Stable Idiopathic Pulmonary Fibrosis Research Articles

Dynapenia is highly prevalent in older patients with advanced idiopathic pulmonary fibrosis

Body composition and muscle strength are emerging aspects in idiopathic pulmonary fibrosis (IPF) clinical assessment. We aimed to study the relationships of handgrip strength (HGS) with anthropometric variables, body composition, and disease staging, and to evaluate the prevalence of dynapenia in 102 clinically stable IPF patients (70 M; mean age: 69.4 years). Fat-free mass (FFM), skeletal muscle (SM) were estimated with bioimpedance analysis. HGS was measured with a digital handle dynamometer for both dominant and non-dominant body sides. Dynapenia was identified according to six recognized criteria sets. Mean body mass index (BMI) was 28.2 ± 4.7 kg/m2, with a prevalence of overweight (BMI > 25 and < 30 kg/m2) and obesity (BMI ≥ 30 kg/m2) of 35% and 37%, respectively. FFM and SM were greater in males, whereas percentage body fat was higher in women. HGS was higher and declined with age slightly more rapidly in men, showing a stronger correlation with FFM and SM. Dynapenia prevalence ranged from 20.6 to 56.9%, depending on the criteria used, and was more frequent in older patients and advanced disease. Dynapenia is highly prevalent in IPF. HGS is a promising proxy marker of muscle function to be used in clinical evaluation and follow-up programs.

Progranulin and Activin A Concentrations are Elevated in Serum from Patients with Acute Exacerbations of Idiopathic Pulmonary Fibrosis

PurposeIdiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrotic lung disease of unknown cause with a variable course. Acute exacerbations of IPF (AE-IPF) is sudden accelerations of the disease or a superimposed idiopathic acute injury significantly reducing lung function. To examine the serum concentrations of Progranulin (PGRN) and activin A in patients with AE-IPF in a pilot study.MethodsTwenty-one patients with AE-IPF were compared with 23 patients with stable IPF as a control group. Serum PGRN and activin A levels, arterial blood gas measurements, and lung function were determined in these two groups.ResultsPeripheral blood PGRN and activin A levels in patients with AE-IPF were 83.7 + 10.0 and 14.2 ± 1.7 ng/ml (mean + SD), respectively; higher than those in the control group 61.0 + 5.8 and 5.8 + 1.0 (p < 0.001). PGRN and activin A levels were significantly negatively correlated with carbon monoxide diffusion capacity r = − 0.857 (p < 0.001) and r = − 0.757 (p < 0.001).ConclusionProgranulin (PGRN) and activin A may be involved in the pathogenesis of AE-IPF. They may be possible markers of disease activity in AE-IPF.

Liquid Biopsy Is a Promising Tool for Genetic Testing in Idiopathic Pulmonary Fibrosis.

Liquid biopsy, which allows the isolation of circulating cell-free (ccf) DNA from blood, is an emerging noninvasive tool widely used in oncology for diagnostic and prognosis purposes. Previous data have shown that serum cfDNA discriminates idiopathic pulmonary fibrosis (IPF) from other interstitial lung diseases. Our study aimed to measure plasma levels of ccfDNA in 59 consecutive therapy-naive and clinically stable IPF patients. The single nucleotide polymorphism (SNP) of the MUC5B gene promoter (rs35705950), associated with increased susceptibility of developing IPF, has been sought in plasma cfDNA and genomic DNA for comparison. Thirty-five age- and sex-matched healthy volunteers were recruited as the control group. Our results show that concentrations of small-size ccfDNA fragments were significantly higher in IPF patients than in controls and inversely correlated with lung function deterioration. Moreover, the median level of 104 ng/mL allowed discriminating patients with mild disease from those more advanced. The rs35705950 polymorphism was found in 11.8% of IPF patients and 8% of controls, with no differences. Complete concordance between ccfDNA and genomic DNA was detected in all control samples, while four out of seven IPF cases (57%) carrying the rs35705950 polymorphism were discordant from genomic DNA (7% of total IPF). Liquid biopsy is a suitable tool with optimistic expectations of application in the field of IPF. In analogy with cancer biology, finding some discrepancies between ccfDNA and genomic DNA in IPF patients suggests that the former may convey specific genetic information present in the primary site of the disease.

