Neisseria species as pathobionts in bronchiectasis.

Neisseria species are frequently identified in the bronchiectasis microbiome, but they are regarded as respiratory commensals. Using a combination of human cohorts, next-generation sequencing, systems biology, and animal models, we show that bronchiectasis bacteriomes defined by the presence of Neisseria spp. associate with poor clinical outcomes, including exacerbations. Neisseria subflava cultivated from bronchiectasis patients promotes the loss of epithelial integrity and inflammation in primary epithelial cells. In vivo animal models of Neisseria subflava infection and metabolipidome analysis highlight immunoinflammatory functional gene clusters and provide evidence for pulmonary inflammation. The murine metabolipidomic data were validated with human Neisseria-dominant bronchiectasis samples and compared with disease in which Pseudomonas-, an established bronchiectasis pathogen, is dominant. Metagenomic surveillance of Neisseria across various respiratory disorders reveals broader importance, and the assessment of the home environment in bronchiectasis implies potential environmental sources of exposure. Thus, we identify Neisseria species as pathobionts in bronchiectasis, allowing for improved risk stratification in this high-risk group.

High Frequency of Allergic Bronchopulmonary Aspergillosis in Bronchiectasis-COPD Overlap.

BACKGROUND: Allergic bronchopulmonary aspergillosis (ABPA) is associated with frequent exacerbations and poor outcomes in chronic respiratory disease, but remains underdiagnosed. The role of fungal sensitization in bronchiectasis-COPD overlap (BCO) is unknown. RESEARCH QUESTION: What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap? STUDY DESIGN: Prospective, observational, cross-sectional study. METHODS: We prospectively recruited 280 patients during periods of clinical stability with bronchiectasis (n = 183), COPD (n = 50), and BCO (n = 47) from six hospitals across three countries (Singapore, Malaysia, and Scotland). We assessed sensitization responses (as specific IgE) to a panel of recombinant Aspergillus fumigatus allergens and the occurrence of ABPA in relationship to clinical outcomes. RESULTS: Individuals with BCO show an increased frequency and clinical severity of ABPA compared with those with COPD and bronchiectasis without overlap. BCO-associated ABPA is associated with more severe disease, higher exacerbation rates, and lower lung function when compared with ABPA occurring in the absence of overlap. BCO with a severe bronchiectasis severity index (BSI; > 9) is associated significantly with the occurrence of ABPA that is unrelated to underlying COPD severity. CONCLUSIONS: BCO demonstrates a high frequency of ABPA that is associated with a severe BSI (> 9) and poor clinical outcomes. Clinicians should maintain a high index of suspicion for the potential development of ABPA in patients with BCO with high BSI.

Obstructive Sleep Apnea and Lung Cancer: A Systematic Review and Meta-Analysis.

Rationale: In 2020, lung cancer was the leading cause of cancer deaths and the most common cancer in men. Although obstructive sleep apnea (OSA) has been postulated to be carcinogenic, epidemiological studies are inconclusive. Objectives: To investigate the associations between OSA and the incidence and mortality of lung cancer. Methods: Four electronic databases (PubMed, Embase, Cochrane Library, and Scopus) were searched from inception until 6 June 2021 for randomized controlled trials and observational studies examining the association between sleep apnea and incident lung cancer. Two reviewers selected studies, extracted data, graded the risk of bias using the Newcastle-Ottawa scale and the quality of evidence using the Grading of Recommendations Assessment, Development, and Evaluation system. Random-effects models were used to meta-analyze the maximally covariate-adjusted associations. Results: Seven studies were included in our systematic review, among which four were suitable for meta-analysis, comprising a combined cohort of 4,885,518 patients. Risk of bias was low to moderate. OSA was associated with a higher incidence of lung cancer (hazard ratio, 1.25; 95% confidence interval, 1.02-1.53), with substantial heterogeneity (I2 = 97%). Heterogeneity was eliminated, with a stable pooled effect size, when including the three studies with at least 5 years of median follow-up (hazard ratio, 1.32; 95% confidence interval, 1.27-1.37; I2 = 0%). Conclusions: In this meta-analysis of 4,885,518 patients from four observational studies, patients with OSA had an approximately 30% higher risk of lung cancer compared with those without OSA. We suggest more clinical studies with longer follow-up as well as biological models of lung cancer be performed to further elucidate this relationship.

