Fibrotic Nonspecific Interstitial Pneumonia Research Articles

Clustered Cystic Changes in Long-Term Follow-Up Thin-Section Computed Tomographic Findings in Fibrotic Nonspecific Interstitial Pneumonia.

The purpose of this study was to retrospectively assess cystic changes in findings on follow-up CT scans of patients with fibrotic nonspecific interstitial pneumonia (NSIP). The initial and last high-resolution CT scans of 58 patients with pathologically proven fibrotic NSIP were evaluated retrospectively. The median follow-up periods were 48 months (range, 12-183 months). The pattern, extent, and distribution of abnormal CT findings were compared with findings in the same region on previous and subsequent CT scans with a focus on cystic lesions. Cystic lesions in a cluster were shown in 16 patients (28%) with fibrotic NSIP on the last CT scans. Focal clustered cysts were found in 5 cases and diffuse clustered cysts were seen in 11 cases. Focal clustered cysts mimicked honeycombing seen in usual interstitial pneumonia (UIP). Diffuse cysts were uniform in size in 7 of the 11 cases. Traction bronchiectasis in a cluster was seen in 3 of the 7 cases. The clustered cystic changes on CT during the course of NSIP mainly consisted of traction bronchiectasis and bronchiolectasis. Long-standing NSIP did not form honeycombing. The clustered cysts in patients with fibrotic NSIP were mainly remodeling of bronchiectasis.

Idiopathic Fibrotic Nonspecific Interstitial Pneumonia with Cicatricial Organizing Pneumonia and Intraluminal Pulmonary Ossification Containing Bone Marrow

Idiopathic Fibrotic Nonspecific Interstitial Pneumonia with Cicatricial Organizing Pneumonia and Intraluminal Pulmonary Ossification Containing Bone Marrow

Histologic Analysis of Idiopathic Pulmonary Fibrosis by Morphometric and Fractal Analysis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disorder, ultimately leading to respiratory failure and death. Despite great research advances in understanding the mechanisms underlying the disease, its diagnosis, and its treatment, IPF still remains idiopathic without known biological or histological markers able to predict disease progression or response to treatment. The histologic hallmark of IPF is usual interstitial pneumonia (UIP), with its intricate architectural distortion and temporal inhomogeneity. We hypothesize that normal lung alveolar architecture can be compared to fractals, such as the Pythagoras tree with its fractal dimension (Df), and every pathological insult, distorting the normal lung structure, could result in Df variations. In this study, we aimed to assess the UIP histologic fractal dimension in relationship to other morphometric parameters in newly diagnosed IPF patients and its possible role in the prognostic stratification of the disease. Clinical data and lung tissue specimens were obtained from twelve patients with IPF, twelve patients with non-specific interstitial pneumonia (NSIP), and age-matched "healthy" control lung tissue from patients undergoing lung surgery for other causes. Histology and histomorphometry were performed to evaluate Df and lacunarity measures, using the box counting method on the FracLac ImageJ plugin. The results showed that Df was significantly higher in IPF patients compared to controls and fibrotic NSIP patients, indicating greater architectural distortion in IPF. Additionally, high Df values were associated with higher fibroblastic foci density and worse prognostic outcomes in IPF, suggesting that Df may serve as a potential novel prognostic marker for IPF. The scalability of Df measurements was demonstrated through repeated measurements on smaller portions from the same surgical biopsies, which were selected to mimic a cryobiopsy. Our study provides further evidence to support the use of fractal morphometry as a tool for quantifying and determining lung tissue remodeling in IPF, and we demonstrated a significant correlation between histological and radiological Df in UIP pattern, as well as a significant association between Df and FF density. Furthermore, our study demonstrates the scalability and self-similarity of Df measurements across different biopsy types, including surgical and smaller specimens.

Stattic alleviates pulmonary fibrosis in a mouse model of rheumatoid arthritis-relevant interstitial lung disease.

Approximately 20% of rheumatoid arthritis (RA) patients have RA-related interstitial lung disease (RA-ILD). Stattic, an STAT3 inhibitor, has been confirmed to be relevant to both RA and ILD. Therefore, this study explored the effect of Stattic on the progression of joint disease and pulmonary fibrosis in zymosan-treated female SKG mice, an established model for autoimmune arthritis. The experimental mice developed pulmonary interstitial pneumonia, which is similar to human cellular and fibrotic nonspecific interstitial pneumonia. Oral gavage of Stattic (60 mg/kg/d) was initiated 10 weeks after zymosan injection. Arthritis and lung fibrosis outcome scores decreased significantly following Stattic treatment. An obvious decrease in lung collagen levels, measured using hydroxyproline level determination and collagen staining, was detected after 6 weeks in Stattic-exposed mice with established disease. Stattic also dramatically restricted arthritis progression, based on joint evaluation. Transforming growth factor beta 1 (TGF-β1) is a pivotal fibrosis-causing cytokine, used here to treat myofibroblasts, thereby establishing a lung fibrosis cell model. Stattic treatment can mitigate the TGF-β1-triggered inflammatory response, myofibroblast activation, oxidative stress, and hyperproliferation by modulating the JAK1/STAT3 pathway. Our observations support a direct role of Stattic-inhibited STAT3 activation in lung fibrosis, which may be particularly relevant in the RA-ILD context.

