Radiology. 2021 Jul 27:204149. doi: 10.1148/radiol.2021204149. Online ahead of print.

ABSTRACT

Background Recent studies demonstrate that antifibrotic drugs previously reserved for idiopathic pulmonary fibrosis (IPF) may slow progression in other interstitial lung diseases (ILDs), creating an urgent need for tools that can sensitively assess disease activity, progression, and therapy response across ILDs. Hyperpolarized xenon 129 (129Xe) MRI and spectroscopy have provided noninvasive measurements of regional gas-exchange abnormalities in IPF. Purpose To assess gas exchange function using 129Xe MRI in a group of study participants with nonspecific interstitial pneumonia (NSIP) compared with healthy control participants. Materials and Methods In this prospective study, participants with NSIP and healthy control participants were enrolled between November 2017 and February 2020 and underwent 129Xe MRI and spectroscopy. Quantitative imaging provided three-dimensional maps of ventilation, interstitial barrier uptake, and transfer into the red blood cell (RBC) compartment. Spectroscopy provided parameters of the static RBC and barrier uptake compartments, as well as cardiogenic oscillations in RBC signal amplitude and chemical shift. Differences between NSIP and healthy control participants were assessed using the Wilcoxon rank-sum test. Results Thirty-six participants with NSIP (mean age, 57 years ± 11 [standard deviation]; 27 women) and 15 healthy control participants (mean age, 39 years ± 18; two women) were evaluated. Participants with NSIP had no difference in ventilation compared with healthy control participants (median, 4.4% [first quartile, 1.5%; third quartile, 8.7%] vs 6.0% [first quartile, 2.8%; third quartile, 6.9%]; P = .91), but they had a higher barrier uptake (median, 6.2% [first quartile, 1.8%; third quartile, 23.9%] vs 0.53% [first quartile, 0.33%; third quartile, 2.9%]; P = .003) and an increased RBC transfer defect (median, 20.6% [first quartile, 11.6%; third quartile, 27.8%] vs 2.8% [first quartile, 2.3%; third quartile, 4.9%]; P < .001). NSIP participants also had a reduced ratio of RBC-to-barrier peaks (median, 0.24 [first quartile, 0.19; third quartile, 0.31] vs 0.57 [first quartile, 0.52; third quartile, 0.67]; P < .001) and a reduced RBC chemical shift (median, 217.5 ppm [first quartile, 217.0 ppm; third quartile, 218.0 ppm] vs 218.2 ppm [first quartile, 217.9 ppm; third quartile, 218.6 ppm]; P = .001). Conclusion Participants with nonspecific interstitial pneumonia had increased barrier uptake and decreased red blood cell (RBC) transfer compared with healthy controls measured using xenon 129 gas-exchange MRI and reduced RBC-to-barrier ratio and RBC chemical shift measured using spectroscopy. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Wild in this issue.

PMID:34313473 | DOI:10.1148/radiol.2021204149

Sci Rep. 2021 Jul 26;11(1):15145. doi: 10.1038/s41598-021-94655-x.

ABSTRACT

Most epidemiologic studies of patients with idiopathic pulmonary fibrosis (IPF) have been conducted in North America and Europe. Moreover, there are limited data concerning the cause of death and cause-specific mortality rate of IPF patients in population-based studies. We analyzed information from the Korean National Health Insurance Service database from 2006 to 2016. Patients with a diagnosis code of IPF were extracted from the database and we included those who satisfied the narrow definition of IPF diagnosis. Age- and sex-matched controls were randomly selected at a case-to-control rate of 1:3. We included 42,777 patients newly diagnosed with IPF during the study period. Their mean age was 64.6 years, and 65.4% were male. The age-standardized mortality rates were 85.66 (95% confidence interval [CI] 84.45-86.89) per 1000 person-years. The survival rates of IPF patients 1, 2, 3, 5, and 10 years after IPF diagnosis were 84.5%, 77.4%, 71.9%, 62.9%, and 48.4%, respectively. The standardized mortality ratio of IPF patients compared to that of the normal population was 4.66. The leading cause of death in IPF patients was respiratory causes, followed by cancer. Patients with IPF in Korea showed significantly higher mortality compared to the general population.

