Abstract

Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, chronic obstructive pulmonary disease (COPD) accounting for approximately 3 million deaths annually. Frequent acute exacerbations (AEs) of COPD (AECOPD) drive clinical and functional decline in COPD and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs. Infections with a small subgroup of pathogens precipitate the majority of AEs and consequently constitute a significant comorbidity in COPD. However, current pharmacological interventions are ineffective in preventing infectious exacerbations and their treatment is compromised by the rapid development of antibiotic resistance. Thus, alternative preventative therapies need to be considered. Pathogen adherence to the pulmonary epithelium through host receptors is the prerequisite step for invasion and subsequent infection of surrounding structures. Thus, disruption of bacterial–host cell interactions with receptor antagonists or modulation of the ensuing inflammatory profile present attractive avenues for therapeutic development. This review explores key mediators of pathogen–host interactions that may offer new therapeutic targets with the potential to prevent viral/bacterial-mediated AECOPD. There are several conceptual and methodological hurdles hampering the development of new therapies that require further research and resolution.

Respiratory infections are a major determinant of pulmonary morbidity in chronic obstructive pulmonary disease (COPD)

Chronic respiratory diseases are among the leading causes of mortality worldwide, with the major contributor, COPD, accounting for approximately three million deaths annually [1–4]. Acute exacerbations of COPD (AECOPD) are most often precipitated by respiratory tract infections, and are associated with accelerated loss of lung function, increased mortality, decreased health-related quality of life and significant economic costs [1,3,5–11]. However, as is the case for many chronic respiratory diseases, the mechanisms that promote increased susceptibility of COPD patients to infections are poorly understood [12–14].

Recurrent acute infections with bacterial and/or viral pathogens are strongly linked with the occurrence of exacerbations and contribute considerably to the clinical course of COPD. As such, these infections constitute a significant comorbidity in COPD [15]. Approximately 50% of AECOPD are caused by bacterial pathogens and in severe exacerbations requiring ventilatory support, the frequency exceeds 70% [12,13]. In AECOPD, nontypeable Haemophilus influenzae (NTHi) is the most frequent bacterium isolated, followed by Streptococcus pneumoniae and Moraxella catarrhalis. In healthy individuals and stable COPD, these bacteria are common colonizers of the nasopharynx and migration to privileged anatomical sites is typically facilitated by a combination of bacterial pathogenic mechanisms and defects in host innate immune defences [16–18].

Despite enhanced expression of an antiviral immune response, COPD epithelial cells exhibit increased vulnerability to viral infection [19]. PCR-based studies have detected viral contribution in 34-60% of cases, most frequently with human rhinoviruses (HRV) accounting for 36-50% of viruses [20–23]. Influenza virus and respiratory syncytial virus (RSV) are also detected in approximately 16% and 29% of exacerbations, respectively [22]. Viral and bacterial co-infection is a frequent occurrence and is strongly associated with worse exacerbations of respiratory disease and enhanced inflammation [3,24,25].

The healthy human bronchial tree and lung parenchyma have a remarkable ability to maintain a healthy status in spite of repeated exposure to microbial aspiration [15]. However, in COPD this innate lung defence appears to be disrupted, enabling proliferation of a dysbiotic lung microbiome [26–29]. Pathogen adherence to the pulmonary epithelium through host receptors is the pre-requisite step for migration and subsequent infection of surrounding structures [30]. After attachment to the mucosal surface, pathogens use a variety of mechanisms to enhance their persistence such as antigenic variation, immune evasion and invasion of host respiratory cells [3,31–33]. Persistence of pathogens in the lower respiratory tract acts as a reservoir for exacerbation-inducing infections and is considered a major determinant of pulmonary morbidity [7,18,28]. Interestingly, even in the absence of clinical exacerbations, airway colonization by bacterial pathogens in COPD has been associated with a clinically significant increase in daily symptoms [3,34,35]. Thus, elucidating key mediators of pathogen-host interactions may reveal new therapeutic targets with the potential to prevent viral/bacterial mediated exacerbations in COPD.

Current COPD management necessitates alternative preventative strategies

Management of COPD typically involves avoidance of risk factors to prevent disease progression and pharmacotherapy to control symptoms, exacerbation rates and severity [2]. Existing therapies are of limited effectiveness and do not affect the overall course of COPD. Despite prescription of therapies shown to reduce exacerbation frequency, approximately one-third of COPD patients still experience one or more exacerbations every year [36,37].

Loss of lung function and disease progression is exemplified by declines in forced expiatory volume in 1 second (FEV1) over time, and frequency of exacerbations [38]. However, it is important to consider the inherent limitations of measuring these disease features. FEV1 measurement requires an artificial manoeuvre that does not always correlate with clinically relevant outcomes such as dyspnoea, exacerbations, health status or exercise capacity [38]. There is also no standardised definition of an exacerbation; differential diagnoses such as pneumonia, heart failure, ischaemic heart disease and pulmonary embolism have to be taken into account [39]. These limitations make comparative evaluations of clinical studies difficult. This is further complicated by the lack of established biomarkers that reflect the inflammatory and destructive process in the lung or that indicate responsiveness to treatment [40,41].

Pharmacotherapy

The most widely adopted therapeutic approach for COPD management are the recommendations of the Global Initiative of Chronic Obstructive Lung Disease (GOLD). The GOLD approach recommends combination therapy with long acting β2-adrenergic receptor agonists (LABAs), long-acting muscarinic antagonists (LAMAs) and inhaled corticosteroids (ICSs) for patients with severe disease or frequent exacerbations [42]. LABAs and LAMAs achieve bronchodilation to increase lung function parameters such as FEV1 while ICSs are administered for their anti-inflammatory effects [43]. Although these treatments may be effective in improving quality of life, FEV1 and reduce exacerbation rates, there is currently no conclusive evidence that any existing medications for COPD modify mortality rates or the long-term decline in lung function [44–48]. The highly variable nature of responses to pharmacological treatment has further complicated treatment options. Irrespective of symptom severity and/or the level of risk, patients do not respond equally to all drugs [49]. The GOLD approach attempts to address this by stratifying patients into phenotypes based on disease severity, assessed by spirometry, symptoms and exacerbation history, to determine the most appropriate therapy. However, these clinical phenotypes require prospective validation regarding their prognostic value and treatment responses [50].

The anti-inflammatory effects of ICS therapy is important in the management of mild-moderate persistent asthma [14,51], however; the role of ICSs in the treatment of COPD remains controversial [52]. The inflammatory process in COPD has been shown to be fundamentally different to that of asthma [53], and there is conflicting evidence surrounding the efficacy of ICSs in preventing exacerbations [42,54]. Double-blind placebo-controlled studies found that even high doses of ICS do not reduce inflammatory cell numbers, concentrations of cytokines, or proteases [55–57]. Additionally, early trials found no clinical benefit of long-term ICS in the treatment of mild-advanced COPD [58,59]. Despite this, several trials revealed some benefit of ICS treatment showing a reduction in the overall frequency of AECOPD [47,60–62]. However, it has been suggested these conclusions were based upon questionable statistical analyses and that other studies that used potentially more appropriate statistical approaches found no significant effects of ICS treatment [63–65]. Those that did find a reduction in exacerbations, had no significant effect on the survival of COPD patients [66]. These inconsistencies may be confounded by large patient-to-patient variability in responsiveness to ICS treatment [67], or difficulties in measuring ICS efficacy, particularly as commonly used variables such as FEV1 may not adequately reflect the overall health status of patients [48,50,68]. Additionally, the use of ICS is associated with adverse effects such as bruising, accelerated bone loss, and increased risk of subcapsular cataracts [69]. Recent GOLD recommendations propose an individualised approach to ICS administration to mitigate the associated risks in patients unlikely to benefit from this treatment. Data modelling shows that blood eosinophilia may be predictive of a higher risk of exacerbations [70] and a favourable response to ICS therapies in patients with stable and moderate-severe COPD [71–75]. This evidence has formed the basis for a predictive (>300 cells/uL) threshold which can be used to identify patients with the greatest likelihood of treatment benefit with ICSs (in combination with LABAs). ICS-containing regimes have little or no effect at a blood eosinophil count <100cells/uL [76]. Although studies assessing the benefit of ICS treatment in eosinophilic COPD consistently report a reduction in exacerbation frequency, they are all based on retrospective evidence [72,75]. Thus, clinical trials are required to validate these benefits and elucidate underlying mechanisms.

The clinical use of ICS is based on the supposition that airway wall inflammation is a primary driver of disease progression, a paradigm that is now being challenged [77–81]. Recent evidence suggests the contrary, whereby COPD lungs exhibit dysfunctional immune responses due to decreases in key immune cells and/or their function [79]. We have previously reported that “total” airway wall cellularity decreases in COPD patients compared to never-smokers, with a strong association with smoking history [26,82]. A similar trend was observed for airway wall vascularity [83]. Inhaled fluticasone propionate did not change total airway wall cellularity but improved lamina propria vascularity in COPD ex-smokers [82,83]. Our data from a confirmatory cross-sectional study demonstrated hypocellularity of both large and small airway walls in COPD compared to never-smokers. However, there was no change in the proportions of key immune cell populations such as neutrophils, macrophages (CD68+), CD8+ and CD4+ cells [26]. The only increase was observed for CD8+ cells in small airways but not in the large airways of COPD [26]. In addition, we noted that CD68+ expression was non-specific and localised to macrophages and a mesenchymal cell population [26]. We further identified differential macrophage switching in small airway wall, lumen and alveolar macrophages (AMs) [84]. The airway wall in never-smokers was predominantly M2 (CD163+), which switched to a more M1 phenotype (CD68+ iNOS+ dual positive) in COPD, while, the AMs in contrast switched towards a more M2 phenotype. Furthermore, AMs from COPD patients had comparatively reduced iNOS expression than never-smokers, again confirming immune dysfunction and possibly explaining their inability to mount an effective response to infection and efferocytosis [85].

Thus, the immune-inhibitory function of ICSs may exacerbate the inherent immune dysfunction and increase susceptibility to persistent infections [77]. This may explain the increased incidence of pneumonia in ICS users compared to non-users [42,86,87]. Several studies have associated ICS use with a 70% increase in the risk of being hospitalized for pneumonia, the effect of which is ICS dose-dependent [42,69,86,87]. This association is strengthened by a recent study of over 10,000 COPD patients that compared a fifty-two-week, once-daily combination of fluticasone furoate (ICS), umeclidinium (LAMA) and vilanterol (LABA) either in triple or dual therapy. There was a higher incidence of pneumonia in the triple therapy (ICS-LABA-LAMA) and fluticasone furoate-vilanterol (ICS-LABA) groups than in the umeclidium-vilantrol (LAMA-LABA) group [88]. A recent study also found a 37% decrease in the risk of pneumonia in patients withdrawn from ICS therapy over three-six months [89]. Experimental mouse models have also described ICS-mediated impairment of macrophage bactericidal properties and the IFN-mediated antiviral immune response, resulting in impaired clearance of pneumococci, Klebsiella pneumoniae [90,91] and HRV [92]. Despite the predictiveness of eosinophilia in ICS treatment response, a meta-analysis of five studies comprising of 12, 496 patients with moderate-to-severe COPD showed an increase in the risk of pneumonia in the high eosinophil group with ICS-including treatments, compared to the low eosinophil group [72]. This indicates that the risk of pneumonia is a result of ICS treatment, irrespective of eosinophil count [74,75,93]. Proposed drugs targeted against eosinophil recruitment by antibody inhibition of IL-5, such as Mepolizumab may therefore be ineffective in reducing pneumonia and infectious exacerbations. Indeed, trials have found no beneficial effects of IL-5 inhibitors on pneumonia or infectious exacerbations [94–96] and may even be detrimental. Eosinophils have been shown to contribute to the immune response against infection and counts ≥2% predicted an overall lower risk of bacterial presence at exacerbation [70,97–99]. Therefore, their inhibition may increase susceptibility to infectious exacerbations.

Clinical and experimental studies suggest that there are ICS intra-class differences regarding pneumonia risk with some evidence of increased risk with fluticasone propionate (43-78%) compared to budesonide therapy [100]. Such disparity may be the consequence of physiochemical and pharmacokinetic differences resulting in the prolonged presence of slowly dissolving fluticasone propionate particles in the airway epithelial lining fluid compared with budesonide. This may cause protracted local immunosuppression that could impair the clearance of airway pathogens, leading to their airway/lung colonization, which may develop into pneumonia. The correlation between higher bacterial load and higher ICS dose in stable COPD patients exemplified this theory [100]. Current therapies and clinical trials in COPD are summarised in Table 1.

