MUC5B启动子rs35705950、rs868903基因多态性与特发性肺纤维化的相关性研究

目的 探讨MUC5B启动子rs35705950、rs868903基因多态性与特发性肺纤维化(IPF)患病风险及预后的关系.方法 选取2014年1月至2018年12月于我院确诊的IPF患者114例作为病例组,另随机选择同期健康体检者100例作为对照组.采用PCR法检测所有研究对象MUC5B启动子rs35705950、rs...     

Several specific high-resolution computed tomography patterns correlate with survival in patients with idiopathic pulmonary fibrosis

BackgroundEvidence of honeycombing in high-resolution computed tomography (HRCT) is a recognized risk factor for shortened survival in patients with idiopathic pulmonary fibrosis (IPF), but few studies have evaluated the feasibility of exploiting other specific patterns for predicting survival. The aim of this study was to examine the extent of specific HRCT patterns in IPF and determine whether they correlate with clinical features, pulmonary function tests (PFT), and survival.MethodsBoth the presence and extent of specific HRCT patterns, such as traction bronchiectasis, honeycombing, architectural distortion, reticulation, emphysema, and ground glass opacity, in 129 HRCT examinations were scored semi-quantitatively in three zones of each lung. HRCT examinations were also re-classified according to the 2011 and 2018 international statements. Correlations were calculated between the scores of specific HRCT patterns, clinical features, PFT, and patient survival.ResultsThe extent of traction bronchiectasis was found to be an independent risk factor of shortened survival (HR 1.227, P=0.001). Patients with a possible usual interstitial pneumonia (UIP) pattern had a better median survival than the patients with a definite UIP pattern (61 vs. 37 months, P=0.026). The extents of traction bronchiectasis, honeycombing, and architectural distortion displayed an inverse correlation with all PFT values at the time of diagnosis. There were few differences between the radiological classifications of the 2011 and 2018 international statements.ConclusionsWe conclude that several specific HRCT patterns displayed a correlation with shortened survival in IPF; these may help in evaluating the risk of death in IPF patients.     

Clinical and functional outcomes in Middle Eastern patients with idiopathic pulmonary fibrosis

Background: Baseline clinical and physiological variables have been described as relevant predictors of survival among patients with idiopathic pulmonary fibrosis (IPF). However, substantial heterogeneity in both survival time and mortality has been observed with many of these predictive factors. The incidence and mortality rates of IPF vary from country to country, with race potentially contributing to such variations. Objective: We sought to describe baseline clinical features to determine their predictive value among Middle Eastern patients diagnosed with IPF. Methods: We retrospectively examined 61 patients diagnosed with IPF at a university hospital in Riyadh, Saudi Arabia. Results: At presentation, most patients exhibited either dyspnea or cough. The median survival time for all patients was 92 months. Diminished survival was significantly associated with finger clubbing (P = 0.01). Factors not influencing survival were age, gender, percent predicted forced vital capacity, percent predicted forced expiratory volume in 1 s, percent predicted total lung capacity, percent predicted diffusion capacity of the lung for carbon monoxide and resting oxygen saturation. Conclusions: Finger clubbing is a significant predictive variable and was associated with a 5‐fold increase in mortality. Other baseline demographic characteristics as well as pulmonary function tests were not predictive of prognosis in Middle Eastern patients with IPF. It appears that IPF patients of Middle Eastern descent have a longer median survival curve compared to other races. Please cite this paper as: Alhamad EH, Masood M, Shaik SA and Arafah M. Clinical and functional outcomes in Middle Eastern patients with idiopathic pulmonary fibrosis. The Clinical Respiratory Journal 2008; 2: 220–226.     

