Purpose Frequent exacerbators are a specific phenotype of chronic obstructive pulmonary disease (COPD), whose clinical characteristics and prognostic biomarkers during severe acute exacerbation (AECOPD) have not yet been fully elucidated. The aim of this study was to investigate the clinical features of severe AECOPD in frequent exacerbators and explore the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for outcome in this phenotype during severe exacerbation. Patients and Methods A total of 604 patients with severe AECOPD were retrospectively included in the study. Subjects were defined as frequent exacerbators if they experienced two or more exacerbations in the past year. Clinical characteristics and worse outcome (ICU admission, or invasive ventilation, or in-hospital mortality) during severe AECOPD were compared between frequent exacerbators and non-frequent ones. Furthermore, the relationship between NLR and worse outcome in frequent exacerbators was analyzed using logistic regression and receiver operating characteristic (ROC). Results Among 604 patients with severe AECOPD, 282 (46.69%) were frequent exacerbators and 322 (53.31%) were non-frequent exacerbators. Compared with the non-frequent ones, frequent exacerbators presented higher levels of NLR (5.93 [IQR, 3.40–9.28] vs 4.41 [IQR, 2.74–6.80]; p <0.001), and more worse outcome incidence (58 [20.57%] vs 38 [11.80%]; p =0.003). Moreover, among the frequent exacerbators, NLR levels in the patients with worse outcome were much higher than in those without worse outcome (11.09 [IQR, 7.74–16.49] vs 5.28 [IQR, 2.93–7.93]; p <0.001). Increased NLR was significantly associated with a higher risk of worse outcome in frequent exacerbators (OR, 1.43; 95% CI, 1.28–1.64; p <0.001). Furthermore, ROC analysis revealed that a cut-off value of 10.23, NLR could predict worse outcome of severe AECOPD in frequent exacerbators (sensitivity 62.1%, specificity 92.0%, AUC 0.833). Conclusion Frequent exacerbators exhibited an increased level of NLR and a higher proportion of worse outcome during severe AECOPD. NLR is expected to be a promising predictive biomarker for the prognosis of severe AECOPD in frequent exacerbators.

Patients with chronic obstructive pulmonary disease (COPD) respond poorly to corticosteroids. Histone deacetylase-2 (HDAC-2) plays a pivotal role in many cases of steroid insensitivity. The main aim of this study was to restore the smoking-induced reduction in corticosteroid sensitivity by increasing HDAC-2 activity using low-dose theophylline. Rats were exposed to cigarette smoke (CS) and treated with budesonide and two doses of theophylline. Besides the pathologic examination and cell counting in the bronchoalveolar lavage fluid (BALF), the expression of HDAC-2 and CXC chemokine ligand-8 (CXCL-8) were measured. Airway inflammation induced by CS was demonstrated by pathologic changes of lung tissue and increased level of CXCL-8. CS exposure also markedly decreased HDAC-2 expression. Moreover, a negative correlation was found between HDAC-2 activity and a lung destruction index. The index was restored to control levels with inhaled corticosteroid treatment in combination with a low, not a high, dose of theophylline. These results indicate that low-dose theophylline might provide protection from smoke damage and improve the anti-inflammatory effects of steroids by increasing HDAC-2 activity.

Frequent exacerbators are a specific phenotype of chronic obstructive pulmonary disease (COPD), whose clinical characteristics and prognostic biomarkers during severe acute exacerbation (AECOPD) have not yet been fully elucidated. The aim of this study was to investigate the clinical features of severe AECOPD in frequent exacerbators and explore the predictive value of the neutrophil-to-lymphocyte ratio (NLR) for outcome in this phenotype during severe exacerbation. Patients and Methods: A total of 604 patients with severe AECOPD were retrospectively included in the study. Subjects were defined as frequent exacerbators if they experienced two or more exacerbations in the past year. Clinical characteristics and worse outcome (ICU admission, or invasive ventilation, or in-hospital mortality) during severe AECOPD were compared between frequent exacerbators and non-frequent ones. Furthermore, the relationship between NLR and worse outcome in frequent exacerbators was analyzed using logistic regression and receiver operating characteristic (ROC). Results: Among 604 patients with severe AECOPD, 282 (46.69%) were frequent exacerbators and 322 (53.31%) were non-frequent exacerbators. Compared with the non-frequent ones, frequent exacerbators presented higher levels of NLR (5.93 [IQR,; p<0.001), and more worse outcome incidence (58 [20.57%] vs 38 [11.80%]; p=0.003). Moreover, among the frequent exacerbators, NLR levels in the patients with worse outcome were much higher than in those without worse outcome (11.09 [IQR,]; p<0.001). Increased NLR was significantly associated with a higher risk of worse outcome in frequent exacerbators (OR, 1.43; 95% CI, p<0.001). Furthermore, ROC analysis revealed that a cut-off value of 10.23, NLR could predict worse outcome of severe AECOPD in frequent exacerbators (sensitivity 62.1%, specificity 92.0%, AUC 0.833). Conclusion:Frequent exacerbators exhibited an increased level of NLR and a higher proportion of worse outcome during severe AECOPD. NLR is expected to be a promising predictive biomarker for the prognosis of severe AECOPD in frequent exacerbators.