ICS-Formoterol in Children: Reconciling GINA and NHLBI on SMART by Age
Two major guidelines endorse the same inhaler strategy yet disagree on when childhood treatment can begin — and the evidence explains why.
One-Minute Takeaway
- ICS-formoterol — one inhaler pairing a corticosteroid with a fast-acting bronchodilator — lowers asthma attacks in children, whether used as a reliever or as maintenance-and-reliever therapy (highest tier: randomised trials and meta-analysis).
- In the CARE trial (ages 5–15), as-needed budesonide–formoterol reduced attacks versus salbutamol: 0.23 versus 0.41 per child-year (RR 0.55, 95% CI 0.35–0.86).
- In children aged 4–11 uncontrolled on inhaled corticosteroids, maintenance-and-reliever therapy cut exacerbations needing medical intervention versus fixed-dose regimens.
- Pooled trial data link single maintenance-and-reliever therapy to fewer exacerbations than same-dose ICS-LABA (RR 0.68, 95% CI 0.58–0.80).
- The guidelines differ by age: NHLBI recommends the strategy from age 4, while GINA prefers it from age 12 and offers it as an option at ages 6–11.
Why ICS-Formoterol in Children Matters
Asthma is the most common chronic disease of childhood, and attacks can be frightening, disruptive, and occasionally fatal. Reducing how often they happen is a public-health priority.
The stakes are concrete. Childhood asthma drives emergency visits, missed school, and hospital admissions, and a minority of attacks become life-threatening. Any regimen that lowers attack frequency without adding safety concerns therefore carries weight for families and health systems alike.
Standard care long paired a short-acting reliever, usually salbutamol, with a separate daily inhaled corticosteroid. Two weaknesses limit that model in children. Daily controller adherence is often poor, and a reliever-only response to worsening symptoms leaves airway inflammation untreated.
ICS-formoterol addresses both problems at once. Formoterol is a long-acting bronchodilator with a rapid onset, so the combination relieves symptoms quickly while delivering a corticosteroid dose with each actuation. Anti-inflammatory treatment therefore rises automatically as a child reaches for the inhaler more often.
The approach also targets over-reliance on short-acting relievers. Frequent salbutamol use signals uncontrolled inflammation, yet on its own it does nothing to treat that inflammation. Building a corticosteroid into the reliever couples symptom relief to anti-inflammatory treatment at the moment a child needs both.
Two authoritative bodies endorse this approach: the Global Initiative for Asthma (GINA) and the US National Heart, Lung, and Blood Institute (NHLBI), through its NAEPP expert panel. They agree on the mechanism but set different age thresholds, which creates real uncertainty at the bedside.
What the Guidelines Recommend
The two guidelines use different names for the same regimens. NHLBI calls single-inhaler dual use SMART, for single maintenance and reliever therapy. GINA calls the identical regimen MART, for maintenance and reliever therapy, and describes reliever-only use as AIR, for anti-inflammatory reliever.
The distinction between AIR and MART matters in practice. AIR uses the ICS-formoterol inhaler for symptom relief only, with no scheduled daily dose, and suits milder disease. MART adds a fixed daily maintenance dose on top of the same as-needed reliever, and suits more persistent asthma at higher steps.
The NAEPP 2020 focused update issued a strong recommendation for SMART with ICS-formoterol in individuals aged 4 years and older with moderate-to-severe persistent asthma. It specifies low-dose ICS-formoterol at step 3 and medium-dose ICS-formoterol at step 4. Budesonide-formoterol was the combination studied, apart from a single trial that used beclomethasone.
GINA takes a more age-stratified position. For adults and adolescents aged 12 and older, ICS-formoterol is the preferred reliever across its Track 1 — reliever-only at the lowest steps, and maintenance-and-reliever at higher steps.
For children aged 6–11, GINA lists MART with budesonide-formoterol as an evidence-based option at steps 3 and 4 rather than the sole preferred choice. Below age 6, GINA makes no MART or AIR recommendation, and trials in that age group are ongoing.
GINA has advised against treating adolescents and adults with a short-acting reliever alone since 2019, and it extends that reasoning cautiously into childhood. NHLBI reached its position through a formal evidence review that pooled ICS-formoterol trials, most of which enrolled older patients. The two panels read overlapping evidence and drew the age line in different places.
Only ICS-formoterol combinations can be used this way. Their fast-onset bronchodilator makes single-inhaler reliever use possible. ICS-LABA inhalers containing salmeterol or vilanterol cannot substitute, because those bronchodilators act too slowly for reliever use.
