Step-up and step-down treatments for optimal asthma control in children and adolescents

Figures & data

Figure 1. Strategies for asthma management in adolescents.

Figure 2. GINA stepwise management of asthma [2]. FEV₁, forced expiratory volume in 1 second; GINA, Global Initiative for Asthma; HDM, house dust mite; ICS, inhaled corticosteroid; IgE, immunoglobulin E; IL, interleukin; LABA, long-acting beta-2-agonist; LTRA, leukotriene receptor antagonist; med, medium dose; OCS, oral corticosteroids; SABA, short-acting beta-2-agonist; SLIT, sublingual immunotherapy. *Not for children <12 years old. **For children 6–11 years old, the preferred Step 3 treatment is medium dose ICS. ^#Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/formoterol or low dose beclometasone/formoterol maintenance and reliever therapy. ^†Tiotropium by mist inhaler is an add-on treatment for patients with a history of exacerbations; it is not indicated in children <12 years old.

Table 1. Stepwise management of asthma in children and adolescents as per GINA 2018 guidelines [2].

GINA	Adolescents: ≥12–17 years old	Children: 6–<11 years old
Step 1: As-needed reliever inhaler (SABA)	No controller treatment Alternatively, consider low dose ICS	No controller treatment Alternatively, consider low dose ICS
Step 2: Low dose controller medication plus as-needed reliever medication (SABA)	Start low dose ICS if not already started Alternatively, consider LTRA or low dose theophylline	Start low dose ICS if not already started Alternatively, consider LTRA
Step 3: One or two controllers plus as-needed reliever medication (SABA or low dose ICS/formoterol)	Add LABA to low dose ICS Alternatively, Consider low dose ICS + LTRA (or theophylline) in adolescents who have still not completed growth OR Consider medium/high dose ICS^a in adolescents who have completed growth	Increase dose of ICS and start medium dose ICS^a Alternatively, consider low dose ICS + LTRA
Step 4: Two or more controllers plus as-needed reliever medication (SABA or low dose ICS/formoterol)	Refer to asthma specialist Increase ICS dose to medium/high dose ICS^a with LABA Alternatively, Start tiotropium add-on treatment for patients with a history of exacerbations OR Consider high dose ICS + LTRA (or theophylline)	Refer to asthma specialist Increase ICS dose to medium/high dose ICS^a with LABA Alternatively, consider high dose ICS^a+LTRA
Step 5: Higher level care and/or add-on treatment (SABA or low dose ICS/formoterol)	Asthma specialist care is required Add tiotropium, omalizumab, mepolizumab, or benralizumab to high dose ICS^a Alternatively, low dose OCS may be considered in adolescents who have completed growth	Asthma specialist care is required Add omalizumab to high dose ICS^a Alternatively, low dose OCS may be considered^a

Notes. For children aged 6–11 years, increasing the ICS dose is preferred over combination ICS/LABA.

For adolescents with exacerbations despite other therapies, the risk of exacerbations is reduced with combination low dose ICS/formoterol (with beclomethasone or budesonide) as both maintenance and reliever, compared with maintenance controller treatment plus as-needed SABA.

For patients with persistent symptoms and/or exacerbations despite 2–3 months of controller treatment, consider step-up after ruling out common problems such as wrong inhaler technique, poor adherence, persistent allergen exposure, comorbidities, and incorrect diagnosis.

Consider step-down once good asthma control has been achieved and maintained for about 3 months, to determine the patient’s lowest treatment that controls both symptoms and exacerbations.

GINA: Global Initiative for Asthma; ICS: inhaled corticosteroid; LABA: long-acting beta-2-agonist; LTRA: leukotriene receptor antagonist; OCS: oral corticosteroids; SABA: short-acting beta-2-agonist.

^aAt any time in treatment, if medium/high dose ICS or low dose OCS is started in adolescents who have not completed growth, monitor growth regularly and consider changing to other alternatives or stepping down at the earliest possible time.

Table 2. Efficacy and safety of tiotropium in children and adolescents in pivotal clinical trials.

