Form Of Interstitial Lung Disease Research Articles

Hypomorphic pathogenic variant in SFTPB leads to adult pulmonary fibrosis.

Biallelic pathogenic variants in the surfactant protein (SP)-B gene (SFTPB) have been associated with fatal forms of interstitial lung diseases (ILD) in newborns and exceptional survival in young children. We herein report the cases of two related adults with pulmonary fibrosis due to a new homozygous SFTPB pathogenic variant, c.582G>A p.(Gln194=). In vitro transcript studies showed that this SFTPB synonymous pathogenic variant induces aberrant splicing leading to three abnormal transcripts with the preservation of the expression of a small proportion of normal SFTPB transcripts. Immunostainings on lung biopsies of the proband showed an almost complete loss of SP-B expression. This hypomorphic splice variant has thus probably allowed the patients' survival to adulthood while inducing an epithelial cell dysfunction leading to ILD. Altogether, this report shows that SFTPB pathogenic variants should be considered in atypical presentations and/or early-onset forms of ILD particularly when a family history is identified.

Hypersensitivity pneumonitis: Principles in diagnosis and management.

Hypersensitivity pneumonitis: Principles in diagnosis and management.

Expanded T regulatory cells fail to control germinal center responses in the lung lymph nodes of pulmonary fibrosis patients

Abstract Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung diseases (ILD), which is characterized by progressive scarring of the lung. While immune suppression is a viable therapeutic option for many ILDs, it is detrimental in IPF. Nevertheless, enlargement of lung-draining lymph nodes (LLN) is prevalent and predicts survival outcomes in all ILD patients, including IPF, suggesting that there is also an immune component to IPF pathogenesis. To test this hypothesis, we investigated the cellular composition of the LLN in IPF and non-IPF ILD patients. All ILD patients’ LLN had increased germinal centers (GC), implicating that immune responses are not being resolved. As T regulatory cells (Tregs) are key in the control and resolution of immune responses, we investigated the phenotype of Tregs in the LLN of both IPF and non-IPF ILD patients to reveal their role in lung fibrosis. Tregs were expanded in LLN of all ILD patients compared to controls. Interestingly, there was a predominance of GATA3-expressing Tregs in ILD patients’ LLN. However, Tregs of ILD patients expressed significantly elevated levels of ICOS and CD137 compared to controls, indicating recent activation. Surprisingly, CD25 expression was significantly lower on Tregs from ILD patients’ LLN. Sc-RNAseq confirms similar Treg phenotypes in the lungs of IPF patients. In a mouse model of bleomycin-induced pulmonary fibrosis, Tregs expand and display a similar activated phenotype. Preliminary experiments suggest that GATA3 expression in Tregs is detrimental in this model. Together, these data indicate that there are unresolved GC responses in the LLN of all ILD patients, including IPF, and suggest that Tregs are ineffectual at controlling the GC response. American Heart Association Postdoctoral Fellowship, Award number (835938)

The role of radiological research methods in the diagnosis of rare forms of interstitial lung diseases in newborns

Introduction. Interstitial lung diseases in newborns associated with diffuse pulmonary developmental disorders are a difficult to detect, as they are rare, formed at the early stages of embryonic development, clinically manifested in the first hours of life as severe respiratory distress syndrome in newborns. The aim. To demonstrate the role of radiation research methods and the difficulties of differential diagnosis of rare forms of interstitial lung diseases associated with diffuse impaired lung development. Materials and methods. Clinical cases of congenital alveolar dysplasia and alveolar-capillary dysplasia with an abnormal location of the pulmonary veins are described in detail, the radiological data, confirmed by the histological data, are presented. Results. Specific changes in the lungs in ILD of newborns associated with a diffuse disorder of lung development, according to X-ray data in the first day of life, are not determined, however, a progressive negative trend has been noted. The lungs computed tomography allows a detailed diagnosis of structural changes in the lung parenchyma, their severity and prevalence. Issues of differential diagnosis of diffuse disorders of lung development in newborns are discussed; the obtained results correlate with the published data. Conclusions. Histological examination is the “gold standard” in the diagnosis of interstitial lung diseases associated with diffuse lung developmental disorders in newborns, but is most often performed at autopsy. The role of radiological methods in the algorithmic approach of diagnostics is increasing due to the accumulated data, the improvement in the quality of detection and recognition of rare variants of interstitial lung diseases in newborns according to CT of the chest organs.

ORGANIZING PNEUMONIA: AN UNUSUAL SEQUELA OF COVID-19 INFECTION.

