Bronchiectasis (BE) is the third most prevalent chronic inflammatory airway disease, after asthma and chronic obstructive pulmonary disease (COPD), and it is closely related to both.1–4 It is usually presented as a clinical syndrome characterized by coughing, daily expectoration, and recurring episodes (exacerbations) of an infectious profile5–7 In February 2015, the Spanish Registry of Bronchiectasis (RIBRON)8 began to collect information and now has a well-characterized series of more than 2000 patients that makes it possible to conduct large-scale studies.

Both the number and severity of the exacerbations in BE patients have been shown to have a negative impact on the disease's natural history.9–15 In fact, some authors have mentioned the possible existence of a group of patients who share similar clinical pictures, prognoses, and treatments as a result of a particularly high number of exacerbations (“exacerbator phenotype”).16,17

Furthermore, a number of BE patients present an increase in some markers of systemic inflammation, which has been associated with greater severity of the disease.18–20 One of the inflammatory biomarkers most extensively studied is C-reactive protein (CRP).21 An increase in the systemic concentration of this molecule has been associated with greater severity of asthma, COPD, and cystic fibrosis (CF).22–27 However, data on the relationship between the concentration of CRP in clinically stable state and BE is still scarce, particularly with respect to the number and severity of exacerbations.28 Our working hypothesis is based on the fact that, as in the case of other inflammatory airway diseases, the peripheral concentration of CRP could be related to a greater number and severity of future exacerbations of BE. Thus, its evaluation in a stable phase of the disease may have a clinical application in such patients.

The objective of the present study is therefore to analyze the prognostic capacity of the peripheral levels of ultra-sensitive CRP (henceforth, CRP) on the frequency and severity of the exacerbations in a large series of BE patients taken from the RIBRON registry when they were in a clinically stable state.

Patient characteristics at baseline are shown in Table 1. Of the 2039 patients included in the RIBRON at the time of the analysis, 802 (39.3%) were valid for the purposes of the study (Fig. 1). The patients who were not included presented CF (n=165), or they had not yet completed a year of follow-up in the registry (n=1030), or they presented invalid or non-validated CRP values (n=42). A comparison of these patients who were not included in the study with those who were did not reveal any significant differences (apart from the cases with CF) (data not shown). The baseline characteristics of the 802 patients included in the study are shown in Table 1.

Fig. 1.

Flow-chart of the study.

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The mean age was 68.1 (11.1) and 65% were female. The most common etiology was post-infection (42.6%). CBI by PA was found in 25.8% of the patients. The mean value (SD) of the CRP concentration was 6.5mg/L (17.6). 33.8% of the patients had more than two exacerbations and 13% had at least one severe exacerbation during this first year of follow-up.

Table 2 shows the comparative characteristics between patients depending on the CRP concentration (in tertiles). Those patients who presented in its third tertile presented more severity, worse lung function, increased percentage of CBI by PA and higher number of exacerbations.

The multivariate logistic regression analysis (Table 3) shows the variables independently associated with an increase in the risk of severe exacerbations in the future. There was a linear relationship between the tertiles of rising values of CRP and a higher risk of severe exacerbations. Thus, the tertile with the greatest concentration presented a 4.2 times greater risk of presenting a severe exacerbation in the first year of the follow-up than the control group (first tertile). No prognostic capacity was observed in gender (OR 0.7 [95%CI: 0.5–1.3]), radiological extension (OR 1.1 [0.88–1.4]), the Charlson Index (OR 1.1 [0.9–1.2]), or any of the treatments analyzed.

However, the values of the concentration of CRP were not associated with any increase in the future risk of mild-moderate exacerbations, as shown in Table 4.

Moreover, other variables such as the degree of dyspnea, lung function, and previous severe exacerbations did present a significant prognostic value for future exacerbations, independently of the severity of the exacerbation. However, CBI by PA, like the CRP value, was only associated with severe exacerbations.

Fig. 2 shows that those patients who presented CPR in its third tertile, CBI by PA and at least one severe exacerbation in the previous year presented a 40% probability of presenting at least one severe exacerbation in the coming year; in contrast, this probability was 1% in patients with none of these three characteristics (OR: 51.5 [CI95%:11–242]).

Fig. 2.

Tree of probability of future severe exacerbation according to the combination of different predictive variables.

CRP. C-reactive protein (mg/L); CBI: Chronic bronchial infection; PA: Pseudomonas aeruginosa.

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Finally, Table 5 shows how the prognostic capacity for at least one severe exacerbation in the first year of follow-up of the value of the CRP concentration, measured in accordance with the usual multidimensional scales, remained constant regardless of the severity of the BE.

According to the results of our study, which was carried out in a large, well-characterized cohort of BE patients taken from the RIBRON, peripheral CRP concentration presented a significant independent prognostic value for future severe exacerbations, but not for mild-moderate exacerbations. This risk presented a linear relationship, so the higher the CRP concentration, the greater the risk of a severe exacerbation. We believe that this finding, could have an important application in clinical practice, as it allows a clinician to predict which patients (while free of an exacerbation process) will have the greatest risk of experiencing a severe exacerbation of their disease in the future; this knowledge would therefore make it possible to anticipate any necessary preventive and therapeutic measures.

