Period Of Clinical Stability Research Articles

Endotypes of Exacerbation in Bronchiectasis: An Observational Cohort Study.

Rationale: Bronchiectasis is characterized by acute exacerbations, but the biological mechanisms underlying these events are poorly characterized. Objectives: To investigate the inflammatory and microbial characteristics of exacerbations of bronchiectasis. Methods: A total of 120 patients with bronchiectasis were enrolled and presented with acute exacerbations within 12 months. Spontaneous sputum samples were obtained during a period of clinical stability and again at exacerbation before receipt of antibiotic treatment. A validated rapid PCR assay for bacteria and viruses was used to classify exacerbations as bacterial, viral, or both. Sputum inflammatory assessments included label-free liquid chromatography-tandem mass spectrometry and measurement of sputum cytokines and neutrophil elastase activity. 16 s rRNA sequencing was used to characterize the microbiome. Measurements and Main Results: Bronchiectasis exacerbations showed profound molecular heterogeneity. At least one bacterium was identified in 103 samples (86%), and a high bacterial load (total bacterial load > 107 copies/g) was observed in 81 patients (68%). Respiratory viruses were identified in 55 (46%) patients, with rhinovirus being the most common virus (31%). PCR testing was more sensitive than culture. No consistent change in the microbiome was observed at exacerbation. Exacerbations were associated with increased neutrophil elastase, proteinase-3, IL-1β, and CXCL8. These markers were particularly associated with bacterial and bacterial plus viral exacerbations. Distinct inflammatory and microbiome profiles were seen between different exacerbation subtypes, including bacterial, viral, and eosinophilic events in both hypothesis-led and hypothesis-free analysis using integrated microbiome and proteomics, demonstrating four subtypes of exacerbation. Conclusions: Bronchiectasis exacerbations are heterogeneous events with contributions from bacteria, viruses, and inflammatory dysregulation.

Two and five-factor models of negative symptoms in schizophrenia are differentially associated with trait affect, defeatist performance beliefs, and psychosocialfunctioning.

Recent factor analytic evidence supports both two-factor (motivation and pleasure, MAP; diminished expression, EXP) and five-factor (anhedonia, asociality, avolition, blunted affect, alogia) conceptualizations of negative symptoms. However, it is unclear whether these two conceptualizations of the latent structure of negative symptoms have differential associations with external correlates. The current study evaluated external correlates of the two- and five-factor structures by examining associations with variables known to have critical relations with negative symptoms: trait affect, defeatist performance beliefs, neurocognition, and community-based psychosocial functioning. Participants included a total of 245 outpatients diagnosed with schizophrenia who were rated on the Brief Negative Symptom Scale and completed a battery of additional measures during periods of clinical stability. These additional measures included the Positive and Negative Affect Schedule, Defeatist Performance Beliefs scale, MATRICS Consensus Cognitive Battery, and Level of Function Scale. Pearson correlations indicated differential patterns of associations between the BNSS scores and the external correlates. Support for the two-factor model was indicated by a stronger association of MAP with positive affect and psychosocial functioning, compared to EXP with neurocognition. Significance tests examining a differential magnitude of associations showed that the two-dimension negative symptom structure masked unique correlational relationships among the five negative symptom domains with neurocognition and social/vocational community functioning and captured unique patterns of correlation with trait affect. Support for the five-factor model was shown by a stronger association between Blunted Affect with Attention/Vigilance, and stronger associations between Avolition, Anhedonia, and Asociality with psychosocial functioning. Results offer support for both the two-dimension and five-domain model of negative symptoms as well as a hierarchical two-dimensions-five-domains model of negative symptoms. Findings may have implications for diagnostic criteria and descriptions of the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM-5), as well as possible treatment targets of negative symptoms.

Variability of clinically measured lung clearance index in children with cystic fibrosis.

The lung clearance index (LCI) is increasingly being used in the clinical surveillance of patients with cystic fibrosis (CF). However, there are limited data on long-term variability and physiologically relevant changes in LCI during routine clinical surveillance. To evaluate the long-term variability of LCI and propose a threshold for a physiologically relevant change. In children aged 4-18 years with CF, LCIwas measuredevery 3 months as part of routine clinical surveillance during 2011-2020 in two centers. The variability of LCI during periods of clinical stability was assessed using mixed-effects models and was used to identify thresholds for physiologically relevant changes. Repeated LCI measurements of acceptable quality (N = 858) were available in 100 patients with CF; for 74 patients, 399 visits at clinical stability were available. The variability of repeated LCI measurements over time expressed as the coefficient of variation (CV%) was 7.4%. The upper limit of normal (ULN) for relative changes in LCI between visits was 19%. We report the variability of LCI in children and adolescents with CF during routine clinical surveillance. According to our data, a change in LCI beyond 19% may be considered physiologically relevant. These findings will help guide clinical decisions according to LCI changes.

