Allergy, Asthma & Immunology Research

The Korean Academy of Asthma, Allergy and Clinical Immunology (대한천식알레르기학회)
권호 표지
DOI QR코드

DOI QR Code

Lung Function Trajectory Types in Never-Smoking Adults With Asthma: Clinical Features and Inflammatory Patterns

  • Kim, Joo-Hee (Division of Pulmonology, Allergy and Critical Care, Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine) ;
  • Chang, Hun Soo (Genome Research Center for Allergy and Respiratory Diseases) ;
  • Shin, Seung Woo (Genome Research Center for Allergy and Respiratory Diseases) ;
  • Baek, Dong Gyu (Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang Graduate School) ;
  • Son, Ji-Hye (Department of Interdisciplinary Program in Biomedical Science Major, Soonchunhyang Graduate School) ;
  • Park, Choon-Sik (Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital) ;
  • Park, Jong-Sook (Division of Allergy and Respiratory Medicine, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital)
  • Received : 2018.03.06
  • Accepted : 2018.05.25
  • Published : 2018.11.01
⟨ Previous Next ⟩

Abstract

Purpose: Asthma is a heterogeneous disease that responds to medications to varying degrees. Cluster analyses have identified several phenotypes and variables related to fixed airway obstruction; however, few longitudinal studies of lung function have been performed on adult asthmatics. We investigated clinical, demographic, and inflammatory factors related to persistent airflow limitation based on lung function trajectories over 1 year. Methods: Serial post-bronchodilator forced expiratory volume (FEV) 1% values were obtained from 1,679 asthmatics who were followed up every 3 months for 1 year. First, a hierarchical cluster analysis was performed using Ward's method to generate a dendrogram for the optimum number of clusters using the complete post-FEV1 sets from 448 subjects. Then, a trajectory cluster analysis of serial post-FEV1 sets was performed using the k-means clustering for the longitudinal data trajectory method. Next, trajectory clustering for the serial post-FEV1 sets of a total of 1,679 asthmatics was performed after imputation of missing post-FEV1 values using regression methods. Results: Trajectories 1 and 2 were associated with normal lung function during the study period, and trajectory 3 was associated with a reversal to normal of the moderately decreased baseline FEV1 within 3 months. Trajectories 4 and 5 were associated with severe asthma with a marked reduction in baseline FEV1. However, the FEV1 associated with trajectory 4 was increased at 3 months, whereas the FEV1 associated with trajectory 5 was persistently disturbed over 1 year. Compared with trajectory 4, trajectory 5 was associated with older asthmatics with less atopy, a lower immunoglobulin E (IgE) level, sputum neutrophilia and higher dosages of oral steroids. In contrast, trajectory 4 was associated with higher sputum and blood eosinophil counts and more frequent exacerbations. Conclusions: Trajectory clustering analysis of FEV1 identified 5 distinct types, representing well-preserved to severely decreased FEV1. Persistent airflow obstruction may be related to non-atopy, a low IgE level, and older age accompanied by neutrophilic inflammation and low baseline FEV1 levels.

