Journal Mobile Options
Table of Contents
Vol. 80, No. 2, 2010
Issue release date: July 2010
Section title: Clinical Investigations
Respiration 2010;80:120–126
(DOI:10.1159/000242113)

Relationship between Small Airway Function and Health Status, Dyspnea and Disease Control in Asthma

Takeda T.a · Oga T.b · Niimi A.a · Matsumoto H.a · Ito I.a · Yamaguchi M.a · Matsuoka H.a · Jinnai M.a · Otsuka K.a · Oguma T.a · Nakaji H.a · Chin K.b · Mishima M.a
Departments of aRespiratory Medicine, and bRespiratory Care and Sleep Control Medicine, Graduate School of Medicine, Kyoto University, Kyoto, Japan
email Corresponding Author

Abstract

Background: Small airways play important roles in the pathophysiology of asthma. However, relationships between small airway involvement and health status and dyspnea have not been investigated. Objectives: It was the aim of this study to assess the relationships between proximal and peripheral airway functions and health status, dyspnea and disease control in patients with asthma, using impulse oscillometry (IOS). Methods: We performed IOS, spirometry and assessment of health status (Asthma Quality of Life Questionnaire and St. George’s Respiratory Questionnaire), dyspnea (Baseline Dyspnea Index) and disease control (Asthma Control Questionnaire) in 65 asthmatics and evaluated their relationships. Results: Peripheral airway function as evaluated by IOS [R5–R20 (the fall in resistance from 5 to 20 Hz) and X5 (reactance at 5 Hz)], in addition to the proximal airway index (R20), significantly correlated with health status, dyspnea and disease control. Multiple regression analyses revealed that peripheral airway function significantly contributes to these, independently of the proximal airway index. In contrast, forced expiratory volume in 1 s did not significantly contribute to health status or dyspnea. Conclusions: IOS correlated better with clinical symptoms and asthma control than spirometry in patients with asthma. Peripheral and proximal airway functions as assessed separately by IOS independently contribute to health status, dyspnea and disease control, indicating that peripheral airways also represent an important therapeutic target.

© 2009 S. Karger AG, Basel


  

Key Words

  • Asthma
  • Dyspnea
  • Impulse oscillometry
  • Peripheral airways
  • Spirometry

 Introduction

Health status (health-related quality of life) and dyspnea are important clinical outcomes in asthma. These patient-reported outcomes imply functional impairments that are important to asthma patients during everyday life [1,2]. Although asthma is characterized by variable airflow limitation, health status and dyspnea are often only weakly correlated with the forced expiratory volume in 1 s (FEV1), the gold standard for the assessment of airflow limitation, and are considered to be measured independently of clinical physiological measurements [1,2].

Autopsy studies of patients dying from asthma have shown that inflammation and remodeling involve both large and small airways [3,4]. Increasing evidence indicates that inflammation of peripheral airways plays an important role in the pathophysiology of asthma [5,6,7]. Therefore, significant effects of peripheral airways on health status and dyspnea are expected in asthma, but the issue remains unclear, probably due to methodological difficulties in evaluating peripheral airways. Strong correlations between FEV1 and health status and dyspnea may be lacking because FEV1 mainly reflects expiratory flow at high and middle lung volumes, and thus, cannot provide accurate or specific information on peripheral airways. Forced expiratory flow technique may not be appropriate for assessing peripheral airways, as forced expiratory flow rates at mid-to-low lung volumes exhibit marked variability and may be affected by changes in proximal airway patency and lung volumes [8].

Recently, impulse oscillometry (IOS) has been utilized as a simple and noninvasive method of assessing pulmonary function without forced maneuvers in the investigations of asthma and chronic obstructive pulmonary disease [9,10,11,12]. IOS can separately quantify the degree of proximal and peripheral airway abnormalities, and thus, has been increasingly used in both adults [13,14,15,16] and children [17,18].

We hypothesized that significant relationships would exist between peripheral airway function and both health status and dyspnea in patients with asthma, and that this could be detected using IOS. Therefore, the present cross-sectional study examined interrelationships between pulmonary function as assessed by IOS and spirometry, and patient-reported outcomes of health status, dyspnea and disease control.

 

 Materials and Methods


 Subjects

Subjects comprised 65 consecutive outpatients with clinically stable asthma at Kyoto University Hospital asthma clinic. Entry criteria for the study were as follows: (1) meeting the definition of asthma by the American Thoracic Society [19]; (2) confirmation of airway hyperresponsiveness [20,21,22] on past evaluations; (3) never smokers or ex-smokers who had smoked <5 pack-years but had not smoked for >1 year [20]; (4) regular attendance at our clinic for >3 months; (5) no exacerbation of asthma over the last 4 weeks; (6) no changes in treatment within 4 weeks, and (7) no evidence of chronic obstructive pulmonary disease or other respiratory diseases. All subjects finished the following examinations between 9 and 12 a.m. on the same day, including IOS followed by spirometry and assessment of health status, dyspnea and asthma control. The research protocol was approved by the ethics committee of Kyoto University.

