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Prevalence of asthma–COPD overlap syndrome among primary care asthmatics with a smoking history: a cross-sectional study

Prevalence of asthma–COPD overlap syndrome among primary care asthmatics with a smoking history:... www.nature.com/npjpcrm All rights reserved 2055-1010/15 ARTICLE OPEN Prevalence of asthma–COPD overlap syndrome among primary care asthmatics with a smoking history: a cross-sectional study 1 2 3 4 5 Toni Kiljander , Timo Helin , Kari Venho , Antero Jaakkola and Lauri Lehtimäki BACKGROUND: The overlap between asthma and chronic obstructive pulmonary disease (COPD) is an important clinical phenomenon. However, the prevalence of asthma–COPD overlap syndrome (ACOS) is not known. AIMS: To investigate the prevalence of ACOS among asthmatic patients with a smoking history, and evaluate the factors predicting ACOS in this patient group. METHODS: We investigated 190 primary care asthma patients with no previous diagnosis of COPD, but who were either current or ex-smokers, with a smoking history of at least 10 pack-years. Spirometry was performed on all the patients while they were taking their normal asthma medication. Patients were considered to have ACOS if their postbronchodilator forced expiratory volume in 1 s/forced vital capacity was o0.70. RESULTS: Fifty-two (27.4%) of the patients were found to have ACOS. Age ⩾ 60 years and smoking for ⩾ 20 pack-years were the best predictors of ACOS. If both of these criteria were met, the odds ratio (95% confidence interval) for ACOS was 6.08 (2.11–17.49), compared with the situation where neither of these criteria were fulfilled. CONCLUSIONS: There is a high prevalence of ACOS among primary health care asthmatics with a positive smoking history but no previous diagnosis of COPD. In this population, age over 60 years and a smoking history of more than 20 pack-years were the best predictors of ACOS. npj Primary Care Respiratory Medicine (2015) 25, 15047; doi:10.1038/npjpcrm.2015.47; published online 16 July 2015 INTRODUCTION with asthma. The prevalence of overlap syndrome has been shown to increase with age, which may reflect the fact that, over Asthma and chronic obstructive pulmonary disease (COPD) are the years, asthmatics may develop fixed airway obstruction, the two most common obstructive pulmonary diseases. Although especially if they do not use anti-inflammatory medication or if asthma and COPD most often represent two distinct diseases, 13 11 1,2 they smoke. Soriano et al. found that as many as half of the there is also significant overlap between these two diseases. patients with obstructive pulmonary disease, aged 50 years or The definition of asthma–COPD overlap syndrome (ACOS) is more, had simultaneously more than one obstructive condition. undetermined. Most commonly, it is defined as either the The aim of the present study was to investigate the prevalence diagnosis of COPD in a patient with previously diagnosed asthma, of undiagnosed ACOS among primary health care asthma patients or as incompletely reversible airway obstruction accompanied by who are current or ex-smokers, and the factors predicting ACOS in symptoms or signals of increased reversibility of the obstruction. this patient group. A recent update of the GINA report recommended a stepwise approach to the diagnosis of ACOS, and defined it as a syndrome characterized by persistent airflow limitation with several features MATERIALS AND METHODS usually associated with asthma and several features usually 1 This was a cross-sectional study. Patients were recruited mostly from the associated with COPD. appointments of primary care physicians and through newspaper Compared with asthma or COPD alone, ACOS is associated advertisements. In addition, a few patients were also recruited by private 4,5 with worse health-related quality of life, more frequent pulmonologists treating primary care-like asthma patients. 5,6 6,7 exacerbations, increased hospitalisation and higher health The study was approved by the Ethics Committee of Pirkanmaa Health care costs. Although ACOS appears to be clinically highly Care District, and every patient gave written informed consent before any significant, little is known about the treatment of these patients, study-related procedures were performed. as they are typically excluded from therapy trials for asthma or COPD. Patients There is only some data on the prevalence of ACOS. Hardin The inclusion criteria were as follows: age 18–70 years, current or et al. found that 13% of the COPD patients in the COPDGene ex-smoker with 10 or more pack-years, doctor-diagnosed asthma with study reported a history of doctor-diagnosed asthma. Similarly, special reimbursement for asthma medication granted by the National Miravitlles et al. reported that 17.4% of COPD patients in the Health Insurance. To qualify for this reimbursement, patients must have EPI-SCAN study reported that they had been previously diagnosed fulfilled at least one of the following criteria: (1)⩾ 12% (and 200 ml) 1 2 3 Department of Respiratory Diseases, Terveystalo Hospital, Turku, Finland; Department of Allergology, Helsinki University Central Hospital, Helsinki, Finland; Department of 4 5 Respiratory Medicine, Central Hospital of Central Finland, Jyväskylä, Finland; Boehringer Ingelheim Finland, Helsinki, Finland and Department of Respiratory Medicine, University of Tampere, Tampere, Finland. Correspondence: Dr T Kiljander (toni.kiljander@fimnet.fi) Received 13 April 2015; accepted 1 June 2015 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al reversibility in forced expiratory volume in 1 s (FEV ) or forced vital capacity The patients were considered to have ACOS if their postbronchodilator (FVC) in a bronchodilation test, (2) during a 2-week peak expiratory flow FEV /FVC was less than 0.70. Patients with ACOS were divided into GOLD grades of airway obstruction according to the GOLD report. monitoring at least three times either a bronchodilator response of ⩾ 15% Patients were considered to have had an exacerbation during the (and 60 l/min) or a diurnal variation of ⩾ 20%, (3) moderate-to-severe previous year if they had been hospitalised, or had used a course of oral bronchial hyperresponsiveness in histamine or methacholine inhalation corticosteroids, for their asthma during the previous year. challenge or (4) FEV had improved more than 15% during a corticosteroid treatment test. The exclusion criteria were as follows: any severe illness, any