A roadmap to precision treatments for familial pulmonary fibrosis.

Interstitial lung diseases (ILDs) in adults and children (chILD) are a heterogeneous group of lung disorders leading to inflammation, abnormal tissue repair and scarring of the lung parenchyma often resulting in respiratory failure and death. Inherited factors directly cause, or contribute significantly to the risk of developing ILD, so called familial pulmonary fibrosis (FPF), and monogenic forms may have a poor prognosis and respond poorly to current treatments. Specific, variant-targeted or precision treatments are lacking. Clinical trials of repurposed drugs, anti-fibrotic medications and specific treatments are emerging but for many patients no interventions exist. We convened an expert working group to develop an overarching framework to address the existing research gaps in basic, translational, and clinical research and identified areas for future development of preclinical models, candidate medications and innovative clinical trials. In this Position Paper, we summarise working group discussions, recommendations, and unresolved questions concerning precision treatments for FPF.

Review of codelists used to define hypertension in electronic health records and development of a codelist for research.

BACKGROUND AND AIMS: Hypertension is a leading risk factor for cardiovascular disease. Electronic health records (EHRs) are routinely collected throughout a person's care, recording all aspects of health status, including current and past conditions, prescriptions and test results. EHRs can be used for epidemiological research. However, there are nuances in the way conditions are recorded using clinical coding; it is important to understand the methods which have been applied to define exposures, covariates and outcomes to enable interpretation of study findings. This study aimed to identify codelists used to define hypertension in studies that use EHRs and generate recommended codelists to support reproducibility and consistency. ELIGIBILITY CRITERIA: Studies included populations with hypertension defined within an EHR between January 2010 and August 2023 and were systematically identified using MEDLINE and Embase. A summary of the most frequently used sources and codes is described. Due to an absence of Systematized Nomenclature of Medicine Clinical Terms (SNOMED CT) codelists in the literature, a recommended SNOMED CT codelist was developed to aid consistency and standardisation of hypertension research using EHRs. FINDINGS: 375 manuscripts met the study criteria and were eligible for inclusion, and 112 (29.9%) reported codelists. The International Classification of Diseases (ICD) was the most frequently used clinical terminology, 59 manuscripts provided ICD 9 codelists (53%) and 58 included ICD 10 codelists (52%). Informed by commonly used ICD and Read codes, usage recommendations were made. We derived SNOMED CT codelists informed by National Institute for Health and Care Excellence guidelines for hypertension management. It is recommended that these codelists be used to identify hypertension in EHRs using SNOMED CT codes. CONCLUSIONS: Less than one-third of hypertension studies using EHRs included their codelists. Transparent methodology for codelist creation is essential for replication and will aid interpretation of study findings. We created SNOMED CT codelists to support and standardise hypertension definitions in EHR studies.

Feasibility and acceptability of remotely monitoring spirometry and pulse oximetry as part of interstitial lung disease clinical care: a single arm observational study.

BACKGROUND: Remote monitoring of patient-recorded spirometry and pulse oximetry offers an alternative approach to traditional hospital-based monitoring of interstitial lung disease (ILD). Remote spirometry has been observed to reasonably reflect clinic spirometry in participants with ILD but remote monitoring has not been widely incorporated into clinical practice. We assessed the feasibility of remotely monitoring patients within a clinical ILD service. METHODS: Prospective, single-arm, open-label observational multi-centre study (NCT04850521). Inclusion criteria included ILD diagnosis, age ≥ 18 years, FVC ≥ 50% predicted. 60 participants were asked to record a single spirometry and oximetry measurement at least once daily, monitored weekly by their local clinical team. Feasibility was defined as ≥ 68% of participants with ≥ 70% adherence to study measurements and recording measurements ≥ 3 times/week throughout. RESULTS: A total of 60 participants were included in the analysis. 42/60 (70%) were male; mean age 67.8 years (± 11.2); 34/60 (56.7%) had idiopathic pulmonary fibrosis (IPF), Median ILD-GAP score was 3 (IQR 1-4.75). Spirometry adherence was achieved for ≥ 70% of study days in 46/60 participants (77%) and pulse oximetry adherence in 50/60 participants (83%). Recording ≥ 3 times/week every week was provided for spirometry in 41/60 participants (68%) and pulse oximetry in 43/60 participants (72%). Mean difference between recent clinic and baseline home spirometry was 0.31 L (± 0.72). 85.7% (IQR 63.9-92.6%) home spirometry attempts/patient were acceptable or usable according to ERS/ATS spirometry criteria. Positive correlation was observed between ILD-GAP score and adherence to spirometry and oximetry (rho 0.24 and 0.38 respectively). Adherence of weekly monitoring by clinical teams was 80.95% (IQR 64.19-95.79). All participants who responded to an experience questionnaire (n = 33) found remote measurements easy to perform and 75% wished to continue monitoring their spirometry at the conclusion of the study. CONCLUSION: Feasibility of remote monitoring within an ILD clinical service was demonstrated over 3 months for both daily home spirometry and pulse oximetry of patients. Remote monitoring may be more acceptable to participants who are older or have more advanced disease. TRIAL REGISTRATION: clinicaltrials.gov NCT04850521 registered 20th April 2021.

