Chris J. Scotton

Objective: To understand how prevalence estimates of single and multiple organ fibrosis have changed from 2012 to 2022. Design: Retrospective population-based cohort study. Setting: Data from primary (Clinical Practice Research Datalink Aurum) and secondary care (Hospital Episode Statistics Admitted Patient Care) electronic health records were used to conduct this study. Participants: Adults aged 18 years and older whose primary and secondary care records were available for research. Main outcome measure: Fibrotic conditions previously determined from a Delphi survey of clinicians; diagnoses were found in either primary or secondary care records. The primary analysis estimated the prevalence of both single and multiple organ fibrosis. A secondary analysis used Cox proportional hazards models to investigate the association between the time-updated number of fibrotic conditions and risk of death, adjusting for age and sex. Results: The cohort consisted of 5 839 459 people with at least one fibrotic condition and a denominator of 18 784 962 people. Over the study period, prevalence of fibrotic conditions increased by 6.72%, and as of 2022, 19.95% (95% CI 19.92% to 19.98%) of adults had at least one fibrotic condition. The prevalence of multiple organ fibrosis increased from 4.78% (95% CI 4.76% to 4.79%) in 2012 to 8.51% (95% CI 8.50% to 8.53%) in 2022. In the year preceding diagnosis of single organ fibrosis, the median number of primary care consultations was 14 compared with 21 consultations for people with multiple organ fibrosis. Compared with people with single organ fibrosis, people with two fibrotic conditions had a mortality HR of 2.90 (95% CI 2.87 to 2.93), while people with three fibrotic conditions had a mortality HR of 5.22 (95% CI 5.14 to 5.30). Conclusions: The prevalence of single and multiple organ fibrosis has substantially increased over a decade. People with multiple organ fibrosis access healthcare more than people with single organ fibrosis and are at a greater risk of mortality. Multiple organ fibrosis is estimated to affect more than 3 million people in the UK and is increasing. Better understanding of patterns of fibrotic multimorbidity may help to aid earlier diagnosis and opportunities for reducing mortality.

Background: Fibrotic interstitial lung disease (F-ILD) has high mortality. Evidence suggests short telomere causality and sex hormone interactions. STARSHIP aimed to assess feasibility for future F-ILD sex hormone trials. Methods: Leukocyte telomere length (LTL), complete blood count, sex hormone (testosterone and oestrogen), sex hormone binding globulin (SHBG) and albumin concentrations were determined in 102 F-ILD outpatients (age 49-89, male N=80 [78%]) and age/sex-matched controls (ASMCs). Patients undertook routine pulmonary function tests, 93 (91%) participated in bespoke telephone interviews. Survival was assessed at median 33 (28-39) months. Results: 77/79 (97.4%) male patients had haemoglobin and haematocrit below the upper reference limit. Mean LTL was shorter for patients than ASMCs (4.57kb [95%CI:4.46-4.69] vs 4.78kb [95%CI:4.67-4.89]; pβ =3.31, p=2.4×10 ^-4 ) and FVC% ( β =2.76, p=0.0030). FVC% associated with FAI in females ( β =34.3, p=0.0029). In all-confounder-adjusted Cox analysis, low free testosterone associated with mortality (HR=2.66, p=0.023, N=77) in male patients. Lower FAI (adjusted for age/lung function) suggested similar effects but more studies needed for females (HR=3.59, p=0.22, N=18). Conclusions: ILD patients have low sex hormones concentration(s), which associated with reduced lung function and survival. Sex hormone supplementation studies are needed. Key messages: Using population data, we have previously shown a three-way association between short telomeres, low sex hormones and higher pulmonary fibrosis (PF) prevalence. However, no clinical data on sex hormone concentrations for PF patients and links with lung function and survival have been reported. Here we show, in a prospective clinical study, that male and female patients presenting to the interstitial lung disease clinic with PF have lower sex hormone concentrations than age- and sex-matched controls, which is associated with worse lung function and reduced survival. The findings highlight the need to explore potential benefits of hormone supplementation in PF.

