INTRODUCTION

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Bronchopulmonary dysplasia (BPD) is a major cause of long-term morbidity in infants born prematurely. In follow-up studies of pulmonary function, BPD is associated with bronchial obstruction and hyperresponsiveness, persisting until school age or young adulthood (1). However, prematurely born children without BPD have also been observed to have obstructed airway function in childhood (8). Despite obstructive changes in spirometry, prematurely born children are often asymptomatic (2). The average surviving preterm baby today is more premature than previously. This may lead to increased severity of pulmonary disease and a poorer outcome. In our previous study of the pulmonary functional sequelae of extreme prematurity, significant bronchial obstruction was a common finding, regardless of BPD (14). However, only a few children complained of subjective respiratory symptoms. The clinical significance of these measurable functional abnormalities has not been clearly established. An important question is whether these obstructive changes are reversible and responsive to treatment.

With the aim of evaluating bronchial lability and responsiveness (15) in every-day life in school children born very preterm, we recorded the diurnal variation of peak expiratory flow (PEF) and the response to an inhaled ₂-agonist, using a novel home spirometer. Bronchial responsiveness to histamine and to a ₂-agonist were also measured at hospital visits.

	METHODS

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Subjects

The patients belonged to a group of very low birth weight (VLBW) infants (< 1,250 g) treated at the neonatal intensive care unit of the Children's Hospital, University of Helsinki, Finland, between 1980 and 1985. Among the total of 168 survivors, 70 children (42%) had required oxygen therapy for > 28 d, and 22 children (13%) were still oxygen-dependent at the age of 36 postconceptional wk, which was used as the criterion of BPD (16). Of the 22 children with histories of BPD, 12 were traced and were able to participate in our study. Their gestational ages at birth and the duration of oxygen therapy did not differ significantly from those of the remaining BPD children who were not examined (median gestational age at birth: 27.0 versus 26.5 wk; median duration of oxygen therapy: 80.5 versus 78.5 d). Twenty children without BPD but comparable in birth weight and gestational age were also included; 17 of them completed the study.

Neonatal data were collected from the hospital records (Table 1). The median duration of oxygen dependency was 81 d in the BPD children as compared with 35 d in the non-BPD children (p < 0.0001). No significant differences in gestational age, birth weight, or sex were observed between these two groups. Ventilator treatment had been provided using a Baby Bird respirator. Four children had been treated with exogenous surfactant. Bronchoscopy was performed in five children (one non-BPD and four BPD children) because of respiratory distress after extubation. In these children, the duration of artificial ventilation was prolonged, ranging from 45 to 165 d (median: 85 d). Tracheal or bronchial stenosis was found in all five children. The stenosis was treated with dilatations in one child, and tracheostomy was performed in another child. Depending on the grade of the stenosis, these five children were followed by rescopies up to the age of 1.5 to 6 yr. Bronchoscopies were discontinued when the stenosis was totally absent or only mild stenotic changes were observed.

A group of 22 healthy, nonatopic local schoolchildren of the same age, all of whom were born at term, were recruited as a control group of spirometry. Lung function of seven control children was monitored twice daily at home for 4 wk. All these children were attending school and had no respiratory symptoms at the time of study. Selection was based on the date of birth.

The principal investigator did not know the neonatal history of the premature children at the time of testing. Informed consent was obtained from the parents. The study was approved by the ethics committee of the hospital.

Study Design

In this cross-sectional study, the children visited hospital twice. All 29 study children underwent lung function testing with the same protocol and equipment. At the first hospital visit, clinical status, height, and weight were studied, and the child and the parent(s) were interviewed and filled in questionnaires, especially about the child's respiratory symptoms during the preceding year. Flow-volume spirometry and a bronchodilator test were performed, and the children were shown how to use a home spirometer. In addition, skin-prick tests were made. Lung function was monitored twice daily at home for 4 wk. The effect of a ₂-agonist was measured by performing spirometry every morning and evening before and after terbutaline inhalation. At the second visit, flow-volume spirometry and a histamine challenge test were performed, and the data of the home spirometer were downloaded.

