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Asthma — overview

TL;DR — Asthma is heterogeneous airway disease with variable symptoms and airflow limitation; objective variability is essential because wheeze and cough have many mimics. GBD estimated 260 million cases and 436,000 deaths in 2021 (GBD 2021 Asthma Collaborators 2025, PMID 40147466). ICS-containing treatment prevents severe attacks, and as-needed ICS–formoterol replaced SABA-only treatment as the preferred safety strategy for many adolescents/adults with mild asthma (O'Byrne 2018, PMID 29768149; Beasley 2019, PMID 31112386). Severe type-2 asthma can respond dramatically to matched biologics, while non-type-2 disease has fewer options (Fahy 2015, PMID 25534623). Before escalation, diagnosis, inhaler technique, adherence, exposure and comorbidity must be rechecked.

Definition and diagnostic anchors

  • Asthma features episodic wheeze, breathlessness, chest tightness and/or cough that vary over time and intensity, plus variable expiratory airflow limitation.
  • Objective evidence includes bronchodilator reversibility, peak-flow variability, response to anti-inflammatory therapy or bronchial challenge; normal spirometry between attacks does not exclude asthma (Rothe 2018, PMID 29614508).
  • Differential diagnoses include inducible laryngeal obstruction, COPD, bronchiectasis, heart failure, dysfunctional breathing, eosinophilic bronchitis, foreign body and anxiety-related hyperventilation.
  • Severe asthma is asthma remaining uncontrolled despite optimized high-dose ICS/LABA and management of contributory factors, or worsening when high-dose treatment is reduced.
  • Acute life-threatening features include exhaustion, altered consciousness, cyanosis/hypoxemia, hypotension, silent chest, poor respiratory effort or rising carbon dioxide (Garner 2022, PMID 35218742).

Epidemiology and burden

GBD 2021 estimated 260 million prevalent asthma cases and 436,000 deaths in 2021; prevalence rates are often higher in high-income settings, while mortality rates are disproportionately high in lower-resource regions (GBD 2021 Asthma Collaborators 2025, PMID 40147466).

Asthma begins at any age and follows multiple trajectories: early transient wheeze, allergic childhood disease, persistent asthma, adult-onset eosinophilic disease, obesity-associated disease and occupational asthma. Predicting persistence or remission remains imprecise (Sears 2015, PMID 26449797).

Climate change, air pollution, wildfire smoke and changing pollen seasons can increase exposure and attacks, interacting with allergic sensitization and inequitable housing/occupation (D'Amato 2023, PMID 36917187).

Burden has at least four separable layers:

Layer Examples Measurement
Current impairment Symptoms, night waking, activity restriction Validated control score and functional history
Future risk Severe attacks, death, lung-function loss Prior attacks, spirometry, reliever/OCS exposure, biomarkers
Treatment burden Daily devices, injections, adverse effects, cost Medication history, cumulative steroids and patient report
Structural burden Pollution, housing, school/work and access Place/exposure and care-access assessment

Good symptom control does not erase attack risk, and low day-to-day symptom burden does not make SABA-only treatment safe.

Mechanism sketch

Airway epithelium senses viruses, allergens and pollutants and releases alarmins including TSLP, IL-33 and IL-25. In type-2 disease, Th2 cells and ILC2s drive IL-4/IL-13, IgE, eosinophils, mucus and hyperresponsiveness. Many but not all patients show this pattern (Fahy 2015, PMID 25534623; Gans 2020, PMID 31678040).

Non-type-2 asthma may involve neutrophilic inflammation, obesity/metabolic biology, infection, irritants or paucigranulocytic airway dysfunction; reliable targeted therapies lag type-2 disease (Kuruvilla 2019, PMID 30206782).

Chronic inflammation and bronchoconstriction can produce smooth-muscle hypertrophy, goblet-cell change and fixed airflow limitation. Asthma genetics is polygenic and context-dependent; GWAS implicates immune and epithelial loci but does not diagnose disease (Ober 2016, PMID 27027959; Ntontsi 2021, PMID 33673725).

Phenotype is not endotype

Term Meaning Example
Phenotype Observable clinical pattern Late-onset asthma with nasal polyps
Endotype Disease mechanism linked to treatment response IL-5-associated eosinophilic inflammation
Treatable trait Actionable dimension regardless of label Smoking, eosinophilia, reflux symptoms, poor adherence

Markers and labels change with treatment and time. A patient can have overlapping allergic, eosinophilic, obesity-associated and occupational traits.

Clinical map

  1. Suspect asthma from a variable symptom pattern and triggers.
  2. Confirm variable expiratory airflow before long-term treatment when feasible.
  3. Assess symptoms and future risk separately.
  4. Start an ICS-containing strategy appropriate to age, severity and local guidance.
  5. Teach the device and a written action plan using teach-back.
  6. Review response, attacks, lung function, adverse effects and patient goals.
  7. Optimize adherence, exposure and comorbidity before stepping up.
  8. Phenotype recurrent severe disease and minimize systemic corticosteroids.
  9. Step down cautiously after sustained control while retaining ICS protection.

