INTRODUCTION — The use of long-term controller medications in the treatment of persistent asthma in children <12 years of age is reviewed here. The recommendations that follow are based upon major published asthma guidelines [1-4], with additional therapies added as they become available and approaches modified based upon subsequently published data. Assessing initial asthma severity, determining when to start daily controller therapy, and assessing and monitoring control to determine if therapy modifications are needed are discussed in detail separately. (See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)
The initial evaluation and diagnosis of asthma, use of quick-relief medications, and management of acute exacerbations in children are all discussed separately. A general overview of asthma management and control of triggers are also presented separately, as is the management of asthma in adolescents and adults.
●(See "Asthma in children younger than 12 years: Initial evaluation and diagnosis".)
●(See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)
●(See "Asthma in children younger than 12 years: Quick-relief (rescue) treatment for acute symptoms".)
●(See "Acute asthma exacerbations in children younger than 12 years: Emergency department management".)
●(See "Acute asthma exacerbations in children younger than 12 years: Inpatient management".)
●(See "An overview of asthma management".)
●(See "Trigger control to enhance asthma management".)
●(See "Treatment of intermittent and mild persistent asthma in adolescents and adults".)
●(See "Treatment of moderate persistent asthma in adolescents and adults".)
●(See "Treatment of severe asthma in adolescents and adults".)
GOALS OF TREATMENT — The overarching goals of treatment are to maintain control of asthma symptoms and reduce exacerbations with the least amount of medications and fewest side effects.
TYPES OF CONTROLLER MEDICATIONS — The most commonly used controller medications for children <12 years of age are inhaled glucocorticoids (also called inhaled corticosteroids [ICS]), plus inhaled long-acting beta agonists (LABAs) or oral leukotriene receptor antagonists (LTRAs) in combination with inhaled glucocorticoids (table 1 and table 2). Long-acting anticholinergic agents (or long-acting muscarinic antagonists [LAMAs]; tiotropium, for children ≥6 years of age) and biologic agents (monoclonal antibodies against immunoglobulin E [IgE] and interleukin [IL] 5, for children ≥6 years of age (table 3)) are used as step-up therapy in patients whose asthma is not well controlled on other medications. Oral glucocorticoids; inhaled chromones (in the United States, nedocromil is not available in any form, and cromolyn is available only for use in a nebulizer); and sustained-release oral theophylline are very rarely used for daily asthma control.
Inhaled glucocorticoids — Glucocorticoids are the most effective antiinflammatory agents available for the treatment of asthma. They act by inhibiting most steps in the cascade of the inflammatory response [5,6]. The benefits of glucocorticoids include reduced bronchial hyperresponsiveness, prevention of the late asthmatic response, and enhanced lung function. Inhaled glucocorticoids delivered directly to the airways at a dose much lower than needed when given systemically have minimal side effects. In addition, much of the small amount of drug that is absorbed at low doses is deactivated after one pass through the liver. (See "Molecular effects of inhaled glucocorticoid therapy in asthma".)
●Specific preparations – The inhaled glucocorticoid preparations available in the United States and approved by the US Food and Drug Administration (FDA) for use in children <12 years are listed in the table (table 1). Off-label use of inhaled beclomethasone or inhaled fluticasone administered by metered dose inhaler (MDI) with spacers or valved holding chamber devices (some will need a facemask) are reasonable alternatives for young children [7]. This table also includes information on potency and dosing. Potency refers to the dose required to achieve the same clinical effect. (See "The use of inhaler devices in children".)
●Efficacy – Inhaled glucocorticoid treatment is associated with reduction in measures associated with impairment (symptom frequency and severity, functional limitations) and risk (side effects from medications, irreversible decline in lung function, likelihood of asthma exacerbations) (table 4A-B) [8-10]. Improvements in these parameters are generally greater and occur more frequently than changes seen with LTRAs (montelukast). Efficacy for each indication is discussed below. (See 'Initiating controller therapy' below and 'Step-up therapy' below and 'Daily LTRA' below.)
●Time to improvement – A reduction in asthma symptoms may occur rapidly, and reduced inflammation is seen within hours. Lung function continues to improve over four weeks and then plateaus. It may take as long as three months to reach a plateau in response, and any changes in dose should be made at intervals of three months or more [11].
●Time to loss of effect after discontinuation – When inhaled glucocorticoids are discontinued, there may be a gradual increase in symptoms and airway responsiveness back to pretreatment values. In a study of preschool children, the benefits were only seen while taking inhaled glucocorticoids, with symptoms worsening soon after the inhaled glucocorticoids were stopped [12]. A study of older children also showed that the effects of long-term daily treatment with inhaled glucocorticoids on asthma control and lung function did not persist once these medications were discontinued [13]. Nonetheless, step-down therapy should be attempted at appropriate intervals. (See 'Step-down therapy' below.)
●Dosing – Initial dosing of inhaled glucocorticoids (table 1) depends upon the severity of asthma symptoms at the time treatment is initiated (table 5A-B). The dose-response curve for the clinical efficacy of inhaled glucocorticoids is relatively flat, with most benefit obtained at the lowest doses used and only small additional benefit attained with higher doses. Long-term control therapy is then stepped up or down at one- to six-month intervals, depending upon clinical response and the ongoing severity of disease. Treatment for acute exacerbations is discussed in detail separately. (See 'Initiating controller therapy' below and 'Step-up therapy' below and 'Step-down therapy' below and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Inhaled glucocorticoids' and "Asthma in children younger than 12 years: Quick-relief (rescue) treatment for acute symptoms".)
●Delivery – The mode of delivery for inhaled glucocorticoids greatly influences drug deposition in the lungs and the frequency of local and systemic side effects [14-16]. Delivery systems include MDIs (with or without spacers or valved holding chambers), nebulizers, and dry powder inhalers (DPIs). These delivery systems are discussed separately. (See "Delivery of inhaled medication in children" and "Use of medication nebulizers in children" and "The use of inhaler devices in children".)
●Impact on disease progression – Although inhaled glucocorticoids play a critical role in the chronic management of infants with wheezing and children with asthma, consistent use in childhood does not appear to alter the natural history of asthma once medication is discontinued [17]. (See "Natural history of asthma".)