Table 1
Current therapies and clinical trials in COPD
Reference Drug names/combinations and target COPD condition and stage Clinical trial (Phase) Study details and patient numbers Outcomes and conclusions 
Triple versus dual therapies with combination of inhaled corticosteroids, LABA and LAMA 
Halpin et al., FULFIL study [452Once daily triple therapy (ICS+LABA+LAMA) fluticasone furoate/umeclidinium/vilanterol compared to twice-daily dual therapy (ICS+LABA) budesonide/formoterol Moderate to severe Phase III clinical trials A total of 2240 patients participated; 1121 patients received triple therapy while 1119 received dual therapy. Once daily triple therapy showed reductions in moderate- severe exacerbation rates compared with twice-daily dual therapy. The effectiveness of the therapy was regardless of disease severity or exacerbation history or prior COPD medication. 
Lipson et al., IMPACT study [88Once daily triple therapy (ICS+LABA+LAMA) fluticasone furoate umeclidinium/vilanterol compared to fluticasone dual therapy (ICS + ultra LABA) furoate–vilanterol and dual bronchodilator (LAMA+ ultra LABA) umeclidinium–vilanterol Moderate to severe Phase III clinical trials A total 10,355 patients of which 4151 received triple therapy and the rest were administered dual therapy. Once-daily triple therapy reduced moderate or severe COPD exacerbations and improved lung function and quality of life than both dual therapy. 
Singh et al., TRILOGY Study [453Once daily triple therapy (ICS+LABA+LAMA) with single inhaler containing ultrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide compared to twice daily (ICS+LABA) beclometasone dipropionate and formoterol fumarate Moderate to severe Randomised, double-blinded active-controlled trial done in 159 sites across 14 countries A total of 1367 patients of which 687 were on triple therapy and 680 on dual therapy. Triple therapy showed greater benefit than dual therapy in reduction of moderate to severe exacerbations and quality of life. Triple therapy effectively increased bronchodilation increased in patients with severe exacerbations however, no changes in dyspnea was observed. 
Papi et al., TRIBUTE study [454Once daily triple therapy (ICS+LABA+LAMA) beclometasone dipropionate/formoterol fumarate compared to (LABA+LAMA) indacaterol and glycopyrronium Moderate to Severe Phase 3b clinical trials done at 187 sites across 17 countries A total of 1532 patients of which 764 were on triple therapy and 768 on dual therapy. The triple therapy again was found to be effective in reducing the rate of moderate-to-severe COPD exacerbations than dual bronchodilator combination, without increasing the risk of pneumonia 
Dual/monotherapy involving ICS/LABA/LAMA comparative clinical studies 
Wedzicha et al., FLAME study [455Dual therapy with LABA indacaterol/LAMA glycopyrronium once daily compared to LABA salmeterol + ICS fluticasone twice daily Moderate to severe A multicentre randomized, double-blind, double-dummy, parallel-group, non-inferiority trial A total of 3362 patients underwent randomization; 1680 were assigned to the indacaterol–glycopyrronium group, and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium was consistently more effective than salmeterol–fluticasone in preventing exacerbations and was associated with no detectable increase in adverse events. 
Anzueto et al. [456Comparison of dual therapy (LABA+LAMA) indacaterol and glycopyrronium(IND+GLY) and monotherapy (LAMA) tiotropiun (TIO) (SHINE study)and dual therapy (LABA+ICS) salmeterol/fluticasone (SFC) (LANTERN study) Moderate to severe Multi-centre, Phase III randomized clinical trial as part of IGNITE program A total of 954 patients for SHINE study of which 474 administered (IND+GLY) and 480 TIO monotherapy. In LANTERN study 1,263 patients 630 (IND+GLY) and 633 with SFC. Dual bronchodilator therapy with IND+GLY offered significant benefits over treatment with a single-agent LAMA or a LABA/ICS both in terms of the incidence and time to clinically important deterioration (CID). 
Kardos et al., FAVOR study [457Comparison of dual therapy (LABA+LAMA) indacaterol and glycopyrronium (IND+GLY) and monotherapy (LAMA) tiotropium. Moderate to severe Randomized, open-label, multicenter, crossover study was conducted at 18 centres in Germany Total of 176 patients 88 in each arm. The combination of LABA/LAMA improved lung function in COPD patients compared to monotherapy with Tiotropium. 
Roflumilast (PDE4 inhibitor) in COPD clinical studies 
Martinez et al., RESPOND study [458Roflumilast compared with placebo Moderate to Severe Phase IV multicentre, randomized, double-blind, placebo-controlled A total of 2,354 COPD patients were randomized  1,178 treated with roflumilast and  1,176 placebo. The study found roflumilast effective in reducing moderate to severe exacerbation and was more pronounced in patients with history of COPD-related hospitalization and those with frequent COPD exacerbations. 
Martinez et al., REACT study [459Roflumilast compared with placebo Moderate to Severe Phase III/IV multi-center, randomized, double-blind, placebo-controlled 1945 participants, 973 to the roflumilast group and 972 placebos. Roflumilast effectively reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and severe exacerbations. 
Rabe KF et al., ROBERT study [460Roflumilast compared with placebo Moderate to severe and chronic bronchitis Double-blind, placebo-controlled trial done at 18 sites in five countries 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo but reduced the eosinophil biopsy numbers. 
Statins in COPD clinical trials 
Balaguer et al. [461Simvastatin compared with placebo Moderate to severe Randomised control trial 18 eligible participants, 9 in each arm. No significant change was observed on pulmonary/systemic inflammation and lung function in simvastatin treated COPD patients compared to placebo. 
Reference Drug names/combinations and target COPD condition and stage Clinical trial (Phase) Study details and patient numbers Outcomes and conclusions 
Triple versus dual therapies with combination of inhaled corticosteroids, LABA and LAMA 
Halpin et al., FULFIL study [452Once daily triple therapy (ICS+LABA+LAMA) fluticasone furoate/umeclidinium/vilanterol compared to twice-daily dual therapy (ICS+LABA) budesonide/formoterol Moderate to severe Phase III clinical trials A total of 2240 patients participated; 1121 patients received triple therapy while 1119 received dual therapy. Once daily triple therapy showed reductions in moderate- severe exacerbation rates compared with twice-daily dual therapy. The effectiveness of the therapy was regardless of disease severity or exacerbation history or prior COPD medication. 
Lipson et al., IMPACT study [88Once daily triple therapy (ICS+LABA+LAMA) fluticasone furoate umeclidinium/vilanterol compared to fluticasone dual therapy (ICS + ultra LABA) furoate–vilanterol and dual bronchodilator (LAMA+ ultra LABA) umeclidinium–vilanterol Moderate to severe Phase III clinical trials A total 10,355 patients of which 4151 received triple therapy and the rest were administered dual therapy. Once-daily triple therapy reduced moderate or severe COPD exacerbations and improved lung function and quality of life than both dual therapy. 
Singh et al., TRILOGY Study [453Once daily triple therapy (ICS+LABA+LAMA) with single inhaler containing ultrafine beclometasone dipropionate, formoterol fumarate, and glycopyrronium bromide compared to twice daily (ICS+LABA) beclometasone dipropionate and formoterol fumarate Moderate to severe Randomised, double-blinded active-controlled trial done in 159 sites across 14 countries A total of 1367 patients of which 687 were on triple therapy and 680 on dual therapy. Triple therapy showed greater benefit than dual therapy in reduction of moderate to severe exacerbations and quality of life. Triple therapy effectively increased bronchodilation increased in patients with severe exacerbations however, no changes in dyspnea was observed. 
Papi et al., TRIBUTE study [454Once daily triple therapy (ICS+LABA+LAMA) beclometasone dipropionate/formoterol fumarate compared to (LABA+LAMA) indacaterol and glycopyrronium Moderate to Severe Phase 3b clinical trials done at 187 sites across 17 countries A total of 1532 patients of which 764 were on triple therapy and 768 on dual therapy. The triple therapy again was found to be effective in reducing the rate of moderate-to-severe COPD exacerbations than dual bronchodilator combination, without increasing the risk of pneumonia 
Dual/monotherapy involving ICS/LABA/LAMA comparative clinical studies 
Wedzicha et al., FLAME study [455Dual therapy with LABA indacaterol/LAMA glycopyrronium once daily compared to LABA salmeterol + ICS fluticasone twice daily Moderate to severe A multicentre randomized, double-blind, double-dummy, parallel-group, non-inferiority trial A total of 3362 patients underwent randomization; 1680 were assigned to the indacaterol–glycopyrronium group, and 1682 to the salmeterol–fluticasone group. Indacaterol–glycopyrronium was consistently more effective than salmeterol–fluticasone in preventing exacerbations and was associated with no detectable increase in adverse events. 
Anzueto et al. [456Comparison of dual therapy (LABA+LAMA) indacaterol and glycopyrronium(IND+GLY) and monotherapy (LAMA) tiotropiun (TIO) (SHINE study)and dual therapy (LABA+ICS) salmeterol/fluticasone (SFC) (LANTERN study) Moderate to severe Multi-centre, Phase III randomized clinical trial as part of IGNITE program A total of 954 patients for SHINE study of which 474 administered (IND+GLY) and 480 TIO monotherapy. In LANTERN study 1,263 patients 630 (IND+GLY) and 633 with SFC. Dual bronchodilator therapy with IND+GLY offered significant benefits over treatment with a single-agent LAMA or a LABA/ICS both in terms of the incidence and time to clinically important deterioration (CID). 
Kardos et al., FAVOR study [457Comparison of dual therapy (LABA+LAMA) indacaterol and glycopyrronium (IND+GLY) and monotherapy (LAMA) tiotropium. Moderate to severe Randomized, open-label, multicenter, crossover study was conducted at 18 centres in Germany Total of 176 patients 88 in each arm. The combination of LABA/LAMA improved lung function in COPD patients compared to monotherapy with Tiotropium. 
Roflumilast (PDE4 inhibitor) in COPD clinical studies 
Martinez et al., RESPOND study [458Roflumilast compared with placebo Moderate to Severe Phase IV multicentre, randomized, double-blind, placebo-controlled A total of 2,354 COPD patients were randomized  1,178 treated with roflumilast and  1,176 placebo. The study found roflumilast effective in reducing moderate to severe exacerbation and was more pronounced in patients with history of COPD-related hospitalization and those with frequent COPD exacerbations. 
Martinez et al., REACT study [459Roflumilast compared with placebo Moderate to Severe Phase III/IV multi-center, randomized, double-blind, placebo-controlled 1945 participants, 973 to the roflumilast group and 972 placebos. Roflumilast effectively reduces exacerbations and hospital admissions in patients with severe chronic obstructive pulmonary disease and severe exacerbations. 
Rabe KF et al., ROBERT study [460Roflumilast compared with placebo Moderate to severe and chronic bronchitis Double-blind, placebo-controlled trial done at 18 sites in five countries 158 patients were randomly assigned: 79 to the roflumilast group, and 79 to the placebo group. 16 weeks of treatment with roflumilast did not affect the number of CD8 cells in bronchial submucosa compared with placebo but reduced the eosinophil biopsy numbers. 
Statins in COPD clinical trials 
Balaguer et al. [461Simvastatin compared with placebo Moderate to severe Randomised control trial 18 eligible participants, 9 in each arm. No significant change was observed on pulmonary/systemic inflammation and lung function in simvastatin treated COPD patients compared to placebo. 

The role of antibiotics

Although first-line pharmacological interventions have been shown to reduce AECOPD, they are not an effective means of preventing exacerbations of an infectious origin [101]. Thus, current guidelines advocate the use of intermittent antibiotic therapy for moderate and severe exacerbations that exhibit symptoms consistent with respiratory infection, i.e. increase in dyspnoea, sputum volume and sputum purulence [42]. Usual initial empirical treatment is aminopenicillin with clavulanic acid, doxycycline or macrolide treatment due to their additional anti-inflammatory properties [36,102]. Studies suggest that long-term or intermittent antibiotic therapy may have a beneficial effect on the outcome of COPD patients and may improve quality of life by reducing exacerbation frequency or by prolonging time to next exacerbation through local and systemic effects [103–107]. Antibiotic therapy may reduce exacerbation frequency by eradicating colonizing bacteria with the potential to cause infection, however there is limited information to support this hypothesis [35]. This hypothesis is also not correlated with microbiome data that show an overrepresentation of potential pathogens and associated inflammatory response in COPD airways despite antibiotic therapy [18,28,29,108].

Antibiotic therapy is complicated by the lack of guidelines pertaining to the most appropriate drug and administration regime, as well as the optimal duration of therapy [101]. Furthermore, antibiotics do not offer long-term protection against re-infection and relapse is common [109]. Inadequate antibiotic efficacy, which through incomplete resolution of the initial exacerbation and persistent bacterial colonization is likely to influence risk of relapse [35,110,111]. Prolonged and sub-inhibitory antibiotic concentrations in COPD airways may also promote antibacterial resistance by providing a conducive environment for the amplification of antibiotic-resistant subpopulations [101,111]. Management of pneumococcal and NTHi infections, have been compromised (in particular NTHi) by the rapid development of antibiotic resistance and infections are frequently refractory to first- and second-line antibiotics [109]. Intermittent or long-term use of macrolides and penicillins have been associated with the failure to eradicate resistant strains of S. pneumoniae and H. influenzae from the sputum of COPD patients [35,102,111,112]. Fluoroquinolones, in particular moxifloxacin, have proved to be effective at eradicating common COPD pathogens and resistance to this class of antibiotic is currently low [102,113]. However, fluoroquinolone-resistant NTHi isolates have been detected worldwide and treatment failure with other fluoroquinolones such as ofloxacin or levofloxacin has also been described [114–116]. A randomised control trial reported a direct comparison of 13-week antibiotic therapy using tetracyclines, macrolides and quinolones. Total bacterial load did not decrease significantly after three months and there was a large increase in antibiotic resistance in all treatment groups where mean inhibitory concentrations of culture isolates increased by at least three-fold over the placebo group [117].

Long-term use of particular antibiotics has also been associated with adverse side effects, further reducing antibiotic treatment options. For example, azithromycin use has been associated with hearing impairment and increases in cardiovascular events [36].

Vaccination

Prevention of infectious exacerbations by vaccination has the potential to increase quality of life and patient survival. However, the availability of vaccines that protect COPD patients from key pathogens is restricted and the efficacy of currently used formulations are variable [118]. International guidelines recommend that patients with COPD should be immunized with influenza and pneumococcal vaccines. A systematic review of injectable polyvalent pneumococcal vaccines in COPD patients identified seven studies for inclusion (2 for 14-valent vaccine and 5 for 23-valent) and observed reductions in the incidence of pneumococcal pneumonia and AECOPD that did not reach statistical significance [119]. However, the pneumococcal conjugate vaccines, PPSV13 and PPSV23, have been shown to reduce the incidence of community-acquired pneumonia in COPD patients [120,121].

The majority of clinical trials evaluating the efficacy of influenza vaccines in COPD patients indicate long-term benefits of annual seasonal influenza vaccination, such as reduced frequency of exacerbations, reduced hospitalizations and outpatient visits, and decreased all-cause and respiratory mortality [122–124]. Despite this, patients with COPD still remain highly vulnerable to adverse outcomes from influenzae infections. [123,125] There is also evidence that suggests COPD patients exhibit a significantly lower humoral immune response to the influenza vaccination compared to healthy participants. A study assessing the immunogenicity of the 2010 trivalent influenza vaccine found a lower rate of seroconversion in COPD participants (43%) compared to healthy participants (90%) [126]. This altered immune response was associated with reductions in both T-cell and B-cell function [127,128]. Further investigations are warranted to examine the mechanisms behind this altered immune response with the potential for new vaccination approaches in COPD that maximise protection against influenza infections.

Development of new vaccination strategies is further complicated by the intrinsic heterogeneity of pathogen target proteins, as is the case with an oral whole-cell killed NTHi vaccine developed to reduce acute exacerbations in COPD. Trials with this vaccine showed no significant beneficial effects to warrant widespread vaccination [7,129]. Similarly, vaccination is not feasible against viruses such as HRV due to the large number of serotypes with low antibody cross-reactivity [130]. Despite the feasibility of vaccination, no vaccine is currently licensed to prevent RSV infection [131,132].

Antiviral agents

Although not currently utilised in COPD, antiviral agents have been suggested as an approach to mitigate viral-induced exacerbations and associated complications particularly as there are currently no therapies recommended for treatment of viral infections in COPD [133,134]. Although vaccination may be a useful prophylactic treatment it has no benefit during an active infection.

Only two classes of drugs are currently approved for the treatment of influenza: M2 ion channel blockers (adamantanes) and neuraminidase (NA) inhibitors. Adamantanes inhibit influenza A replication by blocking virus entry while NA inhibitors (e.g., peramivir, zanamivir and oseltamivir) block the release of virions after budding from the host cell in both influenza A and B viruses [135–138]. Zanamivir has been shown to prevent influenza infection or reduce symptoms if begun early in the infection process. The clinical efficacy and safety of zanamivir has been demonstrated in all age groups and in healthy and immunocompromised individuals [137,139–141]. Albeit limited, evidence suggests similar benefits and safety profile of zanamivir for the treatment of influenza in COPD [125]. However, the evidence produced by this study was unable to rule out adverse events such as bronchospasm. zanamivir was shown to promote resolution of influenza, without adversely affecting pulmonary function [142]. Oseltamivir has shown a similar efficacy to zanamivir in healthy adults and children with reductions in illness severity and duration, viral shedding, and lower respiratory tract complications [143]. Oseltamivir has not been associated with any significant respiratory adverse effects in healthy individuals, but no data exists on the safety and efficacy in patients with underlying respiratory disease [144,145]. Likewise, there are no trials of M2 inhibitors in COPD patients, however there are serious safety concerns in otherwise healthy patients with this class of antiviral. Side effects involving the central nervous system occur in 5%–29% of patients treated with amantadine, and include headache, light-headedness, dizziness, difficulty in concentrating, and insomnia [142].

