Cardiol J. 2022;29(2):364-365. doi: 10.5603/CJ.2022.0019.

NO ABSTRACT

PMID:35411934 | DOI:10.5603/CJ.2022.0019

Int Immunopharmacol. 2022 Apr 9;108:108704. doi: 10.1016/j.intimp.2022.108704. Online ahead of print.

ABSTRACT

BACKGROUND: Overexpression of human epididymis protein 4 (HE4) was previously described in idiopathic pulmonary fibrosis (IPF), but whether serum HE4 can be considered as a potential biomarker in connective tissue disease-associated interstitial lung disease (CTD-ILD) with usual interstitial pneumonia (UIP) pattern was still unknown.

METHOD: A total of 55 CTD-ILD patients with UIP pattern (UIP-CTD) and 52 healthy controls were enrolled in this study. The serum levels of HE4 and Krebs von den Lungen-6 (KL-6) were evaluated in both cohorts. In addition, immunohistochemistry analysis for HE4 was performed on the lung sections of 6 patients with rheumatoid arthritis-associated UIP (UIP-RA) and 6 patients with early-stage lung cancer as normal control.

RESULTS: The levels of serum HE4 and KL-6 were higher in patients with UIP-CTD than in healthy controls (292.3 pmol/L versus 79.5 pmol/L for HE4, p < 0.001; 1091.0 IU/mL versus 171.5 IU/mL for KL-6, p < 0.001). Significant correlations between serum HE4 levels and percentpredicted forced vital capacity (FVC%) (r = -0.425, p = 0.004), percent predicted diffusing capacity of the lung for carbon monoxide (DLCO%) (r = -0.447, p = 0.003), and Gender-Age-Physiology (GAP) index (r = 0.494, p < 0.001) were observed in UIP-CTD patients. In immunohistochemistry analysis, elevated expression of HE4 in bronchiolar epithelium and mesenchyme was observed in patients with UIP-RA compared with controls. The serum levels of HE4 (≥277.5 pmol/L) and GAP index were related to an increased risk of mortality (HR = 3.884, p = 0.034; HR = 1.480, p = 0.028, respectively).

CONCLUSION: The expression of HE4 in serum and lung specimens was significantly elevated in UIP-CTD patients. Moreover, serum HE4 may be utilized as a biomarker to evaluate the severity of disease and predict the prognosis of UIP-CTD patients.

PMID:35413677 | DOI:10.1016/j.intimp.2022.108704

Am J Respir Crit Care Med. 2022 Apr 12. doi: 10.1164/rccm.202112-2765LE. Online ahead of print.

NO ABSTRACT

PMID:35412453 | DOI:10.1164/rccm.202112-2765LE

BMJ Open Respir Res. 2022 Apr;9(1):e001194. doi: 10.1136/bmjresp-2021-001194.

ABSTRACT

INTRODUCTION: Lung cancer is a major challenge facing modern medicine. It is the leading cause of cancer-related death in the USA. Little is known of the incidence, prevalence and disease characteristics in lung transplant recipients, a population unique in its vulnerability and exposure to carcinogenic risk factors. We aimed to elaborate these characteristics of lung cancer in our population through a retrospective cohort study.

METHODS: We retrospectively reviewed our institution's 8-year experience with lung transplantation and searched for patients with a post-transplant diagnosis of lung cancer, neoplasia or mass. We focused on patient demographics, indication for transplant, smoking history, stage at diagnosis, location of the tumour, length of time between transplant and diagnosis, the treatment offered and length of time from diagnosis to death or last follow-up. Descriptive statistics and survival analysis standard Kaplan-Meier method was conducted from the date of cancer diagnosis to death from all-cause mortality or last follow-up as of August 2021.

RESULTS: We identified 24 patients with de novo lung cancer postlung transplant in 905 recipients. More patients with an underlying diagnosis of idiopathic pulmonary fibrosis developed lung cancer. Twenty-one patients were diagnosed with non-small cell lung cancer and three had small cell lung cancer. The remaining native lung was involved most in single lung recipients with 17 patients. Patients with a diagnosis of lung cancer had a mean survival of 17.6 months after diagnosis.

DISCUSSION: The incidence rate of lung cancer in our cohort was higher than reported for smokers from the general population in previous studies. In this study, we compare our findings with available literature. We also explore screening strategies, treatment modalities, survival and postulated mechanisms for the development of lung cancer in lung transplant recipients.

