Interstitial Lung Diseases

In recent years, healthcare utilisation has steadily risen, with estimated annual growth between 1.5% and 5.1% reported in the USA between 2011 and 2017 [1]. This trend towards increased expenditure is expected to continue with the ageing of the population and an increased prevalence of chronic diseases [2 – 6]. In this review, we will discuss the postulated burden of interstitial lung diseases (ILDs) that may present a progressive fibrosing phenotype, and the factors impacting healthcare utilisation. Healthcare utilisation is defined here as the quantity of healthcare services accessed by a population, quantified by assessing the number of hospital admissions per year, medical procedures or tests, physician visits ( primary care or specialist, at inpatient or outpatient facilities), and prescription drug use [4, 7, 8]. Within the various ILDs, a subset of patients develop a progressive fibrosing phenotype. This is characterised by progressive pulmonary fibrosis, worsening respiratory symptoms, declining lung function

ABSTRACT Pulmonary hypertension (PH) is a common complication of interstitial lung diseases (ILDs), particularly in idiopathic pulmonary fibrosis and ILD associated with connective tissue disease. However, other lung diseases, such as combined pulmonary fibrosis and emphysema syndrome, pulmonary Langerhans cell histiocytosis, and lymphangioleiomyomatosis, may also include PH in their clinical manifestations. In all of these diseases, PH is associated with reduced exercise capacity and poor prognosis. The degree of PH in ILDs is typically mild-to-moderate. However, some of these patients may develop a disproportionate increase in PH that cannot be justified solely by hypoxia and parenchymal injury: this condition has been termed ‘‘out-of-proportion’’ PH. The pathogenesis of PH in these diseases is various, incompletely understood and may be multifactorial. The clinical suspicion (i.e. increased dyspnoea, low diffusion capacity) and echocardiographic assessment are the first steps towards proper diagnosis of PH; however, right heart catheterisation remains the current gold standard for diagnosis of PH. At present, no specific therapies have been approved for the treatment of PH in patients with ILDs.

ABSTRACT 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.

ABSTRACT A proportion of patients with interstitial lung diseases (ILDs) are at risk of developing a progressive-fibrosing phenotype, which is associated with a deterioration in lung function and early mortality. In addition to idiopathic pulmonary fibrosis (IPF), fibrosing ILDs that may present a progressive phenotype include idiopathic nonspecific interstitial pneumonia, connective tissue disease-associated ILDs, hypersensitivity pneumonitis, unclassifiable idiopathic interstitial pneumonia, ILDs related to other occupational exposures and sarcoidosis. Corticosteroids and/or immunosuppressive therapies are sometimes prescribed to patients with these diseases. However, this treatment regimen may not be effective, adequate on its own or well tolerated, suggesting that there is a pressing need for efficacious and better tolerated therapies. Currently, the only approved treatments to slow disease progression in patients with IPF are nintedanib and pirfenidone. Similarities in pathobiological mechanisms leading to fibrosis between IPF and other ILDs that may present a progressive-fibrosing phenotype provide a rationale to suggest that nintedanib and pirfenidone may be therapeutic options for patients with the latter diseases.

Interstitial lung diseases (ILDs) represent a heterogeneous group of pathologies characterised by alveolar and interstitial space damage, pulmonary inflammation (usually coupled with fibrosis), decreased pulmonary capacity and impaired gas exchange [1]. ILD can be attributed to a known or an unknown aetiology [2] (figure 1). The former includes pneumoconiosis, hypersensitivity pneumonitis, iatrogenic and post-infectious ILD. The idiopathic forms are represented by ILD in the context of systemic diseases, such as those related to connective tissue diseases [3] and the recently described forms of interstitial pneumonia with autoimmune features [4] as well as the idiopathic interstitial pneumonias (IIPs). The classification of IIPs has been revised periodically [5 – 7], and older classifications included patients that today are classified differently. The most recent update of the international multidisciplinary classification of the IIPs distinguishes major, rare and unclassifiable forms on the basis of patient ’ s clinical history and high-resolution computed tomography peculiar features [8]. Among the IIPs, the most relevant clinical picture is represented by idiopathic pulmonary fibrosis (IPF), which is defined as a form of “chronic, progressive fibrosing interstitial lung disease, of unknown cause, characterised by a progressive worsening of dyspnoea and lung function and associated with a poor prognosis” [9, 10]. Additional, alternative groupings have been proposed according to a disease behaviour approach [8].