Of growing concern is the reduced susceptibility to currently used antivirals, which has been demonstrated in influenza A and B strains [146,147]. Clinical cases of influenza viruses harbouring single or multiple NA or haemagglutinin (HA) substitutions or deletions have been reported [148]. H1N1 influenza viruses containing a mutation conferring resistance to oseltamivir, one of the most common resistance mutations seen in treated patients since 2004, have now circled the globe [149]. Adamantane resistance increased in frequency from 0.4% of influenza A viruses isolated in 1994–1995 to 12.3% in 2003–2004. Of concern is the fact that the currently circulating strains of avian H5N1 influenza are highly resistant, thus if human infections do become more frequent, the M2 inhibitors will have no useful therapeutic role [142]. Combination therapy of antivirals with different mechanisms of action has demonstrated greater clinical efficacy than monotherapy [150,151] and has been promoted for the treatment of strains resistant to one of the NA inhibitors [152]. However, mutations resulting in a cross-resistant phenotype to zanamivir and oseltamivir have been reported and are more likely to occur in immunocompromised individuals [147,153]. While these resistant phenotypes tend to arise from prolonged treatment with NA inhibitors, it is generally immunocompromised patients that required prolonged therapy in the first place. Given that the only approved antivirals against influenza are already inducing emergence of resistant mutants, there is an urgent need for the development of new antiviral approaches.

A number of other HRV-targeted antiviral agents have been developed but have so far not been approved for human use. These agents typically target the HRV capsid to prevent binding to host cells, or inhibit viral 3C protease, the activity of which is essential to viral replication [154,155]. However, considering these are viral targets and the high mutation rates of RNA viruses, the efficacy of these antiviral classes are likely to be undermined by resistant mutants. During phase II clinical trials with the capsid binder pleconaril, virus variants with reduced susceptibility or even full resistance were detected in 11% and 3% of the drug-treated subjects, respectively. All capsid binders, including vapendavir and pleconaril, share the same target so drug-resistant mutants exhibit cross-resistance [133]. Development is further complicated by formulation bioavailability and toxicity [133].

Thus, whilst the treatment of viral-induced AECOPD may confer long-term benefits in COPD patients, the need for new antiviral targets that will not instigate resistance is needed, particularly given the likelihood of prolonged treatment regimens in these patients.

Non-pharmacological therapy

Non-pharmacological therapy, such as patient education, pulmonary rehabilitation, long term oxygen and minimising exposure to particulate matter are also important for improving health-related quality of life in COPD patients [156,157]. However, smoking cessation is one of the few interventions that slows the rate of progression of COPD and prolongs life expectancy [158,159]. The Lung Health Study, a five-year early intervention study involving 3,926 smokers with mild to moderate airflow limitation due to COPD demonstrated the benefit of sustained smoking cessation. Participants who ceased smoking experienced half the rate of decline in FEV1 than continuing smokers, which was comparable to those that had never smoked [160]. This benefit persisted for at least an additional six years in those that remained abstinent [161]. In addition, smoking cessation, regardless of the severity of lung disease, has been shown to have a mortality benefit, secondary to the reduction in cardiovascular and lung cancer mortality [162]. Addiction to the nicotine component of tobacco and the behavioural dependence on smoking has resulted in a large proportion (30.4% to 43.0%) of moderate to severe COPD patients continuing to smoke [156]. This is in spite of the two-fold increase in smoking cessation in patients undergoing nicotine replacement therapy as relapse rates are high in COPD compared to the general population [163,164]. The recommendation of oxygen therapy came from early experiments that showed long-term treatment with supplemental oxygen reduced mortality among patient with COPD [165]. However, recent studies have refuted the benefits of oxygen therapy, finding no effect on survival of COPD patients with moderate hypoxemia [165–167]. The Long-Term Oxygen Treatment trial of 738 COPD patients followed for 1-6 years, found no significant benefits of long-term oxygen therapy on survival, hospitalization rates, exacerbations or other outcomes such as quality of life, lung function and exercise capacity [165,168].

Nicotine replacement therapy can be administered in various formulations such as gums, lozenges, transdermal patches, inhalers and nasal sprays. However, each method comes with issues regarding nicotine delivery and/or side effects [156]. Electronic cigarettes (EC), have gained rapid popularity as a mode of nicotine replacement therapy, with the concept that they are a safer alternative to cigarette smoking. Despite their increasing use, there is limited research regarding the impact of EC on human health and effects on the lungs [164,169]. EC vapour typically contains nicotine, together with a variety of flavourings, additives, and other contaminants that have the potential to affect normal lung biology. They also may be gateway formulations to conventional smoking and be particularly deleterious in COPD patients [170].

Evidence shows that EC aerosols have immune modulatory activity on human and mouse airway epithelial cells in vitro and mice in vivo, resulting in oxidative stress [171], low levels of inflammatory cell recruitment [172–174], and DNA damage that reduced repair activity [175]. Two-week EC aerosol exposure in mice resulted in reduced bacterial clearance and increased susceptibility to influenza virus infection compared to air-exposed controls, despite appropriate recruitment of neutrophils and alveolar macrophages. The impaired immune defence was attributed to reduced levels of cytokines (IL-17A, IFNγ, and TNF) involved in protective immunity against infection. Reduced IL-17 responses and defective bacterial phagocytic function of alveolar macrophages has also been observed. Increases in phosphatidylinositol 3-kinase and miR-125a/b, and impaired stress granule formation have all been implicated in increased susceptibility to influenza virus infection in COPD [31,176]. Miyashita et al. reported that nicotine-containing EC vapour may increase susceptibility to pneumococcal infection by upregulating expression of platelet-activating factor receptor in primary cells and mouse nasal epithelium, which is associated with pathogen attachment [177].

It is unclear which component(s) of EC vapour elicits these immunomodulatory effects. Nicotine has many immunosuppressive effects, including impairing antibacterial defences against S. pneumoniae and Legionella pneumophilia [178,179], and alteration of macrophage activation that suppresses adherence, chemotaxis, phagocytosis and killing of bacteria [180–182]. The effects of other components on pulmonary function are less clear but constituents such as propylene glycol are known to elicit detrimental effects on lung function of workers exposed to theatrical smoke machines [183]. In a small study, acute exposure to nicotine-rich aerosols in healthy naïve subjects affected the biology of small airway epithelium, alveolar macrophages and the alveolar capillary endothelium. Gene expression changes in small airway epithelium and alveolar macrophages were also observed in the nicotine-free group, suggesting that EC vapour may have harmful long-term effects [175]. We recently showed that in a manner very similar to cigarette smoke, EC and IQOS (heat-not-burn smoking device) has the potential to increase oxidative stress and inflammation, infections, airway remodelling and initiate epithelial mesenchymal transition (EMT) related changes in the airways of users of these devices. However, prospective clinical studies must be conducted to verify these in vitro, cell-based findings on EC and IQOS [ 184].

New therapeutic targets for the prevention of infectious AECOPD

Microbial pathogenesis involves a number of vital steps in order to infect and survive in the host environment. Upon access to the respiratory tract, pathogens must find a way to attach to host tissue, avoid destruction by host immune defences and replicate despite harsh environmental pressures and antimicrobial therapies (Figure 1). Development of new therapeutic agents has focussed on subverting these pertinent steps; inhibition of attachment/invasion, disruption of cell membrane, inhibition of microbial replication or enhancing clearance by the immune response (Figure 1) [185]. The rising concern of antiviral and antibiotic resistance has also lead to the focus on specific host cellular processes essential for viral replication and modulation of the inflammatory profile in COPD, which is currently unresponsive to current pharmacotherapies [186]. These strategies are less likely to induce antimicrobial resistance as a missing cellular function is more difficult for a pathogen to adapt to, and should affect replication independent of the type, strain and antigenic properties of the invading pathogen [138]. New therapeutic targets that mitigate host-pathogen attachment and immune subversion have been summarised in Tables 2 and 3, respectively.

New potential therapies targeting pathogen-host binding and immune signalling pathways involved in infectious exacerbations of COPD

Figure 1
New potential therapies targeting pathogen-host binding and immune signalling pathways involved in infectious exacerbations of COPD

Bacterial and viral pathogens inhaled from the upper respiratory tract or the environment exploit upregulated host cell receptors for attachment via their cognate ligands. Pathogen adhesion to host receptors causes further upregulation of some host receptors which facilitates chronic colonization and invasion of COPD airways. Epithelial binding triggers immune defences which are mitigated by the invading pathogen at various steps in the immune signalling pathway. Avoidance of immune clearance by a dysfunctional immune response allows pathogens to further facilitate chronic colonization and cause acute exacerbations that contribute to progression of COPD. The additive effects of macrophage dysfunction, pathogen persistence and oxidative stress also contribute to disease progression through thickening of the airway wall. Potential therapeutic agents/inhibitors of pathogen host-cell attachment and the altered immune response are demonstrated in orange. NTHi, nontypeable Haemophilus influeanzae; RSV, respiratory syncytial virus; HRV, human rhinovirus; ChoP, phosphorylcholine; gG, glycoprotein G; gF, glycoprotein F; HA, haemagglutinin; OMP, outer membrane protein; UspA1, ubiquitous surface protein A1; EBP, entry-blocking peptide; Mab, monoclonal neutralising antibody; CEACAM, anti-carcinoembryonic antigen cell adhesion molecule; ICAM-1, intracellular adhesion molecule 1; PAFr, platelet-activating factor receptor; GAG, glycosaminoglycan; SA, sialic acid; RV, resveratrol; NS1, non-structural protein; IFN, interferon; IFITM, interferon-inducible transmembrane; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositide 3-kinase; SOCS, suppressor of cytokine signalling; PKC, protein kinase C; PKR, protein kinase R; EGFR, epidermal growth factor receptor; TLR, toll-lik receptor; PDE, phosphodiesterase; COPD, chronic obstructive pulmonary disease; IL-8, interleukin 8.

Figure 1
New potential therapies targeting pathogen-host binding and immune signalling pathways involved in infectious exacerbations of COPD

Bacterial and viral pathogens inhaled from the upper respiratory tract or the environment exploit upregulated host cell receptors for attachment via their cognate ligands. Pathogen adhesion to host receptors causes further upregulation of some host receptors which facilitates chronic colonization and invasion of COPD airways. Epithelial binding triggers immune defences which are mitigated by the invading pathogen at various steps in the immune signalling pathway. Avoidance of immune clearance by a dysfunctional immune response allows pathogens to further facilitate chronic colonization and cause acute exacerbations that contribute to progression of COPD. The additive effects of macrophage dysfunction, pathogen persistence and oxidative stress also contribute to disease progression through thickening of the airway wall. Potential therapeutic agents/inhibitors of pathogen host-cell attachment and the altered immune response are demonstrated in orange. NTHi, nontypeable Haemophilus influeanzae; RSV, respiratory syncytial virus; HRV, human rhinovirus; ChoP, phosphorylcholine; gG, glycoprotein G; gF, glycoprotein F; HA, haemagglutinin; OMP, outer membrane protein; UspA1, ubiquitous surface protein A1; EBP, entry-blocking peptide; Mab, monoclonal neutralising antibody; CEACAM, anti-carcinoembryonic antigen cell adhesion molecule; ICAM-1, intracellular adhesion molecule 1; PAFr, platelet-activating factor receptor; GAG, glycosaminoglycan; SA, sialic acid; RV, resveratrol; NS1, non-structural protein; IFN, interferon; IFITM, interferon-inducible transmembrane; PTEN, phosphatase and tensin homolog; PI3K, phosphoinositide 3-kinase; SOCS, suppressor of cytokine signalling; PKC, protein kinase C; PKR, protein kinase R; EGFR, epidermal growth factor receptor; TLR, toll-lik receptor; PDE, phosphodiesterase; COPD, chronic obstructive pulmonary disease; IL-8, interleukin 8.