Despite the different age lines, the shared goal is the same: fewer attacks with less reliance on a bronchodilator that treats symptoms without touching inflammation. Both guidelines frame ICS-formoterol as a way to deliver a corticosteroid at the point of need, and both restrict single-inhaler reliever use to formoterol-containing combinations for that reason.
Evidence Reviewed
The comparative evidence spans dedicated pediatric trials, an adolescent subgroup analysis, and meta-analyses drawn largely from adult and adolescent populations. Each row below was confirmed against its primary source.
| Study / Source | Design | N | Population (age) | Comparison | Key result | Confidence |
|---|---|---|---|---|---|---|
| CARE — Hatter 2025DOI ↗ | Open-label RCT, 52 weeks | 360 | Children 5–15, mild asthma, SABA-only | As-needed budesonide–formoterol vs as-needed salbutamol | Attacks 0.23 vs 0.41 per child-year; RR 0.55 (95% CI 0.35–0.86) | V |
| Bisgaard 2006DOI ↗ | Double-blind RCT, 12 months | 341 | Children 4–11, uncontrolled on ICS | Budesonide–formoterol MART vs fixed-dose combination vs higher-dose budesonide | Exacerbations needing intervention 0.08 vs 0.28 vs 0.40 per patient | V |
| Jorup 2018DOI ↗ | Post hoc pooled subgroups (6 RCTs) | 1,847 adolescents | Adolescents 12–17, persistent asthma | Budesonide–formoterol MART vs comparators | Time to first severe exacerbation, pooled HR 0.49 (95% CI 0.34–0.70) | V |
| Hatter 2021DOI ↗ | Systematic review + meta-analysis (4 RCTs) | 8,065 | Mild asthma; predominantly adults | As-needed ICS-formoterol vs maintenance ICS + SABA | Time to first severe exacerbation HR 0.85 (95% CI 0.73–1.00) | V |
| Sobieraj 2018DOI ↗ | Systematic review + meta-analysis | 8,473 (this comparison) | Persistent asthma; predominantly adults | ICS-formoterol SMART vs same-dose ICS-LABA + SABA | Exacerbation risk RR 0.68 (95% CI 0.58–0.80) | V |
The two dedicated pediatric datasets — Bisgaard 2006 and CARE — anchor the childhood evidence. The meta-analyses that shaped NHLBI’s recommendation drew mostly from older patients, a point that matters for the age question that follows.
That meta-analysis also compared single maintenance-and-reliever therapy against a higher-dose ICS-LABA regimen and again found lower exacerbation risk, so the benefit did not hinge on the choice of comparator. Most of the pediatric and adolescent evidence uses budesonide–formoterol specifically. A beclometasone–formoterol combination has been studied as maintenance-and-reliever therapy in broader asthma populations, but the childhood data centre on the budesonide product that both guidelines cite.
Key Findings on ICS-Formoterol in Children
Read across the age spectrum, the evidence is strongest at the top and thinnest at the bottom. That gradient explains most of the guideline divergence.
Adolescents 12 and Older — Concordant Ground
For adolescents, both guidelines point the same way, and the data are the most mature. The large as-needed and maintenance-and-reliever trials enrolled adolescents alongside adults. A pooled analysis of adolescent subgroups reported a lower risk of a first severe exacerbation with MART versus comparators. Because that analysis was performed post hoc, the estimate is best read as an association rather than a definitive causal effect.
The trials underpinning this confidence — including the SYGMA programme, Novel START, and PRACTICAL — enrolled adolescents aged 12 and older alongside adults, and consistently favoured ICS-formoterol reliever regimens over short-acting reliever comparators. A separate meta-analysis of as-needed ICS-formoterol against maintenance ICS plus a short-acting reliever found a longer time to a first severe exacerbation (HR 0.85, 95% CI 0.73–1.00). Both guidelines lean on this body of work for the adolescent recommendation.
Children 6 to 11 — Where Emphasis Diverges
This band is where the guidelines read differently despite similar evidence. Bisgaard’s 12-month trial in children aged 4–11 showed that MART prolonged the time to a first exacerbation and reduced exacerbations needing intervention, measured against both a fixed-dose combination and a fourfold-higher maintenance steroid dose. The recent CARE trial then added reliever-only data in children aged 5–15.