Profile of COVID-19 Patients with Persistent Respiratory Symptoms

Background and objective: COVID pandemic struck the entire world causing high mortality and morbidity. After-effects of the infection were manifested in various clinical forms for the varying duration. As the pandemic waxes and wanes, COVID has become one of the differential diagnoses for various clinical and radiological pictures and triggers for respiratory diseases. While COVID sequelae are still much to explore, this study aimed to assess the clinicoradiological profile of COVID-19 patients who have persistent symptoms pertaining to the respiratory system. Materials and methods: This prospective study was conducted for 1 year from December 2020 to December 2021. COVID-19 patients aged between 10 and 85 years with persistent respiratory symptoms were included in this study. Results: There were a total of 90 patients. The mean age was 50.79 years. Forty-eight (53.3%) patients were males and 42 (46.7%) were females. Among these patients, eight patients (8.9%) had an asymptomatic or minimal symptomatic gap of at least 2 weeks from the date of positivity to the development of full-blown symptoms. The maximum duration of symptoms reported was more than 1 year and continuing. Dyspnea on exertion was the predominant symptom, in 59 patients (65.6%). Hypoxia at rest was seen in 35 (38.9%) patients, whereas seven patients with normal oxygen saturation showed exertional desaturation. Out of the 33 patients with post-COVID changes in computed tomography (CT) of the thorax, ground-glass opacities were seen in all 33 patients (100%), consolidation in 18 patients (54.5%), septal thickening in 18 patients (54.5%), and fibrosis in 15 patients (45.4%). Predominant CT finding was that of organizing pneumonia, but a few had fibrotic picture similar to usual interstitial pneumonia (UIP) or fibrotic nonspecific interstitial pneumonia (fibrotic NSIP). Hypoxia severity was significantly associated with diabetes (p = 0.028), hypertension (p = 0.028), chronic kidney disease (p = 0.027), chronic obstructive pulmonary disease (p = 0.001), obesity (p = 0.000), and smoking (p = 0.004). CT severity scoring was significantly associated with hypoxia severity. Conclusion: After the initial weeks, COVID patients can present with varying respiratory symptoms. They can present with respiratory failure as late as 1 month after the test positivity. Although CT picture was predominantly that of organizing pneumonia, COVID lung sequelae can masquerade as UIP or fibrotic NSIP as in idiopathic pulmonary fibrosis and connective tissue disease-associated interstitial lung disease, whereas atypical infections and malignancy can masquerade as COVID lung. Irreversible changes like honeycombing can occur as early as 2nd month after COVID.

Сучасні відомості про патогенетичні механізми формування пневмосклерозу

The purpose of the study was to analyze literary sources on the study of modern views on information about the pathogenetic mechanisms of the formation of pulmonary fibrosis. Materials and methods. Analytical and bibliosemantic methods were used in the research. During the scientific search, 39 sources of modern domestic and foreign literature were reviewed and analyzed. Results and discussion. Pulmonary fibrosis is a heterogeneous group of chronic, progressive and incurable interstitial lung diseases characterized by scar formation and irreversible destruction of the lung parenchyma and is accompanied by disorders of elasticity and gas exchange in pathologically altered areas. The mechanism of development of pulmonary fibrosis is determined by its root causes. There are three distinct pathologic patterns of pulmonary fibrosis: usual interstitial pneumonia, fibrotic nonspecific interstitial pneumonia, and airway fibrosis. Their morphological differences are based on the distribution of fibrosis (diffuse or spotty) and anatomical location. The development of pulmonary fibrosis in most cases is a consequence of a previous acute inflammation of the lungs caused by various etiological factors, which in the case of untimely started or incorrectly selected treatment causes the deposition of fibrous tissue in the lungs. It is believed that the appearance and subsequent progression of pulmonary fibrosis can be attributed to reparative processes after repeated injuries of alveolar epithelial cells in response to various stimuli, including injuries. Loss of function or reduction in the number of alveolar epithelial cells can lead to improper repair of the lung parenchyma, which can lead to fibrosis. Various cytokines such as transforming growth factor-β1, tumor necrosis factor-α, and platelet-derived growth factor can be released when alveolar epithelial cells are damaged. These cytokines can promote the accumulation of fibroblasts. In addition to the cytokine response, the lung’s response to injury includes the stimulation of myofibroblasts, which when activated serve as the primary collagen-producing cell. This leads to massive deposition of collagen and subsequently affects the normal structure and function of lung tissue. Conclusion. Pulmonary fibrosis is a progressive lung disease that leads to morpho-functional restructuring of lung tissue. In the course of the work, the presence of three models of the development of pulmonary fibrosis were analyzed. Despite the long history of study and good coverage of the problem in the scientific literature, currently the mechanisms of formation of pulmonary fibrosis remain insufficiently studied

