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Background and objective A proportion of patients with fibrotic hypersensitivity pneumonitis (fHP) follow a progressive disease course despite immunosuppressive treatment. Little is known about predictors of mortality in fHP. We aimed to investigate the impact of short-term lung function changes in fHP on mortality. Methods Baseline demographics for 145 consecutive patients with a multi-disciplinary team diagnosis of fHP, as well as baseline and 1-year follow-up of lung function, baseline echocardiographic findings, bronchoalveolar lavage (BAL) cellularity and all-cause mortality were recorded. Changes in forced vital capacity (FVC) ≥ 5% and ≥10%, and diffusion capacity of the lung for carbon monoxide (DLCO) ≥ 10% and ≥15% at 1 year were calculated. Cox proportional hazards analysis was performed to test for associations with mortality. Results Baseline lung function severity, age, presence of honeycombing on computed tomography (CT) and echocardiographic pulmonary arterial systolic pressure (PASP) ≥ 40 mm Hg were associated with early mortality, while BAL lymphocytosis was associated with improved survival. A decline in FVC ≥ 5% (hazard ratio [HR]: 3.10, 95% CI: 2.00–4.81, p

Supported by the National Health and Medical Research Council Centre of Research Excellence in Pulmonary Fibrosis (GNT1116371), and by foundation partner, Boehringer Ingelheim, and program partners, Roche and Galapagos. Rationale : The interstitial lung disease (ILD) multidisciplinary meetings (MDM), composed of pulmonologists, radiologists, and pathologists, is integral to the rendering of an accurate ILD diagnosis. However, there is significant heterogeneity in the conduct of ILD MDMs, and questions regarding their best practices remain unanswered. Objectives : To achieve consensus among ILD experts on essential components of an ILD MDM. Methods : Using a Delphi methodology, semi-structured interviews with ILD experts were used to identify key themes and features of ILD MDMs. These items informed two subsequent rounds of online questionnaires that were used to achieve consensus among a broader, international panel of ILD experts. Experts were asked to rate their level of agreement on a five-point Likert scale. An a priori threshold for consensus was set at a median score 4 or 5 with an interquartile range of 0. Results : We interviewed 15 ILD experts, and 102 ILD experts participated in the online questionnaires. Five items and two exploratory statements achieved consensus on being essential for an ILD MDM following two questionnaire rounds. There was consensus that the presence of at least one radiologist, a quiet setting with a visual projection system, a high-quality chest high-resolution computed tomography, and a standardized template summarizing collated patient data are essential components of an ILD MDM. Experts also agreed that it would be useful for ILD MDMs to undergo an annual benchmarking process and a validation process by fulfilling a minimum number of cases annually. Twenty-seven additional features were considered to be either highly desirable or desirable features based on the degree of consensus. Although our findings on desirable features are similar to the current literature, several of these remain controversial and warrant further research. The study also showed an agreement among participants on several future concepts to improve the ILD MDM, such as performing regular self-assessments and conducting research into shared practices to develop an international expert guideline statement on ILD MDMs. Conclusions : This Delphi study showed consensus among international ILD experts on essential and desirable features of an ILD MDM. Our data represent an important step toward potential collaborative research into future standardization of ILD MDMs. Postprint

Background and objective The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) is highly variable, and accurate prognostic markers are needed. KL-6 is a mucin-like glycoprotein (MUC1) expressed by type II pneumocytes, while CYFRA 21-1 is expressed by alveolar and bronchiolar epithelial cells. Both are released into the blood from cell injury. Methods Serum KL-6 and CYFRA 21-1 levels were measured in a retrospective (n = 189) and a prospective (n = 118) cohort of SSc patients. Genotyping of MUC1 rs4072037 was performed. Linear mixed-effect models were used to evaluate the relationship with change in lung function parameters over time, while association with survival was evaluated with Cox proportional hazard analysis. Results In both cohorts, KL-6 and CYFRA 21-1 were highest in patients with lung involvement, and in patients with extensive rather than limited ILD. KL-6 was higher in patients carrying the MUC1 rs4072037 G allele in both cohorts. In patients with SSc-ILD, serum KL-6, but not CYFRA 21-1, was significantly associated with DLCO decline in both cohorts (P = 0.001 and P = 0.004, respectively), and with FVC decline in the retrospective cohort (P = 0.005), but not the prospective cohort. When combining the cohorts and subgrouping by severity (median CPI = 45.97), KL-6 remained predictive of decline in DLCO in both milder (P = 0.007) and more severe disease (P = 0.02) on multivariable analysis correcting for age, gender, ethnicity, smoking history and MUC1 allele carriage. Conclusion Our results suggest serum KL-6 predicts decline in lung function in SSc, suggesting its clinical utility in risk stratification for progressive SSc-ILD.

