Comparative microbiome analysis in cystic fibrosis and non-cystic fibrosis bronchiectasis.

BACKGROUND: Bronchiectasis is a condition characterized by abnormal and irreversible bronchial dilation resulting from lung tissue damage and can be categorized into two main groups: cystic fibrosis (CF) and non-CF bronchiectasis (NCFB). Both diseases are marked by recurrent infections, inflammatory exacerbations, and lung damage. Given that infections are the primary drivers of disease progression, characterization of the respiratory microbiome can shed light on compositional alterations and susceptibility to antimicrobial drugs in these cases compared to healthy individuals. METHODS: To assess the microbiota in the two studied diseases, 35 subjects were recruited, comprising 10 NCFB and 13 CF patients and 12 healthy individuals. Nasopharyngeal swabs and induced sputum were collected, and total DNA was extracted. The DNA was then sequenced by the shotgun method and evaluated using the SqueezeMeta pipeline and R. RESULTS: We observed reduced species diversity in both disease cohorts, along with distinct microbial compositions and profiles of antimicrobial resistance genes, compared to healthy individuals. The nasopharynx exhibited a consistent microbiota composition across all cohorts. Enrichment of members of the Burkholderiaceae family and an increased Firmicutes/Bacteroidetes ratio in the CF cohort emerged as key distinguishing factors compared to NCFB group. Staphylococcus aureus and Prevotella shahii also presented differential abundance in the CF and NCFB cohorts, respectively, in the lower respiratory tract. Considering antimicrobial resistance, a high number of genes related to antibiotic efflux were detected in both disease groups, which correlated with the patient's clinical data. CONCLUSIONS: Bronchiectasis is associated with reduced microbial diversity and a shift in microbial and resistome composition compared to healthy subjects. Despite some similarities, CF and NCFB present significant differences in microbiome composition and antimicrobial resistance profiles, suggesting the need for customized management strategies for each disease.

Objective sputum colour assessment and clinical outcomes in bronchiectasis: data from the European Bronchiectasis Registry (EMBARC).

BACKGROUND: A validated 4-point sputum colour chart can be used to objectively evaluate the levels of airway inflammation in bronchiectasis patients. In the European Bronchiectasis Registry (EMBARC), we tested whether sputum colour would be associated with disease severity and clinical outcomes. METHODS: We used a prospective, observational registry of adults with bronchiectasis conducted in 31 countries. Patients who did not produce spontaneous sputum were excluded from the analysis. The Murray sputum colour chart was used at baseline and at follow-up visits. Key outcomes were frequency of exacerbations, hospitalisations for severe exacerbations and mortality during up to 5-year follow-up. RESULTS: 13 484 patients were included in the analysis. More purulent sputum was associated with lower forced expiratory volume in 1 s (FEV1), worse quality of life, greater bacterial infection and a higher bronchiectasis severity index. Sputum colour was strongly associated with the risk of future exacerbations during follow-up. Compared to patients with mucoid sputum (reference group), patients with mucopurulent sputum experienced significantly more exacerbations (incident rate ratio (IRR) 1.29, 95% CI 1.22-1.38; p<0.0001), while the rates were even higher for patients with purulent (IRR 1.55, 95% CI 1.44-1.67; p<0.0001) and severely purulent sputum (IRR 1.91, 95% CI 1.52-2.39; p<0.0001). Hospitalisations for severe exacerbations were also associated with increasing sputum colour with rate ratios, compared to patients with mucoid sputum, of 1.41 (95% CI 1.29-1.56; p<0.0001), 1.98 (95% CI 1.77-2.21; p<0.0001) and 3.05 (95% CI 2.25-4.14; p<0.0001) for mucopurulent, purulent and severely purulent sputum, respectively. Mortality was significantly increased with increasing sputum purulence, hazard ratio 1.12 (95% CI 1.01-1.24; p=0.027), for each increment in sputum purulence. CONCLUSION: Sputum colour is a simple marker of disease severity and future risk of exacerbations, severe exacerbations and mortality in patients with bronchiectasis.

Bronchiectasis with Chronic Rhinosinusitis Is Associated with Eosinophilic Airway Inflammation and Is Distinct from Asthma.

