Christopher J. Ryerson’s research while affiliated with St. Paul's Hospital and other places

Background Long-term oxygen therapy (LTOT) improves survival in patients with chronic severe resting hypoxaemia, but effects on hospitalisation are unknown. This study evaluated the potential impact of starting LTOT on acute exacerbation and hospital burden in patients with chronic obstructive pulmonary disease (COPD), interstitial lung disease (ILD) and pulmonary hypertension (PH). Methods Longitudinal analysis of consecutive patients in the population-based Swedish DISCOVERY cohort who started LTOT between 2000 and 2018 with a follow-up duration≥3 months. Total and hospitalised acute exacerbations of the underlying disease, all-cause hospitalisations, and all-cause outpatient visits were annualised and compared between the year before and after LTOT initiation for each disease cohort, and by hypercapnic status in patients with COPD. Results Patients with COPD (n=10 134) had significant reduction in annualised rates of total and hospitalised acute exacerbations, as well as all-cause hospitalisations, following LTOT initiation, with increment in those with ILD (n=2507) and PH (n=850). All-cause outpatient visits increased across all cohorts following LTOT initiation. Similar findings were observed in patients with hypercapnic and non-hypercapnic COPD. Sensitivity analyses of patients with 12 months of follow-up showed reduced acute exacerbations and all-cause hospitalisations in the ILD and PH cohorts. Conclusion LTOT is associated with reduced rates of both total and hospitalised acute exacerbations and all-cause hospitalisations in patients with COPD, as well as patients with ILD and PH with 12 months of follow-up. There is increased all-cause outpatient visits in all disease groups following LTOT initiation.

Background Comorbidities can affect drug tolerability and health outcomes in patients with fibrotic interstitial lung disease. This systematic review and meta-analysis evaluated the types and prevalence of comorbidities amongst participants in pharmaceutical randomised controlled trials (RCTs) of idiopathic pulmonary fibrosis (IPF) and progressive pulmonary fibrosis (PPF). Methods Ovid Medline, Embase and CENTRAL databases were searched to identify phase II and III pharmaceutical RCTs of IPF or PPF. Reporting of comorbidities was evaluated, with meta-analyses being performed for the prevalence of different conditions. Results 34 articles were included, with 23 unique trials for IPF and one for PPF. A mean of 14 (range 1–44) comorbidities per study was reported in the IPF RCTs, with 11 being reported in the PPF RCT. Common comorbidities in the IPF RCT cohorts were systemic hypertension (pooled prevalence 45%, 95% CI 39–50%), hyperlipidaemia (38%, 95% CI 27–49%), gastro-oesophageal reflux disease (45%, 95% CI 36–54%), ischaemic heart disease (18%, 95% CI 13–42%) and diabetes mellitus (16%, 95% CI 13–20%). The PPF trial cohort had similar types and prevalence of comorbidities to those reported in the IPF trial cohorts. Conclusions Reporting of comorbidities varied across previous IPF RCTs, with limited data available for PPF. Prevalence of comorbidities reported in the IPF and PPF trial cohorts appear to be lower than those reported in prospective patient registries. There is a need for careful consideration of trial eligibility criteria with detailed reporting of comorbidities in future pharmaceutical RCTs to better understand the applicability of trial findings to real-world patients.

Background Advances in the field of genetics of interstitial lung diseases (ILDs) have led to the recent consensus statements made by expert groups. International standards for genetic testing in ILD have not yet been established. We aimed to examine current real-world strategies employed by pulmonologists working with familial ILD. Methods A panel of pulmonologists with expertise in ILD developed an international survey aimed at clinicians working with ILD. The survey consisted of 74 questions divided into eight topics: characteristics of respondents, diagnosis, screening of first-degree relatives, screening tools, genetic testing methods, lung transplantation, ethical concerns, and future needs. Results Overall, 237 pulmonologists from 50 countries participated. A family history of ILD was asked for by 91% of respondents while fewer asked for symptoms related to telomere disorders. Respondents stated that 59% had access to genetic testing, and 30% to a genetic multidisciplinary team (MDT). Many respondents were unaware of specific genetic testing methods. Pathogenic genetic variants were seen as a potential contraindication for lung transplantation in 6–8% of respondents. Genetic screening of relatives was supported by 80% of respondents who indicated insufficient evidence and a lack of formal guidelines for genetics and ILD. Only 16% had a standardized program. Conclusion Most pulmonologists ask for a family history of ILD and recommend genetic testing for ILD and screening in relatives but have limited knowledge of specific tests and access to genetic MDT. Evidence-based guidelines to inform patients, relatives, and physicians are still warranted.

Extent of fibrosis, defined by the amount of honeycombing and traction bronchiectasis, was consistently associated with death or lung transplant across all interstitial lung disease subtypes in a dose-dependent fashion.

Background The role of epigenetic aging in the environmental pathogenesis and prognosis of fibrotic interstitial lung disease (fILD) is unclear. We evaluated whether ambient particulate matter ≤2.5 μm (PM 2.5 ) and neighbourhood disadvantage exposures are associated with accelerated epigenetic aging, and whether epigenetic age is associated with adverse clinical outcomes in patients with fILD. Methods This multicentre, international, cohort study included patients with fILD from the University of Pittsburgh (UPitt, n=306) and University of British Columbia (UBC, n=170). Five-year PM 2.5 exposures were estimated using satellite-derived models. Neighbourhood disadvantage was calculated using U.S. and Canadian Census-based metrics. Epigenetic age difference (EAD=epigenetic age – chronological age) was calculated using GrimAge analysis of blood DNA methylation data. Linear models assessed associations of exposures with EAD. Cox models assessed associations of EAD with transplant-free survival. Causal mediation analysis evaluated EAD mediation of exposure-survival relationships. Results Median epigenetic age was 11.7 years older than chronological age in patients with fILD. In combined cohort analysis, each interquartile range (IQR) PM 2.5 increase was associated with 2.88 years (95%CI 1.39–4.38, p<0.001) increased EAD. In UPitt, each IQR neighbourhood disadvantage increase was associated with 1.16 years (95%CI 0.22–2.09, p=0.02) increased EAD. Increased EAD was associated with worse transplant-free survival (HR=1.17 per 1-year increase EAD, 95%CI 1.10–1.24, p<0.001), with EAD mediating 40% of PM 2.5 -survival relationship and 59% of neighbourhood disadvantage-survival relationships. Epigenetic age was also more strongly associated with transplant-free survival than chronological age. Conclusions Epigenetic age acceleration is associated with worse survival and mediates adverse exposure impacts in fILD.

