Primary ciliary dyskinesia

Study objective: There is growing evidence that regular [[Beta].sub.2]-agonist use in patients with asthma is associated with decreased airway caliber and increased bronchial responsiveness. The aim of this study was to determine whether regular treatment with [[Beta].sub.2]-agonists induces changes in lung function and bronchial responsiveness in patients with primary ciliary dyskinesia.

Design: A randomized, double-blind, placebo-controlled, crossover study.

Patients: Nineteen children with primary ciliary dyskinesia.

Interventions: Subjects received inhaled salbutamol or identical placebo (2 x 100 [micro]g qid) for periods of 6 weeks with a wash-out period of 4 weeks.

Measurements and results: [FEV.sub.1] was measured before and 3 weeks and 6 weeks after salbutamol or placebo treatment. High-dose methacholine inhalation tests were performed before and 6 weeks after each treatment. The provocative concentration of methacholine producing a 20% fall in [FEV.sub.1] ([PC.sub.20]) and maximal airway narrowing (M[Delta]F[FEV.sub.1]) was measured. No significant change in [FEV.sub.1] was observed during the salbutamol or placebo periods. No significant differences in the parameters of bronchial responsiveness ([PC.sub.20] and M[Delta]F[FEV.sub.1]) were noted as the result of either salbutamol or placebo treatment.

Conclusion: Our data have shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial responsiveness in subjects with primary ciliary dyskinesia.

(CHEST 2000; 117:427-433)

Key words: [Beta]-agonist; bronchial responsiveness; lung function; primary ciliary dyskinesia; salbutamol

Abbreviations: [Delta]F[FEV.sub.1] = percentage fall in [FEV.sub.1]; M[Delta]F[FEV.sub.1] = maximal airway narrowing, expressed as maximal percentage fall in [FEV.sub.1]; [PC.sub.20] = provocative concentration producing a 20% fall in [FEV.sub.1]

Inhaled [[Beta.sub.2]-agonists are highly effective in attenuating the bronchoconstriction caused by a variety of stimuli, and they provide rapid relief of symptoms in individuals with asthma.[1] While it is argued that regular use of inhaled [[Beta].sub.2]-agonists is safe and offers round-the-clock protection against bronchoconstriction,[2] there is growing evidence that regular [[Beta].sub.2]-agonist use is associated with diminished asthma control, decreased baseline airway caliber, and increased bronchial responsiveness.[3,4]

Primary ciliary dyskinesia, formerly referred to as immotile cilia syndrome, is an autosomal recessive disorder. It is characterized by chronic upper and lower respiratory tract infections, which are caused by the grossly impaired mucociliary transport.[5] The treatment for this disease focuses on improving mucociliary transport. Treatment frequently includes the regular use of inhaled [[Beta].sub.2]-agonists,[6] which increase ciliary beat frequency in vitro[7] and increase mucociliary transport in some diseases such as cystic fibrosis.[8] Inhaled [[Beta].sub.2]-agonists may also improve transport by other mechanisms, such as bronchodilation and the promotion of thinner secretions.[9]

However, we found no information in the literature on the effect of regular treatment with inhaled [[Beta].sub.2]-agonists on the pulmonary function and bronchial responsiveness in patients with primary ciliary dyskinesia. These effects are of more than theoretical importance. For example, bronchial hyperresponsiveness may play a part in the pathogenesis of bronchiectasis, the major pulmonary complication of primary ciliary dyskinesia, by reducing the efficiency of respiratory clearance mechanisms, thereby promoting microbial colonization and inflammation.[10] If adverse changes in lung function or bronchial responsiveness occur with regular [[Beta].sub.2]-agonist treatment, this would have a detrimental effect on the course of primary ciliary dyskinesia.

The aim of this study was to determine whether regular treatment with [[Beta].sub.2]-agonists induces changes in lung function and bronchial responsiveness in patients with primary ciliary dyskinesia. In this investigation, we conducted a randomized, double-blind, placebo-controlled, crossover study to assess the effect of a 6-week course of salbutamol treatment on lung function and bronchial responsiveness. We measured [FEV.sub.1], the provocative concentration of methacholine producing a 20% fall in [FEV.sub.1] ([PC.sub.20]), and maximal airway narrowing in the dose-response curve to methacholine, before and after salbutamol or placebo treatment.

