What is the treatment plan for asthma based on phenotypes and genotypes?

Treatment Plan for Asthma Based on Phenotypes and Genotypes

Asthma treatment should be stratified by Type 2 (T2) inflammatory status and clinical phenotype, with inhaled corticosteroids as first-line therapy for persistent asthma, escalating to combination therapy with long-acting beta-agonists, and reserving targeted biologics for severe T2-high phenotypes with specific biomarker profiles. 1, 2

Core Treatment Framework: Stepwise Approach

The foundation of asthma management requires four integrated components regardless of phenotype: assessment and monitoring, patient education, environmental control, and medications adjusted through a stepwise approach based on severity and control. 1

Initial Severity Classification and Treatment Initiation

• Determine baseline severity using pre-treatment pulmonary function measurements, symptom frequency, and rescue medication use to select the appropriate starting step. 1, 2
• Initiate inhaled corticosteroids (ICS) as the most effective long-term control therapy for all patients with persistent asthma, regardless of phenotype. 1, 2
• Step up to combination ICS/long-acting beta-agonist (LABA) therapy for patients not responding adequately to ICS alone. 2, 3

Phenotype-Directed Treatment Strategies

T2-High Asthma Phenotype (Eosinophilic/Allergic)

This phenotype is characterized by eosinophilic airway inflammation, elevated IgE, and allergic sensitization, predominantly seen in children but also present in adults. 1, 4

Treatment Algorithm:

• First-line: ICS at appropriate doses based on severity. 1, 2
• Second-line: Add LABA if inadequate control (e.g., fluticasone propionate/salmeterol combination). 3
• Biomarker assessment: Measure blood eosinophil counts, fractional exhaled nitric oxide (FeNO), and serum total IgE to guide biologic selection. 5
• Biologic therapy for severe uncontrolled disease:
  • Anti-IgE therapy (omalizumab) for patients with elevated IgE and clear allergen sensitization. 1
  • Anti-IL-5 therapy specifically for patients with steroid-refractory eosinophilia (blood eosinophils remaining elevated despite high-dose oral corticosteroids), which reduces exacerbations by 50% in this select population. 1
  • Anti-IL-13 therapy shows statistically significant effects when assessed in stratified T2-high populations. 1

T2-Low Asthma Phenotype (Neutrophilic/Paucigranulocytic)

This phenotype lacks eosinophilia and elevated IgE, features neutrophilic or paucigranulocytic inflammation driven by IL-8, IL-17, and IL-22, and is more common in adults. 1, 4

Treatment Approach:

• Standard ICS therapy remains the foundation, though response may be less robust than in T2-high asthma. 1
• Avoid inappropriate biologic selection: Anti-IL-5 and anti-IL-13 therapies are ineffective in T2-low phenotypes and should not be used. 1
• Consider alternative mechanisms: Evaluate for occupational exposures, smoking history, and irritant triggers that may drive neutrophilic inflammation. 1, 4
• Optimize adherence and technique before escalating therapy, as poor response may reflect inadequate ICS delivery rather than true steroid resistance. 2

Age-Specific Phenotypic Considerations

Children (0-4 years):

• Initiate daily long-term control therapy for children with ≥2 wheezing episodes lasting >1 day in the past year PLUS positive asthma risk profile (parental asthma history, atopic dermatitis, OR ≥2 of: food sensitization, ≥4% blood eosinophilia, wheezing apart from colds). 1
• Monitor response closely over 4-6 weeks; if no clear benefit with satisfactory technique and adherence, stop treatment and consider alternative diagnoses. 1
• Reassess need for therapy every 3 months if benefit is sustained, as spontaneous remission rates are high in this age group. 1

Children (5-11 years):

• Involve child in treatment planning and address their specific concerns about medication use and asthma action plans. 1
• Monitor growth regularly as inhaled corticosteroids can affect linear growth velocity. 3

Adults with childhood-onset asthma:

• Track lung function trajectories over time, as approximately 11% of patients with persistent childhood asthma develop COPD-level obstruction by early adulthood. 1
• Identify high-risk patterns: Two patterns show reduced lung growth from early childhood, and two show early decline after age 20 years. 1

Genetic and Pharmacogenetic Considerations

While asthma has strong genetic components (80% of children with two asthmatic parents develop asthma), current treatment decisions are not routinely based on specific genotypes. 6, 4

Emerging Pharmacogenetic Factors:

• Genetic polymorphisms are associated with variable responses to corticosteroids, leukotriene receptor antagonists, and beta-2 adrenergic receptor agonists, though odds ratios of ≥10 are needed for clinically useful predictors. 1
• Gene-environment interactions (e.g., TLR2 polymorphisms modulating farm environment protective effects) may influence disease expression but do not yet guide treatment selection. 6

Biomarker-Guided Treatment Monitoring

Essential biomarkers for phenotype-directed therapy:

• Blood eosinophil counts: Guide anti-IL-5 therapy selection (target steroid-refractory eosinophilia). 1, 5
• Fractional exhaled nitric oxide (FeNO): Indicates T2 inflammation and ICS responsiveness. 5
• Serum total IgE: Required for anti-IgE therapy eligibility. 5
• Sputum eosinophilia: Predicts therapeutic response to T2 cytokine blockade in severe asthma. 7

Composite Assessment:

• Use Composite Asthma Severity Index (CASI) to assess overall disease burden, incorporating symptoms, pulmonary function, treatment step, and exacerbations. 1
• Monitor regularly to identify patients requiring step-up or eligible for step-down therapy. 1

Special Phenotypes Requiring Targeted Approaches

Occupational Asthma

• Remove exposure to the causative agent as the primary intervention, though complete recovery is not guaranteed. 2
• IgE-mediated occupational asthma develops after latency with sensitization to high-molecular-weight agents; treat similarly to allergic asthma. 2
• Irritant-induced occupational asthma may occur without latency; neutrophilic inflammation predominates. 2

Cough-Variant Asthma

• Diagnose through positive response to standard asthma medications when cough is the principal or only manifestation. 1, 2
• Confirm with bronchoprovocation testing or peak flow monitoring if spirometry is normal. 1, 2

Severe Steroid-Refractory Asthma

• Verify true steroid resistance by ensuring adequate adherence, proper inhaler technique, and addressing comorbidities (GERD, obesity, obstructive sleep apnea, rhinosinusitis). 1
• Refer to asthma specialist for consideration of biologics or alternative immunomodulators. 1

Critical Pitfalls in Phenotype-Based Treatment

Avoid grouping patients without phenotypic stratification: Meta-analyses that ignore subphenotypes may fail to recognize effective treatments (e.g., sodium cromoglycate potentially effective in appropriate T2-low patients but removed from WHO approval list based on unstratified analysis). 1

Do not use biologics in inappropriate phenotypes: Anti-IL-5 and anti-IL-13 therapies show no benefit in unselected asthma populations; efficacy emerges only with proper phenotypic targeting. 1

Recognize that clinical phenotypes may not correlate with inflammatory profiles: Symptom patterns alone without objective biomarker testing can lead to misdiagnosis and inappropriate treatment selection. 2

Treatment Adjustment Algorithm

1. Assess current control using validated questionnaires, spirometry, and exacerbation frequency. 1
2. Step up therapy if control inadequate despite verified adherence and technique. 1, 2
3. Add phenotype-specific biomarker assessment when considering biologics (blood eosinophils, FeNO, total IgE). 5
4. Select biologic based on biomarker profile and phenotype, not clinical features alone. 1, 5
5. Step down therapy once good control maintained for ≥3 months to identify minimum effective treatment. 1, 8