Disrupted network switching in euthymic bipolar disorder: Working memory and self-referential paradigms

BackgroundPatients with bipolar disorder (BD) frequently suffer from neurocognitive deficits that can persist during periods of clinical stability. Specifically, impairments in executive functioning such as working memory and in self-processing have been identified as the main components of the neurocognitive profile observed in euthymic BD patients. The study of the neurobiological correlates of these state-independent alterations may be a prerequisite to develop reliable biomarkers in BD. MethodsA sample of 27 euthymic BD patients and 25 healthy participants (HC) completed working memory and self-referential functional Magnetic Resonance Imaging (fMRI) tasks. Activation maps obtained for each group and contrast images (i.e., 2-back > 1-back/self > control) were used for comparisons between patients and HC. ResultsEuthymic BD patients, in comparison to HC, showed a higher ventromedial prefrontal cortex activation during working memory, a result driven by the lack of deactivation in BD patients. In addition, euthymic BD patients displayed a greater dorsomedial and dorsolateral prefrontal cortex activation during self-reference processing. LimitationsPharmacotherapy was described but not included as a confounder in our models. Sample size was modest. ConclusionOur findings revealed a lack of deactivation in the anterior default mode network (aDMN) during a working memory task, a finding consistent with prior research in BD patients, but also a higher activation in frontal regions within the central executive network (CEN) during self-processing. These results suggest that an imbalance of neural network dynamics underlying external/internal oriented cognition (the CEN and the aDMN, respectively) may be one of the first reliable biomarkers in euthymic bipolar patients.

P283 PROGRESSION OF PULMONARY ARTERIAL HYPERTENSION OR LEFT HEART DISEASE? DO EXERCISE!

Abstract An 80–year–old man, diagnosed with idiopathic pulmonary arterial hypertension (PAH) in 2012 and treated with sildenafil, experienced his first hospitalization for heart failure in June 2019. He had several cardiovascular risk factors (overweight, hypertension, diabetes) and comorbidities (ischemic heart disease, and mild chronic obstructive pulmonary disease), whose progression was excluded. Since this event, he complained a progressive deterioration of the exertional dyspnea (NYHA III), with overt signs of fluid overload, right chambers dilation and high NTproBNP (1366 ng/L). However, the center taking care of this patient neither decided to fully re–evaluate him nor to escalate PAH–treatment due to his clinical profile (high suspicion of left heart disease, LHD). He then came to our pulmonary hypertension (PH) center where we decided to perform a cardiac catheterization, which showed the persistence of precapillary PH with high pulmonary vascular resistance, PVR (7.6 WU), low cardiac output, CO (2.2 L/min/m2), high right atrial pressure, RAP (12 mmHg). Pulmonary artery wedge pressure (PAWP) and left ventricular end–diastolic pressure (LVEDP) were at the upper limits of normal (13 mmHg and 16 mmHg, respectively) (Figure 1). Based on these “borderline” PAWP values, with an intermediate–high pre–test probability of left heart disease, we performed an exercise test with concomitant gas–exchange analysis on a cycle ergometer in the cath lab (Figure 2). Exercise induced a steep increase in pulmonary pressure (TPR 9 WU), unrelated to an exaggerate increase in PAWP or LVEDP (whose peak values reached 20 mmHg, with a PAWP/CO slope <2 mmHg/L/min), but entirely dependent on the precapillary component. Transpulmonary gradient (TPG)/CO slope was high, leading to an absent reduction in PVR (6.4 WU at peak), associated to severe increase in RAP (27 mmHg at peak, RAP/PAWP 1.4) (Figure 3). CO reserve was reduced (at peak 3.4 L/min/m2), due to both reduced increase in stroke volume and chronotropic incompetence. Accordingly, functional capacity was moderately–severely reduced (peak oxygen consumption was 8 ml/kg/min, 39% of predicted), with exercise hyperventilation. Once excluded LHD as the responsible of clinical worsening, and in consideration of the high–intermediate risk profile of this patient, we upgraded the PAH–specific therapy by adding macitentan, obtaining a subjective clinical improvement and a 3–years period of clinical stability.