Although several genetic associations with scleroderma (SSc) are defined, very little is known on genetic susceptibility to SSc-associated interstitial lung disease (SSc-ILD). A number of common polymorphisms have been associated with SSc-ILD, but most have not been replicated in separate populations. Four SNPs in IRF5, and one in each of STAT4, CD226 and IRAK1, selected as having been previously the most consistently associated with SSc-ILD, were genotyped in 612 SSc patients, of European descent, of whom 394 had ILD. The control population (n = 503) comprised individuals of European descent from the 1000 Genomes Project. After Bonferroni correction, two of the IRF5 SNPs, rs2004640 (OR (95% CI)1.30 (1.10–1.54), pcorr = 0.015) and rs10488631 (OR 1.48 (1.14–1.92), pcorr = 0.022), and the STAT4 SNP rs7574865 (OR 1.43 (1.18–1.73), pcorr = 0.0015) were significantly associated with SSc compared with controls. However, none of the SNPs were significantly different between patients with SSc-ILD and controls. Two SNPs in IRF5, rs10488631 (OR 1.72 (1.24–2.39), pcorr = 0.0098), and rs2004640 (OR 1.39 (1.11–1.75), pcorr = 0.03), showed a significant difference in allele frequency between controls and patients without ILD, as did STAT4 rs7574865 (OR 1.86 (1.45–2.38), pcorr = 6.6 × 10−6). A significant difference between SSc with and without ILD was only observed for STAT4 rs7574865, being less frequent in patients with ILD (OR 0.66 (0.51–0.85), pcorr = 0.0084). In conclusion, IRF5 rs2004640 and rs10488631, and STAT4 rs7574865 were significantly associated with SSc as a whole. Only STAT4 rs7574865 showed a significant difference in allele frequency in SSc-ILD, with the T allele being protective against ILD.Key points• We confirm the associations of the IRF5 SNPs rs2004640 and rs10488631, and the STAT4 SNP rs7574865, with SSc as a whole.• None of the tested SNPs were risk factors for SSc-ILD specifically.• The STAT4 rs7574865 T allele was protective against the development of lung fibrosis in SSc patients.• Further work is required to understand the genetic basis of lung fibrosis in association with scleroderma.

Introduction The recovery of patients after COVID-19 has been poorly described. Related coronavirus infections (SARS-COV1 and MERS) have protracted recovery time-courses with significant respiratory morbidity,1 suggesting the same may be true for COVID-19. A service evaluation was therefore undertaken to evaluate the short-term effects of COVID-19. Methods Respiratory specialist doctors conducted structured telephone consultations of patients admitted between 17th March 2020 and 2nd May 2020 with a diagnosis of COVID-19 pneumonia at a teaching hospital. Using time from discharge patients were allocated into 3 groups: 3–4 weeks, 4–5 weeks and 5+. Patients were asked to recall acute COVID-19 symptoms, current symptoms, activity levels, and exercise capacity after discharge. Exercise capacity was quantified by self-assessment of walking distance on flat (metres), stairs (flights). Patient reported outcome measures (MRC dyspnoea scale and WHO performance status) were also collated. Results A total of 102 patients were screened, 70 were included in the study, with the rest being unreachable (n=32) Cough, dyspnoea, fever and lethargy were the most common symptoms at time of admission. All these symptoms, except lethargy, improved following discharge (figure 1). Prevalence in the 5+ week cohort of other symptoms is as follows: dyspnoea 35.7%, cough 11.5%, fever 0%; however, 70% of patients had at least 1 symptom 5 weeks after discharge. Self-reported exercise capacity and MRC dyspnoea score also improved after discharge. Despite this 21.4% of patients had a persistent impairment in walking ability on the flat, 17.8% in stair-climbing with 28.5% persistent deficit in MRC dyspnoea score after 5 weeks. In contrast 40% of patients had a deficit in WHO performance status and this was not affected by time after discharge. In conclusion patients did improve following discharge from hospital for COVID-19 pneumonia, however many were left with residual symptoms and a functional deficit in short term (5 weeks). It remains to be seen whether this results in long term health problems. *highlights joint authorship Reference Hui DS, Wong KT, Ko FW, et al. The 1-year impact of severe acute respiratory syndrome on pulmonary function, exercise capacity, and quality of life in a cohort of survivors. Chest. 2005;128(4):2247–2261.

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.

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.

A 40-year-old woman, who was an ex-smoker, presented with a 2-month history of dry cough, and sensation of fluid movement within the thorax. Past medical history included only liver haemangiomas, for which she was under surveillance. Computed tomography (CT) of the thorax, axial image of lung and

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.