Lung transplantation for interstitial lung disease: evolution over three decades

BackgroundInterstitial lung disease (ILD) has emerged as the most common indication for lung transplantation globally. However, post-transplant survival varies depending on the underlying disease phenotype and comorbidities. This study aimed...

Serum KL-6 as a Biomarker of Progression at Any Time in Fibrotic Interstitial Lung Disease.

The development of a progressive phenotype of interstitial lung disease (ILD) is still unpredictable. Whereas tools to predict mortality in ILD exist, scores to predict disease progression are missing. The aim of this study was to investigate whether baseline serum KL-6 as an established marker to assess disease activity in ILD, alone or in combination with clinical variables, could improve stratification of ILD patients according to progression risk at any time. Consecutive patients with fibrotic ILD, followed at our institution between 2008 and 2015, were investigated. Disease progression was defined as relative decline of ≥10% in forced vital capacity (FVC) or ≥15% in diffusing capacity of the lung for carbon monoxide (DLco)% from baseline at any time. Serum KL-6 was measured using an automated immunoassay (Fujirebio Europe, Gent, Belgium). A stepwise logistic regression was performed to select variables to be included in the score. A total of 205 patients (49% idiopathic pulmonary fibrosis (IPF), 51% fibrotic nonspecific interstitial pneumonia (NSIP)) were included, of them 113 (55%) developed disease progression during follow up. Male gender (G) and serum KL-6 strata (K) were significant predictors of progression at regression analysis and were included in the GK score. A threshold of 2 GK score points was best for discriminating patients at high risk versus low risk to develop disease progression at any time. Serum KL-6 concentration, alone or combined in a simple score with gender, allows an effective stratification of ILD patients for risk of disease progression at any time.

Clinical and Radiological Features of Interstitial Lung Diseases Associated with Polymyositis and Dermatomyositis.

Polymyositis and dermatomyositis are autoimmune idiopathic systemic inflammatory diseases, characterized by various degrees of muscle inflammation and typical cutaneous lesions-the latter found in dermatomyositis. The underlying pathogenesis is characterized by a high level of uncertainty, and recent studies suggest diseases may have different immunopathological mechanisms. In polymyositis, components of the cellular immune system are involved, whereas in dermatomyositis, the pathogenesis is mainly mediated by the humoral immune response. The interstitial lung disease occurs in one-third of polymyositis and dermatomyositis patients associated with worse outcomes, showing an estimated excess mortality rate of around 40%. Lung involvement may also appear, such as a complication of muscle weakness, mainly represented by aspiration pneumonia or respiratory insufficiency. The clinical picture is characterized, in most cases, by progressive dyspnea and non-productive cough. In some cases, hemoptysis and chest pain are found. Onset can be acute, sub-acute, or chronic. Pulmonary involvement could be assessed by High Resolution Computed Tomography (HRCT), which may identify early manifestations of diseases. Moreover, Computed Tomography (CT) appearances can be highly variable depending on the positivity of myositis-specific autoantibodies. The most common pathological patterns include fibrotic and cellular nonspecific interstitial pneumonia or organizing pneumonia; major findings observed on HRCT images are represented by consolidations, ground-glass opacities, and reticulations. Other findings include honeycombing, subpleural bands, and traction bronchiectasis. In patients having Anti-ARS Abs, HRCT features may develop with consolidations, ground glass opacities (GGOs), and reticular opacities in the peripheral portions; nonspecific interstitial pneumonia or nonspecific interstitial pneumonia mixed with organizing pneumonia have been reported as the most frequently encountered patterns. In patients with anti-MDA5 Abs, mixed or unclassifiable patterns are frequently observed at imaging. HRCT is a sensitive method that allows one not only to identify disease, but also to monitor the effectiveness of treatment and detect disease progression and/or complications; however, radiological findings are not specific. Therefore, aim of this pictorial essay is to describe clinical and radiological features of interstitial lung diseases associated with polymyositis and dermatomyositis, emphasizing the concept that gold standard for diagnosis and classification-should be based on a multidisciplinary approach.

