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Importance of concomitant local and systemic eosinophilia in uncontrolled asthma

Florence Nicole Schleich, Anne Chevremont, Virginie Paulus, Monique Henket, Maité Manise, Laurence Seidel, Renaud Louis
European Respiratory Journal 2014 44: 97-108; DOI: 10.1183/09031936.00201813
Florence Nicole Schleich
13, Liege
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  • For correspondence: fschleich@chu.ulg.ac.be
Anne Chevremont
13, Liege
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Virginie Paulus
13, Liege
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Monique Henket
13, Liege
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Maité Manise
13, Liege
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Laurence Seidel
2Medical Informatics and Biostatistics, University of Liege, Liege, Belgium
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Renaud Louis
13, Liege
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  • Figure 1–
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    Figure 1–

    Demographic, functional and inflammatory characteristics of patients according to their local and systemic eosinophil count. FEV1: forced expiratory volume in 1 s; FVC; forced vital capacity; BHR: bronchial hyperresponsiveness; FeNO: exhaled nitric oxide fraction; QoL: quality of life.

  • Figure 2–
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    Figure 2–

    Asthma Control Questionnaire (ACQ) score according blood and sputum eosinophil count. The presence of both local and systemic eosinophilic inflammation was associated with lower asthma control in the a) retrospective (n=508) and b) prospective cohort (n=250). Data are presented as mean±sem.

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    Figure 3–

    Exhaled nitric oxide fraction (FeNO) levels in patients classified according to the presence and/or absence of blood and sputum eosinophilia. Patients exhibiting both local and systemic inflammation had the highest level of FeNO (n=508). The presence of uncontrolled eosinophilic inflammation either at local or systemic level was associated with intermediate levels of FeNO. The group of asthmatics showing no increase in eosinophilic inflammation had the lowest level of FeNO. Data are presented as mean±sem.

  • Figure 4–
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    Figure 4–

    Correlation between Asthma Control Questionnaire (ACQ) score and a) sputum and b) blood eosinophil count when combining the prospective and retrospective cohorts (n=758). Asthma is considered uncontrolled if the ACQ score is >1.5.

Tables

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  • Table 1– Demographic, control and treatment characteristics for the whole population
    CharacteristicsRetrospective cohortProspective cohort
    Subjects n508250
    Males/females n201/30799/151
    Age years52 (19–88)50 (16–85)
    Age of onset
     <12 years2422
     12–40 years3736
     ≥40 years3942
    Height cm167±9168±9
    Weight kg74±1673±17
    Atopy yes/no (%)296/212 (58)148/102 (59)
    Current smokers101 (20)55 (22)
     Exposure pack-years22 (0.5–60)25 (2–60)
    Ex-smokers99 (19)38 (15)
     Exposure pack-years15 (0.5–90)17 (0.5–63)
    Bronchiectasis19ƒ17
    Gastro-oesophageal reflux7971*
    Nasal polyposis22##27
    Sinusitis42##41
    Rhinitis5856
    Exacerbations per patient per year#0.68±1.50¶¶0.86±2.02++
    LABA319 (63)141 (56)
    LTRA93 (18)50 (20)
    Theophylline16 (3)11 (4)
    ICS
     Steroid naïve153 (30)82 (33)
     Low dose¶73 (14)35 (14)
     Moderate dose+138 (27)63 (25)
     High dose§144 (28)70 (28)
    Oral corticosteroids32 (6)25 (10)
    • Data are presented as median (range), %, mean±sd or n (%), unless otherwise stated. Exacerbations were evaluated during the year prior to the visit. LABA: long-acting β2-agonist; LTRA: leukotriene receptor antagonist; ICS: Inhaled corticosteroids. High dose: >1000 μg·day−1 beclomethasone. #: during the year prior to the visit; ¶: ≤500 μg per day beclomethasone; +: 500–1000 μg per day beclomethasone; §: >1000 μg per day beclomethasone; ƒ: n=174; ##: n=273; ¶¶: n=428; ++: n=237. *: p<0.05.

  • Table 2– Functional and inflammatory characteristics for the whole population
    CharacteristicsRetrospective cohortProspective cohort
    FEV1 % predicted84±1982±21
    FEV1/FVC %73±1171±15*
    PC20 mg·mL−1 geometric mean (range)3.20 (0.025–16)2.92 (0.05–16)
    Reversibility %11±149±10
    ACQ score2.01±1.382.00±1.25
    AQLQ score4.61±1.354.46±1.39
    Blood eosinophil count cells per mm3230 (0–3220)188 (0–1133)*
    FeNO ppb27 (0–247)25 (4–348)
    Sputum eosinophils %2 (0–94)2.8 (0–90)
    Sputum neutrophils %45 (0–100)49 (0–100)
    • Data are presented as mean±sd or median (range), unless otherwise stated. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; PC20: provocative concentration of methacholine causing a 20% fall in FEV1; ACQ: Asthma Control Questionnaire; AQLQ: Asthma Quality of Life Questionnaire; FeNO: exhaled nitric oxide fraction. *: p<0.05.