Skin tests were performed with the skin-prick technique, using eight major allergen extracts. A negative control solution and histamine hydrochloride (10 mg/ml) as a positive control were used. Atopy was defined as at least one wheal  3 mm in diameter as a reaction to an allergen in the absence of a response to the negative control solution. Familial atopy was defined as physician-diagnosed allergy among first-degree relatives.

Lung Function Measurements

Flow-volume spirometry was done with a pneumotachograph (Spirotrac III^®; Vitalograph Ltd, Buckingham, UK). At least three technically correct forced expiratory curves should be made according to the acceptability criteria of the American Thoracic Society (ATS). The curve was reproducible if the largest FVC and FEV₁ and second largest FVC and FEV₁ from acceptable curves did not vary by > 5% of reading (expressed as a percentage of the largest observed FVC and FEV₁ regardless of the curve on which it occurred) (17). The curve with the highest sum of FEV₁ and FVC values was selected for statistical analysis. Results of lung function tests were analyzed as percentages of predicted values, according to Polgar and Promadhat (18). Flow-volume spirometry was measured with the same method in the healthy children of the reference group. The following spirometric parameters were recorded: FVC, FEV₁, FEV₁/FVC ratio, PEF, and forced expiratory flow at 50% and at 75% of FVC (FEF₅₀ and FEF₇₅). Bronchial obstruction was defined as at least two of the following spirometric values: FEV₁ < 80%, PEF < 75%, or FEF₅₀ < 62% (18).

In the bronchodilator test at the office, flow-volume spirometry was measured before and 15 min after inhalation of 0.5 mg terbutaline from a dry powder inhaler (terbutaline sulfate, 0.25 mg/dose; Bricanyl Turbuhaler^®; Astra Draco AB, Lund, Sweden). During each terbutaline inspiration, peak inspiratory flow through the Turbuhaler (PIF_TBH) was recorded. The lowest acceptable PIF_TBH value was 30 L/min (19). The changes in FEV₁ and PEF values after terbutaline were expressed as the differences (%) between the values before and after terbutaline inhalation (FEV₁ and PEF).

At home, lung function was recorded using a Vitalograph Data Storage Spirometer (Vitalograph) particularly designed for long-term recording and storage of lung function parameters. The device consists of a pneumotachograph and a computer. Before use, the device was calibrated with a standard volume (variation within ± 1%). After home recordings, the calibration was checked. The difference between these two calibration values (before and after home monitoring) was  5%. At home, FVC, FEV₁, PEF, and PIF_TBH values were recorded. The test was repeated, a maximum of five times, until the results of the two best curves met the criteria of the ATS. If this was not achieved with five tests, failure was recorded. The spirometer stored the curve with the largest sum of FEV₁ and FVC in the built-in electronic diary. The compliance of inhalation therapy was recorded by measuring PIF_TBH. During the first 2 wk of home monitoring, the children inhaled terbutaline 0.25 mg twice daily. They performed spirometry every morning and evening, before and 15 min after terbutaline inhalation. The data from the home spirometer were analyzed after 4 wks of monitoring. Home monitoring with the same method was also performed in the seven healthy children of the control group. The number of PEF increments  15% after terbutaline was used for the analysis (20). Diurnal PEF variation of the whole 4 wk of recordings was calculated as the difference between the morning and evening PEF values and was expressed as the percentages of the greater PEF value. The number of PEF  20% was used in the analysis. PEF  20% has been shown to be a good indicator of bronchial lability (21, 22). The number of positive terbutaline responses and the number of PEF  20% were expressed as the percentages of all tests during home monitoring (Figure 2). The mean PEF value, defined as the mean of the morning PEF values during the last week of home monitoring, was used in the correlation analysis of spirometric data at home and at the office.

View larger version (13K): [in this window] [in a new window]   Figure 2.   The number of PEF measurements with an increment  15% after terbutaline and diurnal PEF variations  20% during home monitoring expressed as the percentages of all tests during home monitoring (open circles: history of tracheal/bronchial stenosis). Medians are expressed as horizontal lines. Significant difference is expressed in the figure.