ABSTRACT Imaging techniques are an essential component of the diagnostic process for interstitial lung diseases (ILDs). Chest radiography is frequently the initial indicator of an ILD, and comparison of radiographs taken at different time points can show the rate of disease progression. However, radiography provides only limited specificity and sensitivity and is primarily used to rule out other diseases, such as left heart failure. High-resolution computed tomography (HRCT) is a more sensitive method and is considered central in the diagnosis of ILDs. Abnormalities observed on HRCT can help identify specific ILDs. HRCT also can be used to evaluate the patient ’ s prognosis, while disease progression can be assessed through serial imaging. Other imaging techniques such as positron emission tomography-computed tomography and magnetic resonance imaging have been investigated, but they are not commonly used to assess patients with ILDs. Disease severity may potentially be estimated using quantitative methods, as well as visual analysis of images. For example, comprehensive assessment of disease staging and progression in patients with ILDs requires visual analysis of pulmonary features that can be performed in parallel with quantitative analysis of the extent of fibrosis. New approaches to image analysis, including the application of machine learning, are being developed.

ABSTRACT In the present review we provide currently available evidence for the use of macrolides in the treatment of diffuse interstitial lung diseases (ILDs). Up to now, research on macrolides has mainly focused on three areas. First, macrolides have shown some promising results in cellular models and case reports as antifibrotic agents, by promoting autophagy and clearance of intracellular protein aggregates and acting as regulators of surfactant homeostasis. Secondly, macrolides have an immunomodulatory effect, which has been applied in some organising pneumonia cases. In particular, macrolides have been tested in association with systemic corticosteroids as steroid-sparing agents and alone as either first-line agents in mild cases or second-line agents where steroids were poorly tolerated or had failed. Thirdly, a recent area of research concerns the possible role of macrolides as modulators of lung microbiota and the host–microbiota interaction. This function has been particularly studied in idiopathic pulmonary fibrosis patients, in whom changes in microbiota have been proved to be associated with disease progression. However, the lack of high-quality studies makes the application of macrolide therapy in ILDs a field in which research should be conducted on a large scale.

BALf was obtained from patients with diffuse lung dis- eases. All patients gave informed consent to bronchos- copy and sampling of BALf and the study was approved by the Ethics Committee at the Medical University of Warsaw (No. KB/106/2004). Eighty three individuals in total were involved in the study, suffering from sarcoidosis (n = 22, mean age 42 yr., range 26–73 yr., 12 male/10 female), smoking-related interstitial lung diseases (sr-ILD) (n = 11, mean age 53 yr., range 27– 77 yr., 8 males/3 females), eosinophilic disorders (n = 8, mean age 53 yr., range 30–69, 3 males/5 females), and lung fibrosis (n = 42, mean age 62 yr., range 30–80 yr., 27 males/15 females). Diagnosis of interstitial lung dis- eases was established according to ATS/ERS Inter- national Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias [19]. The follow- ing diseases were included in the group of eosinophilic disorders: chronic eosinophilic pneumonia (CEP), Churg Strauss Syndrome, and Wegener granulomatosis. The large group of lung fibrosis patients included patients with lung fibrosis in the course of hypersensitivity pneu- monitis, with connective diseases, and with idiopathic pulmonary fibrosis (IPF).

We have demonstrated here the power of focusing on the key regulatory components, the transcription factors and miRNAs, in order to gain insight into the networks perturbed in complex diseases such as ILDs. The inferred network: 1. provides a global view of the effects of DETFs and DEmiRNAs, 2. is not limited to individual molecular processes or pathways, and 3. uses informa- tion beyond curated databases to link molecules and networks. Despite the apparent conceptual simplicity of this approach, it is difficult to construct such networks, and most of the miRNA and TF mediated interactions are not yet well-characterized. In addition, there is no definitive method by which to modularize the network so that functional implications can be easily viewed and extracted. Our approach therefore needs further devel- opment in data integration and visualization; neverthe- less, it represents a significant step in the global view of perturbed network in the complex of interstitial lung diseases. Lacking longitudinal time-course samples or samples accurately matched to disease state progression prohibits following the dynamic changes in ILD. Tem- poral dynamics is one of the most powerful elements needed to fully unravel the biology of a system. Integrat- ing data from properly chosen model systems should allow us to gain a better understanding of disease initia- tion and progression. We would expect that some of the same networks are perturbed in these models, and allow us to build better network-based molecular models to identify, test and predict new therapeutic interventions.