Rheumatoid arthritis and idiopathic pulmonary fibrosis: a bidirectional Mendelian randomisation study.

BACKGROUND: A usual interstitial pneumonia (UIP) pattern of lung injury is a key feature of idiopathic pulmonary fibrosis (IPF) and is also observed in up to 40% of individuals with rheumatoid arthritis (RA)-associated interstitial lung disease (RA-ILD). The RA-UIP phenotype could result from either a causal relationship of RA on UIP or vice versa, or from a simple co-occurrence of RA and IPF due to shared demographic, genetic or environmental risk factors. METHODS: We used two-sample bidirectional Mendelian randomisation (MR) to test the hypothesis of a causal effect of RA on UIP and of UIP on RA, using variants from genome-wide association studies (GWAS) of RA (separately for seropositive (18 019 cases and 991 604 controls) and seronegative (8515 cases and 1 015 471 controls) RA) and of IPF (4125 cases and 20 464 controls) as genetic instruments. Sensitivity analyses were conducted to assess the robustness of the results to violations of the MR assumptions. FINDINGS: IPF showed a significant causal effect on seropositive RA, with developing IPF increasing the risk of seropositive RA (OR=1.06, 95% CI: 1.04 to 1.08, p<0.001) which was robust under all models. For the MR in the other direction, seropositive RA showed a significant protective effect on IPF (OR=0.93; 95% CI: 0.87 to 0.99; p=0.032), but the effect was not significant when sensitivity analyses were applied. This was likely because of bias due to exclusion of patients with RA from among the cases in the IPF GWAS, or possibly because our genetic instruments did not fully capture the effect of the complex human leucocyte antigen region, the strongest RA genetic risk factor. INTERPRETATION: Our findings support the hypothesis that RA-UIP may be due to a cause-effect relationship between UIP and RA, rather than due to a coincidental occurrence of IPF in patients with RA. The significant causal effect of IPF on seropositive RA suggests that pathomechanisms involved in the development of UIP may promote RA, and this may help inform future guidelines on screening for ILD in patients with RA.

Adaptive multi-interventional trial platform to improve patient care for fibrotic interstitial lung diseases.

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD). METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure. RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results. CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

Mycophenolate and azathioprine efficacy in interstitial lung disease: a systematic review and meta-analysis.