Integrative microbiomics in bronchiectasis exacerbations.

Bronchiectasis, a progressive chronic airway disease, is characterized by microbial colonization and infection. We present an approach to the multi-biome that integrates bacterial, viral and fungal communities in bronchiectasis through weighted similarity network fusion ( https://integrative-microbiomics.ntu.edu.sg ). Patients at greatest risk of exacerbation have less complex microbial co-occurrence networks, reduced diversity and a higher degree of antagonistic interactions in their airway microbiome. Furthermore, longitudinal interactome dynamics reveals microbial antagonism during exacerbation, which resolves following treatment in an otherwise stable multi-biome. Assessment of the Pseudomonas interactome shows that interaction networks, rather than abundance alone, are associated with exacerbation risk, and that incorporation of microbial interaction data improves clinical prediction models. Shotgun metagenomic sequencing of an independent cohort validated the multi-biome interactions detected in targeted analysis and confirmed the association with exacerbation. Integrative microbiomics captures microbial interactions to determine exacerbation risk, which cannot be appreciated by the study of a single microbial group. Antibiotic strategies probably target the interaction networks rather than individual microbes, providing a fresh approach to the understanding of respiratory infection.

Metagenomics Reveals a Core Macrolide Resistome Related to Microbiota in Chronic Respiratory Disease.

Rationale: Long-term antibiotic use for managing chronic respiratory disease is increasing; however, the role of the airway resistome and its relationship to host microbiomes remains unknown.Objectives: To evaluate airway resistomes and relate them to host and environmental microbiomes using ultradeep metagenomic shotgun sequencing.Methods: Airway specimens from 85 individuals with and without chronic respiratory disease (severe asthma, chronic obstructive pulmonary disease, and bronchiectasis) were subjected to metagenomic sequencing to an average depth exceeding 20 million reads. Respiratory and device-associated microbiomes were evaluated on the basis of taxonomical classification and functional annotation including the Comprehensive Antibiotic Resistance Database to determine airway resistomes. Co-occurrence networks of gene-microbe association were constructed to determine potential microbial sources of the airway resistome. Paired patient-inhaler metagenomes were compared (n = 31) to assess for the presence of airway-environment overlap in microbiomes and/or resistomes.Measurements and Main Results: Airway metagenomes exhibit taxonomic and metabolic diversity and distinct antimicrobial resistance patterns. A "core" airway resistome dominated by macrolide but with high prevalence of ß-lactam, fluoroquinolone, and tetracycline resistance genes exists and is independent of disease status or antibiotic exposure. Streptococcus and Actinomyces are key potential microbial reservoirs of macrolide resistance including the ermX, ermF, and msrD genes. Significant patient-inhaler overlap in airway microbiomes and their resistomes is identified where the latter may be a proxy for airway microbiome assessment in chronic respiratory disease.Conclusions: Metagenomic analysis of the airway reveals a core macrolide resistome harbored by the host microbiome.

Increased Chitotriosidase Is Associated With Aspergillus and Frequent Exacerbations in South-East Asian Patients With Bronchiectasis.