Association of serum monomeric periostin level with outcomes of acute exacerbation of idiopathic pulmonary fibrosis and fibrosing nonspecific interstitial pneumonia.

BackgroundThe associations of serum monomeric periostin (M-PN) level and serial change in M-PN with acute exacerbation of chronic fibrosing interstitial pneumonia (AE-FIP) are unclear.MethodsWe prospectively measured serum M-PN level from onset of AE to day 14 in 37 patients with AE-FIP and evaluated its association with outcome. To determine localization of periostin expression, immunohistochemical staining of pathological lung tissue from autopsy cases of AE-IPF was evaluated.ResultsData from 37 AE-FIP patients (28 men; age 73.9±7.8 years) were analyzed. With healthy controls as reference, serum M-PN level was significantly higher in patients with AE-FIP (P=0.02) but not in those with stable idiopathic pulmonary fibrosis (P=1.00). M-PN was significantly lower on day 7 than at AE-FIP onset in survivors [14.6±5.8 vs. 9.3±2.8 ng/mL (onset to day 7: P<0.001)] but not in non-survivors [14.6±5.1 vs. 13.2±5.1 ng/mL (onset to day 7: P=0.07)]. In analysis using a cut-off value for serial change in M-PN (ΔM-PN), 3-month survival was 92.3% in the ΔM-PN decrease group and 36% in the ΔM-PN increase group (P=0.002). In multivariate analysis, 3-month survival tended to be associated with high ΔM-PN (OR: 12.4, 95% CI: 0.82–187.9, P=0.069).ConclusionsSerial change in serum M-PN level may be a prognostic indicator of AE-FIP.

The Role of Microbiome and Virome in Idiopathic Pulmonary Fibrosis

The interest in the lung microbiome and virome and their contribution to the pathogenesis, perpetuation and progression of idiopathic pulmonary fibrosis (IPF) has been increasing during the last decade. The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations. In stable IPF, higher microbial burden is associated with worse prognosis but no specific microbe has been identified to contribute to this. Additionally, no causative relation has been established. Regarding viral infections, although in the past they have been associated with IPF, causation has not been proved. Although in the past the diagnosis of acute exacerbation of IPF (AE-IPF) was not considered in patients with overt infection, this was amended in the last few years and infection is considered a cause for exacerbation. Besides this, a higher microbial burden has been found in the lungs of patients with AE-IPF and an association with higher morbidity and mortality has been confirmed. In contrast, an association of AE-IPF with viral infection has not been established. Despite the progress during the last decade, a comprehensive knowledge of the microbiome and virome in IPF and their role in disease pathogenesis are yet elusive. Although association with disease severity, risk for progression and mortality has been established, causation has not been proven and the potential use as a biomarker or the benefits of antimicrobial therapeutic strategies are yet to be determined.

Concurrence of 1- and 3-Min Sit-to-Stand Tests with the 6-Min Walk Test in Idiopathic Pulmonary Fibrosis

Background: In idiopathic pulmonary fibrosis (IPF), some physiological parameters measured during a 6-min walk test (6-MWT) impart reliable prognostic information. Sit-to-stand tests (STSTs) are field exercise tests that are easier to implement than the 6-MWT in daily practice. Objectives: The aims of the study were to test the reproducibility and compare 2 STSTs (the 1-min STST [1-STST] and the semi-paced 3-min chair rise test [3-CRT]) in IPF, and to determine if selected physiological parameters (speed of displacement and changes in pulse oxygen saturation [SpO₂]) are interchangeable between the STSTs and the 6-MWT. Methods: Thirty-three patients with stable IPF were studied in 3 French expert centers. To test reproducibility, intra-class correlations (ICCs) of parameters measured during tests performed 7–14 days apart were calculated. To test interchangeability, the agreement and correlation of physiological responses measured during STSTs and during 6-MWT were studied. Results: Vertical displacements and changes in SpO₂ during both STSTs were reproducible, with ICCs ranging from 0.78 [0.63–0.87] to 0.95 [0.92–0.97]. Vertical displacements during 1-STST and 3-CRT were correlated with 6-MWT distance (correlation coefficients (r) of 0.72 and 0.77, respectively; p < 0.001). Similarly, correlations were found between changes in SpO₂ measured during the 2 STSTs and the 6-MWT, with coefficients ranging from 0.73 to 0.91 (p < 0.001). Distance walked and SpO₂ during 6-MWT were well estimated from vertical displacement and SpO₂ during the 2 STSTs, respectively. Conclusion: The correlations found between the 2 STSTs and the 6-MWT suggest that STSTs may be of interest to assess displacement and exercise-induced changes in SpO₂ in IPF patients.

