Characteristics of phenotypes of elderly patients with asthma

Allergology International xxx (2015) 1e6

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Original article

Characteristics of phenotypes of elderly patients with asthma Hiroyuki Sano*, Takashi Iwanaga, Osamu Nishiyama, Akiko Sano, Yuji Higashimoto, Katsuyuki Tomita, Yuji Tohda Department of Respiratory Medicine and Allergology, Kinki University Faculty of Medicine, Osaka, Japan

a r t i c l e i n f o

a b s t r a c t

Article history: Received 19 October 2015 Received in revised form 15 November 2015 Accepted 30 November 2015 Available online xxx

Background: The characteristics of phenotypes of elderly patients with asthma are unknown. The aim of this study was to classify these phenotypes using lung function tests and images from high-resolution computed tomography (HRCT), and to identify associations between clinical characteristics and phenotypes. Methods: A cross-sectional study was conducted in 165 elderly patients (>65 years of age) who underwent a multidimensional assessment of clinical and functional status and comorbidity. The patients were divided into three phenotypes: (1) asthma-predominant, (2) asthma-obstructive airway disease (OAD) overlap without emphysema, and (3) asthma-OAD overlap with emphysema (asthma-emphysema overlap) based on chest HRCT. A receiver operating characteristic (ROC) curve was constructed to evaluate the cutoff for differentiating between the two OAD phenotypes. Multivariate analysis was also used to distinguish between these two phenotypes. Results: The phenotypes were asthma-predominant in 48 patients (29%), asthma-OAD without emphysema in 36 (22%), and asthma-emphysema in 81 (49%). Patients with asthma-emphysema were more frequent smokers. In multivariate analysis, smoking status (odds ratio 2.92: 95% CI 1.21e7.00, P ¼ 0.03) and % predicted FEV1 70% (odds ratio 3.18: 95% CI 1.13e8.92, P ¼ 0.03) differed significantly between the asthma-emphysema and asthma-OAD without emphysema phenotypes. Conclusions: Half of elderly patients with asthma are characterized by asthma-emphysema overlap. Our results showed that elderly patients with asthma who are smokers and have moderate or severe OAD are also likely to have emphysema. Copyright © 2015, Japanese Society of Allergology. Production and hosting by Elsevier B.V. This is an open access

Keywords: ACOS Elderly asthma Emphysema HRCT Phenotype Abbreviations: ACOS, asthma-COPD overlap syndrome; AHR, Airway hyperresponsiveness; COPD, chronic obstructive pulmonary disease; DLCO, diffusion capacity of the lung for carbon monoxide; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in one second; HRCT, highresolution computed tomography; ICS, inhaled corticosteroids; LABA, longacting beta2-bronchodilator agonists; LAMA, long-acting muscarinic antagonists; OAD, asthma-obstructive airway disease; PC20, provocative concentration that causes a positive reaction to a 20% fall in FEV1; ROC, receiver operating characteristic

article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Introduction Asthma is an allergic disease that commonly develops at a young age, is characterized physiologically by reversible airflow obstruction, and responds well to anti-inflammatory treatment. In contrast, chronic obstructive pulmonary disease (COPD) is characterized by incomplete reversible airflow limitation, is typically

* Corresponding author. Department of Respiratory Medicine and Allergology, Kinki University School of Medicine, 377-2 Ohnohigashi, Osaka-Sayama, Osaka 5898511, Japan. E-mail address: [email protected] (H. Sano). Peer review under responsibility of Japanese Society of Allergology.