Table 2
A summary of host-pathogen interactions that promote susceptibility to infection in COPD and the therapeutic potential of interrupting these interactions
HOST-ASSOCIATED PATHOGEN-ASSOCIATED DISRUPTION OF HOST-PATHOGEN INTERACTION 
Receptor and normal function Aberrations in COPD Pathogen and ligand Effects/benefits Therapeutic Potential Challenges 
PAFr; mediates phospholipid-induced inflammation. Upregulated in COPD airway epithelium.
Upregulated by smoking and nicotine-rich E-cigarette vapour in vitro. 
NTHi; pCho Confers persistence-related effects (adherence, internalization and resistance to some host-derived antimicrobials). PAFr antagonists; WEB-2086 and CV-3988 shown to attenuate pathogen adhesion. The exact constituents of CSE responsible for PAFr upregulation is unknown. 
  S.pneumoniae;pCho  PCho as a vaccine target; may be effective in combination with conserved immunogens. Variability in immune stimulation.
Subject to phase variation. 
ICAM-1; mediates normal leukocyte recruitment and T-cell development. Upregulated in chronic bronchitis and smoking-related chronic airflow limitation.
Upregulated by NTHi and HRV via NF-κβ pathways. 
NTHi; P5 fimbria and PilA
HRV (60-90% of serotypes) 
Long-term colonization, persistence and biofilm formation.
RSV enhances the attachment of NTHi. 
Specific antibody blockade of ICAM-1; prevents entry of two HRV serotypes and decreases associated inflammation and viral load in mice. Reduces NTHi adhesion. Potential for non-specific immune effects. 
    Antibodies against PilA and P5; shown to eradicate biofilms and be protective against NTHi in rat and chinchilla models of middle ear infection. Subject to antigenic variability. May be overcome by delivering P5- and PilA-targeted immunogens together with an adjuvant. 
CEACAM-1; involved in signalling events that mediate key cell processes. Upregulated by NTHi and M. catarrhalis. NTHi; OMP P1
M.catarrhalis; UspA1 
Efficient adhesion, and internalization.
Induces apoptosis and suppression of TLR2/4 immune recognition. 
Antibodies against CEACAM-1;
YTH71.3 effectively blocked NTHi attachment to chinchilla nasopharynx. 
May increase susceptibility to viral infection.
Direct correlation between CEACAM-1 and COPD needs to be elucidated. 
Sialic acid; sugar residues found on host cell membrane glycoproteins. plays a central role in the functioning of biological systems. Increased levels in saliva.
Sugar changes within sputum linked to COPD severity. 
Influenza virus; HA-A Cell internalization and infection. Block receptor sites of HA-A with small peptide molecules; Arbidol (umifenovir) demonstrated broad-spectrum antiviral activity and was protective against influenza when administered prophylactically. Reduces frequency of viral-induced exacerbations in COPD. Only Arbidol has been approved for administration in humans, making it difficult to anticipate adverse events.
Both approaches are sensitive to mutations in HA-A and are only effective during early viral replication.
Potentially undiscovered mechanisms of influenza A virus attachment and host membrane fusion. 
    Neutralising MAbs targeted against HA-A subunits; a range of Abs with varying subtype binding and/or neutralization spectra have been found to neutralise a number of influenza subtypes.  
HOST-ASSOCIATED PATHOGEN-ASSOCIATED DISRUPTION OF HOST-PATHOGEN INTERACTION 
Receptor and normal function Aberrations in COPD Pathogen and ligand Effects/benefits Therapeutic Potential Challenges 
PAFr; mediates phospholipid-induced inflammation. Upregulated in COPD airway epithelium.
Upregulated by smoking and nicotine-rich E-cigarette vapour in vitro. 
NTHi; pCho Confers persistence-related effects (adherence, internalization and resistance to some host-derived antimicrobials). PAFr antagonists; WEB-2086 and CV-3988 shown to attenuate pathogen adhesion. The exact constituents of CSE responsible for PAFr upregulation is unknown. 
  S.pneumoniae;pCho  PCho as a vaccine target; may be effective in combination with conserved immunogens. Variability in immune stimulation.
Subject to phase variation. 
ICAM-1; mediates normal leukocyte recruitment and T-cell development. Upregulated in chronic bronchitis and smoking-related chronic airflow limitation.
Upregulated by NTHi and HRV via NF-κβ pathways. 
NTHi; P5 fimbria and PilA
HRV (60-90% of serotypes) 
Long-term colonization, persistence and biofilm formation.
RSV enhances the attachment of NTHi. 
Specific antibody blockade of ICAM-1; prevents entry of two HRV serotypes and decreases associated inflammation and viral load in mice. Reduces NTHi adhesion. Potential for non-specific immune effects. 
    Antibodies against PilA and P5; shown to eradicate biofilms and be protective against NTHi in rat and chinchilla models of middle ear infection. Subject to antigenic variability. May be overcome by delivering P5- and PilA-targeted immunogens together with an adjuvant. 
CEACAM-1; involved in signalling events that mediate key cell processes. Upregulated by NTHi and M. catarrhalis. NTHi; OMP P1
M.catarrhalis; UspA1 
Efficient adhesion, and internalization.
Induces apoptosis and suppression of TLR2/4 immune recognition. 
Antibodies against CEACAM-1;
YTH71.3 effectively blocked NTHi attachment to chinchilla nasopharynx. 
May increase susceptibility to viral infection.
Direct correlation between CEACAM-1 and COPD needs to be elucidated. 
Sialic acid; sugar residues found on host cell membrane glycoproteins. plays a central role in the functioning of biological systems. Increased levels in saliva.
Sugar changes within sputum linked to COPD severity. 
Influenza virus; HA-A Cell internalization and infection. Block receptor sites of HA-A with small peptide molecules; Arbidol (umifenovir) demonstrated broad-spectrum antiviral activity and was protective against influenza when administered prophylactically. Reduces frequency of viral-induced exacerbations in COPD. Only Arbidol has been approved for administration in humans, making it difficult to anticipate adverse events.
Both approaches are sensitive to mutations in HA-A and are only effective during early viral replication.
Potentially undiscovered mechanisms of influenza A virus attachment and host membrane fusion. 
    Neutralising MAbs targeted against HA-A subunits; a range of Abs with varying subtype binding and/or neutralization spectra have been found to neutralise a number of influenza subtypes.  
Table 3
A summary of host immune responses and signalling pathways implicated in the increased susceptibility to infections in COPD and potential therapeutic approaches
NORMAL IMMUNE RESPONSE ABERRATIONS IN COPD DOWNSTREAM EFFECTS THERAPEUTIC APPROACHES CHALLENGES 
IMMUNE RESPONSE 
M1 macrophages; produces high levels of pro-inflammatory cytokines and ROS.
M2 macrophages; immunomodulation, tissue remodelling and fibrosis and efferocytosis. Modulates tissue damaging effects of M1 macrophages, including. 
Phenotypic switch towards the M1 phenotype in the airway wall and M2 in the airway lumen. Promotion of a pro-infectious environment and ineffective resolution of inflammation.
Chronic bacterial colonization/infection, excessive inflammation and subsequent lung tissue damage and remodelling that contributes to the progression of COPD. 
Restoration of AM phenotype; roflumilast altered phenotype to a more reparative M2 type.
Endogenous pro-resolving mediators; may promote resolution of inflammation and arrest airway thickening. Dysfunctional Annexin A1 is associated with influenza infection and COPD disease severity. 
Conflicting evidence on the expression of annexin A1 and role in COPD pathogenesis is unclear. 
 Dysfunctional bacterial phagocytosis and efferocytosis.  Restoration of AM function;
Efferocytosis restored by PDE-4 inhibitor aminophylline/theophylline in mouse lung macrophages. Phagocytosis improved by macrolides and statins in vitro. 
Further research is required to determine if they can correct defective bacterial phagocytosis/efferocytosis in COPD. 
 Dysregulated TLR-mediated pathogen recognition and cytokine response.  Synthetic TLR agonists or adjuvant therapy that corrects dysfunctional TLR-mediated responses. May be difficult to manage and relies on effective macrophage function. Current studies may suffer from lack of appropriate controls. 
Oxidative oxygen species; antimicrobial defence produced by immune cells. Increase burden of oxidative stress in COPD airways due to continuous ROS production.
Reduced antioxidant capacity
Impairs AM phagocytosis and efferocytosis, leading to reduced pathogen clearance. Excessive ROS may promote viral infection.
Cycle of continuous ROS production by pathogen persistence and smoking, and reduced resolution of inflammation, causes airway tissue damage and contributes to pathogenesis of COPD. 
Increase endogenous antioxidant enzyme activity; administration of the Gpx mimetic ebselen, or a SOD mimetic, significantly reduces influenza A virus-, and cigarette smoke-induced lung inflammation in mice. Limited research regarding their efficacy and safety in humans. Inability of overexpressed antioxidative enzymes to resolve oxidative burden may suggest dysfunctional antioxidant capacity. 
   Inhibit enzymatic sources of ROS production; specific NOX2 inhibitor, apocynin, supresses viral titre, airway inflammation and cell superoxide production following viral infection in COPD mice models. Apocynin reduced exhaled breath concentrate ROS levels in COPD patients. Possible immunosuppressive side effect of NOX2 inhibitors may contribute to increased infection and/or autoimmune disorders.
Mechanisms of NOX promotion of viral pathogenicity are unclear. Differences in NOX isoforms may affect treatment strategies. 
Microbiome; resident bacteria aid in establishing a balanced immunological phenotype, compete with potentially harmful micro-organisms and synthesize a variety of beneficial biomolecules. Airway dysbiosis; reduction in microbe diversity with over-representation of taxa associated with subclinical lung inflammation and decreased abundance of bacteria with anti-inflammatory capabilities.
Increased iron levels in COPD airways. 
Promotes a pro-infectious environment in COPD airways and increases susceptibility to infection and exacerbation.
Increased airway inflammation and oxidative stress promotes airway damage.
Viral infection enhances risk of infection with pathogenic bacteria. 
Probiotic-mediated stimulation of innate and adaptive immunity; shown to modulate TLR-response, stimulate NK cell function, IFN production and balance between Th1/Th2 cell response.
Probiotic inhibition of pathogen colonization by direct competition of vital nutrients; Haemophilus haemolyticus can inhibit NTHi growth by restricting its access to haem. 
There is a lack of research in the development of respiratory probiotics. 
   Pharmacological iron chelation; a gel loaded with the iron chelator deferiprone and the heme-analogue gallium-protoporphyrin showed significant antibiofilm activity against pathogens in sinusitis. Unknown side-effects of iron chelation in the respiratory tract. 
IMMUNE SIGNALLING PATHWAYS 
PKC; responsible for diverse regulatory roles in membrane structure events, immune responses, gene transcription and cell growth. Excessive PKC activation by influenza virus and RSV.
Dysregulated PKC inhibition due to dysregulated and/or dysfunctional defensin response. 
Ineffective antiviral response.
Promotion of viral host-cell entry and infectivity. 
Increase defensin-mediated PKC inhibition; over-expression of alpha- and beta-defensins in mice were protective against influenza and RSV infections, respectively.
Interference of PKC signalling; resveratrol has broad-spectrum antiviral activity and is protective against RSV and influenza in mice. Nasal spray formulation was found to reduce the severity and recurrence of respiratory infections in children. 
Full mechanism of PKC-mediated viral entry is unknown. Variability of antiviral activity, some viruses enhanced.
Limited effectiveness during active infection.
Long-term increases in defensin levels carry safety concerns. 
PKR; a key executor of antiviral response, along with other IFN-stimulated gene products. Deficient IFN-induction in COPD cells ex vivo, and COPD mice. Influenza virus avoids
PKR-mediated antiviral response by inhibiting IFN expression either directly or via NS1 protein. 
Inhibit NS1-actived signalling cascades; peptide-mediated inhibition of NS1-CPSF30 binding has been shown to limit virus replication in tissue culture. Yet to be tested in vivo and there are safety concerns in COPD. IFN-antagonistic properties are strain- and type- specific. 
   Augmentation of IFN antiviral pathways; prophylactic treatment with intranasal recombinant IFN-α2b (SNG001) was protective against HRV and prevented exacerbations in asthmatics. IFITM proteins that mediate IFN’s broad-spectrum antiviral role against influenza A virus. Uncertainties surrounding antiviral activity of IFITM. IFN response may be dysfunctional and non-responsive to increased IFN levels. Unknown effect on uninfected tissue. 
P13K-p110a; roles in anti-apoptosis, cell proliferation, growth, metabolism and cytokine production/signalling. Exaggerated expression and response of PI3K and decreased expression of the negative regulator PTEN in COPD lungs. Confers increased susceptibility to viral infection and enhanced inflammation and impaired lung function. Specific inhibition PI3K-p110α prior to infection attenuated influenza infection and enhanced IFN-β antiviral responses in COPD lung epithelial cells. The p100α isoform is expressed on all cells, which may cause off-target effects.
The more specific PI3Ky isoform has not yet been characterised in COPD. 
EGFR; important role in the regeneration of damaged tissue, mucin production and elastase-induced IL-8 production in lung epithelial cells Increased EGFR activity which subsequently increases PI3K/Akt signalling and IL-8 secretion. Exacerbated by long-term smoking.
Downregulation of EGFR regulator, Socs5 in COPD airway. 
EGFR promotes influenza A infection either directly or indirectly through activation of PI3K/Akt signalling.
Further activation of EGFR and Il-8 by influenza virus, HRV and M. catarrhalis 
MAbs that prevent endogenous ligand engagement. Research in MAbs has primarily focused on treatments for lung cancer and have not yet been contextualised for COPD. 
   Inhibiting EGFR signalling; restoration of SOCS5 levels restricted influenza virus infection. Fucoidan, exhibits broad anti-influenza activity in mice by enhancing the immune response and blocking EGFR-mediated viral entry. Studies assessing the therapeutic potential of fucoidan in humans is limited. 
NORMAL IMMUNE RESPONSE ABERRATIONS IN COPD DOWNSTREAM EFFECTS THERAPEUTIC APPROACHES CHALLENGES 
IMMUNE RESPONSE 
M1 macrophages; produces high levels of pro-inflammatory cytokines and ROS.
M2 macrophages; immunomodulation, tissue remodelling and fibrosis and efferocytosis. Modulates tissue damaging effects of M1 macrophages, including. 
Phenotypic switch towards the M1 phenotype in the airway wall and M2 in the airway lumen. Promotion of a pro-infectious environment and ineffective resolution of inflammation.
Chronic bacterial colonization/infection, excessive inflammation and subsequent lung tissue damage and remodelling that contributes to the progression of COPD. 
Restoration of AM phenotype; roflumilast altered phenotype to a more reparative M2 type.
Endogenous pro-resolving mediators; may promote resolution of inflammation and arrest airway thickening. Dysfunctional Annexin A1 is associated with influenza infection and COPD disease severity. 
Conflicting evidence on the expression of annexin A1 and role in COPD pathogenesis is unclear. 
 Dysfunctional bacterial phagocytosis and efferocytosis.  Restoration of AM function;
Efferocytosis restored by PDE-4 inhibitor aminophylline/theophylline in mouse lung macrophages. Phagocytosis improved by macrolides and statins in vitro. 
Further research is required to determine if they can correct defective bacterial phagocytosis/efferocytosis in COPD. 
 Dysregulated TLR-mediated pathogen recognition and cytokine response.  Synthetic TLR agonists or adjuvant therapy that corrects dysfunctional TLR-mediated responses. May be difficult to manage and relies on effective macrophage function. Current studies may suffer from lack of appropriate controls. 
Oxidative oxygen species; antimicrobial defence produced by immune cells. Increase burden of oxidative stress in COPD airways due to continuous ROS production.
Reduced antioxidant capacity
Impairs AM phagocytosis and efferocytosis, leading to reduced pathogen clearance. Excessive ROS may promote viral infection.
Cycle of continuous ROS production by pathogen persistence and smoking, and reduced resolution of inflammation, causes airway tissue damage and contributes to pathogenesis of COPD. 
Increase endogenous antioxidant enzyme activity; administration of the Gpx mimetic ebselen, or a SOD mimetic, significantly reduces influenza A virus-, and cigarette smoke-induced lung inflammation in mice. Limited research regarding their efficacy and safety in humans. Inability of overexpressed antioxidative enzymes to resolve oxidative burden may suggest dysfunctional antioxidant capacity. 
   Inhibit enzymatic sources of ROS production; specific NOX2 inhibitor, apocynin, supresses viral titre, airway inflammation and cell superoxide production following viral infection in COPD mice models. Apocynin reduced exhaled breath concentrate ROS levels in COPD patients. Possible immunosuppressive side effect of NOX2 inhibitors may contribute to increased infection and/or autoimmune disorders.
Mechanisms of NOX promotion of viral pathogenicity are unclear. Differences in NOX isoforms may affect treatment strategies. 
Microbiome; resident bacteria aid in establishing a balanced immunological phenotype, compete with potentially harmful micro-organisms and synthesize a variety of beneficial biomolecules. Airway dysbiosis; reduction in microbe diversity with over-representation of taxa associated with subclinical lung inflammation and decreased abundance of bacteria with anti-inflammatory capabilities.
Increased iron levels in COPD airways. 
Promotes a pro-infectious environment in COPD airways and increases susceptibility to infection and exacerbation.
Increased airway inflammation and oxidative stress promotes airway damage.
Viral infection enhances risk of infection with pathogenic bacteria. 
Probiotic-mediated stimulation of innate and adaptive immunity; shown to modulate TLR-response, stimulate NK cell function, IFN production and balance between Th1/Th2 cell response.
Probiotic inhibition of pathogen colonization by direct competition of vital nutrients; Haemophilus haemolyticus can inhibit NTHi growth by restricting its access to haem. 
There is a lack of research in the development of respiratory probiotics. 
   Pharmacological iron chelation; a gel loaded with the iron chelator deferiprone and the heme-analogue gallium-protoporphyrin showed significant antibiofilm activity against pathogens in sinusitis. Unknown side-effects of iron chelation in the respiratory tract. 
IMMUNE SIGNALLING PATHWAYS 
PKC; responsible for diverse regulatory roles in membrane structure events, immune responses, gene transcription and cell growth. Excessive PKC activation by influenza virus and RSV.
Dysregulated PKC inhibition due to dysregulated and/or dysfunctional defensin response. 
Ineffective antiviral response.
Promotion of viral host-cell entry and infectivity. 
Increase defensin-mediated PKC inhibition; over-expression of alpha- and beta-defensins in mice were protective against influenza and RSV infections, respectively.
Interference of PKC signalling; resveratrol has broad-spectrum antiviral activity and is protective against RSV and influenza in mice. Nasal spray formulation was found to reduce the severity and recurrence of respiratory infections in children. 
Full mechanism of PKC-mediated viral entry is unknown. Variability of antiviral activity, some viruses enhanced.
Limited effectiveness during active infection.
Long-term increases in defensin levels carry safety concerns. 
PKR; a key executor of antiviral response, along with other IFN-stimulated gene products. Deficient IFN-induction in COPD cells ex vivo, and COPD mice. Influenza virus avoids
PKR-mediated antiviral response by inhibiting IFN expression either directly or via NS1 protein. 
Inhibit NS1-actived signalling cascades; peptide-mediated inhibition of NS1-CPSF30 binding has been shown to limit virus replication in tissue culture. Yet to be tested in vivo and there are safety concerns in COPD. IFN-antagonistic properties are strain- and type- specific. 
   Augmentation of IFN antiviral pathways; prophylactic treatment with intranasal recombinant IFN-α2b (SNG001) was protective against HRV and prevented exacerbations in asthmatics. IFITM proteins that mediate IFN’s broad-spectrum antiviral role against influenza A virus. Uncertainties surrounding antiviral activity of IFITM. IFN response may be dysfunctional and non-responsive to increased IFN levels. Unknown effect on uninfected tissue. 
P13K-p110a; roles in anti-apoptosis, cell proliferation, growth, metabolism and cytokine production/signalling. Exaggerated expression and response of PI3K and decreased expression of the negative regulator PTEN in COPD lungs. Confers increased susceptibility to viral infection and enhanced inflammation and impaired lung function. Specific inhibition PI3K-p110α prior to infection attenuated influenza infection and enhanced IFN-β antiviral responses in COPD lung epithelial cells. The p100α isoform is expressed on all cells, which may cause off-target effects.
The more specific PI3Ky isoform has not yet been characterised in COPD. 
EGFR; important role in the regeneration of damaged tissue, mucin production and elastase-induced IL-8 production in lung epithelial cells Increased EGFR activity which subsequently increases PI3K/Akt signalling and IL-8 secretion. Exacerbated by long-term smoking.
Downregulation of EGFR regulator, Socs5 in COPD airway. 
EGFR promotes influenza A infection either directly or indirectly through activation of PI3K/Akt signalling.
Further activation of EGFR and Il-8 by influenza virus, HRV and M. catarrhalis 
MAbs that prevent endogenous ligand engagement. Research in MAbs has primarily focused on treatments for lung cancer and have not yet been contextualised for COPD. 
   Inhibiting EGFR signalling; restoration of SOCS5 levels restricted influenza virus infection. Fucoidan, exhibits broad anti-influenza activity in mice by enhancing the immune response and blocking EGFR-mediated viral entry. Studies assessing the therapeutic potential of fucoidan in humans is limited. 

