0
Original Research: Obstructive Lung Diseases |

Airway IL-1β and Systemic Inflammation as Predictors of Future Exacerbation Risk in Asthma and COPDInflammatory Predictors of Exacerbation FREE TO VIEW

Juan-juan Fu, MD, PhD; Vanessa M. McDonald, PhD; Katherine J. Baines, PhD; Peter G. Gibson, MBBS
Author and Funding Information

From the Respiratory Group (Dr Fu), Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Sichuan, China; the Priority Research Centre for Asthma and Respiratory Diseases (Drs Fu, McDonald, Baines, and Gibson) and the School of Nursing and Midwifery (Dr McDonald), Faculty of Health, University of Newcastle, Newcastle, NSW, Australia; and Hunter Medical Research Institute (Drs Baines and Gibson), Newcastle, NSW, Australia.

CORRESPONDENCE TO: Peter G. Gibson, MBBS, Department of Respiratory and Sleep Medicine, John Hunter Hospital, Lookout Rd, New Lambton 2305, NSW, Australia; e-mail: Peter.Gibson@hnehealth.nsw.gov.au


A subset of the data in this study has been presented in abstract form (Fu JJ, McDonald VM, Baines KJ, et al. Airway IL-1 pathway activation and systemic inflammation predict future exacerbation risk in asthma and COPD. D12. Exacerbation of lung disease: shared mechanisms. Am Thorac Soc. 2014:A5357) and as an oral presentation at the 2014 American Thoracic Society Conference in, May 21, 2014, San Diego, CA.

FUNDING/SUPPORT: The authors have reported to CHEST that no funding was received for this study.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians. See online for more details.


Chest. 2015;148(3):618-629. doi:10.1378/chest.14-2337
Text Size: A A A
Published online

BACKGROUND:  The innate inflammatory pathways involved in the frequent exacerbator phenotypes of asthma and COPD are not well understood. This study aimed to investigate airway innate immune activation and systemic inflammation as predictors of exacerbations in asthma and COPD.

METHODS:  In this prospective cohort study, baseline airway IL-1β, serum C-reactive protein, and IL-6 were assessed in 152 participants with stable asthma (n = 63) or COPD (n = 89) and were related to exacerbations over the following 12 months. Clinical characteristics and inflammatory biomarkers were compared between the frequent (two or more exacerbations in the follow-up) and infrequent exacerbators. The frequent exacerbation phenotype and exacerbation frequency were analyzed with multivariable modeling. The relationships among airway inflammation, systemic inflammation, and future exacerbations were examined using path analysis.

RESULTS:  Ninety-four participants experienced a total of 201 exacerbations, and 36.4% had two or more exacerbations. Serum IL-6 and sputum gene expression of IL-1β at baseline were higher in the frequent exacerbators with COPD. Significant pathways initiated by previous exacerbations were identified as occurring through activation of the IL-1β-systemic inflammatory axis leading to future exacerbations in COPD. Systemic inflammation was also associated with increased exacerbation risk in asthma.

CONCLUSIONS:  Airway IL-1β and systemic inflammation are associated with frequent exacerbations and may mediate a vicious cycle between previous and future exacerbations in COPD. Treatment strategies aimed at attenuating these inflammatory pathways to reduce COPD exacerbations deserve further investigation.

Figures in this Article

Asthma and COPD are common diseases that cause exacerbations of deteriorating symptoms and lung function that can result in hospitalization, increased health-care use, and death.1,2 Exacerbations impose a substantial economic burden and result in a faster decline in lung function3,4 and a poorer quality of life.5,6 A subset of patients experience frequent exacerbations4,7,8 and require more effective management strategies. Although there are some known clinical factors that are associated with frequent exacerbations of asthma2,9 and COPD,10 the underlying mechanisms, including the role of inflammation and innate immunity in frequent exacerbations, are not well established. If inflammation were a determinant of exacerbations, this would permit both disease monitoring using biomarkers and novel approaches to treatment.

Inflammation in COPD and asthma has airway and systemic components.11,12 Elevated circulating levels of C-reactive protein (CRP) and IL-6 are indicators of a systemic inflammation. In COPD, a subset of patients experience chronic low-grade systemic inflammation during stable disease. This inflammation is associated with a rapid decline in lung function,13 increased mortality,14 and a higher exacerbation rate15,16; however, the mechanisms behind the observed association between systemic inflammation and exacerbations in COPD16 remain unclear. Although systemic inflammation is increased in asthma,12 the effect on future exacerbation risk is not known.

IL-1β is a typical innate immune cytokine involved in the initiation and persistence of inflammation.17,18 IL-1β secretion is increased in stable and exacerbating COPD19,20 and asthma.18,21 We reported previously that airway IL-1β was associated with systemic inflammation in asthma12,18,21 and hypothesize that the airway innate immune activation and/or systemic inflammation are important determinants of exacerbation risk in asthma and COPD. We, therefore, conducted a prospective cohort study of patients with asthma and COPD to investigate the determinants of future exacerbation risk and focused on innate immune responses including airway IL-1β and systemic inflammation (CRP and IL-6). Additionally, we conducted a statistical pathway analysis to explore the relationships among clinical risk factors, airway inflammation, systemic inflammation, and future exacerbations.