Clinically Amyopathic Dermatomyositis With Rapid Progressive Interstitial Lung Disease Diagnosed in a Patient on Extracorporeal Membrane Oxygenation

Clinically amyopathic dermatomyositis (CADM) is characterized by skin manifestations with minimal to no muscle involvement. It is a unique subset of dermatomyositis, which may create a diagnostic challenge due to its vague presentation. Establishing the diagnosis is crucial as CADM is highly associated with rapidly progressive interstitial lung disease (RP-ILD), and patients who suffer from thereof have an abysmal prognosis. Herein, we described a case of a 46-year-old male who presented with a history of skin rash and then started to experience shortness of breath. His respiratory symptoms were progressing swiftly and affected his daily life activities. The initial blood tests were normal, but his chest imaging revealed fibrotic nonspecific interstitial pneumonia. The patient required intubation due to a critical respiratory condition, and later, he needed extracorporeal membrane oxygenation (ECMO). While the patient was connected to an ECMO machine, a bedside open lung biopsy (BOLB) was performed, and the results were in keeping with RP-ILD and CADM. The patient was started on cyclophosphamide without a response, and his chest computed tomography showed acute respiratory distress syndrome. His hospital course was complicated with pneumonia, severe kidney dysfunction requiring dialysis, and candidemia, which resulted in the patient’s death.

Evaluation of the Interstitial Histological Lesions in Pulmonary Langerhans Cell Histiocytosis.

Pulmonary Langerhans cell histiocytosis is a cystic lung disease characterized by the proliferation of parenchymal dendritic cells. The disease can become chronic or even cause pulmonary fibrosis. Our aim in this study was to investigate the typical histological findings and interstitial fibrosis in pulmonary Langerhans cell histiocytosis cases. In the study, cases that had undergone diagnostic resection were screened. Smoking, histological stage (subacute, subacute-chronic), and cystic and eosinophilic granulomas were confirmed in the cases. In addition to emphysema, chronic nonspecific bronchiolitis, interstitial fibrosis (subpleural-paraseptal fibrosis, peribronchial fibrosis, fibrotic nonspecific interstitial pneumonia), honeycomb-type fibrocysts, and unexpected lesions were investigated. Descriptive and comparative (Fisher exact test) statistical analyses were used in the study (p < 0.05). A total of 27 cases were detected; age distribution was 17-68 (36.4). Smoking was present in 15 (55.5%) cases. Six (22.2%) cases were subacute, and 21 (7.7%) cases were subacute-chronic histological stage. A cystic lesion was present in 22 (81.4%) cases. All cases had emphysema accompanying the underlying lesions. Chronic nonspecific bronchiolitis was detected in 14 (51.8%) cases. Interstitial fibrosis was detected in 8 (29.6%) patients. Compared to interstitial fibrosis and nonfibrosis, there was no significant difference between being younger than 39 years, gender, smoking, and histological stage (p=0.41; 1; 0.69; 0.63, respectively). There is a risk of developing interstitial fibrosis patterns and honeycomb-type fibrocysts in the progression of pulmonary Langerhans cell histiocytosis. Histopathological evaluation can play an important role in the detection of risk groups.

Clinical characteristics and prognostic factors of fibrotic nonspecific interstitial pneumonia.

Aim:Several studies have reported favorable outcomes of nonspecific interstitial pneumonia (NSIP); however, its prognosis and prognostic factors remain unclear. This study aimed to determine the outcomes of fibrotic NSIP and the prognostic factors for progression, relapse, and survival.Methods:In this retrospective study, we reviewed the clinical data of 204 patients diagnosed with fibrotic NSIP by surgical lung biopsy at Samsung Medical Center. The factors associated with survival and disease progression or relapse were determined using Cox proportional hazard analysis.Results:The median age of patients was 54 years and 67 (33%) patients were male. Also, 47 patients (23%) were current or ex-smokers. In all, 141 (69%) patients were diagnosed with idiopathic NSIP, while 63 (31%) patients were associated with connective tissue diseases. Progression or relapse was observed in 100 (49%) patients. The 5-year and 10-year survival rates were 94.6% and 90.4%, respectively. The factors associated with disease progression and relapse were diffusing capacity for carbon monoxide (DLco) <60% [adjusted hazard ratio (HR), 1.739; 95% confidence interval (CI), 1.036–2.921; p = 0.036], bronchoalveolar lavage (BAL) lymphocyte >15% (adjusted HR, 0.592; 95% CI, 0.352–0.994; p = 0.047), and treatment with corticosteroid and azathioprine (adjusted HR, 0.556; 95% CI, 0.311–0.955; p = 0.048). Disease progression or relapse was associated with mortality (adjusted HR, 7.135; 95% CI, 1.499–33.971; p = 0.014).Conclusion:Preserved lung function, BAL lymphocytosis, and treatment with corticosteroids and azathioprine were associated with lower risks of disease progression and relapse, which were risk factors for mortality.

