Imaging in the diagnosis and management of fibrosing interstitial lung diseases.

High-resolution computed tomography (HRCT) plays a pivotal role in the diagnosis and management of interstitial lung diseases (ILDs), particularly given the approval of antifibrotic agents for conditions like idiopathic pulmonary fibrosis and progressive pulmonary fibrosis. Diagnosing fibrotic pulmonary disorders through HRCT involves a detailed and methodical examination. The identification of specific lung tissue changes, including ground-glass opacities and reticulation, along with signs of fibrosis like honeycombing, traction bronchiectasis and lung volume loss, establishes clear HRCT patterns indicative of various ILDs. The reliability of these patterns in predicting pathological conditions depends largely on the clinical context. For instance, when a usual interstitial pneumonia pattern is present, the predictive value of this diagnosis is so high that a lung biopsy is considered to be redundant. This review intends to delineate the HRCT signs of fibrosis, elucidate the specific radiological patterns of fibrotic lung diseases, and identify the clinical circumstances under which these patterns emerge. Additionally, we introduce and discuss novel imaging techniques that hold promise for the diagnosis, screening and early detection of ILDs.

Overnight desaturation in interstitial lung diseases: links to pulmonary vasculopathy and mortality.

Background: Overnight desaturation predicts poor prognosis across interstitial lung diseases (ILDs). The aim of the present study was to investigate whether nocturnal desaturation is associated with pulmonary vasculopathy and mortality. Methods: A retrospective single centre study of 397 new ILD patients was carried out including patients with idiopathic pulmonary fibrosis (IPF) (n=107) and patients with non-IPF fibrotic ILD (n=290). This is the largest study to date of the effect of significant nocturnal desaturation (SND) (≥10% of total sleep time with oxygen saturation ≤90% measured by pulse oximetry). Results: The prevalence of SND was 28/107 (26.2%) in IPF and 80/290 (27.6%) in non-IPF ILD. The prevalence of SND was higher in non-IPF ILDs than in IPF (p=0.025) in multivariate analysis. SND was associated with noninvasive markers of pulmonary hypertension (PH): tricuspid regurgitation velocity (TRV) (p<0.0001), brain natriuretic peptide (p<0.007), carbon monoxide transfer coefficient (p<0.0001), A-a gradient (p<0.0001), desaturation >4% in 6-min walking test (p<0.03) and pulmonary artery diameter (p<0.005). SND was independently associated with high echocardiographic PH probability in the entire cohort (OR 2.865, 95% CI 1.486-5.522, p<0.002) and in non-IPF fibrotic ILD (OR 3.492, 95% CI 1.597-7.636, p<0.002) in multivariate analysis. In multivariate analysis, SND was associated with mortality in the entire cohort (OR 1.734, 95% CI 1.202-2.499, p=0.003) and in IPF (OR 1.908, 95% CI 1.120-3.251, p=0.017) and non-IPF fibrotic ILD (OR 1.663, 95% CI 1.000-2.819, p=0.041). Separate models with exclusion of each one of the diagnostic subgroups showed that no subgroup was responsible for this finding in non-IPF ILDs. SND was a stronger marker of 5-year mortality than markers of PH. Conclusion: SND was associated with high echocardiographic probability and mortality and was a stronger predictor of mortality in IPF and non-IPF ILDs grouped together to power the study.

Recent advances in the treatment of systemic sclerosis associated interstitial lung disease.

Connective tissue diseases (CTDs) are a heterogenous group of systemic inflammatory disorders. The development of connective tissue disease-associated interstitial lung disease (CTD-ILD) is a key complication associated with significant morbidity and mortality. The aim of this review is to explore the pathogenesis of CTD-ILD and summarize the recent evidence from clinical trials for novel treatment options, including the role of antifibrotics and immunomodulatory therapies with a focus on systemic sclerosis associated ILD. Further clinical trials are ongoing to explore combination therapies and more targeted therapeutic options. Clinicians remain faced with the difficult challenge of appropriately selecting patients who will benefit from the available therapies and timing the start of therapy at the most suitable part of the disease course.

Bilateral mediastinal lymphadenopathy with cough and shortness of breath.

Silicosis and sarcoidosis have very similar radiological appearances and a thorough occupational history may be the only clue to the diagnosis https://bit.ly/3Usxcj7.

Collagen 1a1 Expression by Airway Macrophages Increases In Fibrotic ILDs and Is Associated With FVC Decline and Increased Mortality.

Within the Interstitial Lung Diseases (ILD), patients with idiopathic pulmonary fibrosis (IPF) and a subset of those with non-IPF fibrotic ILD have a distinct clinical phenotype of progression despite management. This group of patients has been collectively termed the progressive fibrotic phenotype (PFP). Their early recognition may facilitate access to antifibrotic therapies to prevent or slow progression. Macrophages/monocytes within the lung orchestrate the progression and maintenance of fibrosis. A novel role for monocyte-derived macrophages during tissue damage and wound healing is the expression of collagens. We examined Collagen 1a1 expression in airway macrophages from ILD patients at diagnosis. COL1A1 mRNA levels from BAL cells were elevated in IPF and Non-IPF patients. The presence of a UIP pattern and a subsequent progressive phenotype were significantly associated with the higher BAL COL1A1 levels. In Non-IPF patients, higher COL1A1 levels were associated with a more than twofold increase in mortality. The intracellular localisation of COL1A1 in airway macrophages was demonstrated by confocal microscopy in CD45 and CD163 co-staining assays. Additionally, airway macrophages co-expressed COL1A1 with the profibrotic SPP1 gene product osteopontin. The levels of SPP1 mRNA and OPN in the BAL were significantly higher in IPF and Non-IPF patients relative to healthy. Our results suggest that profibrotic airway macrophages are increased in the BAL of patients with IPF and other ILDs and co-express COL1A1 and OPN. Importantly, COL1A1 expression by pro-fibrotic airway macrophages could be a marker of disease progression and poor survival in ILDs.