Treatment landscape

ICS-containing safety strategy

SABA relieves bronchoconstriction but does not treat airway inflammation. Nationwide SABINA data associated dispensing ≥3 SABA canisters/year with progressively higher exacerbation and mortality risk, although confounding by severity/adherence remains (Nwaru 2020, PMID 31949111).

SYGMA 1 found as-needed budesonide–formoterol superior to SABA-only terbutaline for symptom control and severe-exacerbation prevention, with lower steroid exposure than maintenance budesonide (O'Byrne 2018, PMID 29768149). SYGMA 2 found as-needed budesonide–formoterol noninferior to maintenance budesonide for severe exacerbations but inferior for symptom control (Bateman 2018, PMID 29768147).

Novel START pragmatically found as-needed budesonide–formoterol superior to albuterol alone for exacerbation prevention and comparable to maintenance budesonide for severe exacerbations (Beasley 2019, PMID 31112386). Network meta-analysis supports SMART/MART and as-needed ICS–formoterol strategies across severity contexts (Rogliani 2020, PMID 32430423).

Severe asthma and biologics

Phenotyping uses exacerbations, maintenance steroid exposure, blood eosinophils, FeNO, allergic sensitization/IgE, nasal polyps and age of onset. These are probability modifiers, not perfect response tests.

Target Anchor evidence
IgE: omalizumab INNOVATE severe allergic asthma trial (Humbert 2005, PMID 15679715)
IL-5: mepolizumab DREAM and MENSA severe eosinophilic asthma trials (Pavord 2012, PMID 22901886; Ortega 2014, PMID 25199059)
IL-5R: benralizumab SIROCCO reduced exacerbations in eosinophilic severe asthma (Bleecker 2016, PMID 27609408)
IL-4Rα: dupilumab Reduced severe exacerbations and improved FEV1, especially with type-2 markers (Castro 2018, PMID 29782217)
TSLP: tezepelumab NAVIGATOR reduced exacerbations across a broad severe-asthma population, with larger effects at higher type-2 markers (Menzies-Gow 2021, PMID 33979488)

Biologics should reduce attacks and oral-steroid burden; response is reassessed rather than assumed indefinitely.

What response should mean

Outcome Meaningful direction
Severe attacks Fewer events and more attack-free time
Oral steroids Lower cumulative and maintenance exposure
Symptoms Improvement exceeding instrument noise/minimal important difference
Lung function Reproducible improvement or stabilized decline
Participation Restored sleep, school, work, exercise and roles
Treatment burden Acceptable device, dosing, appointments and cost

Biomarker depletion alone is not adequate success if attacks and life restriction continue.

Oral steroids, procedures and allergy treatment

Systemic corticosteroids are lifesaving in severe exacerbations but cumulative bursts produce metabolic, bone, infection, eye and cardiovascular harms. Even short courses were associated with sepsis, venous thromboembolism and fracture in a large US cohort (Waljee 2017, PMID 28404617).

Bronchial thermoplasty reduces airway smooth muscle by controlled radiofrequency heating; evidence and long-term selection are narrower than for modern biologics, with transient procedure-related worsening (Mainardi 2019, PMID 30691712).

Allergen immunotherapy can improve selected allergic asthma when disease is controlled, but uncontrolled/severe asthma raises systemic-reaction risk and product-specific evidence matters (Caimmi 2022, PMID 35818140).

Pregnancy management prioritizes control because exacerbations harm parent and fetus; most standard inhaled therapies have more reassuring evidence than uncontrolled disease, while biologic data remain less mature (Vyawahare 2023, PMID 38186538).

Biomarkers and frontier

Blood eosinophils and FeNO are the most actionable accessible markers but vary over time and with steroids, infection and adherence. Patient-level ORACLE2 analysis links inflammatory and clinical risk factors to attacks, supporting multidimensional prediction rather than one cutoff (Meulmeester 2025, PMID 40215991).

Frontiers are non-type-2 therapy, remission induction, prevention from early-life risk, and lower-cost access to ICS and biologics. Environmental prevention trials have not yet produced a universal primary-prevention strategy.

Across the life course

Preschool wheeze is a probability problem: many children remit, while persistent symptoms, atopy, eosinophilia, severe episodes and impaired lung function raise later-asthma risk. In school-age children, objective testing becomes more feasible, while growth, caregiver technique and school access remain central.

Adolescence transfers medication responsibility during a period of stigma, changing routines and emerging smoking/vaping exposure. Adult-onset asthma requires occupational assessment and attention to nasal polyps, eosinophilia, obesity and mimics. In older adults, fixed obstruction, cardiac disease, polypharmacy, cognition and device capability complicate interpretation.

