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Background Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear. Methods In this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification. Results Statistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue. Conclusion This is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

© 2020 The Authors. Respirology published by John Wiley & Sons Australia, Ltd on behalf of Asian Pacific Society of Respirology. Pulmonary complications in CTD are common and can involve the interstitium, airways, pleura and pulmonary vasculature. ILD can occur in all CTD (CTD-ILD), and may vary from limited, non-progressive lung involvement, to fulminant, life-threatening disease. Given the potential for major adverse outcomes in CTD-ILD, accurate diagnosis, assessment and careful consideration of therapeutic intervention are a priority. Limited data are available to guide management decisions in CTD-ILD. Autoimmune-mediated pulmonary inflammation is considered a key pathobiological pathway in these disorders, and immunosuppressive therapy is generally regarded the cornerstone of treatment for severe and/or progressive CTD-ILD. However, the natural history of CTD-ILD in individual patients can be difficult to predict, and deciding who to treat, when and with what agent can be challenging. Establishing realistic therapeutic goals from both the patient and clinician perspective requires considerable expertise. The document aims to provide a framework for clinicians to aid in the assessment and management of ILD in the major CTD. A suggested approach to diagnosis and monitoring of CTD-ILD and, where available, evidence-based, disease-specific approaches to treatment have been provided.

BACKGROUND AND OBJECTIVE: People living with pulmonary fibrosis (PF) report unmet needs for information and support. Lung Foundation Australia (LFA) have developed the Peer Connect Service to facilitate telephone support for people with PF across Australia. This project documented the experiences of participants and the resources required to support the service. METHODS: Consenting participants took part in semi-structured interviews by telephone. Primary peers (peers who agreed to initiate contact) and secondary peers (eligible patients who sought a peer match) were interviewed. Thematic analysis was undertaken by two independent researchers. Data were collected on the number of matches and contacts required to establish each match. RESULTS: Interviews were conducted with 32 participants (16 primary peers, 15 secondary peers and 1 who was both), aged from 53 to 89 years with 56% being male. Major themes included the value of shared experiences, providing mutual support and the importance of shared personal characteristics (e.g. gender and hobbies) in allowing information and emotional support needs to be met. Participants saw face-to-face contact with peers as highly desirable whilst acknowledging the practical difficulties. Primary peers were cognizant that their role was not to provide medical advice but to listen and share experiences. In the 12-month period, 60 peer matches were made, each match requiring a minimum of seven staff contacts. CONCLUSION: The Peer Connect Service provides a unique opportunity for people with PF to share experiences and offer mutual support. This telephone matching model may be useful in providing peer support for individuals with rare diseases who are geographically dispersed.

Background The purpose of the National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis (CRE-PF) is to improve and extend the lives of patients living with pulmonary fibrosis through the development of a comprehensive and integrated program of basic and clinical research and education across Australia. A key objective of the CRE-PF was establishment of a unique national training scheme, CREATE, for early-career researchers (ECRs) in respiratory research. CREATE ECRs are broadly drawn from two main fields of researchers: clinicians and scientists, where clinicians tend to be involved in part-time translational research and scientists are involved in broad scientific research including laboratory or genetic research, health economics or population research. Methods We describe the CREATE Program which, with limited budget and the assistance of key organisations, has provided funding opportunities (scholarships, fellowships, prizes, travel and collaboration grants), professional development (mentoring program, symposia, presentation opportunities and on-line training) and fostered a connected, supportive research community for respiratory ECRs. Results The CREATE program has successfully fostered the development of the supported researchers, contributing substantially to the future of pulmonary fibrosis research in Australia. During the life of the program the CRE-PF has offered 10 PhD scholarships and five postdoctoral fellowships, awarded 13 travel grants and three grants to promote collaboration between ECRs from different institutes. A mentoring program has been established and CREATE Symposia have been held in association with key meetings. During COVID-19 restrictions, a series of virtual research meetings has offered 12 CREATE ECRs from seven universities the opportunity to present their research to a national audience. CREATE research-related achievements are impressive, including over 80 first-author publications by ECRs, and many conference presentations. Contributions to the research community, measured by committee membership, is also strong. Conclusions In spite of a very limited budget, wide geographic distribution of participants and the multi-disciplinary nature of the cohort, we have succeeded in providing a unique, supportive academic development environment for CREATE ECRs. Lessons learned in the process of developing this program include the importance of leveraging funding, being flexible, building networks and seeking and responding to ECR input.

BackgroundInterstitial lung disease is a debilitating condition associated with significant dyspnoea, fatigue, and poor exercise tolerance. Pulmonary rehabilitation is an effective and key intervention in people with interstitial lung disease. However, despite the best efforts of patients and clinicians, many of those who participate are not achieving clinically meaningful benefits. This assessor-blinded, multi-centre, randomised controlled trial aims to compare the clinical benefits of high intensity interval exercise training versus the standard pulmonary rehabilitation method of continuous training at moderate intensity in people with fibrotic interstitial lung disease.MethodsEligible participants will be randomised to either a standard pulmonary rehabilitation group using moderate intensity continuous exercise training or high intensity interval exercise training. Participants in both groups will undertake an 8-week pulmonary rehabilitation program of twice-weekly supervised exercise training including aerobic (cycling) and strengthening exercises. In addition, participants in both groups will be prescribed a home exercise program.Outcomes will be assessed at baseline, upon completion of the intervention and at six months following the intervention by a blinded assessor. The primary outcome is endurance time on a constant work rate test. Secondary outcomes are functional capacity (6-min walk distance), health-related quality of life (Chronic Respiratory Disease Questionnaire (CRQ), St George’s Respiratory Questionnaire idiopathic pulmonary fibrosis specific version (SGRQ-I), breathlessness (Dyspnoea 12, Modified Medical Research Council Dyspnoea Scale), fatigue (fatigue severity scale), anxiety (Hospital Anxiety and Depression Scale), physical activity level (GeneActiv), skeletal muscle changes (ultrasonography) and completion and adherence to pulmonary rehabilitation.DiscussionThe standard exercise training strategies used in pulmonary rehabilitation may not provide an optimal exercise training stimulus for people with interstitial lung disease. This study will determine whether high intensity interval training can produce equivalent or even superior changes in exercise performance and symptoms. If high intensity interval training proves effective, it will provide an exercise training strategy that can readily be implemented into clinical practice for people with interstitial lung disease.Trial registrationClinicalTrials.gov Registry (NCT03800914). Registered 11 January 2019,https://clinicaltrials.gov/ct2/show/NCT03800914Australian New Zealand Clinical Trials Registry ACTRN12619000019101. Registered 9 January 2019,https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376050&isReview=true

IntroductionRecent 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 analysisA 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.Ethics and disseminationEthics approval has been granted in Australia by the Metro South Human Research Ethics Committee (HREC/2020/QMS/66385). The study will be conducted and reported according to Standard Protocol Items: Recommendations for Interventional Trials guidelines. Results will be published in peer-reviewed journals and presented at international and national conferences.Trial registration numbersNCT04638517; Australian New Zealand Clinical Trials Registry (ACTRN12620001363976p).

