Richness of Sputum Microbiome in Acute Exacerbations of Eosinophilic Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease (COPD) is a chronic lung condition characterized by persistent respiratory symptoms and irreversible airflow limitation. Despite similar clinical presentations, COPD is a highly heterogeneous disease, and recent evidence suggests that eosinophils play a significant role in some patients. Eosinophilic COPD is recognized as a distinct phenotype of the disease, with high numbers of eosinophils appearing in up to 28% of cases of acute exacerbations of COPD (AECOPD). Patients with eosinophilic inflammation have fewer allergies but experience more frequent exacerbations. Importantly, eosinophilic COPD responds best to corticosteroid treatments. While inhaled corticosteroids (ICS) can increase the risk of pneumonia in non-eosinophilic COPD, patients with eosinophilic COPD show better improvement in forced expiratory volume in 1 second (FEV1) and shorter hospitalization times after using corticosteroids.
The lung is considered a relatively sterile environment, but with the development of culture-independent techniques for microbe identification and quantification, such as 16S ribosomal RNA (rRNA) high-throughput sequencing, increasing evidence shows that the lungs contain many different microbes. Imbalance in the lung bacterial community, known as “bacterial dysbiosis,” has been associated with an increased risk of exacerbations and accelerated loss of lung function in COPD. Factors such as age, smoking, disease course, drugs, and microanatomy have been associated with changes in the relative abundance and diversity of bacterial communities in the lungs. Recent studies have demonstrated that the lung microbiota differ between eosinophilic and non-eosinophilic patients with AECOPD. Additionally, treatment with ICS has been correlated with lung microbiota composition and enrichment in stable COPD.
This study aimed to investigate the dynamic changes of the airway microbiome in patients with acute exacerbations of eosinophilic COPD. The study also analyzed the levels of inflammatory mediators, including interleukin (IL)-6 and IL-8, in the plasma before and after treatment to determine the effects of treatment. Furthermore, the corticosteroid sensitivity of patients with AECOPD was quantified in vitro using isolated peripheral blood mononuclear cells (PBMCs) to study the degree of IL-8 inhibition produced by increasing concentrations of dexamethasone (Dex). The hypothesis was that differences in the induced sputum microbiota are associated with the amount of blood eosinophils and responsiveness to ICS treatment.
The study enrolled 57 patients with acute exacerbations of COPD from the First Affiliated Hospital of Guangxi Medical University between June 2017 and June 2018. Patients were divided into two groups based on the number of eosinophils in their peripheral blood upon admission. Patients with eosinophils ≥300 cells/mL were assigned to the eosinophilic group (Eos), and those with eosinophils <300 cells/mL were assigned to the non-eosinophilic group (Noneos). All patients received similar treatment, including inhaled budesonide, according to the guidelines. The induced sputum microbiome was analyzed on the 1st and 7th day of treatment using the 16S rRNA method. The levels of IL-6 and IL-8 were measured in the plasma, and the sensitivity to corticosteroids was determined in isolated PBMCs.
The baseline clinical characteristics were similar between the Eos and Noneos groups, with no significant differences in age, sex, smoking history, body mass index (BMI), Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage, or medications. The mean eosinophil counts in both the blood and sputum were significantly higher in the Eos group than in the Noneos group. The induced sputum samples were qualified in ten patients in each group.
The alpha diversity (Shannon index) of the microbiome was similar between the Eos and Noneos groups prior to treatment. After 7 days of treatment, the Shannon index increased significantly in both groups. However, the microbiome richness (Ace index) was significantly lower in the Eos group compared to the Noneos group after treatment. The composition of the phyla was similar between the Eos and Noneos groups prior to treatment, but after treatment, the relative abundances of Bacteroidetes and Fusobacteria increased in the Eos group, while the relative abundances of Acidobacteria and Chloroflexi decreased. In the Noneos group, only the relative abundance of Fusobacteria increased after treatment.
The levels of inflammatory cytokines IL-6 and IL-8 were similar between the two groups prior to treatment but decreased significantly in both groups after 7 days of treatment. The decrease in IL-6 and IL-8 levels was more significant in the Eos group compared to the Noneos group. The levels of C-reactive protein (CRP) also decreased significantly in both groups after treatment.
The levels of arterial partial pressure of oxygen (PaO2), FEV1% predicted, and FEV1/forced vital capacity (FVC) were significantly higher in both groups after treatment compared to those before treatment. The arterial partial pressure of carbon dioxide (PaCO2) levels and COPD assessment test (CAT) scores significantly decreased in both groups after treatment. There was no significant difference in the levels of blood gas, lung function, and CAT scores between the Eos and Noneos groups before and after treatment.
The 50% inhibitory concentration of Dex (IC50-Dex) and the percentage of inhibition of IL-8 were similar between the Eos and Noneos groups prior to treatment. After 7 days of treatment, the IC50-Dex significantly decreased in both groups, and the IC50-Dex was significantly lower in the Eos group compared to the Noneos group. The percentage of inhibition of IL-8 at Dex concentrations 10^-8 to 10^-6 mol/L was significantly higher in the Eos group than in the Noneos group after 7 days of treatment.
In conclusion, the study demonstrated that eosinophilic and non-eosinophilic patients responded differently to conventional AECOPD treatment with broad-spectrum antibiotics and ICS. Eosinophilic patients responded with significantly lower sputum microbial richness and lower levels of inflammatory mediators IL-8 and IL-6. The microbiome composition also changed after treatment, with the relative abundances of Bacteroidetes and Fusobacteria increasing in the eosinophilic patients, while Acidobacteria and Chloroflexi decreased. Only Fusobacteria increased in the non-eosinophilic patients. This might be due to higher sensitivity to corticosteroids among eosinophilic patients, as shown by in vitro inhibition studies using isolated PBMCs.
The findings suggest that the eosinophilic patients were more responsive to treatment and may recover more rapidly than patients with non-eosinophilic AECOPD. The study highlights the importance of considering eosinophil levels in the treatment of COPD and the potential benefits of ICS in eosinophilic patients. Further research is needed to explore the mechanisms underlying the differences in microbiome composition and corticosteroid sensitivity between eosinophilic and non-eosinophilic patients with COPD.
doi.org/10.1097/CM9.0000000000000677
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