Within the spectrum of chronic airway obstruction, there are individuals with asthma who smoke, asthmatics who develop airflow obstruction that is not completely reversible and non-smokers who develop chronic airflow obstruction. Smokers with asthma have features that mimic COPD, with less response to corticosteroids, a lower frequency of eosinophilic inflammation and a greater probability of neutrophilia in the airways.12,13 On the other hand, there are epidemiological studies about the incidence of COPD which demonstrate that young asthmatics who develop COPD have a disease with different characteristics than the non-asthmatics who also develop COPD. In the first case, allergic rhinitis is more frequent, along with nonspecific bronchial hyperreactivity and the presence of wheezing, and plasma IgE concentrations are higher14; all of which indicate that it is a mixed asthma-COPD syndrome.

The prevalence of the mixed phenotype is unknown, but there are different estimations of its importance in the context of COPD. One initial study that was small in size estimated that 25% of COPD patients with COPD have significant reversibility and presented clinical response to inhaled corticosteroids (IC).15 Soriano et al.4 estimated that approximately 23% of COPD patients between the ages of 50 and 59 could have a mixed phenotype, which increased with age up to 52% between the ages of 70 and 79.4 Other studies have quantified the prevalence of the mixed phenotype (identified by eosinophilia in sputum) in patients with COPD at 38%, directly associated with the therapeutic response to IC.16 If we use the bronchodilator test as a reference, 31.5% of the patients identified with COPD in the EPI-SCAN epidemiological study had a positive test.17 Based on these results, we can conclude that, together, between 20% and 40% of COPD patients can be carriers of a mixed phenotype.

The clinical justification for the mixed phenotype lies in its demonstrated sensitivity to the anti-inflammatory action of IC. The basis that explains the response to corticosteroids in COPD patients with greater reversibility lies within the etiopathogeny of the disease. Papi et al.18 demonstrated that reversible patients, even those who were only partially reversible (increase in FEV1>200ml, but <12%) had greater eosinophilic bronchial inflammation compared with the irreversible ones, in whom neutrophilic inflammation predominated. In fact, several studies have used the greater airflow reversibility,4,19–21 a high concentration of eosinophils in spontaneous or induced sputum16,22 or a greater concentration of exhaled NO23–25 as markers of the response to IC in COPD, both at the lung function level15,16,19–23,25 as well as the improvement of the symptoms.22,24,25 A more recent study classified a small group of patients into 3 different phenotypes, according to the findings from chest computed tomography (CT).26 The authors demonstrated a relationship between the response to the bronchodilator test, the response to treatment with IC and the concentration of eosinophils in sputum in each of the 3 phenotypes.26 There is even a randomized clinical assay that compared the treatment with IC in patients with COPD, directed in accordance with the current guidelines or according to the concentration of eosinophils in induced sputum. The results demonstrated a significant reduction of the exacerbations during one year in those patients who took IC based on their eosinophilic inflammation profile.27 All these results justify a personalized focus in IC treatment based on the clinical, functional and inflammatory characteristics of COPD patients.28,29

With regards to the combined treatment of long-acting beta-2 adrenergics (LABA) and IC, it is important to remember that the first published results demonstrated that the combined treatment with fluticasone/salmeterol (FSC) was effective for achieving an important bronchodilation in COPD patients, but it should be remembered that half of the patients studied had a positive bronchodilator test at the beginning of the study.30 When the results were analyzed separately, the reversible patients achieved a maximum bronchodilator effect of 319ml FEV1, while the irreversible patients reached 195ml.30