Introduction: Hospitalisation for respiratory-related events is an important contributor to morbidity and mortality in individuals with fibrotic interstitial lung disease (fILD). Many such hospitalisations are due to acute exacerbations (AE-fILD), but AEs are poorly understood and there are limited evidence-based guidelines for their management. Most research in this area focuses on AEs of idiopathic pulmonary fibrosis (IPF), the commonest fILD and AEs of non-IPF fILD are less well studied. Furthermore, patients with fILD who are hospitalised with a respiratory-related event but do not meet the diagnostic criteria for AE are an important under-studied group. The INterstitial lung Disease EXacerbations (INDEX) study will describe in detail a large real-world population with fILD admitted to hospital for respiratory-related causes, including AE-fILD, as well as identify potential prognostic factors. Methods and analysis: This multicentre retrospective cohort study will analyse case notes for patients admitted to hospital between 1 September 2022 and 31 August 2023. Patient demographic data, clinical features on hospital admission, pre and postadmission investigation results, treatment approaches taken and mortality data will be collected. These data will be used to describe the patient population and to identify associations between patient, clinical presentation and treatment factors and outcomes. The primary outcome will be transplant-free survival at 90 days following the commencement of the index admission. Ethics and dissemination: The study has been approved by the Health Research Authority (HRA) (IRAS 317419) and has been prospectively registered on clinicaltrials.gov ( NCT06685874 ). The HRA waivered the requirement for Research Ethics Committee approval due to only anonymised routinely collected clinical data being collected. Conclusion: This study will enhance our understanding of respiratory-related hospital admissions in fILD, including AE-fILD. The resulting data will describe a real-world patient population, define current standard care and may indicate prognostic and treatment factors to be assessed in future clinical trials.

Summary: Background: Idiopathic pulmonary fibrosis (IPF) and telomere length (TL) are both strongly linked to rare and common genetic variation. Shortened TL itself may be causal for IPF. Whether rare and common variants compete or cooperate to confer genetic risk of IPF uniformly is unknown. Methods: We used whole genome sequencing (WGS) data from a discovery case-control cohort sequenced at Columbia (777 IPF, 2905 controls) and validated findings using WGS data from Trans-Omics for Precision Medicine (TOPMed, 1148 IPF, 5202 controls) and the UK Biobank (UKBB, 2739 IPF, 395331 controls). In all cohorts, we identified rare damaging variants in disease-associated genes and computed control-normalized polygenic risk scores for IPF (IPF-PRS) and telomere length (TL-PRS). Telomere length of blood leukocytes was measured using a qPCR assay for two cohorts. We determined the association of the MUC5B rs35705950 polymorphism, an IPF-PRS excluding MUC5B (IPF-PRS-no MUC5B ), and a TL-PRS with IPF risk in the overall cohort and in subgroups stratified by genetic endotypes (rare variant carriers, non-carriers stratified by TL cutoffs). We calculated cross-validated area under the receiver operator curve (AUC) and compared the liability of IPF explained by genetic variables. Findings: We identified independent associations between IPF risk and rare variants, the MUC5B SNP, and both polygenic scores in the discovery cohort and replicated these findings in the TOPMed and UKBB cohorts. The adjusted effect size of the TL-PRS, which includes >180 SNPs not previously associated with IPF, was comparable to the IPF-PRS-no MUC5B in the discovery (ORTL-PRS 1.63 [95% CI 1.47, 1.81] vs. ORIPF-PRS 1.60 [1.44, 1.77]) and replication cohorts (TOPMed ORTL-PRS 1.47 [1.36, 1.59] vs. ORIPF-PRS 1.37 [1.25, 1.50]; UKBB ORTL-PRS 1.24 [1.19, 1.29] vs. ORIPF-PRS 1.25 [1.21, 1.30]). The TL-PRS incrementally improved disease prediction beyond known IPF common and rare genetic predictors and clinical variables in discovery (combined AUC: 0.89, pDelong = 0.006), TOPMed (combined AUC: 0.89, pDelong = 0.01), and UKBB cohorts (combined AUC: 0.77, pDelong = 0.03). Rare and common variants jointly contributed to genetic liability of IPF. The TL-PRS increased liability of IPF explained by 13% in the discovery cohort and 8% and 13% in the TOPMed and UKBB cohorts, respectively. In IPF subjects with damaging rare variants, the TL-PRS was consistently associated with disease risk whereas the IPF-PRS-no MUC5B was not. The TL-PRS also conferred nominally greater odds of disease risk than the IPF-PRS-no MUC5B in patients with shorter TL, in the discovery and UKBB cohorts. Together, 23-43% of IPF cases have damaging rare variants or telomeres 180 genetic loci not previously associated with IPF, increases the risk of disease specifically in certain IPF endotypes. Polygenic risk from telomere-associated common variants is a key feature of IPF genetic heterogeneity. Funding: National Institutes of Health (NIH), Medical Research Council (MRC), National Institute for Health and Care Research (NIHR) Research in context: Evidence before this study: We performed a search on PubMed for “common variants”, “rare variants”, “polygenic score”, “endotype”, and “IPF” on April 20 ^th , 2025, to identify integrated genetic studies of rare and common variants in IPF. We found no original articles that comprehensively examined common and rare IPF variants together. Nearly all articles analyzed common or rare variants in isolation; one article included both common and rare variant analyses but reported results separately without studying their combined effects. We identified numerous reviews that discuss or conceptualize the relative contributions of rare and common genetic risk to IPF risk; no studies provided or cited empiric data. Although “IPF endotypes” have been defined using transcriptomics and proteomics, we did not find any articles that utilized this terminology based on genetic factors, although several studies distinguish IPF with rare variants or telomere length below 10 ^th percentile. Added value of this study: We describe the first comprehensive survey of common and rare risk variants together in IPF and identify subtype-specific genetic risk factors that substantially improve genetic explanation and disease prediction. We uncover complex relationships between polygenic factors and rare variants, including preliminary evidence of polygenic modifiers in IPF carriers of rare damaging variants that might serve as an explanation for incomplete penetrance. Genetic studies in IPF have been limited by sample size leading to “missing heritability”. We demonstrate value in leveraging large-scale genetic studies of causal molecular traits like telomere length to overcome these limitations and improve genetic understanding of IPF. These telomere-associated common variants are context-specific risk factors in certain endotypes, highlighting previously unrecognized genetic heterogeneity that will be important for future discovery of novel, reproducible genetic risk factors in IPF. Implications of all the available evidence: A genetic basis for disease heterogeneity allows for research that focuses on relevant endotypes instead of “all-comer” disease and advances precision medicine approaches to IPF. Polygenic factors that can modify the effects of a high-risk rare variant represent a target for understanding disease-modifying pathways in IPF.

