Skip to content

Mild and moderate asthma

TL;DR — “Mild” asthma can still produce severe attacks, so treatment intensity and current symptoms should not be mistaken for future safety. In SYGMA 1, as-needed budesonide–formoterol reduced annual severe-exacerbation rates from 0.20 with terbutaline alone to 0.07 (rate ratio 0.36, 95% CI 0.27–0.49), while maintenance budesonide produced better week-to-week symptom control (O'Byrne 2018, PMID 29768149). SYGMA 2 found as-needed budesonide–formoterol noninferior to maintenance budesonide for severe attacks (rate ratio 0.97; one-sided upper 95% limit 1.16) with a median metered ICS dose of 66 versus 267 μg/day, but symptoms favored maintenance treatment (Bateman 2018, PMID 29768147). Across 27 trials and 50,496 participants, ICS–formoterol and ICS–SABA relievers reduced severe exacerbations versus SABA alone by RR 0.65 (0.60–0.72) and 0.84 (0.73–0.95), respectively (Rayner 2025, PMID 39465893). Step-up should follow confirmation, technique and adherence review; step-down should preserve an ICS-containing safety strategy and be monitored.

Mild does not mean harmless

Asthma severity is retrospective: it is inferred from the treatment needed to maintain control after diagnosis, technique, adherence and exposures are optimized. A patient with infrequent symptoms can still have high attack risk from a prior severe event, low lung function, high type-2 biomarkers or SABA overuse.

The treatment problem has two axes:

Axis Question Preferred measure
Current impairment Are symptoms, sleep, activity and reliever use controlled? Validated control score plus functional history
Future risk Will the patient have a severe attack, lung-function loss or treatment toxicity? Prior attacks, systemic steroids, spirometry, eosinophils/FeNO and medication exposure

A regimen can improve one axis more than the other. Maintenance ICS often improves daily symptom control, while symptom-driven ICS–formoterol can achieve similar attack protection at lower total ICS exposure in mild disease (Bateman 2018, PMID 29768147).

Why ICS is the safety anchor

ICS suppresses airway inflammation, reduces hyperresponsiveness and prevents attacks. In the START trial, 7,241 people with recent-onset mild persistent asthma were randomized to budesonide or placebo for three years: severe events occurred in 117/3,597 versus 198/3,568, HR 0.56 (95% CI 0.45–0.71) (Pauwels 2003, PMID 12672309).

The same trial found small lung-function differences and, among children under 11, 1.34 cm less growth over three years with budesonide, concentrated in the first year (Pauwels 2003, PMID 12672309). This quantifies the central balance: clinically meaningful attack prevention versus dose-dependent adverse effects.

Long-term CAMP follow-up randomized 1,041 children to budesonide, nedocromil or placebo for four to six years. Budesonide improved control measures but did not alter the primary long-term post-bronchodilator FEV1-growth outcome, and growth velocity effects required monitoring (Childhood Asthma Management Program Research Group 2000, PMID 11027739).

Reliever strategies

Strategy Anti-inflammatory drug delivered when symptoms worsen? Main evidence implication
SABA alone No Relieves bronchoconstriction but leaves inflammation untreated; higher attack risk than ICS-containing relievers
As-needed ICS–formoterol Yes, in same inhaler Strong mild-asthma and MART evidence; formoterol has rapid onset
As-needed ICS–SABA Yes, fixed combination or sequential use Reduces severe attacks versus SABA alone; evidence base and availability differ from ICS–formoterol
Maintenance ICS + SABA Daily ICS independent of symptoms Strong symptom and attack efficacy when adhered to
Maintenance-and-reliever ICS–formoterol (MART/SMART) Daily plus additional symptom-driven ICS/formoterol Reduces severe attacks in moderate-to-severe disease

LABAs other than formoterol do not have the same rapid-onset evidence for reliever use. Device, formulation and maximum daily use are regimen-specific; “ICS/LABA” is not a single interchangeable reliever category.

Mild-asthma trials

SYGMA 1

SYGMA 1 randomized 3,849 patients aged at least 12 years for 52 weeks among as-needed terbutaline, as-needed budesonide–formoterol and maintenance budesonide plus terbutaline (O'Byrne 2018, PMID 29768149).

