Bacterial–viral load and the immune response in stable and exacerbated COPD: significance and therapeutic prospects

D’Anna, Silvestro Ennio; Balbi, Bruno; Cappello, Francesco; Carone, Mauro; Di Stefano, Antonino

Relative abundance and an increasing "diversity" of the bacterial population in COPD was observed by Pragman et al 24 who studied BAL samples from 22 patients with moderate-to-severe COPD and ten controls, and Wu et al 25 who analyzed sputum of ten COPD and control subjects. Garcia-Nuñez et al 26 studied with nonculture-based techniques the bronchial microbiome in the sputum of 17 stable COPD patients and observed that, in patients with more severe disease, the Proteobacteria phylum was overrepresented, together with a diminution of bacteria belonging to the Firmicutes phylum. The authors speculated that changes in the lung microbiome in more severe COPD patients could be due either to alterations of the airways typical of very severe diseased patients or to the repeated use of antibiotics. The alteration in microbiome composition observed may induce further lung inflammation contributing to the worsening of the disease. 26 More recently, Sze et al 27 examining 40 lung samples from five COPD (GOLD stage 4) subjects have confirmed the reduction in microbial diversity with a relative increase of Proteobacteria and Actinobacteria and a reduction of Firmicutes and Bacteroidetes phyla. The authors, moreover, reported a significant association between the alterations of the microbiome, the extent of emphysema, remodeling of bronchi and alveoli, and their infiltration by CD4 + T-cells. Sze et al hypothesize that the increased abundance of Proteobacteria and Actinobacteria in COPD (GOLD stage 4) airways could stimulate a more intense lung inflammation. 27 These findings are in contrast to other studies. 24, 25 The discrepancy could be due to the small number of patients analyzed in these studies and differences in study design (Table 1) . Furthermore, the study by Erb-Downward et al 21 was based on samples obtained from BAL and bronchial brushes while in the study by Sze et al, 23,27 the samples were obtained from lung tissue, rendering the findings less directly comparable. A limitation of the study by Sze et al 23 there is a predominance of emphysema, while in others, chronic bronchitis is prevalent; moreover, the different drugs used to treat the disease in COPD patients could have altered the lung microbiome: some patients were treated with antibiotics and others with steroids or β2 agonists. A well-defined washout period from antibiotic and corticosteroid use is not reported in these studies. Some studies considered COPD patients in a stable state after 4 weeks had lapsed from the last exacerbation. [19] [20] [21] [22] [23] [24] [25] [26] [27] [28] [29] [30] One study indicated the antibiotics used during the exacerbation phase of the patients but no data are available about the dose of corticosteroid during that phase. 30 One study reported the antibiotic dosage used. 26 Since many of these studies use a quantitative approach quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) for microbiome evaluation, it is mandatory to define precisely the pharmacologic treatments and the washout duration for antibiotics and corticosteroids. We suggest that a 3-month washout period for antibiotic treatment, and at least 1-month washout for oral or inhaled corticosteroid use should be considered when evaluating COPD patients in stable conditions. Even with the limitations described and the need for studies with larger sample size and a well-defined pharmacological treatment regimen, it appears that the airways of COPD patients have a