Inhal Toxicol. 2021 Dec 30:1-10. doi: 10.1080/08958378.2021.2019859. Online ahead of print.

ABSTRACT

OBJECTIVE: Epidemiological studies indicate association between elevated air pollution and adverse health effects. Several mechanisms have been suggested, including translocation of inhaled ultrafine carbon (UFC) particles into the bloodstream. Previous studies in healthy subjects have shown no significant pulmonary translocation of UFC-particles. This study aimed to assess if UFC-particles translocate from damaged alveolar compartment in subjects suffering from chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF).

METHODS: Eleven COPD and nine IPF subjects were exposed to a 100 nm UFC-particle-aerosol labeled with Indium-111. Activity in the body was followed up for 10 days using gamma camera planar-imaging as well as in blood and urine samples.

RESULTS: The pulmonary central to periphery activity ratio was significantly higher for COPD as compared to IPF subjects at exposure, 1.8 and 1.4, respectively and remained constant throughout the test period. Ten days after exposure, the estimated median pulmonary translocation of UFC particles was 22.8 and 25.8% for COPD and IPF, respectively. Bound activity was present in blood throughout the test period, peaking at 24-h postinhalation with a median concentration of 5.6 and 8.9 Bq/ml for the COPD and IPF, respectively. Median bound activity excreted in urine (% of inhaled) after 10 days was 1.4% in COPD and 0.7% in IPF. Activity accumulation in liver and spleen could not be demonstrated.

CONCLUSIONS: Our results suggest that UFC particles leak through the damaged alveolar barrier to the bloodstream in COPD and IPF patients probably distributing in a wide spectrum of whole-body tissues.

PMID:34969348 | DOI:10.1080/08958378.2021.2019859

Adv Respir Med. 2021;89(6):589-596. doi: 10.5603/ARM.a2021.0113.

ABSTRACT

The current COVID-19 pandemic has spread like wildfire worldwide and has affected millions of people. The novel corona virus mainly affects the lungs leading to life threatening disease like acute respiratory distress syndrome (ARDS). The aftermath of the disease in form of pulmonary fibrosis is upcoming cause of further increase in morbidity and mortality. Nintedanib is an oral antifibrotics with proven role in idiopathic pulmonary fibrosis, however its use in COVID-19 related pulmonary fibrosis has not been studied. We report our early experience of use of nintedanib in COVID-19 related pulmonary fibrosis.

PMID:34966994 | DOI:10.5603/ARM.a2021.0113

Can Respir J. 2021 Dec 20;2021:4595019. doi: 10.1155/2021/4595019. eCollection 2021.

ABSTRACT

BACKGROUND: Hemosiderin-laden macrophages (HLMs) have been identified in the bronchoalveolar lavage fluid (BALF) of patients with idiopathic pulmonary fibrosis (IPF). This retrospective study examined the ability of HLMs in BALF to predict the acute exacerbation (AE) of chronic idiopathic interstitial pneumonias (IIPs).

METHODS: Two hundred and twenty-one patients with IIP diagnosed by bronchoscopy were enrolled in the study (IPF, n = 87; IIPs other than IPF, n = 134). Giemsa stain was used to detect HLMs in BALF specimens. Prussian blue stain was used to quantify HLMs in BALF, and a hemosiderin score (HS) was given to the specimens containing HLMs.

RESULTS: Twenty-four patients had a positive HS (range: 7‒132). The receiver-operating characteristic curve analysis identified the cutoff HS value for predicting the AE of IIPs to be 61.5. Seven cases had a higher HS (≥61.5) and 214 had a lower HS. AE occurred significantly earlier in the higher HS group (4/7 cases) than in the lower HS group (41/214 cases) during a median observation period of 1239 days (log-rank test, p = 0.026). Multivariate Cox proportional hazard regression analysis showed that a higher HS was a significant predictor of AE in addition to IPF, percent predicted forced vital capacity, and modified Medical Research Council score. The C-statistics for the prediction of AE did not significantly improve by all the above parameters with HS as compared without HS.

CONCLUSIONS: A higher HS was a significant predictor of AE in IIPs but did not significantly improve the predictive ability of other parameters.