CT Morphologic Characteristics and Variant Patterns of Interstitial Pulmonary Fibrosis in Systemic Lupus Erythematosus.

To assess CT features of pulmonary fibrosis in patients with systemic lupus erythematosus (SLE) and to assess the presence of several distinctive patterns of fibrosis associated with connective tissue disease. A cross-sectional retrospective analysis was performed. An institutional clinical database was queried for the years of 2005-2015 to identify CT examination reports of patients with SLE and fibrotic lung disease, which yielded 50 patients (median age, 49 years; age range, 22-71 years; 46 women). CT examination reports were scored by two subspecialty thoracic radiologists using a standard multilevel semiquantitative system. Readers noted the presence or absence of several recently described CT signs of variant patterns of fibrosis in connective tissue disease (the "anterior upper lobe," "straight-edge," and "exuberant honeycombing" signs), as well as two other morphologic characteristics (an "island-like" appearance of areas of well-defined fibrosis with angular margins surrounded by normal lung and confluent regions of lucent lung destruction). The most common CT patterns were characterized as either fibrotic nonspecific interstitial pneumonia (38%, 19 of 50) or variant fibrosis (44%, 22 of 50). CT signs of variant fibrosis were identified by both readers in up to 62% of patients, with good κ agreement (0.44-0.64); the island-like sign (62%) and anterior upper lobe sign (52%) were most commonly observed. Pulmonary function test results showed correlations with several imaging findings but did not show correlations with CT signs of variant fibrosis. When present, pulmonary fibrosis in SLE often has a distinctive appearance and may also manifest as several variant fibrotic patterns.Keywords: CT, Lung© RSNA, 2021See also the commentary by White in this issue.

Biopsy in interstitial lung disease: specific diagnosis and the identification of the progressive fibrotic phenotype.

The evaluation of progression in fibrotic interstitial lung diseases (ILDs) may require a multidimensional approach. This review will cover the role and usefulness of lung biopsy in diagnosis and assessment of the progressive fibrotic phenotype. The identification of specific findings and the balance between inflammation and fibrosis on lung biopsy may help distinguishing different disease entities and may likely determine the effect of treatment and possibly prognosis. The fibrotic morphological patterns potentially associated with a progressive phenotype include usual interstitial pneumonia (UIP), fibrotic nonspecific interstitial pneumonia, pleuroparenchymal fibroelastosis, desquamative interstitial pneumonia, fibrotic hypersensitivity pneumonitis and other less common fibrotic variants, with histopathological findings of UIP at the time of diagnosis being predictive of worse outcome compared with other patterns. The prognostic significance of lung biopsy findings has been assessed after both surgical lung biopsy (SLB) and transbronchial lung cryobiopsy (TBLC), the latter becoming a valid alternative to SLB, if performed in experienced centres, due to significantly lower morbidity and mortality. Lung biopsy plays an important role in diagnosis and identification of the progressive fibrotic phenotype. The introduction of less invasive procedures could potentially expand the role of lung sampling, including for example patients with a known diagnosis of ILD or at an earlier stage of the disease.

The effects of direct hemoperfusion with polymyxin B-immobilized fiber in patients with acute exacerbation of interstitial lung disease.

BackgroundAcute exacerbation of interstitial lung disease (AE-ILD) causes clinically significant deterioration and has an extremely poor prognosis with high mortality. Recently, several studies reported the effectiveness of direct hemoperfusion with a polymyxin B-immobilized fiber column (PMX-DHP) in patients with AE-ILD as a potential therapy. This study describes the clinical effectiveness and safety of PMX-DHP in patients with AE-ILD. MethodsWe retrospectively reviewed the medical records of 10 patients (11 episodes) with AE-ILD treated with PMX-DHP from January 2018 to June 2019. We compared laboratory and physiologic data of the ratio of partial pressure arterial oxygen to fraction of inspired oxygen (P/F ratio) and level of inflammatory markers before and after implementation of PMX-DHP. ResultsTen patients were included according to the 2016 revised definition of acute exacerbation of idiopathic pulmonary fibrosis (IPF). Nine patients had IPF and one patient had fibrotic nonspecific interstitial pneumonia. Most patients (90.9%) were treated with a steroid pulse, and four patients (36.4%) were treated with an immunosuppressant. The median number of PMX-DHP cycles was 2, and the median duration of each cycle was 6 hours. After PMX-DHP, the mean P/F ratio improved (86 [range, 63–106] vs. 145 [86–260], P=0.030) and interleukin-6 and c-reactive protein decreased (79 [35–640] vs. 10 [5–25], P=0.018 and 14 [4–21] vs. 5 [2–6], P=0.019, respectively). The 30-day mortality rate was 27.3% and the 90-day mortality rate was 72.7%.ConclusionsPMX-DHP treatment improved P/F ratio and reduced inflammatory markers in AE-ILD patients.