caused by tobacco smoking, and develops at an old age. There is a considerable pathologic and functional overlap between these two heterogeneous disorders, particularly among the elderly, who may have components of both diseases. This condition is referred to as asthma-COPD overlap syndrome (ACOS), in which asthma and COPD are at the opposite ends of the disease spectrum.1,2 ACOS is defined as a post-bronchodilator ratio of forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) 65 years in each group, and to characterizes the clinical features of these phenotypes based on lung function and chest CT findings. Methods

taken three times. The greatest FEV1 from acceptable tests for each subject was selected. The subjects were instructed to take complete inspirations and expirations that lasted approximately 3 s.13 Reversibility of the reduction in FEV1 was measured 15 min after inhalation of 20 mg procaterol. AHR is expressed as the methacholine concentration that caused a 20% decrease in FEV1 from baseline (PC20). The test was administered at least 8 h after the last dose of short-acting bronchodilators and 24 h after inhaled corticosteroids (ICS) or long-acting bronchodilators. The diffusion capacity of the lung for carbon monoxide (DLCO) was determined using the single-breath method. Alveolar volume (VA) was measured during the single-breath maneuver using helium as the inert gas. A % predicted DLCO 80% indicates emphysema of the lung. ATS guidelines were followed for all lung function tests.14

Subjects A single-center cross-sectional study was conducted in the outpatient department at Kinki University Hospital between October 2011 and September 2012. The subjects were 170 patients with asthma aged 65 years old who were recruited from the Department of Respiratory Medicine and Allergology. Diagnoses of asthma and COPD were made by the subjects' physician consistent with the definitions for these diseases in the Global Initiative for Asthma10 and the Global Initiative for Chronic Obstructive Lung Disease11 guidelines, respectively. All subjects were assessed at visits in which the disease had been stable for at least 8 weeks since exacerbation, which was defined as an increase in symptoms necessitating a course of oral corticosteroids and/or antibiotic therapy. All subjects provided written informed consent and the study was approved by the Kinki University Hospital ethics committee. Objective and procedures To identify the clinical characteristics of comorbidity of COPD in elderly patients with asthma, the subjects were divided into three phenotypes: asthma-predominant, based on the absence of airflow obstruction; asthma-OAD overlap, defined as irreversible airway obstruction without emphysema on chest high-resolution CT (HRCT); and asthma-emphysema overlap, a combination of airflow obstruction and emphysema. Measurements Physicians interviewed each patient to establish details of medical history, family history, smoking history and respiratory symptoms based on questionnaires. Subjects were defined as never, former or current smokers of tobacco (cigarettes, cigars or pipes). Cumulative cigarette consumption was calculated in pack-years, with 1 pack-year equivalent to 20 cigarettes per day for 1 year. Blood samples Blood was collected for measurement of total serum IgE and complete blood count. Total and specific IgE were measured with a third-generation chemiluminescent enzyme immunoassay (Immulite 2000; Siemens Medical, Deerfield, IL, USA). Atopy was defined as any specific IgE to common allergen >0.35 kU/L. Pulmonary function tests Spirometry was performed with a portable spirometer (Minato, Tokyo, Japan) according to American Thoracic Society (ATS) criteria.12 FEV1 and FVC were measured and FEV1 was used to evaluate airway obstruction. After several practice measurements with a trained technician, measurements for data collection were

