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Clinical characteristics of patients with chronic obstructive pulmonary disease overlapped with bronchial asthma
Ann Allergy Asthma Immunol 118 (2017) 564e569
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Clinical characteristics of patients with chronic obstructive pulmonary disease overlapped with bronchial asthma Jing-bo Liang, MD *; Li-jin Liu, MD y; Qiu-hong Fang, PhD z * Department
of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China Medical Experimental Center, General Hospital of Chinese People’s Armed Police Forces, Beijing, China z Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China y
A R T I C L E
I N F O
Article history: Received for publication October 25, 2016. Received in revised form February 18, 2017. Accepted for publication February 20, 2017.
A B S T R A C T
Background: The clinical characteristics of patients with chronic obstructive pulmonary disease overlapped with bronchial asthma (COPD-BA) have not been discussed thoroughly. Objective: To reveal the clinical features of patients with COPD-BA, to evaluate the risk factors of COPD-BA, and to provide suggestions for COPD individualized therapy. Methods: A retrospective observational study was performed. A total of 182 patients with COPD (90 with COPD-BA and 92 with pure COPD) were recruited in the study. Information on the following items was collected: demographics, clinical manifestations, complications, laboratory findings, other histories, and inpatient treatments during exacerbation. Results: A total of 182 patients were diagnosed with COPD, with 90 (49.45%) being classified as having COPD-BA. Patients with COPD-BA were more likely to be female (P ¼ .004) and experienced more severe respiratory exacerbations (P ¼ .04) despite being younger (P ¼ .008). Those patients at onset of recurrent cough and sputum production were younger (P ¼ .001). Significantly, a positive asthmatic family history (P ¼ .03) was observed. Patients with COPD-BA usually had higher level of total serum IgE (although no differences were observed), had higher positive rates of the serum specific IgE (P ¼ .004), and were more like to have an allergic history (P ¼ .003). Allergic factor was the risk factor of COPD-BA (odds ratio, 4.477). During hospitalization, patients with COPD-BA tended to be treated with systemic corticosteroids (P ¼ .008). Conclusion: Patients with COPD-BA were characterized by persistent airflow limitation with unique clinical features. Allergic factor was associated with the presence of asthmatic characteristics in patients with COPD. When hospitalized for exacerbation, the individualized therapy for COPD-BA might include the use of corticosteroids systemically. Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Distinguishing asthma from chronic obstructive pulmonary disease (COPD) can be problematic, particularly in patients who share the clinical features of both asthma and COPD. Previous studies have revealed that 15% to 20% of patients may have asthma and COPD simultaneously.1 Approximately 33% of patients with COPD additionally report a history of asthma.1 Thus, the term asthma-COPD overlap syndrome (ACOS) has been introduced. ACOS Reprints: Qiu-hong Fang, PhD, Department of Respiratory and Critical Care Medicine, Beijing Chao-yang Hospital, No. 8 Gongren Tiyuchang Nanlu, Chao-yang District, Beijing 100020, China; E-mail: [email protected]. Disclosures: Authors have nothing to disclose. Funding Sources: The development of the Good Clinical Practice evaluation system in the field of respiratory diseases with advanced technology was supported by grant 2014ZX09303302 provided by the Ministry of Science and Technology of China.
is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD, although a specific definition for ACOS does not exist.2 There is increasing evidence that the patients with ACOS experience more frequent exacerbations,3 have poorer quality of life and higher mortality,1,4e6 and consume a more disproportionate amount of health care resources7,8 than those with COPD alone. Despite these facts, the characteristics of this overlap population have not been well described, especially for hospitalized patients with ACOS. ACOS includes heterogeneous phenotypes on the basis of clinical characteristics, such as asthma with COPD features, COPD with asthma features, and COPD overlapped with asthma. Each phenotype might have specific clinical manifestations. Our study mainly focused on hospitalized patients with COPD and bronchial asthma (COPD-BA), who are supposed to be one subgroup of ACOS,
http://dx.doi.org/10.1016/j.anai.2017.02.019 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
J.-b. Liang et al. / Ann Allergy Asthma Immunol 118 (2017) 564e569
to investigate their clinical characteristics by comparing them with patients with pure COPD. We assumed that patients with COPD-BA might experience distinctive clinical features during their exacerbations. Methods Study Participants We performed a retrospective observational study among patients with COPD to compare clinical characteristics of COPD-BA with pure COPD. The research data were collected from patients with a COPD exacerbation hospitalized in the respiratory ward of Peking University Ninth Hospital (Beijing Shijitan Hospital) from January 2014 to January 2015. COPD was defined by persistent respiratory symptoms and airflow limitation that is attributable to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.2 A postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity ratio less than 0.7 was necessary.2 Exacerbation was defined by an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.2 In our study, asthma was defined by either of the following conditions: (1) they were diagnosed inward this time by their physician according to the criteria of asthma put forward by the Global Initiative for Asthma (GINA)9 or (2) the patients reported that they had had asthma diagnosed by other physicians before. All patients with COPD were classified as having COPD-BA if they had been diagnosed with asthma simultaneously or previously. Exclusion criteria included respiratory disorders other than asthma and COPD and acute myocardial infarction, congestive heart failure, cancer, or any other serious systemic disease. Procedures All the following information was collected from the patients: demographics, clinical manifestations, complications, laboratory findings, other histories, and inpatient treatments during exacerbation. Clinical manifestations included clinical symptoms during the stable period and exacerbation; severe exacerbation, which was defined as respiratory exacerbations in the year before enrollment that resulted in hospitalization or emergency treatment10; and the causes of exacerbation this time. Complications included respiratory failure, spontaneous pneumothorax, and cor pulmonale. Spirometry was measured before inhalation of 400 mg of albuterol and 15 to 30 minutes after inhalation. The total serum IgE level and serum specific IgE test were measured. Other histories included allergic history, family history of asthma, smoking history, and occupational exposure. The therapy received for exacerbation in the hospital included antibiotics, glucocorticoids, and mechanical ventilation. Statistical Analysis Values are expressed as the mean (SD) or percentage. Differences between groups were analyzed using the c2 or t test. A logistic regression model was created to assess potential contributing factors to the diagnosis of COPD-BA in patients who have COPD. P < .05 was considered statistically significant. Results Demographics Of 182 patients with COPD, 90 (49.45%) had COPD-BA. Compared with those with pure COPD, patients with COPD-BA were younger (P ¼ .008) and more likely to be female (P ¼ .004). No differences in height, body weight, and body mass index were observed (Table 1).