Dyspnoea is a cardinal symptom of fibrotic interstitial lung disease (ILD), with a lack of proven effective therapies. With emerging evidence of the role of facial and nasal airflow for relieving breathlessness, this pilot study was conducted to examine the feasibility of conducting a clinical trial of a handheld fan (HHF) for dyspnoea management in patients with fibrotic ILD. In this mixed-methods, randomised, assessor-blinded, controlled trial, 30 participants with fibrotic ILD who were dyspnoeic with a modified Medical Research Council Dyspnoea grade ≥ 2 were randomised to a HHF for symptom control or no intervention for 2 weeks. Primary outcomes were trial feasibility, change in Dyspnoea-12 scores at Week 2, and participants’ perspectives on using a HHF for dyspnoea management. Study recruitment was completed within nine months at a single site. Successful assessor blinding was achieved in the fan group [Bang’s Blinding Index − 0.08 (95% CI − 0.45, 0.30)] but not the control group [0.47 (0.12, 0.81)]. There were no significant between-group differences for the change in Dyspnoea-12 or secondary efficacy outcomes. During qualitative interviews, participants reported that using the HHF relieved breathlessness and provided relaxation, despite initial scepticism about its therapeutic benefit. Oxygen-experienced participants described the HHF being easier to use, but not as effective for symptomatic relief, compared to oxygen therapy. Our results confirmed the feasibility of a clinical trial of a HHF in fibrotic ILD. There was a high level of patient acceptance of a HHF for managing dyspnoea, with patients reporting both symptomatic benefits and ease of use.

IntroductionInterstitial lung diseases are characterised by scarring of lung tissue that leads to reduced transfer of oxygen into the blood, decreased exercise capacity and premature death. Ambulatory oxygen therapy may be used to treat exertional oxyhaemoglobin desaturation, but there is little evidence to support its efficacy and there is wide variation in clinical practice. This study aims to compare the clinical efficacy and cost-effectiveness of ambulatory oxygen versus ambulatory air in people with fibrotic interstitial lung disease and exertional desaturation.Methods and analysisA randomised, controlled trial with blinding of participants, clinicians and researchers will be conducted at trial sites in Australia and Sweden. Eligible participants will be randomised 1:1 into two groups. Intervention participants will receive ambulatory oxygen therapy using a portable oxygen concentrator (POC) during daily activities and control participants will use an identical POC modified to deliver air. Outcomes will be assessed at baseline, 3 months and 6 months. The primary outcome is change in physical activity measured by number of steps per day using a physical activity monitor (StepWatch). Secondary outcomes are functional capacity (6-minute walk distance), health-related quality of life (St George Respiratory Questionnaire, EQ-5D-5L and King’s Brief Interstitial Lung Disease Questionnaire), breathlessness (Dyspnoea-12), fatigue (Fatigue Severity Scale), anxiety and depression (Hospital Anxiety and Depression Scale), physical activity level (GENEActive), oxygen saturation in daily life, POC usage, and plasma markers of skeletal muscle metabolism, systematic inflammation and oxidative stress. A cost-effectiveness evaluation will also be undertaken.Ethics and disseminationEthical approval has been granted in Australia by Alfred Hospital Human Research Ethics Committee (HREC/18/Alfred/42) with governance approval at all Australian sites, and in Sweden (Lund Dnr: 2019-02963). The results will be published in peer-reviewed scientific journals, presented at conferences and disseminated to consumers in publications for lay audiences.Trial registration numberClinicalTrials.gov Registry (NCT03737409).

Hypoxemia is a cardinal feature of fibrotic interstitial lung disease (ILD). The incidence, progression, and prognostic significance of hypoxemia in patients with fibrotic ILD currently is unknown.What are the epidemiologic features of hypoxemia and its additive prognostic value in a current risk prediction model of fibrotic ILD?We identified 848 patients with fibrotic ILD (258 with idiopathic pulmonary fibrosis [IPF]) in five prospective ILD registries from Australia, Canada, and Switzerland. Cumulative incidence of exertional and resting hypoxemia from the time of diagnosis was estimated at 1-year intervals in patients with baseline 6-min walk tests, adjusted for competing risks of death and lung transplantation. Likelihood ratio tests were used to determine the prognostic significance of exertional and resting hypoxemia for 1-year mortality or transplantation when added to the ILD-GAP model. The cohort was divided into derivation and validation subsets to evaluate performance characteristics of the extended model (the ILD-GAP-OThe 1-, 2-, and 5-year overall cumulative incidence was 6.1%, 17.3%, and 40.1%, respectively, for exertional hypoxemia and 2.4%, 5.6%, and 16.5%, respectively, for resting hypoxemia, which were significantly higher in patients with IPF compared with patients without IPF (P .001 for both). Addition of exertional or resting hypoxemia to the ILD-GAP model improved 1-year mortality and transplantation prediction (P .001 for both). The ILD-GAP-OPatients with IPF have higher cumulative incidence of exertional and resting hypoxemia than patients without IPF. The extended ILD-GAP-O

In addition to facilitating healthcare delivery planning, reliable information about prognosis is essential for treatment decisions in patients with idiopathic pulmonary fibrosis (IPF). This review aimed to evaluate the prognosis of patients with IPF without anti-fibrotic therapy. We included all cohort studies and the placebo arms of randomised controlled trials (RCTs) in IPF and follow-up of ≥12 months. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. A total of 154 cohort studies and 16 RCTs were included. The pooled proportions of mortality were 0.12 (95% CI 0.09–0.14) at 1–2 years, 0.38 (95% CI 0.34–0.42) between 2–5 years, and 0.69 (95% CI 0.59–0.78) at ≥5 years. The pooled mean overall survival was 4 years (95% CI 3.7–4.6) for studies with a follow-up duration of 10 years. At versuscohort study participants (0.14 (95% CI 0.12–0.17)). This review provides comprehensive information on the prognosis of IPF, which can inform treatment discussions with patients and comparisons for future studies with new therapies.

Background and objective Current guidelines for the diagnosis of idiopathic pulmonary fibrosis (IPF) provide specific criteria for diagnosis in the setting of multidisciplinary discussion (MDD). We evaluate the utility and reproducibility of these diagnostic guidelines, using clinical data from the Australian IPF Registry. Methods All patients enrolled in the registry undergo a diagnostic review whereby international IPF guidelines are applied via a registry MDD. We investigated the clinical applicability of these guidelines with regard to: (i) adherence to guidelines, (ii) Natural history of IPF diagnostic categories and (iii) Concordance for diagnostic features. Results A total of 417 participants (69% male, 70.6 ± 8.0 years) with a clinical diagnosis of IPF underwent MDD. The 23% of participants who did not meet IPF diagnostic criteria displayed identical disease behaviour to those with confirmed IPF. Honeycombing on radiology was associated with a worse prognosis and this translated into poorer prognosis in the ‘definite’ IPF group. While there was moderate agreement for IPF diagnostic categories, agreement for specific radiological features, other than honeycombing, was poor. Conclusion In clinical practice, physicians do not always follow IPF diagnostic guidelines. We demonstrate a cohort of IPF patients who do not meet IPF diagnostic guideline criteria, based largely on their radiology and lack of lung biopsy, but who have outcomes identical to those with IPF.

BACKGROUND: The aim of this work was to investigate the short- and long-term test-retest reliability of the 6-min walk distance (6MWD), peak heart rate, and nadir oxygen desaturation in idiopathic pulmonary fibrosis (IPF). METHODS: A reliability study of 70 adults with IPF was undertaken within out-patient pulmonary rehabilitation programs at 2 tertiary hospitals. Participants completed 2 baseline 6-min walk tests using a standard protocol, with continuous measures of percutaneous SpO2 and heart rate via pulse oximetry. The 6-min walk test was completed immediately following an intervention period and 6 months after. Reproducibility was assessed by intraclass correlation coefficient and Bland-Altman analysis. RESULTS: Participants with a mean ± SD diffusing capacity of the lung for carbon monoxide of 48 ± 14% were included. The reliability of the 6MWD was high (intraclass correlation coefficient = 0.96) with a mean learning effect of 21 m (95% CI 12–30 m). The learning effect persisted at 8 weeks (mean 14 m, 95% CI 5–23 m) but not 6 months (mean 15 m, 95% CI −1 to 30 m). Using the best (greatest) 6MWD significantly reduced the proportion of participants who were classified as having a clinically important response to rehabilitation compared with using the first 6MWD (40% vs 54%, P = .002). Nadir SpO2 was reproducible, with a mean difference of 0.7 ± 2.2%, and limits of agreement of −4 to 5%. Peak heart rate was more variable, with mean difference 5 ± 9 beats/min and limits of agreement of −12 to 20 beats/min. CONCLUSIONS: The 6MWD is a reproducible measure of exercise capacity in people with IPF. Whereas the nadir SpO2 may be accurately determined from one test, evaluating change in 6MWD with interventions may require 2 tests on each occasion. (ClinicalTrials.gov registration NCT0016828.)