 Outcome Measures

Health Status. Health status was assessed using the Japanese versions of the standardized version of the Asthma Quality of Life Questionnaire (AQLQ) [23] and the St. George’s Respiratory Questionnaire (SGRQ) [24,25]. One of the authors (T.T.) reviewed the survey to ensure that subjects did not unintentionally omit any questions.

The AQLQ consists of 32 items comprising 4 domains: symptoms (12 items), activity limitations (11 items), emotional function (5 items) and exposure to environmental stimuli (4 items). The present study used the self-administered version. Patients were asked to recall their experiences during the previous 2 weeks and to score each item using a 7-point scale (1 = maximal impairment, 7 = no impairment). Domain scores were calculated as the mean score from the items forming each domain, and the overall score was calculated as the mean of the sum of all items.

The SGRQ comprises 50 items divided into 3 components: symptoms (8 items), activity (16 items) and impacts (26 items). The total score was also calculated from all component items. SGRQ scores ranged from 0 to 100 (0 = best health, 100 = worst health).

Dyspnea. Dyspnea during daily activities was evaluated using the Japanese version of the Baseline Dyspnea Index (BDI) [26,27], which was developed as a discriminative instrument to measure dyspnea at a single point in time in various respiratory diseases, including asthma [28]. The BDI recognizes 5 grades from 0 (severe) to 4 (not impaired) for each of the following 3 categories: functional impairment, magnitude of task and magnitude of effort. The total BDI score was calculated as the sum of these 3 categories.

Asthma Control. To measure asthma control, the Japanese version of the Asthma Control Questionnaire (ACQ) [29] was used. This questionnaire examines 5 symptoms (night-time waking, symptoms on waking, activity limitation, shortness of breath, wheeze), a question about rescue β2-agonist use and another about FEV1, with this last question completed by clinic staff. Patients recall their experiences during the previous 7 days and respond to each question using a 7-point scale. The items are equally weighted and the ACQ score is given as the mean of the 7 items and is therefore between 0 (well controlled) and 6 (extremely poorly controlled).

Spirometry. Subjects underwent spirometric testing according to the recommended method [30], using a ChestGraph HI-701 spirometer (Chest, Tokyo, Japan). Pre-bronchodilator values of FEV1 were examined.

Impulse Oscillometry. Measurement of respiratory impedance by IOS was conducted using an oscillatory system (MS-IOS; Erich Jaeger, Hoechberg, Germany), fulfilling standard recommendations [9]. In short, rectangular mechanical impulses containing the whole frequency spectrum were applied to the respiratory system through a mouthpiece while the patient was breathing quietly. The resulting pressure and flow signals were analyzed for amplitude and phase differences to determine resistance (R) and reactance (X) of the total respiratory system. Impedance measurements included resistance from 5 to 35 Hz (R5–R35), reactance from 5 to 35 Hz (X5–X35) and frequency of resonance, which represents the point at which the usually negative reactance reaches 0, measured in Hertz. In the present study, we used respiratory resistance at 5 and 20 Hz (R5 and R20) as indices of total and proximal airway resistance, respectively, and considered the fall in resistance from 5 to 20 Hz (R5–R20) as a surrogate for the resistance of peripheral airways, as reported previously [10,12,16,17,31,32]. Moreover, reactance at 5 Hz (X5), which may be determined by homogenous distribution of ventilation, effective ventilation capacity, and compliance of the lung and chest wall, was also considered representative of peripheral airway abnormalities such as those caused by inflammation [10,12,17,33].

 Statistical Analysis

Results are expressed as means ± standard deviation. Relationships between different outcome measurements were analyzed using Pearson’s correlation coefficient tests. For ordinal variables such as the BDI, we performed additional correlations using Spearman’s rank correlation coefficient tests to confirm that values for these correlations were compatible with Pearson’s correlation coefficients. We then chose to present all results as Pearson’s correlation coefficients for ease of comprehension and comparison across relationships [28]. Forward and backward stepwise multiple regression analyses were performed to identify variables that could best predict health status, dyspnea and disease control, using pulmonary function indices and medications as independent variables. Independent variables including the daily doses of inhaled corticosteroids were used as continuous variables, except that the categoric variables such as use of long-acting β2-agonists, leukotriene modifiers and theophylline were coded as 1 (administered) or 0 (not administered) for the analysis. Values of p < 0.05 were considered statistically significant.

 

 Results

Subject characteristics are presented in table 1. Among the 65 patients, 58 had never smoked. Severity of asthma was intermittent (step 1) in 7 patients, mild persistent (step 2) in 20, moderate persistent (step 3) in 28, and severe persistent (step 4) in 10, based on the classification according to the Global Initiative for Asthma guidelines [34].