Keywords

Acknowledgement

Supported by : Ministry of Health & Welfare

References

  1. Reddel HK, Bateman ED, Becker A, Boulet LP, Cruz AA, Drazen JM, et al. A summary of the new GINA strategy: a roadmap to asthma control. Eur Respir J 2015;46:622-39. https://doi.org/10.1183/13993003.00853-2015
  2. Fajt ML, Wenzel SE. Development of new therapies for severe asthma. Allergy Asthma Immunol Res 2017;9:3-14. https://doi.org/10.4168/aair.2017.9.1.3
  3. Sears MR. Lung function decline in asthma. Eur Respir J 2007;30:411-3. https://doi.org/10.1183/09031936.00080007
  4. Newby C, Agbetile J, Hargadon B, Monteiro W, Green R, Pavord I, et al. Lung function decline and variable airway inflammatory pattern: longitudinal analysis of severe asthma. J Allergy Clin Immunol 2014;134:287-94. https://doi.org/10.1016/j.jaci.2014.04.005
  5. Moore WC, Meyers DA, Wenzel SE, Teague WG, Li H, Li X, et al. Identification of asthma phenotypes using cluster analysis in the Severe Asthma Research Program. Am J Respir Crit Care Med 2010;181:315-23. https://doi.org/10.1164/rccm.200906-0896OC
  6. Shaw DE, Berry MA, Hargadon B, McKenna S, Shelley MJ, Green RH, et al. Association between neutrophilic airway inflammation and airflow limitation in adults with asthma. Chest 2007;132:1871-5. https://doi.org/10.1378/chest.07-1047
  7. Amelink M, de Groot JC, de Nijs SB, Lutter R, Zwinderman AH, Sterk PJ, et al. Severe adult-onset asthma: a distinct phenotype. J Allergy Clin Immunol 2013;132:336-41. https://doi.org/10.1016/j.jaci.2013.04.052
  8. Chung KF. Neutrophilic asthma: a distinct target for treatment? Lancet Respir Med 2016;4:765-7. https://doi.org/10.1016/S2213-2600(16)30232-6
  9. Chang HS, Lee TH, Jun JA, Baek AR, Park JS, Koo SM, et al. Neutrophilic inflammation in asthma: mechanisms and therapeutic considerations. Expert Rev Respir Med 2017;11:29-40. https://doi.org/10.1080/17476348.2017.1268919
  10. Newby C, Heaney LG, Menzies-Gow A, Niven RM, Mansur A, Bucknall C, et al. Statistical cluster analysis of the British Thoracic Society Severe refractory Asthma Registry: clinical outcomes and phenotype stability. PLoS One 2014;9:e102987. https://doi.org/10.1371/journal.pone.0102987
  11. Loza MJ, Djukanovic R, Chung KF, Horowitz D, Ma K, Branigan P, et al. Validated and longitudinally stable asthma phenotypes based on cluster analysis of the ADEPT study. Respir Res 2016;17:165. https://doi.org/10.1186/s12931-016-0482-9
  12. Boudier A, Curjuric I, Basagana X, Hazgui H, Anto JM, Bousquet J, et al. Ten-year follow-up of clusterbased asthma phenotypes in adults. A pooled analysis of three cohorts. Am J Respir Crit Care Med 2013;188:550-60. https://doi.org/10.1164/rccm.201301-0156OC
  13. Kim TB, Jang AS, Kwon HS, Park JS, Chang YS, Cho SH, et al. Identification of asthma clusters in two independent Korean adult asthma cohorts. Eur Respir J 2013;41:1308-14. https://doi.org/10.1183/09031936.00100811
  14. Park SY, Baek S, Kim S, Yoon SY, Kwon HS, Chang YS, et al. Clinical significance of asthma clusters by longitudinal analysis in Korean asthma cohort. PLoS One 2013;8:e83540. https://doi.org/10.1371/journal.pone.0083540
  15. Savenije OE, Granell R, Caudri D, Koppelman GH, Smit HA, Wijga A, et al. Comparison of childhood wheezing phenotypes in 2 birth cohorts: ALSPAC and PIAMA. J Allergy Clin Immunol 2011;127:1505-1512.e14. https://doi.org/10.1016/j.jaci.2011.02.002
  16. Panico L, Stuart B, Bartley M, Kelly Y. Asthma trajectories in early childhood: identifying modifiable factors. PLoS One 2014;9:e111922. https://doi.org/10.1371/journal.pone.0111922
  17. Lodrup Carlsen KC, Mowinckel P, Hovland V, Haland G, Riiser A, Carlsen KH. Lung function trajectories from birth through puberty reflect asthma phenotypes with allergic comorbidity. J Allergy Clin Immunol 2014;134:917-923.e7. https://doi.org/10.1016/j.jaci.2014.05.020
  18. Bisgaard H, Jensen SM, Bonnelykke K. Interaction between asthma and lung function growth in early life. Am J Respir Crit Care Med 2012;185:1183-9. https://doi.org/10.1164/rccm.201110-1922OC
  19. Rasmussen F, Taylor DR, Flannery EM, Cowan JO, Greene JM, Herbison GP, et al. Risk factors for airway remodeling in asthma manifested by a low postbronchodilator FEV1/vital capacity ratio: a longitudinal population study from childhood to adulthood. Am J Respir Crit Care Med 2002;165:1480-8. https://doi.org/10.1164/rccm.2108009
  20. Guerra S, Sherrill DL, Kurzius-Spencer M, Venker C, Halonen M, Quan SF, et al. The course of persistent airflow limitation in subjects with and without asthma. Respir Med 2008;102:1473-82. https://doi.org/10.1016/j.rmed.2008.04.011