Rationale: Current diagnosis of chronic hypersensitivity pneumonitis (cHP) involves considering a combination of clinical, radiological, and pathological information in multidisciplinary team discussions. However, this approach is highly variable with poor agreement between centers. Objectives: We aimed to identify diagnostic criteria for cHP that reach consensus among international experts. Methods: A three-round modified Delphi survey was conducted between April and August 2017. A total of 45 experts in interstitial lung disease from 14 countries participated in the online survey. Diagnostic items included in round 1 were generated using expert interviews and literature review. During rounds 1 and 2, experts rated the importance of each diagnostic item on a 5-point Likert scale. The a priori threshold of consensus was 75% or greater of experts rating a diagnostic item as very important or important. In the third round, experts graded the items that met consensus as important and provided their level of diagnostic confidence for a series of clinical scenarios. Measurements and Main Results: Consensus was achieved on 18 of the 40 diagnostic items. Among these, experts gave the highest level of importance to the identification of a causative antigen, time relation between exposure and disease, mosaic attenuation on chest imaging, and poorly formed nonnecrotizing granulomas on pathology. In clinical scenarios, the diagnostic confidence of experts in cHP was heightened by the presence of these diagnostic items. Conclusions: This consensus-based approach for the diagnosis of cHP represents a first step toward the development of international guidelines for the diagnosis of cHP.

BackgroundIdiopathic pulmonary fibrosis (IPF) is a progressive lung disease in which circulatory biomarkers have the potential for guiding management in clinical practice. We assessed the prognostic role of serum biomarkers in three independent IPF cohorts: Australian Idiopathic Pulmonary Fibrosis Registry (AIPFR), Trent Lung Fibrosis (TLF) and Prospective Observation of Fibrosis in the Lung Clinical Endpoints (PROFILE).MethodsIn the AIPFR cohort, candidate proteins were assessed by ELISA as well as in an unbiased proteomic approach. LASSO (least absolute shrinkage and selection operator) regression was used to restrict the selection of markers that best accounted for the progressor phenotype at 1 year in the AIPFR cohort, and subsequently prospectively selected for replication in the validation TLF cohort and assessed retrospectively in the PROFILE cohort. Four significantly replicating biomarkers were aggregated into a progression index model based on tertiles of circulating concentrations.Results189 participants were included in the AIPFR cohort, 205 participants from the TLF cohort and 122 participants from the PROFILE cohort. Differential biomarker expression was observed by ELISA and replicated for osteopontin, matrix metallopeptidase-7, intercellular adhesion molecule-1 and periostin for those with a progressor phenotype at 1 year. Proteomic data did not replicate. The progression index in the AIPFR, TLF and PROFILE cohorts predicted risk of progression, mortality and progression-free survival. A statistical model incorporating the progression index demonstrated the capacity to distinguish disease progression at 12 months, which was increased beyond the clinical GAP (gender, age and physiology) score model alone in all cohorts, and significantly so within the incidence-based TLF and PROFILE cohorts.ConclusionA panel of circulatory biomarkers can provide potentially valuable clinical assistance in the prognosis of IPF patients.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease associated with debilitating symptoms of dyspnoea and cough, resulting in respiratory failure, impaired quality of life and ultimately death. Diagnosing IPF can be challenging, as it often shares many features with other interstitial lung diseases. In this article, we summarise recent joint position statements on the diagnosis and management of IPF from the Thoracic Society of Australia and New Zealand and Lung Foundation Australia, specifically tailored for physicians across Australia and New Zealand. Main suggestions: A comprehensive multidisciplinary team meeting is suggested to establish a prompt and precise IPF diagnosis. Antifibrotic therapies should be considered to slow disease progression. However, enthusiasm should be tempered by the lack of evidence in many IPF subgroups, particularly the broader disease severity spectrum. Non-pharmacological interventions including pulmonary rehabilitation, supplemental oxygen, appropriate treatment of comorbidities and disease-related symptoms remain crucial to optimal management. Despite recent advances, IPF remains a fatal disease and suitable patients should be referred for lung transplantation assessment.

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2–5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death. Until recently, there were no effective therapies for IPF; however, with the publication of two landmark clinical trials in 2014, the anti-fibrotic therapies, nintedanib and pirfenidone, have gained widespread approval. This position paper aims to highlight the current evidence for the treatment of IPF, with particular application to the Australian and New Zealand population. We also consider areas in which evidence is currently lacking, especially with regard to the broader IPF severity spectrum and treatment of co-morbid conditions. The utility of non-pharmacological therapies including pulmonary rehabilitation, oxygen as well as symptom management thought to be important in the holistic care of IPF patients are also discussed.

Interstitial lung disease (ILD) in systemic sclerosis (SSc) is a major cause of morbidity and mortality, mostly presenting as non-specific interstitial pneumonia. Little is known about the prevalence of pleuroparenchymal fibroelastosis (PPFE), a specific entity affecting the visceral pleura and subpleural parenchyma. We set out to estimate PPFE prevalence in two large cohorts of SSc patients and to assess its impact on survival and functional decline.A total of 359 SSc patients, derived from two referral centres in two different countries (UK and Italy), were included. The first available high-resolution computed tomography scan was independently evaluated by two radiologists blind to clinical information, to quantify ILD extent, freestanding bronchial abnormalities, and lobar percentage involvement of PPFE on a four-point categorical scale. Discordant scores were adjudicated by a third scorer. PPFE extent was further classified as limited (≤2/18) or extensive (>2/18). Results were evaluated against functional decline and mortality.The overall prevalence of PPFE in the combined SSc population was 18% (11% with extensive PPFE), with no substantial difference between the two cohorts. PPFE was significantly linked to free-standing bronchial abnormalities (61% versus 25% in PPFE versus no PPFE; pIn the current study, we provide an exhaustive description of PPFE prevalence and clinical impact in the largest cohort of SSc subjects published so far. PPFE presence should be carefully considered, due to its significant prognostic implications.

Idiopathic pulmonary fibrosis (IPF) is a chronic disease characterised by progressive decline in pulmonary function. The rate of decline can vary, with some patients remaining stable over longer periods of time and others rapidly progressing [1]. tThe variable progression of this disease makes it difficult to elucidate pathogenic pathways involved in the initiation and progression of IPF. Advances in high-throughput gene-expression analyses have led to improvements in our understanding of disease biology and prognostic gene signatures. We hypothesise that IPF has a unique circulatory transcriptional profile compared to healthy controls, with additional differences between stable and progressive disease likely related to disease pathogenesis. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Miss Clynick has nothing to disclose. Conflict of interest: Dr. Jo has nothing to disclose. Conflict of interest: Dr. Corte has nothing to disclose. Conflict of interest: Dr. Glaspole has nothing to disclose. Conflict of interest: Dr. Grainge has nothing to disclose. Conflict of interest: Dr. Hopkins has nothing to disclose. Conflict of interest: Dr. Reynolds has nothing to disclose. Conflict of interest: Dr. Chapman has nothing to disclose. Conflict of interest: Dr. Walters has nothing to disclose. Conflict of interest: Dr. Zappala has nothing to disclose. Conflict of interest: Dr. Keir has nothing to disclose. Conflict of interest: Dr. Cooper has nothing to disclose. Conflict of interest: Dr. Mahar has nothing to disclose. Conflict of interest: Dr. Ellis has nothing to disclose. Conflict of interest: Dr. Goh has nothing to disclose. Conflict of interest: Dr. Baltic has nothing to disclose. Conflict of interest: Miss Ryan has nothing to disclose. Conflict of interest: Dr. Tan has nothing to disclose. Conflict of interest: Dr. Moodley has nothing to disclose.