Study Design and Protocol

Participants (N = 152) with doctor-diagnosed asthma (n = 63) or COPD (n = 89) were recruited from research registers and were enrolled in a prospective cohort study (e-Apppendix 1). Participants gave written informed consent, and the study was approved by the Hunter New England Research Ethics Committee, Australia (Reference No. 10/08/18/5.03).

Participants attended a baseline visit to assess demographics, smoking status, exacerbation history prior to the study entry, medical history, medication use, symptoms (visual analog scale), comorbidity (Charlson comorbidity index),22 and for the asthma group, to complete the Asthma Control Questionnaire.23 Pre- and postbronchodilator spirometry, sputum induction,24 and venipuncture were performed (e-Appendix 1).

After baseline clinical assessment, clinical interviews were conducted by telephone every 3 months for 12 months to assess medication use and exacerbation frequency and severity (Fig 1). Respiratory hospitalization, ED visits, unscheduled primary care doctor visits, and medication use were recorded at each assessment. An exacerbation of COPD was defined as a COPD-related episode that led to (1) hospitalization, (2) an ED visit, or (3) the need for oral corticosteroids, antibiotics, or both for ≥ 3 days.8 An exacerbation of asthma was defined using the severe asthma exacerbation criteria of the American Thoracic Society/European Respiratory Society Task Force25 or when an asthma exacerbation with lower respiratory tract infection required antibiotics.26 A “frequent exacerbator” was defined as a participant who had two or more exacerbations during the 12 months of follow-up.5,8

Figure Jump LinkFigure 1 –  Study flowchart. ELISA = enzyme-linked immunosorbent assay; OAD = obstructive airways disease; qPCR = quantitative real-time polymerase chain reaction.Grahic Jump Location

Details of biomarker measurements are provided in e-Appendix 1. Sputum gene expression was measured using quantitative real-time polymerase chain reaction as described previously.18 Levels of sputum IL-1β, IL-1 receptor antagonist proteins, serum high-sensitivity CRP, and IL-6 were measured using enzyme-linked immunosorbent assay. Elevated CRP and IL-6 levels were defined as CRP ≥ 4.12 mg/L and IL-6 ≥ 1.55 pg/mL based on prior data.12

Statistical Analysis

Data were analyzed using STATA 13 (StataCorp LP) and were reported as mean (SD) or median (quartile 1-3) depending on the distribution. Comparisons between two independent groups were performed using the Student t test or the two-sample Wilcoxon rank sum test. The Fisher exact test was used to test categorical data. Differences in exacerbation rates (number of events per participant) were analyzed by Poisson regression adjusted for follow-up time and corrected by robust variance estimation. Multivariable logistic and Poisson regression analyses were performed to identify predictors of frequent exacerbations and the number of exacerbations in the asthma and COPD groups separately. Variables that were tested in univariable regression with P < .1 were selected for inclusion in the multivariable regression model, followed by a stepwise approach always adjusting for age and sex. P < .05 was considered significant.

Path analysis using generalized structural equation modeling was performed to explore the relationships among exacerbation history, airway inflammation (sputum IL-1β gene expression), systemic inflammation (serum IL-6 level), and exacerbation frequency in the following year. Each variable was modeled, and an overall model of future exacerbations was constructed. Change in cycle threshold of IL-1β gene expression assay compared with β-actin and ln(IL-6) were used in this analysis because of the normality of the data.

Baseline Characteristics of the Participants

Of the 152 participants who underwent the baseline assessments, 13 withdrew and one died during the follow-up period, leaving 138 participants who completed the 12-month follow-up. Exacerbation data were available prior to withdrawal for a further two participants, and data from 140 participants were analyzed (Fig 1).

Participants with COPD were older (68.9 years) than those with asthma (60.5 years) and had greater tobacco smoke exposure and airflow limitation. Inhaled corticosteroid use was similar between the asthma and COPD groups, but there was greater comorbidity in the COPD group (e-Table 1). Systemic inflammatory markers tended to be similar between the groups, but airway neutrophils were greater in the COPD group (e-Table 2).

Exacerbations by Asthma and COPD Group

There were 1.10 exacerbations/participant in the asthma group and 1.67 exacerbations/participant in the COPD group over the 12-month follow-up period (P = .056) (Table 1). The distribution of total exacerbation number (Fig 2) and the exacerbation types (Table 1) were similar between asthma and COPD. Overall, from this cohort, 94 participants (67.1%) experienced a total of 201 exacerbations during a median follow-up period of 53.4 (52.4-57.0) weeks. Forty-three participants (30.7%) experienced one exacerbation, and 51 participants (36.4%) reported two or more exacerbations.

