2021 Canadian Thoracic Society Guideline – A focused update on the management of very mild and mild asthma

Figures & data

Table

Healthcare	Non-healthcare
Allergists; Certified respiratory educators; Internists; Nurse practitioners/Physician Assistants; Pediatricians; Pharmacists; Primary care physicians; Respirologists; and Respiratory Therapists	Healthcare decision-makers (i.e., national, provincial, and local policy makers); Healthcare researchers and knowledge translation specialists; Patient advocates; and Patients

Table 1. Severity classification.

Asthma severity	Treatment required 1999	Treatment required 2021
Very mild	Well-controlled on no medication or inhaled SABA rarely	Well-controlled on PRN SABA
Mild	Well-controlled on SABA (occasionally) and low dose ICS	Well-controlled on: Low dose ICS (or leukotriene receptor antagonists (LTRA)) and PRN SABA or PRN bud/form
Moderate	Well-controlled on SABA and low to moderate dose ICS +/- additional therapy	Well-controlled on: Low dose ICS + second controller and PRN SABA or Moderate doses of ICS +/- second controller medication and PRN SABA or Low-moderate dose bud/form + PRN bud/form
Severe	Well-controlled on SABA and high dose ICS + additional therapy	High doses of ICS + second controller for the previous year or systemic steroids for 50% of the previous year to prevent it from becoming uncontrolled, or is uncontrolled despite this therapy
Very severe	Well- or poorly-controlled on SABA and high dose ICS + additional therapy + oral steroids	Category removed

Table 2. Comparative inhaled corticosteroids (ICS) dosing categories in preschoolers, children and adults.

	Preschoolers (1-5 years of age)		Children (6-11 years of age)			Adults and Adolescents (12 years of age and over)
Corticosteroid (tradename)	Low	Medium	Low	Medium	High	Low	Medium	High **
Beclomethasone dipropionate HFA (QVAR)	100	200	≤200	201-400	>400	≤200	201-500	>500 (max 800)
Budesonide* (Pulmicort)	n/a	n/a	≤400	401-800	>800	≤400	401-800	>800 (max 2400)
Ciclesonide* (Alvesco)	100	200	≤200	201-400	>400	≤200	201-400	>400 (max 800)
Fluticasone furoate* (Arnuity)	n/a	n/a	n/a	n/a	n/a	100		200 (max 200)
Fluticasone propionate (Flovent)	<200	200-250	≤200	201-400	>400	≤250	251-500	>500 (max 2000)
Mometasone furoate* (Asthmanex)	n/a	n/a	100	≥200 - <400	≥400	100-200	>200-400	>400 (max 800)

Dosing categories are approximate, based on a combination of approximate dose equivalency as well as safety and efficacy data.

* Licensed for once daily dosing in Canada.

** Maximum doses are the maximum doses approved for use in Canada.

Doses highlighted  are not approved for use in Canada with the following exceptions: Beclomethasone is approved for children ≥ 5 years of age; Mometasone is approved for children ≥ 4 years of age; Maximum dose of fluticasone propionate is 200 mcg/day in children 1-4 years of age (250 mcg was included in this age group because the 125 mcg inhaler is often used for adherence and cost), Maximum dose of fluticasone propionate is 400 mcg/day in children 4-16 years of age.

Table 3. Well-controlled asthma criteria.

Characteristic	Frequency or value
Daytime symptoms	≤2 days/week
Nighttime symptoms	<1 night/week and mild
Physical activity	Normal
Exacerbations	Mild and infrequent*
Absence from work or school due to asthma	None
Need for a reliever (SABA or bud/form)^†	≤2 doses per week
FEV1 or PEF	≥90% of personal best
PEF diurnal variation	<10–15%^#
Sputum eosinophils	<2–3%•

A patient who meets all of the above criteria would be considered to have well-controlled asthma.

*A mild exacerbation is an increase in asthma symptoms from baseline that does not require systemic steroids, an ED visit, or a hospitalization. “Infrequent” is not specifically defined, since the frequency of mild exacerbations that patients consider an impairment to quality of life varies. If the patient feels that the frequency of mild exacerbations is impairing their quality of life, then their asthma should be considered poorly-controlled. If a patient is having frequent mild exacerbations, they should be assessed to determine if at baseline, they have poorly-controlled asthma.

†There are no established criteria for control when using bud/form as a reliever; however, use of a reliever often indicates that a patient is having symptoms and is a criterion that can be objectively assessed.

#Diurnal variation is calculated as the highest peak expiratory flow (PEF) minus the lowest divided by the highest peak flow multiplied by 100, for morning and night (determined over a 2-week period).

•Consider in adults ≥18 years of age with uncontrolled moderate to severe asthma who are assessed in specialist centers.

Figure 1. 2021 Asthma management continuum preschoolers, children and adults.

Management relies on an accurate diagnosis of asthma and regular reassessment of control and risk of exacerbation. All individuals with asthma should be provided with self-management education, including a written action plan. Adherence to treatment, inhaler technique, exposure to environmental triggers, and the presence of comorbidities should be reassessed at each visit and optimized.

Individuals with well controlled asthma on no medication or PRN SABA at lower risk of exacerbation can use PRN SABA, daily ICS + PRN SABA, and if ≥ 12 years of age PRN bud/form*.