Despite a lack of evidence, ambulatory oxygen therapy is frequently prescribed for patients with interstitial lung disease (ILD) and exertional desaturation. Patients often prefer portable oxygen concentrators to oxygen cylinders. This study aimed to examine the feasibility of conducting a clinical trial of ambulatory oxygen delivered via portable concentrators in patients with ILD.Is it feasible to conduct a clinical trial of ambulatory oxygen delivered via portable concentrators in patients with ILD?In this randomized, triple-blinded, sham-controlled trial, 30 participants with ILD and isolated exertional desaturation to 90% on 6-minute walk tests were randomized to 12-week ambulatory oxygen or air delivered via portable concentrators, with assessments performed at baseline and weeks 4, 12, and 18. Primary outcomes were trial feasibility and the change in 6-minute walk distance (6MWD) on room air at week 12.Study recruitment was completed within 18 months, with six withdrawals. Participant blinding was successful, with the Bang's Blinding Index being 0 (95% CI, -0.40 to 0.40) for the oxygen group and 0 (95% CI, -0.42 to 0.42) for the sham group. No significant difference in 6MWD was seen between groups at week 12 (mean difference of -34 m [95% CI, -105 to 36], P = .34). For secondary outcomes, compared with the sham group, the oxygen group had a significantly higher Leicester Cough Questionnaire psychological domain score, indicating better cough-related quality of life (mean difference of 0.9 [95% CI, 0.2 to 1.6], P = .01), but a shorter duration of moderate-to-vigorous activities (mean difference of -135 [95% CI, -267 to -3], P = .04) at week 12.Based on the results of this pilot study, a definitive randomized controlled trial with a longer intervention duration is warranted to clarify therapeutic impacts of ambulatory oxygen in patients with ILD.Australian New Zealand Clinical Trials Registry; No.: ACTRN12617000054314; URL: www.anzctr.org.au/.

Objective To evaluate the inter-rater and intra-rater reliability of the hand held dynamometer in measuring muscle strength in people with interstitial lung disease (ILD). Design Test retest reliability of hand-held dynamometry for elbow flexor and knee extensor strength between two independent raters and two testing sessions. Setting Physiotherapy department within a tertiary hospital. Participants Thirty participants with ILD of varying aetiology were included. Twenty participants completed the inter-rater reliability protocol (10 idiopathic pulmonary fibrosis, mean (SD) age 73 (10) years, 11 male) and 21 participants completed the intra-rater reliability protocol (10 idiopathic pulmonary fibrosis, mean age 71 (10) years, 11 male). Main outcome measures Mean muscle strength (kg). Agreement between the two raters and testing sessions was analyzed using Bland–Altman plots and reliability was estimated using intraclass correlation coefficients (ICC). Results For elbow flexor strength there was a mean difference between raters of −0.6kg (limits of agreement (LOA) −5.6 to 4.4kg) and within raters of −0.3kg (LOA −2.8 to 2.3kg). The ICCs were 0.95 and 0.98, respectively. For knee extensor strength there was a mean difference between raters of −1.5kg (LOA −6.9 to 3.9kg) and within raters of −0.7kg (LOA −3.9 to 2.4kg). The ICCs were 0.95 and 0.97, respectively. Conclusions Hand-held dynamometry is reliable in measuring elbow flexor and knee extensor strength in people with ILD.

Long-term oxygen therapy (LTOT) is universally accepted as standard care for patients with severe resting hypoxaemia, irrespective of underlying diagnosis, with the aim being to improve patient survival. Chronic obstructive pulmonary disease (COPD) and fibrotic interstitial lung disease (ILD) are the two most common indications for LTOT globally [1–4]. As therapeutic benefits of LTOT have only been established in patients with COPD [5, 6], current prescribing recommendations are based on the study entry criteria used in the pivotal clinical trials of LTOT in COPD [5, 6]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of interest: Dr. Khor reports in-kind clinical trial support from Air Liquide Healthcare, grants and personal fees from Boehringer Ingelheim, and personal fees from Roche, outside the submitted work. Conflict of interest: Dr. Harrison has nothing to disclose. Conflict of interest: Dr. Robinson has nothing to disclose. Conflict of interest: Dr. Goh reports in-kind clinical trial support from Air Liquide Healthcare, grants and personal fees from Boehringer Ingelheim, and personal fees from Roche, outside the submitted work. Conflict of interest: Dr. Glaspole reports personal fees from Boehringer Ingelheim, Roche, and Menarini, outside the submitted work. Conflict of interest: Dr. McDonald reports in-kind clinical trial support from Air Liquide Healthcare, grants from Boehringer Ingelheim, personal fees from GSK and Novartis, and others from Menarini, outside the submitted work.

BackgroundPeople with pulmonary fibrosis often experience a protracted time to diagnosis, high symptom burden and limited disease information. This review aimed to identify the supportive care needs reported by people with pulmonary fibrosis and their caregivers.MethodsA systematic review was conducted according to PRISMA guidelines. Studies that investigated the supportive care needs of people with pulmonary fibrosis or their caregivers were included. Supportive care needs were extracted and mapped to eight pre-specified domains using a framework synthesis method.ResultsA total of 35 studies were included. The most frequently reported needs were in the domain of information/education, including information on supplemental oxygen, disease progression and prognosis, pharmacological treatments and end-of-life planning. Psychosocial/emotional needs were also frequently reported, including management of anxiety, anger, sadness and fear. An additional domain of “access to care” was identified that had not been specified a priori; this included access to peer support, psychological support, specialist centres and support for families of people with pulmonary fibrosis.ConclusionPeople with pulmonary fibrosis report many unmet needs for supportive care, particularly related to insufficient information and lack of psychosocial support. These data can inform the development of comprehensive care models for people with pulmonary fibrosis and their loved ones.

Blood monocytes have been recently proposed as a potential prognostic marker for IPF. Data from the Australian IPF registry have shown that elevated monocytes, neutrophils and total leukocytes significantly predict poorer survival in IPF patients.http://bit.ly/38GP7f0

BACKGROUND AND OBJECTIVE: Patients with interstitial lung disease (ILD) are often prescribed disease-targeted and symptomatic therapies, both of which can cause significant treatment burden due to polypharmacy and drug-disease interactions. This study aimed to evaluate medication regimen complexity before and after introduction of ILD-specific therapies. Potential drug-disease interactions were evaluated for patients who were prescribed prednisolone. METHODS: In this study, 214 patients with ILD were assessed for demographic information, co-morbidities and medication use. Medication lists were reviewed prior to and after the introduction of ILD-specific therapies. Complexity of treatment regimen was examined using the validated Medication Regimen Complexity Index (MRCI). RESULTS: Of the 214 patients, 75 had idiopathic pulmonary fibrosis (IPF) while the rest had inflammatory ILD (chronic hypersensitivity pneumonitis: 45; connective tissue disease-related ILD: 41). Polypharmacy was common at baseline (IPF: 51%, inflammatory ILD: 63%). Following introduction of ILD-specific therapies, median total MRCI scores significantly increased from 8 (interquartile range (IQR) = 8-15) to 22.5 (17.5-27.5) and 14.5 (8.5-21) to 21.5 (16-30) for IPF and inflammatory ILD groups, respectively (P < 0.0001 for both). Complex dosing instructions contributed the most to total MRCI scores for ILD-specific therapies. Among patients receiving prednisolone (n = 113), 88% had ≥1 co-morbidity which may be impacted. Common co-morbidities included gastrointestinal diseases (56%), obesity (37%), osteoporosis (24%) and diabetes mellitus (18%). CONCLUSION: Polypharmacy and complex medication regimen are common in patients with ILD of different aetiologies. There is a high frequency of potential drug-disease interactions among patients who are prescribed systemic corticosteroids. These findings highlight the need for careful evaluation of the impact of therapeutic complexity and burden in patients with ILD.

