Frequent Chronic Obstructive Pulmonary Disease Exacerbators: How Much Real, How Much Fictitious?

ABSTRACT

Exacerbations are important events in the natural history of chronic obstructive pulmonary disease (COPD). The higher the number of COPD exacerbations, the worse are the clinical and economical consequences. The distribution of COPD exacerbations is however highly variable. Some patients do not exhibit exacerbations at all whereas others suffer frequent events (i.e., “frequent COPD exacerbators”). We review the scientific evidence regarding the impact of COPD exacerbation frequency and assess whether or not these frequent exacerbators represent a unique population of COPD patients with higher morbidity and mortality risks. A definition of “frequent COPD exacerbators” is suggested to differentiate it from other related terms, such as “treatment failure” and “recurrence.” The standardization of this terminology seems to be necessary to further identify COPD phenotypes in patients who have an individual susceptibility to develop frequent exacerbations. It can also be of help to refine the most appropriate therapeutic and preventative measures.

Keywords: :

• Daily life activities
• Definition
• Frequency
• Lung function
• Mortality
• Quality of life

Different studies have shown that exacerbations are important determinants of the natural history of chronic obstructive pulmonary disease (COPD), with considerable implications in economical costs, health status, lung function, and mortality (1–9). The higher the number of COPD exacerbations, the worse are the clinical and economical consequences such that one of the most important goals of the management of patients with COPD should be to minimize the frequency of these acute events. However, the number of exacerbations can be highly variable between patients. Some do not suffer exacerbations at all whereas others are prone to develop frequent exacerbations (i.e., “frequent COPD exacerbators”). We review the impact of this subset of patients and the potential factors involved in the increased frequency of COPD exacerbations. We also propose a definition for the term “frequent COPD exacerbators.”

Several studies have shown that COPD exacerbations are more frequent with increasing severity of airflow limitation (10–13). However, there is a non-lineal association between clinical and functional parameters. Preliminary data from the Eclipse study include that near a third of patients with very severe COPD were not associated with exacerbations at all, whereas others with less advanced disease may have repeated acute episodes (13). In a randomized controlled trial of severe COPD patients (FEV₁ <50% predicted) assessing the severity of exacerbations more than 15% of patients did not exhibit exacerbations over a three-year follow-up (3). Alternatively, 12% of COPD patients who were followed at a specialized clinic presented repeated severe exacerbations (≥3.0 exacerbations per year). Interestingly, the latter patients were responsible for 57% of all hospital admissions and for 61% of all emergency room visits (12). Hospitalization has emerged as the main cause of healthcare resource use costs related to COPD exacerbations and probably explains why 73% of these costs are attributed to the 10% of COPD patients with repeated exacerbations alone (14).

Table 1.  Impact of frequent exacerbations on health related quality of life, using the St George's Respiratory Questionnaire (SGRQ)

	Number of patients	Study design	Duration (years)	Threshold for frequent exacerbations (n exacerbations per year)	Impact of frequent exacerbations on HRQoL (differences between frequent and infrequent exacerbations, expressed as score units)
					Baseline	End of study
Seemungal et al., 1998 (2)	70	Observational	1	≥3.0	NR	+15.1
Miravitlles et al., 2004 (3)	336	Observational	2	≥3.0	+7.2	+9.3
Soler et al., 2004 (4)	64	Case–control	1	≥3.0	+16.4	NR
Spencer et al., 2004 (5)	613	RCT	3	>1.65	+4.0	NR
Bourbeau et al., 2007 (6)	336	Observational	0.5	≥2.0	+4.0	+12.0

NC, no change compared to baseline; NR, not reported; RCT, randomized controlled trial.

Beyond economical implications, other studies have suggested that COPD patients with frequent exacerbations exhibit a higher morbidity and a worse prognosis than those with less frequent exacerbations (2–9). We have shown that exacerbation frequency increases the risk of death irrespective of severity of disease. Thus, patients who are “frequent COPD exacerbators,” herein defined as those who had ≥3.0 severe exacerbations per year, had a fourfold increased risk of death (95% confidence interval [CI], 1.80–9.45) compared with patients who did not have exacerbations at all (9). These findings suggest that the term “frequent COPD exacerbator” corresponds to a specific subset of COPD patients with higher morbidity and mortality risks who can also share some differential traits (i.e., “exacerbator phenotype”). Notwithstanding, we ignore so far how much real or fictitious is this population of COPD patients with exacerbations.