PMID:34966470 | PMC:PMC8712187 | DOI:10.1155/2021/4595019

Respir Med. 2021 Dec 23;191:106722. doi: 10.1016/j.rmed.2021.106722. Online ahead of print.

ABSTRACT

RATIONALE: Longitudinal data on the impact of continued, switched or discontinued antifibrotic therapy in patients with idiopathic pulmonary fibrosis (IPF) who have disease progression is needed.

OBJECTIVE: We hypothesized that ongoing antifibrotic use (versus discontinuation) in the setting of forced vital capacity (FVC) decline would be associated with less future decline and lower likelihood of a composite outcome of FVC decline, lung transplant, or death.

METHODS: We performed a multicenter cohort study using data from the Canadian Registry for Pulmonary Fibrosis in patients with IPF with FVC decline ≥10% over 6 months on antifibrotic therapy. The association of continued, switched or discontinued therapy with (1) further change in FVC and (2) a composite of FVC decline ≥10%, transplant, or death, in the subsequent 6 months, was assessed using adjusted linear and logistic regression modelling, respectively. Generalized estimating equations accounted for repeated observations per patient.

RESULTS: 165 patients had a decline in FVC ≥10% over 6 months while receiving antifibrotic therapy. Compared to continued use, antifibrotic discontinuation after FVC decline was associated with greater additional FVC decline (-207 mL 95%CI -353 to -62, p = 0.005) and higher odds of FVC decline ≥10%, transplant, or death (odds ratio 12.2 95%CI 1.2 to 130.5, p = 0.04). There was no difference between continued versus switched antifibrotic therapy.

CONCLUSIONS: Ongoing antifibrotic therapy in the setting of FVC decline is associated with less future FVC decline and lower odds of FVC decline ≥10%, transplant, or death in a real-world cohort of IPF.

PMID:34959146 | DOI:10.1016/j.rmed.2021.106722

Adv Ther. 2021 Dec 27. doi: 10.1007/s12325-021-02014-z. Online ahead of print.

ABSTRACT

INTRODUCTION: Among the various types of progressive fibrosing interstitial lung diseases (PF-ILDs), substantial survival data exist for idiopathic pulmonary fibrosis (IPF) but not for other types. This hinders evidence-based decisions about treatment and management, as well as the economic modelling needed to justify research into new treatments and reimbursement approvals. Given the clinical similarities between IPF and other PF-ILDs, we reasoned that patient survival data from four major IPF trials could be used to estimate long-term survival in other PF-ILDs.

METHODS: We used propensity score matching to match patients with IPF taking either nintedanib or placebo in the TOMORROW, INPULSIS-1, INPULSIS-2 and INPULSIS-ON trials to patients with PF-ILDs other than IPF in the INBUILD trial. Seven models were fitted to the survival data for the matched patients with IPF, and the three best-fitting models were used to generate informative priors in a Bayesian framework to extrapolate patient survival of the INBUILD population.

RESULTS: After propensity score matching, the analysis included data from 1099 patients with IPF (640 nintedanib patients; 459 placebo patients) and 654 patients with other PF-ILDs (326 nintedanib patients; 328 placebo patients). Gamma, log-logistic and Weibull models best fit the survival of the matched patients with IPF. All three models led to consistent Bayesian estimates of survival for the matched patients with other PF-ILDs, with median rates of overall survival ranging from 6.34 to 6.50 years after starting nintedanib. The corresponding control group survival estimates were 3.42 to 3.76 years.

CONCLUSION: We provide the first estimates of long-term overall survival for patients with PF-ILDs other than IPF, and our analysis suggests that nintedanib may prolong their survival. Our Bayesian approach to estimating survival of one disease based on clinical trial data from a similar disease may help inform economic modelling of rare, orphan and newly defined disorders.

PMID:34957531 | DOI:10.1007/s12325-021-02014-z

Int J Biochem Cell Biol. 2021 Dec 23:106142. doi: 10.1016/j.biocel.2021.106142. Online ahead of print.