Airway remodeling, characterized by subepithelial fibrosis, smooth muscle hypertrophy, enlargement of glands, neovascularization, and epithelial alterations, has been noted in endobronchial biopsies from children with severe asthma and is significantly related to bronchodilator responsiveness. However, the evidence that any asthma therapies affect airway remodeling remains uncertain [18-20].
A small number of studies have addressed this question [12,21-25]. Three of these studies that enrolled infants and young children who were defined as "at risk" for asthma development and assessed whether the use of inhaled glucocorticoids altered later clinical outcomes found that the early use of inhaled glucocorticoids did not impact the subsequent development of asthma [12,22,23]. A larger study of older children also showed that the effects of long-term daily treatment with inhaled glucocorticoids on asthma control and lung function did not persist once these medications were discontinued [13].
●Adverse effects – The effect of chronic inhaled glucocorticoid use in children on adult height appears small. Ciclesonide appears to have lower systemic absorption and therefore fewer systemic side effects, but a systematic review found no clear benefit-to-harm ratio favoring ciclesonide over budesonide or fluticasone [26]. The potential side effects of inhaled glucocorticoids are reviewed in greater detail separately. (See "Major side effects of inhaled glucocorticoids".)
Leukotriene receptor antagonists (LTRAs) — LTRAs are another class of asthma controller medications. Cysteinyl leukotrienes (LTC4, LTD4, and LTE4) are potent bronchoconstrictors and also promote production of mucus and proinflammatory cytokines [27-29]. They have been identified in plasma, nasal secretions, sputum, and bronchoalveolar lavage fluid in patients with asthma [30]. Medications that block leukotriene receptors are less effective than inhaled glucocorticoids for treating asthma in most patients. However, some patients have a good response to monotherapy with LTRAs. In addition, results from one randomized trial suggest that, in a minority of patients, LTRAs may be more effective as add-on therapy to inhaled glucocorticoids than adding a LABA or increasing the dose of glucocorticoid [31,32]. Unfortunately, there is no effective way to predict who will respond well to LTRAs. The US FDA has added a boxed warning to the package insert stating that serious neuropsychiatric events that may include suicidal thoughts or actions have been reported in patients taking montelukast. The efficacy of LTRAs as monotherapy or add-on therapy with inhaled glucocorticoids for persistent asthma is discussed below and in greater detail separately. (See 'Daily LTRA' below and 'Inhaled glucocorticoid plus LTRA' below and "Antileukotriene agents in the management of asthma".)
Among the LTD4 receptor antagonists, montelukast is US FDA approved for control of asthma in children ≥12 months of age, and zafirlukast is approved for children ≥5 years. Dosing is reviewed in the table (table 2). Montelukast has an onset of action within one hour. No tachyphylaxis or change in the safety profile has been evidenced after up to 80 weeks of montelukast therapy in pediatric patients aged 6 to 14 years [33].
Quick-relief use of LTRAs and daily use for exercise-induced asthma are also discussed in detail separately. (See "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Leukotriene receptor antagonists' and "Exercise-induced bronchoconstriction", section on 'Prolonged or recurrent exercise'.)
Long-acting beta agonists (LABAs) — LABAs (salmeterol, formoterol), which have a duration of action of at least 12 hours, are used as an adjunct to inhaled glucocorticoids to provide long-term control of asthma symptoms and prevent nocturnal symptoms and exercise-induced bronchoconstriction [34-38]. Monotherapy with LABAs does not treat the inflammatory component of asthma [39,40]. As such, LABAs should not be used as monotherapy. Rather, they should only be used in combination products that contain inhaled glucocorticoids or concomitantly with an inhaled glucocorticoid if no combination product is available. Dosing of combination products is reviewed in the table (table 2). The onset of action of formoterol is similar to that of albuterol (three minutes), whereas salmeterol is slower (≥30 minutes).
Inhalers containing a LABA, including those using a LABA in combination with an inhaled glucocorticoid, were labeled in the United States from 2010 through 2017 with a boxed warning that advised health care professionals and patients that these agents may increase the chance of severe asthma episodes and asthma-related death when these episodes occur. Subsequent to the placement of this warning, a large (n = 6208), well-conducted trial found no excess of serious asthma events in children receiving a combination inhaler containing both fluticasone propionate (inhaled glucocorticoid) and salmeterol (LABA) versus fluticasone alone [41]. A review of this trial and three others prompted the removal of the boxed warning in December 2017 [42]. Long-term use of LABAs in conjunction with inhaled glucocorticoids is reviewed in greater detail separately. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Long-term maintenance therapy with LABAs'.)
Long-acting anticholinergic agents (LAMAs) — Tiotropium, an anticholinergic bronchodilator, is approved by the US FDA for long-term maintenance treatment in patients ≥6 years of age with severe symptomatic asthma not well controlled on inhaled glucocorticoids and other maintenance therapies at a dose of 2.5 mcg/day given as two inhalations of 1.25 mcg once daily (the 5 mcg/day dose is an off-label option) (table 2). Tiotropium should not be used for initial treatment nor as sole therapy for persistent asthma. While either the addition of a LABA or LAMA has been shown to lower the risk of exacerbations and improve lung function over inhaled glucocorticoids alone, triple therapy was not associated with a lower risk of exacerbations [43]. Nonetheless, tiotropium can be added to inhaled glucocorticoids plus a LABA. (See 'Add on tiotropium' below.)
Biologic agents — Biologic agents for use in children ≥6 years of age with severe asthma (table 6) who have not responded to usual therapy include omalizumab (anti-IgE), dupilumab (anti-IL-4), and mepolizumab (anti-IL-5) (table 3).
●Anti-IgE therapy – Omalizumab, a monoclonal antibody against IgE (anti-IgE), is a treatment option for patients with evidence of sensitization to at least one perennial aeroallergen and moderate-to-severe asthma that is not well controlled with standard therapy. Omalizumab is approved for children ≥6 years of age. Dosing is based upon total serum IgE level and weight. Anti-IgE therapy is discussed in greater detail separately. (See "Anti-IgE therapy", section on 'Omalizumab therapy in asthma'.)