CLINICAL CONSEQUENCES OF FREQUENT EXACERBATIONS

Health status

Table 1 includes five studies that, using the St George's Respiratory Questionnaire (SGRQ) total scoring system, assessed the impact of COPD exacerbation frequency on health-related quality of life (HRQoL) (2–6). Overall, they demonstrated a strong association between increased exacerbation frequency and HRQoL deterioration. Irrespective of the criteria used to define frequent COPD exacerbations, patients with repeated exacerbations tended to have further HRQoL worsening. Thus, the mean baseline difference between frequent and infrequent COPD exacerbators ranged between +4.0 and +16.4 units (3–6). These findings raise concerns whether or not HRQoL worsening is secondary to the exacerbation per se or just predisposes to the risk of more exacerbations. In the study by Spencer et al. (5), patients with frequent COPD exacerbations (≥1.65 episodes per year) deteriorated HRQoL significantly faster (mean, +2.9 units yr⁻¹) than those with infrequent exacerbations (+2.4 units yr⁻¹) and those with no exacerbations at all (+2.0 units yr⁻¹). A further analysis demonstrated that baseline scores and annual rates of SGRQ deterioration were independently related to exacerbation frequency. Moreover, exacerbations induced an additional negative effect on HRQoL so that there were patients who could not recover from their previous heath-related condition because of the appearance of frequent exacerbations (5). Bourbeau et al. (6) assessed health status at the beginning of exacerbations, during the recovery period, and then at 6 months, showing its worsening during exacerbations with a trend to return to baseline conditions 2 weeks later. In patients without exacerbations, HRQoL improved during the first month of follow-up without subsequent changes (mean total SGRQ score at first month and at 6 months, −6.2 and −6.9 units) and a similar pattern was observed in patients with one only exacerbation (−4.7 and −4.2 units, respectively). In contrast, patients who suffered from two or more exacerbations health status conditions did not ameliorate during the first month while remaining unvaried during the next 6 months.

Disease progression

(Table 2). The impact of repeated exacerbations on lung function still remains unsettled (14) despite that several studies have investigated the effect of exacerbations on accelerated FEV₁ decline (3, 5, 7, 8, 15–17). Overall, FEV₁ decreased faster in patients with more frequent exacerbations in studies with longer follow-ups (7, 8, 17). Using a daily symptoms diary, Donaldson et al. (8) reported an 8 mL yr⁻¹ greater decline in FEV₁ over 4 years in 32 patients with moderate-to-severe COPD who had frequent exacerbations, compared with those with less frequent acute episodes. In the Lung Health Study (7), where a visit to a physician due to a respiratory tract infection was quoted as an exacerbation only, active smokers, either continuous or intermittently, with repeated episodes of exacerbations had a rapid FEV₁ decline of the order of 7 mL yr⁻¹, hence suggesting an interaction between active smoking and the presence of repeated respiratory infections. Another study has confirmed that both smoking and frequent exacerbations may have a negative impact on lung function with some interactions between them (16). Although the most accelerated FEV₁ decline was observed in patients with frequent exacerbations who were active smokers, this association was significant in the former smokers as well. The TORCH (Toward a Revolution in COPD Health) trial (17) has also demonstrated a negative association between exacerbation frequency and FEV₁ decline, with higher rates of lung function deterioration in those patients experiencing more exacerbations.

Other studies have not been able to find significant interactions between COPD exacerbations and faster FEV₁ reductions (3, 5, 15). A study of moderate exacerbations showed a mean FEV₁ decline of 140 mL after the first year and of 90 mL at the second year, a difference that did not reach statistical significance (15). We ignore whether the severity of an exacerbation but not its frequency can have a distinct impact on lung function.

