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BackgroundNintedanib slows lung function decline for patients with non-idiopathic pulmonary fibrosis progressive pulmonary fibrosis (PPF) in clinical trials, but the real-world safety and efficacy are not known.MethodsIn this retrospective cohort study, standardised data were collected from patients in whom nintedanib was initiated for PPF between 2019 and 2020 through an early-access programme across eight centres in the United Kingdom. Rate of lung function change in the 12 months pre- and post-nintedanib initiation was the primary analysis. Symptoms, drug safety, tolerability and stratification by interstitial lung disease subtype and computed tomography pattern were secondary analyses.Results126 patients were included; 67 (53%) females; mean±sdage 60±13 years. At initiation of nintedanib, mean forced vital capacity (FVC) was 1.87 L (58% predicted) and diffusing capacity of the lung for carbon monoxide (DLCO) was 32.7% predicted. 68% of patients were prescribed prednisolone (median dose 10 mg) and 69% were prescribed a steroid-sparing agent. In the 12 months after nintedanib initiation, lung function decline was significantly lower than in the preceding 12 months: FVC −88.8 mLversus−239.9 mL (p=0.004), and absolute decline inDLCO−2.1%versus−6.1% (p=0.004). Response to nintedanib was consistent in sensitivity and secondary analyses. 89 (71%) out of 126 patients reported side-effects, but 86 (80%) of the surviving 108 patients were still taking nintedanib at 12 months with patients reporting a reduced perception of symptom decline. There were no serious adverse events.ConclusionIn PPF, the real-world efficacy of nintedanib replicated that of clinical trials, significantly attenuating lung function decline. Despite the severity of disease, nintedanib was safe and well tolerated in this real-world multicentre study.

While idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therapy [1]. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as progressive fibrotic interstitial lung diseases (PF-ILD) [2]. Historically, treatments for these cases have been limited though given the phenotypic similarities many cases may have been given a multidisciplinary working diagnosis of IPF based on their disease behaviour [3]. The INBUILD trial broadened the scope of treatable fILD by demonstrating a significant benefit of Nintedanib in patients with fILD and progressive disease [4]. In response to this the European Commission approved an additional indication for nintedanib in adults for the treatment of PF-ILD in July 2020., Almost 15% of new referrals with non-IPF fibrotic ILD go on to develop a progressive fibrotic phenotype and would benefit from antifibrotic therapy https://bit.ly/3uPhClN

BackgroundPirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice.MethodsThis is a single-centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between patients with IPF on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range.Results104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared with the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months when comparing the antifibrotic group with the control group. The 12-month post-treatment mean decline in FVC % predicted (−4.6±6.2%) was significantly less than the 12-month pretreatment decline (−10.4±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline Body Mass Index of≤25, baseline diffusion capacity for carbon monoxide percentage predicted of ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381).ConclusionsThis real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first-line antifibrotic therapy, given the lower rates of early treatment discontinuation, although further studies are required to investigate this.

Rationale: The impact of coronavirus disease (COVID-19) on patients with interstitial lung disease (ILD) has not been established. Objectives: To assess outcomes in patients with ILD hospitalized for COVID-19 versus those without ILD in a contemporaneous age-, sex-, and comorbidity-matched population. Methods: An international multicenter audit of patients with a prior diagnosis of ILD admitted to the hospital with COVID-19 between March 1 and May 1, 2020, was undertaken and compared with patients without ILD, obtained from the ISARIC4C (International Severe Acute Respiratory and Emerging Infection Consortium Coronavirus Clinical Characterisation Consortium) cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished idiopathic pulmonary fibrosis from non–idiopathic pulmonary fibrosis ILD and used lung function to determine the greatest risks of death. Measurements and Main Results: Data from 349 patients with ILD across Europe were included, of whom 161 were admitted to the hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching, patients with ILD with COVID-19 had significantly poorer survival (hazard ratio [HR], 1.60; confidence interval, 1.17–2.18; P = 0.003) than age-, sex-, and comorbidity-matched controls without ILD. Patients with an FVC of Conclusions: Patients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

