The role of precision medicine in bronchiectasis: emerging data and clinical implications.

INTRODUCTION: Bronchiectasis is a very heterogeneous disease. This heterogeneity has several consequences: severity cannot be measured by a single variable, so multidimensional scores have been developed to capture it more broadly. Some groups of patients with similar clinical characteristics or prognoses (clinical phenotypes), and even similar inflammatory profiles (endotypes), have been identified, and these have been shown to require a more specific treatment. AREAS COVERED: We comment on this 'stratified' model of medicine as an intermediate step toward the application of the usual concepts on which precision medicine is based (such as cellular, molecular or genetic biomarkers, treatable traits and individual clinical fingerprinting), whereby each subject presents certain specific characteristics and receives individualized treatment. EXPERT OPINION: True precision or personalized medicine is based on concepts that have not yet been fully achieved in bronchiectasis, although some authors are already beginning to adapt them to this disease in terms of pulmonary and extrapulmonary etiologies, clinical fingerprinting (specific to each individual), cellular biomarkers such as neutrophils and eosinophils (in peripheral blood) and molecular biomarkers such as neutrophil elastase. In therapeutic terms, the future is promising, and some molecules with significant antibiotic and anti-inflammatory properties are being developed.

The U-Shaped Relationship Between Eosinophil Count and Bronchiectasis Severity: The Effect of Inhaled Corticosteroids.

BACKGROUND: Although a proven relationship exists between the blood eosinophil count (BEC) and the severity of both asthma and COPD, its relationship with bronchiectasis has not been well established. The objective of this study was to analyze the relationship between BEC and the number and severity of exacerbations, and patients' responses to inhaled corticosteroid (IC) treatment in bronchiectasis RESEARCH QUESTION: Does an association exist among BEC, the number of exacerbations and severity of bronchiectasis, and IC treatment? STUDY DESIGN AND METHODS: This was a multicenter (43 centers) prospective observational study derived from the Spanish Bronchiectasis Registry. Patients with proven bronchiectasis and a known BEC were included, whereas those with asthma or antieosinophilic treatments were excluded. Patients were divided into four groups according to the BEC at the time of inclusion in the study in a steady-state situation: (1) eosinopenic bronchiectasis (< 50 eosinophils/µL), (2) low number of eosinophils (51-100/µL), (3) normal number of eosinophils (101-300/µL), and (4) eosinophilic bronchiectasis (> 300 eosinophils/µL). RESULTS: Nine hundred twenty-eight patients finally were included: 123 patients (13.3%) with < 50 eosinophils/µL (eosinopenic group), 164 patients (17.7%) with 50-100 eosinophils/µL, 488 patients (52.6%) with 101-300 eosinophils/µL, and 153 patients (16.5%) with > 300 eosinophils/µL (eosinophilic group). BEC showed a significant U-shaped relationship with severity, exacerbations, lung function, microbiologic profile, and IC treatment (these being higher in the eosinopenic group compared with the eosinophilic group). IC treatment significantly decreased the number and severity of exacerbations only in the group of bronchiectasis patients with > 300 eosinophils/µL. INTERPRETATION: A significant U-shaped relationship was found between BEC and severity and exacerbations in bronchiectasis that was more pronounced in the eosinopenic group. IC treatment decreased the number and severity of exacerbations only in the eosinophilic group.

Impact of Chronic Bronchial Infection by Staphylococcus aureus on Bronchiectasis.