Background: The unpredictable trajectory and heterogeneity of interstitial lung disease (ILDs) make prognostication challenging. Current prognostic indices and outcome measures have several limitations. Quantitative computed tomography (qCT) provides automated numerical assessment of CT imaging and has shown promise when applied to the prognostication and disease monitoring of ILD. This systematic review aims to highlight the current evidence underpinning the prognostic value of qCT in predicting outcomes in ILD.Methods: A comprehensive search of four databases (Medline, EMCare, Embase and CINAHL (Cumulative Index to Nursing and Allied Health Literature)) was conducted for studies published up to and including 22 November 2024. A modified CHARMS (CHecklist for critical Appraisal and data extraction for systematic Reviews of prediction Modelling Studies) checklist was used for data extraction. The risk of bias was assessed using a Quality in Prognostic Studies template.Results: The search identified 1134 unique studies, of which 185 studies met inclusion and exclusion criteria. Commonly studied ILD subtypes included idiopathic pulmonary fibrosis (41%, n=75), mixed subtypes (26%, n=48) and systemic sclerosis ILD (16%, n=30). Numerous studies showed significant prognostic signals, even when adjusted for common covariates and/or significant correlation between serial qCT biomarkers and conventional outcome measures. Heterogenous and nonstandardised reporting methods meant that direct comparison or meta-analysis of studies was not possible. Studies were limited by the use of retrospective methodology without prospective validation and significant study attrition.Discussion: qCT has shown efficacy in the prognostication and disease monitoring of a range of ILDs. Hurdles exist to widespread adoption including governance concerns, appropriate algorithm anchoring and standardisation of image acquisition. International collaboration is underway to address these hurdles, paving the way for regulatory approval and ultimately patient benefit.