known Statistical analysis pulmonary disease other than asthma, use of inhaled anticholinergic or The primary outcome was the prevalence of ACOS, as defined above, indacaterol or oral roflumilast. among asthmatics with a smoking history of at least 10 pack-years. The sample size calculation was based on the assumption that the prevalence of ACOS in asthmatics is approximately 45%. Using the large sample Methods normal approximation, 265, 195, 149, 118 or 96 patients would be required After informed consent was received, the investigator and the patient to estimate the prevalence to be 95% confident that the estimate will not completed a questionnaire including questions about the inclusion and differ from the true prevalence by more than 6, 7, 8, 9 or 10 percent, exclusion criteria, and the patient’s asthma medication, symptoms and respectively. The final sample size of 219 recruited patients was assessed to be large enough to obtain a sufficient precision. The 95% confidence exacerbations. The investigator stored the data in a database. Body mass interval for prevalence was calculated using the large sample normal index and current smoking status were recorded as a standard procedure approximation. The distribution of the variables was checked using the when spirometry was performed. Kolmogorov–Smirnov test and graphical plots. The distributions of Spirometries (Medikro Kuopio, Finland) were performed according to demographic continuous data were skewed and are expressed as medians the guidelines before and after administration of 400 μg of inhaled (interquartile range). The nonparametric Mann–Whitney U-test was used to salbutamol while the patients were taking their usual asthma medication. compare the groups with and without ACOS with respect to continuous variables. The Chi-square test and the exact Fisher's test, when appropriate, were used for categorical variables. Spearman’s rank correlation (Rho) was Asthma patients, used to study the associations between postbronchodilator FEV /FVC n =219 versus age and pack-years. The receiver operating curve analysis (ROC) was used to determine the best cut-off values of age and pack-years Spirometry measurements to differentiate between asthma patients with and without overlap were not available, syndrome. Sensitivity and specificity were assessed to be equally important n =26 when the best cut-off values were chosen. In addition, positive predictive values and negative predictive values were calculated. The potential Spirometry measurements prognostic factors for overlap were sex, age, body mass index, current were available, smoking status and pack-years of smoking. Univariable logistic regression n =193 analyses were performed to study the associations. The results are given as odds ratios with 95% confidence intervals. P values less than 0.05 were Spirometry was not valid, considered statistically significant. The analyses were performed using IBM n =3 SPSS Statistics for Windows (version 22.0, Armonk, NY, USA, IBM Corp.). Patients included in analysis, RESULTS n =190 Two hundred and nineteen patients were recruited and 190 of them were included in the analysis (Figure 1). Their median age (range) was 58 (23–70) years, they had smoked for 20 (10–60) pack-years, and their body mass index was 27.5 (16.1–50.3) kg/m . Postbronchodilator Postbronchodilator Eighty-three (44.1%) of the patients were current smokers and 112 FEV1/FVC < 0.70, FEV1/FVC > 0.70, (58.9%) were female. n = 52 (27.4%) n = 138 (72.6%) Fifty-two (27.4%, 95% confidence interval 21–34%) patients Figure 1. Flow of participants. FEV , forced expiratory volume in 1 s; were found to have postbronchodilator FEV /FVC o0.70 and FVC, forced vital capacity. were thus considered to have ACOS. Twelve (23.1%), 38 (73.1%) Table 1. Characteristics of 190 asthmatics with and without overlap syndrome Patients with overlap syndrome Patients with asthma only P value (N = 52) (N = 138) Age (years) 63.0 (52.5–66.5) 57.0 (49.0–64.0) 0.008 Pack-years 24.5 (20.0–37.0) 20.0 (13.0–28.0) 0.003 BMI (kg/m ) 26.2 (23.2–29.9) 27.8 (24.6–31.6) 0.09 Current smokers 28 (54.9%) 55 (40.1%) 0.07 Females 31 (59.6%) 81 (58.7%) 0.91 Inhaled corticosteroid (ICS) 50 (96.2%) 129 (93.5%) 0.48 Inhaled corticosteroid+inhaled long-acting β -agonist (ICS+LABA) 36 (69.2%) 86 (62.3%) 0.38 Short-acting β-agonist (SABA) more often than twice a week 19 (36.5%) 37 (26.8%) 0.19 Exacerbation during previous year 16 (30.8%) 35 (25.4%) 0.45 Significant reversibility 8 (15.4%) 9 (6.5%) 0.08 All patients were current or ex-smokers. Results are given as median (interquartile range) or number (%). Abbreviation: BMI, body mass index. Mann–Whitney U-test was used for continuous variables and Chi-squared test for categorical variables. Fisher's exact test. npj Primary Care Respiratory Medicine (2015) 15047 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al 1.0 1.0 0.9 0.9 Pack-years20 0.8 0.8 0.7 0.7 Age60 0.6 0.6 0.5 0.5 Rho= –0.28 0.4 0.4 P < 0.001 0.3 0.3 20 30 40 50 60 70 Age (years) 0.2 Age 0.1 Pack-years 1.0 0.9 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.8 1-Specificity 0.7 Figure 3. Receiver operating curve (ROC) analysis of age and pack-years in 190 asthmatic patients. The cut-off points of 60 years 0.6 of age yielded 63.5% sensitivity and 59.4% specificity and the cut-off point of 20 pack-years yielded 80.8% sensitivity and 42.8% specificity 0.5 to detect overlap syndrome. Rho= – 0.25 0.4 P < 0.001 0.3 10 20 30 40 50 60 Table 2. The best cut-off values of age and pack-years and their combination to detect asthma–COPD overlap syndrome among 190 Pack-years asthmatics with positive smoking history Figure 2. Scatter plots and regression lines showing the association between age and pack-years versus postbronchodilator FEV /FVC in 1 Sensitivity Specificity PPV NPV 190 asthma patients with a positive smoking history. FEV , forced (%) (%) (%) (%) expiratory volume in 1 s; FVC, forced vital capacity. Age ⩾ 60 years 63.5 59.4 37.1 81.2 Pack-years ⩾ 20 80.8 42.8 34.7 85.5 and 2 (3.8%) belonged to GOLD stages 1, 2 and 3, respectively. Age ⩾ 60 years or pack-years ⩾ 20 90.4 27.5 32.0 88.4 Age ⩾ 60 years and pack-years ⩾ 20 53.8 74.6 44.4 81.1 None of the patients belonged to GOLD stage 4. A comparison of the patients with ACOS and those with asthma Abbreviations: COPD, chronic obstructive pulmonary disease; NPV, alone is shown in Table 1. Patients with overlap syndrome were negative predictive value; PPV, positive predictive value. older