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(Chest. 1999;116:301-305.)
© 1999 American College of Chest Physicians

Serum Eosinophil Cationic Protein and Bronchial Responsiveness in Pediatric and Adolescent Asthma Patients*

Wilfried Gruber, MD; Ernst Eber, MD; Andreas Pfleger, MD; Manfred Modl, MD; Ingrid Meister, MD; Elisabeth Weinhandl and Maximilian S. Zach, MD

* From the Respiratory and Allergic Disease Division, Pediatric Department, University of Graz, Austria.

Correspondence to: Maximilian S. Zach, MD, Respiratory and Allergic Disease Division, Pediatric Department, University of Graz, Univ.-Klinik für Kinder- und Jugendheilkunde, Auenbruggerplatz 30, A-8036 Graz, Austria; e-mail: maximilian.zach{at}kfunigraz.ac.at


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Background: Serum eosinophil cationic protein (ECP) has been promoted as a marker of inflammatory activity in bronchial asthma. Bronchial responsiveness, measured either by inhaling pharmacologically active substances such as histamine or methacholine, or by applying physical stimuli such as the hyperventilation of cold dry air, is also considered to be an indirect marker of bronchial inflammation.

Objectives: In this study, we investigated the possible relationship between serum ECP and bronchial responsiveness to both cold dry air and histamine in presently symptom- and medication-free pediatric and adolescent asthma patients.

Subjects: Thirty-six children and adolescents with atopic asthma were studied.

Methods: On 2 consecutive days, bronchial responsiveness was assessed nonpharmacologically by cold dry air and pharmacologically by histamine in random order. Blood samples for determination of ECP were collected before each challenge.

Results: Serum ECP levels correlated with neither cold dry air-induced changes in FEV1 nor the provocation concentrations of histamine causing a 20% fall in FEV1. Subjects with bronchial hyperresponsiveness to cold dry air and histamine had somewhat higher levels of serum ECP than subjects with normal responses, but these differences were insignificant.

Conclusions: Our results indicate a lack of relationship both between serum ECP and bronchial responsiveness to cold dry air and between serum ECP and bronchial responsiveness to histamine.

Key Words: asthma • bronchial responsiveness • children • cold dry air challenge • eosinophil cationic protein • histamine provocation


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
In recent years, it has repeatedly been demonstrated that bronchial asthma is associated with an inflammation of the bronchial mucosa that is characterized by epithelial desquamation and infiltration with eosinophils.1 Activated eosinophils release several proteins from their granules, one of which is eosinophil cationic protein (ECP), which has been demonstrated to cause damage to the respiratory epithelium.2 ECP can be measured by a commercially available assay in sputum, BAL fluid, and blood. Blood measurements of ECP, which can be easily performed, could be a valuable diagnostic tool in the management of asthma, provided that ECP levels reflect the inflammatory activity in the bronchial mucosa.3

Bronchial hyperresponsiveness (BHR) is a consequence of bronchial inflammation; therefore, it could be used as an indirect marker of disease activity.4 Bronchial responsiveness (BR) can be measured by inhaling pharmacologically active substances, such as histamine or methacholine, or by applying physical stimuli, such as exercise or the hyperventilation of cold dry air. By evoking intermediate events such as the release of mediators from reactive cell systems in the mucosa, nonpharmacologic challenges might provide measurements of greater clinical relevance than pharmacologic ones.5 6 7 8 9 Cold dry air challenge (CACh) has the additional advantage of avoiding the problems of correcting an aerosol stimulus for size.9 This problem of correction for size has remained unresolved for aerosol challenges, thus jeopardizing the comparison of results over a wider range of ages and sizes.10

Many studies in pediatric and adult asthma patients examined the relationship between serum ECP and BR as markers of bronchial inflammation.11 12 13 14 15 16 17 18 19 20 Most of these studies were performed with pharmacologic challenges,11 13 14 15 16 17 18 19 20 whereas only two studies, which were conducted in adult asthma patients, used a nonpharmacologic stimulus for assessing BR.12 13 These investigations have produced differing results for both pediatric and adult asthma. So far, however, the relationship of serum ECP and BR that is assessed by a nonpharmacologic challenge has not been studied in pediatric and adolescent asthma patients.

