特发性肺纤维化的临床研究进展

特发性肺纤维化(IPF)是一种慢性进行性发展的并以普通性间质性肺炎为特征性病理改变的一种间质性肺疾病.新的指南中IPF定义为病因不明的疾病,但2011指南指出了IPF可能的高危因素,比如吸烟、环境及遗传因素等.IPF患者在临床症状出现后,大多死于呼吸衰竭,中位生存期只有2~5年.目前并没有药物能够明确改善患者的预后,本文强调临床检查血气分析、肺功能、凝血及血常规、6分钟步行试验、高分辨率CT对IPF的诊断意义,并通过检查了解疾病发展情况,从而对疾病做出综合评估,掌握常见的IPF并发症,做出合适的临床处理意见.     

Serum amyloid A in patients with idiopathic pulmonary fibrosis

BackgroundSerum amyloid A (SAA) is an apo-lipoprotein (12–14 kDa) produced by the liver in response to proinflammatory cytokines from activated monocytes. The precursor of SAA is an acute-phase protein involved in the pathogenesis of sarcoidosis and has been found to be increased during exacerbation of chronic obstructive pulmonary disease and lung cancer. However, no data are available on SAA levels in patients with idiopathic pulmonary fibrosis (IPF), the most common and severe idiopathic form of interstitial pneumonitis associated with a usual interstitial histological and radiological pattern. The aim of this preliminary study was to evaluate SAA concentration in patients with IPF and to explore its potential use as a clinical biomarker.MethodsSAA levels were determined by enzyme-linked immunosorbent assay in a population of 21 patients with IPF (14 male, aged 64.8 ± 8.1 years) and compared with those in 11 healthy controls (3 male, aged 55 ± 11.3 years). Clinical, functional, and immunological data were collected in a database.ResultsSAA levels were significantly higher in patients with IPF than in controls (p = 0.03). In patients with IPF, statistically significant correlations were found between SAA and HDL cholesterol levels (r = ?0.62, p = 0.05) and FVC % predicted value (r = ?0.52, p = 0.01).ConclusionsSAA is a promising marker of disease severity in patients with IPF. Our preliminary data suggest a potential pathogenetic role of alteration in lipid metabolism in this rare disease.     

Osteoporosis as an Hereditary Disease

Osteoporosis is a common disease with a strong genetic component characterized by reduced bone mass and increased risk of fragility fractures. Twin and family studies have shown that bone mineral density (BMD) and other determinants of fracture risk such as ultrasound properties of bone, skeletal geometry, and bone turnover have a significant heritable component. Osteoporotic fractures also have a genetic component but heritability reduces dramatically with increasing age. Many different genetic variants contribute to the regulation of these phenotypes; most are common variants of small effect size, but there is evidence that rare variants of large effect size also contribute in some individuals. Genome wide association studies have recently been successfully employed to identifying genes that predispose to osteoporosis, although some of these had already been identified through the study of rare bone diseases. Although there has been extensive progress in understanding the genetic basis of osteoporosis over the past 10 years, most of the genetic variants that regulate bone mass remained to be discovered.     

Grundlagen, Epidemiologie und Pathogenese der idiopathischen Lungenfibrose

Within the group of idiopathic interstitial pneumonitis, idiopathic pulmonary fibrosis (IPF) is the most frequent form and is a devastating disease with a mean survival time of 28 months. Familiar and sporadic variants are described. While familiar IPF is often caused by gene mutations, evolution of sporadic IPF is thought to be influenced by multiple factors including genetics. Risk factors for sporadic IPF are advanced age, male gender, cigarette smoking, dust exposure and microaspiration. The underlying pathomechanisms of IPF are derailed wound healing and aberrant repair processes.     

Idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), known in Europe as cryptogenic fibrosing alveolitis, is a rare, progressive and usually fatal form of idiopathic interstitial pneumonia. IPF is characterized by failure of alveolar re-epithelization, persistence of fibroblasts, deposition of extracellular matrix, and distortion of lung architecture which ultimately results in respiratory failure. Current consensus statements reserve the term IPF to refer to a specific clinical entity associated with the histopatological pattern of usual interstitial pneumonia (UIP). UIP is characterized by temporal heterogeneity, with alternating areas of interstitial fibrosis, fibroblastic foci (areas of proliferating fibroblasts and myofibroblasts), inflammation, honeycomb lung, and normal parenchyma. Fibroblastic foci are associated with progressive disease. Treatment of IPF remains clinical problem. Currently, there is no conservative therapy improving the survival of patients. Lung transplantation, however, improves survival. Identification of pathways crucial to fibrogenesis might offer potentially novel therapeutic targets to slow or halt progression of IPF.     

Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?

The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.     

Clinical course and prediction of survival in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressive, life-threatening, interstitial lung disease of unknown etiology. The median survival of patients with IPF is only 2 to 3 years, yet some patients live much longer. Respiratory failure resulting from disease progression is the most frequent cause of death. To date we have limited information as to predictors of mortality in patients with IPF, and research in this area has failed to yield prediction models that can be reliably used in clinical practice to predict individual risk of mortality. The goal of this concise clinical review is to examine and summarize the current data on the clinical course, individual predictors of survival, and proposed clinical prediction models in IPF. Finally, we will discuss challenges and future directions related to predicting survival in IPF.     

Identification of spontaneous feline idiopathic pulmonary fibrosis: morphology and ultrastructural evidence for a type II pneumocyte defect

STUDY OBJECTIVES: Idiopathic pulmonary fibrosis (IPF) is a poorly understood chronic respiratory disease of humans, which has no correlate in other animals. Understanding the role that inflammation, alveolar epithelial cells, and myofibroblasts play in the progression of the disease is controversial, and hampered by the lack of an animal model. We have identified spontaneous IPF in domestic cats and hypothesized that this newly identified disease shares the pathology of human IPF; further, this work provides data suggesting that the disease is related to a defect in type II pneumocyte biology. SETTING AND SUBJECTS: Chronic respiratory disease with pathology consistent with usual interstitial pneumonia (UIP) spontaneously developed in 16 domestic cats. RESULTS: The histopathology of feline IPF consisted of the following: (1) interstitial fibrosis with fibroblast/myofibroblast foci, (2) honeycombing with alveolar epithelial metaplasia and type II pneumocyte hyperplasia, and (3) alveolar interstitial smooth-muscle metaplasia. Interstitial inflammation was not a prominent feature of the disease. alpha-Smooth muscle actin-positive myofibroblasts were prominent in myofibroblast foci, beneath honeycomb and hyperplastic epithelium, and in alveolar septa away from the remodeling. Feline IPF type II pneumocyte ultrastructure is similar to a heritable form of human IPF, with abnormal cytoplasmic lamellar body-like inclusions. CONCLUSIONS: We conclude the following: (1) chronic respiratory disease with clinical and pathology features of UIP/IPF occurs in the domestic cat; (2) as in human IPF, the type II pneumocyte and myofibroblasts are important cellular constituents of feline IPF; and (3) type II cell ultrastructure suggests feline IPF is a defect in the type II pneumocyte.     

特发性肺纤维化的综合诊断进展

特发性肺纤维化是最常见的一种特发性间质性肺炎,组织病理表现为普通型间质性肺炎,临床表现为进行性呼吸困难伴有刺激性干咳,确诊依赖于外科肺活检。但肺活检风险大、费用高,不易被患者接受。近年来研究发现综合HRCT、血清标志物、以及肺功能、支气管肺泡灌洗液等检查,可以对IPF作出早期准确的诊断。本文将从上述几个方面作一介绍。     

开胸肺活检对肺间质疾病的诊断价值

目的探讨开胸肺活检对肺间质疾病的诊断作用。方法对１９９３～１９９８年６月２４例开胸肺活检的肺间质疾病患者进行回顾性分析。结果２４例患者均获病理确诊,其中普通型间质性肺炎（ＵＩＰ）７例,闭塞性细支气管炎伴机化性肺炎（ＢＯＯＰ）３例,结节病３例,弥漫性泛细支气管炎（ＤＰＢ）２例,肺结核２例。其他急性间质性肺炎（ＡＩＰ）、呼吸性细支气管炎伴肺间质病（ＲＢＩＬＤ）、肺组织细胞增生症Ｘ、炎性结节、多发性肺脓肿、肺组织炎症和肺泡细胞癌各１例。结论开胸肺活检作为一种诊断方法,能获得足够的肺组织,具有很高的敏感性和特异性,能明确病变的部位和程度。对常规和纤维支气管镜未能确诊的病例,尤其是一些罕见病和不典型的病例,具有较大的价值。     

特发性肺纤维化急性加重

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是最常见的一种特发性间质性肺炎,目前病因不明,组织病理表现为普通型问质性肺炎.既往认为IPF是一个逐渐进展的疾病,后来认识到部分IPF患者在病程中可以无明显原因出现症状的急剧恶化,这种现象被称为 IPF急性加重(acute exacerbations of IPF,AE-IPF).最近,AE-IPF得到了广泛的重视和研究.本文将对AE-IPF的发病率和病死率、病因、临床特点、病理改变、诊断和治疗进展等方面作一综述.     