TAB01
Table 1. Characteristics of 65 patients with asthma

Table 2 shows correlation coefficients between health status, dyspnea and disease control and pulmonary function and medications. Regarding health status, the overall score for the AQLQ and the total score for the SGRQ significantly but weakly correlated with FEV1 (correlation coefficient, r = 0.33 and 0.35), moderately correlated with R20 (r = 0.54 and 0.51), R5–R20 (r = 0.50 and 0.50) and X5 (r = 0.49 and 0.48), and weakly to moderately correlated with dose of inhaled corticosteroid and administration of theophylline (r = 0.35–0.41). Regarding dyspnea, the BDI moderately correlated with FEV1, R20, R5–R20 and X5 (r = 0.41–0.57) and weakly correlated with administration of theophylline (r = 0.32). Regarding disease control, the ACQ score moderately correlated with FEV1, R20, R5–R20 and X5 (r = 0.43–0.55), and weakly to moderately correlated with dose of inhaled corticosteroid and administration of long-acting β2-agonists, leukotriene modifiers and theophylline (r = 0.28–0.46).

TAB02
Table 2. Correlation coefficients between pulmonary function and medications and health status, dyspnea and disease control

Table 3 shows the results of stepwise multiple regression analyses performed to identify which variables of pulmonary function or medications could predict health status, dyspnea and disease control. Regarding health status, R20, X5 and dose of inhaled corticosteroid significantly accounted for the AQLQ (r2 = 0.21, 0.12 and 0.10, respectively). R20, R5–R20 and administration of theophylline and long-acting β2-agonists significantly accounted for the SGRQ (r2 = 0.18, 0.11, 0.10 and 0.07, respectively). Regarding dyspnea, R20 and R5–R20 significantly explained the BDI (r2 = 0.13 and 0.24, respectively). Regarding disease control, FEV1, X5 and administration of theophylline significantly accounted for the ACQ score (r2 = 0.19, 0.16 and 0.12, respectively).

TAB03
Table 3. Results of stepwise multiple regression analyses to predict health status, dyspnea and disease control

 

 Discussion

We assessed relationships between proximal and peripheral airway function and health status, dyspnea and disease control of patients with asthma, using the different instruments of IOS and spirometry. We demonstrated that peripheral airway function (R5–R20 and X5), in addition to proximal airway function (R20), as evaluated by IOS, correlated significantly with health status, dyspnea and disease control. In multiple regression analyses, peripheral airway function contributed significantly to these parameters, independent of proximal airway function (R20). In contrast, the index of spirometry (FEV1) did not significantly contribute to health status or dyspnea by multiple regression analyses, unlike the indices of IOS.

In the present study, peripheral airway function as evaluated by R5–R20 or X5 in addition to proximal airway function evaluated by R20 moderately correlated with the AQLQ, SGRQ and BDI. A number of previous studies have indicated only weak correlations between these health status and dyspnea measurements, and airflow limitation evaluated by FEV1 [1,2], which may preferentially reflect obstruction of proximal airways. Using the IOS technique, we have demonstrated significant correlations between peripheral airway dysfunction and both health status and dyspnea. The importance of peripheral airways in asthma has been well recognized. Peripheral airway disease has been associated with airway hyperresponsiveness [5,20,35], nocturnal asthma [5,36], exacerbation of asthma [5,37], severe asthma [5,20,38], increased asthma symptoms [39], exercise-induced asthma [40], and others. Therefore, significant relationships between peripheral airway function on IOS and health status and dyspnea would be understandable. Certainly, the data should be interpreted and discussed keeping in mind the issue of multiple testing and the possibility of type 1 statistical error.

Using multiple regression analyses, peripheral airway dysfunction (R5–R20 or X5) contributed significantly to the AQLQ, SGRQ and BDI, independent of proximal airway dysfunction (R20). The degrees of these contributions were almost equivalent between proximal and peripheral airway indices. To the best of our knowledge, this is the first study to demonstrate a comparative contribution of proximal and peripheral airway abnormalities to health status and dyspnea.

FEV1 was only weakly correlated with the AQLQ, SGRQ and BDI, as often reported previously [1,2,41,42]. FEV1 did not significantly contribute to these measures according to multiple regression analyses. Thus, the present study indicates that the status of airways as measured by spirometry does not well reflect the health status or dyspnea in asthma, unlike the case with separate measurements of proximal and peripheral airways by IOS. Two reasons may be taken into consideration. First, as suggested by Wagner et al. [44], despite the apparent lack of pulmonary impairments assessed by FEV1 and forced vital capacity, patients with asthma experience significantly increased peripheral airway resistance compared with normal subjects. Forced expiratory maneuvers with spirometry involve deep inspiration, which may affect airway tone. IOS measurements might more accurately reflect changes in airway caliber than spirometry measurements. Second, airflow indices of spirometry may only roughly reflect the presence of airway inflammation [45,46]. IOS might more precisely reflect such underlying airway inflammation, which may affect deterioration of health status or dyspnea, although this speculation remains yet to be clarified. This supposition could be tested by correlating IOS measures with noninvasive assessment of the alveolar fraction of exhaled nitric oxide or direct invasive determination of inflammatory changes in the distal lung through transbronchial biopsies or peripheral lung brushings.

