Background
Asthma is a heterogeneous condition characterized by chronic inflammation of the pulmonary airways [
1] that currently afflicts 300 million people worldwide [
2].
Bronchiectasis (BE) is defined as bronchial dysfunction secondary to an infectious, inflammatory or reparative process in the airways that permanently damages the bronchial walls and causes irreversible enlargement of the airways. Although the real prevalence of BE is unknown, it has been estimated as being anywhere between 42 and 566 cases per 100,000 people and it particularly affects women and the elderly, but a significant trend toward under-diagnosis has also been acknowledged [
3,
4]. However, the number of diagnoses is quickly rising, due, among other factors, to the population’s greater longevity, the greater chronicity of the diseases that trigger BE and, above all, the greater reliability of the high-definition tomographic techniques now in use [
5]. Thus, its incidence and prevalence are increasing, particularly in older age groups, and it is associated with a marked increase in mortality [
6], making it probably the third most frequent chronic inflammatory airway disorder [
5].
Asthma and bronchiectasis are different conditions that frequently coexist. Furthermore, in our experience, a diagnosis of bronchiectasis in asthma patients could lead to modifications to both therapy and prognosis (as in the case of COPD patients [
7‐
9]). Most studies of the prevalence or characteristics of bronchiectasis in asthmatic patients are retrospective [
10‐
14], involving a small sample [
15‐
18], and including biases such as smoking [
10,
18,
19], or allergic bronchopulmonary aspergillosis (ABPA) [
10‐
12,
17], while high-resolution CT scanning (HRCT) was not always performed [
11,
13,
14]. This study sought to determine the prevalence of bronchiectasis in non-smokers with uncontrolled moderate-to-severe asthma (UMSA), based on the largest sample ever used and on HRCT findings. Another objective was to identify factors associated with the presence of bronchiectasis in these patients.
Discussion
This study reveals a 28.4% prevalence of bronchiectasis in UMSA patients, 20.6% for moderate, and 33.6% for severe asthma.
According to the literature, the prevalence of bronchiectasis among patients with asthma ranges from 2.2% [
14] to 77% [
19]. Such discrepancies can be explained by inconsistencies in the methodologies used, as some studies included smokers [
10,
18,
19], ABPA [
10‐
12,
17], diseases related to bronchiectasis [
45], and the inclusion of asthma patients with different degrees of severity [
13,
15,
17,
18,
46], while not all patients underwent HRCT [
11,
13,
14].
After demonstrating the effectiveness of HRCT in diagnosing bronchiectasis in ABPA, Neeld et al. [
47] observed a high incidence of bronchiectasis in asthma patients and found cylindrical bronchiectasis in asthmatic patients without ABPA. Several authors have reported the presence of bronchiectasis in subjects with asthma and without ABPA [
15,
46], supporting our findings. We also found other studies with similar percentages of BE in patients with asthma: Grenier et al. [
18] and Khadadah et al. [
16] conducted two studies in which they found a 28.5% prevalence of bronchiectasis in patients with asthma of varying degrees of severity. Gupta el al. [
10] found a 40% prevalence of bronchiectasis in patients with severe asthma, although 5% met the criteria for ABPA, and the rate dropped to 26% when smokers were excluded. Menzies et al. [
12] conducted a retrospective study of medical records that included patients meeting ABPA criteria and found a 35.3% prevalence of bronchiectasis.
In keeping with previous studies [
15,
18,
46,
48], we found a higher prevalence of cylindrical (92.9%) and bilateral (73.5%) bronchiectasis, mainly in the lower lobes.
Multivariate analysis revealed that chronic bronchial expectoration was associated with bronchiectasis in UMSA. This variable has scarcely been investigated, although studies on bronchiectasis not associated with cystic fibrosis—such as that conducted by Goeminne et al. [
49] — demonstrate that purulent sputum indicates the severity of inflammatory damage and the activity of proteolytic enzymes. Other studies of bronchiectasis not associated with cystic fibrosis have also found a relationship between the color of expectoration and the presence of PPM [
24]. In our study, we observed that chronic bronchial expectoration and purulent sputum were more frequent in patients with asthma and bronchiectasis (31.9% vs 16.1%) compared to those with no bronchiectasis (8% vs. 2.5%). Chronic expectoration and purulent sputum are important factors for consideration in patients with asthma and bronchiectasis, especially given that they are not only correlated with
PPM and a greater use of antibiotics but are also independent risk factors for the presence of bronchiectasis in asthmatic patients.
Another factor related to bronchiectasis was a history of pneumonia (a relationship known since the last century) [
50].
Another predictor of bronchiectasis in UMSA is asthma severity. The results obtained are consistent with the literature [
13,
15,
17,
18,
46] and show a higher prevalence of bronchiectasis in patients with severe asthma, compared to milder cases.