The limited reduction in mortality observed in the Towards a Revolution in COPD Health (TORCH) study with FSC can be explained, at least in part, by the patient selection. One of the inclusion criteria was to have a negative bronchodilator test, which is reflected in a mean reversibility of the participants of only 3.7%.31 Therefore, TORCH explains the long-term effect of the FSC combination in those patients who are less susceptible of being responders to IC. Contrarily, a more recent study has compared FSC with salmeterol in treating patients with severe COPD (FEV1 <50%).32 Its results showed a significant reduction (35%) during one year in the rate of moderate or severe exacerbations with FSC compared with salmeterol alone. This study did not take into account the reversibility of FEV1 among its inclusion criteria, and in fact the mean reversibility of its patients was 7%, almost the double of TORCH, and the result was a spectacular reduction in the frequency of exacerbations by adding fluticasone to the treatment with salmeterol. In the same direction, in a recent study it was demonstrated that treatment with FSC at a dosage of 250/50 every 12h produced an increase in the area under the curve 6h after FEV1 that was more than double in reversible patients (1.98lh in week 8) than in irreversible ones (0.74lh). This provides more evidence of the different response to IC or combined treatment depending on the response to the bronchodilator test.20 It has also been recently shown that there is a direct and significant correlation between the response to the bronchodilator test with salbutamol in COPD and the improvement in lung function after 3 months of treatment with LABA+IC.21 In contrast, patients with a defined phenotype such as emphysema-dominant did not present any improvement in lung function with the same treatment.21 It should be expected that these findings described in the studies carried out with salmeterol or with SAL/FLU may be extrapolatable to other IC or LABA/IC combinations.

In short, the conclusions that we may draw from the existing studies are: (a) the patients with mixed phenotype, who present certain characteristics (sputum or peripheral eosinophilia, history of asthma and/or atopy, frequent exacerbations, very positive bronchodilator test or wheezing as a guiding sign) are susceptible for presenting a good response to IC, whatever the lung function; (b) COPD patients who do not present the former characteristics will obtain marginal clinical benefits with the use of IC added to long-acting bronchodilators.

Table 3 compiles the main risk factors linked to the presence of repeated exacerbations.38,40,41,43–61 The severity of the airflow limitation is without doubt one of the most well-known factors.38,40,46,62,63 However, the relationship between FEV1 and number of exacerbations is not linear, and in fact close to 40% of the severe or very severe patients do not present exacerbations, while more than 20% of the moderate patients frequently present them.38,46 This suggests the existence of other conditioning factors. Of all of them, the history of previous exacerbations is the most frequent factor referenced in the literature,38,40,43,49–53 which emphasizes the existence of a certain individual susceptibility that may either be hereditary or acquired.

Although there is very little information available, the existence of a marked heterogeneity in the defense mechanisms of the host against the pathogen could indicate a certain genetic susceptibility. This fact has been supported by the finding of some polymorphisms in patients with frequent exacerbations. Differences in the genotype-dependent expression of the CCL1 protein, a chemotactic factor for the monocytes and macrophages, could produce alterations in the activation of the innate immune system versus respiratory infections.74 Likewise, polymorphisms have been described in the MBL2 (mannose binding lectin) connected with a greater frequency of hospitalizations.75 MBL is a protein of the innate immune system that inactivates a large number of microorganisms by means of the activation of the complement. Its deficiency, due to MBL2 polymorphisms, can potentially increase the susceptibility to infection.76

Traditionally, COPD exacerbations have been considered clinical decompensations that are more or less transitory, whose repercussions were limited to the duration of the event itself. However, today we know that an important proportion of patients do not completely recover after an exacerbation, and this can cause later consequences, both pulmonary as well as systemic. In the cases in which repeated exacerbations are produced (exacerbator phenotype), the consequences can accumulate. Numerous studies have demonstrated the existence of a close relationship between the frequency of the exacerbations and the deterioration of the health-related quality of life (HRQL).38,40,77–79 The same is true with different extrapulmonary manifestations, such as depression, myopathy, myocardial infarction or GERD,39,53,54 much more frequent among the “exacerbator” patients. An accelerated deterioration in lung function has also been documented, which has been estimated at 8ml/year more among the patients with frequent exacerbations62 and even a persistent worsening of the BODE index.80 Finally, and perhaps as a consequence of all that has been mentioned, a poorer prognosis has been demonstrated because, as the frequency of exacerbations increases, so does the risk for death, regardless of the baseline severity of the disease.40,42 Thus, we believe that “exacerbator” patients form a special group of patients with a high risk for morbidity and mortality, whose therapeutic approach should be different and intensive. These patients are also an enormous burden for the health-care system as it is estimated that they are responsible for 60% of hospital services rendered.41