Pirfenidone in patients with progressive fibrotic interstitial lung diseases other than idiopathic pulmonary fibrosis (RELIEF): a double-blind, randomised, placebo-controlled, phase 2b trial

Pirfenidone has been shown to slow disease progression in patients with idiopathic pulmonary fibrosis (IPF). However, there are few treatment options for progressive fibrotic interstitial lung diseases (ILDs)) other than IPF. In view of the pathomechanistic and clinical similarities between IPF and other progressive fibrotic ILDs, we aimed to assess the efficacy and safety of pirfenidone in patients with four non-IPF progressive fibrotic ILDs. We did a multicentre, double-blind, randomised, placebo-controlled, parallel phase 2b trial (RELIEF) in 17 centres with expertise in ILD in Germany. Eligible participants were patients aged 18-80 years with progressive fibrotic ILD due to four diagnoses: collagen or vascular diseases (ie, connective tissue disease-associated ILDs), fibrotic non-specific interstitial pneumonia, chronic hypersensitivity pneumonitis, or asbestos-induced lung fibrosis. Other eligibility criteria included a forced vital capacity (FVC) of 40-90% predicted, a diffusing capacity of the lung for carbon monoxide of 10-90% predicted, and an annual decline of FVC of at least 5% predicted despite conventional therapy, based on at least three measurements within 6-24 months before enrolment. Patients who had received any previous antifibrotic therapy were excluded. We randomly assigned patients (1:1) to either oral pirfenidone (267 mg three times per day in week 1, 534 mg three times per day in week 2, and 801 mg three times per day thereafter) or matched placebo, added to their ongoing medication. Randomisation was done centrally using permuted block randomisation with varying block sizes stratified by the four diagnostic groups. Patients, investigators, statisticians, monitors, and the study coordinator were masked to treatment assignment until database closure. The placebo-controlled study period was 48 weeks (including up-titration). The primary endpoint was absolute change in percentage of predicted FVC (FVC % predicted) from baseline to week 48 in the intention-to-treat population, with imputation of missing data by the smallest sum of squared differences and attribution of deceased patients to the lowest rank in a rank ANCOVA model. Additionally, we did linear mixed-model repeated measures slope analyses of FVC % predicted longitudinal data over the course of the study as a prespecified sensitivity analysis and post-hoc sensitivity analyses of the primary endpoint in the intention-to-treat population using imputation methods of last observation carried forward [LOCF] and a regression-based multiple imputation procedure. Safety was assessed in all patients who received at least one dose of study medication. This trial is registered with EudraCT 2014-000861-32; DRKS00009822 and is no longer recruiting. Between April 5, 2016, and Oct 4, 2018, we randomly assigned 127 patients to treatment: 64 to pirfenidone, 63 to placebo. After 127 patients had been randomised, the study was prematurely terminated on the basis of an interim analysis for futility triggered by slow recruitment. After 48 weeks and in the overall population of 127 patients, rank ANCOVA with diagnostic group included as a factor showed a significantly lower decline in FVC % predicted in the pirfenidone group compared with placebo (p=0·043); the result was similar when the model was stratified by diagnostic group (p=0·042). A significant treatment effect was also observed when applying the LOCF and multiple imputation methods to analyses of the primary endpoint. The median difference (Hodges-Lehmann estimate) between pirfenidone and placebo groups for the primary endpoint was 1·69 FVC % predicted (95% CI -0·65 to 4·03). In the linear mixed-model repeated measures slope analysis of FVC % predicted, the estimated difference between treatment and placebo groups from baseline to week 48 was 3·53 FVC % predicted (95% CI 0·21 to 6·86) with imputation of deaths as prespecified, or 2·79 FVC % predicted (95% CI 0·03 to 5·54) without imputation. One death (non-respiratory) occurred in the pirfenidone group (2%) and five deaths (three of which were respiratory) occurred in the placebo group (8%). The most frequent serious adverse events in both groups were infections and infestations (five [8%] in the pirfenidone group, ten [16%] in the placebo group); general disorders including disease worsening (two [3%] in the pirfenidone group, seven [11%] in the placebo group); and cardiac disorders (one ([2%] in the pirfenidone group, 5 [8%] in the placebo group). Adverse events (grade 3-4) of nausea (two patients on pirfenidone, two on placebo), dyspnoea (one patient on pirfenidone, one on placebo), and diarrhoea (one patient on pirfenidone) were also observed. In view of the premature study termination, results should be interpreted with care. Nevertheless, our data suggest that in patients with fibrotic ILDs other than IPF who deteriorate despite conventional therapy, adding pirfenidone to existing treatment might attenuate disease progression as measured by decline in FVC. German Center for Lung Research, Roche Pharma.