Airway responsiveness to histamine, expressed as the histamine dose (mg) resulting in a 15% decrease in FEV₁ (PD₁₅FEV₁), was determined using an automatic, inhalation-synchronized, dosimetric jet nebulizer (Spira Elektro 2; Respiratory Care Centre, Hämeenlinna, Finland) (23). The device incorporates a turbine flow sensor for monitoring tidal volume and inspiratory flow. With a two-bar driving pressure, the airflow to the nebulizer is 7.5 L/min. The nebulization time is 0.4 s, set to start at 100 ml after the beginning of inspiration. During the test, the child is breathing with a tidal volume of 0.3 to 0.5 L. The peak inspiratory flow is not allowed to exceed 0.5 L/s during administration of the aerosol. One, four, eight, and 16 tidal inspirations of buffered histamine diphosphate in saline solution with concentration of 4 and 16 mg/ml are employed using a four-step dosage scheme. The calculated noncumulative doses of histamine to the lungs and airways at each step are 0.025, 0.1, 0.4, 0.8, and 1.6 mg, respectively. The FEV₁ measured with a pneumotachograph is used to determine the response to histamine. The PD₁₅FEV₁ will be determined by plotting manually the dose of histamine against the percent fall in FEV₁ using a logarithmic scale for the histamine doses. The PD₁₅FEV₁ is obtained by linear interpolation between the last two points. PD₁₅FEV₁  1.6 mg histamine is considered normal for adults (23). Reference values for children are not yet available. After the last histamine dose, 0.5 mg terbutaline was given. Terbutaline was inhaled from a metered-dose inhaler with a valved spacer device (Nebuhaler; Astra Draco AB). If the child had a respiratory infection, the test was not performed until 2 wk after the infection had ended. The children were not allowed to use ₂-agonists for at least 12 h before the challenge test.

Statistical Methods

Results of lung function tests were analyzed as percentages of predicted values (Polgar and Promadhat). The significances of the differences between the three study groups were tested using one-way analysis of variance for normally distributed data. The normality of the data distribution was confirmed with a Kolmogorov-Smirnov one-sample test. A Kruskall-Wallis nonparametric test was used if the distribution was not normal or if the variances were not homogeneous. The Fisher exact test and the Mann-Whitney test were used for assessing the significance of differences between the two groups. Spearman's rank correlation (r_s) was used in analysis for the association between current symptoms and the lung function parameters. Multiple stepwise regression analysis was used to evaluate the relationship between the neonatal (independent variable) and current pulmonary function (dependent variable) data. The following neonatal variables were evaluated: birth weight, duration of oxygen therapy (FI_O2 > 0.40 and FI_O2 > 0.21), duration of ventilator treatment, postconceptional age when oxygen was discontinued, and the history of tracheal/bronchial stenosis. Statistical analyses were performed using the Statgraphics computer program.

	RESULTS

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Patients

Age, absolute height and weight, and weight expressed as a percentage of the mean weight of children of same sex and height (24) did not differ between the groups (Table 2). Heights as SD in relation to age of the BPD children were significantly lower than those of the full-term control children (p = 0.014).

History of Respiratory Symptoms and Atopy

Fourteen children (48%) had had dyspneic symptoms at least once and, in addition, two children had suffered from continuous coughing for > 3 wk during the previous year. Five children had asthma diagnosed by a physician. Four of them were receiving continuous budesonide inhalation therapy and one child in the BPD group used ₂-agonists during infections. The groups did not differ in individual or familial atopy or in parental smoking. Atopy was found in 17% of patients in the BPD group and in 29% in the non-BPD group. The respective percentages of familial atopy was 50% versus 41%. The percentages of parental smoking were high in both groups: 50% in the BPD group and 47% in the non-BPD group.

Basic Lung Function

Ten children (83%) in the BPD group and four (24%) in the non-BPD group had subnormal spirometric values at the office indicating bronchial obstruction. The children with the history of tracheal or bronchial stenosis had bronchial obstruction at school age. Of the children with obstruction, 11 (79%) reported respiratory symptoms during the past year, nine children had dyspneic symptoms, and two children had prolonged coughing. One child with the history of tracheal stenosis had severe symptoms and was not able to perform the histamine challenge test or carry out home monitoring.