The objective of the study was to analyze the factors associated with chronic bronchial infection (CBI) due to methicillin-susceptible Staphylococcus aureus (SA) and assess the clinical impact on severity, exacerbations, hospitalizations, and loss of lung function compared to patients with no isolation of PPMs in a large longitudinal series of patients from the Spanish bronchiectasis registry (RIBRON). Material and methods: A prospective, longitudinal, multicenter study was conducted with patients included in the RIBRON registry between January 2015 and October 2020. The inclusion criteria were an age of 18 years or older and an initial diagnosis of bronchiectasis. Patients recorded in the registry had a situation of clinical stability in the absence of an exacerbation in the four weeks before their inclusion. All patients were encouraged to provide a sputum sample at each visit for microbiological culture. Annual pulmonary function tests were performed according to the national spirometry guidelines. Results: A total of 426 patients were ultimately included in the study: 77 patients (18%) with CBI due to SA and 349 (82%) who did not present any isolation of PPMs in sputum. The mean age was 66.9 years (16.2), and patients 297 (69.7%) were female, with an average BMI of 25.1 (4.7) kg/m2 and an average Charlson index of 1.74 (1.33). The mean baseline value of FEV1 2 L was 0.76, with a mean FEV1% of 78.8% (23.1). One hundred and seventy-two patients (40.4%) had airflow obstruction with FEV1/FVC < 0.7. The mean predictive FACED score was 1.62 (1.41), with a mean value of 2.62 (2.07) for the EFACED score and 7.3 (4.5) for the BSI score. Patients with CBI caused by SA were younger (p < 0.0001), and they had a lower BMI (p = 0.024) and more exacerbations in the previous year (p = 0.019), as well as in the first, second, and third years of follow-up (p = 0.020, p = 0.001, and p = 0.018, respectively). As regards lung function, patients with CBI due to SA had lower levels of FEV1% at the time of inclusion in the registry (p = 0.021), and they presented more frequently with bronchial obstruction (p = 0.042). A lower age (OR: 0.97; 95% CI: 0.94−0.99; p < 0.001), lower FEV1 value% (OR: 0.98; 95% CI: 0.97−0.99; p = 0.035), higher number of affected lobes (OR: 1.53; 95% CI: 1.2−1.95; p < 0.001), and the presence of two or more exacerbations in the previous year (OR: 2.33; 95% CI: 1.15−4.69; p = 0.018) were observed as independent factors associated with CBI due to SA. The reduction in FEv1% in all patients included in the study was −0.31%/year (95% CI: −0.7; −0.07) (p = 0.110). When the reduction in FEv1% is analyzed in the group of patients with CBI due to SA and the group without pathogens, we observed that the reduction in FEV1% was −1.19% (95% CI: −2.09, −0.69) (p < 0.001) in the first group and −0.02% (95% CI: −0.07, −0.01) (p = 0.918) in the second group. According to a linear regression model (mixed effects) applied to determine which factors were associated with a more pronounced reduction in FEv1% in the overall group (including those with CBI due to SA and those with no PPM isolation), age (p = 0.0019), use of inhaled corticosteroids (p = 0.004), presence of CBI due to SA (p = 0.007), female gender (p < 0.001), and the initial value of FEV1 (p < 0.001) were significantly related. Conclusions: Patients with non-CF bronchiectasis with CBI due to SA were younger, with lower FEV1% values, more significant extension of bronchiectasis, and a higher number of exacerbations of mild to moderate symptoms than those with no PPM isolation in respiratory secretions. The reduction in FEV1% was −1.19% (95% CI: −2.09, −0.69) (p < 0.001) in patients with CBI caused by SA.

Blood Neutrophil Counts Define Specific Clusters of Bronchiectasis Patients: A Hint to Differential Clinical Phenotypes.

We sought to investigate differential phenotypic characteristics according to neutrophil counts, using a biostatistics approach in a large-cohort study from the Spanish Online Bronchiectasis Registry (RIBRON). The 1034 patients who met the inclusion criteria were clustered into two groups on the basis of their blood neutrophil levels. Using the Mann-Whitney U test to explore potential differences according to FACED and EFACED scores between the two groups, a neutrophil count of 4990 cells/µL yielded the most balanced cluster sizes: (1) above-threshold (n = 337) and (2) below-threshold (n = 697) groups. Patients above the threshold showed significantly worse lung function parameters and nutritional status, while systemic inflammation levels were higher than in the below-threshold patients. In the latter group, the proportions of patients with mild disease were greater, while a more severe disease was present in the above-threshold patients. According to the blood neutrophil counts using biostatistics analyses, two distinct clinical phenotypes of stable patients with non-CF bronchiectasis were defined. Patients falling into the above-threshold cluster were more severe. Severity was characterized by a significantly impaired lung function parameters and nutritional status, and greater systemic inflammation. Phenotypic profiles of bronchiectasis patients are well defined as a result of the cluster analysis of combined systemic and respiratory variables.

