Table 1

Characteristics of included studies

StudySample sizeParticipant ageDescription of intervention and control armsPrimary outcome and definition of exacerbationDuration
Chlumsky 200614
  • 55 randomised Eosinophil strategy, n=30

  • Standard strategy, n=25

  • Eosinophil strategy: mean age 42 (SD 19), 13 males

  • Standard strategy: mean age 48 (SD 16)

  • Standard strategy arm: treatment decisions were based on morning PEF variation, frequency of daytime symptoms or SABA use/week, frequency of night time symptoms or SABA/week.

  • Eosinophil strategy: treatment decisions were based on the same as the standard strategy arm plus sputum eosinophils as a % of total cell count

  • Primary outcome: rate of asthma exacerbations

  • Secondary outcomes: FEV1, postbronchodilator FEV1 and FEV1/inspiratory vital capacity ratio.

  • Exacerbation: a doubling of the frequency of symptoms or number of puffs of rescue salbutamol or a reduction in morning PEF by ≥30% on at least two consecutive days or two of the aforementioned or all three.

Participants were assessed every 3 months for 18 months
deJongste 200921
  • 151 children randomised

  • FeNO group, n=75

  • Symptom group, n=72

  • FeNO group: mean age 11.6 (SD 2.6), 46 males.

  • Symptom group: mean age 11.8 (SD 4.3), 54 males

All participants scored asthma symptoms in an electronic diary over 30 weeks. The FeNO group received a portable nitric oxide analyser. Data were transmitted daily to centres, patients were phoned every 3 weeks and their steroid dose was adapted according to FeNO and symptoms (FeNO group) or according to symptoms (symptom group).
  • Primary outcome: proportion of symptom-free days over the last 12 study weeks.

  • Secondary outcomes: cumulative symptom scores, ICS dose as budesonide equivalent, FEV1 and reversibility, FeNO 0.05, prednisone courses, emergency visits, hospitalisations for asthma and PACQLQ scores.

  • Exacerbation: emergency visit, hospitalisation or prednisolone course

Children were seen at 3, 12, 21 and 30 weeks for examination, assessment of FeNO, spirometry before and after salbutamol and recording of adverse events. Study concluded at 30 week visit.
Fritsch 200616
  • 52 patients entered the study.

  • FeNO group n=22

  • Control group n=25

  • FeNO group: mean age 11.3 (SD 3.4), 14 males.

  • Control group: mean age 12.1 (SD 2.8), 14 males.

  • FeNO group: treatment was based on symptoms, β-agonists use, lung function and FeNO.

  • Control group: treatment based on symptoms, β-agonists and lung function only.

  • Primary outcome: FEV1

  • Secondary outcomes: no. of exacerbations, MEF 50% predicted, better symptom control, less SABAs and ICS dose.

  • Exacerbation defined by 4 parameters: oral steroid courses, and/or off-scheduled visit because of asthma symptoms over the past 4 weeks, and/or increase of asthma symptoms from a symptom score 0 or 1 to a symptom score 2 and/or decline of FEV1 (litres) >10% compared with the previous visit.

Visits were at 6, 12, 18 and 24 weeks after 4 week run-in.
Green 200215
  • 74 randomised

  • Sputum management group, n=37 BTS management group, n=37

  • Sputum management group: median age 50, range 19–73, 19 males.

  • BTS management group: median age 47, range 20–75, 21 males.

  • Sputum management group: anti-inflammatory treatment was based on maintenance of sputum eosinophil count <3% with a minimum dose of anti-inflammatory treatment.

  • BTS management group: treatment decisions were based on traditional assessments of symptoms, PEF and use of β2-agonists.

  1. No. of severe asthma exacerbations

  2. Control of eosinophilic airway inflammation measured by the induced sputum eosinophil count

  3. Exhaled nitric oxide concentrations

  4. Symptom scores (0–3 for daytime and night time symptoms)

  5. Total asthma quality of life scores

  6. Peak flow amplitude as a proportion of the mean

  7. FEV1

  8. Changes from baseline of methacholine PC20

  9. Drug use

  10. Admissions for asthma

  11. Severe exacerbations defined as a decrease in morning PEF to >30% below baseline value on 2 consecutive days, or deterioration in symptoms needing rescue course of oral corticosteroid.

Study duration was for 12 months with visits at months 1, 2, 3, 4, 6, 8, 10 and 12.
Jayaram 200622
  • 117 randomised

  • Sputum strategy group, n=50

  • Clinical strategy group, n=52

  • Sputum strategy group: mean age 46 (SD 13.8), 15 males

  • Clinical strategy group mean age 43.5 (SD 13.9), 15 males

  • Sputum strategy: dose of inhaled steroid was guided solely by induced sputum eosinophils to keep <2%. Spirometry was used to identify clinical control, exacerbations and other treatment.