PMID:34312485 | DOI:10.1038/s41598-021-94655-x

Respir Investig. 2021 Jul 23:S2212-5345(21)00118-0. doi: 10.1016/j.resinv.2021.06.009. Online ahead of print.

ABSTRACT

Idiopathic pulmonary hemosiderosis (IPH) is a rare immunological disease with a genetic predisposition. It is characterized by recurrent episodes of diffuse alveolar hemorrhage (DAH). Timely use of immunosuppressive medications has significantly improved overall outcomes, including mortality. Still, uncontrolled and frequent episodes of DAH can eventually cause pulmonary fibrosis, leading to end-stage lung disease (ESLD). The objective of the present project was to scrutinize the literature and summarize the demographic, clinical, radiological, and histopathological features, as well as the overall outcomes, in this patient population following lung transplant. The Medline database was searched using the PubMed platform. Articles published in English between 1960 and 2020 were included in the search. Different search terms were used to identify all patients who underwent lung transplantation to manage ESLD due to IPH. Only four cases of lung transplantation have been reported in the literature in patients with IPH. All but one of these underwent deceased donor lung transplant; recurrence was reported in two of these patients and suspected in the third. One patient received living donor lung transplant and had no recurrence during a five-year follow-up. Patients with IPH should not be excluded from lung transplantation because the disease may not recur in all patients, and even when it does recur it can be promptly treated by increasing immunosuppression.

PMID:34312096 | DOI:10.1016/j.resinv.2021.06.009

Evid Based Complement Alternat Med. 2021 Jul 7;2021:8634705. doi: 10.1155/2021/8634705. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic respiratory disease with high incidence, morbidity, and mortality rates. Jinshui Huanxian formula (JHF) is an empirical formula that targets the pathogenesis of lung-kidney qi deficiency and phlegm-blood stasis in pulmonary fibrosis (PF). The purpose of this study was to explore JHF's potential pharmacological mechanisms in IPF therapy using network intersection analysis. JHF's primary active components and corresponding target genes were predicted using various databases. Two sets of IPF disease genes were obtained from the DisGeNET and GEO databases and two sets of IPF drug targets were collected. The disease and drug target genes were analyzed. The JHF target genes that intersected with IPF's differentially expressed genes were identified to predict JHF's targets of action in IPF. The functions and pathways of predicted targets acting on IPF were analyzed using the DAVID and KEGG pathway databases. Finally, the resulting drug target mechanisms were validated in a rat model of PF. The initial analyses identified 494 active compounds and 1,304 corresponding targets for JHF. The intersection analysis revealed four common genes for the JHF targets, IPF disease, and anti-IPF drugs in the KEGG database. Furthermore, these genes were targeted by several JHF compounds. Seventy-two JHF targets were closely related to IPF, which suggests that they are therapeutically relevant. Target screening revealed that they regulate IPF through 18 pathways. The targets' molecular functions included regulation of oxidoreductase activity, kinase regulator activity, phosphotransferase activity, and transmembrane receptor protein kinase activity. In vivo experiments showed that JHF alleviated the degree of PF, including decreases in collagen deposition and epithelial-mesenchymal transition. This study systematically explored JHF's mechanisms to identify the specific target pathways involved in IPF. The generated pharmacological network, paired with in vivo validation, elucidates the potential roles and mechanisms of JHF in IPF therapy.

PMID:34306156 | PMC:PMC8279870 | DOI:10.1155/2021/8634705

J Clin Endocrinol Metab. 2021 Jul 24:dgab553. doi: 10.1210/clinem/dgab553. Online ahead of print.

ABSTRACT

CONTEXT: Diabetes mellitus (DM) is a systemic disease characterized by chronic hyperglycemia associated with inflammation and oxidative stress, and the lung may be a target organ of diabetic microvascular damage. Several studies have indicated a positive association between idiopathic pulmonary fibrosis (IPF) and diabetes with controversial findings.