  21. Choi JS, Jang AS, Park JS, Park SW, Paik SH, Park JS, et al. Role of neutrophils in persistent airway obstruction due to refractory asthma. Respirology 2012;17:322-9. https://doi.org/10.1111/j.1440-1843.2011.02097.x
  22. Kim DK, Park YB, Oh YM, Jung KS, Yoo JH, Yoo KH, et al. Korean Asthma Guideline 2014: summary of major updates to the Korean Asthma Guideline 2014. Tuberc Respir Dis (Seoul) 2016;79:111-20. https://doi.org/10.4046/trd.2016.79.3.111
  23. Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, et al. An official American Thoracic Society/European Respiratory Society statement: asthma control and exacerbations: standardizing endpoints for clinical asthma trials and clinical practice. Am J Respir Crit Care Med 2009;180:59-99. https://doi.org/10.1164/rccm.200801-060ST
  24. Everitt BS. Cluster Analysis. 3rd ed. New York: John Wiley; 1993.
  25. Genolini C, Falissard B. KmL: a package to cluster longitudinal data. Comput Methods Programs Biomed 2011;104:e112-21. https://doi.org/10.1016/j.cmpb.2011.05.008
  26. Tepper RS, Wise RS, Covar R, Irvin CG, Kercsmar CM, Kraft M, et al. Asthma outcomes: pulmonary physiology. J Allergy Clin Immunol 2012;129:S65-87. https://doi.org/10.1016/j.jaci.2011.12.986
  27. Pellegrino R, Viegi G, Brusasco V, Crapo RO, Burgos F, Casaburi R, et al. Interpretative strategies for lung function tests. Eur Respir J 2005;26:948-68. https://doi.org/10.1183/09031936.05.00035205
  28. Chung KF, Wenzel SE, Brozek JL, Bush A, Castro M, Sterk PJ, et al. International ERS/ATS guidelines on definition, evaluation and treatment of severe asthma. Eur Respir J 2014;43:343-73. https://doi.org/10.1183/09031936.00202013
  29. Engelkes M, Janssens HM, de Jongste JC, Sturkenboom MC, Verhamme KM. Medication adherence and the risk of severe asthma exacerbations: a systematic review. Eur Respir J 2015;45:396-407. https://doi.org/10.1183/09031936.00075614
  30. Tay TR, Hew M. Comorbid "treatable traits" in difficult asthma: current evidence and clinical evaluation. Allergy. Forthcoming 2017.
  31. Fahy JV. Eosinophilic and neutrophilic inflammation in asthma: insights from clinical studies. Proc Am Thorac Soc 2009;6:256-9. https://doi.org/10.1513/pats.200808-087RM
  32. Kupczyk M, ten Brinke A, Sterk PJ, Bel EH, Papi A, Chanez P, et al. Frequent exacerbators--a distinct phenotype of severe asthma. Clin Exp Allergy 2014;44:212-21. https://doi.org/10.1111/cea.12179
  33. van Veen IH, Ten Brinke A, Gauw SA, Sterk PJ, Rabe KF, Bel EH. Consistency of sputum eosinophilia in difficult-to-treat asthma: a 5-year follow-up study. J Allergy Clin Immunol 2009;124:615-7. https://doi.org/10.1016/j.jaci.2009.06.029
  34. Chung KF. Targeting the interleukin pathway in the treatment of asthma. Lancet 2015;386:1086-96. https://doi.org/10.1016/S0140-6736(15)00157-9
  35. Shaw DE, Sousa AR, Fowler SJ, Fleming LJ, Roberts G, Corfield J, et al. Clinical and inflammatory characteristics of the European U-BIOPRED adult severe asthma cohort. Eur Respir J 2015;46:1308-21. https://doi.org/10.1183/13993003.00779-2015
  36. Kim TB, Jang AS, Kwon HS, Park JS, Chang YS, Cho SH, et al. Identification of asthma clusters in two independent Korean adult asthma cohorts. Eur Respir J 2013;41:1308-14. https://doi.org/10.1183/09031936.00100811
  37. Lee T, Lee YS, Bae YJ, Kim TB, Kim SO, Cho SH, et al. Smoking, longer disease duration and absence of rhinosinusitis are related to fixed airway obstruction in Koreans with severe asthma: findings from the COREA study. Respir Res 2011;12:1. https://doi.org/10.1186/1465-9921-12-1
  38. Cerveri I, Cazzoletti L, Corsico AG, Marcon A, Niniano R, Grosso A, et al. The impact of cigarette smoking on asthma: a population-based international cohort study. Int Arch Allergy Immunol 2012;158:175-83. https://doi.org/10.1159/000330900
  39. Thomson NC, Chaudhuri R, Heaney LG, Bucknall C, Niven RM, Brightling CE, et al. Clinical outcomes and inflammatory biomarkers in current smokers and exsmokers with severe asthma. J Allergy Clin Immunol 2013;131:1008-16. https://doi.org/10.1016/j.jaci.2012.12.1574
  40. Gibson PG, McDonald VM. Asthma-COPD overlap 2015: now we are six. Thorax 2015;70:683-91. https://doi.org/10.1136/thoraxjnl-2014-206740
  41. Montnemery P, Hansson L, Lanke J, Lindholm LH, Nyberg P, Lofdahl CG, et al. Accuracy of a first diagnosis of asthma in primary health care. Fam Pract 2002;19:365-8. https://doi.org/10.1093/fampra/19.4.365
  42. Lucas AE, Smeenk FW, Smeele IJ, van Schayck CP. Overtreatment with inhaled corticosteroids and diagnostic problems in primary care patients, an exploratory study. Fam Pract 2008;25:86-91. https://doi.org/10.1093/fampra/cmn006

Cited by

  1. A Systematic Review of Asthma Phenotypes Derived by Data-Driven Methods vol.11, pp.4, 2021, https://doi.org/10.3390/diagnostics11040644