Ann Transl Med. 2021 Oct;9(20):1570. doi: 10.21037/atm-21-4545.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a highly fatal lung disease of unknown etiology with a median survival after diagnosis of only 2-3 years. Its poor prognosis is due to the limited therapy options available as well as the lack of effective prognostic indicators. This study aimed to construct a novel prognostic signature for IPF to assist in the personalized management of IPF patients during treatment.

METHODS: Differentially-expressed genes (DEGs) in IPF patients versus healthy individuals were analyzed using the "limma" package of R software. Immune-related genes (IRGs) were obtained from the ImmPort database. Univariate Cox regression analysis was adopted to screen significantly prognostic IRGs for IPF patients. Multiple Cox regression analysis was used to identify optimal prognostic IRGs and construct a prognostic signature.

RESULTS: Compared with healthy individuals, there were a total of 52 prognosis-related DEGs in the bronchoalveolar lavage (BAL) samples of IPF patients, of which 37 genes were identified as IRGs. Of these, five genes (CXCL14, SLC40A1, RNASE3, CCR3, and RORA) were significantly associated with overall survival (OS) in IPF patients, and were utilized for establishment of the prognostic signature. IPF patients were divided into high- and low-risk groups based on the prognostic signature. Marked differences in the OS probability were observed between high- and low-risk IPF patients. The area under curves (AUCs) of the receiver operating characteristic (ROC) curve for the prognostic signature in the training and validation cohorts were 0.858 and 0.837, respectively. The expression levels between RNASE3 and SLC40A1 (P<0.01, r=0.394), between RORA and CXCL14 (P<0.01, r=-0.355), between CCR3 and CXCL14 (P<0.01, r=0.258), as well as between RNASE3 and CCR3 (P<0.01, r=0.293) were significantly correlated.

CONCLUSIONS: We developed a validated and reproducible IRG-based prognostic signature that should be helpful in the personalized management of patients with IPF, providing new insights into the relationship between the immune system and IPF.

PMID:34790776 | PMC:PMC8576669 | DOI:10.21037/atm-21-4545

Eur Respir Rev. 2021 Nov 17;30(162):210105. doi: 10.1183/16000617.0105-2021. Print 2021 Dec 31.

ABSTRACT

Sex and gender differences influence key domains of research, lung health, healthcare access and healthcare delivery. In interstitial lung diseases (ILDs), mouse models of pulmonary fibrosis are clearly influenced by sex hormones. Additionally, short telomeres, a biomarker of telomere regulation gene mutations, are impacted by sex, while heritability unexplained by genetic variation may be attributable to gendered environmental factors that drive epigenetic control. Diseases like idiopathic pulmonary fibrosis, hypersensitivity pneumonitis, occupational ILDs, connective tissue-associated ILDs and lymphangioleiomyomatosis have different prevalence and prognosis between men and women. These differences arise from a complex interplay between biological sex and sociocultural gender influencing genetics, epigenomic modifiers, hormones, immune function, response to treatment and interaction with healthcare systems. Much work remains to be done to systematically integrate sex and gender analysis into relevant domains of science and clinical care in ILD, from strategic considerations for establishing research priorities to guidelines for establishing best clinical practices. Accounting for sex and gender in ILD is essential to the practice of individualised, patient-centred medicine.

PMID:34789464 | DOI:10.1183/16000617.0105-2021

BMC Genomics. 2021 Nov 17;22(1):827. doi: 10.1186/s12864-021-08073-4.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive fibroproliferative disorder that has one of the poorest prognoses amongst interstitial lung diseases. Recently, the finding of aberrant expression levels of miRNAs in IPF patients has drawn significant attention to the involvement of these molecules in the pathogenesis of this disease. Clarification of the differential expression of miRNAs in health and disease may identify novel therapeutic strategies that can be employed in the future to combat IPF. This study evaluates the miRNA expression profiles in a sheep model for lung fibrosis and compares them to the miRNA profiles of both IPF patients and the mouse bleomycin model for pulmonary fibrosis. Pathway enrichment analyses were performed on differentially expressed miRNAs to illustrate which biological mechanisms were associated with lung fibrosis.