There is detectable variation in the lipidomic profile between stable and progressive patients with idiopathic pulmonary fibrosis (IPF)

BackgroundIdiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease characterized by fibrosis and progressive loss of lung function. The pathophysiological pathways involved in IPF are not well understood. Abnormal lipid metabolism has been described in various other chronic lung diseases including asthma and chronic obstructive pulmonary disease (COPD). However, its potential role in IPF pathogenesis remains unclear.MethodsIn this study, we used ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) to characterize lipid changes in plasma derived from IPF patients with stable and progressive disease. We further applied a data-independent acquisition (DIA) technique called SONAR, to improve the specificity of lipid identification.ResultsStatistical modelling showed variable discrimination between the stable and progressive subjects, revealing differences in the detection of triglycerides (TG) and phosphatidylcholines (PC) between progressors and stable IPF groups, which was further confirmed by mass spectrometry imaging (MSI) in IPF tissue.ConclusionThis is the first study to characterise lipid metabolism between stable and progressive IPF, with results suggesting disparities in the circulating lipidome with disease progression.

Telomere length across different UIP fibrotic-Interstitial Lung Diseases: a prospective Greek case-control study

IntroductionShort telomeres are recognized as risk factor for idiopathic pulmonary fibrosis (IPF). We aimed to assess the role of telomere length (TL) in fibrotic-Interstitial Lung Diseases (f-ILDs) associated with a usual interstitial pneumonia (UIP) pattern as well as in IPF acute exacerbation (IPF-AE). Aim and methodsTL was measured from peripheral white blood cells using a multiplex quantitative polymerase chain reaction in consecutive patients with f-ILDs, all presenting UIP pattern in the high-resolution chest-computed-tomography and compared to age-matched healthy controls. ResultsSeventy-nine individuals were included (mean age 69.77 ± 0.72 years); 24 stable IPF, 18 IPF-AE, 10 combined pulmonary fibrosis and emphysema, 7 Rheumatoid arthritis-UIP-ILDs and 20 controls. TL in all patients was significantly shorter compared to controls [mean T/S ratio (SE) 0.77 (±0.05) vs 2.26 (±0.36), p < 0.001] as well as separately in each one of f-ILD subgroups. IPF-AE patients presented significantly shorter TL compared to stable IPF (p = 0.029). Patients with IPF and shorter than the median TL (0−0.72) showed reduced overall survival (p = 0.004). T/S < 0.72 was associated with increased risk for IPF-AE (OR = 30.787, 95% CI: 2.153, 440.183, p = 0.012) independent of age, gender, smoking and lung function impairment. A protective effect of TL was observed, as it was inversely associated with risk of death both in UIP-f-ILDs (HR = 0.174, 95%CI: 0.036, 0.846, p = 0.030) and IPF patients (HR = 0.096, 95%CI: 0.011, 0.849, p = 0.035). ConclusionsShorter TL characterizes different UIP f-ILDs. Although no difference was observed in TL among diverse UIP subgroups, IPF-AE presented shorter TL compared to stable IPF. Reduced overall survival and higher hazard ratio of death are associated with shorter TL in IPF.

Clinical predictors and explant lung pathology of acute exacerbation of idiopathic pulmonary fibrosis.

