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Increased Interleukin-4 and Decreased Interferon- in Exhaled Breath Condensate of Children with Asthma

Department of Thoracic Medicine, National Heart and Lung Institute, and Department of Pediatrics, Royal Brompton Hospital, London, United Kingdom

Correspondence and requests for reprints should be addressed to Peter J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Dovehouse Street, London SW3 6PY, UK. E-mail: p.j.barnes{at}ic.ac.uk

	ABSTRACT

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Exhaled breath condensate analysis for noninvasive quantification of airway inflammation in asthma is a potentially useful research tool in children. There is an imbalance between T-helper (Th)-2 cells, which secrete interleukin (IL)-4, and Th1 cells, which secrete interferon (IFN)-, in asthma. We measured concentrations of IL-4 and IFN- in breath condensates of 37 children (11 normal, 12 steroid-naive, and 14 steroid-treated children with asthma). Exhaled IFN- was significantly lower in steroid-naive and steroid-treated children with asthma compared with normal control subjects (3.7 ± 0.2 versus 5.1 ± 0.4 pg/ml, p < 0.01 and 4.1 versus 5.1 pg/ml, p < 0.05). By contrast, mean exhaled IL-4 was elevated in asthma (53.7 ± 4.2 pg/ml) compared with normal children (35.7 ± 6.2 pg/ml, p < 0.05) and concentrations were lower with steroid treatment (37.5 ± 5.6 pg/ml, p < 0.05). Exhaled IL-4 was significantly lower in children with asthma on more than 600 µg inhaled steroid/day. The IL-4/IFN- ratio was significantly greater in children with asthma compared with control children and the children with asthma on inhaled steroid therapy. We have shown for the first time that IFN- and IL-4 can be assayed in exhaled breath condensate and shows an increased ratio of IL-4/IFN-, consistent with predominance of Th2 cells in airways of children with asthma. Exhaled breath condensate analysis may have a useful role in studying allergic inflammation in childhood asthma.

Key Words: asthma • exhaled breath condensate • interferon- • interleukin-4 • Th2 cells

	INTRODUCTION

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Childhood asthma is a growing global health problem, giving rise to significant morbidity, mortality, school absenteeism, emergency hospital visits, and is an increasing strain on national health care costs (1, 2). Objective monitoring of airway inflammation in this chronic disorder may be important in titrating the dose of inhaled steroids for optimal control of asthma with minimal systemic effects. There is no single noninvasive test that reliably quantifies airway inflammation. Bronchial biopsies are invasive and unsuitable for monitoring inflammation in children, whereas induced sputum is only possible in older children and is labor intensive. For these reasons, diagnosis and monitoring of asthma in children continues to be largely based on clinical judgment.

Several inflammatory mediators with molecular weight less than 65 kD are known to be exhaled out with the expired water vapor in normal individuals or those with asthma. Measurement of these markers of inflammation in exhaled breath condensate is a novel, noninvasive research tool that is being increasingly used (3, 4). It is simple to perform, noninvasive, rapid, and effort independent, and gives objective values. It may therefore be a better monitoring device for quantifying inflammation in children with asthma. Leukotrienes, prostaglandins, hydrogen peroxide, nitrotyrosine and 8-isoprostane have all been measured in this exhaled breath condensate, but there are few studies in children and the number of mediators so far reported is limited (4).

Invasive studies involving bronchoalveolar lavage (BAL) fluid and lung biopsies have confirmed that a T helper (Th)-2–like mediated immune response is seen in asthma (5–7). There is elevation of interleukin (IL)-4 and depression of interferon (IFN)- in the airway and blood of subjects with asthma (8–12). This imbalance in production of these two cytokines is also seen in children with atopic asthma, and corticosteroids appear to correct it (13, 14). We hypothesized that this imbalance in airways may be reflected in the exhaled breath condensate. It may be possible to noninvasively quantify this ongoing Th2 response in the airways, and this may guide therapy. We therefore determined whether IFN- and IL-4 could be assayed in the exhaled breath condensate of children and studied the concentrations in normal children and those with asthma who were untreated or treated with inhaled corticosteroids.

