Asthma is a heterogenous disease characterized by chronic airway inflammation. Symptoms include wheeze, shortness of breath, chest tightness and cough that vary over time and are related to bronchoconstriction, airway wall thickening, increased mucus and variable expiratory airflow limitation.

Relevant Guidelines

GINA 2021 Guidelines

Diagnosis of Asthma

Diagnosis requires a:
- History of variable symptoms (wheeze, SOB, chest tightness, cough) which are variable over time and variable in intensity; often worse at night or on waking; often triggered by exercise, laughter, allergens, and cold air; worsened with viral infections.
- Confirmed variable expiratory airflow limitation
  - (1) Positive spirometry with reversible airway obstruction: FEV1/FVC < LLN; and increase in FEV1 after bronchodilator or after a course of controller therapy of >=12% and a minimum of 200 mL
  - (2) Peak expiratory flow
    - >60LPM (min 20%) increase after bronchodilator or after a course of controller therapy
    - Diurnal variation > 8% based on twice-daily readings, or >20% based on multiple daily readins
  - (3) Positive challenge test
    - Methacholine PC20 <4 mg/mL or PD20 <0.5 umol
Expiratory airflow limitation, at least once during the diagnostic process, confirmed with reduced FEV1/FVC below the LLN
Variability, demonstrated by one of:
1. Positive bronchodilator reversibility (10-15 minutes post 200-400 mcg salbutamol) -- improvement in FEV1 by >12% and 200 mL post BD
2. Improvement with anti-inflammatory treatment x 4 weeks -- improvement in FEV1 by >12% and 200 mL
3. Excessive FEV1 variation in lung function between visits (improvement in FEV1 by >12% and 200 mL)
4. Peak flow variability > 10%
5. Positive bronchial challenge test
  1. Methacholine challenge. Look for a drop in FEV1 by 20%:
    1. PC20 < 4 mg/mL = positive
    2. PC20 4 - 16 = borderline
    3. PC20 > 16 negative
  2. Exercise challenge: fall in FEV of >10% and 200 mL

Contraindications to Bronchial Challenge Testing

Asthma Mimics

Bronchiectasis
Cystic Fibrosis
EGPA
Vocal cord dysfunction
ABPA
Reactive airways dysfunction syndrome (RADS) -- acute irritant induced asthma following a single high dose exposure to irritant. Lasts >3 months. Treat like an asthma exacerbation

Assessing Control

Control is the goal of asthma management (i.e. symptoms and risk of adverse outcomes). Assess at each visit. Asthma control implies all of the following CTS criteria:

Uncontrolled vs Severe Asthma

uncontrolled: poor symptom control, frequent exacerbations, severe hospitalization in the past year, sustained airflow reduction. Usually due to poor adherence, technique, or ongoing trigger.
Severe (5% of patients): requiring treatment with high-dose ICS + 2nd controller for the previous year, or oral steroids for 50% of the year, to prevent it from becoming uncontrolled. Please refer for specialty consultation and add-on therapies.

Asthma Treatment (GINA 2023)

Reliever Medication

Low-dose ICS + SABA (e.g. budesonide-formoterol -- Symbicort) is the preferred reliever medication for all asthmatics.
- based on the principle that asthma is an inflammatory condition
- SABA PRN alone increases the risk of exacerbation, decreased lung function, severe exacerbations.
- SYGMA 1 + 2 trials (NEJM 2018) showed that PRN Symbicort is superior to SABA PRN in reducing exacerbations (64%) and non-inferior to maintenance ICS + PRN SABA.
Alternative reliever: PRN SABA

Controller Medications

Control level	Preferred controller	Alternatives
Symptoms less than twice monthly	PRN low-dose ICS-formoterol	Low-dose ICS whenever a SABA is taken
Symptoms less than daily	Daily low-dose ICS, or PRN low-dose ICS-formoterol	Daily leukotriene receptor antagonist [LTRA] or low-dose ICS whenever a SABA is taken
Symptoms most days or waking with asthma more than once weekly	Low-dose ICS-LABA	Medium-dose ICS, or low dose ICS + LTRA
Symptoms most days or waking with asthma more than once weekly, and low lung function	Medium-dose ICS-LABA	High-dose ICS, add-on tiotropium, or add-on LTRA
"Severe Asthma"	High-dose ICS-LABA. Refer for phenotypic assessment +/- add on tiotropium, anti-IgE, anti-IL5, anti-IL4	Add low-dose OCS

Never use LABA monotherapy - increased risk of death.

Non-Pharmacological

confirm diagnosis, asthma action plan
weight loss, exercise training
allergen and trigger avoidance, allergen immunotherapy
smoking cessation
vaccinations
avoid NSAIDs/beta blockers if possible

LTRA

may be appropriate as initial controlled if ICS not possible for some reasons, but less effective than ICS at prevention exacerbations.
- most effective in aspirin-exacerbated asthma, exercise-induced symptoms, allergic rhinitis
- FDA black box warning: increased suicidality in adolescents and adults
LABA-ICS is superior to ICS-LTRA for those stepping up from low-dose ICS maintenance

Management of Severe Asthma

Workup
- Total IgE
- peripheral eosinophil count
- sputum eosinophilis and FeNO where available
Treatment (see above GINA table)
- tiotropium mist inhaler --> increases time to first severe exacerbation
- Macrolides if uncontrolled despite ICS/LABA. LANCET AMAZES trial 2017
- Biologics
- Low-dose OCS
- Bronchial thermoplasty

Biologic Asthma Therapy

Used for uncontrolled severe asthma.

MOA	Agents	Indications
Anti-IgE	Omalizumab	Allergic asthma IgE 30-700, sensitive to a perennial allergen, or severe despite high dose ICS and one other controller.
Anti-IL5	Mepolizumab, resilzumab, benralizumab	Severe eosinophilic asthma (>300), and recurrent exacerbations despite high-dose ICS and one other controller
Anti-IL4	Dupilumab	Not yet in guidelines. Two trials in NEJM 2018.

Special Populations

Population	Management
Seasonal allergic asthma	start ICS immediately when symptoms commence, and continue for 4 weeks after the relevant pollen season ends
Exercise induced	Salbutamol pre-exercise, if needed add LTRA pre-exercise, if needed try regular ICS
Pregnancy	Continue ICS/oral steroids if exacerbating, most evidence for budesonide
ASA exacerbated respiratory disease	Avoid ASA/NSAIDs, treat like normal, good response to LTRA. Desensitive to ASA if needed.

References

IMR slides 2021
GINA 2020
CTS 2017