MATERIALS AND METHODS

We studied 19 children with primary ciliary dyskinesia (11 boys; median age, 12 years; range, 7 to 16 years), of whom 5 had Kartagener's syndrome and 6 were three pairs of siblings. The diagnosis of primary ciliary dyskinesia was suspected on clinical grounds and proved by the appearance of cilia on electron microscopy, In all patients, respiratory symptoms had started in early childhood. They all presented with typical symptoms of bronchitis and recurrent sinusitis or otitis. Bronchiectasis was documented by high-resolution CT in 16 patients. Four patients had clubbing. The cilia were taken from a mucosal biopsy of the inferior nasal turbinate in the absence of local infection. Their abnormal ultrastructure was revealed on transmission electron microscopy (total absence of outer dynein arms, n = 2; total absence of inner dynein arms, n = 4; total absence of outer and inner dynein arms, n = 4; partial absence of outer and inner dynein arms, n = 3; total absence of radial spokes with eccentric central core, n = 2; absence of the central pair of tubules with transposition of outer doublet to the center, n = 1 ; partial absence of outer and inner dynein arms, and absence of the central pair of tubules with transposition of outer doublet to the center, n = 3).

Among 23 children with primary ciliary dyskinesia who had been followed up at our clinic and were old enough to perform pulmonary function tests, 2 with an [FEV.sub.1] [is less than] 65% predicted[11] were excluded because of the possible relationship of the degree of airflow obstruction with the increase in bronchial responsiveness.[12] The other two patients subsequently dropped out of the study because of noncompliance with medication. All the subjects were in a stable clinical state at the time of study. They continued conventional physiotherapy (a combination of percussion and postural drainage in which the patient assumes different positions favoring gravitational emptying of a specific lobe or lung region while the chest wall is clapped vigorously by the cupped hand) and other prescribed treatments (use of a flutter valve device and mucolytics such as ambroxol or S-carboxymethylcysteine) throughout the study. No other concomitant pulmonary medication was allowed except during exacerbation, for which a 10-day course of antibiotics based on the in vitro antimicrobial sensitivity testing was administered. There was no history of upper respiratory tract infection for at least 4 weeks prior to the study. The parents of the patients gave informed consent for the study, and the protocol was approved by the Hospital Ethics Committee.

The study was a double-blind, randomized, crossover study in which the subjects used identical inhalers containing placebo or salbutamol for 6 weeks. The drugs were inhaled from a novel multiple dose inhaler (Respolin Autohaler; 3M Pharmaceuticals; Thornleigh, Australia), 100 [micro]g/inhalation. The study commenced with a run-in period of 4 weeks during which the subject's usual [[Beta].sub.2]-agonist was withheld. At the end of this period, patients were randomly allocated in a double-blind manner to one of two treatment arms. On the first day of the first treatment period, subjects underwent a methacholine challenge test at 8:00 AM. Subjects were then instructed to take two inhalations from their test inhaler qid, at 7:00 AM, noon, 5:00 PM, and 10:00 PM. The patients visited the clinic after 3 weeks, and spirometry was performed. On the last day of the treatment period, methacholine challenge testing was done as on the first day. Thereafter, there was a 4-week wash-out interval during which no treatment was given. Following the wash-out period, each subject was crossed over to repeat the protocol with the alternative treatment. Subjects were instructed not to use the test inhaler for [is greater than or equal to] 8 h and caffeine for [is greater than or equal to] 24 h before all visits. In order to assure that the intended dose was actually received by the patient, the drug canisters were weighed at each visit. The measurements suggested that all but two patients had complied with the instructions for taking the medications.