	METHODS

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Study Population
We studied normal or children with asthma 2–18 years of age who were able to cooperate with the test. Children who had wheeze due to concomitant nonasthmatic chronic airway diseases like cystic fibrosis or patients with asthma who had suffered an exacerbation within a month of the study period were excluded from the study. Children with asthma were recruited from the Pediatric Outpatients Clinics of Royal Brompton Hospital. Normal age-matched control subjects were recruited from a local church or from hospital staff relatives. We obtained approval for the study from the Ethics Committee of the Royal Brompton Hospital and Harefield NHS Trust, and the children's parents or guardians gave informed consent.

Study Design
A detailed history was taken and physical examination performed on each child. Weight and height were recorded. Asthma was diagnosed when the child had episodic cough, breathlessness, and wheeze responsive to bronchodilators with or without steroids (15). The children with asthma not on inhaled steroids were included in the steroid-naive group; whereas those on inhaled steroids were subdivided into a low-dose steroid group ( 600 µg/day of beclomethasone dipropionate [BDP] or equivalent) and a high-dose steroid group (> 600 µg/day).

Each child had an allergy skin-prick test to four common aeroallergens (house dust mite, grass pollen, Aspergillus fumigatus, and cat fur; ALK Abelló, Hørsholm, Denmark). Measurement of exhaled nitric oxide (NO) and spirometry were then performed. Exhaled NO was measured using a chemilumiscence analyzer (NiOx, Aerocrine, Sweden), according to the Americn Thoracic Society guidelines (16). Lung function was measured by dry spirometer (Vitalograph, Buckingham, UK). This was followed by exhaled breath condensate collection.

Exhaled Breath Condensate Analysis
Subjects breathed tidally for 10 minutes, using a nose-clip, into the special chamber of a condenser (Ecoscreen, Jaeger, Hoechberg, Germany), which froze the exhaled water vapor to -20° C. The collected condensate was melted and aliquots of 110 µl stored in small plastic tubes at -80° C. The mean volume collected was 0.6 (range 0.2–1.0) ml.

Biochemical Assays
IFN- was assayed using a chemiluminescent enzyme immunoassay (EIA) in a 96-well plate (Pierce Endogen, Rockford, IL), with a detection limit of 0.5 pg/ml. IL-4 was assayed by specific enzyme-linked immunosorbent assay (ELISA) (Cayman, Ann Arbor, MI), with a detection limit of 20 pg/ml. The intra-and interassay coefficients of variation of the kits were 10% or less and every sample was assayed in duplicate. For the IFN- assay, two standard curves were prepared; one using the sample diluent and the other with distilled water. As the difference in relative light units (RLU) of corresponding points of these two standard curves was more than 10%, the standard curve obtained using distilled water was used for calculation of results (as per manufacturer's directions).

Data Analysis
All data are expressed as means ± SEM. Comparison of demographic data was done by a chi-square test. Continuous data of two subgroups were tested for significant difference by unpaired Student's t test for normally distributed data. Correlations were studied by Pearson's correlation test in case of normally distributed data. Significance was considered when p value was less than 0.05 (17).

