Description of management strategies

First author [ref.]Basis for decisionsTreatments indicated
Smith [24]FeNO, with a safety measure based on symptoms, bronchodilator use and spirometry
FeNO <35 ppb (equivalent at 50 mL·s−1) defined as controlled asthma
FeNO ≥35 ppb defined as uncontrolled asthma
Safety measure: if one or more of the following clinical criteria are met, increase one step:
 1) Symptom score for previous 7 days ≥1 point   more than mean during run-in and   minimum score of 2 out of 5
 2) Nocturnal wakening on ≥3 nights per week   more than mean during run-in
 3) Mean daily bronchodilator use ≥3 times   that of mean during run-in and minimum   use of 15 occasions during prior 7 days
 4) Diurnal peak flow variation ≥30% and/or   FEV1 of <85% of baseline
GINA 2002: symptoms, bronchodilator use, spirometerDose steps: placebo, inhaled fluticasone 100 µg, 250 µg, 500 µg, 750 µg and 1000 µg
Phase 1: until optimal dose reached
Phase 2: up titrate one step at a time; down titrate if controlled for two visits, but not lower than optimal dose
Patients had personalised self-management plans, which instructed them to take oral prednisone 40 mg per day when morning peak flows fell below 70% of mean run-in values, until it reached >85%, at which time they took 20 mg per day for the same number of days
As for intervention, but without the personalised management plan
Shaw [25]FeNO plus symptoms (Juniper score)
Exhaled nitric oxide <16 ppb on first occasion or exhaled nitric oxide 16–26 ppb on second occasion with
 1) Juniper score ≤1.57: step-down   anti-inflammatory treatment, step-down    bronchodilator treatment once off steroids.
 2) Juniper score >1.57: step-down   anti-inflammatory treatment, step-up   bronchodilator treatment
Exhaled nitric oxide >26 ppb with
 1) Juniper score ≤1.57: step-up   anti-inflammatory treatment, no change   in bronchodilator treatment
 2) Juniper score >1.57: step-up   anti-inflammatory treatment, step-up   bronchodilator treatment once on maximum   anti-inflammatory treatment
Safety measure: patients on 2000 µg beclomethasone per day with >26 ppb FeNO and had not fallen to 60% of baseline had sputum checked. If no eosinophilic inflammation, treatment reduced stepwise, unless FeNO increased by >60% of baseline.
BTS/SIGN guidelines using Juniper scale to score symptoms:
 1) treatment doubled   if score >1.57
 2) treatment halved if   score <1.57 for   2 consecutive months
Hierarchy of anti-inflammatory treatment:
 1) Low dose ICS (100–200 μg BDP   twice daily)
 2) Moderate dose ICS (200–800 μg BDP   twice daily)
 3) High dose ICS (800–2000 μg BDP   twice daily)
 4) High dose ICS (800–2000 μg BDP   twice daily) plus LTRA
 5) Higher dose ICS (2000 μg BDP   twice daily) plus LTRA
 6) Higher dose ICS (2000 μg BDP   twice daily) plus LTRA plus oral   prednisolone 30 mg for 2 weeks, then   titrate the dose reducing by   5 mg·week−1
Hierarchy of bronchodilator treatment
 1) SABA as needed
 2) LABA
 3) LABA plus theophylline
 4) LABA plus theophylline plus nebulised  bronchodilator
Step 1: SABA as required
Step 2: Add ICS  200–800 μg·day−1 BDP equivalent
Step 3: Add inhaled LABA
Step 4: increase ICS up to 2000 μg·day−1 and addition of fourth drug, e.g. LTRA, theophylline or LABA
Step 5: oral prednisolone, high dose ICS, refer to specialist care
Syk [14]FeNO only
FeNO <19 ppb (men), <21 ppb (women): decrease one step
FeNO 19–23 ppb (men), 21–25 ppb (women): no change
FeNO ≥24 ppb (men), ≥26 ppb (women): increase one step (no change in treatment step if on step 4 or 5 and using ≤2 inhalations of SABA per week)
FeNO ≥30 ppb (men), ≥32 ppb (women): increase two steps (only if on treatment step 1)
Grey zone of 5 ppb applied to avoid frequent dose changes