We have recently reported the usefulness of high-resolution computed tomography in the assessment of small airways in asthma [20]. Other methods to assess peripheral airways include closing volume measurement [37] and the multiple breath washout test [47]. As compared with these methods, IOS is easier and less invasive and time consuming, thus representing a more practical tool to evaluate peripheral airway function [11]. In addition, as demonstrated in the present study, IOS indices reflected patient-reported outcomes better than spirometry, considering the separate effects of proximal and peripheral airway functions. In clinical trials investigating drug effects on asthma, as compared with control drugs, improvements in health status and disease control may be observed even though spirometric indices such as FEV1 or peak expiratory flow may not be significantly affected [48,49]. These results may be attributable to treatment effects on peripheral airways, which might have been detected by IOS.

The present study also evaluated the relationship between disease control and pulmonary function and medications. All pulmonary function indices were significantly and moderately correlated with the ACQ, and in multiple regression analyses, X5 and FEV1 contributed equivalently significantly to the ACQ, indicating the importance of both proximal and peripheral airways on asthma control.

There is also some evidence that IOS is a quantification of both proximal and peripheral airway abnormalities. We have recently shown that in patients with asthma, R20 correlated moderately with peak expiratory flow and that R5–R20 correlated moderately with mid-forced expiratory flow, residual volume and residual volume/total lung capacity, respectively, supporting the assumption that R20 is a marker of proximal airways, while R5–R20 reflects peripheral airway disease [12]. We have then shown that IOS was useful in detecting the effects of an ultrafine-particle inhaled corticosteroid on peripheral airways compared with a large-particle inhaled corticosteroid [12]. Jain et al. [50] demonstrated that IOS values such as the reversibility of X5 after bronchodilators were significantly correlated with the degree of air trapping as assessed by high-resolution computed tomography, indicating that both measurements reflect peripheral airway abnormalities. Other studies demonstrated that long-acting β2-agonists combined with inhaled corticosteroids [13] or oral leukotriene modifiers [17] improved peripheral airway function as well as proximal airway function by using IOS.

In the present study, doses of inhaled corticosteroids or administration of long-acting β2-agonists or theophylline significantly accounted for health status or disease control. This may be due to the fact that the dose of inhaled corticosteroid was increased and other drugs were added based on the severity of disease. Our study was conducted in a cross-sectional fashion, and longitudinal studies should be expected to investigate the effects of those drugs on patient-reported measurements.

The AQLQ and the SGRQ are 2 of the most widely used disease-specific health status instruments in asthma. Both significantly and similarly correlate with global estimates of asthma severity [51] and other important asthma outcomes and have shown high reliability and validity, as well as high levels of responsiveness. We have found that the patterns of contributions of proximal and peripheral airways to the AQLQ and SGRQ are nearly the same.

In conclusion, IOS correlated better with clinical symptoms and asthma control than spirometry in patients with asthma. Both peripheral and proximal airway function as assessed by IOS significantly and independently contributed to health status, dyspnea and disease control in patients with asthma. From the perspective of patient-reported outcomes, peripheral airways also are a potentially important therapeutic target in asthma.