Individuals at higher risk of exacerbation even if well-controlled on PRN SABA or no medication, and those with poorly-controlled asthma on PRN SABA or no medication should be started on daily ICS + PRN SABA. In individuals ≥ 12 years old with poor adherence despite substantial asthma education and support, PRN bud/form* can be considered. LTRA are second-line monotherapy for asthma. If asthma is not adequately controlled by daily low doses of ICS with good technique and adherence, additional therapy should be considered. In children 1-11 years old, ICS should be increased to medium dose and if still not controlled in children 6-11 years old, the addition of a LABA or LTRA should be considered. In individuals 12 years of age and over, a LABA in the same inhaler as an ICS is first line adjunct therapy. If still not controlled, the addition of a LTRA or tiotropium should be considered.

In children who are not well-controlled on medium dose ICS, a referral to an asthma specialist is recommended. After achieving asthma control, including no severe exacerbations, for at least 3-6 months, medication should be reduced to the minimum necessary dose to maintain asthma control and prevent future exacerbations.

HFA: hydrofluoroalkane; SABA: short-acting beta-agonist, LABA: long-acting beta-agonist, ICS: inhaled corticosteroid, LTRA: leukotriene receptor antagonist, bud/form: budesonide-formoterol in a single inhaler.

Figure 2. Treatment approach for patients on PRN SABA or no medication.

Table 4. Risk factors associated with severe asthma exacerbations

(This table is adapted from SIGN 158 - British guideline on the management of asthma by kind permission of the Scottish Intercollegiate Guidelines Network).²²

Greatly increased risk (Odds Ratio (OR) > 2.5*)
≥12 years of age	6-11 years of age	<6 years of age
History of previous severe exacerbation	History of previous severe exacerbation Poorly-controlled asthma FEV1 <60% predicted	History of previous severe exacerbation
Moderate increased risk (OR 1.5-2.5*)
Poorly-controlled asthma Excessive SABA use (>2 inhalers/year^48) Current smoker**	Excessive SABA use (>2 inhalers/year) Comorbid atopic/allergic disease Low socioeconomic status Vitamin D deficiency (<30 nmol/L) FEV1 60–80% predicted
Slightly increased risk (OR 1.1-1.5*)
Older age (especially >55 years of age) Female FEV1 < 70% predicted Obesity Previous smoker** Depression	Exposure to environmental tobacco smoke** Younger age Obesity Low parental education	Comorbid atopic/allergic disease Raised blood eosinophils (>300/μL) Younger age Low socioeconomic status Male gender Underweight

* OR reported represent the OR found in the majority of studies examining the risk factor.^22,47

** Studies have examined the risk of tobacco smoking; however, vaping and smoking of other substances should also be considered risk factors.^49,50

Table 5. Risk factors associated with near-fatal or fatal asthma^10,51

(This table is adapted from SIGN 158 - British guideline on the management of asthma by kind permission of the Scottish Intercollegiate Guidelines Network).²²

Any previous near-fatal asthma exacerbation (e.g., previous ICU admission, ventilation, respiratory acidosis)