ABSTRACT

Alveolar epithelial cell senescence is a core event in the development of pulmonary fibrosis. Endoplasmic reticulum stress accelerates cellular senescence significantly; however, whether this stress promotes alveolar epithelial cell senescence in pulmonary fibrosis and its mechanisms are unclear. As a common intersection of endoplasmic reticulum stress signaling pathways, CCAAT/enhancer-binding protein (C/EBP) homologous protein (CHOP) activates the oxidative stress pathway, which in turn accelerates cellular senescence. Therefore, we speculated CHOP pathway activation would affect endoplasmic reticulum stress-induced alveolar epithelial cell senescence in pulmonary fibrosis. In this study, we observed that alveolar epithelial cell senescence was accompanied by CHOP overexpression in idiopathic pulmonary fibrosis lung tissues. Bleomycin and tunicamycin combination models in vivo and in vitro showed that CHOP downregulation rescued alveolar epithelial cell senescence, reduced fibroblast activation mediated by the senescence-associated secretory phenotype, and improved pulmonary fibrosis pathology. Mechanistic studies showed that CHOP accelerated alveolar epithelial cell senescence by promoting reactive oxygen species generation, which activated the nuclear factor-kappa B pathway. Our study suggested that CHOP activates the downstream nuclear factor-kappa B pathway, thus contributing to endoplasmic reticulum stress-induced alveolar epithelial cell senescence and pulmonary fibrosis. DATA AVAILABILITY STATEMENT: All data generated or analyzed during this study are included in this published article.

PMID:34954323 | DOI:10.1016/j.biocel.2021.106142

Exp Mol Pathol. 2021 Dec 22:104737. doi: 10.1016/j.yexmp.2021.104737. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease of the lung tissue that causes symptoms such as coughing and asthma. It is caused by inflammatory factors and oxidative stress. In vivo model of IPF is induced by bleomycin (BLM,) a chemotherapeutic agent. We have investigated the effect of dapsone on bleomycin-induced IPF in adult male Wistar rats due to its anti-inflammatory and anti-oxidative stress effects. The animals were randomly divided into 5 groups (Control, BLM, BLM + dapsone 1, BLM + Dapsone 3, BLM + Dapsone 10). The control group received normal water and food. In the fibrosis group, bleomycin (BLM) (5 mg/kg) was used to induce pulmonary fibrosis by intratracheal administration. Three groups of animals were treated daily with single doses of 1, 3, and 10 mg dapsone by intraperitoneal injection 1 h after receiving BLM for 2 weeks. The activity of antioxidant enzymes superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and oxidative stress markers such as myeloperoxidase (MPO), malondialdehyde (MDA), protein carbonyl (PC) and nitrite were measured to evaluate bleomycin and therapeutic effect of dapsone. The histological assays of lung tissues were done by Hematoxylin-eosin (H & E) and Masson's trichrome staining. BLM reduced the activity of oxidative enzymes and increased the oxidative stress markers, while treatment with dapsone has reversed the results. In addition, the total number of cells as inflammatory cells such as neutrophils and eosinophils were examined. It has been indicated BLM increased these cells, and dapsone decreased them. The results of H & E and Masson's trichrome staining showed that dapsone reduced inflammation and alveolar wall thickness and BLM-induced pulmonary fibrosis. According to the findings of this study, dapsone seems to have therapeutic effects on pulmonary fibrosis through its anti-inflammatory and anti-oxidative stress properties and reduction of the toxic effects of bleomycin.

PMID:34953919 | DOI:10.1016/j.yexmp.2021.104737

J Biol Chem. 2021 Dec 22:101530. doi: 10.1016/j.jbc.2021.101530. Online ahead of print.

