Figures
- Fig. 1—
Study design and profile. CS: clinical strategy; SS: sputum strategy; MT: maintenance treatment.
- Fig. 2—
Maintenance inhaled steroid dose in clinical strategy (░) and sputum strategy (▒). The distribution of each dose of inhaled corticosteroid was similar in both study groups.
- Fig. 3—
Mean number of exacerbations from maintenance visit to the end of the scheduled follow-up or withdrawal. For clinical strategy (═; n = 52 patients, 79 exacerbations) and sputum strategy (SS: –––; n = 48, 47 exacerbations). The SS resulted in a reduction in the rate of exacerbations which was not statistically significant. (relative risk = 0.71, 95% confidence interval = 0.45–1.12, p = 0.14).
- Fig. 4—
Analyses by exacerbation type: a) Mean number of eosinophilic exacerbations in clinical strategy (CS; (═) patients (n = 34, 26 exacerbations) and sputum strategy (SS; –––) patients (n = 34, 6 exacerbations). b) Mean number of noneosinophilic exacerbations in CS (n = 49, 37 exacerbations) and SS (n = 48, 33 exacerbations) patients. Both a) and b) show data from maintenance to the end of the study or to withdrawal. SS reduced the rate of eosinophilic exacerbations by 72% (relative risk (RR): 0.28, 95% confidence interval: 0.10–0.74; p = 0.01), but had no effect on the number of noneosinophilic exacerbations (RR = 1.07, 95% CI = 0.61–1.85; p = 0.82). c)–e) Show individual plots for sputum total cell counts (TCCs) (c), eosinophils (d) and neutrophils (e) in the eosinophilic (Eos) and noneosinophilic (Non-Eos) exacerbations. ○: indicate Non-Eos exacerbations in CS; ▵: Non-eos exacerbations in SS; •: Eos exacerbations in CS; ▴: Eos exacerbations in SS; - - - -: represent upper limit of normal values; –––: represent the median values. **: p-values <0.01 for comparisons between Eos and Non-Eos exacerbations. In comparison with Eos exacerbations, the Non-Eos exacerbations were characterised by a higher and higher percentage of neutrophils.
- Fig. 5—
Analysis by severity of asthma defined by the minimum dose of inhaled steroid to maintain control: mean number of exacerbations from maintenance to the end of the study or to withdrawal in a) very mild to mild asthma for clinical strategy (CS) patients (═; n = 15, 11 exacerbations) and sputum strategy (SS) patients (–––; n = 15, 13 exacerbations) and in b) moderate-to-severe asthma for CS patients (n = 37, 68 exacerbations) and SS patients (n = 33, 34 exacerbations). While patients with very mild or mild asthma did not benefit from the SS (relative risk (RR) = 1.34, 95% confidence interval = 0.52–3.46, p = 0.54) those with moderate-to-severe asthma had a 37% risk reduction for exacerbations after maintenance (RR = 0.63, 95% CI = 0.38, 1.03, p = 0.07).
- Fig. 6—
Analyses by use (necessity for) of long acting β2-agonist (LABA). Mean number of exacerbations from maintenance to the end of the study or withdrawal in patients on LABA (a) with clinical strategy (CS, ═) patients n = 26, 52 exacerbations) and sputum strategy (SS, –––) patients (n = 16, 15 exacerbations) and b) not on LABA with CS patients; n = 26, 27 exacerbations) and SS patients (n = 32, 32 exacerbations). Those on LABA in the SS had a 47% reduction in events (relative risk (RR) = 0.53, 95% confidence interval = 0.24–1.14; p = 0.11) and those not on LABA had no reduction (RR = 1.05, 95% CI = 0.62–1.79; p = 0.85).