BACKGROUND: Approximately one‐third of individuals with interstitial lung disease (ILD) have associated connective tissue disease (CTD). The connective tissue disorders most commonly associated with ILD include scleroderma/systemic sclerosis (SSc), rheumatoid arthritis, polymyositis/dermatomyositis, and Sjögren's syndrome. Although many people with CTD‐ILD do not develop progressive lung disease, a significant proportion do progress, leading to reduced physical function, decreased quality of life, and death. ILD is now the major cause of death amongst individuals with systemic sclerosis. Cyclophosphamide is a highly potent immunosuppressant that has demonstrated efficacy in inducing and maintaining remission in autoimmune and inflammatory illnesses. However this comes with potential toxicities, including nausea, haemorrhagic cystitis, bladder cancer, bone marrow suppression, increased risk of opportunistic infections, and haematological and solid organ malignancies. Decision‐making in the treatment of individuals with CTD‐ILD is difficult; the clinician needs to identify those who will develop progressive disease, and to weigh up the balance between a high level of need for therapy in a severely unwell patient population against the potential for adverse effects from highly toxic therapy, for which only relatively limited data on efficacy can be found. Similarly, it is not clear whether histological subtype, disease duration, or disease extent can be used to predict treatment responsiveness. OBJECTIVES: To assess the efficacy and adverse effects of cyclophosphamide in the treatment of individuals with CTD‐ILD. SEARCH METHODS: We performed searches on CENTRAL, MEDLINE, Embase, CINAHL, and Web of Science up to May 2017. We handsearched review articles, clinical trial registries, and reference lists of retrieved articles. SELECTION CRITERIA: We included randomised controlled parallel‐group trials that compared cyclophosphamide in any form, used individually or concomitantly with other immunomodulating therapies, versus non‐cyclophosphamide‐containing therapies for at least six months, with follow‐up of at least 12 months from the start of treatment. DATA COLLECTION AND ANALYSIS: We imported studies identified by the search into a reference manager database. We retrieved the full‐text versions of relevant studies, and two review authors independently extracted data. Primary outcomes were change in lung function (change in forced vital capacity (FVC) % predicted and diffusing capacity of the lung for carbon monoxide (DLCO) % predicted), adverse events, and health‐related quality of life measures. Secondary outcomes included all‐cause mortality, dyspnoea, cough, and functional exercise testing. When appropriate, we performed meta‐analyses and subgroup analyses by severity of lung function, connective tissue disease diagnosis, and radiological pattern of fibrosis. We assessed the evidence using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach and created 'Summary of findings' tables. MAIN RESULTS: We included in the analysis four trials with 495 participants (most with systemic sclerosis). We formed two separate comparisons: cyclophosphamide versus placebo (two trials, 195 participants) and cyclophosphamide versus mycophenolate (two trials, 300 participants). We found evidence to be of low quality, as dropout rates were high in the intervention groups, and as we noted a wide confidence interval around the effect with small differences, which affected the precision of results. The data demonstrates significant improvement in lung function with cyclophosphamide compared with placebo (post‐treatment FVC % mean difference (MD) 2.83, 95% confidence interval (CI) 0.80 to 4.87; P = 0.006) but no significant difference in post‐treatment DLCO (% MD ‐1.68, 95% CI ‐4.37 to 1.02; P = 0.22; two trials, 182 participants). Risk of adverse effects was increased in the cyclophosphamide treatment groups compared with the placebo groups, in particular, haematuria, leukopenia, and nausea, leading to a higher rate of withdrawal from cyclophosphamide treatment. The data demonstrates statistically significant improvement in one‐measure of quality of life in one trial favouring cyclophosphamide over placebo and clinically and statistically significant improvement in breathlessness in one trial favouring cyclophosphamide compared with placebo, with no significant impact on mortality. Trialists reported no significant impact on lung function when cyclophosphamide was used compared with mycophenolate at 12 months (FVC % MD ‐0.82, 95% CI ‐3.95 to 2.31; P = 0.61; two trials, 149 participants; DLCO % MD ‐1.41, 95% CI ‐10.40 to 7.58; P = 0.76; two trials, 149 participants). Risk of side effects was increased with cyclophosphamide versus mycophenolate, in particular, leukopenia and thrombocytopenia. The data demonstrates no significant impact on health‐related quality of life, all‐cause mortality, dyspnoea, or cough severity in the cyclophosphamide group compared with the mycophenolate group. No trials reported outcomes associated with functional exercise tests. We performed subgroup analysis to determine whether severity of lung function, connective tissue disease diagnosis, or radiological pattern had any impact on outcomes. One trial reported that cyclophosphamide protected against decreased FVC in individuals with worse fibrosis scores, and also showed that cyclophosphamide may be more effective in those with worse lung function. No association could be made between connective tissue disease diagnosis and outcomes. AUTHORS' CONCLUSIONS: This review, which is based on studies of varying methodological quality, demonstrates that overall, in this population, small benefit may be derived from the use of cyclophosphamide in terms of mean difference in % FVC when compared with placebo, but not of the difference in % DLCO, or when compared with mycophenolate. Modest clinical improvement in dyspnoea may be noted with the use of cyclophosphamide. Clinical practice guidelines should advise clinicians to consider individual patient characteristics and to expect only modest benefit at best in preserving FVC. Clinicians should carefully monitor for adverse effects during treatment and in the years thereafter. Further studies are required to examine the use of cyclophosphamide; they should be adequately powered to compare outcomes within different subgroups, specifically, stratified for extent of pulmonary infiltrates on high‐resolution computed tomography (HRCT) and skin involvement in SSc. Studies on other forms of connective tissue disease are needed. Researchers may consider comparing cyclophosphamide (a potent immunosuppressant) versus antifibrotic agents, or comparing both versus placebo, in particular, for those with evidence of rapidly progressive fibrotic disease, who may benefit the most.

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. Electronic supplementary material The online version of this article (10.1186/s12890-018-0575-y) contains supplementary material, which is available to authorized users.

Domiciliary oxygen therapy (DOT) is commonly prescribed for patients with interstitial lung disease (ILD) and hypoxemia, although evidence supporting benefit is limited.The aim of this study was to explore perspectives of respiratory physicians about DOT in patients with ILD.A qualitative study was undertaken with 26 respiratory physicians from Australia. Interviews were transcribed verbatim and coded independently by two investigators. Themes were established by consensus.Physicians reported symptomatic relief as the main indication for prescribing DOT in ILD. Concerns were raised regarding the applicability of current clinical guidelines for DOT to ILD. Compared with patients with other lung diseases, there was a lower threshold for DOT prescription for patients with ILD. Physicians perceived that patients with ILD complied better with recommended DOT prescription. There was significant variation in infrastructure for oxygen assessment and prescription, patient support, and equipment provision among institutions and states. Various patients' attitudes and experiences toward DOT were reported, but most notable was physicians' perception of significant anxiety in most patients using DOT because of social stigma and concerns that DOT signified end-stage disease.Oxygen therapy was primarily prescribed for symptomatic management in patients with ILD. Education provision and supports regarding DOT varied significantly.