Lung function was measured with a computerized spirometer (Microspiro-HI 298; Chest Corp; Tokyo, Japan), and the largest value of the triplicate [FEV.sub.1] at each time point was adopted for analysis. At the time of the study, the baseline [FEV.sub.1] was [is greater than] 65% of the predicted value.[11]

High-dose methacholine inhalation tests were carried out using a modification of the method described by Chai et al.[13] The concentrations (0.075, 0.15, 0.3, 0.625, 1.25, 2.5, 5, 10, 25, 50, 100, 150, and 200 mg/mL) of methacholine (Sigma Diagnostics; St. Louis, MO) were prepared with dilution in buffered saline solution (pH 7.4). A Rosenthal-French dosimeter (Laboratory for Applied Immunology; Baltimore, MD), triggered by a solenoid valve set to remain open for 0.6 s, was used to generate the aerosol from a DeVilbiss 646 nebulizer (DeVilbiss Health Care, Inc; Somerset, PA), with pressurized air at 20 pounds per square inch. Each subject inhaled five inspiratory capacity breaths of buffered saline solution and increasing concentrations of methacholine at 5-min intervals. This gave an output of 0.009 [+ or -] 0.0014 mL (mean [+ or -] SD) per inhalation. [FEV.sub.1] was measured 60 to 90 s after inhalation of each concentration level. The procedure was terminated when [FEV.sub.1] had fallen by [is greater than] 40% from the postsaline value, or when a maximal response plateau had been established. This was considered to occur if three or more data points of the highest concentrations fell within a 5% response range.[14] An additional 5 or 10 inhalations of the 200 mg/mL solution were taken if the last three data points of less than a 40% fall did not satisfy the above criteria. For safety reasons, subjects were given the opportunity to stop the challenge test if they felt too much discomfort.

The response was expressed as the percentage fall in [FEV.sub.1] ([Delta]F[FEV.sub.1]) from the postsaline solution value, and was plotted against logged concentrations of inhaled methacholine. The dose-response curves were characterized by their position and maximal response. The position was expressed as [PC.sub.20], which was calculated by log-linear interpolation between two adjacent data points. Although the sensitivity of the airways is a useful indicator of the degree of bronchial responsiveness, the maximal extent of airway narrowing has also been recognized as an important measurement in recent years.[15] The maximal airway narrowing (M[Delta]F[FEV.sub.1]) was defined as the level of maximal response plateau by averaging the consecutive points on the plateau. We used the last data point of the dose-response curve if a plateau could not be obtained.

Mean values and SDs were calculated for the variables. All [PC.sub.20] values were log-transformed, and the geometric mean and range of 1 SD were calculated. Comparisons of [FEV.sub.1], [PC.sub.20], and M[Delta]F[FEV.sub.1] before treatment and after treatment were analyzed using paired t tests. A p value of [is less than] 0.05 was considered statistically significant.

RESULTS

All of the subjects completed the six assessment visits of the study. Ten subjects had been randomized to receive salbutamol treatment first. All of the patients, with the exception of two in the placebo period, remained clinically stable without any evidence of infective exacerbations. These two patients experienced acute exacerbations, as evidenced by fever and increased cough and sputum production. Sputum cultures recovered Pseudomonas aeruginosa in one case and Haemophilus influenzae in the other. Cephalosporin (cefotaxime) was prescribed for one patient, and [Beta]-lactam plus [Beta]-lactamase inhibitor (amoxicillin/clavulanate) for the other, based on in vitro antimicrobial sensitivity testing.

Before entering each treatment period, the mean value ([+ or -] SD) of [FEV.sub.1] (% predicted) was not significantly different between salbutamol (83.3 [+ or -] 10.1%) and placebo period (83.7 [+ or -] 9.7%). At 3 and 6 weeks after treatment, no significant difference in the mean [FEV.sub.1] was observed vs the pretreatment measurement, either with salbutamol (82.9 [+ or -] 9.4%, 83.2 [+ or -] 8.5%) or placebo period (81.8 [+ or -] 9.8%, 82.9 [+ or -] 9.3%). Two patients experienced a change in [FEV.sub.1] of [is greater than] 10% during the salbutamol period and three during the placebo period.

The high-dose methacholine inhalation tests were well tolerated in most subjects. Two subjects had to stop one test (one before the placebo treatment and the other after the placebo treatment) because of dyspnea before a plateau was reached with [Delta]F[FEV.sub.1] [is greater than] 20%. These two subjects were excluded in the analysis of change in M[Delta]F[FEV.sub.1] over the placebo treatment period. In the two tests covering the salbutamol treatment period, a [PC.sub.20] of [is greater than] 200 mg/mL was observed before treatment in one subject, after treatment in another, and both before and after treatment in three. A [Delta]F[FEV.sub.1] of [is greater than] 40% without evidence of plateau was seen before treatment in two subjects, after treatment in three, and on both occasions in three others. In the two tests covering the placebo treatment period, a [PC.sub.20] of [is greater than] 200 mg/mL was noted after treatment in two subjects and both before and after treatment in three. A [Delta]F[FEV.sub.1] of [is greater than] 40% without evidence of plateau was observed before treatment in one subject, after treatment in two, and on both occasions in three.