ABSTRACT

Various forms of fibrosis, comprising tissue thickening and scarring, are involved in 40% of deaths across the world. Since the discovery of scarless, functional healing in fetuses prior to a certain stage of development, scientists have attempted to replicate scarless wound healing in adults with little success. While the extracellular matrix (ECM), fibroblasts, and inflammatory mediators have been historically investigated as separate branches of biology, it has become increasingly necessary to consider them as parts of a complex and tightly regulated system that becomes dysregulated in fibrosis. With this new paradigm, revisiting fetal scarless wound healing provides a unique opportunity to better understand how this highly regulated system operates mechanistically. In the following review, we navigate the 4 stages of wound healing (hemostasis, inflammation, repair, and remodeling) against the backdrop of adult versus fetal wound healing, while also exploring the relationships between the ECM, effector cells, and signaling molecules. We conclude by singling out recent findings that offer promising leads to alter the dynamics between the ECM, fibroblasts, and inflammation to promote scarless healing. One factor that promises to be significant is fibroblast heterogeneity and how certain fibroblast subpopulations might be predisposed to scarless healing. Altogether, reconsidering fetal wound healing by examining the interplay of the various factors contributing to fibrosis provides new research directions that will hopefully help us better understand and address fibroproliferative diseases such as idiopathic pulmonary fibrosis, liver cirrhosis, systemic sclerosis, progressive kidney disease, and cardiovascular fibrosis.

PMID:34953859 | DOI:10.1016/j.jbc.2021.101530

Int Immunopharmacol. 2021 Dec 21;103:108470. doi: 10.1016/j.intimp.2021.108470. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a pathological consequence of interstitial pulmonary diseases, and is characterized by the persistence of fibroblasts and excessive deposition of extracellular matrix (ECM). The etiology of IPF is multifactorial. Although the role of inflammation in fibrogenesis is controversial, it is still recognized as an important component and epiphenomenon of IPF. Stimulus increase production of pro-inflammatory cytokines and activation of NF-κB, which will further promote inflammation response and myofibroblast transition. Lenalidomide is an immunomodulatory drug. Previous studies have revealed its anti-tumor effects through regulating immune response. Here we investigate the effect of lenalidomide on post-inflammation fibrosis. In vitro study revealed that lenalidomide inhibited NF-κB signaling in LPS-induced macrophage, and further attenuated macrophage-induced myofibroblast activation. Meanwhile, lenalidomide could inhibit TGF-β1-induced myofibroblast activation through suppressing TGF-β1 downstream MAPK signaling. In vivo study showed that lenalidomide inhibited pro-inflammatory cytokines TNF-α and IL-6 while enhanced anti-fibrotic cytokines IFN-γ and IL-10 in bleomycin-induced inflammation model, and attenuated pulmonary fibrosis and collagen deposition in the following fibrosis stage. In conclusion, our results demonstrate that lenalidomide possesses potential anti-fibrotic effects through suppressing NF-κB signaling.

PMID:34952465 | DOI:10.1016/j.intimp.2021.108470

Thorax. 2021 Dec 23:thoraxjnl-2021-217652. doi: 10.1136/thoraxjnl-2021-217652. Online ahead of print.

ABSTRACT

BACKGROUND: Air pollution exposure is associated with disease severity, progression and mortality in patients with idiopathic pulmonary fibrosis (IPF). Combined impacts of environmental and socioeconomic factors on outcomes in patients with IPF are unknown. The objectives of this study were to characterise the relationships between relative environmental and social disadvantage with clinical outcomes in patients with IPF.

METHODS: Patients with IPF were identified from a longitudinal database at University of California, San Francisco. Residential addresses were geocoded and linked to the CalEnviroScreen 3.0 (CES), a tool that quantifies environmental burden in California communities, combining population, environmental and pollution vulnerability into individual and composite scores (higher scores indicating greater disadvantage). Unadjusted and adjusted linear and logistic regression and Fine and Gray proportional hazards models were used.

RESULTS: 603 patients were included. Higher CES was associated with lower baseline forced vital capacity (β=-0.073, 95% CI -0.13 to -0.02; p=0.006) and diffusion capacity of the lung for carbon monoxide (β=-0.11, 95% CI -0.16 to -0.06; p<0.001). Patients in the highest population vulnerability quartile were less likely to be on antifibrotic therapy (OR=0.33; 95% CI 0.18 to 0.60; p=0.001) at time of enrolment, compared with those in the lowest quartile. An association between CES and mortality was suggested, but sensitivity analyses demonstrated inconsistent results. Relative disadvantage of the study cohort appeared lower compared with the general population.

