Table 1 – Biomarker Tests Recommended For Asthma Phenotyping1

Test Comments
Serum lgE • Allergic asthma
• Aids in identifying allergic triggers that can be avoided
Blood Eosinophils • TH2-type inflammatory asthma
Induced sputum • Considered gold standard test to analyze airway inflammation and inflammatory phenotype
• Noninvasive test
• Assesses other inflammatory cell levels (i.e. neutrophils)
• Widespread use not currently feasible
FeNO • Used in asthma diagnosis
• Assesses eosinophilic airway inflammation, frequency of symptoms, and frequency of use of emergency care
• Steroid responsiveness biomarker (high FeNO = more likely to respond to ICS)
• Authors recommend testing at diagnosis; if not possible, test patient if not responsive to high-dose ICS + LABA therapy but prior to OCS use

Abbreviations: FeNO (fractional exhaled nitric oxide); ICS (inhaled corticosteroid); LABA (long-acting β2-agonists); OCS (oral corticosteroids); TH2 (T-helper cell type 2)

Figure 1 – Treatment Algorithm Based on Phenotype of Severe Asthma1


Abbreviations: BT (bronchial thermoplasty)

Table 2 – Treatment Options For Severe Asthma1

Therapy Background Data Panel Recommendations
Tiotropium • Maintenance therapy for asthma patients ≥6 years old
• Dosed once daily
• MOA: airway muscarinic acetylcholine receptor antagonist
• Superior to doubling dose of ICS; non-inferior to ICS+ LABA therapy in African American patients with uncontrolled asthma
• Increases time to severe exacerbations in poorly controlled asthma patients receiving ICS + LABA
• Improves FEV1 at 12 weeks in 6-17-year-old severe asthma patients receiving controller therapy
• AEs: asthma, bronchitis, peak expiratory flow rate decrease, headache, rhinitis, nasopharyngitis, infection (respiratory tract, viral), tonsillitis
• Add to high-dose ICS + LABA therapy in uncontrolled asthma patients
• Should be used prior to daily OCS therapy, new biologics, and BT
• Aim: lung function improvement, symptom control, prevention of exacerbations
Omalizumab • Treatment of moderate-to-severe persistent asthma in patients ≥6 years old with uncontrolled symptoms despite ICS therapy
• Patient must have either a positive skin test reaction or in vitro reactivity to a perennial aeroallergen and serum IgE ≥30 IU/mL
• Decreased exacerbations by 25% and improved QOL in patients with severe asthma not controlled by high-dose ICS + LABA
o Decrease of exacerbations greater in patients with higher TH2 biomarker levels
• Effectiveness and safety is sustained long-term in children and adults
• Should be considered first line for IgE+ allergic severe asthma patients who have failed high-dose ICS + LABA + tiotropium therapy
• Use prior to OCS, new biologics, or BT
IL-5 Target Therapies
• Mepolizumab, reslizumab: anti-IL-5 antagonist mAb
• Benralizumab: eosinophil IL-5 receptor blocker

Mepolizumab:

• Add-on maintenance therapy in severe asthma patients ≥12 years old with an eosinophilic phenotype (≥150 cells/uL at screening or ≥300 cells/uL within 1 year prior to enrollment)
• Administration: SC every 4 weeks

Mepolizumab:

• Efficacy has been demonstrated in patients with severe asthma and eosinophilia in several trials
• AEs: headache, reactions at the injection site, back pain, fatigue, hypersensitivity reactions (rare), Herpes zoster infection (rare)

• Should be considered first line for eosinophilic severe asthma patients who have failed high-dose ICS + LABA + tiotropium therapy
• Use prior to OCS, new biologics, or BT
• Can be used for patients with IgE+ with eosinophilia that inadequately responded to omalizumab
• No recommendation on which IL-5 agent should be used first

Reslizumab:

• Add-on maintenance therapy in severe asthma patients ≥18 years old with an eosinophilic phenotype (≥400 cells/uL)
• Administration: IV every 4 weeks
• BBW: anaphylaxis

Reslizumab:

• Efficacy has been demonstrated in patients with severe asthma and eosinophilia in several trials
• Versus placebo: decreased airflow obstruction and exacerbations, improved the Asthma Quality of Life Questionnaire score
• AEs: oropharyngeal pain

Benralizumab:

• Add-on maintenance therapy in severe asthma patients ≥12 years old with an eosinophilic phenotype2 • Increased efficacy due to IL receptor blockade, causing luminal depletion of eosinophils
• Administration: SC every 4 weeks (x 3 doses), then every 8 weeks

Benralizumab:

• Demonstrated decreased oral maintenance glucocorticoid therapy use and sustained asthma control in severe eosinophilic asthma patients

Macrolide Antibiotics • Used in patients with poor symptom control who test positive for M pneumoniae and C pneumoniae
• MOA unclear; believed to exert therapeutic effect through antimicrobial and anti-inflammatory properties
• Improved predicted FEV1 percentage and Asthma Control Test scores after 6 months of treatment • Should be considered in patients with non-TH2 type inflammation asthma
BT • Used in adult severe asthma patients with uncontrolled symptoms despite ICS and long-acting bronchodilator treatment
• Decreases smooth muscle mass in airways by ≥60%, alters collagen deposition, decreases -smooth muscle actin, reduces inflammatory cytokines
• Uses the Alair Bronchial Thermoplasty System to deliver thermal energy targeted at different areas of the lung
• Conducted in 3 sessions (at 3 week intervals)
• Asthma Research Intervention (AIR) trial: moderate-to-severe asthma patients experienced a reduction in mild exacerbations and an increase in symptom-free days, asthma control, and QOL vs control at 3 and 12 months
• Sham-controlled AIR-2 trial: increase in QOL, and decrease in lost work days, severe exacerbations (32%), and health care usage
• 5-year trial follow-ups: sustained reductions in exacerbations and health care resource usage, and no additional decline in lung function was seen
• AEs: temporary respiratory-related symptom worsening
• First option for patients with nonallergic, non-eosinophilic severe asthma with persistent symptoms and variable airflow obstruction after failing therapy with high-dose ICS + LABA + tiotropium
• Use prior to OCS or targeted biologic
• An alternative treatment option for allergic or eosinophilic asthma patients with an inadequate response to therapy with biologics
Dupilumab • Currently being investigated
• Inhibits signaling of IL-4 and IL-13 cytokines of TH2 cells by binding to the IL-4 receptor
• Early investigation showed decrease in odds of asthma exacerbations
• Phase 2b study: improved FEV1 by 210-260 mL vs placebo and decreased exacerbations by 54-71% in patients with severe asthma despite treatment with medium- to high-dose ICS + LABA
• AEs: upper respiratory tract infection, injection site reactions
• Will likely be considered a therapeutic option for the treatment of eosinophilic and non-eosinophilic, elevated FeNO severe asthma after failing high-dose ICS + LABA + tiotropium and prior to OCS use

Abbreviations: AEs (adverse events); BBW (black box warning); BT (bronchial thermoplasty); FeNO (fractional exhaled nitric oxide); FEV1 (forced expiratory volume in 1 second); ICS (inhaled corticosteroid); IgE (immunoglobulin E); IL (interleukin); IV (intravenous); LABA (long-acting β2-agonists); mAb (monoclonal antibody); MOA (mechanism of action); OCS (oral corticosteroids); QOL (quality of life); TH2 (T-helper cell type 2)