RESULTS: We discovered 49 differentially expressed miRNAs in the sheep fibrosis model, in which 32 miRNAs were significantly down regulated, while 17 miRNAs were significantly upregulated due to bleomycin-induced lung injury. Moreover, the miRNA families miR-29, miR-26, miR-30, let-7, miR-21, miR-19, miR-17 and miR-199 were aberrantly expressed in both sheep and mouse models, with similar differential miRNAs expression observed in IPF cases. Importantly, 18 miRNAs were aberrantly expressed in both the sheep model and IPF patients, but not in mice.

CONCLUSION: Together with pathway enrichment analyses, these results show that the sheep model can potentially be used to characterize previously unrecognized biological pathways associated with lung fibrosis.

PMID:34789159 | DOI:10.1186/s12864-021-08073-4

Respir Med. 2021 Sep 2;190:106599. doi: 10.1016/j.rmed.2021.106599. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a rapidly progressive interstitial lung disease with high mortality. Lung transplant remains a cornerstone of treatment despite the advent of antifibrotic therapy. In light of the increasing number of patients on antifibrotic therapy prior to lung transplantation it is paramount to demonstrate these medications do not augment postoperative complications following transplant.

RESEARCH QUESTION: Does antifibrotic therapy increase perioperative complications and mortality in lung transplant recipients?

STUDY DESIGN AND METHODS: We conducted a retrospective chart review of all patients actively listed for lung transplant at Temple University Hospital from June 2014 to April 2017 with a listing diagnosis of IPF. Subjects who received treatment with antifibrotic therapy (either pirfenidone or nintedanib) up until the time of lung transplantation were compared to subjects not on therapy. Data was collected regarding baseline demographics, pulmonary function tests, IPF exacerbations, perioperative bleeding and cardiac events, and outcomes in the postoperative period.

RESULTS: A total of 94 subjects were included in the study: 42 subjects on antifibrotic therapy (28 pirfenidone, 14 nintedanib) and 52 subjects not on therapy in the pre-transplant period. Baseline characteristics were similar between study groups. Subjects treated with antifibrotic therapy pre-transplant were noted to have less FVC decline, fewer hospitalizations, and greater weight loss while on the transplant waiting list. No difference in post-transplant airway anastomosis complications, bleeding or mortality was observed between study groups.

INTERPRETATION: Subjects with IPF on antifibrotic therapy prior to lung transplantation had better preservation of lung function in the pre-transplant period, and similar outcomes in the postoperative period compared to those not on antifibrotic therapy before lung transplant.

PMID:34788735 | DOI:10.1016/j.rmed.2021.106599

Chest. 2021 Nov 14:S0012-3692(21)04292-6. doi: 10.1016/j.chest.2021.11.008. Online ahead of print.

ABSTRACT

BACKGROUND: Mortality risk assessment in interstitial lung disease (ILD) is challenging. Our objective was to determine the prognostic significance of body mass index (BMI) and change in weight in the most common fibrotic ILD subtypes.

RESEARCH QUESTION: Could BMI and weight loss over time be reliable prognostic indicators in patients with fibrotic ILD?

STUDY DESIGN AND METHODS: This observational retrospective multicenter cohort study enrolled patients with fibrotic ILD from the six-center CAnadian REgistry for Pulmonary Fibrosis (CARE-PF, derivation) and the ILD registry at the University of California, San Francisco (UCSF, validation). Patients were subcategorized as underweight (BMI <18.5kg/m2), normal weight (BMI 18.5-24.9kg/m2), overweight (BMI 25-29.9kg/m2), or obese (BMI >30kg/m2). Annual change in weight was calculated for all years of follow-up as the slope of best fit using the least square method based on every available measurement. Separate multivariable analyses evaluated the associations of BMI and change in weight with mortality, adjusting for common prognostic variables.

