Functional lower airways genomic profiling of the microbiome to capture active microbial metabolism.

BACKGROUND: Microbiome studies of the lower airways based on bacterial 16S rRNA gene sequencing assess microbial community structure but can only infer functional characteristics. Microbial products, such as short-chain fatty acids (SCFAs), in the lower airways have significant impact on the host's immune tone. Thus, functional approaches to the analyses of the microbiome are necessary. METHODS: Here we used upper and lower airway samples from a research bronchoscopy smoker cohort. In addition, we validated our results in an experimental mouse model. We extended our microbiota characterisation beyond 16S rRNA gene sequencing with the use of whole-genome shotgun (WGS) and RNA metatranscriptome sequencing. SCFAs were also measured in lower airway samples and correlated with each of the sequencing datasets. In the mouse model, 16S rRNA gene and RNA metatranscriptome sequencing were performed. RESULTS: Functional evaluations of the lower airway microbiota using inferred metagenome, WGS and metatranscriptome data were dissimilar. Comparison with measured levels of SCFAs shows that the inferred metagenome from the 16S rRNA gene sequencing data was poorly correlated, while better correlations were noted when SCFA levels were compared with WGS and metatranscriptome data. Modelling lower airway aspiration with oral commensals in a mouse model showed that the metatranscriptome most efficiently captures transient active microbial metabolism, which was overestimated by 16S rRNA gene sequencing. CONCLUSIONS: Functional characterisation of the lower airway microbiota through metatranscriptome data identifies metabolically active organisms capable of producing metabolites with immunomodulatory capacity, such as SCFAs.

Evaluation of the airway microbiome in nontuberculous mycobacteria disease.

Aspiration is associated with nontuberculous mycobacterial (NTM) pulmonary disease and airway dysbiosis is associated with increased inflammation. We examined whether NTM disease was associated with a distinct airway microbiota and immune profile.297 oral wash and induced sputum samples were collected from 106 participants with respiratory symptoms and imaging abnormalities compatible with NTM. Lower airway samples were obtained in 20 participants undergoing bronchoscopy. 16S rRNA gene and nested mycobacteriome sequencing approaches characterised microbiota composition. In addition, inflammatory profiles of lower airway samples were examined.The prevalence of NTM+ cultures was 58%. Few changes were noted in microbiota characteristics or composition in oral wash and sputum samples among groups. Among NTM+ samples, 27% of the lower airway samples were enriched with Mycobacterium A mycobacteriome approach identified Mycobacterium in a greater percentage of samples, including some nonpathogenic strains. In NTM+ lower airway samples, taxa identified as oral commensals were associated with increased inflammatory biomarkers.The 16S rRNA gene sequencing approach is not sensitive in identifying NTM among airway samples that are culture-positive. However, associations between lower airway inflammation and microbiota signatures suggest a potential role for these microbes in the inflammatory process in NTM disease.

Patient knowledge in chronic obstructive pulmonary disease: back to basics.

Patient education is integral to the care of patients with chronic obstructive pulmonary disease (COPD), and a cornerstone of self-management in chronic illness. We aimed to assess information needs and knowledge of patients with COPD. The Lung Information Needs Questionnaire (LINQ) and The Mount Sinai Hospital Questionnaire (MSHQ) were used. The LINQ identifies what COPD information the patient has, or is lacking. Higher scores in the LINQ define a greater information need. The MSHQ assesses a patients' COPD knowledge. Higher scores in the MSHQ questionnaire indicate greater knowledge. Subjects, in (n = 38) and outpatients (n = 43) were aged (mean ± SD) 69 ± 9 years, 53% were women, and 36% had not completed high school. COPD was diagnosed 9 ± 7 years previously. Forty percent had recalled receiving specific COPD education. Mean forced expiratory volume in 1 second (FEV1) was 1.1 ± 0.6 Liters. Patients on average had a 29 ± 14% need for information as assessed by the LINQ. Patients indicated a 52 ± 34% need for information on diet and 43 ± 25% for self-management. The mean total score for the MSHQ was 71 ± 13%. The score on treatment was 76 ± 20% and 60 ± 14% on pathophysiology. There was a positive relationship between having prior COPD education, finishing high school and total MSHQ score (p < 0.05) and a positive correlation of prior COPD education and reduced LINQ total score (p < 0.01). Patients with COPD have received information and demonstrate some knowledge about their disease. However, there remains a need for more education on diet and self-management.

Fatigue in COPD: prevalence and effect on outcomes in pulmonary rehabilitation.