Fraction of exhaled nitric oxide (FeNO) FeNO was measured online by NOA280i (Severs, GE Analytical Instruments, Boulder, CO, USA) at a constant expiratory flow rate (50 mL/s) before any forced expiratory maneuvers, consistent with published guidelines.15 All readings were obtained by technical staff. High-resolution computed tomography (HRCT) The severity of radiological emphysema on chest HRCT (2-mm sections at 15-mm intervals) was visually assessed by three independent pulmonologists using the Goddard scoring system.16 Six images of three lung slices (the right and left lungs were evaluated separately) were analyzed for each patient. Each image was classified and scored as normal (score 0), 5% affected (score 0.5), 25% affected (score 1), 50% affected (score 2), 75% affected (score 3) and >75% affected (score 4). The mean score of the six images was taken as representative of the severity of emphysema. Each image was then classified as normal (score 0), very mild (>0 to 0.5), mild (>0.5 to 1), moderate (>1 to 2), and (E) severe (>2). Emphysema was diagnosed as airway obstruction on a pulmonary function test (FEV1/FVC 0). Statistical analysis Differences in continuous variables between groups were analyzed by KruskaleWallis test followed by post hoc analysis by Dunn test. For categorical variables, a c2 test (or Fisher exact test for small proportions) was used, P < 0.05 was considered significant. A receiver operating characteristics (ROC) curve was constructed to evaluate the best cutoff for differentiating asthma-emphysema overlap from asthma-OAD overlap. Multivariate logistic regression analysis was used to distinguish asthma-emphysema from asthma-OAD without emphysema, with the results reported as the odds ratio (OR) with a 95% confidence interval (CI). All analyses were performed using SPSS ver. 19.0 (SPSS Inc, Chicago, IL, USA). Results Patient characteristics Of the 170 elderly patients with asthma enrolled in the study, we excluded five patients due to an absence of lung function tests or HRCT, leaving 165 patients in the analysis. The demographic and clinical features of the study population are shown in Table 1. There were 92 males (54.1%), the average age was 73.8 ± 5.4 years old, and 89 patients (52.4%) had a smoking history, including 47% with >10 pack-years. An atopic disposition was present in 76 patients and the

Please cite this article in press as: Sano H, et al., Characteristics of phenotypes of elderly patients with asthma, Allergology International (2015), http://dx.doi.org/10.1016/j.alit.2015.11.007

H. Sano et al. / Allergology International xxx (2015) 1e6

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(A) % predicted FEV1

Table 1 Clinical characteristics of elderly patients with asthma. Item

Data

Number of patients Sex, % male Age, years Duration of asthma, years Smoking status Never/former/current >10 Pack-years, % Serum IgE level, IU/mL Atopic status, % Post-bronchodilator FEV1/FVC ratio % Predicted FEV1 % Predicted FEV1 < 80%, % Reversibility, % %DLCO, % PC20, mg/mL FeNO, ppb Treatment, % ICS/LABA/LAMA ICS/LABA ICS/LAMA ICS alone

165 54% 73.8 ± 5.4 16.4 ± 19.3 78/75/12 47% 493.4 ± 920.0 46% 63.8 ± 12.5 80.1 ± 19.4 47% 10% 120.6 ± 32.5 13.6 ± 19.4 40.0 ± 38.8 6% 48% 4% 43%

Abbreviations: DLCO, diffusion capacity of the lung for carbon monoxide; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in one second; ICS, inhaled corticosteroids; LABA, long-acting beta2-bronchodilator agonists; LAMA, long-acting muscarinic antagonists; PC20, provocative concentration that causes a positive reaction to a 20% fall in FEV1.

average duration of asthma was 16.1 ± 16.0 years old. The mean % FEV1 was 63.8 ± 12.5% and 70.9% of the patients had OAD. The mean diffusion capacity of the lung indicated by %DLCO or %DLCO/VA was in the normal range, but the level of exhaled NO was elevated to 40.0 ± 38.8 ppb. Low attenuation areas (LAAs) on chest HRCT had a

P < 0.001 P < 0.001

(%) 120 100 80 60 40 20 0

Asthma

(B) % DLCO

(%) 180 160 140 120 100 80 60 40 20 0

Asthma

(C) FeNO

Asthma-OAD Asthma-emphysema overlap overlap

Asthma-OAD Asthma-emphysema overlap overlap P = 0.02

(ppb) 120 100

Table 2 Clinical characteristics of phenotypes of elderly patients with asthma.

