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      Natural History of Chronic Obstructive Pulmonary Disease Exacerbations in a General Practice–based Population with Chronic Obstructive Pulmonary Disease

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          Abstract

          <p class="first" id="d1998480e197"> <b>Rationale:</b> Acute exacerbations of chronic obstructive pulmonary disease (AECOPDs) are important adverse events in the natural history of chronic obstructive pulmonary disease (COPD). </p><p id="d1998480e202"> <b>Objectives:</b> To investigate the natural history of AECOPDs over 10 years of follow-up. </p><p id="d1998480e207"> <b>Methods:</b> We identified 99,574 patients with COPD from January 1, 2004, to March 31, 2015, from the UK Clinical Practice Research Datalink. We defined moderate AECOPDs as those managed outside hospital and severe as those requiring hospitalization. During the baseline period (first year of follow-up), patients were grouped according to the number and severity of AECOPDs and then followed for a maximum of 10 years (mean, 4.9 yr). We investigated the effect of baseline AECOPD number and severity on risk of further events and death. </p><p id="d1998480e212"> <b>Measurements and Main Results:</b> Around one-quarter of the patients with COPD did not exacerbate during follow-up. Compared with no AECOPDs in the baseline period, AECOPD number predicted the future long-term rate of AECOPDs in a graduated fashion, ranging from hazard ratio (HR) of 1.71 (1.66–1.77) for one event to HR of 3.41 (3.27–3.56) for five or more events. Two or more moderate AECOPDs were also associated with an increased risk of death in a graduated fashion, ranging from HR of 1.10 (1.03–1.18) for two moderate AECOPDs to HR of 1.57 (1.45–1.70) for five or more moderate AECOPDs, compared with those with no AECOPDs at baseline. Severe AECOPDs were associated with an even higher risk of death (HR, 1.79; 1.65–1.94). </p><p id="d1998480e217"> <b>Conclusions:</b> A large proportion of patients with COPD do not exacerbate over a maximum 10 years of follow-up. AECOPD frequency in a single year predicts long-term AECOPD rate. Increasing frequency and severity of AECOPDs is associated with risk of death and highlights the importance of preventing AECOPDs. </p>

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          Susceptibility to exacerbation in chronic obstructive pulmonary disease.

          Although we know that exacerbations are key events in chronic obstructive pulmonary disease (COPD), our understanding of their frequency, determinants, and effects is incomplete. In a large observational cohort, we tested the hypothesis that there is a frequent-exacerbation phenotype of COPD that is independent of disease severity. We analyzed the frequency and associations of exacerbation in 2138 patients enrolled in the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. Exacerbations were defined as events that led a care provider to prescribe antibiotics or corticosteroids (or both) or that led to hospitalization (severe exacerbations). Exacerbation frequency was observed over a period of 3 years. Exacerbations became more frequent (and more severe) as the severity of COPD increased; exacerbation rates in the first year of follow-up were 0.85 per person for patients with stage 2 COPD (with stage defined in accordance with Global Initiative for Chronic Obstructive Lung Disease [GOLD] stages), 1.34 for patients with stage 3, and 2.00 for patients with stage 4. Overall, 22% of patients with stage 2 disease, 33% with stage 3, and 47% with stage 4 had frequent exacerbations (two or more in the first year of follow-up). The single best predictor of exacerbations, across all GOLD stages, was a history of exacerbations. The frequent-exacerbation phenotype appeared to be relatively stable over a period of 3 years and could be predicted on the basis of the patient's recall of previous treated events. In addition to its association with more severe disease and prior exacerbations, the phenotype was independently associated with a history of gastroesophageal reflux or heartburn, poorer quality of life, and elevated white-cell count. Although exacerbations become more frequent and more severe as COPD progresses, the rate at which they occur appears to reflect an independent susceptibility phenotype. This has implications for the targeting of exacerbation-prevention strategies across the spectrum of disease severity. (Funded by GlaxoSmithKline; ClinicalTrials.gov number, NCT00292552.)
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            Mechanisms and impact of the frequent exacerbator phenotype in chronic obstructive pulmonary disease

            Exacerbations of chronic obstructive pulmonary disease (COPD) are important events that carry significant consequences for patients. Some patients experience frequent exacerbations, and are now recognized as a distinct clinical subgroup, the ‘frequent exacerbator’ phenotype. This is relatively stable over time, occurs across disease severity, and is associated with poorer health outcomes. These patients are therefore a priority for research and treatment. The pathophysiology underlying the frequent exacerbator phenotype is complex, with increased airway and systemic inflammation, dynamic lung hyperinflation, changes in lower airway bacterial colonization and a possible increased susceptibility to viral infection. Frequent exacerbators are also at increased risk from comorbid extrapulmonary diseases including cardiovascular disease, gastroesophageal reflux, depression, osteoporosis and cognitive impairment. Overall these patients have poorer health status, accelerated forced expiratory volume over 1 s (FEV1) decline, worsened quality of life, and increased hospital admissions and mortality, contributing to increased exacerbation susceptibility and perpetuation of the frequent exacerbator phenotype. This review article sets out the definition and importance of the frequent exacerbator phenotype, with a detailed examination of its pathophysiology, impact and interaction with other comorbidities.
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              Temporal clustering of exacerbations in chronic obstructive pulmonary disease.

              Exacerbations are important events in chronic obstructive pulmonary disease. Preventing exacerbations is a key treatment goal. Observational data suggest that after a first exacerbation, patients may be at increased risk of a second exacerbation, but this has not been specifically studied. We hypothesized that exacerbations may cluster together in time, a finding that would have important implications for targeting preventative interventions and the analysis of clinical trial data. To assess whether exacerbations are random events, or cluster in time. A total of 297 patients in the London chronic obstructive pulmonary disease cohort recorded daily symptoms and were assessed for a total of 904 patient-years. The observed timing of second exacerbations after an initial exacerbation was compared with that expected should exacerbations occur randomly. The observed timing distribution of second exacerbations differed significantly (P < 0.001) from the expected exponential function (shape parameter of the fitted Weibull function, 0.966 [95% confidence interval, 0.948-0.985]), suggesting that more second exacerbations occurred sooner than later and that exacerbations cluster together in time. Twenty-seven percent of first exacerbations were followed by a second recurrent event within 8 weeks. Approximately one third of exacerbations were recurrent exacerbations. Although initial exacerbations were milder than isolated events, they were not less likely to receive treatment, and under-treatment of initial events is not a plausible explanation for exacerbation recurrence. Recurrent exacerbations contribute significantly to overall exacerbation frequency (rho = 0.81; P < 0.0001). Exacerbations are not random events but cluster together in time such that there is a high-risk period for recurrent exacerbation in the 8-week period after an initial excerbation.
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                Author and article information

                Journal
                American Journal of Respiratory and Critical Care Medicine
                Am J Respir Crit Care Med
                American Thoracic Society
                1073-449X
                1535-4970
                August 15 2018
                August 15 2018
                : 198
                : 4
                : 464-471
                Affiliations
                [1 ]Respiratory Epidemiology, Occupational Medicine and Public Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom
                [2 ]Faculty of Epidemiology and Population Health, London School of Hygiene and Tropical Medicine, London, United Kingdom; and
                [3 ]Respiratory Epidemiology, GlaxoSmithKline R&amp;D, Uxbridge, United Kingdom
                Article
                10.1164/rccm.201710-2029OC
                6118021
                29474094
                68ad18f9-1a95-4aba-8972-140c0db1a556
                © 2018
                History

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