Effects of periodontal treatment. pulmonary disease and chronic periodontitis: A 2-year pilot randomized controlled trial

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1 J Clin Periodontol 2014; 41: doi: /jcpe Effects of periodontal treatment on lung function and exacerbation frequency in patients with chronic obstructive pulmonary disease and chronic periodontitis: A 2-year pilot randomized controlled trial Xuan Zhou 1, Jing Han 1, Zhiqiang Liu 1, Yiqing Song 2, Zuomin Wang 1 and Zheng Sun 3 1 Department of Stomatology, Beijing ChaoYang Hospital affiliated to Capital Medical University, Beijing, China; 2 Department of Epidemiology, Indiana University Richard M. Fairbanks School of Public Health, Indianapolis, IN, USA; 3 Department of Oral Medicine, Capital Medical University School of Stomatology, Beijing, China Zhou X, Han J, Liu Z, Song Y, Wang Z, Sun Z. Effects of periodontal treatment on lung function and exacerbation frequency in patients with chronic obstructive pulmonary disease and chronic periodontitis: A 2-year pilot randomized controlled trial. J Clin Periodontol 2014; 41: doi: /jcpe Abstract Aim: To evaluate the direct effects of periodontal therapy in Chronic Obstructive Pulmonary Disease (COPD) patients with chronic periodontitis (CP). Materials and Methods: In a pilot randomized controlled trial, 60 COPD patients with CP were randomly assigned to receive scaling and root planing (SRP) treatment, supragingival scaling treatment, or oral hygiene instructions only with no periodontal treatment. We evaluated their periodontal indexes, respiratory function, and COPD exacerbations at baseline, 6 months, 1, and 2 years. Results: Compared with the control group, measurements of periodontal indexes were significantly improved in patients in two treatment groups at 6-month, 1-year, and 2-year follow-up (all p < 0.05). Overall, the means of forced expiratory volume in the first second/forced vital capacity (FEV1/FVC) and FEV1 were significantly higher in the two therapy groups compared with the control group during the follow-up (p < 0.05). In addition, the frequencies of COPD exacerbation were significantly lower in the two therapy groups than in the control group at 2-year follow-up (p < 0.05). Conclusions: Our preliminary results from this pilot trial suggest that periodontal therapy in COPD patients with CP may improve lung function and decrease the frequency of COPD exacerbation. View the pubcast on this paper at Key words: chronic obstructive pulmonary disease; chronic periodontitis; dental scaling; randomized controlled trial; root planing Accepted for publication 27 February 2014 Conflict of interest and source of funding statement This study was supported by the National Natural Science Foundation of China (No and No ) and Beijing Science and Technology Program Fund (Z ). The authors declare that they have no conflict of interests related to the study. 564

2 Periodontal therapy on COPD with CP 565 Periodontal diseases have been associated with a number of systemic diseases such as chronic respiratory diseases (Scannapieco et al. 2003, Sharma & Shamsuddin 2011, Si et al. 2012), cardiovascular disease (Seymour et al. 2007, Ouyang et al. 2011, Dietrich et al. 2013), and diabetes mellitus (Ryan et al. 2003, Taylor 2003, Taiyeb-Ali et al. 2011, Borgnakke et al. 2013). Chronic Obstructive Pulmonary Disease (COPD) is one of the most common and costly respiratory diseases. The high prevalence and mortality of COPD worldwide pose an immense public health and medical challenge for development and implementation of effective preventive and treatment strategies (Murray & Lopez 1997). It is the third leading cause of death in the United States, affecting as many as 24 million Americans, and resulting in 700,000 hospital admissions and 124,000 deaths annually (Corbridge et al. 2012). COPD is an inflammatory disease characterized by progressive deterioration of pulmonary function and increasing airway obstruction, including chronic bronchitis and emphysema. The association between periodontitis and COPD has been increasingly recognized over the last two decades. As reviewed by Azarpazhooh & Leake, four cross-sectional studies suggested an association between poor oral health (including alveolar bone loss, periodontal attachment loss, oral hygiene index, and oral plaque colonization) and chronic pulmonary disease (Hayes et al. 1998, Scannapieco et al. 1998, Russell et al. 1999, Scannapieco & Ho 2001, Azarpazhooh & Leake 2006). Garcia s study found a consistent association between periodontitis and COPD even after stratification for smoking (Garcia et al. 2001). Katancik s study of 860 elderly patients found that all periodontal measures among former smokers were associated with pulmonary disease status (Katancik et al. 2005). Another cross-sectional epidemiological study suggested that current smokers with 4 mm mean loss of attachment had a high risk of COPD (odds ratio: 3.71) (Hyman & Reid 2004). Three recent case control studies also reported that poor periodontal health status, including