All spirometric values except FEV₁/FVC were significantly lower in the BPD group than in the non-BPD group (Figure 1). When the children with a history of tracheal/bronchial stenosis were excluded from the analyses, the difference in FEV₁ and PEF values between the groups still remained significant. All spirometric values were significantly lower in both preterm groups than in the full-term control group (p < 0.01; Figure 1).

View larger version (13K): [in this window] [in a new window]   View larger version (13K): [in this window] [in a new window]   Figure 1.   FEV1, FVC, and FEV1/FVC (A) and PEF, FEF50, and FEF75 (B) values as percentages of predicted values of the children in different study groups (open circles: history of tracheal/bronchial stenosis). Medians are expressed as horizontal lines. Significant differences are expressed in the figure.

Bronchodilator Test and Diurnal PEF Variation

In the bronchodilator test at the office, none of the study children had a significant response to terbutaline (FEV₁  15%) (20). Five children had FEV₁  10% (one non-BPD and four BPD children). There was no significant difference between the BPD and non-BPD groups; the median FEV₁ was 5.8% (range: 5.1 to 14.3%) in the BPD group and 1.4% (range: 2.1 to 12.2%) in the non-BPD group.

During the 2 wk of recording at home, PEF increments  15% after terbutaline were observed at least three times ( 11%, expressed as the percentages of all tests during home monitoring) in 31% of the patients. According to this definition, none of the seven control children had positive bronchodilator test at home. The difference between BPD group and healthy control group was significant (p = 0.01) (Figure 2). Six children (21%) had diurnal PEF variation  20% at least four times ( 14% of all tests) during home monitoring. According to this definition, none of the control children had abnormal diurnal PEF variation (Figure 2). A significant response in the bronchodilator test and/or abnormal diurnal PEF variation were observed in 11 of all 29 children tested (38%) and in eight (57%) of the 14 children with verified obstruction.

The number of acceptable individual measurements made at home was high: 92% (range: 76 to 99%). Spirometric PEF values at the office showed a good correlation with the mean morning PEF values of the last week of home monitoring (r_s = 0.82, p < 0.001).

Bronchial Responsiveness

Median histamine PD₁₅FEV₁ was significantly lower in the BPD group than in the non-BPD group; 0.8 (range: 0.06 to > 1.6) versus > 1.6 (range: 0.44 to > 1.6) (p = 0.002; Figure 3). No significant differences were observed between the non-BPD group and the healthy adult control group (median PD₁₅FEV₁: > 1.6 versus > 1.6 mg) (23).

View larger version (12K): [in this window] [in a new window]   Figure 3.   The result of histamine challenge test as PD15FEV1 of the children in different study groups (open circles: history of tracheal/ bronchial stenosis). Medians are expressed as horizontal lines. Significant difference is expressed in the figure.

Association of Neonatal Variables with Subsequent Lung Function

In stepwise multiple regression analysis, the duration of ventilator treatment was significantly associated with FVC, FEV₁, and FEF₅₀. The history of tracheal/bronchial stenosis and the duration of oxygen therapy were associated with PEF and FEF₇₅. Duration of oxygen therapy had an association with PD₁₅FEV₁ values (Table 3). Neither gestational age nor birthweight was associated with the spirometric data or bronchial responsiveness. According to Spearman's rank correlation test, symptoms during the previous year correlated inversely with FEV₁, FEV₁/FVC, FEF₅₀, and FEF₇₅ values at the office and with PD₁₅FEV₁ values (range of r = 0.37 to 0.47; p < 0.05 for all).

	DISCUSSION

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At the office, we used conventional flow-volume spirometry, the bronchodilator test, and the dosimetric histamine challenge test. At home, lung function was recorded with a novel device, a computerized home spirometer. Monitoring pulmonary function throughout successive days provides information that might be missed with the single "snapshot" obtained at the office. Home monitoring is therefore an important way to measure changes in pulmonary function, both within a day and from day to day. The presence of bronchial lability is reflected by reduced PEF values during the early morning hours (15). However, absolute values of PEF obtained with standard devices, such as mini-flow meters, may be inaccurate, especially in children (25). The new computerized home spirometer affords the following advantages: (1) compliance control of spirometry and medication by recording the time of measurement and inhalation of the drug, (2) control of the repeatability and acceptability of measurements, and (3) the possibility to calibrate the device (26). In the present study, 92% of the measurements during home monitoring were acceptable according to the ATS criterion. In addition, PEF at the office showed a strikingly good correlation with the home recordings. This suggests that the study children had learned correctly the technique to perform spirometry and also that both devices were comparable.