Mediators of pathogen-host cell attachment

Platelet-activating receptor (PAFr)

The PAFr is a widespread G protein-coupled receptor that is expressed on the surface of the majority of innate immune cells and is a potent mediator of phospholipid-induced inflammation [187]. The PAFr recognises the phosphorylcholine (pCHo) determinant on the eukaryotic pro-inflammatory chemokine PAF, which is synthesised by various cells, such as leukocytes, macrophages and platelets [188]. PAFr-PAF binding mobilises Ca2+ and activates numerous signalling pathways, such as those involving phospholipase C and A2, and protein kinase C with downstream immune modulatory effects [189,190]. Like PAF, the cell wall of NTHi and S. pneumoniae express pCho residues which engage the PAFr through molecular mimicry and induce cytoskeleton remodelling and subsequent host cell internalization [187,191]. This exploitation confers several persistence-related effects, including adherence, invasion and resistance to some host-derived antimicrobials [129,192–194].

PAFr is of particular interest as cigarette smoke exposure, the major risk factor for the development of COPD [5,187], has been shown to significantly upregulate its expression in the airway epithelium [195–198]. Studies have found significant increases in PAFr expression in both large and small airway epithelium and alveoli of active smokers and COPD patients, suggesting a ubiquitous expression of the receptor throughout the airways. The effect on adhesion is not limited to the most distal epithelial cells, since cigarette smoke extract (CSE)-stimulated adhesion has been shown in the bronchial epithelial cell line (BEAS2-B) and human primary bronchoepithelial cells (hpBECs) [195,197]. Increased PAFr mRNA and protein levels in CSE-exposed A549 cells suggests a major role in CSE-induced adhesion [195]. Similar mechanisms could also be active in idiopathic interstitial lung disease [199].

Significant increases in S. pneumoniae and NTHi adherence to cultured primary human bronchial epithelial cells (hpBECs) exposed to CSE has also been demonstrated [195,196]. Adhesion by these pathogens was attenuated by the PAFr antagonist, WEB-2086, to levels in non-CSE-exposed cells [196]. We also found that adhesion was attenuated by a specific PAFr antagonist (CV-3988). Compatible with previous studies in cytokine-stimulated A549 cells, blocking of PAFr attenuated stimulated, but not unstimulated adhesion of pneumococci to these cells [195]. The exact constituents of CSE responsible for PAFr upregulation remains unknown. However, a recent study showed upregulation of PAFr expression in nasal epithelium in response to nicotine-rich E-cigarette vapour in vitro, suggesting that nicotine may be involved [200].

These investigations suggest that the upregulation of PAFr levels on the respiratory epithelial cell surface may increase susceptibility to infections in COPD patients [197]. PAFr antagonists may therefore be a new drug target for inhibiting PAFr-dependent respiratory infections in smokers and COPD patients [196]. The PAFr bacterial ligand, PCho would be a poor vaccine target for NTHi given the constant phase variation and variable nature in which it stimulates protective immunity [192,201]. However, it may be more promising if combined with immunogens (e.g. proteins) that are conserved across NTHi strains.

Intracellular adhesion molecule-1 (ICAM-1; CD54)

ICAM-1 is expressed constitutively on a wide variety of cells and is a key molecule in processes critical to normal leukocyte recruitment and T-cell development such as reversible cell-cell adhesion that enables intercellular communication and signal transduction [202]. Additionally, aberrant ICAM-1 levels have been implicated in pathological complications such as acquired immunodeficiency syndrome, malignancies and allergic asthma [203]. NTHi and 60-90% of HRV serotypes utilise ICAM-1 in attaching to host bronchial and alveolar epithelial cells [204–206]. More data is required to determine the frequency at which NTHi uses this mechanism of adhesion. However, blockade of cell surface ICAM-1 with a specific antibody reduced the adhesion of NTHi to A549 respiratory epithelial cells by 37% and to CHO-ICAM-1 cells by 69%; suggesting a cell-dependent role of ICAM-1 as a binding target [202].

Evidence suggests that expression of ICAM-1 is stimulated via the activation of nuclear factor-kappa-B (NF-κβ) pathways by NTHi and HRV [207]. We previously reported increased ICAM-1 levels on the airway epithelium of patients with chronic bronchitis and smoking-related chronic airflow limitation [208]. In vitro, incubation of respiratory epithelial cells with NTHi increased ICAM-1 expression four-fold and the binding of HRV39 in a TNF-dependant manner [129,202,205,209]. Additionally, all HRV serotypes, regardless of the receptor used for cell attachment, have been shown to enhance ICAM-1 expression [207]. This suggests a mechanism for additive or synergistic effects between bacterial and viral infection that may explain why COPD patients are more susceptible to viral infections and NTHi-HRV co-infections [209].

Vaccine development against NTHi and HRV infections is difficult given the high degree of antigenic heterogeneity. Antibodies produced in response to vaccines provide little or no cross-protection against newly-acquired strains [201,210]. This makes host ICAM-1 an enticing therapeutic target for the prevention of both NTHi and HRV infection in COPD patients. The therapeutic potential of this approach was assessed using a mouse anti-human ICAM-1 antibody (14C11) that specifically binds domain 1 of human ICAM-1. When administered topically or systemically, the antibody prevented the entry of two major groups of HRVs and reduced cellular inflammation, pro-inflammatory cytokine production and virus load in vivo [211]. Inhibiting ICAM-1, therefore, offers a promising means of supressing HRV entry and may also have application in preventing the common cold and exacerbations of bronchiolitis, asthma, COPD and pneumonia in patients [210,212]. However, inhibiting ICAM-1 has the potential to induce deficient normal host defences and cell trafficking as a side-effect.

NTHi ligands for ICAM-1, namely the outer membrane protein P5 fimbria and the type IV pilin, PilA, have also been investigated as potential therapeutic targets [129,205]. Expression of PilA contributes significantly to ICAM-1-mediated adherence and mucosal colonization and also has important roles in biofilm formation and the ability of NTHi to exhibit competence [213]. Each of these phenotypes has important implications for the initiation and establishment of long-term colonization of humans, as well as the ability to induce disease, cause recurrence and promote the chronicity of NTHi-induced diseases [205]. It has also been shown that respiratory syncytial virus (RSV) enhances the attachment of NTHi to epithelial cells which is largely mediated by the bacterium’s P5-fimbria-binding receptors [214].

NTHi PilA may also be a therapeutic target. Disruption of the pil locus diminished the ability of NTHi to adhere to normal human bronchial epithelial cells (NHBEs) in vitro or to form stable, robust biofilms in a continuous flow chamber. Additionally, a pilA mutant was not as capable of maintaining colonization of the mucosal epithelial surface in the chincilla nasopharynx [213]. Antibodies against PilA induces the formation of antibodies that eradicate NTHi from middle ear fluids and mucosal biofilms of experimental otitis media from the chinchilla middle ear [215]. Antibodies directed against P5 have also shown to be protective in rat and chinchilla models of middle-ear infection [205]. During chronic infections with NTHi, P5 is antigenically variable, potentially permitting the bacteria to evade immune recognition and killing [202]. However, this may be overcome by delivering P5- and PilA-targeted immunogens together with an adjuvant. This immunisation strategy has been shown to induce significantly earlier clearance of NTHi from the nasopharynges and middle ears of chinchillas compared to immunogen or adjuvant alone [215].

Carcinoembryonic antigen-related cell adhesion molecule-1 (CEACAM-1)

NTHi and M. catarrhalis are able to utilize CEACAM-1 as a receptor for efficient adhesion, and internalization, and to induce apoptosis and suppression of Toll-like receptor-2 (TLR2) and TLR4 as an immune-evasion strategy [216]. The CEACAM family is a group of 12 highly glycosylated intercellular adhesion molecules involved in signalling events that mediate key processes including cell adhesion, proliferation and differentiation, as well as tumour suppression and apoptosis [217]. CEACAM-1 binding is mediated by P1, an outer membrane protein in NTHi, and ubiquitous surface protein A1 (UspA1), an outer membrane protein in M. catarrhalis [218]. Both pathogens can increase the expression CEACAM-1 on host cells, thereby increasing host susceptibility to bacterial infection [218]. An in vivo study with chinchillas reported that anti-CEACAM-1 antibody (YTH71.3) effectively blocked NTHi attachment to the nasopharynx [218]. However, a direct correlation between CEACAM-1 levels and COPD has not yet been found [217]. Despite a lack of correlation, inhibition of binding to CEACAM-1 may be effective in preventing infection with NTHi and M. catarrhalis. However, studies have also shown that the intrinsic signalling of CEACAM-1 is also essential for generating efficient B-cell survival and protective anti-viral antibody response. CEACAM-1 may function as broad-spectrum antiviral suppressor including influenza virus [219] and the absence of CEACAM-1 on B-cells leads to insufficient anti-viral B-cell response in mice [220]. Similarly, CEACAM1 is found to be an important regulator of virus-specific CD8+ T cell functions in mice and humans [221]. Thus, blocking this pathway may increase susceptibility to viral infection. However, a study of mice with altered expression of Ceacam1a failed to develop clinical signs of viral infection with mouse hepatitis virus, produced smaller viral load in the liver and survived a dose 100-fold higher than wild-type mice. This was a result of the reduced expression of CEACAM-1a/D1-4 proteins and altering the ratios between two- and four- domain CEACAM-1a isoforms in vivo. These results suggest an isoform-dependent activity of CEACAM-1, which may be relevant in COPD [222].

Sialic acid (SA) and Haemagglutinin A (HA-A)

SAs are a group of nine-carbon monosaccharides that decorate the surface of most mammalian cells, mostly in cell membrane glycoproteins. These residues contribute to the functioning of several biological systems, including the stabilization of glycoproteins and cellular membranes, and assisting in cell-cell recognition and interactions [223]. There have been reports of increased levels of SA in the serum and saliva if COPD patients [224,225]. Influenza viruses primarily infect bronchoepithelial cells (BECs) through the binding of viral HA-A to specific host SA–terminated glycoproteins. SAa2,6Gal and SAa2,3Gal residues are mainly found on upper and lower respiratory epithelial cells and are preferentially bound by human and avian influenza viruses, respectively [31,226]. Following anchorage to host cells, the influenza virus is internalized by endocytosis into the endosome. The low pH environment of the endosome allows the viral HA-A to undergo a conformational change and fuse with the endosomal membrane, thereby allowing the release of viral genes into the host cytoplasm [125,227,228].

Disruption of viral attachment has been proposed by two main mechanisms. The first is direct competition with SA binding by blocking receptor sites of HA-A, either directly with small peptide molecules [229,230] or by neutralising antibodies targeted against HA-A subunits [231]. The second strategy involves interference of the HA-A conformational change necessary for viral fusion [232–234], thus preventing the subsequent release of viral RNA into host cells [235]. Preventing viral replication early in the infection cycle has proved to be a promising tactic in preventing and treating viral infections and may provide cross-protection of different viral strains [236].

A plethora of entry-blocking peptides are in development that display broad anti-influenza virus activity [236,237]. Of these peptide-based inhibitors, only Arbidol (umifenovir) has been approved for administration in humans, albeit only in Russia and China [236]. Arbidol has the ability to elicit protective broad-spectrum antiviral activity against a number of respiratory viruses such as influenza, RSV, HRV, coxsackie virus and adenovirus in vitro and in vivo [152,238]. By functioning as molecular glue, Arbidol stabilizes the prefusion conformation of HA that inhibits the large conformational rearrangements associated with membrane fusion in the low pH of the endosome [239]. Arbidol has been found to reverse the main symptoms, reduce incidence of complications and contribute to the stabilization of adaptive reactions in patients with acute respiratory viral infections [240]. A study of 100 patients with COPD or asthma found that seasonal and post-exposure prophylaxis using Arbidol was associated with 2.6-times reduction in influenza and acute respiratory viral infection-related morbidity during an epidemic period. This study also showed that prophylactic administration of Arbidol before and during flu season reduced the frequency of infectious exacerbations of COPD [241]. Although clinical effectiveness has been shown, anticipating adverse events are difficult as Arbidol is the only available drug that targets HA-A and the structural information on drug-HA complexes is limited [239]. Although there are no reports of Arbidol resistance so far, [242] drug resistance is still a concern as influenza viruses mutate frequently and unpredictably, especially in the HA-A gene [243].

As an alternative to vaccines, neutralizing monoclonal antibodies (MAbs) represent a passive therapeutic strategy to provide immediate protected against influenza virus infection [244]. The MAb, HA-7 was found to potently neutralise and completely protected mice against lethal challenges of H5N1 [231]. This MAb specifically targets the highly conserved epitope HA-A “head” subunit (HA1), which is mainly responsible for receptor binding [231]. MAb CR6261 was found to neutralize multiple influenza subtypes by blocking the conformational rearrangements associated with membrane fusion. It was also protective from lethal challenge of mice from H5N1, and also with H1N1 when administered up to 5 days post-infection [245]. MAb CR8020 exhibited neutralizing activity against most group 2 viruses, including H3N2 and H7N7 [246] and MAbs 5A7 and 46B8 have shown anti-influenza B activity conferring protection in mice. [247] Finally, a MAb that recognizes the HA glycoprotein of all 16 subtypes and neutralizes both group 1 and group 2 influenza A viruses conferred protection to mice and ferrets when passively transferred [248]. It is evident that there are a range of MAbs with varying subtype binding and/or neutralization spectra which raises the possibility of combining different MAbs that could provide broad protection against all seasonal and pandemic influenza A viruses [249].

Entry-blocking with small molecule peptides and MAbs both manipulate the HA-A-mediated attachment to host SA. However, two HA-A subtypes, H17 and H18 from influenza viruses isolated from bats, do not bind to SA and the receptor for these viruses is not yet known [250]. This suggests a novel mechanism of influenza A virus attachment and activation of membrane fusion for entry into host cells. Thus, bats may constitute a potentially important reservoir for influenza viruses [251]. Although it is unlikely, there is the possibility that bat-derived genomes could exchange genetic information with human influenza viruses through reassortment, resulting in an immunologically unrecognisable influenza strain. The prospect of natural reassortment has been realised by the in vitro reassortment of a H1N1 virus with NS1 from the bat strain H17N10 that was able to propagate [252]. Furthermore, an infectious bat-derived chimeric influenza virus containing HA-A and NA from a human influenza virus was shown to replicate well in a broad range of mammalian cell cultures including, human primary airway epithelial cells and in mice in vivo [253].