  • Table 3– Retrospective cohort: demographic and treatment characteristics of asthmatics (n=508) according to blood and sputum eosinophil count
    Blood eosinophils <400 cells per mm3, sputum eosinophils <3%#Blood eosinophils <400 cells per mm3, sputum eosinophils ≥3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils <3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils ≥3%
    Subjects249 (49)128 (25)34 (7)97 (19)
    Males/females n78/17154/74*16/1853/44***
    Age years52 (21–86)53 (21–88)51 (21–85)51 (19–86)
    Age of onset
     <12 years22.627.626.523.3
     12–40 years34.536.232.345.6
     ≥40 years42.936.241.231.1
    Height cm166±9168±9169±9169±9
    Weight kg73±1674±1576±1775±17
    BMI kg·m−226.3±526.4±526.3±4.826.4±5.3
    Atopy yes/no (%)126/123 (51)82/46 (64)*22/12 (65)66/31 (68)**
    Current smokers54 (22)29 (23)6 (18)12 (12)*
    Bronchiectasis¶,+19131726
    Gastro-oesophageal reflux77818677
    Nasal polyposis§925***37***43***
    Sinusitis§,ƒ34384261***
    Rhinitis53597265
    Exacerbations per patient per year##0.42±0.90.93±2.72*0.59±0.981.5±2.5***
    ICS
     Steroid naïve82 (33)31 (24)9 (26)31 (32)
     Low dose¶¶30 (12)20 (16)5 (15)18 (19)
     Moderate++70 (28)37 (29)11 (32)20 (21)
     High dose§§67 (27)40 (31)*9 (26)28 (29)
    • Data are presented as n (%), median (range), % or mean±sd, unless otherwise stated. BMI: body mass index; ICS: inhaled corticosteroids. #: comparator group; ¶: n=174; +: based on chest computed tomography (CT); §: based on sinus CT and nasal endoscopy; ƒ: n=273; ##: during the year prior to the visit; ¶¶: ≤500 μg per day beclomethasone; ++: 500–1000 μg per day beclomethasone; §§: >1000 μg per day beclomethasone. *: p<0.05; **: p<0.01; ***: p<0.001.

  • Table 4– Retrospective cohort: functional characteristics, asthma control and quality of life of asthmatics (n=508) according to blood and sputum eosinophil count
    Blood eosinophils <400 cells per mm3, sputum eosinophils <3%#Blood eosinophils <400 cells per mm3, sputum eosinophils ≥3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils <3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils ≥3%
    FEV1 % predicted87±1983±20*84±2375±19***
    FEV1/FVC %75±1072±9*77±1071±10***
    TLC % predicted101±16101±2092±21103±15
    FRC % predicted109±29108±2097±30101±18
    KCO % predicted89±1992±2099±14**94±26*
    PC20 mg·mL−1 geometric mean (range)3.99 (0.05–16)2.32 (0.025–16)*4.53 (0.05–16)1.49 (0.05–16)**
    Reversibility %8±913±14*9±1217±16***
    ACQ score1.88±1.391.87±1.191.98±1.52.54±1.45***
     <0.7558 (23)26 (20)7 (21)10 (10)**
     0.75–1.545 (18)30 (23)10 (29)15 (15)
     >1.5146 (59)72 (56)17 (50)72 (74)*
    AQLQ score4.67±1.364.84±1.34.47±1.264.3±1.4*
    • Data are presented as mean±sd or n (%), unless otherwise stated. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; TLC: total lung capacity; FRC: functional residual capacity; KCO: transfer coefficient of the lung for carbon monoxide; PC20: provocative concentration of methacholine causing a 20% fall in FEV1; ACQ: Asthma Control Questionnaire; AQLQ: Asthma Quality of Life Questionnaire. #: comparator group. *: p<0.05; **: p<0.01; ***: p<0.001.