The changes in [PC.sub.20] for the two treatment periods are depicted in Figure 1. In the salbutamol treatment period, for the 14 subjects with a measurable [PC.sub.20] both before and after treatment, the geometric mean value (range of 1 SD) was 32.4 mg/mL (10.2 to 102.3 mg/mL) before treatment and 33.9 mg/mL (10.5 to 109.6 mg/mL) after treatment (p = 0.81). Two subjects exhibited an increase in [PC.sub.20] and two subjects a decrease in [PC.sub.20] by a twofold magnitude. In addition, with a [PC.sub.20] value of 200 mg/mL assigned to the occasion of [PC.sub.20] [is greater than] 200 mg/mL for comparison in all subjects, the change was not significant (51.3 mg/mL [14.5 to 182.0 mg/mL] before treatment vs 52.5 mg/mL [14.8 to 186.2 mg/mL] after treatment; p = 0.76). In the placebo period, there was no significant change in [PC.sub.20] whether values of [PC.sub.20] [is greater than] 200 mg/mL were excluded (n = 14; 28.2 mg/mL [9.1 to 87.1 mg/mL vs 30.9 mg/mL [10.2 to 93.3 mg/mL]; p = 0.63) or not (n = 19; 46.8 mg/mL [12.9 to 169.8 mg/mL] vs 50.1 mg/mL [14.1 to 177.8 mg/mL]; p = 0.52).

[Figure 1 ILLUSTRATION OMITTED]

The changes in M[Delta]F[FEV.sub.1] are presented in Figure 2. In the salbutamol treatment period, for the 11 subjects who attained the maximal response plateau on both occasions, the mean ([+ or -] SD) of the plateau level was 25.5 [+ or -] 8.6% before treatment and 23.8 [+ or -] 7.7% after treatment (p = 0.31). For comparison in all subjects, [Delta]F[FEV.sub.1] [is greater than] 40% at the end of the protocol was assigned to the occasions in which the maximal response plateau was not attained. With this approach, the change was also not significant (n = 19; 32.1 [+ or -] 10.6% before treatment vs 31.2 [+ or -] 11.0% after treatment; p = 0.58). In the placebo period, there was no significant change in M[Delta]F[FEV.sub.1 whether values of [Delta]F[FEV.sub.1] [is greater than] 40% without evidence of plateau were excluded (n = 11; 24.8 [+ or -] 7.4% vs 24.1 [+ or -] 7.4%; p = 0.47) or not (n = 17; 30.5 [+ or -] 10.3% vs 30.6 [+ or -] 11.0%; p = 0.94).

[Figure 2 ILLUSTRATION OMITTED]

DISCUSSION

This study has shown that salbutamol, inhaled regularly for 6 weeks, did not cause either a decline in lung function or an increase in bronchial responsiveness (bronchial sensitivity and maximal airway narrowing) in subjects with primary ciliary dyskinesia. The results of our study provide new information on the possible adverse effects of regular use of [[Beta].sub.2]-agonists, and offer reassurance that [[Beta].sub.2]-agonist drug can be regularly administered without concern in patients with primary ciliary dyskinesia.

Primary ciliary dyskinesia is characterized by chronic pulmonary symptoms including excessive phlegm, cough, and recurrent infections, which eventually cause a progressive deterioration in lung function.[5] The recurrent pulmonary infections are caused by the grossly impaired mucociliary transport in the respiratory tract causing stasis of the mucus within the bronchi. The mainstay of treatment for primary ciliary dyskinesia involves chest physical therapy to enhance the clearance of bronchial secretions. It is dearly advantageous to ensure maximal bronchodilation prior to physical therapy. Children with primary ciliary dyskinesia have been shown to exhibit bronchodilation to [[Beta].sub.2]-agonists.[16] Furthermore, [[Beta].sub.2]-agonists may increase ciliary beat frequency in human airway epithelial cells in vitro[7] and augment mucociliary clearance in patients with cystic fibrosis,[8] in whom mucociliary transport is more or less impaired. Therefore, coupled with chest percussion and postural drainage, inhaled [[Beta].sub.2]-agonists are cornerstones of therapy for primary ciliary dyskinesia and related syndromes.[6]

