Speaker's Highlight

• Don Sin University of British Columbia, St. Paul Hospital (Canada)
  Kenneth R. Chapman Toronto General Hospital Research Institute (Canada)
• Parameswaran Nair McMaster University (Canada)
  Carolyn Calfee UCSF (U.S.A.)
• Gregory P. Downey University of Colorado School of Medicine (U.S.A.)
  David A. Schwartz University of Colorado School of Medicine (U.S.A.)
• Neil Schluger Tuberculosis Control Branch, California Department of Public Health (U.S.A.)
  Nick Kim Critical Care & Sleep Medicine, University of California San Diego (U.S.A.)
• Nicola Hananiah Baylor College of Medicine (U.S.A.)
  Jae-Joon Yim Seoul National University College of Medicine (Republic of Korea)
• Koichiro Asano Tokai University School of Medicine (Japan)
  Diahn-Warng Perng Taipei Veterans General Hospital (Taiwan)
• Konstantinos Kostikas University of Ioannina (Greece)
  Karin Klooster University Medical Center Groningen (Kingdom of the Netherlands)

• Corticosteroid resistance in severe asthma

  Severe asthma remains uncontrolled for some patients even when inhaled corticosteroids (ICS) are prescribed at high doses and combined with long-acting bronchodilators. When symptoms, airflow limitation, or exacerbations persist, clinicians must determine whether the disease is genuinely resistant to corticosteroids or whether another remediable factor is limiting treatment response.

  This distinction matters in respiratory medicine because apparent treatment failure can arise from incorrect diagnosis, poor inhaler technique, inconsistent use, smoking exposure, untreated comorbidities, or ongoing environmental triggers. A systematic assessment can prevent unnecessary escalation and support earlier use of targeted therapies.

  For congress discussions involving asthma specialists, pulmonologists, and allied healthcare professionals, corticosteroid resistance offers a valuable framework for examining airway inflammation, immune regulation, biomarkers, and personalized treatment.

  What corticosteroid resistance means

  Corticosteroid resistance describes an inadequate clinical, physiological, or inflammatory response to glucocorticoids despite appropriate treatment and confirmed adherence. It differs from corticosteroid insensitivity, which may reflect a reduced response across different steroid exposures and biological systems. In practice, the terms are sometimes used interchangeably, although their mechanisms may vary.

  Some patients have persistent symptoms because airway inflammation is driven by pathways that respond poorly to steroids. Others have a partial response: exacerbations become less frequent, yet airflow obstruction or daily symptoms remain. True resistance should therefore be considered only after treatment delivery, diagnosis, and relevant comorbid conditions have been carefully reviewed.

  Why severe asthma may respond poorly

  Corticosteroids regulate gene transcription through the glucocorticoid receptor, suppressing many inflammatory signals and reducing eosinophil survival. Resistance can develop when receptor expression, receptor movement into the cell nucleus, or downstream gene regulation is impaired. Increased activation of inflammatory transcription factors, including pathways associated with oxidative stress, may further weaken steroid effects.

  The inflammatory profile also influences responsiveness. Type 2 inflammation, characterized by eosinophils, interleukins such as IL-4, IL-5, and IL-13, and elevated fractional exhaled nitric oxide, often remains steroid responsive but may require intensive treatment. Neutrophilic or paucigranulocytic inflammation may be less responsive to corticosteroids. Obesity, recurrent infections, smoking, air pollution, and chronic exposure to irritants can intensify these patterns.

  Confirming treatment-refractory disease

  Before labeling a patient as steroid resistant, clinicians should verify the asthma diagnosis with objective testing when possible. Spirometry with bronchodilator reversibility, peak-flow variability, bronchial provocation testing, and assessment of alternative diagnoses can clarify whether persistent breathlessness results from asthma, vocal cord dysfunction, bronchiectasis, chronic obstructive pulmonary disease, cardiac disease, or dysfunctional breathing.

  Treatment exposure requires equal attention. Reviewing refill records, observing inhaler technique, checking device suitability, and discussing barriers without blame can reveal inadequate drug delivery. Comorbid allergic rhinitis, chronic rhinosinusitis with nasal polyps, gastroesophageal reflux, obstructive sleep apnea, anxiety, depression, and obesity may amplify symptoms or increase exacerbation risk without representing steroid failure.

