Eosinophils and eosinophilic cationic protein in induced sputum and blood: effects of budesonide and terbutaline treatment

doi:10.1016/S1081-1206(10)62087-X

Annals of Allergy, Asthma & Immunology

Volume 89, Issue 5, November 2002, Pages 492-497

https://doi.org/10.1016/S1081-1206(10)62087-X Get rights and content

Background

There is a need for easily measurable markers of airway inflammation to guide the use of anti-inflammatory treatment in asthma. Eosinophilic cationic protein (ECP) levels in sputum and blood correlate with clinical severity, and serial measurements of ECP have been proposed as a suitable candidate.

Aims and Methods

Our aim was to confirm that sputum and serum ECP measurements would provide a more sensitive indicator of responses to asthma treatment than eosinophil counts per se, in a randomized, placebo-controlled, crossover study of terbutaline, budesonide, and their combination in patients with chronic persistent asthma. We compared the changes in eosinophil counts and ECP in induced sputum and blood during each treatment period.

Results

Budesonide and combined treatment caused a significant reduction in sputum eosinophils (−2.7% and −2.3%, respectively, P < 0.05). Sputum eosinophils increased with terbutaline (+3.9%, P = 0.049). In contrast, the changes for sputum ECP were not significant. There was a similar treatment effect on blood eosinophils, but not for serum ECP. Correlations between sputum and blood eosinophils were significant with and without budesonide, but were nonsignificant between sputum and blood ECP during the active treatments. Correlations between sputum eosinophils and ECP, and between blood eosinophils and serum ECP were greatest during treatment with placebo or terbutaline alone: budesonide weakened or abolished these relationships.

Conclusions

Compared with eosinophil counts, ECP measurements in either induced sputum or serum failed to reflect treatment-related changes in chronic asthma. We conclude that ECP is not a sensitive or reliable means of evaluating airway inflammation, and can not be recommended for assessing responses to anti-inflammatory therapy.

REFERENCES (25)

P Venge
Monitoring of asthma inflammation by serum measurements of eosinophil cationic protein (ECP). A new clinical approach to asthma management
Respir Med
(1995)
E Pizzichini et al.
Measuring airway inflammation in asthma: eosinophils and eosinophilic cationic protein in induced sputum compared with peripheral blood
J Allergy Clin Immunol
(1997)
K Fujimoto et al.
Eosinophil cationic protein levels in induced sputum correlate with the severity of bronchial asthma
Chest
(1997)
DM Claman et al.
Analysis of induced sputum to examine the effects of prednisone on airway inflammation in asthmatic subjects
J Allergy Clin Immunol
(1994)
A Niimi et al.
Serum measurement of eosinophil cationic protein in the management of asthma
Curr Opin Pulm Med
(1999)
I Pin et al.
Use of induced sputum cell counts to investigate airway inflammation in asthma
Thorax
(1992)
JV Fahy et al.
Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects
Am Rev Respir Dis
(1993)
P Venge et al.
Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease
Clin Exp Allergy
(1999)
A Vatrella et al.
Serum eosinophil cationic protein (ECP) as a marker of disease activity and treatment efficacy in seasonal asthma
Allergy
(1996)
P Tarodo de la Fuente et al.
Eosinophilic inflammation assessed by induced sputum in corticoste-roid-dependent asthma
Respir Med
(1999)

MM Pizzichini et al.

Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment

Am J Respir Crit Care Med

(1997)

E Adelroth et al.

Inflammatory cells and eosinophilic activity in asthmatics investigated by bronchoalveolar lavage. The effects of anti-asthmatic treatment with budesonide or terbutaline

Am Rev Respir Dis

(1990)

Cited by (36)