RESULTS: The derivation and validation cohorts included 1786 and 1779 patients, respectively. Compared to patients with normal BMI, mortality was highest in patients who were underweight (HR 3.19, 95%CI 1.88-5.43, P<0.001) and was lowest in those who were overweight (HR 0.52, 95% CI 0.36-0.75, P<0.001) or obese (HR 0.55, 95%CI 0.37-0.83, P<0.001) in the analysis adjusted for the ILD-GAP Index. Patients who had a weight loss ≥2kg within 1 year had increased risk of death in the subsequent year (HR 1.41, 95%CI 1.01-1.97, P=0.04) after adjustment for the ILD-GAP Index and baseline BMI category, with a plateau in risk for patients with greater weight loss. Consistent results were observed in the validation cohort.

INTERPRETATION: Both BMI and weight loss are independently associated with 1-year mortality in fibrotic ILD. BMI and weight loss may be clinically useful prognostic indicators in fibrotic ILD.

PMID:34788669 | DOI:10.1016/j.chest.2021.11.008

Intern Emerg Med. 2021 Nov 16. doi: 10.1007/s11739-021-02883-w. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive, fibrosing interstitial pneumonia of unknown cause that leads to respiratory failure and death within few years of diagnosis. Pulmonary hypertension (PH) is a common complication in IPF, where it is strongly associated with increased morbidity and mortality. Patients with IPF and PH have particularly poor prognosis, despite current best medical therapies and the anti-fibrotic therapy with pirfenidone or nintedanib. The aim of our study was to assess the clinical and prognostic impact of PH in patients affected by IPF, already treated with pirfenidone or nintedanib. Seventy-four consecutive outpatients with a diagnosis of IPF, in therapy with pirfenidone or nintedanib, were prospectively enrolled in the study. All patients underwent pulmonary and cardiology assessment by clinical exam, spirometry, DLCO test, chest CT, 6MWT and echocardiography performed by a cardiologist experienced in PH in an ambulatory setting under resting conditions. GAP index has been determinate for all patients. During follow-up, all patients were evaluated every 6 months, or less if necessary. Data about mortality were then collected in a 3-year follow-up. Of the seventy-four patients enrolled, 38 were treated with pirfenidone and 36 with nintedanib. The two groups were comparable for age, gender, FVC, DLCO and PAPS. The patients were also divided in four groups, based on presence of mild/moderate/severe PH by echocardiography at baseline. Significant differences were found for DLCO and the GAP index. Severity of PH was significantly associated with a reduction of DLCO and with an increased GAP index. Survival was directly correlated with 6MWT (R = 0.48), DLCO (R = 0.29, p < 0.01), and reversely with tGAP index (- 0.31, p < 0.01 in all cases), while no significant correlation was found with PAsP. 36-month survival analysis showed an HR of 4.05 (95% CI 1.07-7.34, p = 0.02) for DLCO < 50% and of 1.56 (95% CI 1.02-2.39, p = 0.03) for GAP index. The development and progression of PH in patients affected by IPF reduce the survival and the severity of PH is associated with a reduction of DLCO value and an increase of the GAP index. Echocardiographic stratification based on PAsP values may be useful in stratifying prognosis in IPF patients and deciding specific PAH drugs.

PMID:34787802 | DOI:10.1007/s11739-021-02883-w

Expert Opin Ther Targets. 2021 Nov 16. doi: 10.1080/14728222.2021.2006186. Online ahead of print.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease with high associated morbidity and mortality. The therapeutic landscape has significantly changed in the last 20 years with two drugs currently approved that have demonstrated the ability to slow disease progression. Despite these developments, survival in IPF is limited, so there is a major interest in therapeutic targets which could serve to open up new therapeutic avenues.

AREAS COVERED: We review the most recent information regarding drug targets and therapies currently being investigated in preclinical and early-stage clinical trials.

EXPERT OPINION: The complex pathogenesis of IPF and variability in disease course and response to therapy highlights the importance of a precision approach to therapy. Novel technologies including transcriptomics and the use of serum biomarkers, will become essential tools to guide future drug development and therapeutic decision making particularly as it pertains to combination therapy.

PMID:34784834 | DOI:10.1080/14728222.2021.2006186

Am Fam Physician. 2021 Nov 1;104(5):Online.

NO ABSTRACT

PMID:34783499

Respirology. 2021 Nov 15. doi: 10.1111/resp.14185. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: In Australia, little is known about delivery of care for people with idiopathic pulmonary fibrosis (IPF). This study examined the organization of IPF care across Australia, how it aligns with guidance for best practice, and identified barriers and facilitators to best care.