plaque index (PLI), alveolar bone loss, and dental care, was significantly associated with increased risk of COPD (Leuckfeld et al. 2008, Wang et al. 2009, Si et al. 2012). A meta-analysis of 14 observational studies suggested that periodontal disease is a significant and independent risk factor of COPD (Zeng et al. 2012). Several recent studies have reported the positive association between periodontitis and COPD exacerbations (Liu et al. 2012, Takahashi et al. 2012). However, these were all observational studies. Only Kucukcoskun s trial suggested that initial periodontal therapy in patients with COPD and chronic periodontitis (CP) could decrease the exacerbation frequency (Kucukcoskun et al. 2013); however, the trial was not randomized. Adequately powered randomized clinical trials that test the efficacy of periodontal interventions on the progression of COPD are required (Linden & Herzberg 2013a). Several mechanisms have been proposed to explain the association of periodontal disease and COPD. As summarized by the European Federation of Periodontology and American Academy of Periodontology (EFP/ AAP), COPD inflammatory status may be modified either by aspiration of dental plaque and/or haematogenous dissemination of inflammatory mediators and plaque organisms from periodontal pockets (Linden et al. 2013b). Thus, we hypothesized that reducing periodontal inflammation by periodontal treatment may help to prevent the progressive deterioration of lung function and reduce the frequency of exacerbations in COPD patients with CP. Due to the lack of direct evidence from randomized trials, however, it remains unclear whether and to what extent conventional periodontal therapy would impact on COPD patients. Therefore, we conducted a pilot randomized controlled trial to evaluate the feasibility and potential clinical effects of periodontal therapy on lung function and exacerbation frequency in COPD patients with CP. Materials and Methods Sample size calculation We assumed two-sided hypothesis testing with 5% type I error and 80% statistical power to detect the differences between treatment groups. We estimated the sample size based on the primary outcome of forced expiratory volume in first second (FEV1), which represented the severity of COPD. According to previous published randomized controlled trials of COPD patients, the magnitude of clinically meaningful difference in FEV1 was Based on the median values (to avoid unstable outliers), a SD of 0.15 in difference for the groups was chosen for our sample size and power calculation. Considering periodontal treatment was an adjunctive treatment for COPD patients, the change in FEV1 may be small. We designed this study to detect an absolute between-group difference in improvement in FEV1 of 0.10 with an expected within-group standard deviation (SD) of For a two-sided test, 18 subjects were needed in each group. To allow for a dropout rate of <10%, 20 patients were recruited in each group. Study design This was a single-centre randomized controlled clinical trial in which all participants were enrolled and received randomized assigned periodontal care in the Department of Stomatology of Beijing ChaoYang Hospital. We aimed to randomly assign at least 60 patients to one of three groups: scaling and root planing (SRP) and maintenance care of SRP (SRP group), supragingival scaling alone and maintenance supragingival scaling (Scaling group), or no periodontal treatment (control group). The participants were followed-up for 2 years. The study protocol was approved by the ethics committee of the Beijing ChaoYang Hospital, and each patient provided written informed consent before enrolment. Patient screening and selection Patients with COPD were screened in the Stomatology Department and the Respiratory Department of Beijing ChaoYang Hospital from March 2007 to November Criteria used for the diagnosis of COPD and classification of severity were based on the Global Initiative for Chronic Obstructive Lung Disease (GOLD)

3 566 Zhou et al. spirometry guidelines (Rabe et al. 2007). Patients with symptoms including chronic cough, sputum production, and/or shortness of breath on effort were recruited. Subjects who fulfilled the inclusion criteria were invited to participate in the study. Inclusion criteria: (1) aged 40 years with 15 teeth; (2) physician-diagnosed COPD from stage II to IV (moderate to very severe), post-bronchodilator forced expiratory volume in first second/forced vital capacity (FEV1/FVC) ratio <0.7 and FEV1 < 80% of predicted value; (3) physician-diagnosed CP with destruction of the periodontal supporting tissues as evidenced by the presence of at least one site with >3 mm probing depth and >3 mm periodontal attachment loss. Accordingly, the gingival margin is at or apical to the cemento-enamel junction (CEJ) (Albandar et al. 1999). Exclusion criteria: (1) having fever, worsening of respiratory symptoms, or medication change in the 4-week period prior to baseline interview; (2) primary diagnosis of asthma; (3) history of lung volume reduction