PMID:35410891 | DOI:10.1136/bmjresp-2021-001194

Respir Res. 2022 Apr 11;23(1):89. doi: 10.1186/s12931-022-02006-9.

ABSTRACT

BACKGROUND: Patients suffering from combined obstructive and interstitial lung disease (O-ILD) represent a pathological entity which still has to be well clinically described. The aim of this descriptive and explorative study was to describe the phenotype and functional characteristics of a cohort of patients suffering from functional obstruction in a population of ILD patients in order to raise the need of dedicated prospective observational studies and the evaluation of the impact of anti-fibrotic therapies.

METHODS: The current authors conducted a retrospective study including 557 ILD patients, with either obstructive (O-ILD, n = 82) or non-obstructive (non O-ILD, n = 475) pattern. Patients included were mainly males (54%) with a mean age of 62 years.

RESULTS: Patients with O-ILD exhibited a characteristic functional profile with reduced percent predicted forced expired volume in 1 s (FEV1) [65% (53-77) vs 83% (71-96), p < 0.00001], small airway involvement assessed by maximum expiratory flow (MEF) 25/75 [29% (20-41) vs 81% (64-108), p < 0.00001], reduced sGaw [60% (42-75) vs 87% (59-119), p < 0.01] and sub-normal functional residual capacity (FRC) [113% (93-134) vs 92% (75-109), p < 0.00001] with no impaired of carbon monoxide diffusing capacity of the lung (DLCO) compared to those without obstruction. Total lung capacity (TLC) was increased in O-ILD patients [93% (82-107) vs 79% (69-91), p < 0.00001]. Of interest, DLCO sharply dropped in O-ILD patients over a 5-year follow-up. We did not identify a significant increase in mortality in patients with O-ILD. Interestingly, the global mortality was increased in the specific sub-group of patients with O-ILD and no progressive fibrosing ILD phenotype and in those with connective tissue disease associated ILD especially in case of rheumatoid arthritis.

CONCLUSIONS: The authors individualized a specific functional-based pattern of ILD patients with obstructive lung disease, who are at risk of increased mortality and rapid DLCO decline over time. As classically those patients are excluded from clinical trials, a dedicated prospective study would be of interest in order to define more precisely treatment response of those patients.

PMID:35410260 | DOI:10.1186/s12931-022-02006-9

Respir Res. 2022 Apr 11;23(1):91. doi: 10.1186/s12931-022-02001-0.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high morbidity and limited treatment options. Type 2 diabetes mellitus (T2DM) is a common comorbid illness among patients with IPF and is often treated with metformin, the first-line agent in the management of T2DM. There is growing evidence demonstrating metformin's anti-fibrotic properties; however, there is little real-world clinical data regarding its potential effectiveness in IPF. This study aims to evaluate the clinical benefit of metformin in patients with IPF and T2DM.

METHODS: This nationwide cohort study used de-identified administrative claims data from OptumLabs® Data Warehouse to identify 3599 adults with IPF and concomitant T2DM between January 1, 2014 and June 30, 2019. Two cohorts were created: a cohort treated with metformin (n = 1377) and a cohort not treated with metformin (n = 2222). A final 1:1 propensity score-matched cohort compared 1100 patients with IPF and T2DM receiving metformin to those with both diagnoses but not receiving metformin; matching accounted for age, sex, race/ethnicity, residence region, year, medications, oxygen use, smoking status, healthcare use, and comorbidities. Outcomes were all-cause mortality (primary) and hospitalizations (secondary).

RESULTS: Among 2200 patients with IPF and T2DM included in this matched analysis, metformin therapy was associated with a reduction in all-cause mortality (hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.36-0.58; p < 0.001) and hospitalizations (HR, 0.82; 95% CI, 0.72-0.93; p = 0.003) compared to patients not receiving metformin.

CONCLUSIONS: Among patients with IPF and T2DM, metformin therapy may be associated with improved clinical outcomes. However, further investigation with randomized clinical trials is necessary prior to metformin's broad implementation in the clinical management of IPF.

