Clinical features of Japanese patients with exacerbations of chronic obstructive pulmonary disease

A total of 729 patients with the International Classification of Diseases, 10th Revision, Clinical Modification [ICD-10-CM] code for COPD (J449) in their medical records at the Saga University Hospital between 2009 and 2019 were retrospectively reviewed. From among these patients, two expert pulmonary physicians extracted 481 patients with COPD, considering the following definition criteria referring to the previous reports [16‐19]: (1) age > 40 years; (2) forced expiratory volume in 1.0 s (FEV1.0)/forced vital capacity (FVC) ratio < 0.7; (3) smoking index > 10 pack-years; (4) persistent respiratory symptoms such as dyspnea, cough, and sputum; and (5) no medical history or current diagnosis of asthma. A severe exacerbation was defined as any sustained increase in respiratory symptoms compared with the stable phase and need for hospitalization considering symptoms, respiratory condition, and clinical findings with treatment of systemic corticosteroid or antibiotics, alone or combination. The need for hospitalization with an exacerbation was determined by the pulmonary physician. Causes of exacerbations were classified into 3 groups as bacterial infection, viral infection, and others, including unknown, considering respiratory sample cultures, examination of viral antigens for influenza, and radiological findings with physical findings. To standardize exacerbation frequency, the annual exacerbation rate was determined, and the maximum number of severe exacerbations per year from 2009 to 2019 was examined. Additionally, an infrequent exacerbator was defined as a patient whose maximum annual exacerbation rate was 1/year, and a frequent exacerbator was defined as a patient whose maximum annual exacerbation rate was more than 2/year. To assess the correlations between the maximum annual exacerbation rate and clinical factors, patients’ characteristics, COPD assessment test (CAT) score, modified Medical Research Council (mMRC) dyspnea scale, laboratory data, pulmonary function test results, transtricuspid pressure gradient (TRPG) on echocardiography, and treatment regimens were evaluated in the stable phase which was defined as no use of oral corticosteroids or antibiotics, no unscheduled doctor’s visit, or no hospitalization due to exacerbation of COPD in the past 4 weeks. Blood eosinophil was also evaluated in the stable phase according to the previous report [20]. For patients who never experienced exacerbations, the newest data in the medical record were evaluated. A critical exacerbation was defined as one with a fatal outcome. CO₂ retention was defined as CO₂ > 45 mmHg on arterial blood gas analysis. This study was approved by the ethics committee of Saga University Hospital (approval number: 2020-01-R-04, approval date: Mar 30, 2020) and was performed in accordance with the 1964 Declaration of Helsinki.

Hypertension, diabetes mellitus, hyperlipidemia and cardiovascular disease were diagnosed by the physicians. Cardiovascular disease included coronary artery disease, valvular disease, cardiac arrhythmias such as atrial fibrillation, and chronic heart failure diagnosed by echocardiography.

In the present study, 481 patients with COPD were analyzed. To examine the clinical impact of severe exacerbations, the 481 patients were divided into 393 patients who never experienced severe exacerbations and 88 patients who experienced severe exacerbations from 2009 to 2019. There were no significant differences in age, sex, height, and smoking history, but weight and the body mass index were significantly lower in patients with exacerbations than in those without exacerbations (p < 0.01, respectively). As comorbidities, hypertension, diabetes mellitus, and hyperlipidemia were not different in the 2 groups, but cardiovascular disease was significantly more common in patients with exacerbations than in those without exacerbations (30.7% vs 15.4%, p < 0.01). The CAT score and the mMRC dyspnea scale were higher in patients with exacerbations than in those without exacerbations (both p < 0.01). Of the laboratory data, the white blood cell count and blood eosinophil were not different between the 2 groups, but serum albumin was significantly lower in patients with exacerbations than in those without exacerbations (p < 0.01). On pulmonary function testing, VC, FVC, FEV 1.0, FEV1.0/FVC, %FEV1.0, and diffusing capacity of the lung for carbon monoxide (DLco) were significantly lower in patients with severe exacerbations than in those without severe exacerbations (all p < 0.01). TRPG, which is one of the predictors of pulmonary hypertension, was also higher in patients with exacerbations (p < 0.01). As for treatment, long-term oxygen therapy, long acting β₂ adrenergic agonists (LABAs), ICS, and macrolides were used significantly more in patients with exacerbations than in those without exacerbations (all p < 0.01) (Table 1). These data showed that severe exacerbations were closely associated with the physical and clinical characteristics of patients with COPD.