In the present study, we therefore investigated the relationship of serum ECP to BR assessed nonpharmacologically by a CACh and compared this relationship with the one of serum ECP and BR assessed pharmacologically by a histamine challenge in symptom- and medication-free pediatric and adolescent asthma patients.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
For obtaining a statistically significant correlation between serum ECP levels and the results of bronchial challenge testing with a power of 80%, a minimum sample size of 28 patients was calculated. Thirty-six patients, 12 girls and 24 boys, with a mean ± SD age of 15.3 ± 2.3 years (range, 10.2 to 20.0 years) participated in this study. All subjects were recruited from the outpatient clinic of the local pediatric respiratory center and had to fulfill the following criteria: (1) a diagnosis of bronchial asthma on the basis of clinical criteria,21 (2) no asthma symptoms and no antiasthma medication for at least 1 year, (3) the presence of atopy, indicated by radioallergosorbent testing class > 2 to one or more common inhalant allergens, (4) no symptoms of a respiratory infection 4 weeks before the study, and (5) no signs of atopic dermatitis or of acute allergic rhinitis.

Serum ECP
Blood samples for the determination of ECP were collected using silicone-containing tubes (Vacutainer Hemogard SST tube; Becton Dickinson Vacutainer Systems Europe; Meylan, France). After a clotting time between 60 and 120 min at room temperature (20°C), the samples were centrifuged at 1350g for 10 min. After centrifugation, the sera were collected and recentrifuged to ensure that no remaining eosinophils were present in the samples. The sera were then frozen at -20°C and stored for analysis at the end of the study.

The serum concentrations of ECP were measured with a commercially available fluoroimmunoassay (CAP ECP FEIA; Pharmacia Diagnostics AB; Uppsala, Sweden).

CACh
CACh was performed in accordance with an established protocol.22 23 Cold dry air was produced by a commercially available heat exchanger (RHES; Jaeger; Wuerzburg, Germany). After the measurement of the prechallenge FEV1, subjects hyperventilated absolutely dry, -10°C air at 75% of their maximal voluntary ventilation for 4 min. Three minutes after termination of the challenge, FEV1 was measured again. The change in FEV1 ({Delta}FEV1) from the pre-CACh to the post-CACh measurement was expressed in percent baseline FEV1. For this method, a {Delta}FEV1 >= -9% defines BHR.22 24

Histamine Challenge
Histamine challenge was done according to the present Austrian standardization, which is based on the method of Cockcroft et al.25 As a tidal breathing method, this approach is identical to a later European standardization,26 with the exception of using a nebulizer with a higher output.

Briefly, each step of this multiple-step protocol consisted of a 2-min inhalation by quiet tidal breathing through a mouthpiece using a nose clip. The first aerosol, inhaled after the baseline measurement of FEV1, was the diluent, and this was followed at 5-min intervals by doubling concentrations of histamine from 0.03 to 8.0 mg/mL. FEV1 was measured before and at 30 s and 90 s after each inhalation. The test was discontinued when FEV1 had fallen by >= 20%, or after having gone through all concentrations of histamine. A dose-response curve was constructed by plotting the percentage fall in FEV1 against the concentration of histamine on a log scale. The result was expressed as the provocative concentration of histamine causing a 20% fall in FEV1 (PC20). From the output of the nebulizer used (Inhalierboy; Pari; Starnberg, Germany), a PC20 < 2 mg/mL defines BHR.

Study Protocol
The two different bronchial challenges were done in random order, between 9 AM and 11 AM, on 2 consecutive days. This 24-h interval was believed to be long enough to avoid refractoriness and to be short enough to minimize any spontaneous intraindividual variation of BR. Before the first challenge, a brief history was taken and a clinical examination was performed. Before each challenge, subjects rested for 1 h in a controlled climate (20°C, 40% relative humidity).

Ten minutes before each bronchial challenge, venous blood was drawn from a cubital vein for analysis of ECP. IgE levels and radioallergosorbent testing were determined from the blood sample taken before the first bronchial challenge.

Lung function testing was done on a pneumotachograph spirometer (MasterLab Pro; Jaeger) in accordance with standardized guidelines.27 FEV1 was expressed in absolute terms and in percent predicted as based on established reference standards.28 After each challenge, recovery of lung function was observed for 20 min; if by then the FEV1 had not returned to baseline, the patient was treated with nebulized salbutamol. Such treatment was also administered after the challenge when the patient subjectively felt any shortness of breath.

