Interstitial lung disease incidence and mortality in the United Kingdom and the European Union: an observational study, 2001-2017

Objective: To compare the trends in age-standardised incidence and mortality from interstitial lung diseases (ILD) in the United Kingdom (UK) and the European Union (EU). Design: Observational study using data obtained from the Global Burden of Disease Study. Setting and Participants: Residents of the UK and of the twenty-seven EU countries. Main outcome measures: ILD age-standardised incidence rates per 100 000 (ASIR), age-standardised death rates per 100 000 (ASDR), and mortality-to-incidence ratio (MIRs) are presented for males and females separately for each country, for the years 2001–2017. Trends were analysed using Joinpoint regression analysis. Results: For men, in 2017, the median incidence of ILD was 7.22 (IQR 5.57–8.96) per 100 000 population. For women, in 2017, the median incidence of ILD was 4.34 (IQR 3.36–6.29) per 100 000 population. For men, in 2017, the median ASDR attributed to ILD was 2.04 (IQR 1.13–2.71) per 100 000 population. For women, the median ASDR in 2017 for ILD was 1.02 (0.68–1.37) per 100 000 population. There was an overall increase in ASDR during the observation period with a median change of +20.42% (IQR 5.44–31.40) for men and an increase of +15.44% (IQR −1.01–31.52) for women. Despite increases in mortality over the entire observation period, there were decreasing mortality trends in the majority of countries at the end of the observation period (75% for men and 86% for women). Conclusion: Over the past two decades, there have been increases in the incidence and mortality of interstitial lung diseases in Europe. The most recent trends, however, demonstrate decreases in mortality from ILD in the majority of European countries for both men and women. These data support the ongoing improvements in the diagnosis and management of ILD

Maternal personality traits, antenatal depressive symptoms and the postpartum mother-infant relationship: a prospective observational study

PURPOSE: Maternal depression has been associated with bonding difficulties and lower maternal sensitivity in observed mother-infant interactions. However, little research has examined the impact of disordered personality traits in mothers on these outcomes. We investigated the association between disordered personality traits in mothers measured during pregnancy and postnatal (a) self-reported bonding with infant; (b) observational mother-infant interactions. // METHODS: Five hundred fifty-six women were recruited during early pregnancy and subsequently followed up at mid-pregnancy (approximately 28 weeks' gestation) and when infants were aged approximately 3 months (n = 459). During early pregnancy, data were collected on disordered personality traits (using the Standardised Assessment of Personality Abbreviated Scale) and depressive symptoms (using the Edinburgh Postnatal Depression Scale). At 3 months postpartum, self-reported perceived bonding (using the Postpartum Bonding Questionnaire) were collected. A sub-sample of women additionally provided observational mother-infant interaction data (n = 206) (coded using the Child-Adult Relationship Experimental Index). // RESULTS: Higher disordered personality traits was not associated with maternal perceptions of bonding impairment, but was associated with reduced maternal sensitivity during observational mother-infant interactions [adjusted for age, education, having older children, substance misuse prior to pregnancy, infant sex and gestational age: coefficient = - 0.28, 95% CI = - 0.56 to - 0.00, p < 0.05]. After adjusting for depressive symptoms, the association was attenuated [coefficient = - 0.19, 95% CI = - 0.48 to 0.11, p = 0.217]. // CONCLUSIONS: Mothers with disordered personality traits did not perceive themselves as having bonding impairments with their infants but were less sensitive during observed interactions, though depressive symptoms attenuated this relationship. Both depression and disordered personality traits need to be addressed to optimize mother-infant interactions

A Pilot Programme to Facilitate the Use of Mental Health Treatment Requirements: Professional Stakeholders' Experiences

Mental Health Treatment Requirements (MHTRs) have been available in England and Wales since 2005 but are rarely used, despite high rates of mental health problems amongst offenders. In 2018, a new protocol to facilitate the use of MHTRs was piloted in five sites in England. Aims: Understanding the experiences of professional stakeholders and identify barriers to use MHTRs. Methods: Semi-structured qualitative interviews were conducted with thirty-eight professional stakeholders and thematic analysis applied. Results: Interviewees were positive about the content and implementation of the new protocol. Interviewees described key benefits as increasing options in community sentencing, addressing a gap in service provision and facilitating offenders’ access to other services. Challenges described, included multi-agency working, sustainability of funding and the range and complexity of needs of offenders receiving MHTRs and the variation in their motivation to engage. Success factors described were having a strong steering group, staff dedicated to the project and being able to provide a broad range of support to meet offender needs. Conclusion: The MHTR pilot protocol was generally well-received and appeared to address previous barriers to the use of MHTRs. Future work is needed to evaluate the effectiveness of MHTRs and the experience of offenders who receive them

Wearable in-ear PPG: detailed respiratory variations enable classification of COPD

An ability to extract detailed spirometry-like breath-ing waveforms from wearable sensors promises to greatly improve respiratory health monitoring. Photoplethysmography (PPG) has been researched in depth for estimation of respiration rate, given that it varies with respiration through overall intensity, pulse amplitude and pulse interval. We compare and contrast the extraction of these three respiratory modes from both the ear canal and finger and show a marked improvement in the respiratory power for respiration induced intensity variations and pulse amplitude variations when recording from the ear canal. We next employ a data driven multi-scale method, noise assisted multivariate empirical mode decomposition (NA-MEMD), which allows for simultaneous analysis of all three respiratory modes to extract detailed respiratory waveforms from in-ear PPG. For rigour, we considered in-ear PPG recordings from healthy subjects, both older and young, patients with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) and healthy subjects with artificially obstructed breathing. Specific in-ear PPG waveform changes are observed for COPD, such as a decreased inspiratory duty cycle and an increased inspiratory magnitude, when compared with expiratory magnitude. These differences are used to classify COPD from healthy and IPF waveforms with a sensitivity of 87% and an overall accuracy of 92%. Our findings indicate the promise of in-ear PPG for COPD screening and unobtrusive respiratory monitoring in ambulatory scenarios and in consumer wearables

Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

The transferrin receptor CD71 delineates functionally distinct airway macrophage subsets during idiopathic pulmonary fibrosis

RATIONALE: Idiopathic pulmonary fibrosis (IPF) is a devastating progressive disease with limited therapeutic options. Airway macrophages (AMs) are key components of the defence of the airways and are implicated in the pathogenesis of IPF. Alterations in iron metabolism have been described during fibrotic lung disease and in murine models of lung fibrosis. However, the role of transferrin receptor-1 (CD71)-expressing AMs in IPF is not known. OBJECTIVES: To assess the role of CD71 expressing AMs in the IPF-lung. METHODS: We utilized multi-parameter flow cytometry, gene expression analysis and phagocytosis/transferrin uptake assays to delineate the role of AMs expressing, or lacking, CD71 in the BAL of patients with IPF or healthy controls. MEASUREMENTS AND MAIN RESULTS: There was a distinct increase in proportions of AMs lacking CD71 in IPF patients in comparison to healthy controls. Levels of BAL transferrin were enhanced in IPF-BAL and furthermore, CD71- AMs had an impaired ability to sequester transferrin. CD71+ and CD71- AMs were phenotypically, functionally and transcriptionally distinct, with CD71- AMs characterised by reduced expression of markers of macrophage maturity, impaired phagocytosis and enhanced expression of pro-fibrotic genes. Importantly, proportions of AMs lacking CD71 were independently associated with worse survival, underlining the importance of this population in IPF and as a potential therapeutic target. CONCLUSIONS: Taken together these data highlight how CD71 delineates AM subsets which play distinct roles in IPF and furthermore, CD71- AMs may be an important pathogenic component of fibrotic lung disease

Modelling forced vital capacity in idiopathic pulmonary fibrosis: optimising trial design.

INTRODUCTION: Forced vital capacity is the only registrational endpoint in idiopathic pulmonary fibrosis clinical trials. As most new treatments will be administered on top of standard of care, estimating treatment response will become more challenging. We developed a simulation model to quantify variability associated with forced vital capacity decline. METHODS: The model is based on publicly available clinical trial summary and home spirometry data. A single, illustrative trial setting is reported. Model assumptions are 400 subjects randomised 1:1 to investigational drug or placebo over 52 weeks, 50% of each group receiving standard of care (all-comer population), and a 90-mL treatment difference in annual forced vital capacity decline. Longitudinal profiles were simulated and the impact of varying clinical scenarios evaluated. RESULTS: Power to detect a significant treatment difference was 87-97%, depending on the analysis method. Repeated measures analysis generally outperformed analysis of covariance and mixed linear models, particularly with missing data (as simulated data were non-linear). A 15% yearly random dropout rate led to 0.6-5% power loss. Forced vital capacity decline-related dropout introduced greater power loss (up to 12%), as did subjects starting/stopping standard of care or investigational drug. Power was substantially lower for a 26-week trial due to the smaller assumed treatment effect at week 26 (sample size would need doubling to reach a power similar to that of a 52-week trial). CONCLUSIONS: Our model quantifies forced vital capacity decline and associated variability, with all the caveats of background therapy, permitting robust power calculations to inform future idiopathic pulmonary fibrosis clinical trial design. FUNDING: Galapagos NV (Mechelen, Belgium)

DNA Methylome Alterations are Associated with Airway Macrophage Differentiation and Phenotype During Lung Fibrosis

RATIONALE: Airway macrophages (AMs) are key regulators of the lung environment and are implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a fatal respiratory disease with no cure. However, knowledge of epigenetics of AMs in IPF are limited. METHODS: We undertook DNA methylation profiling using Illumina EPIC (850k) arrays in sorted AMs from Healthy (n=14) and IPF (n=30) donors. Cell-type deconvolution was performed using reference myeloid-cell DNA methylomes. MEASUREMENTS AND MAIN RESULTS: Our analysis revealed epigenetic heterogeneity was a key characteristic of IPF-AMs. DNAm 'clock' analysis indicated epigenetic alterations in IPF-AMs was not associated with accelerated ageing. In differential DNAm analysis, we identified numerous differentially methylated positions (DMPs, n=11) and regions (DMRs, n=49) between healthy and IPF AMs respectively. DMPs and DMRs encompassed genes involved in lipid (LPCAT1) and glucose (PFKFB3) metabolism and importantly, DNAm status was associated with disease severity in IPF. CONCLUSIONS: Collectively, our data identify that changes in the epigenome are associated with development and function of AMs in the IPF lung

Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: a prospective cohort study.

BACKGROUND AND OBJECTIVE: Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome. METHODS: In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event. RESULTS: 4MGS declined over 6 months (mean [95% CI] change: -0.05 [-0.09 to -0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan-Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >-0.07 m/s versus minor decline/improvers: ≤-0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23-15.83]). Similar results were observed in multiple imputation analysis. CONCLUSION: In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death