ABSTRACT Although these conditions are rare, a proportion of patients with interstitial lung diseases (ILDs) may develop a progressive-fibrosing phenotype. Progressive fibrosis is associated with worsening respiratory symptoms, lung function decline, limited response to immunomodulatory therapies, decreased quality of life and, potentially, early death. Idiopathic pulmonary fibrosis may be regarded as a model for other progressive-fibrosing ILDs. Here we focus on other ILDs that may present a progressive-fibrosing phenotype, namely idiopathic nonspecific interstitial pneumonia, unclassifiable idiopathic interstitial pneumonia, connective tissue disease-associated ILDs (e.g. rheumatoid arthritis-related ILD), fibrotic chronic hypersensitivity pneumonitis, fibrotic chronic sarcoidosis and ILDs related to other occupational exposures. Differential diagnosis of these ILDs can be challenging, and requires detailed consideration of clinical, radiological and histopathological features. Accurate and early diagnosis is crucial to ensure that patients are treated optimally.

4. Pathogenetic pathways during aberrant angiogenesis Several transcription factors play instrumental role in pro- moting angiogenesis and sensing the environmental cues that drive this process. Strieter et al. [22] identified two transcription factors that stand out and appreciated the "master switches" that control aberrant angiogenesis. These are nuclear factor- κ B (NF- κ B) and hypoxia induci- ble factor-1a (HIF-1a). Both factors are under strict regula- tion. NF-κB plays an essential role as a "master switch" in the transactivation of angiogenic CXC chemokines as shown in detail for CXCL8 (Figure 1). Generation of reac- tive oxygen species activates NF- κ B and sets in motion a process that releases NF- κ B in the cytoplasm and leads to its translocation into the nucleus where it binds with the promoters of angiogenic CXC chemokines resulting to the activation of target genes [23]. In addition, it has been shown that VEGF promotes the expression of angiogenic chemokines (i.e CXCL8) from endothelial cells in an autocrine and paracrine way [13] (Figure 1). On the other hand, HIF-1a serves as a critical transcription factor for cellular and systemic oxygen homeostasis. Under hypoxic conditions HIF-1a is subsequent to activation and translo- cation into the nucleus. There it dimerizes with HIF-1b and the heterodimer recognizes the hypoxia response ele- ment found in the promoter region of several target genes (i.e VEGF) resulting to gene expression (Figure 1) [24,25]. Angiogenesis in Interstitial Lung Diseases a. Angiogenesis in Idiopathic Interstitial Pneumonias (Tables 2, 3, 4)

Interstitial lung diseases (ILDs) are rare diseases that share a number of common clinical and pathophysiological features, but also demonstrate a diverse aetiology and prognosis [1]. Varying proportions of patients with ILDs develop a chronic progressive-fibrosing phenotype. Idiopathic pulmonary fibrosis (IPF) can be viewed as the prototype progressive-fibrosing ILD; it is relatively well understood both in terms of epidemiology and disease behaviour [2, 3]. While IPF is by definition a chronic progressive-fibrosing interstitial pneumonia [4], only a proportion of patients with other ILDs develop this phenotype. In those other ILDs, progressive fibrosis can develop at any time during the disease course, but very little is known about why and how frequently this occurs [2]. A terminology recently used to describe fibrosing ILDs with a progressive phenotype is progressive-fibrosing ILD (PF-ILD) [2]. For details on the

Interstitial lung diseases (ILD’s) are a group of heterogenous chronic, fero- ciously progressive lung diseases. The aetiology of the aforementioned dis- eases is not always recognisable. The diagnosis of these dismal diseases is a vivid challenge for the physicians. Through the intervening years different diagnostic algorithms have been implemented towards more accurate out- come. Different types of ILD’s demand diverse diagnostic approaches. In the latest years a novel diagnostic mini invasive approach seems to gain conti- nuously terrain towards the diagnosis of ILD’s. Transbronchial cryobiopsy may be the Holy Grail in the diagnosis of these diseases or a misleading di- agnostic tool in this challenging field.

ARF: Acute respiratory failure; COP: Cryptogenic organizing pneumonia; CPAP: Continuous positive airway pressure; CTD: Connective tissue diseases; ECMO: Extra-corporeal membrane oxygenation; ETI: Endotracheal intubation; HDU: High dependency units; HP: Hypersensitivity pneumonitis; HRCT: High resolution CT; ICU: Intensive care unit; DILD: Diffuse interstitial lung diseases; IPF: Idiopathic pulmonary fibrosis; IQR: Interquartile range; LOS: Length of stay in the hospital; NIV: Noninvasive ventilation; NSIP: Non-specific interstitial pneumonia; PSV: Pressure support ventilation; RCT: Randomized clinical trial; UIP: Usual interstitial pneumonia.

