Relationship between gut microbiota and lung function decline in patients with chronic obstructive pulmonary disease: a 1-year follow-up study

Objective Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory lung disease characterized by a persistent limitation in airflow. Gut microbiota is closely correlated with lung inflammation. However, gut microbiota has not been studied in patients with declining lung function, due to chronic lung disease progression. Subjects and methods Stool samples were obtained from 55 patients with COPD that were in stable condition at enrolment (stage 1) and at a 1-year follow-up (stage 2). After extracting stool DNA, we performed next generation sequencing to analyse the distribution of gut microbiota. Results Patients were divided to control and declining lung function groups, based on whether the rate of forced expiratory volume in 1 s (FEV1) had declined over time. An alpha diversity analysis of initial and follow-up stool samples showed a significant difference in the community richness of microbiota in the declining function group, but not in the control group. At the phylum level, Bacteroidetes was more abundant in the control group and Firmicutes was more abundant in the declining function group. The Alloprevotella genus was more abundant in the control group than in the declining function group. At 1-year follow-up, the mean proportions of Acinetobacter and Stenotrophomonas significantly increased in the control and declining function groups, respectively. Conclusion Some community shifts in gut microbiota were associated with lung function decline in COPD patients under regular treatment. Future studies should investigate the mechanism underlying alterations in lung function, due to changes in gut bacterial communities, in COPD.

Impact of lung function decline on time to hospitalisation events in systemic sclerosis-associated interstitial lung disease (SSc-ILD): a joint model analysis

Background Interstitial lung disease (ILD) is a common organ manifestation in systemic sclerosis (SSc) and is the leading cause of death in patients with SSc. A decline in forced vital capacity (FVC) is an indicator of ILD progression and is associated with mortality in patients with SSc-associated ILD (SSc-ILD). However, the relationship between FVC decline and hospitalisation events in patients with SSc-ILD is largely unknown. The objective of this post hoc analysis was to investigate the relationship between FVC decline and clinically important hospitalisation endpoints. Methods We used data from SENSCIS®, a phase III trial investigating the efficacy and safety of nintedanib in patients with SSc-ILD. Joint models for longitudinal and time-to-event data were used to assess the association between rate of decline in FVC% predicted and hospitalisation-related endpoints (including time to first all-cause hospitalisation or death; time to first SSc-related hospitalisation or death; and time to first admission to an emergency room [ER] or admission to hospital followed by admission to intensive care unit [ICU] or death) during the treatment period, over 52 weeks in patients with SSc-ILD. Results There was a statistically significant association between FVC decline and the risk of all-cause (n = 78) and SSc-related (n = 42) hospitalisations or death (both P < 0.0001). A decrease of 3% in FVC corresponded to a 1.43-fold increase in risk of all-cause hospitalisation or death (95% confidence interval [CI] 1.24, 1.65) and a 1.48-fold increase in risk of SSc-related hospitalisation or death (95% CI 1.23, 1.77). No statistically significant association was observed between FVC decline and admission to ER or to hospital followed by admission to ICU or death (n = 75; P = 0.15). The estimated slope difference for nintedanib versus placebo in the longitudinal sub-model was consistent with the primary analysis in SENSCIS®. Conclusions The association of lung function decline with an increased risk of hospitalisation suggests that slowing FVC decline in patients with SSc-ILD may prevent hospitalisations. Our findings also provide evidence that FVC decline may serve as a surrogate endpoint for clinically relevant hospitalisation-associated endpoints. Trial registration ClinicalTrials.govNCT02597933. Registered on 8 October 2015.