The Association of N-Terminal Pro-Brain Natriuretic Peptide With Time to Clinical Worsening in Hispanic Patients With Pulmonary Arterial Hypertension.

BackgroundMeasurement of N-terminal pro-brain natriuretic peptide (NT-proBNP) level is an important parameter in the risk assessment of patients with pulmonary arterial hypertension (PAH). Data about the prognostic value of NT-proBNP in the Hispanic PAH population are lacking. Historically, clinical trials in PAH have only included a minority of Hispanic patients. It has been reported that baseline NT-proBNP levels differ between different ethnicities. Furthermore, NT-proBNP levels can be impacted by declining renal function, making its interpretation difficult regarding clinical decision making.MethodsIn a retrospective single-center cohort analysis, Hispanic patients with PAH had a baseline outpatient NT-proBNP level drawn during a period of clinical stability and were followed for 1 year to monitor for time to clinical worsening (TTCW). The association of baseline NT-proBNP and TTCW was assessed in patients with normal and abnormal renal function.ResultsA total of 26 patients (22%) met the clinical endpoint of clinical worsening. Twenty-seven patients (24%) had chronic kidney disease (CKD). At baseline NT-proBNP levels showed a significant inverse correlation with 6-min walk test (6MWD, r = -0.382, P = 0.02), and a significant positive correlation with renal function (r = 0.273, P = 0.05). NT-proBNP levels did not correlate with age (r = 0.19, P = 0.11) or body mass index (BMI) (r = -0.292, P = 0.061). NT-proBNP levels of > 1,415 ng/L were significantly associated with shorter TTCW (P < 0.01) in all patients and in patients with CKD (P = 0.03). A stepwise increase in NT-proBNP levels by 100 ng/L was associated with a higher risk of meeting the clinical endpoint of TTCW in patients with normal renal function (hazard ratio (HR) = 1.8, P < 0.01) and CKD (HR = 1.5, P < 0.01).ConclusionsIn Hispanic patients with PAH, NT-proBNP is a valuable tool to predict 1-year TTCW, independent of renal function.

Predicting long-term trends in inflammatory neuropathy outcome measures using latent class modelling.

Immunoglobulin (Ig) is used to treat chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) and multifocal motor neuropathy with conduction block (MMNCB). Regular infusions may be used for symptom control. Disease activity is monitored with clinical outcome measurements. We examined outcome measure variation during clinically stable periods in Ig-treated CIDP and MMNCB patients. We explored utility of serial outcome measurement in long-term outcome prediction. Retrospective longitudinal analysis of a single neuroscience centre's Ig-treated CIDP and MMNCB patients, 2009-2020, was performed. Mean and percentage change for grip strength, Rasch-built overall disability scales (RODS) and MRC sum scores (MRC-SS) during periods of clinical stability were compared to score-specific minimal clinically important differences (MCID). Latent class mixed modelling (LCMM) was used to identify longitudinal trends and factors influencing long-term outcome. We identified 85 CIDP and 23 MMNCB patients (1423 datapoints; 5635 treatment-months). Group-averaged outcome measures varied little over time. Intra-individual variation exceeded MCID for RODS in 44.2% CIDP and 16.7% MMNCB datapoints, grip strength in 10.6% (CIDP) and 8.8%/27.2% (MMNCB right/left hand) and MRC-SS in 43.5% (CIDP) and 20% (MMNCB). Multivariate LCMM identified subclinical trends towards improvement (32 patients) and deterioration (73 patients) in both cohorts. At baseline, CIDP 'deteriorators' were older than 'improvers' (66.2 vs 57 years, P= .025). No other individual factors predicted categorisation. The best model for 'deteriorator' identification was contiguous sub-MCID decline in more than one outcome measure (CIDP: sensitivity 74%, specificity 59%; MMNCB: sensitivity 73%, specificity 88%). Outcome measure interpretation determines therapeutic decision-making in Ig-dependent neuropathy patients, but intra-individual variation is common, often exceeding MCID. Here we show sub-MCID contiguous changes in more than one outcome measurement are a better predictor of long-term outcome.