Recurrent hospitalizations or ED visits in last year

Severe asthma

Overuse of short-acting beta-agonists

Poor adherence to treatment plans

Failure to attend clinic appointments

Depression, anxiety or other psychiatric illness

Alcohol or other substance use

Obesity

Severe domestic, marital, employment, local stress

Denial of illness or severity of illness

Table

PICO Question	Recommendations	Strength of Recommendation*	Certainty of Evidence
	Asthma control and risk for exacerbation should be assessed at each clinical encounter.	Strong	Consensus
1) In individuals on PRN SABA with well-controlled asthma is: Daily ICS + PRN SABA safe and more effective than PRN SABA? PRN bud/form safe and more effective than PRN SABA? PRN bud/form safe and more effective than daily ICS + PRN SABA?	1.1 For individuals ≥12 years of age on PRN SABA with well-controlled asthma at lower risk for exacerbations, we recommend continuing PRN SABA or switching to either daily ICS + PRN SABA or PRN bud/form (based on patient preference). 1.2 For individuals ≥12 years of age on PRN SABA with well-controlled asthma at higher risk for exacerbations, we recommend switching to either daily ICS + PRN SABA or PRN bud/form. In individuals with poor adherence to daily medication despite substantial asthma education and support, we recommend PRN bud/form over daily ICS + PRN SABA. 1.3 For individuals <12 years of age with well-controlled asthma on PRN SABA at lower risk for exacerbations, we recommend continuing PRN SABA or switching to daily ICS + PRN SABA (based on patient preference). 1.4 For individuals <12 years of age with well-controlled asthma on PRN SABA at higher risk for exacerbations, we recommend switching to daily ICS + PRN SABA.	Strong	Daily ICS + PRN SABA vs PRN SABA: (all age groups) Moderate certainty PRN bud/form vs PRN SABA: ≥ 18 years of age: Low certainty 12-17 years of age: Very Low certainty PRN bud/form vs Daily ICS + PRN SABA: ≥ 18 years of age: Low certainty 12-17 years of age: Very Low certainty
2) In individuals on PRN SABA with well-controlled asthma is ICS taken each time SABA is taken (PRN ICS-SABA) safe and more effective than PRN SABA?	2.1 We suggest that individuals on PRN SABA with well-controlled asthma who are at lower risk for exacerbations continue to take PRN SABA alone instead of taking an ICS each time PRN SABA is taken. As a harm reduction strategy, individuals ≥18 years of age at higher risk for exacerbations who are unable to take a daily ICS or PRN bud/form (as per recommendation 1.2) can be given the option of taking an ICS each time a SABA is taken. As per recommendation 1.4, individuals <12 years of age with well-controlled asthma at higher risk for exacerbations should take a daily ICS + PRN SABA instead of taking PRN SABA alone. Similarly, as per recommendation 1.2, individuals 12-18 years of age with well-controlled asthma at higher risk for exacerbations should take either daily ICS + PRN SABA or PRN bud/form.	Weak	Very low certainty
3) In individuals on PRN SABA with poorly-controlled asthma is: Daily ICS + PRN SABA safe and more effective than PRN SABA? PRN bud/form safe and more effective than daily ICS + PRN SABA?	3.1 We recommend that all individuals on PRN SABA with poorly-controlled asthma take a daily ICS + PRN SABA instead of PRN SABA or PRN bud/form. 3.2 In individuals ≥12 years of age with poor adherence to daily medication despite substantial asthma education and support, we recommend PRN bud/form instead of daily ICS + PRN SABA.	Strong	Daily ICS vs PRN SABA: High certainty PRN bud/form vs Daily ICS + PRN SABA: Moderate certainty
4) In individuals on PRN SABA with poorly-controlled asthma is ICS taken each time SABA is taken (PRN ICS-SABA) safe and more effective than daily ICS + PRN SABA?	4.1 We recommend that individuals on PRN SABA with poorly-controlled asthma take daily ICS instead of taking an ICS each time a SABA is taken. As a harm mitigation strategy, we recommend that individuals ≥18 years of age at higher risk for exacerbations who are unable to take a daily ICS + PRN SABA or PRN bud/form (as per recommendations 3.1 and 3.2), can be given the option of taking an ICS each time a SABA is taken.	Strong	≥ 12 years of age, 6-11 years of age: Low to moderate certainty with no discrete data for severe exacerbations 1-5 years of age: Low certainty
5) In individuals on PRN SABA with poorly-controlled asthma or individuals on daily ICS with well-controlled asthma, is the use of a daily SABA inhalation immediately prior to daily ICS inhalation + PRN SABA safer or more effective than daily ICS + PRN SABA?	5.1 We recommend that individuals on PRN SABA with poorly-controlled asthma or individuals on daily low dose ICS with well-controlled asthma, take daily ICS + PRN SABA instead of daily ICS with a daily SABA inhalation immediately prior to ICS inhalation + PRN SABA.	Strong	≥ 18 years of age: Low to Moderate certainty <18 years of age: Very low certainty
6) In individuals on PRN SABA with well- or poorly-controlled asthma is a short course of very high dose ICS taken with acute loss of asthma control safe and more effective than PRN SABA?	6.1 We do not suggest that individuals on PRN SABA with well- or poorly-controlled asthma take a very high-dose short course of ICS with acute loss of asthma control. As per recommendations 1.1 and 1.3, we recommend that: individuals on PRN SABA with well-controlled asthma at lower risk of asthma exacerbation have the option of taking PRN SABA monotherapy or daily ICS + PRN SABA, with those ≥12 years of age being provided with the additional option of PRN bud/form. As per recommendations 1.2 and 1.4, individuals on PRN SABA with well-controlled asthma at higher risk of exacerbations should take daily ICS (all ages), with those ≥12 years of age being provided with the additional option of PRN bud/form. As per recommendation 3.1, individuals on PRN SABA with poorly-controlled asthma should take a daily ICS with PRN SABA.	Weak	Low to moderate certainty

*Strength of recommendation is based on certainty of evidence, balance of desirable and undesirable effects, patient values, preferences, resource use, health equity, acceptability of an intervention and feasibility of implementation. Details of the results are shown in the following section.

Study Inclusion/Exclusion Criteria

PICO 1. In individuals where the CTS currently recommend SABA PRN monotherapy (well-controlled as per CTS criteria) what are the best options for management?

Criteria	Inclusion		Exclusion
Study Type	Randomized control trials Systematic reviews Systematic review/Meta-Analysis Meta-Analysis		Commentaries, editorials, Letters to the editor that do not provide primary source data. Conference abstracts. Other study types (i.e., Cohort) Not English
Age	1 and above
Population	well-controlled as per CTS criteria on SABA PRN CTS Asthma Control		Asthma not well-controlled on SABA PRN
	Characteristic Daytime symptoms Nighttime symptoms Physical activity Exacerbations Absence from work or school due to asthma Need for a fast-acting beta2-agonist FEV1 or PEF PEF diurnal variation Sputum eosinophils§ § in individuals 18 years and over with moderate to severe asthma assessed in specialized centers.	Frequency or Value <4 days/week* <1 night/week* Normal Mild, infrequent None <4 doses/week* >90% personal best <10–15% <2–3%
Intervention	PRN ICS-formoterol, PRN low dose ICS-SABA, Maintenance ICS plus PRN SABA, or other pharmacologic treatment		Wrong intervention Nonpharmacological treatment
Comparator	PRN SABA		Wrong comparator Nonpharmacological treatment
Outcomes	# of exacerbations time to first exacerbation (other exacerbation outcomes as per papers), categorize exacerbations as severe (requiring oral steroids, ED visit, hospitalization) versus non-severe asthma control (frequency of symptoms, asthma control test) lung function (FEV1) markers of inflammation (sputum cell count, FeNO) mortality adherence safety markers		If outcome is other than what is described in the inclusion criteria

*If paper uses different criteria, i.e., daytime symptoms ≤2 days/week, make note but include in this question.

