The 1-min sit-to-stand test as a screening tool to assess exercise-induced oxygen desaturation in normoxemic people with interstitial lung disease.

BACKGROUND: In patients with interstitial lung disease (ILD), exercise-induced desaturation during the 6-min walk test (6MWT), specifically nadir oxygen saturation (nSpO2) of ≤88 % is a negative prognostic marker. As the 6MWT is often impractical for ILD patients, the aim of this study is to compare the 1-min sit-to-stand test (1minSTS) with the 6MWT to detect exercise-induced desaturation. METHODS: Participants were recruited from a tertiary referral clinic with both tests performed on the same day. Utilising Bland-Altman analysis, the relationship between nSpO2 on 1minSTS and 6MWT was determined. An area under the receiver operating characteristic curve (AUC) determined the ability of nSpO2 on 1minSTS test to predict SpO2 ≤88 % on 6MWT. RESULTS: Fifty participants completed the study (idiopathic pulmonary fibrosis n = 24, 48 %; connective tissue disease associated ILD n = 20, 40 %; other ILD n = 6, 12 %). Mean (SD) FVC%pred was 73 ± 16 %, mean DLCO%pred 57 ± 16 % and resting SpO2 99 ± 1 %. The 1minSTS resulted in less exercise-induced oxygen desaturation, with a median IQR nSpO2 of 95 % (89-98) and 93 % (85-96) respectively (p < 0.001). Moderate agreement was determined between the nSpO2 on both tests, with a mean difference of 3.2 % [-14 to +3.0 %]. The 1minSTS test accurately identified participants with nSpO2 ≤88 % on 6MWT (AUC 0.96). Oxygen desaturation ≤94 % during the 1minSTS test provided 100 % sensitivity and 87 % specificity for oxygen desaturation ≤88 % at 6MWT. CONCLUSION: This study demonstrates that exercise-induced oxygen desaturation during the 1minSTS test correlates with oxygen desaturation on 6MWT. The 1minSTS may be a practical screening tool for ILD patients who would benefit from further exercise testing.

Cluster analysis of blood biomarkers to identify molecular patterns in pulmonary fibrosis: assessment of a multicentre, prospective, observational cohort with independent validation.

BACKGROUND: Pulmonary fibrosis results from alveolar injury, leading to extracellular matrix remodelling and impaired lung function. This study aimed to classify patients with pulmonary fibrosis according to blood biomarkers to differentiate distinct disease patterns, known as endotypes. METHODS: In this cluster analysis, we first classified patients from the PROFILE study, a multicentre, prospective, observational cohort of individuals with incident idiopathic pulmonary fibrosis or non-specific interstitial pneumonia in the UK (Nottingham University Hospitals, Nottingham; and Royal Brompton Hospital, London). 13 blood biomarkers representing extracellular matrix remodelling, epithelial stress, and thrombosis were measured by ELISA in the PROFILE study. We classified patients by unsupervised consensus clustering. To evaluate generalisability, a machine learning classifier trained on biomarker signatures derived from consensus clustering was applied to a replication dataset from the Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR). Biomarker associations with mortality and change in percentage of predicted forced vital capacity (FVC%) were assessed, adjusting for age, gender, baseline FVC%, and antifibrotic treatment and steroid treatment before and after baseline. Mortality risk associated with the clusters in the PROFILE cohort was evaluated with Cox proportional hazards models, and mixed-effects models were used to analyse how clustering was associated with longitudinal FVC% in the PROFILE and AIPFR cohorts. FINDINGS: 455 of 580 participants from the PROFILE study (348 [76%] men and 107 [24%] women; mean age 72·4 years [SD 8·3]) were included in the analysis. Within this group, three clusters were identified based on blood biomarkers. A basement membrane collagen (BM) cluster (n=248 [55%]) showed high concentrations of PRO-C4, PRO-C28, C3M, and C6M, whereas an epithelial injury (EI) cluster (n=109 [24%]) showed high concentrations of MMP-7, SP-D, CYFRA211, CA19-9, and CA-125. The third cluster (crosslinked fibrin [XF] cluster; n=98 [22%]) had high concentrations of X-FIB. In the replication dataset (117 of 833 patients from AIPFR; 87 [74%] men and 30 [26%] women; mean age 72·9 years [SD 7·9]), we identified the same three clusters (BM cluster, n=93 [79%]; EI cluster, n=8 [7%]; XF cluster, n=16 [14%]). These clusters showed similarities with clusters in the PROFILE dataset regarding blood biomarkers and phenotypic signatures. In the PROFILE dataset, the EI and XF clusters were associated with increased mortality risk compared with the BM cluster (EI vs BM: adjusted hazard ratio [HR] 1·88 [95% CI 1·42-2·49], p<0·0001; XF vs BM: adjusted HR 1·53 [1·13-2·06], p=0·0058). The EI cluster showed the greatest annual FVC% decline, followed by the BM and XF clusters. A similar FVC% decline pattern was observed in these clusters in the AIPFR replication dataset. INTERPRETATION: Blood biomarker clustering in pulmonary fibrosis identified three distinct blood biomarker signatures associated with lung function and prognosis, suggesting unique pulmonary fibrosis biomarker patterns. These findings support the presence of pulmonary fibrosis endotypes with the potential to guide targeted therapy development. FUNDING: None.

