Clinical significance of radiological pleuroparenchymal fibroelastosis pattern in interstitial lung disease patients registered for lung transplantation: a retrospective cohort study.
ABSTRACT: Radiological pleuroparenchymal fibroelastosis (PPFE) lesion is characterized by pleural thickening with associated signs of subpleural fibrosis on high-resolution computed tomography (HRCT). This study evaluated the clinical significance of radiological PPFE as an isolated finding or associated with other interstitial lung diseases (ILDs) in patients having fibrotic ILDs and registered for cadaveric lung transplantation (LT).This retrospective study included 118 fibrotic ILD patients registered for LT. Radiological PPFE on HRCT was assessed. The impact of radiological PPFE on clinical features and transplantation-censored survival were evaluated.Radiological PPFE was observed in 30/118 cases (25%): definite PPFE (PPFE concentrated in the upper lobes, with involvement of lower lobes being less marked) in 12 (10%) and consistent PPFE (PPFE not concentrated in the upper lobes, or PPFE with features of coexistent disease present elsewhere) in 18 (15%). Of these, 12 had late-onset non-infectious pulmonary complications after hematopoietic stem-cell transplantation and/or chemotherapy (LONIPCs), 9 idiopathic PPFE, and 9 other fibrotic ILDs (idiopathic pulmonary fibrosis, IPF; other idiopathic interstitial pneumonias, other IIPs; connective tissue disease-associated ILD, CTD-ILD, and hypersensitivity pneumonia, HP). Radiological PPFE was associated with previous history of pneumothorax, lower body mass index, lower percentage of predicted forced vital capacity (%FVC), higher percentage of predicted diffusion capacity of carbon monoxide, less desaturation on six-minute walk test, and hypercapnia. The median survival time of all study cases was 449 days. Thirty-seven (28%) received LTs: cadaveric in 31 and living-donor lobar in six. Of 93 patients who did not receive LT, 66 (71%) died. Radiological PPFE was marginally associated with better survival after adjustment for age, sex, %FVC, and six-minute walk distance
Project description:Pleuroparenchymal fibroelastosis (PPFE) has been described in hypersensitivity pneumonitis (HP) yet its functional implications are unclear. Combined pulmonary fibrosis and emphysema (CPFE) has occasionally been described in never-smokers with HP, but epidemiological data regarding its prevalence is sparse. CTs in a large HP cohort were therefore examined to identify the prevalence and effects of PPFE and emphysema.233 HP patients had CT extents of interstitial lung disease (ILD) and emphysema quantified to the nearest 5%. Lobar percentage pleural involvement of PPFE was quantified on a 4-point categorical scale: 0?=?absent, 1?=?affecting <10%, 2?=?affecting 10-33%, 3?=?affecting >33%. Marked PPFE reflected a total lung score of ?3/18. Results were evaluated against FVC, DLco and mortality.Marked PPFE prevalence was 23% whilst 23% of never-smokers had emphysema. Following adjustment for patient age, gender, smoking status, and ILD and emphysema extents, marked PPFE independently linked to reduced baseline FVC (p?=?0.0002) and DLco (p?=?0.002) and when examined alongside the same covariates, independently linked to worsened survival (p?=?0.01). CPFE in HP demonstrated a characteristic functional profile of artificial lung volume preservation and disproportionate DLco reduction. CPFE did not demonstrate a worsened outcome when compared to HP patients without emphysema beyond that explained by CT extents of ILD and emphysema.PPFE is not uncommon in HP, and is independently associated with impaired lung function and increased mortality. Emphysema was identified in 23% of HP never-smokers. CPFE appears not to link to a malignant microvascular phenotype as outcome is explained by ILD and emphysema extents.
Project description:A proportion of patients with fibrosing interstitial lung diseases (ILDs) develop a progressive phenotype characterised by decline in lung function, worsening quality of life and early mortality. Other than idiopathic pulmonary fibrosis (IPF), there are no approved drugs for fibrosing ILDs and a poor evidence base to support current treatments. Fibrosing ILDs with a progressive phenotype show commonalities in clinical behaviour and in the pathogenic mechanisms that drive disease worsening. Nintedanib is an intracellular inhibitor of tyrosine kinases that has been approved for treatment of IPF and has recently been shown to reduce the rate of lung function decline in patients with ILD associated with systemic sclerosis (SSc-ILD). In vitro data demonstrate that nintedanib inhibits several steps in the initiation and progression of lung fibrosis, including the release of pro-inflammatory and pro-fibrotic mediators, migration and differentiation of fibrocytes and fibroblasts, and deposition of extracellular matrix. Nintedanib also inhibits the proliferation of vascular cells. Studies in animal models with features of fibrosing ILDs such as IPF, SSc-ILD, rheumatoid arthritis-ILD, hypersensitivity pneumonitis and silicosis demonstrate that nintedanib has anti-fibrotic activity irrespective of the trigger for the lung pathology. This suggests that nintedanib inhibits fundamental processes in the pathogenesis of fibrosis. A trial of nintedanib in patients with progressive fibrosing ILDs other than IPF (INBUILD) will report results in 2019.