  Biomarkers and phenotyping

  A structured phenotype assessment helps distinguish steroid-resistant inflammation from fixed airway remodeling or noninflammatory symptoms. Blood eosinophils, sputum eosinophils, fractional exhaled nitric oxide, total IgE, allergen sensitization, and a history of exacerbations can guide interpretation. No single biomarker proves corticosteroid resistance, and results should be considered alongside current treatment and recent systemic steroid exposure.

  Clinical feature	Possible interpretation	Practical focus
  Persistent eosinophilia despite high-dose ICS	Ongoing type 2 inflammation or inadequate exposure	Check adherence, triggers, and eligibility for biologic therapy
  Low eosinophils with frequent symptoms	Non-eosinophilic inflammation, obesity, or an alternative cause	Reassess diagnosis and comorbidities before increasing steroids
  High FeNO	Active IL-13-related inflammation, atopy, or poor ICS use	Review technique, adherence, allergen exposure, and treatment response
  Fixed airflow obstruction	Airway remodeling or coexisting COPD	Confirm lung function pattern and smoking history
  Repeated oral steroid bursts	Uncontrolled disease and substantial treatment toxicity	Pursue specialist review and steroid-sparing strategies

  Managing severe asthma with limited steroid response

  Management begins with optimization rather than automatic escalation of oral corticosteroids. Patients should receive an individualized inhaler plan, education on device technique, vaccination advice, smoking cessation support, and guidance for recognizing exacerbations. Trigger reduction and treatment of upper-airway disease can improve control even when lower-airway inflammation is difficult to suppress.

  For eligible patients, biologic therapies can reduce exacerbations and oral corticosteroid exposure. Anti-IgE treatment may benefit severe allergic asthma, while anti-IL-5 or anti-IL-5 receptor therapies target eosinophilic disease. Anti-IL-4 receptor therapy can address type 2 inflammation, and other emerging agents may broaden options for patients with different biomarker profiles. Selection should reflect phenotype, exacerbation history, biomarker results, comorbidities, access, and response over time.

  Reducing the burden of systemic steroids

  Long-term or repeated oral corticosteroid use can produce hypertension, diabetes, osteoporosis, cataracts, weight gain, infection risk, adrenal suppression, and psychological effects. A patient may appear clinically improved while accumulating substantial harm. Steroid stewardship should therefore be treated as a central outcome, alongside symptom control and lung function.

  After initiating a steroid-sparing intervention, clinicians can track exacerbations, rescue medication use, asthma control scores, spirometry, biomarkers, and daily activity. Tapering systemic steroids requires individualized supervision because withdrawal symptoms and adrenal insufficiency can mimic worsening asthma. The lowest effective dose should be pursued, with clear monitoring and rapid review if control deteriorates.

  Priorities for clinical and congress discussion

  • Define objective criteria for distinguishing true corticosteroid resistance from undertreatment or misdiagnosis.
  • Compare biomarker-guided approaches for eosinophilic, allergic, and non-type 2 severe asthma.
  • Examine how smoking, obesity, infection, pollution, and airway remodeling alter treatment response.
  • Share real-world evidence on biologic therapies and reductions in oral corticosteroid exposure.
  • Include multidisciplinary strategies for adherence, inhaler technique, comorbidity care, and patient safety.

  Corticosteroid resistance in severe asthma is best understood as a clinical signal requiring investigation rather than a final diagnosis. Bringing together mechanistic research, biomarker science, and practical respiratory care can help specialists identify treatable traits and reduce dependence on systemic steroids. APSR and KATRD congress sessions provide an appropriate setting to exchange evidence, refine phenotyping strategies, and translate advances in severe asthma management into safer, more individualized care.

  Richard Russell Nuffield Department of Clinical Medicine, University of Oxford (United Kingdom)
• Mona Bafadhel King’s College London (United Kingdom)
  David Jackson Guy’s and St Thomas’ Hospital, King’s College London (United Kingdom)
• James Chalmers University of Dundee (United Kingdom)
  David Price University of Aberdeen (United Kingdom)