Predictors of exacerbation frequency in chronic obstructive pulmonary disease

A total of 227 COPD patients were recruited consecutively between 1 January 2000 and 31 December 2006 for inclusion in a study of exacerbation frequency ranging from the inclusion start date to 31 December 2011 at the Outpatient Department of Respiration of the Shougang Hospital of Beijing University (Beijing, China). The study protocol was approved by the Medical ethics committee of Shou-Gang Hospital Affiliated to Peking University. All patients provided written informed consent for participation.

Inclusion criteria included a COPD diagnosis, defined as a forced expiratory volume in 1 second (FEV₁) of < 80% of the predicted value after bronchodilator use and a ratio of FEV₁ to forced vital capacity (FVC) of < 70% after bronchodilator use. We recruited participants between the ages of 45 and 85 years who were in a stable condition, having experienced no exacerbations in the month preceding enrollment, and who could provide medical records indicating the number of times in the preceding year they had been hospitalizations as a result of COPD. Patients who did not consent to long-term follow-up or were diagnosed with another condition that limited life expectancy were excluded from the analysis.

We defined an exacerbation as sustained worsening of respiratory symptoms, such as breathlessness or increased sputum volume or purulence beyond the basal variability and that required treatment with oral corticosteroids or antibiotics [11, 12]. In this study we recorded only those exacerbations resulting in hospitalization, and exacerbations separated by ≥ 14 days were considered distinct events [13‐16]. Reported exacerbations were recorded for the year preceding enrollment, and annually thereafter until the end of the study or death. Patients were grouped by the median annual exacerbation frequency into those experiencing infrequent exacerbations (Group 1: less than one exacerbation annually) and frequent exacerbations (Group 2: one or more exacerbation annually). Patients experiencing frequent exacerbations were further divided into those experiencing moderately frequent exacerbations (Group 2A: fewer than two exacerbations per year) and severely frequent exacerbations (Group 2B: two or more exacerbations per year) (Figure 1).

During initial clinical examinations, patient demographics were recorded, including sex, age, height, weight, body mass index (BMI), and smoking history. Clinical characteristics were recorded for each patient, including lung function, drug history (including bronchial-dilating agents, glucocorticoids), comorbidities, number of hospitalization as a result of COPD exacerbations in the year preceding enrollment, and every year throughout the follow-up period, and use of long-term oxygen therapy (LTOT), home mechanical ventilation (HMV) used for chronic hypercapnia of COPD, and non-invasive positive pressure ventilation (NPPV, used for exacerbations accompanied by acute respiratory failure) during hospitalization. Follow-up was conducted by telephone interview and review of appropriate medical records every 6 months until the end of the study. Quint et al. have previously determined that patient recall was a sufficiently accurate tool for stratification of patients into those experiencing frequent and infrequent exacerbations [16].

Lung function was assessed using a volumetric storage spirometer (HP 47-804; Hewlett-Packard, Waltham, MA, USA) to measure arterial carbon dioxide tension (PaCO₂); arterial oxygen tension (PaO₂); forced expiratory volume in one second (FEV₁); and forced vital capacity (FVC) at baseline (year 0) and thereafter at 2-year intervals for the first 4 years. GOLD grades were calculated according to the Global Initiative for Chronic Obstructive Lung Disease.

At the end of follow-up, the Charlson comorbidity index was computed and analyzed. The Charlson Index assigns a score to each underlying condition proportional to its corresponding disease-related risk of death [17]. The arithmetical sum of scores for individual comorbidities was used as an index for each patient.

A total of 227 patients were enrolled. The mean age of participants was 71.7 ± 6.8 years, and ranged from 45 to 85 years. Of these participants, 70% were male. Patients were grouped by the median annual exacerbation frequency. A total of 51.1% (116/227) of the patients experienced infrequent exacerbations (less than one exacerbation annually) and were assigned to Group 1, and 48.9% (111/227) experienced frequent exacerbations (one or more exacerbations annually) were assigned to Group 2. Patients experiencing frequent exacerbations were further subdivided by exacerbation frequency. Of these, 28.2% (64/227) experienced moderately frequent exacerbations (fewer than two exacerbations per year) and were assigned to Group 2A. Another 20.1% (47/227) experienced severely frequent exacerbations (two or more exacerbations per year) and were assigned to Group 2B (Table 1).

The mean follow-up time was 5.15 years per patient. The number of exacerbations in the year before recruitment into this study, FEV₁, FVC, PaCO₂, cor pulmonale, comorbidity, and the Charlson Index score of patients varied significantly between groups (P < 0.05, Table 1).

More frequent exacerbations were significantly associated with lower FEV₁ and FVC, a higher frequency of exacerbation in the preceding year, higher PaCO₂, higher incidence of cor pulmonale, and a higher rate of comorbidities (P < 0.05, Table 1). The most common comorbidity was cardiovascular disease, though cerebrovascular disease, diabetes mellitus, and neoplasm were also observed.