References

  1. Juniper EF: Health-related quality of life in asthma. Curr Opin Pulm Med 1999;5:105–110.
  2. Lougheed MD, O’Donnell DE: Dyspnea in asthma; in Mahler DA, O’Donnell DE (eds): Dyspnea: Mechanisms, Measurement, and Management, ed 2. New York, Taylor and Francis Group, 2005, pp 59–86.
  3. Carroll N, Elliot J, Morton A, James A: The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–410.
  4. James AL, Pare PD, Hogg JC: The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989;139:242–246.
  5. Martin RJ: Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol 2002;109:S447–S460.
  6. Kraft M: The distal airways: are they important in asthma? Eur Respir J 1999;14:1403–1417.
  7. Tulic MK, Hamid Q: New insights into the pathophysiology of the small airways in asthma. Clin Chest Med 2006;27:41–52.
  8. Sherter CB, Connolly JJ, Schilder DP: The significance of volume – adjusting the maximal midexpiratory flow in assessing the response to a bronchodilator drug. Chest 1978;73:568–571.
  9. Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, Marchal F, ERS Task Force on Respiratory Impedance Measurements: The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:1026–1041.
  10. Goldman MD, Saadeh C, Ross D: Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol Neurobiol 2005;148:179–194.
  11. King GG, Salome CM: Multimodality measurements of small airways disease. Eur Respir J 2006;27:250–252.
  12. Yamaguchi M, Niimi A, Ueda T, Takemura M, Matsuoka H, Jinnai M, Otsuka K, Oguma T, Takeda T, Ito I, Matsumoto H, Hirai T, Chin K, Mishima M: Effect of inhaled corticosteroids on small airways in asthma: investigation using impulse oscillometry. Pulm Pharmacol Ther 2009;22:326–332.
  13. Houghton CM, Lawson N, Borrill ZL, Wixon CL, Yoxall S, Langley SJ, Woodcock A, Singh D: Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma. Respir Res 2007;8:52.
  14. Park JW, Lee YW, Jung YH, Park SE, Hong CS: Impulse oscillometry for estimation of airway obstruction and bronchodilation in adults with mild obstructive asthma. Ann Allergy Asthma Immunol 2007;98:546–552.
  15. Houghton CM, Woodcock AA, Singh D: A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma. Br J Clin Pharmacol 2005;59:152–159.
  16. Cao J, Que C, Wang G, He B: Effect of posture on airway resistance in obstructive sleep apnea-hypopnea syndrome by means of impulse oscillation. Respiration 2009;77:38–43.
  17. Nieto A, Pamies R, Oliver F, Medina A, Caballero L, Mazon A: Montelukast improves pulmonary function measured by impulse oscillometry in children with asthma (Mio study). Respir Med 2006;100:1180–1185.
  18. Marotta A, Klinnert MD, Price MR, Larsen GL, Liu AH: Impulse oscillometry provides an effective measure of lung dysfunction in 4-year-old children at risk for persistent asthma. J Allergy Clin Immunol 2003;112:317–322.
  19. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225–244.
  20. Ueda T, Niimi A, Matsumoto H, Takemura M, Hirai T, Yamaguchi M, Matsuoka H, Jinnai M, Muro S, Chin K, Mishima M: Role of small airways in asthma: investigation using high-resolution computed tomography. J Allergy Clin Immunol 2006;118:1019–1025.
  21. Takishima T, Hida W, Sasaki H, Suzuki S, Sasaki T: Direct-writing recorder of the dose-response curves of the airway to methacholine. Clinical application. Chest 1981;80:600–606.
  22. Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M: Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med 2003;168:983–988.
  23. Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR: Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115:1265–1270.
  24. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T: Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003;167:544–549.
  25. Jones PW, Quirk FH, Baveystock CM, Littlejohns P: A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327.
  26. Mahler DA, Weinberg DH, Wells CK, Feinstein AR: The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984;85:751–758.
  27. Oga T, Nishimura K, Tsukino M, Hajiro T, Mishima M: Dyspnoea with activities of daily living versus peak dyspnoea during exercise in male patients with COPD. Respir Med 2006;100:965–971.
  28. Mahler DA, Wells CK: Evaluation of clinical methods for rating dyspnea. Chest 1988;93:580–586.
  29. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR: Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902–907.
  30. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force: Standardisation of spirometry. Eur Respir J 2005;26:319–338.
  31. Skloot G, Goldman M, Fischler D, Goldman C, Schechter C, Levin S, Teirstein A: Respiratory symptoms and physiologic assessment of ironworkers at the World Trade Center disaster site. Chest 2004;125:1248–1255.
  32. Oppenheimer BW, Goldring RM, Herberg ME, Hofer IS, Reyfman PA, Liautaud S, Rom WN, Reibman J, Berger KI: Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure. Chest 2007;132:1275–1282.
  33. Smith H, Reinhold P, Goldman M: Forced oscillation technique and impulse oscillometry. Eur Respir Mon 2005;31:72–105.

    External Resources

  34. Global strategy for asthma management and prevention: publication No 02-3659. Bethesda, National Institute of Health/National Heart, Lung, and Blood Institute, 2004.
  35. Wagner EM, Bleecker ER, Permutt S, Liu MC: Direct assessment of small airways reactivity in human subjects. Am J Respir Crit Care Med 1998;157:447–452.
  36. Sutherland ER: Nocturnal asthma. J Allergy Clin Immunol 2005;116:1179–1186.
  37. In ‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ: Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:1902–1906.

    External Resources

  38. Wenzel SE, Busse WW, the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program: Severe asthma: lessons from the Severe Asthma Research Program. J Allergy Clin Immunol 2007;119:14–21.
  39. Kraft M, Cairns CB, Ellison MC, Pak J, Irvin C, Wenzel S: Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast. Chest 2006;130:1726–1732.
  40. Anderson SD, Holzer K: Exercise-induced asthma: is it the right diagnosis in elite athletes? J Allergy Clin Immunol 2000;106:419–428.
  41. Shingo S, Zhang J, Reiss TF: Correlation of airway obstruction and patient reported endpoints in clinical studies. Eur Respir J 2001;17:220–224.
  42. Grazzini M, Scano G, Foglio K, Duranti R, Bianchi L, Gigliotti E, Rosi E, Stendardi L, Ambrosino N: Relevance of dyspnoea and respiratory function measurements in monitoring of asthma: a factor analysis. Respir Med 2001;95:246–250.
  43. McFadden E Jr, Linden D: A reduction in maximum mid-expiratory flow rate: a spirographic manifestation of small airway disease. Am J Med 1972;52:725–737.
  44. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER: Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584–588.
  45. Fortuna AM, Feixas T, González M, Casan P: Diagnostic utility of inflammatory biomarkers in asthma: exhaled nitric oxide and induced sputum eosinophil count. Respir Med 2007;101:2416–2421.
  46. Ren CL: What is the best way to measure lung function? Chest 2003;123:667–668.
  47. Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W: Small airway function improvement after smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med 2006;174:853–857.
  48. Juniper EF, Price DB, Stampone PA, Creemers JP, Mol SJ, Fireman P: Clinically important improvements in asthma-specific quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropionate. Chest 2002;121:1824–1832.
  49. Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD, Sayre JW, Liu W, Elashoff R, Tashkin DP: Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J 2006;27:307–315.
  50. Jain N, Covar RA, Gleason MC, Newell JD Jr, Gelfand EW, Spahn JD: Quantitative computed tomography detects peripheral airway disease in asthmatic children. Pediatr Pulmonol 2005;40:211–218.
  51. Barley EA, Jones PW: A comparison of global questions versus health status questionnaires as measures of the severity and impact of asthma. Eur Respir J 1999;14:591–596.