BackgroundIdiopathic pulmonary fibrosis (IPF) is characterised by constant threat of acute exacerbation of IPF (AE-IPF). It would be significant to identify risk factors of AE-IPF. We sought to determine the prognostic value of lung transplantation candidacy testing for AE-IPF and describe explant pathology of recipients with and without AE-IPF before lung transplantation.MethodsRetrospective cohort study of 89 IPF patients listed for lung transplantation. Data included pulmonary function testing, echocardiography, right heart catheterisation, imaging, oesophageal pH/manometry and blood tests. Explanted tissue was evaluated by pulmonary pathologists and correlated to computed tomography (CT) findings.ResultsOut of 89 patients with IPF, 52 were transplanted during stable IPF and 37 had AE-IPF before transplantation (n=28) or death (n=9). There were no substantial differences in candidacy testing with and without AE-IPF. AE-IPF had higher rate of decline of forced vital capacity (FVC) (21±22% versus 4.8±14%, p=0.00019). FVC decline of >15% had a hazard ratio of 7.2 for developing AE-IPF compared to FVC decline of <5% (p=0.004). AE-IPF had more secondary diverse histopathology (82% versus 29%, p<0.0001) beyond diffuse alveolar damage. There was no correlation between ground-glass opacities (GGO) on chest CT at any point to development of AE-IPF (p=0.077), but GGO during AE-IPF predicted secondary pathological process beyond diffuse alveolar damage.ConclusionsLung transplantation candidacy testing including reflux studies did not predict AE-IPF besides FVC absolute decline. CT did not predict clinical or pathological AE-IPF. Secondary diverse lung pathology beyond diffuse alveolar damage was present in most AE-IPF, but not in stable IPF.

Spliceosome-associated protein 130: a novel biomarker for idiopathic pulmonary fibrosis.

BackgroundSpliceosome-associated protein 130 (SAP130), a novel danger-associated molecular pattern (DAMP), is involved in inflammatory disease. However, no data are available about SAP130 in idiopathic pulmonary fibrosis (IPF). Our study aimed to investigate SAP130 in the serum and lung tissue of patients with IPF and to determine its clinical significance.MethodsSAP130 levels in the serum of 83 IPF patients and 38 healthy subjects were measured. Additionally, immunohistochemical staining for SAP130 was performed in lung specimens of IPF patients and control subjects. Correlation between serum SAP130 levels and clinical parameters were investigated.ResultsSerum SAP130 levels were elevated in IPF patients compared with healthy controls. In parallel, the expression of SAP130 in lung tissue was elevated in IPF. SAP130 levels were higher in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) than patients with stable IPF (P=0.0144). The area under curve (AUC) of the ROC curve for the diagnosis of IPF was 0.944 (95% CI, 0.810–0.997) for SAP130. The sensitivity (92.1%) and specificity (69.9%) were obtained for the cutoff value of 643.87 pg/mL. In patients with stable IPF, the SAP130 level correlated positively with fibrosis on high-resolution CT (HRCT) (r=0.4164, P=0.0029) and serum KL-6 (r=0.4564, P=0.0010), and inversely with FEV1 (r=−0.3562, P=0.0120) and DLCO (r=−0.5550, P<0.0001). In patients with AE-IPF, the SAP130 level correlated positively with fibrosis (r=0.3735, P=0.0296) and ground-glass opacity (r=0.4697, P=0.0051) on HRCT and serum Krebs von den Lungen 6 (KL-6) (r=0.5470, P= 0.0008).ConclusionsThe study suggested that SAP130 was a potential noninvasive biomarker that correlates well with disease severity of IPF. A prospective, multicentre study is required to validate the clinical and pathophysiological utility of SAP130 in IPF.

Associations of Serological Biomarkers of sICAM-1, IL-1β, MIF, and su-PAR with 3-Month Mortality in Acute Exacerbation of Idiopathic Pulmonary Fibrosis.