OBJECTIVE: Primary outcomes were to compare the prevalence of DM among individuals with IPF to non-IPF controls, and the prevalence of IPF among individuals with DM to non-DM controls.

DATA SOURCES: PubMed, EMBASE and the Cochrane Library.

STUDY SELECTION: Studies contained sufficient data to calculate the prevalence of DM among individuals with and without IPF, or the prevalence of IPF among individuals with and without DM.

DATA EXTRACTION: Two investigators independently identified eligible studies and extracted data. Pooled odds ratio (OR) with 95% CIs was the summary effect measure.

DATA SYNTHESIS: Eighteen studies including 26,410,623 individuals met eligibility criteria, of which 16 recruited people with IPF and 2 recruited people with DM. The OR of DM in IPF subjects was 1.54 (95% CI: 1.30-1.84; P<0.001) compared to that in non-IPF controls. However, compared with that in non-DM patients, the risk of IPF in DM patients was not found to be significantly reduced (OR: 0.89, 95% CI: 0.64-1.25; P=0.497).

CONCLUSION: This meta-analysis suggests that people with IPF have 1.54 times increased odds of diabetes compared to non-IPF controls, while whether patients with DM have an increased risk of IPF is still controversial. Further large, prospective cohort studies investigating the prevalence of IPF in diabetic patients are warranted.

PMID:34302736 | DOI:10.1210/clinem/dgab553

J Clin Med. 2021 Jul 18;10(14):3167. doi: 10.3390/jcm10143167.

ABSTRACT

INTRODUCTION: The goal of this study is to determine whether Advanced glycosylated end-products (AGE), Advanced oxidation protein products (AOPP) and Matrix metalloproteinase 7 (MMP7) could be used as differential biomarkers for idiopathic pulmonary fibrosis (IPF) and connective tissue disease-associated interstitial lung disease (CTD-ILD).

METHOD: Seventy-three patients were enrolled: 29 with IPF, 14 with CTD-ILD, and 30 healthy controls. The study included a single visit by participants. A blood sample was drawn and serum was analysed for AGE using spectrofluorimetry, AOPP by spectrophotometry, and MMP7 using sandwich-type enzyme-linked immunosorbent assay.

RESULTS: AGE, AOPP and MMP7 serum levels were significantly higher in both IPF and CTD-ILD patients versus healthy controls; and AGE was also significantly elevated in CTD-ILD compared to the IPF group. AGE plasma levels clearly distinguished CTD-ILD patients from healthy participants (AUC = 0.95; 95% IC 0.86-1), whereas in IPF patients, the distinction was moderate (AUC = 0.78; 95% IC 0.60-0.97).

CONCLUSION: In summary, our results provide support for the potential value of serum AGE, AOPP and MMP7 concentrations as diagnostic biomarkers in IPF and CTD-ILD to differentiate between ILD patients and healthy controls. Furthermore, this study provides evidence, for the first time, for the possible use of AGE as a differential diagnostic biomarker to distinguish between IPF and CTD-ILD. The value of these biomarkers as additional tools in a multidisciplinary approach to IPF and CTD-ILD diagnosis needs to be considered and further explored. Multicentre studies are necessary to understand the role of AGE in differential diagnosis.

PMID:34300333 | DOI:10.3390/jcm10143167

J Clin Med. 2021 Jul 16;10(14):3153. doi: 10.3390/jcm10143153.

ABSTRACT

Patients with fibrosing interstitial lung disease (FILD) have poor health-related quality of life (HRQOL). We analyzed predictors of short-term improvement of HRQOL after starting pulmonary rehabilitation (PR) in moderate to severe FILD patients. This study involved 28 consecutive patients with FILD (20 males, median age of 77.5 years), who participated in PR program of our hospital for >6 weeks. The St. George's Respiratory Questionnaire (SGRQ) score and the 6-min walk distance (6MWD) were evaluated before and after PR, and the predictors of efficacy of PR were analyzed. The duration from diagnosis of FILD to start of PR showed a positive correlation with the increase in the SGRQ score, and the baseline SGRQ score showed a negative correlation with increase in the 6MWD. The FILD subtype, modified Medical Research Council score, and treatment history were not associated with the endpoints. According to the receiver operating characteristic curve (ROC) analyses, starting PR within 514 days after diagnosis of FILD was a significant favorable predictor of improvement in the SGRQ total score more than a minimal clinically important difference of 4. In this study, early intervention of PR and lower SGRQ score were associated with the favorable response to PR. PR for FILD should be initiated early before the disease becomes severe.