PMID:35410255 | DOI:10.1186/s12931-022-02001-0

J Clin Med. 2022 Apr 6;11(7):2065. doi: 10.3390/jcm11072065.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) and sarcoidosis are two distinct clinical entities with different aetiology, epidemiology, risk factors, symptoms and chest imaging. A number of papers have reported an overlap of the two diseases and have suggested the existence of a distinct phenotype defined as combined sarcoidosis and idiopathic pulmonary fibrosis (CSIPF). We used the scoping review protocol to review the literature on CSIPF. We also enrolled a cohort of nine CSIPF patients and compared them with lone-IPF and fibrotic sarcoidosis patients. Our CSIPF cohort showed male prevalence and only ex-smokers. Functional assessment at baseline showed mild to moderate restrictive impairment of lung volumes in lone-IPF and CSIPF patients, associated with moderate-to-severe reduction in DLco percentages. Although all CSIPF patients were on antifibrotic treatments, functional impairment occurred in the two years of follow up. This suggests the importance of considering these patients at high risk of rapid deterioration and lung damage.

PMID:35407673 | DOI:10.3390/jcm11072065

Cells. 2022 Apr 3;11(7):1209. doi: 10.3390/cells11071209.

ABSTRACT

Lipids are major actors and regulators of physiological processes within the lung. Initial research has described their critical role in tissue homeostasis and in orchestrating cellular communication to allow respiration. Over the past decades, a growing body of research has also emphasized how lipids and their metabolism may be altered, contributing to the development and progression of chronic lung diseases such as pulmonary fibrosis. In this review, we first describe the current working model of the mechanisms of lung fibrogenesis before introducing lipids and their cellular metabolism. We then summarize the evidence of altered lipid homeostasis during pulmonary fibrosis, focusing on their extracellular forms. Finally, we highlight how lipid targeting may open avenues to develop therapeutic options for patients with lung fibrosis.

PMID:35406772 | DOI:10.3390/cells11071209

Cells. 2022 Mar 25;11(7):1112. doi: 10.3390/cells11071112.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive lung disease. Lesions in the lung epithelium cause alterations in the microenvironment that promote fibroblast accumulation. Extracellular vesicles (EVs) transport proteins, lipids, and nucleic acids, such as microRNAs (miRNAs). The aim of this study was to characterize the differentially expressed miRNAs in the cargo of EVs obtained from the LL97 and LL29 fibroblast cell lines isolated from IPF lungs versus those derived from the CCD19 fibroblast cell line isolated from a healthy donors. We characterized EVs by ultracentrifugation, Western blotting, and dynamic light scattering. We identified miRNAs by small RNA-seq, a total of 1144 miRNAs, of which 1027 were known miRNAs; interestingly, 117 miRNAs were novel. Differential expression analysis showed that 77 miRNAs were upregulated and 68 were downregulated. In addition, pathway enrichment analyses from the Gene Ontology and Kyoto Encyclopedia of Genomes identified several miRNA target genes in the categories, cell proliferation, regulation of apoptosis, pathways in cancer, and proteoglycans in cancer. Our data reveal that miRNAs contained in EVs cargo could be helpful as biomarkers for fibrogenesis, diagnosis, and therapeutic intervention of IPF.

PMID:35406675 | DOI:10.3390/cells11071112

Ther Adv Respir Dis. 2022 Jan-Dec;16:17534666221089468. doi: 10.1177/17534666221089468.

ABSTRACT

AIM: Several studies have reported favorable outcomes of nonspecific interstitial pneumonia (NSIP); however, its prognosis and prognostic factors remain unclear. This study aimed to determine the outcomes of fibrotic NSIP and the prognostic factors for progression, relapse, and survival.

METHODS: In this retrospective study, we reviewed the clinical data of 204 patients diagnosed with fibrotic NSIP by surgical lung biopsy at Samsung Medical Center. The factors associated with survival and disease progression or relapse were determined using Cox proportional hazard analysis.

RESULTS: The median age of patients was 54 years and 67 (33%) patients were male. Also, 47 patients (23%) were current or ex-smokers. In all, 141 (69%) patients were diagnosed with idiopathic NSIP, while 63 (31%) patients were associated with connective tissue diseases. Progression or relapse was observed in 100 (49%) patients. The 5-year and 10-year survival rates were 94.6% and 90.4%, respectively. The factors associated with disease progression and relapse were diffusing capacity for carbon monoxide (DLco) <60% [adjusted hazard ratio (HR), 1.739; 95% confidence interval (CI), 1.036-2.921; p = 0.036], bronchoalveolar lavage (BAL) lymphocyte >15% (adjusted HR, 0.592; 95% CI, 0.352-0.994; p = 0.047), and treatment with corticosteroid and azathioprine (adjusted HR, 0.556; 95% CI, 0.311-0.955; p = 0.048). Disease progression or relapse was associated with mortality (adjusted HR, 7.135; 95% CI, 1.499-33.971; p = 0.014).