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Table 1 Demographics of Patients With COPD Only or COPD-BAa Demographic
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
P value
Female sex Age, mean (SD), y Height, mean (SD), cm Body weight, mean (SD), kg BMI, mean (SD) COPD group A B C D
26 76.27 164.39 65.23 23.74
(28.26) (8.52) (18.31) (10.53) (4.02)
44 72.69 165.66 63.81 23.18
(48.89) (9.35) (7.76) (12.31) (3.72)
.004 .008 .58 .48 .39
8 9 9 66
(8.70) (9.78) (9.78) (71.74)
12 8 10 60
(13.33) (8.89) (11.11) (66.67)
.76
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
Clinical Manifestations In patients with COPD-BA, the symptoms of recurrent cough and sputum production tended to start younger (P ¼ .001). Such individuals were more likely to have a severe COPD exacerbation (P ¼ .04). During acute exacerbation, patients with COPD-BA were more likely to have rhonchus (P ¼ .001). No difference was found in other clinical manifestations between COPD subgroups (Table 2). Complications The incidence of spontaneous pneumothorax (3.33% with COPD-BA compared with 2.17% with COPD, P ¼ .63), respiratory failure (20.00% with COPD-BA compared with 28.26% with COPD, P ¼ .19) and cor pulmonale (24.44% with COPD-BA compared with 16.30% with COPD, P ¼ .17) appeared high in both groups, but there were no differences in those findings. Laboratory Findings We focused on 3 kinds of laboratory examinations, including the total serum IgE level, the serum specific IgE level, and spirometry. Patients with COPD-BA presented wih a similar degree of severity in terms of spirometry (Table 3). Seventy-seven patients received the serum IgE test (61 with the COPD-BA phenotype). Some of the patients with COPD-BA had an Table 2 Clinical Manifestations of Patients With COPD Only or COPD-BAa Variable
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
P value
Recurrent cough and sputum production 86 (93.48) 76 (84.44) .051 Age at onset of recurrent cough and sputum 60.27 (14.69) 51.92 (16.04) .001 production, mean (SD), y Course of recurrent cough and sputum 15.04 (13.2) 17.90 (15.36) .18 production, mean (SD), y Shortness of breath 73 (79.35) 71 (78.89) .94 Age at onset of shortness of breath, mean 68.52 (9.92) 65.35 (12.04) .09 (SD), y Course of shortness of breath, mean (SD), y 6.28 (7.76) 6.45 (7.38) .88 Rhonchi (during exacerbation) 47 (51.89) 68 (75.56) .001 Moist rale (during exacerbation) 57 (62.00) 30 (33.33) <.001 Severe exacerbation 45 (50.00) 60 (65.22) .04 Causes for exacerbation Infection 88 (95.65) 76 (84.44) Allergy 0 (0) 4 (4.44) .02 Other 4 (4.35) 10 (11.12) Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
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Table 3 Mean (SD) Spirometry Result of Patients With COPD Only or COPD-BA
Table 5 Inpatient Treatment of Patients With COPD Only or COPD-BAa
Variable
COPD only (n ¼ 62)
COPD-BA (n ¼ 77)
P value
Treatment
FRC, % predicted RV, % predicted TLC, % predicted RV/TLC, % FEV1 (postbronchodilator), % predicted Postbronchodilator change in FEV1, % FVC (postbronchodilator), L FEV1/FVC (postbronchodilator), % VC (postbronchodilator), L MMEF (postbronchodilator), L/s Postbronchodilator change in PEF, %
136.68 165.26 108.93 63.24 48.67 6.15 2.13 53.89 2.23 0.50 6.15
147.24 168.75 113.85 62.59 50.28 7.76 2.12 54.69 2.24 0.60 7.76
.24 .77 .35 .80 .62 .32 .93 .69 .93 .61 .32
Systemic corticosteroids received (men or women) Cumulative dose of systemic corticosteroids, mg Ventilation (men or women) Neither Invasive Noninvasive Length of antibiotic treatment, mean (SD), d Combined with antifungal agents Length of hospitalization, mean (SD), d
(45.56) (66.85) (27.26) (13.43) (19.07) (9.52) (0.77) (11.76) (0.79) (0.32) (9.52)
(60.28) (69.86) (33.14) (15.70) (19.19) (9.53) (0.69) (11.35) (0.69) (0.62) (9.53)
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma; FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; MMEF, maximum midexpiratory flow; PEF, peak expiratory flow; RV, residual volume; TLC, total lung capacity; VC, vital capacity.
increased serum IgE level. However, no difference was found in serum total IgE level between the 2 groups (172.94 vs 331.00 IU/mL, P ¼ .37). Regarding the serum specific IgE level, patients with COPD-BA were more likely to receive this test (21.74% vs 63.33%, P < .001), and more than half of them had positive results (57.89% vs 42.11%, P ¼ .004). Other Histories Compared with patients with pure COPD, patients with COPDBA were more inclined to have an allergic history (57.78% vs 35.87%, P ¼ .003) or a positive family history of asthma (15.56% vs 5.54%, P ¼ .03). Most of the patients had smoking history, and 17 of 66 patients with pure COPD and 25 of 71 patients with COPD-BA were current smokers. No differences in smoking history were observed (Table 4). Inpatient Treatment During Exacerbation When hospitalized, more patients with COPD-BA tended to be treated with systemic corticosteroids (41.11% vs 22.83%, P ¼ .008). No difference was found in other inpatient treatments between COPD subgroups (Table 5). Logistic Regression Model A logistic regression analysis examined the possible predictors for the presence of asthma in patients with COPD, including allergic factors, sex, family history, severe exacerbation, age, pack-years of smoking, and body mass index. Allergic factors included allergic history, the total serum IgE level higher than 165 IU/mLm or a positive serum specific IgE test result. In the analysis, allergic factors were associated with a 4-fold increase in the risk of
Table 4 Other Histories of Patients With COPD Only or COPD-BAa History Allergic history Family history of asthma History of occupational exposure Smoking history Pack-years, mean (SD)
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
33 (35.87) 5 (5.43) 16 (17.39)
52 (57.78) 14 (15.56) 13 (14.44)
66 (71.74) 28.52 (28.45)
71 (78.89) 34.41 (36.10)
P value .003 .03 .59 .26 .22
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
COPD only (n ¼ 92) 21 (22.83) 183.43 (100.22)
74 2 16 13.65
(80.43) (2.17) (17.40) (13.39)
26 (28.26) 10.89 (9.87)
COPD-BA (n ¼ 90) 37 (41.11) 216.27 (158.17)
80 1 9 12.33
P value
.008 .40
(88.89) (1.11) (10) (10.80)
.29
22 (24.44) 10.10 (6.03)
.56 .52
.47
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
diagnosis of COPD-BA (odds ratio, 4.477). Male sex was a protective factor associated with the presence of asthmatic characteristics in patients with COPD (odds ratio, 0.382) (Table 6). Subgroup Analysis for COPD-BA On the basis of allergic factors, patients with COPD-BA were divided into 2 subgroups. No differences in sex, age, height, body weight, and body mass index were observed. However, patients with COPD-BA and allergic factors were more likely to be treated with systemic corticosteroids during exacerbation (P ¼ .04). No difference was found in other inpatient treatments between those 2 subgroups (Table 7). Discussion Clinical Features of COPD-BA The prevalence of COPD-BA observed in our study (49.45%) was slightly higher than in previous studies, which reported an estimated prevalence of 15% to 20%.2 This finding is possibly because patients with COPD-BA usually experience more severe respiratory exacerbations,3 which in return leads to a higher amount of them hospitalized. Meanwhile, most of the patients in our study had endstage COPD and required hospitalization. Even though different prevalence was reported, it is accepted that there is a high prevalence of COPD-BA in patients with COPD admitted to the hospital. In addition, we found that patients with COPD-BA have distinct characteristics compared with patients with pure COPD. Typical symptoms of recurrent cough, sputum production, and shortness of breath did not have the sensitivity or specificity to distinguish these 2 subgroups. However, patients with COPD-BA at onset of recurrent cough and sputum production were a mean of 10 years younger than those with pure COPD. In addition, those patients were more likely to be female and experienced more severe respiratory exacerbations despite being younger. During acute exacerbation, rhonchus was more likely to be heard on physical examination. As a chronic airway disease, spirometry is crucial for patients with COPD-BA. In our study, COPD-BA was characterized by Table 6 Logistic Regression for Patients With Asthma Among Patients With COPD Variable
OR (95% CI)
P value
Allergic factors Male
4.477 (2.032e9.866) 0.382 (0.174e0.835)
<.001 .02
Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio.
