Novedades diagnósticas y terapéuticas en fibrosis pulmonar progresiva

In addition to idiopathic pulmonary fibrosis (IPF), other diffuse interstitial lung diseases (ILD) are also associated with pulmonary fibrosis and occur in a variable proportion of patients, depending on the entity. The name given to this fibrotic component, that may progress despite treatment, is progressive pulmonary fibrosis (PPF). In this context, PPF is not an entity per se but a common clinical condition or behavior that may occur in association with different types of fibrosing diffuse ILDs, compromising patient prognosis. PPF is identified from worsening clinical, physiological, and/or radiological criteria during patient follow-up. Randomized clinical trials in patients with IPF or progressive non-IPF ILD have shown that treatment with antifibrotic drugs, either nintedanib or pirfenidone, slows progression. We are seeing the start of a new era in the clinical management of this subgroup of patients, offering the perfect opportunity for exploring still uncharted territories.     

Polymyxin B-immobilized fiber columns: A column to breathe new life into the treatment of interstitial lung disease?

Acute exacerbations of idiopathic pulmonary fibrosis (IPF) is a severe respiratory condition with high mortality rate. Direct hemoperfusion with polymyxin B-immobilized fiber columns (PMX-DHP) was originally introduced for the treatment of septic shock. Application of PMX-DHP to the treatment of acute exacerbations of IPF may improve oxygenation and survival of the patients with the disease. In addition to acute exacerbations of IPF, PMX-DHP has been applied to acute respiratory failure from various causes; an amyopathic dermatomyositis patient who developed rapidly progressive interstitial lung disease (ILD) with elevated anti-CADM-140/MDA5 autoantibody and a patient with severe amiodarone pulmonary toxicity. It is also demonstrated that PMX-DHP performed on the first day of steroid pulse therapy may improve the prognosis of patients with rapidly progressive ILDs in a case-control setting. PMX treatment decreases not only various circulating molecules but also inflammatory cells, in particular activated monocytes, producing such mediators. Although the incidence of acute exacerbations of IPF is too low for proper randomization, in order to test the effects of PMX-DHP on the disease, a cohort or case-control analytic study needs to be conducted, preferably from more than one center or research group.     

Association of the RAGE/RAGE-ligand axis with interstitial lung disease and its acute exacerbation

The receptor for advanced glycation end product (RAGE) is a transmembrane receptor highly expressed in type 1 pneumocytes of healthy lungs. RAGE is considered to play a homeostatic role in the lung, as RAGE knockout mice develop lung fibrosis as they age. In contrast, RAGE can bind numerous ligands, including high-mobility group box 1 (HMGB1). These interactions initiate pro-inflammatory signaling associated with the pathogenesis of lung injury and interstitial lung disease (ILD), including idiopathic pulmonary fibrosis (IPF).ILD is a broad category of diffuse parenchymal lung disease characterized by various extents of lung fibrosis and inflammation, and IPF is a common and progressive ILD of unknown cause. The prognosis of patients with IPF is poor, and acute exacerbation of IPF (AE-IPF) is one of the main causes of death. Recent reports indicate that acute exacerbations can occur in other ILDs (AE-ILD). Notably, ILD is frequently observed in patients with lung cancer, and AE-ILD after surgical procedures or the initiation of chemotherapy for concomitant lung cancer are clinically important due to their association with increased mortality.In this review, we summarize the associations of RAGE/soluble RAGE (sRAGE)/RAGE ligands with the pathogenesis and clinical course of ILD, including IPF and AE-IPF. Additionally, the potential use of sRAGE and RAGE ligands as predictive markers of AE-IPF and cancer treatment-triggered AE-ILD is also discussed.     