and had smoked more than patients with asthma alone. Overlap patients tended to be more often current smokers and to have more often significant reversibility, but these differences syndrome was 11.6% (5/43 patients). If one of the criteria was met, were not statistically significant. then overlap syndrome was found in 22.6% (19/84) of the patients. A negative correlation between postbronchodilator FEV /FVC 1 If both criteria were met the prevalence of overlap syndrome was and age (Spearman Rho = − 0.28, Po0.001) and pack-years found to be 44.4% (28/63 patients). (Rho = − 0.25, Po0.001) was found (Figure 2). ROC analysis for age and pack-years revealed that age ⩾ 60 years and smoking for ⩾ 20 pack-years were the best predictors of DISCUSSION ACOS in the study population (Figure 3). The area under the ROC Main findings curve was 0.625 and 0.639 for age and pack-years, respectively. We found the prevalence of asthma–COPD overlap syndrome to The cut-off point of 60 years of age yielded 63.5% sensitivity and be 27.4% among primary health care asthmatics with no previous 59.4% specificity, and the cut-off point of 20 pack-years 80.8% diagnosis of COPD, but who were either current or ex-smokers sensitivity and 42.8% specificity, to detect overlap syndrome with a smoking history of at least 10 pack-years. The patients (Table 2). However, the combination of both age ⩾ 60 years and with ACOS were older and had smoked more than patients with smoking for ⩾ 20 pack-years yielded the best area under the ROC asthma alone. curve: 0.670, and 53.8% sensitivity and 74.6% specificity. The results of the logistic regression analysis are shown in Strengths and limitations of this study Table 3. Using the cut-off points given by the ROC analysis, age The current study has its weaknesses. First, the number of and pack-years were the only significant factors predicting overlap participants was relatively small to investigate the differences syndrome. If the patient was at least 60 years old and had between patients with ACOS and asthma alone. However, we simultaneously smoked for at least 20 pack-years, the odds ratio were able to find that older age and heavier smoking history (95% confidence interval) for overlap syndrome was 6.08 predict ACOS, which are the most common variables found in (2.11–17.49), P = 0.001, compared with the situation where neither other studies too. Moreover, with 190 participants, we were able of these criteria were fulfilled. In patients with one criterion to evaluate the prevalence of ACOS among asthmatics with a fulfilled (age ⩾ 60 or smoking for ⩾ 20 pack-years), the risk of positive smoking history, which was the primary objective of the ACOS was about twice as high as for patients who were younger study. Second, as we did not investigate consecutive patients, than 60 years and had smoked less than 20 pack-years. In there might have been selection bias. On the other hand, as we other words, if neither of the criteria (age ⩾ 60 years and smoking ⩾ 20 pack-years) were fulfilled, the prevalence of overlap excluded patients with known COPD, and even those using the © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2015) 15047 FEV (l)/FVC(l) FEV (l)/FVC(l) 1 1 Sensitivity Prevalence of asthma–COPD overlap syndrome T Kiljander et al SCAN population reported they had previously been diagnosed Table 3. Asthma–COPD overlap syndrome in association to with asthma, and thus presented with asthma–COPD overlap. demographic characteristics in 190 asthma patients with positive In the PLATINO study, 22.8% of patients with FEV /FVC o0.7 smoking history. Results are given by univariable binary logistic reported a prior diagnosis of asthma and can be considered as regression analyses overlap patients. The 27.4% prevalence of asthma–COPD overlap syndrome found in our study is slightly higher than in previous Overlap Unadjusted P value studies. We believe that the major reason for this difference may syndrome be the fact that we investigated a different patient population. a We studied asthmatic patients and investigated how often N (%) OR 95% CI their postbronchodilator FEV /FVC is o0.7, whereas other 5,10,15 Sex studies have investigated how often patients with post- Female 31/112 (27.7) 1.00 bronchodilator FEV /FVC o0.7 report that they have previously Male 21/78 (26.9) 0.96 0.50–1.84 0.91 been diagnosed with asthma. On the other hand, prevalences of overlap even higher than ours have been suggested. For example, Smoking 11 Soriano et al. found that as many as 50% of patients with Ex-smoker 23/105 (21.9) 1.00 obstructive pulmonary disease, aged 50 years or more, may suffer Current smoker 28/83 (33.7) 1.82 0.95–3.47 0.07 simultaneously from more than one obstructive condition. The high prevalence of ACOS may be explained by the fact that BMI, kg/m asthma and airway hyperresponsiveness are suggested to be risk o25.0 18/56 (32.1) 1.00 2 16 25.0–29.9 21/72 (29.2) 0.87 0.41–1.85 0.72 factors for developing COPD. Lange et al. have shown that ⩾ 30.0 12/60 (20.0) 0.53 0.23–1.23 0.14 decline in pulmonary function is faster in asthmatics than among those without asthma, and that the decline is fastest among those Age, years asthmatics who smoke. In the study by Vonk et al., 16% of 20–59 19/101 (18.8) 1.00 patients with asthma developed irreversible airway obstruction 60–70 33/89 (37.1) 2.54 1.32–4.91 0.005 during a 26-year follow-up. It has been shown that airway hyperresponsiveness, even without asthma, is an important risk Pack-years factor for developing COPD. 10–19 10/69 (14.5) 1.00 Smoking is the most important risk factor for COPD. Therefore, 20–60 42/121 (34.7) 3.14 1.46–6.76 0.004 it is not surprising that the ACOS patients in our study had smoked Age and pack-years more than those with asthma alone. Also in the study by Age o60 and 5/43 (11.6) 1.00 Lee et al., greater amount of cigarette smoking was related to pack-years o20 the development of fixed airway obstruction among asthmatic Age ⩾ 60 or pack-years 19/84 (22.6) 2.22 0.77–6.43 0.14 patients. ⩾ 20 We found ACOS patients to be older than patients with asthma Age ⩾ 60 and pack- 28/63 (44.4) 6.08 2.11–17.49 0.001 alone. In the study by Menezes et al., patients with asthma–COPD years ⩾ 20 overlap were also older than patients with asthma alone. In that Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmon- study, and in the COPDGene study, patients with COPD were ary disease; OR, odds ratio. older than the overlap patients. These findings might suggest a Number