Aspergillus and progression of lung disease in children with cystic fibrosis

Thorax ◽  
2018 ◽  
Vol 74 (2) ◽  
pp. 125-131 ◽  
Author(s):  
Sabariah Noor Harun ◽  
Claire E Wainwright ◽  
Keith Grimwood ◽  
Stefanie Hennig
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Bronchoalveolar Lavage ◽  
Lung Disease ◽  
Lung Function Decline ◽  
Air Trapping ◽  
Cross Sectional ◽  
Progression Model ◽  
Non Linear ◽  
The Impact

BackgroundThe impact of Aspergillus on lung disease in young children with cystic fibrosis is uncertain.AimsTo determine if positive respiratory cultures of Aspergillus species are associated with: (1) increased structural lung injury at age 5 years; (2) accelerated lung function decline between ages 5 years and 14 years and (3) to identify explanatory variables.MethodsA cross-sectional analysis of association between Aspergillus positive bronchoalveolar lavage (BAL) cultures and chest high-resolution CT (HRCT) scan findings at age 5 years in subjects from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study was performed. A non-linear mixed-effects disease progression model was developed using FEV1% predicted measurements at age 5 years from the ACFBAL study and at ages 6–14 years for these subjects from the Australian Cystic Fibrosis Data Registry.ResultsPositive Aspergillus BAL cultures at age 5 years were significantly associated with increased HRCT scores for air trapping (OR 5.53, 95% CI 2.35 to 10.82). However, positive Aspergillus cultures were not associated with either FEV1% predicted at age 5 years or FEV1% predicted by age following adjustment for body mass index z-score and hospitalisation secondary to pulmonary exacerbations. Lung function demonstrated a non-linear decline in this population.ConclusionIn children with cystic fibrosis, positive Aspergillus BAL cultures at age 5 years were associated contemporaneously with air trapping but not bronchiectasis. However, no association was observed between positive Aspergillus BAL cultures on FEV1% predicted at age 5 years or with lung function decline between ages 5 years and 14 years.

scholarly journals Sputum microbiota is predictive of long-term clinical outcomes in young adults with cystic fibrosis

Thorax ◽  
2018 ◽  
Vol 73 (11) ◽  
pp. 1016-1025 ◽  
Author(s):  
Nicole Acosta ◽  
Alya Heirali ◽  
Ranjani Somayaji ◽  
Michael G Surette ◽  
Matthew L Workentine ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Microbial Communities ◽  
Multivariable Analysis ◽  
Alpha Diversity ◽  
Illumina Miseq ◽  
Disease Stage ◽  
Sample Collection ◽  
Lung Function Decline

BackgroundComplex polymicrobial communities infect cystic fibrosis (CF) lower airways. Generally, communities with low diversity, dominated by classical CF pathogens, associate with worsened patient status at sample collection. However, it is not known if the microbiome can predict future outcomes. We sought to determine if the microbiome could be adapted as a biomarker for patient prognostication.MethodsWe retrospectively assessed prospectively collected sputum from a cohort of 104 individuals aged 18–22 to determine factors associated with progression to early end-stage lung disease (eESLD; death/transplantation <25 years) and rapid pulmonary function decline (>−3%/year FEV1 over the ensuing 5 years). Illumina MiSeq paired-end sequencing of the V3-V4 region of the 16S rRNA was used to define the airway microbiome.ResultsBased on the primary outcome analysed, 17 individuals (16%) subsequently progressed to eESLD. They were more likely to have sputum with low alpha diversity, dominated by specific pathogens including Pseudomonas. Communities with abundant Streptococcus were observed to be protective. Microbial communities clustered together by baseline lung disease stage and subsequent progression to eESLD. Multivariable analysis identified baseline lung function and alpha diversity as independent predictors of eESLD. For the secondary outcomes, 58 and 47 patients were classified as rapid progressors based on absolute and relative definitions of lung function decline, respectively. Patients with low alpha diversity were similarly more likely to be classified as experiencing rapid lung function decline over the ensuing 5 years when adjusted for baseline lung function.ConclusionsWe observed that the diversity of microbial communities in CF airways is predictive of progression to eESLD and disproportionate lung function decline and may therefore represent a novel biomarker.

scholarly journals A cluster-based analysis evaluating the impact of comorbidities in fibrotic interstitial lung disease