COVID-19 pneumonia is one of the secondary causes of organizing pneumonia (OP).Early initiation of steroids in OP is associated with improvement in symptoms and prognosis.A prolonged course of steroids may be needed in COVID-induced OP.

GROUND GLASS OPACITIES: SIGN OF CAUTION IN TYPICAL INTERSTITIAL PNEUMONIA

Typical interstitial pneumonia (IP) is mainly the fibrotic form of interstitial lung disease. In some cases with typical IP, a certain amount of ground-glass opacity (GGO) can be detected on high-resolution computed tomography, however, some important issues, such as the co-existence of GGO and typical IP, still require further investigation by biopsy. After the diagnosis of typical IP, anti-fibrosis treatment is usually considered. Here, we hypothesized that GGO in typical IP could be a manifestation of an acute inflammatory attack requiring immunosuppressive therapy or an indicator of ongoing contact with trigger factors that initiate pathological reactions in typical IP.

Pleuroparenchymal Fibroelastosis following Asbestos Exposure

Background: Pleuroparenchymal fibroelastosis is considered a rare form of interstitial lung disease. There are a growing number of case reports, however no large-scale studies detailing both clinical and histopathological features along with long term follow-up. An association with asbestos exposure has been described however this too has been limited to a few case reports. Case Report: A 73-year-old man with a history of interstitial lung disease and asbestos exposure presented with dyspnea with biopsy and imaging suggestive of pleuroparenchymal fibroelastosis. Despite steroid and anti-fibrotic therapy, the disease advanced rapidly causing the patient and family to pursue palliative care. Conclusion: Asbestos exposure is a significant risk factor for pleuroparenchymal fibroelastosis, a rare but increasingly recognized entity. Biopsy and image findings are the mainstay of diagnosis, pulmonary function tests are useful in prognostication. Treatment is supportive.

Role of Circular RNAs in Pulmonary Fibrosis.

Pulmonary fibrosis is a chronic progressive form of interstitial lung disease, characterized by the histopathological pattern of usual interstitial pneumonia. Apart from aberrant alterations of protein-coding genes, dysregulation of non-coding RNAs, including microRNAs, long non-coding RNAs, and circular RNAs (circRNAs), is crucial to the initiation and progression of pulmonary fibrosis. CircRNAs are single-stranded RNAs that form covalently closed loops without 5′ caps and 3′ tails. Different from canonical splicing of mRNA, they are produced from the back-splicing of precursor mRNAs and have unique biological functions, as well as potential biomedical implications. They function as important gene regulators through multiple actions, including sponging microRNAs and proteins, regulating transcription, and splicing, as well as protein-coding and translation in a cap-independent manner. This review comprehensively summarizes the alteration and functional role of circRNAs in pulmonary fibrosis, with a focus on the involvement of the circRNA in the context of cell-specific pathophysiology. In addition, we discuss the diagnostic and therapeutic potential of targeting circRNA and their regulatory pathway mediators, which may facilitate the translation of recent advances from bench to bedside in the future.

Effects of transplanted mesenchymal stem cells on repair of the lung tissue of rats with experimental pulmonary fibrosis

Pulmonary fibrosis is one of the commonest forms of interstitial lung diseases with poorly studied methods of its treatment in both human and veterinary medicines. Therefore, this paper focused on seeking alternative methods of its diagnostics and treatment. The article provides the results of the study of bronchoalveolar lavage fluid of rats with experimental lung fibrosis and influence of transplanted allogeneic mesenchymal stem cells of the bone marrow on stimulation of regenerative processes in damaged lung tissues. The studies were conducted on female Wistar rats with pulmonary fibrosis modeled using single transthoracic injection of solution of bleomycin hydrochloride. For the purpose of treatment, we used allogeneic mesenchymal stem cells introduced by various methods and the traditional treatment. We determined that best normalization of the parameters of the studied brochoalveolar lavage occurred in animals that received mesenchymal stem cells. The most active repair processes were in the experimental group that received the mesenchymal stem cells directly to the lung tissue. The animals that received intravenous injection of mesenchymal stemm cells were observed to have lower clinical parameters of the brochoalveolar lavage, but still better than such in the group treated traditionally. The lowest parameters were in animals that received the traditional treatment; they were greater than the phisological parameters, but significantly exceeded them in animals of the control group, indicating presence of inflammatory process in the lung tissue. The conducted cytological assays of the samples of the brochoalveolar lavage revealed that experimental animals with experimental pulmonary fibrosis had development of macrophage and lymphocytic reactions under the influence of transplanted mesenchymal stemm cells. We observed no atypical cells in all the experimental groups. This allows us to draw a conclusion that using stem cells by various methods of transplantation does not stimulate the onset of negative reactons (formation of atypical cells, metastatic processes, etc). Thus, the results of the study of the influence of transplanted mesenchymal stem cells demonstrate that in the conditions of experimental pulmonary fibrosis, the activity of regenerative processes in pathologically altered lung tissue may be an effective method of treatment of animals with this kind of pathology.