OBJECTIVES: Mycophenolate mofetil (MMF) and azathioprine (AZA) are immunomodulatory treatments in interstitial lung disease (ILD). This systematic review aimed to evaluate the efficacy of MMF or AZA on pulmonary function in ILD. DESIGN: Population included any ILD diagnosis, intervention included MMF or AZA treatment, outcome was delta change from baseline in per cent predicted forced vital capacity (%FVC) and gas transfer (diffusion lung capacity of carbon monoxide, %DLco). The primary endpoint compared outcomes relative to placebo comparator, the secondary endpoint assessed outcomes in treated groups only. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and prospective observational studies were included. No language restrictions were applied. Retrospective studies and studies with high-dose concomitant steroids were excluded. DATA SYNTHESIS: The systematic search was performed on 9 May. Meta-analyses according to drug and outcome were specified with random effects, I2 evaluated heterogeneity and Grading of Recommendations, Assessment, Development and Evaluation evaluated certainty of evidence. Primary endpoint analysis was restricted to RCT design, secondary endpoint included subgroup analysis according to prospective observational or RCT design. RESULTS: A total of 2831 publications were screened, 12 were suitable for quantitative synthesis. Three MMF RCTs were included with no significant effect on the primary endpoints (%FVC 2.94, 95% CI -4.00 to 9.88, I2=79.3%; %DLco -2.03, 95% CI -4.38 to 0.32, I2=0.0%). An overall 2.03% change from baseline in %FVC (95% CI 0.65 to 3.42, I2=0.0%) was observed in MMF, and RCT subgroup summary estimated a 4.42% change from baseline in %DLCO (95% CI 2.05 to 6.79, I2=0.0%). AZA studies were limited. All estimates were considered very low certainty evidence. CONCLUSIONS: There were limited RCTs of MMF or AZA and their benefit in ILD was of very low certainty. MMF may support preservation of pulmonary function, yet confidence in the effect was weak. To support high certainty evidence, RCTs should be designed to directly assess MMF efficacy in ILD. PROSPERO REGISTRATION NUMBER: CRD42023423223.

REMOTE-ILD study: Description of the protocol for a multicentre, 12-month randomised controlled trial to assess the clinical and cost-effectiveness of remote monitoring of spirometry and pulse oximetry in patients with interstitial lung disease.

INTRODUCTION: Remote monitoring of home physiological measurements has been proposed as a solution to support patients with chronic diseases as well as facilitating virtual consultations and pandemic preparedness for the future. Daily home spirometry and pulse oximetry have been demonstrated to be safe and acceptable to patients with interstitial lung disease (ILD) but there is currently limited evidence to support its integration into clinical practice. AIM: Our aim is to understand the clinical utility of frequent remote physiological measurements in ILD and the impact of integrating these into clinical practice from a patient, clinical and health economic perspective. METHODS AND ANALYSIS: 132 patients with fibrotic ILD will be recruited and randomised to receive either usual care with remote digital monitoring of home spirometry and pulse oximetry or usual care alone for 12 months. All participants will complete health-related quality of life and experience questionnaires.The primary outcome compares the availability of spirometry measurements within the 2 weeks preceding planned clinic appointments. Secondary outcomes will explore other aspects of clinical and cost-effectiveness of the remote monitoring programme. ETHICS AND DISSEMINATION: The study has been approved by the Camden and Kings Cross Research Ethics Committee (22/LO/0309). All participants will provide informed consent.This study is registered with www. CLINICALTRIALS: gov (NCT05662124).The results of the study will be submitted for presentation at regional and national conferences and submitted for peer-reviewed publication. Reports will be prepared for study participants with the support from our public involvement representatives through the charity Action for Pulmonary Fibrosis.

Prognostic factors associated with mortality in acute exacerbations of idiopathic pulmonary fibrosis: A systematic review and meta-analysis.

BACKGROUND: Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) increases mortality risk, but which factors increase mortality is unknown. We aimed to perform a prognostic review of factors associated with mortality in patients with IPF. STUDY DESIGN: and methods: We searched MEDLINE, EMBASE, and CINAHL for studies that reported on the association between any prognostic factor and AE-IPF. We assessed risk of bias using the QUIPS tool. We conduced pairwise meta-analyses using REML heterogeneity estimator, and GRADE approach to assess the certainty of the evidence. RESULTS: We included 35 studies in our analysis. We found that long-term supplemental oxygen at baseline (aHR 2.52 [95 % CI 1.68 to 3.80]; moderate certainty) and a diagnosis of IPF compared to non-IPF ILD (aHR 2.19 [95 % CI 1.22 to 3.92]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. A diffuse pattern on high resolution computed tomography (HRCT) compared to a non-diffuse pattern (aHR 2.61 [95 % CI 1.32 to 2.90]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. We found that using corticosteroids prior to hospital admission (aHR 2.19 [95 % CI 1.26 to 3.82]; moderate certainty) and those with increased neutrophils (by % increase) in bronchoalveolar lavage (BAL) during the exacerbation is associated with a higher risk of death (aHR 1.02 [1.01 to 1.04]; moderate certainty). INTERPRETATION: Our results have implications for healthcare providers in making treatment decisions and prognosticating the clinical trajectory of patients, for researchers to design future interventions to improve patient trajectory, and for guideline developers in making decisions about resource allocation.

