A composite serum biomarker index for the diagnosis of systemic sclerosis interstitial lung disease: a multicentre, observational, cohort study

OBJECTIVE: In patients with systemic sclerosis (SSc), we investigated composite serum biomarker panels for the diagnosis and risk-stratification of SSc-associated interstitial lung disease (SSc-ILD). METHODS: Twenty-eight biomarkers were analysed in 640 participants: 259 with SSc-ILD and 179 SSc-controls without ILD (Australian Scleroderma Cohort Study), 172 idiopathic pulmonary fibrosis (IPF)-controls (Australian IPF Registry), and 30 healthy controls. A composite index was developed from biomarkers associated with ILD in multivariable analysis derived at empirical thresholds. Performance of the index to identify ILD, and specifically SSc-ILD, and its association with lung function, radiological extent, health-related quality of life (HRQoL) were evaluated in derivation and validation cohorts. Biomarkers to distinguish SSc-ILD from IPF-controls were identified. RESULTS: A composite biomarker index, comprising SP-D, Ca15-3 and ICAM-1, was strongly associated with SSc-ILD diagnosis, independent of age, sex, smoking and lung function (index=3: pooled adjusted OR 12.72, 95%CI 4.59-35.21, p<0.001). The composite index strengthened the performance of individual biomarkers for SSc-ILD identification. In SSc patients, a higher index was associated with worse baseline disease severity (index=3 relative to index=0: adjusted absolute change in FVC% - 17.84% and DLCO% - 20.16%, both p<0.001). CONCLUSION: A composite serum biomarker index, comprising SP-D, Ca15-3 and ICAM-1 may improve the identification and risk-stratification of ILD in SSc patients at baseline

Gastroesophageal reflux and antacid therapy in IPF: analysis from the Australia IPF Registry

BACKGROUND AND OBJECTIVE:Gastroesophageal reflux disease (GORD) is highly prevalent in idiopathic pulmonary fibrosis (IPF) and may play a role in its pathogenesis. Recent IPF treatment guidelines suggest that all patients with IPF be considered for antacid therapy. However, emerging evidence suggests that antacid therapy does not improve IPF patient outcomes and may increase the risk of pulmonary infection. METHODS:Using prospectively collected data from the Australian IPF Registry including use of antacid therapy, GORD diagnosis and GORD symptoms, the relationship of these GORD variables to survival and disease progression was assessed. The severity of GORD symptoms using the frequency scale for symptoms of GORD (FSSG) and its relationships to outcomes was also assessed for the first time in an IPF cohort. RESULTS:Five hundred eighty-seven (86%) of the 684 patients in the Australian IPF Registry were eligible for inclusion. Patients were mostly male (69%), aged 71.0 ± 8.5 years with moderate disease (FVC 81.7 ± 21.5%; DLco 48.5 ± 16.4%). Most patients were taking antacids (n = 384; 65%), though fewer had a diagnosis of GORD (n = 243, 41.4%) and typical GORD symptoms were even less common (n = 171, 29.1%). The mean FSSG score was 8.39 ± 7.45 with 43% (n = 251) having a score > 8. Overall, there was no difference in survival or disease progression, regardless of antacid treatment, GORD diagnosis or GORD symptoms. CONCLUSIONS:Neither the use of antacid therapy nor the presence of GORD symptoms affects longer term outcomes in IPF patients. This contributes to the increasing evidence that antacid therapy may not be beneficial in IPF patients and that GORD directed therapy should be considered on an individual basis to treat the symptoms of reflux.Helen E. Jo, Tamera J. Corte, Ian Glaspole, Christopher Grainge, Peter M. A. Hopkins ... Peter A. Bampton ... et al

Disease progression in idiopathic pulmonary fibrosis with mild physiological impairment: analysis from the Australian IPF registry