Outcome Terbutaline PRN Budesonide–formoterol PRN Budesonide maintenance
Well-controlled weeks 31.1% 34.4% 44.4%
Annual severe-exacerbation rate 0.20 0.07 0.09
PRN ICS–formoterol comparison — vs terbutaline RR 0.36 (95% CI 0.27–0.49) vs maintenance RR 0.83 (0.59–1.16)

The trial established that the symptom-control and attack-prevention rankings were different: maintenance ICS produced more well-controlled weeks, while both ICS-containing strategies protected against severe attacks.

SYGMA 2

SYGMA 2 randomized 4,215 people; severe-exacerbation rates were 0.11/year with as-needed budesonide–formoterol and 0.12/year with maintenance budesonide, rate ratio 0.97 with upper one-sided 95% confidence limit 1.16, meeting the prespecified noninferiority margin of 1.2 (Bateman 2018, PMID 29768147).

Median metered ICS exposure was 66 μg/day with the as-needed strategy versus 267 μg/day with maintenance budesonide. Symptoms favored daily maintenance treatment.

Novel START and PRACTICAL

Novel START randomized 675 adults under pragmatic open-label conditions. Annual exacerbation rates were 0.195 with as-needed budesonide–formoterol versus 0.400 with albuterol alone, relative rate 0.49 (95% CI 0.33–0.72); severe exacerbations numbered 9 versus 23 (Beasley 2019, PMID 31112386).

PRACTICAL compared as-needed budesonide–formoterol with maintenance budesonide plus terbutaline in adults with mild-to-moderate asthma over 52 weeks and showed fewer severe exacerbations with the as-needed combination under open-label practice-like conditions (Hardy 2019, PMID 31451207).

Open-label designs can change behavior and symptom reporting, but they also test how regimens work when adherence is less artificially supported.

Pooled reliever evidence

A 2025 systematic review included 27 RCTs and 50,496 adult and pediatric participants. Versus SABA alone:

  • ICS–formoterol reduced severe exacerbations: RR 0.65 (95% CI 0.60–0.72), absolute risk difference −10.3% (−11.8% to −8.3%);
  • ICS–SABA reduced severe exacerbations: RR 0.84 (0.73–0.95), absolute risk difference −4.7% (−8.0% to −1.5%) (Rayner 2025, PMID 39465893).

The absolute risk difference depends on baseline risk; the relative estimate should not be applied to a population with a very different event rate without recalibration.

Moderate asthma: maintenance and reliever therapy

For patients needing maintenance ICS/LABA, using ICS–formoterol for both maintenance and relief aligns extra anti-inflammatory dose with worsening symptoms.

A patient-level meta-analysis of 4,863 poorly controlled adolescents/adults found that switching to budesonide–formoterol SMART prolonged time to first severe exacerbation compared with continuing or stepping up conventional ICS/LABA plus SABA (Beasley 2022, PMID 35230437).

A network meta-analysis of 21 studies and 32,096 patients ranked low-to-medium-dose SMART highly for exacerbation prevention across moderate-to-severe disease, while recognizing differences in populations and dosing (Rogliani 2020, PMID 32430423).

Step-up choices

Before increasing pharmacologic intensity, recheck four high-yield causes of apparent failure:

  1. the diagnosis is objectively supported;
  2. the device is used correctly;
  3. medication is available and taken;
  4. smoking, occupational exposure and relevant comorbidity are addressed.
If still uncontrolled Evidence-informed option Tradeoff
Low-dose ICS alone Add LABA or use ICS–formoterol maintenance/reliever strategy LABA should not be used without ICS in asthma
ICS/LABA plus SABA Switch to MART/SMART when formulation/age permits Requires education that the same inhaler serves both roles
Medium/high ICS/LABA Add LAMA/triple therapy Modest exacerbation and lung-function benefit; little average symptom difference
Persistent type-2 disease with attacks Severe-asthma assessment/biologic eligibility Confirm modifiable factors first

Triple-therapy meta-analysis included 20 RCTs and 11,894 participants. ICS/LABA/LAMA reduced severe exacerbations from 27.4% to 22.7% versus ICS/LABA, RR 0.83 (95% CI 0.77–0.90); average symptom and quality-of-life changes did not reach their minimal important differences (Kim 2021, PMID 34009257).

CAPTAIN and TRIMARAN/TRIGGER support lung-function and selected exacerbation benefits of single-inhaler triple therapy, but effects vary with ICS dose, baseline risk and biomarker pattern (Lee 2021, PMID 32918892; Virchow 2019, PMID 31582314).