Objective To investigate prognostic values of serum biomarkers of soluble intercellular adhesion molecule 1 (sICAM-1), macrophage migration inhibitor factor (MIF), interleukin 1β (IL-1β), and soluble urokinase plasminogen activator receptor (su-PAR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods From August 2017 to November 2019, 122 consecutive IPF patients treated in our center were classified as stable IPF and AE-IPF based on the newly published international guidelines. Serum levels of four biomarkers at admission were measured by the enzyme-linked immunosorbent assay (ELISA). The primary endpoint was 3-month mortality. The log-rank test and logistic regression analysis were used to evaluate the effects of these biomarkers for survival in patients with AE-IPF. Cox proportional hazards analysis was performed to evaluate the prognostic values of serological biomarkers and clinical data. Results Eighty-one patients were diagnosed with stable IPF, and 41 AE-IPF patients were enrolled in the study. Serum levels of sICAM-1 (p < 0.001), IL-1β (p < 0.001), MIF (p < 0.001), and su-PAR (p < 0.001) in patients with IPF were significantly increased compared to those in healthy controls. All the four biomarkers were elevated in patients with AE-IPF compared to those with stable IPF. The 3-month mortality in AE-IPF was 56.1% (23/41). Increased levels of MIF (p = 0.01) and IL-1β (>5 pg/mL, p = 0.033) were independent risk factors for 3-month mortality in patients with AE-IPF. Conclusions We showed the higher serum levels of IL-1β, and MIF had prognostic values for 3-month mortality in AE-IPF. This study provided a clue to promote our understanding in the pathogenesis of the disease.

Association of serum macrophage-mannose receptor CD206 with mortality in idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. Macrophages are known to regulate the fibrotic process in idiopathic pulmonary fibrosis. ObjectiveWe investigated if two new macrophage-specific serum biomarkers, soluble mannose receptor (MR, sCD206) and soluble CD163 (sCD163), increased in serum obtained from patients with AE-IPF compared to stable IPF (S-IPF). MethodsA total of 36 IPF patients with AE status, 54 IPF patients with stable status, and 27 normal controls were enrolled in this study. The levels of serum sCD206 and sCD163 were compared among the three groups and analysed with the clinical features and mortality of IPF. ResultsThe serum concentrations of both markers were higher in patients with AE-IPF than in those with S-IPF (580.0 ng/ml vs 335 ng/ml for sCD206 and 69.2 ng/ml vs 37.9 ng/ml for sCD163). The level of sCD206 was related to an increased risk of mortality (HR = 1.002, p < 0.001). The best separation between decedents and survivors was obtained by sCD206 (area under the receiver operating characteristic curve [AUC] 0.712 and 95% confidence interval 0.595–0.830). ConclusionOur data demonstrated that the macrophage-related markers sCD206 and sCD163 were significantly higher in patients with IPF, especially sCD206 in AE-IPF patients. The high level of serum sCD206 was associated with mortality in idiopathic pulmonary fibrosis.

Lung Transplant Outcomes in Patients Hospitalized with Stable or Acute Exacerbations of Interstitial Lung Disease

Acute exacerbations of interstitial lung disease (AE-ILD) have a poor prognosis, and lung transplantation can be lifesaving. Previous studies have reported significantly higher mortality in patients transplanted with acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) compared to stable IPF. These results have yet to be corroborated, and whether they apply to the wide spectrum of AE-ILD beyond IPF is unknown. This study aimed to compare outcomes between transplanted AE-ILD patients, non-transplanted AE-ILD patients, and stable ILD patients hospitalized to undergo lung transplantation. This was a retrospective review of adults hospitalized with AE-ILD and stable patients hospitalized for elective lung transplantation due to end-stage ILD between January 2014 and February 2019. An acute exacerbation was defined using the revised definition and diagnostic criteria for AE-IPF. The primary outcome was post-hospitalization survival. For hospitalized transplanted patients, secondary outcomes included hospital length of stay post-transplant, grade of primary graft dysfunction, graft rejection, re-hospitalization, and cause of death. Twenty-nine patients were stable and electively admitted for lung transplantation, and 53 were hospitalized with AE-ILD, of whom 23 received a lung transplant and 28 did not. The average lung allocation score at the time of transplant for stable ILD patients was 41.79 compared to 81.61 for patients with AE-ILD (p<0.0001). Average follow-up was 17±10 months. Every lung transplant recipient survived, whereas only 8 of 28 (28%) non-transplanted patients with ILD exacerbations survived to hospital discharge. Secondary outcomes were not statistically significantly different between AE-ILD and stable ILD lung transplant recipients. Mortality rates were significantly higher in patients with AE-ILD who were not transplanted, but survival and post-hospitalization outcomes were comparable in patients transplanted with AE-ILD versus stable ILD. These results highlight the important role played by lung transplantation in eligible patients admitted with AE-ILD.