Pregnancy is a period for tighter coordination, not controller withdrawal. The known harm of uncontrolled disease and attacks must be compared with medication-specific evidence and uncertainty.

Common safety failures

Failure Consequence Preventive control
Diagnosis based on symptoms alone Mimics treated with escalating steroids Objective testing and periodic reconfirmation
No ICS-containing strategy Preventable attacks and SABA reliance Controller/anti-inflammatory reliever access
Technique never observed Prescribed dose not delivered Device-specific teach-back at every change
Adherence assumed False severe-asthma label Nonjudgmental history plus objective evidence
OCS courses viewed separately Cumulative toxicity hidden Shared annual dose/course counter
Post-attack discharge without follow-up High-risk transition unmanaged Action plan, medication repair and rapid review
Comorbidity treated as the whole explanation Active asthma or dangerous mimic missed Measure each mechanism and outcome separately

Open questions

  • Can asthma remission be induced rather than observed? (Sears 2015, PMID 26449797)
  • Which marker chooses among biologics with overlapping eligibility? (Gans 2020, PMID 31678040; Menzies-Gow 2021, PMID 33979488)
  • What effective targeted therapy exists for non-type-2 asthma? (Fahy 2015, PMID 25534623)
  • How can oral-steroid exposure be minimized without increasing attacks? (Waljee 2017, PMID 28404617)
  • Which policy closes the mismatch between global prevalence and preventable mortality? (GBD 2021 Asthma Collaborators 2025, PMID 40147466)

References

  1. Rothe T, et al. Diagnosis and management of asthma. Respiration. 2018. PMID 29614508
  2. GBD 2021 Asthma and Allergic Diseases Collaborators. Global burden of asthma and atopic dermatitis, 1990–2021. Lancet Respir Med. 2025. PMID 40147466
  3. Fahy JV. Type 2 inflammation in asthma. Nat Rev Immunol. 2015. PMID 25534623
  4. Gans MD, et al. Immunology, biomarkers and asthma endotypes. Med Clin North Am. 2020. PMID 31678040
  5. Kuruvilla ME, et al. Asthma phenotypes, endotypes and mechanisms. Clin Rev Allergy Immunol. 2019. PMID 30206782
  6. Ober C, et al. Asthma genetics in the post-GWAS era. Ann Am Thorac Soc. 2016. PMID 27027959
  7. Ntontsi P, et al. Genetics and epigenetics in asthma. Int J Mol Sci. 2021. PMID 33673725
  8. O'Byrne PM, et al. As-needed budesonide–formoterol in mild asthma. N Engl J Med. 2018. PMID 29768149
  9. Bateman ED, et al. As-needed budesonide–formoterol versus maintenance budesonide. N Engl J Med. 2018. PMID 29768147
  10. Beasley R, et al. Novel START trial. N Engl J Med. 2019. PMID 31112386
  11. Rogliani P, et al. SMART and as-needed asthma therapies. Eur Respir J. 2020. PMID 32430423
  12. Nwaru BI, et al. SABA overuse, exacerbation and mortality: SABINA. Eur Respir J. 2020. PMID 31949111
  13. Humbert M, et al. INNOVATE omalizumab trial. Allergy. 2005. PMID 15679715
  14. Pavord ID, et al. DREAM mepolizumab trial. Lancet. 2012. PMID 22901886
  15. Ortega HG, et al. Mepolizumab in severe eosinophilic asthma. N Engl J Med. 2014. PMID 25199059
  16. Bleecker ER, et al. SIROCCO benralizumab trial. Lancet. 2016. PMID 27609408
  17. Castro M, et al. Dupilumab in uncontrolled asthma. N Engl J Med. 2018. PMID 29782217
  18. Menzies-Gow A, et al. NAVIGATOR tezepelumab trial. N Engl J Med. 2021. PMID 33979488
  19. Waljee AK, et al. Short-term oral corticosteroids and harms. BMJ. 2017. PMID 28404617
  20. Mainardi AS, et al. Bronchial thermoplasty. N Engl J Med. 2019. PMID 30691712
  21. Caimmi D, et al. Allergen immunotherapy in asthma. Front Pediatr. 2022. PMID 35818140
  22. Vyawahare AP, et al. Asthma in pregnancy. Cureus. 2023. PMID 38186538
  23. Meulmeester FL, et al. ORACLE2 asthma-attack risk factors. Lancet Respir Med. 2025. PMID 40215991
  24. Sears MR. Predicting asthma outcomes. J Allergy Clin Immunol. 2015. PMID 26449797
  25. D'Amato G, et al. Climate, pollution, pollen and extreme events. Multidiscip Respir Med. 2023. PMID 36917187
  26. Garner O, et al. Management of life-threatening asthma. Chest. 2022. PMID 35218742