PICO 2. In individuals where the CTS currently recommends ICS maintenance therapy + PRN SABA (not well-controlled on PRN SABA or well-controlled on daily low dose ICS + PRN SABA) what are the preferred treatment options for management?

Criteria	Inclusion		Exclusion
Study Type	Randomized control trials Systematic reviews Systematic review/Meta-Analysis Meta-Analysis		Commentaries, editorials, Letters to the editor that do not provide primary source data. Conference abstracts. Other study types (i.e. Cohort) Not English
Age	1 and above
Population	Individuals where the CTS recommends ICS maintenance therapy (not well-controlled on PRN SABA or well-controlled on daily low dose ICS)		Well-controlled on PRN SABA based on CTS criteria for asthma control
	Characteristic Daytime symptoms Nighttime symptoms Physical activity Exacerbations Absence from work or school due to asthma Need for a fast-acting beta2-agonist FEV1 or PEF PEF diurnal variation Sputum eosinophils^§ ^§in individuals 18 years and over with moderate to severe asthma assessed in specialized centres.	Frequency or Value <4 days/week* <1 night/week* Normal Mild, infrequent None <4 doses/week* >90% personal best <10-15% <2-3%
Intervention	PRN ICS formoterol or PRN low dose ICS-SABA or SABA PRN or other pharmacologic treatment		Wrong intervention Nonpharmacological treatment
Comparator	Daily low dose ICS + PRN SABA		Wrong comparator Nonpharmacological treatment
Outcomes	# of exacerbations time to first exacerbation (other exacerbation outcomes as per papers), categorize exacerbations as severe (requiring oral steroids, ED visit, hospitalization) versus non-severe asthma control (frequency of symptoms, asthma control test) lung function (FEV1) markers of inflammation (sputum cell count, FeNO) mortality adherence safety markers		If outcome is other than what is described in the inclusion criteria

*If paper uses different criteria, i.e., daytime symptoms ≤2 days/week, make note but include in this question.