2020 ◽  
Vol 21 (1) ◽  
Author(s):  
Alyson W. Wong ◽  
Tae Yoon Lee ◽  
Kerri A. Johannson ◽  
Deborah Assayag ◽  
Julie Morisset ◽  
...  
Keyword(s):  
Interstitial Lung Disease ◽  
Lung Function ◽  
Pulmonary Fibrosis ◽  
Lung Disease ◽  
Disease Progression ◽  
Rapid Decline ◽  
Agglomerative Clustering ◽  
Lung Function Decline ◽  
Obstructive Sleep ◽  
The Impact

Abstract Background Comorbidities are frequent and have been associated with poor quality of life, increased hospitalizations, and mortality in patients with interstitial lung disease (ILD). However, it is unclear how comorbidities lead to these negative outcomes and whether they could influence ILD disease progression. The goal of this study was to identify clusters of patients based on similar comorbidity profiles and to determine whether these clusters were associated with rate of lung function decline and/or mortality. Methods Patients with a major fibrotic ILD (idiopathic pulmonary fibrosis (IPF), fibrotic hypersensitivity pneumonitis, connective tissue disease-associated ILD, and unclassifiable ILD) from the CAnadian REgistry for Pulmonary Fibrosis (CARE-PF) were included. Hierarchical agglomerative clustering of comorbidities, age, sex, and smoking pack-years was conducted for each ILD subtype to identify combinations of these features that frequently occurred together in patients. The association between clusters and change in lung function over time was determined using linear mixed effects modeling, with adjustment for age, sex, and smoking pack-years. Kaplan Meier curves were used to assess differences in survival between the clusters. Results Discrete clusters were identified within each fibrotic ILD. In IPF, males with obstructive sleep apnea (OSA) had more rapid decline in FVC %-predicted (− 11.9% per year [95% CI − 15.3, − 8.5]) compared to females without any comorbidities (− 8.1% per year [95% CI − 13.6, − 2.7]; p = 0.03). Females without comorbidities also had significantly longer survival compared to all other IPF clusters. There were no significant differences in rate of lung function decline or survival between clusters in the other fibrotic ILD subtypes. Conclusions The combination of male sex and OSA may portend worse outcomes in IPF. Further research is required to elucidate the interplay between sex and comorbidities in ILD, as well as the role of OSA in ILD disease progression.

Rapid lung function decline in adults with early-stage cystic fibrosis lung disease

2020 ◽  
Vol 19 (4) ◽  
pp. 527-533
Author(s):  
Elliott C. Dasenbrook ◽  
Aliza K. Fink ◽  
Michael S. Schechter ◽  
Don B. Sanders ◽  
Stefanie J. Millar ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Early Stage ◽  
Cystic Fibrosis Lung ◽  
Lung Function Decline ◽  
Cystic Fibrosis Lung Disease

scholarly journals A Volatile and Dynamic Longitudinal Microbiome Is Associated With Less Reduction in Lung Function in Adolescents With Cystic Fibrosis

2021 ◽  
Vol 11 ◽  
Author(s):  
Marisa I. Metzger ◽  
Simon Y. Graeber ◽  
Mirjam Stahl ◽  
Olaf Sommerburg ◽  
Marcus A. Mall ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
16S Rrna Gene Sequencing ◽  
Rrna Gene ◽  
Contributing Factors ◽  
Lung Function Decline ◽  
Cross Sectional ◽  
Lung Microbiome ◽  
The Stability ◽  
The Individual

Progressive impairment in lung function caused by chronic polymicrobial airway infection remains the major cause of death in patients with cystic fibrosis (CF). Cross-sectional studies suggest an association between lung function decline and specific lung microbiome ecotypes. However, longitudinal studies on the stability of the airway microbiome are missing for adolescents with CF constituting the age group showing the highest rate of decline in lung function. In this study, we analyzed longitudinal lung function data and sputum samples collected over a period of 3 to 5 years from 12 adolescents with CF. The sputum microbiome was analyzed using 16S rRNA gene sequencing. Our results indicate that the individual course of the lung microbiome is associated with longitudinal lung function. In our cohort, patients with a dynamic, diverse microbiome showed a slower decline of lung function measured by FEV1% predicted, whereas a more stable and less diverse lung microbiome was related to worse outcomes. Specifically, a higher abundance of the phyla Bacteroidetes and Firmicutes was linked to a better clinical outcome, while Proteobacteria were correlated with a decline in FEV1% predicted. Our study indicates that the stability and diversity of the lung microbiome and the abundance of Bacteroidetes and Firmicutes are associated with the lung function decline and are one of the contributing factors to the disease severity.