Prognostic value of circulating KL-6 in idiopathic pulmonary fibrosis

OBJECTIVE: Circulating levels of KL-6, a high MW glycoprotein (MUC1 mucin), are elevated in a majority of patients with a number of interstitial lung diseases, including idiopathic pulmonary fibrosis (IPF). However, KL-6 levels vary from patient to patient. The aim of the present study was to determine whether the serum KL-6 level at the time of diagnosis predicts prognosis in IPF. METHODS: The relationship between clinical variables and prognosis in 27 patients with IPF were analysed retrospectively. The diagnosis was made by histological examination (n = 16) or on clinical findings including high-resolution CT scanning (n = 11). All patients were followed up for at least 3 years. Variables such as age, FVC%, PaO(2) at rest, initial LDH level, C-reactive protein and KL-6 were used for analysis. RESULTS: At the cut-off level determined by receiver operating characteristic curves, LDH and KL-6 showed a significant correlation with the patient's prognosis by univariate analysis. However, multivariate analysis revealed that only KL-6 was a predictor of prognosis. The patients were categorized by their serum KL-6 levels (as above or below the cut-off level of 1000 U/mL) and their survival estimated using the Kaplan-Meier method. The difference in median survival between the two groups was significant. The median survival of patients with low KL-6 was more than 36 months, whereas that of patients with high KL-6 was only 18 months. CONCLUSION: These results suggest that initial evaluation of serum KL-6 level can predict survival in patients with IPF.     

Racial and ethnic disparities in antifibrotic therapy in idiopathic pulmonary fibrosis

Background and Objective

Racial disparities have been documented in care of many respiratory diseases but little is known about the impact of race on the treatment of interstitial lung diseases. The purpose of this study was to determine how race and ethnicity influence treatment of idiopathic pulmonary fibrosis.

Methods

Adults with idiopathic pulmonary fibrosis (>18 years) were identified using TriNetX database and paired-wised comparisons were performed for antifibrotic treatment among White, Black, Hispanic and Asian patients. Mortality of treated and untreated IPF patients was compared after propensity score matching for age, sex, nicotine dependence, oxygen dependence and predicted FVC. Additional comparisons were performed in subgroups of IPF patients older than 65 years of age and with lower lung function.

Results

Of 47,184 IPF patients identified, the majority were White (35,082), followed by Hispanic (6079), Black (5245) and Asian (1221). When subgroups were submitted to matched cohort pair-wise comparisons, anti-fibrotic usage was lower among Black patients compared to White (6.2% vs. 11.4%, p-value <0.0001), Hispanic (10.8% vs. 20.2%, p-value <0.0001) and Asian patients (9.6% vs. 14.7%, p-value = 0.0006). Similar treatment differences were noted in Black individuals older than 65 years and those with lower lung function. Mortality among White patients, but not Hispanic, Black, or Asian patients, was lower in patients on antifibrotic therapy versus not on therapy.

Conclusion

This study demonstrated that Black IPF patients had lower antifibrotic use compared to White, Hispanic and Asian patients. Our findings suggest that urgent action is needed to understand the reason why racial disparities exist in the treatment of IPF.     

Platelet-derived growth factor can predict survival and acute exacerbation in patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis is a fibrotic disease of unknown aetiology and has a poor prognosis. Some patients experience episodes of rapid deterioration known as acute exacerbations (AEs), which are often fatal. This study aimed to clarify whether serum cytokine levels can predict the outcome of idiopathic pulmonary fibrosis.MethodsThis retrospective study included 69 patients with idiopathic pulmonary fibrosis diagnosed according to the 2018 guideline. AE of idiopathic pulmonary fibrosis was diagnosed using the Japanese Respiratory Society criteria. Serum levels of 27 cytokines were measured using the Bio-Plex method. Cytokine production was estimated per lung volume using the serum cytokine level/percent predicted forced vital capacity (%FVC) value. The ability of the serum cytokine level and serum cytokine level/%FVC value to predict the prognosis and AE was examined in a univariate Cox proportional hazards regression model; significant factors were subjected to multivariate analysis with adjustment for significant clinical parameters, including the modified Medical Research Council score.ResultsThe study included 57 men and 12 women (median age, 67 years). The modified Medical Research Council score was ≤1 in 47 patients and ≥2 in 22. None of the serum cytokine levels measured could predict survival or AE; however, the serum platelet-derived growth factor/%FVC and interleukin-9/%FVC values were significant prognostic factors and the serum platelet-derived growth factor/%FVC and interleukin-13/%FVC values were significant predictors of AE. Serum platelet-derived growth factor/%FVC alone was a significant predictor of the prognosis and AE after adjustment for clinical parameters.ConclusionsThe prognosis of idiopathic pulmonary fibrosis and AEs of the disease could be predicted by the serum platelet-derived growth factor/%FVC value.     