Effect of a 4-Week Telerehabilitation Program for People with Post-COVID Syndrome on Physical Function and Symptoms: Protocol for a Randomized Controlled Trial.

OBJECTIVE: COVID-19 has led to significant morbidity and mortality globally. Post-COVID sequelae can persist beyond the acute and subacute phases of infection, often termed Post-COVID Syndrome (PCS). There is limited evidence on the appropriate rehabilitation for people with PCS. The aim of this study is to evaluate the effect on exercise capacity, symptoms, cognition, anxiety, depression, health-related quality of life (HRQoL), and fatigue, of a 4-week, twice-weekly supervised pulmonary telerehabilitation program compared to usual medical care for people with PCS with persistent respiratory symptoms. METHODS: The study will be a multi-site randomized controlled trial (RCT) with assessor blinding. Participants with confirmed previous COVID-19 infection and persistent respiratory symptoms who attend a post-COVID respiratory clinic will be randomized 1:1 to either an intervention group (IG) of 4 weeks, twice-weekly pulmonary telerehabilitation or a control group (CG) of usual medical care. Participants in the CG will be invited to cross-over into the IG after the week 4 assessment. Primary outcome: exercise capacity measured by the 1-minute sit-to-stand test. Secondary outcomes: 5 repetition sit-to-stand test; Montreal Cognitive Assessment; COVID-19 Yorkshire Rehabilitation Scale; COPD Assessment Test; 36-Item Short-Form Health Survey; Hospital Anxiety and Depression Scale; Fatigue Severity Scale; and the Kessler Psychological Distress Scale. Outcomes will be collected at baseline, after 4-weeks intervention or control period, after intervention in the cross-over group, and at 12-month follow-up. IMPACT STATEMENT: Research into effective rehabilitation programs is crucial given the substantial morbidity associated with PCS and the lack of long-term data for COVID-19 recovery. A short duration pulmonary telerehabilitation program, if effective compared to usual care, could inform practice guidelines and direct future clinical trials for the benefit of individuals with persistent respiratory symptoms post-COVID.

Unravelling the health and economic burden of interstitial lung diseases in adults in Australia.

BACKGROUND: Interstitial lung diseases (ILD) are a heterogenous group of over 200 disorders affecting the pulmonary interstitium. Although there have been advances in knowledge on ILDs in Australia, the characterisation of the health and economic burden of disease remained largely undetermined until recently. OBJECTIVE: The main objective of this review is to provide a synopsis of health and economic burden of ILDs in Australia, based on recently completed research. DISCUSSION: Recent research has demonstrated that idiopathic pulmonary fibrosis (IPF) is the most frequent ILD in Australia. Incidence and prevalence of IPF have demonstrated an increasing trend over the past decades. Mortality has also increased over the past decades, but has shown a slight decreasing trend recently, since the introduction of antifibrotic medication. Health-related quality of life is poor in patients with IPF, and care is estimated to cost approximately AU$299 million per year in Australia. Early diagnosis and referral to tertiary care is crucial for favourable outcomes, and general practitioners are considerably important to this as the first interface to identify patients at risk and detect early symptoms of ILDs.

Genetics and Genomics of Pulmonary Fibrosis: Charting the Molecular Landscape and Shaping Precision Medicine.