scholarly journals Progressive ventilation inhomogeneity in infants with cystic fibrosis after pulmonary infection

2015 ◽  
Vol 46 (6) ◽  
pp. 1680-1690 ◽  
Author(s):  
Shannon J. Simpson ◽  
Sarath Ranganathan ◽  
Judy Park ◽  
Lidija Turkovic ◽  
Roy M. Robins-Browne ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Pulmonary Infection ◽  
Pulmonary Inflammation ◽  
First Year ◽  
Cross Sectional ◽  
Ventilation Inhomogeneity ◽  
Multiple Breath Washout ◽  
First Year Of Life ◽  
The Impact

Measures of ventilation distribution are promising for monitoring early lung disease in cystic fibrosis (CF). This study describes the cross-sectional and longitudinal impacts of pulmonary inflammation and infection on ventilation homogeneity in infants with CF.Infants diagnosed with CF underwent multiple breath washout (MBW) testing and bronchoalveolar lavage at three time points during the first 2 years of life.Measures were obtained for 108 infants on 156 occasions. Infants with a significant pulmonary infection at the time of MBW showed increases in lung clearance index (LCI) of 0.400 units (95% CI 0.150–0.648; p=0.002). The impact was long lasting, with previous pulmonary infection leading to increased ventilation inhomogeneity over time compared to those who remained free of infection (p<0.05). Infection with Haemophilus influenzae was particularly detrimental to the longitudinal lung function in young children with CF where LCI was increased by 1.069 units for each year of life (95% CI 0.484–1.612; p<0.001).Pulmonary infection during the first year of life is detrimental to later lung function. Therefore, strategies aimed at prevention, surveillance and eradication of pulmonary pathogens are paramount to preserve lung function in infants with CF.

scholarly journals Structural determinants of long-term functional outcomes in young children with cystic fibrosis

2020 ◽  
Vol 55 (5) ◽  
pp. 1900748 ◽  
Author(s):  
Lidija Turkovic ◽  
Daan Caudri ◽  
Tim Rosenow ◽  
Oded Breuer ◽  
Conor Murray ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Chest Ct ◽  
Lung Damage ◽  
Wall Thickening ◽  
Lung Function Decline ◽  
Children's Hospital ◽  
Children’S Hospital

BackgroundAccelerated lung function decline in individuals with cystic fibrosis (CF) starts in adolescence with respiratory complications being the most common cause of death in later life. Factors contributing to lung function decline are not well understood, in particular its relationship with structural lung disease in early childhood. Detection and management of structural lung disease could be an important step in improving outcomes in CF patients.MethodsAnnual chest computed tomography (CT) scans were available from 2005 to 2016 as a part of the AREST CF cohort for children aged 3 months to 6 years. Annual spirometry measurements were available for 89.77% of the cohort (167 children aged 5–6 years) from age 5 to 15 years through outpatient clinics at Perth Children's Hospital (Perth, Australia) and The Royal Children's Hospital in Melbourne (Melbourne, Australia) (697 measurements, mean±sd age 9.3±2.1 years).ResultsChildren with a total CT score above the median at age 5–6 years were more likely to have abnormal forced expiratory volume in 1 s (FEV1) (adjusted hazard ratio 2.67 (1.06–6.72), p=0.037) during the next 10 years compared to those below the median chest CT score. The extent of all structural abnormalities except bronchial wall thickening were associated with lower FEV1 Z-scores. Mucus plugging and trapped air were the most predictive sub-score (adjusted mean change −0.17 (−0.26 – −0.07) p<0.001 and −0.09 (−0.14 – −0.04) p<0.001, respectively).DiscussionChest CT identifies children at an early age who have adverse long-term outcomes. The prevention of structural lung damage should be a goal of early intervention and can be usefully assessed with chest CT. In an era of therapeutics that might alter disease trajectories, chest CT could provide an early readout of likely long-term success.

scholarly journals Functional respiratory imaging in relation to classical outcome measures in cystic fibrosis: a cross-sectional study