J.-b. Liang et al. / Ann Allergy Asthma Immunol 118 (2017) 564e569 Table 7 Subgroup Analysis for COPD-BAa Variable
With allergic factors (n ¼ 68)
Without allergic factors (n ¼ 22)
P Value
Female sex Age, mean (SD), y Height, mean (SD), cm Body weight, mean (SD), kg BMI, mean (SD) Systemic corticosteroids received (men or women) Cumulative dose of systemic corticosteroids, mean (SD), mg Ventilation (men or women) Neither Invasive Noninvasive Length of antibiotic treatment, mean (SD), d Combined with antifungal agents Length of hospitalization, mean (SD), d
33 72.47 166.16 64.61 23.33 32
11 73.36 163.75 60.81 22.63 52
(50.00) (10.87) (5.81) (10.57) (3.43) (2.73)
.90 .70 .27 .28 .51 .04
153.60 (49.85)
.35
(91.18) (1.47) (7.35) (10.57)
18 (81.82) 0 (0.00) 4 (18.18) 13.82 (11.62)
.30
16 (23.53) 9.78 (5.69)
6 (27.27) 11.09 (7.03)
.72 .43
(48.53) (8.88) (8.16) (12.68) (3.81) (47.06)
226.06 (167.34)
62 1 5 11.85
.46
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
persistent airflow limitation, which was similar to that of patients with COPD alone. Therefore, it would be rather limiting to define patients with COPD-BA based on only FEV1 or bronchodilator response. This is consistent with the findings of the previous studies that found that spirometry confirms chronic airflow limitation but is of more limited value in distinguishing between COPD and ACOS.2 Furthermore, a large number of patients with COPD-BA had complications, although no difference existed between the COPD subgroups. The incidence of spontaneous pneumothorax especially appeared high in both groups. The possible explanations for this are as follows. First, COPD becomes the leading cause of secondary spontaneous pneumothorax for its emphysematous bullae and hyperinflated lungs.11 Second, most patients in our study were already in the end stage of COPD, accounting for 66.67% of all patients with COPD-BA and 71.74% of all patients with COPD. Therefore, they were more likely to have spontaneous pneumothorax. Factors That Influence Disease Development and Progression Most of the evidence concerning risk factors for COPD-BA comes from cross-sectional epidemiologic studies that identify associations rather than cause-and-effect relationships. As far as we known, no longitudinal studies of COPD-BA have been performed until now. Thus, current understanding of risk factors for COPD-BA is still incomplete in many respects. Our study found that patients with COPD-BA were more inclined to have a positive family history of asthma, indicating genetics may contribute to the development of COPD-BA. Previous studies also indicated the same result, reporting that the gene encoding matrix metalloproteinase 12 is related to children with asthma and smokers with COPD.12 In addition, age may be a powerful factor that contributes to the manifestation of COPD-BA. Our findings are supplemental to the results of previous studies, suggesting that patients with COPD-BA tend to be younger than patients with pure COPD and the prevalence of overlap syndrome increases from mid to later life progressively, especially in those older than 60 years.13 Other studies have found that elderly patients with asthma have more features of fixed obstruction than their younger counterparts.14 Their asthma may manifest itself as chronic persistent airflow obstruction mimicking COPD.15 However, it is unclear how aging reflects the manifestations, whether by the sum of cumulative exposures of
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pathogenic factors throughout life, the deterioration of lung function naturally with aging, or other unknown factors. Asthma may be a risk factor for the development of COPD-BA, although the evidence is not conclusive. In a report from a longitudinal cohort study of the Tucson Epidemiological Study of Airway Obstructive Disease, compared with individuals without asthma, those with active asthma had a 10 times higher risk of acquiring symptoms of chronic bronchitis, a 17 times higher risk of receiving a diagnosis of emphysema, and a 12.5 times higher risk of fulfilling COPD criteria, even after adjusting for smoking history and other potential confounders.16 Likewise, Lange et al17 found a significantly greater annual rate of decline in FEV1 in both men and women with asthma, independent of smoking, compared with nonasthmatic controls. Those studies found that patients with asthma have a higher risk of acquiring COPD or COPD-like symptoms that develop into COPD-BA than those without asthma. Finally, this study concentrated on the potential association between COPD-BA and allergy especially. A previous study found that a positive skin test result was revealed in 37% of patients with asthma vs 8.3% of patients with COPD, whereas patients with asthma also had higher serum total IgE levels compared with patients with COPD.18 Scichilone et al19 reported an increased incidence of allergic history in patients with asthma 65 years or older. Thus, we selected the allergic history, the specific IgE test, and the total serum IgE level as parameters to assess the possible effects of allergy to BA-COPD. Our study found that some of the patients with COPD-BA had a higher level of IgE in serum, although no difference was found between the 2 groups within limited sampling size. Considering the specific IgE test, patients with COPD-BA were more likely to receive this test. Meanwhile, more than half of them had positive results. Therefore, we used allergic history, a total serum IgE level higher than 165 IU/mL, or a positive serum specific IgE test result to try to confirm that allergen exposure plays an important role in the development of BA-COPD. Ultimately, we additionally found a greater portion of patients with COPD-BA had allergic factors. These results suggest that allergic factors might be specific for COPD-BA. This conclusion is supported by our logistic regression analysis for clinical predictors of the diagnosis of COPD-BA in which we found that patients with COPD with allergic factors were 4 times as likely to have asthma compared with the other group. In addition, Lee et al20 found that total IgE level was significantly increased in patients with COPD-BA compared with the pure asthma group and concluded that more severe degree of allergy in patients with asthma may lead to the development of mixed phenotype.20 On the basis of these findings, we conclude that allergy may contribute to the overlap phenotype in chronic airway disease. The mechanisms through which allergy may affect patients with COPD could include airway inflammation. A study comparing inflammatory markers in allergic vs nonallergic patients with COPD found a higher serum level of IL-8 in patients with COPD who were allergic to mites, indicating that IL-8erelated airway inflammation in COPD may be up-regulated by allergy.21 Despite the possible role that the presence of allergy might play in COPD, the precise mechanisms still need further research. In conclusion, the mechanisms behind COPD-BA involve a geneenvironment interaction or even more complex ways. Deeper understanding of the associations and interactions among risk factors requires further investigation. Individualized Treatment Approach for COPD-BA During Exacerbation Currently, there are no randomized clinical trial data to help guide the therapeutic interventions in those overlap populations. On the basis of our study, we recommend comprehensive therapies,