BACKGROUND: Chitinase activity is an important innate immune defence mechanism against infection that includes fungi. The 2 human chitinases: chitotriosidase (CHIT1) and acidic mammalian chitinase are associated to allergy, asthma, and COPD; however, their role in bronchiectasis and bronchiectasis-COPD overlap (BCO) is unknown. RESEARCH QUESTION: What is the association between chitinase activity, airway fungi and clinical outcomes in bronchiectasis and bronchiectasis-COPD overlap? STUDY DESIGN AND METHODS: A prospective cohort of 463 individuals were recruited across five hospital sites in three countries (Singapore, Malaysia, and Scotland) including individuals who were not diseased (n = 35) and who had severe asthma (n = 54), COPD (n = 90), bronchiectasis (n = 241) and BCO (n = 43). Systemic chitinase levels were assessed for bronchiectasis and BCO and related to clinical outcomes, airway Aspergillus status, and underlying pulmonary mycobiome profiles. RESULTS: Systemic chitinase activity is elevated significantly in bronchiectasis and BCO and exceed the activity in other airway diseases. CHIT1 activity strongly predicts bronchiectasis exacerbations and is associated with the presence of at least one Aspergillus species in the airway and frequent exacerbations (≥3 exacerbations/y). Subgroup analysis reveals an association between CHIT1 activity and the "frequent exacerbator" phenotype in South-East Asian patients whose airway mycobiome profiles indicate the presence of novel fungal taxa that include Macroventuria, Curvularia and Sarocladium. These taxa, enriched in frequently exacerbating South-East Asian patients with high CHIT1 may have potential roles in bronchiectasis exacerbations. INTERPRETATION: Systemic CHIT1 activity may represent a useful clinical tool for the identification of fungal-driven "frequent exacerbators" with bronchiectasis in South-East Asian populations.

Distinct "Immunoallertypes" of Disease and High Frequencies of Sensitization in Non-Cystic Fibrosis Bronchiectasis.

RATIONALE: Allergic sensitization is associated with poor clinical outcomes in asthma, chronic obstructive pulmonary disease, and cystic fibrosis; however, its presence, frequency, and clinical significance in non-cystic fibrosis bronchiectasis remain unclear. OBJECTIVES: To determine the frequency and geographic variability that exists in a sensitization pattern to common and specific allergens, including house dust mite and fungi, and to correlate such patterns to airway immune-inflammatory status and clinical outcomes in bronchiectasis. METHODS: Patients with bronchiectasis were recruited in Asia (Singapore and Malaysia) and the United Kingdom (Scotland) (n = 238), forming the Cohort of Asian and Matched European Bronchiectasis, which matched recruited patients on age, sex, and bronchiectasis severity. Specific IgE response against a range of common allergens was determined, combined with airway immune-inflammatory status and correlated to clinical outcomes. Clinically relevant patient clusters, based on sensitization pattern and airway immune profiles ("immunoallertypes"), were determined. MEASUREMENTS AND MAIN RESULTS: A high frequency of sensitization to multiple allergens was detected in bronchiectasis, exceeding that in a comparator cohort with allergic rhinitis (n = 149). Sensitization was associated with poor clinical outcomes, including decreased pulmonary function and more severe disease. "Sensitized bronchiectasis" was classified into two immunoallertypes: one fungal driven and proinflammatory, the other house dust mite driven and chemokine dominant, with the former demonstrating poorer clinical outcome. CONCLUSIONS: Allergic sensitization occurs at high frequency in patients with bronchiectasis recruited from different global centers. Improving endophenotyping of sensitized bronchiectasis, a clinically significant state, and a "treatable trait" permits therapeutic intervention in appropriate patients, and may allow improved stratification in future bronchiectasis research and clinical trials.

Immunological corollary of the pulmonary mycobiome in bronchiectasis: the CAMEB study.

Understanding the composition and clinical importance of the fungal mycobiome was recently identified as a key topic in a "research priorities" consensus statement for bronchiectasis.Patients were recruited as part of the CAMEB study: an international multicentre cross-sectional Cohort of Asian and Matched European Bronchiectasis patients. The mycobiome was determined in 238 patients by targeted amplicon shotgun sequencing of the 18S-28S rRNA internally transcribed spacer regions ITS1 and ITS2. Specific quantitative PCR for detection of and conidial quantification for a range of airway Aspergillus species was performed. Sputum galactomannan, Aspergillus specific IgE, IgG and TARC (thymus and activation regulated chemokine) levels were measured systemically and associated to clinical outcomes.The bronchiectasis mycobiome is distinct and characterised by specific fungal genera, including Aspergillus, Cryptococcus and ClavisporaAspergillus fumigatus (in Singapore/Kuala Lumpur) and Aspergillus terreus (in Dundee) dominated profiles, the latter associating with exacerbations. High frequencies of Aspergillus-associated disease including sensitisation and allergic bronchopulmonary aspergillosis were detected. Each revealed distinct mycobiome profiles, and associated with more severe disease, poorer pulmonary function and increased exacerbations.The pulmonary mycobiome is of clinical relevance in bronchiectasis. Screening for Aspergillus-associated disease should be considered even in apparently stable patients.