Introduction: Nocturnal desaturation may contribute to long-term pulmonary vascular stress in interstitial lung disease (ILD). We studied the prevalence and prognostic utility of nocturnal desaturation across ILDs. Methods: ILD patients with overnight oximetry (January 2010-December 2013) were included (n=437; Idiopathic Pulmonary Fibrosis, n=122; Connective Tissue Disease-ILD, n=48; Hypersensitivity Pneumonitis, n=60; Non-specific Interstitial Pneumonia, n=56; unclassifiable, n=27; Sarcoidosis, n=66; other, n=58). Desaturation index (DI) was defined as the number of desaturation events >4%/hr. Results: DI was higher in NSIP and CTD-ILD than in IPF (p=0.03 and p=0.02 respectively). In the whole cohort, DLco and serum BNP predicted mortality (HR 0.95; 95% CI 0.94, 0.96; p Conclusion: DI is more prevalent and it is a stronger predictor of mortality in immune-mediated ILDs than in IPF and may be an important manifestation of these disorders.

Introduction: Interstitial lung diseases (ILDs) represent a heterogeneous group of rare disorders that include more than 200 entities, mostly associated with high mortality. In recent years, the progress regarding the understanding of the pathogenesis of these diseases led to the approval of specific treatments. In ILDs, the presence of comorbidities has a significant impact on the quality of life and the survival of patients and, therefore, their diagnosis and treatment has a pivotal role in management and could improve overall outcome. Areas covered: We discuss key diagnostic issues with regard to the most frequent comorbidities in ILDs. Treatment options are also discussed as the decision to investigate more definitively in order to identify specific comorbidities (including lung cancer, pulmonary hypertension, GE reflux, and obstructive sleep apnoea) is critically dependent upon whether comorbidity-specific treatments are likely to be helpful in individual patients, judged on a case by case basis. Expert opinion: The extent to which clinicians proactively pursue the identification of comorbidities depends on realistic treatment goals in individual patients.

The landscape of idiopathic pulmonary fibrosis (IPF) has changed. The significant progress regarding our knowledge on the pathogenesis of the disease together with the experience achieved after a series of negative trials has led to the development of two drugs for the treatment of IPF. Both pirfenidone and nintedanib can slow significantly the rate of disease progression. They are safe with side effects that can be either prevented by close collaboration between health care professionals and patients or treated successfully when they occur, rarely leading to treatment discontinuation. However, there are still few unanswered questions regarding the application of the beneficial results of pharmaceutical trials in the general population of IPF patients. Long-term “real-life” studies are being undertaken to answer these questions. In this article, we focus on the advances that have led to the development of the antifibrotic agents with particular focus on pirfenidone.

Interstitial Lung Diseases (ILDs) encompass a complex group of pulmonary disorders with varying prognosis and clinical behavior. Idiopathic pulmonary fibrosis(IPF) is the most common and most lethal among the fibrosing ILDs. The role of pulmonary macrophages in the pathogenesis of IPF remains poorly understood however, macrophages within the lung may orchestrate the progression and maintenance of fibrosis. In this study we analysed the expression of microRNA Let7c, required for the differentiation of alternatively activated macrophages, in BAL cells from IPF patients and other f-ILDs (CHP, fNSIP, RA-ILD, SSc-ILD, and SLE-ILD ) relative to controls, at the time of diagnosis, as a possible marker for disease progression. Alternatively activated alveolar macrophages were phenotypically characterized by CD45, CD11c, CD14, and CD163. Let7c was significantly lower in IPF as compared to other f-ILDs although it was not different from controls. In contrast CD163 positive macrophages were significantly higher in IPF and fibrotic ILDs relative to controls. Low Let7c levels were significantly associated with lower survival in patients with fibrotic lung disease, while a similar trend was observed within the non-IPF f-ILDs group. Additionally, disease progression at 6, 12 and 24 months following diagnosis was moderately negatively correlated with the levels of Let7c at baseline through the pulmonary fibrosis groups. Transcription in BAL cells in IPF is significantly affected in IPF relative to other f-ILDs, and gene expression related to alveolar macrophage activation may serve as diagnostic and disease progression marker.