The Human Mycobiome in Chronic Respiratory Diseases: Current Situation and Future Perspectives.

Microbes play an important role in the pathogenesis of chronic lung diseases, such as chronic obstructive pulmonary disease, cystic fibrosis, non-cystic fibrosis bronchiectasis, and asthma. While the role of bacterial pathogens has been extensively studied, the contribution of fungal species to the pathogenesis of chronic lung diseases is much less understood. The recent introduction of next-generation sequencing techniques has revealed the existence of complex microbial lung communities in healthy individuals and patients with chronic respiratory disorders, with fungi being an important part of these communities' structure (mycobiome). There is growing evidence that the components of the lung mycobiome influence the clinical course of chronic respiratory diseases, not only by direct pathogenesis but also by interacting with bacterial species and with the host's physiology. In this article, we review the current knowledge on the role of fungi in chronic respiratory diseases, which was obtained by conventional culture and next-generation sequencing, highlighting the limitations of both techniques and exploring future research areas.

Systemic Inflammatory Biomarkers Define Specific Clusters in Patients with Bronchiectasis: A Large-Cohort Study.

Differential phenotypic characteristics using data mining approaches were defined in a large cohort of patients from the Spanish Online Bronchiectasis Registry (RIBRON). Three differential phenotypic clusters (hierarchical clustering, scikit-learn library for Python, and agglomerative methods) according to systemic biomarkers: neutrophil, eosinophil, and lymphocyte counts, C reactive protein, and hemoglobin were obtained in a patient large-cohort (n = 1092). Clusters #1-3 were named as mild, moderate, and severe on the basis of disease severity scores. Patients in cluster #3 were significantly more severe (FEV1, age, colonization, extension, dyspnea (FACED), exacerbation (EFACED), and bronchiectasis severity index (BSI) scores) than patients in clusters #1 and #2. Exacerbation and hospitalization numbers, Charlson index, and blood inflammatory markers were significantly greater in cluster #3 than in clusters #1 and #2. Chronic colonization by Pseudomonas aeruginosa and COPD prevalence were higher in cluster # 3 than in cluster #1. Airflow limitation and diffusion capacity were reduced in cluster #3 compared to clusters #1 and #2. Multivariate ordinal logistic regression analysis further confirmed these results. Similar results were obtained after excluding COPD patients. Clustering analysis offers a powerful tool to better characterize patients with bronchiectasis. These results have clinical implications in the management of the complexity and heterogeneity of bronchiectasis patients.

Differences in Nutritional Status and Inflammatory Biomarkers between Female and Male Patients with Bronchiectasis: A Large-Cohort Study.

We hypothesized that systemic inflammatory and nutritional parameters may differ between male and female patients with non-CF bronchiectasis. In a large patient cohort from the Spanish Online Bronchiectasis Registry (RIBRON), clinical features, systemic inflammatory and nutritional parameters were analyzed in male and female patients with bronchiectasis. Lung function, disease severity using several scores, nutritional status, systemic inflammatory parameters, and multivariate regression analyses were performed to identify differences between male and female patients in the target variables. The number of female patients included in the registry was greater than male patients and they had a less severe disease as measured by all three indices of disease severity, a lower degree of airway obstruction, worse diffusion capacity and airway trapping, better nutritional parameters, and lower levels of inflammatory biomarkers. Multivariate regression analysis evidenced that strong relationships were found between female gender and the following variables: total numbers of leukocytes and neutrophils, hemoglobin, hematocrit, creatinine, and body mass index (BMI). Multivariate regression analyses evidenced that nutritional parameters and inflammatory biomarkers may be reliable indicators of gender-related differences in patients with non-CF bronchiectasis. These findings deserve further attention in follow-up investigations in which the potential predictive value of those biomarkers should be thoroughly explored.

Phenotypic Clustering in Non-Cystic Fibrosis Bronchiectasis Patients: The Role of Eosinophils in Disease Severity.