Long-term variability of impulse oscillometry and spirometry in stable COPD and asthma

BackgroundWhile optimizing spirometry is a challenge for lung function labs, long-term variability if any between IOS (impulse oscillometry) parameters and spirometry is not clearly known in stable COPD (chronic obstructive pulmonary disease) and chronic asthma. The forced oscillation technique is increasingly employed in routine lung function testing. Our aim in this study was to determine the variability in oscillometric parameters between clinic visits over weeks or months in two patient groups during a period of clinical stability. Moreover, the research assessed relationships between IOS parameters long-term variability and COPD severity.MethodsWe used data from 73 patients with stable COPD and 119 patients with stable asthma at the Shanghai Pulmonary Hospital Affiliated to Tongji University. Patients were included if they had three or more clinic visits where spirometry and IOS were performed during a clinically stable period. Data recorded from the first three visits were used. The standard deviation (SDbv), the coefficient of variation (COV), intraclass correlation coefficient (ICC) and the coefficient of repeatability (COR) were calculated, Wilcoxon Mann–Whitney test was used for data that did not conform to normality of distributions, Kruskal Wallis test was used to compare with multiple groups, post hoc comparison was analyzed by Bonferroni, Spearman correlation coefficients for non-parametric data, the multiple regression analyses to determine the relationship between long-term variability and airflow obstruction.Results(1) The repeatability of IOS resistance parameters with ICC values > 0.8 was high in COPD and asthma. ICC values of IOS resistance parameters were higher than IOS reactance parameters; (2) the repeatability of spirometry parameters with ICC values < 0.8 was lower than IOS resistance parameters in different GOLD (the Global Initiative for Chronic Obstructive Lung Disease) stages, the higher the stage the worse the repeatability; (3) the severity of airflow obstruction was correlated with long-term variability of R5 (R at 5 Hz) (P < 0.05) in GOLD4, not with long-term variability of R20 (R at 20 Hz) (P > 0.05) and R5-R20 (P > 0.05).ConclusionIOS resistance parameters have good long-term repeatability in asthma and COPD. Additionally, repeatability of spirometry parameters is lower than IOS resistance parameters in different GOLD stages.

High Frequency of Allergic Bronchopulmonary Aspergillosis in Bronchiectasis-COPD Overlap

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. What is the occurrence and clinical relevance of Aspergillus sensitization and ABPA in BCO when compared with individuals with COPD or bronchiectasis without overlap? Prospective, observational, cross-sectional study. 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. 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. 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.

Pregnancy in multiple sclerosis women with relapses in the year before conception increases the risk of long-term disability worsening

Background: The influence of pregnancy on long-term disability in multiple sclerosis (MS) is still controversial. Objective: To assess the risk of long-term disability worsening after pregnancy in MS women as compared with a propensity-score (PS) matched group of MS women without pregnancy. Methods: In the setting of the Italian Pregnancy Dataset, MS patients with (pregnancy group (PG)) and without pregnancy (control group (CG)) were recruited. Time to disability worsening on the Expanded Disability Status Scale (EDSS) was assessed through a multivariable Cox regression model. Results: The PS-matching retained 230 PG and 102 CG patients. After a follow-up of 6.5 +/- 3.1 years, disability worsening occurred in 87 (26.2%) women. In the multivariable analysis, disability worsening was associated with pregnancy in women with relapses in the year before conception (adjusted hazard ratio (aHR) = 1.74; 95% confidence interval (CI) 1.06–2.84; p = 0.027), higher EDSS (aHR = 1.39; 95% CI 1.12–1.74; p = 0.003), younger age (aHR = 0.95; 95% CI 0.91–0.99; p = 0.022) and shorter DMD exposure over the follow-up (p < 0.008). Conclusion: Pregnancy in MS women with relapses in the year before conception increases the risk of long-term disability worsening. Our findings underscore the importance of counselling in MS women facing a pregnancy that should be planned after a period of clinical stability, favouring treatment optimization in patients with recent disease activity.