surgery, lung transplantation, or pneumonectomy; (4) history of any periodontal treatment in the last 6 months; (5) other inflammatory diseases except COPD and periodontitis; and (6) expected survival of <2 years. In total, 306 patients with COPD were screened in this study. Of 306 COPD patients, 204 did not satisfy the inclusion criteria or meet the exclusion criteria. In the 102 eligible COPD with CP patients, 60 agreed to participate and 42 declined either because they lived too far from the hospital treatment site or because they were not willing to take part in the study. In total, 60 eligible and willing participants with both COPD and CP signed informed consent forms. Baseline demographic information, such as age, gender, lifestyle, and smoking status, was collected by trained interviewers using standard questionnaires, and anthropometric parameters including height, weight, and blood pressure were measured by skilled nurses according to standard guidelines. Randomization and allocation concealment Patients were assigned consecutive and ascending numbers at the enrolment visit. Prior to the beginning of active therapy, each subject was randomized within blocks to one of three groups. The COPD severities were balanced with the use of blocks of six patients. There were six moderate COPD (GOLD stage II) blocks and four severe (GOLD stage III or IV) blocks. Randomization was according to a computergenerated list. Allocation was implemented by a statistical programmer who was not directly involved with the examination or treatment procedures. Each subject was given a code number during the enrolment visit. The identification code was kept concealed from all individuals directly involved in the study, until final examinations and data collection had been concluded. Assessment of lung function by spirometry Lung function was measured using spirometry, which was conducted by trained and certified technicians. During at least five forced expirations for each patient, the technician obtained three acceptable spirograms at least two of which had similar results for forced expiratory volume in one second (FEV1) and FVC. Then, we used the pulmonary evaluation based on FEV1/FVC and the percentage of predicted FEV1 to categorize the severity (Rabe et al. 2007). Air limitation was defined using the fixed-ratio post-bronchodilator as FEV1/FVC <0.70. The degree of limitation is defined by FEV1% of predicted as following: mild limitation (GOLD Stage I): % predicted; moderate (GOLD Stage II): 50 80% predicted; severe (GOLD Stage III): 30 50% predicted; and very severe (GOLD Stage IV): FEV1 below 30% predicted or FEV1 below 50% predicted plus the presence of chronic respiratory failure. Assessing exacerbations of COPD Chronic obstructive pulmonary disease exacerbations were defined as acute deterioration in clinical symptoms in accordance with GOLD guideline definition (Rabe et al. 2007), which is characterized by increased dyspnoea, cough, sputum volume, or sputum purulence compared with their baseline status. A confirmed exacerbation required two or more above symptoms and a change in medication. If two exacerbations occurred within 2 weeks, they were considered as one exacerbation. The frequency of exacerbation in the last 12 months was reported by the patients themselves in the interview. Patients who suffered from <2 exacerbations in the last 12 months were classified as infrequent exacerbation, whereas those who suffered from 2 or more exacerbations in the last 12 months were defined as frequent exacerbation (Miravitlles et al. 2000, Wan et al. 2011). Periodontal examination Oral health examinations were conducted by two trained dentists (JH and ZL) independently who were blinded to the study design and patients COPD status. Following our trial protocol, quality of periodontal examinations and protection of human subjects had been insured by our training and supervision process. The examiners had been trained by an experienced dentist (ZW). The evaluation of oral health included periodontal probing and PLI examination. Periodontal probing included measurement of pocket depth (PD), location of the CEJ to determine clinical attachment level (CAL), and bleeding index (BI) on probing. PD and CEJ were measured with a Williams s periodontal probe at six sites of all teeth (excluding third molars) and recorded in millimetres. Recession was recorded as a positive value if the free gingival margin occurred apical to the CEJ, whereas it was recorded as a negative value if it was coronal to the CEJ. CAL was calculated using the formula: PD + CEJ = CAL. BI on probing was scored on a scale of 0 5 when any visual evidence of bleeding was noted (Mazza et al. 1981). PLI for each tooth was determined on a scale of 0 3 after air drying (Silness & L oe 1964). Replicate examinations were conducted throughout the survey and intra-examiner reliability was assessed. The correlations coefficients of agreement of PD and CAL were 0.92 and 0.95, respectively. The Kappa values of agreement of BI and PLI were 0.82 and 0.85, respectively.