Domiciliary oxygen therapy is commonly prescribed for patients with interstitial lung disease and hypoxemia, either at rest or during exertion, with the aim of improving symptoms and functional status.This study aimed to explore perspectives of adults with interstitial lung disease about domiciliary oxygen therapy, comparing insights from patients using and not using oxygen therapy.A qualitative study using semistructured interviews was undertaken on 24 adults residing in and near Melbourne, Australia who had a diagnosis of interstitial lung disease and met the Thoracic Society of Australia and New Zealand guidelines for domiciliary oxygen therapy. Study subjects included individuals who were oxygen-naive (n = 12) and oxygen-experienced (n = 12). Interviews were transcribed verbatim and coded independently by two investigators in accordance with the grounded theory method of analysis. Themes were established by consensus.Patients using domiciliary oxygen therapy described widespread variation in usage. Oxygen-naive patients expected oxygen therapy to relieve dyspnea, whereas oxygen-experienced patients emphasized the benefits of oxygen on other, non-dyspnea-related physical symptoms. Practical and psychosocial challenges of using oxygen therapy were raised by both groups of patients.This study highlights the different expectations and experiences of domiciliary oxygen therapy for adults with interstitial lung disease. It is important to understand and address patients' concerns about the use of oxygen therapy for these patients.

Ambulatory oxygen therapy is often provided to patients with interstitial lung disease (ILD). Lightweight portable oxygen concentrators (POCs) provide an alternative to traditional portable systems such as compressed oxygen cylinders; however, their efficacy in patients with ILD has not been assessed. This study aimed to evaluate the clinical performance of three ambulatory oxygen systems (two different POCs and a compressed oxygen cylinder) during 6-min walk tests (6MWTs) in patients with ILD and exertional desaturation.A total of 20 participants with ILD of varying aetiologies who demonstrated exertional desaturation to90% on room air during 6MWT were recruited. Each participant performed two 6MWTs while breathing room air. On a subsequent day, two further 6MWTs were performed, in random order: one breathing oxygen via a POC (either the Inogen One G2 POC or the EverGo POC at the setting of 6) and one with a compressed oxygen cylinder (at 5 L/min).There were no significant differences in nadir oxygen saturation (SpOThe performance of the Inogen One G2 POC and the EverGo POC had comparable performance with that of the compressed oxygen cylinder during walking in patients with ILD and exertional desaturation.

Objective.Biomarkers of progression of interstitial lung disease (ILD) are needed to allow early therapeutic intervention in patients with scleroderma-associated disease (SSc-ILD).Methods.A panel of 8 serum cytokines [interleukin 6 (IL-6), IL-8, IL-10, CCL2, CXCL10, vascular endothelial growth factor, fibroblast growth factor 2, and CX3CL1] was assessed by Luminex bead technology in exploratory cohorts of 74 patients with SSc and 58 patients with idiopathic pulmonary fibrosis (IPF). Mortality and significant lung function decline [forced vital capacity (FVC) ≥ 10%; DLCO ≥ 15%] from date of serum collection were evaluated by proportional hazards analysis. Based on these findings, the prognostic value of serum IL-6, evaluated by ELISA, was assessed in a larger test cohort of 212 patients with SSc-ILD.Results.In the exploratory cohort, only serum IL-6 was an independent predictor of DLCO decline in both IPF and SSc-ILD. The IL-6 threshold level most predictive of DLCO decline within a year was 7.67 pg/ml. In the larger test cohort, serum IL-6 > 7.67 pg/ml was predictive of decline in FVC (HR 2.58 ± 0.98, p = 0.01) and in DLCO (HR 3.2 ± 1.7, p = 0.02) within the first year, and predictive of death within the first 30 months (HR 2.69 ± 0.96, p = 0.005). When stratified according to severity (FVC < 70%), serum IL-6 > 7.67 pg/ml was predictive of functional decline or death within the first year in patients with milder disease (OR 3.1, 95% CI 1.4–7.2, p = 0.007), but not in those with severe ILD.Conclusion.In SSc-ILD, serum IL-6 levels appear to be predictive of early disease progression in patients with mild ILD, and could be used to target treatment in this group, if confirmed by prospective studies.

This review aims to establish the impact of oxygen therapy on dyspnoea, health-related quality of life (HRQoL), exercise capacity and mortality in interstitial lung disease (ILD).We included studies that compared oxygen therapy to no oxygen therapy in adults with ILD. No limitations were placed on study design or intervention type. Two reviewers independently evaluated studies for inclusion, assessed risk of bias and extracted data. The primary outcome was dyspnoea.Eight studies evaluated the acute effects of oxygen (n=1509). There was no effect of oxygen therapy on modified Borg dyspnoea score at end exercise (mean difference (MD) −0.06 units, 95% CI −0.24–0.13; two studies, n=27). However, effects on exercise outcomes consistently favoured oxygen therapy. One study showed reduction in dyspnoea at rest with oxygen in patients who were acutely unwell (MD visual analogue scale 30 mm versus 48 mm, pThis systematic review showed no effects of oxygen therapy on dyspnoea during exercise in ILD, although exercise capacity was increased. Future trials should evaluate whether acute improvements in exercise capacity with oxygen can be translated into improved physical activity and HRQoL.

The prevalence of idiopathic pulmonary fibrosis (IPF), a fatal and progressive lung disease, is estimated at 1.25–63 out of 100 000, making large population studies difficult. Recently, the need for large longitudinal registries to study IPF has been recognised.The Australian IPF Registry (AIPFR) is a national registry collating comprehensive longitudinal data of IPF patients across Australia. We explored the characteristics of this IPF cohort and the effect of demographic and physiological parameters and specific management on mortality.Participants in the AIPFR (n=647, mean age 70.9±8.5 years, 67.7% male, median follow up 2 years, range 6 months–4.5 years) displayed a wide range of age, disease severity and co-morbidities that is not present in clinical trial cohorts. The cumulative mortality rate in year one, two, three and four was 5%, 24%, 37% and 44% respectively. Baseline lung function (forced vital capacity, diffusing capacity of the lung for carbon monoxide, composite physiological index) and GAP (gender, age, physiology) stage (hazard ratio 4.64, 95% CI 3.33–6.47, pThe AIPFR provides important insights into the understanding of the natural history and clinical management of IPF.

Supplemental oxygen is commonly prescribed in patients with idiopathic pulmonary fibrosis (IPF), although its benefits have not been proven. The aims of this study were to investigate the effect of oxygen on oxidative stress, cytokine production, skeletal muscle metabolism and physiological response to exercise in IPF.Eleven participants with IPF received either oxygen, at an FiOCompared with air, oxygen did not adversely affect biomarker concentrations at rest and significantly improved endurance time (mean difference = 99 ± 81s, P = 0.002), dyspnoea (-1 ± 1 U, P = 0.02), systolic blood pressure (BP; -11 ± 11 mm Hg, P = 0.006), nadir oxyhaemoglobin saturation (SpOIn patients with IPF, breathing oxygen at FiO

Background Uncertainty exists regarding the clinical relevance of exercise training across the range of interstitial lung diseases (ILDs). Objective To establish the impact of exercise training in patients with ILDs of differing aetiology and severity. Methods 142 participants with ILD (61 idiopathic pulmonary fibrosis (IPF), 22 asbestosis, 23 connective tissue disease-related ILD (CTD-ILD) and 36 with other aetiologies) were randomised to either 8 weeks of supervised exercise training or usual care. Six-minute walk distance (6MWD), Chronic Respiratory Disease Questionnaire (CRDQ), St George Respiratory Questionnaire IPF-specific version (SGRQ-I) and modified Medical Research Council dyspnoea score were measured at baseline, 9 weeks and 6 months. Measurements and main results Exercise training significantly increased 6MWD (25 m, 95% CI 2 to 47 m) and health-related quality of life (CRDQ and SGRQ-I) in people with ILD. Larger improvements in 6MWD, CRDQ, SGRQ-I and dyspnoea occurred in asbestosis and IPF compared with CTD-ILD, but with few significant differences between subgroups. Benefits declined at 6 months except in CTD-ILD. Lower baseline 6MWD and worse baseline symptoms were associated with greater benefit in 6MWD and symptoms following training. Greater gains were seen in those whose exercise prescription was successfully progressed according to the protocol. At 6 months, sustained improvements in 6MWD and symptoms were associated with better baseline lung function and less pulmonary hypertension. Conclusions Exercise training is effective in patients across the range of ILDs, with clinically meaningful benefits in asbestosis and IPF. Successful exercise progression maximises improvements and sustained treatment effects favour those with milder disease. Trial registration number Results, ACTRN12611000416998.