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including antibiotics, corticosteroids, and bronchodilators, during hospitalization. Our study suggests that the major cause of acute exacerbation was infection and the pathogens were mainly bacterium and atypical pathogens, although a few patients were infected by fungus. Therefore, it is important to determine the basis of the pathogen in patients with COPD-BA during hospitalization and to treat promptly with effective antibiotics. The course of antibiotic treatment for COPD-BA was similar to that for pure COPD. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) indicates that patients with COPD could benefit from systemic corticosteroids during exacerbation,2 this therapy remains controversial. Our study focused on the use of systemic corticosteroids during hospitalization, indicating that patients with COPD-BA were more likely to receive corticosteroids systemically. Thus, these patients may require individualized systemic corticosteroids therapy. In addition, we performed a subgroup analysis based on allergic factor. We additionally found that a greater portion of patients with COPD-BA with allergic factors were treated with corticosteroids systemically. These findings would suggest that allergic factors may also be a prior predictor for using corticosteroids systemically within COPD-BA during hospitalization. However, further study should be implemented for the proper cumulative dose of systemic corticosteroids by longitudinal studies. Bronchodilators are widely used in patients with COPD-BA during hospitalization. GOLD recommends treatment with an inhaled corticosteroid and bronchodilator combination, avoiding long-acting b2-agonist monotherapy.2 Smoking cessation, treatment of comorbidities, oxygen supplementation, pulmonary rehabilitation, and vaccines are reasonable interventions. Adjunctive treatments, such as leukotriene receptor antagonists, 5-lipoxygenase inhibitors, methylxanthines, or omalizumab, deserve further study. A Descriptive Definition Based on Our Research The definition of ACOS was introduced by the science committees of GINA and GOLD and was documented in detail in Global Strategy for Asthma Management and Prevention in 2014.22 ACOS is characterized by persistent airflow limitation, with several features usually associated with asthma and several features usually associated with COPD.22 In the joint GINA and GOLD publication, 11 clinical features that best distinguished between asthma and COPD were proposed, such as age at onset of the disease, pattern of symptoms, lung function, history of asthma or COPD, family history of asthma or allergy, improvement after treatment with a bronchodilator or inhaled corticosteroid, and so on.22 If there are similar numbers of features listed for asthma and COPD, the diagnosis of ACOS should be considered.22 ACOS is therefore identified by the features that it shares with asthma and COPD. However, it is a consensus-based descriptive definition, so these criteria are neither specific nor sensitive. ACOS is a heterogeneous syndrome; for the deep understanding, a more detailed classification of patients with overlapping features of asthma and COPD is needed. However, there have been many different criteria of ACOS and classifications of subgroups, which makes it difficult for researchers to design clinical studies in welldefined patients and in turn influences the results. To avoid these problems, our study focused on COPD-BA. This group of patients not only have specific criteria but are explicit as a subgroup of ACOS. Van den Berge and Aalbers23 suggested 2 clinical phenotypes for ACOS: asthma-ACOS and COPD-ACOS. Asthma-ACOS refers to never-, ex-, or current smokers with a history of asthma who have incompletely reversible airflow obstruction. Meanwhile COPDACOS refers to smokers or ex-smokers with COPD according to GOLD criteria who have increased bronchodilator reversibility or
bronchial hyperresponsiveness.23 Thus, patients with COPD-BA in our study can be referred as having the asthma-ACOS subphenotype. Our study is consistent with the definition put forward by GINA that ACOS is a persistent airflow limitation disease, but several features, such as respiratory symptoms, lung function, and time course, are of limited value. Although our study found no difference in these features between 2 groups, several features, such as age at onset, history, and exacerbations, are important for COPD-BA. Because COPD-BA is not like COPD, patients with COPD-BA usually experience unique clinical features in these aspects. Therefore, we recommend allergic factors as a new feature for COPD-BA. Allergic factors were associated with the presence of asthmatic characteristics in our patients with COPD. Our research did not involve airway inflammation or chest radiography. COPD-BA is characterized by persistent airflow limitation, and patients with COPD-BA satisfy the criteria of COPD and asthma previously or simultaneously with or without allergic factors, such as allergic history, high total IgE level, or positive serum specific IgE test result. These patients are more likely to be female, usually younger, experience more severe respiratory exacerbations, and are more inclined to have a positive family history of asthma. One limitation of this retrospective study is that eosinophil counts, allergy skin test results, and IgE levels were available for less than 50% of the patients. Because of missing clinical data, bias might have influenced the significance of our findings. Another limitation is that a1-antitrypsin deficiency (AATD) was not screened. Comparison of AATD might have assisted in comparing the pathologic differences in these 2 groups. However, only approximately 2.5 million of 1,400 million people were estimated to be diagnosed with AATD in Far East Asia in 200524; therefore, AATD was not routinely evaluated in our patients with COPD. In summary, on the basis of mainly medical history, COPD-BA is a chronic airway disease. Just like COPD, COPD-BA is characterized by persistent airflow limitation without much variability. Several features are important to COPD-BA, such as age at onset of disease, exacerbations, family history, and allergic factors. Finally, patients with COPD-BA could commence comprehensive therapies, including antibiotics, corticosteroids, and bronchodilators during hospitalization, and patients with COPD-BA may benefit from systemic corticosteroids.
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[19] Scichilone N, Callari A, Augugliaro G, et al. The impact of age on prevalence of positive skin prick tests and specific IgE tests. Respir Med. 2011;105:651e658. [20] Lee HY, Kang JY, Yoon HK, et al. Clinical characteristics of asthma combined with COPD feature. Yonsei Med J. 2014;55:980e986. [21] Tsai JJ, Liao EC, Hsu JY, et al. The differences of eosinophil- and neutrophilrelated inflammation in elderly allergic and non-allergic chronic obstructive pulmonary disease. J Asthma. 2010;47:1040e1044. [22] Global Strategy for Asthma Management and Prevention. Updated 2014, http:// www.ginasthma.org. Accessed August 12, 2014. [23] Van den Berge M, Aalbers R. The asthma-COPD overlap syndrome: how is it defined and what are its clinical implications? J Asthma Allergy. 2016;9:27e35. [24] Ranes J, Stoller JK. A review of alpha-1 antitrypsin deficiency. Semin Respir Crit Care Med. 2005;26:154e166.