Diagnostic usefulness of bronchoscopy for peripheral pulmonary lesions in patients with idiopathic pulmonary fibrosis

BackgroundAs lung cancers arising in a background of idiopathic pulmonary fibrosis (IPF) are known to show high malignancy grades, early pathologic diagnosis of peripheral pulmonary lesions (PPLs) is important. Meanwhile, the risk of complications associated with diagnostic procedures is high, which prompted us to investigate the role of bronchoscopy, a relatively safe diagnostic procedure. Therefore, we conducted this study to evaluate the usefulness of bronchoscopy for the diagnosis of PPLs in patients with IPF.MethodsData of consecutive patients with IPF who underwent bronchoscopy under radial endobronchial ultrasound (R-EBUS) guidance for PPLs at our institution between April 2014 and March 2019 were retrospectively reviewed. IPF was defined as usual interstitial pneumonia (UIP) or probable UIP, in accordance with the classification in the latest global guidelines. The diagnostic outcomes and the factors independently related to the diagnostic yield were analyzed.ResultsA total of 92 patients were included in the analysis. The median (range) size of the target PPLs was 27.1 (11.4–75.3) mm, and the diagnostic yield was 82.6%. Multivariable analysis identified a larger size [P=0.017; odds ratio (OR), 5.33; 95% confidence interval (CI), 1.29–22.01], positive bronchus sign (P=0.035; OR, 4.99; 95% CI, 1.12–22.18), and not involved with UIP/probable UIP pattern (P=0.023; OR and 95% CI, unmeasurable) as being associated with a significantly higher diagnostic yield. Meanwhile, none of the patients developed acute exacerbation of IPF or pneumothorax following the diagnostic bronchoscopy.ConclusionsBronchoscopy using R-EBUS was safe and showed an acceptable diagnostic yield for PPLs, even in patients with IPF.     

Change in gait speed and adverse outcomes in patients with idiopathic pulmonary fibrosis: A prospective cohort study

Background and Objective

Gait speed is associated with survival in individuals with idiopathic pulmonary fibrosis (IPF). The extent to which four-metre gait speed (4MGS) decline predicts adverse outcome in IPF remains unclear. We aimed to examine longitudinal 4MGS change and identify a cut-point associated with adverse outcome.

Methods

In a prospective cohort study, we recruited 132 individuals newly diagnosed with IPF and measured 4MGS change over 6 months. Death/first hospitalization at 6 months were composite outcome events. Complete data (paired 4MGS plus index event) were available in 85 participants; missing 4MGS data were addressed using multiple imputation. Receiver-Operating Curve plots identified a 4MGS change cut-point. Cox proportional-hazard regression assessed the relationship between 4MGS change and time to event.

Results

4MGS declined over 6 months (mean [95% CI] change: −0.05 [−0.09 to −0.01] m/s; p = 0.02). A decline of 0.07 m/s or more in 4MGS over 6 months had better discrimination for the index event than change in 6-minute walk distance, forced vital capacity, Composite Physiologic Index or Gender Age Physiology index. Kaplan–Meier curves demonstrated a significant difference in time to event between 4MGS groups (substantial decline: >−0.07 m/s versus minor decline/improvers: ≤−0.07 m/s; p = 0.007). Those with substantial decline had an increased risk of hospitalization/death (adjusted hazard ratio [95% CI] 4.61 [1.23–15.83]). Similar results were observed in multiple imputation analysis.

Conclusion

In newly diagnosed IPF, a substantial 4MGS decline over 6 months is associated with shorter time to hospitalization/death at 6 months. 4MGS change has potential as a surrogate endpoint for interventions aimed at modifying hospitalization/death.     

Likelihood of pulmonary hypertension in patients with idiopathic pulmonary fibrosis and emphysema

Background and objective

This study evaluated whether patients with combined pulmonary fibrosis and emphysema (CPFE) have an increased likelihood of pulmonary hypertension (PHT) when compared with idiopathic pulmonary fibrosis (IPF) patients without emphysema.