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Eline Lauwers ◽  
Annemiek Snoeckx ◽  
Kris Ides ◽  
Kim Van Hoorenbeeck ◽  
Maarten Lanclus ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Lung Disease ◽  
Outcome Measures ◽  
Cross Sectional Study ◽  
Ct Scans ◽  
Airway Wall ◽  
Sectional Study ◽  
Air Trapping ◽  
Cross Sectional ◽  
Blood Distribution

Abstract Background Functional Respiratory Imaging (FRI) combines HRCT scans with computational fluid dynamics to provide objective and quantitative information about lung structure and function. FRI has proven its value in pulmonary diseases such as COPD and asthma, but limited studies have focused on cystic fibrosis (CF). This study aims to investigate the relation of multiple FRI parameters to validated imaging parameters and classical respiratory outcomes in a CF population. Methods CF patients aged > 5 years scheduled for a chest CT were recruited in a cross-sectional study. FRI outcomes included regional airway volume, airway wall volume, airway resistance, lobar volume, air trapping and pulmonary blood distribution. Besides FRI, CT scans were independently evaluated by 2 readers using the CF-CT score. Spirometry and the 6-Minute Walk Test (6MWT) were also performed. Statistical tests included linear mixed-effects models, repeated measures correlations, Pearson and Spearman correlations. Results 39 CT scans of 24 (17M/7F) subjects were analyzed. Patients were 24 ± 9 years old and had a ppFEV1 of 71 ± 25% at the time of the first CT. All FRI parameters showed significant low-to-moderate correlations with the total CF-CT score, except for lobar volume. When considering the relation between FRI parameters and similar CF-CT subscores, significant correlations were found between parameters related to airway volume, air trapping and airway wall thickening. Air trapping, lobar volume after normal expiration and pulmonary blood distribution showed significant associations with all spirometric parameters and oxygen saturation at the end of 6MWT. In addition, air trapping was the only parameter related to the distance covered during 6MWT. A subgroup analysis showed considerably higher correlations in patients with mild lung disease (ppFEV1 ≥ 70%) compared to patients with moderate to severe lung disease (ppFEV1 < 70%) when comparing FRI to CF-CT scores. Conclusions Multiple structural characteristics determined by FRI were associated with abnormalities determined by CF-CT score. Air trapping and pulmonary blood distribution appeared to be the most clinically relevant FRI parameters for CF patients due to their associations with classical outcome measures. The FRI methodology could particularly be of interest for patients with mild lung disease, although this should be confirmed in future research.

scholarly journals Single nucleotide variants in Pseudomonas aeruginosa populations from sputum correlate with baseline lung function and predict disease progression in individuals with cystic fibrosis

2021 ◽  
Author(s):  
Morteza M Saber ◽  
Jannik Donner ◽  
Inès Levade ◽  
Nicole Acosta ◽  
Michael D Perkins ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Pseudomonas Aeruginosa ◽  
Genetic Variation ◽  
Lung Function ◽  
Lung Disease ◽  
Disease Severity ◽  
Single Nucleotide Variants ◽  
Lung Function Decline ◽  
Single Nucleotide ◽  
Lung Disease Severity

Complex polymicrobial communities inhabit the lungs of individuals with cystic fibrosis (CF) and contribute to the decline in lung function. However, the severity of lung disease and its progression in CF patients are highly variable and imperfectly predicted by host clinical factors at baseline, CFTR mutations in the host genome, or sputum polymicrobial community variation. The opportunistic pathogen Pseudomonas aeruginosa (Pa) dominates airway infections in the majority of CF adults. Here we hypothesized that genetic variation within Pa populations would be predictive of lung disease severity. To quantify Pa genetic variation within whole CF sputum samples, we used deep amplicon sequencing on a newly developed custom Ion AmpliSeq panel of 209 Pa genes previously associated with the host pathoadaptation and pathogenesis of CF infection. We trained machine learning models using Pa single nucleotide variants (SNVs), clinical and microbiome diversity data to classify lung disease severity at the time of sputum sampling, and to predict future lung function decline over five years in a cohort of 54 adult CF patients with chronic Pa infection. The models using Pa SNVs alone classified baseline lung disease with good sensitivity and specificity, with an area under the receiver operating characteristic curve (AUROC) of 0.87. While the models were less predictive of future lung function decline, they still achieved an AUROC of 0.74. The addition of clinical data to the models, but not microbiome community data, yielded modest improvements (baseline lung function: AUROC=0.92; lung function decline: AUROC=0.79), highlighting the predictive value of the AmpliSeq data. Together, our work provides a proof-of-principle that Pa genetic variation in sputum is strongly associated with baseline lung disease, moderately predicts future lung function decline, and provides insight into the pathobiology of Pa's effect on CF.