  • Table 5– Retrospective cohort: inflammatory characteristics of asthmatics (n=508) according to blood and sputum eosinophil count
    Blood eosinophils <400 cells per mm3, sputum eosinophils <3%#Blood eosinophils <400 cells per mm3, sputum eosinophils ≥3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils <3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils ≥3%
    IgE kU·L−187 (1–7338)211 (3–6785)***180 (13–2329)*225 (1–17183)***
    Blood eosinophils %1.7 (0–5.4)3.2 (0–7)***6 (0.3–15)***8 (0.4–30)***
    Blood eosinophils per mm3140 (0–380)250 (0–390)***490 (400–1220)***590 (400–3220)***
    Blood neutrophils %59 (27–82)57 (34–91)57 (41–76)52 (32–67)***
    Blood neutrophils per mm34180 (76–11 080)4370 (2290–15 410)5040 (1760–10 010)3965 (1820–8670)
    Sputum eosinophils %0.3 (0–2.9)9 (3–79)***0.6 (0–2.8)26 (3.2–94)***
    Sputum eosinophils per mm32.7 (0–1020)70 (6–5226)***4.8 (0–1796)287 (5–33 375)***
    Sputum neutrophils %58 (0–100)39 (0–90)***57 (0.2–99)30 (0.2–91)***
    Sputum neutrophils per mm3422 (0–73 440)334 (1–9588)560 (14–160 974)259 (1–15 441)
    Fibrinogen g·L−13.2 (1.9–10)3 (2–6)3.3 (2.6–5)3.4 (2.2–7)
    CRP mg·L−11.7 (0.2–10)2 (0.2–14)1.4 (0.5–4)1.6 (0.2–13)
    FeNO ppb17 (0–192)37 (2–222)***32 (5–93)**77 (11–247)***
    • Data are presented as median (range). CRP: C-reactive protein; FeNO: exhaled nitric oxide. #: comparator group. *: p<0.05; **: p<0.01; ***: p<0.001.

  • Table 6– Retrospective cohort: demographic, functional and inflammatory characteristics of patients receiving high doses of corticosteroids (n=144)
    Blood eosinophils <400 cells per mm3, sputum eosinophils <3%#Blood eosinophils <400 cells per mm3, sputum eosinophils ≥3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils <3%Blood eosinophils ≥400 cells per mm3, sputum eosinophils ≥3%
    Subject n (%)67 (47)40 (28)9 (6)28 (19)
    Males/females n20/4716/245/415/13
    Age years52 (21–86)59 (26–88)62 (44–85)52 (29–86)
    Age of onset %
     <12 years2535030
     12–40 years33305040
     ≥40 years42355030
    Exacerbations per patient per year¶0.76±1.060.95±1.291.25±1.173.52±5.00***
    FEV1 % predicted77±1777±2071±2865±18**
    FEV1/FVC %73±1168±1370±1164±9**
    ACQ score2.57±1.961.97±1.253.19±1.793.18±1.38
    AQLQ score4.11±1.394.52±1.403.59±1.473.50±1.31
    FeNO ppb14 (4–114)30 (8–119)***10 (5–58)55 (11–139)***
    Blood eosinophils per mm3160 (10–350)225 (0–390)***465 (400–1030)***615 (400–3220)***
    Sputum eosinophils %0.25 (0–2.6)8.4 (3–52.2)***0.4 (0–2.7)22.3 (3.6–94.4)***
    • Data are presented as median (range) or mean±sd, unless otherwise stated. FEV1: forced expiratory volume in 1 s; FVC: forced vital capacity; ACQ: Asthma Control Questionnaire; AQLQ: Asthma Quality of Life Questionnaire; FeNO: exhaled nitric oxide fraction. #: comparator group; ¶: during the year prior to the visit. *: p<0.05; **: p<0.01; ***: p<0.001.

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    • Prospective cohort - Asthma control and exacerbation rate in asthmatics classified according to blood and sputum eosinophil count
  • ERJ Podcast

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    Interviewee: Renaud Louis, Dept of Pulmonary Medicine, CHU Sart-Tilman, Liege, I3GIGA Research Group, University of Liege, Liege, Belgium

    Articles discussed:

    • Kostikas K, Zervas E, Gaga M. Airway and systemic eosinophilia in asthma: does site matter? Eur Respir J 2014; 44: 14-16. Full Text
    • Schleich FN, Chevremont A, Paulus V, et al. Importance of concomitant local and systemic eosinophilia in uncontrolled asthma. Eur Respir J 2014; 44: 97-108. Full Text
    • Ortega H, Chupp G, Bardin P, et al. The role of mepolizumab in atopic and nonatopic severe asthma with persistent eosinophilia. Eur Respir J 2014; 44: 239-241. Full Text

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Importance of concomitant local and systemic eosinophilia in uncontrolled asthma
Florence Nicole Schleich, Anne Chevremont, Virginie Paulus, Monique Henket, Maité Manise, Laurence Seidel, Renaud Louis
European Respiratory Journal Jul 2014, 44 (1) 97-108; DOI: 10.1183/09031936.00201813

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Importance of concomitant local and systemic eosinophilia in uncontrolled asthma
Florence Nicole Schleich, Anne Chevremont, Virginie Paulus, Monique Henket, Maité Manise, Laurence Seidel, Renaud Louis
European Respiratory Journal Jul 2014, 44 (1) 97-108; DOI: 10.1183/09031936.00201813
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