METHODS: Data on the organization of IPF care in Australia were collected from public hospitals using a study-specific questionnaire between February and July 2020. Semi-structured telephone interviews were conducted with respiratory physicians from around Australia between April and December 2020. Interviews were transcribed verbatim and thematic analysis was undertaken.

RESULTS: Almost all hospitals (n = 38, 97%) held multidisciplinary meetings (MDMs) for diagnosing IPF, with 90% of multidisciplinary teams including expert respiratory physicians and radiologists; however, rheumatologists, interstitial lung disease nurses and a histopathologist were often not available. More than 90% of institutions had access to oxygen therapy, pulmonary rehabilitation and advanced care planning, but access to psychological support and clinical trials was limited (53% and 58%, respectively). Fifteen respiratory physicians (27% regional) were interviewed. Approaches to diagnosis, treatment and access to referral services were generally consistent with best practice guidance; however, regional respondents reported barriers related to inadequate staffing, lack of a nurse coordinator, inadequate access to clinical trials and funding models. Telehealth technologies were perceived as facilitators to best care.

CONCLUSION: Clinical management of IPF in Australia generally aligns with best practice guidance, but there may be some inequity of access to specialist services, particularly in regional areas, that should be addressed to ensure optimal care for all.

PMID:34783108 | DOI:10.1111/resp.14185

Syst Rev. 2021 Nov 15;10(1):297. doi: 10.1186/s13643-021-01853-9.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is one of the common types of interstitial lung disease having high prevalence and mortality worldwide. As a result of patient-centred hindering factors of adherence to centre-based pulmonary rehabilitation (PR), home-based PR is an alternate mode of rehabilitating individuals with IPF. This systematic review will evaluate the effectiveness of unsupervised home-based PR on functional capacity and health-related quality of life (HRQoL) in individuals with IPF.

METHODS: Clinically stable, high resolution computed tomography and physician diagnosed IPF participants having modified Medical Research Council score below 5 will be considered for the systematic review. Studies involving home-based PR as an intervention to treat individuals with IPF will be considered. Randomised controlled trials and quasi-randomised studies (with two groups followed up) are eligible to be included. Outcomes of our interest are functional capacity (6-min walk distance, shuttle walk test and incremental shuttle walk test) and secondary outcome measure would include assessment of quality of life and adverse effects of intervention. Electronic databases such as SCOPUS, Medline (PubMed and Web of Science), PEDRo and CINAHL will be searched using database specific terms. Additionally, forward and backward citations of included studies will be searched to identify potential records. Two review authors, independently, will conduct the screening, data extraction using a customised standard tool, and critical appraisal using Cochrane Risk of Bias 2 tool of included studies. If data permits, meta-analysis will be conducted. In case of substantial heterogeneity, we will do a narrative synthesis. Subgroup analysis will be undertaken based on various contextual and interventional factors.

DISCUSSION: This review will provide comprehensive evidence on the effectiveness of unsupervised home-based PR to physiotherapists, policy makers and researchers who are interested in IPF management. Findings from this review may guide the development and evaluation of more robust evidence based home-based PR that aimed to improve functional capacity among people with IPF.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020213883.

PMID:34782011 | DOI:10.1186/s13643-021-01853-9

Xenobiotica. 2021 Nov 15:1-13. doi: 10.1080/00498254.2021.2007553. Online ahead of print.