PMID:34300319 | DOI:10.3390/jcm10143153

Int J Environ Res Public Health. 2021 Jul 6;18(14):7249. doi: 10.3390/ijerph18147249.

ABSTRACT

Mortality from idiopathic pulmonary fibrosis (IPF) is increasing in most European countries, but there are no data for Italy. We analysed the registry data from a region in northeastern Italy to assess the trends in IPF-related mortality during 2008-2019, to compare results of underlying vs. multiple cause of death analyses, and to describe the impact of the COVID-19 epidemic in 2020. We identified IPF (ICD-10 code J84.1) among the causes of death registered in 557,932 certificates in the Veneto region. We assessed time trends in annual age-standardized mortality rates by gender and age (40-74, 75-84, and ≥85 years). IPF was the underlying cause of 1310 deaths in the 2251 certificates mentioning IPF. For all age groups combined, the age-standardized mortality rate from IPF identified as the underlying cause of death was close to the European median (males and females: 3.1 and 1.3 per 100,000/year, respectively). During 2008-2019, mortality rates increased in men aged ≥85 years (annual percent change of 6.5%, 95% CI: 2.0, 11.2%), but not among women or for the younger age groups. A 72% excess of IPF-related deaths was registered in March-April 2020 (mortality ratio 1.72, 95% CI: 1.29, 2.24). IPF mortality was increasing among older men in northeastern Italy. The burden of IPF was heavier than assessed by routine statistics, since less than two out of three IPF-related deaths were directly attributed to this condition. COVID-19 was accompanied by a remarkable increase in IPF-related mortality.

PMID:34299699 | DOI:10.3390/ijerph18147249

Int J Environ Res Public Health. 2021 Jul 6;18(14):7237. doi: 10.3390/ijerph18147237.

ABSTRACT

Spectrophotometric techniques provide qualitative but not quantitative data on lung particles. We aimed to quantitate silica content in biopsies of lung-transplanted silicosis patients by applying X-ray fluorescence (XRF) spectrometry. Lung biopsies of 17 lung-transplanted artificial patients were quantitated for silica and other minerals particles by Niton XL3 XRF spectrometry. Occupational and clinical history data were assessed. Lung biopsies of artificial stone-induced silicosis (ASIS) patients contained significantly higher levels of silica compared to those of idiopathic pulmonary fibrosis (IPF) patients (7284.29 ± 4693.75 ppm vs. 898.88 ± 365.66 ppm, p < 0.0001). Silica content correlated negatively with age, body mass index, and pulmonary function test results. A 1128 ppm silica cut-off value yielded 100% sensitivity and 94% specificity for predicting ASIS (AUC = 0.94, p < 0.0001). In conclusion, XRF measurements in lung biopsies can differentiate between silica and mineral particles in ASIS and IPF.

PMID:34299685 | DOI:10.3390/ijerph18147237

Neuropeptides. 2021 Jul 7;89:102178. doi: 10.1016/j.npep.2021.102178. Online ahead of print.

ABSTRACT

INTRODUCTION: Fatigue, caused by dyspnea associated with progression of interstitial pneumonia (IP), can negatively affect patients' quality of life (QOL). Ninjin'yoeito (NYT), a Chinese herbal medicine, is prescribed for general symptoms of fatigue and for fatigue associated with various respiratory diseases. However, there is a lack of integrated research on the effects of NYT in patients with IP. Therefore, we retrospectively investigated the efficacy of NYT in patients with IP and fatigue.

