Small airway dysfunction is associated to excessive bronchoconstriction in asthmatic patients

Respiratory Research

Alfredo Chetta¹  Gabriele Nicolini²  Dario Olivieri¹  Emilio Marangio¹  Elisa Mariani¹  Panagiota Tzani¹  Roberta Pisi¹  Marina Aiello¹  Veronica Alfieri¹ 

[1] Clinical & Experimental Medicine Department, University of Parma, Padiglione Rasori, via G. Rasori 10, Parma, 43125, Italy;Corporate Clinical Development, Chiesi Farmaceutici S.p.A, Parma, Italy

关键词: Asthma;    Small airways;    Bronchial hyperresponsiveness;   

Others  :  1146260
DOI  :  10.1186/s12931-014-0086-1

 received in 2014-04-01, accepted in 2014-07-20,  发布年份 2014

【 摘 要 】

Background

We investigated whether a relationship between small airways dysfunction and bronchial hyperresponsiveness (BHR), expressed both in terms of ease of airway narrowing and of excessive bronchoconstriction, could be demonstrated in asthma.

Methods

63 (36 F; mean age 42 yr ± 14) stable, mild-to-moderate asthmatic patients (FEV₁ 92% pred ±14; FEV₁/FVC 75% ± 8) underwent the methacholine challenge test (MCT). The degree of BHR was expressed as PD₂₀ (in μg) and as ∆FVC%. Peripheral airway resistance was measured pre- and post-MCT by impulse oscillometry system (IOS) and expressed as R5-R20 (in kPa sL⁻¹).

Results

All patients showed BHR to methacholine (PD₂₀ < 1600 μg) with a PD₂₀ geometric (95% CI) mean value of 181(132–249) μg and a ∆FVC% mean value of 13.6% ± 5.1, ranging 2.5 to 29.5%. 30 out of 63 patients had R5-R20 > 0.03 kPa sL⁻¹ (>upper normal limit) and showed ∆FVC%, but not PD₂₀ values significantly different from the 33 patients who had R5-R20 ≤ 0.03 kPa sL⁻¹ (15.8% ± 4.6 vs 11.5% ± 4.8, p < 0.01 and 156(96–254) μg vs 207 (134–322) μg, p = 0.382). In addition, ∆FVC% values were significantly related to the corresponding pre- (r = 0.451, p < 0.001) and post-MCT (r = 0.376, p < 0.01) R5-R20 values.

Conclusions

Our results show that in asthmatic patients, small airway dysfunction, as assessed by IOS, is strictly associated to BHR, expressed as excessive bronchoconstriction, but not as ease of airway narrowing.

【 授权许可】

   
2014 Alfieri et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

Figure 6.