Corticosteroid resistance in asthma: Cellular and molecular mechanisms
2022, Molecular Aspects of Medicine
Citation Excerpt :
In addition, beclomethasone dipropionate (500μg/twice for 4 weeks) decreased serum ECP levels in stable asthma patients compared to asthma patients treated with only inhaled salmeterol (100μg/die for 4 weeks) (Bacci et al., 2002). In contrast, there were no significant differences in serum ECP levels between asthma patients randomized to receive budesonide (400 μg twice), inhaled terbutaline (1000 μg 4/die), their combination or placebo for 6 weeks (Aldridge et al., 2002). Treatment with prednisolone (30mg/die for 7 days) decreased IL-8 protein release from PBMCs sampled from moderate/severe asthma patients and a further decrease of IL-8 protein release from PBMCs in mild asthma patients.
Inhaled glucocorticoids (GCs) are drugs widely used as treatment for asthma patients. They prevent the recruitment and activation of lung immune and inflammatory cells and, moreover, have profound effects on airway structural cells to reverse the effects of disease on airway inflammation. GCs bind to a specific receptor, the glucocorticoid receptor (GR), which is a member of the nuclear receptor superfamily and modulates pro- and anti-inflammatory gene transcription through a number of distinct and complementary mechanisms. Targets genes include many pro-inflammatory mediators such as chemokines, cytokines, growth factors and their receptors. Inhaled GCs are very effective for most asthma patients with little, if any, systemic side effects depending upon the dose. However, some patients show poor asthma control even after the administration of high doses of topical or even systemic GCs. Several mechanisms relating to inflammation have been considered to be responsible for the onset of the relative GC resistance observed in these patients. In these patients, the side-effect profile of GCs prevent continued use of high doses and new drugs are needed. Targeting the defective pathways associated with GC function in these patients may also reactivate GC responsiveness.
Diagnosing, Monitoring and Treating Asthma
2021, Encyclopedia of Respiratory Medicine, Second Edition
Asthma is the most common long term condition in childhood, yet the frequency with which it is diagnosed belies the complexity and heterogeneity of asthma and the challenges in management. Although most children respond well to low levels of inhaled steroids a significant proportion experience frequent attacks and symptoms which impact on their quality of life. Advances have been made in recent years in understanding the underlying pathobiology of childhood asthma, particularly in those with severe asthma, affording the opportunity for more effective targeted treatments. This article will discuss the important considerations in diagnosing childhood asthma, explore the underlying pathophysiology, describe phenotypes of asthma and how they can be used to direct treatment and finally discuss the key components of asthma monitoring.
Mild Asthma and Life-Threatening Exacerbations: Is it Time to Take Action?
2020, Archivos de Bronconeumologia
Corticosteroid Withdrawal-Induced Loss of Control in Mild to Moderate Asthma Is Independent of Classic Granulocyte Activation
2020, Chest
Citation Excerpt :
Likewise, ECP was not significantly different during loss of control, suggestive of limited or no degranulation and thus minimal activation of eosinophils. It has been suggested previously that compared with eosinophil counts, ECP levels do not adequately reflect airway inflammation in asthma, indicating that eosinophils and their activation (markers) are not necessarily complementary.25-27 However, in’t Veen et al20 found higher (delta) ECP levels following tapering of ICS compared with the fluticasone propionate group.
Loss of asthma control and asthma exacerbations are associated with increased sputum eosinophil counts. However, whether eosinophils, or the also present neutrophils, actively contribute to the accompanying inflammation has not been extensively investigated.
Twenty-three patients with mild to moderate asthma were included in a standardized prospective inhaled corticosteroid (ICS) withdrawal study; 22 of the patients experienced loss of asthma control. The study assessed various immune, inflammatory, and oxidative stress parameters, as well as markers of eosinophil and neutrophil activity, in exhaled breath condensate, plasma, and sputum collected at three phases (baseline, during loss of control, and following recovery).
Loss of asthma control was characterized by increased sputum eosinophils, whereas no differences were detected between the three phases for most inflammatory and oxidative stress responses. There were also no differences detected for markers of activated eosinophils (eosinophil cationic protein and bromotyrosine) and neutrophils (myeloperoxidase and chlorotyrosine). However, free eosinophilic granules and citrullinated histone H₃, suggestive of eosinophil cytolysis and potentially eosinophil extracellular trap formation, were enhanced. Baseline blood eosinophils and changes in asymmetric dimethylarginine (an inhibitor of nitric oxide synthase) in plasma were found to correlate with the decrease in FEV₁ percent predicted upon ICS withdrawal (both, r_s = 0.46; P = .03).
The clinical effect in mild to moderate asthma upon interruption of ICS therapy is not related to the classic inflammatory activation of eosinophils and neutrophils. It may, however, reflect another pathway underlying the onset of loss of disease control and asthma exacerbations.
The Netherlands Trial Register; No.: NTR3316; URL: trialregister.nl/trial/3172.
The utility of sputum eosinophils and exhaled nitric oxide for monitoring asthma control with special attention to childhood asthma
2010, Allergologia et Immunopathologia
The monitoring of sputum eosinophils has received certain attention as a tool for improving asthma management both in children and in adults. The present paper reviews the technique and also the usefulness of induced sputum in the diagnosis and assessment of asthma, together with its ability to predict the response to treatment and to anticipate asthma exacerbations. Special attention is addressed to childhood asthma. The authors conclude that due to cost-effectiveness reasons derived from high labour costs, together with the unpleasantness of the technique and the failure to obtain adequate samples in a non-negligible percentage of children, this technique should be only used for research purposes.
Bromotyrosines in sputum proteins and treatment effects of terbutaline and budesonide in asthma
2009, Annals of Allergy, Asthma and Immunology
Citation Excerpt :
Aldridge et al7 previously showed in individuals with mild to moderate atopic asthma that whereas eosinophil numbers decrease in response to corticosteroid treatment alone and combined with a β2-agonist, ECP levels did not. They concluded from these results that they could not recommend ECP as an adjunct or alternative to sputum or blood eosinophil counts for assessing responses to drug therapy in asthma.7 Eosinophil activation is accompanied by the release of granular proteins and the generation of reactive oxygen species, including superoxide and hydrogen peroxide.8
Inhaled corticosteroids are widely used in the treatment of persistent asthma, usually combined with inhaled β₂-agonists. Previous research suggests that short-acting β₂-agonists (SABAs) may downregulate the anti-inflammatory effects of inhaled corticosteroids, thereby increasing asthma morbidity.
To determine whether 3-bromotyrosine and 3,5-dibromotyrosine levels, specific markers of eosinophil activation, reflect treatment effects on airway inflammation of inhaled corticosteroids and SABAs and support previous conclusions.
Levels of 3-bromotyrosine and 3,5-dibromotyrosine were measured in sputum supernatants using stable isotope dilution gas chromatography-mass spectrometry in a randomized, placebo-controlled, crossover study of treatment with terbutaline, budesonide, and their combination in patients with persistent asthma. Thirty-four individuals were randomized, and 28 completed the study.
Treatment with budesonide lowered median 3-bromotyrosine levels compared with treatment with placebo, terbutaline, and budesonide-terbutaline (0.24 vs 0.64, 0.62, and 0.43 3-bromotyosine/tyrosine [mmol/mol]; P < .05) and lowered median 3,5-dibromotyrosine levels compared with placebo and terbutaline treatments (0.04 vs 0.11 and 0.07 3,5-dibromotyrosine/tyrosine [mmol/mol], P < .05). Unlike eosinophil numbers, 3-bromotyrosine and 3,5-dibromotyrosine levels did not increase with terbutaline treatment compared with placebo treatment but were significantly raised when terbutaline was added to budesonide treatment. 3-Bromotyrosine levels correlated significantly with eosinophil cationic protein levels in all groups.
3-Bromotyrosine and 3,5-dibromotyrosine levels reflect treatment effects in asthma and support previous findings that SABAs impair the anti-inflammatory effects of inhaled corticosteroids. In addition to eosinophil numbers and eosinophil cationic protein levels, these modified tyrosine residues provide useful information about the inflammatory state of the airways.