MATERIALS AND METHODS: From the IP patients who had taken NYT, 19 who met the following inclusion criteria were included: (1) age of ≥20 years, (2) fatigue, and (3) history of NYT administration. The primary endpoint was fatigue, which was assessed using the Chalder Fatigue Scale (CFS). The secondary endpoints were loss of appetite and dyspnea, which were evaluated using the Simplified Nutritional Appetite Questionnaire (SNAQ) and modified Medical Research Council (mMRC) scores, respectively. All items were measured before and after 12 weeks of NYT administration.

RESULTS: In the enrolled 19 patients (male, 12; female, 7; mean age, 65.8 ± 12.7 years), the underlying diseases were idiopathic pulmonary fibrosis (n = 8), idiopathic pleuroparenchymal fibroelastosis (n = 5), connective tissue disease-related interstitial pneumonia (n = 2), chronic hypersensitivity pneumonitis (n = 3), and nonspecific interstitial pneumonia (n = 1). The CFS score decreased from 17.1 ± 6.8 before administration to 13.4 ± 5.7 after administration of NYT (p = 0.0389). The SNAQ score did not change markedly. The median mMRC score decreased from 3 to 2, however, the difference was not significant.

CONCLUSION: Many subtypes of IP are progressive, and a cure cannot be expected in cases of irreversible lung fibrosis. Therefore, a multifaceted approach to improve and maintain the QOL is needed in addition to the standard of care. This study showed that NYT can improve fatigue and help maintain the QOL in IP patients.

PMID:34298370 | DOI:10.1016/j.npep.2021.102178

Front Med (Lausanne). 2021 Jul 6;8:684040. doi: 10.3389/fmed.2021.684040. eCollection 2021.

ABSTRACT

Background: Mycoplasma hominis and Ureaplasma spp. are responsible for opportunistic infections in transplant patients, sometimes causing a life-threatening hyperammonemia syndrome. Both pathogens are not identified with standard microbiology techniques, resulting in missed or delayed diagnosis. We present a clinical case that illustrates the added value that next-generation sequencing (NGS) may offer in the diagnosis of respiratory infections in immune-compromised patients. Results: A 55 years-old man with idiopathic pulmonary fibrosis underwent double lung transplantation. He received antibiotic prophylaxis with piperacillin-tazobactam and azythromycin. At day 4 post-transplantation (PTx), the patient presented an acute respiratory distress. A broncho-alveolar lavage (BAL) was performed. At day 5 PTx, the patient presented a status epilepticus due to diffuse cerebral oedema. Serum ammonia concentration was 661 μg/dL. BAL bacterial culture was negative. Because of the clinical presentation, special cultures were performed and identified 100.000 CFU/mL of M. hominis and Ureaplasma spp. and specific PCRs were positive for M. hominis and Ureaplasma parvum. Antibiotic therapy was shifted to therapeutic dose of azithromycin and doxycycline; within 48 h ammonia serum concentrations returned to normal but the coma persisted several weeks, followed by a persistent frontal lobe syndrome. A follow-up BAL was performed on day 11 Ptx. The Mycoplasma/Ureaplasma culture was negative, yet the specific PCRs remained positive. Bacterial culture found 100 CFU/mL of Staphylococcus aureus and viral culture was positive for Herpes Simplex Virus-1. These results were confirmed by metagenomic next-generation sequencing (mNGS). In the bacterial fraction, the majority of reads belonged to Corynebacterium propinquum (34.7%), S. aureus (24.1%) and Staphylococcus epidermidis (17.1%). Reads assigned to M. hominis, Ureaplasma urealyticum and parvum represented 0.71, 0.13, and 0.04% of the bacterial fraction and corresponded to 6.9 × 103, 9.7 × 102, and 3.7 × 102 genome equivalents per mL of BAL fluid, respectively. These results are in favor of a cure of the atypical infection. Conclusions: mNGS offered added diagnostic and quantitative values compared to PCR tests, which can remain positive after resolved infections. The initiation of appropriate antibiotic therapy would have occurred earlier on, possibly resulting in a better clinical outcome if mNGS had been performed in a routine fashion.

