Pirfenidone in unclassifiable interstitial lung disease: a subgroup analysis by concomitant mycophenolate mofetil and/or previous corticosteroid use

Introduction There are currently no approved treatments solely for unclassifiable interstitial lung disease (uILD); however, a recent trial showed this population can benefit from pirfenidone. We report a subgroup analysis of this trial to assess the effects of immunomodulators (concomitant mycophenolate mofetil [MMF] and/or previous corticosteroids) with pirfenidone in patients with uILD. Methods This was a multicenter, international, double-blind, randomized, placebo-controlled phase II trial of patients with progressive fibrosing uILD (NCT03099187). Patients were randomized (1:1) to receive pirfenidone 2403 mg/day or placebo. This analysis assessed forced vital capacity (FVC) change from baseline measured using site spirometry (key secondary endpoint) and safety over 24 weeks by concomitant MMF use at randomization (pre-specified analysis) and/or previous corticosteroid use (post hoc analysis). Results Overall, 253 patients were randomized, including 45 (17.8%) patients (pirfenidone, n = 23; placebo, n = 22) receiving concomitant MMF with/without previous corticosteroids (MMF subgroup); 79 (31.2%) patients (pirfenidone, n = 44; placebo, n = 35) receiving previous corticosteroids without MMF (corticosteroids/no-MMF subgroup); and 129 (51.0%) patients (pirfenidone, n = 60; placebo, n = 69) not receiving concomitant MMF or previous corticosteroids (no-corticosteroids/no-MMF subgroup). At 24 weeks, difference in mean (95% confidence interval) FVC change from baseline between pirfenidone and placebo was − 55.4 mL (− 206.7, 96.0; P = 0.4645) in the MMF subgroup; 128.4 mL (− 6.4, 263.3; P = 0.0617) in the corticosteroids/no-MMF subgroup; and 115.5 mL (35.1, 195.9; P = 0.0052) in the no-corticosteroids/no-MMF subgroup. All subgroups generally exhibited a similar pattern of treatment-emergent adverse events. Conclusion Although limited by design and small sample sizes, this analysis suggests pirfenidone may be less effective in patients with uILD receiving concomitant MMF, whereas a beneficial treatment effect was observed in patients not receiving concomitant MMF regardless of previous corticosteroid use. Pirfenidone was well tolerated regardless of MMF and/or corticosteroid use. Trial Registration Number ClinicalTrials.gov: NCT03099187

Palliative care in interstitial lung disease: living well

Progressive fibrotic interstitial lung diseases (ILDs) are characterised by major reductions in quality of life and survival and have similarities to certain malignancies. However, palliative care expertise is conspicuously inaccessible to many patients with ILD. Unmet patient and caregiver needs include effective pharmacological and psychosocial interventions to improve quality of life throughout the disease course, sensitive advanced care planning, and timely patient-centred end-of-life care. The incorrect perception that palliative care is synonymous with end-of-life care, with no role earlier in the course of ILD, has created a culture of neglect. Interventions that aim to improve life expectancy are often prioritised without rigorous assessment of the individual's health and psychosocial needs, thereby inadvertently reducing quality of life. As in malignant disorders, radical interventions to slow disease progression and palliative measures to improve quality of life should both be prioritised. Efficient patient-centred models of palliative care must be validated, taking into account religious and cultural differences, as well as variability of resources. Effective implementation of palliative care for ILD will require multidisciplinary participation from clinicians, specialist nurses, psychologists, social workers, and, in some countries, non-governmental faith and community-based organisations with access to palliative care expertise

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

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

Feeder layer- and animal product-free culture of neonatal foreskin keratinocytes: improved performance, usability, quality and safety

Since 1987, keratinocytes have been cultured at the Queen Astrid Military Hospital. These keratinocytes have been used routinely as auto and allografts on more than 1,000 patients, primarily to accelerate the healing of burns and chronic wounds. Initially the method of Rheinwald and Green was used to prepare cultured epithelial autografts, starting from skin samples from burn patients and using animal-derived feeder layers and media containing animal-derived products. More recently we systematically optimised our production system to accommodate scientific advances and legal changes. An important step was the removal of the mouse fibroblast feeder layer from the cell culture system. Thereafter we introduced neonatal foreskin keratinocytes (NFK) as source of cultured epithelial allografts, which significantly increased the consistency and the reliability of our cell production. NFK master and working cell banks were established, which were extensively screened and characterised. An ISO 9001 certified Quality Management System (QMS) governs all aspects of testing, validation and traceability. Finally, as far as possible, animal components were systematically removed from the cell culture environment. Today, quality controlled allograft production batches are routine and, due to efficient cryopreservation, stocks are created for off-the-shelf use. These optimisations have significantly increased the performance, usability, quality and safety of our allografts. This paper describes, in detail, our current cryopreserved allograft production process

