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      Seasonal variations in exacerbations and deaths in patients with COPD during the TIOSPIR ® trial

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          Although COPD exacerbations are known to occur more frequently in winter, there is little information on hospitalizations and cause-specific mortality. This study aimed to examine seasonal variations in mortality and exacerbations in patients with COPD during the TIOtropium Safety and Performance In Respimat ® (TIOSPIR ®) trial.

          Patients and methods

          TIOSPIR was a large-scale, multicenter trial, which assessed the safety and efficacy of tiotropium delivered via HandiHaler ® (18 μg once daily) or Respimat ® Soft Mist™ (2.5 or 5 μg once daily) inhaler in patients with COPD. Patients were aged ≥40 years, with a smoking history ≥10 pack-years, and post-bronchodilator forced expiratory volume in 1 second ≤70% and forced expiratory volume in 1 second/forced vital capacity ≤0.70. COPD exacerbations and deaths were monitored throughout the trial. The data were pooled to examine seasonal patterns. Southern hemisphere data were shifted by 6 months to align with northern hemisphere seasons.


          TIOSPIR was conducted in 43 northern (n=15,968) and 7 southern (n=1,148) hemisphere (n=1,148) countries. The median duration of treatment was 835 days, with a mean follow-up of 2.3 years. Among 19,494 exacerbations, there were clear seasonal differences (winter, 6,646 [34.1%]; spring, 4,515 [23.2%]; summer, 3,198 [16.4%]; autumn, 5,135 [26.3%]). Exacerbations peaked in early winter (December in the northern hemisphere and June in the southern hemisphere), respiratory hospitalizations in midwinter, and respiratory deaths in early spring.


          Although winter poses a 2-fold hazard for COPD exacerbations vs summer, respiratory deaths peak in early spring. These data suggest that seasonal intensification of preventive treatments may impact COPD morbidity and mortality.

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          Most cited references 24

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          Tiotropium Respimat inhaler and the risk of death in COPD.

          Tiotropium delivered at a dose of 5 μg with the Respimat inhaler showed efficacy similar to that of 18 μg of tiotropium delivered with the HandiHaler inhalation device in placebo-controlled trials involving patients with chronic obstructive pulmonary disease (COPD). Although tiotropium HandiHaler was associated with reduced mortality, as compared with placebo, more deaths were reported with tiotropium Respimat than with placebo.
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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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              Excess winter mortality in Europe: a cross country analysis identifying key risk factors.

               B. J. Healy (2003)
              Much debate remains regarding why certain countries experience dramatically higher winter mortality. Potential causative factors other than cold exposure have rarely been analysed. Comparatively less research exists on excess winter deaths in southern Europe. Multiple time series data on a variety of risk factors are analysed against seasonal-mortality patterns in 14 European countries to identify key relations Subjects and setting: Excess winter deaths (all causes), 1988-97, EU-14. Coefficients of seasonal variation in mortality are calculated for EU-14 using monthly mortality data. Comparable, longitudinal datasets on risk factors pertaining to climate, macroeconomy, health care, lifestyle, socioeconomics, and housing were also obtained. Poisson regression identifies seasonality relations over time. Portugal suffers from the highest rates of excess winter mortality (28%, CI=25% to 31%) followed jointly by Spain (21%, CI=19% to 23%), and Ireland (21%, CI=18% to 24%). Cross country variations in mean winter environmental temperature (regression coefficient (beta)=0.27), mean winter relative humidity (beta=0.54), parity adjusted per capita national income (beta=1.08), per capita health expenditure (beta=-1.19), rates of income poverty (beta=-0.47), inequality (beta=0.97), deprivation (beta=0.11), and fuel poverty (beta=0.44), and several indicators of residential thermal standards are found to be significantly related to variations in relative excess winter mortality at the 5% level. The strong, positive relation with environmental temperature and strong negative relation with thermal efficiency indicate that housing standards in southern and western Europe play strong parts in such seasonality. High seasonal mortality in southern and western Europe could be reduced through improved protection from the cold indoors, increased public spending on health care, and improved socioeconomic circumstances resulting in more equitable income distribution.

                Author and article information

                Int J Chron Obstruct Pulmon Dis
                Int J Chron Obstruct Pulmon Dis
                International Journal of COPD
                International Journal of Chronic Obstructive Pulmonary Disease
                Dove Medical Press
                14 February 2018
                : 13
                : 605-616
                [1 ]Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA
                [2 ]Respiratory Medicine, University Hospital Aintree, Liverpool, UK
                [3 ]Biostatistics, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
                [4 ]Clinical Development and Medical Affairs, Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT, USA
                [5 ]Clinical Development and Medical Affairs, Boehringer Ingelheim Pharma GmbH & Co KG, Ingelheim, Germany
                [6 ]Department of Pulmonary Diseases and Critical Care Medicine, University of Texas Health Science Center and South Texas Veterans Health Care System, San Antonio, TX, USA
                Author notes
                Correspondence: Robert A Wise, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University School of Medicine, Johns Hopkins Asthma and Allergy Center, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA, Tel +1 410 550 0545, Fax +1 410 550 2612, Email rwise@
                © 2018 Wise et al. This work is published and licensed by Dove Medical Press Limited

                The full terms of this license are available at and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed.

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