Association of exacerbation phenotype with the sputum microbiome in chronic obstructive pulmonary disease patients during the clinically stable state

BackgroundChronic obstructive pulmonary disease (COPD) is a progressive, life-threatening lung disease with increasing prevalence and incidence worldwide. Increasing evidence suggests that lung microbiomes might play a physiological role in acute exacerbations of COPD. The objective of this study was to characterize the association of the microbiota and exacerbation risk or airflow limitation in stable COPD patients.MethodsThe sputum microbiota from 78 COPD outpatients during periods of clinical stability was investigated using 16S rRNA V3-V4 amplicon sequencing. The microbiome profiles were compared between patients with different risks of exacerbation, i.e., the low risk exacerbator (LRE) or high risk exacerbator (HRE) groups, and with different airflow limitation severity, i.e., mild to moderate (FEV1 ≥ 50; PFT I) or severe to very severe (FEV1 < 50; PFT II).ResultsThe bacterial diversity (Chao1 and observed OTUs) was significantly decreased in the HRE group compared to that in the LRE group. The top 3 dominant phyla in sputum were Firmicutes, Actinobacteria, and Proteobacteria, which were similar in the HRE and LRE groups. At the genus level, compared to that in the LRE group (41.24%), the proportion of Streptococcus was slightly decreased in the HRE group (28.68%) (p = 0.007). However, the bacterial diversity and the proportion of dominant bacteria at the phylum and genus levels were similar between the PFT I and PFT II groups. Furthermore, the relative abundances of Gemella morbillorum, Prevotella histicola, and Streptococcus gordonii were decreased in the HRE group compared to those in the LRE group according to linear discriminant analysis effect size (LEfSe). Microbiome network analysis suggested altered bacterial cooperative regulation in different exacerbation phenotypes. The proportions of Proteobacteria and Neisseria were negatively correlated with the FEV1/FVC value. According to functional prediction of sputum bacterial communities through Phylogenetic Investigation of Communities by Reconstruction of Unobserved States (PICRUSt) analysis, genes involved in lipopolysaccharide biosynthesis and energy metabolism were enriched in the HRE group.ConclusionThe present study revealed that the sputum microbiome changed in COPD patients with different risks of exacerbation. Additionally, the bacterial cooperative networks were altered in the HRE patients and may contribute to disease exacerbation. Our results provide evidence that sputum microbiome community dysbiosis is associated with different COPD phenotypes, and we hope that by understanding the lung microbiome, a potentially modifiable clinical factor, further targets for improved COPD therapies during the clinically stable state may be elucidated.

Current practice and evolution of pediatric respiratory management of Duchenne muscular dystrophy in Canada

RATIONALE: Respiratory management practices for Duchenne muscular dystrophy (DMD) vary across Canada, according to a web-based survey conducted in 2010. Since then, new guidelines for respiratory management of DMD have been published. OBJECTIVES: This study aimed to describe current respiratory management practices of Canadian Pediatric Respirologists for children with DMD across the country. METHODS: A web-based survey on timing and indications for respiratory diagnostic tests and interventions was sent to all practicing Pediatric Respirologists at tertiary care centers in Canada who are involved in the longitudinal management of boys with DMD (N = 20). MEASUREMENTS AND MAIN RESULTS: Responses were received from 17 (85%) Pediatric Respirologists. Pulmonary function testing is regularly performed at least twice yearly after 5-6 years of age or after a patient becomes nonambulatory (13/17, 76%). Maximal expiratory pressures (15/17, 88%) and peak cough flow (12/17, 71%) are used to assess respiratory muscle strength. Sleep evaluation is most commonly performed with polysomnography (14/17, 82%), and is requested with the onset of symptoms (14/17, 82%) or with a forced vital capacity (FVC) < 60% predicted (6/9, 67%). At least once-daily lung volume recruitment exercises are prescribed by 94% (16/17) of respondents during periods of clinical stability, with the most common indication being an FVC < 80% predicted (9/17, 53%). CONCLUSIONS: The majority of Canadian Pediatric Respirologists are providing respiratory care to boys with DMD according to the current guidelines. The greatest change over time is the increased usage of regular LVR/airway clearance during periods of clinical stability.

A case of IVIg responsive paraneoplastic SOX1 peripheral neuropathy in a male with breast carcinoma

Background and aimsSOX1 antibodies are generally associated with small cell lung cancer and anti-Hu antibody overlap is common. This case demonstrates isolated anti-SOX1 antibodies with an uncommon tumor type, and relapse of a paraneoplastic syndrome with recurrence of tumor. MethodsWe describe a case of a 65-year-old male with a paraneoplastic peripheral neuropathy and anti-SOX1 antibody positivity in the context of a prior male breast Grade 2 ductal carcinoma, in remission at the time of the initial neurological presentation. ResultsTreatment response to intravenous immunoglobulin (IVIg) was demonstrated. After period of clinical stability on IVIg in the context of remission of breast carcinoma, the patient experienced a relapse of his neuropathy. This was associated with tumor recurrence and again responded to tumor excision, radiotherapy and IVIg. InterpretationMale breast carcinoma has not previously been associated with anti-SOX1 antibody positive paraneoplastic neuropathy.