Symptoms, lung function, β-agonist use (usual care)Steps 1–6:
Budesonide (µg·day−1): 0, 200, 400, 800, 800+LTRA, 1600+LTRA
Fluticasone (µg·day−1): 0, 100, 250, 500, 500+LTRA, 1000+LTRA
Mometasone (µg·day−1): 0, 100, 200, 400, 400+LTRA, 800+LTRA
Assume same doses as intervention
Calhoun [13]FeNO only
Well controlled, FeNO <22 ppb: down one level
Controlled, FeNO 22–35 ppb: maintain level
Under-controlled, FeNO >35 ppb: up 1 level
NHLBI guidelines (USA version of SIGN guidelines)Dosing beclomethasone HFA:
Level 1=0 μg per day
Level 2=80 μg once daily
Level 3=160 μg twice daily
Level 4=320 μg twice daily
Level 5=640 μg twice daily
As intervention
Honkoop [16]ACQ and FeNO
Where ACQ ≤0.75 with
 1) FeNO ≤25 ppb, step down
 2) FeNO >25 ppb and <50 ppb, no change
 3) FeNO ≥50 ppb, step up
Where ACQ >0.75 and <1.50 with
 1) FeNO ≤25 ppb: and time <3 months,  no change, or change to LABA; if time  >3 months, step down ICS
 2) FeNO >25 ppb and <50 ppb: step-up  (treatment choice)
 3) FeNO ≥50 ppb, step-up ICS by one level
Where ACQ ≥1.50 with
 1) FeNO ≤25 ppb: step-up LABA
 2) FeNO >25 ppb and <50 ppb: step-up  (treatment choice)
 3) FeNO ≥50 ppb: step-up ICS by two levels
ACQ scores
Strict strategy
 ACQ ≤0.75: <3 months,  no change; > 3 months,  step-down
 ACQ >0.75 and <1.50: Step-up: treatment choice
 ACQ ≥1.50: Step-up:  treatment choice
Sufficient strategy
 ACQ ≤0.75: Step-down
 ACQ >0.75 and <1.50:  No change
 ACQ ≥1.50: Step-up:  treatment choice
Step 1: SABA as needed
Step 2: low-dose ICS; or LTRA
Step 3: low-dose ICS + LABA; or medium- or high-dose ICS; or low-dose ICS+LTRA
Step 4: Add one or more of medium- or high-dose ICS + LABA, and/or LTRA
Step 4: Add one or both of OCS (lowest dose), anti-IgE treatment
As intervention for both strategies
Powell [26]FeNO concentration use to adjust dose of ICS
ACQ used to adjust dose of LABA
FeNO >29 ppb: ICS increase one step, LABA no change
FeNO 16–29 ppb and ACQ ≤1.5: ICS no change, LABA no change
FeNO 16–29 ppb and ACQ >1.5: ICS no change, LABA increase one step
FeNO <16 ppb and ACQ ≤1.5: ICS decrease one step, LABA no change
FeNO <16 ppb and ACQ >1.5: ICS decrease one step, LABA increase one step
If a patient had undergone two ICS dose increments and FeNO remained >29 ppb, ICS was not increased further. If still symptomatic (ACQ >1.5) formoterol 6 µg twice daily was added. For patients taking formoterol, the ICS dose could never be 0, but would be reduced to 100 µg twice daily. Patients who remained uncontrolled at maximum doses were referred to a respiratory physician.
Well controlled asthma, ACQ <0.75: reduce treatment one step
Partially controlled asthma, ACQ 0.75–1.50: no treatment change
Uncontrolled asthma, ACQ >1.5: increase one step
Those at maximum dose were referred to a respiratory physician
Steps 1–5
ICS: budesonide 0, 100, 200, 400 or 800 µg twice daily, respectively
 Step 1: salbutamol as required
 Step 2–5: formoterol 6, 12, 24 or  24 µg twice daily, respectively
Step 1: salbutamol as required
Step 2: budesonide 200 µg twice daily plus salbutamol as required
Step 3: budesonide 400 µg twice daily plus salbutamol as required
Step 4: budesonide 400 µg and formoterol 12 µg twice daily
Step 5: budesonide 800 µg twice daily and formoterol 24 µg twice daily
  • FeNO: fractional exhaled nitric oxide; FEV1: forced expiratory volume in 1 s; GINA: Global Initiative for Asthma; BTS: British Thoracic Society; SIGN: Scottish Intercollegiate Guidelines Network; HFA: hydrofluoroalkanes; ICS: inhaled corticosteroid; BDP: beclomethasone dipropionate; LTRA: leukotriene receptor antagonist; SABA: short-acting β2-agonist; LABA: long-acting β2-agonist; NHLBI: National Heart, Lung and Blood Institute; ACQ: Asthma Control Questionnaire; OCS: oral corticosteroid.