  

Author Contacts

A. Niimi, MD, PhD
Department of Respiratory Medicine, Graduate School of Medicine
Kyoto University, 54, Kawahara-cho
Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan)
Tel. +81 75 751 3830, Fax +81 75 751 4643, E-Mail niimi@kuhp.kyoto-u.ac.jp

  

Article Information

Toru Oga and Akio Niimi contributed equally to this article.

Received: February 23, 2009
Accepted after revision: July 6, 2009
Published online: September 22, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 3, Number of References : 51

  

Publication Details

Respiration (Official Journal of the European Association for Bronchology and Interventional Pulmonology (EAB) and the Swiss Society for Pneumology (SGP))

Vol. 80, No. 2, Year 2010 (Cover Date: July 2010)

Journal Editor: Bolliger C.T. (Cape Town)
ISSN: 0025-7931 (Print), eISSN: 1423-0356 (Online)

For additional information: http://www.karger.com/RES


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Small airways play important roles in the pathophysiology of asthma. However, relationships between small airway involvement and health status and dyspnea have not been investigated. Objectives: It was the aim of this study to assess the relationships between proximal and peripheral airway functions and health status, dyspnea and disease control in patients with asthma, using impulse oscillometry (IOS). Methods: We performed IOS, spirometry and assessment of health status (Asthma Quality of Life Questionnaire and St. George’s Respiratory Questionnaire), dyspnea (Baseline Dyspnea Index) and disease control (Asthma Control Questionnaire) in 65 asthmatics and evaluated their relationships. Results: Peripheral airway function as evaluated by IOS [R5–R20 (the fall in resistance from 5 to 20 Hz) and X5 (reactance at 5 Hz)], in addition to the proximal airway index (R20), significantly correlated with health status, dyspnea and disease control. Multiple regression analyses revealed that peripheral airway function significantly contributes to these, independently of the proximal airway index. In contrast, forced expiratory volume in 1 s did not significantly contribute to health status or dyspnea. Conclusions: IOS correlated better with clinical symptoms and asthma control than spirometry in patients with asthma. Peripheral and proximal airway functions as assessed separately by IOS independently contribute to health status, dyspnea and disease control, indicating that peripheral airways also represent an important therapeutic target.

© 2009 S. Karger AG, Basel


  

Author Contacts

A. Niimi, MD, PhD
Department of Respiratory Medicine, Graduate School of Medicine
Kyoto University, 54, Kawahara-cho
Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan)
Tel. +81 75 751 3830, Fax +81 75 751 4643, E-Mail niimi@kuhp.kyoto-u.ac.jp

  

Article Information

Toru Oga and Akio Niimi contributed equally to this article.

Received: February 23, 2009
Accepted after revision: July 6, 2009
Published online: September 22, 2009
Number of Print Pages : 7
Number of Figures : 0, Number of Tables : 3, Number of References : 51

  

Publication Details

Respiration (Official Journal of the European Association for Bronchology and Interventional Pulmonology (EAB) and the Swiss Society for Pneumology (SGP))

Vol. 80, No. 2, Year 2010 (Cover Date: July 2010)

Journal Editor: Bolliger C.T. (Cape Town)
ISSN: 0025-7931 (Print), eISSN: 1423-0356 (Online)

For additional information: http://www.karger.com/RES


Article / Publication Details

First-Page Preview
Abstract of Clinical Investigations

Received: 2/23/2009
Accepted: 7/6/2009
Published online: 9/22/2009
Issue release date: July 2010

Number of Print Pages: 7
Number of Figures: 0
Number of Tables: 3

ISSN: 0025-7931 (Print)
eISSN: 1423-0356 (Online)