Table Graphic Jump Location
TABLE 1 ]  Exacerbations in Asthma and COPD Groups During the 12-Month Observation Period

IRR = incidence rate ratio; OCS = oral corticosteroid.

a 

COPD vs asthma.

b 

Analyzed by Poisson regression.

Figure Jump LinkFigure 2 –  Distribution of the number of exacerbations in the asthma and COPD groups.Grahic Jump Location
Clinical Characteristics of Frequent Exacerbators

The frequent vs infrequent exacerbators in the asthma and COPD groups were compared (Table 2). Prior year exacerbation frequency and symptom scores were higher in frequent exacerbators. Frequent exacerbators with COPD were older and had greater lung function impairment and more comorbidities compared with the infrequent exacerbators with COPD. In asthma, the use of long-acting anticholinergics was greater in the frequent exacerbators than in the infrequent exacerbators.

Table Graphic Jump Location
TABLE 2 ]  Baseline Characteristics of Frequent vs Infrequent Exacerbators With Asthma and COPD

Data are given as No. (%), mean (SD), or median (quartile 1-3) unless otherwise indicated. AHR = airway hyperresponsiveness; BDP = beclometasone dipropionate; BDR = bronchodilator response; CCI = Charlson Comorbidity Index; HMGCoA = 3-hydroxy-3-methylglutaryl-coenzyme A; ICS = inhaled corticosteroid; N/A = not applicable; VAS = visual analog scale.

Airway IL-1β, Systemic Inflammation, and Frequent Exacerbators

Sputum cell counts were not different between the frequent and infrequent exacerbators in either the asthma or the COPD group (Table 3). Sputum IL-1β gene expression was significantly upregulated in frequent exacerbators with COPD (Fig 3C). IL-1β (Fig 3) and IL-1 receptor antagonist (Table 3) protein levels were not different between the frequent and infrequent exacerbators in either the asthma or the COPD group.

Table Graphic Jump Location
TABLE 3 ]  Airway and Systemic Inflammation of Frequent vs Infrequent Exacerbators With Asthma and COPD

Data are presented as median (quartile 1-3) unless indicated otherwise. CRP = C-reactive protein; IL-1Ra = IL-1 receptor antagonist.

Figure Jump LinkFigure 3 –  A-D, Baseline levels of sputum IL-1β gene and protein expression between frequent and infrequent exacerbators. A, B, Asthma. C, D, COPD. Lines in B and D represent median values.Grahic Jump Location

At baseline, serum IL-6 level was significantly higher in the frequent exacerbators with asthma (Fig 4A) and COPD (Fig 4C) compared with the infrequent exacerbators in each group. Baseline CRP was also elevated in frequent asthma exacerbators (Fig 4B), but not in COPD (Fig 4D). Participants were categorized into three groups based on the number of elevated systemic inflammatory markers at baseline. An increased number of elevated systemic markers was associated with the frequent exacerbators phenotype in both asthma and COPD (Table 3). Systemic inflammatory markers were significantly correlated with airway IL-1β gene expression and protein levels (Table 4).

Figure Jump LinkFigure 4 –  A-D, Baseline levels of serum IL-6 and CRP in frequent and infrequent exacerbators. A, B, Asthma. C, D, COPD. Lines represent median values. CRP = C-reactive protein.Grahic Jump Location
Table Graphic Jump Location
TABLE 4 ]  Spearman Rank Correlations of Airway IL-1β With Systemic Inflammation

See Table 3 legend for expansion of abbreviations.

a 

Three groups: with normal CRP and IL-6 levels; with either CRP or IL-6 elevated; and with both CRP and IL-6 elevated.

Predictors of Future Exacerbations

Univariable regression analyses of baseline characteristics that predict exacerbations in asthma (e-Table 3) and COPD (e-Table 4) were performed. After stepwise selection and adjustment for significant clinical parameters in the regression models, baseline sputum IL-1β gene expression and protein level significantly predicted the frequent exacerbation phenotype and the number of exacerbations in COPD (Tables 5-8). Sputum IL-1β gene and protein expression did not predict the frequent exacerbation phenotype and exacerbation number in asthma. Systemic inflammation, represented by the level of IL-6, was an independent predictor of exacerbation frequency in the following year in both asthma and COPD (Table 9).

Table Graphic Jump Location
TABLE 5 ]  Sputum IL-1β Gene Expression Predicted the Frequent Exacerbation Phenotype in COPD

See Table 2 legend for expansion of abbreviation.

Table Graphic Jump Location
TABLE 6 ]  Sputum IL-1β Gene Expression Predicted Exacerbation Frequency in COPD

See Tables 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 7 ]  Sputum IL-1β Protein Level Predicted the Frequent Exacerbation Phenotype in COPD

See Table 2 legend for expansion of abbreviation.