Systemic corticosteroids in fibrotic lung disease: a systematic review and meta-analysis.

OBJECTIVES: We aimed to assess the available evidence for corticosteroids in fibrotic interstitial lung disease (fILD) to inform the randomised embedded multifactorial adaptive platform ILD. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched Embase, Medline, Cochrane CENTRAL and Web of Science databases from inception to April 17 2023. ELIGIBILITY CRITERIA: We included studies that compared corticosteroids with standard care, placebo or no treatment in adult patients with fILD. DATA EXTRACTION AND SYNTHESIS: We report on the change in forced vital capacity (FVC) and mortality. We used random-effects meta-analysis to estimate relative risk (RR) for dichotomous outcomes, and mean difference (MD) and standardised MDs for continuous outcomes, with 95% CIs. RESULTS: Of the 13 229 unique citations identified, we included 10 observational studies comprising 1639 patients. Corticosteroids had an uncertain effect on mortality compared with no treatment (RR 1.03 (95% CI 0.85 to 1.25); very low certainty evidence). The effect of corticosteroids on the rate of decline in FVC (% predicted) was uncertain when compared with no treatment (MD 4.29% (95% CI -8.26% to 16.83%); very low certainty evidence). However, corticosteroids might reduce the rate of decline in FVC in patients with non-idiopathic pulmonary fibrosis (IPF) fILD (MD 10.89% (95% CI 5.25% to 16.53%); low certainty evidence), while an uncertain effect was observed in patients with IPF (MD -3.80% (95% CI -8.94% to 1.34%); very low certainty evidence). CONCLUSIONS: The current evidence on the efficacy and safety of corticosteroids in fILD is limited and of low certainty. Randomised trials are needed to address this significant research gap.

Combination of BAL and Computed Tomography Differentiates Progressive and Non-progressive Fibrotic Lung Diseases.

Rationale: Identifying patients with pulmonary fibrosis (PF) at risk of progression can guide management. Objectives: To explore the utility of combining baseline BAL and computed tomography (CT) in differentiating progressive and nonprogressive PF. Methods: The derivation cohort consisted of incident cases of PF for which BAL was performed as part of a diagnostic workup. A validation cohort was prospectively recruited with identical inclusion criteria. Baseline thoracic CT scans were scored for the extent of fibrosis and usual interstitial pneumonia (UIP) pattern. The BAL lymphocyte proportion was recorded. Annualized FVC decrease of >10% or death within 1 year was used to define disease progression. Multivariable logistic regression identified the determinants of the outcome. The optimum binary thresholds (maximal Wilcoxon rank statistic) at which the extent of fibrosis on CT and the BAL lymphocyte proportion could distinguish disease progression were identified. Measurements and Main Results: BAL lymphocyte proportion, UIP pattern, and fibrosis extent were significantly and independently associated with disease progression in the derivation cohort (n = 240). Binary thresholds for increased BAL lymphocyte proportion and extensive fibrosis were identified as 25% and 20%, respectively. An increased BAL lymphocyte proportion was rare in patients with a UIP pattern (8 of 135; 5.9%) or with extensive fibrosis (7 of 144; 4.9%). In the validation cohort (n = 290), an increased BAL lymphocyte proportion was associated with a significantly lower probability of disease progression in patients with nonextensive fibrosis or a non-UIP pattern. Conclusions: BAL lymphocytosis is rare in patients with extensive fibrosis or a UIP pattern on CT. In patients without a UIP pattern or with limited fibrosis, a BAL lymphocyte proportion of ⩾25% was associated with a lower likelihood of progression.

Characteristics and risk factors for post-COVID-19 breathlessness after hospitalisation for COVID-19.