Impaired Right and Left Ventricular Longitudinal Function in Patients with Fibrotic Interstitial Lung Diseases

Background: Left ventricular (LV) and right ventricular (RV) dysfunction is recognized in idiopathic pulmonary fibrosis (IPF). Little is known about cardiac involvement in non-idiopathic pulmonary fibrosis (no-IPF). This issue can be explored by advanced echocardiography. Methods: Thirty-three clinically stable and therapy-naive fibrotic IPF and 28 no-IPF patients, and 30 healthy controls were enrolled. Exclusion criteria were autoimmune systemic diseases, coronary disease, heart failure, primary cardiomyopathies, chronic obstructive lung diseases, pulmonary embolism, primary pulmonary hypertension. Lung damage was evaluated by diffusion capacity for carbon monoxide (DLCOsb). All participants underwent an echo-Doppler exam including 2D global longitudinal strain (GLS) of both ventricles and 3D echocardiographic RV ejection fraction (RVEF). Results: We observed LV diastolic dysfunction in IPF and no-IPF, and LV GLS but not LV EF reduction only in IPF. RV diastolic and RV GLS abnormalities were observed in IPF versus both controls and no-IPF. RV EF did not differ significantly between IPF and no-IPF. DLCOsb and RV GLS were associated in the pooled pulmonary fibrosis population and in the IPF subgroup (β = 0.708, p < 0.001), independently of confounders including pulmonary arterial systolic pressure. Conclusion: Our data highlight the unique diagnostic capabilities of GLS in distinguishing early cardiac damage of IPF from no-IPF patients.

Stratification of long-term outcome in stable idiopathic pulmonary fibrosis by combining longitudinal computed tomography and forced vital capacity.

To test HRCT with either visual or quantitative analysis in both short-term and long-term follow-up of stable IPF against long-term (transplant-free) survival, beyond 2years of disease stability. Fifty-eight IPF patients had FVC measurements and HRCTs at baseline (HRCT0), 10-14months (HRCT1) and 22-26months (HRCT2). Visual scoring, CALIPER quantitative analysis of HRCT measures, and their deltas were evaluated against combined all-cause mortality and lung transplantation by adjusted Cox proportional hazard models at each time interval. At HRCT1, a ≥ 20% relative increase in CALIPER-total lung fibrosis yielded the highest radiological association with outcome (C-statistic 0.62). Moreover, the model combining FVC% drop ≥ 10% and ≥ 20% relative increase of CALIPER-total lung fibrosis improved the stratification of outcome (C-statistic 0.69, high-risk category HR 12.1; landmark analysis at HRCT1 C-statistic 0.66, HR 14.9 and at HRCT2 C-statistic 0.61, HR 21.8). Likewise, at HRCT2, the model combining FVC% decrease trend and ≥ 20% relative increase of CALIPER-pulmonary vessel-related volume (VRS) improved the stratification of outcome (C-statistic 0.65, HR 11.0; landmark analysis at HRCT1 C-statistic 0.62, HR 13.8 and at HRCT2 C-statistic 0.58, HR 12.6). A less robust stratification of outcome distinction was also demonstrated with the categorical visual scoring of disease change. Annual combined CALIPER -FVC changes showed the greatest stratification of long-term outcome in stable IPF patients, beyond 2years. • Longitudinal high-resolution computed tomography (HRCT) data is more helpful than baseline HRCT alone for stratification of long-term outcome in IPF. • HRCT changes by visual or quantitative analysis can be added with benefit to the current spirometric reference standard to improve stratification of long-term outcome in IPF. • HRCT follow-up at 12-14months is more helpful than HRCT follow-up at 23-26months in clinically stable subjects with IPF.