Table

Author (REF)	Funding	Study Type	Duration	Age	Asthma Dx	Asthma Severity	Number of patients
							Intervention	Control
PICO 1
1a: Daily ICS + PRN SABA vs PRN SABA
Papi, BEST Ped ^53	Chiesi Farmaceutici	Randomized, double-blind, placebo- controlled	12 weeks	1-4yo	Not specified other than recurrent wheezing episodes	3 or more episodes of wheezing requiring medical attention in previous 6 months, (excluded if previously required systemic steroids or had hospitalization for asthma)	beclomethasone^EUR 400 mcg nebule bid + PRN Salbutamol 2500 mcg in 1 nebule, (Clenny aerosol with face mask), n = 110	PRN Salbutamol 2500 mcg/nebule, 1 nebule (Clenny aerosol with face mask), n = 56
Beasley, NovelSTART ^44	AZ and Health Research Council of NZ	Randomized, open-label	52 weeks	18-75yo	Self-report of MD dx	Use of a SABA as the sole asthma therapy in the previous 3 months and patient report of the use of the SABA on at least 2 occasions, but on an average of 2 or fewer occasions per day in the previous 4 weeks OR severe exacerbation in last 12 months (systemic steroid for at least 3 days or hospitalization or ED visit leading to systemic steroid)	budesonide 200 mcg bid turbuhaler + PRN Salbutamol 100 mcg 2 puffs pMDI, n = 225	PRN Salbutamol 100 mcg 2 puffs pMDI n = 223
Lazarinis ^52	AZ	Randomized, double-blind, placebo- controlled	6 weeks	≥12yo (unclear if any pt <18yo)	At visit 2 needed ≥10% drop in FEV1 post-exercise	Mild asthma with EIB, use of SABA up to 4x/ week, FEV1 > 80% of predicted normal, exercised at least 3x/week	budesonide 400 mcg OD turbuhaler + PRN Terbutaline 500 mcg Turbuhaler n = 21	PRN Terbutaline 500 mcg Turbuhaler n = 22
Pauwels, START ^45	AZ	Randomized, double-blind, placebo- controlled	3 year	4-66yo (27% 5-10yo, 17% 11-17yo)	Reversible airway obstruction (12% bronchodilator response, 15% decrease after exercise challenge, 15% difference in peak flows over 14 days)	Asthma dx in last 2 years, not more than 30 days of inhaled/oral steroids or 1 depot injection, mild persistent asthmas per NHLBI (sx at least weekly but no daily in previous 3 months)	budesonide 400 mcg OD (200 mcg OD if <11 yo) Turbuhaler, n = 3597	Placebo n = 3568
1b: PRN bud/form vs PRN SABA
Beasley, NovelSTART ^44	AZ and Health Research Council of NZ	Randomized, open-label	52 weeks	18-75yo	Self-report of MD dx	Use of a SABA as the sole asthma therapy in the previous 3 months and patient report of the use of the SABA on at least 2 occasions, but on an average of 2 or fewer occasions per day in the previous 4 weeks OR severe exacerbation in last 12 months (systemic steroid for at least 3 days or hospitalization or ED visit leading to systemic steroid)	PRN bud/form 200/6 mcg 1 puff Turbuhaler n = 220	PRN Salbutamol 100 mcg 2 puffs pMDI n = 223
Lazarinis ^52	AZ	Randomized, double-blind, placebo-controlled	6 weeks	≥12 yo (unclear if any pt <18 yo)	At visit 2 needed ≥10% drop in FEV1 post-exercise	Mild asthma with EIB, use of SABA up to 4x/week, FEV1 > 80% of predicted normal, exercised at least 3x/week	PRN bud/form 200/6 mcg 1 puff Turbuhaler n = 23	PRN Terbutaline 500 mcg Turbuhaler n = 22
1c: PRN bud/form vs Daily ICS + PRN SABA
Beasley, NovelSTART ^44	AZ and Health Research Council of NZ	Randomized, open-label	52 weeks	18-75 yo	Self-report of MD dx	Use of a SABA as the sole asthma therapy in the previous 3 months and patient report of the use of the SABA on at least 2 occasions, but on an average of 2 or fewer occasions per day in the previous 4 weeks OR severe exacerbation in last 12 months (systemic steroid for at least 3 days or hospitalization or ED visit leading to systemic steroid)	PRN bud/form 200/6 mcg 1 puff Turbuhaler n = 220	budesonide 200 mcg bid Turbuhaler + PRN Salbutamol 100 mcg 2puffs pMDI n = 225
Lazarinis ^52	AZ	Randomized, double-blind, placebo- controlled	6 weeks	≥12 yo (unclear if any pt <18 yo)	At visit 2 needed ≥10% drop in FEV1 post-exercise	Mild asthma with EIB, use of SABA up to 4x/week, FEV1 > 80% of predicted normal, exercised at least 3x/week	PRN bud/form 200/6 mcg 1 puff Turbuhaler n = 23	budesonide 400 mcg OD Turbuhaler + PRN Terbutaline 500 mcg Turbuhaler n = 21
PICO 2: PRN SABA vs PRN ICS-SABA
Papi, BEST Ped ^53	Chiesi Farmaceutici	Randomized, double-blind, placebo- controlled	12 weeks	1-4 yo	Not specified other than recurrent wheezing episodes	3 or more episodes of wheezing requiring medical attention in previous 6 months, (excluded if previously required systemic steroids or had hospitalization for asthma)	PRN (beclomethasone^EUR 800 mcg/ Salbutamol 1600 mcg in 1 nebule, one nebule (Clenny aerosol with face mask), n = 110	PRN Salbutamol 2500 mcg/nebule, 1 nebule (Clenny aerosol with face mask), n = 56
Martinez, TREXA ^36	NHLBI, TEVA provided drug and placebo	Randomized, double-blind, placebo- controlled	44 weeks	6-18yo	Clinical diagnosis (In January 2008, the data and safety monitoring board approved changes in the TREXA eligibility criteria, by which neither FEV1 reversibility of 12% or more or a participant’s methacholine PC20 of 12·5 mg/mL or less were needed for randomization)	Naïve to controller and history of 1-2 exacerbations in last year, tx for last 8 weeks with monotherapy other than ICS, or asthma controlled in last 8 weeks on low dose ICS (≤160 mcg/beclomethasone equiv). During a 2-week run in on beclomethasone HFA 100 mcg/day, controlled, FEV1 ≥ 80%	PRN beclomethasone HFA 50 mcg 2 puffs pMDI each time Salbutamol 100 mcg 2 puffs used pMDI (separate inhalers), unclear if spacer used (n = 71)	PRN Salbutamol 100 mcg pMDI (placebo), n = 74
Papi, BEST ^38	Chiesi Farmaceutici	Randomized, double-blind, placebo- controlled	6 months	18-65yo	Pre-BD FEV1 > 75% with either a 12% increase in FEV1 post 200 mcg salbutamol or PC20  < 8 mg/mL	History of mild persistent asthma for at least 6 months as per GINA 2006. During a 4-week run in on beclomethasone^EUR 250 mcg bid and well-controlled	PRN beclomethasone^EUR 250 mcg/Salbutamol 100 mcg in single pMDI, not clear if spacer used, n = 124	PRN Salbutamol 100 mcg pMDI, not clear if spacer used, n = 118
PICO 3
3a: Daily ICS + PRN SABA vs PRN SABA
