma is persistently uncontrolled despite medium-dose ICS-formoterol or medium- or high-dose ICS-LABA.[3]​ LTRAs are less effective than ICS, but may be considered in combination with ICS-based therapy.[3][173]​​ Serious neuropsychiatric events have been reported in patients taking LTRAs, particularly montelukast.[128]​ These include:

  • new-onset nightmares,

  • headache,

  • behavioral problems (e.g., agitation, hyperactivity, irritability, nervousness, aggression), 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.[3]

LTRAs can be given as a separate inhaler or in a combination ("triple") inhaler that contains ICS, LABA, and LAMA. Inhaler availability varies by country.

LAMA

A LAMA (e.g., tiotropium, glycopyrrolate, or umeclidinium) may be considered if asthma is persistently uncontrolled despite medium- or high-dose ICS-LABA (track 1 or track 2).[3]

Compared with medium-dose ICS alone, medium-dose ICS with either a LAMA or LABA both improve treatment response and reduce moderate-to-severe exacerbations.[111][144]​​[176]​​​ Compared with medium-dose ICS-LABA, switching to medium- or high-dose ICS-LABA-LAMA modestly improves lung function and time to severe exacerbations requiring oral corticosteroids, but not quality of life or mortality, with benefit seen primarily in patients with a history of exacerbations in the previous year.[177][178][179][180][181][182]

LAMAs can be given as a separate inhaler or in a combination ("triple") inhaler that contains ICS, LABA, and LAMA. Inhaler availability varies by country.

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.[3]​ Difficult-to-treat asthma remains an area of significant unmet need.[183]​ 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, several options may be considered at step 5:[3]

  • High-dose ICS

  • Add-on LTRA

  • Add-on LAMA

  • Add-on azithromycin

  • Add-on biologic agent

  • Add-on low-dose oral corticosteroid

  • Add-on bronchial thermoplasty

In chronic management, it is preferable to change only one drug at a time.[3]

High-dose ICS

High-dose ICS may be used on a trial basis for 3-6 months when good asthma control has not been attained with medium-dose ICS plus LABA and/or a third controller (e.g., LTRA or theophylline).[3][144]​​ However, increasing to high-dose ICS usually results in little to no difference in moderate to severe exacerbations compared with medium-dose ICS.[3][144]​​[181]​​

There are two main treatment options:

  • High-dose ICS-formoterol as maintenance therapy plus low-dose ICS-formoterol as reliever therapy (preferred by GINA - track 1).[3]​ For patients taking ICS-formoterol as MART, the maintenance dose is increased by increasing the number of inhalations, but low-dose ICS-formoterol MART is still used as the reliever.[3]

  • High-dose ICS plus LABA as maintenance therapy plus either as-needed SABA or as-needed ICS-SABA as a reliever (preferred by GINA - track 1).

High-dose ICS therapy increases the potential for osteoporosis, cataracts, glaucoma, and adrenal suppression.[175]​ Patients need to be counseled on, and monitored for, these adverse effects.[175][184][185]​​​ Consider therapy to prevent osteoporosis.[3][175]​​ See Complications.

LTRA

An LTRA (e.g., montelukast) may be considered if asthma is persistently uncontrolled despite a high-dose ICS in GINA tracks 1 and 2.[3]​ LTRAs are less effective than ICS, but may be considered in combination with ICS-based therapy.[3][173]​​ However, there is a risk of serious neuropsychiatric events in patients taking LTRAs, particularly montelukast.[128]​ 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.[3]

LAMA

A LAMA (e.g., tiotropium, glycopyrrolate, or umeclidinium) may be considered if asthma is persistently uncontrolled despite a high-dose ICS in GINA tracks 1 and 2.[3]

Compared with medium-dose ICS alone, medium-dose ICS with either a LAMA or LABA both improve treatment response and reduce moderate-to-severe exacerbations.[144]​ Compared with medium-dose ICS-LABA, switching to medium- or high-dose ICS-LABA-LAMA modestly improves lung function and time to severe exacerbations requiring oral corticosteroids, but not quality of life or mortality, with benefit primarily seen in patients with a history of exacerbations in the previous year.[176][177][178][180][181]​