Host immune defence

Macrophage function and phenotype

Macrophages have important roles in the host immune defence against bacterial and viral pathogens in the lung, and their involvement includes recognition of pathogen components via TLRs. Lung macrophages exhibit phenotypic and functional plasticity in order to adapt and respond to a variety of insults [254]. Macrophages can be crudely divided into M1 classically-activated and M2 alternatively-activated subtypes [255]. M1 macrophages promote Th1-type immunity by producing high levels of pro-inflammatory cytokines, such as IL-1β, TNF, and IL-12 induced by exposure to bacterial proteins and IFN-γ. Lipopeptides from NTHi and S. pneumoniae bind to and activate TLR2 [256], while the lipopolysaccharide (LPS) and lipooligosaccharide (LOS) from gram-negative bacteria bind to TLR4; viruses activate TLR3,4,7 and 8 [254]. M1 macrophages have potent bactericidal properties but are cytotoxic to host cells due to their production of high levels of reactive nitrogen and oxygen species. Thus, their tissue damaging effects must be balanced by M2 macrophages that are involved in immunomodulation, tissue remodelling and fibrosis, and promote macrophage efferocytic function. M2 macrophages secrete anti-inflammatory cytokines, including IL-10, TGF-β, CCL18, and CCL22 upon exposure to fungi, immunocomplexes, helminths, complement components, apoptotic cells, macrophage colony-stimulating factors, IL-4, and IL-13 [257].

Despite significant increases in the total number of airway macrophages in COPD, their phagocytosis and elimination of microorganisms and apoptotic cells are impaired, suggesting defective functional properties [258]. We have found evidence for a macrophage phenotypic switch in COPD airways promoting a shift towards the M1 phenotype in the airway wall but towards M2 in the airway lumen compared to normal airways [258]. The divergent biological functions of M1 and M2 macrophages is dictated by the dichotomous regulation of arginine metabolism [259]. Arginase-1 (upregulated in an M2 environment) was found to suppress iNOS activity (M1 inflammatory marker) in the airway wall by competing with the common substrate arginine. The suppression of anti-bacterial iNOS activity by increased arginase-1 activity, along with its own contribution to collagen-1 formation promotes a pro-infectious environment along with increased wall thickening [258]. The cause of this phenotypic switch is unknown but may be an adaptive response to ongoing insult to the COPD airways by cigarette smoke and chronic colonization/infection with bacteria [254].

In addition to immune-related aberrations, COPD macrophages also exhibit dysfunctional bacterial phagocytosis and uptake of dead and apoptotic cells (efferocytosis) which are essential functions in maintaining a healthy lung environment [257,260,261]. Impaired phagocytic ability of alveolar macrophages has been observed in both COPD patients and healthy smokers, compared to control subjects. Phagocytic capacity was greater in COPD patients who had ceased, compared with those continuing to smoke, implicating continuous smoking as a key mediator of macrophage dysfunction [262]. Attenuated phagocytosis and efferocytosis in combination with a pro-inflammatory environment may promote bacterial colonization and lung tissue damage, which collectively contribute to the progression of COPD.

Specific treatments that manipulate macrophage phenotype, efferocytosis and/or bactericidal properties may provide an effective means of clearing the respiratory tract and hasten the resolution of inflammation. The efferocytic ability of lung macrophages can be restored with phosphodiesterase (PDE) inhibitors, such as aminophylline/theophylline, and by levostatin, low-dose oxygen and acute phase reactant α-1 antitrypsin in mouse models [263–265]. Recent studies using roflumilast, a newer PDE-4 inhibitor, revealed alterations in the lung macrophage phenotype to a more reparative M2 type [266]. Macrolides and statins have been shown to improve AM phagocytosis in vitro but further research is required to determine if they can correct defective bacterial phagocytosis in COPD [263,267].

Manipulation of endogenous pro-resolving mediators including lipoxins, E-series resolvins, D-series protectins and maresins may also promote resolution of inflammation in COPD [268]. These mediators are derived from polyunsaturated fatty acids and act on distinct receptors to promote resolution of neutrophilic inflammation by preventing neutrophil recruitment and enhancing the removal of these cells by efferocytosis [269]. The pro-resolving molecule annexin A1 is gaining attention as a potential therapeutic target for both its roles in inflammation and influenza infection [270,271]. Roles in monocyte recruitment, enhanced clearance of apoptotic cells by macrophages, and macrophage reprogramming toward a resolving phenotype, have been described [271]. Annexin A1 is also upregulated during influenza infection and enhances viral binding, replication, apoptosis and endosomal trafficking of the virus to the nucleus [270]. Annexin A1 deficient mice exhibit a survival advantage, and lower viral titres after infection with influenza A virus, accompanied by enhanced inflammatory cell infiltration [270]. Recently, it has been observed that serum annexin A1 expression is upregulated in COPD patients and is positively correlated with the severity of the disease. The inability of annexin A1 to resolve the chronic inflammation profile of COPD suggests that this resolution pathway is dysfunctional. Indeed, systemic levels of pro-resolving mediators are increased and dysfunctional in other chronic inflammatory diseases such as inflammatory bowel disease, preeclampsia, and Alzheimer’s disease [272–274]. Interestingly, in a separate study with a slightly larger sample size, serum annexin A1 was found to be decreased in COPD compared with healthy non-smokers [275]. However, results of both studies agreed that HBE annexin A1 levels increased in response to CSE exposure and that annexin A1 correlated positively with the severity of COPD [275,276]. The discrepancies between these two studies are inexplicable, and the similar methodologies suggest a sample-related factor. However, both can agree that annexin A1 potentially plays a role in COPD pathogenesis and more studies are needed to resolve its true role in COPD. As well as inhibiting infectious exacerbations, modulation of annexin A1 or other pro-resolution molecules may be able to reduce thickening of the airway wall and arrest disease progression in COPD [277]. Such treatments may also be beneficial in other lung diseases such as interstitial pulmonary fibrosis (IPF) and cystic fibrosis (CF) where macrophages also exhibit impaired efferocytosis [278].

Macrophage TLR-mediated response

Dysregulation of TLR-mediated macrophage responses in COPD airways is also implicated in the pathophysiology of the disease. It has been suggested that overactive TLR responses, stimulated by chronic bacterial colonization/infection and cigarette smoke, contributes to excessive inflammation and subsequent airway remodelling and lung tissue damage which accelerates long-term decline in lung function [279]. Whole tissue explants from patients with COPD released higher levels of pro-inflammatory cytokines and chemokines TNF and CCL5 following activation of viral-associated TLR3, 7 and 8, compared with those from smokers [280]. Another study showed that TLR4 followed by TLR2 stimulation of alveolar macrophages enhanced cytokine production from COPD patients compared to those from smokers [281]. While these studies describe mechanisms of how COPD airways may undergo prolonged and excessive inflammatory responses during exacerbations, they fail to explain the inability of these responses to clear pathogens. They also compare tissue and macrophages from smokers and COPD patients without employing a normal non-smoker control for baseline comparison. Contrary to these findings, there is evidence to suggest that alveolar macrophages from the airways of chronic smokers and COPD patients exhibit dysfunctional responses to TLR stimulation [254]. Studies have shown an impaired ability of COPD alveolar macrophages to sense bacterial components via TLR2 and TLR4, a response that was not replicated by TLR3 stimuli [282]. Smoking-mediated oxidative stress reduced the production of a range of cytokines from stimulated and non-stimulated alveolar macrophages compared to those from non-smokers, which has been associated with reduced MAPK and NF-κB signalling [282–287]. Comparative induction of COPD and non-COPD alveolar macrophages by NTHi antigens, LOS and outer membrane protein (OMP) P6 revealed diminished IL-8, TNF, and IL-1β responses of COPD alveolar macrophages [288]. These cytokines are important mediators of acute inflammatory responses, with downstream roles in neutrophil recruitment, cell growth and tissue remodelling [289,290]. These findings support a paradigm of defective alveolar macrophage responsiveness, the inability of the immune response to clear infections and dysfunctional tissue repair in COPD.

Synthetic TLR activators are currently in clinical development for treating asthma, allergies and infections but may also be useful in COPD during infectious exacerbations [291]. TLR agonists or adjuvant therapy with the ability to correct the dysfunctional TLR-mediated responses of COPD macrophages could boost protective inflammatory responses to quickly clear pathogens and reduce the oxidative stress in the airway epithelium. Specific TLR agonists could be used to induce desirable response, such as a Th1 responses that could lead to neutrophilic inflammation, in addition to the suppressive effects on Th2 or regulatory T cells [292]. Intranasal delivery of the TLR7 agonist, imiquimod prevented peak viral replication, bodyweight loss, airway and pulmonary inflammation, and lung neutrophils in mice following influenza A infection. Imiquimod treatment also resulted in a significant reduction in pro-inflammatory neutrophil chemotactic cytokines and prevented the increase in viral-induced lung dysfunction [293]. However, this approach may be difficult to manage as to not amplify unwanted inflammatory tissue destruction. Before utilizing such therapies, the exact mechanisms surrounding inflammatory signalling pathways in COPD need to be fully elucidated.

Oxidative stress

Reactive oxygen species (ROS) and reactive nitrogen species (RNS) produced by immune cells exert antimicrobial activity against a broad range of invading pathogens, performing an important role in immune defence. However, their excessive accumulation or impaired clearance by antioxidant mechanisms results in oxidative tissue damage, including DNA damage, lipid peroxidation, and protein denaturation [294–296]. An increased burden of oxidative stress is recognised as an important feature in airway tissue damage and pathogenesis of COPD as a result of continuous ROS production [296–299]. Despite involvement in driving the onset of COPD, cigarette smoke-induced oxidative stress is not resolved after smoking cessation [300], implicating other endogenous factors, particularly persistent infection or pathogen presence as primary drivers of excessive ROS accumulation [297]. Key COPD pathogens such as Influenza A, RSV and S. pneumoniae have been shown to elicit excessive production of oxidative stress markers in mouse models of COPD [298,301,302]. Despite the defensive role of ROS, their excessive accumulation may have deleterious functional effects on AM phagocytosis and efferocytosis, impairing clearance of pathogens, leading to an increased ROS response with the inability to clear an infection [303]. Thus, interrupting this cumulative cycle of excessive ROS production and impaired bacterial clearance and resolution of inflammation may be the key to managing COPD disease progression as well as reducing infectious exacerbation risk. Decreasing the excessive oxidative burden in COPD may be achieved by either, increasing endogenous antioxidant enzyme activity via enzyme modulators, or by inhibiting enzymatic sources of ROS production [296].

The family of NADPH oxidases (NOX) are important enzymatic sources of ROS and while they share the capacity to transport electrons across the plasma membrane, family members exhibit markedly different activation mechanisms and tissue distribution [304]. Of this family the primary source of inflammatory cell ROS is the NOX2 isoform which targets killing of bacteria and fungi via phagosomal ROS production [301]. However, there is evidence suggesting this elicited ROS response is not protective against and may even promote viral infection. In the absence NOX2, influenza A virus causes substantially less lung inflammation, injury and dysfunction, and leads to lower viral burden in mice [301,305]. Conversely, prophylactic inhibition of NOX2 activity, ameliorated influenza A virus-induced lung inflammation, injury [295] and viral replication in mice [302]. The pivotal role of NOX2 as a primary generator of ROS and its potential role in viral-induced exacerbations makes it an enticing therapeutic target. However, there is also evidence that potentially implicates NOX2 in the pathogenesis of COPD. Gene expression of NOX2 is significantly upregulated, and associated with airway inflammation in COPD [306]. Similarly, macrophage-specific NOX2 has been implicated in the pathogenesis of elastase-induced emphysema in mice [307]. Of the studied NOX2 inhibitors, the most common is apocynin, which preferentially blocks NOX2 by preventing assembly of enzyme subunits [308]. Studies in mice models of COPD have shown that in vivo administration of apocynin significantly suppresses viral titre, airway inflammation and cell superoxide production following viral infection [298,301] and exposure to cigarette smoke [296]. Clinically, COPD patients treated with apocynin exhibited reduced H2O2 and NO2 in their exhaled breath concentrate compared to placebo control [296]. However, there are also concerns about the possible immunosuppressive side effect of NOX2 inhibitors, that may contribute to increased infection and/or autoimmune disorders [309]. Although infection-related symptoms are only seen when the NOX activity is <15–20% of normal in otherwise healthy individuals, [310] it may be difficult to predict a therapeutic threshold in COPD which displays a multifaceted susceptibility to infections. Although NOX2 has taken the spotlight, a study examining the NOX expression in COPD bronchial brushings has highlighted the importance of the different NOX family isoforms [306]. Of note, gene expression of NOX4 and dual oxidase 2 (DUOX2) were increased and NOX1 was decreased compared to normal controls. Multiple regression analyses also identified independent associations between: NOX1 and DUOX2 with airflow obstruction; NOX1 with airway inflammation (neutrophils and eosinophils) [306]. NOX4 may also be involved in promoting airway smooth muscle remodelling in the small airways of COPD [311,312] and is readily induced by cigarette smoke [307]. Thus, isoform differences may impact effectiveness of new therapies targeting NOX-generated ROS, particularly as drugs like apocynin are isoform-specific [308].

Alternatively, increasing antioxidant capacity in COPD has been proposed via manipulation of the glutathione peroxidase (Gpx) family of enzymes or superoxide dismutase (SOD). These enzymes work in tandem to inactivate superoxide produced by cellular respiration and enzymatic ROS generators such as NOX [313,314]. SOD3 is a major extracellular antioxidant enzyme that is highly expressed in lungs and accounts for the majority of SOD activity in airways and vessels [315]. SOD3 plays a major role in the formation of H2O2 by dismutation of superoxide, while the he Gpx family of enzymes, along with catalase, are responsible for the termination of the ROS cascade primarily by reduction of this H2O2 to H2O and O2 [314]. Of the known eight isoforms, Gpx1 is the predominant isoform of cellular Gpx and is ubiquitously expressed throughout the body, including lung epithelium, alveolar epithelial lining fluid and alveolar macrophages [294]. Gpx and SOD3 levels are overexpressed in erythrocytes and sputum, respectively in both COPD and smokers [316,317]. However, the inability of these antioxidants to resolve oxidative burden suggests an overwhelmed or dysfunctional antioxidant capacity. Multiple classes of SOD or Gpx mimetics have been developed and have generally demonstrated effectiveness in animal models of COPD but are yet to be translated into humans. Mice lacking the gpx-1 gene were highly susceptible to oxidative stress [294,299] and administration of the Gpx mimetic ebselen, or a SOD mimetic, significantly inhibited cigarette smoke-induced lung inflammation when given prophylactically and during established inflammation [294,296,299]. Ebselen caused a reduction in influenza A virus-induced lung inflammation [318] and mice with selective overexpression of extracellular SOD displayed significantly less lung injury from influenza virus [313]. This suggests that Gpx-1 or SOD mimetics may have therapeutic utility in preventing viral-induced AECOPD. These antioxidant enzymes have also shown in vivo efficacy in protecting against diseases hallmarked by oxidative stress such as emphysema [299,319], whereas Gpx-1 knockout mice exhibited an exaggerated emphysema phenotype [299]. Several genetic studies have identified an association between SOD3 polymorphisms and altered risk of COPD. A mutation associated with hyper-production of SOD3 was protective against development of COPD among smokers, but not in non-smokers [320]. A different pair of polymorphisms was also associated with reduced lung function in COPD patients compared to normal population [315].