Table Graphic Jump Location
TABLE 8 ]  Sputum IL-1β Protein Level Predicted Exacerbation Frequency in COPD

See Tables 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 9 ]  Systemic Inflammation Predicted Exacerbation Frequency in Asthma and COPD

See Tables 1 and 2 legends for expansion of abbreviations.

Path Analysis of Exacerbation Predictors

In COPD, the number of exacerbations experienced in the prior year, airway IL-1β, and serum IL-6 each independently predicted future exacerbation frequency (Tables 5-9). e-Table 5 shows the modeling of each variable, and an overall model of future exacerbations was constructed in which exacerbation history and serum IL-6 levels were significant baseline variables associated with future exacerbations. The path diagrams (Fig 5) indicate that the number of exacerbations in the past year directly and significantly predicted exacerbation frequency in the following year in COPD. In addition, there was an indirect association between previous and future exacerbations, via an upregulation of airway IL-1β and a subsequent increase in the level of systemic inflammation measured by IL-6.

Figure Jump LinkFigure 5 –  A, Path diagram of generalized structural equation modeling for the predictors of future exacerbation frequency generated by STATA 13. Arrows represent paths between variables, and a path pointing from one variable to another indicates that the first variable affects the second. Numbers under variables represent the overall coefficient of different models, and numbers near the circled ε are the variances of the models. A small number along with the arrow connecting two variables indicates the variable-specific coefficient. Red lines represent statistically significant paths. B, Simplified pathway diagram of the number of exacerbations in the prior year, airway inflammation measured by sputum IL-1β gene expression, systemic inflammation measured by serum IL-6, and the number of future exacerbations based on the modeling. *Variable predicted by age.Grahic Jump Location

To our knowledge, this is the first study to record comprehensive types of exacerbations resulting in hospitalizations, ED visits, and community exacerbations in both asthma and COPD and to link these to airway and systemic inflammation. This prospective cohort study indicates that airway IL-1β and increased systemic inflammation are associated with frequent future exacerbations in COPD; it also indicates, for the first time, that systemic inflammation is associated with exacerbation risk in asthma. Importantly, we identified a potential causal pathway that shows how airway innate immune activation through IL-1β results in systemic inflammation and exacerbations in COPD. This pathway could contribute to a vicious cycle between previous and future exacerbations and may identify potential molecular treatment targets that could reduce exacerbations in COPD.

There is some controversy over the origin of systemic inflammation in COPD. It is hypothesized that there is a “spillover” of local airway inflammation into the systemic circulation. Others propose that COPD is a systemic multiorgan disease with multiple sources of systemic inflammation.27 Structural equation modeling is a collection of statistical techniques that allow a set of relations between one or more independent and dependent variables to be examined; it takes a hypothesis-testing approach to the multivariate analysis of a structural theory that stipulates causal relations. Path analysis is a type of structural equation modeling in which hypotheses of causal relations among multiple variables are modeled.28 We used this approach of novel path analysis to test the hypotheses relating to causal relations among airway inflammation, systemic inflammation, and future exacerbations. Our findings may further support the “spillover” theory because airway IL-1β significantly predicted systemic inflammation in COPD. The path diagram indicates a vicious cycle of exacerbations in patients with COPD, with frequent exacerbations aggravating airway inflammation and leading to increased systemic inflammation, linking previous and future exacerbations. Therefore, the measurement of airway IL-1β and systemic IL-6 may provide additional benefit in the prediction of exacerbation beyond clinical assessments. Antiinflammatory therapies targeting the airway IL-1β-systemic inflammatory pathway, which break the vicious cycle of inflammation leading to exacerbations, show promise as a strategy for preventing exacerbations. In addition, further studies investigating the role of IL-1β, including its relationship to inflammasome activation29 and bacterial colonization,20 are warranted.

Although the importance of systemic inflammation is well established in COPD, our data shows a similar prevalence of systemic inflammation in older patients with asthma and identifies that elevated systemic inflammation is associated with increased future exacerbations in asthma. A greater number of elevated systemic inflammatory markers is a known predictor of COPD exacerbation.16 Our data extend these findings from COPD to asthma. To our knowledge, this is the first report on the prognostic role of systemic inflammation in asthma, indicating that the presence of systemic inflammation is not limited to COPD, but is rather than a feature of obstructive airways disease that predicts future exacerbation risk.

The dissociation between sputum eosinophil counts and asthma exacerbation risk conflicts with the findings of some previous studies.30,31 The primary reason for this would be the small sample size of the asthma group and the fact that only 16 patients with asthma were identified as frequent exacerbators. Additionally, the patients with asthma in our study were recruited from the community and had preserved lung function and well-controlled asthma based on the asthma control questionnaire score (perhaps because of the high-dose ICS therapy), resulting in fewer patients with asthma with eosinophilic bronchitis; some other studies recruited those with severe asthma and participants with increased eosinophils.31,32 This may indicate that sputum eosinophil count is not associated with exacerbations in well-controlled and noneosinophilic asthma. The sample size is also a likely reason why we observed a trend toward an increased IL-1β gene and protein expression in asthma only. There is an urgent need for larger studies in asthma to clarify IL-1β-systemic inflammatory pathway activation and its role in asthma.