To clarify the impact of exacerbation frequency in patients with COPD, the analysis focused on the 88 patients who experienced exacerbations, and the annual exacerbation rate was extracted for the maximum number of severe exacerbations in 1 year from 2009 to 2019. The 88 patients were divided into those whose annual exacerbation rate was once/year (infrequent exacerbators, 62 patients) and the 26 patients whose annual exacerbation rate was ≥ 2 times/year (frequent exacerbators). The annual exacerbation rate of the frequent exacerbators was 2.6 ± 0.3 (range 2–8 times). The total number of exacerbations from 2009 to 2019 was 65 in infrequent exacerbators and 111 in frequent exacerbators. As the causes of the exacerbations, bacterial infection was the most common, and viral infection and others were uncommon in the present study (Table 2).

To address the clinical impact of exacerbation frequency, clinical characteristics were compared between infrequent exacerbators and frequent exacerbators. BMI was significantly lower in frequent exacerbators than in infrequent exacerbators (p = 0.03). Critical exacerbations with fatal outcomes were significantly more common in frequent exacerbators (p < 0.01). There were no differences in comorbidities and the CAT score in these 2 groups. As for the laboratory data, the percentage of blood eosinophils and the blood eosinophil count were significantly higher in frequent exacerbators than in infrequent exacerbators (p < 0.01, p = 0.03 respectively). The frequency of patients with CO₂ retention (> 45 mmHg) on arterial blood gas analysis was higher in frequent exacerbators (p = 0.05). On pulmonary function test results, %FEV1.0 was significantly lower in frequent exacerbators than in infrequent exacerbators (p < 0.01). TRPG was not different between the 2 groups, and a history of mechanical ventilation use for exacerbations was significantly higher in frequent exacerbators (p < 0.01). As for treatment, the frequencies of the use of long-term oxygen therapy, long-acting muscarinic antagonists (LAMAs), and macrolides was higher in frequent exacerbators than in infrequent exacerbators (p < 0.01, p = 0.02, p < 0.01 respectively), but the use of ICS was not different between the 2 groups (Table 3). We also compared clinical characteristics between COPD patients with frequent exacerbations and those without exacerbations. BMI and pulmonary function testing including VC, FVC, FEV 1.0, FEV1.0/FVC, %FEV1.0 are significantly lower (all p < 0.01) and CAT score, blood eosinophil, TRPG are significantly higher in patients with frequent exacerbations than in those without exacerbations (p < 0.01, p = 0.02, p < 0.01 respectively). As for treatment, long-term oxygen therapy, LAMA, LABA, ICS, and macrolides were used significantly more in patients with frequent exacerbations than in those without exacerbations (all p < 0.01) (Additional file 1: Table E1).

To evaluate the most useful predictor of the frequency of exacerbations in COPD patients, multivariate analysis was performed using variables that were significant in frequent exacerbators compared to infrequent exacerbators, such as the rate of critical exacerbations, percentage of blood eosinophils, %FEV1.0, history of mechanical ventilation use, long-term oxygen therapy, macrolide use, BMI and rate of CO₂ retentions on univariate analysis. Critical exacerbation (odds ratio or β value [95% confidence interval] 6.07 [1.06–36.67], p = 0.04) and mechanical ventilation use (5.49 [1.19–25.19], p = 0.03) were significant as independent predictors, and the percentage of blood eosinophils was the most significant of these variables (1.45 [1.12–1.88], p < 0.01) (Table 4). We also performed multivariate analysis using variables that were significant in patient with frequent exacerbations and in those without exacerbation. Long-term oxygen therapy (37.09 [3.95–348], p < 0.01) and the percentage of blood eosinophil (1.64 [1.12–2.64], p = 0.02) were significant as independent predictors (Additional file 1: Table E2).