The aim of this study was to compare radiology-based prediction models in rheumatoid arthritis-related interstitial lung disease (RAILD) to identify patients with a progressive fibrosis phenotype. RAILD patients had computed tomography (CT) scans scored visually and using CALIPER and forced vital capacity (FVC) measurements. Outcomes were evaluated using three techniques, as follows. 1) Scleroderma system evaluating visual interstitial lung disease extent and FVC values; 2) Fleischner Society idiopathic pulmonary fibrosis (IPF) diagnostic guidelines applied to RAILD; and 3) CALIPER scores of vessel-related structures (VRS). Outcomes were compared to IPF patients. On univariable Cox analysis, all three staging systems strongly predicted outcome (scleroderma system hazard ratio (HR) 3.78, p=9×10−5; Fleischner system HR 1.98, p=2×10−3; and 4.4% VRS threshold HR 3.10, p=4×10−4). When the scleroderma and Fleischner systems were combined, termed the progressive fibrotic system (C-statistic 0.71), they identified a patient subset (n=36) with a progressive fibrotic phenotype and similar 4-year survival to IPF. On multivariable analysis, with adjustment for patient age, sex and smoking status, when analysed alongside the progressive fibrotic system, the VRS threshold of 4.4% independently predicted outcome (model C-statistic 0.77). The combination of two visual CT-based staging systems identified 23% of an RAILD cohort with an IPF-like progressive fibrotic phenotype. The addition of a computer-derived VRS threshold further improved outcome prediction and model fit, beyond that encompassed by RAILD measures of disease severity and extent., Combining the scleroderma and Fleischner staging systems in RAILD identifies patients with an IPF-like progressive fibrotic phenotype. CALIPER VRS scores further improve model fit, beyond that encompassed by RAILD measures of disease severity and extent. http://ow.ly/SUcV30mmeYI

Background: Hypersensitivity pneumonitis (HP) varies in widely behaviour, from self-limiting disease to inexorably progressive lung scarring. Given its unpredictability, we set out to assess whether short term changes in lung function could identify patients at risk. Methods: Consecutive adult patients with hypersensitivity pneumonitis attending the RBH ILD clinic and performing PFTs according to ATS guidelines, seen between 2011 and 2014 with at least one follow up lung function test were considered eligible. Results: 205 subjects were included (91 males, age 65.1 ±10, never smokers=135). At baseline, FVC (mean ±SD) was: 66.8±21.6% -FEV1:67.7±20.8% -DLCO: 39.3±15.2%. The diagnosis of HP was reached through MDT consensus. Patients were followed up for a median of 3.7 years (range 0.33 to 7); 89 deaths occurred. A decline in FVC≥10% from baseline, within the first year, and a decline in DLCO by at least 15% over same period, were assessed against mortality. On univariate analysis, a DLCO drop≥15% (HR: 2.4 – 95% CI: 1.5-3.9, p Conclusions: To our knowledge, this is the largest retrospective study to assess short termFVC and DLCO changes in relation to mortality in HP. In this cohort, both a decline in FVC of≥10% and in DLCO ≥15% occurring within the first year, are predictive of survival, suggesting their potential validity as outcome variables in clinical trials in HP.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial disease characterised by accumulation of elastin-rich fibrosis and predominant upper lobe shrinkage. The pathogenesis is poorly understood but idiopathic and secondary forms are recognised; an association with Aspergillus infection has been reported. We evaluated computed tomography (CT) and clinical/serological indices to identify factors influencing progression and mortality in patients with PPFE. CT studies in 72 patients, with a multidisciplinary diagnosis of PPFE, were consensus scored by two thoracic radiologists. The presence and severity of traction bronchiectasis in areas of PPFE correlated with the extent, severity and progression of PPFE (all p 40 mgA/L) was seen in 18/72 (25%) patients and was higher than in reference cohorts of idiopathic pulmonary fibrosis (20/105; 19%) and chronic hypersensitivity pneumonitis (12/111; 11%) (p=0.04). These data highlight the importance of platythorax as a clinico-radiological marker of volume loss and, more importantly, an index of poor outcome in PPFE, potentially reflecting inexorable physiological decline. The possibility that fungal sensitisation may form part of a pathogenetic or progressive PPFE profile warrants further investigation.

Interstitial lung disease (ILD) is the main cause of death in systemic sclerosis (SSc). The progression of SSc associated ILD (SSc-ILD) is highly variable, and markers predictive of progressive ILD are needed early in the disease course, to aim treatment towards patients likely to develop irreversible fibrosis. KL-6 is a mucin-like glycoprotein expressed on type II pneumocytes, prominently expressed/solubilised when epithelial cell injury occurs. Serum levels of KL-6 were measured in both a retrospective (n=180) and a prospective (n=118) cohort of SSc patients. Genotyping of rs4072037 in MUC1 was carried out using a TaqMan assay. Statistical analysis was performed using STATA12. In both cohorts, KL-6 was lowest in patients without ILD (median:374 (IQR:226-666) U/ml), and highest in patients with extensive (1371 (446-1245) U/ml), rather than limited ILD (729 (872-2816) U/ml, p= 0.0001), according to our staging system based on CT extent, integrated as necessary by FVC. Serum KL-6 was higher in patients carrying the C allele of rs4072037 in both cohorts (981 (U/ml vs 491U/ml p=0.0001 and 932 (568-1310) U/ml vs 1419 (905-2254) U/ml p=0.0015). In the retrospective cohort, on both univariate and multivariate analyses (adjusting for severity, allele carriage, gender, age, ethnicity, and smoking), serum KL-6 was an independent marker of survival and time to decline in FVC ≥5%, FVC ≥10%, and DLCO ≥15%. The association with decline in DLCO15% was replicated in the prospective cohort. Our results suggest that serum KL-6 may be an effective biomarker for predicting decline in lung function, and mortality, in SSc-ILD. This suggests that epithelial cell damage plays an important role in pathogenesis.