Rapidly non-ipf progressive fibrosing interstitial lung disease: a phenotype with an ipf-like behavior.

BACKGROUND: A subgroup of patients with fibrotic ILD experience progression and several risk factors for ILD progression have been reported, such as male sex, older age, lower baseline pulmonary function, and a radiological or pathological pattern of usual interstitial pneumonia. OBJECTIVE: To describe a possible new phenotype of rapidly non IPF progressive fibrosing with an IPF-like outcome. METHODS: Three previously fit and well patients who developed a rapidly progressive ILD and died within 6 to 7 months from the initial development of respiratory symptoms. RESULTS: Unlike what is currently known, our patients developed a severe fibrosing ILD with an IPF-like outcome despite a) being younger than the average patient with IPF, b) having received a non-IPF MDT diagnosis, c) having a non-UIP pattern on HRCT. Moreover and similarly to IPF, they failed to respond to immunosuppressive treatment which is the preferred treatment option in these cases. CONCLUSION: We believe that patients who present with similar characteristics should be considered as likely to develop a phenotype of rapidly progressive ILD and be treated with antifibrotic medications instead of immunosuppressive ones according to the favourable treatment response to antifibrotic therapy observed in clinical trials of patients with progressive fibrosing ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (2): 231-233).

Diagnosing complications and co-morbidities of fibrotic interstitial lung disease.

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.

Pirfenidone improves survival in IPF: results from a real-life study.

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< 30%), in unadjusted analysis, the survival in the UHH cohort was better than in the RBH cohort (HR:0.32, 95% CI: 0.19-0.53, p < 0.0001). After adjustment for age, gender and FVC, the survival remained higher in the UHH cohort (HR:0.28, 95% CI: 0.16-0.48, p < 0.0001). We observed a similar safety profile compared to previously published data and a lower rate of drug discontinuation due to photosensitivity reactions. CONCLUSION: Pirfenidone provides a survival benefit in a real-life IPF cohort compared to previously used medications. Counselling patients and proactively managing possible adverse effects can reduce the necessity to discontinue pirfenidone.

Paroxysmal cough and left sacroiliac joint pain in a 50-year-old Caucasian man.

Can you diagnose this patient with pulmonary symptoms, thoracic and laboratory test abnormalities and sacroiliac joint pain? http://ow.ly/LPyy30kaViz.

Personalised medicine in interstitial lung diseases: Number 6 in the Series "Personalised medicine in respiratory diseases" Edited by Renaud Louis and Nicolas Roche.

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.

Comorbidities in interstitial lung diseases.

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.

Toll-like receptors and autophagy in interstitial lung diseases.

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.

Patient eligibility for anti-fibrotic therapy in idiopathic pulmonary fibrosis can be altered by use of different sets of reference values for calculation of FVC percent predicted.

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.

Pirfenidone in the treatment of idiopathic pulmonary fibrosis: an evidence-based review of its place in therapy.

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.

NLRP3 inflammasome expression in idiopathic pulmonary fibrosis and rheumatoid lung.

In this study we investigated the implication of NLRP3 inflammasomes in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and rheumatoid arthritis-usual interstitial pneumonia (RA-UIP).NLRP3 inflammasome activation at baseline and following stimulation with lipopolysaccharide/ATP was evaluated by measuring interleukin (IL)-1ß and IL-18 levels released in the bronchoalveolar lavage fluid (BALF) fluid and by cultures of BALF cells. IL-1ß and IL-18 levels were significantly elevated in the BALF and BALF macrophage cultures from RA-UIP patients, consistent with pre-existing inflammasome activation in these patients. In contrast, in IPF, BALF levels of IL-1ß were significantly less elevated relative to RA-UIP and IL-18 was lower than controls. Furthermore, upon inflammasome stimulation, IPF BALF macrophage cultures failed to upregulate IL-1ß and partly IL-18 secretion, in contrast to controls, which showed robust IL-1ß and IL-18 upregulation. Interestingly, RA-UIP BALF cell cultures treated with lipopolysaccharide/ATP showed a potent stimulation of IL-18 secretion but not IL-1ß, the latter being already elevated in the unstimulated cultures, while examination of the intracellular IL-1ß levels in RA-UIP BALF cells upon NLRP3 inflammasome stimulation showed a significant upregulation of IL-1ß suggesting the NLRP3 pathway could be further activated.Taken together, our results suggest distinct inflammasome activation profiles between autoimmune and idiopathic lung fibrosis.