●Anti-IL-4/IL-13 therapy – Dupilumab, a monoclonal antibody against the IL-4 receptor (anti-IL-4R) that inhibits both IL-4 and IL-13 signaling, is approved as add-on maintenance treatment for children ≥6 years of age with moderate-to-severe asthma. Dosing is weight and age based. The dosing for atopic dermatitis should be used if the patient has both atopic dermatitis and asthma. Use in adolescents and adults is reviewed in greater detail separately. (See "Treatment of atopic dermatitis (eczema)", section on 'Dupilumab' and "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)'.)
●Anti-IL-5 therapy – Mepolizumab, a monoclonal antibody against the IL-5 receptor (anti-IL-5R), is approved as add-on maintenance treatment for children ≥6 years of age with severe eosinophilic asthma [44]. Dosing is 40 mg given subcutaneously every four weeks. Use in adolescents and adults is reviewed in greater detail separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Mepolizumab'.)
ASSESSING ASTHMA SEVERITY — Asthma severity is classified based upon current impairment, which includes symptoms; rescue medication use; and, in older children, pulmonary function testing, and future risk of exacerbations that require treatment with systemic glucocorticoids, as outlined in the tables (table 5A-B). Assessment of asthma severity before initiating controller therapy is discussed in detail separately. (See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control", section on 'Assessment of severity in patients not on daily therapy'.)
INITIATING CONTROLLER THERAPY
Mild, persistent asthma — We suggest low-dose, daily inhaled glucocorticoids as initial controller therapy for children with mild, persistent asthma (step 2 therapy) (table 5A-B and table 1) [1,2,4,45,46]. Alternatives to daily inhaled glucocorticoids for mild, persistent asthma or step 2 therapy include a daily leukotriene receptor antagonist (LTRA) or intermittent low-dose inhaled glucocorticoids taken whenever a short-acting beta agonist (SABA) is used (table 2) [1,3,47]. The Global Initiative for Asthma (GINA) guidelines offer two options for adolescents and adults with mild, persistent asthma: as-needed, low-dose inhaled glucocorticoid plus fast-acting long-acting beta agonist (LABA) or inhaled glucocorticoid plus fast-acting LABA as both maintenance and reliever therapy (SMART) [47]. However, further studies are needed in children to determine whether intermittent inhaled glucocorticoids are an effective alternative to daily therapy in at least some patients and to define the optimal threshold at which patients should begin taking daily controller medication. (See "Treatment of intermittent and mild persistent asthma in adolescents and adults", section on 'Daily low-dose inhaled glucocorticoids'.)
Low-dose daily inhaled glucocorticoid — Efficacy data are primarily extrapolated from adolescent and adult studies since there are only a few trials in children for each inhaled glucocorticoid. These pediatric clinical trials as a whole have demonstrated that daily inhaled glucocorticoids are safe and effective in improving asthma control (symptoms, rescue medication use, and pulmonary function) [21,41,42,44,45,48-59]. However, these studies have several limitations. The trials are relatively small, many are older studies that used as comparators medications that are no longer commonly in use, and they are heterogeneous with regard to age of the patients, disease severity, specific inhaled glucocorticoid studied, comparators used, and outcomes measured.
The following studies are illustrative:
●In the Childhood Asthma Management Program (CAMP) trial, 311 children aged 5 to 12 years with mild-to-moderate asthma received budesonide (200 mcg twice daily), nedocromil (a chromone), or placebo [21]. Data from the initial six years of the study demonstrated improved asthma control with fewer hospitalizations (2.5 versus 4.4 per 100 person-years), fewer urgent care visits (12 versus 22 per 100 person-years), fewer courses of prednisone for exacerbations (70 versus 122 per 100 person-years), less need for symptomatic treatment with albuterol (decreased by 7.4 versus 5.3 puffs per week), and a smaller percentage of days on which additional asthma medications were needed (6.6 versus 18.7 percent) in patients receiving budesonide compared with placebo.
●In an open-label, controlled trial of children (age one to three years) with recurrent wheezing, 635 children were randomly assigned to receive fluticasone propionate (100 mcg twice per day) or cromolyn via metered dose inhaler (MDI) and spacer device for 52 weeks [55]. Compared with those treated with cromolyn, children in the fluticasone group had fewer episodes of severe exacerbation (7 versus 16 percent) and requirements for oral glucocorticoid treatment (6 versus 12 percent), as well as more symptom-free days (odds ratio [OR] 0.5, 95% CI 0.3-0.7) and days without use of rescue treatment (OR 0.6, 95% CI 0.3-0.9).
All inhaled glucocorticoids appear to be equally effective when appropriately dosed [60]. MDIs may be used for any patients, but dry powder inhalers (DPIs) and breath-actuated devices are only appropriate for use in older children who can properly use the devices. Regarding safety, ciclesonide has less systemic absorption and therefore a lower potential for adverse effects.
Daily LTRA — LTRAs are an alternative to or step-down therapy from inhaled glucocorticoids for mild, persistent asthma, particularly in patients who have difficulty with adherence or inhaler technique [61]. However, use is limited by the risk of neuropsychiatric events, such as suicide, that are associated with this class of drugs. Patients/caregivers should be counseled about these risks. As with inhaled glucocorticoids, much of the efficacy data is extrapolated from adolescent and adult studies. Use of LTRAs for exercise-induced bronchoconstriction is discussed in detail separately. (See 'Leukotriene receptor antagonists (LTRAs)' above and "Antileukotriene agents in the management of asthma" and "Exercise-induced bronchoconstriction", section on 'Prolonged or recurrent exercise'.)
●LTRAs compared with placebo – Montelukast improves asthma symptoms, decreases bronchial hyperreactivity, and decreases the use of beta agonists and systemic glucocorticoids in children aged two to five years with intermittent or persistent asthma [62-64].
In one multicenter, randomized trial, 689 children aged two to five years were randomly assigned 2:1 to montelukast 4 mg or placebo for 12 weeks [63]. Modest improvements were noted in daytime (-0.37 versus -0.26 mean change from baseline) and nighttime (-0.46 versus -0.37) asthma symptom scores, percentage of days with asthma symptoms (mean 59 versus 64 percent), and need for rescue medications (used beta agonists 49 versus 55 days and oral glucocorticoids in 19 versus 28 patients) in the treatment group compared with placebo. Montelukast was shown to modestly improve morning forced expiratory volume in one second (FEV1) compared with placebo in a randomized trial of 336 children aged 6 to 14 years with persistent asthma [65].