Recent genetic and genomic advancements have elucidated the complex etiology of idiopathic pulmonary fibrosis (IPF) and other progressive fibrotic interstitial lung diseases (ILDs), emphasizing the contribution of heritable factors. This state-of-the-art review synthesizes evidence on significant genetic contributors to pulmonary fibrosis (PF), including rare genetic variants and common SNPs. The MUC5B promoter variant is unusual, a common SNP that markedly elevates the risk of early and established PF. We address the utility of genetic variation in enhancing understanding of disease pathogenesis and clinical phenotypes, improving disease definitions, and informing prognosis and treatment response. Critical research gaps are highlighted, particularly the underrepresentation of non-European ancestries in PF genetic studies and the exploration of PF phenotypes beyond usual interstitial pneumonia/IPF. We discuss the role of telomere length, often critically short in PF, and its link to progression and mortality, underscoring the genetic complexity involving telomere biology genes (TERT, TERC) and others like SFTPC and MUC5B. In addition, we address the potential of gene-by-environment interactions to modulate disease manifestation, advocating for precision medicine in PF. Insights from gene expression profiling studies and multiomic analyses highlight the promise for understanding disease pathogenesis and offer new approaches to clinical care, therapeutic drug development, and biomarker discovery. Finally, we discuss the ethical, legal, and social implications of genomic research and therapies in PF, stressing the need for sound practices and informed clinical genetic discussions. Looking forward, we advocate for comprehensive genetic testing panels and polygenic risk scores to improve the management of PF and related ILDs across diverse populations.

Agreement between local and central anti-synthetase antibodies detection: results from the Classification Criteria of Anti-Synthetase Syndrome project biobank.

OBJECTIVES: The CLASS (Classification Criteria of Anti-Synthetase Syndrome) project is a large international multicentre study that aims to create the first data-driven anti-synthetase syndrome (ASSD) classification criteria. Identifying anti-aminoacyl tRNA synthetase antibodies (anti-ARS) is crucial for diagnosis, and several commercial immunoassays are now available for this purpose. However, using these assays risks yielding false-positive or false-negative results, potentially leading to misdiagnosis. The established reference standard for detecting anti-ARS is immunoprecipitation (IP), typically employed in research rather than routine autoantibody testing. We gathered samples from participating centers and results from local anti-ARS testing. As an "ad-interim" study within the CLASS project, we aimed to assess how local immunoassays perform in real-world settings compared to our central definition of anti-ARS positivity. METHODS: We collected 787 serum samples from participating centres for the CLASS project and their local anti-ARS test results. These samples underwent initial central testing using RNA-IP. Following this, the specificity of ARS was reconfirmed centrally through ELISA, line-blot assay (LIA), and, in cases of conflicting results, protein-IP. The sensitivity, specificity, positive likelihood ratio and positive and negative predictive values were evaluated. We also calculated the inter-rater agreement between central and local results using a weighted κ co-efficient. RESULTS: Our analysis demonstrates that local, real-world detection of anti-Jo1 is reliable with high sensitivity and specificity with a very good level of agreement with our central definition of anti-Jo1 antibody positivity. However, the agreement between local immunoassay and central determination of anti-non-Jo1 antibodies varied, especially among results obtained using local LIA, ELISA and "other" methods. CONCLUSIONS: Our study evaluates the performance of real-world identification of anti-synthetase antibodies in a large cohort of multi-national patients with ASSD and controls. Our analysis reinforces the reliability of real-world anti-Jo1 detection methods. In contrast, challenges persist for anti-non-Jo1 identification, particularly anti-PL7 and rarer antibodies such as anti-OJ/KS. Clinicians should exercise caution when interpreting anti-synthetase antibodies, especially when commercial immunoassays test positive for non-anti-Jo1 antibodies.

Drug-induced interstitial lung disease: a narrative review of a clinical conundrum.

INTRODUCTION: Drug-induced interstitial lung disease (DI-ILD) is increasing in incidence, due to the use of many new drugs across a broad range of cancers and chronic inflammatory diseases. The presentation and onset of DI-ILD are variable even for the same drug across different individuals. Clinical suspicion is essential for identifying these conditions, with timely drug cessation an important determinant of outcomes. AREAS COVERED: This review provides a comprehensive and up-to-date summary of epidemiology, risk factors, pathogenesis, diagnosis, treatment, and prognosis of DI-ILD. Relevant research articles from PubMed and Medline searches up to September 2023 were screened and summarized. Specific drugs including immune checkpoint inhibitors, CAR-T cell therapy, methotrexate, and amiodarone are discussed in detail. The potential role of pharmacogenomic profiling for lung toxicity risk is considered. EXPERT OPINION: DI-ILD is likely to be an increasingly important contributor to respiratory disability in the community. These conditions can negatively impact quality of life and patient longevity, due to associated respiratory compromise as well as cessation of evidence-based therapy for the underlying disease. This clinical conundrum is relevant to all areas of medicine, necessitating increased understanding and greater vigilance for drug-related lung toxicity.