This British Thoracic Society (BTS) Clinical Statement addresses the diagnosis, evaluation and management of pulmonary sarcoidosis, with each section summarised with key clinical practice points. In an era in which medical practice is increasingly determined by evidence-based guidelines, it must be acknowledged from the outset that current evidence in sarcoidosis, especially with regard to treatment, is weak. Thus, a number of the conclusions in this Statement are based on expert opinion and accumulated clinical experience. The diagnosis of pulmonary sarcoidosis is often challenging, with ongoing evolution in clinician views on the need for a tissue diagnosis. Historically, a biopsy diagnosis was considered mandatory and we provide guidance on when to offer bronchoscopy and which bronchoscopic procedure to perform. We also stress that decisions made by individual patients to decline bronchoscopy, when there is a highly probable but not definite clinical diagnosis, should be supported in most cases, with careful subsequent monitoring. The document includes sections on the diagnosis of cardiac sarcoidosis and pulmonary hypertension as either disorder may present to respiratory physicians as ‘symptomatic pulmonary sarcoidosis’. Traditional treatment algorithms and their reported application in the medical literature tend to be based on a ‘one size fits all’ approach and this has often led to over-treatment and major steroid-related comorbidity. However, a great many patients do not need to be treated: the broad indications for initiating therapy are (1) a high risk of mortality or disability due to major organ involvement; and (2) unacceptable loss of quality of life. In this statement, we focus on the management of pulmonary disease; the management of concurrent cardiac sarcoidosis or pulmonary hypertension requires referral to expert subspecialist teams. Key pulmonary management considerations are discussed in this Statement. While higher dose treatment regimens may be required in high-risk disease, a highly flexible patient-centred approach is …

While Idiopathic pulmonary fibrosis (IPF) remains the exemplar progressive fibrotic lung disease, there remains a cohort of non-IPF fibrotic lung diseases (fILD) which adopt a similar clinical behaviour to IPF despite therap. This phenotypically related group of conditions, where progression of disease is similar to that seen in IPF, have recently been described as Progressive Fibrotic Interstitial Lung diseases (PF-ILD). Previous estimates suggest that between 18 to 40% of all fILD will develop progressive disease, however, the exact burden remains unknown. This retrospective, observational study therefore aimed to estimate the incidence of PF-ILD across England.All new referrals seen across nine UK centres for their first outpatient clinic appointment between 1st August 2017 and 31st January 2018 were assessed against the diagnostic criteria for PF-ILD laid out in the INBUILD trial. A total of 1749 patients with fILD were assessed. In this cohort of patients at risk of developing PF-ILD the INBUILD criteria were met in 14.5% (253/1749) of all new non-IPF fILD referrals. The average time from referral to specialist centre to diagnosis of progressive phenotype was 311 days. Of the progression events the majority were driven by a measured drop in FVC, with more than half of patients experiencing a drop of 10%. Almost one quarter of patients (24.1%) were diagnosed with progressive disease on the basis of radiological and symptomatic progression alone without a spirometric deterioration.This study represents a fair and balanced approach to assessing the incidence of objectively measurable and treatable PF-ILDs in the UK. A rate of 14.5% of new referrals with non-IPF ILD is less than that reported in previous studies however our methodology is likely to give a more accurate result than estimates based on extrapolation from general disease statistics, from physician-reported estimates prone to significant biases, or insurance claim processes also substantially prone to bias. This information has implication for workforce planning and the funding of anti-fibrotic therapy in the UK and beyond.