Contemporary Concise Review 2022: Interstitial lung disease

• Novel genetic associations for idiopathic pulmonary fibrosis (IPF) risk have been identified. Common genetic variants associated with IPF are also associated with chronic hypersensitivity pneumonitis.
• The characterization of underlying mechanisms, such as pathways involved in myofibroblast differentiation, may reveal targets for future treatments.
• Newly identified circulating biomarkers are associated with disease progression and mortality.
• Deep learning and machine learning may increase accuracy in the interpretation of CT scans.
• Novel treatments have shown benefit in phase 2 clinical trials.
• Hospitalization with COVID-19 is associated with residual lung abnormalities in a substantial number of patients.
• Inequalities exist in delivering and accessing interstitial lung disease specialist care.

     

High short-term mortality following lung biopsy for usual interstitial pneumonia.

Usual interstitial pneumonia (UIP) is a specific histological pattern of interstitial pneumonia most often associated with the clinical syndrome of idiopathic pulmonary fibrosis (IPF). There is controversy regarding the use of surgical lung biopsy in the diagnosis of UIP, and the risk of lung biopsy in these patients is largely unknown. This study investigated the 30 day surgical mortality rate in patients undergoing surgical lung biopsy for UIP. Patients undergoing surgical lung biopsy over a 10-yr period from 1986-1995 with the ultimate diagnosis of UIP (with or without underlying connective tissue disease) were identified. Pathology, computed tomography, medical records, and survival were assessed. Ten of sixty patients with usual interstitial pneumonia were found to be dead within 30 days of surgical biopsy. All of these were patients with idiopathic UIP, unassociated with connective tissue disease (clinical condition of IPF). In conclusion, patients with usual interstitial pneumonia of the idiopathic type, who present with atypical features, may be at higher risk for death following surgical biopsy than patients presenting with more typical features or patients with other interstitial illnesses.     

What parameters can be used to identify early idiopathic pulmonary fibrosis?

Elucidating the disease process of early idiopathic pulmonary fibrosis (IPF) will help clinicians in addressing the contentious issues of when and in which patients, therapeutic intervention should be initiated. Here, we discuss several possible parameters for diagnosing early IPF and their clinical impacts. Physiologically, early IPF can be considered as IPF with normal or mild impairment in pulmonary function. Radiologically, early IPF can be considered as IPF with a small extent and/or early features of fibrosis. Symptomatically, early IPF can be considered as asymptomatic or less symptomatic IPF. IPF at Gender-Age-Physiology index stage I can be considered early IPF. Interstitial lung abnormalities are defined as parenchymal abnormalities in more than 5% of the lung in patients with no prior history of interstitial lung disease, and in some cases, this seems to be equivalent to early IPF. Previous clinical trials showed the effect of antifibrotic therapies in early IPF, but the effects of therapy are uncertain in early IPF outside of clinical trials, such as in cases of IPF with normal pulmonary function, IPF without honeycombing or traction bronchiectasis, and asymptomatic IPF. Moreover, little has been reported on disease progression in such conditions. Because the conceptual framework of early IPF may vary depending on its definition, not only is a diagnosis of early IPF important but prediction of disease progression is also crucial. Further investigations are needed to identify biomarkers that can detect patients who may experience greater degrees of disease progression and require treatment even with those forms of early IPF.     

Evolving concepts of apoptosis in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive fibrosing disease of the lung of unknown etiology. Significant progress has been made in recent years in elucidating key aspects of the pathobiology of IPF. Insights into disease pathogenesis have come from studies of cell biology, growth factor/cytokine signaling, animal models of pulmonary fibrosis, and human IPF cells and tissue. A consistent finding in the ultrastructural pathology of IPF is alveolar epithelial cell injury and apoptosis. Another consistent finding in the histopathology of human IPF, described as usual interstitial pneumonia, is the accumulation of aggregates of myofibroblasts in fibroblastic foci. The extent or profusion of fibroblastic foci in lung biopsies is strongly correlated with increased mortality in patients with IPF. There is emerging evidence that myofibroblasts in IPF/usual interstitial pneumonia, both in the in vivo microenvironment and during the process of differentiation in vitro, acquire resistance to apoptosis. Here, we review the current evidence and mechanisms for this apparent "apoptosis paradox" in the pathogenesis of IPF.     