Interstitial lung disease pathology in systemic sclerosis

Interstitial lung disease is a relatively frequent manifestation of systemic sclerosis with approximately one-third of patients developing clinical restrictive lung disease. Fibrotic nonspecific interstitial pneumonia is the most common cause of diffuse parenchymal lung disease in patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD), followed by usual interstitial pneumonia (UIP). Radiographic pleuroparenchymal fibroelastosis-like changes may accompany other forms of interstitial lung disease, most commonly UIP. In an appropriate clinical setting with supportive high-resolution computed tomography findings, lung biopsy is not needed to confirm the presence of interstitial lung disease and surgical lung biopsies are often reserved for atypical presentations. In this review, we discuss the histological findings that define the most common patterns of SSc-ILD and outline other findings sometimes encountered in lung biopsies obtained from systemic sclerosis patients, including pulmonary vascular changes, aspiration, chronic pleuritis, and diffuse alveolar damage.

CASE SERIES: SERIOUS PULMONARY TOXICITY SECONDARY TO PEMBROLIZUMAB; AN IMMUNE CHECKPOINT INHIBITOR

SESSION TITLE: Medical Student/Resident Diffuse Lung Disease SESSION TYPE: Med Student/Res Case Rep Postr PRESENTED ON: October 18-21, 2020 INTRODUCTION: Immune checkpoint inhibitors (ICIs) which target the programmed cell death 1 (PD-1) / programmed cell death ligand 1 (PDL-1) pathway [1,2,3] have been effective in cancer treatment. ICIs carry a high risk of lung injury with potential for permanent damage and death [1]. We describe 3 patients with lung injury from use of PD-1 Inhibitor (Pembrolizumab) that outlines the spectrum of injury and outcome. CASE PRESENTATION: Case one:74-year-old male was treated for metastatic urinary bladder carcinoma with pembrolizumab and 2 months later developed nonspecific interstitial pneumonia (NSIP)(Figure 1) leading to hypoxemic respiratory failure requiring ventilator support. This progressed over 1 month to fibrotic NSIP. Course was complicated by Sepsis and multi organ failure and the patient died. Case two:48-year-old male was treated for metastatic renal cell carcinoma with pembrolizumab. Two months later he developed hypoxemic respiratory failure secondary to organizing pneumonia (Figure 2). The drug was discontinued and in spite of treatment with steroids and mycophenolate, he progressed to fibrotic organizing pneumonia and now has poor functional status and is oxygen dependent. Also noted were abnormal liver function, raised troponin and raised lipase suggestive of drug induced toxicity.Case three:74-year-old with metastatic stage IV Non-small cell lung cancer treated with chemotherapy and pembrolizumab. Two months later he developed hypoxemic respiratory failure secondary to organizing pneumonia (Figure 3) but rapidly responded to steroid treatment. DISCUSSION: Patients treated with PD-1 inhibitors such as Pembrolizumab, are high risk for lung injury [1]. Patterns of Injury described include organizing pneumonia, nonspecific interstitial pneumonia (NSIP), Hypersensitivity pneumonitis, acute interstitial pneumonia, radiation recall pneumonitis and bronchiolitis. Median time to occurrence of lung injury is 3 months. More than 50 % of patients also exhibit signs of inflammatory dysfunction in the heart, skin, thyroid or colon. Up to 12% of patients progress to lethal disease despite immunosuppression [2,3]. Two of our patients developed lung injury in the form of organizing pneumonia with one responding to steroids and the other progressing to fibrotic disease and oxygen dependency. The third patient progressed to fibrotic NSIP and died with complications of sepsis and organ failure. CONCLUSIONS: Lung injury secondary to PD-1 inhibitor treatment can lead to severe and lethal outcomes [2,3] and we report our experience to highlight this. Close monitoring is recommended and early discontinuation at first sign of lung injury is essential. Response to immunosuppression is unpredictable and early recognition is the key. Reference #1: 1.Khunger, M. et al. Incidence of Pneumonitis With Use of Programmed Death 1 and Programmed Death-Ligand 1 Inhibitors in Non-Small Cell Lung Cancer: A Systematic Review and Meta-Analysis of Trials. Chest 152, 271–281 (2017). Reference #2: 2.Rickard, Frances et al. "Pneumonitis: a serious adverse effect of PD-L1 inhibitors including pembrolizumab.” BMJ case reports vol. 2018 bcr2018224485. 7 May. 2018, https://doi.org/10.1136/bcr-2018-224485 Reference #3: 3.Jun, Jiho et al. "Pneumonitis and concomitant bacterial pneumonia in patients receiving pembrolizumab treatment: Three case reports and literature review.” Medicine vol. 98,25 (2019): e16158. https://doi.org/10.1097/MD.0000000000016158 DISCLOSURES: No relevant relationships by Abdul Basit, source=Web Response No relevant relationships by Aaron Douen, source=Web Response No relevant relationships by Pushpinder Kaur, source=Web Response No relevant relationships by padmanabhan krishnan, source=Web Response No relevant relationships by David Michael, source=Web Response No relevant relationships by Nikolas St.Cyr, source=Web Response