Reference	Szefler [51] NCT01634152/Viva	Hamelmann [47] NCT01257230/Ruba	Hamelmann [48] NCT01277523/Pensie	Huang [53]	Vogelberg [50] NCT01383499	Vogelberg [49] NCT01122680
N, treated patients	400	397	392	80	101	105
Asthma severity	Severe	Moderate	Severe	Moderate	Not mentioned	Moderate
Study population	Children: 6–11 years	Adolescents: 12–17 years	Adolescents: 12–17 years	Children/Adolescents: 6–14 years	Children: 6–11 years	Adolescents: 12–17 years
Study phase	III	III	III	Not mentioned	II	II
Treatment arms	TioR 2.5 μg QD, TioR 5 μg QD, PboR QD	TioR 2.5 μg QD, TioR 5 μg QD, PboR QD	TioR 2.5 μg QD, TioR 5 μg QD, PboR QD	Fluticasone propionate aerosol, Fluticasone propionate aerosol + tiotropium	TioR 1.25 μg QD, TioR 2.5 μg QD, TioR 5 μg QD, PboR QD	TioR 1.25 μg QD, TioR 2.5 μg QD, TioR 5 μg QD, PboR QD
Maintenance treatment	High-dose ICS +1 or more controller therapies (e.g., LABA or LTRA) or medium-dose ICS +2 or more controller therapies (e.g., LABA and/or LTRA and/or sustained-release theophylline)	ICS background therapy, with or without LTRA; LABA therapy was not permitted during the study	High-dose ICS +1 or more controller therapies (e.g., LABA or LTRA) or medium-dose ICS +2 or more controller therapies (e.g., LABA and/or LTRA and/or sustained-release theophylline)		Medium-dose ICS background therapy, with or without LTRA; LABA therapy was not permitted during the study	Medium-dose ICS background therapy with or without LTRA; LABA therapy was not permitted during the study
Study duration	12 weeks	48 weeks^a	12 weeks	12 weeks	Three 4-week treatment periods (Total 12 weeks)	Three 4-week treatment periods (Total 12 weeks)
Efficacy	Compared with placebo, tiotropium 5 μg add-on therapy improved the primary endpoint, peak FEV1, within 3 h after dosing	Improvement in peak FEV1 within 3 h after dosing at 24 weeks (primary endpoint) was statistically significant with both tiotropium doses compared with placebo. Significant improvements in trough FEV1 at week 24 (a secondary endpoint) were observed with the 5-μg dose only	The primary endpoint of efficacy (change from baseline in FEV1(0–3h)) was not met, although positive trends for improvement in lung function and asthma control were observed	Tiotropium significantly improved lung function, reduced the use of SABAs, and improved sleep	For the primary efficacy endpoint, statistically significant differences in peak FEV1(0–3h) response after 4 weeks of treatment were observed for each TioR dose group versus PboR. There was no dose-dependent response observed in patients treated with TioR. Compared to placebo, TioR also improved secondary and additional efficacy endpoint, including trough FEV1 response, FEV1 AUC(0–3h) response, and FEV1 response over 3 h post-dosing	Peak FEV1(0–3h) (the primary endpoint), trough FEV1, and FEV1 AUC(0–3h) responses for TioR 5 μg were superior to those for PboR and were greater than those observed with the 2.5-μg or 1.25-μg doses of TioR. Morning PEF response for all 3 TioR and evening PEF response in the TioR 5 μg and 2.5 μg groups were significantly higher than in the PboR group
Safety	Well-tolerated	Once-daily tiotropium was safe and well tolerated	Well-tolerated	Few adverse reactions with tiotropium	Well-tolerated across all three doses	Well-tolerated across all three doses

Notes. AUC: area under curve; FEV₁: forced expiratory volume in 1 s; ICS: inhaled corticosteroid; LABA: long-acting beta-2-agonist; LTRA: leukotriene receptor antagonist; PboR: placebo Respimat^®; PEF: peak expiratory flow; QD: once daily; SABA: short-acting beta-2-agonist; TioR: tiotropium Respimat^®.

^aPrimary pulmonary function endpoint was assessed after 24 weeks of treatment.

Table 3. Efficacy and safety of omalizumab in children and adolescents in pivotal clinical trials.

Reference	Busse 2011 [58] NCT00377572	Lanier 2009 [59] NCT00079937	Milgrom 2001 [60]
N, treated patients	419	627	334
Asthma severity	Allergic asthma of all levels of severity, 73% moderate-to-severe asthma	Moderate-to-severe, inadequately controlled allergic asthma	Moderate-to-severe allergic asthma requiring treatment with ICS
Study population	Children, adolescents, and young adults: 6–20 years	Children: 6–12 years	Males and premenarchal females: 6–12 years
Study phase	IV	III	Not available
Treatment arms	Omalizumab and Placebo	Omalizumab and Placebo	Omalizumab and Placebo
Maintenance treatment	Not clearly mentioned, LABA, ICS	The first 24 weeks of the treatment period was a fixed steroid phase, where the steroid dose was maintained constant; in the following 28 weeks the steroid dose was adjustable, depending on the patient's condition.	Beclomethasone dipropionate: The dose (initial range 168–420 mg/day) was kept stable for 16 weeks (stable-steroid phase), reduced over 8 weeks to the minimum effective dose (steroid-reduction phase), and maintained constant for the final 4 weeks.
Study duration	60 weeks	52 weeks	28 weeks
Efficacy	Omalizumab (vs. placebo) significantly reduced the number of days with asthma symptoms and the proportion of participants who had ≥1 exacerbations	Over the 24-week and 52-week periods, omalizumab reduced the rates of clinically significant asthma exacerbations and the exacerbation rate, respectively, compared with placebo	More participants in the omalizumab (vs. placebo) group decreased their beclomethasone dipropionate dose, with greater mean reductions in dose. Omalizumab reduced the requirement for rescue medication, incidence and frequency of clinically significant asthma exacerbations, asthma exacerbations requiring hospitalization, school absenteeism, and serum free IgE levels.
Safety	Comparable safety profiles	Comparable safety profiles	Comparable safety profiles

Note. ICS: inhaled corticosteroid; IgE: immunoglobulin E; LABA: long-acting beta-2-agonist.

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