●LTRAs compared with inhaled glucocorticoids – Several studies in adults and children have shown that inhaled glucocorticoids as initial therapy to control asthma are more effective than leukotriene modifiers for most patients [48,66-71]. A 2010 meta-analysis of randomized trials found that children with mild-to-moderate, persistent asthma who were treated with inhaled glucocorticoids had better pulmonary function and asthma control (eg, fewer asthma exacerbations requiring systemic glucocorticoids, less albuterol use, and lower symptom scores) than those treated with montelukast [72]. In one study of 342 children (6 to 12 years of age) with persistent asthma randomly assigned to fluticasone (50 mcg twice daily) or montelukast (5 mg daily) for 12 weeks, for example, fluticasone significantly increased pulmonary function measurements (11 versus 5 percent increase) and percent of rescue-free days (45 versus 35) and reduced nighttime symptom scores [66]. In another trial, children with greater signs of allergic inflammation and poorer pulmonary function were more likely to respond to fluticasone, whereas younger children with shorter disease duration were more likely to respond to montelukast [71]. In addition, one randomized trial found that fluticasone was more cost effective than montelukast for treatment of mild-to-moderate, persistent asthma in children [73]. These findings support the use of inhaled glucocorticoids as the first-line controller agent (table 5A-B).
Intermittent inhaled glucocorticoid with or without SABA or LABA — Asthma treatment guidelines recommend the daily use of inhaled glucocorticoids as first-line controller therapy for all children with persistent asthma (table 5A-B) [1,2,4]. However, many patients, particularly those with milder baseline disease, only use inhaled glucocorticoids intermittently, either at the onset of an upper respiratory infection (URI) or at the onset of lower respiratory symptoms. Additionally, many clinicians recommend symptom-based, intermittent therapy for patients with mild, persistent asthma [74-76]. (See "Asthma in children younger than 12 years: Quick-relief (rescue) treatment for acute symptoms", section on 'Combination inhaled glucocorticoid and beta agonist'.)
Based upon the limited data from randomized trials and a meta-analysis, we suggest daily over intermittent use of inhaled glucocorticoids for treatment of persistent asthma in children. If intermittent inhaled glucocorticoids are used and the child fails treatment (ie, requires an unscheduled visit or a course of oral glucocorticoids for asthma), daily therapy should be initiated.
There are limited data from randomized trials on preventive use of intermittent inhaled glucocorticoids in children with persistent asthma, and the results are mixed [77-80]. A meta-analysis of randomized trials published through December 2011 that examined intermittent use of inhaled glucocorticoids for persistent asthma in children and adults found no significant difference between intermittent and daily inhaled glucocorticoid therapy with regard to need for rescue oral glucocorticoids or rate of serious adverse health events [81]. In addition, daily therapy was associated with slightly poorer growth in children compared with intermittent therapy. However, daily therapy was superior to intermittent therapy in several other measures, including asthma control, lung function, use of rescue beta agonists, and symptom-free days.
The use of intermittent inhaled glucocorticoids in young children with recurrent virus-induced wheezing is discussed in detail separately. (See "Treatment of recurrent virus-induced wheezing in young children", section on 'Intermittent preventive therapy'.)
Intermittent LTRA — Limited data suggest that intermittent use of leukotriene receptor antagonists (LTRAs) is not effective in preventing the development of asthma symptoms. Montelukast was not effective in preventing the seasonal increase in asthma symptoms, rescue medication use (beta agonists and oral glucocorticoids), and unanticipated health care visits when initiated at the start of the school year in a randomized trial of 1162 children aged 6 to 14 years with asthma of any severity [82].
Moderate-to-severe, persistent asthma — We suggest low-dose inhaled glucocorticoid in combination with a LABA as initial controller therapy for children with moderate, persistent asthma (step 3 therapy) (table 5A-B). The alternatives are medium-dose inhaled glucocorticoids or low-dose inhaled glucocorticoids plus an LTRA. For initial therapy in children with severe, persistent asthma, we suggest medium-dose inhaled glucocorticoids in combination with a LABA (step 4 therapy). The alternatives are medium-dose inhaled glucocorticoids plus a LTRA or, in children ≥5 years of age, high-dose inhaled glucocorticoids or medium-dose inhaled glucocorticoid-LABA plus tiotropium or LTRA.
Children who are started on controller therapy at the time of an acute exacerbation or who have moderate-to-severe disease and are at high risk for an exacerbation may also require a short course of oral glucocorticoids. Inhaled glucocorticoids are not sufficient for the management of asthma exacerbations [83]. The use of inhaled and systemic glucocorticoids as rescue agents for asthma exacerbations is reviewed in greater detail separately. (See "Acute asthma exacerbations in children younger than 12 years: Overview of home/office management and severity assessment" and "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Systemic glucocorticoids' and "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Inhaled glucocorticoids'.)
Inhaled glucocorticoid plus LABA — Studies in adolescents and adults indicate that long-acting inhaled beta agonists (LABAs; salmeterol, formoterol) have the potential to improve overall asthma control when added to inhaled glucocorticoids in patients who are inadequately controlled with inhaled glucocorticoids alone (table 5A-B and table 2) [84-91]. Formoterol is fast onset, whereas salmeterol is slower onset. The use of combined therapy is associated with better linear growth [92], but higher doses of inhaled glucocorticoid monotherapy appear to better control lung inflammation [68]. A systematic review and meta-analysis of 33 trials in 6381 children found that the addition of LABAs was associated with greater improvement in lung function and reduced use of rescue inhalers compared with a baseline or increased dose of inhaled glucocorticoids but did not appear to have a greater effect on other measures of asthma control, such as number of exacerbations requiring treatment with oral glucocorticoids or hospital admissions [92]. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Long-term maintenance therapy with LABAs' and "Major side effects of inhaled glucocorticoids".)
LABAs should always be used in combination with an inhaled glucocorticoid because of safety concerns regarding the use of LABAs alone [93]. A large clinical trial has provided reassurance about the safety of combination inhaled glucocorticoids and LABAs in children [41,94]. The potential safety issues surrounding long-term use of LABAs are discussed in greater detail separately. (See "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Evidence of LABA-ICS safety'.)