Correlation between pulmonary fibrosis and the lung pressure-volume curve

The severity of pulmonary fibrosis is the main prognostic factor for survival of patients with interstitial lung diseases (ILD). Unfortunately, lung biopsy, which is the best method to assess fibrosis quantitatively, is done only once during the evolution of the disease. In this study we analyzed the relationship between the degree of fibrosis and the exponential constant k, derived from the lung pressure-volume curve (LPVC) in 33 patients with chronic ILD, 19 with pigeon breeder's disease (PBD), and 14 with idiopathic pulmonary fibrosis (IPF). Pulmonary function tests, including the LPVC, were obtained before biopsy. A semiquantitative histologic assessment of the severity of fibrosis was performed on lung tissues. All patients showed a decrease of total lung capacity, residual volume, compliance, and PaO₂. The mean value of the constant k was 0.08 ± 0.06. When expressed as a percent of normal values, 25 patients exhibited values of k lower than 70% of predicted; of the remaining 8 patients whose values were above 70% of predicted, 7 had PBD and only one IPF. On morphologic analysis, 19 patients displayed more than 50% fibrosis. No significant correlations were found between the extent of the lesion or severity of lung fibrosis and the conventional pulmonary function tests. By contrast, a moderate but significant correlation was found between k and the severity of lung fibrosis (r = –0.38, p < 0.05). These findings show that the shape of the LPVC, represented by the constant k, predicts the degree of lung fibrosis and could be useful in the clinical assessment and follow-up of patients with ILD. Offprint requests to: M. Selman     

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.     

特发性肺纤维化急性加重1例并文献复习

目的提高对特发性肺纤维化急性加重的认识,并探讨其诊断标准和治疗原则。方法报告并分析中国医科大学附属第一医院呼吸内科2005-11-30收治的1例特发性肺纤维化急性加重的病例,经糖皮质激素大量冲击治疗后好转,并复习国外相关文献。结果通过复习特发性肺纤维化急性加重的临床诊断标准,以强调在没有明确诱因的情况下,少数特发性肺纤维化的患者在自然病程中可出现急性加重,糖皮质激素冲击治疗可缓解部分病人病情。结论少数特发性肺纤维化患者可在自然病程中出现急性加重。     

Treatment of idiopathic pulmonary fibrosis in Australia and New Zealand: A position statement from the Thoracic Society of Australia and New Zealand and the Lung Foundation Australia

Idiopathic pulmonary fibrosis (IPF) is a fibrosing interstitial lung disease (ILD) of unknown aetiology with a median survival of only 2–5 years. It is characterized by progressive dyspnoea and worsening lung function, ultimately resulting in death. Until recently, there were no effective therapies for IPF; however, with the publication of two landmark clinical trials in 2014, the anti‐fibrotic therapies, nintedanib and pirfenidone, have gained widespread approval. This position paper aims to highlight the current evidence for the treatment of IPF, with particular application to the Australian and New Zealand population. We also consider areas in which evidence is currently lacking, especially with regard to the broader IPF severity spectrum and treatment of co‐morbid conditions. The utility of non‐pharmacological therapies including pulmonary rehabilitation, oxygen as well as symptom management thought to be important in the holistic care of IPF patients are also discussed.     

Undifferentiated Connective Tissue Disease-Associated Interstitial Lung Disease: Changes in Lung Function

Undifferentiated connective tissue disease (UCTD) is a distinct clinical entity that may be accompanied by interstitial lung disease (ILD). The natural history of UCTD-ILD is unknown. We hypothesized that patients with UCTD-ILD would be more likely to have improvement in lung function than those with idiopathic pulmonary fibrosis (IPF) during longitudinal follow-up. We identified subjects enrolled in the UCSF ILD cohort study with a diagnosis of IPF or UCTD. The primary outcome compared the presence or absence of a ≥5% increase in percent predicted forced vital capacity (FVC) in IPF and UCTD. Regression models were used to account for potential confounding variables. Ninety subjects were identified; 59 subjects (30 IPF, 29 UCTD) had longitudinal pulmonary function data for inclusion in the analysis. After accounting for baseline pulmonary function tests, treatment, and duration between studies, UCTD was associated with substantial improvement in FVC (odds ratio = 8.23, 95% confidence interval, 1.27–53.2; p = 0.03) during follow-up (median, 8 months) compared with IPF. Patients with UCTD-ILD are more likely to have improved pulmonary function during follow-up than those with IPF. These findings demonstrate the clinical importance of identifying UCTD in patients presenting with an “idiopathic” interstitial pneumonia.     