Low-eosinophil mild asthma

In a 42-week crossover trial, 73% of 295 mild persistent-asthma participants had sputum eosinophils below 2%. Neither mometasone nor tiotropium showed a statistically significant prespecified differential response over placebo in that low-eosinophil group, although the study was limited by response definitions and crossover complexity (Lazarus 2019, PMID 31112384).

This does not justify withholding ICS-containing attack protection from every low-eosinophil patient. It does show that average daily-control benefits can be smaller in biomarker-low mild disease and motivates better treatment-response markers.

Leukotriene-receptor antagonists

Montelukast is orally administered and can benefit asthma, exercise-induced bronchoconstriction and allergic rhinitis, but it is generally less effective than ICS for control.

Adult exacerbation meta-analysis found montelukast better than placebo, OR 0.60 (95% CI 0.49–0.74), NNT 17 (12–29), but inferior to ICS and ICS/LABA first-line strategies (Zhang 2014, PMID 24992547).

In pediatric systematic review, ICS produced better daytime and night-time symptom scores than montelukast; versus placebo, montelukast improved global asthma symptoms (Mayoral 2023, PMID 37852659).

Neuropsychiatric safety requires explicit discussion. A 59-study review found no consistent association with suicide or ICD-coded depression but possible adult anxiety and sleep-disorder associations; evidence differed by design and age (Lo 2023, PMID 37758273).

ICS safety and dose discipline

Local adverse effects include dysphonia and candidiasis; spacer use and mouth rinsing reduce oropharyngeal deposition for appropriate devices. Systemic effects become more probable with high dose, long duration, interacting drugs and repeated systemic steroids.

Potential systemic outcomes include adrenal suppression, growth-velocity reduction, bone effects, cataract/glaucoma and metabolic effects, with magnitude depending on molecule, dose and delivery (Heffler 2018, PMID 29408385).

The correct comparison is not ICS versus zero risk. It is the lowest ICS exposure that protects against attacks versus the systemic-steroid exposure, hospitalization and mortality risk of undertreated disease.

Step-down

Step-down is a monitored experiment after sustained control, not discontinuation by default.

Before reduction During reduction Reasons to defer
Confirm stable symptoms and no recent severe attack Change one component at a time Recent exacerbation/systemic steroid
Check lung function and risk markers Document baseline control and action plan Pregnancy with unstable control
Choose a low-risk season when possible Review within a defined interval Poor access to urgent care or medication
Preserve an ICS-containing strategy Reinstate promptly if deterioration occurs Unresolved adherence/diagnostic uncertainty

In 459 controlled patients on medium-dose ICS/LABA, reduced-dose ICS/LABA and LABA withdrawal had similar composite treatment-failure timing, but LABA withdrawal produced greater lung-function decline and more hospitalizations; reduced-dose ICS/LABA did not meet noninferiority versus stable therapy (Rogers 2018, PMID 28974349).

In a 225-person pragmatic low-dose ICS/LABA trial, both LABA discontinuation and once-daily reduction failed noninferiority; treatment failure was 0% with maintenance versus 9.46% and 9.09% with the two step-down approaches over six months (Kim 2021, PMID 33940213).

Evidence does not support a single sequence for every patient. Risk, prior response, formulation and preference determine whether to reduce ICS dose, dosing frequency or another component (Rogers 2012, PMID 22081088).

Open questions

  • Which biomarker-low mild-asthma patients can safely use the lowest-exposure anti-inflammatory reliever strategy? (Lazarus 2019, PMID 31112384)
  • How do ICS–formoterol and ICS–SABA reliever strategies compare directly across ages, devices and baseline controller levels? (Rayner 2025, PMID 39465893)
  • Which step-down sequence preserves attack protection with the lowest cumulative steroid/LABA exposure? (Rogers 2018, PMID 28974349)
  • Can digital adherence data identify true pharmacologic failure before step-up without widening inequity?
  • What is the long-term developmental balance of early ICS exposure and prevented systemic-steroid bursts in children? (Pauwels 2003, PMID 12672309; Childhood Asthma Management Program Research Group 2000, PMID 11027739)

