Background: Information on the role of fungi in non-cystic fibrosis (CF) bronchiectasis is lacking. Objectives: Our aim was to determine the prevalence of and factors associated with the isolation and persistence of fungi from sputum in these patients. Methods: We performed a multicenter observational study comprising adult patients with non-CF bronchiectasis. Persistence of Aspergillus spp. and Candida albicans was defined as the presence of ≥2 positive sputum cultures taken at least 6 months apart within a period of 5 years. Results: A total of 252 patients (62.7% women with a mean ± SD age of 55.3 ± 16.7 years) were included in the study. All patients had at least 1 sputum sample cultured for fungi, with a mean ± SD of 7 ± 6 cultures per patient. Eighteen (8.7%) and 71 (34.5%) patients had persistent positive cultures for Aspergillus spp. and C. albicans, respectively. Patients with persistence of Aspergillus spp. and C. albicans were older and had more daily purulent sputum. In addition, patients with persistent C. albicans had worse postbronchodilator forced expiratory volume in the first second (FEV1), more frequent cystic bronchiectasis, and more hospital-treated exacerbations. They were also more frequently treated with long-term antibiotics. Multivariate analysis showed that daily purulent sputum (OR = 3.75, p = 0.045) and long-term antibiotics (OR = 2.37, p = 0.005) were independently associated with persistence of Aspergillus spp. and C. albicans, respectively. Conclusions: Isolation and persistence of Aspergillus spp. and C. albicans are frequent in patients with non-CF bronchiectasis. Daily purulent sputum and chronic antibiotic treatment were associated with persistence of Aspergillus spp. and C. albicans, respectively.

Non-cystic fibrosis (CF) bronchiectasis is a chronic airway disease characterized by progressive dilation and destruction of the bronchial tree. Associated dysfunctional mucociliary clearance leads to persistent bacterial infection, chronic inflammation of the bronchial tree, and progressive tissue destruction [1].

In patients with non-CF bronchiectasis, the airway is usually colonized by bacterial pathogens and other microorganisms, such as yeasts and filamentous fungi. In healthy individuals, fungal spores are quickly cleared by the mucociliary escalator and phagocytozed by cells of the innate immune system. However, in patients with chronic lung conditions such as bronchiectasis, impaired mucociliary clearance and mucus plugging can lead to the persistence of spores in the respiratory tract [2,3].

The prevalence of colonization of the airways by Aspergillus spp. and Candida albicans in patients with CF is high [4,5,6] and can vary according to geography, local surveillance methods for endobronchial fungal infections, and the definition of fungal colonization, infection, and persistence [6,7]. Although risk factors for persistence of these fungi in the airways of patients with CF have been investigated [4,8], they have yet to be clarified. In the case of non-CF bronchiectasis, published data on the prevalence and fungus-associated factors are lacking. Therefore, the aim of this study was to determine the prevalence and factors associated with the isolation and persistence of fungi from sputum in patients with non-CF bronchiectasis.

Study Population

The study population comprised 296 consecutive patients, all of whom were aged ≥18 years and had been diagnosed with non-CF bronchiectasis of widely varying causes, with radiological extension and clinical and functional impairment. Patients were evaluated over a 5-year period between December 31, 2002, and December 31, 2010. The exclusion criteria were CF and not having at least 1 sputum sample cultured for fungi during a clinically stable phase within a period of 5 years after the diagnosis.

According to the recommendations of the Spanish Society of Pulmonology and Thoracic Surgery, the causes ruled out in idiopathic bronchiectasis were as follows: immune deficiencies with evidence of defective antibody production, gastroesophageal reflux disease, allergic bronchopulmonary aspergillosis, mycobacterial infection, CF, primary ciliary dyskinesia, and α1-antitrypsin deficiency [9]. Patients with allergic bronchopulmonary aspergillosis (n = 4) [10] were excluded because they comprise a subgroup that differs from patients with other causes of non-CF bronchiectasis in terms of the prevalence and pathogenic significance of Aspergillus colonization. CF was ruled out by 2 negative sweat test results in patients with bronchiectasis of unknown cause or with a clinical presentation compatible with CF. The study was approved by the Ethics and Research Committee of each center (registration number of the coordinating center: 0088-89-2011).

Study Design

We performed an observational study of historical cohorts from 4 Spanish centers that were homogeneous in terms of the participating specialists and the type of outpatient clinic.