SLC6A14 impacts cystic fibrosis lung disease severity via mTOR and epithelial repair modulation

Cystic fibrosis (CF), due to variants in CFTR gene, is associated with chronic infection/inflammation responsible for airway epithelium alteration and lung function decline. Modifier genes induce phenotype variability between people with CF (pwCF) carrying the same CFTR variants. Among these, the gene encoding for the amino acid transporter SLC6A14 has been associated with lung disease severity and age of primary airway infection by the bacteria Pseudomonas aeruginosa. In this study, we investigated whether the single nucleotide polymorphism (SNP) rs3788766, located within SLC6A14 promoter, is associated with lung disease severity in a large French cohort of pwCF. We also studied the consequences of this SNP on SLC6A14 promoter activity using a luciferase reporter and the role of SLC6A14 in mammalian target of rapamycin (mTOR) signaling pathway and airway epithelial repair. We confirm that SLC6A14 rs3788766 SNP is associated with lung disease severity in pwCF (p=0.020; n=3,257, pancreatic insufficient, aged 6 to 40 years old), with the minor allele G being deleterious. In bronchial epithelial cell lines deficient for CFTR, SLC6A14 promoter activity is reduced in the presence of the rs3788766 G allele. SLC6A14 inhibition with a specific pharmacological blocker reduced 3H-arginine transport, mTOR phosphorylation and bronchial epithelial repair rates in wound healing assays. To conclude, our study highlights that SLC6A14 genotype might affect lung disease severity of people with cystic fibrosis via mTOR and epithelial repair mechanisms modulation in the lung.

IgE is associated with exacerbations and lung function decline in COPD

Background Both allergen-specific IgE and total IgE in serum play a major role in asthma. However, the role of IgE in chronic obstructive pulmonary disease (COPD) is poorly understood. It was the aim of this study to systematically analyze the relationship between serum IgE levels and disease characteristics in large COPD cohorts. Methods COSYCONET is a comprehensively characterized cohort of patients with COPD: total IgE and IgE specific to common aeroallergens were measured in serum of 2280 patients, and related to clinical characteristics of the patients. WISDOM is another large COPD population (2477 patients): this database contains the information whether total IgE in serum was elevated (≥ 100 IU/l) or normal in patients with COPD. Results Both in COSYCONET and WISDOM, total IgE was elevated (≥ 100 IU/l) in > 30% of the patients, higher in men than in women, and higher in currently than in not currently smoking men. In COSYCONET, total IgE was elevated in patients with a history of asthma and/or allergies. Men with at least one exacerbation in the last 12 months (50.6% of all men in COSYCONET) had higher median total IgE (71.3 IU/l) than men without exacerbations (48.3 IU/l): this difference was also observed in the subgroups of not currently smoking men and of men without a history of asthma. Surprisingly, a history of exacerbations did not impact on total IgE in women with COPD. Patients in the highest tertiles of total IgE (> 91.5 IU/ml, adjusted OR: 1.62, 95% CI 1.12–2.34) or allergen-specific IgE (> 0.19 IU/ml, adjusted OR: 2.15, 95% CI 1.32–3.51) were at risk of lung function decline (adjusted by: age, gender, body mass index, initial lung function, smoking status, history of asthma, history of allergy). Conclusion These data suggest that IgE may play a role in specific COPD subgroups. Clinical trials using antibodies targeting the IgE pathway (such as omalizumab), especially in men with recurrent exacerbations and elevated serum IgE, could elucidate potential therapeutic implications of our observations.

Lung function decline in relation to COVID-19 in the general population: a matched cohort study with pre-pandemic assessment of lung function

Objective To quantify the potential decline in dynamic lung volumes following coronavirus disease 2019 (COVID-19) in the general population. Methods A prospective matched cohort study of adult Copenhagen General Population Study (CGPS) participants with a pre-pandemic spirometry available. CGPS individuals with a positive SARS-CoV-2 polymerase chain reaction (PCR) test performed a repeat spirometry, a questionnaire regarding respiratory symptoms and a diffusing capacity test for carbon monoxide. A matched uninfected CGPS control sample was used, and simple regression and linear mixed effect models were computed to study lung function decline. Results A total of 606 were included. 92/107 (85.9%) of individuals with a positive SARS-CoV-2 PCR test experienced COVID-19 symptoms and 12 (11.2%) were hospitalized. Spirometry was performed at a median (interquartile range) of 5.6 (3.9-12.8) months after positive SARS-CoV-2 PCR test. COVID-19 was associated with an adjusted 7.3 mL (95%CI: 0.3-14.3) and 22.6 mL (95%CI: 13.1-32.0) steeper decline in annual FEV1 and FVC or a total of 113.8 and 301.3 ml lower FEV1 and FVC from baseline to follow up. Results were robust in analyses restricted to individuals not requiring hospitalization. Conclusion COVID-19 related decline of dynamic lung volumes in the general population not requiring hospitalization were small but measurable.