Outcomes other than FEV₁ could be affected by exacerbations. Thus, patients with frequent COPD exacerbations had a significant increase in the BODE index (i.e., body mass index [B], degree of airway obstruction [O], dyspnea [D], and exercise [E]) compared with those with one exacerbation alone (1.14 versus 0.81 points increase, respectively) (15). Moreover, the number of exacerbations and that of hospitalizations during this study period were significantly less associated with the changes in the BODE index.

Table 2.  Impact of frequent exacerbators on FEV₁ decline

	Number of patients	Study design	Duration (in years)	Frequent exacerbator definition (n of exacerbations per year)	Rate of accelerated FEV1 decline
					Infrequent exacerbations	Frequent exacerbations	p values
Kanner et al., 2001 (7)	5,887	Epidemiologic	5	≥1.50	Smoking status:	Smoking status:
					Sustained quitter: −13.0 mL yr^−1	Sustained quitter: −12.0 mL yr^−1.	NS
					Intermittent quitter: −32.6 mL yr^−1	Intermittent quitter: −52.0 mL yr^−1	<.05
					Continuous smoker: −55.4 mL yr^−1	Continued smoker: −69.4 mL yr^−1	<.001
Donaldson et al., 2002 (8)	32	Observational	4	≥2.92	−32.1 mL yr^−1	−40.1 mL yr^−1	<.05
Miravitlles et al., 2004 (3)	336	Observational	2	≥3.0	NR	NR	NS
Spencer et al., 2004 (5)	613	RCT	3	>1.65	−55 mL yr ^−1	−54 mL yr ^−1	NS
Cote et al., 2007 (15)	205	Observational	2	>2.0	NC	−4.0 (% predicted)	NS
Makris et al., 2007 (16)	102	Observational	3	>2.85	Smoking status:	Smoking status:
					Ex-smokers: −0.85 (% predicted)	Ex-smokers: −2.80 (% predicted)	= .017
					Smokers: −3.15 (% predicted)	Smokers: −4.10 (% predicted)

For abbreviations, see Table 1.

Mortality

Several studies have documented a high mortality rate in COPD patients admitted to hospital for an exacerbation (18–20). However, none of them have specifically assessed the prognostic impact of an exacerbation. In a study of severe COPD patients, we observed that the risk of death augmented in parallel to increased frequency and severity of exacerbations, irrespective of other standard prognostic factors such as age, FEV₁, body mass index, arterial blood gases, or concomitant disorders (i.e., comorbidities) (9). Thus, patients with frequent exacerbations had the highest mortality rate with a 4.3 times greater risk of death (95% CI, 2.62–7.02). The potential implications of this finding can be relevant since the prevention of future exacerbations could have a beneficial impact on survival.

We have also recently reported in COPD patients that severe exacerbations were an independent prognostic factor, including the BODE index (21); likewise, frequent COPD exacerbators exhibited the highest mortality risk with an adjusted mortality risk greater than patients without exacerbations (21). However, since our studies (9, 21) only addressed the role of severe exacerbations, the prognostic implications of less severe COPD exacerbations remain unknown.

Other implications

One of the most reported implications in patients suffering exacerbations is the impact on daily life activities (DLA). In an observational investigation in moderate-to-severe COPD patients (22), approximately 90% of them reported DLA abnormalities during an exacerbation and half of them had to completely stop all their physical activities. Patients with frequent exacerbations were prone to remain at home reducing both their physical activity and social relationships as much as possible (23).

Exacerbations also have a relevant influence on mood behavior such that almost 65% of COPD patients report a variety of negative feelings, such as irritability, isolation, anxiety, bad mood, guiltiness, and depression. A relationship between depression and exacerbation frequency in patients with COPD has been shown (24). Patients with frequent exacerbations had significantly higher depression scores that increased more abruptly at the time of an exacerbation than those with infrequent episodes.

Beyond the impact of exacerbations on the pulmonary component, recent evidence also suggests the presence of various systemic, extra-pulmonary effects. Tashkin et al. (25) have shown that the incidence of deleterious non-respiratory effects after suffering a COPD exacerbation increased 3.6 times in relation to stable conditions. Cardiac events increased approximately four times, malignant problems had a twofold increase, and metabolic sequelae had a fivefold increase. Although there are no specific data on patients with frequent COPD exacerbations, it is most likely that the effects may be more relevant in this subset of patients.