Ministry of Health Clinical Practice Guidelines: Chronic Obstructive Pulmonary Disease.

The Ministry of Health (MOH) has updated the Clinical Practice Guidelines on Chronic Obstructive Pulmonary Disease (COPD) to provide doctors and patients in Singapore with evidence-based treatment for COPD. This article reproduces the introduction and executive summary (with recommendations from the guidelines) from the MOH Clinical Practice Guidelines on COPD, for the information of SMJ readers. Chapters and page numbers mentioned in the reproduced extract refer to the full text of the guidelines, which are available from the Ministry of Health website: https://www.moh.gov.sg/content/moh_web/healthprofessionalsportal/doctors/guidelines/cpg_medical.html. The recommendations should be used with reference to the full text of the guidelines. Following this article are multiple choice questions based on the full text of the guidelines.

Optimal Body Mass Index Cut-offs for Identification of Patients with Coronary Artery Disease at High Risk of Obstructive Sleep Apnoea.

BACKGROUND: We sought to evaluate the relationship between Body Mass Index (BMI) and obstructive sleep apnoea (OSA) in Chinese patients hospitalised with coronary artery disease, and to determine the optimal BMI cut-off for prediction of OSA. METHODS: Consecutive Chinese patients who were hospitalised with symptomatic coronary artery disease were recruited to undergo an in-hospital sleep study. RESULTS: A total of 587 patients were recruited. Using cut-off for Asians, 81.2% of the cohort was overweight (BMI ≥23kg/m(2)) and 31.6% was obese (≥27kg/m(2)). A total of 59.5% was diagnosed with OSA, defined as apnoea-hypopnoea index ≥15. Body mass index, hypertension and smoking were predictors of OSA. Multiple logistic regression analysis showed that BMI remains an independent predictor of OSA (odds ratio: 1.11 [95% confidence interval: 1.06 to 1.17], p<0.001) after adjusting for smoking and hypertension. Further analysis using BMI and Apnoea-Hypopnoea Index (AHI) as continuous variables showed significant correlation between BMI and AHI (Pearson's r =0.25, P<0.001). In adjusted models, optimal BMI cut-offs to screen for OSA were 27.3kg/m(2), 23.0-23.9kg/m(2), and 20kg/m(2) for patients with neither, either, or both predictors (smoking and hypertension) respectively. The area under the curve for the adjusted and unadjusted models were similar (0.6013 vs 0.6262, p=0.118). CONCLUSIONS: Body mass index represents a convenient and readily available tool for bedside identification of patients at high risk of OSA. Body mass index cut-offs to predict risks of OSA in Chinese patients with symptomatic coronary artery disease are defined in this study.

Sleep apnea is associated with new-onset atrial fibrillation after coronary artery bypass grafting.

PURPOSE: New-onset atrial fibrillation (AF) after coronary artery bypass grafting (CABG) remains a prevalent problem. We investigated the relationship between sleep apnea and new-onset post-CABG AF during inhospital stay. MATERIALS AND METHODS: We prospectively recruited 171 patients listed for an elective CABG for an overnight sleep study. Sleep apnea was defined as apnea-hypopnea index greater than or equal to 5. RESULTS: Among the 160 patients who completed the study, those in the sleep apnea group (n=128; 80%) had larger left atrial diameter (40.4±5.4 vs 38.4±6.0 mm; P=.03) and left ventricular end-diastolic dimension (52.6±7.9 vs 49.2±6.8 mm; P=.03) than those in the non-sleep apnea group. The incidence of new-onset post-CABG AF was higher for the sleep apnea than non-sleep apnea groups (24.8% vs 9.7%; P=.07). There was 1 inhospital death and 2 patients with acute renal failure requiring dialysis after CABG in the sleep apnea group. None of the patients developed inhospital stroke. Multiple logistic regression analysis showed that sleep apnea was an independent predictor of post-CABG AF (odds ratio, 4.4; 95% confidence interval, 1.1-18.1; P=.04). CONCLUSION: Sleep apnea is prevalent in patients undergoing CABG. It increases the susceptibility to new-onset AF after CABG, probably related to atrial and ventricular remodeling.