Rationale: Bronchiectasis is an airway inflammatory disease that is frequently associated with chronic rhinosinusitis (CRS). An eosinophilic endotype of bronchiectasis has recently been described, but detailed testing to differentiate eosinophilic bronchiectasis from asthma has not been performed. Objectives: This prospective observational study aimed to test the hypotheses that bronchiectasis with CRS is enriched for the eosinophilic phenotype in comparison with bronchiectasis alone and that the eosinophilic bronchiectasis phenotype exists as a separate entity from bronchiectasis associated with asthma. Methods: People with idiopathic or postinfectious bronchiectasis were assessed for concomitant CRS. We excluded people with asthma or primary ciliary dyskinesia and smokers. We assessed sputum and blood cell counts, nasal NO and fractional excreted NO, methacholine reactivity, skin allergy testing and total and specific immunoglobulin (Ig) E, cytokines in the sputum and serum, and the microbiome in the sputum and nasopharynx. Results: A total of 22 people with CRS (BE + CRS) and 17 without CRS (BE - CRS) were included. Sex, age, Reiff score, and bronchiectasis severity were similar. Median sputum eosinophil percentages were 0% (IQR, 0-1.5%) in BE - CRS and 3% (1-12%) in BE + CRS (P = 0.012). Blood eosinophil counts were predictive of sputum eosinophilia (counts ⩾3%; area under the receiver operating characteristic curve, 0.68; 95% confidence interval, 0.50-0.85). Inclusion of CRS improved the prediction of sputum eosinophilia by blood eosinophil counts (area under the receiver operating characteristic curve, 0.79; 95% confidence interval, 0.65-0.94). Methacholine tests were negative in 85.7% of patients in the BE - CRS group and 85.2% of patients in the BE + CRS group (P > 0.99). Specific IgE and skin testing were similar between the groups, but total IgE levels were increased in people with increased sputum eosinophils. Microbiome analysis demonstrated distinct microbiota in nasopharyngeal and airway samples in the BE + CRS and BE - CRS groups, without significant differences between groups. However, interactome analysis revealed altered interactomes in individuals with high sputum eosinophil counts and CRS. Conclusions: Bronchiectasis with CRS is associated with an eosinophilic airway inflammation that is distinct from asthma.

[Secondary non-tuberculous mycobacterium infection in patients with bronchiectasis caused by Marfan syndrome].

In this article, we reported a 28-year-old female patient who presented with intermittent hemoptysis, cough, and sputum production. Laboratory tests showed no abnormalities in the blood counts or inflammatory markers, and the sputum cultures were negative. A chest computed tomography scan showed bronchiectasis associated with infection in the middle and lower lobes of the right lung and right pleural thickening. We performed bronchoalveolar lavage by bronchoscopy in the dorsal segment of the right lower lobe and found Mycobacterium avium intracellulare complex (MAC) by Next Generation Sequencing (NGS) of bronchoalveolar lavage fluid (BALF). The patient's symptoms improved significantly after anti-mycobacterium treatment and the extent of infection was reduced on imaging. To further identify the cause of bronchiectasis, the patient is tall and thin, with slender limbs. Cardiac color ultrasound showed the widening of aortic sinus. Her genetic testing of blood samples revealed the gene mutation in the FBN1 gene (c.4349G>A). Based on these results, she was diagnosed with Marfan syndrome.

A case-control study on the risk factors associated with the occurrence of non-tuberculous mycobacteria pulmonary disease in bronchiectasis patients.

OBJECTIVE: The objective of this study is to analyze the risk factors associated with bronchiectasis combined with non-tuberculous mycobacteria pulmonary disease(NTM-PD) and provide a basis for more effective prevention and treatment strategies. METHODS: The study subjects for this manuscript were patients with bronchiectasis who were admitted to the infection department between January 2021 and June 2023.There were 34 patients with NTM-PD in the observation group, and 52 patients with simple bronchiectasis in the control group. Basic information, imaging features, serum albumin levels, and infection indicators were collected from both groups of patients.Univariate and multivariate logistic regression analysis were performed to analyze the risk factors for NTM-PD in patients with bronchiectasis. RESULTS: Multivariate logistic regression analysis revealed that bronchiectasis exacerbation occurring at least twice a year(OR = 3.884, 95% CI: 1.200-12.568), involvement of three or more lung lobes with bronchiectasis (OR = 3.932, 95% CI: 1.208-12.800), hypoalbuminemia (OR = 3.221, 95% CI: 1.015-10.219), and the NLR index (OR = 1.595, 95% CI: 1.200-2.119) were significant risk factors for non-tuberculous mycobacteria pulmonary disease in individuals with bronchiectasis (P < 0.05). CONCLUSION: Patients with bronchiectasis accompanied by NTM-PD present specific risk factors that should be promptly addressed through prevention and treatment.