Exacerbations, particularly severe ones, are a key factor when it comes to evaluating the severity or prognosis of BE. It is hardly surprising, therefore, that they appear, with a relatively substantial weight, in some of the recently published multidimensional scores on BE, such as the Bronchiectasis Severity Index (BSI)29 and the E-FACED,30 and they have been associated with a more marked decline in lung function,9 as occur in other airway diseases.32 This implies that these easily measurable factors that prognosticate which patients are more susceptible to presenting frequent or severe exacerbations could be extremely useful in clinical practice.

It is well-established that a considerable percentage of BE patients present a degree of systemic inflammation, as measured by the peripheral concentration of molecules such as neutrophilic elastase.33 The most widely accepted hypothesis is that these patients present a more severe form of the disease, as the appearance of this systemic inflammation has been associated with a greater degree of local inflammation and with various factors associated with a poor prognosis.18–20 However, although systemic inflammation has been widely studied as a prognostic factor for exacerbations in other airway diseases, such as COPD33,34 and CF,36,37 very little information is available in this respect on BE, particularly as regards CRP. In fact, there has only been one small retrospective study in 69 patients, which found that a CRP concentration >4.26mg/L was significantly associated with a higher percentage of patients with at least two hospitalizations in the previous year. Only idiopathic BE was included, however, and the small number of patients makes it impossible to draw any valid conclusions.28

Our results point in the same direction as studies undertaken on COPD and CF, as a higher peripheral concentration of CRP was associated with a higher risk of future exacerbations, after adjusting the results for variables with a proven predictive value or associated with exacerbations in BE.32–35 In fact, a CRP value between 0.4 and 2.7mg/L, or higher than 2.7mg/L, multiplied by 2.9 and 4.2 times, respectively, the risk of a severe exacerbation in the following year, compared to the control group. If this high risk of severe exacerbations in association with a high CRP value is combined with other clinically significant high-risk variables, such as the presence of a CBI by PA or previous severe exacerbations (both variables with a known prognostic value for exacerbations of BE), the resulting information could be clinically relevant, as shown in Fig. 2. For example, those patients with a CRP >2.7mg/L and a CBI by PA in a clinically stable phase who had had at least one hospitalization in the previous year presented a 51 times greater probability of a future hospitalization than those who did no present any of these three characteristics (40% of possibilities versus 1%).

Furthermore, this prognostic capacity of CRP values with respect to future severe exacerbations was independent of the severity of BE as evaluated by traditional scores, which indicates that this easily obtainable and interpretable biomarker could provide prognostic data that would complement the information already provided by these scores, particularly the BSI and E-FACED.

It should be noted, however, that the CRP concentration did not present any prognostic value for mild-moderate exacerbations. This finding could mean that CRP is indeed exclusively a marker of severe forms of exacerbation, but it could also mean that some mild-moderate exacerbations could have passed unnoticed or unrecorded in the registry, thereby rendering the analysis less trustworthy in this respect.

Two of the strengths of our study are undoubtedly the considerable number of patients included and their good characterization, reflecting their presence on a national registry with strict quality control measures. Another strength is the study's multicenter nature, as it involved 43 different centers from the whole of Spain. The study also presents some limitations, however. On the one hand, only 42.8% of the total number of patients could be analyzed, largely because many did not reach the end of the first year of the follow-up – although the latter's baseline characteristics were analyzed and did not diverge from those of the patients who were finally included. On the other hand, it is well-known that the CRP value is very unspecific since, as an acute-phase reactant, it can produce a high reading in many patients as a result of a number of inflammatory or infectious diseases.20 This is why great caution was taken to extract patients’ blood when they were in a clinically stable state with respect to both BE and any other disease that could alter their levels of CRP, beyond the etiology of BE itself. Finally, since this is data from a non-controlled source, there are bias that cannot be ascertained such as differences in the classification of exacerbations between or even within centers.

In conclusion, CRP concentration, especially above 2.7mg/L, is a good prognostic marker of severe exacerbations in patients with BE, regardless of its severity. As CRP is readily available and easy to measure, its evaluation in conjunction with other clinically relevant variables can enable clinicians to make an early identification of patients with a greater probability of severe exacerbations in the future and implement any necessary preventive and therapeutic measures. Future studies based on other national or international registries are required for the external validation of our results.

Development of electronic databases, costs of statistical analysis, and translation of the manuscript. There was no intervention by the sponsor in the design of the study, collection and analysis of data, or writing of the manuscript.

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  Concept and design: TP and MAMG

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  Acquisition of data: GO, CV, YD, RG, CO, LM, MGC, OS, RG, JR, EB,

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  JLR, RM, CP, DR

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  Drafting of manuscript and critical revision of major intellectual content: All authors.

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  Final approval of the version to be published: All authors.

RIBRON has a grant from Zambon-Pharma.

The authors declare that there is no conflict of interest regarding the publication of this article.