Sleep apnoea and unscheduled re-admission in patients undergoing coronary artery bypass surgery.

INTRODUCTION: Although it has been recognised as a cardiovascular risk factor, data on sleep apnoea screening before coronary artery bypass grafting (CABG) are scarce. This study sought to determine the prevalence, predictors and effects of sleep apnoea on re-admission in patients undergoing CABG. METHOD: We prospectively recruited 152 patients to undergo an overnight sleep study before CABG. Sleep apnoea was defined as an apnoea-hypopnoea index of ≥15 events per hour. Data on unscheduled re-admission due to cardiovascular events were collected. RESULTS: Among the 138 patients who completed the sleep study, sleep apnoea was diagnosed in 69 (50%). The patients who had sleep apnoea had a lower left ventricular ejection fraction (p = 0.029), a larger left atrial diameter (p = 0.014) and a larger left ventricular end-systolic dimension (p = 0.019) than those who did not. Angiographic SYNTAX and Gensini scores were similar in patients with and without sleep apnoea. The generalised structural equation model revealed that hypertension, a high body mass index and chronic renal failure were independent predictors of sleep apnoea (p < 0.05). After an average follow-up of 6 ± 3 months, 12 patients with sleep apnoea (17.3%) and three patients without sleep apnoea (4.3%) were involved in unscheduled re-admission. Patients with sleep apnoea were almost five times more likely to have an unscheduled re-admission due to cardiovascular events (adjusted odds ratio: 4.63, 95% CI: 1.24-17.31, p = 0.023) than those without sleep apnoea. CONCLUSIONS: Sleep apnoea was prevalent and predictive of unscheduled re-admissions in patients scheduled for CABG.

Use of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) in the diagnosis of granulomatous mediastinal lymphadenopathy.

INTRODUCTION: This study assessed the clinical utility of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for the diagnosis of suspected granulomatous mediastinal lymphadenopathy. MATERIALS AND METHODS: Retrospective chart review of all patients who underwent EBUS-TBNA for suspected granulomatous mediastinal lymphadenopathy at Singapore General Hospital between December 2008 and December 2011 inclusive. RESULTS: Over a period of 3 years, a total of 371 patients underwent EBUS-TBNA of whom 33 (9%) had the procedure performed for evaluation of suspected granulomatous mediastinal lymphadenopathy - 18 for suspected tuberculosis (TB) and non-tuberculous mycobacterial (NTM) lymphadenitis, and 15 for suspected sarcoidosis. EBUS-TBNA was diagnostic in 9 of the 13 patients with a final diagnosis of TB/NTM. EBUS-TBNA cultures were positive in 6 of them (46%), 1 showed acid-fast bacilli (AFB) although cultures were negative, and 2 had necrotising granulomatous inflammation from EBUS-TBNA biopsies and sputum cultures grew TB. EBUS-TBNA was diagnostic in 9 of the 14 patients with a final diagnosis of sarcoidosis through histology showing non-caseating granulomatous inflammation. The sensitivities of EBUS-TBNA for diagnosis of TB/NTM, sarcoidosis and overall granulomatous mediastinal lymphadenopathy were 69%, 64%, 64%; the negative predictive values were 56%, 17%, 33%; and accuracies were 78%, 67%, 70%, respectively. CONCLUSION: EBUS-TBNA can be useful in the diagnosis of suspected granulomatous mediastinal lymphadenopathy with sensitivities and accuracies of >60%.

Severe endobronchitis and airway stricture caused by inhalation of cosmetic talc.