CONCLUSIONS: Higher environmental exposures and vulnerability were associated with lower baseline lung function and lower antifibrotic use, suggesting that relative socioenvironmental disadvantage has meaningful impacts on patients with IPF.

PMID:34949724 | DOI:10.1136/thoraxjnl-2021-217652

Int J Mol Sci. 2021 Dec 14;22(24):13421. doi: 10.3390/ijms222413421.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with an unmet need of biomarkers that can aid in the diagnostic and prognostic assessment of the disease and response to treatment. In this two-part explorative proteomic study, we demonstrate how proteins associated with tissue remodeling, inflammation and chemotaxis such as MMP7, CXCL13 and CCL19 are released in response to aberrant extracellular matrix (ECM) in IPF lung. We used a novel ex vivo model where decellularized lung tissue from IPF patients and healthy donors were repopulated with healthy fibroblasts to monitor locally released mediators. Results were validated in longitudinally collected serum samples from 38 IPF patients and from 77 healthy controls. We demonstrate how proteins elevated in the ex vivo model (e.g., MMP7), and other serum proteins found elevated in IPF patients such as HGF, VEGFA, MCP-3, IL-6 and TNFRSF12A, are associated with disease severity and progression and their response to antifibrotic treatment. Our study supports the model's applicability in studying mechanisms involved in IPF and provides additional evidence for both established and potentially new biomarkers in IPF.

PMID:34948231 | DOI:10.3390/ijms222413421

Cells. 2021 Dec 11;10(12):3502. doi: 10.3390/cells10123502.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) remains an intractably fatal disorder, despite the recent advent of anti-fibrotic medication. Successful treatment of IPF, like many chronic diseases, may benefit from the concurrent use of multiple agents that exhibit synergistic benefit. In this light, phosphodiesterase type 5 inhibitors (PDE5-Is), have been studied in IPF primarily for their established pulmonary vascular effects. However, recent data suggest certain PDE5-Is, particularly vardenafil, may also reduce transforming growth factor beta 1 (TGF-β1) activation and extracellular matrix (ECM) accumulation, making them a potential target for therapy for IPF. We evaluated fibroblast TGF-β1-driven extracellular matrix (ECM) generation and signaling as well as epithelial mesenchymal transformation (EMT) with pretreatment using the PDE5-I vardenafil. In addition, combinations of vardenafil and nintedanib were evaluated for synergistic suppression of EMC using a fibronectin enzyme-linked immunosorbent assay (ELISA). Finally, the effects of vardenafil on fibrosis were investigated in a bleomycin mouse model. Our findings demonstrate that vardenafil suppresses ECM generation alone and also exhibits significant synergistic suppression of ECM in combination with nintedanib in vitro. Interestingly, vardenafil was shown to improve fibrosis markers and increase survival in bleomycin-treated mice. Vardenafil may represent a potential treatment for IPF alone or in combination with nintedanib. However, additional studies will be required.

PMID:34944010 | DOI:10.3390/cells10123502

Cells. 2021 Dec 7;10(12):3437. doi: 10.3390/cells10123437.

ABSTRACT

Chronic lung diseases (CLDs) represent a set of disorders characterized by the progressive loss of proper lung function. Among severe CLDs, the incidence of chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) has grown over the last decades, mainly in the elderly population. Several studies have highlighted an increased expression of senescence-related markers in the resident progenitor cells in COPD and IPF, possibly undermining epithelial integrity and contributing to the progression and the aggravation of both diseases. Recently, the chronic activation of the canonical Wnt/β-catenin pathway was shown to induce cellular senescence. Here, we investigated the localization and the expression of leucin-rich repeat-containing G-protein-coupled receptor 6 (LGR6), a protein that activates and potentiates the canonical Wnt signalling. Through immunohistochemical analyses, we identified a lesion-associated rise in LGR6 levels in abnormal lung epithelial progenitors in COPD and IPF when compared to histologically normal tissues. Moreover, in areas of aberrant regeneration, chronic damage and fibrosis, LGR6-expressing epithelial progenitors displayed a major increase in the expression of senescence-associated markers. Our study suggests the involvement of LGR6 in the chronic activation of the Wnt/β-catenin pathway, mediating the impairment and exhaustion of epithelial progenitors in COPD and IPF.