CONCLUSION: Preserved lung function, BAL lymphocytosis, and treatment with corticosteroids and azathioprine were associated with lower risks of disease progression and relapse, which were risk factors for mortality.

PMID:35400267 | DOI:10.1177/17534666221089468

Chest. 2022 Apr 8:S0012-3692(22)00590-6. doi: 10.1016/j.chest.2022.03.044. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive, often fatal form of interstitial lung disease (ILD) characterized by the absence of a known cause and usual interstitial pneumonitis (UIP) pattern on chest CT and/or histopathology. Distinguishing UIP/IPF from other ILD subtypes is essential given different treatment and prognosis. Lung biopsy is necessary when noninvasive data are insufficient to render a confident diagnosis.

RESEARCH QUESTION: Can we improve noninvasive diagnosis of UIP by predicting ILD histopathology from CT scans using deep learning?

STUDY DESIGN AND METHODS: We retrospectively identified a cohort of 1239 patients in a multicenter database with pathologically proven interstitial lung disease who had chest CT imaging. Each case was assigned a label based on histopathologic diagnosis (UIP or non-UIP). A custom deep learning model was trained to predict class labels from CT images (training set n=894) and was evaluated on a 198-patient test set. Separately, two subspecialty-trained radiologists manually labeled each CT in the test set according to the 2018 American Thoracic Society IPF guidelines. The performance of the model in predicting histopathologic class was compared against radiologists using area under the receiver operating characteristic curve (AUC) as the primary metric. Deep learning model reproducibility was compared against intra-rater and inter-rater radiologist reproducibility.

RESULTS: Mean patient age was 62 ± 12 years and 605 patients were female (49%) for the whole cohort. Deep learning performance was superior to visual analysis in predicting histopathologic diagnosis (AUC 0.87 versus 0.80, respectively; p < 0.05). Deep learning model reproducibility was significantly greater than radiologist inter-rater and intra-rater reproducibility (95% CI for difference in Krippendorff's alpha did not include zero) INTERPRETATION: Deep learning may be superior to visual assessment in predicting UIP/IPF histopathology from CT and may serve as an alternative to invasive lung biopsy.

PMID:35405110 | DOI:10.1016/j.chest.2022.03.044

Chest. 2022 Apr 8:S0012-3692(22)00589-X. doi: 10.1016/j.chest.2022.04.001. Online ahead of print.

NO ABSTRACT

PMID:35405109 | DOI:10.1016/j.chest.2022.04.001

J Clin Biochem Nutr. 2022 Mar;70(2):129-139. doi: 10.3164/jcbn.21-7. Epub 2021 Oct 1.

ABSTRACT

Idiopathic pulmonary fibrosis, a chronic and progressive lung disease with poor prognosis, presents with acute exacerbation. Pathophysiology and treatments for this acute exacerbation, and an appropriate animal model to perform such examinations, have not established yet. We presented a rat model for assessing acute exacerbation in cases of idiopathic pulmonary fibrosis. Wistar rats were intratracheally administered bleomycin (3 mg/kg) to induce pulmonary fibrosis. After 7 days, lipopolysaccharide (0, 0.05, or 0.15 mg/kg) was administered. In the bleomycin or lipopolysaccharide group, there were almost no change in the oxygen partial pressure, arterial blood gas (PaO2), plasma nitrite/nitrate, nitric oxide synthase, and lung nitrotyrosine levels. In the bleomycin (+)/lipopolysaccharide (+) groups, these three indicators deteriorated significantly. The plasma nitrite/nitrate and PaO2 levels were significantly correlated in the bleomycin (+) groups (r = 0.758). Although lung fibrosis was not different with or without lipopolysaccharide in the bleomycin (+) groups, macrophage infiltration was marked in the bleomycin (+)/lipopolysaccharide (+) group. There were many NOS2-positive macrophages, and the PaO2 levels decrease may be induced by the nitric oxide production of macrophages in the lung. This model may mimic the pathophysiological changes in cases of acute exacerbation during idiopathic pulmonary fibrosis in humans.

PMID:35400816 | PMC:PMC8921716 | DOI:10.3164/jcbn.21-7

Transl Lung Cancer Res. 2022 Mar;11(3):472-496. doi: 10.21037/tlcr-21-880.