Objective: Patient reported experience measures (PREMs) are a key component of healthcare accountability frameworks, health policy, integrated care board (ICB) commissioning and integrated care partnerships (ICPs) generating data which are crucial markers of patient care quality. The Rheumatoid Arthritis Patient Reported Experience Measure (RA-PREM) incorporates the eight core elements of NHS Patient Experience Framework and is validated in a range of rheumatic conditions. Our objective is to determine the acceptability and feasibility of the RA-PREM for an ILD population. Design: A mixed-methods patient-centred approach incorporating an interdisciplinary research steering group with patient-partners. Patient surveys evaluated the language and meaning of the RA-PREM eight domains, twenty-four statements and response categories. A patient focus group examined contentious statements. A consensus group of expert patient-partners agreed statements for the modified RA-PREM. Focus group participants reviewed the modified instrument (ILD-PREM) for acceptability and face/content validity. Setting: A single NHSE-commissioned, regional ILD service/UK. Results: Thirteen patients (10 male) diagnosed with ILD participated in focus group discussions. Critical discussion of the RA-PREM resulted in nuanced modifications of four statements of three domains. Five patients (3 male) and three healthcare researchers attained consensus on the face/content validity of statements. Seventy-three patients completed the ILD-PREM following outpatient contact. Conclusion: The ILD-PREM retains twenty-four statements representing the eight domains of the RA-PREM. It meets face/content validity criteria and is acceptable to an ILD population. Longitudinal validation of the ILD-PREM across ILD services including further testing in global minority groups will establish criterion and construct validity and objective measures of reliability. Key Messages: What is already known on this topic Patient experience metrics are a key component of healthcare quality frameworks. Better patient experience is associated with better quality of care, higher treatment adherence and improved patient outcomes. What this study adds The RA-PREM has been adapted for use within ILD, using patient-centred methods. The ILD-PREM retains twenty-four statements capturing level of agreement which map to the eight indicators of the NHS Patient Experience Framework. The ILD-PREM has face/content validity and clinical utility for an ILD population. How this study might affect research, practice, or policy This is the first disease-specific PREM for ILD enabling data collection for service evaluation and improvement. It is judicious to modify validated measures to obviate the need for resource intensive development of a new instruments where possible.

Platelets are a rich source of profibrotic TGFβ; however, the role of platelets in idiopathic pulmonary fibrosis (IPF) is unclear. We identified that patients with IPF have significantly more platelets, neutrophils, and active TGFβ in their airways than control patients. Using an animal model of IPF, we demonstrated that platelet-derived TGFβ does not significantly drive lung fibrosis or inflammation. Our findings offer a better understanding of platelets in both human and animal studies of IPF.

Background: Idiopathic pulmonary fibrosis (IPF) is a progressive and incurable disease requiring novel therapeutics. High baseline monocyte count associates with increased risk of progression and mortality in IPF. Perturbations in monocyte phenotype and mitochondrial function, IL6 production, ACOD1 gene expression and metabolism have been observed in IPF patients. IPF patients also have reduced biosynthetic capacity for the immunomodulatory gas hydrogen sulfide (H2S) - an endogenous regulator of mitochondrial function and inflammation. However, the impact of H2S modulation in monocytes is unknown. Aims: Investigate the anti-fibrotic and anti-inflammatory effects of mitochondrial-targeted H2S donor compounds (mtH2SD) in human monocytes. Methods: Longitudinal monocyte counts were investigated in a retrospective IPF cohort (n=131). Fresh monocytes were isolated from healthy donors (n=11), stimulated with IFNγ/TNFα (20ng/ml) +/- mtH2SD (100nM) for 24 hours prior to multispectral flow cytometry, Seahorse metabolic assays, ELISA, qPCR analysis. Results: Rising monocyte count (>0.01 K/µL/month) was associated with worse survival (p=0.04). In vitro mtH2SD treatment of stimulated monocytes resulted in reduced pro-fibrotic marker levels (CD206 and CD163; p<0.05), more energetic and glycolytic metabolism, augmentation of anti-fibrotic ACOD1 expression, decreased IL-6 production and gene expression (p<0.01). Conclusions: Monocytic functionality is implicated in IPF pathogenesis. Modulation of phenotype and metabolism, pro-fibrotic and pro-inflammatory gene expression by mtH2SD may have therapeutic potential. Future work will recapitulate these data in IPF-derived monocytes.