ABSTRACT

Pirfenidone is a first-line drug for the treatment of idiopathic pulmonary fibrosis. The primary metabolic pathways of pirfenidone in humans are 5-hydroxylation and subsequent oxidation to 5-carboxylpirfenidone. The aims of this study were to determine the cytochrome P450 isoforms responsible for pirfenidone 5-hydroxylation and to evaluate their contributions in human liver microsomes (HLM).Among the recombinant P450 isoforms, CYP1A2, CYP2D6, CYP2C19, CYP2A6, and CYP2B6 were shown to catalyze the 5-hydroxylation of pirfenidone. Pirfenidone 5-hydroxylase activity by HLM was inhibited by α-naphthoflavone (by 45%), 8-methoxypsolaren (by 84%), tranylcypromine (by 53%), and quinidine (by 15%), which are CYP1A2, CYP1A2/CYP2A6/CYP2C19, CYP2A6/CYP2C19, and CYP2D6 inhibitors, respectively.In 17 individual HLM donors, pirfenidone 5-hydroxylase activity was significantly correlated with phenacetin O-deethylase (r = 0.89, P < 0.001) and S-mephenytoin 4'-hydroxylase activities (r = 0.51, P < 0.05), which are CYP1A2 and CYP2C19 marker activities, respectively.By using the relative activity factors, the contributions of CYP1A2, CYP2C19 and CYP2D6 to pirfenidone 5-hydroxylation in the human liver were 72.8%, 11.8%, and 8.9%, respectively.In conclusion, we clearly demonstrated the predominant P450 involved in pirfenidone 5-hydroxylation in the human liver is CYP1A2, with CYP2C19 and CYP2D6 playing a minor role.

PMID:34779706 | DOI:10.1080/00498254.2021.2007553

Intern Med. 2021 Nov 13. doi: 10.2169/internalmedicine.8330-21. Online ahead of print.

ABSTRACT

An 82-year-old Japanese man with idiopathic pulmonary fibrosis (IPF) experienced dyspnea after using a waterproofing spray in a closed room. He presented with hypoxemia and his chest computed tomography showed additive bilateral diffuse ground-glass attenuation on fibrosis, which was diagnostic of an acute exacerbation of IPF (AE-IPF). Combined treatment with high-dose corticosteroids and immunosuppressants were ineffective, and he later died of respiratory failure. Autopsy findings showed diffuse alveolar damage with honeycombing. His medical history and autopsy histopathology suggested AE-IPF caused by the inhalation of a waterproofing spray.

PMID:34776487 | DOI:10.2169/internalmedicine.8330-21

Int J Mol Sci. 2021 Oct 31;22(21):11830. doi: 10.3390/ijms222111830.

ABSTRACT

Chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) are chronic, progressive lung ailments that are characterized by distinct pathologies. Early detection biomarkers and disease mechanisms for these debilitating diseases are lacking. Extracellular vesicles (EVs), including exosomes, are small, lipid-bound vesicles attributed to carry proteins, lipids, and RNA molecules to facilitate cell-to-cell communication under normal and diseased conditions. Exosomal miRNAs have been studied in relation to many diseases. However, there is little to no knowledge regarding the miRNA population of bronchoalveolar lavage fluid (BALF) or the lung-tissue-derived exosomes in COPD and IPF. Here, we determined and compared the miRNA profiles of BALF- and lung-tissue-derived exosomes of healthy non-smokers, smokers, and patients with COPD or IPF in independent cohorts. Results: Exosome characterization using NanoSight particle tracking and TEM demonstrated that the BALF-derived exosomes were ~89.85 nm in size with a yield of ~2.95 × 1010 particles/mL in concentration. Lung-derived exosomes were larger in size (~146.04 nm) with a higher yield of ~2.38 × 1011 particles/mL. NGS results identified three differentially expressed miRNAs in the BALF, while there was one in the lung-derived exosomes from COPD patients as compared to healthy non-smokers. Of these, miR-122-5p was three- or five-fold downregulated among the lung-tissue-derived exosomes of COPD patients as compared to healthy non-smokers and smokers, respectively. Interestingly, there were a large number (55) of differentially expressed miRNAs in the lung-tissue-derived exosomes of IPF patients compared to non-smoking controls. Conclusions: Overall, we identified lung-specific miRNAs associated with chronic lung diseases that can serve as potential biomarkers or therapeutic targets.

PMID:34769265 | DOI:10.3390/ijms222111830

PLoS One. 2021 Nov 12;16(11):e0259784. doi: 10.1371/journal.pone.0259784. eCollection 2021.

ABSTRACT

BACKGROUND: Current studies showed that idiopathic pulmonary fibrosis (IPF) may lead to a poor prognosis of lung cancer. We conducted a meta-analysis to explore the impact of concomitant IPF in lung cancer and its prognostic value.