Recent advances in the management of pulmonary hypertension with interstitial lung disease.

Pulmonary hypertension (PH) is known to complicate various forms of interstitial lung disease (ILD), including idiopathic pulmonary fibrosis, the interstitial pneumonias and chronic hypersensitivity pneumonitis. Pathogenesis of PH-ILD remains incompletely understood, and probably has overlap with other forms of pre-capillary pulmonary hypertension. PH-ILD carries a poor prognosis, and is associated with increased oxygen requirements, and a decline in functional capacity and exercise tolerance. Despite most patients having mild-moderate pulmonary hypertension, more severe pulmonary hypertension and signs of right heart failure are observed in a subset of cases. Clinical suspicion and findings on pulmonary function, computed tomography and echocardiography are often the initial steps towards diagnosis. Definitive diagnosis is obtained by right heart catheterisation demonstrating pre-capillary pulmonary hypertension. Drugs approved for pulmonary arterial hypertension have been investigated in several randomised controlled trials in PH-ILD patients, leading to discouraging results until the recent INCREASE study. This review provides an overview of the current understanding, approach to diagnosis and recent advances in treatment.

Caveolin-1 scaffolding domain peptide abrogates autophagy dysregulation in pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common and fatal form of interstitial lung disease. IPF is characterized by irreversible scarring of the lungs leading to lung function decline. Although the etiology remains poorly understood, dysregulated autophagy in alveolar-epithelial cells (AECs) together with interplay between apoptotic-AECs and proliferative-myofibroblasts have been strongly implicated in IPF pathogenesis. Recent studies have revealed that a caveolin-1-derived 7-mer peptide, CSP7, mitigates established PF at least in part by improving AEC viability. In the present study, we aimed to determine whether and how CSP7 regulates autophagy in fibrotic-lung AECs. We found that p53 and autophagic proteins were markedly upregulated in AECs from mice with single/multi-doses of bleomycin—or silica-induced PF. This was abolished following treatment of PF-mice with CSP7. Further, CSP7 abrogated silica- or bleomycin-induced p53 and autophagy proteins in AECs. Immunoprecipitation further revealed that CSP7 abolishes the interaction of caveolin-1 with LC3BII and p62 in AECs. AEC-specific p53-knockout mice resisted silica- or bleomycin-induced changes in autophagy proteins, or CSP7 treatment. Our findings provide a novel mechanism by which CSP7 inhibits dysregulated autophagy in injured AECs and mitigates existing PF. These results affirm the potential of CSP7 for treating established PF, including IPF and silicosis.

Treating Autoimmune-Related Interstitial Lung Disease With B Cell Depletion.

Autoimmune rheumatic diseases may affect vital organs with lung involvement being severe and difficult to treat manifestation. Systemic sclerosis (SSc) commonly affects the lung in the form of interstitial lung disease (ILD). ILD may be also seen in patients with rheumatoid arthritis (RA), Sjögren's syndrome (SS), systemic lupus erythematosus (SLE), inflammatory myositis (IM), antisynthetase syndrome (AS), and the ANCA-associated vasculitides (AAV). Rituximab (RTX) is an anti-CD20 B lymphocyte depleting mAb, often administered in the treatment of autoimmune rheumatic diseases. Although RTX is an off-label treatment for CTD–ILD, there are numerous reports providing data that is effective in improving both pulmonary function tests (PFTs) and chest computed tomography findings consistent with ILD. There are retrospective uncontrolled studies that assess RTX as a treatment of ILD in autoimmune diseases. These studies, apart from one, do not include patients with AAV-ILD. In SSc-ILD, in particular, there are both controlled and uncontrolled studies displaying encouraging results following B cell depletion. In addition, a number of retrospective uncontrolled studies and fewer prospective studies evaluate RTX in connective tissue diseases CTD–ILD. Although RTX is an approved treatment for AAV there are scarce only data focusing on patients with AAV-ILD specifically. The results of a handful of studies comparing treatment of CTD-ILD with RTX to treatment with other agents are in favor of RTX. Results from large, still ongoing controlled trials are awaited to ascertain RTX effects in ILD encountered in autoimmune rheumatic diseases. We review herein the results of the different RTX trials in patients with autoimmune disease–associated with ILD. Despite the heterogeneity of these studies, RTX may be considered an alternative and safe but still off-label treatment for patients with refractory CTD–ILD.