Papi, BEST Ped ^53	Chiesi Farmaceutici	Randomized, double-blind, placebo- controlled	12 weeks	1-4yo	Not specified other than recurrent wheezing episodes	3 or more episodes of wheezing requiring medical attention in previous 6 months, (excluded if previously required systemic steroids or had hospitalization for asthma)	beclomethasone^EUR 400 mcg nebule bid + PRN Salbutamol 2500 mcg in 1 nebule, (Clenny aerosol with face mask), n = 110	PRN Salbutamol 2500 mcg/nebule, 1 nebule (Clenny aerosol with face mask), n = 56
Martinez, TREXA ^36	NHLBI, TEVA provided drug and placebo	Randomized, double-blind, placebo- controlled	44 weeks	6-18yo	Clinical diagnosis (In January 2008, the data and safety monitoring board approved changes in the TREXA eligibility criteria, by which neither FEV1 reversibility of 12% or more or a participant’s methacholine PC20 of 12·5 mg/mL or less were needed for randomization)	Naïve to controller and history of 1-2 exacerbations in last year, tx for last 8 weeks with monotherapy other than ICS, asthma controlled in last 8 weeks on low dose ICS (≤160 mcg/beclomethasone equiv). During 2 week run in on beclomethasone HFA 100 mcg/day, controlled, FEV1 ≥ 80%, adherence >75% to meds	beclomethasone HFA 50 mcg bid pMDI, unclear if spacer used + PRN Salbutamol, n = 72	PRN Salbutamol pMDI, unclear if spacer used, n = 74
Pauwels, START ^45	AZ	Randomized, double-blind, placebo-controlled	3 year	4-66yo (27% 5-10yo, 17% 11-17yo)	Reversible airway obstruction (12% bronchodilator response, 15% decrease after exercise challenge, 15% difference in peak flows over 14 days)	Asthma dx in last 2 years, not more than 30 days of inhaled/oral steroids or 1 depot injection, mild persistent asthmas per NHLBI (sx at least weekly but no daily in previous 3 months)	budesonide 400 mcg OD (200 mcg OD if <11yo) Turbuhaler, n = 3597	Placebo, n = 3568
O'Byrne, SYGMA1 ^37	AZ	Randomized, double-blind, placebo-controlled	52 weeks	12 and older (12.5% 12-18 yo)	Asthma ≥6 m with reversible obstruction	Uncontrolled on SABA alone on controlled on ICS monotherapy or LTRA, SABA PRN needed at least 3 days in the last week of run-in (not more than 6 inhalations/day for ≥2 days), FEV1 > 60% pre-BD (>80% post- BD if on SABA alone), FEV > 80% if on maintenance	budesonide 200 mcg bid Turbuhaler + PRN Terbutaline 500 mcg Turbuhaler, n = 1290	PRN Terbutaline 500 mcg Turbuhaler, n = 1280
Beasley, NovelSTART ^44	AZ and Health Research Council of NZ	Randomized, open-label	52 weeks	18-75yo	Self-report of MD dx	Use of a SABA as the sole asthma therapy in the previous 3 months and patient report of the use of the SABA on at least 2 occasions, but on an average of 2 or fewer occasions per day in the previous 4 weeks OR severe exacerbation in last 12 months (systemic steroid for at least 3 days or hospitalization or ED visit leading to systemic steroid)	budesonide 200 mcg bid Turbuhaler + PRN Salbutamol 100 mcg 2 puffs pMDI n = 225	PRN Salbutamol 100 mcg 2 puffs pMDI n = 223
Papi, BEST ^38	Chiesi Farmaceutici	Randomized, double-blind, placebo- controlled	6 months	18-65yo	Pre-BD FEV1 > 75% with either a 12% increase in FEV1 post 200 mcg salbutamol or PC20 < 8 mg/mL	History of mild persistent asthma for at least 6 months as per GINA 2006? During a 4-week run in on beclomethasone DIP 250 mcg bid and well-controlled	beclomethasone^EUR 250 mcg bid pMDI and PRN Salbutamol 100 mcg pMDI, not clear if spacer used, n = 106	PRN Salbutamol 100 mcg pMDI, not clear if spacer used, n = 118
3b: PRN bud/form vs Daily ICS + PRN SABA
Bateman, SYGMA2 ^34	AZ	Randomized, double-blind, placebo- controlled	52 weeks	12 and older (10% 12-18yo)	Asthma x ≥6 m with reversible obstruction	GINA step 2 treatment (uncontrolled on SABA alone on controlled on ICS monotherapy or LTRA). FEV1 > 60% pre-BD (>80% post-BD if on SABA alone), FEV > 80% if on maintenance. SABA PRN needed at least 3 separate days in the last week of run-in.	PRN bud/form 200/6 mcg 1 puff Turbuhaler, n = 2089	budesonide 200 mcg bid Turbuhaler + PRN Terbutaline 500 mcg Turbuhaler, n = 2087
O'Byrne, SYGMA1 ^37	AZ	Randomized, double-blind, placebo-controlled	52 weeks	12 and older (12.5% 12-18 yo)	Asthma ≥6 m with reversible obstruction	Uncontrolled on SABA alone on controlled on ICS monotherapy or LTRA, SABA PRN needed at least 3 days in the last week of run-in (not more than 6 inhalations/day for ≥2 days), FEV1 > 60% pre-BD (>80% post- BD if on SABA alone), FEV > 80% if on maintenance	PRN bud/form 200/6 mcg 1 puff Turbuhaler, n = 1144 (n =1 279 randomized)	budesonide 200 mcg bid Turbuhaler + PRN Terbutaline 500mcg Turbuhaler, n = 1135 (1290 randomized)
Beasley, NovelSTART ^44	AZ and Health Research Council of NZ	Randomized, open-label	52 weeks	18-75yo	Self-report of MD dx	Use of a SABA as the sole asthma therapy in the previous 3 months and patient report of the use of the SABA on at least 2 occasions, but on an average of 2 or fewer occasions per day in the previous 4 weeks OR severe exacerbation in last 12 months (systemic steroid for at least 3 days or hospitalization or ED visit leading to systemic steroid)	PRN bud/form 200/6 mcg 1 puff Turbuhaler, n = 220	budesonide 200 mcg bid Turbuhaler + PRN Salbutamol 100 mcg 2 puffs pMDI, n = 225
Hardy, PRACTICAL ^15	Health Research Council of NZ	Randomized, open-label	52 weeks	18-75 yo	Self-report of MD dx	SABA alone or low to moderate dose ICS in 12 weeks before randomization. If on SABA alone, asthma symptoms or need for SABA ≥2x in last 4 weeks, or waking because of asthma at least once in the past 4 weeks, of a history of severe asthma exacerbation requiring oral corticosteroids in the past 52 weeks. For those on ICS in prior 12 weeks at low or moderate doses (≤800 mcg/day budesonide), partly or well-controlled asthma as defined by GINA 2014 or uncontrolled asthma with poor adherence or unsatisfactory inhaler technique.	PRN bud/form 200/6 mcg 1 puff Turbuhaler, n = 437	budesonide 200 mcg bid Turbuhaler and PRN terbutaline 500 mcg, Turbuhaler, n = 448
PICO 4: PRN ICS-SABA vs Daily ICS + PRN SABA
Fitzpatrick, INFANT ^35	NHLBI AsthmaNet	Randomized, double-blind, placebo-controlled, 3 x 3 cross-over	48 weeks with 2-8 wk run-in	12-59 months (1-5 yo)	Not specified	Asthma requiring treatment with a daily controller, ICS / LTRA naive children requiring step up, day sx > 2 day/week averaged over 4 week, or 4 or more wheezing episodes (each lasting >24 hr) in last year, night wakening ≥1 in last 4 weeks OR if not on controller, 2 or more exacerbations requiring systemic steroids in last 6 months OR if on controller for more than 90 days in last 6 months, 2 or more exacerbations requiring systemic steroids in last 12 months	PRN fluticasone propionate 50 mcg 2 puffs pMDI co-administered with open-label Salbutamol 100 mcg 2 puffs pMDI, n = 230	fluticasone propionate 50 mcg 2 puffs bid pMDI + PRN salbutamol pMDI (valved holding chamber with mask), n = 230