METHODS: We searched the databases of PubMed, Web of Science, Embase up to Feb 10th, 2021 for relevant researches and merged the hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate the association between concomitant IPF and overall survival (OS) in patients with lung cancer.

RESULTS: Twelve studies involving 58424 patients were included in our meta-analysis. The results indicated that concomitant IPF was correlated with poor prognosis of lung cancer patients (HR = 1.99, 95%CI, 1.59-2.51). The association remained consistent after subgroup analysis and meta-regression stratified by study region, sample size, tumor histology, and therapy. In addition, our results were robust even after sensitivity analysis.

CONCLUSIONS: Concomitant IPF may be a prognostic factor of lung cancer, which can lead to poor survival. However, further studies were necessary for evidence in clinical application.

PMID:34767608 | DOI:10.1371/journal.pone.0259784

MedComm (Beijing). 2021 Sep 2;2(3):351-380. doi: 10.1002/mco2.74. eCollection 2021 Sep.

ABSTRACT

Mesenchymal stromal/stem cells (MSCs) have a great potential to proliferate, undergo multi-directional differentiation, and exert immunoregulatory effects. There is already much enthusiasm for their therapeutic potentials for respiratory inflammatory diseases. Although the mechanism of MSCs-based therapy has been well explored, only a few articles have summarized the key advances in this field. We hereby provide a review over the latest progresses made on the MSCs-based therapies for four types of inflammatory respiratory diseases, including idiopathic pulmonary fibrosis, acute respiratory distress syndrome, chronic obstructive pulmonary disease, and asthma, and the uncovery of their underlying mechanisms from the perspective of biological characteristics and functions. Furthermore, we have also discussed the advantages and disadvantages of the MSCs-based therapies and prospects for their optimization.

PMID:34766151 | PMC:PMC8554668 | DOI:10.1002/mco2.74

Eur Respir J. 2021 Nov 11:2101790. doi: 10.1183/13993003.01790-2021. Online ahead of print.

ABSTRACT

There is a lack of fully validated patient-reported outcome measures for progressive fibrosing interstitial lung disease (PF-ILD). We aimed to validate the King's Brief Interstitial Lung Disease questionnaire (KBILD) for measuring health-related quality of life (HRQoL) in these patients. We also estimated the meaningful change threshold for interpreting stabilisation of HRQoL as a clinical endpoint in PF-ILD, where the current goal of treatment is disease stability and slowing progression. This analysis evaluated data from 663 patients with PF-ILD other than idiopathic pulmonary fibrosis from the INBUILD trial. Validation of the measurement properties was assessed for internal consistency, test-retest reliability, construct validity, known-groups validity, and responsiveness. We calculated meaningful change thresholds for treatment response using anchor-based (within-patient) and distribution-based methods. The KBILD had strong internal consistency (Cronbach alpha was 0.94 for total score, 0.88 for KBILD domain breathlessness and activities, 0.91 for psychological and 0.79 for chest symptoms). Test-retest reliability intraclass correlation coefficient was 0.74 for KBILD total score. The KBILD demonstrated weak correlations with forced vital capacity (FVC)% predicted. Known-groups validity showed significant differences in KBILD scores for patient groups with different disease severity based on use of supplemental oxygen or baseline FVC% predicted (<70 or >70%). We estimated a meaningful change threshold of ≥-2 for the KBILD total score for defining patients who remain stable/improved versus those with progressive deterioration. Our results validate the KBILD as a tool for assessing HRQoL in patients with PF-ILD and set a meaningful change threshold of ≥-2 for KBILD total score.

PMID:34764181 | DOI:10.1183/13993003.01790-2021

ERJ Open Res. 2021 Nov 8;7(4):00416-2021. doi: 10.1183/23120541.00416-2021. eCollection 2021 Oct.