DEFINITION OF FREQUENT COPD EXACERBATIONS

There is no consensual definition for a “frequent COPD exacerbator” as yet. Decramer and colleagues (26), the first to face this difficulty, used the term “COPD patients with high medical consumption” to identify the need of hospital admission, which was extended to any COPD patient needing two or more hospitalizations per year for exacerbations. Once the evidence is established regarding both morbidity and mortality irrespective of the economical impact, the term “frequent COPD exacerbator” seems to be the most extensively utilized. However, there is no widespread agreement on this definition.

Some studies use as a cutoff point the median of recorded exacerbations per year to define the concept of “frequent COPD exacerbator” (2, 5, 27). For example, Seemungal et al. (2) observed more than 2.96 episodes, Spencer et al. (5) more than 1.65, and more recently Hurst et al. (27) found 1.97 events, yearly. Differences in these thresholds are likely related to differences in the characteristics of the populations investigated and also to the different definitions used for COPD exacerbation. While some studies use an event-driven definition (5), others use a symptom-based approach (2, 27). The latter attempt detects a higher number of exacerbations because it also encompasses unreported events. Langestmo et al. (28) have reported a mean of 2.7 exacerbations per year, of which only 0.8 episodes were documented. Instead of median values, other investigators propose three or more exacerbations per year to define the term of frequent COPD exacerbator (3, 4, 8, 9). Both the TORCH trial (29) and the UPLIFT (Understanding the Potential Long-term Impacts on Function with Tiotropium) study (30) have provided important information regarding longitudinal changes after COPD exacerbations. However, we ignore how many patients had specifically two, three, or more exacerbations per year in these trials while learning that overall the average number of exacerbations per year was relatively low. In the TORCH trial (29), 1.13 exacerbations per year were observed in the placebo arm compared with 0.85 in the salmeterol/fluticasone one while in the UPLIFT study (30), 0.73 was observed in the tiotropium branch. These figures therefore point to two or more exacerbations per year as the more realistic cutoff point to define the term “frequent COPD exacerbator.”

Furthermore, the concepts of “treatment failure” and “recurrence” for COPD exacerbations need to be clarified as well (Figure 1). Compared with a usual exacerbation pattern (Figure 1a), “treatment failure” (Figure 1b) has to be considered when symptoms worsen during the exacerbation event to the point that further treatment is deemed necessary (31). Some studies in the outpatient context have shown a “treatment failure” index of the order of 12% to 26% (32). This term can be at the origin of persistent patient disability, including the need of more anti-COPD medication, the attendance to the emergency room or even the need of hospital admission such that almost 63% of the costs of exacerbations can be related to “treatment failure” (33). By contrast, “recurrence” (Figure 1C) should be considered when symptoms reappear after a period of relatively good health status (34) such that readmission can be viewed synonymous with recurrence if hospitalization is required. To properly differentiate the concept of “treatment failure” from “recurrence,” the recovery time of an exacerbation may be vital. Thus, Perera et al. (35) have observed that the median recovery time after an exacerbation is 9 days (range, 4–18) with an average duration of approximately 2 weeks. However, 23% of exacerbations symptoms have not completely recovered by 35th day (36) and there are data that show that the majority of exacerbations need 4–6 weeks after they begin to completely recover (37, 38). This is why a new acute episode either 4–6 weeks from the beginning of an original exacerbation or four weeks after the completion of its treatment could be suggested as a more appropriate timeframe to define a “recurrence” of COPD exacerbation.

Figure 1.  Schemes of different terms related to COPD exacerbation. In (a) (“usual pattern”), symptoms increase beyond the usual daily variation and can decrease with or without treatment to complete recovery; in (b) (“treatment failure”), symptoms worsen during the exacerbation event such that further treatment is deemed; in (c) (“recurrence”), a new episode follows an earlier exacerbation with an interim period (namely, more than 4 weeks) of usually relatively good health status.