Papi, BEST Ped ^53	Chiesi Farmaceutici	Randomized, double-blind, placebo-controlled	12 weeks	1-4 yo	Not specified other than recurrent wheezing episodes	3 or more episodes of wheezing requiring medical attention in previous 6 months, included if had another episode of wheezing (above the 3)	PRN beclomethasone^EUR 800 mcg /Salbutamol 1600 mcg in 1 nebule, 1 nebule (Clenil aerosol with face mask), n = 110	beclomethasone^EUR 400 mcg/nebule, 1 nebula bid + PRN Salbutamol 2500 mcg/nebule 1 nebule (Clenil aerosol with face mask), n = 110
Martinez, TREXA ^36	NHLBI, TEVA provided drug and placebo	Randomized, double-blind, placebo-controlled	44 weeks	6-18 yo	Not clear, clinical diagnosis likely given most diagnosed at 4 yo	Naïve to controller and history of 1-2 exacerbations in last year, tx for last 8 weeks with monotherapy other than ICS, asthma controlled in last 8 weeks on low dose ICS (≤160 ug/beclomethasone equiv). During a 2-week run in on beclomethasone HFA 100 mcg/day, controlled, FEV1 ≥ 80%, adherence >75% to meds	PRN beclomethasone HFA 50 mcg 2 puffs pMDI each time Salbutamol 100 mcg 2 puffs pMDI used (separate inhalers), pMDI unclear if spacer used (n = 71)	beclomethasone HFA 50 mcg bid pMDI + PRN Salbutamol pMDI (pMDI, unclear if spacer used) PRN, n = 72
Papi, BEST ^38	Chiesi Farmaceutici	Randomized, double-blind, placebo-controlled	6 months	18-65 yo	Pre-BD FEV1 > 75% with either a 12% increase in FEV1 post 200 mcg salbutamol or PC20 < 8 mg/mL	History of mild persistent asthma for at least 6 months as per GINA 2006. During a 4-week run in on beclomethasone^EUR DIP 250 mcg bid and well-controlled	PRN beclomethasone^EUR 250 mcg/Salbutamol 100 mcg in single pMDI, not clear if spacer used, n = 124	beclomethasone^EUR 250 mcg bid and PRN Salbutamol 100 mcg pMDI, not clear if spacer used, n = 106
Calhoun, BASALT ^58	NHLBI	Randomized, double-blind, placebo-controlled	9 months	≥18 yo	MD dx asthma and either reversible airflow obstruction (≥12% improvement in FEV1 after 360 mcg salbutamol) or airway hyperresponsiveness (PC20  < 8 mg/mL)	"Mild to moderate persistent asthma" well-controlled or partially controlled asthma with low-dose ICS	Symptom based (SB): PRN Salbutamol 2 puffs and beclomethasone 50mcg 2 puffs each time salbutamol used (separate inhalers), n = 113	Physician based care (PB): beclomethasone HFA 50 mcg 2 puffs bid + PRN Salbutamol, dose adjusted by MD as per guidelines q2-6week, n = 114
PICO 5: Daily SABA + Daily ICS + PRN SABA vs Daily ICS + PRN SABA
Papi, BEST ^38	Chiesi Farmaceutici	Randomized, double-blind, placebo-controlled	6 months	18-65 yo	Pre-BD FEV1 > 75% with either a 12% increase in FEV1 post 200 mcg salbutamol or PC20 < 8 mg/mL	History of mild persistent asthma for at least 6 months as per GINA 2006? During a 4-week run in on beclomethasone DIP 250 mcg bid and well-controlled	beclomethasone^EUR 250 mcg / Salbutamol 100 mcg bid in a single pMDI + PRN Salbutamol 100 mcg, pMDI n = 109	beclomethasone^EUR 250 mcg bid pMDI and PRN Salbutamol 100 mcg, pMDI n = 106
PICO 6: Short course very high dose ICS vs PRN SABA
Bacharier ^67	NHLBI, drug and placebo donated by Merck and AZ	Randomized, double-blind, placebo-controlled	1 year	12-59 months old	At least 2 episodes of wheezing in context of RTI, 1 in last 6 months and 1 documented by health care provider	Moderate-severe intermittent wheezing: at least 2 episodes of wheezing in the context of a viral RTI in last year with at least 1 episode in last 6 months; 2 urgent care visits for acute wheezing in the last year or 2 wheezing episodes where corticosteroids were required.	budesonide 1mg nebule bid x 7d at start of URTI (PARI LC + facemask or mouthpiece) n = 96	Salbutamol 200 mcg with aerochamber/ mask OR 2.5 mg nebule qid when awake x 48 hour then PRN, n = 47
Ducharme ^69	Grant from GSK plus funding from RSR Québec	Randomized, double-blind, placebo-controlled	12 months	1-6 yo	Not specified other than recurrent wheezing episodes	3 or more wheezing episodes in lifetime triggered by URTI, asymptomatic in between AND at least 1 course of oral steroid in last 6 months or 2 courses in last 12 months	fluticasone 750 mcg bid pMDI + PRN Salbutamol 100 mcg 2-4 puffs q4h until 48hr without symptoms (with aerochamber and mask or mouthpiece) n = 62	PRN Salbutamol 100 mcg 2-4 puffs q4h (with aerochamber and mask or mouthpiece) n = 67
Connett ^68	Royal Alexandra Hospital Rocking Horse Appeal	Randomized, double-blind, placebo-controlled	Variable, after 2 URTI	1-5 yo	Acute wheezing with clinical response to bronchodilators. Consistent wheezing after URTIs and asymptomatic between attacks	At least 2 attacks in last 6 months	budesonide 800 mcg bid pMDI with Nebuhaler spacer and mouthpiece or 1600mcg bid pMDI with spacer and mask + PRN terbutaline for 7 days or sx resolved for 24 hours, n = 28 treatment pairs (n = 25 pt)	PRN Terbutaline 250 mcg/puff 4-8 puffs q4h (pMDI with spacer and mask or spacer and mouthpiece), n = 28 treatment pairs (n = 25 pt)
Wilson ^71	pMDI provided by GSK. Funding by Asthma Research Council	Randomized, double-blind, placebo-controlled	4 acute episodes	1-5 yo	Not specified other than recurrent wheezing episodes	At least 2 episodes of acute wheeze in last 3 months, attacks severe enough to require bronchodilator during the night on at least 2 occasions per episode	beclomethasone 750 mcg tid x 5d (pMDI with volumatic spacer) with 2 puffs of SABA prior to each treatment, n = 24	Placebo, n = 24
Svedmyr ^70	Unclear	Randomized, double-blind, placebo-controlled	12 months or max of 6 treatments	1-3 yo	MD dx of wheezy bronchitis or asthma	At least 3 episodes of wheezing during URTI and asthma sx during last 2 airway infections, sx lasted at least 3 days during URTI, no glucocorticosteroids within 2 months preceding inclusion	budesonide 400 mcg qid pMDI with Nebuhaler spacer and mask x 3d, 400 mcg bid for next 7 days, n = 28 (put 2 puffs into spacer at once)	Not specified but inhaled beta-agonist and theophylline was allowed, n = 27