Patients were selected for 2 separate analyses. For the primary analysis, we compared patients who had at least 1 filamentous fungus or yeast in sputum over the course of the study with those who had not. For the secondary analysis, we compared patients with persistent Aspergillus spp. and C. albicans and patients without persistent Aspergillus spp. and C. albicans.

Data Collection

Data were collected from all patients during a 4-week clinically stable phase and included the following: age, gender, body mass index, etiology, smoking habit (pack-years), dyspnea according to the modified Medical Research Council scale, patient-reported macroscopic appearance of sputum (mucoid, mucopurulent, or purulent), type of bronchiectasis (cystic, noncystic), radiological findings (number of lobes affected by bronchiectasis), presence of respiratory insufficiency (defined as an oxyhemoglobin saturation <90% when breathing room air), spirometry [forced vital capacity (FVC) and postbronchodilator forced expiratory volume in the first second (FEV1), as both absolute values and % predicted], and peripheral levels of C-reactive protein (IU/ml) as a marker of systemic inflammation. We also recorded hospitalizations secondary to severe exacerbation, number of exacerbations, and number of courses of oral corticosteroids administered for exacerbations. A stable clinical condition was defined as the absence of clinical criteria of exacerbation and no requirement for antibiotics or corticosteroids in the preceding 4 weeks [11]. Exacerbation was defined as the acute onset and persistence of changes in sputum characteristics (increased volume, thicker consistency, greater purulence, or hemoptysis) and/or increased breathlessness unrelated to other causes [12].

All variables were obtained a maximum of 6 months after the radiological diagnosis of bronchiectasis, except for hospitalizations, number of exacerbations, and number of courses of oral corticosteroids for exacerbations, which were obtained during the year after the radiological diagnosis.

Long-term treatments (inhaled or oral antibiotics, oral macrolides, and corticosteroids) taken for at least 1 year after the radiological diagnosis of bronchiectasis were recorded.

Diagnosis of Bronchiectasis

Bronchiectasis was diagnosed by a high-resolution computed tomography scan of the chest and interpreted by radiologists experienced in respiratory disorders. Images were obtained in full inspiration (1-mm collimation and 10-mm intervals from the apex to the base of the lungs). The presence of bronchiectasis was based on the criteria published by Naidich et al. [13]. The extent of the bronchiectasis was evaluated according to the number of lobes and segments affected, with the lingula and middle lobe considered as independent lobes.

Microbiology

Only sputum samples with more than 25 polymorphonuclear leukocytes and fewer than 10 squamous cells on Gram stain were considered valid samples and processed for bacterial and fungal culture. For fungal isolation, the samples were plated on Sabouraud chloramphenicol plates and incubated at 30 and 37°C. Cultures were evaluated for growth every 24 h during the first 7 days and weekly till 28 days. If filamentous fungi were detected, colonies were cultured in potato dextrose agar and Czapek agar, and subcultures were incubated at 30, 37, and 42°C in order to identify the species.

Bacterial chronic lung infection was defined as isolation of the same potentially pathogenic microorganism after the diagnosis of bronchiectasis in >50% of respiratory cultures during the 5-year study [14]. Persistent Aspergillus spp. and C. albicans were defined as the presence of 2 or more positive sputum cultures for Aspergillus spp. and C. albicans, respectively, taken at least 6 months apart over a period of 5 years.

Statistical Analysis

The data for patients with at least 1 filamentous fungus or yeast isolated in sputum and for patients with persistent Aspergillus spp. and C. albicans were presented and analyzed separately. The statistical analysis was performed using SPSS, version 15.0 (SPSS, Chicago, Ill., USA). All data were expressed as mean ± SD or median (IQR) for quantitative variables and as absolute values and percentages for qualitative variables. The normality of the distribution was assessed using the Kolmogorov-Smirnov test. Nonparametric tests were used in the absence of a normal distribution. The t test or Mann-Whitney test was used to compare 2 means, and the χ2 test or Fisher's exact test were used for qualitative or dichotomous variables. Variables of clinical interest (according to the current literature or researchers' opinion) and those that presented statistically significant differences in the univariate analysis were included as independent variables in 2 logistic regression models based on the backward stepwise technique (Wald test). The dependent variables were isolation of at least 1 filamentous fungus or yeast and persistent Aspergillus spp. or C. albicans. In the case of elevated collinearity between 2 variables (Spearman or Pearson correlation coefficient >0.6), the variable with greater clinical significance was chosen, based on the judgment of the authors. The odds ratio (OR) and 95% confidence intervals (CI) for the independent variables were also calculated, and p values ≤0.05 were considered significant.