It has recently been shown that nearly one-third of exacerbations cluster together in time with a high-risk period prone to suffer a second event within the preceding 8 weeks after the original exacerbation (27). In this context, “frequent COPD exacerbators” were defined as patients whose median annual exacerbation frequency was equal to or greater than 1.97 exacerbations, largely including those who had experienced recurrences (85%). Moreover, there was a significant, not random, correlation between the number of exacerbations per year and that of recurrences per year. According to Hurst et al. (27), “recurrence” should be defined as a second exacerbation with a gap of at least 5 days from the original one on which no symptoms were recorded on diary cards, followed by a high-risk period for another acute episode within the 8 weeks after suffering from the first exacerbation. However, further studies may be needed to better differentiate the concept of “recurrence” as five asymptomatic days may be too short a timeframe to establish a clear-cut difference with a previous exacerbation.

In a systematic review of counting, analysis, and report of COPD exacerbations (39), all included randomized controlled trials were referred to as new exacerbations without any other complementary observation. The Optimal trial (40) considered patients to have experienced a new exacerbation if they had been off from both systemic glucocorticosteroids and antibiotics for at least 14 days after the previous exacerbation. Accordingly, approximately 25% of possible exacerbations were judged not to be new episodes. Not unsurprisingly, if these suspected events had not been excluded by adjudication, the rate of exacerbations in each arm would have increased. Moreover, this overestimation could lead to an imbalance between interventions, resulting in small but significant changes with different rates of exacerbations in each intervention. We therefore suggest that the usual approach followed in most randomized controlled trials, without making distinctions between “treatment failure” and “recurrence,” may be insufficient due to an overestimation of the number of events. The greater the counting of exacerbations the higher will be the chances to find significant differences between different interventions. In our opinion, future trials targeting preventative aspects of exacerbations can clarify these concepts.

There is no agreement regarding the severity of exacerbations. Most of the studies only consider their frequency without assessing staging severity. When assessing the influence of exacerbations on HRQoL or lung function, investigators do not usually characterize the influential role of COPD exacerbations severity. Notwithstanding, most of the studies addressing the prognostic impact of frequent exacerbations refer to three or more severe exacerbations (i.e., those requiring hospitalization) (9, 21). In our experience, patients attending the emergency room without needing hospitalization did not have a superior mortality risk (9), suggesting that not only frequency but also severity of COPD exacerbations becomes a relevant outcome. Although a study has demonstrated that unreported COPD exacerbations affect deleteriously health status (28), patients who report exacerbations had on average the worst outcomes. Currently, the prognostic impact of unreported exacerbations remains unsettled.

All in all we propose to define “frequent COPD exacerbator” as a COPD patient who has a mean of at least two or more exacerbations per year. Exacerbations should be spaced at least 4 weeks after the end of the treatment of the previous exacerbation or 6 weeks after its onset, hence differentiating a new exacerbation from “treatment failure.” Alternatively, a “recurrence” will be an acute episode that shows up between 4–6 weeks from the beginning of an original exacerbation or 4 weeks after the end of its treatment. Although this concept may help to identify the exacerbator phenotype, more evidence is warranted to support a more refined definition. Probably, exacerbation frequency may have a different impact as a function of disease severity, an association that might not be lineal.

FACTORS PRONE TO FREQUENT EXACERBATIONS

As alluded to, several studies indicate that the frequency of exacerbations increases in parallel to the FEV₁ decline (8, 10–12, 16, 41). In a retrospective study in COPD outpatients, an accelerated FEV₁ decline was independently associated with increased risk of having at least one exacerbation per year (11). Furthermore, FEV₁ impairment was associated with increased risk of hospital admissions during the same period of time. It has been shown that patients with an FEV₁ higher than 60% predicted had a mean of 1.6 exacerbations per year compared with 1.9 in those with an FEV₁ of 59%–40% and 2.3 when the FEV₁ is lower than 40% (8, 41). However, patients with moderate COPD can have repeated severe exacerbations and, conversely, those with more advanced disease can show no exacerbations at all (12). These findings clearly suggest that the number of exacerbations does not increase linearly with FEV₁ decline. Other factors, therefore, can influence the frequency of exacerbations whose specific weight is unknown as yet.