Detection and Early Referral of Patients With Interstitial Lung Abnormalities: An Expert Survey Initiative

Background: Interstitial lung abnormalities (ILA) may represent undiagnosed early-stage or subclinical interstitial lung disease (ILD). ILA are often observed incidentally in patients who subsequently develop clinically overt ILD. There is limited information on consensus definitions for, and the appropriate evaluation of, ILA. Early recognition of patients with ILD remains challenging, yet critically important. Expert consensus could inform early recognition and referral. Research Question: Can consensus-based expert recommendations be identified to guide clinicians in the recognition, referral, and follow-up of patients with or at risk of developing early ILDs? Study Design and Methods: Pulmonologists and radiologists with expertise in ILD participated in two iterative rounds of surveys. The surveys aimed to establish consensus regarding ILA reporting, identification of patients with ILA, and identification of populations that might benefit from screening for ILD. Recommended referral criteria and follow-up processes were also addressed. Threshold for consensus was defined a priori as ≥ 75% agreement or disagreement. Results: Fifty-five experts were invited and 44 participated; consensus was reached on 39 of 85 questions. The following clinically important statements achieved consensus: honeycombing and traction bronchiectasis or bronchiolectasis indicate potentially progressive ILD; honeycombing detected during lung cancer screening should be reported as potentially significant (eg, with the Lung CT Screening Reporting and Data System “S-modifier” [Lung-RADS; which indicates clinically significant or potentially significant noncancer findings]), recommending referral to a pulmonologist in the radiology report; high-resolution CT imaging and full pulmonary function tests should be ordered if nondependent subpleural reticulation, traction bronchiectasis, honeycombing, centrilobular ground-glass nodules, or patchy ground-glass opacity are observed on CT imaging; patients with honeycombing or traction bronchiectasis should be referred to a pulmonologist irrespective of diffusion capacity values; and patients with systemic sclerosis should be screened with pulmonary function tests for early-stage ILD. Interpretation: Guidance was established for identifying clinically relevant ILA, subsequent referral, and follow-up. These results lay the foundation for developing practical guidance on managing patients with ILA

Parental alcohol use and adolescent school adjustment in the general population: Results from the HUNT study

<p>Abstract</p> <p>Background</p> <p>This study investigates the relationship between parental drinking and school adjustment in a total population sample of adolescents, with independent reports from mothers, fathers, and adolescents. As a group, children of alcohol abusers have previously been found to exhibit lowered academic achievement. However, few studies address which parts of school adjustment that may be impaired. Both a genetic approach and social strains predict elevated problem scores in these children. Previous research has had limitations such as only recruiting cases from clinics, relying on single responders for all measures, or incomplete control for comorbid psychopathology. The specific effects of maternal and paternal alcohol use are also understudied.</p> <p>Methods</p> <p>In a Norwegian county, 88% of the population aged 13-19 years participated in a health survey (N = 8984). Among other variables, adolescents reported on four dimensions of school adjustment, while mothers and fathers reported their own drinking behaviour. Mental distress and other control variables were adjusted for. Multivariate analysis including generalized estimation equations was applied to investigate associations.</p> <p>Results</p> <p>Compared to children of light drinkers, children of alcohol abusers had moderately elevated attention and conduct problem scores. Maternal alcohol abuse was particularly predictive of such problems. Children of abstainers did significantly better than children of light drinkers. Controlling for adolescent mental distress reduced the association between maternal abuse and attention problems. The associations between parental reported drinking and school adjustment were further reduced when controlling for the children's report of seeing their parents drunk, which itself predicted school adjustment. Controlling for parental mental distress did not reduce the associations.</p> <p>Conclusions</p> <p>Parental alcohol abuse is an independent risk factor for attention and conduct problems at school. Some of the risk associated with mothers' drinking is likely to be mediated by adolescent mental distress. Despite lowered adjustment on the externalizing dimensions, children of alcohol abusers report that they enjoy being at school as much as other children.</p