特发性肺纤维化的治疗进展

特发性肺纤维化是一种慢性、弥散性肺间质病变,以普通型间质性肺炎为特征性组织学表现。特发性肺纤维化以进行性肺损伤、炎症、肺组织纤维化为特征。糖皮质激素和免疫抑制剂/细胞毒性药物临床效果欠佳,提示炎症并未在肺纤维化中起重要的病理生理作用,研究发现肺泡上皮损伤可以直接导致肺纤维化。目前尚无有效的治疗方案能取得肯定的疗效。因此,新的治疗措施引发了研究者浓厚的兴趣。然而特发性肺纤维化的研究进展缓慢,预后很差,诊断后中期生存率小于3年。本文主要介绍特发性肺纤维化在治疗方面的进展。     

The Aging Lung and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is one of many clinical syndromes that are associated with aging, and is increasing in both incidence and prevalence with the rapid rise in aging populations world-wide. There is accumulating data on how the biology of aging may influence the susceptibility to lung fibrosis in the elderly. In this review, we explore some of the known “hallmarks of aging,” including telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, cellular senescence and mitochondrial dysfunction in the pathobiology of IPF. Additionally, we discuss age-associated alterations in extracellular matrix that may contribute to the development and/or progression of IPF.     

Ethnic differences in idiopathic pulmonary fibrosis: The Japanese perspective

Epidemiologic data suggest that there are ethnic differences between Japanese and other populations with regard to the important clinical aspects of interstitial lung disease (ILD), such as the cause of death and prognostic factors in patients with idiopathic pulmonary fibrosis (IPF). Acute exacerbation (AE) of IPF may be more common in Japan than in the rest of the world, although this suggestion remains controversial. Moreover, AE of ILD induced by gefitinib may also be more common in Japan, indicating that Japanese patients have a genetic vulnerability or susceptibility to AE. Recent large-scale studies are starting to reveal ethnic differences in the genetics of ILD, including the prevalence of the genetic polymorphisms associated with the clinical course of ILD. We anticipate that ongoing and upcoming research regarding ethnic differences will continue to provide valuable insights into the pathogenesis and management of ILD.     

Interpretation of HRCT Scans in the Diagnosis of IPF: Improving Communication Between Pulmonologists and Radiologists

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease (ILD). In this review, we describe the central role of high-resolution computed tomography (HRCT) in the diagnosis of IPF and discuss how communication between pulmonologists and radiologists might be improved to make the interpretation of HRCT scans more effective. Clinical information is important in the interpretation of HRCT scans, as the likelihood that specific radiologic features reflect IPF is not absolute, but dependent on the clinical context. In cases where the clinical context or HRCT pattern are inconclusive, multidisciplinary discussion (MDD) between a pulmonologist and radiologist (and, where relevant, a pathologist and rheumatologist) experienced in the differential diagnosis of ILD is necessary to establish a diagnosis. While it can be challenging to convene a face-to-face meeting, MDD can be conducted virtually or by telephone to enable each specialty group to contribute. To make the MDD most effective, it is important that relevant clinical information (for example, on the patient’s clinical history, exposures and the results of serological tests) is shared with all parties in advance. A common lexicon to describe HRCT features observed in ILD can also help improve the effectiveness of MDD. A working diagnosis may be made in patients who do not fulfill all the diagnostic criteria for any specific type of ILD, but this diagnosis should be reviewed at regular intervals, with repeat of clinical, radiological, and laboratory assessments as appropriate, as new information pertinent to the patient’s diagnosis may become available.     

Idiopathic pulmonary fibrosis: phenotypes and comorbidities

Idiopathic pulmonary fibrosis (IPF) is a progressive fatal disease of the lung with an unknown etiology and limited treatment options. Three distinct phenotypes of IPF have been proposed: combined pulmonary fibrosis and emphysema, disproportionate pulmonary hypertension in IPF, and rapidly progressive IPF. Although treatment options for IPF are limited, much can be done to identify and alleviate symptoms from comorbidities, potentially improving the overall quality of life and well-being of these patients. This article describes emerging evidence to support the hypothesis that there is more than one phenotype for IPF and describes the common comorbidities seen in this disease.     