4 Periodontal therapy on COPD with CP 567 Intervention All dental therapies were performed by two experienced dentists in the department of stomatology of Beijing ChaoYang Hospital. The dentists had completed their training in performing periodontal procedures according to the study protocol, under the supervision of an experienced dentist (ZW). There were three groups each of which contained 20 participants at baseline. The SRP therapy group received oral hygiene instructions, full-mouth supragingival, and subgingival SRP using hand instruments and ultrasonic devices under local anaesthesia. The scaling therapy group only received oral hygiene instructions and supragingival scaling with no local anaesthesia. The control group only received oral hygiene instructions, but no periodontal therapy. Oral hygiene instructions included recommending the Modified Bass tooth-brushing method and the use of inter-dental aids in plaque removal to the patients. The education included that embrasures with no gingival recession are adequately cleaned using dental floss, while larger spaces with exposed root surfaces require the use of an interproximal brush. No antibiotics were prescribed and no rinses were used after the treatment. We re-evaluated clinical periodontal parameters of each patient at 6 months, 1, and 2 years. All patients in the SRP therapy group received further SRP if necessary at 6 months, 1, and 2 years follow-up. All patients in scaling group got maintenance care of supragingival scaling at each follow-up. Patients in the control group were followed-up without periodontal therapy at baseline, 6 months, 1, and 2 years. Given the slow changes in lung function, respiratory exams were not performed at 6 months. The frequencies of COPD exacerbation were also assessed at 1- and 2-year follow-up. Outcome measures The primary outcomes of the study were the changes in the pulmonary function (FEV1% of predicted and FEV1/FVC) after the periodontal treatment. The secondary outcome measures were the changes in the periodontal indexes (PD, CAL, BI, and PLI) and the frequencies of COPD exacerbation after periodontal treatment. Masking The dentists who performed the periodontal examinations were blinded to the patients COPD status. The technicians who examined the lung function measurements were also blinded to group assignment of the patients. Statistical analysis SPSS statistical package (Version 18.0; SPSS Inc., Chicago, IL, USA) was used for the data analyses. Baseline characteristics among groups were compared using ANOVA for continuous variables and v 2 test for categorical variables. The significance of differences in periodontal indexes and respiratory variables among groups was compared using analysis of covariance (ANCOVA) adjusted for the covariate of baseline measures. The pair-wise comparisons of the two groups were performed by the method of least significant difference (LSD). The paired samples t-test was used to compare within-group changes. The v 2 test was also used to compare crude frequency of COPD exacerbation among three groups. Logistic regression was performed to calculate the odds ratio (OR) and 95% confidence interval (CI) of frequent COPD exacerbations among different groups. To control for potential confounding, we also performed multivariateadjusted models by including age, sex, body mass index, smoking status, and baseline frequency of COPD exacerbations. The level of significance was set at p < Results 306 subjects assessed for eligibility 60 subjects randomized Subject retention Figure 1 presents the flow chart of the study design. All the patients were treated by one experienced dentist in Beijing ChaoYang Hospital. All 60 patients returned for the 6-month Excluded (n = 246) Not meeting inclusion criteria (n = 204) Declined to participate (n = 42) SRP group; n = 20 Scaling group; n = 20 Control group; n = 20 Lost during follow up: n = 1 Reason: moved from the city n = 19 with complete data Lost during follow up: n = 1 Reason: could not be contacted n = 19 with complete data Lost during follow up: n =1 Reason: could not be contacted n = 18 with complete data Fig. 1. Flow chart of the study design. SRP, scaling and root planing. Screening Allocation 6 months 1 year 2 years