Our study’s contribution is the correlation found between higher FeNO levels and a lower probability of bronchiectasis. FeNO is a non-invasive biomarker of the inflammation of the airways in asthma; high levels are associated with eosinophilic inflammation of the airways [
51‐
54]. Its concentration has been shown to be higher in patients with bronchial asthma than in a healthy population [
55]. Moreover, numerous studies have demonstrated that FeNO values in asthma patients are associated with other characteristics of the disease, such as bronchial hyper-reactivity, the intensity of the symptoms, or the number of eosinophils in samples from the airways [
51]. In this respect, FeNO has been defined as a biological marker of inflammation in asthma.
However, some studies of FeNO levels in BE have presented contradictory results. Thus, Kharitonov et al. [
56] showed that high levels of FeNO in BE correlated with disease severity, as in the case of asthma, whereas Cho et al [
57] found, in keeping with our results, that the FeNO levels in BE patients are lower than those found in asthma patients. Furthermore, BE is normally associated with neutrophilic inflammation [
58,
59]. However, one recently published study [
60] used induced sputum and FeNO in 40 BE patients as non-invasive measures of inflammation. These authors found that, compared with patients with BE and neutrophilic inflammation or paucigranulocytic phenotype, patients with BE and eosinophilic or mixed (neutrophilic-eosinophilic) inflammation had higher levels of FeNO and greater reversibility to bronchodilation, as in the case of asthma [
51]. Their findings in other inflammatory parameters (IL-13 increased slightly in bronchiectasis, even in patients with eosinophilic inflammation) led them to establish the hypothesis that eosinophilic inflammation in bronchiectasis is not primarily Th2-driven and that another pathway through ILC2 cells possibly plays a role in eosinophilic inflammation; this has yet to be demonstrated, however. Furthermore, Tsikrika et al. do not provide data about circumstances such as the presence of atopy, which could impinge on the inflammatory phenotype and explain the eosinophilia found in these patients. The authors also point out that one of the limitations of their study is their inability to rule out the possibility that some of their subjects could have concomitant asthma.
In fact, few studies have assessed FeNo in subjects with asthma and bronchiectasis. In a recent retrospective study, Chen et al [
61] measured FeNO levels in 99 patients with bronchiectasis (20 of them with asthma) and found higher FeNO levels in subjects with bronchiectasis and asthma, compared to subjects who had only bronchiectasis. The authors also demonstrated that FeNO levels can help distinguish patients with bronchiectasis and asthma from those with bronchiectasis but not asthma, and they established a cut-off point of 22.5 ppb, with an estimated AUC-ROC of 0.832. This is consistent with our results, as the optimal cut-off for FeNO levels that distinguished asthmatic subjects with bronchiectasis from asthmatic patients without bronchiectasis was 20.5 ppb, with a lower AUC-ROC. This is supported by the literature, since FeNO has been proposed by several guidelines [
20,
62] for the diagnosis of asthma. In contrast, FeNO has not been proposed for the diagnosis of bronchiectasis, as FeNO levels in bronchiectasis are generally low [
57], probably due to the prevalence of neutrophilic inflammation in these patients. According to the results obtained, FeNO’s most useful characteristic for the prognosis of bronchiectasis in asthma patients is its negative predictive value (81%).We found that FeNO levels can help rule out the presence of bronchiectasis since—as shown in Fig.
3a— asthmatic patients with high FeNO levels are unlikely to have bronchiectasis. Since FeNO is not effective in predicting the presence of bronchiectasis in asthmatic subjects (although it is effective for predicting its absence), we developed an innovative score with a good negative predictive value and excellent specificity. Thus, 95% of patients without bronchiectasis had a NOPES score of ≤2, and 76% of subjects with low scores did not have bronchiectasis, while 67% of patients with a high NOPES score had bronchiectasis. Furthermore, the likelihood of bronchiectasis rises as the NOPES score increases (according to the presence or absence of the four variables proposed). Low scores indicate the absence of bronchiectasis, whereas high scores suggest its presence.
As FeNO is not available in all centers, we made a score with three variables (excluding FeNO but retaining the other three variables), but it proved to be of little value in comparison with the score with four variables (AUC-ROC 0.648 and Nagelkerke’s R Square 0.08 vs AUC-ROC 0.7 and Nagelkerke’s R Square 0.145) and was therefore discarded.
We therefore propose the NOPES score as a clinically valuable, easy-to-use tool for predicting bronchiectasis in patients with uncontrolled asthma.
The strength of this study is its use of the largest prospective study of patients subjected to HRCT. It provides real data on the prevalence of bronchiectasis in patients with uncontrolled asthma, without biases such as smoking, ABPA, or other diseases causing bronchiectasis, as these conditions were excluded.
One limitation of this study, despite its large sample, is that patients were grouped according to the presence or absence of different variables, leaving some study arms with very few patients, as in the cases of subjects likely to develop bronchiectasis according to a NOPES score of 0% and 100%, where the highest n was 4; consequently, this probability can be underestimated in the former case and overestimated in the latter. Furthermore, induced sputum is unfortunately unavailable in our center, and so we were unable to establish our patients’ inflammatory phenotypes. Another limitation is that all the patients were treated in the same center, so a multicenter study would be required to confirm the results.