Bronchial Obstruction

The finding of bronchial obstruction in our BPD children agrees with earlier observations (1). However, in our children, the level of obstruction was more severe, possibly because of the difference in selection; our children were more premature than those examined in previous studies. As the numbers of VLBW survivors have increased, mild to moderate obstructive airway dysfunction at school age has been found in children without a history of BPD, as in our study (8- 14). The definition of BPD that we used (oxygen dependency at the age of 36 postconceptional wk) (16) seems to be a sensitive predictor of abnormal pulmonary outcome in VLBW children at school age; 83% of the BPD children had bronchial obstruction. However, bronchial obstruction was also observed in 24% of the non-BPD children. We found that bronchial obstruction was associated with the duration of mechanical ventilation. This suggests a close association of the severity and/or the duration of the neonatal treatment with pulmonary function at school age. In contrast to previous studies (3, 9, 11), birth weight and gestational age were not associated with pulmonary function, obviously because of the narrow range of gestational ages in our children. In agreement with a previous study (27), FVC was significantly smaller in both our preterm groups than in the control group. Because plethysmographic measurements were not performed in the present study, it is not certain that these lower FVC values really do reflect smaller thoracic gas volumes or air trapping because of bronchial obstruction.

Bronchial Responsiveness and Lability

In contrast to previous studies, we found that none of our children showed a significant response to a ₂-agonist in the conventional bronchodilator test at the office. A weak response was noticed in 17% of the children, all but one in the BPD group. In a previous study by Northway and colleagues (2), responsiveness of  10% in the bronchodilator test was observed in 44% of the patients with a history of BPD as compared with our 33%. Andreasson and coworkers and Kleine and associates also found that in the prematurely born and ventilated children of school age, after ₂-agonist inhalation, FEV₁ was higher than in the reference group, regardless of BPD (4, 5). During home monitoring, the bronchodilator test was positive in 43% of our study children with obstruction. In addition, 36% of these children had increased diurnal PEF variation, indicating bronchial lability. None of our control children had abnormal diurnal PEF variation or positive bronchodilator test during home monitoring. Our observation is in accordance with the criteria used in adults (21).

We found that BPD children were significantly more responsive to histamine than non-BPD children and normal healthy, adult subjects. At school age, bronchial hyperresponsiveness has been observed not only in children with BPD (2, 6) but also in prematurely born children without BPD (10, 11, 28). In contrast to previous reports (2), we obtained data on respiratory symptoms from the majority of the children with verified obstruction. In our study, a significant association was noticed between respiratory symptoms and PD₁₅FEV₁ values. This suggests that airway responsiveness is of clinical significance. Those children whose PD₁₅FEV₁ was < 1 mg were all symptomatic. Similarly, Chan and colleagues reported a strong relationship between respiratory symptoms and airway responsiveness (13). In asthma, bronchial hyperresponsiveness is associated with inflammation of the bronchial mucosa. In BPD, however, this association has not been verified. In symptomatic, low birth weight children of school age with increased airway responsiveness, treatment with inhaled beclomethasone dipropionate had no significant effect on bronchial responsiveness (29). In contrast to Chan and colleagues (13), we observed an association between PD₁₅FEV₁ and the duration of oxygen treatment, suggesting that bronchial hyperresponsiveness may be a sequel of airway damage during neonatal respiratory therapy.

In conclusion, bronchial obstruction, bronchial lability, and increased bronchial responsiveness are common in school children born very preterm, regardless of BPD. Half of the children with obstruction responded to a ₂-agonist or had abnormal diurnal PEF variation. However, the variability of the bronchial obstruction could be detected only by recording PEF values at home for a longish period. The possible inflammatory basis and the benefits of long-term treatment remain to be assessed in future studies.