ABSTRACT

BACKGROUND AND OBJECTIVE: Translational research is a source of continuous innovation in medicine, more particularly for clinical research on new treatment modalities in idiopathic pulmonary fibrosis (IPF) patients. However, the heterogeneity of the disease is well recognized, and different pathological and molecular settings have been identified. The molecular mechanisms by which IPF proceeds in time and space remains poorly understood. Although some IPF features are reminiscent of cancer, the dynamics of malignant divergent clonal selective pressure and heterogeneity clearly differ from those occurring in IPF. This is reflected in the absence of patient proper selection and stratification to biological agents (pirfenidone, nintedanib) which limit therapeutic efficacy. Consequently, increased costs are related to the clinical management of advanced IPF patients. Steady collaboration and fluid communication between pneumo-oncologists, radiologists and molecular biologists is a clear priority for the correct interpretation of tests and the definition of effective personalized strategies against this orphan disease. The present work aims at providing the most relevant hints shared by cancer and IPF.

METHODS: A systematic literature review was performed to identify all relevant data. The examined databases were Scopus, Web of Science, Cochrane, Google Scholar, and PubMed. The last search was run on January 5, 2022. We have primarily conducted separated research for lung cancer, IPF, genetics, epigenetics, surgery in IPF and cancer.

KEY CONTENT AND FINDINGS: The data here presented mainly focus on gene mutations, epigenetics and novel therapeutic approaches. Moreover, epidemiology, prognostic variables and in new treatment strategies adopted in patients with IPF and lung cancer are discussed as well.

CONCLUSIONS: Overall, the findings of this narrative review will be of help in defining the key molecular features that could applied in IPF setting with promising rationale to improve therapy and to better manage those cases carrying IPF and cancer concomitantly.

PMID:35399571 | PMC:PMC8988078 | DOI:10.21037/tlcr-21-880

Respir Investig. 2022 Apr 6:S2212-5345(22)00025-9. doi: 10.1016/j.resinv.2022.03.001. Online ahead of print.

ABSTRACT

BACKGROUND: The antifibrotic agent nintedanib has been reported to effectively prevent the decline in forced vital capacity (FVC) in a broad range of interstitial lung diseases. However, the efficacy of nintedanib against idiopathic pleuroparenchymal fibroelastosis (iPPFE) remains unclear.

METHODS: We retrospectively examined patients with idiopathic PPFE or idiopathic pulmonary fibrosis (IPF) who received nintedanib for more than 6 months. We evaluated annual changes in %FVC, radiological PPFE lesions, and body weight before and during nintedanib treatment. To investigate radiological PPFE lesions, we examined the fibrosis score, which was defined as the mean percentage of the high attenuation area in the whole lung parenchyma using three axial computed tomography images.

RESULTS: Overall, 15 patients with iPPFE and 27 patients with IPF were included in the present study. In patients with IPF, the annual rate of decline in %FVC was significantly lower during nintedanib treatment than that before treatment (-2.01%/year [-7.64 to 3.21] versus -7.64%/year [-10.8 to -4.44], p = 0.031). Meanwhile, in patients with iPPFE, the annual rate of decline in %FVC during nintedanib treatment was higher than that before treatment (-18.0%/year [-21.6 to -12.7] versus -9.40%/year [-12.3 to -8.23], p = 0.109). In addition, nintedanib treatment failed to inhibit the annual rate of increase in fibrosis score in patients with iPPFE (6.53/year [1.18-15.3] during treatment versus 2.70/year [0.27-12.2] before treatment, p = 0.175).

CONCLUSIONS: Nintedanib efficacy may be limited in patients with iPPFE.

PMID:35398003 | DOI:10.1016/j.resinv.2022.03.001

Int Immunopharmacol. 2022 Apr 6;108:108728. doi: 10.1016/j.intimp.2022.108728. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis is a chronic progressive disease associated with substantial morbidity and mortality despite advances in medical therapy. Increasing evidence suggests that peroxisome proliferator-activated receptors (PPARs) play important roles in the fibrosis-related diseases and their agonists may become effective therapeutic targets. Pemafibrate is a selective PPARα agonist, but the efficacy against pulmonary fibrosis and mechanisms involved have not been systematically evaluated. Thus, the aims of this study were to explore the role of PPARα in the pulmonary fibrosis and to assess the effect of pemafibrate in vivo and in vitro.