Project description:Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in ILD are presented. A total of 1194 patients with ILD and 116 healthy subjects were tested for antibodies specific for Ks, Ha, Zo?, and cN1A with a line-blot assay on serum available at the time of diagnosis. Autoantibodies were demonstrated in 63 (5.3%) patients and one (0.9%) healthy control (p = 0.035). Autoantibodies were found more frequently in females (p = 0.042) and patients without a histological and/or radiological usual interstitial pneumonia (UIP; p = 0.010) and a trend towards CTD-ILDs (8.4%) was seen compared with other ILDs (4.9%; p = 0.090). The prevalence of antibodies specific for Ks, Ha, Zo?, and cN1A was, respectively, 1.3%, 2.0%, 1.4%, and 0.9% in ILD. Anti-Ha and Anti-Ks were observed in males with unclassifiable idiopathic interstitial pneumonia (unclassifiable IIP), hypersensitivity pneumonitis (HP), and various CTD-ILDs, whereas anti-cN1A was seen in females with antisynthetase syndrome (ASS), HP, and idiopathic pulmonary fibrosis (IPF). Anti-Zo? was associated with CTD-ILD (OR 2.5; 95%CI 1.11-5.61; p = 0.027). In conclusion, a relatively high prevalence of previously unknown myositis autoantibodies was found in a large cohort of various ILDs. Our results contribute to the awareness that circulating autoantibodies can be found in ILDs with or without established CTD. Whether these antibodies have to be added to the standard set of autoantibodies analysed in conventional myositis blot assays for diagnostic purposes in clinical ILD care requires further study.
Project description:Fibrosing interstitial lung disease (ILD) is one of the most important causes of morbidity and mortality in patients with connective tissue diseases (CTDs), which include systemic sclerosis, rheumatoid arthritis, Sjögren's syndrome, idiopathic inflammatory myositis and systemic lupus erythematosus. The treatment of CTD-ILDs is challenging due to the paucity of proven effective treatments. Recently, two antifibrotic drugs conditionally approved for use in patients with idiopathic pulmonary fibrosis, nintedanib and pirfenidone, have been trialled in CTD-ILDs based on overlapping pathological and clinical features between the two diseases. In this narrative review, we discuss the experimental evidence and clinical trials investigating the efficacy and safety of antifibrotic drugs in patients with CTD-ILDs and the potential mechanisms of action involved. Results from clinical trials suggest that nintedanib use retards lung function decline in progressive fibrotic CTD-ILDs. By contrast, the evidence for the efficacy of pirfenidone in these groups is not equally compelling. Further, well-designed randomized clinical trials are needed to evaluate the efficacy and safety of individual antifibrotic drugs in specific CTD-ILD subgroups.
Project description:Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease characterized by the fibrotic thickening of subpleural and parenchymal areas of the upper lobes. It may be both idiopathic or secondary to infections, interstitial lung diseases and/or drug exposure. Often PPFE patients report recurrent lower respiratory tract infections, suggesting that repeated inflammatory alterations induced by pulmonary infections may contribute to the development/progression of PPFE. Here, we report for the first time the case of a patient affected by Giant cell Arteritis with histologically proven PPFE. The lung involvement in GCA is rare and interstitial lung diseases are usually reported as an uncommon clinical manifestation of GCA. Our patient is probably the first case presenting PPFE associated with GCA and we wonder if this is a real associative disease or a coincidence perhaps, secondary to drug effects.
Project description:We used data from the INBUILD and INPULSIS trials to investigate the natural history of progressive fibrosing interstitial lung diseases (ILDs).Subjects in the two INPULSIS trials had a clinical diagnosis of idiopathic pulmonary fibrosis (IPF) while subjects in the INBUILD trial had a progressive fibrosing ILD other than IPF and met protocol-defined criteria for ILD progression despite management. Using data from the placebo groups, we compared the rate of decline in forced vital capacity (FVC) (mL·year-1) and mortality over 52?weeks in the INBUILD trial with pooled data from the INPULSIS trials.The adjusted mean annual rate of decline in FVC in the INBUILD trial (n=331) was similar to that observed in the INPULSIS trials (n=423) (-192.9?mL·year-1 and -221.0?mL·year-1, respectively; nominal p-value=0.19). The proportion of subjects who had a relative decline in FVC >10% predicted at Week 52 was 48.9% in the INBUILD trial and 48.7% in the INPULSIS trials, and the proportion who died over 52?weeks was 5.1% in the INBUILD trial and 7.8% in the INPULSIS trials. A relative decline in FVC >10% predicted was associated with an increased risk of death in the INBUILD trial (hazard ratio 3.64) and the INPULSIS trials (hazard ratio 3.95).These findings indicate that patients with fibrosing ILDs other than IPF, who are progressing despite management, have a subsequent clinical course similar to patients with untreated IPF, with a high risk of further ILD progression and early mortality.