It is well known that a history of exacerbation is the single best clinical predictor of future exacerbations in COPD.8 Our study extends this finding from COPD to asthma. Interestingly, the severity of respiratory symptoms measured by visual analog scale symptom score also predicted the exacerbation frequency in both asthma and COPD. This finding supports the concepts of the combined assessment, which integrates both symptoms and risk assessments as recommended in the 2014 GOLD (Global Initiative for Chronic Obstructive Lung Disease) document33 and promotes the clinical use of combined assessment and individualized management in asthma and COPD.

Several limitations of the study should be noted. We examined only two systemic inflammatory markers; other mediators may also be involved.16 Agustí et al15 defined persistent systemic inflammation as stability of elevated systemic inflammatory markers over 1 year. Therefore, future studies that examine more biomarkers and at different time points are desired. Because of the limitations imposed by telephone interviews, we were not able to identify the causes of exacerbations or their duration, and this warrants further investigation. Although structural equation modeling allows for the testing of causal hypotheses, the statistical technique does not prove causal relationships without satisfying the necessary conditions for causal inference.28 We proved the causal hypotheses using path analysis, but we cannot make warranted causal claims based on this data set; therefore, replication of the findings is needed. A weak to modest correlation between airway and systemic inflammation may suggest the complexity of the cross-talking and that other confounders can also affect each of the two dimensions. Therefore, the hypotheses presented in this study need to be evaluated and may be further proved by interventional studies blocking specific components of the pathway.

In summary, we have identified that an increase in systemic inflammation predicted more frequent exacerbations in asthma and demonstrated that frequent exacerbations in COPD are associated with both increased airway IL-1β and systemic inflammation. Although an exacerbation history predicted future exacerbations, an indirect association also existed between previous and future exacerbation through the airway IL-1β-systemic inflammatory pathway, contributing to a vicious cycle of exacerbations in COPD. These are important observations that identify a specific subset of patients with COPD who are at high risk of future exacerbations and the specific inflammatory pathway and molecules that related to future exacerbations. Treatment strategies aimed at attenuating airway IL-1β and systemic inflammation to reduce COPD exacerbation deserve further investigation.

Author contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. J. F. and P. G. G. contributed to the study design; P. G. G. contributed to the supervision of the clinical recruitment; J. F. and V. M. M. contributed to the data collection; J. F. contributed to the laboratory gene and protein assays, statistical analysis, and drafting of the manuscript; K. J. B. contributed to the novel biomarkers identification and supervision of the laboratory analysis; V. M. M. and K. J. B. contributed to the data analysis; V. M. M. and P. G. G. contributed to the data interpretation; V. M. M., K. J. B., and P. G. G. contributed to the critical revision of the manuscript; and J. F., V. M. M., K. J. B., and P. G. G. contributed to the approval of the final manuscript.

Financial/nonfinancial disclosures: The authors have reported to CHEST the following conflicts of interest: Dr McDonald is supported by the Lung Foundation of Australia and Boehringer-Ingelheim GmbH’s COPD research fellowship and has participated in educational symposia funded by GlaxoSmithKline, AstraZeneca, Menarini, Boehringer-Ingelheim GmbH, and Novartis AG. She has participated in studies funded by GlaxoSmithKline and on advisory boards for Novartis AG, AstraZeneca, and Menarini. Dr Gibson holds a National Health and Medical Research Council Practitioner Fellowship. He has participated in educational symposia funded by AstraZeneca, Boehringer-Ingelheim GmbH, GlaxoSmithKline, and Novartis AG and has participated in studies funded by Pharmaxis and GlaxoSmithKline. Drs Fu and Baines have reported that no potential conflicts of interest exist with any companies/organizations whose products or services may be discussed in this article.

Other contributions: The authors acknowledge Jodie Simpson, PhD; Thomas Wright, BMedSci; Kelly Steel, BNursing; Penelope Baines, BPhysiotherapy; Rebecca Oldham, BSci; Anne-Marie Gibson, BPhysiotherapy; Naomi Fibbens, DipPathTech; and Michelle Gleeson, DipPathTech, for their technical and clinical assistance, and Patrick McElduff, PhD, and Heather Powell, M Clinical Epidemiology, for their statistical advice.

Additional information: The e-Appendix and e-Tables can be found in the Supplemental Materials section of the online article.

Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 pt 1):959-967. [CrossRef] [PubMed]
 
McDonald VM, Gibson PG. Exacerbations of severe asthma. Clin Exp Allergy. 2012;42(5):670-677. [CrossRef] [PubMed]
 
Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations predict excess lung function decline in asthma. Eur Respir J. 2007;30(3):452-456. [CrossRef] [PubMed]
 
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852. [CrossRef] [PubMed]
 
Kupczyk M, ten Brinke A, Sterk PJ, et al; BIOAIR investigators. Frequent exacerbators—a distinct phenotype of severe asthma. Clin Exp Allergy. 2014;44(2):212-221. [CrossRef] [PubMed]
 
Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23(5):698-702. [CrossRef] [PubMed]
 
Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy. 2009;39(2):193-202. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. [CrossRef] [PubMed]
 
ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J. 2005;26(5):812-818. [CrossRef] [PubMed]
 
Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48(3):86-98. [CrossRef] [PubMed]
 
Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007;62(3):211-218. [CrossRef] [PubMed]
 
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest. 2012;142(1):86-93. [CrossRef] [PubMed]
 
Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995-2004. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250-255. [CrossRef] [PubMed]
 
Agustí A, Edwards LD, Rennard SI, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE. 2012;7(5):e37483. [CrossRef] [PubMed]
 
Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353-2361. [CrossRef] [PubMed]
 
Slack J, McMahan CJ, Waugh S, et al. Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors. J Biol Chem. 1993;268(4):2513-2524. [PubMed]
 
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J Allergy Clin Immunol. 2011;127(1):153-160. [CrossRef] [PubMed]
 
Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 2011;38(5):1019-1028. [CrossRef] [PubMed]
 
Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671. [CrossRef] [PubMed]
 
Fu JJ, Baines KJ, Wood LG, Gibson PG. Systemic inflammation is associated with differential gene expression and airway neutrophilia in asthma. OMICS. 2013;17(4):187-199. [CrossRef] [PubMed]
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. [CrossRef] [PubMed]
 
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(4):902-907. [CrossRef] [PubMed]
 
Gibson PG, Wlodarczyk JW, Hensley MJ, et al. Epidemiological association of airway inflammation with asthma symptoms and airway hyperresponsiveness in childhood. Am J Respir Crit Care Med. 1998;158(1):36-41. [CrossRef] [PubMed]
 
Reddel HK, Taylor DR, Bateman ED, et al; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. 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(1):59-99. [CrossRef] [PubMed]
 
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-329. [CrossRef] [PubMed]
 
Agustí A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don’t know (but should). Proc Am Thorac Soc. 2007;4(7):522-525. [CrossRef] [PubMed]
 
Lei PW, Wu Q. Introduction to structural equation modeling: issues and practical considerations. Educ Meas Issues Pract. 2007;26(3):33-43. [CrossRef]
 
Dolinay T, Kim YS, Howrylak J, et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med. 2012;185(11):1225-1234. [CrossRef] [PubMed]
 
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-1721. [CrossRef] [PubMed]
 
Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483-494. [CrossRef] [PubMed]
 
Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. 2002;57(2):178-182. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management and prevention of COPD. GOLD website. http://www.goldcopd.com. Updated 2014. Accessed August 30, 2015.
 

Figures

Figure Jump LinkFigure 1 –  Study flowchart. ELISA = enzyme-linked immunosorbent assay; OAD = obstructive airways disease; qPCR = quantitative real-time polymerase chain reaction.Grahic Jump Location
Figure Jump LinkFigure 2 –  Distribution of the number of exacerbations in the asthma and COPD groups.Grahic Jump Location
Figure Jump LinkFigure 3 –  A-D, Baseline levels of sputum IL-1β gene and protein expression between frequent and infrequent exacerbators. A, B, Asthma. C, D, COPD. Lines in B and D represent median values.Grahic Jump Location
Figure Jump LinkFigure 4 –  A-D, Baseline levels of serum IL-6 and CRP in frequent and infrequent exacerbators. A, B, Asthma. C, D, COPD. Lines represent median values. CRP = C-reactive protein.Grahic Jump Location
Figure Jump LinkFigure 5 –  A, Path diagram of generalized structural equation modeling for the predictors of future exacerbation frequency generated by STATA 13. Arrows represent paths between variables, and a path pointing from one variable to another indicates that the first variable affects the second. Numbers under variables represent the overall coefficient of different models, and numbers near the circled ε are the variances of the models. A small number along with the arrow connecting two variables indicates the variable-specific coefficient. Red lines represent statistically significant paths. B, Simplified pathway diagram of the number of exacerbations in the prior year, airway inflammation measured by sputum IL-1β gene expression, systemic inflammation measured by serum IL-6, and the number of future exacerbations based on the modeling. *Variable predicted by age.Grahic Jump Location

Tables

Table Graphic Jump Location
TABLE 1 ]  Exacerbations in Asthma and COPD Groups During the 12-Month Observation Period

IRR = incidence rate ratio; OCS = oral corticosteroid.

a 

COPD vs asthma.

b 

Analyzed by Poisson regression.