Whether high blood eosinophil counts may define a better phenotype in bronchiectasis patients, as shown in chronic obstructive pulmonary disease (COPD), remains to be investigated. Differential phenotypic characteristics according to eosinophil counts were assessed using a biostatistical approach in a large cohort study from the Spanish Online Bronchiectasis Registry (RIBRON). The 906 patients who met the inclusion criteria were clustered into two groups on the basis of their eosinophil levels. The potential differences according to the bronchiectasis severity index (BSI) score between two groups (Mann-Whitney U test and eosinophil count threshold: 100 cells/µL) showed the most balanced cluster sizes: above-threshold and below-threshold groups. Patients above the threshold exhibited significantly better clinical outcomes, lung function, and nutritional status, while showing lower systemic inflammation levels. The proportion of patients with mild disease was higher in the above-threshold group, while the below-threshold patients were more severe. Two distinct clinical phenotypes of stable patients with non-cystic fibrosis (CF) bronchiectasis of a wide range of disease severity were established on the basis of blood eosinophil counts using a biostatistical approach. Patients classified within the above-threshold cluster were those exhibiting a mild disease, significantly better clinical outcomes, lung function, and nutritional status while showing lower systemic inflammatory levels. These results will contribute to better characterizing bronchiectasis patients into phenotypic profiles with their clinical implications.

RIBRON: The spanish Online Bronchiectasis Registry. Characterization of the First 1912 Patients. / RIBRON: el registro español informatizado de bronquiectasias. Caracterización de los primeros 1.912 pacientes.

INTRODUCTION: The SEPAR Spanish Bronchiectasis Registry (RIBRON) began as a platform for the collection of longitudinal data on patients with this disease. The objective of this study is to describe its operation and to analyze the characteristics of bronchiectasis patients according to sex. METHODS: A total of 1912 adult patients diagnosed with bronchiectasis in 43 centers were included between February 2015 and 2019. All patients had complete data consisting of at least 79 basic required variables, controlled by an external audit. RESULTS: Mean age was 67.6 (15.2) years; 63.9% were women. The most common symptom was productive cough (78.3%) which was mucopurulent-purulent in 45.9% of cases. The most common etiology was post-infectious (40.4%), while 18.5% were idiopathic. Pseudomonas aeruginosa was the most frequently isolated microorganism (40.4%), of which 25.6% were associated with chronic infection. The annual number of mild-to-moderate/severe exacerbations was 1.62 (1.9)/0.59 (1.3). Half of the patients (50%) presented with airflow obstruction (17% severe). The most frequent radiological localization was lower lobes. The average FACED/E-FACED/BSI values were 2.06 (1.7)/2.67 (2.2)/7.8 (4.5), respectively. Overall, 66.7% of patients were taking inhaled corticosteroids, 19.2% macrolides, and 19.5% inhaled antibiotics. Women presented a less severe profile than men in clinical and functional terms, and a similar infectious, radiological and therapeutic profile. CONCLUSIONS: RIBRON represents an excellent map of the characteristics of bronchiectasis in our country. Two thirds of patients are women who presented lower disease severity as a specific characteristic.

C-Reactive Protein Concentration in Steady-State Bronchiectasis: Prognostic Value of Future Severe Exacerbations. Data From the Spanish Registry of Bronchiectasis (RIBRON).

BACKGROUND: Both systemic inflammation and exacerbations have been associated with greater severity of bronchiectasis. Our objective was to analyze the prognostic value of the peripheral concentration of C-reactive protein (CRP) for the number and severity of exacerbations in patients with bronchiectasis. METHODS: Patients from the Spanish Bronchiectasis Registry (RIBRON) with valid data on their CRP value (in a clinically stable phase) and valid data on exacerbations during the first year of follow-up were included. A logistic regression analysis was used to evaluate the prognostic value of the CRP concentration (divided into tertiles) with the presence of at least one severe exacerbation or at least two mild-moderate exacerbations during the first year of follow-up. RESULTS: 802 patients (mean age: 68.1 [11.1 years], 65% female) were included. Of these, 33.8% and 13%, respectively, presented ≥2 mild-moderate exacerbations or at least one severe exacerbation during the first year of follow-up. The mean value of the CRP was 6.5 (17.6mg/L). Patients with a CRP value between 0.4 and 2.7mg/L (second tertile) and ≥2.7mg/L (third tertile) presented a 2.9 (95%CI: 1.4-5.9) and 4.2 (95%CI: 2.2-8.2) times greater probability, respectively, of experiencing a severe exacerbation than those with <0.4mg/L (control group), regardless of bronchiectasis severity or a history of previous exacerbations. However, the CRP value did not present any prognostic value for the number of mild-moderate exacerbations. CONCLUSIONS: The CRP value was associated with a greater risk of future severe exacerbations but not with mild or moderate exacerbations in patients with steady-state bronchiectasis.