Microbiome Data Enhances Predictive Models of Lung Function in People With Cystic Fibrosis.

Microbiome sequencing has brought increasing attention to the polymicrobial context of chronic infections. However, clinical microbiology continues to focus on canonical human pathogens, which may overlook informative, but nonpathogenic, biomarkers. We address this disconnect in lung infections in people with cystic fibrosis (CF). We collected health information (lung function, age, and body mass index [BMI]) and sputum samples from a cohort of 77 children and adults with CF. Samples were collected during a period of clinical stability and 16S rDNA sequenced for airway microbiome compositions. We use ElasticNet regularization to train linear models predicting lung function and extract the most informative features. Models trained on whole-microbiome quantitation outperformed models trained on pathogen quantitation alone, with or without the inclusion of patient metadata. Our most accurate models retained key pathogens as negative predictors (Pseudomonas, Achromobacter) along with established correlates of CF disease state (age, BMI, CF-related diabetes). In addition, our models selected nonpathogen taxa (Fusobacterium, Rothia) as positive predictors of lung health. These results support a reconsideration of clinical microbiology pipelines to ensure the provision of informative data to guide clinical practice.

High-Resolution Longitudinal Dynamics of the Cystic Fibrosis Sputum Microbiome and Metabolome through Antibiotic Therapy.

Microbial diversity in the cystic fibrosis (CF) lung decreases over decades as pathogenic bacteria such as Pseudomonas aeruginosa take over. The dynamics of the CF microbiome and metabolome over shorter time frames, however, remain poorly studied. Here, we analyze paired microbiome and metabolome data from 594 sputum samples collected over 401 days from six adult CF subjects (subject mean = 179 days) through periods of clinical stability and 11 CF pulmonary exacerbations (CFPE). While microbiome profiles were personalized (permutational multivariate analysis of variance [PERMANOVA] r 2 = 0.79, P < 0.001), we observed significant intraindividual temporal variation that was highest during clinical stability (linear mixed-effects [LME] model, P = 0.002). This included periods where the microbiomes of different subjects became highly similar (UniFrac distance, <0.05). There was a linear increase in the microbiome alpha-diversity and in the log ratio of anaerobes to pathogens with time (n = 14 days) during the development of a CFPE (LME P = 0.0045 and P = 0.029, respectively). Collectively, comparing samples across disease states showed there was a reduction of these two measures during antibiotic treatment (LME P = 0.0096 and P = 0.014, respectively), but the stability data and CFPE data were not significantly different from each other. Metabolome alpha-diversity was higher during CFPE than during stability (LME P = 0.0085), but no consistent metabolite signatures of CFPE across subjects were identified. Virulence-associated metabolites from P. aeruginosa were temporally dynamic but were not associated with any disease state. One subject died during the collection period, enabling a detailed look at changes in the 194 days prior to death. This subject had over 90% Pseudomonas in the microbiome at the beginning of sampling, and that level gradually increased to over 99% prior to death. This study revealed that the CF microbiome and metabolome of some subjects are dynamic through time. Future work is needed to understand what drives these temporal dynamics and if reduction of anaerobes correlate to clinical response to CFPE therapy.IMPORTANCE Subjects with cystic fibrosis battle polymicrobial lung infections throughout their lifetime. Although antibiotic therapy is a principal treatment for CF lung disease, we have little understanding of how antibiotics affect the CF lung microbiome and metabolome and how much the community changes on daily timescales. By analyzing 594 longitudinal CF sputum samples from six adult subjects, we show that the sputum microbiome and metabolome are dynamic. Significant changes occur during times of stability and also through pulmonary exacerbations (CFPEs). Microbiome alpha-diversity increased as a CFPE developed and then decreased during treatment in a manner corresponding to the reduction in the log ratio of anaerobic bacteria to classic pathogens. Levels of metabolites from the pathogen P. aeruginosa were also highly variable through time and were negatively associated with anaerobes. The microbial dynamics observed in this study may have a significant impact on the outcome of antibiotic therapy for CFPEs and overall subject health.