METHODS: The effects of pemafibrate were evaluated in bleomycin-challenged murine pulmonary fibrosis model and transforming growth factor-beta 1 (TGF-β1) stimulated lung fibroblasts.

RESULTS: Bleomycin instillation induced body weight loss, declined lung function, pulmonary fibrosis, and extensive collagen deposition in the mice, accompanied with decreased pulmonary expression of PPARα, all of which were partially improved by pemafibrate at a dose of 2 mg/kg. Besides, pemafibrate effectively inhibits TGF-β1-induced myofibroblast differentiation and extracellular matrix (ECM) production in vivo and in vitro. Furthermore, we showed that pemafibrate not only inhibited pulmonary expression of NLRP3 and cleaved caspase-1 in bleomycin-inhaled mice, but also repressed activation of NLRP3/caspase-1 axis in TGF-β1 stimulated lung fibroblasts.

CONCLUSION: Our data suggest that pemafibrate exerts a marked protection against from the development of pulmonary fibrosis, which could constitute a novel candidate for the treatment for pulmonary fibrosis.

PMID:35397395 | DOI:10.1016/j.intimp.2022.108728

Phytochem Anal. 2022 Apr 9. doi: 10.1002/pca.3120. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a serious lung disease with a high mortality rate. Baoyuan decoction (BYD), a classic medicinal food homology recipe, has anti-apoptotic effects, enhances immune function, and alleviates fibrosis, suggesting that it may be a potential therapeutic drug for IPF.

OBJECTIVES: We aimed to identify the main active ingredients of BYD, determine the basis of its efficacy, prove its anti-IPF effects, and explore the mechanisms underlying its anti-IPF effects.

MATERIALS AND METHODS: In this study, the active components of BYD were detected and analysed by ultra-high-performance liquid chromatography coupled with hybrid quadrupole Orbitrap mass spectrometry (UHPLC-Q-Exactive Orbitrap-MS). A network pharmacology analysis was performed to determine the potential targets and relevant pathways of BYD in treating IPF. Western blotting and quantitative real-time polymerase chain reaction (qPCR) were conducted to verify the efficacy of BYD against IPF. Finally, molecular docking and qPCR were performed to identify the central targets of BYD.

RESULTS: A total of 39 components of BYD were identified. After performing the network pharmacology analysis, 35 active components and eight presumptive targets of BYD were found to play a central role in its anti-IPF effects. The molecular docking results indicated that most of the active components of BYD exhibited good binding activity with these eight central target proteins. In addition, the expression of collagen, α-SMA, and these eight targets in human pulmonary fibroblast (HPF) cells was suppressed from treatment with BYD.

CONCLUSION: This study determined the efficacy of BYD against IPF and clarified its multiple-target and multiple-pathway mechanisms. Furthermore, the study also provides a new method for exploring the chemical and pharmacological bases of other traditional Chinese medicine (TCM).

PMID:35396886 | DOI:10.1002/pca.3120

BMJ Open Respir Res. 2022 Apr;9(1):e001163. doi: 10.1136/bmjresp-2021-001163.

ABSTRACT

BACKGROUND: Markers of idiopathic pulmonary fibrosis (IPF) severity are based on measurements of forced vital capacity (FVC), diffusing capacity (DLCO) and CT. The pulmonary vessel volume (PVV) is a novel quantitative and independent prognostic structural indicator derived from automated CT analysis. The current prospective cross-sectional study investigated whether respiratory oscillometry provides complementary data to pulmonary function tests (PFTs) and is correlated with PVV.

METHODS: From September 2019 to March 2020, we enrolled 89 patients with IPF diagnosed according to international guidelines. We performed standard spectral (5-37 Hz) and novel intrabreath tracking (10 Hz) oscillometry followed by PFTs. Patients were characterised with the gender-age-physiology (GAP) score. CT images within 6 months of oscillometry were analysed in a subgroup (26 patients) using automated lung texture analysis. Correlations between PFTs, oscillometry and imaging variables were investigated using different regression models.