Impact of Pseudomonas aeruginosa Infection on Patients with Chronic Inflammatory Airway Diseases.

Pseudomonas aeruginosa (P. aeruginosa) is a ubiquitous and opportunistic microorganism and is considered one of the most significant pathogens that produce chronic colonization and infection of the lower respiratory tract, especially in people with chronic inflammatory airway diseases such as asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis (CF), and bronchiectasis. From a microbiological viewpoint, the presence and persistence of P. aeruginosa over time are characterized by adaptation within the host that precludes any rapid, devastating injury to the host. Moreover, this microorganism usually develops antibiotic resistance, which is accelerated in chronic infections especially in those situations where the frequent use of antimicrobials facilitates the selection of "hypermutator P. aeruginosa strain". This phenomenon has been observed in people with bronchiectasis, CF, and the "exacerbator" COPD phenotype. From a clinical point of view, a chronic bronchial infection of P. aeruginosa has been related to more severity and poor prognosis in people with CF, bronchiectasis, and probably in COPD, but little is known on the effect of this microorganism infection in people with asthma. The relationship between the impact and treatment of P. aeruginosa infection in people with airway diseases emerges as an important future challenge and it is the most important objective of this review.

Long-term docosahexaenoic acid (DHA) supplementation in cystic fibrosis patients: a randomized, multi-center, double-blind, placebo-controlled trial.

BACKGROUND: Cystic fibrosis (CF) patients have an alteration in fatty acid (FA) metabolism, associated with increased omega-6 and low omega-3 FA. Previous studies on supplementation with omega-3 FA in CF had contradictory results, and to date there is no evidence to recommend routine use of omega-3 supplements in CF patients. We hypothesized that long-term supplementation with docosahexaenoic acid (DHA) will have beneficial effects in these patients, by reducing pulmonary, systemic and intestinal inflammation. METHODS: This was a randomized, double-blind, parallel, placebo-controlled trial. CF patients (age >2 months) were randomized to receive a seaweed DHA oil solution (50 mg/Kg/day) or matching placebo for 48 weeks. Primary outcomes were pulmonary (interleukin [IL]-8), systemic (IL-8) and intestinal (calprotectin) inflammatory biomarkers. Secondary outcomes included other pulmonary (IL-1ß, IL-6, neutrophil elastase, lactate and calprotectin) and systemic (serum-IL-1ß, IL-6) inflammatory biomarkers, as well as clinical outcomes (FEV1, pulmonary exacerbations, antibiotic use, nutritional status and quality of life). RESULTS: Ninety six CF patients, 44 female, age 14.6±11.9 years (48 DHA and 48 placebo) were included. At trial completion, there were no differences in all primary outcomes [serum-IL-8 (p=0.909), respiratory-IL-8 (p=0.384) or fecal calprotectin (p=0.948)], all secondary inflammatory biomarkers, or in any of the clinical outcomes evaluated. There were few adverse events, with similar incidence in both study groups. CONCLUSION: In this study, long-term DHA supplementation in CF patients was safe, but did not offer any benefit on inflammatory biomarkers, or in clinical outcomes compared with placebo. (NCT01783613).

Prevalence of modifiable factors limiting treatment efficacy of poorly controlled asthma patients: EFIMERA observational study.