Background Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Our aim was to test their effectiveness and safety in clinical practice.Methods This is a single centre retrospective observational study undertaken at a specialised interstitial lung disease centre in England. Data including progression-free survival (PFS), mortality and drug tolerability were compared between IPF patients on antifibrotic therapies and an untreated control group who had a forced vital capacity percentage (FVC %) predicted within the licensed antifibrotic treatment range.Results 104 patients received antifibrotic therapies and 64 control patients were identified. PFS at 6 months was significantly greater in the antifibrotic group (75.0%) compared to the control group (56.3%) (p=0.012). PFS was not significant at 12 or 18 months. The 12-month post-treatment mean decline in FVC% predicted (-4.6±6.2%) was significantly less than the 12-month pre-treatment decline (-10.4 ±11.8%) (p=0.039). The 12-month mortality rate was not significantly different between the antifibrotic group (25.3%) and the control group (35.5%) (p=0.132). Baseline BMI≤25, baseline DLco% predicted ≤35 and antifibrotic discontinuation within 3 months were independent predictors of 12-month mortality. Antifibrotic discontinuation was significantly higher by 3 and 6 months for patients on pirfenidone than those on nintedanib (p=0.006 and p=0.044, respectively). Discontinuation at 12 months was not significantly different (p=0.381).Conclusion This real-world study revealed that antifibrotics are having promising effects on PFS, lung function and mortality. These findings may favour commencement of nintedanib as first line antifibrotic therapy, given the lower rates of early treatment discontinuation.

RationaleThe impact of COVID-19 on patients with Interstitial Lung Disease (ILD) has not been established.ObjectivesTo assess outcomes following COVID-19 in patients with ILD versus those without in a contemporaneous age, sex and comorbidity matched population.MethodsAn international multicentre audit of patients with a prior diagnosis of ILD admitted to hospital with COVID-19 between 1 March and 1 May 2020 was undertaken and compared with patients, without ILD obtained from the ISARIC 4C cohort, admitted with COVID-19 over the same period. The primary outcome was survival. Secondary analysis distinguished IPF from non-IPF ILD and used lung function to determine the greatest risks of death.Measurements and Main ResultsData from 349 patients with ILD across Europe were included, of whom 161 were admitted to hospital with laboratory or clinical evidence of COVID-19 and eligible for propensity-score matching. Overall mortality was 49% (79/161) in patients with ILD with COVID-19. After matching ILD patients with COVID-19 had higher mortality (HR 1.60, Confidence Intervals 1.17-2.18 p=0.003) compared with age, sex and comorbidity matched controls without ILD. Patients with a Forced Vital Capacity (FVC) of ConclusionsPatients with ILD are at increased risk of death from COVID-19, particularly those with poor lung function and obesity. Stringent precautions should be taken to avoid COVID-19 in patients with ILD.

Introduction Pirfenidone and nintedanib are the only disease-modifying treatments available for idiopathic pulmonary fibrosis (IPF). Clinical trials have demonstrated a disease-stabilising effect of these medications in controlled conditions. Our aim was to test their efficacy, tolerability and safety in routine clinical practice. Methods Data was collected retrospectively on patients with IPF seen in the ILD MDT between 2011–2017. This included patients treated with antifibrotics and those untreated, but with an FVC% predicted in the treatment range (control patients). Variables collected from the electronic patient records included demographics, lung function, survival, progression-free survival (PFS) – progression defined as 10% reduction in FVC or death – and drug tolerability outcomes including discontinuations. Results Of 104 patients prescribed antifibrotics, 54 received pirfenidone only, 36 received nintedanib only and 14 received both. There were 64 control patients. The 365-day mortality rate was 25.3% for the antifibrotic group and 35.5% for the control group (p=0.169). PFS at 6 months was significantly improved in the antifibrotic group (73.7%) compared to the control group (54.8%) (p=0.015). At 12 months, PFS was improved in the antifibrotic group (49.5% in the antifibrotic group and 37.1% in the control group), although the result was not statistically significant (p=0.127). The 12-month post-treatment mean decline in FVC% predicted (4.8±6.7%) was significantly less than the 12-month pre-treatment decline (11.7±12.2%) (p=0.041). Antifibrotic discontinuation by 3 months was significantly higher for patients on pirfenidone (31.7%) than those on nintedanib (11.4%) (p=0.026). By 12 months, discontinuation was higher in the pirfenidone group (48.3%) than the nintedanib group (40%) but the difference was not statistically significant (p=0.431). The 365-day mortality rate for the antifibrotic group, excluding patients who discontinued treatment within 3 months, was 20.3% and the difference between this and the control group (35.5%) was statistically significant (p=0.043). Conclusion Promising results were shown for mortality, PFS and lung function for patients on antifibrotics, although this data may favour commencement of nintedanib as first line therapy, given the lower rates of treatment discontinuation by 3 months. Patients who were able to tolerate antifibrotic therapy for the first 3 months were shown to have a significantly improved mortality.