Table Graphic Jump Location
TABLE 2 ]  Baseline Characteristics of Frequent vs Infrequent Exacerbators With Asthma and COPD

Data are given as No. (%), mean (SD), or median (quartile 1-3) unless otherwise indicated. AHR = airway hyperresponsiveness; BDP = beclometasone dipropionate; BDR = bronchodilator response; CCI = Charlson Comorbidity Index; HMGCoA = 3-hydroxy-3-methylglutaryl-coenzyme A; ICS = inhaled corticosteroid; N/A = not applicable; VAS = visual analog scale.

Table Graphic Jump Location
TABLE 3 ]  Airway and Systemic Inflammation of Frequent vs Infrequent Exacerbators With Asthma and COPD

Data are presented as median (quartile 1-3) unless indicated otherwise. CRP = C-reactive protein; IL-1Ra = IL-1 receptor antagonist.

Table Graphic Jump Location
TABLE 4 ]  Spearman Rank Correlations of Airway IL-1β With Systemic Inflammation

See Table 3 legend for expansion of abbreviations.

a 

Three groups: with normal CRP and IL-6 levels; with either CRP or IL-6 elevated; and with both CRP and IL-6 elevated.

Table Graphic Jump Location
TABLE 5 ]  Sputum IL-1β Gene Expression Predicted the Frequent Exacerbation Phenotype in COPD

See Table 2 legend for expansion of abbreviation.

Table Graphic Jump Location
TABLE 6 ]  Sputum IL-1β Gene Expression Predicted Exacerbation Frequency in COPD

See Tables 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 7 ]  Sputum IL-1β Protein Level Predicted the Frequent Exacerbation Phenotype in COPD

See Table 2 legend for expansion of abbreviation.

Table Graphic Jump Location
TABLE 8 ]  Sputum IL-1β Protein Level Predicted Exacerbation Frequency in COPD

See Tables 1 and 2 legends for expansion of abbreviations.

Table Graphic Jump Location
TABLE 9 ]  Systemic Inflammation Predicted Exacerbation Frequency in Asthma and COPD

See Tables 1 and 2 legends for expansion of abbreviations.

References

Connors AF Jr, Dawson NV, Thomas C, et al. Outcomes following acute exacerbation of severe chronic obstructive lung disease. The SUPPORT investigators (Study to Understand Prognoses and Preferences for Outcomes and Risks of Treatments). Am J Respir Crit Care Med. 1996;154(4 pt 1):959-967. [CrossRef] [PubMed]
 
McDonald VM, Gibson PG. Exacerbations of severe asthma. Clin Exp Allergy. 2012;42(5):670-677. [CrossRef] [PubMed]
 
Bai TR, Vonk JM, Postma DS, Boezen HM. Severe exacerbations predict excess lung function decline in asthma. Eur Respir J. 2007;30(3):452-456. [CrossRef] [PubMed]
 
Donaldson GC, Seemungal TA, Bhowmik A, Wedzicha JA. Relationship between exacerbation frequency and lung function decline in chronic obstructive pulmonary disease. Thorax. 2002;57(10):847-852. [CrossRef] [PubMed]
 
Kupczyk M, ten Brinke A, Sterk PJ, et al; BIOAIR investigators. Frequent exacerbators—a distinct phenotype of severe asthma. Clin Exp Allergy. 2014;44(2):212-221. [CrossRef] [PubMed]
 
Spencer S, Calverley PM, Burge PS, Jones PW. Impact of preventing exacerbations on deterioration of health status in COPD. Eur Respir J. 2004;23(5):698-702. [CrossRef] [PubMed]
 
Dougherty RH, Fahy JV. Acute exacerbations of asthma: epidemiology, biology and the exacerbation-prone phenotype. Clin Exp Allergy. 2009;39(2):193-202. [CrossRef] [PubMed]
 
Hurst JR, Vestbo J, Anzueto A, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Susceptibility to exacerbation in chronic obstructive pulmonary disease. N Engl J Med. 2010;363(12):1128-1138. [CrossRef] [PubMed]
 
ten Brinke A, Sterk PJ, Masclee AA, et al. Risk factors of frequent exacerbations in difficult-to-treat asthma. Eur Respir J. 2005;26(5):812-818. [CrossRef] [PubMed]
 
Miravitlles M, Calle M, Soler-Cataluña JJ. Clinical phenotypes of COPD: identification, definition and implications for guidelines. Arch Bronconeumol. 2012;48(3):86-98. [CrossRef] [PubMed]
 
Simpson JL, Grissell TV, Douwes J, Scott RJ, Boyle MJ, Gibson PG. Innate immune activation in neutrophilic asthma and bronchiectasis. Thorax. 2007;62(3):211-218. [CrossRef] [PubMed]
 
Wood LG, Baines KJ, Fu J, Scott HA, Gibson PG. The neutrophilic inflammatory phenotype is associated with systemic inflammation in asthma. Chest. 2012;142(1):86-93. [CrossRef] [PubMed]
 