Introduction Persistent lung abnormalities following COVID-19 infection are common. Similar parenchymal changes are observed in idiopathic pulmonary fibrosis (IPF). We investigated whether common genetic risk factors in IPF are associated with developing lung parenchymal abnormalities following severe COVID-19 disease. Methods Consecutive adults hospitalised for laboratory-confirmed COVID-19 infection were prospectively recruited from March to May 2020. Three single-nucleotide polymorphisms (SNPs) conferring risk for IPF were genotyped ( MUC5B rs35705950 , ATP11A rs1278769 and DPP9 rs12610495). High-resolution CT and pulmonary function tests were performed at 3 months postdischarge from hospital. Ground glass opacities and reticulation on imaging were visually quantified by two expert thoracic radiologists. Linear regression was used to evaluate the association between risk alleles at each of the three SNPs and (a) lung parenchymal abnormalities as well as (b) pulmonary function, adjusted for age, sex, smoking history and days spent on supplemental oxygen during acute illness. Results 71 patients were included. Mean age was 63±16 years, 62% were male, 31% were ever-smokers and median hospital length of stay was 9±11 days, with 23% requiring mechanical ventilation. The MUC5B risk allele was associated with a significant decrease in ground glass (β=−0.8, 95% CI −1.5 to –0.1, p=0.02) at 3 months, and this finding was paralleled by a concurrent but non-significant trend towards increased diffusion capacity for carbon monoxide (DLCO) (β=8.8, 95% CI −1.2 to 18.8, p=0.08) compared with patients without this risk allele. None of the risk alleles were significantly associated with reticulation at 3 months. Conclusion In an adjusted analysis controlling for severity of infection, MUC5B was associated with reduced ground glass and a trend towards concordant higher DLCO at 3 months after severe COVID-19 illness. This hypothesis-generating result suggests a possible protective effect of MUC5B in postinfectious lung abnormalities as compared with fibrosis in IPF, highlighting a plausible trade-off between its role in immune defence and epithelial cell function.

Fibrotic interstitial lung diseases (ILDs) result from excessive deposition of extracellular matrix (ECM) proteins in the lung, causing irreversible damage to the lung architecture. Clinical management of ILDs differs depending on the diagnosis, but differentiation between subtypes can be difficult and better clinical biomarkers are needed. In this study, we use a 166-gene NanoString assay to investigate whether there are ILD subtype-specific transcripts in whole blood. We identified one transcript, killer cell lectin like receptor 1 (KLRF1), as differentially expressed between idiopathic pulmonary fibrosis (IPF) and systemic sclerosis-associated ILD (SSc-ILD), and identified two transcripts (VCAN, LTK) associated with IPF expression against other ILD subtypes. These findings were validated by examining their expression in ILD lung, with KLRF1 expression significantly higher in SSc-ILD compared to IPF and hypersensitivity pneumonitis (HP) samples. Taken together, this pilot study provides support for the use of the peripheral transcriptome in identifying diagnostic biomarkers of ILD with biological relevance.

Objective Gene expression (transcriptomics) studies have revealed potential mechanisms of interstitial lung disease (ILD), yet sample sizes of studies are often limited and between-subtype comparisons are scarce. The aim of this study was to identify and validate consensus transcriptomic signatures of ILD subtypes. Methods We performed a systematic review and meta-analysis of fibrotic ILD transcriptomics studies using an individual participant data approach, and included studies examining bulk transcriptomics of human adult ILD samples and excluding those focusing on individual cell populations. Patient-level data and expression matrices were extracted from 43 studies and integrated using a multivariable integrative algorithm to develop ILD classification models. Results Using 1459 samples from 24 studies, we identified transcriptomic signatures for idiopathic pulmonary fibrosis (IPF), hypersensitivity pneumonitis (HP), idiopathic nonspecific interstitial pneumonia (NSIP), and systemic sclerosis-associated ILD (SSc-ILD) against control samples, which were validated on 308 samples from 8 studies (area under receiver operating curve [AUC]=0.99 [95% CI: 0.99–1.00], HP AUC=0.91 [0.84–0.99], NSIP AUC=0.94 [0.88–0.99], SSc-ILD AUC=0.98 [0.93–1.00]). Significantly, meta-analysis allowed, for the first time, identification of robust lung transcriptomics signatures to discriminate IPF (AUC=0.71 [0.63–0.79]) and HP (AUC=0.76 [0.63–0.89]) from other fibrotic ILDs, and unsupervised learning algorithms identified putative molecular endotypes of ILD associated with decreased forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (D LCO ) % predicted. Transcriptomics signatures were reflective of both cell-specific and disease-specific changes in gene expression. Conclusion We present the first systematic review and largest meta-analysis of fibrotic ILD transcriptomics to date, identifying reproducible transcriptomic signatures with clinical relevance.