Comparison of treatment outcomes between intermittent and daily regimens in non-cavitary nodular bronchiectatic-type Mycobacterium avium complex pulmonary disease in relation to sputum smear results: a retrospective cohort study.

This study retrospectively analyzed the treatment outcomes of 110 patients with non-cavitary nodular bronchiectatic-type Mycobacterium avium complex pulmonary disease who received intermittent or daily treatment with a three-drug oral antibiotic regimen (i.e., a macrolide, ethambutol, and rifampin) at a tertiary referral center in South Korea. Among these patients, 36 had sputum smear positivity. Of these 36 patients, intermittent treatment led to a lower culture conversion rate than daily treatment [50.0% (8/16) vs 85.0% (17/20), P = 0.034].

Nontuberculous mycobacterial (NTM) infections in bronchiectasis patients: A retrospective US registry cohort study.

RATIONALE: Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease. OBJECTIVES: To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR). METHODS: This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008-2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort). RESULTS: Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009-2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged >65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (>90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively. CONCLUSIONS: A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines.

Inflammatory Molecular Endotypes in Bronchiectasis: A European Multicenter Cohort Study.

Rationale: Although inflammation and infection are key disease drivers in bronchiectasis, few studies have integrated host inflammatory and microbiome data to guide precision medicine. Objectives: To identify clusters among patients with bronchiectasis on the basis of inflammatory markers and to assess the association between inflammatory endotypes, microbiome characteristics, and exacerbation risk. Methods: Patients with stable bronchiectasis were enrolled at three European centers, and cluster analysis was used to stratify the patients according to the levels of 33 sputum and serum inflammatory markers. Clusters were compared in terms of microbiome composition (16S ribosomal RNA sequencing) and exacerbation risk over a 12-month follow-up. Measurements and Main Results: A total of 199 patients were enrolled (109 [54.8%] female; median age, 69 yr). Four clusters of patients were defined according to their inflammatory profiles: cluster 1, milder neutrophilic inflammation; cluster 2, mixed-neutrophilic and type 2; cluster 3, most severe neutrophilic; and cluster 4, mixed-epithelial and type 2. Lower microbiome diversity was associated with more severe inflammatory clusters (P < 0.001), and ß-diversity analysis demonstrated distinct microbiome profiles associated with each inflammatory cluster (P = 0.001). Proteobacteria and Pseudomonas at phylum and genus levels, respectively, were more enriched in clusters 2 and 3 than in clusters 1 and 4. Furthermore, patients in cluster 2 (rate ratio [RR], 1.49; 95% confidence interval [CI], 1.16-1.92) and cluster 3 (RR, 1.61; 95% CI, 1.12-2.32) were at higher risk of exacerbation over a 12-month follow-up compared with cluster 1, even after adjustment for prior exacerbation history. Conclusions: Bronchiectasis inflammatory endotypes are associated with distinct microbiome profiles and future exacerbation risk.

Advances in pharmacotherapy for bronchiectasis in adults.

INTRODUCTION: Bronchiectasis has become a growing concern of chronic airway disease because of the enormous socioeconomic burden. Four cardinal interdependent components - impaired airway defense, recurrent airway infections, inflammatory response, and airway damage, in conjunction with the underlying etiology, have collectively played a role in modulating the vicious vortex of the pathogenesis and progression of bronchiectasis. Current pharmacotherapy aims to target at these aspects to break the vicious vortex. AREAS COVERED: The authors retrieve and review, in MEDLINE, Web of Science and ClinicalTrials.gov registry, the studies about pharmacotherapy for bronchiectasis from these aspects: antibiotics, mucoactive medications, bronchodilators, anti-inflammatory drug, and etiological treatment. EXPERT OPINION: Future drug development and clinical trials of bronchiectasis need to pay more attention to the different phenotypes or endotypes of bronchiectasis. There is a need for the development of novel inhaled antibiotics that could reduce bacterial loads, improve quality-of-life, and decrease exacerbation risks. More efforts are needed to explore the next-generation neutrophil-targeted therapeutic drugs that are expected to ameliorate respiratory symptom burden, reduce exacerbation risks, and hinder airway destruction in bronchiectasis.

Sputum pathogen spectrum and clinical outcomes of upper respiratory tract infection in bronchiectasis exacerbation: a prospective cohort study.