Methods

Two consecutive IPF populations having undergone transthoracic echocardiography were examined (n = 223 and n = 162). Emphysema and interstitial lung disease (ILD) extent were quantified visually; ILD extent was also quantified by a software tool, CALIPER. Echocardiographic criteria categorized PHT risk.

Results

The prevalence of an increased PHT likelihood was 29% and 31% in each CPFE cohort. Survival at 12 months was 60% across both CPFE cohorts with no significantly worsened outcome identified when compared with IPF patients without emphysema. Using logistic regression models in both cohorts, total computed tomography (CT) disease extent (ILD and emphysema) predicted the likelihood of PHT. After adjustment for total disease extent, CPFE had no stronger association with PHT likelihood than IPF patients without emphysema.

Conclusion

Our findings indicate that the reported association between CPFE and PHT is explained by the summed baseline CT extents of ILD and emphysema. Once baseline severity is taken into account, CPFE is not selectively associated with a malignant microvascular phenotype, when compared with IPF patients without emphysema.

     

Perceptions of fatigue in patients with idiopathic pulmonary fibrosis or sarcoidosis

BackgroundFatigue is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF) or sarcoidosis. However, the difference in fatigue perceptions for these patients is unknown and this may be important to better understand what fatigue means to the individual patient.MethodsThis cross-sectional quantitative study aims to determine the different perceptions of fatigue as ‘frustrating’, ’exhausting’, ‘pleasant’, ‘frightening’ using the Fatigue Quality List and to assess determinants related to these perceptions of fatigue. Beside the fatigue quality connotations, demographics, lung function, fatigue severity (Checklist Individual Strength subscale Fatigue), dyspnea (modified-Medical Research Council), fatigue catastrophizing (Fatigue Catastrophizing Scale), anxiety/depression (Hospital Anxiety and Depression Scale) and general health status (EuroQoL 5-dimension 5-level) were assessed.ResultsMean frequency score of fatigue-related perceptions in patients with IPF was 3.4 points and in patients with sarcoidosis 4.0 points. Severely fatigued patients with IPF reported their fatigue less ‘pleasant’ significantly more often than patients without severe fatigue. Fatigue severity, dyspnea, catastrophizing and general health were significantly correlated with the negative connotation categories of the Fatigue Quality List in patients with IPF. Severely fatigued sarcoidosis patients reported their fatigue perceptions significantly more often as ‘frustrating’, ’exhausting’, ‘frightening’ and less ‘pleasant’ than patients without severe fatigue. Moreover, in patients with sarcoidosis fatigue severity, dyspnea, catastrophizing and depression were significantly associated with all four categories of the Fatigue Quality List that describe the experienced fatigue (P<0.05).ConclusionsThe current findings of experiences of fatigue in patients with IPF or pulmonary sarcoidosis provide insights for professionals treating these patients. Although similarities were found in the several experiences of fatigue across non-severely and severely fatigued patients, differences were also evident and could be mapped for IPF and sarcoidosis.     

特发性肺纤维化患者血清结缔组织生长因子和纤维连接蛋白水平研究

目的研究特发性肺间质纤维化（IPF）患者血清结缔组织生长因子（CTGF）和纤维连接蛋白（Fn）水平及其与肺纤维化严重程度的关系。方法用临床-影像-生理（CTa）评分系统评价IPF患者肺纤维化严重程度,并分为高分组和低分组,用酶联免疫吸附试验（ELISA）测定IPF组（n=44）和键康对照组（n=44）的血清CTGF和Fn水平,用WilCoxon秩和检验比较各组间CrGF、Fn水平差异,用Spearman秩相关分析CRP分数与CTGF、Fn之间的相关性。结果高分组与对照组比较,血清CrGF和Fn水平增高（P〈0．05）;低分组与对照组比较,血清CrGF和Fn水平无差异（P〉0．05）;高分组CRP分数与血清CTGF及Fn之间的秧相关数分别为0．52和0．45,即它们之间呈正相关。结论肺纤维化程度较重的IPF患者血清CTGF、Fn水平增高。且随肺纤维化严重程度而增加。     

A novel seven-gene risk profile in BALF to identify high-risk patients with idiopathic pulmonary fibrosis