View all citing articles on Scopus

View full text

ORIGINAL ARTICLESEosinophils and eosinophilic cationic protein in induced sputum and blood: effects of budesonide and terbutaline treatment

Background

Aims and Methods

Results

Conclusions

Respir Med

J Allergy Clin Immunol

Chest

J Allergy Clin Immunol

Serum measurement of eosinophil cationic protein in the management of asthma

Curr Opin Pulm Med

Use of induced sputum cell counts to investigate airway inflammation in asthma

Thorax

Cellular and biochemical analysis of induced sputum from asthmatic and from healthy subjects

Am Rev Respir Dis

Eosinophil cationic protein (ECP): molecular and biological properties and the use of ECP as a marker of eosinophil activation in disease

Clin Exp Allergy

Serum eosinophil cationic protein (ECP) as a marker of disease activity and treatment efficacy in seasonal asthma

Allergy

Eosinophilic inflammation assessed by induced sputum in corticoste-roid-dependent asthma

Respir Med

Sputum in severe exacerbations of asthma: kinetics of inflammatory indices after prednisone treatment

Am J Respir Crit Care Med

Inflammatory cells and eosinophilic activity in asthmatics investigated by bronchoalveolar lavage. The effects of anti-asthmatic treatment with budesonide or terbutaline

Am Rev Respir Dis

ORIGINAL ARTICLES
Eosinophils and eosinophilic cationic protein in induced sputum and blood: effects of budesonide and terbutaline treatment