Upper respiratory tract infection (URTI) is common in humans. We sought to profile sputum pathogen spectrum and impact of URTI on acute exacerbation of bronchiectasis (AE). Between March 2017 and December 2021, we prospectively collected sputum from adults with bronchiectasis. We stratified AEs into events related (URTI-AE) and unrelated to URTI (non-URTI-AE). We captured URTI without onset of AE (URTI-non-AE). We did bacterial culture and viral detection with polymerase chain reaction, and explored the pathogen spectrum and clinical impacts of URTI-AE via longitudinal follow-up. Finally, we collected 479 non-AE samples (113 collected at URTI-non-AE and 225 collected at clinically stable) and 170 AE samples (89 collected at URTI-AE and 81 collect at non-URTI-AE). The viral detection rate was significantly higher in URTI-AE (46.1%) than in non-URTI-AE (4.9%) and URTI-non-AE (11.5%) (both P < 0.01). Rhinovirus [odds ratio (OR): 5.00, 95% confidence interval (95%CI): 1.06-23.56, P = 0.03] detection was independently associated with URTI-AE compared with non-URTI-AE. URTI-AE tended to yield higher viral load and detection rate of rhinovirus, metapneumovirus and bacterial shifting compared with URTI-non-AE. URTI-AE was associated with higher initial viral loads (esp. rhinovirus, metapneumovirus), greater symptom burden (higher scores of three validated questionnaires) and prolonged recovery compared to those without. Having experienced URTI-AE predicted a greater risk of future URTI-AE (OR: 10.90, 95%CI: 3.60-33.05). In summary, URTI is associated with a distinct pathogen spectrum and aggravates bronchiectasis exacerbation, providing the scientific rationale for the prevention of URTI to hinder bronchiectasis progression.

The effect of azithromycin on sputum inflammatory markers in bronchiectasis.

BACKGROUND: Long term macrolide treatment has been found beneficial in bronchiectasis (BE) -pathogical bronchial dilatation- possibly due to a combined anti-bacterial and immunomodulatory effect. The exact mechanism of inflammatory response is unknown. Here, we investigated the effect of maintenance macrolide treatment on the inflammatory response in BE. In addition, we assessed the inflammatory profile in BE in relation to disease severity. METHODS: During the BAT randomized controlled trial (investigating the effect of 1 year of azithromycin (AZM) in 83 BE patients), data on BE severity, lung function and sputum microbiology was collected. For the current study, a wide range of inflammatory markers were analysed in 3- monthly sputum samples in all participants. RESULTS: At baseline, marked neutrophilic but also eosinophilic inflammation was present in both groups, which remained stable throughout the study and was not affected by AZM treatment. Significant upregulation of pro-inflammatory markers correlated with FEV1 < 50% (TNFα, ECP, IL-21, IL-1, p = 0.01- 0.05), H. influenzae (HI) colonization (MPO, ECP, MIP-1, TNFα, IL-21, Il-8, IL-1, IL-1α, p < 0.001 - 0.04) and number of exacerbations (MPO, ECP, VEGF, MMP-9, p = 0.003 - 0.01). Surprisingly, colonization with P. aeruginosa (PA) was found to correlate with an attenuated inflammatory response compared to non-PA colonized. In placebo-treated patients, presence of an infectious exacerbation was reflected by a significant excessive increase in inflammation as compared to a non-significant upregulation in the AZM-treated patients. CONCLUSION: One year of AZM treatment did not result in attenuation of the inflammatory response in BE. Increasing disease severity and the presence of an exacerbation were reflected by upregulation of pro-inflammatory markers.

The roles of neutrophils in non-tuberculous mycobacterial pulmonary disease.

Non-tuberculous Mycobacterial Pulmonary Disease (NTM-PD) is an increasingly recognised global health issue. Studies have suggested that neutrophils may play an important role in controlling NTM infection and contribute to protective immune responses within the early phase of infection. However, these cells are also adversely associated with disease progression and exacerbation and can contribute to pathology, for example in the development of bronchiectasis. In this review, we discuss the key findings and latest evidence regarding the diverse functions of neutrophils in NTM infection. First, we focus on studies that implicate neutrophils in the early response to NTM infection and the evidence reporting neutrophils' capability to kill NTM. Next, we present an overview of the positive and negative effects that characterise the bidirectional relationship between neutrophils and adaptive immunity. We consider the pathological role of neutrophils in driving the clinical phenotype of NTM-PD including bronchiectasis. Finally, we highlight the current promising treatments in development targeting neutrophils in airways diseases. Clearly, more insights on the roles of neutrophils in NTM-PD are needed in order to inform both preventative strategies and host-directed therapy for these important infections.