NHLBI treats ICS-formoterol as the preferred step 3–4 therapy from age 4, so children aged 6–11 fall squarely inside a strong recommendation. GINA lists MART as one acceptable option at steps 3–4 for the same children. The disagreement is about emphasis and preference, not whether the regimen may be used.
CARE also captured the regimen’s wider effects in children. Fewer children had at least one attack on budesonide–formoterol than on salbutamol (17% versus 32%), and fewer had a severe attack (9% versus 16%). Night waking and daytime symptoms were lower with the combination inhaler as well.
Reliever-only regimens carry one trade-off worth noting. In pooled adult data, as-needed ICS-formoterol slightly lowered symptom-control scores compared with daily maintenance ICS, though the difference stayed below the threshold considered clinically meaningful. The same regimen reduced cumulative corticosteroid exposure, a relevant consideration in growing children.
Children Under 6 — The Evidence Frontier
Below age 6 the picture changes because the trials largely stop. The youngest randomised pediatric data come from Bisgaard’s lower age limit of 4 and CARE’s lower limit of 5, and neither was powered to isolate the 4-to-5-year-old group. No adequately powered trial has tested MART or AIR as a strategy in preschool children.
This is the real fault line. NHLBI’s threshold of age 4 rests on the thin lower edge of the pediatric evidence. GINA, by contrast, holds its recommendation at age 6 and awaits results from trials now under way in children aged 5 and younger. Neither position is unreasonable; they weight the same sparse data differently.
Several trials are now addressing this gap directly, including studies of ICS-formoterol as reliever therapy in children aged 5 and younger. Until they report, the age-4 threshold remains an extrapolation rather than a directly tested recommendation. Clinicians treating preschoolers are working at the edge of the evidence, not within it.
SMART and MART name the identical single-inhaler regimen — the guidelines are not recommending different treatments. Their disagreement is almost entirely about the age at which to begin, not about mechanism, drug, or dosing principle.
Quality and Consistency of the Evidence
Confidence in ICS-formoterol for children tracks closely with the patient’s age.
- High — adolescents and adults. Fewer exacerbations with ICS-formoterol reliever or MART. Multiple randomised trials and independent meta-analyses converge on the same direction.
- Moderate — children aged 6–11. Fewer exacerbations supported by one dedicated MART trial and one reliever trial, the latter open-label.
- Insufficient — below age 6. No adequately powered randomised trial of the strategy exists in this group.
Several design features temper the pediatric estimates. CARE was open-label, the adolescent estimate came from a post hoc analysis, and the two largest meta-analyses drew predominantly from adults. None of these features overturns the direction of benefit, but each argues for measured language.
Taken together, the pediatric evidence justifies confidence at ages 6 and above and caution below. It supports ICS-formoterol as an effective attack-reducing strategy in school-aged children, while leaving the youngest patients genuinely under-studied.
What the Evidence Does Not Show
The gaps are specific, and naming them keeps the recommendations honest.
- No adequately powered randomised trial of MART or AIR in children younger than 6.
- No head-to-head trial in children comparing reliever-only AIR with full maintenance-and-reliever MART.
- Limited long-term data on growth and adrenal function under variable, symptom-driven ICS-formoterol dosing in young children.
- No direct trial evidence confirming benefit specifically in 4-to-5-year-olds, the group that separates the two guideline thresholds.
- Sparse real-world effectiveness and adherence data for pediatric SMART in routine US practice, with implementation trials still ongoing.
Practical Implications
The evidence supports a small number of practical positions rather than rigid rules. Clinical judgement and local prescribing information still govern any individual decision.
- Adolescents aged 12 and older. Both guidelines support ICS-formoterol as reliever or MART, making it a reasonable default for this group.
- Children aged 6–11 with moderate-to-severe asthma. MART is an evidence-based option both guidelines accept, and NHLBI frames it as the preferred step 3–4 therapy.
- Product choice. Use only an ICS-formoterol combination for single-inhaler reliever use; ICS-LABA inhalers containing salmeterol or vilanterol are not interchangeable.
- Dose ceilings. Respect the pediatric limits — GINA caps formoterol at 36 µg delivered per day for ages 6–11, and NHLBI caps total actuations at 8 per day for ages 5–11.
- Under age 6. Neither the evidence nor GINA supports MART, and NHLBI’s age-4 wording runs ahead of direct data, so individualise and reassess as trials report.