Medium-dose inhaled glucocorticoid — Efficacy data are primarily extrapolated from adolescent and adult studies, with limited studies performed in children [31,95]. Typically, patients respond better to the addition of a LABA rather than an increase in the dose of the inhaled glucocorticoid. However, some children, particularly those of African American heritage, may respond better to a higher dose of inhaled glucocorticoid. Thus, if one approach is tried and is unsuccessful in attaining asthma control, an alternative should be chosen. (See 'Low-dose daily inhaled glucocorticoid' above and "Treatment of moderate persistent asthma in adolescents and adults".)
Inhaled glucocorticoid plus LTRA — In randomized trials in children between the ages of 6 and 14 years receiving inhaled glucocorticoids for asthma, a greater improvement in morning FEV1 and decreased need for rescue use of SABAs were seen with the addition of montelukast compared with the addition of cromolyn or placebo [65,96,97]. However, increasing the dose of inhaled glucocorticoids may provide better protection from exacerbations and need for systemic glucocorticoids compared with the combination of montelukast and low-dose inhaled glucocorticoids [32]. This was illustrated in a trial in which 71 children, aged 6 to 14 years, were randomly assigned to combined therapy with montelukast (5 mg daily) plus budesonide (100 mcg twice daily) or budesonide (200 mcg twice daily) for 12 weeks [98]. The two therapies resulted in similar lung function parameters and weekly asthma symptom scores, although more children in the group receiving combined therapy had acute exacerbations (33 versus 9 percent) and these exacerbations were more severe. An additional concern is the adherence to taking two separate medications rather than one (inhaled glucocorticoid alone or inhaled glucocorticoid plus LABA) [99].
Patient/caregiver education — The child and caregivers should receive instruction regarding the proper use of the medication delivery system(s) prescribed to ensure that the child receives the full benefit of the medication(s). Potential side effects should also be discussed with the child's caregivers. (See "Use of medication nebulizers in children" and "The use of inhaler devices in children" and "Major side effects of inhaled glucocorticoids" and "Antileukotriene agents in the management of asthma", section on 'Adverse effects' and "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Adverse effects'.)
ASSESSING ASTHMA CONTROL — Asthma control is periodically assessed in patients with established asthma on therapy. It is defined as the extent to which therapy reduces or eliminates the manifestations of asthma. In addition to assessing the components of current impairment and future risk, it also includes evaluation for medication side effects. Assessment of control is reviewed in the tables and discussed in greater detail separately (table 4A-B). (See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control", section on 'Assessment of control'.)
STEP-UP THERAPY — Step-up therapy is recommended if asthma control (table 4A-B) is not achieved with the proper and consistent use of the prescribed medications. Proper technique for medication administration and adequate adherence should be confirmed before stepping up therapy. Patients who are not well controlled on their current regimen are usually stepped up one step. Patients who are very poorly controlled may be stepped up two steps rather than one. Some patients with very poorly controlled asthma may also require a short course of oral glucocorticoids to attain asthma control. Patients should be reassessed in four to six weeks. For patients who do not respond to one step-up therapy, another at that step level may be tried before moving up a step unless the patient is very poorly controlled. Monitoring asthma control and determining need for step-up therapy are reviewed in greater detail separately. (See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)
Step-up therapy for mild-to-moderate asthma — Step-up therapy for mild-to-moderate asthma involves increasing the inhaled glucocorticoid dose and/or adding a long-acting beta agonist (LABA) or leukotriene receptor antagonist (LTRA) (table 5A-B and table 4A-B) [31].
●In patients who were started on an alternative to inhaled glucocorticoids as initial therapy for mild, persistent asthma (step 2) and failed, we suggest low-dose inhaled glucocorticoids alone.
●In patients who are not well controlled on low-dose inhaled glucocorticoids as initial therapy, we suggest stepping up their therapy by adding a LABA (step 3) (table 1 and table 2) [1,31,100]. Reasonable alternatives are to add an LTRA to low-dose inhaled glucocorticoids or increase inhaled glucocorticoids to a moderate dose.
●The preferred step up for patients who are not well controlled on step 3 therapy is a medium-dose inhaled glucocorticoid combined with a LABA (step 4) since the risk of side effects increases with the inhaled glucocorticoid dose. A reasonable alternative is to add an LTRA. For patients who do not respond to the preferred step 4 therapies, the option is high-dose inhaled glucocorticoids alone. (See 'Inhaled glucocorticoids' above.)
In a systematic review and meta-analysis, outcomes were similar for low-dose inhaled glucocorticoid plus LABA and moderate-dose inhaled glucocorticoids with regard to risk of exacerbations requiring oral glucocorticoids and risk of hospital admission, but better improvement in lung function was seen in patients on a LABA [92]. However, data from a trial in 280 Black children aged 5 to 11 years who were not well controlled on low-dose inhaled glucocorticoids showed that almost half responded better to high-dose inhaled glucocorticoids, whereas the other nearly half of patients responded better to moderate-dose inhaled glucocorticoids plus a LABA [95]. Thus, if any patient is not well controlled after the first option is tried, the alternative approach should be taken.
Use of inhaled glucocorticoids combined with a LABA is not recommended for acute exacerbations in children who are not on maintenance controller therapy or are on inhaled glucocorticoid monotherapy. However, one randomized trial using combination therapy (inhaled glucocorticoid plus a fast-acting LABA, budesonide-formoterol) for both maintenance and rescue therapy, compared with combination therapy or inhaled glucocorticoid for maintenance and a short-acting beta agonist (SABA; terbutaline) for rescue therapy, found a lower rate of exacerbations in the first group [101]. This study suggests that as-needed use of combination therapy in conjunction with maintenance combination therapy is beneficial in children with moderate asthma that is not well controlled.
Step-up therapy for severe asthma — In children less than six years of age, the preferred approach is to increase to high-dose inhaled glucocorticoids in combination with a LABA, or alternatively an LTRA (step 5). Additional agents are available for children ≥6 years of age who have moderate-to-severe asthma that is difficult to control (table 6) [102].