Donaldson GC, Seemungal TA, Patel IS, et al. Airway and systemic inflammation and decline in lung function in patients with COPD. Chest. 2005;128(4):1995-2004. [CrossRef] [PubMed]
 
Dahl M, Vestbo J, Lange P, Bojesen SE, Tybjaerg-Hansen A, Nordestgaard BG. C-reactive protein as a predictor of prognosis in chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007;175(3):250-255. [CrossRef] [PubMed]
 
Agustí A, Edwards LD, Rennard SI, et al; Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) Investigators. Persistent systemic inflammation is associated with poor clinical outcomes in COPD: a novel phenotype. PLoS ONE. 2012;7(5):e37483. [CrossRef] [PubMed]
 
Thomsen M, Ingebrigtsen TS, Marott JL, et al. Inflammatory biomarkers and exacerbations in chronic obstructive pulmonary disease. JAMA. 2013;309(22):2353-2361. [CrossRef] [PubMed]
 
Slack J, McMahan CJ, Waugh S, et al. Independent binding of interleukin-1 alpha and interleukin-1 beta to type I and type II interleukin-1 receptors. J Biol Chem. 1993;268(4):2513-2524. [PubMed]
 
Baines KJ, Simpson JL, Wood LG, Scott RJ, Gibson PG. Transcriptional phenotypes of asthma defined by gene expression profiling of induced sputum samples. J Allergy Clin Immunol. 2011;127(1):153-160. [CrossRef] [PubMed]
 
Pauwels NS, Bracke KR, Dupont LL, et al. Role of IL-1α and the Nlrp3/caspase-1/IL-1β axis in cigarette smoke-induced pulmonary inflammation and COPD. Eur Respir J. 2011;38(5):1019-1028. [CrossRef] [PubMed]
 
Bafadhel M, McKenna S, Terry S, et al. Acute exacerbations of chronic obstructive pulmonary disease: identification of biologic clusters and their biomarkers. Am J Respir Crit Care Med. 2011;184(6):662-671. [CrossRef] [PubMed]
 
Fu JJ, Baines KJ, Wood LG, Gibson PG. Systemic inflammation is associated with differential gene expression and airway neutrophilia in asthma. OMICS. 2013;17(4):187-199. [CrossRef] [PubMed]
 
Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: development and validation. J Chronic Dis. 1987;40(5):373-383. [CrossRef] [PubMed]
 
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(4):902-907. [CrossRef] [PubMed]
 
Gibson PG, Wlodarczyk JW, Hensley MJ, et al. Epidemiological association of airway inflammation with asthma symptoms and airway hyperresponsiveness in childhood. Am J Respir Crit Care Med. 1998;158(1):36-41. [CrossRef] [PubMed]
 
Reddel HK, Taylor DR, Bateman ED, et al; American Thoracic Society/European Respiratory Society Task Force on Asthma Control and Exacerbations. 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(1):59-99. [CrossRef] [PubMed]
 
Brusselle GG, Vanderstichele C, Jordens P, et al. Azithromycin for prevention of exacerbations in severe asthma (AZISAST): a multicentre randomised double-blind placebo-controlled trial. Thorax. 2013;68(4):322-329. [CrossRef] [PubMed]
 
Agustí A. Systemic effects of chronic obstructive pulmonary disease: what we know and what we don’t know (but should). Proc Am Thorac Soc. 2007;4(7):522-525. [CrossRef] [PubMed]
 
Lei PW, Wu Q. Introduction to structural equation modeling: issues and practical considerations. Educ Meas Issues Pract. 2007;26(3):33-43. [CrossRef]
 
Dolinay T, Kim YS, Howrylak J, et al. Inflammasome-regulated cytokines are critical mediators of acute lung injury. Am J Respir Crit Care Med. 2012;185(11):1225-1234. [CrossRef] [PubMed]
 
Green RH, Brightling CE, McKenna S, et al. Asthma exacerbations and sputum eosinophil counts: a randomised controlled trial. Lancet. 2002;360(9347):1715-1721. [CrossRef] [PubMed]
 
Jayaram L, Pizzichini MM, Cook RJ, et al. Determining asthma treatment by monitoring sputum cell counts: effect on exacerbations. Eur Respir J. 2006;27(3):483-494. [CrossRef] [PubMed]
 
Gibson PG, Fujimura M, Niimi A. Eosinophilic bronchitis: clinical manifestations and implications for treatment. Thorax. 2002;57(2):178-182. [CrossRef] [PubMed]
 
Global strategy for the diagnosis, management and prevention of COPD. GOLD website. http://www.goldcopd.com. Updated 2014. Accessed August 30, 2015.
 
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Supporting Data

Online Supplement

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Find Similar Articles
CHEST Journal Articles
Structural Changes in Airway Diseases*: Characteristics, Mechanisms, Consequences, and Pharmacologic Modulation
PubMed Articles
  • CHEST Journal
    Print ISSN: 0012-3692
    Online ISSN: 1931-3543