Number of patients (%) Sex, % male Age, years Duration of asthma, years Smoking status Never/former/ current >10 Pack-years, % Serum IgE level, IU/mL Atopic status, % Postbronchodilator FEV1/FVC ratio % Predicted FEV1 % Predicted FEV1 < 80%, % Reversibility, % %DLCO, % PC20, mg/mL FeNO, ppb Treatment, % ICS/LABA/LAMA ICS/LABA ICS/LAMA ICS alone

Asthmapredominant


48 (29%)

36 (22%)

81 (49%)

29% 73.3 ± 4.6 13.0 ± 12.9

36% 74.0 ± 6.6 19.9 ± 14.2

74%* 73.8 ± 5.3 16.1 ± 18.0

32/15/1

23/11/2

23/49/9

29% 345.0 ± 714.2 35% 77.6 ± 5.5

33% 412.8 ± 507.3 47% 63.4 ± 4.4**

63%* 613.6 ± 1133.0 52%* 55.9 ± 10.8**

93.8 ± 16.0 21%

79.9 ± 15.5** 72.1 ± 18.5** 50%* 62%*

4% 119.3 ± 22.2 21.1 ± 21.7 38.4 ± 40.0

6% 129.0 ± 32.0 39.1 ± 9.1 55.6 ± 60.7**

10%** 117.6 ± 37.4 12.8 ± 19.1 33.7 ± 19.8

2% 36% 2% 58%

0% 44% 6% 50%

10% 57% 3% 30%

Abbreviations: DLCO, diffusion capacity of the lung for carbon monoxide; FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in one second; ICS, inhaled corticosteroids; LABA, long-acting beta2-bronchodilator agonists; LAMA, long-acting muscarinic antagonists; PC20, provocative concentration that causes a positive reaction to a 20% fall in FEV1. *P < 0.05, **P < 0.01 vs. asthma-predominant by KruskaleWallis test followed by post-hoc Dunn test.

80 60 40 20 0

Asthma


Fig. 1. %FEV1 (A), %DLCO (B) and FENO (C) for the asthma-predominant, asthma-OAD overlap without emphysema, and asthma-OAD overlap with emphysema (asthmaemphysema overlap) phenotypes. Bars show mean and standard deviation.

low mean value of 2.3 ± 4.5 in the Goddard classification. All patients were treated with ICS. Classification of phenotypes of elderly patients with asthma The elderly patients with asthma were classified into asthmapredominant (n ¼ 48, 29%), asthma-OAD overlap (n ¼ 36, 22%), and asthma-emphysema overlap (n ¼ 81, 49%) phenotypes (Table 2). The asthma-emphysema overlap group had most males, the highest rate of smoking >10 pack-years, and the most frequent atopic status. The % predicted FEV1 in patients with asthmaemphysema and asthma-OAD without emphysema was significantly lower than that in the asthma-predominant group (P < 0.001). %DLCO in asthma-emphysema did not differ significantly from those for other phenotypes (Fig. 1A and B). FeNO in asthma-OAD without emphysema was significantly higher than that in asthma-emphysema (P ¼ 0.02) (Fig. 1C).


4


(A) % predicted FEV1

To assess the characteristics of the three phenotypes, the patients were classified into five categories based on severity of emphysema: 74 had no abnormal findings, 59 had very mild emphysema, and 15, 11 and 6 patients had mild, moderate and severe emphysema, respectively, based on the modified Goddard classification (Fig. 2). Ten patients in the asthma-predominant group had very mild emphysema. Discrimination of asthma-OAD without emphysema from asthmaemphysema A ROC curve was constructed to establish a cutoff to discriminate asthma-emphysema from asthma-OAD without emphysema. The optimal cutoffs for % predicted FEV1 (Fig. 3A) and FeNO (Fig. 3B) to discriminate between these phenotypes were 70% (sensitivity 64%, specificity 67%) and 70 ppb (sensitivity 62%, specificity 72%), respectively. Age and atopic status were excluded in univariate analysis of confounding factors associated with comparison of the two phenotypes. In logistic regression analysis, smoking history >10 pack-years (OR 2.92: 95% CI 1.21e7.00, P ¼ 0.03) and %predicted FEV1 70% (OR 3.18: 95% CI 1.13e8.92, P ¼ 0.03) (Table 3) were associated with asthma-emphysema, and FeNO >70 ppb (OR 0.27: 95% CI 0.08e0.91, P ¼ 0.02) was a predictor for asthma-OAD without emphysema.