Table 3 gives a list of risk factors that influence exacerbations, the presence of previous exacerbations being one of the most plausible factors (2, 6, 42–44). Seemungal et al. (2) observed that frequent past exacerbations constitute one of the factors most strongly associated with frequent exacerbations. In other studies, the number of past COPD exacerbations was also a risk factor for new exacerbations (6, 42–44) and this was independent of COPD severity. Therefore, these findings indicate that only a subset of patients can be more prone to develop frequent exacerbations.

Table 3.  Risk factors

Older age (2, 4, 12)

Severity of COPD:

Increased baseline dyspnea (4, 12)

Low FEV1 (8, 10–12, 16, 41)

Low PaO2 (4, 12)

Frequent past exacerbations (2, 6, 42–44)

Chronic bronchial mucus hypersecretion (51)

Inflammation:

Higher airway inflammation (8, 45)

Higher systemic inflammation (46, 50)

Bacterial load (stable phase) (45)

Comorbidities/systemic manifestations:

Cardiovascular (4, 44)

Anxiety and depression (24)

Myopathy (26)

The individual susceptibility to have more frequent exacerbations may have a genetic background and/or may be acquired by the persistence of an unsolved factor. It has been shown that patients with frequent exacerbations have increased airway interleukin (IL)-6 and IL-8 levels compared with those patients who have infrequent exacerbations (45). Likewise, the study showed that airway inflammation correlates with the bacterial load measured outside of an exacerbation (46). These findings point to the view that airway microorganisms that are not eradicated (or colonized) could induce bronchial inflammation of low severity to facilitate new COPD acute episodes. Indeed, the underlying mechanisms that can produce a new COPD exacerbation still remain unsettled. In this regard, an increased bacterial load has been proposed to be a plausible mechanism. However, Sethi et al. (47) have unquestionably demonstrated that changes in the bacterial load are unlikely to be a determinant mechanism for exacerbations. Only when new strains were isolated, higher bacterial loads in the airways were shown. It was therefore concluded that new strain acquisition becomes a key process while an increased bacterial load cannot be considered an independent mechanism for exacerbations induction.

Although a rising bacterial load may not be the main cause of the development of repeated COPD exacerbations, underlying chronic airway inflammation could modulate somehow the host response. In this regard, the relevance of viral infections in triggering exacerbations has been strengthened. A study of the combined effect of bacterial and viral infections during exacerbations has revealed a synergistic effect between airway inflammation and clinical severity (48). Viral infections play an important role in modulating the airway immune and inflammatory responses which may alter the fragile balance between colonizing bacteria and host response. Hurst et al. (49) have demonstrated that patients with frequent exacerbations experience more frequent colds, hence suggesting that COPD patients with frequent exacerbations are prone to the acquisition of colds. Airway inflammation has been linked to a rapid FEV₁ decline (8) related to disease progression and, possibly, to a greater bronchial infection risk.

Systemic inflammatory manifestations can be increased in parallel with the number of COPD exacerbations (50). These extra-pulmonary effects have been linked to different concomitant disorders, such as muscular skeletal or cardiovascular disorders. Decramer et al. (26) reported that the more severe the miopathy, the greater is the risk of frequent hospitalization due to exacerbation, and a similar relationship has been shown for cardiovascular disease (44). Furthermore, an increased cardiovascular risk during exacerbations has been preliminarily reported (52). COPD exacerbations trigger the mobilization of circulating endothelial progenitor cells in patients with cardiovascular disorders, possibly related to increased systemic consequences and/or further arterial hypoxemia during the acute events. Moreover, patients with an elevated number of concomitant disorders may also be more prone to exacerbations. In a case–control study of severe COPD patients, we observed that patients with frequent exacerbations had a higher number of cardiac problems but the same level of clinical severity than controls (4). Almost 30% of severe exacerbations reported symptoms suggesting cardiac failure, a diagnosis not easily established at the bedside (53). Exacerbations may worsen cardiac failure and, conversely, the latter condition may in turn increase the clinical severity of COPD exacerbations by deteriorating the levels of dyspnea. Cardiac troponin-1 is often increased during COPD exacerbations needing hospitalization without evidence of an acute coronary event, hence indicating that COPD exacerbations can be detrimental to the cardiac muscle (54). Accordingly, cardiovascular disease should be properly detected to avoid further clinical problems. An increased pro-thrombotic status during COPD exacerbations, as assessed by increased fibrinogen levels, has also been reported (55). Nevertheless, there is still some controversy whether or not pulmonary embolism is more frequent during COPD exacerbations (56, 57).