of patients with overlap syndrome/number of all patients in continuum from reversible airway obstruction, via overlap, to the group. irreversible obstruction in some patients. There is evidence that some patients with asthma developed irreversible airway obstruc- tion during long-enough follow-up, and that longer duration of drugs most commonly prescribed for COPD, one could speculate asthma may be associated with irreversible airway obstruction. that the result might rather be biased the other way. Third, as a Unfortunately, in the current study, we were unaware of how long few patients were recruited by private pulmonologists, one could the patients had had asthma. However, we believe that the age of argue that we did not investigate exclusively primary care the patients indirectly reflects the duration of asthma, and patients. However, in Finland, treatment of the most severe therefore, our finding that age is associated with low FEV /FVC asthmatics is concentrated in central and university hospitals, and is in keeping with the results of the studies suggesting that longer the recruiting private pulmonologists were emphasised to recruit duration of asthma may be associated with irreversible airway only patients who could also be treated by general practitioners. obstruction. On the other hand, aging per se causes changes in Moreover, as ACOS patients’ COPD was mostly mild, with 96% lung elastic recoil and pulmonary mechanics that causes FEV /FVC being classed as GOLD stages 1 and 2, we strongly believe that we to decrease; hence, older subjects may be more prone to fulfil the investigated primary health care outpatients as was intended. diagnostic criteria of ACOS regardless of the duration of their The study also has its strengths. First, as the criteria for special asthma. reimbursement for asthma medication are strict, we are positive that all the patients investigated really had asthma. Second, as far Implications for future research, policy and practice as we know this is the first study to investigate the prevalence of In the current study, the best predictors of ACOS were smoking for ACOS among primary health care asthmatics with a positive ⩾ 20 pack-years and age ⩾ 60 years. If both of these criteria were smoking history but without a previous diagnosis of COPD. In met, then ACOS was found in almost half of the patients. most earlier studies, the prevalence of ACOS has been evaluated Lee et al. found that longer duration of asthma and greater among COPD patients by asking them if they have doctor- amount of cigarette smoking were associated with fixed airway 5,10,15 diagnosed asthma. obstruction, that is, ACOS, in patients with severe asthma. In everyday life, this could mean that in the case of an elderly Interpretation of findings in relation to previously published work asthmatic with a clearly positive smoking history, whose asthma is Hardin et al. found the prevalence of asthma–COPD overlap difficult to treat, attention should be given not just to the known to be 13% among COPD patients in the COPDGene population. asthma, but also one should take the COPD component of Miravitlles et al. found that 17.4% of COPD patients in the EPI- possible ACOS into account as well. npj Primary Care Respiratory Medicine (2015) 15047 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al Conclusions 6 Menezes AMB, de Oca MM, Perez-Padilla R, Nadeau G, Wehrmeister FC, Lopez-Varela MV et al. Increased risk of exacerbation and hospitalization in There is a high prevalence of ACOS among asthmatics with a subjects with an overlap phenotype. Chest 2014; 145:297–304. positive smoking history but no previous diagnosis of COPD. Age 7 Andersen H, Lampela P, Nevanlinna A, Säynäjäkangas O, Keistinen T. High over 60 years and smoking for more than 20 pack-years were the hospital burden in overlap syndrome of asthma and COPD. Clin Respir J 2013; 7: best predictors of ACOS in this population. 342–346. 8 Rhee CK, Yoon HK, Yoo KH, Kim YS, Lee SW, Park YB et al. Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease ACKNOWLEDGEMENTS and asthma. COPD 2014; 11:163–170. 9 Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its Tuija Poussa is acknowledged for her help with the statistical analyses. features and how important is it? Thorax 2009; 64: 728–735. 10 Miravitlles M, Soriano JB, Ancochea J, Munoz L, Duran-Tauleria E, Sanchez G et al. Characterisation of the overlap COPD-asthma phenotype. Focus on physical CONTRIBUTIONS activity and health status. Respir Med 2013; 107: 1053–1060. All the authors were involved in planning of the study and writing the manuscript. TK 11 Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional was responsible for writing the manuscript. Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 2003; 124: 474–481. 12 Vonk JM, Jongepier H, Panhuysen CIM, Schouten JP, Bleecker ER, Postma DS. Risk COMPETING INTERESTS factors associated with the presence of irreversible airflow limitation and reduced TK received personal fees from Boehringer Ingelheim Finland, GSK, Novartis and transfer coefficient in patients with asthma after 26 years of follow up. Thorax Mundipharma. TH received personal fees from Boehringer Ingelheim Finland and 2003; 58:322–327. Takeda. KV received personal fees from Boehringer Ingelheim Finland, Chiesi, GSK, 13 Perret JL, Dharmage SC, Matheson MC, Johns DP, Gurrin LC, Burgess JA et al. The interplay between the effects of lifetime asthma, smoking, and atopy on Novartis, Takeda, Teva, Mundipharma and Almirall. AJ is an employee of Boehringer fixed airway obstruction in middle age. Am J Respir Crit Care Med 2013; 187: Ingelheim Finland. LL received personal fees from Almirall, Astra-Zeneca, Boehringer 42–48. Ingelheim Finland, Chiesi, GSK, Novartis, Orion Pharma, Takeda and Mundipharma. 14 Miller MR, Hankinson J, Busasco V, Burgos F, Casaburi R, Coates A et al. Standardisation of spirometry. Eur Respir J 2005; 26:319–338. 15 Talamo C, de Oca MM, Halbert R, Perex-Padilla R, Jardim JRB, Muino A et al. FUNDING Diagnostic labeling of COPD in five Latin American cities. Chest 2007; 131:60–67. The study was funded by Boehringer-Ingelheim, Finland. 16 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. 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Prevalence of asthma–COPD overlap syndrome among primary care asthmatics with a smoking history: a cross-sectional study

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Medicine & Public Health; Medicine/Public Health, general; Primary Care Medicine; Internal Medicine; Pneumology/Respiratory System; Thoracic Surgery