1.0 0.8 Sensitivity

Severity of emphysema based on chest HRCT

0.4 0.2

AUC: 0.67 (0.56-0.78) P-value = 0.003 Cut-off level: 70%

0.0 0.0 0.2 0.4 0.6 0.8 1.0 1 - specificity

(B) FeNO 1.0 0.8

Elderly patients with asthma were classified into asthmapredominant (29%), asthma-OAD overlap (22%), and asthmaemphysema overlap (49%) phenotypes using pulmonary function tests and chest HRCT. COPD is thought of as an overlap of chronic bronchitis, emphysema and subtypes of asthma associated with chronic airflow limitation. Snider et al. first represented these phenotypes in a non-proportional Venn diagram17 and the three phenotypes of elderly patients with asthma in the current study are shown in this style in Fig. 4, based on the diagram produced by the ATS.18 To the best of our knowledge, this study is the first to classify

80 70 60

Sensitivity

Discussion

Distribution (persons)

0.6

0.6 0.4

0.2

AUC: 0.69 (0.59-0.79) P-value = 0.001 Cut-off level: 70 ppb

0.0 0.0 0.2 0.4 0.6 0.8 1.0 1 - specificity Fig. 3. ROC analysis for distinguishing between asthma-emphysema overlap and asthma-OAD overlap. The cut-offs separating the two groups were %FEV1 of 70% (A) and FENO of 70 ppb (B).

50 40

30 20 10

E. Severe

D. Moderate

C. Mild

B. Very mild

A. Normal

0

Fig. 2. Distribution of the severity of emphysema on chest HRCT in elderly patients with asthma. The severity of emphysema on HRCT was assessed using the modified Goddard scoring system. The mean score of six images for each patient was classified as (A) normal (score 0), (B) very mild (>0 to 0.5), (C) mild (>0.5 to 1), (D) moderate (>1 to 2), and (E) severe (>2). Ten patients in the asthma-predominant group had very mild emphysema.

elderly patients with asthma using pulmonary function tests and chest HRCT. The phenotype of asthma-emphysema was characterized by mild LAAs with irreversible airway obstruction. In addition, 37% of patients with this phenotype were non-smokers and approximately half were atopic. Braman et al.19 found that non-smoking patients with long-term asthma might develop chronic persistent airflow obstruction and thereby mimic chronic bronchitis and emphysema (COPD). The characterization of this phenotype may be partially explained by the “Dutch hypothesis”,20 which states that asthma and AHR predispose patients to COPD later in life. Some LAAs were present in the asthma-emphysema group on chest HRCT, but there was no significant difference in diffusion capacity, compared with the asthma-predominant group (Table 2). This may be explained by the very mild to mild emphysema. Donohue et al.


H. Sano et al. / Allergology International xxx (2015) 1e6 Table 3 Factors distinguishing between asthma-OAD without emphysema and asthmaemphysema (ACOS). Confounding factor

Univariate analysis OR (95% CI), P-value

Multivariate analysis OR (95% CI), P-value

Age, >74 years Smoking status Atopic status % Predicted FEV1, 69 ppb

1.27 3.40 1.20 4.21 0.17

e 2.92 (1.21e7.00), 0.02 e 3.18 (1.13e8.92), 0.03 0.27 (0.08e0.91), 0.02

(0.58e2.78), (1.49e7.77), (0.55e2.64), (1.58e11.2), (0.05e0.55),

0.56 0.004 0.64 0.004 0.003

Abbreviations: FeNO, fraction of exhaled nitric oxide; FEV1, forced expiratory volume in one second.