Long-acting bronchodilators, which are the first step in treating COPD, have been shown to reduce the frequency of exacerbations.81 When exacerbations persist despite bronchodilator treatment, the introduction of anti-inflammatories is indicated. In this context, various clinical practice guidelines7,82,83 recognize the usefulness of the use of IC in patients who present frequent exacerbation as their use, especially when associated with bronchodilators, produces a significant reduction in the number of exacerbations and an improvement in HRQL.31,32,84 Traditionally, this effect has been accepted for severe or very severe patients (FEV1<50%) with frequent exacerbations. However, some studies in patients with less functional severity also back the use of these drugs; therefore, it seems that the main determinant of the benefit is precisely the presence of repeated exacerbations.31 Roflumilast is a new oral anti-inflammatory drug that acts by selectively inhibiting phosphodiesterase IV which has been approved for preventing exacerbations in patients with severe COPD who present cough and chronic expectoration and also suffer frequent exacerbations85,86; therefore it is indicated for the exacerbator phenotype with chronic bronchitis. Macrolides, administered for a prolonged amount of time, could also have a specific indication for some of these patients as they have anti-inflammatory and immunomodulatory actions in addition to their possible antibacterial action.87 Some clinical assays suggest that the use of these drugs in stable patients with severe COPD significantly reduces the number of exacerbations, but with a possible increase in the risk of the appearance of bacterial resistances.88–91

Finally, and given the potential role of PPM, it has also been suggested that the use of antibiotics during periods of stability (antibiotic chemoprophylaxis or treatment of the chronic bronchial infection) could be useful for reducing exacerbations.92 In this direction, the PULSE (Pulsed moxifloxacin Usage and its Long-term impact on the reduction of Subsequent Exacerbation) study is a clinical trial that studied the efficacy of the administration of 5-day cycles of 400mg of moxifloxacin every 8 weeks in patients with stable COPD.93 The results indicate that this treatment reduced the risk for exacerbation by 20% in the intention-to-treat (ITT) analysis, 25% in the per-protocol (PP) analysis and 45% in patients who presented purulent or mucopurulent sputum, also by means of a PP analysis, without a significant increase in bacterial resistances. In another study done in patients with severe COPD colonized by Pseudomonas aeruginosa, the administration of nebulized tobramycin reduced the number of severe exacerbations by 42%, also reducing bronchial inflammation.94 More studies are required to help adequately profile candidate patients as well as the duration and the type of antibiotic treatment necessary. It is very likely that the patients who would most benefit from this option would be those who present frequent exacerbations and purulence in sputum during stable phases.

The different phenotypic expression of the pulmonary disease in smokers is determined in part by genetic factors. Specifically, in family studies using HRCT, we have observed that there is family aggregation, regardless of the emphysema phenotype, which indicates the presence of genetic determinants that define this phenotype.108 More recent studies have identified single nucleotide polymorphisms (SNP) that are significantly associated with the extension of low-density areas in pulmonary HRCT,109 and even certain genetic loci have been significantly related with the presence and extension of the emphysema in large COPD patient populations.110 These studies justify the differentiation of the emphysema phenotype as a characteristic genetic-base process in smokers.

One special case is congenital emphysema due to alpha-1-antitrypsin deficiency, as it is produced by a genetic mutation in the gene that codifies this protein. Patients who are homozygote for the deficiency mutation have an increased risk for developing emphysema that is predominantly basal and early-onset.10 This type of emphysema has been used as a model for understanding the physiopathology of emphysema in smokers.