Contents lists available at ScienceDirect
Clinical characteristics of patients with chronic obstructive pulmonary disease overlapped with bronchial asthma Jing-bo Liang, MD *; Li-jin Liu, MD y; Qiu-hong Fang, PhD z * Department
of Respiratory and Critical Care Medicine, Beijing Shijitan Hospital, Capital Medical University, Beijing, China Medical Experimental Center, General Hospital of Chinese People’s Armed Police Forces, Beijing, China z Department of Respiratory and Critical Care Medicine, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China y
A R T I C L E
I N F O
Article history: Received for publication October 25, 2016. Received in revised form February 18, 2017. Accepted for publication February 20, 2017.
A B S T R A C T
Background: The clinical characteristics of patients with chronic obstructive pulmonary disease overlapped with bronchial asthma (COPD-BA) have not been discussed thoroughly. Objective: To reveal the clinical features of patients with COPD-BA, to evaluate the risk factors of COPD-BA, and to provide suggestions for COPD individualized therapy. Methods: A retrospective observational study was performed. A total of 182 patients with COPD (90 with COPD-BA and 92 with pure COPD) were recruited in the study. Information on the following items was collected: demographics, clinical manifestations, complications, laboratory findings, other histories, and inpatient treatments during exacerbation. Results: A total of 182 patients were diagnosed with COPD, with 90 (49.45%) being classified as having COPD-BA. Patients with COPD-BA were more likely to be female (P ¼ .004) and experienced more severe respiratory exacerbations (P ¼ .04) despite being younger (P ¼ .008). Those patients at onset of recurrent cough and sputum production were younger (P ¼ .001). Significantly, a positive asthmatic family history (P ¼ .03) was observed. Patients with COPD-BA usually had higher level of total serum IgE (although no differences were observed), had higher positive rates of the serum specific IgE (P ¼ .004), and were more like to have an allergic history (P ¼ .003). Allergic factor was the risk factor of COPD-BA (odds ratio, 4.477). During hospitalization, patients with COPD-BA tended to be treated with systemic corticosteroids (P ¼ .008). Conclusion: Patients with COPD-BA were characterized by persistent airflow limitation with unique clinical features. Allergic factor was associated with the presence of asthmatic characteristics in patients with COPD. When hospitalized for exacerbation, the individualized therapy for COPD-BA might include the use of corticosteroids systemically. Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
Introduction Distinguishing asthma from chronic obstructive pulmonary disease (COPD) can be problematic, particularly in patients who share the clinical features of both asthma and COPD. Previous studies have revealed that 15% to 20% of patients may have asthma and COPD simultaneously.1 Approximately 33% of patients with COPD additionally report a history of asthma.1 Thus, the term asthma-COPD overlap syndrome (ACOS) has been introduced. ACOS Reprints: Qiu-hong Fang, PhD, Department of Respiratory and Critical Care Medicine, Beijing Chao-yang Hospital, No. 8 Gongren Tiyuchang Nanlu, Chao-yang District, Beijing 100020, China; E-mail: [email protected]. Disclosures: Authors have nothing to disclose. Funding Sources: The development of the Good Clinical Practice evaluation system in the field of respiratory diseases with advanced technology was supported by grant 2014ZX09303302 provided by the Ministry of Science and Technology of China.
is characterized by persistent airflow limitation with several features usually associated with asthma and several features usually associated with COPD, although a specific definition for ACOS does not exist.2 There is increasing evidence that the patients with ACOS experience more frequent exacerbations,3 have poorer quality of life and higher mortality,1,4e6 and consume a more disproportionate amount of health care resources7,8 than those with COPD alone. Despite these facts, the characteristics of this overlap population have not been well described, especially for hospitalized patients with ACOS. ACOS includes heterogeneous phenotypes on the basis of clinical characteristics, such as asthma with COPD features, COPD with asthma features, and COPD overlapped with asthma. Each phenotype might have specific clinical manifestations. Our study mainly focused on hospitalized patients with COPD and bronchial asthma (COPD-BA), who are supposed to be one subgroup of ACOS,
http://dx.doi.org/10.1016/j.anai.2017.02.019 1081-1206/Ó 2017 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.
J.-b. Liang et al. / Ann Allergy Asthma Immunol 118 (2017) 564e569
to investigate their clinical characteristics by comparing them with patients with pure COPD. We assumed that patients with COPD-BA might experience distinctive clinical features during their exacerbations. Methods Study Participants We performed a retrospective observational study among patients with COPD to compare clinical characteristics of COPD-BA with pure COPD. The research data were collected from patients with a COPD exacerbation hospitalized in the respiratory ward of Peking University Ninth Hospital (Beijing Shijitan Hospital) from January 2014 to January 2015. COPD was defined by persistent respiratory symptoms and airflow limitation that is attributable to airway and/or alveolar abnormalities usually caused by significant exposure to noxious particles or gases.2 A postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity ratio less than 0.7 was necessary.2 Exacerbation was defined by an acute event characterized by a worsening of the patient’s respiratory symptoms that is beyond normal day-to-day variations and leads to a change in medication.2 In our study, asthma was defined by either of the following conditions: (1) they were diagnosed inward this time by their physician according to the criteria of asthma put forward by the Global Initiative for Asthma (GINA)9 or (2) the patients reported that they had had asthma diagnosed by other physicians before. All patients with COPD were classified as having COPD-BA if they had been diagnosed with asthma simultaneously or previously. Exclusion criteria included respiratory disorders other than asthma and COPD and acute myocardial infarction, congestive heart failure, cancer, or any other serious systemic disease. Procedures All the following information was collected from the patients: demographics, clinical manifestations, complications, laboratory findings, other histories, and inpatient treatments during exacerbation. Clinical manifestations included clinical symptoms during the stable period and exacerbation; severe exacerbation, which was defined as respiratory exacerbations in the year before enrollment that resulted in hospitalization or emergency treatment10; and the causes of exacerbation this time. Complications included respiratory failure, spontaneous pneumothorax, and cor pulmonale. Spirometry was measured before inhalation of 400 mg of albuterol and 15 to 30 minutes after inhalation. The total serum IgE level and serum specific IgE test were measured. Other histories included allergic history, family history of asthma, smoking history, and occupational exposure. The therapy received for exacerbation in the hospital included antibiotics, glucocorticoids, and mechanical ventilation. Statistical Analysis Values are expressed as the mean (SD) or percentage. Differences between groups were analyzed using the c2 or t test. A logistic regression model was created to assess potential contributing factors to the diagnosis of COPD-BA in patients who have COPD. P < .05 was considered statistically significant. Results Demographics Of 182 patients with COPD, 90 (49.45%) had COPD-BA. Compared with those with pure COPD, patients with COPD-BA were younger (P ¼ .008) and more likely to be female (P ¼ .004). No differences in height, body weight, and body mass index were observed (Table 1).