For additional information: http://www.karger.com/RES


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Juniper EF: Health-related quality of life in asthma. Curr Opin Pulm Med 1999;5:105–110.
  2. Lougheed MD, O’Donnell DE: Dyspnea in asthma; in Mahler DA, O’Donnell DE (eds): Dyspnea: Mechanisms, Measurement, and Management, ed 2. New York, Taylor and Francis Group, 2005, pp 59–86.
  3. Carroll N, Elliot J, Morton A, James A: The structure of large and small airways in nonfatal and fatal asthma. Am Rev Respir Dis 1993;147:405–410.
  4. James AL, Pare PD, Hogg JC: The mechanics of airway narrowing in asthma. Am Rev Respir Dis 1989;139:242–246.
  5. Martin RJ: Therapeutic significance of distal airway inflammation in asthma. J Allergy Clin Immunol 2002;109:S447–S460.
  6. Kraft M: The distal airways: are they important in asthma? Eur Respir J 1999;14:1403–1417.
  7. Tulic MK, Hamid Q: New insights into the pathophysiology of the small airways in asthma. Clin Chest Med 2006;27:41–52.
  8. Sherter CB, Connolly JJ, Schilder DP: The significance of volume – adjusting the maximal midexpiratory flow in assessing the response to a bronchodilator drug. Chest 1978;73:568–571.
  9. Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, Marchal F, ERS Task Force on Respiratory Impedance Measurements: The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003;22:1026–1041.
  10. Goldman MD, Saadeh C, Ross D: Clinical applications of forced oscillation to assess peripheral airway function. Respir Physiol Neurobiol 2005;148:179–194.
  11. King GG, Salome CM: Multimodality measurements of small airways disease. Eur Respir J 2006;27:250–252.
  12. Yamaguchi M, Niimi A, Ueda T, Takemura M, Matsuoka H, Jinnai M, Otsuka K, Oguma T, Takeda T, Ito I, Matsumoto H, Hirai T, Chin K, Mishima M: Effect of inhaled corticosteroids on small airways in asthma: investigation using impulse oscillometry. Pulm Pharmacol Ther 2009;22:326–332.
  13. Houghton CM, Lawson N, Borrill ZL, Wixon CL, Yoxall S, Langley SJ, Woodcock A, Singh D: Comparison of the effects of salmeterol/fluticasone propionate with fluticasone propionate on airway physiology in adults with mild persistent asthma. Respir Res 2007;8:52.
  14. Park JW, Lee YW, Jung YH, Park SE, Hong CS: Impulse oscillometry for estimation of airway obstruction and bronchodilation in adults with mild obstructive asthma. Ann Allergy Asthma Immunol 2007;98:546–552.
  15. Houghton CM, Woodcock AA, Singh D: A comparison of plethysmography, spirometry and oscillometry for assessing the pulmonary effects of inhaled ipratropium bromide in healthy subjects and patients with asthma. Br J Clin Pharmacol 2005;59:152–159.
  16. Cao J, Que C, Wang G, He B: Effect of posture on airway resistance in obstructive sleep apnea-hypopnea syndrome by means of impulse oscillation. Respiration 2009;77:38–43.
  17. Nieto A, Pamies R, Oliver F, Medina A, Caballero L, Mazon A: Montelukast improves pulmonary function measured by impulse oscillometry in children with asthma (Mio study). Respir Med 2006;100:1180–1185.
  18. Marotta A, Klinnert MD, Price MR, Larsen GL, Liu AH: Impulse oscillometry provides an effective measure of lung dysfunction in 4-year-old children at risk for persistent asthma. J Allergy Clin Immunol 2003;112:317–322.
  19. American Thoracic Society: Standards for the diagnosis and care of patients with chronic obstructive pulmonary disease (COPD) and asthma. Am Rev Respir Dis 1987;136:225–244.
  20. Ueda T, Niimi A, Matsumoto H, Takemura M, Hirai T, Yamaguchi M, Matsuoka H, Jinnai M, Muro S, Chin K, Mishima M: Role of small airways in asthma: investigation using high-resolution computed tomography. J Allergy Clin Immunol 2006;118:1019–1025.
  21. Takishima T, Hida W, Sasaki H, Suzuki S, Sasaki T: Direct-writing recorder of the dose-response curves of the airway to methacholine. Clinical application. Chest 1981;80:600–606.
  22. Niimi A, Matsumoto H, Takemura M, Ueda T, Chin K, Mishima M: Relationship of airway wall thickness to airway sensitivity and airway reactivity in asthma. Am J Respir Crit Care Med 2003;168:983–988.
  23. Juniper EF, Buist AS, Cox FM, Ferrie PJ, King DR: Validation of a standardized version of the Asthma Quality of Life Questionnaire. Chest 1999;115:1265–1270.
  24. Oga T, Nishimura K, Tsukino M, Sato S, Hajiro T: Analysis of the factors related to mortality in chronic obstructive pulmonary disease: role of exercise capacity and health status. Am J Respir Crit Care Med 2003;167:544–549.
  25. Jones PW, Quirk FH, Baveystock CM, Littlejohns P: A self-complete measure of health status for chronic airflow limitation. The St. George’s Respiratory Questionnaire. Am Rev Respir Dis 1992;145:1321–1327.
  26. Mahler DA, Weinberg DH, Wells CK, Feinstein AR: The measurement of dyspnea. Contents, interobserver agreement, and physiologic correlates of two new clinical indexes. Chest 1984;85:751–758.
  27. Oga T, Nishimura K, Tsukino M, Hajiro T, Mishima M: Dyspnoea with activities of daily living versus peak dyspnoea during exercise in male patients with COPD. Respir Med 2006;100:965–971.
  28. Mahler DA, Wells CK: Evaluation of clinical methods for rating dyspnea. Chest 1988;93:580–586.
  29. Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR: Development and validation of a questionnaire to measure asthma control. Eur Respir J 1999;14:902–907.
  30. Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R, Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N, McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J, ATS/ERS Task Force: Standardisation of spirometry. Eur Respir J 2005;26:319–338.
  31. Skloot G, Goldman M, Fischler D, Goldman C, Schechter C, Levin S, Teirstein A: Respiratory symptoms and physiologic assessment of ironworkers at the World Trade Center disaster site. Chest 2004;125:1248–1255.
  32. Oppenheimer BW, Goldring RM, Herberg ME, Hofer IS, Reyfman PA, Liautaud S, Rom WN, Reibman J, Berger KI: Distal airway function in symptomatic subjects with normal spirometry following World Trade Center dust exposure. Chest 2007;132:1275–1282.
  33. Smith H, Reinhold P, Goldman M: Forced oscillation technique and impulse oscillometry. Eur Respir Mon 2005;31:72–105.