The study was approved by the Ethics Committee of the University of Graz. Informed consent for this investigation was obtained from both the patient and the parents.

Statistical Analysis
The least squares method was used to assess the correlation between (1) the levels of serum ECP and the responses to cold dry air and histamine, and (2) the responses to cold dry air and histamine. Comparisons of serum ECP levels between hyperreactive and normoreactive subjects were done by using one-way analysis of variance. Data were expressed as means ± SD. A p value <= 0.05 was taken as indicating statistical significance.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
In three subjects, a 20% fall of FEV1 could not be effected in the entire histamine challenge, and a PC20 could thus not be determined. These subjects were excluded from further analysis.

In the remaining 33 subjects, the baseline FEV1 measurements before CACh (99.9 ± 13.7% predicted; range, 73 to 133%) did not differ from those before histamine challenge (95.2 ± 11.9% predicted; range, 70 to 123%).

{Delta}FEV1 (CACh) was -14.3 ± 11.0% baseline (range, + 4 to -57%). The PC20 (histamine) was 1.69 ± 1.24 mg/mL (range, 0.05 to 4.60 mg/mL). The correlation of {Delta}FEV1 (CACh) to PC20 (histamine) was statistically significant (r = 0.388; p = 0.026).

The serum ECP levels before CACh (17.7 ± 13.0 µg/L; range, 4.28 to 62.6 µg/L) did not differ statistically from those before histamine challenge (16.7 ± 11.0 µg/L; range, 2.87 to 47.5 µg/L).

The correlations of serum ECP to {Delta}FEV1 (CACh) and to PC20 (histamine), respectively, are shown in Figure 1 . These correlations remained statistically insignificant.



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  		Figure 1. Relationships between serum ECP and bronchial responsiveness to cold dry air ({Delta}FEV1, top) and histamine (PC20, bottom).

 
The mean level of serum ECP was almost identical in those subjects with BHR to CACh (n = 22) and in those with a normal BR (17.8 ± 12.4 µg/L vs 17.4 ± 13.4 µg/L). Subjects with a hyperreactive response to histamine (n = 22) showed a tendency toward higher levels of serum ECP when compared with those with a normal response (17.9 ± 11.6 µg/L vs 14.2 ± 9.7 µg/L; p = 0.368), but this difference did not reach statistical significance.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study demonstrates (1) a lack of relationship between serum ECP levels and the responses to CACh and histamine provocations in pediatric and adolescent asthma patients, and (2) no difference between serum ECP levels of hyperreactive and normoreactive subjects.

Serum ECP levels observed in our study population of atopic symptom-free asthma patients were within the range reported by others for comparable groups.15 17 These levels are higher than those of normal subjects and those of children with allergic rhinitis.15 17

Several studies have evaluated the correlation between serum ECP levels and BR in adult asthma patients; most of these investigations used a pharmacologic stimulus for assessing BR.11 13 14 16 18 19 20 With one exception,11 these investigations showed a statistically weak relationship or none at all.13 14 16 18 19 20 Two other studies evaluated the relationship between serum ECP and pharmacologically measured BR in childhood asthma.15 17 One of these demonstrated a significant correlation between serum ECP and BR to methacholine in Dermatophagoides farinae-sensitized patients without symptoms, whereas such a correlation could not be found in those with asthma symptoms.17 The other study explored the relationship between serum ECP and BR to methacholine or histamine in symptomatic asthma, asymptomatic asthma, and allergic rhinitis.15 These authors found no differences between the serum ECP levels of these three groups and, in addition, no correlation between serum ECP level and BR. Their conclusions were (1) that serum ECP is a poor indicator of inflammatory activity in pediatric asthma, and (2) that it cannot differentiate bronchial from nasal inflammation.

In summary, this literature suggests that the results of pharmacologic challenges only correlate poorly or not at all with serum ECP levels in both adult and pediatric asthma patients. One explanation for these findings could be the type of challenge used in these studies. Both histamine and methacholine provocations use stimuli that effect a direct constriction of bronchial smooth muscles; thus, they might be an inaccurate marker of bronchial inflammation in asthma.7 It follows from these studies that a poor correlation between serum ECP measurements on the one hand, and pharmacologic BR measurements on the other, does not necessarily discredit serum ECP as a possible noninvasive marker of inflammatory activity in asthma.