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Table 1 Demographics of Patients With COPD Only or COPD-BAa Demographic
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
P value
Female sex Age, mean (SD), y Height, mean (SD), cm Body weight, mean (SD), kg BMI, mean (SD) COPD group A B C D
26 76.27 164.39 65.23 23.74
(28.26) (8.52) (18.31) (10.53) (4.02)
44 72.69 165.66 63.81 23.18
(48.89) (9.35) (7.76) (12.31) (3.72)
.004 .008 .58 .48 .39
8 9 9 66
(8.70) (9.78) (9.78) (71.74)
12 8 10 60
(13.33) (8.89) (11.11) (66.67)
.76
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
Clinical Manifestations In patients with COPD-BA, the symptoms of recurrent cough and sputum production tended to start younger (P ¼ .001). Such individuals were more likely to have a severe COPD exacerbation (P ¼ .04). During acute exacerbation, patients with COPD-BA were more likely to have rhonchus (P ¼ .001). No difference was found in other clinical manifestations between COPD subgroups (Table 2). Complications The incidence of spontaneous pneumothorax (3.33% with COPD-BA compared with 2.17% with COPD, P ¼ .63), respiratory failure (20.00% with COPD-BA compared with 28.26% with COPD, P ¼ .19) and cor pulmonale (24.44% with COPD-BA compared with 16.30% with COPD, P ¼ .17) appeared high in both groups, but there were no differences in those findings. Laboratory Findings We focused on 3 kinds of laboratory examinations, including the total serum IgE level, the serum specific IgE level, and spirometry. Patients with COPD-BA presented wih a similar degree of severity in terms of spirometry (Table 3). Seventy-seven patients received the serum IgE test (61 with the COPD-BA phenotype). Some of the patients with COPD-BA had an Table 2 Clinical Manifestations of Patients With COPD Only or COPD-BAa Variable
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
P value
Recurrent cough and sputum production 86 (93.48) 76 (84.44) .051 Age at onset of recurrent cough and sputum 60.27 (14.69) 51.92 (16.04) .001 production, mean (SD), y Course of recurrent cough and sputum 15.04 (13.2) 17.90 (15.36) .18 production, mean (SD), y Shortness of breath 73 (79.35) 71 (78.89) .94 Age at onset of shortness of breath, mean 68.52 (9.92) 65.35 (12.04) .09 (SD), y Course of shortness of breath, mean (SD), y 6.28 (7.76) 6.45 (7.38) .88 Rhonchi (during exacerbation) 47 (51.89) 68 (75.56) .001 Moist rale (during exacerbation) 57 (62.00) 30 (33.33) <.001 Severe exacerbation 45 (50.00) 60 (65.22) .04 Causes for exacerbation Infection 88 (95.65) 76 (84.44) Allergy 0 (0) 4 (4.44) .02 Other 4 (4.35) 10 (11.12) Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
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Table 3 Mean (SD) Spirometry Result of Patients With COPD Only or COPD-BA
Table 5 Inpatient Treatment of Patients With COPD Only or COPD-BAa
Variable
COPD only (n ¼ 62)
COPD-BA (n ¼ 77)
P value
Treatment
FRC, % predicted RV, % predicted TLC, % predicted RV/TLC, % FEV1 (postbronchodilator), % predicted Postbronchodilator change in FEV1, % FVC (postbronchodilator), L FEV1/FVC (postbronchodilator), % VC (postbronchodilator), L MMEF (postbronchodilator), L/s Postbronchodilator change in PEF, %
136.68 165.26 108.93 63.24 48.67 6.15 2.13 53.89 2.23 0.50 6.15
147.24 168.75 113.85 62.59 50.28 7.76 2.12 54.69 2.24 0.60 7.76
.24 .77 .35 .80 .62 .32 .93 .69 .93 .61 .32
Systemic corticosteroids received (men or women) Cumulative dose of systemic corticosteroids, mg Ventilation (men or women) Neither Invasive Noninvasive Length of antibiotic treatment, mean (SD), d Combined with antifungal agents Length of hospitalization, mean (SD), d
(45.56) (66.85) (27.26) (13.43) (19.07) (9.52) (0.77) (11.76) (0.79) (0.32) (9.52)
(60.28) (69.86) (33.14) (15.70) (19.19) (9.53) (0.69) (11.35) (0.69) (0.62) (9.53)
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma; FEV1, forced expiratory volume in 1 second; FRC, functional residual capacity; FVC, forced vital capacity; MMEF, maximum midexpiratory flow; PEF, peak expiratory flow; RV, residual volume; TLC, total lung capacity; VC, vital capacity.
increased serum IgE level. However, no difference was found in serum total IgE level between the 2 groups (172.94 vs 331.00 IU/mL, P ¼ .37). Regarding the serum specific IgE level, patients with COPD-BA were more likely to receive this test (21.74% vs 63.33%, P < .001), and more than half of them had positive results (57.89% vs 42.11%, P ¼ .004). Other Histories Compared with patients with pure COPD, patients with COPDBA were more inclined to have an allergic history (57.78% vs 35.87%, P ¼ .003) or a positive family history of asthma (15.56% vs 5.54%, P ¼ .03). Most of the patients had smoking history, and 17 of 66 patients with pure COPD and 25 of 71 patients with COPD-BA were current smokers. No differences in smoking history were observed (Table 4). Inpatient Treatment During Exacerbation When hospitalized, more patients with COPD-BA tended to be treated with systemic corticosteroids (41.11% vs 22.83%, P ¼ .008). No difference was found in other inpatient treatments between COPD subgroups (Table 5). Logistic Regression Model A logistic regression analysis examined the possible predictors for the presence of asthma in patients with COPD, including allergic factors, sex, family history, severe exacerbation, age, pack-years of smoking, and body mass index. Allergic factors included allergic history, the total serum IgE level higher than 165 IU/mLm or a positive serum specific IgE test result. In the analysis, allergic factors were associated with a 4-fold increase in the risk of
Table 4 Other Histories of Patients With COPD Only or COPD-BAa History Allergic history Family history of asthma History of occupational exposure Smoking history Pack-years, mean (SD)
COPD only (n ¼ 92)
COPD-BA (n ¼ 90)
33 (35.87) 5 (5.43) 16 (17.39)
52 (57.78) 14 (15.56) 13 (14.44)
66 (71.74) 28.52 (28.45)
71 (78.89) 34.41 (36.10)
P value .003 .03 .59 .26 .22
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
COPD only (n ¼ 92) 21 (22.83) 183.43 (100.22)
74 2 16 13.65
(80.43) (2.17) (17.40) (13.39)
26 (28.26) 10.89 (9.87)
COPD-BA (n ¼ 90) 37 (41.11) 216.27 (158.17)
80 1 9 12.33
P value
.008 .40
(88.89) (1.11) (10) (10.80)
.29
22 (24.44) 10.10 (6.03)
.56 .52
.47
Abbreviations: COPD, chronic obstructive pulmonary disease; COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
diagnosis of COPD-BA (odds ratio, 4.477). Male sex was a protective factor associated with the presence of asthmatic characteristics in patients with COPD (odds ratio, 0.382) (Table 6). Subgroup Analysis for COPD-BA On the basis of allergic factors, patients with COPD-BA were divided into 2 subgroups. No differences in sex, age, height, body weight, and body mass index were observed. However, patients with COPD-BA and allergic factors were more likely to be treated with systemic corticosteroids during exacerbation (P ¼ .04). No difference was found in other inpatient treatments between those 2 subgroups (Table 7). Discussion Clinical Features of COPD-BA The prevalence of COPD-BA observed in our study (49.45%) was slightly higher than in previous studies, which reported an estimated prevalence of 15% to 20%.2 This finding is possibly because patients with COPD-BA usually experience more severe respiratory exacerbations,3 which in return leads to a higher amount of them hospitalized. Meanwhile, most of the patients in our study had endstage COPD and required hospitalization. Even though different prevalence was reported, it is accepted that there is a high prevalence of COPD-BA in patients with COPD admitted to the hospital. In addition, we found that patients with COPD-BA have distinct characteristics compared with patients with pure COPD. Typical symptoms of recurrent cough, sputum production, and shortness of breath did not have the sensitivity or specificity to distinguish these 2 subgroups. However, patients with COPD-BA at onset of recurrent cough and sputum production were a mean of 10 years younger than those with pure COPD. In addition, those patients were more likely to be female and experienced more severe respiratory exacerbations despite being younger. During acute exacerbation, rhonchus was more likely to be heard on physical examination. As a chronic airway disease, spirometry is crucial for patients with COPD-BA. In our study, COPD-BA was characterized by Table 6 Logistic Regression for Patients With Asthma Among Patients With COPD Variable
OR (95% CI)
P value
Allergic factors Male
4.477 (2.032e9.866) 0.382 (0.174e0.835)
<.001 .02
Abbreviations: CI, confidence interval; COPD, chronic obstructive pulmonary disease; OR, odds ratio.