Disease Behaviour Classification: A pragmatic model for predicting outcomes in Interstitial Lung Disease.

BACKGROUND AND OBJECTIVE: The interstitial lung diseases (ILD) are a heterogenous group of disorders with similar clinical presentation, but widely varying prognoses. The use of a pragmatic disease behaviour classification (DBC), first proposed in international guidelines in 2013, categorises diseases into five behavioural classes based on their predicted clinical course. This study aimed to determine the prognostic utility of the DBC in an ILD cohort. METHODS: Consecutive patients presented at the weekly multidisciplinary meeting (MDM) of a specialist ILD centre were included. MDM consensus was obtained for diagnosis and DBC category (1-5). Baseline and serial clinical and physiological data were collected over the study period (median 3.9 years, range 0-5.4 years). The relationship between DBC and prognostic outcomes was explored. RESULTS: 137 ILD patients, [64 (47%) female] were included with mean age 67.0 ± 1.1 years, baseline FVC% 72.7 ± 1.7, and baseline DLco% 57.8 ± 1.6%. Patients were stratified into DBC by consensus at MDM: DBC1 n = 0 (0%), DBC2 n = 16 (12%), DBC3 n = 10 (7.3%), DBC4 n = 55 (40%), and DBC5 n = 56 (41%). On univariable Cox regression, increasing DBC class was associated with poorer progression-free survival (HR 1.6, 95% CI 1.2-2.0, p < 0.001). On multivariable Cox regression, DBC remained predictive of PFS when combined with age and gender (HR 1.4, 95% CI 1.1-1.9, p = 0.011), baseline FVC% (HR 1.5, 95% CI 1.1-1.8, p = 0.003) and ILD diagnosis (HR 1.6, 95% CI 1.2-2.2, p < 0.0001). CONCLUSION: DBC as determined at ILD multidisciplinary meeting may be a useful prognostic tool for the management of ILD patients.

Multiple serum biomarkers associate with mortality and interstitial lung disease progression in systemic sclerosis.

OBJECTIVES: To investigate the prognostic utility of 28 serum biomarkers in systemic sclerosis (SSc), SSc-associated interstitial lung disease (SSc-ILD) and clinically relevant disease subgroups. METHODS: Participants with sera, high-resolution computed tomography, and lung function within 12 months of baseline were identified from the Australian Scleroderma Cohort Study. Baseline was the time of serum collection. 27 of the prespecified 28 serum biomarkers were analysed and biomarker associations with mortality and ILD progression were investigated in univariable and multivariable analyses, including within disease subgroups and combined with established risk factors for poorer prognosis in SSc. RESULTS: 407 participants were identified, 252 (61.9%) with SSc-ILD. The median follow up after biomarker measurement was 6.31 (3.11-9.22) years. 16 biomarkers were associated with increased mortality. High levels of VCAM-1 were most strongly associated with mortality (HR 3.55; 95%CI 2.37-5.33; p< 0.001). Five additional biomarkers had a HR > 2: SP-D (2.28, 1.57-3.31; p< 0.001), E-selectin (2.19; 1.53-3.14; p< 0.001), IL-6 (2.15 1.50-3.09; p< 0.001), MMP3 (1.42-2.95; p< 0.001) and ET-1 (2.03, 1.40-2.92; p< 0.001). 11 biomarkers were independently associated with mortality following adjustment for sex, age and baseline forced vital capacity (FVC%predicted). Three biomarkers were associated with ILD progression at one year follow up: CXCL4 (OR 2.67, 1.46-4.88; p= 0.001), MMP-1 (2.56, 1.43-4.59; p= 0.002) and ET-1 (2.18, 1.24-3.83; p= 0.007). CONCLUSION: Multiple biomarkers, especially VCAM-1, E-Selectin, SP-D and CXCL4, provide prognostic utility beyond that of established risk factors for patients with SSc.

Zinpentraxin Alfa for Idiopathic Pulmonary Fibrosis: The Randomized Phase III STARSCAPE Trial.