While inhibiting ROS-production or enhancing ROS-resolution shows potential clinical utility in preventing viral-induced exacerbations and disease progression of COPD, there is limited research regarding their efficacy and safety in humans. Elucidating mechanism by which ROS production paradoxically promotes virus pathogenicity and COPD pathogenesis will allow development of a multifaceted therapy.

Respiratory microbiome

The role of a beneficial, healthy bacterial microbiota is well established in the gastrointestinal tract, where resident bacteria aid in establishing a balanced immunological phenotype, compete with potentially harmful micro-organisms and synthesize a variety of beneficial biomolecules [321]. The respiratory system was initially thought to be a sterile environment but novel culture-independent techniques of microbial identification have since revealed the previously unappreciated complexity to the respiratory microbiome [322]. Recent research has made it evident that a variety of chronic lung disorders, including asthma, COPD, and cystic fibrosis, are strongly linked to airway dysbiosis, generally accompanied by a loss in bacterial diversity due to the overgrowth of certain pathogenic bacteria [323,324]. Bacterial composition of the bronchial microbiome remains relatively stable in clinically stable COPD but exhibits overrepresentation of COPD-associated bacteria such as Haemophilus, Moraxella, and Neisseria during an exacerbation [325–329]. Potentially pathogenic members of the Pseudomonadaceae, Enterobacteriaceae, and Helicobacteraceae families, not typically associated with COPD, were also isolated from COPD patients experiencing severe exacerbations [330] and strongly correlated with presence of Haemophilus influenzae [325,326]. These correlative relationships across Proteobacteria members suggests that pathogenesis of exacerbations could involve a polymicrobial process. COPD airways have also been found to be enriched with oral taxa associated with subclinical lung inflammation, such as Prevotella and Veillonella [331], as well as gut-associated species [330]. These findings suggest that the upper respiratory tract (URT) and gastrointestinal tract may act as a microbial reservoir for seeding the airways in COPD, and provide an association between a distinct human microbiome and inflammation in the lung [331,332]. COPD airways also exhibit a decreased abundance of other bacteria whose predicted metagenomes suggest functional capacities to produce a variety of anti-inflammatory compounds [325].

Given that carriage is prerequisite for the development of disease, maintaining balance of the URT microbiome is vital in maintaining respiratory health. Introduction of bacteria to the lower respiratory tract (LRT) occurs through physiological episodes of micro-aspiration [333]. The importance of oral health and micro-aspiration was highlighted by a study in residents of nursing homes, showing that neglect of oral health measures leads to a dramatic increase in incidence of and mortality by pneumonia [334]. Likewise, absence of methicillin-resistant Staphylococcus aureus carriage in the nasopharynx negatively predicted a lower respiratory tract infection caused by the organism, with a negative predictive value of 98.5% [335]. Strong evidence suggests that a healthy URT microbiome infers colonization resistance by preventing acquisition and establishment of a new pathogens, or by containment of potentially pathogenic bacteria residing amidst harmless commensals [336]. Although potential pathogens such as NTHi and S. pneumoniae comprise the normal URT flora, a state of bacterial symbiosis may be protective against short-term infection and inflammation [329]. However, natural microbiome and immune defences against overgrowth of a potential pathogen are susceptible to malfunction following acquisition of a new bacterium or viral co-infection [329]. This resultant state of temporary dysbiosis in the absence of adaptive immunity may be resolved by administration of a probiotic that can diminish pathogen colonization either by direct competition or indirect stimulation of innate and adaptive immunity [336].

Immune modulation

Viral and bacterial pathogens have a complex and potentially synergistic relationship in the respiratory tract. Viral infection, particularly with HRV, RSV or influenza results in enhanced growth of pathogenic bacteria, mainly of the Proteobacteria phylum (e.g., H. influenzae and Moraxella), which could explain the predisposition to secondary bacterial infections in COPD [323]. Several studies have also reported a persistent presence of potentially pathogenic microbes in the LRT of individuals with COPD coinciding with a reduction in microbe diversity [328,332,337]. Conversely, presence of potentially pathogenic bacteria is predictive of RSV bronchiolitis in children and in some cases could be linked to severity of the infection [338]. TLR3 expression, and consequently recognition of viral structures and antiviral type I/III IFN production, was shown to be impaired in bronchial epithelial cells exposed to Moraxella catarrhalis [338]. Thus, a healthy respiratory microbiome may also aid in limiting risk and severity of viral infections as well as the tissue damage following excessive inflammation induced by viral infection [321]. Colonization of the URT with commensal bacteria has been shown to drastically reduce influenza-induced acute lung injury and mortality in mice [339,340]. Microbiome modulation was more effective in preventing virus induced hyper-reactivity than pre-treatment with synthetic TLR agonists [341]. An intact microbiome has also been shown to be required for the formation of an adaptive response against influenza virus in mice [342].

These protective benefits have been implicated with probiotic-mediated regulation of monocyte recruitment, production of anti and proinflammatory cytokines, and balance between types of T cell responses such as Th1/Th2, Treg, and Th17 responses [340,343]. It has also been proposed that the protective effects of probiotics (both intranasal and oral) are also associated with stimulation of NK cell function including production of IFN-γ, as well as induction of M2 macrophages within the airway mucosa [343]. NK cell activity and cytokine release is critically important to the early control of viral infection but is impaired in smokers [343], and in COPD [344–346].

Direct competition

The battle for similar nutrients and the bacterial secretion of antimicrobials provide a direct means of competition between beneficial and harmful microbes [336]. For commensals and pathogens living in or invading human tissues, iron is often a limiting nutrient, particularly in the respiratory tract where iron concentrations are considered to be low [347]. In bacteria, iron is a co-factor for many enzymes and plays a crucial role in diverse physiological processes such as DNA replication, transcription and central metabolism [348]. The primary iron source for bacteria is haem, protoporphyrin IX (ppIX) that contains an iron ion at its centre [349]. The entire haem molecule is also essential to the function of haemoproteins, which are involved in energy generation by the electron transport chain, detoxification of host immune effectors and other vital processes [349]. To restrict microbial growth, free haem and iron are tightly regulated by the host and is sequestered in high-affinity haemoproteins or macrophages, respectively [348,350]. Iron-regulatory responses differ between macrophage phenotypes: M1 cells accumulate iron as part of a bacteriostatic stratagem linked to the anaemia of chronic inflammation, whereas the opposite is the case for M2 cells, where iron release is favoured [347].

Indirect evidence provides insight whereby increased iron levels in the lungs of smokers, COPD or CF patients may contribute to the increased susceptibility to airway infections [351]. A rat study showed that airway iron was elevated after exposure to cigarette smoke, leading to increased tissue-damaging oxidative stress and release of IL-8 [352]. An increase in IL-8 may contribute to the increased susceptibility to viral infection via activation of EGFR [353–355]. Increased iron levels in COPD lung occurs as a result of genetic dysregulation of iron regulatory protein (IRP2) and deposition of inhaled iron from cigarette smoke [356]. The iron status of the host is very important in determining the risk of pulmonary infection. For example, correction of iron deficiency led to activation of previously suppressed, pre-existing infections including malaria, brucellosis and tuberculosis, in a group of Somali nomads [356]. As iron repletion advanced, infectious activity reached a peak, showing that iron repletion can also allow infectious diseases to become more clinically overt [356].

Given the role of iron in the pathophysiology and increased susceptibility to infection in COPD lungs, inhaled iron chelators may be a potential therapeutic approach to AECOPD [347]. Intracellular iron chelators such as deferiprone, which specifically target intracellular iron deposits and relocate them outside the cell to prevent cellular iron loading [357,358] may have more therapeutic efficacy than regular cell-impermeable iron chelators such as deferoxamine [359]. A surgical wound-gel loaded with the iron chelator deferiprone and the heme-analogue gallium-protoporphyrin showed significant antibiofilm activity against multi-drug resistant Staphylococcus aureus, Staphylococcus epidermidis, Pseudomonas aeruginosa and Acinetobacter johnsonii. The gel also potentiated the antibacterial activity of ciprofloxacin against these organisms [358]. This study provides a “proof of principle” for the efficacy of therapies that take advantage of bacterial nutritional requirements and may be useful in the inhibition on diverse bacterial species. However, applying this concept to an inhaled preparation would require further studies that assess the effects of using inhaled iron chelators on systemic iron metabolism [347].

NTHi is uniquely susceptible to haem restriction as, unlike most bacteria, it cannot make its own and relies solely on haem acquisition from the host [349,360,361]. As such, expression of haem-acquisition genes in NTHi is an important determinant of survival and modulation of virulence factors, which is highlighted by the increased prevalence of these genes in middle ear strains compared to colonizing throat strains [362]. Deletion of multiple genes related to haem-iron scavenging, utilisation and regulation have resulted in the attenuation these virulence factors, and disease severity and duration in animal models of otitis media [350,361,363]. Similarly, an isogenic mutant of two haem-acquisition pathways was unable to sustain bacteraemia or produce meningitis in a rat model of invasive disease [364]. Thus, haem-acquisition pathways represent potentially high value targets for the development of novel therapies for the eradication NTHi from the respiratory tract, particularly in COPD [365,366]. Alternatively, a probiotic approach that takes advantage of NTHi’s reliance on haem-acquisition has been proposed. Haemophilus hameolyticus (Hh) is considered a respiratory commensal and recent observations support the bacterium as a potential probiotic candidate against NTHi colonization and infection [367]. In an in vitro cell culture model of human lung epithelium, pre-treatment with Hh significantly inhibited colonization and transcytosis of NTHi to cell monolayers [6]. A bacteriocin-like substance produced by a minority of Hh strains was isolated with the ability to inhibit NTHi growth in vitro. The inhibitory mechanism of this substance has not been fully elucidated but ongoing research indicates the inhibitory effect is due to its capacity to bind haem, thus limiting its access to NTHi [368]. Eradication of NTHi carriage from the nasopharynx and subsequent migration to the lower airways would be an effective means of preventing infection with the organism. However, further research is required to investigate the inhibitory effect of this substance in cell culture models and implications on co-colonization of the shared nasopharyngeal niche.

Immune signalling pathways

Multiple kinases play a critical role in modulating inflammation and downstream antiviral immune responses [369,370]. However, respiratory viruses possess numerous mechanisms of subverting these responses to facilitate viral entry into host cells and replication. Kinases are an enticing therapeutic target but must overcome developmental hurdles, such as specificity and off-target effects, before implementation as effective preventive therapy for viral-induced AECOPD [369,370].

Protein kinase C (PKC)

The protein kinase C (PKC) superfamily is linked to several downstream signalling pathways and is therefore responsible for diverse regulatory roles in membrane structure events, immune responses, gene transcription and cell growth [371]. The influenza virus and the viral HA can rapidly activate PKCs upon binding to host-cell surface receptors [138]. In vitro experiments show that host cell entry and infectivity of several enveloped viruses, including influenza A and B, could be inhibited by PKC inhibitors, implicating the critical involvement of PKCs critical the enveloped viral entry process [372,373]. Although the full mechanism of PKC-mediated viral entry has not been elucidated, the PKCbII isoform has been implicated as an important regulator of late endosomal sorting events needed for influenza virus entry and infection [138,374]. In vitro kinase activity assays of infected A549 cells showed that RSV infection also resulted in the upregulation of multiple PKC isoforms with subsequent downstream activation of extracellular signal-regulated kinases. The RSV-mediated upregulation of PKC activation was implicated in the host cell fusion process, a pivotal step in inducing a successful infection [371]. Blocking of PKC was also found to significantly impair RSV infection of NHBE cells when the inhibitory agent was administered at the onset of infection [375].

These observations suggest pharmacological interference of PKC might help to prevent influenza and RSV infections during initial entry of virions into their target cells [138]. One approach to interference is the use of defensins. Defensins are antimicrobial peptides of polymorphonuclear neutrophils and other leukocytes that are important effectors of the innate immune system and have been shown to inhibit a variety of bacteria and fungi [376]. Recent evidence also suggests alpha-defensins can modulate viral infection with both enveloped and nonenveloped viruses, including influenza [237,377] via inhibition of PKC activation [377]. Beta-defensin has also been shown to act as an antiviral molecule against RSV [378]. Treatment of cell cultures with alpha-defensin soon after infection resulted in marked inhibition of influenza virus replication and viral protein synthesis. Additionally, treatment of cells with alpha-defensin followed by its removal before infection also inhibited viral replication, suggesting an effective prophylactic approach [377]. However defensin-mediated inhibition of PKC would have little effectiveness during an active infection as inhibitory activity is only effective when administered during the first 60 minutes of viral infection [373].

Regardless of the naturally occurring in vivo antiviral effects of defensins, humans still become infected, suggesting that baseline defensin levels are not sufficient to fully protect the host from viral infections. Prophylactic overexpression of defensins in mice were protective against a lethal influenza A infection and a reduction of the viral lung titre was observed [379]. However, more studies are needed to determine if this strategy can be translated to preventing viral infection in COPD [376]. Basal alpha-defensin was found to be elevated in COPD and further increased post infection with HRV but did not correlate to any changes in viral load [380–382]. Additionally, exposure of pBECs to CSE decreased alpha-defensin 1 production in healthy controls but remained unchanged in pBECs from COPD patients [380]. Basal beta-defensin 2 levels have been described in very low titres in COPD central airways, but not in distal airways, and are not affected by viral infections [380,383]. These results suggest a variable role of defensins which is dependent on type and may point toward dysregulation or dysfunction of defensins in COPD. Long-term increases in defensin levels carry safety concerns as high concentrations of human alpha defensin have been found to induce cytotoxicity in vitro [384]. Additionally, higher expression of beta-defensin genes can be associated with diseases such as psoriasis [385], and human defensins have also been shown to have effects on tumour microenvironment by either promoting or supressing tumour growth [386]. There is also a potential that defensins may enhance certain viral infections, while inhibiting others. For example, human alpha-defensin 5 and 6 were shown to increase HIV infectivity by enhancing attachment by concentrating virus particles on the target cells [387].

The plant polyphenol, resveratrol (RV), is an antiviral compound with a broad-spectrum of antiviral activity against DNA and RNA viruses, including HRV and influenza A [130,388]. The antiviral effects of RV are elicited by interfering with several intracellular signalling pathways, including PKC and its dependent pathways [136,389]. In vivo studies showed that RV also improved survival and decreased pulmonary viral titres in influenza virus–infected mice [136]. When administered in the form of a nasal spray, RV was found to be safe and effective in reducing the severity and recurrence of respiratory infections in children [130,388].

Protein kinase R (PKR) and viral non-structural (NS1) protein

The presence and replication of viral nucleic acids in vertebrate cells triggers a potent antiviral innate immune response, in particular the induction of type-I IFN genes and the activation of viral enzymes [390]. The double-stranded RNA-dependent PKR is a key executor of this antiviral response, along with other IFN-stimulated gene products [390]. As a defence against this antiviral response, influenza viruses express a multifunctional NS1 protein with the major function being to counteract or prevent the PKR-mediated antiviral response [391,392]. NS1 protein can prevent PKR detection by binding to viral RNA [393,394] or, by direct binding, can inhibit PKR-mediated viral mRNA suppression and induction of apoptosis. Additionally, some strains are able to directly inhibit the expression of IFN [395,396]. NS1 not only mediates antiviral suppression but also modulates other important aspects of the virus replication cycle, which may additionally contribute towards efficient virus replication and virulence during infection [397]. Additional roles of NS1 include viral RNA replication, viral protein synthesis, and general host-cell physiology [125,390,392].