Real-life experiences in a single center: efficacy of pirfenidone in idiopathic pulmonary fibrosis and fibrotic idiopathic non-specific interstitial pneumonia patients.

Background:Pirfenidone is the first antifibrotic drug approved for the treatment of idiopathic pulmonary fibrosis (IPF) and it is used in the treatment of other interstitial pneumonias, such as unclassifiable interstitial lung disease (ILD) and connective tissue-related ILD. This study examined the efficacy of pirfenidone in patients with IPF and fibrotic idiopathic non-specific interstitial pneumonia (f-iNSIP).Methods:In a retrospective real-life study, 67 IPF and 24 f-iNSIP patients were enrolled and classified into a pirfenidone group and a non-antifibrotic group. The level of forced vital capacity (FVC) and diffusing capacity of lung for carbon monoxide (DLco) at baseline, 6, 12 and 24 months were recorded. The level of KL-6 in serum was detected by chemiluminescence enzyme immunoassay (CLEIA). The prognosis and safety outcomes were collected from patients.Results:In IPF patients, pirfenidone decreased the mean change of FVC and DLco, and decreased the proportion of patients with a ⩾10% decline in FVC or a ⩾15% decline in DLco compared with the non-antifibrotic group. There was no difference in the mean change of FVC and DLco between smokers and non-smokers who received pirfenidone treatment. There was an improvement in progression-free survival, defined as the time to the first occurrence of acute exacerbation or death related to pulmonary fibrosis. Moreover, the ratio of patients who experienced acute exacerbation and death related to pulmonary fibrosis was lower in the pirfenidone group. There was no change in lung function and prognosis between the pirfenidone and non-antifibrotic groups in f-iNSIP patients. The KL-6 level slightly decreased after 1 year of pirfenidone treatment but not significantly. Gastrointestinal and skin-related adverse events were most common, and four patients ceased treatment due to the side effects.Conclusions:Pirfenidone safely reduced disease progression by improving the lung function and progression-free survival in IPF patients, with acceptable side effects. The efficacy of pirfenidone on f-iNSIP was not significant, suggesting the need for further studies.The reviews of this paper are available via the supplemental material section.

Evaluation of changes in the serum levels of Krebs von den Lungen-6 and surfactant protein-D over time as important biomarkers in idiopathic fibrotic nonspecific interstitial pneumonia.

Some cases of idiopathic fibrotic nonspecific interstitial pneumonia (f-NSIP) show a progressive course that is similar to that of idiopathic pulmonary fibrosis. However, it is difficult to predict poor patient outcomes. This study aimed to evaluate whether serial changes in serum levels of Krebs von den Lungen-6 (KL-6) and surfactant protein-D (SP-D) can predict disease progression. We retrospectively analyzed the medical records of 75 patients with idiopathic f-NSIP. Disease behavior was categorized into two groups depending on long-term change of pulmonary function: progressive type (≥5%/year relative decline in the slope of forced vital capacity [FVC] and/or ≥7.5%/year relative decline in the slope of %diffusing capacity of the lung for carbon monoxide [%DLCO]) and stable type. Levels of KL-6 and SP-D and results of pulmonary function tests, which were performed parallelly, were reviewed and analyzed using a linear mixed-effects model. The study subjects comprised 62 patients with stable type and 13 patients with progressive type disease behavior. Among these subjects, 50 patients fulfilled the diagnostic criteria of interstitial pneumonia with autoimmune features (IPAF). Serum levels of both KL-6 and SP-D at baseline showed a negative correlation with %DLCO, but not with FVC, and these biomarkers were not related to disease progression. Persistently high levels of KL-6 and SP-D correlated with progressive type disease behavior in idiopathic (non-IPAF) f-NSIP. Changes in serum KL-6 and SP-D levels over time may provide useful predictive information on disease behavior during treatment in patients with idiopathic f-NSIP and especially in those with non-IPAF f-NSIP.