Irrespective of the underlying inflammatory changes, host defense factors against pathogens may also play a considerable role during frequent COPD exacerbations. However, there are very few studies on the genetic determinants of COPD exacerbations. Takabatake et al. (58) suggested a marked heterogeneity in host defense mechanisms against the offending pathogens and in the inflammatory response during COPD exacerbations, in part explained by individual susceptibility. This was supported by the association between the single nucleotide polymorphisms (SNPs) and the frequency and severity of COPD exacerbations, and may be attributed, at least in part, to the genetic variance of CCL1, a gene encoding a chemotactic factor for a series of leukocytes including monocytes and macrophages. Carriage of SNP3-A, acting as the risk allele, may predispose COPD patients to exacerbations. In contrast, carriage of the SPN3-T may relatively protect against exacerbations. These investigators hypothesized with the concept that differences in the genotype-dependent expression of CCL1 protein may lead to abnormalities of the subsequent activation of the innate immune system and inflammatory exposure through the altered formation of the chemokine-receptor network against acute pulmonary infections.

Yang et al. (59) observed that a polymorphism in mannose binding lectin (MBL2) was associated with an increased frequency of hospital admissions for COPD exacerbations. More recently, polymorphisms in surfactant protein B have also been associated with susceptibility to frequent exacerbations in severe COPD patients (60). Pulmonary alveolar surfactant is composed of phospholipids and four surfactant proteins that reduce surface tension and prevent alveolar collapse at low lung volume; surfactant protein B promotes adhesion and spreading of surfactant phospholipids and stabilizes the phospholipid monolayer (29, 30). In addition to alveolar stabilization, improved pulmonary compliance, removal of particles, and enhancement of mucociliary clearance, surfactant and its components have altogether immunologic properties (61).

CONCLUSIONS

“Frequent COPD exacerbators” can be considered a real, non-fictitious population of COPD patients who generate considerable healthcare resources use and higher morbidity and mortality. These COPD patients seem to develop an individual susceptibility to be prone to frequent exacerbations that could be related to a combination of airway and systemic inflammatory events, concomitant disorders, and genetic factors with a specific phenotype. Nevertheless, factors defining this susceptibility have not been sufficiently sorted out as yet. Further studies, possibly using multicentric designs, are warranted to both identify and refine their differential traits. As a result, a better management and more beneficial therapeutic and preventative measures can also be approached.

Declaration of interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper. JJSC has participated as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, AstraZeneca, Boehringer Ingelheim, Esteve, GlaxoSmithKline, Nycomed and Pfizer; serves on advisory board for AstraZeneca, Boehringer Ingelheim and Pfizer; and received laboratory research support from Almirall, AstraZeneca, Boehringer Ingelheim, Glaxo-SmithKline, Esteve and Pfizer. In the past RRR participated, always as a lecturer and speaker in scientific meetings and courses under the sponsorship of Almirall, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Kyorin, Novartis, Pfizer, and UCB; consulted with several pharmaceutical companies (Almirall, AstraZeneca, Boehringer Ingelheim, GlaxoSmith-Kline, Novartis, Nycomed, and Pfizer); serves on advisory boards for AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, Merck, Novartis, Nycomed, Pfizer, and Procter & Gamble; has been sponsored for several clinical trials by, and received laboratory research support from, Almirall, AstraZeneca, Boehringer Ingelheim, Glaxo-SmithKline, Esteve, and Pfizer. At present, RRR is chair of the Executive Committee of GOLD.

ACKNOWLEDGMENT

Dr RRR is supported by the CibeRes (CB06/06) and the Generalitat de Catalunya (2005SGR-00822).