Chronic Obstructive Pulmonary Diseases: Journal of the COPD Foundation The Journal Club: Computed Tomography and COPD

2 Frequency of Exacerbations in Patients with Chronic Obstructive Pulmonary Disease: An Analysis of the SPIROMICS Cohort BACKGROUND: Present treatment strategies to stratify exacerbation risk in patients with chronic obstructive pulmonary disease (COPD) rely on a history of two or more events in the previous year. We aimed to understand year to year variability in exacerbations and factors associated with consistent exacerbations over time. Han MK, Quibrera PM, Carretta EE, et al and SPRIOMICS Investigators. Lancet Respir Med. 2017;5(8):619-626. doi: https://doi.org/10.1016/S2213-2600(17)30207-2 METHODS: In this longitudinal, prospective analysis of exacerbations in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort, we analysed patients aged 40-80 years with COPD for whom 3 years of prospective data were available, identified through various means including care at academic and non-academic medical centres, word of mouth, and existing patient registries. Participants were enrolled in the study between Nov 12, 2010, and July 31, 2015. We classified patients according to yearly exacerbation frequency: no exacerbations in any year; one exacerbation in every year during 3 years of follow-up; and those with inconsistent exacerbations (individuals who had both years with exacerbations and years without during the 3 years of follow-up). Participants were characterised by the Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric category (1-4) on the basis of post-bronchodilator FEV1. Stepwise logistic regression was used to compare factors associated with one or more acute exacerbations of COPD every year for 3 years versus no exacerbations in the same timeframe. Additionally, a stepwise zeroinflated negative binomial model was used to assess predictors of exacerbation count during follow-up in all patients with available data. Baseline symptom burden was assessed with the COPD assessment test. This trial is registered with ClinicalTrials.gov, number NCT01969344. FINDINGS: 2981 patients were enrolled during the study. 1843 patients had COPD, of which 1105 patients had 3 years of complete, prospective follow-up data. 538 (49%) of 1105 patients had at least one acute exacerbation during the 3 years of follow-up, whereas 567 (51%) had none. 82 (7%) of 1105 patients had at least one acute exacerbation each year, whereas only 23 (2%) had two or more acute exacerbations in each year. An inconsistent pattern (both years with and without acute exacerbations) was common (456 [41%] of the group), particularly among GOLD stages 3 and 4 patients (256 [56%] of 456). In logistic regression, consistent acute exacerbations (≥1 event per year for 3 years) were associated with higher baseline symptom burden, previous exacerbations, greater evidence of small airway abnormality on CT, lower interleukin-15 concentrations, and higher 327 The Journal Club journal.copdfoundation.org JCOPDF © 2017 Volume 4 • Number 4 • 2017 For personal use only. Permission required for all other uses. Comments The SPIROMICS investigators found that CT-defined small airway disease (assessed by the degree of air trapping) was associated with “consistent acute exacerbators” (defined as at least 1 acute exacerbation per year) during 3 years of prospective follow-up. The forced expiratory volume in 1 second (FEV1) percentage predicted was associated with exacerbation rate in univariate analysis but it was not significant in multivariate analysis. The investigators primary target group for the study was the “frequent exacerbator” group (≥ 2 exacerbations/year) but they actually found only about 2% of the individuals studied fit this criterion. As such, they were not able to find any correlations for this particular group. The significance of this finding is open to interpretation. The SPIROMICS cohort was recruited from academic centers and non-academic medical centers between 2010 and 2015. It would be interesting to know how many of the patients recruited for SPIROMICS were from the centers where these investigators are based. If so, this patient population may not be representative of the general COPD population in terms of their access to expert care. While they found no difference in exacerbation frequency between different types of centers over this period of time, many patients with severe to very severe COPD (Global initiative for chronic Obstructive Lung Disease [GOLD] stages III and IV1) would have presumably been on, or were put on, inhaled corticosteroids, long-acting beta2-agonists interleukin-8 concentrations, than were no acute exacerbations. INTERPRETATION: Although acute exacerbations are common, the exacerbation status of most individuals varies markedly from year to year. Among patients who had any acute exacerbation over 3 years, very few repeatedly had two or more events per year. In addition to symptoms and history of exacerbations in the year before study enrolment, we identified several novel biomarkers associated with consistent exacerbations, including CT-defined small airway abnormality, and interleukin-15 and interleukin-8 concentrations. FUNDING: National Institutes of Health, and National Heart, Lung, and Blood Institute. and/or long-acting muscarinic antagonists during the study. While it was a prospective observational study it appears that they did not control or track patient use of maintenance medications. The early GOLD guidelines recommendations are based on the presumption that patients are maintenance therapy naïve. This low prevalence number for frequent exacerbators may actually be a testament to the impact current standard therapies have in their ability to reduce exacerbations. While it is challenging to track the medications of this cohort over time it would have been interesting to see what maintenance therapies these patients were on over the 3year period. It could further inform what should be the future therapeutic goals and outcomes to assess in patients on maintenance therapies. BACKGROUND: Traditional metrics of lung disease such as those derived from spirometry and static single-volume CT images are used to explain respiratory morbidity in patients with COPD, but are insufficient. We hypothesised that the mean Jacobian determinant, a measure of local lung expansion and contraction with respiration, would contribute independently to clinically relevant functional outcomes. METHODS: We applied image registration techniques to paired inspiratory-expiratory CT scans and derived the Jacobian determinant of the deformation field between the two lung volumes to map local volume change with respiration. We analysed 490 participants with COPD with multivariable regression models to assess strengths of association between traditional CT metrics of disease and the Jacobian determinant with respiratory morbidity including dyspnoea (modified Medical Research Council), St Georges Respiratory Questionnaire (SGRQ) score, 6-min Abstract 3 Biomechanical CT Metrics Are Associated with Patient Outcomes in COPD Bodduluri S, Bhatt SP, Hoffman EA, et al and the COPDGene Investigators. Thorax. 2017; 72(5):409-414. doi: https://doi.org/10.1136/thoraxjnl-2016-209544 328 The Journal Club journal.copdfoundation.org JCOPDF © 2017 Volume 4 • Number 4 • 2017 For personal use only. Permission required for all other uses. walk distance (6MWD) and the Body Mass Index, Airflow Obstruction, Dyspnoea and Exercise Capacity (BODE) index, as well as all-cause mortality. RESULTS: The Jacobian determinant was significantly associated with SGRQ (adjusted regression coefficient β=-11.75,95% CI -21.6 to -1.7; p=0.020), and with 6MWD (β=321.15, 95% CI 134.1 to 508.1; p<0.001), independent of age, sex, race, body mass index, FEV1, smoking pack-years, CT emphysema, CT gas trapping, airway wall thickness and CT scanner type. The mean Jacobian determinant was also independently associated with the BODE index (β=-0.41, 95% CI -0.80 to -0.02; p=0.039) and mortality on follow-up (adjusted HR=4.26, 95% CI 0.93 to 19.23; p=0.064). CONCLUSIONS: Biomechanical metrics representing local lung expansion and contraction improve prediction of respiratory morbidity and mortality and offer additional prognostic information beyond traditional measures of lung function and static single-volume CT metrics. TRIAL REGISTRATION NUMBER: NCT00608764; Post-results.