Tiotropium, a long-acting anticholinergic agent, is approved for long-term maintenance treatment in children with severe symptomatic asthma not well controlled on inhaled glucocorticoids and other maintenance therapies (LABAs and/or LTRAs) [103,104]. (See 'Long-acting anticholinergic agents (LAMAs)' above.)
For children six years of age and older whose asthma is still not controlled after the addition of tiotropium, addition of a biologic agent is another option. Monoclonal anti-IgE therapy with omalizumab is appropriate for children with poorly controlled, moderate-to-severe, persistent asthma; sensitization to at least one perennial aeroallergen; and elevated serum IgE [105]. Mepolizumab, a monoclonal antibody against interleukin 5 (anti-IL-5), is approved as add-on maintenance treatment for children with poorly controlled severe eosinophilic asthma (eosinophilic phenotype is typically determined by blood eosinophil count, but some use fractional exhaled nitric oxide [FeNO] values or sputum eosinophil proportions) [44]. Dupilumab, a monoclonal antibody against the IL-4 receptor alpha subunit, is also approved for treatment of moderate-to-severe, eosinophilic asthma [106]. Use of other biologic agents for asthma is off label in children <12 years of age. (See 'Biologic agents' above and "Anti-IgE therapy", section on 'Omalizumab therapy in asthma' and "Treatment of severe asthma in adolescents and adults", section on 'Persistently uncontrolled asthma'.)
Systemic glucocorticoids are most commonly used for management of acute exacerbations. They are used rarely for long-term control in children with severe, persistent asthma (step 6), particularly with the availability of tiotropium and the biologic agents (table 5A and table 5B and table 2) [1,2,4]. (See 'Systemic glucocorticoids' below and "Acute asthma exacerbations in children younger than 12 years: Emergency department management".)
Add on tiotropium — Accumulating data suggest that tiotropium added on to inhaled glucocorticoids plus one or more additional controller medications improves asthma control and decreases the rate of exacerbations in children 6 to 11 years old with moderate-to-severe symptomatic asthma [107]. In a 12-week randomized trial with 401 participants aged 6 to 11 years, once-daily tiotropium 5 mcg, but not the 2.5 mcg dose, improved lung function and was well tolerated as add-on therapy to inhaled glucocorticoids and other maintenance therapies in children with severe symptomatic asthma [103]. However, consistent with studies in adults, no differences were noted in patient-important outcomes such as asthma symptoms and rescue medication use. A case series also reported benefit from the addition of tiotropium in patients not well controlled on inhaled glucocorticoids and LABAs [104]. (See "Treatment of severe asthma in adolescents and adults", section on 'Inhaled GC/LAMA or GC/LAMA/LABA'.)
Add on a biologic agent — The biologic agents, omalizumab (anti-IgE), mepolizumab (anti-IL-5), and dupilumab (anti-IL-4 and IL-13), are usually reserved for children six years of age and older who have not responded to the addition of tiotropium.
Treatment with omalizumab (compared with placebo) can decrease incidence of exacerbations and result in a significant reduction in the dose of inhaled or oral glucocorticoids required to control symptoms. Omalizumab (anti-IgE) has never been compared directly with other asthma therapies in controlled clinical trials. The efficacy of omalizumab is discussed in greater detail separately. (See "Anti-IgE therapy", section on 'Omalizumab therapy in asthma'.)
Approval of mepolizumab (anti-IL-5) was primarily based upon trials in adolescents and adults as well as pharmacodynamic, pharmacokinetic, and safety data in a small number of children 6 to 11 years of age [108,109]. A subsequent trial of mepolizumab in 290 children and adolescents from low-resource, urban environments with eosinophilic asthma and ≥2 exacerbations/year showed a lesser benefit from mepolizumab on asthma exacerbations compared with studies in adults (0.96 exacerbations per year with mepolizumab versus 1.3 per year with placebo [RR 0.73, 95% CI 0.56-0.96] [110] compared with a RR of 0.49 in a systematic review of adult studies [111]), and no difference was seen with other outcomes. Persistent airway mucus hypersecretion and increased expression of non-type 2 inflammatory pathways were noted in the mepolizumab-treated group, which may explain, in part, the differential response to mepolizumab. Other factors may include ongoing environmental exposures, other asthma mechanisms, biologic changes between childhood and adult asthma, or other differences in the overall study populations. The adverse reaction profile for patients aged 6 to 11 years was similar to that observed in adolescents and adults, as were exploratory efficacy data showing improved asthma control and decreased exacerbation rates [109]. Efficacy data in adolescents and adults are reviewed in greater detail separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Mepolizumab'.)
Dupilumab (anti-IL-4 and IL-13) was approved by the US Food and Drug Administration (FDA) in 2021 as add-on maintenance treatment for children six years of age and older with moderate-to-severe persistent asthma who have an eosinophilic phenotype or who are dependent on oral glucocorticoids [112]. Approval was primarily based upon trials in adolescents and adults as well as efficacy and safety data from a single randomized trial for moderate-to-severe persistent asthma in 408 children 6 to 11 years of age that showed an improvement in lung function and asthma control and a significant reduction in the annual rate of severe exacerbations requiring treatment with systemic glucocorticoids (0.31, 95% CI 0.22-0.42 on dupilumab versus 0.75, 95% CI 0.54-1.03 for placebo; relative risk reduction in dupilumab group 59.3%, 95% CI 39.5-72.6) [113]. Additional safety data were derived from an atopic dermatitis trial in children. Dosing is 100 mg subcutaneous every other week or 300 mg every four weeks for patients 15 to <30 kg and 200 mg every other week for children 6 to 11 years of age who are ≥30 kg. Patients who also have moderate-to-severe atopic dermatitis (AD) should follow dosing for AD. Efficacy and safety data for asthma treatment in adolescents and adults and for atopic dermatitis treatment in children are reviewed in greater detail separately. (See "Treatment of severe asthma in adolescents and adults", section on 'Anti-lL-4 receptor alpha subunit antibody (dupilumab)' and "Management of severe atopic dermatitis (eczema) in children", section on 'Dupilumab' and "Treatment of atopic dermatitis (eczema)", section on 'Efficacy'.)