NOD-like receptors(NLRs) are key cytosolic components of the innate immune system. Upon activation they form the inflammasomes, that mediate the maturation and cleavage of IL-1b, a pro-inflammatory cytokine with fibrotic properties. NLRP3 activation is impaired in alveolar macrophages in Idiopathic Pulmonary Fibrosis (IPF) (Lasithiotaki, ERJ,2016), while decreased NLR pathway expression is associated with abundance of Streptococcus in BAL and decreased progression free survival. Conversely, upregulation of NLRC4 is correlated with worse survival(Salisbury, Curr Opin Pulm Med,2017) Aim of this study is to develop assays for comparison of NLRP3, NLRC4 and AIM2 inflammasomes’ activity at baseline and upon stimulation in alveolar macrophages(AMs) and in Peripheral blood leukocytes(PBMCs) in IPF, other fibrotic lung diseases and healthy subjects. PBMCs and AMs, obtained from blood and BAL of healthy volunteers and patients with lung fibrosis were primed with LPS, followed by inflammasome specific stimuli, including addition of ATP for NLRP3, or transection with Flagellin for NLRC4 and Poly(dA-dT) for AIM2. Stimulation of all three inflammasomes resulted in IL-1b release in PBMCs and AMs. Our preliminary data suggest that, LPS lead to significant IL-1b secretion in CPFE AMs, suggesting that inflammasome stimuli are present in the cells. NLPR3 stimulation resulted in significantly higher IL-1b secretion, in CPFE compared to other fibrotic diseases and IPF. AIM2 and NLRC4 also resulted in higher activation compared to other fibrotic diseases Our preliminary data suggests a particular role of NLRs and IL-1b in CPFE compared to other fibrotic lung diseases.

A 50-year-old Caucasian man who was a lifelong nonsmoker presented with a 3-year history of paroxysmal dry cough, fatigue, nonspecific myalgias, muscle weakness of the lower extremities and left sacroiliac joint pain. Initially, he was reviewed by a pulmonologist and subsequently he was referred to the Dept of Thoracic Medicine (Heraklion University Hospital, Heraklion, Greece) for further investigation. His medical history was remarkable for the presence of arterial hypertension on treatment with amlodipine and irbesartan., Can you diagnose this patient with pulmonary symptoms, thoracic and laboratory test abnormalities and sacroiliac joint pain? http://ow.ly/LPyy30kaViz

Background Pirfenidone is an antifibrotic compound approved for the treatment of idiopathic pulmonary fibrosis (IPF). We present our real-world experience in terms of Pirfenidone’s effect on mortality and adverse events profile outside the restrictions of a clinical trial. Methods This is a retrospective observational intention to treat study of 82 consecutive IPF patients (UHH cohort). Results We observed a high 3-years survival rate of 73% without excluding patients who discontinued treatment for different reasons. The survival was compared to the survival of an IPF cohort from a tertiary referral center (RBH cohort). After exclusion of severe cases (DLco

Idiopathic pulmonary fibrosis (IPF) is a chronic and irreversible interstitial lung disease with a poor prognosis and limited therapeutic options. Over the past decade, research efforts have focused on the pathogenetic mechanisms involved in this enigmatic lung disease. Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease often complicated by the development of interstitial lung disease (ILD), leading to high mortality and morbidity. Autophagy is a process regulating the turnover of subcellular components and organelles, and represents a major cellular homeostatic mechanism. Recent evidence suggests a role of autophagy and mitochondrial dysfunction in the development of IPF, focusing on lung fibroblasts and epithelial cells. The aim of this study was to examine the mRNA levels of molecules involved inthe autophagy pathway in bronchoalveolar lavage fluid (BALF)-derived cellsfrom patients with IPF in comparison topatients with RA demonstrating lung involvement (ILD) by RT-qPCR. The significant upregulation of BECLIN1 was observed in patients with RA-ILD compared with those with IPF. Other genes involved in the autophagy pathway were also examined, such as Unc-51 like autophagy activating kinase 1 (ULK1), BCL2 interacting protein 3 (BNIP3) and p62. No differences in the mRNA expression levels of these genes were observed. As regards the selective degradation of mitochondria and mitophagy, similar PTEN-induced putative kinase 1 (PINK1) and PARKIN; E3 ubiquitin ligase (PRKN) expression, as well as PINK1 protein levels, were observed. On the whole, the findings of this study demonstrate an increased expression of BECLIN1 in BALF cells from patients with RA-ILD compared with those from patients with IPF, while similar levels in other key molecules implicating in the autophagy pathway were observed in patients with IPF and RA-ILD.