ABSTRACT

Nailfold capillaroscopy (NFC) is a non-invasive tool validated for systemic sclerosis diagnosis. The role and interpretation of NFC in interstitial lung disease (ILD) patients for the diagnosis of connective tissue disease associated ILD (CTD-ILD) remains undefined. In a prospective study, quantitative and qualitative NFC by smartphone-dermatoscope (3M Dermlite-DL4ΤΜ attached to iPhone-6plusΤΜ) was performed in 96 patients with well-defined CTD-ILD (n=27) and non-CTD ILD (n=69; idiopathic interstitial pneumonia n=42, interstitial pneumonia with autoimmune features n=27) by ILD-multidisciplinary meeting. NFC scoring was performed by two independent, blinded specialist rheumatologists. Comprehensive baseline clinical, serological, physiological and radiological data were included. Multivariable models for CTD diagnosis in ILD, comprising nailfold characteristics at empirical thresholds determined by receiver operating characteristic curve analysis and clinical variables, were explored. In 94 patients with complete NFC data (total 687 images, median eight images per patient from eight digits), low capillary density (<6 capillaries/millimetre), increased giant capillaries (≥3), avascular areas (≥2) and microhaemorrhages all strongly enhanced the discrimination of CTD-ILD from non-CTD ILD (OR 5.00-7.47) independent of clinical covariates. In multivariable analysis, low capillary density and microhaemorrhages were independent predictors of CTD in ILD additional to the risk conferred by serology and radiology. Microhaemorrhages were also a strong predictor of CTD (adjusted OR 13.45, p=0.006) independent of clinical manifestations. All pre-specified qualitative NFC classification schemes identified CTD-ILD (OR range 3.27-8.47). NFC performed by smartphone-dermatoscope is an accessible, clinically feasible tool that may improve the identification of CTD further to routine clinical assessment of the ILD patient.

PMID:34760999 | PMC:PMC8573234 | DOI:10.1183/23120541.00416-2021

ERJ Open Res. 2021 Nov 8;7(4):00907-2020. doi: 10.1183/23120541.00907-2020. eCollection 2021 Oct.

ABSTRACT

INTRODUCTION: Evidence suggests that abnormalities occur in the lung microvasculature in idiopathic pulmonary fibrosis (IPF). We hypothesised that dynamic contrast-enhanced (DCE)-magnetic resonance imaging (MRI) could detect alterations in permeability, perfusion and extracellular extravascular volume in IPF, thus providing in vivo regional functional information not otherwise available.

METHODS: Healthy controls and IPF subjects underwent DCE-MRI of the thorax using a dynamic volumetric radial sampling sequence and administration of gadoterate meglumine at a dose of 0.1 mmol·kg-1 at 2 mL·s-1. Model-free analysis of signal intensity versus time curves in regions of interest from a lower, middle and upper axial plane, a posterior coronal plane and the whole lung yielded parameters reflective of perfusion and permeability (peak enhancement and rate of contrast arrival (kwashin)) and the extracellular extravascular space (rate of contrast clearance (kwashout)). These imaging parameters were compared between IPF and healthy control subjects, and between fast/slow IPF progressors.

RESULTS: IPF subjects (n=16, 56% male, age (range) 67.5 (60-79) years) had significantly reduced peak enhancement and slower kwashin in all measured lung regions compared to the healthy volunteers (n=17, 65% male, age (range) 58 (51-63) years) on unadjusted analyses consistent with microvascular alterations. kwashout, as a measure of the extravascular extracellular space, was significantly slower in the lower lung and posterior coronal regions in the IPF subjects consistent with an increased extravascular extracellular space. All estimates were attenuated after adjusting for age. Similar trends were observed, but only the associations with kwashin in certain lung regions remained statistically significant. Among IPF subjects, kwashout rates nearly perfectly discriminated between those with rapidly progressive disease versus those with stable/slowly progressive disease.

CONCLUSIONS: DCE-MRI detects changes in the microvasculature and extravascular extracellular space in IPF, thus providing in vivo regional functional information.

PMID:34760997 | PMC:PMC8573229 | DOI:10.1183/23120541.00907-2020

Respir Res. 2021 Nov 11;22(1):290. doi: 10.1186/s12931-021-01892-9.

ABSTRACT

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) is characterised by predominant upper lobe pleural and subpleural lung parenchymal fibrosis. Radiological PPFE-like lesion has been associated with various types of interstitial lung diseases. However, the prevalence and clinical significance of radiological PPFE-like lesion in patients with idiopathic interstitial pneumonias (IIPs) are not fully understood. We aimed to determine the prevalence and clinical impact on survival of radiological PPFE-like lesion in patients with IIPs.