LAMAs can be given as a separate inhaler or in a combination ("triple") inhaler that contains ICS, LABA, and LAMA. Inhaler availability varies by country.[3]

Azithromycin

GINA includes azithromycin as an off-label, add-on option (tracks 1 and 2), for patients ages 18 years and older with severe asthma.[3][186]​​ Secondary analysis of data from the Asthma and Macrolides: the Azithromycin Efficacy and Safety (AMAZES) clinical trial supports this approach in a significant proportion of people with persistent symptomatic asthma.[187][188]

One Cochrane review found macrolides superior to placebo in reducing severe exacerbations and improving symptoms of chronic asthma, but concluded that more robust clinical trial evidence was needed for definite conclusions to be drawn.[189]​ Concerns also remain over the frequency of potential adverse effects, including increased risks of cardiovascular and noncardiovascular deaths.[187][189]​​[190]

Before starting azithromycin, assess the following at baseline:[3]

  • sputum for atypical mycobacteria,

  • the risk of antimicrobial resistance,

  • EKG for a long QTc interval (re-check a month after starting treatment),

  • audiogram for hearing function (repeated if change reported).

Biologic therapy

GINA recommends biologic (type 2-targeted) therapy only for severe asthma and only after existing treatment has been optimized, regardless of regulatory approvals, advising that an initial trial should last at least 4 months (tracks 1 and 2).[3]​ In general, biologics reduce the need for oral corticosteroids and reduce the exacerbation rate in patients with severe uncontrolled asthma.[185]​​​[191][192][193][194]​​​

Biologic therapy is typically well tolerated, safe, and benefits from reducing the adverse effects associated with high-dose ICS or oral corticosteroid use. Although long-term safety data are lacking for some agents, minor injection site reactions are common and hypersensitivity reactions may occur.[195][196][197]

Several monoclonal antibodies are available. Although direct comparisons are complicated by a lack of consistent patient groups and outcome measures among trials, minimal differences are expected in clinical efficacy and safety when biologics are used according to their indications; where comparisons have been attempted, no single agent has shown superiority over another.[191][198][199][200][201][202][203]

Omalizumab binds to high-affinity immunoglobulin E (IgE) receptors on immune cells, preventing cytokine activation and release in response to allergens.[194]​​​

  • Approved as add-on maintenance therapy in adults and adolescents (ages ≥12 years) with severe allergic asthma, elevated IgE levels, and positive testing for a perennial aeroallergen.[3][196]​​[204][205][206]​​[207]

  • Factors associated with response include a history of childhood-onset asthma and a clinical history suggesting allergen-driven symptoms.[3]​ Baseline IgE and blood eosinophil levels are often used to select patients who may benefit from treatment.[3][208][209][210]​​​​ The presence of multiple allergic comorbidities or atopic dermatitis may be more reliable predictors of outcome.[211]

Mepolizumab binds to circulating interleukin (IL)-5, blocking part of the eosinophilic type 2 inflammatory response associated with airway inflammation and remodeling.[194]​​[212]

  • Approved as add-on maintenance treatment in adults and adolescents (ages ≥12 years) with severe asthma and an eosinophilic phenotype.[3][213][214][215]

  • Mepolizumab may also be given as a fixed-dose regimen, regardless of body weight or body mass index.[216]

  • Factors associated with response include high sputum eosinophil count at baseline, high number of severe exacerbations in the last year, adult-onset asthma, nasal polyps, maintenance oral corticosteroid requirement, and low lung function (FEV₁ <65% predicted).[3][217][218]

Reslizumab binds to circulating IL-5, blocking part of the eosinophilic type 2 inflammatory response associated with airway inflammation and remodeling.​[194][212]​​​​​

  • Approved as add-on maintenance therapy only for adults (ages ≥18 years) with severe asthma and an eosinophilic phenotype.[3][212][219]

