Incorvaia et al Tiotropium bromide, a second-generation anticholinergic agent, showed a favorable inﬂuence on the rate of exacerba- tions in COPD patients (Brusasco et al 2003). We sought to evaluate 1) the small airway impairment in COPD patients with frequent or infrequent exacerbations and 2) the effect of treatment with tiotropium bromide on small airway impairment. Methods Patients Seventy-six subjects referred to the Unit of Pulmonary Rehabilitation of the ICP Hospital in Milan were included in the study. To be included, patients had to be in a stable condition, free from exacerbations for at least 2 months, clas- siﬁed in GOLD stage 2–4 according to FEV1 values, and on treatment only with inhaled drugs such as long-acting beta2- agonists (LABA) or inhaled corticosteroids (IC), plus short acting beta2-agonists (SABA) as needed. The patients were divided according to the frequency of exacerbations: patients with more than 2 exacerbations per year formed group A; patients with up to 2 exacerbations per year formed group B. In all patients, treatment with tiotropium, at the currently recommended dose of 18 µ g once daily, was added. For drugs already used, the inhalation technique was optimized by employing spacer devices, if they had not been already introduced. Patients initiating treatment with tiotropium were trained to use the dry powder inhaler device. Pulmonary function was measured at baseline and after 3 months of treatment. Patients were instructed to recognize and report any exacerbation during the study. Pulmonary function The FEV1, the FVC, the expiratory ﬂows at low volumes (FEF25, 50, and 75), the FRC, and the residual volume (RV) were measured by an automated pulmonary function testing center (6200 Autobox DL, Sensor Medics, Yorba Linda, CA, USA) in accordance with recognized standards (American Thoracic Society 1995). Variables were measured at baseline and after the 3-month treatment. Prior to measurement SABA were discontinued for at least 8 hours, LABA and IC for at least 12 hours, and, at the second measurement, tiotropium for 24 hours. Statistical analysis Differences in the number of exacerbations and in pulmonary function in relation to the intervention in patients in groups A and B were analyzed by the Mann Whitney U test, setting a p value lower than 0.05 as signiﬁcant. 124 Results Two out of the 76 patients included in the study did not perform the second plethysmography (1 in group A and 1 in group B) and were not considered in the analysis. Table 1 shows the characteristics of the 74 patients, 37 in each group. The mean number of exacerbations was 3.6 ± 0.64/year in group A and 1.38 ± 0.59/year in group B (p 0.001). The baseline mean value of FEF25–75 was 624 ± 418 mL in group A and 865 ± 372 mL in group B (p = 0.002). Changes in each respiratory parameter versus baseline are reported in Table 2. There were increases in mean FEV1, FVC, and FEF25–75 in both groups, but only the increase in FEF25–75 in group A was statistically signiﬁcant (p = 0.013). During the 3-month study period the mean number of exacerbations was 0.66 ± 0.18 in group A and 0.12 ± 0.05 in group B. Discussion Exacerbations are a serious concern in COPD. They repre- sent an important cause of hospitalization and mortality and consume great medical resources (Garcia-Aymerich et al 2001; Rabe et al 2003). Frequent exacerbations are associ- ated with a higher lung function decline. A longitudinal study with a 4-year follow-up reported that COPD patients with frequent exacerbations (median rate of 4.2/year) had a higher decline of FEV1 (especially in persistent smokers) than those with infrequent exacerbation (median rate of 1.9 per year): FEV1 decline was 40 mL/year versus 32 mL/year in patients with frequent and infrequent exacerbations, respectively (Donaldson et al 2002). This conﬁrmed the results of a previous study on COPD patients with exac- erbations, which showed a higher FEV1 decline in current smokers than in ex-smokers (Kanner et al 2001) and draws the attention to the importance of the underlying damage to the airways. Table 1 Characteristics of patients at inclusion Group A B Gender 22 males, 15 females 23 males, 14 females Mean age (range) 71.7 years (55–85) 72.1 years (56–88) Mean duration of COPD 13.8 years 12.3 years Active smoking history 29/37 31/37 Use of IC 30/37 27/37 Use of LABA 20/37 23/37 Mean FEV1 (mL) 1191 ± 185 1249 ± 373 Mean FVC (mL) 2212 ± 803 2433 ± 649 Abbreviations: IC, inhaled corticosteroids; LABA, long-acting beta2-agonists. International Journal of COPD 2008:3(1)