METHODS: A post-hoc analysis was conducted using data from the Japanese nationwide cloud-based database of patients with IIPs. All the patients in the database were diagnosed as having IIPs by multidisciplinary discussion. Patients diagnosed with idiopathic PPFE were excluded. Clinical data and chest computed tomography (CT) image of 419 patients with IIPs were analysed. The presence of radiological PPFE-like lesion was independently evaluated by two chest radiologists blind to the clinical data.

RESULTS: Of the 419 patients with IIPs, radiological PPFE-like lesions were detected in 101 (24.1%) patients, mainly in idiopathic pulmonary fibrosis (IPF) and unclassifiable IIPs, but less in idiopathic nonspecific interstitial pneumonia. Prognostic analyses revealed that radiological PPFE-like lesion was significantly associated with poor outcome in patients with IIPs, which was independent of age, IPF diagnosis and %FVC. In survival analyses, the patients with radiological PPFE-like lesions had poor survival compared with those without (log-rank, p < 0.0001). Subgroup analyses demonstrated that radiological PPFE-like lesion was significantly associated with poor survival both in patients with IPF and those with unclassifiable IIPs.

CONCLUSION: Radiological PPFE-like lesion is a condition that could exist in IIPs, mainly in IPF and unclassifiable IIPs. Importantly, the radiological PPFE-like lesion is a non-invasive marker to predict poor outcome in patients with IIPs, which should be carefully considered in clinical practice.

PMID:34758816 | DOI:10.1186/s12931-021-01892-9

BMC Pulm Med. 2021 Nov 10;21(1):361. doi: 10.1186/s12890-021-01704-2.

ABSTRACT

BACKGROUND: Interstitial lung disease is a debilitating condition associated with significant dyspnoea, fatigue, and poor exercise tolerance. Pulmonary rehabilitation is an effective and key intervention in people with interstitial lung disease. However, despite the best efforts of patients and clinicians, many of those who participate are not achieving clinically meaningful benefits. This assessor-blinded, multi-centre, randomised controlled trial aims to compare the clinical benefits of high intensity interval exercise training versus the standard pulmonary rehabilitation method of continuous training at moderate intensity in people with fibrotic interstitial lung disease.

METHODS: Eligible participants will be randomised to either a standard pulmonary rehabilitation group using moderate intensity continuous exercise training or high intensity interval exercise training. Participants in both groups will undertake an 8-week pulmonary rehabilitation program of twice-weekly supervised exercise training including aerobic (cycling) and strengthening exercises. In addition, participants in both groups will be prescribed a home exercise program. Outcomes will be assessed at baseline, upon completion of the intervention and at six months following the intervention by a blinded assessor. The primary outcome is endurance time on a constant work rate test. Secondary outcomes are functional capacity (6-min walk distance), health-related quality of life (Chronic Respiratory Disease Questionnaire (CRQ), St George's Respiratory Questionnaire idiopathic pulmonary fibrosis specific version (SGRQ-I), breathlessness (Dyspnoea 12, Modified Medical Research Council Dyspnoea Scale), fatigue (fatigue severity scale), anxiety (Hospital Anxiety and Depression Scale), physical activity level (GeneActiv), skeletal muscle changes (ultrasonography) and completion and adherence to pulmonary rehabilitation.

DISCUSSION: The standard exercise training strategies used in pulmonary rehabilitation may not provide an optimal exercise training stimulus for people with interstitial lung disease. This study will determine whether high intensity interval training can produce equivalent or even superior changes in exercise performance and symptoms. If high intensity interval training proves effective, it will provide an exercise training strategy that can readily be implemented into clinical practice for people with interstitial lung disease. Trial registration ClinicalTrials.gov Registry (NCT03800914). Registered 11 January 2019, https://clinicaltrials.gov/ct2/show/NCT03800914 Australian New Zealand Clinical Trials Registry ACTRN12619000019101. Registered 9 January 2019, https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=376050&isReview=true.

PMID:34758808 | DOI:10.1186/s12890-021-01704-2