FINDINGS: The cohort (29F/60M; age=71.7±7.8 years) had mild IPF (%FVC=70±17, %DLCO=62±17). Spectral oscillometry revealed normal respiratory resistance, low reactance, especially during inspiration at 5 Hz (X5in), elevated reactance area and resonance frequency. Intrabreath oscillometry identified markedly low reactance at end-inspiration (XeI). XeI and X5in strongly correlated with FVC (r2=0.499 and 0.435) while XeI was highly (p=0.004) and uniquely correlated with the GAP score. XeI and PVV exhibited the strongest structural-functional relationship (r2=0.690), which remained significant after adjusting for %FVC, %DLCO and GAP score.

INTERPRETATION: XeI is an independent marker of IPF severity that offers additional information to standard PFTs. The data provide a cogent rationale for adding oscillometry in IPF assessment.

PMID:35396320 | DOI:10.1136/bmjresp-2021-001163

Biosens Bioelectron. 2022 Mar 22;208:114203. doi: 10.1016/j.bios.2022.114203. Online ahead of print.

ABSTRACT

A conducting molecularly imprinted polymer (MIP) film was integrated with an extended-gate field-effect transistor (EG-FET) transducer to determine epitopes of matrix metalloproteinase-1 (MMP-1) protein biomarker of idiopathic pulmonary fibrosis (IPF) selectively. Most suitable epitopes for imprinting were selected with Basic Local Alignment Search Tool software. From a pool of MMP-1 epitopes, the two, i.e., MIAHDFPGIGHK and HGYPKDIYSS, the relatively short ones, most promising for MMP-1 determination, were selected, mainly considering their advantageous outermost location in the protein molecule and stability against aggregation. MIPs templated with selected epitopes of the MMP-1 protein were successfully prepared by potentiodynamic electropolymerization and simultaneously deposited as thin films on electrodes. The chemosensors, constructed of MIP films integrated with EG-FET, proved useful in determining these epitopes even in a medium as complex as a control serum. The limit of detection for the MIAHDFPGIGHK and HGYPKDIYSS epitope was ∼60 and 20 nM, respectively. Moreover, the chemosensors selectively recognized whole MMP-1 protein in the 50-500 nM concentration range in buffered control serum samples.

PMID:35395618 | DOI:10.1016/j.bios.2022.114203

Respir Res. 2022 Apr 7;23(1):85. doi: 10.1186/s12931-022-01974-2.

ABSTRACT

BACKGROUND: In the INBUILD trial in patients with progressive fibrosing interstitial lung diseases (ILDs), nintedanib reduced the rate of decline in forced vital capacity compared with placebo, with side-effects that were manageable for most patients. We used data from the INBUILD trial to characterize further the safety and tolerability of nintedanib.

METHODS: Patients with fibrosing ILDs other than idiopathic pulmonary fibrosis (IPF), who had experienced progression of ILD within the 24 months before screening despite management deemed appropriate in clinical practice, were randomized to receive nintedanib 150 mg twice daily or placebo. To manage adverse events, treatment could be interrupted or the dose reduced to 100 mg twice daily. We assessed adverse events and dose adjustments over the whole trial.

RESULTS: A total of 332 patients received nintedanib and 331 received placebo. Median exposure to trial drug was 17.4 months in both treatment groups. Adverse events led to treatment discontinuation in 22.0% of patients treated with nintedanib and 14.5% of patients who received placebo. The most frequent adverse event was diarrhea, reported in 72.3% of patients in the nintedanib group and 25.7% of patients in the placebo group. Diarrhea led to treatment discontinuation in 6.3% of patients in the nintedanib group and 0.3% of the placebo group. In the nintedanib and placebo groups, respectively, 48.2% and 15.7% of patients had ≥ 1 dose reduction and/or treatment interruption. Serious adverse events were reported in 44.3% of patients in the nintedanib group and 49.5% of patients in the placebo group. The adverse event profile of nintedanib was generally consistent across subgroups based on age, sex, race and weight, but nausea, vomiting and dose reductions were more common among female than male patients.

CONCLUSIONS: The adverse event profile of nintedanib in patients with progressive fibrosing ILDs other than IPF is consistent with its established safety and tolerability profile in patients with IPF and characterized mainly by gastrointestinal events, particularly diarrhea. Management of adverse events using symptomatic therapies and dose adjustment is important to minimize the impact of adverse events and help patients remain on therapy. Trial registration Registered 21 December 2016, https://clinicaltrials.gov/ct2/show/NCT02999178 A video abstract summarizing the key results presented in this manuscript is available at: https://www.globalmedcomms.com/respiratory/cottin/INBUILDsafety .

PMID:35392908 | DOI:10.1186/s12931-022-01974-2