Patients with chronic obstructive pulmonary disease (COPD) complain of dyspnea and fatigue. We sought to estimate the prevalence of high fatigue in this population and to determine whether individuals with high fatigue had a different response to pulmonary rehabilitation. This observational study was embedded within a randomized trial. Participants underwent 3 months of pulmonary rehabilitation including education and exercise training. We divided 251 individuals into low and high fatigue groups using population normal scores of the SF-36 vitality domain. Baseline data included spirometry, 6-minute walk distance (6MWD), peak exercise capacity, constant workrate cycling endurance time, and questionnaires including the St. George's and Chronic Respiratory questionnaires (SGRQ, CRQ). The response to pulmonary rehabilitation was evaluated using changes in these measures at 3 months and 1 year after entry. High fatigue was present in 97/251 (39%) of patients. High fatigue patients were younger, had more depressive symptoms, greater dyspnea and poorer SGRQ scores (p < 0.01). They also had lower 6MWD, endurance times, and peak volume of oxygen consumption (VO(2); p < 0.05). Patients in both groups improved similarly in their dyspnea, the 6MWD and endurance time. High-fatigue patients had greater improvements in both the CRQ fatigue (by 0.74 more points) and the SGRQ scores (by 6.0 points; p < 0.01), with clinically significant gains maintained at 1 year. This study suggests that high levels of fatigue is a common feature in patients with COPD. They have a lower exercise capacity and a lower health status. However, they benefit from pulmonary rehabilitation.

Enhanced cardiac vagal efferent activity does not explain training-induced bradycardia.

Studies of heart rate variability (HRV) have so far produced contradictory evidence to support the common belief that endurance training enhances cardiac parasympathetic tone. This may be related to the fact that most studies failed to specifically isolate the vagally mediated influence of respiration. This study used a cross-sectional comparison of endurance athletes (n=20; ATHL) exhibiting resting bradycardia and age-matched nonathletes (n=12; CRTL) to indirectly assess training effects on amplitude and timing characteristics of respiratory sinus arrhythmia (RSA). Continuous electrocardiogram (ECG) and ventilatory flows were recorded during spontaneous breathing (SP), as well as during breathing at four cycles less than (M4) or more (P4) than SP, to also examine potential repercussions of training on the sensitivity of the cardiac vagal responses to breathing. A fast Fourier transform procedure was used to quantify the standard spectral high-frequency (HF) and low-frequency (LF) components and a respiratory-centered frequency (RCF) component of HRV. RSA was assessed using a breath-by-breath quantification of the amplitude and timing of the maximum change in instantaneous heart rate. Under baseline SP conditions, heart rate was lower in ATHL (62.6+/-6.5 vs. 75.2+/-9 beats/min; p<0.05) while blood pressure (BP), breath cycle duration, tidal volume, and ventilatory drive were similar in both groups. HRV total spectral power density, LF, HF, or RCF was not different between groups at either the SP, M4, or P4 conditions. Changes in total breath duration similarly affected RSA amplitude in all groups, while HR and BP remained unchanged from SP. RSA phase was not affected by training status or by changes in total breath duration. RSA amplitude was negatively related to breathing frequency in all groups (p<0.05), while the mean slope of the relationship (sensitivity) was not different between groups. In as much as RSA is an adequate marker of cardiac vagal efferent activity, these results add support to a contribution of a decrease in intrinsic heart rate to explain training-induced bradycardia.

Examination of pulse oximetry tracings to detect obstructive sleep apnea in patients with advanced chronic obstructive pulmonary disease.

Nocturnal hypoxemia and obstructive sleep apnea (OSA) are common comorbidities in patients with chronic obstructive pulmonary disease (COPD). The authors sought to develop a strategy to interpret nocturnal pulse oximetry and assess its capacity for detection of OSA in patients with stage 3 to stage 4 COPD. A review of consecutive patients with COPD who were clinically prescribed oximetry and polysomnography was conducted. OSA was diagnosed if the polysomnographic apnea-hypopnea index was >15 events/h. Comprehensive criteria were developed for interpretation of pulse oximetry tracings through iterative validation and interscorer concordance of ≥80%. Criteria consisted of visually identified desaturation 'events' (sustained desaturation ≥4%, 1 h time scale), 'patterns' (≥3 similar desaturation/saturation cycles, 15 min time scale) and the automated oxygen desaturation index. The area under the curve (AUC), sensitivity, specificity and accuracy were calculated. Of 59 patients (27 male), 31 had OSA (53%). The mean forced expiratory volume in 1 s was 46% of predicted (range 21% to 74% of predicted) and 52% of patients were on long-term oxygen therapy. Among 59 patients, 35 were correctly identified as having OSA or not having OSA, corresponding to an accuracy of 59%, with a sensitivity and specificity of 59% and 60%, respectively. The AUC was 0.57 (95% CI 0.55 to 0.59). Using software-computed desaturation events (hypoxemia ≥4% for ≥10 s) indexed at ≥15 events/h of sleep as diagnostic criteria, sensitivity was 60%, specificity was 63% and the AUC was 0.64 (95%CI 0.62 to 0.66). No single criterion demonstrated important diagnostic utility. Pulse oximetry tracing interpretation had a modest diagnostic value in identifying OSA in patients with moderate to severe COPD.