Correlation between serum bilirubin levels and the severity as well as the prognosis of idiopathic pulmonary fibrosis.

Bilirubin exerts antioxidant activity that has been associated with respiratory diseases. However, the relationship between serum bilirubin levels and idiopathic pulmonary fibrosis (IPF) is not clear. Therefore, in this study, we evaluated the relationship between serum bilirubin levels and the severity as well as the prognosis of IPF. One hundred and forty-six patients with IPF and 69 healthy individuals as the control group were enrolled as a derivation cohort. Routine blood examination and pulmonary function tests were performed and serum bilirubin levels were measured. To validate the value of serum bilirubin levels to predict the survival of patients with IPF, 40 additional IPF patients were included as a validation cohort. IPF patients were followed-up. Patients with IPF had significantly lower levels of serum total bilirubin (TBIL) and direct bilirubin (DBIL) than those in the control group (P < 0.05). Patients with acute exacerbation of IPF (AE-IPF) had significantly lower levels of serum TBIL and IBIL than those in patients with stable IPF (P < 0.05). The area under the receiver operating characteristic curve (AUROC) of serum TBIL levels for the prediction of the incidence of AE-IPF was 0.72 (95% CI: 0.56–0.87, P = 0.0057). The best cutoff value of serum TBIL level to predict the survival of patients with IPF was 8.8 μmol/l (AUC = 0.75, 95% CI: 0.64–0.87, P = 0.022). The log-rank test showed a significant difference in survival between the two groups (TBIL ≤8.8 μmol/l and TBIL >8.8 μmol/l) in derivation and validation cohort. Cox multiple regression analysis indicated that serum TBIL levels were an independent prognostic factor for IPF prognosis (HR = 0.582, P = 0.026). Serum TBIL levels might be useful for reflecting the severity and predicting the survival of patients with IPF.

The overexpression of peroxiredoxin-4 affects the progression of idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is life-threatening. Several serum biomarkers, such as Krebs von den Lungen-6 (KL-6) and surfactant protein D (SP-D), are clinically used for evaluating AE-IPF, but these biomarkers are not adequate for establishing an early and accurate diagnosis of AE-IPF. Recently, the protective roles of the members of the peroxiredoxin (PRDX) family have been reported in IPF; however, the role of PRDX4 in AE-IPF is unclear.MethodsSerum levels of PRDX4 protein, KL-6, SP-D and lactate dehydrogenase (LDH) in 51 patients with stable IPF (S-IPF), 38 patients with AE-IPF and 15 healthy volunteers were retrospectively assessed using enzyme-linked immunosorbent assay. Moreover, as an animal model of pulmonary fibrosis, wild-type (WT) and PRDX4-transgenic (Tg) mice were intratracheally administered with bleomycin (BLM, 2 mg/kg), and fibrotic and inflammatory changes in lungs were evaluated 3 weeks after the intratracheal administration.ResultsSerum levels of PRDX4 protein, KL-6, SP-D and LDH in patients with S-IPF and AE-IPF were significantly higher than those in healthy volunteers, and those in AE-IPF patients were the highest among the three groups. Using receiver operating characteristic curves, area under the curve values of serum PRDX4 protein, KL-6, SP-D, and LDH for detecting AE-IPF were 0.873, 0.698, 0.675, and 0.906, respectively. BLM-treated Tg mice demonstrated aggravated histopathological findings and poor prognosis compared with BLM-treated WT mice. Moreover, PRDX4 expression was observed in alveolar macrophages and lung epithelial cells of BLM-treated Tg mice.ConclusionsPRDX4 is associated with the aggravation of inflammatory changes and fibrosis in the pathogenesis of IPF, and serum PRDX4 may be useful in clinical practice of IPF patients.