Background: Persistence of respiratory symptoms, particularly breathlessness, after acute coronavirus disease 2019 (COVID-19) infection has emerged as a significant clinical problem. We aimed to characterise and identify risk factors for patients with persistent breathlessness following COVID-19 hospitalisation. Methods: PHOSP-COVID is a multicentre prospective cohort study of UK adults hospitalised for COVID-19. Clinical data were collected during hospitalisation and at a follow-up visit. Breathlessness was measured by a numeric rating scale of 0-10. We defined post-COVID-19 breathlessness as an increase in score of ≥1 compared to the pre-COVID-19 level. Multivariable logistic regression was used to identify risk factors and to develop a prediction model for post-COVID-19 breathlessness. Results: We included 1226 participants (37% female, median age 59 years, 22% mechanically ventilated). At a median 5 months after discharge, 50% reported post-COVID-19 breathlessness. Risk factors for post-COVID-19 breathlessness were socioeconomic deprivation (adjusted OR 1.67, 95% CI 1.14-2.44), pre-existing depression/anxiety (adjusted OR 1.58, 95% CI 1.06-2.35), female sex (adjusted OR 1.56, 95% CI 1.21-2.00) and admission duration (adjusted OR 1.01, 95% CI 1.00-1.02). Black ethnicity (adjusted OR 0.56, 95% CI 0.35-0.89) and older age groups (adjusted OR 0.31, 95% CI 0.14-0.66) were less likely to report post-COVID-19 breathlessness. Post-COVID-19 breathlessness was associated with worse performance on the shuttle walk test and forced vital capacity, but not with obstructive airflow limitation. The prediction model had fair discrimination (concordance statistic 0.66, 95% CI 0.63-0.69) and good calibration (calibration slope 1.00, 95% CI 0.80-1.21). Conclusions: Post-COVID-19 breathlessness was commonly reported in this national cohort of patients hospitalised for COVID-19 and is likely to be a multifactorial problem with physical and emotional components.

Complex roles of TGF-ß signaling pathways in lung development and bronchopulmonary dysplasia.

As survival of extremely preterm infants continues to improve, there is also an associated increase in bronchopulmonary dysplasia (BPD), one of the most significant complications of preterm birth. BPD development is multifactorial resulting from exposure to multiple antenatal and postnatal stressors. BPD has both short-term health implications and long-term sequelae including increased respiratory, cardiovascular, and neurological morbidity. Transforming growth factor ß (TGF-ß) is an important signaling pathway in lung development, organ injury, and fibrosis and is implicated in the development of BPD. This review provides a detailed account on the role of TGF-ß in antenatal and postnatal lung development, the effect of known risk factors for BPD on the TGF-ß signaling pathway, and how medications currently in use or under development, for the prevention or treatment of BPD, affect TGF-ß signaling.

Phosphodiesterase 5 inhibitor treatment and survival in interstitial lung disease pulmonary hypertension: A Bayesian retrospective observational cohort study.

BACKGROUND AND OBJECTIVE: Pulmonary hypertension is a life-limiting complication of interstitial lung disease (ILD-PH). We investigated whether treatment with phosphodiesterase 5 inhibitors (PDE5i) in patients with ILD-PH was associated with improved survival. METHODS: Consecutive incident patients with ILD-PH and right heart catheterisation, echocardiography and spirometry data were followed from diagnosis to death, transplantation or censoring with all follow-up and survival data modelled by Bayesian methods. RESULTS: The diagnoses in 128 patients were idiopathic pulmonary fibrosis (n = 74, 58%), hypersensitivity pneumonitis (n = 17, 13%), non-specific interstitial pneumonia (n = 12, 9%), undifferentiated ILD (n = 8, 6%) and other lung diseases (n = 17, 13%). Final outcomes were death (n = 106, 83%), transplantation (n = 9, 7%) and censoring (n = 13, 10%). Patients treated with PDE5i (n = 50, 39%) had higher mean pulmonary artery pressure (median 38 mm Hg [interquartile range, IQR: 34, 43] vs. 35 mm Hg [IQR: 31, 38], p = 0.07) and percentage predicted forced vital capacity (FVC; median 57% [IQR: 51, 73] vs. 52% [IQR: 45, 66], p=0.08) though differences did not reach significance. Patients treated with PDE5i survived longer than untreated patients (median 2.18 years [95% CI: 1.43, 3.04] vs. 0.94 years [0.69, 1.51], p = 0.003) independent of all other prognostic markers by Bayesian joint-modelling (HR 0.39, 95% CI: 0.23, 0.59, p < 0.001) and propensity-matched analyses (HR 0.38, 95% CI: 0.22, 0.58, p < 0.001). Survival difference with treatment was significantly larger if right ventricular function was normal, rather than abnormal, at presentation (+2.55 years, 95% CI: -0.03, +3.97 vs. +0.98 years, 95% CI: +0.47, +2.00, p = 0.04). CONCLUSION: PDE5i treatment in ILD-PH should be investigated by a prospective randomized trial.