Tables
- Table 1—
Characteristics of patients eligible for analysis#
Baseline Maintenance visit CS SS CS SS Subjects n 52 50 52 50 Clinical characteristics Age, yrs 43.5 (13.9) 46.0 (13.8) Sex, male % 28.8 30 Duration of asthma yrs 19.3 (12.2) 20.0 (16.7) Atopy 90.2 90.2 Symptoms score¶ 5.4 (1.1) 5.6 (1.0) 5.9 (0.9) 6.2 (0.8) Pre BD FEV1+ 78.7 (18.9) 78.4 (18.3) 81.1 (17.0) 82.4 (15.5) Pre BD FEV1/SVC 69.8 (10.4) 69.3 (12.1) 71.7 (11.5) 72.3 (11.0) ΔFEV1 after BD§ 18.3 (12.5) 21.4 (12.5) 7.1 (6.5) 7.6 (6.9) Methacholine PC20 mg·mL−1ƒ 0.82 (5.7) 0.89 (4.0) 1.5 (3.4)§§ 1.4 (4.6)§§ Asthma treatment IS 88.5 86.0 92.3 94.0 IS dose µg·day−1## 500 (0–2000) 500 (0–4000) 625 (0–2000) 750 (0–3000) LABA 34.6 26.0 39.4 36.0 Antileukotriene 7.7 10.0 7.7 12.0 Prednisone<1/emph> 1.9 4.0 0 2.0 Other asthma medication¶¶ 3.8 6.0 3.8 2.0 Nasal steroid 20.8 26.0 34.6 30.0 Induced sputum## Total cell count ×106·g−1 2.9 (0.2–266.7) 2.7 (0.4–48.9) 3.8 (0.5–62.5) 3.3 (0.4–23.8) Neutrophils 26.0 (2.3–94.2) 35.5 (2.0–86.3) 37.0 (4.0–94.55) 41.8 (2.0–94.5) Eosinophils 2.0 (0–79.0) 2.0 (0–71.0) 1.2 (0–53.0) 1.0 (0–2.0) Eosinophilia ≥3% 41.2 30.0 39.6 2.1ƒƒ Data are presented as percentages and presented as mean±sd for continuous and percentages for dichotomous variables, unless otherwise stated. CS: clinical strategy; SS: sputum strategy; Atopy: means ≥1 positive allergy skin-prick test with a wheal of >2 mm than the negative control; Pre: before use; BD: bronchodilator (salbutamol); FEV1: forced expiratory volume in one second; SVC: slow vital capacity; PC20: provocative concentration causing a 20% drop in FEV1; IS: inhaled steroid; LABA: long acting β2-agonist; #: only subjects who achieved maintenance (see fig. 1⇓). ¶: symptoms score varied from 1 (a very great deal of discomfort or distress) to 7 (no discomfort or distress) and is the mean of 7 individual scores; +: FEV1 predicted values from Crapo et al. 23 and are prebronchodilator; §: n = 16 in CS and n = 14 in SS; ƒ: data presented as geometric mean (geometric sd), n = 36 in CS and n = 36 in SS; ##: data presented as median (minimum–maximum); ¶¶: other asthma medication included theophylline or cromone; §§: data from the visit at 6 months in the study, n = 36 in the CS and n = 33 in the SS (of whom 92 and 83%, respectively, were on maintenance treatment at this visit); ƒƒ: p<0.001 within SS at different time points and between treatment strategies at maintenance.
- Table 2—
Physicians guidelines for adjusting therapy
CS SS Phase 1 visits and adjustments to therapy each month or at exacerbations SABA Administer when needed Administer when needed ICS No ICS and controlled No ICS added If sp-eos >2% add fluticasone 125 µg b.i.d. of equivalent, then treatment adjusted as for patients on ICS baseline. If sp-eos ≤2% no ICS is added On ICS and controlled Reduce ICS two-fold each visit until an exacerbation or fluticasone discontinued (after 125 µg·day−1) If sp-eos >2% increase ICS dose two–four-fold If sp-eos ≤2% reduce ICS two-fold each visit until sp-eos >2% or fluticasone discontinued (after 125 µg·day−1) When ICS reduction is followed by an exacerbation Increase ICS dose two–four-fold to regain control and return dose prior to deterioration, this is the MT If sp-eos >2% increase ICS dose two–four-fold# for 2 weeks then reduce to 2-fold above the previous dose, this is the MT If on no ICS and uncontrolled Add fluticasone 125 µg b.i.d. or equivalent. Treatment adjusted as for patients on ICS at baseline If sp-eos >2% add fluticasone 125 µg b.i.d. or equivalent. Then treatment adjusted as for patients with ICS at baseline. If sp-eos ≤2% increase bronchodilator treatment If on ICS and uncontrolled Increase ICS two–four-fold or add LABA or other treatments. When controlled treat as above for controlled asthma If sp-eos >2% increase ICS dose two–four-fold. When controlled treat as above for controlled asthma. If sp-eos ≤2% add LABA or other treatment Exacerbation Control with two–four-fold increase in dose# until controlled for 2 weeks then reduce to two-fold above exacerbation dose. An antibiotic can be added if purulent sputum If sp-eos >2% control with two–four-fold increase in dose¶ until controlled for 2 weeks then reduce to two-fold above exacerbation dose If sp-eos ≤2% add or increase LABA dose if the exacerbation is not severe or add antibiotic if cell count suggests bacterial infection Phase 2 visits and adjustments to therapy every 3 months and exacerbations Maintain minimum treatment+ Maintain minimum treatment§ Adjust treatment for exacerbations as in Phase 1 Adjust treatment for exacerbations as in Phase 1 or for sp-eos >2% as in Phase 1 CS: clinical stategy; SS Sputum strategy; SABA: short acting β2-agonist; ICS: inhaled corticosteroid; sp-eos: sputum eosinophils; MT maintenance therapy; LABA: long acting β2-agonist. #: if exacerbation is considered severe by investigator a course of prednisone can be given; ¶: If exacerbation is considered severe by investigator a course of prednisone can be given; +: maintenance could be readjusted if persistent clinical deterioration or if ICS dose was considered to be too high; §: maintenance could be readjusted if there was a persistent eosinophilia or if ICS dose was considered to be too high.