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www.nature.com/npjpcrm All rights reserved 2055-1010/15 ARTICLE OPEN Prevalence of asthma–COPD overlap syndrome among primary care asthmatics with a smoking history: a cross-sectional study 1 2 3 4 5 Toni Kiljander , Timo Helin , Kari Venho , Antero Jaakkola and Lauri Lehtimäki BACKGROUND: The overlap between asthma and chronic obstructive pulmonary disease (COPD) is an important clinical phenomenon. However, the prevalence of asthma–COPD overlap syndrome (ACOS) is not known. AIMS: To investigate the prevalence of ACOS among asthmatic patients with a smoking history, and evaluate the factors predicting ACOS in this patient group. METHODS: We investigated 190 primary care asthma patients with no previous diagnosis of COPD, but who were either current or ex-smokers, with a smoking history of at least 10 pack-years. Spirometry was performed on all the patients while they were taking their normal asthma medication. Patients were considered to have ACOS if their postbronchodilator forced expiratory volume in 1 s/forced vital capacity was o0.70. RESULTS: Fifty-two (27.4%) of the patients were found to have ACOS. Age ⩾ 60 years and smoking for ⩾ 20 pack-years were the best predictors of ACOS. If both of these criteria were met, the odds ratio (95% confidence interval) for ACOS was 6.08 (2.11–17.49), compared with the situation where neither of these criteria were fulfilled. CONCLUSIONS: There is a high prevalence of ACOS among primary health care asthmatics with a positive smoking history but no previous diagnosis of COPD. In this population, age over 60 years and a smoking history of more than 20 pack-years were the best predictors of ACOS. npj Primary Care Respiratory Medicine (2015) 25, 15047; doi:10.1038/npjpcrm.2015.47; published online 16 July 2015 INTRODUCTION with asthma. The prevalence of overlap syndrome has been shown to increase with age, which may reflect the fact that, over Asthma and chronic obstructive pulmonary disease (COPD) are the years, asthmatics may develop fixed airway obstruction, the two most common obstructive pulmonary diseases. Although especially if they do not use anti-inflammatory medication or if asthma and COPD most often represent two distinct diseases, 13 11 1,2 they smoke. Soriano et al. found that as many as half of the there is also significant overlap between these two diseases. patients with obstructive pulmonary disease, aged 50 years or The definition of asthma–COPD overlap syndrome (ACOS) is more, had simultaneously more than one obstructive condition. undetermined. Most commonly, it is defined as either the The aim of the present study was to investigate the prevalence diagnosis of COPD in a patient with previously diagnosed asthma, of undiagnosed ACOS among primary health care asthma patients or as incompletely reversible airway obstruction accompanied by who are current or ex-smokers, and the factors predicting ACOS in symptoms or signals of increased reversibility of the obstruction. this patient group. A recent update of the GINA report recommended a stepwise approach to the diagnosis of ACOS, and defined it as a syndrome characterized by persistent airflow limitation with several features MATERIALS AND METHODS usually associated with asthma and several features usually 1 This was a cross-sectional study. Patients were recruited mostly from the associated with COPD. appointments of primary care physicians and through newspaper Compared with asthma or COPD alone, ACOS is associated advertisements. In addition, a few patients were also recruited by private 4,5 with worse health-related quality of life, more frequent pulmonologists treating primary care-like asthma patients. 5,6 6,7 exacerbations, increased hospitalisation and higher health The study was approved by the Ethics Committee of Pirkanmaa Health care costs. Although ACOS appears to be clinically highly Care District, and every patient gave written informed consent before any significant, little is known about the treatment of these patients, study-related procedures were performed. as they are typically excluded from therapy trials for asthma or COPD. Patients There is only some data on the prevalence of ACOS. Hardin The inclusion criteria were as follows: age 18–70 years, current or et al. found that 13% of the COPD patients in the COPDGene ex-smoker with 10 or more pack-years, doctor-diagnosed asthma with study reported a history of doctor-diagnosed asthma. Similarly, special reimbursement for asthma medication granted by the National Miravitlles et al. reported that 17.4% of COPD patients in the Health Insurance. To qualify for this reimbursement, patients must have EPI-SCAN study reported that they had been previously diagnosed fulfilled at least one of the following criteria: (1)⩾ 12% (and 200 ml) 1 2 3 Department of Respiratory Diseases, Terveystalo Hospital, Turku, Finland; Department of Allergology, Helsinki University Central Hospital, Helsinki, Finland; Department of 4 5 Respiratory Medicine, Central Hospital of Central Finland, Jyväskylä, Finland; Boehringer Ingelheim Finland, Helsinki, Finland and Department of Respiratory Medicine, University of Tampere, Tampere, Finland. Correspondence: Dr T Kiljander (toni.kiljander@fimnet.fi) Received 13 April 2015; accepted 1 June 2015 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al reversibility in forced expiratory volume in 1 s (FEV ) or forced vital capacity The patients were considered to have ACOS if their postbronchodilator (FVC) in a bronchodilation test, (2) during a 2-week peak expiratory flow FEV /FVC was less than 0.70. Patients with ACOS were divided into GOLD grades of airway obstruction according to the GOLD report. monitoring at least three times either a bronchodilator response of ⩾ 15% Patients were considered to have had an exacerbation during the (and 60 l/min) or a diurnal variation of ⩾ 20%, (3) moderate-to-severe previous year if they had been hospitalised, or had used a course of oral bronchial hyperresponsiveness in histamine or methacholine inhalation corticosteroids, for their asthma during the previous year. challenge or (4) FEV had improved more than 15% during a corticosteroid treatment test. The exclusion criteria were as follows: any severe illness, any known Statistical analysis pulmonary disease other than asthma, use of inhaled anticholinergic or The primary outcome