found that early-onset asthma contributed to greater %LAA in later life.21 Our results showed that 20% of asthma-predominant patients (who had no OAD) had very mild LAA. This implies that there is a different pathophysiology of LAAs between asthma-emphysema and COPD only. From the point of view of phenotypic subgroups of COPD, it was reported that FeNO was one of useful biomarkers to distinct ACOS from COPD.22 In our results, FeNO might contribute to distinguish between asthma-OAD overlap without emphysema and asthmaemphysema overlap (ACOS). The phenotype of asthma-OAD overlap without emphysema was characterized by eosinophilic airway inflammation. This phenotype comprised remodeling asthma and chronic bronchitis associated with COPD; however, in many cases it is very difficult to differentiate patients with remodeling asthma whose airflow obstruction does not remit completely from patients with chronic bronchitis. From sputum cytokine profiling, there are three distinct and overlapping groups of subjects with asthma and COPD: cluster 1: asthma predominant, eosinophilic, high Th2 cytokines; cluster 2: asthma and COPD overlap, neutrophilic; and cluster 3: COPD predominant, mixed eosinophilic and neutrophilic.23 Biomarkers for discrimination of the phenotype of asthmaOAD without emphysema are required. Interestingly, the phenotype of asthma-OAD without emphysema had an earlier age of onset of asthma, a longer disease duration and worse lung function at baseline (FEV1 79.9% predicted) compared to the asthma-predominant (93.8% predicted) group, in agreement with the findings of de Marco et al. for ACOS.24 Airway remodeling occurs throughout the respiratory tract, but

5

remodeling of the small airways is largely responsible for the decline in lung function in COPD and long-standing asthma.25 COPD is substantially underdiagnosed26,27 and frequently misdiagnosed,28 with Soriano et al. showing that 72e93% of COPD patients are not diagnosed with their condition.27 Early diagnosis of COPD has been attempted for high-risk patients29,30 and spirometry was proven to play an important role in COPD screening and early diagnosis. DLCO on pulmonary function tests and a higher rate of airway-to-lung parenchymal abnormalities on lung imaging by HRCT may also distinguish asthma from COPD.29 In this study, we assessed DLCO and LAA severity to distinguish asthma-emphysema (asthma-OAD with emphysema) from asthma-OAD without emphysema. In multivariate logistic analysis, smoking status and moderate or severe OAD were associated with emphysema on chest HRCT in elderly patients with asthma. The limitations of this study include the analysis of a relatively small number of patients at a single center, which has a risk of collection bias. However, our patients had almost similar airways to those in Park et al. in a multicenter cohort,31 in which rates of 78.6%e75.0% for postbronchodilator %predicted FEV1 and 69.6%e 66.8% for the postbronchodilator FEV1/FVC ratio were found in elderly patients with asthma (age 65 years). This finding supports the generalization of our results. Second, as our patients were enrolled under the condition of treatments, there may be posttreatment bias, such as some possibility of estimating low level of FeNO in the patients with asthma-predominant. In conclusion, half of elderly patients with asthma are characterized by a comorbidity of emphysema. The phenotype with features of asthma-emphysema overlap syndrome includes smokers with asthma and nonsmokers with long-standing asthma who progress to COPD. Further studies of the potential relationship of onset of asthma and smoking status with the phenotype of asthmaemphysema overlap are needed. In addition to the uncertainties in the diagnostic criteria for ACOS, it is important to remember that COPD is underdiagnosed in the elderly and that patients with asthma-emphysema overlap are also at a higher risk of being falsely classified as having airflow obstruction using the 70% ratio recommended by GOLD. Acknowledgments This study was funded by Waksman Foundation of Japan. The authors would like to acknowledge I'ROM for the statistical analysis of the data.

Chronic bronchitis (CB)

Emphysema

Obstructive airway disease (OAD)

Conflict of interest YT has received speaker's fees from Kyorin Pharmaceutical and Teijin, and an honorarium from the advisory boards of Kyorin Pharmaceutical and Teijin. The rest of the authors have no conflicts of interest. Authors' contributions HS: study preparation, conduct of the study, analyses, and paper writing; TI, ON, AS, YH: conduct of the study; KT: analyses and paper writing; YT: study preparation and paper writing. All authors read and approved the final manuscript.

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