【 参考文献 】

• [1]van den Berge M, ten Hacken NH, Cohen J, Douma WR, Postma DS: Small airway disease in asthma and COPD: clinical implications. Chest 2011, 139:412-423.
• [2]Takeda T, Oga T, Niimi A, Matsumoto H, Ito I, Yamaguchi M, Matsuoka H, Jinnai M, Otsuka K, Oguma T, Nakaji H, Chin K, Mishima M: Relationship between small airway function and health status, dyspnea and disease control in asthma. Respiration 2010, 80:120-126.
• [3]Pisi R, Tzani P, Aiello M, Martinelli E, Marangio E, Nicolini G, Olivieri D, Chetta A: Small airway dysfunction by impulse oscillometry in asthmatic patients with normal forced expiratory volume in the 1st second values. Allergy Asthma Proc 2013, 34:e14-e20.
• [4]Simon MR, Chinchilli VM, Phillips BR, Sorkness CA, Lemanske RF Jr, Szefler SJ, Taussig L, Bacharier LB, Morgan W: Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values. J Allergy Clin Immunol 2010, 126:527-534.
• [5]Telenga ED, van den Berge M, Ten Hacken NH, Riemersma RA, van der Molen T, Postma DS: Small airways in asthma: their independent contribution to the severity of hyperresponsiveness. Eur Respir J 2013, 41:752-754.
• [6]Cockcroft DW, Davis BE: Mechanisms of airway hyperresponsiveness. J Allergy Clin Immunol 2006, 118:551-559.
• [7]Jansen DF, Schouten JP, Vonk JM, Rijcken B, Timens W, Kraan J, Weiss ST, Postma DS: Smoking and airway hyperresponsiveness especially in the presence of blood eosinophilia increase the risk to develop respiratory symptoms: a 25-year follow-up study in the general adult population. Am J Respir Crit Care Med 1999, 160:259-264.
• [8]Peat JK, Woolcock AJ, Cullen K: Rate of decline of lung function in subjects with asthma. Eur J Respir Dis 1987, 70:171-179.
• [9]Josephs LK, Gregg I, Holgate ST: Does non-specific bronchial responsiveness indicate the severity of asthma? Eur J Respir Dis 1990, 3:220-227.
• [10]Ding DJ, Martin JG, Macklem PT: Effects of lung volume on maximal methacholine-induced bronchoconstriction in normal humans. J Appl Physiol 1987, 62:1324-1330.
• [11]Sly PD, Brown KA, Bates JH, Macklem PT, Milic-Emili J, Martin JG: Effect of lung volume on interrupter resistance in cats challenged with methacholine. J Appl Physiol 1988, 64:360-366.
• [12]Robatto FM, Simard S, Orana H, Macklem PT, Ludwig MS: Effect of lung volume on plateau response of airways and tissue to methacholine in dogs. J Appl Physiol 1992, 73:1908-1913.
• [13]Gibbons WJ, Sharma A, Lougheed D, Macklem PT: Detection of excessive bronchoconstriction in asthma. Am J Respir Crit Care Med 1996, 153:582-589.
• [14]Abisheganaden J, Chan C-C, Chee CBE, Wang Y-T: Methacholine-induced fall in forced vital capacity as a marker of asthma severity. Respir Med 1999, 93:277-282.
• [15]Yoo Y, Choung JT, Yu J, Kim do K, Choi SH, Koh YY: Comparison of percentage fall in FVC at the provocative concentration of methacholine causing a 20% fall in FEV1 between patients with asymptomatic bronchial hyperresponsiveness and mild asthma. Chest 2007, 132:106-111.
• [16]Burgel P-R: The role of small airways in obstructive airway diseases. Eur Respir Rev 2011, 20:23-33.
• [17]King GG, Downie SR, Verbanck S, Thorpe CW, Berend N, Salome CM, Thompson B: Effects of methacholine on small airway function measured by forced oscillation technique and multiple breath nitrogen washout in normal subjects. Respir Physiol Neurobiol 2005, 148:165-177.
• [18]Song TW, Kim KW, Kim ES, Park JW, Sohn MH, Kim KE: Utility of impulse oscillometry in young children with asthma. Pediatr Allergy Immunol 2008, 19:763-768.
• [19]Komarow HD, Skinner J, Young M, Gaskins D, Nelson C, Gergen PJ, Metcalfe DD: A study of the use of impulse oscillometry in the evaluation of children with asthma: analysis of lung parameters, order effect, and utility compared with spirometry. Pediatr Pulmonol 2012, 47:18-26.