Autoimmune Progressive Fibrosing Interstitial Lung Disease: Predictors of Fast Decline

A subset of interstitial lung diseases (ILDs) with autoimmune traits—including connective tissue disease-associated ILD (CTD-ILD) and interstitial pneumonia with autoimmune features (IPAF)—develops progressive fibrosing (PF)-ILD. The aim of our study was to evaluate the clinical characteristics and predictors of longitudinal lung function (LF) changes in autoimmune PF-ILD patients in a real-world setting. All ILD cases with confirmed or suspected autoimmunity discussed by a multidisciplinary team (MDT) between January 2017 and June 2019 (n = 511) were reviewed, including 63 CTD-ILD and 44 IPAF patients. Detailed medical history, LF test, diffusing capacity of the lung for carbon monoxide (DLCO), 6-min walk test (6MWT), blood gas analysis (BGA), and high-resolution computer tomography (HRCT) were performed. Longitudinal follow-up for functional parameters was at least 2 years. Women were overrepresented (70.1%), and the age of the IPAF group was significantly higher as compared to the CTD-ILD group (p &lt; 0.001). Dyspnea, crackles, and weight loss were significantly more common in the IPAF group as compared to the CTD-ILD group (84.1% vs. 58.7%, p = 0.006; 72.7% vs. 49.2%, p = 0.017; 29.6% vs. 4.8%, p = 0.001). Forced vital capacity (FVC) yearly decline was more pronounced in IPAF (53.1 ± 0.3 vs. 16.7 ± 0.2 ml; p = 0.294), while the majority of patients (IPAF: 68% and CTD-ILD 82%) did not deteriorate. Factors influencing progression included malignancy as a comorbidity, anti-SS-A antibodies, and post-exercise pulse increase at 6MWT. Antifibrotic therapy was administered significantly more often in IPAF as compared to CTD-ILD patients (n = 13, 29.5% vs. n = 5, 7.9%; p = 0.007), and importantly, this treatment reduced lung function decline when compared to non-treated patients. Majority of patients improved or were stable regarding lung function, and autoimmune-associated PF-ILD was more common in patients having IPAF. Functional decline predictors were anti-SS-A antibodies and marked post-exercise pulse increase at 6MWT. Antifibrotic treatments reduced progression in progressive fibrosing CTD-ILD and IPAF, emphasizing the need for guidelines including optimal treatment start and combination therapies in this special patient group.

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

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.

The use of treatable traits to address COPD complexity and heterogeneity and to inform the care

COPD is complex and heterogeneous with respect to its aetiology, clinical presentation, phenotypes and biological mechanisms. Despite this, COPD is still diagnosed and treated according to simple clinical measures, including airflow limitation, symptoms and exacerbation frequency, leading to failure to recognise the disease's heterogeneity and/or to provide targeted interventions. COPD continues to have a very large burden of disease with suboptimal outcomes for people with the disease, including frequent hospitalisation with exacerbations, rapid lung function decline, multimorbidity and death from respiratory failure. In light of this, there have been increasing calls for a renewed taxonomy with better characterisation of COPD phenotypes and endotypes. This would allow the unravelling of COPD's complexity and heterogeneity, the implementation of targeted interventions and improved patient outcomes. The treatable traits strategy is a proposed vehicle for the implementation of precision medicine in chronic airway diseases. In this review, in addition to summarising the key knowledge on the heterogeneity of COPD, we refer to the existing evidence pertaining to the treatable traits strategy as applied in COPD and discuss implementation in different settings.