PMID:34295911 | PMC:PMC8290067 | DOI:10.3389/fmed.2021.684040

Breathe (Sheff). 2021 Jun;17(2):200345. doi: 10.1183/20734735.0345-2020.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing lung disease with an estimated median survival of 2-5 years and a significant impact on quality of life (QoL). Current approved medications, pirfenidone and nintedanib, have shown a reduction in annual decline of forced vital capacity but no impact on QoL. The minimal clinically important difference (MCID) is a threshold value for a change in a parameter that is considered meaningful by the patient rather than solely relying on statistically significant change in the parameter. This review provides a brief overview of the MCID methodology along with detailed discussion of reported MCID values for commonly used physiological measures and patient-reported outcome measures in IPF. While there is no gold standard methodology for determining MCID, there are certain limitations in the MCID literature in IPF, mainly the choice of death, hospitalisation and pulmonary function tests as sole anchors, and pervasive use of distribution-based methods which do not take into account the patient's input. There is a critical need to identify accurate thresholds of outcome measures that reflect patient's QoL over time in order to more precisely design and evaluate future clinical trials and to develop algorithms for patient-oriented management of IPF in outpatient clinics.

EDUCATIONAL AIMS: To understand the concept of MCID and the methods used to determine these values.To understand the indications and limitations of MCID values in IPF.

PMID:34295421 | PMC:PMC8291912 | DOI:10.1183/20734735.0345-2020

Breathe (Sheff). 2021 Mar;17(1):200327. doi: 10.1183/20734735.0327-2020.

ABSTRACT

The burden of treatment extends beyond the patient and can have a dramatic impact on the person in a caring role. https://bit.ly/3oekJjo.

PMID:34295403 | PMC:PMC8291923 | DOI:10.1183/20734735.0327-2020

Korean J Intern Med. 2021 Jul 27. doi: 10.3904/kjim.2020.559. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: Pirfenidone slows the progression of idiopathic pulmonary fibrosis (IPF). We investigated its efficacy and safety in terms of dose and disease severity in real-world patients with IPF.

METHODS: This multicenter retrospective cohort study investigated 338 patients treated with pirfenidone between July 2012 and March 2018. Demographics, pulmonary function, mortality, and pirfenidone-related adverse events were also investigated. Efficacy was analyzed according to pirfenidone dose and disease severity using linear mixed-effects models to assess the annual decline rate of forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO).

RESULTS: The mean %FVCpredicted and %DLCOpredicted values were 72.6% ± 13.1% and 61.4% ± 17.9%, respectively. The mean duration of pirfenidone treatment was 16.1 ± 9.0 months. In the standard dose (1,800 mg/day) group, the mean %FVCpredicted was -6.56% (95% confidence interval [CI], -9.26 to -3.87) per year before, but -4.43% (95% CI, -5.87 to -3.00) per year after treatment with pirfenidone. In the non-standard lower dose group, the mean %FVCpredicted was -4.96% (95% CI, -6.82 to -3.09) per year before, but -1.79% (95% CI, -2.75 to -0.83) per year after treatment with pirfenidone. The FVC decline rate was significantly reduced, regardless of the Gender-Age-Physiology (GAP) stage. Adverse events and mortality were similar across dose groups; however, they were more frequent in GAP stages II-III than in the stage I group.

CONCLUSIONS: The effect of pirfenidone on reducing disease progression of IPF persisted even with a consistently lower dose of pirfenidone.

PMID:34293852 | DOI:10.3904/kjim.2020.559

Respirology. 2021 Jul 22. doi: 10.1111/resp.14116. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Antifibrotic therapy with nintedanib or pirfenidone slows disease progression and reduces mortality in patients with idiopathic pulmonary fibrosis (IPF). However, patients with advanced IPF, as defined by forced vital capacity (FVC) < 50% and/or diffusion capacity for carbon monoxide (DLCO) < 30% of predicted, have not been included in randomized trials, and the outcomes of such patients who initiate treatment are not well understood. We determined lung function, disease progression and mortality outcomes following initiation of antifibrotic therapy in patients with advanced IPF at the time of treatment initiation compared to those with mild-moderate IPF.

METHODS: We included 502 patients enrolled in IPF registries from four Nordic countries. Linear mixed models were used to assess change in FVC and DLCO over time. Cox proportional hazards models were used to assess transplant-free survival and progression- and transplant-free survival.