Acute and subacute idiopathic interstitial pneumonias

Idiopathic interstitial pneumonias (IIPs) may have an acute or subacute presentation, or acute exacerbation may occur in a previously subclinical or unrecognized chronic IIP. Acute or subacute IIPs include acute interstitial pneumonia (AIP), cryptogenic organizing pneumonia (COP), nonspecific interstitial pneumonia (NSIP), acute exacerbation of idiopathic pulmonary fibrosis (AE‐IPF) and AE‐NSIP. Interstitial lung diseases (ILDs) including connective tissue disease (CTD) associated ILD, hypersensitivity pneumonitis, acute eosinophilic pneumonia, drug‐induced lung disease and diffuse alveolar haemorrhage need to be differentiated from acute and subacute IIPs. Despite the severe lack of randomized controlled trials for the treatment of acute and subacute IIPs, the mainstream treatment remains corticosteroid therapy. Other potential therapies reported in the literature include corticosteroids and immunosuppression, antibiotics, anticoagulants, neutrophil elastase inhibitor, autoantibody‐targeted treatment, antifibrotics and hemoperfusion therapy. With regard to mechanical ventilation, patients in recent studies with acute and subacute IIPs have shown better survival than those in previous studies. Therefore, a careful value‐laden decision about the indications for endotracheal intubation should be made for each patient. Noninvasive ventilation may be beneficial to reduce ventilator associated pneumonia.     

Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of IPF. The development of effective IPF clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of IPF. Advances in understanding of the pathogenetic processes involved in the development of pulmonary fibrosis have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.     

Clinical characteristics of non-idiopathic pulmonary fibrosis,progressive fibrosing interstitial lung diseases: A single-center retrospective study

Progressive fibrosing interstitial lung disease (PF-ILD) is a progressive phenotype of fibrosing ILDs with varying definitions and elusive clinical characteristics. We aimed to clarify the clinical features and prognosis of PF-ILD cases based on the deterioration of pulmonary function.Altogether, 91 consecutive ILD patients who underwent at least 2 pulmonary function tests (PFTs) with an interval of at least 24 months, as the screening period, between January 2009 and December 2015 were retrospectively reviewed. The deterioration of forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLco) was calculated based on PFT data and screening period. The definition of PF-ILD was

• 1.relative decline of 10% or more in FVC per 24 months or
• 2.relative decline in FVC of 5% or more with decline in DLco of 15% or more per 24 months.

Medical records of 34 patients with idiopathic pulmonary fibrosis (IPF), 11 patients with non-IPF, PF-ILD, and 46 patients with non-IPF, non-PF-ILD were retrospectively analyzed. Patient characteristics, pharmacologic or non-pharmacologic treatment status, and prognosis were compared between the IPF and non-IPF groups and between the non-IPF, PF-ILD and non-IPF, non-PF-ILD groups.Eleven patients (19.3%) showed a progressive phenotype in the non-IPF group. The pulmonary function data at the first PFT were worse in non-IPF, PF-ILD patients than in non-IPF, non-PF-ILD patients. There were no differences in the proportion of patients who were observed without pharmacologic treatment or of those receiving pharmacologic treatment between the non-IPF, PF-ILD and non-IPF, non-PF-ILD groups. Low %FVC at the first PFT and the usual interstitial pneumonia-like fibrotic pattern on high-resolution computed tomography were risk factors for PF-ILD in the non-IPF group. The mortality in the non-IPF, PF-ILD group was significantly worse than that of the non-IPF, non-PF-ILD group and was as poor as that of the IPF group. Multivariate logistic analysis showed that aging and low %DLco at the first PFT were risk factors for mortality within the non-IPF group.The prognosis of non-IPF, PF-ILD patients was as poor as that of IPF patients. Non-IPF, PF-ILD patients require more intensive treatment before disease progression.     