was the prevalence of ACOS, as defined above, indacaterol or oral roflumilast. among asthmatics with a smoking history of at least 10 pack-years. The sample size calculation was based on the assumption that the prevalence of ACOS in asthmatics is approximately 45%. Using the large sample Methods normal approximation, 265, 195, 149, 118 or 96 patients would be required After informed consent was received, the investigator and the patient to estimate the prevalence to be 95% confident that the estimate will not completed a questionnaire including questions about the inclusion and differ from the true prevalence by more than 6, 7, 8, 9 or 10 percent, exclusion criteria, and the patient’s asthma medication, symptoms and respectively. The final sample size of 219 recruited patients was assessed to be large enough to obtain a sufficient precision. The 95% confidence exacerbations. The investigator stored the data in a database. Body mass interval for prevalence was calculated using the large sample normal index and current smoking status were recorded as a standard procedure approximation. The distribution of the variables was checked using the when spirometry was performed. Kolmogorov–Smirnov test and graphical plots. The distributions of Spirometries (Medikro Kuopio, Finland) were performed according to demographic continuous data were skewed and are expressed as medians the guidelines before and after administration of 400 μg of inhaled (interquartile range). The nonparametric Mann–Whitney U-test was used to salbutamol while the patients were taking their usual asthma medication. compare the groups with and without ACOS with respect to continuous variables. The Chi-square test and the exact Fisher's test, when appropriate, were used for categorical variables. Spearman’s rank correlation (Rho) was Asthma patients, used to study the associations between postbronchodilator FEV /FVC n =219 versus age and pack-years. The receiver operating curve analysis (ROC) was used to determine the best cut-off values of age and pack-years Spirometry measurements to differentiate between asthma patients with and without overlap were not available, syndrome. Sensitivity and specificity were assessed to be equally important n =26 when the best cut-off values were chosen. In addition, positive predictive values and negative predictive values were calculated. The potential Spirometry measurements prognostic factors for overlap were sex, age, body mass index, current were available, smoking status and pack-years of smoking. Univariable logistic regression n =193 analyses were performed to study the associations. The results are given as odds ratios with 95% confidence intervals. P values less than 0.05 were Spirometry was not valid, considered statistically significant. The analyses were performed using IBM n =3 SPSS Statistics for Windows (version 22.0, Armonk, NY, USA, IBM Corp.). Patients included in analysis, RESULTS n =190 Two hundred and nineteen patients were recruited and 190 of them were included in the analysis (Figure 1). Their median age (range) was 58 (23–70) years, they had smoked for 20 (10–60) pack-years, and their body mass index was 27.5 (16.1–50.3) kg/m . Postbronchodilator Postbronchodilator Eighty-three (44.1%) of the patients were current smokers and 112 FEV1/FVC < 0.70, FEV1/FVC > 0.70, (58.9%) were female. n = 52 (27.4%) n = 138 (72.6%) Fifty-two (27.4%, 95% confidence interval 21–34%) patients Figure 1. Flow of participants. FEV , forced expiratory volume in 1 s; were found to have postbronchodilator FEV /FVC o0.70 and FVC, forced vital capacity. were thus considered to have ACOS. Twelve (23.1%), 38 (73.1%) Table 1. Characteristics of 190 asthmatics with and without overlap syndrome Patients with overlap syndrome Patients with asthma only P value (N = 52) (N = 138) Age (years) 63.0 (52.5–66.5) 57.0 (49.0–64.0) 0.008 Pack-years 24.5 (20.0–37.0) 20.0 (13.0–28.0) 0.003 BMI (kg/m ) 26.2 (23.2–29.9) 27.8 (24.6–31.6) 0.09 Current smokers 28 (54.9%) 55 (40.1%) 0.07 Females 31 (59.6%) 81 (58.7%) 0.91 Inhaled corticosteroid (ICS) 50 (96.2%) 129 (93.5%) 0.48 Inhaled corticosteroid+inhaled long-acting β -agonist (ICS+LABA) 36 (69.2%) 86 (62.3%) 0.38 Short-acting β-agonist (SABA) more often than twice a week 19 (36.5%) 37 (26.8%) 0.19 Exacerbation during previous year 16 (30.8%) 35 (25.4%) 0.45 Significant reversibility 8 (15.4%) 9 (6.5%) 0.08 All patients were current or ex-smokers. Results are given as median (interquartile range) or number (%). Abbreviation: BMI, body mass index. Mann–Whitney U-test was used for continuous variables and Chi-squared test for categorical variables. Fisher's exact test. npj Primary Care Respiratory Medicine (2015) 15047 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al 1.0 1.0 0.9 0.9 Pack-years20 0.8 0.8 0.7 0.7 Age60 0.6 0.6 0.5 0.5 Rho= –0.28 0.4 0.4 P < 0.001 0.3 0.3 20 30 40 50 60 70 Age (years) 0.2 Age 0.1 Pack-years 1.0 0.9 0 0.1 0.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0 0.8 1-Specificity 0.7 Figure 3. Receiver operating curve (ROC) analysis of age and pack-years in 190 asthmatic patients. The cut-off points of 60 years 0.6 of age yielded 63.5% sensitivity and 59.4% specificity and the cut-off point of 20 pack-years yielded 80.8% sensitivity and 42.8% specificity 0.5 to detect overlap syndrome. Rho= – 0.25 0.4 P < 0.001 0.3 10 20 30 40 50 60 Table 2. The best cut-off values of age and pack-years and their combination to detect asthma–COPD overlap syndrome among 190 Pack-years asthmatics with positive smoking history Figure 2. Scatter plots and regression lines showing the association between age and pack-years versus postbronchodilator FEV /FVC in 1 Sensitivity Specificity PPV NPV 190 asthma patients with a positive smoking history. FEV , forced (%) (%) (%) (%) expiratory volume in 1 s; FVC, forced vital capacity. Age ⩾ 60 years 63.5 59.4 37.1 81.2 Pack-years ⩾ 20 80.8 42.8 34.7 85.5 and 2 (3.8%) belonged to GOLD stages 1, 2 and 3, respectively. Age ⩾ 60 years or pack-years ⩾ 20 90.4 27.5 32.0 88.4 Age ⩾ 60 years and pack-years ⩾ 20 53.8 74.6 44.4 81.1 None of the patients belonged to GOLD stage 4. A comparison of the patients with ACOS and those with asthma Abbreviations: COPD, chronic obstructive pulmonary disease; NPV, alone is shown in Table 1. Patients with overlap syndrome were negative predictive value; PPV, positive predictive value. older and had smoked more than patients with asthma alone. Overlap patients tended to be more often current smokers and