For many years, cigarette smoking has been considered as the leading cause of chronic obstructive pulmonary disease and lung cancer. Recently, however, it has also been associated with the development of diffuse interstitial lung diseases. In the latest classification of the major idiopathic interstitial pneumonias (IIP), the term smoking-related IIP has been introduced, including two entities, namely desquamative interstitial pneumonia (DIP) and respiratory bronchiolitis-interstitial lung disease (RB-ILD). Other entities in which smoking has a definite or suggested role include pulmonary Langerhan's cell histiocytosis, smoking-related interstitial fibrosis, combined pulmonary fibrosis and emphysema syndrome and idiopathic pulmonary fibrosis. In this review, we will focus on the mechanisms of smoking-related lung damage and on the clinical aspects of these disorders with the exception of idiopathic pulmonary fibrosis, which will be reviewed elsewhere in this review series.

The prevalence of obstructive sleep apnoea (OSA) is continuously increasing in patients with idiopathic pulmonary fibrosis (IPF) and, for the first time, the recent IPF guidelines recognise OSA as an important associated comorbidity that can affect patient's survival. Thus, it becomes conceivable that clinicians should refer patients with newly diagnosed IPF to sleep centres for the diagnosis and treatment of OSA as well as for addressing issues regarding the reduced compliance of patients with continuous positive airway pressure therapy. The discovery of biomarkers common to both disorders may help early diagnosis, institution of the most appropriate treatment and follow-up of patients. Better understanding of epigenetic changes may provide useful information about pathogenesis and, possibly, development of new drugs for a dismal disease like IPF.

Idiopathic pulmonary fibrosis (IPF) and lung cancer (LC) constitute two progressively devastating lung diseases with common risk factors including aging and smoking. There is an increasing interest in the investigation of common pathogenic mechanisms between IPF and LC with therapeutic implications. Several oncomirs, microRNAs associated with malignancy, are also linked with IPF. miR‑29a and miR‑185 downregulation is probably involved both in carcinogenesis and fibrogenesis. We have previously observed miR‑29a and miR‑185 downregulation in IPF cells from bronchoalveolar lavage (BAL) and in this study we investigated their expression in LC BAL cells. Common targets of miR‑29a and miR‑185 such as DNA methyltransferase (DNMT)1, DNMT3b, COL1A1, AKT1 and AKT2 were measured. Potential correlations with pulmonary function tests, smoking status and endobronchial findings were investigated. Similar levels of miR‑29a and miR‑185 were detected in IPF and LC while their common targets AKT1 and DNMT3b were not found to differ, suggesting potential pathogenetic similarities at the level of key epigenetic regulators. By conrast, COL1A1 mRNA levels were increased in IPF suggesting a disease‑specific mRNA signature. Notably, DNMT1 was downregulated in the LC group and its expression was further reduced in the presence of increasing malignant burden as it was implied by the endobronchial findings.

Background Increased protein citrullination and peptidylarginine deiminases (PADIs), which catalyze the citrullination process, are central in Rheumatoid arthritis pathogenesis and probably involved in the initial steps towards autoimmunity. Approximately, 10% of RA patients develop clinically significantly ILD. A possible shared role of protein citrullination in rheumatoid arthritis associated interstitial lung disease (RA-ILD), and idiopathic pulmonary fibrosis (IPF) pathogenesis remains unclear. Methods We evaluated PADI2 and PADI4 mRNA expression in bronchoalveolar lavage fluid (BALF) cells of 59 patients with IPF, 27 patients RA-ILD and 10 healthy controls. PADI 2 and 4 expression was analyzed by western blot and immunohistochemistry. Citrullinated protein levels were also quantified. Results PADI4 mRNA and protein levels were higher in RA-ILD and IPF than controls. Furthermore, PADI4 mRNA levels showed an increase among smokers in RA-ILD. PADI4 expression was detected in granulocytes and macrophages in all groups, with the strongest cytoplasmic expression observed in granulocytes in RA-ILD and IPF. PADI2 mRNA and immunostaining of BAL cells, were similar in all groups among smokers. Overall, stronger staining was observed in current smokers. Citrullinated peptides were significantly increased in IPF compared to RA-ILD and controls. In RA-ILD, protein citrullination strongly correlated with PADI4 expression and anti-citrullinated protein antibodies (ACPAs). Conclusions These results suggest that the citrullination pathway is upregulated in IPF and in RA-ILD. Electronic supplementary material The online version of this article (10.1186/s12931-017-0692-9) contains supplementary material, which is available to authorized users.

