The association of delta neutrophil index with the prognosis of acute exacerbation of chronic obstructive pulmonary disease

We conducted a retrospective study of the patients who admitted with AECOPD at Yonsei University Wonju Severance Tertiary Hospital from January 2012 to December 2016 (Fig. 1). Patients were 45 years old or older and had a smoking history of ≥10 pack-years.

The diagnostic criteria for COPD were as follows according to the GOLD guideline; a post-bronchodilator FEV₁/forced vital capacity (FVC) < 70% confirms airflow limitation that is not fully reversible [1, 3]. We reviewed demographic data and comorbidities including diabetes mellitus, cardiac, liver and renal diseases and also investigated the treatments for COPD including long-acting muscarinic antagonists, beta₂ agonist, and inhaled corticosteroids. We evaluated lung function via using the Korean language version of the COPD assessment test (CAT) questionnaire [17], the modified Medical Research Council (mMRC) dyspnea scale, and most recent spirometry performed before admission, respectively. The following patients were excluded; valvular heart disease, myocardial infarction, cerebral infarction or hemorrhage, asthma, untreated malignancy, and renal disease on hemodialysis.

AECOPD can be diagnosed when a patient with COPD experiences a sustained (24–48 h) increase in cough, sputum production, and/or dyspnea [18]. The admission criteria of AECOPD were as follows; 1) failed response to initial medical management, 2) severe symptoms (resting dyspnea, respiratory rates ≥ 30 breaths/min, oxygen saturation ≤ 90%, confusion, or drowsiness), 3) new onset of cyanosis, peripheral edema, or 4) respiratory failure using respiratory muscles or accompanying mental changes [19].

CAP was diagnosed when the following conditions were met; 1) cough and at least one other lower respiratory tract symptom; 2) new focal chest signs on examination; 3) at least one systemic feature of sweating, fevers, aches and and/or temperature ≥ 38 °C) [20]. The causative organism was recognized when detected in sputum or bronchoalveolar lavage fluid and/or blood. Sputum specimens were recognized when > 25 leukocytes and < 10 epithelial cells per high power field [21]. We performed peripheral blood sampling within 1 hour of admission to verify white blood cell (WBC) counts, delta neutrophil index (DNI), hemoglobin, high sensitive C-reactive protein (hs-CRP) and procalcitonin. Oxygen saturation, partial pressure of oxygen (PaO2) and carbon dioxide (PaCO2) were measured on day 1.

We treated enrolled patients with nebulized salbutamol, ipratropium bromide, Budesonide and intravenous prednisolone in a dosage of 30 to 40 mg daily, according to GOLD guidelines [1]. Systemic corticosteroid was given during 10–14 days, and switched to an oral prednisolone on day 4–7. Antibiotics were used in patients with CAP and adjusted according to antimicrobial susceptibilities on sputum or blood culture analysis. Antibiotic therapy was initiated in basic accordance with the ATS/IDSA guidelines [22].

We investigated the mortality rate of AECOPD patients with or without CAP who were readmitted within 6 months after discharge from the hospital. We analyzed cumulative survival rate according to serum DNI level (< 3.5 vs ≥ 3.5%) and readmission duration (≤ 30 vs >  30 days) in AECOPD patients.

SPSS 24.0 (SPSS Inc.; Chicago, IL, USA) were used for statistical analysis. Chi-square or Fisher’s exact test were used for categorical variables and Student t or Mann-Whitney U test used for continuous variables. We used Cox proportional hazards regression model to estimate the survival rate during 6 months between two groups. Relative risks were expressed as hazard ratio (HR) and 95% confidence interval (CI). Cumulative survival rates were expressed using a Kaplan–Meier approach and the log-rank test. Univariate and multivariate analysis was performed to evaluate prognostic factors associated with mortality of the patients. The receiver operating characteristic (ROC) curve was utilized to assess the accuracy of different indicators for mortality of AECOPD. We compared the area under the ROC curve (AUC) according to 1) readmission duration, 2) DNI, 3) readmission duration + DNI, and 4) readmission duration + CAP. The cut-off value for DNI was set at 3.5%. Pearson’s correlation coefficients (r value) test was used for evaluating the relationship between two variables. Descriptive statistics were expressed as mean value ± standard deviation for continuous data and number (%) for categorical data. P-value less than 0.05 were considered to be statistically significant.