Project description:Pleuroparenchymal fibroelastosis (PPFE) is an unusual pulmonary disease with unique clinical, radiological, and pathological characteristics. Designated a rare idiopathic interstitial pneumonia in 2013, its name refers to a combination of fibrosis involving the visceral pleura and fibroelastotic changes predominating in the subpleural lung parenchyma. Although a number of disease associations have been described, no single cause of PPFE has been unequivocally identified. A diagnosis of PPFE is most commonly achieved by identifying characteristic abnormalities on computed tomographic scans. The earliest changes are consistently located in the upper lobes close to the lung apices, the same locations where subsequent disease progression is also most conspicuous. When sufficiently severe, the disease leads to progressive volume loss of the upper lobes, which, in combination with decreased body mass, produces platythorax. Once regarded as a slowly progressing entity, it is now acknowledged that some patients with PPFE follow an inexorably progressive course that culminates in irreversible respiratory failure and early death. In the absence of effective medical drug treatment, lung transplant remains the only therapeutic option for this disorder. This review focuses on improving early disease recognition and evaluating its pathophysiological impact and discusses working approaches for its management.
Project description:Among the interstitial lung diseases (ILDs), idiopathic pulmonary fibrosis (IPF), chronic hypersensitivity pneumonitis, and fibrotic connective tissue disease-related ILD are associated with a worse prognosis, with death occurring as a result of both respiratory failure and serious associated comorbidities. The recent development and approval of the antifibrotic agents nintedanib and pirfenidone, both of which reduced the rate of decline in lung function in patients with IPF in clinical trials, offer hope that it may be possible to alter the increased mortality associated with IPF. Although chronic hypersensitivity pneumonitis and connective tissue disease related-ILD may be associated with an inflammatory component, the evidence for the use of immunosuppressive agents in their treatment is largely limited to retrospective studies. The lack of benefit of immunosuppressive therapy in advanced fibrosis argues for rigorous clinical trials using antifibrotic therapies in these types of ILD as well. Patients with fibrotic ILD may benefit from identification and management of associated comorbid conditions such as pulmonary hypertension, gastroesophageal reflux, and OSA, which may improve the quality of life and, in some cases, survival in affected individuals. Because early assessment may optimize posttransplantation outcomes, lung transplant evaluation should occur early in patients with IPF and those with other forms of fibrotic ILD.
Project description:Fibrotic interstitial lung diseases (ILDs) have a high mortality rate with an unpredictable disease course and clinical features that frequently overlap. Recent data indicate important roles for genomics in the mechanisms underlying susceptibility and progression of pulmonary fibrosis. The impact of these genomic markers on pharmacotherapy and their contribution to outcomes is increasingly recognized. Interstitial lung abnormalities, frequently considered representative of early ILD, have been consistently associated with the MUC5B promoter polymorphism, a common gene variant. Other rare gene variant mutations, including TERT, TERC, SFTPC, and DKC1, may be present in patients with familial interstitial pneumonia and are frequently associated with a usual interstitial pneumonia pattern of fibrosis. The minor allele of the MUC5B rs35705950 genotype is prevalent in several sporadic forms of ILD, including idiopathic pulmonary fibrosis and chronic hypersensitivity pneumonitis. Gene mutations that characterize familial pulmonary fibrosis may be present in patients with connective tissue disease-related ILD, such as rheumatoid arthritis-ILD. Additionally, shorter telomere lengths and mutations in telomere biology-related genes have been demonstrated in both familial and sporadic ILD, with significant implications for disease progression, lung function, and survival. An improved understanding of the impact of genetic and genomic risk factors on disease progression would better guide personalized therapeutic choices in persons with fibrotic ILD.
Project description:Interstitial lung disease (ILD) encompasses a large group of pulmonary conditions sharing common clinical, radiological and histopathological features as a consequence of fibrosis of the lung interstitium. The majority of ILDs are idiopathic in nature with possible genetic predisposition, but is also well recognised as a complication of connective tissue disease or with certain environmental, occupational or drug exposures. In recent years, a concerted international effort has been made to standardise the diagnostic criteria in ILD subtypes, formalise multidisciplinary pathways and standardise treatment recommendations. In this review, we discuss some of the current challenges around ILD diagnostics, the role of serological testing, especially, in light of the new classification of Interstitial Pneumonia with Autoimmune Features (IPAF) and discuss the evidence for therapies targeted at idiopathic and immune-related pulmonary fibrosis.