  • Clinical strategy: guided by symptoms

  1. RR reduction for the first exacerbation

  2. The length of time without exacerbations

  3. Type and severity of exacerbations

  4. The usefulness of monitoring sputum cell counts in relation to the overall serverity of asthma. Defined by the minimum dose of ICS to maintain control

  5. The cumulative dose of ICS needed in Phase 2 adjusted for its duration.

Exacerbation: Loss of symptomatic control requiring increased use of SABAs by 4 extra puffs per day for a minimum of 48 h, or by nocturnal symptoms, or early morning wakening due to respiratory symptoms ≥2 in 1 week. Severe exacerbations were defined as requiring rescue courses of oral prednisone as defined by the investigator.
  • 2 year study duration with monthly visits in Phase 1 until control maintained with minimum treatment (variable duration) or at exacerbations

  • Phase 2: 3 monthly visits or at exacerbations

Pijnenburg 200517
  • 89 children randomised.

  • FeNO group, n=39

  • Symptom group, n=46

  • FeNO group: median age 11.9 (SD 2.9), 25 males.

  • Symptom groupK mean age 12.6 (SD 2.8), 30 males.

  • FeNO group: FeNO-guided ICS dosing according to predetermined algorithm.

  • Symptom group: symptom scores influenced ICS dosing.

  • Primary outcome: cumulative steroid dose (sum of mean daily steroid doses of visits 1–5)

  • Secondary outcomes: mean daily symptom score, mean daily number of bronchodilator doses taken, percentage of symptom-free days during the last 4 weeks of the study, number of oral prednisolone courses during the study and provocative dose of methacholine causing a 20% fall in FEV1 (PD20), FVC, FEV1 and MEF25 during final visit.

  • Exacerbation: deterioration in symptoms requiring oral prednisone course.

Study duration was 12 months with 3 monthly visits.
Shaw 200719
  • 118 adults were randomised.

  • FeNO group, n=58

  • Control group, n=60.

  • FeNO group: median age 50 (range 20–75), 27 males.

  • Control group: median age 52 (range 24–81), 27 males.

  • FeNO group: FeNO >26 ppb, ICS was increased. If FeNO <16 ppb or <26 ppb on 2 separate occasions, treatment was decreased.

  • In control group treatment was doubled if JACS >1.57 and treatment halved if JACS <1.57 for 2 consecutive months.

  • Primary outcome: Number of exacerbations

  • Secondary outcomes: total inhaled corticosteroid dose.

  • Exacerbation: an increase in symptoms requiring oral steroids or antibiotics

Study duration was 12 months with participants being send at baseline, 2 weeks, months 1, 2, 3, 4, 6, 8, 10 and 12.
Smith 20051897 patients randomised from 110 patients recruited.
  • n=46 in FeNO group achieved optimal dose in Phase 1 and n=28 achieved optimal dose in control group.

  • Mean age of randomised patients was 44.8 (range 12–73), 41 males.

  • Phase 1: run-in period was for 6 weeks, after 2 weeks fluticasone 750 μg/day was commenced. Visits were every 4 weeks until optimal dose was achieved.

  • FeNO group: adjustment of dose of ICS was based soley to keep FeNO <15 ppb at 250 ml/s.

  • Control group: dose adjustment based on asthma symptoms, night time waking, bronchodilator use, variation in PEF rate and FEV1.

  • Phase 2: visits every 2 months with upward adjustments made as per Phase 1 but no downward adjustments would be made from optimal dose.

  • Primary outcome: frequency of exacerbation

  • Secondary outcome: mean daily dose of inhaled corticosteroids

  • A minor exacerbation was defined as a daily asthma score of ≥2 on ≥2 consecutive days, whereas a major exacerbation was a daily asthma score of ≥3 on ≥2 consecutive days.

2 phase study, with phase 1 varying in duration (3–12 months) depending when optimal dose was deemed to have been achieved. During phase 2 (12 months) optimal dose from Phase 1 was continued and treatment stepped up if asthma control was lost.
Szefler 200820
  • 546 participants randomised from 780 patients screened.

  • FeNO group n=276.

  • Control group n=270

  • FeNO group: mean age 14.4, 146 males.

  • Control group: mean age 14.4, 142 males.

  • FeNO group: standard treatment modified on the basis of measurements of FeNO

  • Control group: standard treatment based on the guidelines of NAEPP.

  • Primary outcome: no. of days with asthma symptoms.

  • Secondary outcomes: admission to hospital, unscheduled visits to emergency departments or clinics, prednisone courses for asthma, asthma exacerbations, days of wheeze, days of interference with activities, nights of sleep disruption, days of school or work missed, and days of interruption of guardian's activities.

  • Exacerbation: combination of admissions to hospital, unscheduled visits and oral prednisone.

The study duration was 46 weeks with visits every 6–8 weeks.
  • BTS, British Thoracic Society; FeNO, fractional expired nitric oxide; FEV1, forced expiratory flow in 1 s; FVC, forced vital capacity; ICS, inhaled corticosteroid; JACS, Juniper Asthma Control Score; MEF, maximal expiratory flow; NAEPP, National Asthma Education and Prevention Program; PACQLQ, Paediatric Asthma Caregiver's Quality of Life Questionnaire; PEF, peak expiratory flow; SABA, short-acting β-agonist.