The clinical importance of identifying the emphysema-hyperinflation phenotype is based on the fact that the degree of dyspnea,95,96,111 intolerance to exercise95,111 and hyperinflation99 are predictors for mortality that are independent of the severity of the obstruction. In a prospective study with a 5-year follow-up, Casanova et al.99 observed an inverse relationship between the degree of hyperinflation and survival. They demonstrated that patients with COPD and an IC (inspiratory capacity)/TLC (total pulmonary capacity) ratio less of than 0.25 were 3.15 more likely to die than those with higher ratios. In this study, the multivariate analysis demonstrated that this ratio (IC/TLC) continued to be a risk factor, regardless of other parameters, such as FEV1, age, dyspnea, exercise capacity or comorbidity.

A positive relationship has also been demonstrated between the magnitude of the emphysema measured by HRCT, hyperinflation and the BODE index,112 although differences have not been observed in pulmonary attenuation among different quartiles of the BODE index, probably due to the participation of extrapulmonary factors in this prognostic score. Nevertheless, the presence of hyperinflation on HRCT in smokers with normal FEV1 is associated with a faster fall in FEV1113 and, finally, a significant association has been demonstrated between the magnitude of the emphysema evaluated by HRCT with a greater mortality in COPD, regardless of the severity measured by FEV1.114 In this manner, we see the growing evidence of the need for HRCT when evaluating COPD patients for the study of the emphysema as well as to evaluate the possible presence of bronchiectasis.

The impact of emphysema on mortality was also observed in the National Emphysema Treatment Trial (NETT),115 in which the 3 factors—emphysema, hyperinflation and the BODE index—were independent predictors of mortality. However, we should be reminded that this is a cohort of patients with very severe COPD and, therefore, these results are not extrapolatable to all COPD patients. These data are corroborated by studies such as that by Nishimura et al.96 and the one by Martínez et al.,95 where the patients with higher residual volume had a greater mortality, with a similar tendency in cases where the IC/TLC ratio was lower.

Indirectly, dynamic hyperinflation can contribute to a poorer prognosis of COPD by significantly reducing the exercise capacity of patients who are affected by it. Thus, it has been demonstrated that physical activity in patients with moderate-to-severe COPD correlates inversely with degree of dynamic hyperinflation,116 and the patients with less physical activity are those who present a higher rate of hospitalizations and greater mortality.117

Pulmonary hyperinflation can have an effect on the size of the heart and its function. Several studies associate hyperinflation and the presence of diastolic dysfunction. The study by Vassaux et al.118 demonstrates that the cardiac oxygen pulse, as an overall measurement of cardiac function during an exertion test, is lower in patients with COPD and hyperinflation, measured with an IC/TLC ratio ≤0.25. In the study by Jörgensen et al.,119 it was also observed that the size of the right and left ventricles is smaller in patients with severe emphysema and it is accompanied by a decrease in the filling of the left ventricle, a reflection of the reduction of the preload secondary to pulmonary hyperinflation. Recently, the study by Watz et al.120 analyzed the relationship between lung function alterations and echocardiographic measurements of cardiac function and size in COPD patients with different degrees of severity. The results show that hyperinflation (IC/TLC) is significantly associated with the telediastolic diameter of the left ventricle, much better than with the degree of airflow obstruction. Thus, patients with an IC/TLC ratio ≤0.25 had diastolic dysfunction of the left ventricle with overall affectation of the function of the right ventricle, and this was associated with less tolerance for exercise. Also, a population study demonstrated that the degree of emphysema, evaluated by HRCT, was linearly related with the affectation of left ventricle filling and a decrease in the cardiac output.121 These data suggest that the treatment directed at reducing hyperinflation can have a direct impact on the cardiac function and exercise capacity, and at the very least they could partially explain the tendency towards a reduction in mortality with long-acting bronchodilators observed in the large clinical assays with these drugs in COPD.31,122,123