In a multi-centre study, we sought to determine whether extent of disease on high-resolution CT (HRCT) lung, reported using a simple grading system, is predictive of decline and mortality in SSc-related interstitial lung disease (SSc-ILD), independently of pulmonary function tests (PFTs) and other prognostic variables.SSc patients with a baseline HRCT performed at the time of ILD diagnosis were identified. All HRCTs and PFTs performed during follow-up were retrieved. Demographic and disease-related data were prospectively collected. HRCTs were graded according to the percentage of lung disease:20%: extensive;20%: limited; unclear: indeterminate. Indeterminate HRCTs were converted to limited or extensive using a forced vital capacity threshold of 70%. The composite outcome variable was deterioration (need for home oxygen or lung transplantation), or death.Among 172 patients followed for mean (s.d.) of 3.5 (2.9) years, there were 30 outcome events. In Weibull multivariable hazards regression modelling, baseline HRCT grade was independently predictive of outcome, with an adjusted hazard ratio (aHR) = 3.0, 95% CI 1.2, 7.5 and P = 0.02. In time-varying covariate models (based on 1309 serial PFTs and 353 serial HRCTs in 172 patients), serial diffusing capacity of the lung for carbon monoxide by alveolar volume ratio (ml/min/mmHg/l) (aHR = 0.4; 95% CI 0.3, 0.7; P = 0.001) and forced vital capacity (dl) (aHR = 0.9; 95% CI 0.8, 0.97; P = 0.008), were also strongly predictive of outcome.Extensive disease (20%) on HRCT at baseline, reported using a semi-quantitative grading system, is associated with a three-fold increased risk of deterioration or death in SSc-ILD, compared with limited disease. Serial PFTs are informative in follow-up of patients.

Summary Background Pulmonary rehabilitation improves functional capacity and symptoms in the interstitial lung diseases (ILDs), however there is marked variation in outcomes between individuals. The aim of this study was to establish the impact of the aetiology and severity of ILD on response to pulmonary rehabilitation. Methods Forty-four subjects with ILD, including 25 with idiopathic pulmonary fibrosis (IPF), underwent eight weeks of pulmonary rehabilitation. Relationships between disease aetiology, markers of disease severity and response to pulmonary rehabilitation were assessed after eight weeks and six months, regardless of program completion. Results In IPF, greater improvements in 6-minute walk distance (6MWD) immediately following pulmonary rehabilitation were associated with larger forced vital capacity ( r = 0.49, p = 0.01), less exercise-induced oxyhaemoglobin desaturation ( r S = 0.43, p = 0.04) and lower right ventricular systolic pressure ( r = −0.47, p = 0.1). In participants with other ILDs there was no relationship between change in 6MWD and baseline variables. Less exercise-induced oxyhaemoglobin desaturation at baseline independently predicted a larger improvement in 6MWD at six month follow-up. Fewer participants with IPF had clinically important reductions in dyspnoea at six months compared to those with other ILDs (25% vs 56%, p = 0.04). More severe dyspnoea at baseline and diagnosis other than IPF predicted greater improvement in dyspnoea at six months. Conclusions Patients with IPF attain greater and more sustained benefits from pulmonary rehabilitation when disease is mild, whereas those with other ILDs achieve benefits regardless of disease severity. Early referral to pulmonary rehabilitation should be considered in IPF.

Epithelial injury contributes to pathogenesis in idiopathic pulmonary fibrosis (IPF) but its role in the interstitial lung disease (ILD) of systemic sclerosis (SSc) is uncertain. We quantified the prognostic significance of inhaled technetium-99m ((99m)Tc)-labelled diethylene triamine pentacetate (DTPA) pulmonary clearance, a marker of the extent of epithelial injury, in both diseases. Baseline (99m)Tc-DTPA pulmonary clearance was evaluated retrospectively in patients with SSc-ILD (n = 168) and IPF (n = 97) against mortality and disease progression. In SSc-ILD, the rapidity of total clearance (hazard ratio (HR) 1.02, 95% CI 1.01-1.03; p = 0.001) and the presence of abnormally rapid clearance (HR 2.10; 95% CI 1.25-3.53; p = 0.005) predicted a shorter time to forced vital capcity (FVC) decline, independent of disease severity. These associations were robust in both mild and severe disease. By contrast, in IPF, delayed clearance of the slow component, an expected consequence of honeycomb change, was an independent predictor of a shorter time to FVC decline (HR 1.01, 95% CI 1.00-1.02; p

Pulmonary rehabilitation (PR) is recommended for people with interstitial lung disease (ILD); however, the educational content of PR was not designed for this group. This study explored the perspectives of patients and ILD clinicians regarding the educational content of PR for ILD. A qualitative study using individual semi-structured interviews was undertaken. Transcripts were coded independently by two investigators and themes established by consensus. Participants were 18 people with ILD (9 idiopathic pulmonary fibrosis, diffusing capacity for carbon monoxide 54 (20)% predicted) and 14 clinicians from 5 countries and 5 disciplines. Major themes from patient interviews were the importance of knowing what the future might bring and the need for honesty from clinicians. Most were happy to attend standard PR education sessions but wanted ILD-specific content. Patients wanted information about end-of-life planning and most were happy to discuss it in a group. Among clinicians, there was no consensus regarding whether prognosis should be discussed in PR. Most clinicians supported discussion of advanced care planning, however, some thought it should not be discussed in a group. We conclude that people with ILD have specific educational needs that may not be met in the current PR format. Patients and clinicians have some discordant views about programme content.

OBJECTIVE: The lack of randomized controlled trials (RCTs) in pulmonary fibrosis in systemic sclerosis (SSc) has hampered an evidence-based approach to treatment. This RCT was undertaken to investigate the effects of intravenous (IV) cyclophosphamide (CYC) followed by azathioprine (AZA) treatment in pulmonary fibrosis in SSc. METHODS: Forty-five patients were randomized to receive low-dose prednisolone and 6 infusions (monthly) of CYC followed by oral AZA, or placebo. Primary outcome measures were change in percent predicted forced vital capacity (FVC) and change in single-breath diffusing capacity for carbon monoxide (DLCO). Secondary outcome measures included changes in appearance on high-resolution computed tomography and dyspnea scores. An intent-to-treat statistical analysis was performed. RESULTS: At baseline, there were no significant group differences in factors linked to outcome, including severity of pulmonary fibrosis and autoantibody status. Sixty-two percent of the patients completed the first year of treatment. Withdrawals included 9 patients (6 from the placebo group) with significant decline in lung function, 2 with treatment side effects (both from the active treatment group), and 6 with non-trial-related comorbidity. No hemorrhagic cystitis or bone marrow suppression was observed. Estimation of the relative treatment effect (active treatment versus placebo) adjusted for baseline FVC and treatment center revealed a favorable outcome for FVC of 4.19%; this between-group difference showed a trend toward statistical significance (P = 0.08). No improvements in DLCO or secondary outcome measures were identified. CONCLUSION: This trial did not demonstrate significant improvement in the primary or secondary end points in the active treatment group versus the group receiving placebo. However, for FVC there was a trend toward statistical significance between the 2 groups. This suggests that treatment of pulmonary fibrosis in SSc with low-dose prednisolone and IV CYC followed by AZA stabilizes lung function in a subset of patients with the disease. Therapy was well tolerated with no increase in serious adverse events.