RESULTS: Of 502 patients, 66 (13%) had advanced IPF. Annual change in FVC was -125 ml (95% CI -163, -87) among patients with mild-moderate IPF, and +28 ml (95% CI -96, +152) among those with advanced IPF. Advanced IPF at treatment initiation was associated with poorer transplant-free survival (hazard ratio [HR] 2.39 [95% CI 1.66, 3.43]) and progression- and transplant-free survival (HR 1.60 [95% CI 1.15, 2.23]).

CONCLUSION: In a broadly representative IPF population, patients with advanced IPF at the initiation of antifibrotic therapy did not have greater lung function decline over time compared with those with mild-moderate IPF, but had substantially higher mortality. Prospective studies are needed to determine the effect of antifibrotic therapy in patients with advanced IPF.

PMID:34291523 | DOI:10.1111/resp.14116

Front Pharmacol. 2021 Jul 5;12:692551. doi: 10.3389/fphar.2021.692551. eCollection 2021.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung's architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.

PMID:34290610 | PMC:PMC8287856 | DOI:10.3389/fphar.2021.692551

Sci Rep. 2021 Jul 21;11(1):14923. doi: 10.1038/s41598-021-93980-5.

ABSTRACT

Image registration-based local displacement analysis enables evaluation of respiratory motion between two computed tomography-captured lung volumes. The objective of this study was to compare diaphragm movement among emphysema, idiopathic pulmonary fibrosis (IPF) and normal subjects. 29 normal, 50 emphysema, and 51 IPF subjects were included. A mass preserving image registration technique was used to compute displacement vectors of local lung regions at an acinar scale. Movement of the diaphragm was assumed to be equivalent to movement of the basal lung within 5 mm from the diaphragm. Magnitudes and directions of displacement vectors were compared between the groups. Three-dimensional (3D) and apico-basal displacements were smaller in emphysema than normal subjects (P = 0.003, P = 0.002). Low lung attenuation area on expiration scan showed significant correlations with decreased 3D and apico-basal displacements (r = - 0.546, P < 0.0001; r = - 0.521, P < 0.0001) in emphysema patients. Dorsal-ventral displacement was smaller in IPF than normal subjects (P < 0.0001). The standard deviation of the displacement angle was greater in both emphysema and IPF patients than normal subjects (P < 0.0001). In conclusion, apico-basal movement of the diaphragm is reduced in emphysema while dorsal-ventral movement is reduced in IPF. Image registration technique to multi-volume CT scans provides insight into the pathophysiology of limited diaphragmatic motion in emphysema and IPF.

PMID:34290275 | DOI:10.1038/s41598-021-93980-5

Eur Respir J. 2021 Jul 21:2004053. doi: 10.1183/13993003.04053-2020. Online ahead of print.

ABSTRACT

BACKGROUND: Serum lipoproteins, such as high density lipoproteins (HDL), may influence disease severity in idiopathic pulmonary fibrosis (IPF). Here, we investigated associations between serum lipids and lipoproteins and clinical endpoints in IPF.

METHODS: Clinical data and serum lipids were analyzed from a discovery cohort (59 IPF subjects, 56 healthy volunteers) and validated using an independent, multicenter cohort (207 IPF subjects) from the Pulmonary Fibrosis Foundation registry. Associations between lipids and clinical endpoints (FVC, forced vital capacity; 6MWD, 6 min walk distance; GAP (Gender Age Physiology) index; death or lung transplantation) were examined using Pearson's correlation and multivariable analyses.

RESULTS: Serum concentrations of small HDL particles (S-HDLPNMR), measured by nuclear magnetic resonance (NMR) spectroscopy, correlated negatively with the GAP index in the discovery cohort of IPF subjects. The negative correlation of S-HDLPNMR with GAP index was confirmed in the validation cohort of IPF subjects. Higher levels of S-HDLPNMR were associated with lower odds of death or its competing outcome, lung transplantation (OR of 0.9 for each 1 μmol·L-1 increase in S-HDLPNMR, p<0.05), at 1, 2, and 3 years from study entry in a combined cohort of all IPF subjects.