J.-b. Liang et al. / Ann Allergy Asthma Immunol 118 (2017) 564e569 Table 7 Subgroup Analysis for COPD-BAa Variable
With allergic factors (n ¼ 68)
Without allergic factors (n ¼ 22)
P Value
Female sex Age, mean (SD), y Height, mean (SD), cm Body weight, mean (SD), kg BMI, mean (SD) Systemic corticosteroids received (men or women) Cumulative dose of systemic corticosteroids, mean (SD), mg Ventilation (men or women) Neither Invasive Noninvasive Length of antibiotic treatment, mean (SD), d Combined with antifungal agents Length of hospitalization, mean (SD), d
33 72.47 166.16 64.61 23.33 32
11 73.36 163.75 60.81 22.63 52
(50.00) (10.87) (5.81) (10.57) (3.43) (2.73)
.90 .70 .27 .28 .51 .04
153.60 (49.85)
.35
(91.18) (1.47) (7.35) (10.57)
18 (81.82) 0 (0.00) 4 (18.18) 13.82 (11.62)
.30
16 (23.53) 9.78 (5.69)
6 (27.27) 11.09 (7.03)
.72 .43
(48.53) (8.88) (8.16) (12.68) (3.81) (47.06)
226.06 (167.34)
62 1 5 11.85
.46
Abbreviations: BMI, body mass index (calculated as weight in kilograms divided by the square of height in meters); COPD-BA, chronic obstructive pulmonary disease overlapped with bronchial asthma. a Data are presented as number (percentage) of patients unless otherwise indicated.
persistent airflow limitation, which was similar to that of patients with COPD alone. Therefore, it would be rather limiting to define patients with COPD-BA based on only FEV1 or bronchodilator response. This is consistent with the findings of the previous studies that found that spirometry confirms chronic airflow limitation but is of more limited value in distinguishing between COPD and ACOS.2 Furthermore, a large number of patients with COPD-BA had complications, although no difference existed between the COPD subgroups. The incidence of spontaneous pneumothorax especially appeared high in both groups. The possible explanations for this are as follows. First, COPD becomes the leading cause of secondary spontaneous pneumothorax for its emphysematous bullae and hyperinflated lungs.11 Second, most patients in our study were already in the end stage of COPD, accounting for 66.67% of all patients with COPD-BA and 71.74% of all patients with COPD. Therefore, they were more likely to have spontaneous pneumothorax. Factors That Influence Disease Development and Progression Most of the evidence concerning risk factors for COPD-BA comes from cross-sectional epidemiologic studies that identify associations rather than cause-and-effect relationships. As far as we known, no longitudinal studies of COPD-BA have been performed until now. Thus, current understanding of risk factors for COPD-BA is still incomplete in many respects. Our study found that patients with COPD-BA were more inclined to have a positive family history of asthma, indicating genetics may contribute to the development of COPD-BA. Previous studies also indicated the same result, reporting that the gene encoding matrix metalloproteinase 12 is related to children with asthma and smokers with COPD.12 In addition, age may be a powerful factor that contributes to the manifestation of COPD-BA. Our findings are supplemental to the results of previous studies, suggesting that patients with COPD-BA tend to be younger than patients with pure COPD and the prevalence of overlap syndrome increases from mid to later life progressively, especially in those older than 60 years.13 Other studies have found that elderly patients with asthma have more features of fixed obstruction than their younger counterparts.14 Their asthma may manifest itself as chronic persistent airflow obstruction mimicking COPD.15 However, it is unclear how aging reflects the manifestations, whether by the sum of cumulative exposures of
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pathogenic factors throughout life, the deterioration of lung function naturally with aging, or other unknown factors. Asthma may be a risk factor for the development of COPD-BA, although the evidence is not conclusive. In a report from a longitudinal cohort study of the Tucson Epidemiological Study of Airway Obstructive Disease, compared with individuals without asthma, those with active asthma had a 10 times higher risk of acquiring symptoms of chronic bronchitis, a 17 times higher risk of receiving a diagnosis of emphysema, and a 12.5 times higher risk of fulfilling COPD criteria, even after adjusting for smoking history and other potential confounders.16 Likewise, Lange et al17 found a significantly greater annual rate of decline in FEV1 in both men and women with asthma, independent of smoking, compared with nonasthmatic controls. Those studies found that patients with asthma have a higher risk of acquiring COPD or COPD-like symptoms that develop into COPD-BA than those without asthma. Finally, this study concentrated on the potential association between COPD-BA and allergy especially. A previous study found that a positive skin test result was revealed in 37% of patients with asthma vs 8.3% of patients with COPD, whereas patients with asthma also had higher serum total IgE levels compared with patients with COPD.18 Scichilone et al19 reported an increased incidence of allergic history in patients with asthma 65 years or older. Thus, we selected the allergic history, the specific IgE test, and the total serum IgE level as parameters to assess the possible effects of allergy to BA-COPD. Our study found that some of the patients with COPD-BA had a higher level of IgE in serum, although no difference was found between the 2 groups within limited sampling size. Considering the specific IgE test, patients with COPD-BA were more likely to receive this test. Meanwhile, more than half of them had positive results. Therefore, we used allergic history, a total serum IgE level higher than 165 IU/mL, or a positive serum specific IgE test result to try to confirm that allergen exposure plays an important role in the development of BA-COPD. Ultimately, we additionally found a greater portion of patients with COPD-BA had allergic factors. These results suggest that allergic factors might be specific for COPD-BA. This conclusion is supported by our logistic regression analysis for clinical predictors of the diagnosis of COPD-BA in which we found that patients with COPD with allergic factors were 4 times as likely to have asthma compared with the other group. In addition, Lee et al20 found that total IgE level was significantly increased in patients with COPD-BA compared with the pure asthma group and concluded that more severe degree of allergy in patients with asthma may lead to the development of mixed phenotype.20 On the basis of these findings, we conclude that allergy may contribute to the overlap phenotype in chronic airway disease. The mechanisms through which allergy may affect patients with COPD could include airway inflammation. A study comparing inflammatory markers in allergic vs nonallergic patients with COPD found a higher serum level of IL-8 in patients with COPD who were allergic to mites, indicating that IL-8erelated airway inflammation in COPD may be up-regulated by allergy.21 Despite the possible role that the presence of allergy might play in COPD, the precise mechanisms still need further research. In conclusion, the mechanisms behind COPD-BA involve a geneenvironment interaction or even more complex ways. Deeper understanding of the associations and interactions among risk factors requires further investigation. Individualized Treatment Approach for COPD-BA During Exacerbation Currently, there are no randomized clinical trial data to help guide the therapeutic interventions in those overlap populations. On the basis of our study, we recommend comprehensive therapies,