Two further points help at the bedside. Inhaler technique and device suitability vary with age, so the choice of a specific ICS-formoterol product should match what a given child can use reliably. And because single-inhaler regimens change how families use their reliever, clear instruction on when and how much to take is part of prescribing the strategy well.
These positions describe what the current evidence supports; they are not personalised medical advice for a specific child.
Evidence Grade and Bottom Line
Overall grade — Moderate. The rating is High for adolescents, Moderate for children aged 6–11, and Insufficient below age 6.
The grade reflects both the strength of the exacerbation signal and the age at which it was measured. Where children were actually enrolled, the direction of benefit is consistent; where they were not, the grade drops accordingly.
- GINA and NHLBI are more concordant than the age numbers suggest; both endorse the same ICS-formoterol regimen.
- Across the pediatric range actually studied — roughly age 5 and up — ICS-formoterol reduces asthma attacks compared with salbutamol-based care.
- The genuine divergence sits in the 4-to-5-year gap, where direct trial evidence is absent and the guidelines weight extrapolation differently.
- Choosing between the guidelines for a 6-to-11-year-old is a question of emphasis; choosing for a preschooler is a question of missing evidence.
Article Information and References
- Sobieraj DM, Weeda ER, Nguyen E, et al. Association of inhaled corticosteroids and long-acting β-agonists as controller and quick relief therapy with exacerbations and symptom control in persistent asthma: a systematic review and meta-analysis. JAMA. 2018;319(14):1485–1496. DOI: https://doi.org/10.1001/jama.2018.2769
- Hatter L, Bruce P, Braithwaite I, et al. ICS-formoterol reliever versus ICS and short-acting β2-agonist reliever in asthma: a systematic review and meta-analysis. ERJ Open Res. 2021;7(1):00701-2020. DOI: https://doi.org/10.1183/23120541.00701-2020
- Jorup C, Lythgoe D, Bisgaard H. Budesonide/formoterol maintenance and reliever therapy in adolescent patients with asthma. Eur Respir J. 2018;51(1):1701688. DOI: https://doi.org/10.1183/13993003.01688-2017
- Hatter L, Holliday M, Oldfield K, et al. Budesonide–formoterol versus salbutamol as reliever therapy in children with mild asthma (CARE): a 52-week, open-label, multicentre, superiority, randomised controlled trial. Lancet. 2025;406(10511):1473–1483. DOI: https://doi.org/10.1016/S0140-6736(25)00861-X
- Bisgaard H, Le Roux P, Bjåmer D, et al. Budesonide/formoterol maintenance plus reliever therapy: a new strategy in pediatric asthma. Chest. 2006;130(6):1733–1743. DOI: https://doi.org/10.1378/chest.130.6.1733
- Expert Panel Working Group of the NHLBI administered and coordinated NAEPPCC; Cloutier MM, Baptist AP, Blake KV, et al. 2020 Focused Updates to the Asthma Management Guidelines. J Allergy Clin Immunol. 2020;146(6):1217–1270. DOI: https://doi.org/10.1016/j.jaci.2020.10.003
- Cloutier MM, Teach SJ, Lemanske RF Jr, Blake KV. The 2020 focused updates to the NIH asthma management guidelines: key points for pediatricians. Pediatrics. 2021;147(6):e2021050286. DOI: https://doi.org/10.1542/peds.2021-050286
- O’Byrne PM, Bisgaard H, Godard PP, et al. Budesonide/formoterol combination therapy as both maintenance and reliever medication in asthma. Am J Respir Crit Care Med. 2005;171(2):129–136. DOI: https://doi.org/10.1164/rccm.200407-884OC
- Bateman ED, Reddel HK, O’Byrne PM, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378(20):1877–1887. DOI: https://doi.org/10.1056/NEJMoa1715275
- Beasley R, Holliday M, Reddel HK, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med. 2019;380(21):2020–2030. DOI: https://doi.org/10.1056/NEJMoa1901963
- Reddel HK, O’Byrne PM, FitzGerald JM, et al. Efficacy and safety of as-needed budesonide-formoterol in adolescents with mild asthma. J Allergy Clin Immunol Pract. 2021;9(8):3069–3077.e6. DOI: https://doi.org/10.1016/j.jaip.2021.04.016
- Papi A, Corradi M, Pigeon-Francisco C, et al. Beclometasone-formoterol as maintenance and reliever treatment in patients with asthma: a double-blind, randomised controlled trial. Lancet Respir Med. 2013;1(1):23–31. DOI: https://doi.org/10.1016/S2213-2600(13)70012-2