Predictive factors for the long-term use of pirfenidone in patients with fibrosing interstitial lung disease

BackgroundPirfenidone is an anti-fibrotic agent approved for idiopathic pulmonary fibrosis (IPF), and long-term treatment data and the effect of continuation after disease progression have been reported. The efficacy and safety of pirfenidone in fibrosing interstitial lung disease (ILD) patients without IPF have been recently reported in clinical trials; therefore, the benefits of long-term treatment are also expected. This study aims to analyze the long-term treatment data of pirfenidone and clarify the predictive factors for long-term use of pirfenidone in non-IPF patients.MethodsWe retrospectively reviewed the records of consecutive fibrosing ILD patients who started using pirfenidone between 2008 and 2014.ResultsOf the 266 fibrosing ILD patients, 167 patients had IPF, and 99 had non-IPF. Despite the non-significant differences in body size and pulmonary function between IPF and non-IPF patients, the non-IPF patients had better overall survival than the IPF patients (median 4.06 years vs. 2.09 years, p < 0.0001). In addition, the non-IPF patients had a significantly longer time to treatment discontinuation than the IPF patients (median 2.20 years vs. 1.20 years, p = 0.002). Multivariate logistic regression analysis for ≥2 years of use of pirfenidone showed that the percent predicted forced vital capacity (%FVC) and age were predictive factors common to both IPF and non-IPF patients.ConclusionsOur results indicate that non-IPF patients can continue using pirfenidone for longer durations than IPF patients. Initiation of pirfenidone for fibrosing ILD patients with higher %FVC and younger age would lead to long-term use of pirfenidone.     

Idiopathic pulmonary fibrosis: a disorder of epithelial cell dysfunction

Idiopathic pulmonary fibrosis (IPF) is characterized by progressive dyspnea, interstitial infiltrates in lung parenchyma and restriction on pulmonary function testing. IPF is the most common and severe of the idiopathic interstitial pneumonias, with most individuals progressing to respiratory failure. Multiple lines of evidence reveal prominent roles for alveolar epithelial cells (AECs) in disease. The current disease paradigm is that ongoing or repetitive injurious stimuli in the presence of a genetic or acquired dysfunctional type II AEC phenotype results in increased AEC injury/apoptosis, deficiencies in regeneration of normal alveolar structure and aberrant lung repair and fibroblast activation, leading to progressive fibrosis. Although the nature of injurious events and processes involved in aberrant repair of the alveolar epithelium are not well understood, ongoing investigations provide hope to better understand mechanisms by which AECs maintain homeostasis or contribute to fibrosis. These strategies may hold promise for developing novel treatment approaches for IPF.     

特发性肺纤维化的治疗进展

特发性肺间质纤维化是间质性肺疾病的一种特殊类型.至今为止,其病因、发病机制尚不明确,病死率高,传统药物治疗效果欠佳且毒副作用明显.本文参考国内外文献,对当前IPF的研究进展与治疗现状作一概述.     

Evaluation and management of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a most common progressive interstitial lung disease (ILD) of unknown etiology, although majority of patients are elderly male smokers. The main pathogenesis is aberrant recovery of epithelial injury and collagen deposition. Fibrotic nonspecific interstitial pneumonia, connective tissue disease (CTD) especially rheumatoid arthritis (RA) associated ILD, and chronic hypersensitivity pneumonia(CHP) are important differential diagnosis. Main symptoms are non-productive cough and progressive exertional dyspnea. Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing. The serum markers such as lactate dehydrogenase (LDH) and Krebs von den Lungen-6 (KL-6) are sensitive for ILD detection and activity. Both pulmonary function test (PFT) and the 6-minute walk test (6MWT) are useful tool for evaluation of disease progression of IPF. Serial changes of forced vital capacity (FVC) and 6MWT distance predict mortality in IPF effectively. Recently published international IPF guidelines highlight the importance of chest high resolution computed tomography (HRCT) findings such as honeycombing, traction bronchiectasis (TBE), and sub-pleural reticular opacity. IPF is chronic and progressive; therefore, tracking disease behavior is crucial. Unifying clinical, physiological, and imaging information over time is useful. With regard to its management, two anti-fibrotic drugs such as pirfenidone and nintedanib have been available. These drugs can slow the decline of FVC and prevent acute exacerbation (AE). In this review, I outline the clinical characteristics of IPF, physiological, imaging, pathological findings and review diagnosis process and management.