Bronchoalveolar lavage in idiopathic interstitial lung diseases

Bronchoalveolar lavage (BAL) is useful for diagnosing various interstitial lung diseases (ILDs) and monitoring ILD during treatment. The ability to detect specific agents or substances by using BAL is especially helpful in determining whether idiopathic ILD has a background causality. BAL in combination with other intensive examinations may enable the definitive diagnosis of an idiopathic ILD. Among the idiopathic ILDs of concern, this article focuses on idiopathic interstitial pneumonia (IIP) and cryptogenic organizing pneumonia (COP). IIP and COP are classified together as idiopathic interstitial pneumonia (IIP), an integrated clinicoradiographic pathological disease entity. BAL has identified two points important for differentiating the disease entity: a paucity of lymphocytes appears in the BAL fluid of patients with idiopathic pulmonary fibrosis (IPF), and lymphocytosis with a decreased CD4:CD8 ratio appears in patients with COP. These findings can be useful, in combination with high-resolution computed tomographic (HRCT) data, for selecting a favorable treatment option. On the other hand, these rules cannot be applied to IP associated with collagen vascular disease (CVD). Furthermore, some IIP patients may manifest features of CVD during the clinical course after the detection of IP (interstitial pneumonia). Thus the definite role of BAL cell profiles remains to be determined.     

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.     

Does interferon-gamma improve pulmonary function in idiopathic pulmonary fibrosis?

Idiopathic pulmonary fibrosis (IPF) is a disease with progressive and devastating deterioration of lung function and a fatal prognosis, despite aggressive therapeutic attempts, which, in the majority of cases are futile. Recently, a preliminary study of long-term treatment with interferon (IFN)-gamma1b and low-dose prednisolone in patients with IPF suggested that IFN-gamma1b treatment may improve lung function parameters of patients with IPF. Ever since, specialists in respiratory medicine who treat patients with IPF, are called by patients demanding treatment with IFN-gamma1b. Therefore, the authors here present another prospective investigation of IFN-gamma1b in five patients with IPF. According to the previously published design, patients received 200 microg IFN-gamma1b subcutaneously three-times per week and 10 mg prednisolone orally for 12 months. Two patients stopped IFN-gamma1b treatment after 4 months due to side-effects and further lung function deterioration and one patient died 3 months after commencement of therapy. In total, pulmonary function improved in only one patient during IFN-gamma1b treatment, while four patients deteriorated. To conclude, this small series of idiopathic pulmonary fibrosis cases treated with interferon-gamma1b and corticosteroids does not support previous data that this treatment improves pulmonary function or alters the natural course of idiopathic pulmonary fibrosis. Furthermore, in the authors' experience, side-effects of interferon-gamma1b treatment can significantly reduce patients' quality of life.     

ANCA-associated vasculitis in idiopathic pulmonary fibrosis: A case report and brief review of the literature

Rationale:Idiopathic pulmonary fibrosis (IPF) is a progressive disease with poor prognosis. Patients with IPF represent a heterogeneous population with several described clinical phenotypes. More recently, the development of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis in IPF patients, with an incidence higher than that in the general population, has drawn attention.Patient concerns:A 64-year-old woman previously diagnosed with IPF presented to the emergency department with hemoptysis and hypoxemic respiratory failure.Diagnoses:High-resolution chest computed tomography revealed bilateral ground-glass opacities associated with areas of consolidation superimposed on the patient''s fibrotic background pattern. Diffuse alveolar hemorrhage was confirmed by the presence of hemorrhagic bronchoalveolar lavage fluid. Hematological and biochemical investigations revealed an inflammatory syndrome, moderate anemia, and rapidly progressive glomerulonephritis. Serological analysis revealed perinuclear antineutrophil cytoplasmic antibody positivity and high levels of antimyeloperoxidase antibodies antibodies. The patient underwent kidney biopsy, which revealed necrotizing glomerulonephritis. Clinical and laboratory findings were diagnostic of microscopic polyangiitis with lung and renal involvement.Interventions:Cyclophosphamide in combination with methylprednisolone was administered as remission induction therapy. The maintenance therapy consisted of mycophenolate mofetil and prednisone.Outcomes:The patient achieved clinical, radiological, and serological remission within six weeks of treatment.Lessons:The association between IPF and ANCA-associated vasculitis may represent a distinct clinical phenotype. Autoimmune testing for ANCAs should be considered part of the diagnostic work-up and follow-up of patients with IPF because of the clinical and therapeutic implications of developing vasculitis in an already vulnerable patient.