During study period, 827 severe AECOPD patients were admitted to a respiratory center, and 726 patients were eligible for inclusion criteria. Eighty-five patients (47 patients with CAP and 38 patients without CAP) were dropped out because were referred to other hospitals. Finally, 140 AECOPD patients with CAP (19 patients who were readmitted within 30 days and 121 patients who were readmitted after 30 days) and 174 AECOPD patients without CAP (22 patients who were readmitted within 30 days and 152 patients who were readmitted after 30 days) were enrolled during 6 months, respectively (Fig. 1). The mean age was 72.2 ± 9.4 year-old, and 240 patients (76.4%) were male. The demographic characteristics of AECOPD patients who were readmitted between ≤30 days and > 30 days are shown in Table 1. Underlying comorbid conditions except hypertension (P = 0.042), the regular inhaled medications and spirometric results before an admission were not significantly different among four groups (Table 1).

When we investigated the mortality rate of AECOPD patients readmitted between ≤30 days and > 30 days, the mortality rate during 6 months was the highest in AECOPD with CAP group who were readmitted ≤30 days (78.9% vs. 15.7% vs. 40.9% vs. 9.2%, P <  0.001) (Table 1). The causes of mortality were as follows; 30 patients with AECOPD (5 patients with CAP readmitted ≤30 days vs. 13 with CAP readmitted > 30 days vs. 3 patients without CAP readmitted ≤30 days vs. 9 AECOPD without CAP readmitted > 30 days), 18 pneumonias (10 vs. 3 vs. 2 vs. 3), 7 sepsis (0 vs. 3 vs. 1 vs. 3) and 2 pneumothoraxes (0 vs. 0 vs. 2 vs. 2).

At the time of admission, oxygen saturation, PaO₂, PaCO₂, hemoglobin, and procalcitonin were not significantly different, but WBC count (P <  0.001), serum DNI (P <  0.001) and hs-CRP levels (P <  0.001) showed significant differences among four groups (Table 2). Mean DNI values were 9.5 ± 9.2, 5.0 ± 4.6, 2.9 ± 2.6, and 1.7 ± 2.6% respectively, and were significantly higher in AECOPD with CAP (readmitted ≤30 days) than without CAP (Fig. 2).

We identified causative organisms in 72.9% (102 out of 140) of AECOPD with CAP. Streptococcus pneumoniae was the most frequently isolated pathogen (38.6%); Staphylococcus aureus (13.6%), Pseudomonas aeruginosa (12.1%), Klebsiella pneumoniae (5.0%) and other pathogens (3.6%) were isolated, respectively (Table 2).

When we compared the cumulative survival rate of AECOPD patients according to readmission duration (≤ 30 vs > 30 days), AECOPD patients with readmission ≤30 days and CAP showed the lowest cumulative survival rate compared to other groups (P <  0.001) (Fig. 3a). When we compared the cumulative survival rate of AECOPD patients according to readmission duration (≤ 30 vs > 30 days) and DNI level (< 3.5 vs ≥ 3.5%), AECOPD patients with readmission ≤30 days and DNI ≥ 3.5% showed the lowest cumulative survival rate compared to other groups (P <  0.001) (Fig. 3b). Thus, the cumulative survival rate was lower as a serum DNI level (≥ 3.5%) was higher and readmission duration (≤ 30 days) was shorter.

To identify risk factors associated with the mortality of AECOPD patients who were readmitted, multivariate logistic regression analysis was performed using significant variables with P value < 0.05 by univariate analysis. Multivariate analysis using factors that were found to be significant by univariate analysis revealed that readmission duration ≤30 days (HR 7.879, 95% CI 4.554–13.632, P <  0.001); and serum DNI level (HR 1.086, 95% CI 1.043–1.131, P <  0.001) were significantly associated with the mortality of AECOPD patients during 6 months (Table 3). Pearson’s correlation coefficient (r value) of DNI (%) with hs-CRP was 0.433 (P < 0.001), DNI with PCT: 0.419 (P < 0.001), % DNI with PCO₂: - 0.062 (P = 0.276), respectively.

The AUC for readmission duration (≤ 30 days) + DNI level (≥ 3.5%) was 0.753 (95% CI 0.676–0.830, P < 0.001) with a sensitivity of 73.7% and a specificity of 67.3%; AUC for readmission duration + CAP 0.678 (95% CI 0.597–0.758), readmission duration 0.677 (95% CI 0.590–0.765), and DNI 0.654 (95% 0.573–0.735), respectively (Fig. 4).