• [20]Oostveen E, MacLeod D, Lorino H, Farré R, Hantos Z, Desager K, Marchal F: The forced oscillation technique in clinical practice: methodology, recommendations and future developments. Eur Respir J 2003, 22:1026-1041.
• [21]Bateman ED1, Hurd SS, Barnes PJ, Bousquet J, Drazen JM, FitzGerald M, Gibson P, Ohta K, O’Byrne P, Pedersen SE, Pizzichini E, Sullivan SD, Wenzel SE, Zar HJ: Global strategy for asthma management and prevention: GINA executive summary. Eur Respir J 2008, 31:143-178.
• [22]Nathan RA, Sorkness CA, Kosinski M, Schatz M, Li JT, Marcus P, Murray JJ, Pendergraft TB: Development of the asthma control test: a survey for assessing asthma control. J Allergy Clin Immunol 2004, 113:59-65.
• [23]Williamson PA, Clearie K, Menzies D, Vaidyanathan S, Lipworth BJ: Assessment of small-airways disease using alveolar nitric oxide and impulse oscillometry in asthma and COPD. Lung 2011, 189:121-129.
• [24]Zweig MH, Campell G: Receiver-operating characteristic (ROC) plots: a fundamental evaluation tool in clinical medicine. Clin Chem 1993, 39:561-577.
• [25]Cohen J, Postma DS, Douma WR, Vonk JM, De Boer AH, ten Hacken NHT: Particle size matters: diagnostic and treatment of small airways involvement in asthma. Eur Respir J 2011, 37:532-540.
• [26]Ward RJ, Liakakos P, Leonard RF, Reid DW, Johns DP, Walters EH: A critical evaluation of the MefarTM dosimeter. Eur Respir J 1999, 14:430-434.
• [27]Macklem PT: Mechanical factors determing maximum bronchoconstriction. Eur Respir J 1989, 2(Suppl 6):516s-519s.
• [28]Hamid Q, Song Y, Kotsimbos TC, Minshall E, Bai TR, Hegele RG, Hogg JC: Inflammation of small airways in asthma. J Allergy Clin Immunol 1997, 100:44-51.
• [29]Tulic MK, Christodoulopoulos P, Hamid Q: Small airway inflammation in asthma. Respir Res 2001, 2:333-339. BioMed Central Full Text
• [30]Balzar S, Wenzel SE, Chu HW: Transbronchial biopsy as a tool to evaluate small airways in asthma. Eur Respir J 2002, 20:254-259.
• [31]Kuwano K, Bosken CH, Paré PD, Bai TR, Wiggs BR, Hogg JC: Small airways dimensions in asthma and in chronic obstructive pulmonary disease. Am Rev Respir Dis 1993, 148:1220-1225.
• [32]Dolhnikoff M, da Silva LF, de Araujo BB, Gomes HA, Fernezlian S, Mulder A, Lindeman JH, Mauad T: The outer wall of small airways is a major site of remodeling in fatal asthma. J Allergy Clin Immunol 2009, 123:1090-1097.
• [33]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.
• [34]Shi Y, Aledia AS, Tatavoosian AV, Vijayalakshmi S, Galant SP, George SC: Relating small airways to asthma control by using impulse oscillometry in children. J Allergy Clin Immunol 2012, 129:671-678.
• [35]Shi Y, Aledia AS, Galant SP, George SC: Peripheral airway impairment measured by oscillometry predicts loss of asthma control in children. J Allergy Clin Immunol 2013, 131:718-723.
• [36]Sorkness RL, Bleecker ER, Busse WW, Calhoun WJ, Castro M, Chung KF, Curran-Everett D, Erzurum SC, Gaston BM, Israel E, Jarjour NN, Moore WC, Peters SP, Teague WG, Wenzel SE: Lung function in adults with stable but severe asthma: air trapping and incomplete reversal of obstruction with bronchodilation. J Appl Physiol 2008, 104:394-403.
• [37]Cohen J, Douma WR, ten Hacken NHT, Oudkerk M, Postma DS: Physiology of the small airways: A gender difference? Respir Med 2008, 102:1264-1271.
• [38]Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, D’Agostino R Jr, Castro M, Curran-Everett D, Fitzpatrick AM, Gaston B, Jarjour NN, Sorkness R, Calhoun WJ, Chung KF, Comhair SA, Dweik RA, Israel E, Peters SP, Busse WW, Erzurum SC, Bleecker ER: Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010, 181:315-323.