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

Again, the relationship between the degree of inflammation and viral load needs to be studied in patients under well standardized therapeutic conditions. Corticosteroid use could have favored the persistence of viruses in the airways, as observed by Utokaparch et al 35 Numerous data from 1980 onward show an acute decline in forced expiratory volume in 1 second in COPD patients for up to 90 days after an acute infection of influenza virus. 39 Recently, it was demonstrated that infection by respiratory viruses could influence the bacterial microbiome in patients with COPD, and vice versa. Molyneaux et al 36 These data have been confirmed by histologic analyses of infected lung samples from patients who died from 1918 type A and 2009 H1N1 influenza. [41] [42] [43] In these patients, the predominant cause of death was a bacterial superinfection resulting in secondary bacterial pneumonia. In mice, the infection of influenza A virus increases the susceptibility to bacterial respiratory infections such as S. pneumoniae, Staphylococcus aureus, and H. influenzae. 44, 45 Influenza virus may cause this susceptibility to bacterial superinfection through various mechanisms. The damage of the epithelial cells and alterations of the epithelium by viral infection can facilitate the bacterial colonization of the airways. 46 Another mode by which influenza virus can favor bacterial infection is by altering the function of the immune system, resulting in a failure of the control of bacterial replication ( Figure 2 ). Influenza A virus causes apoptosis and alters the function of alveolar macrophages, 47, 48 suppressing their activation in response to secondary bacterial challenge and phagocytic capacity by increasing the expression of CD 200 receptor ligation antigen 49 and reducing the expression in the alveolar macrophages of the scavenger macrophage receptor with collagenous structure (MARCO). 48 The macrophages' reduced production of cytokines and chemokines alters the response of other cells to pathogens, reducing for example the recruitment and activation of neutrophils. Neutrophil function is also altered by influenza A virus either through direct infection of the cells 50 or through the induction of type I interferon secretion that leads to the inhibition of neutrophil infiltration and increased apoptosis. 51 Natural killer cells are also affected by influenza virus: in an infected lung, they show a reduction of cytotoxic activity and the production of chemokines and cytokines 52 such as the antibacterial effector cytokine tumor necrosis factor. 53 There is evidence that the induction of a highly polarized type 1 T helper (Th1) immune response by respiratory viruses leads to a reduction of MARCO expression and impairs macrophages' ability to ingest and kill bacteria. 48 The fine balance of IL-10 production and Th17 response during a viral infection could explain the excessive susceptibility to the bacterial superinfection observed after influenza virus infection. 54, 55 van der Sluijs et al 56 observed that blocking IL-10 production enhanced the clearance of a secondary infection of S. pneumoniae. Another effect due to increased type I interferon production following influenza virus infection is the suppression of the Th17 response during a secondary bacterial infection in mice. 57 These data suggest that Th17 cells are important in organizing the immune response to bacteria such as S. pneumoniae and S. aureus. Viral inhibition of this pathway may