Parenchymal lung abnormalities following hospitalisation for COVID-19 and viral pneumonitis: a systematic review and meta-analysis.

INTRODUCTION: Persisting respiratory symptoms in COVID-19 survivors may be related to development of pulmonary fibrosis. We assessed the proportion of chest CT scans and pulmonary function tests consistent with parenchymal lung disease in the follow-up of people hospitalised with COVID-19 and viral pneumonitis. METHODS: Systematic review and random effects meta-analysis of proportions using studies of adults hospitalised with SARS-CoV-2, SARS-CoV, MERS-CoV or influenza pneumonia and followed up within 12 months. Searches performed in MEDLINE and Embase. Primary outcomes were proportion of radiological sequelae on CT scans; restrictive impairment; impaired gas transfer. Heterogeneity was explored in meta-regression. RESULTS: Ninety-five studies (98.9% observational) were included in qualitative synthesis, 70 were suitable for meta-analysis including 60 SARS-CoV-2 studies with a median follow-up of 3 months. In SARS-CoV-2, the overall estimated proportion of inflammatory sequelae was 50% during follow-up (0.50; 95% CI 0.41 to 0.58; I2=95%), fibrotic sequelae were estimated in 29% (0.29; 95% CI 0.22 to 0.37; I2=94.1%). Follow-up time was significantly associated with estimates of inflammatory sequelae (-0.036; 95% CI -0.068 to -0.004; p=0.029), associations with fibrotic sequelae did not reach significance (-0.021; 95% CI -0.051 to 0.009; p=0.176). Impaired gas transfer was estimated at 38% of lung function tests (0.38 95% CI 0.32 to 0.44; I2=92.1%), which was greater than restrictive impairment (0.17; 95% CI 0.13 to 0.23; I2=92.5%), neither were associated with follow-up time (p=0.207; p=0.864). DISCUSSION: Sequelae consistent with parenchymal lung disease were observed following COVID-19 and other viral pneumonitis. Estimates should be interpreted with caution due to high heterogeneity, differences in study casemix and initial severity. PROSPERO REGISTRATION NUMBER: CRD42020183139.

Persistent isolated impairment of gas transfer following COVID-19 pneumonitis relates to perfusion defects on dual-energy computed tomography.

A novel iodine perfusion score correlates with breathlessness and D LCO in patients post-#COVID19 without obvious interstitial disease on CT, suggesting that lung perfusion assessment may be useful in patients without another cause of dyspnoea https://bit.ly/3U6E2f5.

A lung targeted miR-29 mimic as a therapy for pulmonary fibrosis.

BACKGROUND: MicroRNAs are non-coding RNAs that negatively regulate gene networks. Previously, we reported that systemically delivered miR-29 mimic MRG-201 reduced fibrosis in animal models, supporting the consideration of miR-29-based therapies for idiopathic pulmonary fibrosis (IPF). METHODS: We generated MRG-229, a next-generation miR-29 mimic based on MRG-201 with improved chemical stability due to additional sugar modifications and conjugation with the internalization moiety BiPPB (PDGFbetaR-specific bicyclic peptide)1. We investigated the anti-fibrotic efficacy of MRG-229 on TGF-ß1 treated human lung fibroblasts (NHLFs), human precision cut lung slices (hPCLS), and in vivo bleomycin studies; toxicology was assessed in two animal models, rats, and non-human primates. Finally, we examined miR-29b levels in a cohort of 46 and 213 patients with IPF diagnosis recruited from Yale and Nottingham Universities (Profile Cohort), respectively. FINDINGS: The peptide-conjugated MRG-229 mimic decreased expression of pro-fibrotic genes and reduced collagen production in each model. In bleomycin-treated mice, the peptide-conjugated MRG-229 mimic downregulated profibrotic gene programs at doses more than ten-fold lower than the original compound. In rats and non-human primates, the peptide-conjugated MRG-229 mimic was well tolerated at clinically relevant doses with no adverse findings observed. In human peripheral blood from IPF patients decreased miR-29 concentrations were associated with increased mortality in two cohorts potentially identified as a target population for treatment. INTERPRETATION: Collectively, our results provide support for the development of the peptide-conjugated MRG-229 mimic as a potential therapy in humans with IPF. FUNDING: This work was supported by NIH NHLBI grants UH3HL123886, R01HL127349, R01HL141852, U01HL145567.