P43 The Economic Burden of Idiopathic Pulmonary Fibrosis in Australia

Idiopathic pulmonary fibrosis (IPF) is form of interstitial lung disease which generally occurs in persons 60 years and older.It is characterised by a high symptom burden, and frequent encounters with health services. This study aimed to determine the economic burden of IPF in Australia with a focus on resource utilisation and associated direct costs.

Desquamative interstitial pneumonia in association with chronic necrotizing aspergillosis, a case report and literature review

Desquamative interstitial pneumonia (DIP) is a form of interstitial lung disease that is directly related to smoking. In addition to smoking, other factors have been implicated in its etiology, including: systemic disorders, dangerous materials in the environment, drugs and infectious agents. By reviewing the literature, we find that there are very rare cases that indicate infections as causing DIP. Here the author report on a 58-year-old male who was addict and complained of a dry cough with dyspnea for one month. TBLB was performed and pathology result was consistent with DIP. He received prednisolone 5 mg twice a day, but his symptoms persisted. Open-lung biopsy was performed and it illustrated Aspergillus pneumonia (Chronic necrotizing aspergillosis). He was treated with corticosteroids combined with antifungal agents.

Trajectory of pulmonary function parameters and radiology progress among patients with Idiopathic pulmonary fibrosis treated with Doxycycline

Idiopathic pulmonary fibrosis is the most common and lethal form of interstitial lung diseases, with an associated median survival of only 2 to 3 years. Doxycycline through its matrix metalloproteinase inhibition property may be useful in slowing the disease progression among patients with ILD. However, there are only anecdotal reports in the literature in demonstrating long term trajectory in lung function parameters and radiology progress among IPF patients treated with doxycycline. In this report we describe the clinical course of two patients with IPF treated with doxycycline. We also compared the decline in the pulmonary function parameters in our patients with previously published predicted values for normal ageing (non-IPF), placebo, nintedanib and pirfenidone treated patients.

Predicting Usual Interstitial Pneumonia Histopathology From Chest CT Imaging With Deep Learning

Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal form of interstitial lung disease (ILD) characterized by the absence of a known cause and usual interstitial pneumonitis (UIP) pattern on chest CT imaging and/or histopathology. Distinguishing UIP/IPF from other ILD subtypes is essential given different treatments and prognosis. Lung biopsy is necessary when noninvasive data are insufficient to render a confident diagnosis. Can we improve noninvasive diagnosis of UIP be improved by predicting ILD histopathology from CT scans by using deep learning? This study retrospectively identified a cohort of 1,239 patients in a multicenter database with pathologically proven ILD who had chest CT imaging. Each case was assigned a label based on histopathologic diagnosis (UIP or non-UIP). A custom deep learning model was trained to predict class labels from CT images (training set, n=894) and was evaluated on a 198-patient test set. Separately, two subspecialty-trained radiologists manually labeled each CT scan in the test set according to the 2018 American Thoracic Society IPF guidelines. The performance of the model in predicting histopathologic class was compared against radiologists' performance by using area under the receiver-operating characteristic curve as the primary metric. Deep learning model reproducibility was compared against intra-rater and inter-rater radiologist reproducibility. For the entire cohort, mean patient age was 62 ± 12 years, and 605 patients were female (49%). Deep learning performance was superior to visual analysis in predicting histopathologic diagnosis (area under the receiver-operating characteristic curve, 0.87 vs0.80, respectively; P< .05). Deep learning model reproducibility was significantly greater than radiologist inter-rater and intra-rater reproducibility (95%CI for difference in Krippendorff's alpha did not include zero). Deep learning may be superior to visual assessment in predicting UIP/IPF histopathology from CT imaging and may serve as an alternative to invasive lung biopsy.

Incidence, prevalence and mortality of idiopathic pulmonary fibrosis in Australia.

Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung diseases. While studies have been conducted in other countries to determine the epidemiological burden of IPF, there is limited information in Australia. Our study aimed to address this gap and generate the first estimates for the mortality, incidence and prevalence of IPF in Australia. Estimates were generated by utilizing the novel Mortality Incidence Analysis Model (MIAMOD) method and software based on the illness-death model. Data inputs included population estimates and mortality data from the Australian Bureau of Statistics (ABS) for the period 1997-2015 and participant data from the Australian IPF Registry (AIPFR). Projections were estimated for a 10-year period up to 2025. Overall crude and age-standardized estimates for mortality were 5.9 and 6.3 per 100,000 population; incidence, 10.4 and 11.2 per 100,000 population; and prevalence, 32.6 and 35.1 per 100,000 population. Crude and age-standardized mortality, incidence and prevalence increased over the study period; however, they demonstrated a decreasing trend over the projected period. Persons older than 70 years constituted 9% of the population; however, they accounted for approximately 82%-83% of all deaths, incident and prevalent cases. All estimates were higher in males than in females. Our study provides the first estimates for incidence, prevalence and mortality of IPF in Australia. By reporting national estimates for IPF, our study addresses an information gap important for policy, planning and to help optimize the allocation of resources for the management of patients with IPF.