Pulmonary function in children with primary ciliary dyskinesia is characterized by a mild to moderate obstructive pattern.[17] In this study, the mean [FEV.sub.1] remained approximately unchanged with regular treatment of salbutamol, and only two patients experienced a change in [FEV.sub.1] of [is greater than] 10%. Although marked swings in pulmonary function have been shown to occur over years in primary ciliary dyskinesia,[18] the relative stability in [FEV.sub.1] during the 6-week period of salbutamol inhalation indicates that no important drug-related effects are likely to have occurred.

Several studies have reported an increased prevalence of bronchial hyperresponsiveness to methacholine in patients with bronchiectasis.[19, 20] The frequency of bronchial hyperresponsiveness (36.8%) in this study, defined as a [PC.sub.20] of [is less than] 25 mg/mL[21] is not surprising, as most subjects had bronchiectasis. The role of bronchial hyperresponsiveness in patients with primary ciliary dyskinesia is not clear, but it may imply a less favorable prognosis. Studies in adults and children indicate that bronchial hyperresponsiveness may be an independent determinant of the outcome of chronic airway disease.[22] In patients with cystic fibrosis, it has been shown that those with a positive methacholine challenge test have more severe and advanced lung disease, with more rapid pulmonary deterioration.[23] Furthermore, bronchial hyperresponsiveness may play a part in the pathogenesis of bronchiectasis by reducing the efficiency of respiratory clearance mechanisms and thereby promoting microbial colonization and inflammation.[10]

The estimation of change in bronchial sensitivity in our study population was complicated, because some subjects had [PC.sub.20] values above the upper limit of measurement ([PC.sub.20] [is greater than] 200 mg/mL), either before or after treatment with salbutamol, and repeated measures provided no estimate of change. When we excluded these subjects from the analysis, or assigned patients with [PC.sub.20] values of [is greater than] 200 mg/mL to a value of 200 mg/mL, the geometric mean value of [PC.sub.20] to methacholine was not significantly changed by the 6-week treatment. In asthma, a change of at least one doubling concentration in bronchial sensitivity to a bronchoconstrictor stimulus is considered to be clinically significant in the evaluation of disease progression or response to treatment.[24] In our study, most patients were unchanged on the basis of this criteria, and where changes did occur, their frequency was evenly distributed in either direction.

The estimation of change in the maximal airway narrowing was also complicated because some subjects showed [FEV.sub.1] falls [is greater than] 40% without evidence of plateau. Therefore, repeated measurements in these subjects yielded no estimation of change. One could argue that a proportion of these subjects might have a plateau beyond a 40% fall from baseline [FEV.sub.1], and that more data points should have been obtained for a detailed analysis.[25] However, because of ethical considerations, complete dose-response curves could not be obtained in these patients. Either by including these subjects in our analysis using maximal [FEV.sub.1] falls, or by excluding these subjects, our results indicated that the level of maximal airway narrowing was not changed significantly by the 6-week treatment with salbutamol.

The lack of effect of regular [[Beta].sub.2]-agonist treatment might be attributed to inadequate dosing or duration of salbutamol. However, this is unlikely, as several previous studies clearly have demonstrated a detrimental effect in patients with asthma with a dose of inhaled salbutamol of 600 [micro]g/d[26] and after regular treatment for as short as 1 week.[27] Insufficient bioavailability of salbutamol also seems unlikely, because we used a novel multiple dose inhaler, the Respolin Autohaler.