Methods: We conducted an international study of IPF diagnosis among a large group of physicians and compared their diagnostic performance to a panel of IPF experts (n=34). Participants evaluated 60 consecutive cases of interstitial lung disease. Diagnostic agreement was measured using weighted kappa coefficient (κw). Outcome distinctions between IPF and other diffuse lung diseases were used to validate diagnostic accuracy for first-choice diagnoses of IPF and were compared using the C-index. Results: 404 physicians completed the study. Agreement for IPF diagnosis was higher among expert physicians (κw =0.65 [IQR 0.53-0.72], P 20 years experience and MDT meeting attendance independently predicted prognostic accuracy of IPF diagnosis. The prognostic accuracy of academic physicians with >20 years experience (C-index=0.72, [IQR 0.0-0.73], p=0.229)) and non-university hospital physicians with more than 20 years experience, attending weekly MDT meetings (C-index=0.72, [IQR 0.70-0.72], p=0.052), did not differ significantly (p=0.229 and p=0.052 respectively) from the expert panel (C-index=0.74 [IQR 0.72-0.75]. Conclusion: Experienced respiratory physicians working at university-based institutions make diagnoses of IPF with similar prognostic accuracy to an international panel of IPF experts. Regular MDT meeting attendance improves the prognostic accuracy of experienced non-university practitioners to levels achieved by IPF experts.

Adult-onset Still’s disease is an inflammatory multisystemic disease of unknown etiology. Pleuritis is the most common pulmonary manifestation and pleural effusions are usually exudates with a predominance of neutrophils. We report a case of an eosinophilic pleural effusion as a novel and hitherto unrecognized manifestation of active adult-onset Still’s disease. We also observed a marked NLRP3 inflammasome activation with increased production of IL-1βwhich coincided with the development and resolved upon remission of the pleural effusion suggesting a possible novel pathogenetic pathway for the development of pleural effusions in the context of the auto-inflammatory disorders.

Antifibrotic drugs for idiopathic pulmonary fibrosis patients in England and Scotland are only available to those with FVC percent predicted (FVC%pred) less than or equal to 80%. The prescribing guidance does not state which set of reference values should be used and we show that a patient's FVC%pred can change by 4–6% depending on the choice of reference. We calculated FVC%pred for a group of 528 IPF patients using three different sets of reference values. 90% of patients with FVC%pred 80–85% calculated using European Community Coal and Steel (ECSC) reference values fall into the eligible range when NHANES reference values are used.

For IPF patients, the presence of hiatus hernia is associated with lung function decline and increased mortality. This observation supports the view that hiatus hernia may influence pathogenic mechanisms involved in IPF disease progression.http://ow.ly/hPAY30omE9o

Purpose of the study: Several studies in patients with lung cancer have shown that epidermal growth factor receptor regulates various tumorigenic processes through the phosphoinositide 3-kinase/Akt/mammalian target of rapamycin and Ras/Raf/Mek/Erk (mitogen-activated protein kinase (MAPK)) signalling pathways. The aim of our study is to evaluate whether these pathways are implicated in the pathogenesis of idi- opathic pulmonary fibrosis (IPF) and to seek indirect evidence of a common pathogenetic pathway with lung cancer. m-RNA expression of oncogenes participating in these two signaling pathways, as well as the combined m-RNA expression of the suppressor genes R-kip and p53 in lung tissue of patients with IPF were evaluated. Basic procedures: The study population was composed by two distinct groups. Patients with IPF (n = 25) and control subjects who underwent thoracic surgery for reasons other than interstitial lung disease (n = 10). Expression analysis of the aforementioned oncogenes and suppressor genes was performed using real-time reverse transcription polymerase chain reaction. Main findings: We found no difference in the overall m- RNA expression between controls and IPF in both investigated pathways. However, Braf has been overexpressed in IPF samples (P = 0.01) in contrast with K-ras that has been found downregulated (P < 0.001) in comparison with controls. Principal conclusions: These findings cannot exclude the hypothesis of involvement of Akt and MAPK sig- nalling pathways in pathogenesis of IPF. However, further investigation is needed in order to verify these data.