BACKGROUND:Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal fibrosing lung disease of unknown cause. The advent of anti-fibrotic medications known to slow disease progression has revolutionised IPF management in recent years. However, little is known about the natural history of IPF patients with mild physiological impairment. We aimed to assess the natural history of these patients using data from the Australian IPF Registry (AIPFR). METHODS:Using our cohort of real-world IPF patients, we compared FVC criteria for mild physiological impairment (FVC ≥ 80%) against other proposed criteria: DLco ≥ 55%; CPI ≤40 and GAP stage 1 with regards agreement in classification and relationship with disease outcomes. Within the mild cohort (FVC ≥ 80%), we also explored markers associated with poorer prognosis at 12 months. RESULTS:Of the 416 AIPFR patients (mean age 70.4 years, 70% male), 216 (52%) were classified as 'mild' using FVC ≥ 80%. There was only modest agreement between FVC and DLco (k = 0.30), with better agreement with GAP (k = 0.50) and CPI (k = 0.48). Patients who were mild had longer survival, regardless of how mild physiologic impairment was defined. There was, however, no difference in the annual decline in FVC% predicted between mild and moderate-severe groups (for all proposed criteria). For patients with mild impairment (n = 216, FVC ≥ 80%), the strongest predictor of outcomes at 12 months was oxygen desaturation on a 6 min walk test. CONCLUSION:IPF patients with mild physiological impairment have better survival than patients with moderate-severe disease. Their overall rate of disease progression however, is comparable, suggesting that they are simply at different points in the natural history of IPF disease.Helen E. Jo, Ian Glaspole, Yuben Moodley, Sally Chapman, Samantha Ellis ... Reynolds ... Paul N. Reynolds ... et al

Quantitative computed tomography predicts outcomes in idiopathic pulmonary fibrosis

First published: 25 July 2022Background and objective: Prediction of disease course in patients with progressive pulmonary fibrosis remains challenging. The purpose of this study was to assess the prognostic value of lung fibrosis extent quantified at computed tomography (CT) using data-driven texture analysis (DTA) in a large cohort of well-characterized patients with idiopathic pulmonary fibrosis (IPF) enrolled in a national registry. Methods: This retrospective analysis included participants in the Australian IPF Registry with available CT between 2007 and 2016. CT scans were analysed using the DTA method to quantify the extent of lung fibrosis. Demographics, longitudinal pulmonary function and quantitative CT metrics were compared using descriptive statistics. Linear mixed models, and Cox analyses adjusted for age, gender, BMI, smoking history and treatment with anti-fibrotics were performed to assess the relationships between baseline DTA, pulmonary function metrics and outcomes. Results: CT scans of 393 participants were analysed, 221 of which had available pulmonary function testing obtained within 90 days of CT. Linear mixed-effect modelling showed that baseline DTA score was significantly associated with annual rate of decline in forced vital capacity and diffusing capacity of carbon monoxide. In multivariable Cox proportional hazard models, greater extent of lung fibrosis was associated with poorer transplant-free survival (hazard ratio [HR] 1.20, p < 0.0001) and progression-free survival (HR 1.14, p < 0.0001). Conclusion: In a multi-centre observational registry of patients with IPF, the extent of fibrotic abnormality on baseline CT quantified using DTA is associated with outcomes independent of pulmonary function.Stephen M. Humphries, John A. Mackintosh, Helen E. Jo, Simon L. F. Walsh, Mario Silva, Lucio Calandriello, Sally Chapman, Samantha Ellis, Ian Glaspole, Nicole Goh, Christopher Grainge, Peter M. A. Hopkins, Gregory J. Keir, Yuben Moodley, Paul N. Reynolds, E. Haydn Walters, David Baraghoshi, Athol U. Wells, David A. Lynch, Tamera J. Cort

TELO-SCOPE study: a randomised, double-blind, placebo-controlled, phase 2 trial of danazol for short telomere related pulmonary fibrosis

Introduction: Recent discoveries have identified shortened telomeres and related mutations in people with pulmonary fibrosis (PF). There is evidence to suggest that androgens, including danazol, may be effective in lengthening telomeres in peripheral blood cells. This study aims to assess the safety and efficacy of danazol in adults and children with PF associated with telomere shortening.Methods and analysis: A multi-centre, double-blind, placebo-controlled, randomised trial of danazol will be conducted in subjects aged >5 years with PF associated with age-adjusted telomere length ≤10th centile measured by flow fluorescence in situ hybridisation; or in children, a diagnosis of dyskeratosis congenita. Adult participants will receive danazol 800 mg daily in two divided doses or identical placebo capsules orally for 12 months, in addition to standard of care (including pirfenidone or nintedanib). Paediatric participants will receive danazol 2 mg/kg/day orally in two divided doses or identical placebo for 6 months. If no side effects are encountered, the dose will be escalated to 4 mg/kg/day (maximum 800 mg daily) orally in two divided doses for a further 6 months. The primary outcome is change in absolute telomere length in base pairs, measured using the telomere shortest length assay (TeSLA), at 12 months in the intention to treat population