Study Population

The initial sample comprised 296 patients with non-CF bronchiectasis. Of the 296 patients screened, 252 met the eligibility criteria and were included in the study (fig. 1). The baseline characteristics are shown in tables 1 and 2. The mean ± SD age was 55.3 ± 16.7 years (62.7% females). All patients had respiratory secretions cultured for fungi with a mean ± SD of 7 ± 6 cultures per patient. No patients received antifungal treatment during the study period. The most frequent etiology of bronchiectasis was postinfectious (36.1%). The etiology was unknown in 35.7% of cases. Cystic bronchiectasis was detected in 57 patients (27.1%).

Table 1

Baseline characteristics of the study cohort (n = 252)

Baseline characteristics of the study cohort (n = 252)
Baseline characteristics of the study cohort (n = 252)
Table 2

Microbiological characteristics of the study cohort (n = 252)

Microbiological characteristics of the study cohort (n = 252)
Microbiological characteristics of the study cohort (n = 252)
Fig. 1

Flowchart of the study population. ABPA = Allergic bronchopulmonary aspergillosis.

Fig. 1

Flowchart of the study population. ABPA = Allergic bronchopulmonary aspergillosis.

Close modal

Prevalence of Fungal Species

Filamentous fungi were identified at least once from respiratory tract secretions in 65 patients (25.8%) and yeasts were identified in 114 patients (45.2%). Aspergillus spp. was identified at least once from respiratory tract secretions in 61 patients (24.2%) and C. albicans was identified in 114 patients (45.2%). Nine patients were infected with both. In 26 patients, the isolates of Aspergillus spp. were further classified into distinct fungal species. Aspergillus fumigatus isolates were identified in 20 patients (7.9%) and Aspergillus niger in 6 (2.4%). Other fungal species were recovered from 13 (5.2%) patients and included Penicillium (3 patients), Mucor(1 patient), Scedosporium apiospermum(2 patients), Fusarium(2 patients), Saccharomyces cerevisiae(1 patient), Alternaria(1 patient), and Rhodotorula(1 patients). One patient had S. apiospermum and Mucor, and another had Penicillium and Mucor. Eight patients had Aspergillus spp. and other filamentous fungi. The patient with S. cerevisiae also had C. albicans. Eighteen patients (8.7%) were considered to have persistent Aspergillus spp. and 71 (34.5%) persistent C. albicans.

Cohort Characteristics and Risk Factors for Isolation of Fungi

For the primary analysis, we compared the characteristics of patients who had at least 1 filamentous fungus or yeast with those of patients who had not. When comparing individual characteristics in patients with at least 1 filamentous fungal species, significant differences were only found in the macroscopic appearance of sputum (mucopurulent or purulent appearance; p = 0.01). Isolation of yeast was associated with older age (p = 0.019), female gender (p = 0.049), higher dyspnea (p = 0.025), worse macroscopic appearance of sputum (p = 0.009), more cystic bronchiectasis (p = 0.048), and worse postbronchodilator FEV1, % predicted (p = 0.017). These patients were also more frequently colonized with Pseudomonas aeruginosa (p = 0.029) and less frequently colonized with Haemophilusinfluenzae (p = 0.027). Furthermore, they took more long-term oral and inhaled antibiotics (p = 0.009) and had significantly more hospital-treated exacerbations (p = 0.041).

After adjustment for confounders, the variables that significantly increased the odds of yeast isolation were older age, macroscopic appearance of sputum (mucopurulent or purulent), worse postbronchodilator FEV1, and use of chronic antibiotics (table 3).

Table 3

Multiple logistic regression analysis of risk factors for isolation of yeasta (n = 114)

Multiple logistic regression analysis of risk factors for isolation of yeasta (n = 114)
Multiple logistic regression analysis of risk factors for isolation of yeasta (n = 114)

For the secondary analysis, we compared the characteristics of the patients according to the persistence of Aspergillus spp. and C. albicans(table 4).