References

  1. O'Byrne PM, et al. Inhaled combined budesonide-formoterol as needed in mild asthma. N Engl J Med. 2018;378:1865-1876. PMID 29768149
  2. Bateman ED, et al. As-needed budesonide-formoterol versus maintenance budesonide in mild asthma. N Engl J Med. 2018;378:1877-1887. PMID 29768147
  3. Beasley R, et al. Controlled trial of budesonide-formoterol as needed for mild asthma. N Engl J Med. 2019;380:2020-2030. PMID 31112386
  4. Hardy J, et al. Budesonide-formoterol reliever therapy versus maintenance budesonide plus terbutaline: PRACTICAL. Lancet. 2019;394:919-928. PMID 31451207
  5. Rayner DG, et al. Inhaled reliever therapies for asthma: a systematic review and meta-analysis. JAMA. 2025. PMID 39465893
  6. Pauwels RA, et al. Early intervention with budesonide in mild persistent asthma: a randomised trial. Lancet. 2003;361:1071-1076. PMID 12672309
  7. Childhood Asthma Management Program Research Group. Long-term effects of budesonide or nedocromil in children with asthma. N Engl J Med. 2000;343:1054-1063. PMID 11027739
  8. Beasley R, et al. Evaluation of budesonide-formoterol for maintenance and reliever therapy among patients with poorly controlled asthma. JAMA Netw Open. 2022. PMID 35230437
  9. Rogliani P, et al. SMART and as-needed therapies in mild-to-severe asthma: a network meta-analysis. Eur Respir J. 2020. PMID 32430423
  10. Kim LHY, et al. Triple vs dual inhaler therapy and asthma outcomes in moderate to severe asthma: systematic review and meta-analysis. JAMA. 2021;325:2466-2479. PMID 34009257
  11. Lee LA, et al. Single-inhaler triple therapy versus FF/VI in inadequately controlled asthma: CAPTAIN. Lancet Respir Med. 2021;9:69-84. PMID 32918892
  12. Virchow JC, et al. Single-inhaler extrafine triple therapy in uncontrolled asthma: TRIMARAN and TRIGGER. Lancet. 2019;394:1737-1749. PMID 31582314
  13. Lazarus SC, et al. Mometasone or tiotropium in mild asthma with a low sputum eosinophil level. N Engl J Med. 2019;380:2009-2019. PMID 31112384
  14. Zhang HP, et al. Montelukast for prevention and treatment of asthma exacerbations in adults: systematic review and meta-analysis. Allergy Asthma Proc. 2014. PMID 24992547
  15. Mayoral K, et al. Montelukast in paediatric asthma and allergic rhinitis: systematic review and meta-analysis. Eur Respir Rev. 2023. PMID 37852659
  16. Lo CWH, et al. Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review. Eur Respir Rev. 2023. PMID 37758273
  17. Heffler E, et al. Inhaled corticosteroids safety and adverse effects in patients with asthma. J Allergy Clin Immunol Pract. 2018. PMID 29408385
  18. Rogers L, Reibman J. Stepping down asthma treatment: how and when. Curr Opin Pulm Med. 2012;18:70-75. PMID 22081088
  19. Rogers L, et al. Step-down therapy for asthma well controlled on ICS and LABA: a randomized clinical trial. J Allergy Clin Immunol Pract. 2018;6:633-643. PMID 28974349
  20. Kim SH, et al. Pragmatic randomized trial for stepping down asthma controller treatment. J Allergy Clin Immunol Pract. 2021. PMID 33940213
  21. Papi A, et al. Albuterol-budesonide fixed-dose combination rescue inhaler for asthma. N Engl J Med. 2022;386:2071-2083. PMID 35569035
  22. LaForce C, et al. As-needed albuterol-budesonide in mild asthma. N Engl J Med. 2025. PMID 40388330
  23. Reddel HK, et al. GINA strategy 2021: executive summary and rationale for key changes. Eur Respir J. 2022. PMID 34658302
  24. Sobieraj DM, et al. Association of ICS/LABA controller and quick-relief therapy with exacerbations and harms. JAMA. 2018;319:1485-1496. PMID 29554195
  25. Crossingham I, et al. Combination fixed-dose beta agonist and steroid inhaler as required for mild asthma. Cochrane Database Syst Rev. 2021. PMID 33945639
  26. FitzGerald JM, et al. Safety of as-needed budesonide-formoterol in mild asthma: data from the two phase III SYGMA studies. Drug Saf. 2021. PMID 33548020