  • Factors associated with response include high sputum eosinophil count at baseline, high number of severe exacerbations in the last year, adult-onset asthma, nasal polyps, maintenance oral corticosteroid requirement, and low lung function (FEV₁ <65% predicted).[3]

Benralizumab binds to the IL-5 alpha receptors on eosinophils and basophils, depleting them through cell-mediated cytotoxicity.​​[194]

  • Approved as add-on maintenance therapy in adults and adolescents (ages ≥12 years) with severe asthma and an eosinophilic phenotype.[3][196]​​[212][220][221][222][223]​​

  • Factors associated with response include high sputum eosinophil count at baseline, high number of severe exacerbations in the last year, adult-onset asthma, nasal polyps, maintenance oral corticosteroid requirement, and low lung function (FEV₁ <65% predicted).[3]

Dupilumab binds to the IL-4 alpha receptor, which inhibits IL-4 and IL-13 signaling in hematopoietic, epithelial, and airway smooth muscle cells.[194]​​​

  • Approved as add-on maintenance therapy in adults and adolescents (ages ≥12 years) with moderate-to-severe asthma, an eosinophilic phenotype, or oral corticosteroid-dependent asthma.[3][196]​​[224][225]​​[226][227]

  • Factors associated with response include higher blood eosinophils and higher fractional exhaled nitric oxide (FeNO) levels.[3]

Tezepelumab binds to thymic stromal lymphopoietin, an upstream epithelial alarmin cytokine believed to be involved in airway inflammation.​​[194][228]​​​​​​[229]

  • Approved as add-on maintenance therapy in adults and adolescents (ages ≥12 years) with severe asthma.[3][230][231][232][233][234][235]​​ Clinical utility has been shown in severe uncontrolled asthma regardless of phenotype, offering a safe and effective option for patients without eosinophilic or allergic asthma.[236][237]

  • Factors associated with response include higher blood eosinophils and higher FeNO levels.[3]

There is significant variation in prescribing practices, indicating a need for better defined endotypes and phenotypes to identify those patients who will benefit optimally from each treatment.[199][238][239]​​​​​​​ Some biologics are suitable for self-administration at home after appropriate training.[240]

Asthma therapy may be stepped down in patients with severe asthma who show good response to biologic (type 2-targeted) therapy.[3]​ This should prioritize reducing and stopping maintenance oral corticosteroids.[241][242]​ Evidence also suggests that the maintenance ICS dose can be reduced slowly while still maintaining asthma control in patients receiving benralizumab, indicating that switching to a low-dose MART may be possible.[242]

Stopping biologic therapy is associated with a high risk of relapse.[243][244][245][246][247]​ A trial withdrawal should not generally be considered until at least 12 months of treatment, only if:[3]

  • Asthma remains well controlled on medium-dose ICS therapy

  • Exposure to a previously well-documented allergic trigger can be avoided

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.[245]

Low-dose oral corticosteroids

Reserved for patients with poor symptom control and/or frequent exacerbations (track 1 or track 2) despite:[3]

  • correct inhaler technique,

  • good adherence with other step 5 treatments,

  • having excluded contributory factors, and

  • having tried other add-on treatments, including biologic agents (where appropriate).

Increased markers of type 2 inflammation (i.e., high blood eosinophils and FeNO values) indicate a higher likelihood of treatment response.[248]​ Oral corticosteroids increase the potential for osteoporosis, cataracts, glaucoma, and adrenal suppression.[175]​ Patients need to be counseled on, and monitored for, these adverse effects.[175][184][185]​​​​ Consider therapy to prevent osteoporosis.[3][175]​​​ See Complications.

Bronchial thermoplasty

This bronchoscopic procedure is a potential add-on option at step 5 (tracks 1 and 2) for patients ages ≥18 years when asthma remains uncontrolled despite optimized pharmacologic therapy.[3]

Bronchial thermoplasty involves the application of controlled thermal energy 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 posttreatment period.[249][250][251]

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.[252]​ 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.[111]

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