Table 4

Characteristics of patients with and without persistent Aspergillus spp. and C.albicans in respiratory secretions

Characteristics of patients with and without persistent Aspergillus spp. and C.albicans in respiratory secretions
Characteristics of patients with and without persistent Aspergillus spp. and C.albicans in respiratory secretions

Patients with persistent Aspergillus spp. were significantly older (67 vs. 56 years; p = 0.029) and produced sputum with a worse macroscopic appearance (83.3% of patients with mucopurulent or purulent sputum vs. 61.8%; p = 0.002). No differences were observed with respect to functional impairment, number of pulmonary exacerbations, and long-term antibiotic treatment. Patients with persistent C. albicans were also older (62 vs. 54 years; p = 0.012) and had more advanced lung disease in terms of lung function [FVC, % predicted, 68.1 vs. 78.8 (p = 0.003) and FEV1, postbronchodilator, % predicted, 58.4 vs. 71.0 (p = 0.012)] and more frequent radiological evidence of cystic bronchiectasis (33.8 vs. 21.5%; p = 0.049). Their sputum had a significantly worse macroscopic appearance (73.5% of patients with mucopurulent or purulent sputum vs. 58.5%; p = 0.008), and their dyspnea score was higher (p = 0.017). In addition, patients with persistent C. albicans had significantly more hospital-treated exacerbations (p = 0.049), received more courses of oral corticosteroids for exacerbations (p = 0.001), and were prescribed significantly more long-term oral and inhaled antibiotics (p = 0.004). Of note, they were more frequently colonized with P. aeruginosa (54.9 vs. 38.5%; p = 0.024) and less frequently with H.influenzae (12.7 vs. 28.1%; p = 0.012). Moreover, patients with persistent C. albicans had more exacerbations, and the difference tended toward statistical significance (p = 0.051).

Logistic regression was used to determine the most significant predictors of fungal persistence. The significant variables entered into the multiple logistic regression models for Aspergillus were age and macroscopic appearance of sputum; the variables entered for C. albicans were age, dyspnea, appearance of sputum, presence of cystic bronchiectasis, FEV1 (postbronchodilator, % predicted), chronic P. aeruginosa infection, chronic H. influenzae infection, number of hospitalizations, and chronic antibiotic use. In the final model, after adjustment for confounders, the only factor that significantly increased the odds of persistence of Aspergillus was mucopurulent or purulent sputum. In the case of C. albicans, the only variable that significantly increased the odds of persistence was long-term antibiotic therapy (table 5).

Table 5

Multiple logistic regression analysis of risk factors for persistence of Aspergillus spp. and C.albicans

Multiple logistic regression analysis of risk factors for persistence of Aspergillus spp. and C.albicans
Multiple logistic regression analysis of risk factors for persistence of Aspergillus spp. and C.albicans

To our knowledge, this is the first study to analyze the prevalence of and factors associated with the isolation and persistence of fungi in a large series of patients with non-CF bronchiectasis. Our data show high rates of fungal isolation and persistence in respiratory secretions, where Aspergillus spp. and C. albicans were the most commonly isolated microorganisms. According to our results, the presence of mucopurulent or purulent sputum is associated with persistence of Aspergillus spp.; long-term antibiotic therapy is associated with persistence of C. albicans.

In addition to bacterial colonization, the lower airways of patients with bronchiectasis could be predisposed to fungal growth owing to impaired mucociliary clearance, mucus plugging, and the ability of fungi to evade or interfere with host defenses [15]. The associated factors and the clinical significance for both filamentous fungi and yeasts in this group of patients remain unclear.

In the present study, prevalence rates recorded for isolation of Aspergillus spp. and C. albicans were high, in fact, much higher than the prevalence rate for single isolation of this fungus reported by other authors [16,17,18] and more consistent with the prevalence in patients with chronic obstructive pulmonary disease [19] and CF [2], where the prevalence of Aspergillus ranges from 6 to 58% and that of C. albicans stands at 50%. Although culture of yeast in sputum is a common practice in people receiving inhaled corticosteroids, the high rate of C. albicans isolation in patients with bronchiectasis cannot be explained by use of this medication, since inhaled corticosteroids are not administered routinely in patients with bronchiectasis [9,20].

We found that purulent sputum was independently associated with the persistence of Aspergillus. Although there are no published data on factors associated with Aspergillus in patients with non-CF bronchiectasis, Angrill et al. [16] reported an association between chronic expectoration and colonization by potentially pathogenic bacteria in non-CF patients, probably because of the propensity of bacteria and fungi to grow in thick secretions in chronic airway diseases [2,9]. The clinical factors associated with isolation of Aspergillus in patients with CF are open to debate. It has been suggested that increasing age [5,8,21,22], more severe lung disease [8,21], and azithromycin therapy [23] are risk factors for isolating filamentous fungi in CF. Moreover, chronic antibiotic treatment [8,22,24,25] was also associated with the persistence of Aspergillus spp. In addition, culture of A. fumigatus from sputum samples is a common feature of chronic obstructive pulmonary disease, but the clinical significance of this finding remains uncertain [19].