Association of ADAM17 Expression Levels in Patients with Interstitial Lung Disease

ABSTRACTA disintegrin and metalloproteinases (ADAMs) are believed to be involved in the pathogenesis of many fibrosis-related diseases. However, little is known regarding the significance of ADAM17 as a biomarker for interstitial lung disease (ILD). In this study, by using the RT-PCR, western blotting and ELISA, we detected the expression level of ADAM17 in peripheral blood mononuclear cells and serum from idiopathic pulmonary fibrosis (IPF) patients, connective tissue disease associated ILD (CTD-ILD) patients and healthy controls, and correlations between clinical and laboratory parameters were also analyzed. We found that IPF patients and CTD-ILD patients showed higher levels of ADAM17 than healthy controls. Moreover, ADAM17 in IPF patients with acute exacerbation (AE-IPF) was significantly higher than that in stable IPF (S-IPF) patients. Expression of ADAM17 was positively correlated with disease duration and CRP but negatively correlated with diffusing capacity of carbon monoxide (DLCO) and total lung capacity (TLC). Among the CTD-ILD patients, SSc-ILD patients had the highest serum levels of ADAM17 compared with the RA-ILD, SS-ILD and IIM-ILD groups and ADAM17 expression levels were correlated with image grading. In conclusion, this study showed that ADAM17 is highly expressed in ILD patients and is associated with disease activity and severity. Additionally, ADAM17 expression is not only related to the primary CTDs, but also to image grading. ADAM17 may serve as a new biomarker for ILD.

Serum high‐mobility group box 1 is associated with the onset and severity of acute exacerbation of idiopathic pulmonary fibrosis

High-mobility group box 1 (HMGB1) is a known mediator of acute lung injury through the acceleration of pro-inflammatory -signalling. Previous studies showed that HMGB1 is increased in the lung and circulation of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). This study investigated the predictive value of circulatory HMGB1 for disease progression and prognosis of IPF in the stable phase and AE phase. In total, 76 patients with stable IPF, 17 patients with AE-IPF, 37 patients with chronic obstructive pulmonary disease (COPD) and 74 healthy controls were included. Serum HMGB1 levels were compared among the four groups and the associations of HMGB1 levels with the onset of AE and prognosis were evaluated in patients with stable IPF. The prognostic value of HMGB1 was determined in AE-IPF. Serum HMGB1 levels in patients with stable IPF were significantly higher than those in healthy controls, and in patients with AE-IPF they were even higher than the levels in either of these groups (6.26 ± 5.27, 3.42 ± 2.69 and 19.20 ± 16.76 ng/mL, respectively). There was no significant difference in serum HMGB1 levels between stable IPF patients and COPD patients. Higher levels of HMGB1 were associated with earlier onset of AE in stable IPF patients and with shorter survival in AE-IPF patients (P = 0.030 and 0.001, respectively). Higher levels of serum HMGB1 predict earlier onset of AE in stable IPF patients and shorter survival in AE-IPF patients, indicating that HMGB1 is associated with acute deterioration of the disease.

RNA sequencing of transplant-stage idiopathic pulmonary fibrosis lung reveals unique pathway regulation

Idiopathic pulmonary fibrosis (IPF), the scarring of lung parenchyma resulting in the loss of lung function, remains a fatal disease with a significant unmet medical need. Patients with severe IPF often develop acute exacerbations resulting in the rapid deterioration of lung function, requiring transplantation. Understanding the pathophysiological mechanisms contributing to IPF is key to develop novel therapeutic approaches for end-stage disease.We report here RNA-sequencing analyses of lung tissues from a cohort of patients with transplant-stage IPF (n=36), compared with acute lung injury (ALI) (n=11) and nondisease controls (n=19), that reveal a robust gene expression signature unique to end-stage IPF. In addition to extracellular matrix remodelling pathways, we identified pathways associated with T-cell infiltration/activation, tumour development, and cholesterol homeostasis, as well as novel alternatively spliced transcripts that are differentially regulated in the advanced IPF lung versus ALI or nondisease controls. Additionally, we show a subset of genes that are correlated with percent predicted forced vital capacity and could reflect disease severity.Our results establish a robust transcriptomic fingerprint of an advanced IPF lung that is distinct from previously reported microarray signatures of moderate, stable or progressive IPF and identifies hitherto unknown candidate targets and pathways for therapeutic intervention in late-stage IPF as well as biomarkers to characterise disease progression and enable patient stratification.