STEP-DOWN THERAPY — Decreasing or stepping down therapy is considered once asthma control is attained for at least three months (table 5A-B and table 4A-B). The medication options and approaches are similar to initial therapy and step-up therapy. Monitoring asthma control and determining when a patient is ready for step-down therapy are reviewed in greater detail separately. (See "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)
MINIMIZING ADVERSE EFFECTS OF INHALED GLUCOCORTICOIDS — To minimize the risk of adverse effects of inhaled glucocorticoids in children, we advise the following:
●Step down treatment to the lowest possible dose of inhaled glucocorticoids that maintains symptom control (table 5A-B and table 4A-B).
●Use metered dose inhalers (MDIs) with a spacer. A valved holding chamber is preferred because this type of spacer has an exhalation valve that prevents the patient from breathing back into the spacer and changing the character of the medication/vehicle, making it less effective. Children ≤6 years of age should use a facemask with the valved holding chamber. (See "The use of inhaler devices in children", section on 'Spacers and holding chambers'.)
●Evaluate and treat for conditions which may exacerbate asthma (eg, allergic rhinitis, sinusitis, or gastroesophageal reflux) (table 7). (See "Asthma in children younger than 12 years: Initial evaluation and diagnosis", section on 'Precipitating factors'.)
●Maximize nonpharmacologic treatment (eg, trigger avoidance). (See "Trigger control to enhance asthma management".)
Adverse effects of inhaled glucocorticoids appear to be rare and are dose related; they are reviewed separately. (See "Major side effects of inhaled glucocorticoids".)
ADVICE RELATED TO COVID-19 — The United States Centers for Disease Control and Prevention (CDC) have identified asthma as a risk factor for severe coronavirus disease 2019 (COVID-19; severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2]) [114], although supporting evidence remains mixed, with data largely from studies in adults [115-126]. Several studies that included patients with well-controlled asthma did not indicate increased risk in this population [115-122]. In addition, contrary to that expected for a viral respiratory infection, initial data suggested that COVID-19 did not increase asthma morbidity in children [127-130]. However, other investigations of COVID-19 outcomes have reported increased risk, including a large meta-analysis of over 100,000 patients that reported higher rates of intubation and prolonged mechanical ventilation in adults with asthma [116,123-125]. A comparison of nearly 62,000 children with asthma from 108 health care systems in the United States from March 2020 through February 2021 found that a SARS-CoV-2 polymerase chain reaction (PCR) positive test was associated with increased rates of emergency department visits, hospitalizations, and use of short-acting beta agonists (SABAs) and oral glucocorticoids in the six months following the positive test compared with those who tested negative [126]. These complications probably occur more frequently in those with poorly controlled asthma at baseline. Thus, patients with asthma should continue all regular medications necessary to maintain optimal asthma control, including inhaled glucocorticoids, oral glucocorticoids, and/or biologic agents (omalizumab, dupilumab, mepolizumab) [131-133]. (See "COVID-19: Clinical manifestations and diagnosis in children" and "COVID-19: Management in children".)
INFREQUENTLY USED TREATMENTS — Daily controller medications that are used rarely for persistent asthma include systemic (oral) glucocorticoids, chromones (cromolyn sodium and nedocromil), and theophylline.
Systemic glucocorticoids — Although oral glucocorticoids improve asthma control, the adverse effects of their long-term use must be appreciated. These include adrenal suppression, weight gain, diabetes, hypertension, cataracts, delayed growth, immune suppression, osteoporosis, and psychologic effects [6,134]. Reducing glucocorticoids to the lowest possible dose, administering them every other day, and maximizing all other forms of pharmacologic and preventive therapy minimize these effects. A strategy of substituting inhaled glucocorticoids has generally been successful in older children and adults, as well as in infants [135]. (See "Major side effects of systemic glucocorticoids".)
The use of systemic glucocorticoids as rescue agents for asthma exacerbations is reviewed in greater detail separately. (See "Acute asthma exacerbations in children younger than 12 years: Inpatient management", section on 'Management of inflammation' and "Acute asthma exacerbations in children younger than 12 years: Emergency department management", section on 'Systemic glucocorticoids'.)
Chromones — The drugs cromolyn sodium and nedocromil are commonly grouped together as chromones (also called cromoglycates). These drugs have mast cell-stabilizing properties and appear to diminish the very early stages of an asthmatic response to external triggers. However, their efficacy as controller medications in childhood asthma has not been definitively established [136,137]. Although there are studies in which cromolyn compared favorably with other established therapies, a systematic review of trials of cromolyn versus placebo found no clear therapeutic effect [138-141]. In addition, a meta-analysis found that inhaled glucocorticoids were superior to cromolyn as controller therapy for mild, persistent asthma in children, with improved pulmonary function, fewer exacerbations, lower asthma symptom scores, and less bronchodilator use [142]. Like cromolyn, nedocromil appears to be less effective than inhaled glucocorticoids in controlling asthma [21,143-146]. (See "The use of chromones (cromoglycates) in the treatment of asthma".)
There is no definitive evidence to support the concurrent use of inhaled chromones and glucocorticoids in order to lower the glucocorticoid dose in patients with chronic asthma. The disadvantages of high cost and multiple daily dosing probably outweigh the unproven potential benefit, and concurrent use is not recommended.
Theophylline — Theophylline is a medication with both bronchodilatory and antiinflammatory properties. It may also have steroid-sparing and immunomodulatory effects [147-149]. However, the role of theophylline in the stepwise management of childhood asthma has declined worldwide.
The use of theophylline to treat chronic childhood asthma is problematic due to potentially serious short-term side effects (eg, cardiac arrhythmias, seizures, death) and long-term adverse effects (learning and behavior disorders). A further encumbrance of theophylline is the need for frequent serum monitoring to maintain a serum concentration of 5 to 15 mcg/mL, as well as vigilance regarding potential interactions with other drugs. The use of theophylline is discussed separately. (See "Theophylline use in asthma".)
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 children".)
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 5th to 6th 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 10th to 12th 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 e-mail 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: How to use your child's dry powder inhaler (The Basics)" and "Patient education: Asthma in children (The Basics)" and "Patient education: How to use your child's metered dose inhaler (The Basics)")
●Beyond the Basics topics (see "Patient education: Asthma inhaler techniques in children (Beyond the Basics)" and "Patient education: Asthma treatment in children (Beyond the Basics)" and "Patient education: Asthma symptoms and diagnosis in children (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Treatment goals – The overarching goals are to maintain control of asthma symptoms and reduce exacerbations with the least amount of medication and side effects. (See 'Goals of treatment' above.)