In contrast to histamine and methacholine provocations, nonpharmacologic challenges use physical stimuli to provoke bronchoconstriction. By activating intermediate events, such as the release of bronchoreactive mediators from cells in the bronchial mucosa, they might provide measurements of greater clinical relevance than the inhalation of bronchoconstrictor substances.6 7 8 9 If both nonpharmacologically assessed BR and serum ECP were markers of bronchial inflammation in asthma, they should correlate when assessed in a patient population that covers a range of disease severity. So far, however, two studies in adult patients, both investigating this relationship between nonpharmacologically assessed BR and serum ECP, have produced contradictory results. One found a strong correlation between serum ECP levels and the maximal fall in peak flow after an exercise challenge in untreated asthma patients.12 Another investigation, however, did not find any relationship between the degree of BR to hypertonic saline and serum ECP levels in medication-free patients.13 This discrepancy is even more surprising, as both exercise-induced bronchoconstriction and inhalation of hypertonic saline are believed to share a common bronchoconstrictor stimulus, ie, hyperosmolarity of the periciliary fluid on the surface of the bronchial mucosa.29

The present study not only confirms lack of correlation between pharmacologically measured BR and serum ECP, but also contributes to the scarce literature on the relationship of serum ECP and the results of nonpharmacologic provocations. Our investigation is the first to use hyperventilation of cold and dry air as a stimulus to induce bronchoconstriction. CACh, when compared with other nonpharmacologic challenges, has the advantage of avoiding the complexity of correcting an aerosol stimulus for size, and thus may be considered an osmotic provocation of special accuracy.9 The present finding of lack of correlation between CACh-induced lung function changes and serum ECP levels can speculatively be interpreted in several ways. Serum ECP could be a poor marker, and nonpharmacologically assessed BR a much better marker, of bronchial inflammation in asthma. Alternatively, the reverse interpretation could fit the present findings equally well. BHR is usually associated with bronchial inflammation in asthma; thus, it could be an accurate marker or an only inaccurately related epiphenomenon of this inflammatory process. Third, both measurement of serum ECP and nonpharmacologic assessment of BR could produce results that are of little relevance for the activity of the inflammation process in the asthmatic airway. Ultimately, these questions will only be answered by correlating noninvasive marker candidates with the results of more-direct approaches to the bronchial mucosa such as biopsy and BAL.

To determine the value of ECP as a parameter of bronchial inflammation in asthma, measurements of the local, endobronchial release of ECP are of special interest. Such measurements in BAL fluid and in induced sputum demonstrated elevated concentrations of ECP in patients with asthma,19 20 30 31 32 33 and a correlation between local ECP levels and BR.21 The possible role of serum ECP as a marker of bronchial inflammation in asthma is less clear. Some authors found higher serum ECP levels in asthma patients than in healthy subjects,20 34 but others could not confirm these results.19 A further investigation found that a single measurement of serum ECP cannot discriminate between atopic children with and without asthma.35 These findings, together with the conflicting results of the studies comparing serum ECP and BR, suggest that serum ECP is not an accurate marker of bronchial inflammation in asthma; measurement of ECP in sputum and BAL fluid, however, is more likely to yield clinically relevant information with regard to the inflammatory processes.

In conclusion, the results of the present study indicate that the dimension of nonpharmacologically measured BR cannot be predicted by assessment of serum ECP. In addition, this study contributes to a growing body of evidence for lack of correlation between pharmacologically measured BR and serum ECP. The obtained results do not support the concept of serum ECP being an accurate marker of bronchial inflammation in asthma.


   Footnotes
 
Abbreviations: BHR = bronchial hyperresponsiveness; BR = bronchial responsiveness; CACh = cold dry air challenge; ECP = eosinophil cationic protein; {Delta}FEV1 = change in FEV1 before and after challenge; PC20 = provocation concentration of histamine causing a 20% fall in FEV1

Received for publication August 11, 1998. Accepted for publication February 24, 1999.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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