Interstitial lung diseases in general, and idiopathic pulmonary fibrosis in particular, are complex disorders with multiple pathogenetic pathways, various disease behaviour profiles and different responses to treatment, all facets that make personalised medicine a highly attractive concept. Personalised medicine is aimed at describing distinct disease subsets taking into account individual lifestyle, environmental exposures, genetic profiles and molecular pathways. The cornerstone of personalised medicine is the identification of biomarkers that can be used to inform diagnosis, prognosis and treatment stratification. At present, no data exist validating a personalised approach in individual diseases. However, the importance of the goal amply justifies the characterisation of genotype and pathway signatures with a view to refining prognostic evaluation and trial design, with the ultimate aim of selecting treatments according to profiles in individual patients.

Increased permeability of the pleural microvasculature is generally attributed to the substances that are released in inflammatory and malignant pleural effusions, although the exact pathogenetic mechanisms of malignant pleural effusions are unclear. Current therapies used to prevent the re-accumulation of pleural fluid and relieve symptoms are of variable efficacy and may cause serious adverse effects. Understanding the mechanisms of fluid accumulation would hopefully permit the development of more specific, effective and safer treatment modalities. Angiogenesis, pleural vascular increased permeability and inflammation are considered central to the pathogenesis of malignant pleural effusions. Vascular endothelial growth factor (VEGF) is a member of the VEGF/platelet-derived factor gene family and consists of at least six isoforms. Since it was shown that VEGF contributes to the formation of malignant pleural effusions, there have been some attempts to implicate, therapeutically, this finding using different molecules (ZD6474, PTK 787 and bevacizumab). However, the role of the biological axis of VEGF and angiopoietins needs further investigation in both the pathogenesis and the treatment of malignant pleural effusion. In both non-small-cell lung carcinoma and breast cancer, it has been shown that the ligand for CXCR4, CXCL12 or SDF-1α, exhibited peak levels of expression in organs that were the preferred destination for their respective metastases. Recent findings imply that new therapeutic strategies aimed at blocking the SDF-1-CXCR4 axis may have significant applications for patients by modulating the trafficking of hemato/lymphopoietic cells and inhibiting the metastatic behavior of tumor cells as well. The purpose of this report is to review novel pathogenetic and therapeutic implications regarding the angiogenetic pathways in malignant pleural effusions.

The connective tissue disorders (CTDs), also called collagen vascular diseases (CVDs), represent a heterogeneous group of immunologically mediated inflammatory disorders with a large variety of affected organs. Individuals with a CTD (rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, Sjögren's syndrome, polymyositis/dermatomyositis and mixed connective tissue disease) are susceptible to respiratory involvement. When the lungs are affected, an increasing mortality and morbidity in CVDs occurs. Interstitial lung disease (ILD) is established as a clinical corollary across the spectrum of CTDs, with an overall incidence estimated at 15%. Therefore, pivotal clinical dilemmas remain in the evaluation and management of ILD involvement in CVDs. Critical questions are the presence of fibrosis and whether the disease is clinically significant. Moreover, the clinician has to decide if treatment is warranted and which is the best therapeutic approach. The use of additional tests, such as pulmonary function tests, high-resolution computed tomography scan, bronchoalveolar lavage fluid and surgical lung biopsy, deserves better discussion. The present review focuses on establishing the diagnosis of ILD in CTD, and on evaluating disease activity and prognosis. This will provide the basis for therapeutic decisions that will be discussed, including an overview of recent advances.

Fibrosing lung disorders include a large number of diseases with diverse behaviour. Patients can die because of the progression of their illness, remain stable or even improve after appropriate treatment has been instituted. Comorbidities, such as acute and chronic infection, gastro-oesophageal reflux, pulmonary hypertension, lung cancer, cardiovascular diseases, and obstructive sleep apnoea, can pre-exist or develop at any time during the course of the disease and, if unidentified and untreated, may impair quality of life, impact upon the respiratory status of the patients, and ultimately lead to disease progression and death. Therefore, early identification and accurate treatment of comorbidities is essential.

Interstitial lung diseases (ILDs) include a number of diseases whose pathogenesis still is not fully understood. Idiopathic pulmonary fibrosis (IPF), the most frequent and severe form of ILDs is an epithelial-driven disease and the treatment consists of the use of antifibrotic agents. In the rest of ILDs an inflammation-driven pathway is believed to be the main pathogenetic mechanism and treatment consists of the use of immunomodulatory agents. In both groups it is believed that infection can play an important role in the development and progression of the diseases. The immune system can recognize exogenous threats or endogenous stress through specialized receptors namely pattern recognition receptors (PRRs) which in turn, initiate downstream signaling pathways to control immune responses. Recently, a link between PRRs and autophagy, a specialized biological process involved in maintaining cellular homeostasis but also involved in various immunologic processes, has been described. In this review, we focus on the reciprocal influences of PRRs with particular emphasis on Toll-like receptors and autophagy in modulating innate immune responses.