Sarcoidosis is a multisystem disorder characterized by the formation of non-caseating granulomas in many tissues. A granuloma is an organized aggregate of immune cells; it forms in response to an antigenic stimulus. It contains abnormal macrophages (epithelioid histiocytes, which often fuse to form multinucleated giant cells), lymphocytes, neutrophils, eosinophils, fibroblasts, and collagen.

Chylothorax is an accumulation of lymphatic fluid in the pleural space due to obstruction or injury of the thoracic duct.

Sarcoidosis is a highly variable, systemic granulomatous disease of hitherto unknown aetiology. The GenPhenReSa (Genotype–Phenotype Relationship in Sarcoidosis) project represents a European multicentre study to investigate the influence of genotype on disease phenotypes in sarcoidosis.The baseline phenotype module of GenPhenReSa comprised 2163 Caucasian patients with sarcoidosis who were phenotyped at 31 study centres according to a standardised protocol.From this module, we found that patients with acute onset were mainly female, young and of Scadding type I or II. Female patients showed a significantly higher frequency of eye and skin involvement, and complained more of fatigue. Based on multidimensional correspondence analysis and subsequent cluster analysis, patients could be clearly stratified into five distinct, yet undescribed, subgroups according to predominant organ involvement: 1) abdominal organ involvement, 2) ocular–cardiac–cutaneous–central nervous system disease involvement, 3) musculoskeletal–cutaneous involvement, 4) pulmonary and intrathoracic lymph node involvement, and 5) extrapulmonary involvement.These five new clinical phenotypes will be useful to recruit homogenous cohorts in future biomedical studies.

Sarcoidosis is a multisystem granulomatous disorder characterized by marked T‐cell expansion of T helper 1 (Th1) cells. The cause of T‐cell overactivity is unknown. We hypothesized that interleukin‐10 (IL‐10) production by a yet undefined cell type might be defective, resulting in loss of regulation of T‐cell activity. Focusing on IL‐10‐producing monocytes, we first showed that monocytes isolated from the peripheral blood of corticosteroid‐naïve sarcoidosis patients (n = 51) produced less IL‐10 compared to controls, and were less able to suppress T‐cell proliferation. In addition, monocytic IL‐10 production correlated negatively with disease activity score. As invariant natural killer T (iNKT) cells are known to both interact with monocytes and be reduced in sarcoidosis patients, we then asked whether iNKT‐specific defects might be responsible for this reduced IL‐10 production. We found that greater numbers of circulating iNKT cells was associated with higher IL‐10 production. Moreover, iNKT cells enhanced monocytic IL‐10 production in vitro. Defective IL‐10 production and T‐cell suppression by sarcoidosis monocytes could be restored following their coculture with iNKT cells, in a CD1d‐ and cell contact‐dependent process. We suggest that reduced iNKT‐cell numbers in sarcoidosis may lead to impaired monocytic IL‐10 production and unchecked T‐cell expansion in sarcoidosis. These findings provide fresh insight into the mechanism of sarcoidosis disease, and interaction between iNKT cells and monocytes.

The molecular repertoire of macrophages in health and disease can provide novel biomarkers for diagnosis, prognosis, and treatment. Th2-IL-4-activated macrophages (M2) have been associated with important diseases in mice, yet no specific markers are available for their detection in human tissues. Although mouse models are widely used for macrophage research, translation to the human can be problematic and the human macrophage system remains poorly described. In the present study, we analyzed and compared the transcriptome and proteome of human and murine macrophages under resting conditions (M0) and after IL-4 activation (M2). We provide a resource for tools enabling macrophage detection in human tissues by identifying a set of 87 macrophage-related genes. Furthermore, we extend current understanding of M2 activation in different species and identify Transglutaminase 2 as a conserved M2 marker that is highly expressed by human macrophages and monocytes in the prototypic Th2 pathology asthma.