5 568 Zhou et al. visit and only one from control group did not return for the 1-year visit. One subject from scaling group and another one from control group did not return for the 2-year visit. Clinical findings Baseline characteristics Baseline characteristics of the study population are presented in Table 1. There were no statistically significant differences among the three groups for baseline age, gender, body mass index, smoking status, and severity of COPD (all p > 0.05). Periodontal parameters Table 2 shows the means of the periodontal indexes by treatment groups at baseline, 6-month, 1-, and 2-year follow-up. Compared with baseline measurements, both therapies (SRP or scaling) led to obvious reductions in the means of PD, CAL, BI, and PLI at 6-month, 1-, and 2-year follow-up. Considering the influence of baseline measurements, we used the analysis of covariance (ANCOVA) to analyse the differences in periodontal indexes among groups adjusted for the baseline covariates. The differences in PD, CAL, BI, and PLI measurements were statistically significant among groups at 6-month, 1-, and 2-year follow-up (all p < 0.05). The results of pair-wise comparison showed that periodontal therapy Table 1. Baseline characteristics of the study population Characteristic SRP group (n = 20) Scaling group (n = 20) groups had lower measures of PD, CAL, BI, and PLI in comparison with the control group (all p < 0.05). Pulmonary function Pulmonary function at baseline, 1-, and 2-year follow-up is shown in Table 3. Compared with baseline measurements, the means of FEV1 and FEV1/FVC increased a little at 1- year and at 2-year follow-up in both therapy groups. In the control group, there were statistically significant reductions in FEV1 at 2- year follow-up and FEV1/FVC at 1-year and 2-year follow-up (p < 0.05). The result of ANCOVA analysis adjusted for the influence of baseline measurements showed that the FEV1 means of two treatment groups were significantly higher (p = 0.03) than the control group at 1-year follow-up (means: SRP group: ; scaling group: ; control group: ). The FEV1/FVC means of the treatment groups were higher than the control group at 1- year visit (p = 0.04) and at 2-year follow-up (p = 0.02), respectively, as shown in Table 3. The pair-wise comparisons by LSD method showed that FEV1 and FEV1/FVC in the SRP therapy group were significantly lower than those in the control group at 1-year and 2-year visits (all p < 0.05). However, in the scaling therapy group, Control group (n = 20) p-value * Age (years) (mean SD) Gender [n (%)] Male 16 (80) 15 (75) 16 (80) 0.91 Female 4 (20) 5 (15) 4 (20) Body mass index (BMI) (kg/m 2 ) (mean SD) only FEV1 at 1-year visit and FEV1/FVC at 2-year visit showed a significant difference. Overall, there were no significant differences in FEV1 and FEV1/FVC between the two treatment groups. COPD exacerbation frequency Table 4 shows the frequency of COPD exacerbations. There were no statistically significant differences among the three groups for the frequency of exacerbation at baseline (p = 0.28). Compared with baseline measurements, frequent exacerbation decreased in both the SRP therapy group and scaling therapy group, and changed little in the control group at follow-up. Table 4 shows that at the 2-year visit, the treatment groups had a lower proportion of frequent exacerbations (SRP 30%, Supragingival scaling 15.8%) compared with the control group (66.7%), and across the groups this was statistically significant (p = 0.004). As shown in Table 5, periodontal treatments were significantly associated with reduced risk of COPD exacerbation during a 2-year followup compared with the control group. To minimize potential confounding effects, we adjusted for age, gender body mass index, smoking status, and baseline frequent exacerbations in multivariate-adjusted logistic regression models. At 2-year visit, the adjusted ORs for frequent COPD exacerbation were 0.29 (95% CI: ) for the SRP group and 0.04 (95% CI: ) for the scaling group, compared with the control group, respectively. There were no significant differences between two treatment groups at 2-year visit (Table 5) Discussion In this randomized controlled trial of 60 COPD patients with CP, patients in two periodontal therapy groups (SRP and scaling group, respectively) had higher measurements of lung function and lower frequencies of COPD exacerbation than those in the control group after 2 years of follow-up. At 1-year follow-up, FEV1 (percentage of predicted) and FEV1/FVC of treatment groups indicated a statistically significantly better effect than that of Smoking status [n (%)] Non-smoker 4 (20) 7 (35) 6 (30) 0.83 Former smoker 10 (50) 9 (45) 10 (50) Current smoker 6 (30) 4 (20) 4 (20) COPD severity [n (%)] GOLD stage II 12 (60) 12 (60) 12 (60) 1.00 GOLD stage III or IV 8 (40) 8 (40) 8 (40) *p value obtained from ANOVA for continuous variables and v 2 test for categorical variables. BMI, body mass index; COPD, chronic obstructive pulmonary disease; GOLD, the Global Initiative for Chronic Obstructive Lung Disease; SRP, scaling and root planing.