CONCLUSIONS: Higher serum levels of S-HDLPNMR are negatively correlated with the GAP index, as well as with lower observed mortality or lung transplantation in IPF subjects. These findings support the hypothesis that S-HDLPNMR may modify mortality risk in patients with IPF.

PMID:34289973 | DOI:10.1183/13993003.04053-2020

BMC Pulm Med. 2021 Jul 21;21(1):244. doi: 10.1186/s12890-021-01598-0.

ABSTRACT

BACKGROUND: Nintedanib reduces the rate of decline in forced vital capacity in patients with idiopathic pulmonary fibrosis (IPF), other chronic fibrosing interstitial lung diseases (ILDs) with a progressive phenotype and systemic sclerosis-associated ILD (SSc-ILD). The recommended dose of nintedanib is 150 mg twice daily (BID).

METHODS: Data from Phase II and III trials in IPF and Phase III trials in SSc-ILD and progressive fibrosing ILDs other than IPF were analyzed to investigate the relationship between nintedanib plasma concentrations (exposure) and safety (liver enzyme elevations [defined as transaminase elevations equal or greater than 3 times the upper limit of normal] and diarrhea).

RESULTS: Using data from 1403 subjects with IPF treated with 50-150 mg nintedanib BID, a parametric time-to-first-event model for liver enzyme elevations was established. Besides exposure, gender was a significant covariate, with a three-fourfold higher exposure-adjusted risk in females than males. Subsequent analysis of combined data from IPF, SSc-ILD (n = 576) and progressive fibrosing ILD (n = 663) studies suggested a consistent exposure-liver enzyme elevation relationship across studies. No exposure-diarrhea relationship was found using data from the various fibrosing ILDs, but diarrhea risk was dependent on dose administered.

CONCLUSIONS: The positive correlation between exposure and risk of liver enzyme elevations was consistent across nintedanib studies in IPF, SSc-ILD and progressing fibrosing ILDs other than IPF. The effect size does not warrant a priori dose adjustment in patients with altered plasma exposure (excluding hepatic impairment patients, where there are specific labelling recommendations). For diarrhea, dose administered was a better predictor than exposure.

PMID:34289823 | DOI:10.1186/s12890-021-01598-0

Biomed Res Int. 2021 Jul 4;2021:5545312. doi: 10.1155/2021/5545312. eCollection 2021.

ABSTRACT

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, irreversible, high-mortality lung disease, but its pathogenesis is still unclear. Our purpose was to explore potential genes and molecular mechanisms underlying IPF.

METHODS: IPF-related data were obtained from the GSE99621 dataset. Differentially expressed genes (DEGs) were identified between IPF and controls. Their biological functions were analyzed. The relationships between DEGs and microRNAs (miRNAs) were predicted. DEGs and pathways were validated in a microarray dataset. A protein-protein interaction (PPI) network was constructed based on these common DEGs. Western blot was used to validate hub genes in IPF cell models by western blot.

RESULTS: DEGs were identified for IPF than controls in the RNA-seq dataset. Functional enrichment analysis showed that these DEGs were mainly enriched in immune and inflammatory response, chemokine-mediated signaling pathway, cell adhesion, and other biological processes. In the miRNA-target network based on RNA-seq dataset, we found several miRNA targets among all DEGs, like RAB11FIP1, TGFBR3, and SPP1. We identified 304 upregulated genes and 282 downregulated genes in IPF compared to controls both in the microarray and RNA-seq datasets. These common DEGs were mainly involved in cell adhesion, extracellular matrix organization, oxidation-reduction process, and lung vasculature development. In the PPI network, 3 upregulated and 4 downregulated genes could be considered hub genes, which were confirmed in the IPF cell models.

CONCLUSION: Our study identified several IPF-related DEGs that could become potential biomarkers for IPF. Large-scale multicentric studies are eagerly needed to confirm the utility of these biomarkers.

PMID:34285914 | PMC:PMC8275392 | DOI:10.1155/2021/5545312