Measures of Cystic Fibrosis Airway Microbiota during Periods of Clinical Stability.

Rationale: Differences in cystic fibrosis (CF) airway microbiota between periods of clinical stability and exacerbation of respiratory symptoms have been investigated in efforts to better understand microbial triggers of CF exacerbations. Prior studies have often relied on a single sample or a limited number of samples to represent airway microbiota. However, the variability in airway microbiota during periods of clinical stability is not well known.Objectives: To determine the temporal variability of measures of airway microbiota during periods of clinical stability, and to identify factors associated with this variability.Methods: Sputum samples (N = 527), obtained daily from six adults with CF during 10 periods of clinical stability, underwent sequencing of the V4 region of the bacterial 16S ribosomal RNA gene. The variability in airway microbiota among samples within each period of clinical stability was calculated as the average of the Bray-Curtis similarity measures of each sample to every other sample within the same period. Outlier samples were defined as samples outside 1.5 times the interquartile range within a baseline period with respect to the average Bray-Curtis similarity. Total bacterial load was measured with droplet digital polymerase chain reaction.Results: The variation in Bray-Curtis similarity and total bacterial load among samples within the same baseline period was greater than the variation observed in technical replicate control samples. Overall, 6% of samples were identified as outliers. Within baseline periods, changes in bacterial community structure occurred coincident with changes in maintenance antibiotics (P < 0.05, analysis of molecular variance). Within subjects, bacterial community structure changed between baseline periods (P < 0.01, analysis of molecular variance). Sample-to-sample similarity within baseline periods was greater with fewer interval days between sampling.Conclusions: During periods of clinical stability, airway bacterial community structure and bacterial load vary among daily sputum samples from adults with CF. This day-to-day variation has bearing on study design and interpretation of results, particularly in analyses that rely on single samples to represent periods of interest (e.g., clinical stability vs. pulmonary exacerbation). These data also emphasize the importance of accounting for maintenance antibiotic use and granularity of sample collection in studies designed to assess the dynamics of CF airway microbiota relative to changes in clinical state.

Chronic obstructive pulmonary disease upper airway microbiota alpha diversity is associated with exacerbation phenotype: a case-control observational study

BackgroundChronic obstructive pulmonary disease (COPD) frequent exacerbators (FE) suffer increased morbidity and mortality compared to infrequent exacerbators (IE). The association between the oral and sputum microbiota and exacerbation phenotype is not well defined. The objective of this study was to determine key features that differentiate the oral and sputum microbiota of FEs from the microbiota of IEs during periods of clinical stability.MethodsWe recruited 11 FE and 11 IE who had not used antibiotics or systemic corticosteroids in the last 1 month. Subjects provided oral wash and sputum samples, which underwent 16S V4 MiSeq sequencing and qPCR of 16S rRNA. Data were analyzed using Dada2 and R.ResultsFE and IE were similar in terms of age, FEV1 percent predicted (FEV1pp), pack-years of tobacco exposure, and St. George’s Respiratory Questionnaire score. 16S copy numbers were significantly greater in sputum vs. oral wash (p = 0.01), but phenotype was not associated with copy number. Shannon diversity was significantly greater in oral samples compared to sputum (p = 0.001), and IE samples were more diverse than FE samples (p < 0.001). Sputum samples from FE had more Haemophilus and Moraxella compared to IE sputum samples, due to dominance of these COPD-associated taxa in three FE sputum samples. Amplicon sequencing variant (ASV)-level analysis of sputum samples revealed one ASV (Actinomyces) was significantly more abundant in IE vs. FE sputum (padj = 0.048, Wilcoxon rank-sum test), and this persisted after controlling for FEV1pp. Principal coordinate analysis using Bray-Curtis distance with PERMANOVA analyses demonstrated clustering by anatomic site, phenotype, inhaled corticosteroid use, current tobacco use, COPD severity, and last professional dental cleaning.ConclusionsFE have less diverse oral and sputum microbiota than IE. Actinomyces was significantly more abundant in IE sputum than FE sputum. The oral and sputum microbiota of COPD subjects cluster based on multiple clinical factors, including exacerbation phenotype. Even during periods of clinical stability, the frequent exacerbator phenotype is associated with decreased alpha diversity, beta-diversity clustering, and changes in taxonomic abundance.