- Table 3—
Characteristics at maintenance visit according to asthma severity
Very mild to mild Moderate to severe CS SS CS SS Clinical parameters Subjects n 15 16 37 34 Symptoms score 6.0±0.8 5.8±0.9 5.8±0.9 6.3±0.8 Pre BD FEV1 95.0±12.2 90.0±11.6 76.2 ±15.7* 79.0±16.2* Asthma treatment On inhaled steroid 73.3 81.2 100* 100* On LABA 13.3 12.5 50.0* 47.1* On antileukotriene 6.7 0 8.1 17.6 On prednisone 0 0 0 2.9 Other asthma medication 0 0 5.4 2.9 On nasal steroid 20.0 25.0 40.5 32.4 Induced sputum Total cell count ×106·g−1# 3.0 (0.5–7.0) 3.9 (0.9–23.8) 4.3 (0.6–62.5) 3.1 (0.4–22.7) Neutrophils# 37.0 (4.0–72.0) 52.0 (5.0–94.5) 37.0 (5.0–94.5) 40.0 (2.0–96.8) Eosinophils# 3.0 (0–44.0) 1.0 (0–4.0) 0.7 (0–53.0) 0.6 (0–2.0) Eosinophilia ≥3% 53.3 6.7 33.3** 0** Data are presented as mean±sd (for continuous variables) or % (for dichotomous variables), unless otherwise specified. CS: clinical stategy; SS: sputum strategy; Pre: before use; BD: bronchodilator (salbutamol); FEV1: forced expiratory volume in one second; LABA: long acting β2-agonist; #: data presented as median (minimum–maximum); *: p-value <0.05 within strategy between severity groups; **: p-value <0.01 within strategy between severity groups.
- Table 4—
Relative risk between sputum strategy and clinical strategy from Cox regression models for the time to the first exacerbation and Andersen-Gill models for the multiple exacerbations during maintenance phase
Time to first exacerbation# Multiple event analysis¶ RR 95% CI p-value RR 95% CI p-value All exacerbations 0.61 (0.37–1.02) 0.06 0.71 (0.45–1.12) 0.14 By type of exacerbation Eosinophilic 0.19 (0.05–0.83) 0.03 0.28 (0.10–0.74) 0.01 Noneosinophilic 0.82 (0.44–1.53) 0.53 1.07 (0.61–1.85) 0.82 By use of LABA Not on LABA 0.84 (0.44–1.63) 0.61 1.05 (0.62–1.79) 0.85 On LABA 0.40 (0.18–0.88) 0.02 0.53 (0.24–1.14) 0.11 By asthma severity Very mild to mild 0.99 (0.34–2.81) 0.98 1.34 (0.52–3.46) 0.54 Moderate to severe 0.51 (0.29–0.90) 0.02 0.63 (0.38–1.03) 0.07 RR: relative risks; 95% CI; 95% confidence intervals; LABA: long-acting β2-agonists. #: RR is relative risk from a Cox regression model. ¶: RR is relative risk from an Anderson-Gill model. Asthma severity was based on minimum daily maintenance fluticasone equivalent dose, very mild: 0; mild: <250 µg; moderate: ≥250–500 µg; severe: >500 µg.
- Table 5—
Characteristics of exacerbations in Phase 2
Severe exacerbations Mild exacerbations CS SS p-value CS SS p-value Number n (%) 18 (22.9) 5 (10.6) 0.004 61 (77.1) 42 (89.4) 0.08 Symptoms score 3.5±0.4 3.9±0.9 NS 4.6±1.0 4.4±0.8 NS Pre BD FEV1 % pred 60.5±11.1) 63.8±19.4) NS 74.7±16.9 82.0±16.9 0.03 Occurrence by asthma severity Very mild to mild 1 (9.1) 0 NS 10 (90.9) 13 (100) NS Moderate to severe 17 (25.0) 5 (14.7) NS 51 (75.0) 29 (85.3) NS Data are presented as mean±sd or n (%), unless otherwise stated. CS: clinical strategy; SS: sputum strategy; Pre-BD FEV1 % pred: forced expiratory volume in one second expressed as per cent predicted before administrating bronchodilator (salbutamol).
Supplementary material
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