Background: Interstitial lung disease (ILD) represents a heterogeneous non-infectious group of acute and chronic diseases affecting the lung parenchyma. ILDs are usually associated with significant morbidity and mortality, particularly when fibrosis occurs. ILD is usually associated with mediastinal lymph node enlargement, the extent of lymph node enlargement may correlate to disease activity or progression of fibrosis. In the present study, authors have correlated the spectrum of high-resolution CT findings in ILDs with mediastinal lymph node enlargements.

prevalent, including lesions Grade 3 (Heath & Edwards) even in patients without PH [12]. The analysis of the United Network for Organ Sharing database showed that an increase in the mean pulmonary arterial pressure (mPAP) from the time of wait listing to the time of LTx was associated with poorer survival in patients with COPD and ILD after LTx even in the lung allocation scoring era [6, 13]. Therefore, the early diagnosis of pul- monary vascular disease and PH in COPD and ILD can- didates for LTx could have an impact on survival.

Support of this concept has emanated from in vitro studies and animal models for both nintedanib and pirfenidone. Nintedanib, an intracellular inhibitor of tyrosine kinases [27, 28], has shown antifibrotic, anti-inflammatory and vascular remodelling effects in several non-clinical models of fibrosis [29, 30]. Pirfenidone, a small molecule with antifibrotic, anti-inflammatory and anti-oxidative effects, suppresses the production of transforming growth factor- β , the proliferation and differentiation of myofibroblasts, and the deposition of collagen, and has favourable effects in non-clinical models of lung fibrosis [31 – 34]. Both drugs have demonstrated efficacy in IPF and could be effective to slow down progressive fibrosis in PF-ILDs irrespective of the trigger for the injury. Conceivably, these drugs might also be beneficial when fibrosis affects organs other than the lungs, as fibrogenesis is a very general process in the body [35]. As comprehensively reviewed by C OLLINS and R AGHU [5], a number of clinical trials are on-going to assess

Software development for the detection of pulmonary nodules can be explained by using Data Flow Diagrams (DFD) as in Figure 2. Data Flow Diagrams (DFD) level 1 illustrates the flow of information and transformation which is applied when the data is moved from input to output. At the DFD level 1 detection system of pulmonary nodules present, there is only one entity that is friendly, and there are five processes, namely the process of making the user interface, the process of segmenting the lung, pulmonary nodule segmentation process, the process of detection of pulmonary nodules and pulmonary nodule visualization process

The current childhood ILD classi fi cation system was developed based on clinical-pathologic criteria. This classi- fi cation scheme does not provide guidance in the organization of cases in the absence of lung biopsy. We found that almost one-third of cases were classi fi able based on clinical, genetic, and/or radiographic criteria without lung biopsy. The category most im- pacted by inclusion of non-biopsy cases was “ disorders related to systemic disease processes, ” in which most (65%) were diagnosed based on clini- cal features, serology, and/or biopsy of organs other than the lung, such as the kidney. Surfactant dysfunction dis- orders are another subgroup in which there have been signi fi cant advances facilitating diagnosis without lung bi- opsy. In our cohort, 2 cases originally evaluated by lung biopsy were later found to have genetic etiologies (1 SFTPC mutation and 1 with compound heterozygous ABCA3 mutations). We also identi fi ed 2 additional cases with radiologic and histopathologic fi ndings consistent with surfactant dysfunction in which genetic testing was not pre- viously performed. Therefore, in the

ABSTRACT: Lung is the organ that allows us to breathe and lung disease are the disorders that affect the lungs. This paper presents a computer aided classification Method in Computer Tomography (CT) Images of lungs developed using ANN-BPN. The purpose of the work is to detect and classify the lung diseases by effective feature extraction through Dual-Tree Complex Wavelet Transform (DTCWT) and Gray Level Co-occurrence Matrix (GLCM) Features. The entire lung is segmented from the CT Images and the parameters are calculated from the segmented image. The parameters are calculated using GLCM. We Propose and evaluate the Artificial Neural Network -Back Propagation method designed for classification of Interstitial Lung Disease (ILD) patterns. We collect different types of CT images of lung and train artificial neural network. The parameters give the maximum classification Accuracy. After the result we propose the Fuzzy clustering to segment the lesion part from abnormal lung.