to have more often significant reversibility, but these differences syndrome was 11.6% (5/43 patients). If one of the criteria was met, were not statistically significant. then overlap syndrome was found in 22.6% (19/84) of the patients. A negative correlation between postbronchodilator FEV /FVC 1 If both criteria were met the prevalence of overlap syndrome was and age (Spearman Rho = − 0.28, Po0.001) and pack-years found to be 44.4% (28/63 patients). (Rho = − 0.25, Po0.001) was found (Figure 2). ROC analysis for age and pack-years revealed that age ⩾ 60 years and smoking for ⩾ 20 pack-years were the best predictors of DISCUSSION ACOS in the study population (Figure 3). The area under the ROC Main findings curve was 0.625 and 0.639 for age and pack-years, respectively. We found the prevalence of asthma–COPD overlap syndrome to The cut-off point of 60 years of age yielded 63.5% sensitivity and be 27.4% among primary health care asthmatics with no previous 59.4% specificity, and the cut-off point of 20 pack-years 80.8% diagnosis of COPD, but who were either current or ex-smokers sensitivity and 42.8% specificity, to detect overlap syndrome with a smoking history of at least 10 pack-years. The patients (Table 2). However, the combination of both age ⩾ 60 years and with ACOS were older and had smoked more than patients with smoking for ⩾ 20 pack-years yielded the best area under the ROC asthma alone. curve: 0.670, and 53.8% sensitivity and 74.6% specificity. The results of the logistic regression analysis are shown in Strengths and limitations of this study Table 3. Using the cut-off points given by the ROC analysis, age The current study has its weaknesses. First, the number of and pack-years were the only significant factors predicting overlap participants was relatively small to investigate the differences syndrome. If the patient was at least 60 years old and had between patients with ACOS and asthma alone. However, we simultaneously smoked for at least 20 pack-years, the odds ratio were able to find that older age and heavier smoking history (95% confidence interval) for overlap syndrome was 6.08 predict ACOS, which are the most common variables found in (2.11–17.49), P = 0.001, compared with the situation where neither other studies too. Moreover, with 190 participants, we were able of these criteria were fulfilled. In patients with one criterion to evaluate the prevalence of ACOS among asthmatics with a fulfilled (age ⩾ 60 or smoking for ⩾ 20 pack-years), the risk of positive smoking history, which was the primary objective of the ACOS was about twice as high as for patients who were younger study. Second, as we did not investigate consecutive patients, than 60 years and had smoked less than 20 pack-years. In there might have been selection bias. On the other hand, as we other words, if neither of the criteria (age ⩾ 60 years and smoking ⩾ 20 pack-years) were fulfilled, the prevalence of overlap excluded patients with known COPD, and even those using the © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited npj Primary Care Respiratory Medicine (2015) 15047 FEV (l)/FVC(l) FEV (l)/FVC(l) 1 1 Sensitivity Prevalence of asthma–COPD overlap syndrome T Kiljander et al SCAN population reported they had previously been diagnosed Table 3. Asthma–COPD overlap syndrome in association to with asthma, and thus presented with asthma–COPD overlap. demographic characteristics in 190 asthma patients with positive In the PLATINO study, 22.8% of patients with FEV /FVC o0.7 smoking history. Results are given by univariable binary logistic reported a prior diagnosis of asthma and can be considered as regression analyses overlap patients. The 27.4% prevalence of asthma–COPD overlap syndrome found in our study is slightly higher than in previous Overlap Unadjusted P value studies. We believe that the major reason for this difference may syndrome be the fact that we investigated a different patient population. a We studied asthmatic patients and investigated how often N (%) OR 95% CI their postbronchodilator FEV /FVC is o0.7, whereas other 5,10,15 Sex studies have investigated how often patients with post- Female 31/112 (27.7) 1.00 bronchodilator FEV /FVC o0.7 report that they have previously Male 21/78 (26.9) 0.96 0.50–1.84 0.91 been diagnosed with asthma. On the other hand, prevalences of overlap even higher than ours have been suggested. For example, Smoking 11 Soriano et al. found that as many as 50% of patients with Ex-smoker 23/105 (21.9) 1.00 obstructive pulmonary disease, aged 50 years or more, may suffer Current smoker 28/83 (33.7) 1.82 0.95–3.47 0.07 simultaneously from more than one obstructive condition. The high prevalence of ACOS may be explained by the fact that BMI, kg/m asthma and airway hyperresponsiveness are suggested to be risk o25.0 18/56 (32.1) 1.00 2 16 25.0–29.9 21/72 (29.2) 0.87 0.41–1.85 0.72 factors for developing COPD. Lange et al. have shown that ⩾ 30.0 12/60 (20.0) 0.53 0.23–1.23 0.14 decline in pulmonary function is faster in asthmatics than among those without asthma, and that the decline is fastest among those Age, years asthmatics who smoke. In the study by Vonk et al., 16% of 20–59 19/101 (18.8) 1.00 patients with asthma developed irreversible airway obstruction 60–70 33/89 (37.1) 2.54 1.32–4.91 0.005 during a 26-year follow-up. It has been shown that airway hyperresponsiveness, even without asthma, is an important risk Pack-years factor for developing COPD. 10–19 10/69 (14.5) 1.00 Smoking is the most important risk factor for COPD. Therefore, 20–60 42/121 (34.7) 3.14 1.46–6.76 0.004 it is not surprising that the ACOS patients in our study had smoked Age and pack-years more than those with asthma alone. Also in the study by Age o60 and 5/43 (11.6) 1.00 Lee et al., greater amount of cigarette smoking was related to pack-years o20 the development of fixed airway obstruction among asthmatic Age ⩾ 60 or pack-years 19/84 (22.6) 2.22 0.77–6.43 0.14 patients. ⩾ 20 We found ACOS patients to be older than patients with asthma Age ⩾ 60 and pack- 28/63 (44.4) 6.08 2.11–17.49 0.001 alone. In the study by Menezes et al., patients with asthma–COPD years ⩾ 20 overlap were also older than patients with asthma alone. In that Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmon- study, and in the COPDGene study, patients with COPD were ary disease; OR, odds ratio. older than the overlap patients. These findings might suggest a Number of patients with overlap syndrome/number of all patients in continuum