In idiopathic pulmonary fibrosis, the quantitation of disease severity using pulmonary function tests is often confounded by emphysema. We have identified the composite physiologic index (CPI) most closely reflecting the morphologic extent of pulmonary fibrosis. Consecutive patients with a clinical/computed tomography (CT) diagnosis of idiopathic pulmonary fibrosis (n = 212) were divided into group I (n = 106) and group II (n = 106). The CPI was derived in group I (by fitting pulmonary function tests against disease extent on CT) and was tested in Group II. The formula for the CPI was as follows: extent of disease on CT = 91.0 - (0.65 x percent predicted diffusing capacity for carbon monoxide [DLCO]) - (0.53 x percent predicted FVC) + (0.34 x percent predicted FEV1). In group II, the CPI correlated more strongly with disease extent on CT (r2 = 0.51) than the individual pulmonary function test (DLCO the highest value, r2 = 0.38). A subanalysis demonstrated that the better fit of the CPI was ascribable to a correction of the confounding effects of emphysema. Mortality was predicted more accurately by the CPI than by a pulmonary function test in all clinical subgroups, including a separate cohort of 36 patients with histologically proven usual interstitial pneumonia (CPI, p < 0.0005; FVC, p = 0.002; PO2, p = 0.002). In conclusion, a new CPI, derived against CT and validated using split sample testing, is a more accurate prognostic determinant in usual interstitial pneumonia than an individual pulmonary function test.

Langerhans cell histiocytosis (LCH) is a rare disorder which frequently involves the lungs of affected adults. Recent evidence suggests it is a clonal neoplastic disorder. Prognosis in this disease is variable, but in its multisystem form or when associated with progressive respiratory dysfunction, prognosis is poor. Recent case reports and a phase II trial of the antimonocyte drug 2-chlorodeoxy-adenosine (2CDA) have described success in treating LCH. We used 2CDA to treat a young Australian man with LCH involving lungs and bone. A complete symptomatic remission was achieved with no evidence of recurrence some 5 years after completion of chemotherapy.

Sarcoidosis is a granulomatous disease that has the immunopathological features of being antigen-driven. It is a complex disease that appears to arise from the interaction of one or more triggers with an immunologically predisposed host. Previous reports of familial clustering and varying prevalence of sarcoidosis in different populations could reflect differences in ethnic predisposition or differences in local environmental exposures. This review focuses specifically on these areas that have been the subjects of intensive investigation recently. Specific focus is provided on the issue of an infective trigger and highlights popular candidates. It is concluded that microbes are a likely trigger (but not as an infection) in a genetically predisposed individual and that this initial event culminates in the sarcoidosis granulomatous response.

We have recently shown that anxiety and depression are common comorbidities for people with interstitial lung disease (ILD). In a cross-sectional single-centre study, the prevalence of anxiety was 31% and the prevalence of depression was 23% [1]. Anxiety and depression were not related to physiological parameters; however, dyspnoea and number of comorbidities were important contributors. The aims of this study were to determine the frequency of prolonged anxiety and depression among sufferers of idiopathic pulmonary fibrosis (IPF), and factors contributing to their persistence., Prolonged anxiety and depression occur frequently in IPF and strongly relate to dyspnoea and cough http://ow.ly/iWxV30cLCfl

The prognosis of diffuse fibrotic lung disease (DFLD) is known to be variable, but there is a paucity of literature on prognostic markers independent of precise clinical diagnosis. This study aimed to assess the mortality prediction of three high-resolution computed tomography (HRCT) scores in a heterogeneous population of patients with DFLD. A large radiologist and physician reader group was used to determine agreement among readers of varying background in applying these scores.Institutional review board approval was obtained. Informed consent was waived for this retrospective study. Eighty HRCTs in 68 patients with DFLD (35 men, mean age 72.9 years) were evaluated retrospectively by 18 readers. Readers included thoracic and general radiologists, respiratory physicians and radiology trainees. Features scored were honeycombing, extent of disease and traction bronchiectasis. Demographics, diagnosis and pulmonary function data were collected. Patients were categorised as having either idiopathic pulmonary fibrosis, fibrosis relating to connective tissue disease, 'miscellaneous' DFLD or 'undefined', where no single entity was felt entirely or confidently to explain the pulmonary disease. Agreement was assessed using the kappa statistic. Associations with mortality were analysed using the Cox marginal model.Agreement was better for honeycombing (kappa = 0.44) and disease extent (kappa = 0.47) than traction bronchiectasis (kappa = 0.24). Honeycombing presence (P 0.0005) and disease extent30% (P = 0.002) predicted increased mortality independent of clinical diagnosis. Traction bronchiectasis was non-predictive. Clinical diagnosis was not an independent predictor, but age was independently associated with mortality (P = 0.004). Pulmonary function data were only available for 43 patients, but in a limited subanalysis, the diffusion capacity of carbon monoxide was independently predictive of increased mortality (P = 0.005).The presence of honeycombing and a greater extent of fibrotic lung disease predict increased mortality independent of clinical diagnosis. Our large, mixed-expertise reader group shows moderate interobserver agreement, comparable with agreement values for these scores in the literature.

Dear Editor, We read with interest the article by Wells et al 1 in which the problematic selection of primary end-points for treatment studies in idiopathic pulmonary fibrosis (IPF) patients is addressed. In this document endorsed by respiratory physicians across Europe, the authors explore the implications of using all-cause mortality as a primary end-point in response to a recent statement by a working group on this topic.2 In a rather controversial statement by this working group, Raghu et al suggested that all-cause mortality and all-cause non-elective hospitalisation are the strongest and cleanest clinically meaningful end-points for use in Phase 3 clinical …

SummaryBackgroundReduced chronotropic response to maximal exercise has been associated with poor survival in people without respiratory disease. The contribution of chronotropic response to exercise limitation and survival in interstitial lung disease (ILD) is not well defined. This study investigated the relationships between chronotropic response during 6-min walk test, exercise capacity and survival in ILD.MethodsEligible participants had ILD, were ambulant and free of heart failure and beta blocker therapy. Chronotropic response during the 6-min walk test was defined as peak heart rate (HR) minus resting HR. Survival was recorded at four years.ResultsSixty-two participants (40 idiopathic pulmonary fibrosis) were included, with mean (SD) TLCO 50(18)% predicted and 6-min walk distance (6MWD) 377 (127) metres. A smaller chronotropic response was associated with reduced 6MWD (r = 0.65, p

In interstitial lung disease complicating systemic sclerosis (SSc-ILD), the optimal prognostic use of baseline pulmonary function tests (PFTs) and high-resolution computed tomography (HRCT) is uncertain.To construct a readily applicable prognostic algorithm in SSc-ILD, integrating PFTs and HRCT.The prognostic value of baseline PFT and HRCT variables was quantified in patients with SSc-ILD (n = 215) against survival and serial PFT data.Increasingly extensive disease on HRCT was a powerful predictor of mortality (P0.0005), with an optimal extent threshold of 20%. In patients with HRCT extent of 10-30% (termed indeterminate disease), an FVC threshold of 70% was an adequate prognostic substitute. On the basis of these observations, SSc-ILD was staged as limited disease (minimal disease on HRCT or, in indeterminate cases, FVCor= 70%) or extensive disease (severe disease on HRCT or, in indeterminate cases, FVC70%). This system (hazards ratio [HR], 3.46; 95% confidence interval [CI], 2.19-5.46; P0.0005) was more discriminatory than an HRCT threshold of 20% (HR, 2.48; 95% CI, 1.57-3.92; P0.0005) or an FVC threshold of 70% (HR, 2.11; 95% CI, 1.34-3.32; P = 0.001). The system was evaluated by four trainees and four practitioners, with minimal and severe disease on HRCT defined as clearly20% or clearly20%, respectively, and the use of an FVC threshold of 70% in indeterminate cases. The staging system was predictive of mortality for all scorers, with prognostic separation higher for practitioners (HR, 3.39-3.82) than trainees (HR, 1.87-2.60).An easily applicable limited/extensive staging system for SSc-ILD, based on combined evaluation with HRCT and PFTs, provides discriminatory prognostic information.