Recent studies have suggested that regular use of inhaled [[Beta].sub.2]-agonists in conventional doses may decrease baseline lung function and increase airway responsiveness to methacholine or histamine in asthmatic subjects.[3, 4] These findings raised the concern that patients with primary ciliary dyskinesia may also respond to inhaled [[Beta].sub.2]-agonists in an adverse way. In patients with cystic fibrosis, it seems probable that [[Beta].sub.2]-agonists have rather a beneficial effect than a deleterious effect. On maintenance [[Beta].sub.2]-agonist treatment for 1 year, both spirometric values and spontaneous diurnal variation in peak expiratory flow rate, a simple way to measure bronchial hyperresponsiveness,[28] have been shown to improve.[29] Although further long-term studies are needed, the present study indicates that the regular use of inhaled [[Beta].sub.2]-agonists for 6 weeks is not associated with changes in airway caliber or bronchial responsiveness. This suggests that [[Beta].sub.2]-agonists can be administered regularly without concern in patients with primary ciliary dyskinesia. The causes of the different responses in asthmatic and nonasthmatic subjects are not clear, but are likely to be associated with the different inflammatory process of the airways in these two groups. Our study adds to the growing list of studies suggesting that it may not appropriate to extrapolate the results from asthmatic subjects to nonasthmatic subjects. Boothman-Burrell et al[30] noted that regular inhaled salbutamol taken for 6 weeks causes no change in lung function or bronchial hyperresponsiveness in normal or nonasthmatic atopic subjects. Another study by Evans et al[31] reached a similar conclusion by comparing airway sensitivity and maximal response plateau to methacholine after 4 weeks of treatment with salbutamol in nonasthmatic subjects with rhinitis.

In conclusion, although impairment of spirometric values and increased bronchial hyperresponsiveness have been reported in asthmatic subjects following regular treatment with inhaled [[Beta].sub.2]-agonist drugs, the results of our study suggest that these adverse effects do not occur in patients with primary ciliary dyskinesia. These results offer reassurance that inhaled [[Beta].sub.2]-agonists can be safely prescribed on a regular basis to patients with primary ciliary dyskinesia.

REFERENCES

[1] Spina D. [[Beta].sub.2]-Agonists. In: Page CP, Metzger WJ, eds. Drugs and the lung. New York, NY: Raven, 1994; 1-45

[2] Wanner A. Is the routine use of inhaled [Beta]-adrenergic agonists appropriate in asthma management? Yes. Am J Respir Crit Care Med 1995; 151:597-599

[3] Vathenen AS, Knox AJ, Higgins BG, et al. Rebound increases in bronchial responsiveness after treatment with inhaled terbutaline. Lancet 1988; 1:554-557

[4] Sears MR. Is the routine use of inhaled [Beta]-adrenergic agonists appropriate in asthma management? No. Am J Respir Crit Care Med 1995; 151:600-601

[5] Rossman CM, Newhouse MT. Primary ciliary dyskinesia: evaluation and management. Pediatr Pulmonol 1988; 5:36-50

[6] Stillwell PC. Cilia dyskinesia syndrome. In: Loughlin GM, Eigen H, eds. Respiratory disease in children: diagnosis and management. Baltimore, MD: Williams & Wilkins, 1994; 411-415

[7] Devalia JL, Sapsford RJ, Rusznak C, et al. The effects of salmeterol and salbutamol on ciliary beat frequency of cultured human bronchial epithelial cells, in vitro. Pulm Pharmacol 1992; 5:257-263

[8] Wood RE, Wanner A, Hirsch J, et al. Tracheal mucociliary transport in patients with cystic fibrosis and its stimulation by terbutaline. Am Rev Respir Dis 1975; 111:733-738

[9] Rubin BK. Immotile cilia syndrome (primary ciliary dyskinesia) and inflammatory lung disease. Clin Chest Med 1988; 9:657-668

[10] Cole PJ. A new look at the pathogenesis and management of persistent bronchial sepsis: a "vicious circle" hypothesis and its logical therapeutic connotations. In: Davies RJ, ed. Strategies in the management of chronic bronchial sepsis. Oxford, UK: Medicine Publishing Foundation, 1984; 1-16

[11] Yoon KA, Lim HS, Koh YY, et al. Normal predicted values of pulmonary function tests in Korean school-aged children. J Korean Pediatr Assoc 1993; 36:25-37

[12] Ramsdale EH, Morris MM, Roberts RS, et al. Bronchial responsiveness to methacholine in chronic bronchitis: relationship to airflow obstruction and cold air responsiveness. Thorax 1984; 39:912-918

[13] Chai H, Farr RS, Froelich LA, et al. Standardization of bronchial inhalation challenge procedures. J Allergy Clin Immunol 1975; 56:323-327