Diagnosis of Hypersensitivity Pneumonitis: Review and Summary of American College of Chest Physicians Statement.

Assessment of lung biopsies for the diagnosis of hypersensitivity pneumonitis (HP) is one of the most difficult diagnostic problems for surgical pathologists. It is a form of interstitial lung disease resulting from an immune reaction provoked by an inhaled antigen in susceptible individuals. Although this definition sounds simple, in practice, the diagnosis of HP can be challenging. To address these issues, the American College of Chest Physicians (CHEST) has recently published a guideline for the diagnosis of HP. In this review, we will explore the multidisciplinary diagnostic evaluation of HP with a focus on the pathologic features as outlined in the CHEST guidelines. The histologic criteria are divided into 4 diagnostic categories: (1) Typical nonfibrotic HP or fibrotic HP; (2) Compatible with nonfibrotic HP or fibrotic HP; (3) Indeterminate for nonfibrotic or fibrotic HP; and (4) Alternative Diagnosis. It is important to emphasize that patterns 1 to 3 do not represent discrete histologic entities or pathologic diagnoses. Rather, these categories are meant to serve as a practical guide for organizing a complex set of overlapping histologic patterns into an integrated diagnostic framework for facilitating multidisciplinary discussion. High-resolution computed tomography features are also summarized, emphasizing how the correlation of lung biopsies with computed tomography findings can help to favor the diagnosis, particularly in cases where biopsies are not typical for HP. This review highlights details of the histologic spectrum of HP as well as the utility of different types of biopsies and bronchoalveolar lavage. We also emphasize the importance of multidisciplinary discussion and the complex differential diagnosis.

Development and Validation of a Clinical Diagnostic Scoring System for the Diagnosis of Idiopathic Pulmonary Fibrosis.

Rationale: Interpreting the radiologic data in conjunction with an objective clinical score could help to harmonize idiopathic pulmonary fibrosis (IPF) diagnosis and improve accuracy. Objectives: We sought to establish and validate a multivariable objective scoring model based on clinical parameters by stratifying the risk of patients having IPF diagnosed versus having other forms of interstitial lung disease (ILD) diagnosis. Methods: A clinical score was derived from review of patients evaluated at the Inova Fairfax ILD Program and validated in three distinct cohorts. On the basis of known IPF clinical characteristics, a multivariable model was created and assessed by using receiver operating characteristic curves. Results: There were 844 patients with ILD with either IPF (n = 347, 41%) or non-IPF ILD (n = 497, 59%) diagnosis. On the basis of calculated odds ratios, a score was assigned to each of the following clinical parameters: age, sex, smoking history, race or ethnicity, ILD family history, exposures, presence of connective tissue disease signs or symptoms, and velcro crackles. The final Fairfax IPF Clinical Score (FICS) ranged from 1 to 25. The clinical diagnostic score system was accurate in predicting IPF, as measured by the area under the curve (0.88) in the derivation cohort, with similar areas under the curve of 0.91, 0.81, and 0.71 being demonstrated in the respective validation cohorts. Conclusions: The FICS appears to be an accurate tool for estimating the pretest probability of IPF in patients with ILD. How the FICS performs in conjunction with the various high-resolution computed tomographic patterns remains to be determined. This model could ultimately be useful for increasing the degree of confidence in the final diagnosis and could help to obviate the need for lung biopsy in cases with non-usual interstitial pneumonia patterns on high-resolution computed tomographic images.

Rituximab as a single agent for successful treatment of granulomatous and lymphocytic interstitial lung disease in a pediatric patient with common variable immunodeficiency

Granulomatous and lymphocytic interstitial lung disease (GLILD) occurs in 10% to 20 % of adult patients with common variable immunodeficiency (CVID).1 The frequency of GLILD in pediatric CVID is not well established, but various forms of interstitial lung disease were reported in 15% of children.2 There is a lack of robust scientific evidence on how to treat and when to start treatment of GLILD, but most regiments aim at T and B lymphocytes. Experience with the effectiveness of systemic steroids has been diverse.