6 Periodontal therapy on COPD with CP 569 Table 2. Means (SD) of the periodontal indexes by treatment groups at baseline, 6 months, 1-, and 2-year follow-up Periodontal index SRP group (n = 20) Scaling group (n = 20) Control group (n = 20) p-value PD Baseline months a b < * 1 year a b < * 2 years a b < * CAL Baseline months a b < * 1 year a b < * 2 years a b < * BI Baseline months a b * 1 year a b < * 2 years a b < * PLI Baseline months a b * 1 year a b * 2 years a b < * The significance of differences among groups was assessed using analyses of covariance (*p < 0.05). The pair-wise comparisons of treatment groups were performed by LSD method ( a significant differences between SRP group and control group; b significant differences between scaling group and control group). BI, bleeding index; CAL, clinical attachment lever; LSD, least significant difference; PD, probing depth; PLI, plaque index; SRP, scaling and root planing. Table 3. Means (SD) of the pulmonary function by groups at baseline, 1-, and 2-year follow-up Respiratory variable SRP group (n = 20) Scaling group (n = 20) Control group (n = 20) p-value FEV1 (% of predicted) Baseline year a b * 2 years a FEV1/FVC Baseline year a * 2 years a b * The significance of overall differences among groups was assessed using analysis of covariance (*p < 0.05). The pair-wise comparisons of treatment groups were performed by LSD method ( a significant differences between SRP group and control group; b significant differences between scaling group and control group). FVC, forced vital capacity; FEV1, forced expiratory volume in one second; LSD, least significant difference; SRP, scaling and root planing. Table 4. COPD patients with frequent exacerbation and infrequent exacerbation by groups at baseline, 1-, and 2-year follow-up Time and groups Frequent exacerbation Infrequent exacerbation p-value Baseline [n (%)] SRP group 9 (45.0) 11 (55.0) 0.28 Scaling group 6 (30.0) 14 (70.0) Control group 11 (55.0) 9 (45.0) 1 year [n (%)] SRP group 4 (20.0) 16 (80.0) 0.10 Scaling group 4 (20.0) 16 (80.0) Control group 9 (47.4) 10 (52.6) 2 years [n (%)] SRP group 6 (30.0) 14 (70.0) * Scaling group 3 (15.8) 16 (84.2) Control group 12 (66.7) 6 (33.3) *Statistically significant. p value obtained from v 2 test. COPD, chronic obstructive pulmonary disease; SRP, scaling and root planing. control group. The better effect on FEV1/FVC and frequencies of COPD exacerbation was also presented at 2-year follow-up. We did not observe significantly different effects between two periodontal therapies. In recent years, the association between CP and COPD has been increasingly recognized (Zeng et al. 2012). Periodontitis has been identified as a novel risk factor of COPD, in addition to smoking, chronic exposure to hazardous air pollutants, and genetic conditions. However, previous studies were almost all cross-sectional studies or case control studies. To the best of our

7 570 Zhou et al. Table 5. Adjusted ORs and 95% CIs of frequent COPD exacerbations across the three treatment groups Groups Follow-up OR 95% CI p-value SRP versus control 1 year years * Scaling versus control 1 year years * SRP versus scaling 1 year years *Statistically significant. CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odd ratio; SRP, scaling and root planing. The logistic regression analyses were adjusted for age, gender, body mass index, smoking status, and baseline frequent exacerbations in the last 12 months before randomization. knowledge, this is the first randomized controlled trial to evaluate the direct effects of the adjunctive periodontal therapy in COPD patients with CP. We found that there were significant improvements in lung function and a reduction in the frequency of COPD exacerbations as a result of periodontal treatments. Thus, periodontal therapy may slow down the reduction in lung function and decrease COPD exacerbation among COPD patients. Our results seem to support Kucukcoskun s point that initial periodontal therapy in patients with COPD and CP may decrease the exacerbation frequency (Kucukcoskun et al. 2013). Several mechanisms may be considered for the effect of periodontal therapy on COPD. First, periodontal therapies can reduce plaque and oral mucosa colonization with respiratory pathogens. Respiratory pathogens isolated from bronchoalveolar lavage fluid of nursing home residents and hospitalized patients were the same as pathogens isolated from their dental plaques (Senpuku et al. 2003, El-Solh et al. 2004). Second, periodontal therapies may decrease periodontal pathogens. The products of periodontal pathogens can promote airway inflammation and exacerbations. Brook & Frazier found elevated antibody