scholarly journals Lymphangioleiomyomatosis: a clinical review

Breathe ◽  
2020 ◽  
Vol 16 (2) ◽  
pp. 200007
Author(s):  
Anne M. O'Mahony ◽  
Evelyn Lynn ◽  
David J. Murphy ◽  
Aurelie Fabre ◽  
Cormac McCarthy
Keyword(s):  
Lung Function ◽  
Lung Disease ◽  
Elevated Serum ◽  
Prognostic Indicators ◽  
List Type ◽  
Lung Function Decline ◽  
Management Options ◽  
Cystic Lung ◽  
Cystic Lung Disease ◽  
The Impact

Lymphangioleiomyomatosis (LAM) is a diffuse cystic lung disease. There are two main types of LAM: sporadic, and LAM associated with the tuberous sclerosis complex (TSC), which is caused by mutations in the TSC1 and TSC2 genes. LAM is characterised by cystic lung disease resulting in progressive dyspnoea, renal angiomyolipomas and lymphatic complications. Pneumothorax occurs frequently (70%) and definitive management with pleurodesis is recommended as the risk of recurrence is high. Characteristic thin-walled cysts are seen on computed tomography and the presence of elevated serum levels of a vascular endothelial growth factor-D has good diagnostic specificity. Currently, no single clinical or serological factor has been shown to predict prognosis. However, over the past decade, significant advances in our understanding of the pathophysiology of LAM has led to improved recognition of this rare disease and identification of treatment options. Mechanistic target of rapamycin inhibitors slow the rate of lung function decline and can resolve chylous effusion and regress angiomyolipomas. Life expectancy in patients with LAM is favourable, with a mean transplant-free survival >20 years from the time of diagnosis. Continued advances in understanding the molecular basis of LAM will lead to improved therapeutic targets and the development of more robust prognostic indicators.Educational aimsTo illustrate the clinical features, common presentations and radiological features of LAMTo outline the diagnostic approach to LAM, including the role of VEGF-DTo review the current prognostic indicators in LAM, and outline the impact of lung function, hormonal status, VEGF-D and clinical presentation on outcomeTo inform clinicians on the management options for LAM both pharmacological and nonpharmacological

scholarly journals Prognosis-Based Early Intervention Strategies to Resolve Exacerbation and Progressive Lung Function Decline in Cystic Fibrosis

2021 ◽  
Vol 11 (2) ◽  
pp. 96
Author(s):  
Neeraj Vij
Keyword(s):  
Cystic Fibrosis ◽  
Lung Function ◽  
Lung Disease ◽  
Obstructive Lung Disease ◽  
Unmet Need ◽  
Chronic Obstructive Lung Disease ◽  
Intervention Strategies ◽  
Chronic Obstructive ◽  
Forced Oscillation Technique ◽  
Lung Function Decline

Cystic fibrosis (CF) is a genetic disease caused by a mutation(s) in the CF transmembrane regulator (CFTR), where progressive decline in lung function due to recurring exacerbations is a major cause of mortality. The initiation of chronic obstructive lung disease in CF involves inflammation and exacerbations, leading to mucus obstruction and lung function decline. Even though clinical management of CF lung disease has prolonged survival, exacerbation and age-related lung function decline remain a challenge for controlling the progressive lung disease. The key to the resolution of progressive lung disease is prognosis-based early therapeutic intervention; thus, the development of novel diagnostics and prognostic biomarkers for predicting exacerbation and lung function decline will allow optimal management of the lung disease. Hence, the development of real-time lung function diagnostics such as forced oscillation technique (FOT), impulse oscillometry system (IOS), and electrical impedance tomography (EIT), and novel prognosis-based intervention strategies for controlling the progression of chronic obstructive lung disease will fulfill a significant unmet need for CF patients. Early detection of CF lung inflammation and exacerbations with the timely resolution will not only prolong survival and reduce mortality but also improve quality of life while reducing significant health care costs due to recurring hospitalizations.

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