Given the numerous roles during virus replication, antiviral compounds that inhibit NS1-actived signalling cascades or augmentation of IFN antiviral pathways could be a promising preventative strategy against influenza infection in COPD. Influenza A virus mutants unable to express NS1 (delNS1), or that possess a truncated form of NS1, induce high levels of IFN in infected cells, and are consequently attenuated in IFN- α/β-competent systems [398,399]. Inhibition of IFN pre-mRNA was found to be mediated by the binding of viral NS1 to cellular CPSF30, thus indicating this interaction as a potential therapeutic target [400]. Peptide-mediated inhibition of NS1-CPSF30 binding has been shown to limit virus replication in tissue culture [399,401,402]. However, this strategy is specific to influenza A and is yet to be tested in vivo [399]. Recombinant influenza viruses with truncated or mutated NS1 proteins have also been investigated for their potential as live-attenuated vaccine candidates [392]. Such viruses are partially debilitated in their ability to counteract the host IFN response, but retain immunogenicity and replicative ability, making them an ideal vaccine candidate [392,403,404]. NS1-truncated viruses are generally attenuated, except in cells lacking the ability to produce appropriate levels of IFN [398,399]. There is evidence of deficient IFN-induction in COPD cells ex vivo, and COPD mice [403,405]. Therefore, further studies are required to properly assess the safety of this approach in COPD, perhaps with the consideration of administering recombinant interferon in combination with vaccination. The type- and strain-specific IFN-antagonistic and binding properties of NS1 [392,406,407] may also complicate development of therapies that target NS1. Influenza H5N1 encodes an NS1 protein that is highly effective in inhibiting host antiviral responses that contributes to it high fatality in humans [408,409]. Transfected NS1 of a human H3N2 strain was also found to be more effective in supressing IFN-mediated antiviral response than that of a low pathogenic avian influenza, H11N9, which resulted in a higher replication rate [410].

An alternative approach is augmentation of the IFN response. Mice lacking functional IFN-λ receptors are unable to restrict virus dissemination from the upper airways to the lungs and transmit the virus much more efficiently to naïve contacts compared with wild-type mice [411]. Prophylactic intranasal treatment with IFN-α inhibited initial virus replication in mice, ferrets, guinea pigs or rhesus macaques infected with influenza A [412–414]. However, IFN-α was only effective in protecting ferrets from seasonal influenza viruses, which replicate mainly in the upper respiratory tract, but not from highly pathogenic influenza viruses, which also disseminate to the lung [412]. However, only IFN-λ conferred long-lasting antiviral protection in the upper airways and blocked virus transmission in mice [411]. IFN pre-treatment reduced viral replication in COPD pBECs exposed to HRV, suggesting a broad-spectrum antiviral potential of IFN treatment [415]. Intranasal recombinant IFN-α2b (SNG001) was shown to be an effective prophylactic treatment against HRV and prevented exacerbations in asthmatics. However, stage 2 clinical trials are yet to reveal any efficacy in preventing viral-induced AECOPD [416]. Another promising avenue is the family of interferon-inducible transmembrane IFITM proteins that mediate IFN’s broad-spectrum antiviral role against influenza A virus, West Nile virus and dengue virus. IFITM 1, 2 and 3 restricted early steps in influenza A infection, and there are no reports of viral escape from IFITM restriction [417–419]. Evidence also suggests that Ifitm3−/− mice are more susceptible to RSV infection than their wild-type littermates. However, RSV restriction has not been examined in cultured cells, and it is possible that IFITM proteins protect mice from RSV challenge via means other than inhibition of viral entry [419]. IFITM expression has also been shown to influence the quality of the adaptive immune response to influenza A virus in mice [419].

Augmentation of the antiviral IFN response appears to be an effective prophylactic strategy in animal studies but more trials are required to determine if this effect is translatable to humans and whether there is any benefit in preventing AECOPD. The inability of exogenous IFN-β to fully restore antiviral responses in COPD pBECs, indicates a partially dysfunctional IFN-β-mediated signalling in COPD [31]. Thus, simply artificially increasing IFN levels in COPD airways may not be sufficient to mount an appropriate antiviral response. It is also not clear how augmentation of such a vital host immune response would affect uninfected tissue [392]. Mice studies have shown that excessive IFNαβ signalling in response to acute influenza infection can result in uncontrolled inflammation leading to lung damage and increased morbidity and mortality [420]. Additionally, it causes increased expression of IFN-γ suppressed innate protection against extracellular bacterial pathogens in the lung [421]. This may have serious implications for bacteria-induced exacerbations in COPD.

P13K-p110a signalling pathway

Influenza A NS1 protein is also responsible for the activation of the phosphoinositide 3-kinase (PI3K) and the downstream effector protein kinase Akt by direct interaction with the p85 subunit of PI3K [422,423]. The normal physiological role of PI3K is in various host cell functions such as anti-apoptosis, cell proliferation, growth, metabolism and cytokine production/signalling [125,392]. However, several studies have implicated PI3K in supporting efficient virus propagation. Blocking of the PI3K/Akt pathway results in the inability of influenza to endocytose into AECs [424], a reduction in virus yield, suppression of viral RNA and protein synthesis, and suppression of premature apoptosis at later stages of infection [422,423,425–427]. The role of influenza-induced PI3K activation appears to be dependent on virus type. PI3K is activated during, and regulates early stages of viral entry upon infection with influenza B viruses as opposed to the post-entry events at later stages of infection with influenza A [422]. Although initial viral replication is dependent on PI3K activation, influenza virus produces NS1, which further activates PI3K to further amplify replication [31,428]. Influenza viruses containing a truncated NS1 failed to activate the PI3K/Akt pathway, grew slower and formed small plaques in tissue culture [429]. The truncated NS1 protein also conferred an attenuated phenotype due to its inability to inhibit host antiviral responses [430].

Hyperexpression of PI3K in lungs of COPD patients has been described, not only providing a mechanism of increased viral susceptibility but also may be linked to pathogenesis of the disease [431]. Increased expression of PI3K and decreased expression of a negative regulator of PI3K (PTEN) correlated with more severe airflow obstruction, regardless of disease stage [431]. In primary bronchial epithelial cells and BEAS-2B cells, CSE decreased PTEN protein, and PTEN knockdown potentiated Akt phosphorylation and enhanced production of proinflammatory cytokines [432]. An exaggerated PI3K response has also been described in COPD pBECs, which conferred increased susceptibility to influenza infection. Smoke exposed mice also supported increased influenza viral replication and produced deficient antiviral responses, with exacerbated inflammation and impaired lung function [31]. PI3K-p110α was identified as the predominant isoform hyper-expressed in COPD pBECs. Specific inhibition of this isoform prior to infection attenuated influenza infection and enhances IFN-β antiviral responses in COPD, as well as healthy pBECs [31]. Identification of offending isoforms is beneficial to developing more specific inhibitors and limit off-target activity. The PI3Ky subunit has also been shown to have a critical role in the clearance of viral infection [433]. PI3Ky is a more specific target as it is only expressed on cells of haemopoietic origin as opposed to p100α which is expressed on all cells [434], however PI3Ky has not yet been characterised in COPD.

Epidermal Growth Factor Receptor (EGFR)

EGFR is a receptor kinase which is well known to play an important role in the regeneration of damaged tissue, mucin production and elastase-induced IL-8 production in lung epithelial cells [353,435,436]. IL-8 production is particularly important in the context of COPD as concentrations are increased during an exacerbation or in patients that experience frequent exacerbations [437,438]. EGFR has been shown to promote influenza A infection of host cells either directly or indirectly through activation of PI3K/Akt signalling [354]. Influenza virus and HRV induce upregulation of ligands that further activate EGFR and IL-8 production in bronchial epithelial cells in vitro, further facilitating viral attachment to airway epithelium [353,355]. EGFR inhibition has been shown to completely block IL-8 and the EGFR ligand, ICAM-1, expression to basal levels during HRV infection [355]. Furthermore, aberrant EGFR activity has also been described in COPD which subsequently increases PI3K/Akt signalling and IL-8 secretion [439], the effect of which is exacerbated by long-term smoking [440,441]. Persistent activation of EGFR by viral infection or through a defect in glutathione secretion in COPD may contribute to airway remodelling, an important driver of airway lumen obstruction [442–444]. EGFR has also been shown to have an indirect role in the IFN-mediated antiviral response. Activation by influenza A virus and HRV suppressed IFN-γ production and increased viral replication in BEAS-2B cells [445]. Inhibition of EGFR in mice during viral infection augmented IFN- γ production, which resulted in decreased viral titres in vitro and in vivo [445]. M. cattarrhalis, another common precipitant of COPD exacerbation, has also been shown to activate EGFR [446]. This evidence suggests that inhibition of EGFR may be a multifaceted therapeutic approach with the potential to not only prevent bacterial and viral-induced exacerbations, but also affect the overall pathophysiology of COPD.

Strategies developed for antagonising EGFR signalling include MAbs that prevent endogenous ligand engagement, [447,448] or small molecule inhibitors which target specific downstream EGFR signalling pathway components [369]. However, research in MAbs has primarily focused on treatments for lung cancer and have not yet been contextualised for COPD [369]. Suppressor of cytokine signalling (SOCS) protein regulation of EGFR has shown a pivotal role in restricting influenza A virus in airway epithelium. Socs5-deficient mice exhibit heightened disease severity, with increased viral titres and weight loss [32,449]. In COPD airway epithelial cells, Socs5 was found to be downregulated, which correlated with increased susceptibility to influenza infection. Importantly, restoration of SOCS5 levels restricted influenza virus infection, suggesting that manipulating SOCS5 expression and/or SOCS5 targets might be a novel therapeutic approach to influenza [32]. Fucoidan, an algae-derived sulphated polysaccharide has also exhibited broad anti-influenza activity in mice by enhancing the immune response [450] and blocking EGFR-mediated viral entry [354,451]. Studies assessing the therapeutic potential of fucoidan in humans is limited but reveals an additional immune-modulatory role that may increase vaccine efficacy in immunocompromised individuals. Elderly participants treated with Mekabu fucoidan produced higher antibody titres and exhibited an increase in natural killer activity against influenza strains in a seasonal influenza vaccine [450]. Further studies are required to assess these effects in COPD.

Conclusions

Infectious exacerbations are a primary driver of clinical and functional decline in COPD, but existing therapies are of limited effectiveness and do not effect the overall course of the disease. The rapid development of antibiotic resistance and microbial evasion of vaccination strategies further complicates the treatment and prevention of these infections. In order to mount an infection, a pathogen must exploit host-cell surface receptors for attachment and evade clearance by host immune responses. Therefore, novel therapeutic strategies that disrupt bacterial-host cell interactions or that mediate the host inflammatory response present an attractive approach to reducing infectious exacerbations in COPD. The usefulness of pathogen proteins as vaccine candidates are limited by antigenic variation, thus targeting specific host receptors may be a more promising approach. Modulation of the aberrant inflammatory response in COPD by altering immune cell function, signalling pathways, balancing the microbiome or reducing oxidative burden may have added utility of affecting disease progression as well as preventing infectious exacerbations. However, due to integrated nature and complexity of the immune response, a combination of approaches may be required to elicit any benefits. These strategies are less likely to induce antimicrobial resistance as a missing cellular function is more difficult for a pathogen to adapt to, and should affect replication independent of the type, strain and antigenic properties of the invading pathogen. However, host-targeted approaches may be more complex to manage due to the increased concern of off-target side effects, and their development may be hindered by the uncertainty surrounding the mechanisms of COPD pathogenesis. It is imperative that the mechanisms driving COPD pathogenesis be resolved, which will facilitate the development of effective treatment strategies. Further development of such preventative strategies has the potential to significantly reduce AECOPD, prevent disease progression and associated mortality and economic costs, as well as improving health-related quality of life for affected individuals.

Funding

This work is supported by the Clifford Craig Foundation Launceston General Hospital [grant numbers 143, 153, 187 (to S.S.S.)]; The Rebecca L. Cooper Medical Research Foundation[grant number PG2019498 (to S.S.S.)]; The Thoracic Society of Australia & New Zealand (TSANZ) Boehringer Ingelheim COPD Research Award [grant number S0026084 (to S.S.S.)]; The Lung Foundation Australia and Cancer Council Tasmania [grant numbers S0026528, L0026561 (to S.S.S.)]; PMH is supported the National Health and Medical Research Council (NHMRC), Cancer Council New South Wales, Australian Research Council [grant numbers 1079187, 1156589, 1157073, 190100091 (to P.M.H.)]; and the Rebecca L. Cooper Medical Research Foundation [grant number PG2018113 (to P.S.)].

Competing Interests

The authors declare that there are no competing interests associated with the manuscript.

Author Contribution

All authors contributed to the writing of this manuscript and approved the final version.

Abbreviations

     
  • AE

    acute exacerbation

  •  
  • AM

    alveolar macrophage

  •  
  • BEC

    bronchial epithelial cell

  •  
  • CEACAM-1

    carcinoembryonic antigen-related cell adhesion molecule-1

  •  
  • CF

    cystic fibrosis

  •  
  • COPD

    chronic obstructive pulmonary disease

  •  
  • CSE

    cigarette smoke extract

  •  
  • EC

    electronic cigarette

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • FEV1

    forced expiatory volume in 1 secomd

  •  
  • GOLD

    Global Initiative of Chronic Obstructive Lung Disease

  •  
  • Gpx

    glutathione peroxidase

  •  
  • HA

    haemagglutinin

  •  
  • HA-A

    haemagglutinin A

  •  
  • Hh

    Haemophilus haemolyticus

  •  
  • hpBEC

    primary human BEC

  •  
  • HRV

    human rhinovirus

  •  
  • ICAM-1

    intracellular adhesion molecule-1

  •  
  • ICS

    inhaled corticosteroid

  •  
  • IFNγ

    interferon γ

  •  
  • IFITM

    IFN-inducible transmembrane

  •  
  • IL

    interleukin

  •  
  • iNOS

    inducible nitric oxide synthase

  •  
  • LABA

    long-acting β2-adrenergic receptor agonist

  •  
  • LAMA

    long-acting muscarinic antagonist

  •  
  • LOS

    lipooligosaccharide

  •  
  • LRT

    lower respiratory tract

  •  
  • MAb

    monoclonal antibody

  •  
  • NA

    neuraminidase

  •  
  • NHBE

    normal human BEC

  •  
  • NOX

    NADPH oxidase

  •  
  • NS1

    non-structural

  •  
  • NTHi

    non-typeable Haemophilus influenzae

  •  
  • PAFr

    platelet-activating receptor

  •  
  • PDE

    phosphodiesterase

  •  
  • PI3K

    phosphoinositide 3-kinase

  •  
  • PKC

    protein kinase C

  •  
  • PKR

    protein kinase R

  •  
  • PTEN

    phosphatase and tensin homologue

  •  
  • ROS

    reactive oxygen species

  •  
  • RSV

    respiratory syncytial virus

  •  
  • RV

    resveratrol

  •  
  • SA

    sialic acid

  •  
  • SOCS

    suppressor of cytokine signalling

  •  
  • SOD

    superoxide dismutase

  •  
  • TLR

    toll-like receptor

  •  
  • TNF

    tumour necrosis factor

  •  
  • URT

    upper respiratory tract

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