Short-term lung function changes predict mortality in patients with fibrotic hypersensitivity pneumonitis.

BACKGROUND AND OBJECTIVE: A proportion of patients with fibrotic hypersensitivity pneumonitis (fHP) follow a progressive disease course despite immunosuppressive treatment. Little is known about predictors of mortality in fHP. We aimed to investigate the impact of short-term lung function changes in fHP on mortality. METHODS: Baseline demographics for 145 consecutive patients with a multi-disciplinary team diagnosis of fHP, as well as baseline and 1-year follow-up of lung function, baseline echocardiographic findings, bronchoalveolar lavage (BAL) cellularity and all-cause mortality were recorded. Changes in forced vital capacity (FVC) ≥ 5% and ≥10%, and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 10% and ≥15% at 1 year were calculated. Cox proportional hazards analysis was performed to test for associations with mortality. RESULTS: Baseline lung function severity, age, presence of honeycombing on computed tomography (CT) and echocardiographic pulmonary arterial systolic pressure (PASP) ≥ 40 mm Hg were associated with early mortality, while BAL lymphocytosis was associated with improved survival. A decline in FVC ≥ 5% (hazard ratio [HR]: 3.10, 95% CI: 2.00-4.81, p < 0.001), FVC ≥ 10% (HR: 3.11, 95% CI: 1.94-4.99, p < 0.001), DLCO ≥ 10% (HR: 2.80, 95% CI: 1.78-4.42, p < 0.001) and DLCO ≥ 15% (HR: 2.92, 95% CI: 1.18-4.72, p < 0.001) at 1 year was associated with markedly reduced survival on univariable and multivariable analyses after correcting for demographic variables, disease severity, honeycombing on CT and treatment, as well as BAL lymphocytosis and PASP ≥ 40 mm Hg on echocardiography, in separate models. CONCLUSION: Worsening in FVC and DLCO at 1 year, including a marginal decline in FVC ≥ 5% and DLCO ≥ 10%, is predictive of markedly reduced survival in fHP.

Lysyl oxidase like 2 is increased in asthma and contributes to asthmatic airway remodelling.

BACKGROUND: Airway smooth muscle (ASM) cells are fundamental to asthma pathogenesis, influencing bronchoconstriction, airway hyperresponsiveness and airway remodelling. The extracellular matrix (ECM) can influence tissue remodelling pathways; however, to date no study has investigated the effect of ASM ECM stiffness and cross-linking on the development of asthmatic airway remodelling. We hypothesised that transforming growth factor-ß (TGF-ß) activation by ASM cells is influenced by ECM in asthma and sought to investigate the mechanisms involved. METHODS: This study combines in vitro and in vivo approaches: human ASM cells were used in vitro to investigate basal TGF-ß activation and expression of ECM cross-linking enzymes. Human bronchial biopsies from asthmatic and nonasthmatic donors were used to confirm lysyl oxidase like 2 (LOXL2) expression in ASM. A chronic ovalbumin (OVA) model of asthma was used to study the effect of LOXL2 inhibition on airway remodelling. RESULTS: We found that asthmatic ASM cells activated more TGF-ß basally than nonasthmatic controls and that diseased cell-derived ECM influences levels of TGF-ß activated. Our data demonstrate that the ECM cross-linking enzyme LOXL2 is increased in asthmatic ASM cells and in bronchial biopsies. Crucially, we show that LOXL2 inhibition reduces ECM stiffness and TGF-ß activation in vitro, and can reduce subepithelial collagen deposition and ASM thickness, two features of airway remodelling, in an OVA mouse model of asthma. CONCLUSION: These data are the first to highlight a role for LOXL2 in the development of asthmatic airway remodelling and suggest that LOXL2 inhibition warrants further investigation as a potential therapy to reduce remodelling of the airways in severe asthma.