Unilateral hemidiaphragm weakness is associated with positional hypoxemia in REM sleep.

BACKGROUND: Patients with unilateral diaphragmatic paralysis (UDP) have been reported to have varied respiratory symptoms and often reduced lung function. We sought to describe the polysomnographic respiratory characteristics in patients with UDP without obstructive sleep apnea. METHODS: We prospectively collected 5 cases with clinical investigation regarding symptoms, lung function, and nocturnal polysomnography. The respiratory sleep characteristics were analyzed with standardized scoring of respiratory events in 30-sec epochs and comparison according to sleep-wake stages and body position with respect to oximetry. The cases were compared to 5 controls matched for age, gender, and body mass index. RESULTS: Three of 5 patients had significant awake lung restriction with a mean (range) forced vital capacity of 1.89 (1.48-2.24) liters, 72% (45% to 102%) predicted. All had REM sleep with few apneas and episodes of prolonged hypopneas characterized by important desaturation noted on oximetry. These desaturations were greatest during REM sleep when the patients slept supine with a mean (SD) saturation of 90.8% (4.5%) and minimum of 64% or on the side unaffected by UDP with a mean saturation of 87.8% (5.3%) and minimum of 67% (p < 0.0001 compared to same positions awake). Other sleep stages had few, if any significant desaturations and these events rarely occurred when the patient slept in the supine position. Saturation was lower in all sleep-wake stages and sleep positions compared to controls (p < 0.0001). CONCLUSION: Patients with UDP demonstrate position-dependent hypopneas in REM sleep with frequent desaturations.

Oxygen desaturation during a 6 min walk test is a sign of nocturnal hypoxemia.

UNLABELLED: BACKGROUND/ OBJECTIVES: Patients with chronic obstructive pulmonary disease (COPD) may experience sleep disordered breathing with nocturnal desaturation. An exploratory study was performed to determine whether any commonly measured clinical parameters were useful in predicting nocturnal desaturation in patients with COPD. A validation study was subsequently performed to confirm the utility of the parameter identified in the exploratory study as most useful in this regard. METHODS: A total of 103 (exploratory cohort) and 200 (validation cohort) consecutive patients with COPD admitted for pulmonary rehabilitation were evaluated. Standard outcome measures including nocturnal oximetry and the 6 min walk test (6MWT) on room air with continuous pulse oximetry were assessed. Patients with sleep apnea or those undergoing long-term oxygen therapy were excluded. RESULTS: In the exploratory study, the mean (± SD) patient age was 70 ± 9.9 years, with forced expiratory volume in 1 s of 0.76 ± 0.34 L, which was 36 ± 16% of predicted. Body mass index, arterial oxygen tension, oxygen saturation by pulse oximetry at rest and during the 6MWT all demonstrated significant correlations with percentage of time spent with a saturation <90%. When the lowest pulse oximetry during the 6MWT was ≤88%, 10 of 21 patients demonstrated a saturation <90% for at least 30% of sleep time. This measure yielded a positive likelihood ratio of 3.77 (95% CI 1.87 to 7.62) compared with those who did not reach this threshold value. The validation study confirmed similar detection characteristics. CONCLUSIONS: Results from the present study suggest that monitoring oxygen saturation changes during a 6MWT is useful in helping to identify COPD patients who may experience significant nocturnal desaturation.

Success in pulmonary rehabilitation in patients with chronic obstructive pulmonary disease.

BACKGROUND: Pulmonary rehabilitation (PR) is beneficial for some, but not all, patients with chronic lung disease. OBJECTIVES: To determine the success rate of a comprehensive PR program for patients with chronic obstructive pulmonary disease (COPD) and to characterize the differences between responders and nonresponders. METHODS: A chart review was performed on patients with a clinical diagnosis of COPD who were referred for PR. Success was defined according to clinically important changes in St George's Respiratory Questionnaire scores and/or 6 min walk test distance. RESULTS: The majority of subjects were men (58%) with a mean (± SD) age of 69±10 years (n=177). Sixty-two per cent of participants had a successful outcome with PR, with proportionally more responders noting subjective improvement than objective improvement on a 6 min walk test (73% versus 51%). Subjects with poor baseline St George's Respiratory Questionnaire scores tended to improve the most (P=0.011 [ANOVA]). Successful participants had a greater forced expired volume in 1 s (1.1 L versus 0.9 L; P<0.05) and a lower BODE index (body mass index, airflow obstruction, dyspnea, and exercise capacity index) at baseline (9.6 versus 10.3; P<0.05). Success of PR was not correlated with age, sex, chronic hypoxemic respiratory failure or other chronic conditions. Successful participants were more likely to be compliant and to experience fewer adverse events (P≤0.001). CONCLUSIONS: Our study reinforced the belief that the majority of participants with COPD benefit from PR. Few baseline characteristics were predictive of success. Subjectively measured improvement occurred more frequently than objectively measured improvement and was greatest in those with the poorest baseline values.