AZ = AstraZeneca; BD = bronchodilator; bud/form = Budesonide and Formoterol; DIP = Dipropionate; dx = diagnosis; ED = Emergency Department; EIB = Exercise induced bronchoconstriction; FEV₁ = Forced expiratory volume in second; GSK = GlaxoSmithKline; HFA = Hydrofluoroalkanes; ICS = Inhaled corticosteroids; LTRA = Leukotriene receptor antagonists; mcg = microgram; MD = doctor; NED = Nebule; NHLBI = National Heart, Lung, and Blood Institute; NZ = New Zealand; OD = Once daily; PC20 = Provocation concentration cause a 20% fall in FEV₁; pMDI = Pressurized metered-dose inhaler; PRN = as needed; pt = patient; q = every; q4h – every 4 hours; quid = 4 times a day; RSR = Réseau de recherche en santé respiratoire; RTI = Respiratory Tract Infection; SABA = Short acting beta agonist; sx = symptoms; tx = treatment; tid = 3 times a day; URTI = Upper respiratory tract infection; yo = years of age.

Table

Odds Ratio (OR) >2.5
≥12 years of age	6-11 years of age	<6 years of age
History of previous severe exacerbation	History of previous severe exacerbation Poorly-controlled asthma FEV1 < 60% predicted^73	History of previous severe exacerbation^74
OR 1.5-2.5
Persistent asthma symptoms (1)	Suboptimal drug regimen (ICS:SABA refill ratio <0.5) (2)
Excessive SABA use (>2 inhalers/year) (3)	Comorbid atopic/allergic disease
Current smoker (4)	Low socioeconomic status
	Vitamin D deficiency (<30 nmol/L)
	FEV1 60–80% predicted^73
OR 1.1-1.5
Older age (esp. age >55 years of age)	Exposure to environmental tobacco smoke	Comorbid atopic/allergic disease^35
Female	Younger age	Raised blood eosinophils ≥300/µL)^35
FEV1 < 70% predicted^75	Obesity	Younger age
Obesity	Low parental education	Low socioeconomic status
Previous smoker (4)	Male	Male gender
Depression		Underweight

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