from reversible airway obstruction, via overlap, to the group. irreversible obstruction in some patients. There is evidence that some patients with asthma developed irreversible airway obstruc- tion during long-enough follow-up, and that longer duration of drugs most commonly prescribed for COPD, one could speculate asthma may be associated with irreversible airway obstruction. that the result might rather be biased the other way. Third, as a Unfortunately, in the current study, we were unaware of how long few patients were recruited by private pulmonologists, one could the patients had had asthma. However, we believe that the age of argue that we did not investigate exclusively primary care the patients indirectly reflects the duration of asthma, and patients. However, in Finland, treatment of the most severe therefore, our finding that age is associated with low FEV /FVC asthmatics is concentrated in central and university hospitals, and is in keeping with the results of the studies suggesting that longer the recruiting private pulmonologists were emphasised to recruit duration of asthma may be associated with irreversible airway only patients who could also be treated by general practitioners. obstruction. On the other hand, aging per se causes changes in Moreover, as ACOS patients’ COPD was mostly mild, with 96% lung elastic recoil and pulmonary mechanics that causes FEV /FVC being classed as GOLD stages 1 and 2, we strongly believe that we to decrease; hence, older subjects may be more prone to fulfil the investigated primary health care outpatients as was intended. diagnostic criteria of ACOS regardless of the duration of their The study also has its strengths. First, as the criteria for special asthma. reimbursement for asthma medication are strict, we are positive that all the patients investigated really had asthma. Second, as far Implications for future research, policy and practice as we know this is the first study to investigate the prevalence of In the current study, the best predictors of ACOS were smoking for ACOS among primary health care asthmatics with a positive ⩾ 20 pack-years and age ⩾ 60 years. If both of these criteria were smoking history but without a previous diagnosis of COPD. In met, then ACOS was found in almost half of the patients. most earlier studies, the prevalence of ACOS has been evaluated Lee et al. found that longer duration of asthma and greater among COPD patients by asking them if they have doctor- amount of cigarette smoking were associated with fixed airway 5,10,15 diagnosed asthma. obstruction, that is, ACOS, in patients with severe asthma. In everyday life, this could mean that in the case of an elderly Interpretation of findings in relation to previously published work asthmatic with a clearly positive smoking history, whose asthma is Hardin et al. found the prevalence of asthma–COPD overlap difficult to treat, attention should be given not just to the known to be 13% among COPD patients in the COPDGene population. asthma, but also one should take the COPD component of Miravitlles et al. found that 17.4% of COPD patients in the EPI- possible ACOS into account as well. npj Primary Care Respiratory Medicine (2015) 15047 © 2015 Primary Care Respiratory Society UK/Macmillan Publishers Limited Prevalence of asthma–COPD overlap syndrome T Kiljander et al Conclusions 6 Menezes AMB, de Oca MM, Perez-Padilla R, Nadeau G, Wehrmeister FC, Lopez-Varela MV et al. Increased risk of exacerbation and hospitalization in There is a high prevalence of ACOS among asthmatics with a subjects with an overlap phenotype. Chest 2014; 145:297–304. positive smoking history but no previous diagnosis of COPD. Age 7 Andersen H, Lampela P, Nevanlinna A, Säynäjäkangas O, Keistinen T. High over 60 years and smoking for more than 20 pack-years were the hospital burden in overlap syndrome of asthma and COPD. Clin Respir J 2013; 7: best predictors of ACOS in this population. 342–346. 8 Rhee CK, Yoon HK, Yoo KH, Kim YS, Lee SW, Park YB et al. Medical utilization and cost in patients with overlap syndrome of chronic obstructive pulmonary disease ACKNOWLEDGEMENTS and asthma. COPD 2014; 11:163–170. 9 Gibson PG, Simpson JL. The overlap syndrome of asthma and COPD: what are its Tuija Poussa is acknowledged for her help with the statistical analyses. features and how important is it? Thorax 2009; 64: 728–735. 10 Miravitlles M, Soriano JB, Ancochea J, Munoz L, Duran-Tauleria E, Sanchez G et al. Characterisation of the overlap COPD-asthma phenotype. Focus on physical CONTRIBUTIONS activity and health status. Respir Med 2013; 107: 1053–1060. All the authors were involved in planning of the study and writing the manuscript. TK 11 Soriano JB, Davis KJ, Coleman B, Visick G, Mannino D, Pride NB. The proportional was responsible for writing the manuscript. Venn diagram of obstructive lung disease: two approximations from the United States and the United Kingdom. Chest 2003; 124: 474–481. 12 Vonk JM, Jongepier H, Panhuysen CIM, Schouten JP, Bleecker ER, Postma DS. Risk COMPETING INTERESTS factors associated with the presence of irreversible airflow limitation and reduced TK received personal fees from Boehringer Ingelheim Finland, GSK, Novartis and transfer coefficient in patients with asthma after 26 years of follow up. Thorax Mundipharma. TH received personal fees from Boehringer Ingelheim Finland and 2003; 58:322–327. Takeda. KV received personal fees from Boehringer Ingelheim Finland, Chiesi, GSK, 13 Perret JL, Dharmage SC, Matheson MC, Johns DP, Gurrin LC, Burgess JA et al. The interplay between the effects of lifetime asthma, smoking, and atopy on Novartis, Takeda, Teva, Mundipharma and Almirall. AJ is an employee of Boehringer fixed airway obstruction in middle age. Am J Respir Crit Care Med 2013; 187: Ingelheim Finland. LL received personal fees from Almirall, Astra-Zeneca, Boehringer 42–48. Ingelheim Finland, Chiesi, GSK, Novartis, Orion Pharma, Takeda and Mundipharma. 14 Miller MR, Hankinson J, Busasco V, Burgos F, Casaburi R, Coates A et al. Standardisation of spirometry. Eur Respir J 2005; 26:319–338. 15 Talamo C, de Oca MM, Halbert R, Perex-Padilla R, Jardim JRB, Muino A et al. FUNDING Diagnostic labeling of COPD in five Latin American cities. Chest 2007; 131:60–67. The study was funded by Boehringer-Ingelheim, Finland. 16 Lange P, Parner J, Vestbo J, Schnohr P, Jensen G. A 15-year follow-up study of ventilatory function in adults with asthma. 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