	RESULTS

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Clinical Characteristics
Thirty-seven children were enrolled into the study, with an age range of 4.5–17 years, with mean of 10.8 years. There were 11 normal control subjects, 12 steroid-naive children with asthma and 14 children with asthma on regular inhaled corticosteroids (Table 1). There was no significant difference in the age and sex of the children recruited in the three groups. The children were from the following ethnic groups: white (15), Philippino (11), Chinese (8), Indian (2), and African (1). Twenty-five of the total children studied were atopic. Twenty-one of 25 children were skin-prick test positive to grass pollen (6 were positive only to grass pollen), 17 had reactivity to the house dust mite extract (4 alone), and 8 showed positive reaction to cat dander (1 singly). Sensitivity to A. fumigatus was seen in only one child of the steroid-naive group who was also reactive to grass pollen and house dust mite. Atopic dermatitis was present in 7 children. There were 11 mild intermittent and 1 child with moderate persistent asthma in the steroid-naive group when graded according to the Global Initiative on Asthma (GINA) guidelines (18). In the steroid-treated group, the mean inhaled steroid dose was 749 µg/day with a range of 100–3000 µg/day of inhaled BDP or equivalent. Nine of the children in the steroid-treated group were on 600 µg/day or less (low-dose steroid group) and 5 on more than 600 µg/day (high-dose steroid group).

View this table: [in this window] [in a new window]   TABLE 1. Clinical characteristics of the study populations

Exhaled IFN-
IFN- was detected in breath condensate in all subjects. Mean exhaled IFN- was significantly lower in steroid-naive children with asthma (3.7 ± 0.2 pg/ml) compared with normal control subjects (5.1 ± 0.4 pg/ml; p < 0.01). Mean IFN- concentrations were higher in the steroid-treated children with asthma compared with steroid-naive subjects (4.1 ± 0.3 versus 3.7 ± 0.2 pg/ml), but this was not significant (Figure 1A) . IFN- concentrations did not correlate with the dose of inhaled steroids (r = -0.14, p = NS) (Figure 1A).

View larger version (18K): [in this window] [in a new window]   Figure 1. Mean interferon- (IFN-, A), interleukin-4 (IL-4, B), and IL-4/IFN- ratio (C) in exhaled breath in normal children, and those with asthma who were steroid-naive and steroid treated. ICS = inhaled corticosteroids, NS = nonsignificant.

IL-4/IFN- Ratio
The mean IL-4/IFN- ratio was significantly higher in children with asthma who were not on inhaled steroids compared with that in normal children or steroid-treated children with asthma (14.9 ± 1.3 versus 8.4 ± 1.6, p < 0.01, and 14.9 ± 1.3 versus 10.3 ± 1.7, p < 0.05, respectively) (Figure 1C).

Correlations
Exhaled NO had a weak negative correlation with exhaled IFN- (r = -0.36, p < 0.05), but not with exhaled IL-4. Forced expiratory volume in 1 second (FEV₁) did not show any correlation with either exhaled NO, exhaled IFN-, or IL-4. Exhaled IL-4 and IFN- concentrations showed no correlation (r = 0.04).

Atopy and Exhaled Cytokines
The concentrations of exhaled cytokines in atopic and non-atopic normal children and those with asthma is depicted in Figure 2 and shows no relation between the concentrations of IFN- and IL-4, and atopic status.

View larger version (18K): [in this window] [in a new window]   Figure 2. Mean IFN- (A), IL-4 (B), and IL-4/IFN- ratio (C) in exhaled breath in nonatopic and atopic children of normal, steroid-naive, and steroid-treated groups with asthma.

	DISCUSSION

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The measurement of IFN- and IL-4 in the exhaled breath condensate in normal children and those with asthma was by ELISA. IFN- was in the detectable range in all, whereas IL-4 was above the detectable range in over 90% of subjects. There was a decrease of IFN- and increase in IL-4, with a consequent increase in IL-4/IFN- ratio, in the exhaled breath condensate of children with asthma. Hence the Th2 immune response described in asthma is mirrored in the exhaled breath condensate of these children. There was a weak correlation between exhaled IFN- and exhaled NO, but no correlation between IL-4 and exhaled NO or between either cytokine and FEV₁. We have not compared the concentrations of these two inflammatory markers with direct measures of airway inflammation, such as BAL fluid, as these investigations are difficult in young children.