Understanding FEV1 for the purpose of cystic fibrosis registry comparisons: Does bias in annual review FEV1 affect between-centre comparison within the UK? An analysis of registry data.

We previously demonstrated that annual review %FEV1 underestimates lung health of adults with CF compared with %FEV1 captured during periods of clinical stability. This has implications in the comparisons against registries with encounter-based FEV1 , such as the United States. It is uncertain whether this bias affects between-centre comparison within the United Kingdom. Previous funnel plot analyses have identified variation in annual review %FEV1 according to centre size; hence, we investigated whether paired differences between annual review and best %FEV1 also vary according to centre size. This registry analysis included 18 adult CF centres in the United Kingdom with ≥80% completeness for best FEV1 data in 2014. Mean discrepancy between annual review and best %FEV1 is a surrogate for the extent by which annual review %FEV1 underestimates lung health, and was plotted against centre size. A local polynomial regression (LOESS) curve was used to explore the relationship between the two variables. An appropriate model is fitted based on the LOESS curve to determine the strength of relationship between discrepancies in %FEV1 and centre size. There is an inverted U-shaped relationship between mean discrepancies in %FEV1 and centre size. A regression of the paired mean difference in %FEV1 against centre size showed a significant improvement in the goodness of fit for a quadratic model (R2 =23.8% for a quadratic model compared with 0.4% for a linear one; P=0.048 for the quadratic term). Annual review %FEV1 underestimated lung health of adults from small and large centres in the United Kingdom to a greater extent compared with medium-sized centres. A plot of %FEV1 against centre size (eg, funnel plot comparison) would be affected by systematic bias in annual review %FEV1 . Therefore, annual review %FEV1 is an unreliable metric to compare health outcomes of adult CF centres within the United Kingdom.

Characteristics of patients who progress from bridging to long-term oxygen therapy.

Patients with persistent hypoxia following an acute hospital admission may be discharged with 'bridging' domiciliary oxygen as per criteria defined by the Thoracic Society of Australia and New Zealand. The need for continuous long-term oxygen therapy (LTOT) is then reassessed at a clinic review 1-2 months later. To describe the characteristics of patients discharged from an acute hospital admission with continuous short-term oxygen therapy (STOT), and subsequently to investigate for differences between subjects who proceeded to qualify for continuous LTOT versus those who were able to cease STOT at review. This is a retrospective cohort study involving all subjects discharged from Alfred Health between 2011 and 2015 inclusive with bridging domiciliary oxygen. Multiple biochemical, physiological and demographic characteristics were collated and analysed. Of all patients prescribed continuous STOT at time of discharge, 47.3% qualified for LTOT at outpatient review. This cohort had a significantly lower PaO2 measurement at time of discharge, compared with those who no longer qualified. PaO2 at time of discharge provides a signal with the potential to identify who will require continuous LTOT following an acute hospital admission. Additionally, this study highlights the need to re-evaluate patients' oxygen requirements during a period of clinical stability.

Poliomielite e seus efeitos tardios: viver ao ritmo da doença

Introduction: Many survivors of polio develop complications after a period of clinical stability. This case report demonstrates the need for the family physician to become familiar with the multiple facets of the late effects of polio and to recognize them as a disease entity. Description of the case: A 69 year-old woman had polio with sequelae. Her life story showed how the struggle to overcome deficiency was central to her trajectory. Decades after the onset of the acute disease, she presented with progressive complaints of muscle weakness, fatigue, myalgia, polyarthralgia, tingling of her hands, and depression. This caused increasing functional disability, intolerance to cold, urinary incontinence, sleep disturbance, and fasciculation. Physical examination and diagnostic tests showed chronic nerve injury in the lower limbs, carpal tunnel syndrome, and various musculoskeletal disorders. Faced with new symptoms, old feelings associated with disability that she felt she had overcome, were awakened. The treatment plan involved a multidisciplinary team. It included control of symptoms and disease progression, treating coexisting psychopathology, promotion of a healthy lifestyle, changes in her housing, prescription of assistive devices, combating isolation, mobilization of informal resources, health and social services, and transmission of information about the disease and related problems. Comment: The late effects of polio can be minimized by following suggested guidelines. Effective management requires a doctor who can identify the characteristic cluster of signs and symptoms and their psychosocial effects and formulate an individualized treatment plan.