Gastroesophageal Reflux Disease Increases Susceptibility to Nontuberculous Mycobacterial Pulmonary Disease.

BACKGROUND: Gastroesophageal reflux disease (GERD) is a common comorbidity of nontuberculous mycobacteria (NTM) pulmonary disease (PD). Although GERD is associated with more symptoms and severe disease in patients with NTM PD, whether GERD is associated with an increased risk of NTM PD developing is unknown. RESEARCH QUESTION: Does GERD influence the development of NTM PD? Are there any factors associated with an increased risk of NTM PD among patients with GERD? What is the impact of NTM PD on the health-care use of patients with GERD? STUDY DESIGN AND METHODS: Data from the Korean National Health Insurance Service National Sample Cohort between 2002 and 2015 were used. The incidence and risk of NTM PD were compared between patients with GERD (GERD cohort; n = 17,424) and patients matched for age, sex, type of insurance, and Charlson Comorbidity Index (matched cohort; n = 69,696). Using the GERD cohort, the factors associated with incident NTM PD also were evaluated. RESULTS: During a median follow-up duration of 5.1 years, the age- and sex-adjusted incidence of NTM PD was significantly higher in the GERD cohort (34.8 per 100,000 person-years [PY]) than in the matched cohort (10.5 per 100,000 PY; P < .001), with a subdistribution hazard ratio (HR) of 3.36 (95% CI, 2.10-5.37). Regarding risk factors associated with NTM PD, age of 60 years or older (adjusted HR, 3.57; 95% CI, 1.58-8.07) and bronchiectasis (adjusted HR, 18.69; 95% CI, 6.68-52.28) were associated with an increased risk of incident NTM PD in the GERD cohort. Compared with patients with GERD who did not demonstrate NTM PD, those with NTM PD showed higher all-cause (13,321 PY vs 5,932 PY; P = .049) and respiratory disease-related (5,403 vs 801; P = .011) ED visits or hospitalizations. INTERPRETATION: GERD is associated with an increased incidence of NTM PD. Older age and bronchiectasis are risk factors for NTM PD in patients with GERD. NTM PD in patients with GERD is associated with increased health-care use.

Pathophysiology of Chronic Bronchial Infection in Bronchiectasis.

Bronchiectasis is a complex and heterogeneous disease. Its pathophysiology is poorly understood, but chronic bronchial infection plays an important role in its natural history, and is associated with poor quality of life, more exacerbations and increased mortality. Pseudomonas aeruginosa, Haemophilus influenzae and Staphylococcus aureus are the most common bacteria related to chronic bronchial infection. Non-tuberculous mycobacteria, fungi and respiratory viruses are also present during clinical stability, and may increase the risk of acute exacerbation. Chronic inflammation is present in bronchiectasis, especially neutrophilic inflammation. However, macrophages and eosinophils also play a key role in the disease. Finally, airway epithelium has innate mechanisms such as mucociliary clearance and antibacterial molecules like mucins and antimicrobial peptides that protect the airways from pathogens. This review addresses how the persistence of microorganisms in the airways and the imbalance of the immune system contribute to the development of chronic bronchial infection in bronchiectasis.

Factors Predicting Worse Outcomes in an Asian Cohort of Patients With Bronchiectasis.

BACKGROUND/AIM: Bronchiectasis has long been neglected, unlike chronic obstructive pulmonary disease (COPD) and asthma. Recent clinical trials have shown that long-term use of azithromycin or erythromycin reduce exacerbations of non-cystic fibrosis (non-CF) bronchiectasis. Because of this, we should actively try to treat patients susceptible to severe status. PATIENTS AND METHODS: We enrolled patients who had been diagnosed with bronchiectasis at five branches of the Catholic Medical Center between January 2015 to December 2017. We retrospectively analyzed these patients for demographic characteristics such as sex, age, body mass index (BMI), history of smoking and tuberculosis, bacterial colonization, pulmonary function, hospitalizations, and other exacerbations. RESULTS: Colonization was shown to have a statistically significant association with hospitalization. A three-year follow up period showed that the mean frequency of hospitalization in patients without colonization was 0.8 times, compared to 0.7 times and 1.9 times, respectively in patients with NTM colonization and with other bacterial colonization (p-value=0.03). Patients with a lower BMI also had an increased risk of hospitalization (p-value=0.024). Current smokers had increased risk of mortality as compared to those who had never smoked (HR=11.29, p-value 0.015). Patients with a high BMI also had low risk of mortality as compared to patients with a low BMI (HR=0.76, p-value 0.005). CONCLUSION: Patients with bronchiectasis having chronic colonization, low BMI, or who are current smokers tend to be at greater risk for severe illness. Therefore, physicians should actively treat these patients to prevent exacerbations and mortality.