Several modifiable factors leading to poor asthma control have been described. We aimed to determine the proportion of patients with inadequate treatment, adherence to it, or critical mistakes with inhaler technique, and their impact on asthma control. We conducted a cross-sectional multicenter observational study including asthma patients referred from primary to specialist care for the first time. Data collected were adequate prescription according to guidelines, treatment adherence, and disease control. Of the 1682 patients (age 45 ± 17 years, 64.6% men), 35.9% showed inadequate prescription, 76.8% low adherence, and 17% critical mistakes with inhaler technique, with significantly less critical mistakes among Easyhaler users versus other dry powder inhaler users (10.3 versus 18.4%; p < 0.05). Factors related to bad asthma control were inadequate prescription (OR: 3.65), non-adherence to treatment (OR: 1.8), and inhaler misuse (OR: 3.03). A higher number of risk factors were associated with a higher probability of having badly controlled asthma.

Bronchiectasis: A Complex, Heterogeneous Disease. / Las bronquiectasias: una enfermedad compleja y heterogénea.

Most areas of respiratory medicine continue to use an Oslerian approach, based on signs and symptoms, in which the disease is the center of all activity. However, this paradigm is changing. Now that lung diseases have been recognized as heterogeneous and complex, we are moving towards more personalized, precise, patient-oriented medicine. The aim of this review was to define the current state of the knowledge on bronchiectasis, or, more accurately, the bronchiectasis syndrome, as a multidimensional, systemic, heterogeneous, complex disease. We explore the advances that have already been made, and above all the many steps that are still to be taken. We also propose some tools which might facilitate the application of these concepts in clinical practice, and help us continue our journey towards a more holistic view of this disease.

Asthma patient satisfaction with different dry powder inhalers.

BACKGROUND: The preferences and opinions of patients are important when choosing the optimal inhaler device for asthma management. We compared patient satisfaction of three dry powder inhalers in patients with moderate to severe asthma. METHODS: We selected a group of patients treated with EasyhalerTM (n = 164) and a second group of patients treated with TurbuhalerTM (n = 100) or DiskusTM (AccuhalerTM) (n = 64) from the register of an observational, multicenter study. Data of patients were paired according to age, gender, and asthma severity. Patient satisfaction with the inhaler type was assessed with the specific 'Feeling of Satisfaction with Inhaler' (FSI-10) questionnaire. RESULTS: Specific satisfaction with inhaler was statistically significantly higher with EasyhalerTM, as well as the percentage of patients with high satisfaction with inhaler. (FSI-10 score ≥43). Scores for EasyhalerTM were also statistically significantly better for individual FSI-10 items such as learning how to use, inhaler preparation, inhaler use, weight and size, and portability. There were no significant differences in asthma control (ACT, Mini-AQLQ) and adherence (TAI global score). CONCLUSIONS: Specific satisfaction with inhaler was higher with EasyhalerTM in a homogeneous population of patients with moderate to severe asthma. However, the relationship between satisfaction with the inhaler and adherence and asthma control deserves more investigation.

Prediction of the intestinal resistome by a three-dimensional structure-based method.

The intestinal microbiota is considered to be a major reservoir of antibiotic resistance determinants (ARDs) that could potentially be transferred to bacterial pathogens via mobile genetic elements. Yet, this assumption is poorly supported by empirical evidence due to the distant homologies between known ARDs (mostly from culturable bacteria) and ARDs from the intestinal microbiota. Consequently, an accurate census of intestinal ARDs (that is, the intestinal resistome) has not yet been fully determined. For this purpose, we developed and validated an annotation method (called pairwise comparative modelling) on the basis of a three-dimensional structure (homology comparative modelling), leading to the prediction of 6,095 ARDs in a catalogue of 3.9 million proteins from the human intestinal microbiota. We found that the majority of predicted ARDs (pdARDs) were distantly related to known ARDs (mean amino acid identity 29.8%) and found little evidence supporting their transfer between species. According to the composition of their resistome, we were able to cluster subjects from the MetaHIT cohort (n = 663) into six resistotypes that were connected to the previously described enterotypes. Finally, we found that the relative abundance of pdARDs was positively associated with gene richness, but not when subjects were exposed to antibiotics. Altogether, our results indicate that the majority of intestinal microbiota ARDs can be considered intrinsic to the dominant commensal microbiota and that these genes are rarely shared with bacterial pathogens.