    External Resources

  34. Global strategy for asthma management and prevention: publication No 02-3659. Bethesda, National Institute of Health/National Heart, Lung, and Blood Institute, 2004.
  35. Wagner EM, Bleecker ER, Permutt S, Liu MC: Direct assessment of small airways reactivity in human subjects. Am J Respir Crit Care Med 1998;157:447–452.
  36. Sutherland ER: Nocturnal asthma. J Allergy Clin Immunol 2005;116:1179–1186.
  37. In ‘t Veen JC, Beekman AJ, Bel EH, Sterk PJ: Recurrent exacerbations in severe asthma are associated with enhanced airway closure during stable episodes. Am J Respir Crit Care Med 2000;161:1902–1906.

    External Resources

  38. Wenzel SE, Busse WW, the National Heart, Lung, and Blood Institute’s Severe Asthma Research Program: Severe asthma: lessons from the Severe Asthma Research Program. J Allergy Clin Immunol 2007;119:14–21.
  39. Kraft M, Cairns CB, Ellison MC, Pak J, Irvin C, Wenzel S: Improvements in distal lung function correlate with asthma symptoms after treatment with oral montelukast. Chest 2006;130:1726–1732.
  40. Anderson SD, Holzer K: Exercise-induced asthma: is it the right diagnosis in elite athletes? J Allergy Clin Immunol 2000;106:419–428.
  41. Shingo S, Zhang J, Reiss TF: Correlation of airway obstruction and patient reported endpoints in clinical studies. Eur Respir J 2001;17:220–224.
  42. Grazzini M, Scano G, Foglio K, Duranti R, Bianchi L, Gigliotti E, Rosi E, Stendardi L, Ambrosino N: Relevance of dyspnoea and respiratory function measurements in monitoring of asthma: a factor analysis. Respir Med 2001;95:246–250.
  43. McFadden E Jr, Linden D: A reduction in maximum mid-expiratory flow rate: a spirographic manifestation of small airway disease. Am J Med 1972;52:725–737.
  44. Wagner EM, Liu MC, Weinmann GG, Permutt S, Bleecker ER: Peripheral lung resistance in normal and asthmatic subjects. Am Rev Respir Dis 1990;141:584–588.
  45. Fortuna AM, Feixas T, González M, Casan P: Diagnostic utility of inflammatory biomarkers in asthma: exhaled nitric oxide and induced sputum eosinophil count. Respir Med 2007;101:2416–2421.
  46. Ren CL: What is the best way to measure lung function? Chest 2003;123:667–668.
  47. Verbanck S, Schuermans D, Paiva M, Meysman M, Vincken W: Small airway function improvement after smoking cessation in smokers without airway obstruction. Am J Respir Crit Care Med 2006;174:853–857.
  48. Juniper EF, Price DB, Stampone PA, Creemers JP, Mol SJ, Fireman P: Clinically important improvements in asthma-specific quality of life, but no difference in conventional clinical indexes in patients changed from conventional beclomethasone dipropionate to approximately half the dose of extrafine beclomethasone dipropionate. Chest 2002;121:1824–1832.
  49. Zeidler MR, Kleerup EC, Goldin JG, Kim HJ, Truong DA, Simmons MD, Sayre JW, Liu W, Elashoff R, Tashkin DP: Montelukast improves regional air-trapping due to small airways obstruction in asthma. Eur Respir J 2006;27:307–315.
  50. Jain N, Covar RA, Gleason MC, Newell JD Jr, Gelfand EW, Spahn JD: Quantitative computed tomography detects peripheral airway disease in asthmatic children. Pediatr Pulmonol 2005;40:211–218.
  51. Barley EA, Jones PW: A comparison of global questions versus health status questionnaires as measures of the severity and impact of asthma. Eur Respir J 1999;14:591–596.