Multidrug-resistant Pseudomonas aeruginosa is predisposed to lasR mutation through up-regulated activity of efflux pumps in non-cystic fibrosis bronchiectasis patients.

Background: Multidrug-resistant (MDR) Pseudomonas aeruginosa is a frequent opportunistic pathogen that causes significant mortality in patients with non-cystic fibrosis bronchiectasis (NCFB). Although the quorum sensing (QS) system is a potential target for treatment, lasR mutants that present with a QS-deficient phenotype have been frequently reported among clinical P. aeruginosa isolates. We aimed to investigate whether antibiotic resistance would select for lasR mutants during chronic P. aeruginosa lung infection and determine the mechanism underlying the phenomenon. Methods: We prospectively evaluated episodes of chronic P. aeruginosa lung infections in NCFB patients over a 2-year period at two centers of our institution. QS phenotypic assessments and whole-genome sequencing (WGS) of P. aeruginosa isolates were performed. Evolution experiments were conducted to confirm the emergence of lasR mutants in clinical MDR P. aeruginosa cultures. Results: We analyzed episodes of P. aeruginosa infection among 97 NCFB patients and found only prior carbapenem exposure independently predictive of the isolation of MDR P. aeruginosa strains. Compared with non-MDR isolates, MDR isolates presented significantly QS-deficient phenotypes, which could not be complemented by the exogenous addition of 3OC12-HSL. The paired isolates showed that their QS-phenotype deficiency occurred after MDR was developed. Whole-genome sequencing analysis revealed that lasR nonsynonymous mutations were significantly more frequent in MDR isolates, and positive correlations of mutation frequencies were observed between genes of lasR and negative-efflux-pump regulators (nalC and mexZ). The addition of the efflux pump inhibitor PAßN could not only promote QS phenotypes of these MDR isolates but also delay the early emergence of lasR mutants in evolution experiments. Conclusions: Our data indicated that MDR P. aeruginosa was predisposed to lasR mutation through the upregulated activity of efflux pumps. These findings suggest that anti-QS therapy combined with efflux pump inhibitors might be a potential strategy for NCFB patients in the challenge of MDR P. aeruginosa infections.

Treatment Outcomes of Cavitary Nodular Bronchiectatic-Type Mycobacterium avium Complex Pulmonary Disease.

We investigated the treatment outcomes of patients with cavitary nodular bronchiectatic (C-NB)-type Mycobacterium avium complex (MAC) pulmonary disease (PD) via outcome comparisons between the fibrocavitary (FC) and C-NB types treated with guideline-based therapy (GBT) composed of daily three-drug oral antibiotics and injectable aminoglycoside. Additionally, we analyzed whether treatment with oral antibiotics alone would result in acceptable outcomes for the C-NB type. From 2002 to 2019, patients with cavitary MAC-PD who received three-drug oral antibiotics with or without an injectable aminoglycoside for ≥1 year were retrospectively enrolled at a tertiary referral center in South Korea. We compared the rates of culture conversion at 12 months according to the radiological type and treatment regimen. The overall culture conversion rate at 12 months of 154 patients with cavitary MAC-PD who received GBT was 75.3%. Among them, the culture conversion rates of 114 patients with the C-NB type were higher than that of 40 patients with the FC-type (80.7% versus 60.0%, respectively; P = 0.009). Of 166 patients with the C-NB-type treated with oral medications with or without an injectable drug, 83.7% achieved culture conversion at 12 months. The conversion rates of those who received oral medications alone and those treated with oral medications and an injectable aminoglycoside were similar (90.4% versus 80.7%, respectively; P = 0.117). In conclusion, the culture conversion rates of the patients with C-NB type treated with GBT were significantly higher than those of patients with the FC type. Additionally, the C-NB type could be treated with oral medications alone.