We detected IFN- in exhaled breath in all the samples. The mean concentration of exhaled IFN- was significantly lower in steroid-naive children with asthma compared with the values in healthy children. This is consistent with the study of Walker and coworkers who reported BAL concentrations of IFN- that were lower and IL-4 higher in allergic adult patients with asthma (7). The mean concentrations of IL-4 and IFN- in the BAL fluid in their study ranged from less than 10–36.1 and 6.4–10.1 pg/ml, respectively. These are almost comparable to those in the exhaled breath condensate in our study. These authors concentrated the BAL fluid 18–20 times before IFN- and IL-4 could be measured, however. In our study, we were able to measure these cytokines in exhaled breath of children without the need for concentration. BAL causes a dilution of at least 200 times, which is a disadvantage, as the dilution factor may vary according to the amount off saline used and the recovery efficiency. In this respect, exhaled breath condensate has an important advantage over BAL and may be a better approach to the measurement of inflammatory mediators in asthmatic airways. The elevated IL-4/IFN- ratio seen in children with asthma in our study has also been reported by others (7, 19). The steroid-naive children with asthma enrolled in our study had mostly mild asthma and the raised IL-4 and decreased IFN- suggests the presence of inflammation and the need for anti-inflammatory therapy (20). If subjects with asthma of greater severity on no inhaled steroids were also enrolled in the study, the difference in the concentrations between subjects with asthma and normal subjects may have been even greater. Both atopy and asthma are associated with low IFN- and high IL-4 concentrations (12, 21). Hence the presence of more atopic children in the steroid-naive group with asthma could have confounded the results. This is also the case in the normal children in whom the mean exhaled IL-4 tended to be lower in the non-atopic group, although this was not significant. Similarly in the group with asthma, there was no difference between the atopic and non-atopic children, although the numbers of non-atopic children were low. It would be useful to see what the concentrations of these cytokines would be in non-atopic steroid-naive children with asthma of varying severity and non-atopic normal control subjects.

In our study, inhaled steroid treatment was associated with a significant decrease in IL-4 and an elevation in IFN- concentrations in exhaled condensate. The children with asthma who were on high-dose steroids had greater suppression of exhaled IL-4 compared with those on low-dose steroids. Previous studies have shown that steroids inhibit both IL-4 and IFN- synthesis, but that the inhibitory action on IFN- is less marked (14). Also IL-4 and IFN- exhibit mutual inhibition, hence a decrease in IL-4 results in an elevation of IFN-. It would be more meaningful to look for change in exhaled IFN- in the same child before and after initiation of treatment with inhaled steroids.

Except for a weak negative correlation between exhaled NO and exhaled IFN-, we could not document any correlation between other markers of asthma control. There was no correlation between lung function measurements and exhaled IFN- and IL-4. This may be anticipated as a child with asthma may have underlying airway inflammation without airway obstruction marked enough to be picked up by routine spirometry and vice versa. It would be valuable to validate these measurements with those in BAL fluid and/or biopsy specimen of these patients, but there are major difficulties in performing such invasive tests in children.

Our study has shown that measurements of IFN- and IL-4 in exhaled breath condensate in children with asthma appear to follow the pattern of these cytokines in the airways. Hence, these measurements in exhaled breath could play a role in noninvasive monitoring of airway inflammation and optimizing the dose of prescribed inhaled corticosteroids in children with asthma. Our preliminary study showed that measurable concentrations of IFN- and IL-4 are present in exhaled breath in normal children and those with asthma. IFN- is depressed and IL-4 elevated in exhaled breath in children with asthma in contrast with that in healthy children. Breath condensate analysis is currently a research procedure, but there is increasing evidence that it may have an important place in the diagnosis and monitoring of asthma in the future.

	Acknowledgments

 
The authors thank Francisca C. Gonio, Research nurse, NHLI, for her technical help and all the staff of Pediatrics Department, Royal Brompton Hospital.

	FOOTNOTES

 
Supported by the Royal Brompton Hospital Clinical Research Committee and Aerocrine, Sweden and a study grant from the Association of Commonwealth Universities for the year 2000–2001 (S. K. S.).

Received in original form August 20, 2001; accepted in final form January 31, 2002

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