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including antibiotics, corticosteroids, and bronchodilators, during hospitalization. Our study suggests that the major cause of acute exacerbation was infection and the pathogens were mainly bacterium and atypical pathogens, although a few patients were infected by fungus. Therefore, it is important to determine the basis of the pathogen in patients with COPD-BA during hospitalization and to treat promptly with effective antibiotics. The course of antibiotic treatment for COPD-BA was similar to that for pure COPD. Although the Global Initiative for Chronic Obstructive Lung Disease (GOLD) indicates that patients with COPD could benefit from systemic corticosteroids during exacerbation,2 this therapy remains controversial. Our study focused on the use of systemic corticosteroids during hospitalization, indicating that patients with COPD-BA were more likely to receive corticosteroids systemically. Thus, these patients may require individualized systemic corticosteroids therapy. In addition, we performed a subgroup analysis based on allergic factor. We additionally found that a greater portion of patients with COPD-BA with allergic factors were treated with corticosteroids systemically. These findings would suggest that allergic factors may also be a prior predictor for using corticosteroids systemically within COPD-BA during hospitalization. However, further study should be implemented for the proper cumulative dose of systemic corticosteroids by longitudinal studies. Bronchodilators are widely used in patients with COPD-BA during hospitalization. GOLD recommends treatment with an inhaled corticosteroid and bronchodilator combination, avoiding long-acting b2-agonist monotherapy.2 Smoking cessation, treatment of comorbidities, oxygen supplementation, pulmonary rehabilitation, and vaccines are reasonable interventions. Adjunctive treatments, such as leukotriene receptor antagonists, 5-lipoxygenase inhibitors, methylxanthines, or omalizumab, deserve further study. A Descriptive Definition Based on Our Research The definition of ACOS was introduced by the science committees of GINA and GOLD and was documented in detail in Global Strategy for Asthma Management and Prevention in 2014.22 ACOS is characterized by persistent airflow limitation, with several features usually associated with asthma and several features usually associated with COPD.22 In the joint GINA and GOLD publication, 11 clinical features that best distinguished between asthma and COPD were proposed, such as age at onset of the disease, pattern of symptoms, lung function, history of asthma or COPD, family history of asthma or allergy, improvement after treatment with a bronchodilator or inhaled corticosteroid, and so on.22 If there are similar numbers of features listed for asthma and COPD, the diagnosis of ACOS should be considered.22 ACOS is therefore identified by the features that it shares with asthma and COPD. However, it is a consensus-based descriptive definition, so these criteria are neither specific nor sensitive. ACOS is a heterogeneous syndrome; for the deep understanding, a more detailed classification of patients with overlapping features of asthma and COPD is needed. However, there have been many different criteria of ACOS and classifications of subgroups, which makes it difficult for researchers to design clinical studies in welldefined patients and in turn influences the results. To avoid these problems, our study focused on COPD-BA. This group of patients not only have specific criteria but are explicit as a subgroup of ACOS. Van den Berge and Aalbers23 suggested 2 clinical phenotypes for ACOS: asthma-ACOS and COPD-ACOS. Asthma-ACOS refers to never-, ex-, or current smokers with a history of asthma who have incompletely reversible airflow obstruction. Meanwhile COPDACOS refers to smokers or ex-smokers with COPD according to GOLD criteria who have increased bronchodilator reversibility or
bronchial hyperresponsiveness.23 Thus, patients with COPD-BA in our study can be referred as having the asthma-ACOS subphenotype. Our study is consistent with the definition put forward by GINA that ACOS is a persistent airflow limitation disease, but several features, such as respiratory symptoms, lung function, and time course, are of limited value. Although our study found no difference in these features between 2 groups, several features, such as age at onset, history, and exacerbations, are important for COPD-BA. Because COPD-BA is not like COPD, patients with COPD-BA usually experience unique clinical features in these aspects. Therefore, we recommend allergic factors as a new feature for COPD-BA. Allergic factors were associated with the presence of asthmatic characteristics in our patients with COPD. Our research did not involve airway inflammation or chest radiography. COPD-BA is characterized by persistent airflow limitation, and patients with COPD-BA satisfy the criteria of COPD and asthma previously or simultaneously with or without allergic factors, such as allergic history, high total IgE level, or positive serum specific IgE test result. These patients are more likely to be female, usually younger, experience more severe respiratory exacerbations, and are more inclined to have a positive family history of asthma. One limitation of this retrospective study is that eosinophil counts, allergy skin test results, and IgE levels were available for less than 50% of the patients. Because of missing clinical data, bias might have influenced the significance of our findings. Another limitation is that a1-antitrypsin deficiency (AATD) was not screened. Comparison of AATD might have assisted in comparing the pathologic differences in these 2 groups. However, only approximately 2.5 million of 1,400 million people were estimated to be diagnosed with AATD in Far East Asia in 200524; therefore, AATD was not routinely evaluated in our patients with COPD. In summary, on the basis of mainly medical history, COPD-BA is a chronic airway disease. Just like COPD, COPD-BA is characterized by persistent airflow limitation without much variability. Several features are important to COPD-BA, such as age at onset of disease, exacerbations, family history, and allergic factors. Finally, patients with COPD-BA could commence comprehensive therapies, including antibiotics, corticosteroids, and bronchodilators during hospitalization, and patients with COPD-BA may benefit from systemic corticosteroids.
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