Significantly higher Charlson Index scores were observed in Group 2B than in both Group 1 and Group 2A (P = 0.014, Figure 2). There was no significant difference in GOLD grades between the three groups (P > 0.05, Figure 3). All GOLD grades were represented in each group, with the exception that Group 2b contained no patients with a Gold grade of 1. For GOLD grades 1 to 3, the number of exacerbations increased significantly in all three groups (P < 0.05, Figure 3). Notably, patients with a GOLD grade of 4 experienced a significantly lower frequency of exacerbations than patients with a GOLD grade of 3 (P < 0.05, Figure 3).

The proportion of comorbidities in patients assigned a GOLD grade of 4 was significantly lower that of patients with GOLD grades 1, 2 and 3 (63.8% versus 100%, 82.8% and 80.7%, respectively, all P < 0.05). Increased exacerbation frequency was significantly associated with higher rates of comorbidities (P < 0.05, Table 2).

The rate of NPPV use by GOLD 4 patients (40.8%) was significantly higher than the rate of NPPV use by GOLD 3 (28.4%) or GOLD 2 (10.3%) patients (all P < 0.05). NPPV use in Group 2A (35.9%) and Group 2B (51.1%) was significantly higher than NPPV use in Group 1 (16.4%, OR 2.864, 95% CI 1.410 to 5.819, and OR 5.327, 95% CI 2.507 to 11.326, respectively, Table 2). Increased exacerbation frequency was significantly associated with higher levels of NPPV use (P < 0.05, Table 2).

Logistic analysis revealed that increased exacerbation frequency was significantly associated with worsening lung function, measured by post-bronchodilator FEV₁ (P < 0.05, Table 2). Over the 4 years of follow-up, the FEV₁ of patients in Group 2A and 2B declined faster than in Group 1, with the most notable decline occurring in the last 2 years (Figure 4A). Patients in Group 2B experienced consistent decline over the 4 years, compared with Group 2A patients, who experienced more rapid decline in the first 2 years of the study (Figure 4B), suggesting discreet stages of disease progression. Overall, FEV₁ was reduced in Groups 1, 2A, and 2B by an average of 38 mL, 46 mL, and 44.6 mL per year respectively, representing no significant variation between groups (P > 0.05).

A history of previous exacerbations was also significantly associated with increased exacerbation frequency (P < 0.05, Table 2).

A total of 135 (59.5%) patients died during the follow-up window, and 2 (0.01%) patients were lost to follow-up. By the endpoint of the study, the overall mortality was 50.0%, in Group 1, 67.2%, in Group 2A, and 72.3% in Group 2B, but did not differ significantly between the three groups. The cumulative survival time of Group 1 was significantly longer than that of Group 2A and 2B, but did not differ significantly between Group 2A and 2B (Figure 5).

Deaths were due to respiratory failure (51.1%), comorbidities (46.7%), and unknown factors (2.2%). Of those deaths related to comorbidities (63 in total), 38.1% were related to infections, 25.4% were related to neoplasms, including lung cancer (62.5%), cerebrovascular disease (15.9%), cardiovascular disease (14.3%), and pulmonary embolism (6.3%).

Patients in Group 2B and 2A had mortality rates approximately 2.6 fold and 2.0 fold greater, respectively, than patients in Group 1 (95% CI 1.253 to 5.457; 95% CI 1.084 to 3.868). Significantly different 5- and 10-year cumulative survival rates were observed in Groups 1 (58% and 41%), 2A (58% and 41%) and 2B (29% and 23%) (P = 0.003, Table 1). More patients in Group 1 died as a result of a comorbidity than respiratory failure (51.7% versus 39.7%), whereas the majority of patients in group 2A died of respiratory failure (60.5% versus 34.9%). Patients in Group 2B died of respiratory failure and comorbidities at a similar rate (50.0% versus 44.1%).

COX analysis by age, sex, smoking, BMI, PH, PaCO₂, PaO₂, FEV₁, FEV₁%, FVC, cor pulmonale, comorbidity, total comorbidities, Charlson Index, NPPV, exacerbations in the year preceding the study and exacerbation frequency preceding enrollment provided verification that higher rates of exacerbation frequency in the past are an independent prognostic factor of exacerbation frequency in the future (Table 3). In addition to variable exacerbation frequency, this analysis also indicated that FEV₁, age, cor pulmonale, BMI, Charlson Index, total comorbidities, and NPPV use were also independent prognostic factors for exacerbation frequency (Table 3). However, as NPPV is administrated during the hospitalization for acute exacerbation of chronic obstructive pulmonary disease with acute respiratory failure, increased frequency of acute exacerbation resulted in increased administration of NPPV, and NPPV is not a predictor of acute exacerbation frequency.