Pulmonary disease caused by talc is well described, but previous reports mainly describe lung parenchymal involvement. We describe what is, to our knowledge, the first case in which inhalation of cosmetic talc led to intense endobronchitis and airway stricture. A 70-year-old woman presented with new-onset wheezing and was found to have right upper lobe collapse on chest radiography. CT imaging of the thorax showed right upper lobe collapse with occlusion of the right upper lobe. Bronchoscopy showed severe endobronchitis with thickened mucosa throughout the right and left main stem bronchi and a fibrotic stricture occluding the right upper lobe. Bronchial biopsy specimens showed foreign-body granulomatosis encasing birefringent crystalline material. Spectral analysis confirmed the crystals to be consistent with cosmetic talc used by the patient. We hypothesize that the patient inhaled a large amount of talc, which was trapped in the larger airways and resulted in intense foreign-body granulomatosis, leading to an airway stricture.

Simplifying STOP-BANG: use of a simple questionnaire to screen for OSA in an Asian population.

OBJECTIVE: We aim to assess the utility of a simple-to-use 8-point questionnaire in screening for moderate-severe obstructive sleep apnea (OSA) and to assess the validity of cutoffs used to score body mass index (BMI) in this questionnaire. METHODS: Patients undergoing diagnostic polysomnography (PSG) were asked to fill in a questionnaire with a simple dichotomized 8-point questionnaire, represented by the mnemonic STOP-BANG. A score of 3 or more out of a possible 8 was taken to indicate high risk for presence of OSA. These were then evaluated versus results from the overnight, monitored PSG. RESULTS: Three hundred and forty-eight patients underwent overnight diagnostic PSG, of whom 319 (91.2%) completed the questionnaire. Seventy-four (22.7%) were classified as being at low risk of OSA and 252 (77.3%) were classified as being high risk. The sensitivities of the STOP-BANG screening tool for an AHI of >5, >15, and >30 were 86.1%, 92.8%, and 95.6%, respectively, with negative predictive values of 84.5% and 93.4% for moderate and severe OSA, respectively. Using cutoffs of 30 or 35 for scoring the BMI did not significantly change the performance of the screening tool. CONCLUSION: STOP-BANG is a clinically useful tool with high sensitivity that can be used to screen patients for moderate and severe OSA. Using cutoffs of 30 for BMI, 40 cm for neck circumference, and 50 years for age simplifies the application of the tool without affecting performance.

Massive hemoptysis requiring intensive care.

OBJECTIVES: Massive hemoptysis can cause airway or hemodynamic compromise requiring intensive care. We reviewed the management and outcome of this group of patients in our institution. DESIGN: Retrospective analysis. SETTING: Medical intensive care unit (MICU) in a tertiary care hospital. PATIENTS: Patients (29 patients with 31 episodes) who were admitted to the MICU for massive hemoptysis (greater than 300 ml/24 h or requiring intubation) between August 1997 and April 2001. MANAGEMENT: Patients were intensively monitored and electively intubated if there was danger of airway compromise. Fiberoptic bronchoscopy was performed to assess the site of bleeding and patients had bronchial artery embolisation if deemed suitable. Patients in whom bleeding could not be controlled were referred for emergency surgery. RESULTS: In 26/31 (84%) episodes, patients required intubation. Bronchoscopy was more helpful in localising the bleeding (site of bleeding identified in 90%) than chest X-ray alone (identified site of bleeding in 64%). Bleeding was stopped with medical therapy in 8/31 (26%) patient; 16/31(51%) patients were successfully treated with embolisation. Only four (13%) patients went for emergency surgery, of whom one died. Overall in-hospital mortality was 4/31 patients (13%). Over a 2 year follow-up, 6/27 (22%) survivors had recurrent hemoptysis and another 4 (15%) died of unrelated causes. CONCLUSIONS: Intensive care and monitoring with endotracheal intubation, when necessary, are useful in massive hemoptysis. Bronchoscopy should be performed to help localise the bleeding site. Embolisation is a suitable first-line treatment for massive hemoptysis, reserving emergency surgery for cases where the above measures are insufficient to control bleeding.