BackgroundIdiopathic pulmonary fibrosis (IPF) is a fatal heterogeneous disease with a varied clinical course that is difficult to predict. Accurate predictive models are urgently needed to identify individuals with poor survival for the optimal timing of referral for transplantation and provide some clues for mechanistic research on disease progression.MethodsWe obtained the gene expression profiles of bronchoalveolar lavage fluid (BALF) from the Gene Expression Omnibus. Individuals from the {"type":"entrez-geo","attrs":{"text":"GPL14550","term_id":"14550"}}GPL14550 platform were assigned to the derivation cohort (n=112) and individuals from the {"type":"entrez-geo","attrs":{"text":"GPL17077","term_id":"17077"}}GPL17077 platform to the validation cohort (n=64). Univariate Cox and least absolute shrinkage and selection operator (LASSO) regression analyses were applied to select candidate genes for overall survival. A nomogram model was constructed based on Cox hazard regression analysis. The model was assessed by C-statistic, calibration curve, and decision curve analysis (DCA) and was externally validated.ResultsA nomogram model comprising seven genes was constructed. Excellent discrimination and calibration were observed in the derivation (C-index 0.815) and validation (C-index 0.812) cohorts. The AUCs for predicting 1-, 2- and 3-year survival were 0.857, 0.918, 0.930 in the derivation cohort and 0.850, 0.880, 0.925 in the validation cohort, respectively. DCA confirmed the clinical applicability of the model. A risk score based on the model was an independent prognostic predictor and could divide patients into high- and low-risk groups. The Kaplan-Meier analysis displayed that high-risk patients exhibited significantly poorer survival compared with low-risk patients. Gene Set Enrichment Analysis (GSEA) showed that high-risk patients were primarily enriched in inflammatory hallmarks, and single sample GSEA (ssGSEA) indicated that the high-risk group is closely correlated with the immune process. These lead to increased insight into mechanisms associated with IPF progression that inflammation mediated by immune response might be involved in the disease progression.ConclusionsThe novel BALF seven-gene model performed well in risk stratification and individualized survival prediction for patients with IPF, facilitating personalized management of IPF patients. It deepened the understanding of the role of inflammation in IPF progression, which needs to be further studied.     

The molecular mechanism of Ligusticum wallichii for improving idiopathic pulmonary fibrosis: A network pharmacology and molecular docking study

Background:At present, there was no evidence that any drugs other than lung transplantation can effectively treat Idiopathic Pulmonary Fibrosis (IPF). Ligusticum wallichii, or Chinese name Chuan xiong has been widely used in different fibrosis fields. Our aim is to use network pharmacology and molecular docking to explore the pharmacological mechanism of the Traditional Chinese medicine (TCM) Ligusticum wallichii to improve IPF.Materials and methods:The main chemical components and targets of Ligusticum wallichii were obtained from TCMSP, Swiss Target Prediction and Phammapper databases, and the targets were uniformly regulated in the Uniprot protein database after the combination. The main targets of IPF were obtained through Gencards, OMIM, TTD and DRUGBANK databases, and protein interaction analysis was carried out by using String to build PPI network. Metascape platform was used to analyze its involved biological processes and pathways, and Cytoscape3.8.2 software was used to construct “component-IPF target-pathway” network. And molecular docking verification was conducted through Auto Dock software.Results:The active ingredients of Ligusticum wallichii were Myricanone, Wallichilide, Perlolyrine, Senkyunone, Mandenol, Sitosterol and FA. The core targets for it to improve IPF were MAPK1, MAPK14, SRC, BCL2L1, MDM2, PTGS2, TGFB2, F2, MMP2, MMP9, and so on. The molecular docking verification showed that the molecular docking affinity of the core active compounds in Ligusticum wallichii (Myricanone, wallichilide, Perlolyrine) was <0 with MAPK1, MAPK14, and SRC. Perlolyrine has the strongest molecular docking ability, and its docking ability with SRC (−6.59 kJ/mol) is particularly prominent. Its biological pathway to improve IPF was mainly acted on the pathways in cancer, proteoglycans in cancer, and endocrine resistance, etc.Conclusions:This study preliminarily identified the various molecular targets and multiple pathways of Ligusticum wallichii to improve IPF.