Apart from the well-known occurrence in patients with asthma and CF, Aspergillus hypersensitivity can also occur in patients with chronic obstructive pulmonary disease [26] and pulmonary tuberculosis-related fibrocavitary disease [27]. The presence of Aspergillus hypersensitivity correlates with reduced lung function in patients with asthma and pulmonary tuberculosis-related fibrocavitary disease [27,28,29,30], while this correlation is more equivocal in patients with CF bronchiectasis [31,32].

However, the clinical relevance and the therapeutic implications of Aspergillus sensitization in these diseases require further investigation. Unfortunately, we did not perform allergy testing to investigate the association between sensitization to A. fumigatus, A. fumigatus culture, and pulmonary function.

Our results revealed a univariate association between respiratory impairment and persistence of C. albicans. Furthermore, patients with persistent C. albicans in their respiratory secretions had significantly more hospital-treated exacerbations, more frequently received oral corticosteroids for exacerbations, and were prescribed more long-term antibiotic treatment. Although patients with more severe disease are more frequently treated with chronic antibiotics than patients with less severe lung impairment, the results obtained in the multivariate analysis suggest that the association between chronic antibiotic therapy and persistence of C. albicans cannot be explained by increased disease severity. In addition, the frequent chronic antibiotic treatment prescribed to our patients could explain the higher ranges of persistence of C. albicans we detected compared with other authors [16,17,18]. Although there are no data on long-term antipseudomonal treatment in these reports, the small number of patients colonized with Pseudomonas spp. makes it unlikely that this treatment was administered.

Despite the lack of published data on non-CF bronchiectasis, our results are in keeping with those from previous reports on CF, which suggest that long-term antibiotic therapy and frequent courses of antibiotics can lead to increased isolation of and colonization by C. albicans [24,33]. Moreover, in the univariate analysis, we found that persistence of C. albicans was significantly associated with colonization by P. aeruginosa but not with colonization by H.influenzae. Chronic antibiotic treatment is widely used to treat infection by P. aeruginosa but not infection by H. influenzae. Antipseudomonal treatment may lead to increases in the sputum density of patients harboring C. albicans without eradicating P. aeruginosa. The relationship between these organisms has been described elsewhere [34,35], and in vitro studies showed that P. aeruginosa can form dense biofilms on C. albicans hyphae and does not bind to or kill C. albicans [36].

We found an increased persistence of C. albicans - but not Aspergillus spp. - in non-CF bronchiectasis patients receiving long-term antibiotic therapy, possibly because sputum sampling can significantly underestimate persistence of Aspergillus, as suggested in previous works in CF involving serum immune responses to this fungus [5,29,37,38] or DNA-based techniques [39]. Another potential explanation could be that chronic antibiotics are not really a risk factor for persistence of Aspergillus.

Apart from the logical limitations related to the inclusion of a historical series in our analyses, there are other limitations which are worthy of being mentioned. First, it is still unknown whether a positive sputum culture of filamentous fungi or yeasts represents true bronchial colonization. Second, although the optimal definition of fungal infection in the lower airways is unclear, more samples are recommended for defining other chronic lung infections, such as Pseudomonas, in CF patients [40]. Furthermore, our study has other methodological limitations: contamination by C. albicans was not assessed by physical examination (Candida is a commensal in the oral cavity), and patients were not tested for HIV.

In summary, we found a high prevalence of persistence of Aspergillus spp. and C. albicans in clinically stable patients with non-CF bronchiectasis. We also observed that the presence of daily sputum purulence was associated with persistence of Aspergillus and that long-term antibiotic treatment was associated with persistence of C. albicans. Our results highlight the need to better understand the relevance of fungi in non-CF bronchiectasis.

Further prospective studies are necessary to evaluate the epidemiologic trends, associated factors, and the clinical implications of fungal persistence in non-CF bronchiectasis. Also, the effect of fungal colonization and sensitization on airway inflammation and lung function in these patients should be explored.

We thank Dr. Elia Gómez de la Pedrosa for her helpful collaboration in microbiological studies and Ana Royuela and Nieves Plana for their help with the statistical analysis.

Funding of the study was received from Praxis Pharmaceutical. This study is included in the PII of Bronchiectasis of SEPAR (Spanish Society of Pulmonology and Thoracic Surgery). The authors declare that they have no conflicts of interest.

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