The importance of Real-Life research in Respiratory Medicine: Manifesto of the Respiratory Effectiveness Group:Endorsed by the International Primary Care Respiratory Group and the World Allergy Organization

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Diagnostic accuracy of a clinical diagnosis of idiopathic pulmonary fibrosis: An international case-cohort study

We conducted an international study of idiopathic pulmonary fibrosis (IPF) diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts. A total of 1141 respiratory physicians and 34 IPF experts participated. Participants evaluated 60 cases of interstitial lung disease (ILD) without interdisciplinary consultation. Diagnostic agreement was measured using the weighted kappa coefficient (\u3baw). Prognostic discrimination between IPF and other ILDs was used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the Cindex. A total of 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (\u3baw=0.65, IQR 0.53-0.72, p20 years of experience (C-index=0.72, IQR 0.0-0.73, p=0.229) and non-university hospital physicians with more than 20 years of experience, attending weekly MDT meetings (C-index=0.72, IQR 0.70-0.72, p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 IQR 0.72-0.75). Experienced respiratory physicians at university-based institutions diagnose IPF with similar prognostic accuracy to IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts

Health-related quality of life of patients with idiopathic pulmonary fibrosis: a systematic review and meta-analysis

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung disease presenting in persons 50 years and older. Through a comprehensive review of available studies, we aimed to assess health-related quality of life (HRQoL) of people living with IPF and the instruments used in this assessment.Searches were conducted up to May, 2020. Quality appraisal and data extraction were performed using pre-designed forms. Narrative synthesis approach was used to report results of the systematic review and a random effects model was used for the meta-analysis. A leave-one-out sensitivity analysis was performed, and a trim and fill method was used to assess publication bias.The review included 134 studies. The most used instruments to measure HRQoL were St George's Respiratory Questionnaire (SGRQ), Short Form 36 (SF36) and EuroQoL (EQ5D). Standardised mean scores (95% confidence interval) for these instruments were as follows: SGRQ total score: 44.72 (42.21-47.22); SF36 physical component score (PCS): 37.00 (34.74-39.26) SF36 mental component score (MCS): 50.18 (48.41-51.95); King's Brief Interstitial Lung Disease questionnaire total score: 58.38 (55.26-61.51); and EQ5D utility: 0.73 (0.68-0.79). Analysis of standardised means for both SGRQ and SF36 demonstrated worse scores in physical health domains as compared to mental health domains.This systematic review confirms that IPF negatively affected HRQoL, mostly impacting the physical health domains. This study also demonstrated that a diverse number of instruments are used to evaluate HRQoL. In view of this diversity, a standardised approach to measurement of HRQoL for IPF is important to ensure that comparisons made are reliable

A systematically derived exposure assessment instrument for Chronic Hypersensitivity Pneumonitis

BACKGROUND: Chronic hypersensitivity pneumonitis (CHP) is an immune mediated interstitial lung disease, caused by inhalational exposure to environmental antigens, resulting in parenchymal fibrosis. By definition, a diagnosis of CHP assumes a history of antigen exposure, but only half of all patients eventually diagnosed with CHP will have a causative antigen identified. Individual clinician variation in eliciting a history of antigen exposure may affect the frequency and confidence of CHP diagnosis. METHODS: A list of potential causative exposures were derived from a systematic review of the literature. A Delphi method was applied to an international panel of ILD experts, to obtain consensus regarding technique for the elicitation of exposure to antigens relevant to a diagnosis of CHP. The consensus threshold was set at 80% agreement, and median ≤ 2, IQR = 0 on a five-point Likert scale (1: strongly agree, 2: tend to agree, 3: neither agree nor disagree, 4: disagree, 5: strongly disagree). RESULTS: In two rounds, 36/40 experts participated. Experts agreed on 18 exposure items to ask every patient with suspected CHP. Themes included CHP inducing exposures, features that contribute to an exposure's relevance, and quantification of a relevant exposure. Based on the results from the literature review and Delphi process, a CHP exposure assessment instrument was derived. Using cognitive interviews, the instrument was revised by ILD patients for readability and usability. CONCLUSIONS: This Delphi survey provides items that ILD experts agree are important to ask in all patients presenting with suspected CHP and provides basis for a systematically derived CHP exposure assessment instrument. Clinical utility of this exposure assessment instrument may be affected by different local prevalence patterns of exposures. Ongoing research is required to clinically validate these items and consider their impact in more geographically diverse settings