levels against Fusobacterium nucleatum and Prevotella intermedia, two important periodontal pathogens, in the sputum of patients with an acute exacerbation of chronic bronchitis (Brook & Frazier 2003). Takahashi suggested that normal-igg titre for periodontitisrelated antibody could be an independent predictor of COPD frequent exacerbations (Takahashi et al. 2012). Pavord suggested that the coexistence of multiple inflammatory stimuli may be a key factor leading to the development of more severe airway disease (Pavord et al. 2006). A large number of inflammatory factors are released continuously from periodontal lesions and peripheral mononuclear cells, and this may induce a more severe inflammatory response in COPD. Thus, it seems reasonable to speculate that periodontal SRP, which effectively reduces the dental plaque burden could reduce exposure to pathogens in the respiratory tract, which subsequently could slow the progression of pulmonary dysfunction and decrease the frequency of COPD exacerbation. Our results indicated that periodontal treatment and oral health care is an effective adjunctive therapy for COPD patients with CP. In our study, both SRP group and scaling group had lower measures of PD, CAL, BI, and PLI in comparison with the control group at 6-month, 1-, and 2-year follow-up. In both therapy groups, the lung function and the exacerbation frequencies were similarly changed after treatment. The similarity of changes in the SRP and supragingival scaling groups might be due to relatively low statistical power. Alternatively, both treatments may have removed large numbers of plaque bacteria, including both periodontal and respiratory pathogens, reducing the bacterial load in the saliva. Furthermore, considering the fact that the scaling is a relatively simple treatment and with no side effect, we suggest that it may be a cost-effective periodontal treatment for COPD patients. In our study, 102 patients with COPD and CP met the inclusion criteria, but 42 patients declined to participate. We were aware that volunteer bias may exist due to differences between those COPD patients who chose to participate in this study and those who did not. The patients declined to participate mostly because they lived far from our hospital and had difficulties in making our follow-up schedule. Some had not received any periodontal treatment in their whole life and did not want to receive periodontal therapy. Because of the lack of detailed information on many demographic, lifestyle, and psychosocial characteristics between those who were willing to participate in this trial and those who did not volunteer, it is indeed difficult to assess the potential impact of such selection/volunteer bias on the final results. Although the results may not be generalizable to all COPD patients, enrolment of eligible and willing patients should allow the trial to be completed with a high level of internal validity, with low rates of loss of follow-up. This study has several limitations that merit consideration. First, this study had a relatively small number of patients in each group. Despite such limited sample size, this study showed significant changes in lung function and COPD exacerbations by adjunctive periodontal therapy. Second, some positive effect may be caused by bronchodilator medications. Slight differences in pulmonary medicines for COPD among different groups may influence the results, especially when the number of participants in each group was small. Third, bias due to misclassification may exist as the exacerbation frequencies were reported by the patients themselves. In addition, COPD exacerbations were associated with many other known factors such as comorbid conditions and depression. In conclusion, our randomized controlled trial in COPD patients with CP suggests that periodontal therapy may slow down the reduction in lung function and decrease the frequency of COPD exacerbation. Periodontal therapies could be included as an effective adjunctive treatment for the management of

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9 572 Zhou et al. Clinical Relevance Scientific rationale for the study: The effect of treatment for periodontitis on chronic obstructive pulmonary disease (COPD) is unclear due to the lack of direct evidence from randomized controlled trials. Principal findings: The FEV1, FEV1/ FVC, and frequencies of COPD exacerbation in patients receiving either of two periodontal therapies were significantly better than those receiving no periodontal therapy. Practical implications: Periodontal treatment may slow down the reduction in lung function and decrease the frequency of COPD exacerbation in COPD patients with CP.