Rationale: A phase II trial reported clinical benefit over 28 weeks in patients with idiopathic pulmonary fibrosis (IPF) who received zinpentraxin alfa. Objectives: To investigate the efficacy and safety of zinpentraxin alfa in patients with IPF in a phase III trial. Methods: This 52-week phase III, double-blind, placebo-controlled, pivotal trial was conducted at 275 sites in 29 countries. Patients with IPF were randomized 1:1 to intravenous placebo or zinpentraxin alfa 10 mg/kg every 4 weeks. The primary endpoint was absolute change from baseline to Week 52 in FVC. Secondary endpoints included absolute change from baseline to Week 52 in percent predicted FVC and 6-minute walk distance. Safety was monitored via adverse events. Post hoc analysis of the phase II and phase III data explored changes in FVC and their impact on the efficacy results. Measurements and Main Results: Of 664 randomized patients, 333 were assigned to placebo and 331 to zinpentraxin alfa. Four of the 664 randomized patients were never administered study drug. The trial was terminated early after a prespecified futility analysis that demonstrated no treatment benefit of zinpentraxin alfa over placebo. In the final analysis, absolute change from baseline to Week 52 in FVC was similar between placebo and zinpentraxin alfa (-214.89 ml and -235.72 ml; P = 0.5420); there were no apparent treatment effects on secondary endpoints. Overall, 72.3% and 74.6% of patients receiving placebo and zinpentraxin alfa, respectively, experienced one or more adverse events. Post hoc analysis revealed that extreme FVC decline in two placebo-treated patients resulted in the clinical benefit of zinpentraxin alfa reported by phase II. Conclusions: Zinpentraxin alfa treatment did not benefit patients with IPF over placebo. Learnings from this program may help improve decision making around trials in IPF. Clinical trial registered with www.clinicaltrials.gov (NCT04552899).

Treatment of idiopathic pulmonary fibrosis and progressive pulmonary fibrosis: A position statement from the Thoracic Society of Australia and New Zealand 2023 revision.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease leading to significant morbidity and mortality. In 2017 the Thoracic Society of Australia and New Zealand (TSANZ) and Lung Foundation Australia (LFA) published a position statement on the treatment of IPF. Since that time, subsidized anti-fibrotic therapy in the form of pirfenidone and nintedanib is now available in both Australia and New Zealand. More recently, evidence has been published in support of nintedanib for non-IPF progressive pulmonary fibrosis (PPF). Additionally, there have been numerous publications relating to the non-pharmacologic management of IPF and PPF. This 2023 update to the position statement for treatment of IPF summarizes developments since 2017 and reaffirms the importance of a multi-faceted approach to the management of IPF and progressive pulmonary fibrosis.

The impact of air pollution on interstitial lung disease: a systematic review and meta-analysis.

Introduction: There is a growing body of evidence suggesting a causal relationship between interstitial lung disease (ILD) and air pollution, both for the development of the disease, and driving disease progression. We aim to provide a comprehensive literature review of the association between air pollution, and ILD, including idiopathic pulmonary fibrosis (IPF). Methods: We systematically searched from six online database. Two independent authors (DL and CF) selected studies and critically appraised the risk of bias using the Newcastle-Ottawa Scale (NOS). Findings are presented through a narrative synthesis and meta-analysis. Meta-analyses were performed exclusively when there was a minimum of three studies examining identical pollutant-health outcome pairs, all evaluating equivalent increments in pollutant concentration, using a random effects model. Results: 24 observational studies conducted in 13 countries or regions were identified. Pollutants under investigation encompassed ozone (O3), nitrogen dioxide (NO2), Particulate matter with diameters of 10 micrometers or less (PM10) and 2.5 micrometers or less (PM2.5), sulfur dioxide (SO2), carbon monoxide (CO), nitric oxide (NO) and nitrogen oxides (NOx). We conducted meta-analyses to assess the estimated Risk Ratios (RRs) for acute exacerbations (AE)-IPF in relation to exposure to every 10 µg/m3 increment in air pollutant concentrations, including O3, NO2, PM10, and PM2.5. The meta-analysis revealed a significant association between the increased risk of AE-IPF in PM2.5, yielding RR 1.94 (95% CI 1.30-2.90; p = 0.001). Findings across all the included studies suggest that increased exposure to air pollutants may be linked to a range of health issues in individuals with ILDs. Conclusion: A scarcity of available studies on the air pollutants and ILD relationship underscores the imperative for further comprehensive research in this domain. The available data suggest that reducing levels of PM2.5 in the atmosphere could potentially reduce AE frequency and severity in ILD patients.