●Severity assessment – Asthma severity is classified based upon current impairment, which includes symptoms; quick-relief medication use; and, in older children, pulmonary function testing, and future risk of exacerbations that require treatment with systemic glucocorticoids, as outlined in the tables (table 5A-B). (See 'Assessing asthma severity' above and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control".)
●Initiating controller therapy – Our general approach to initiating controller therapy is as follows (table 5A-B) (see 'Initiating controller therapy' above):
•Mild, persistent asthma – For children <12 years of age with mild, persistent asthma, we suggest low-dose inhaled glucocorticoids (table 1) for initial controller therapy (step 2 therapy) rather than other therapies (Grade 2C). Reasonable alternatives are a daily leukotriene receptor antagonist (LTRA) or intermittent, low-dose inhaled glucocorticoids used whenever short-acting beta agonist (SABA) quick-relief therapy is used (table 2). (See 'Mild, persistent asthma' above.)
•Moderate, persistent asthma – For children <4 years of age with moderate, persistent asthma, we suggest a low-dose inhaled glucocorticoid in combination with a long-acting beta agonist (LABA) or an LTRA as initial controller therapy (step 3 therapy) (Grade 2C). A reasonable alternative is medium-dose inhaled glucocorticoids. (See 'Moderate-to-severe, persistent asthma' above.)
For children 5 to 11 years of age with moderate, persistent asthma, we suggest low-dose inhaled glucocorticoid in combination with a fast-onset LABA rather than other therapies (Grade 2C). This combination inhaler can also be used for relief of acute symptoms. Reasonable alternatives include a low-dose inhaled glucocorticoid in combination with a slower-onset LABA, medium-dose inhaled glucocorticoids, or low-dose inhaled glucocorticoids plus an LTRA. (See 'Moderate-to-severe, persistent asthma' above and "Asthma in children younger than 12 years: Quick-relief (rescue) treatment for acute symptoms", section on 'Combination inhaled glucocorticoid and beta agonist'.)
•Severe, persistent asthma – For initial therapy in children with severe, persistent asthma, we suggest medium-dose inhaled glucocorticoids in combination with a LABA (step 4 therapy) rather than other therapies (Grade 2C). A fast-onset LABA is preferred in children ≥4 years of age. Reasonable alternatives include medium-dose inhaled glucocorticoids plus a LTRA or, in children ≥5 years of age, high-dose inhaled glucocorticoids or medium-dose inhaled glucocorticoid-LABA plus tiotropium. (See 'Moderate-to-severe, persistent asthma' above.)
•Patient/caregiver education – When inhaled glucocorticoids are prescribed, it is essential to provide adequate instruction to the child's caregivers regarding proper use of the medication delivery system. Potential side effects of all medications should also be discussed with the child's caregivers. (See 'Patient/caregiver education' above and "Use of medication nebulizers in children" and "The use of inhaler devices in children" and "Major side effects of inhaled glucocorticoids" and "Antileukotriene agents in the management of asthma", section on 'Adverse effects' and "Beta agonists in asthma: Acute administration and prophylactic use", section on 'Adverse effects'.)
●Adjusting therapy – Asthma control should be monitored regularly (table 4A-B) and controller therapy adjusted as necessary (table 5A-B). The minimum effective medication regimen for each patient should be determined. However, this can change over time. (See 'Assessing asthma control' above and 'Step-up therapy' above and 'Step-down therapy' above and "Asthma in children younger than 12 years: Overview of initiating therapy and monitoring control", section on 'Monitoring and dosing adjustment' and "An overview of asthma management".)
•Step-up therapy – If asthma control (table 4A-B) is not achieved with the proper and consistent use of the prescribed medications, step-up therapy is appropriate. Proper technique and adequate adherence should be confirmed before stepping up therapy. (See 'Step-up therapy' above.)
-Not-well-controlled asthma – Patients who are not well controlled on their current regimen are usually stepped up one step. One exception is patients who failed intermittent inhaled glucocorticoids for step 2 therapy. For those patients, we suggest switching to daily low-dose inhaled glucocorticoids rather than moving up to step 3 therapy (Grade 2C).
Patients should be reassessed in four to six weeks. For patients who do not respond to one step-up therapy, another at that step level may be tried before moving up a step unless the patient is very poorly controlled.
-Poorly controlled asthma – Patients who are very poorly controlled may be stepped up two steps rather than one. Some patients with very poorly controlled asthma may also require a short course of oral glucocorticoids to attain asthma control.
-Severe asthma – For children ≤5 years of age with severe asthma that is not controlled on preferred step 4 therapy, we suggest high-dose inhaled glucocorticoid in combination with a LABA (step 5) (Grade 2C). A reasonable alternative is high-dose inhaled glucocorticoid plus an LTRA.
For children 6 to 11 years of age with severe asthma that is not controlled on step 4 therapy, we suggest adding the long-acting anticholinergic agent, tiotropium (step 5) rather than other add-on therapies (Grade 2C). Reasonable alternatives are a combination of medium-dose inhaled glucocorticoid plus both LABA and LTRA or high-dose inhaled glucocorticoids in addition to a LABA or LTRA. The biologic agents, omalizumab (anti-immunoglobulin E [IgE]), mepolizumab (anti-interleukin [IL] 5), and dupilumab (anti-IL-4 and IL-13), are usually reserved for children six years of age and older who have not responded to the addition of tiotropium. (See 'Long-acting anticholinergic agents (LAMAs)' above and 'Biologic agents' above.)
Longer-term use of oral glucocorticoids is reserved for step 6 therapy when all other therapy has failed because of the significant adverse effects associated with this treatment. (See 'Systemic glucocorticoids' above and "Major side effects of systemic glucocorticoids".)
•Step-down therapy – Decreasing or stepping down therapy is considered once asthma control is attained for at least three months. The medication options and approaches are similar to initial therapy and step-up therapy. (See 'Step-down therapy' above.)