[14] Sterk PJ, Timmers MC, Dijkman JH. Maximal airway narrowing in humans in vivo: histamine compared with methacholine. Am Rev Respir Dis 1986; 134:714-718

[15] Sterk PJ, Bel EH. Bronchial hyperresponsiveness: the need for a distinction between hypersensitivity and excessive airway narrowing. Eur Respir J 1989; 2:267-274

[16] Phillips GE, Thomas S, Heather S, et al. Airway response of children with primary ciliary dyskinesia to exercise and [[Beta].sub.2]-agonists challenge. Eur Respir J 1998; 11:1389-1391

[17] Corkey CWB, Levison H, Turner JAP. The immotile cilia syndrome: a longitudinal survey. Am Rev Respir Dis 1981; 124:544-548

[18] Hellinckx J, Demedts M, De Boeck K. Primary ciliary dyskinesia: evolution of pulmonary function. Eur J Pediatr 1998; 157:422-426

[19] Pang J, Chan HS, Sung JY. Prevalence of asthma, atopy, and bronchial hyperreactivity in bronchiectasis: a controlled study. Thorax 1989; 44:948-951

[20] Ip M, Lam WK, So SY, et al. Analysis of factors associated with bronchial hyperreactivity to methacholine in bronchiectasis. Lung 1991; 169:43-51

[21] Shapiro GG, Furukawa CT, Pierson WE, et al. Methacholine bronchial challenge in children. J Allergy Clin Immunol 1982; 69:365-369

[22] Postma DS, De Vries K, Koeter GH, et al. Independent influence of reversibility of air-flow obstruction and nonspecific hyperreactivity on the long-term course of lung function in chronic air-flow obstruction. Am Rev Respir Dis 1986; 134:276-280

[23] Eggleston PA, Rosenstein BJ, Stackhouse CM, et al. A controlled trial of long-term bronchodilator therapy in cystic fibrosis. Chest 1991; 99:1088-1092

[24] Barnes PJ. A new approach to the treatment of asthma. N Engl J Med 1989; 321:1517-1527

[25] Prieto JL, Gutierrez V, Berto JM, et al. Sensitivity and maximal response to methacholine in perennial and seasonal allergic rhinitis. Clin Exp Allergy 1996; 26:61-67

[26] Van Essen-Zandvliet EE, Hughes MD, Waalkens HJ, et al. Effects of 22 months of treatment with inhaled corticosteroids and/or beta-2-agonists on lung function, airway responsiveness, and symptoms in children with asthma. Am Rev Respir Dis 1992; 146:547-554

[27] Inman MD, O'Byrne PM. The effect of regular inhaled albuterol on exercise-induced bronchoconstriction. Am J Respir Crit Care Med 1996; 153:65-69

[28] Higgins BG, Britton JR, Chinn S, et al. Comparison of bronchial reactivity and peak expiratory flow variability measurements for epidemiologic studies. Am Rev Respir Dis 1992; 145:588-593

[29] Konig P, Gayer D, Barbero GJ, et al. Short-term and long-term effects of albuterol aerosol therapy in cystic fibrosis: a preliminary report. Pediatr Pulmonol 1995; 20:205-214

[30] Boothman-Burrell D, Jones D, Herbison GP, et al. The effect of regular salbutamol on lung function and bronchial hyperresponsiveness in normal subjects and nonasthmatic atopic subjects with allergic rhinitis. Chest 1997; 112:12-18

[31] Evans DW, Salome CM, King GG, et al. Effect of regular inhaled salbutamol on airway responsiveness and airway inflammation in rhinitic non-asthmatic subjects. Thorax 1997; 52:136-142

(*) From the Departments of Pediatrics (Drs. Koh, Park, and Jeong), Otolaryngology (Dr. Min), and Pathology (Dr. Chi), Seoul National University Hospital, Seoul, Korea; and the Clinical Research Institute (Drs. Koh, Kim, and Min), Seoul National University Hospital, Seoul, Korea.

Manuscript received March 18, 1999; revision accepted August 17, 1999.

Correspondence to: Young Yull Koh, MD, Department of Pediatrics, Seoul National University Hospital, 28 Yongon-dong, Chongno-gu, Seoul 110-744, Korea; e-mail: kohyy@plaza.snu.ac.kr

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