PMID:34943945 | DOI:10.3390/cells10123437

Diagnostics (Basel). 2021 Dec 4;11(12):2274. doi: 10.3390/diagnostics11122274.

ABSTRACT

The course of systemic sclerosis-associated interstitial lung disease (SSc-ILD) varies among individuals. Red blood cell distribution width (RDW) has been reported to be a predictor of idiopathic pulmonary fibrosis. However, there are no studies on the relationship between RDW and SSc-ILD. We conducted a retrospective study of 28 patients who were diagnosed with SSc-ILD on their first visit to our hospital and were followed-up for 5 years. The correlation between the changes in RDW, KL-6, and SP-D (ΔRDW, ΔKL-6, ΔSP-D) and the changes in percent-predicted forced lung volume and % carbon monoxide diffusion (Δ%FVC, Δ%DLco) was investigated. ΔRDW at 1 year after diagnosis was significantly inversely correlated with Δ%FVC at 5 years after diagnosis (r = -0.51, p < 0.001) and Δ%DLco at 5 years after diagnosis (r = -0.47, p < 0.001), whereas ΔKL-6 and ΔSP-D at 1 year were not correlated with Δ%FVC or Δ%DLco at 5 years. In the group of SSc-ILD patients with RDW increase in the first year after diagnosis, %FVC and %DLco were significantly lower than baseline at 3-, 4-, and 5-year assessments. In the group of patients without RDW increase in the first year, %FVC and %DLco did not decrease during the follow-up period. In conclusion, the changes in RDW in the first year after diagnosis may be useful surrogate markers to predict the long-term course of SSc-ILD.

PMID:34943510 | DOI:10.3390/diagnostics11122274

PLoS One. 2021 Dec 23;16(12):e0261684. doi: 10.1371/journal.pone.0261684. eCollection 2021.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial pneumonia of unknown etiology. In several randomized clinical trials, and in the clinical practice, pirfenidone is used to effectively and safely treat IPF. However, sometimes it is difficult to use the dose of pirfenidone used in clinical trials. This study evaluated the effects of low-dose pirfenidone on IPF disease progression and patient survival in the real-world.

METHODS: This retrospective, observational study enrolled IPF patients seen at the time of diagnosis at a single center from 2008 to 2018. Longitudinal clinical and laboratory data were prospectively collected. We compared the clinical characteristics, survival, and pulmonary function decline between patients treated and untreated with various dose of pirfenidone.

RESULTS: Of 295 IPF patients, 100 (33.9%) received pirfenidone and 195 (66.1%) received no antifibrotic agent. Of the 100 patients who received pirfenidone, 24 (24%), 50 (50%), and 26 (26%), respectively, were given 600, 1200, and 1800 mg pirfenidone daily. The mean survival time was 57.03 ± 3.90 months in the no-antifibrotic drug group and 73.26 ± 7.87 months in the pirfenidone-treated group (p = 0.027). In the unadjusted analysis, the survival of the patients given pirfenidone was significantly better (hazard ratio [HR] = 0.69, 95% confidence interval [CI]: 0.48-0.99, p = 0.04). After adjusting for age, gender, body mass index, and the GAP score [based on gender (G), age (A), and two physiological lung parameters (P)], survival remained better in the patients given pirfenidone (HR = 0.56, 95% CI: 0.37-0.85, p = 0.006). In terms of pulmonary function, the decreases in forced vital capacity (%), forced expiratory volume in 1 s (%) and the diffusing capacity of lung for carbon monoxide (%) were significantly smaller (p = 0.000, p = 0.001, and p = 0.007, respectively) in patients given pirfenidone.

CONCLUSIONS: Low-dose pirfenidone provided beneficial effects on survival and pulmonary function decline in the real-world practice.

PMID:34941933 | DOI:10.1371/journal.pone.0261684

ERJ Open Res. 2021 Dec 20;7(4):00441-2021. doi: 10.1183/23120541.00441-2021. eCollection 2021 Oct.

ABSTRACT

BACKGROUND: Acute exacerbations (AEs) and disease progression in interstitial lung disease (ILD) pose important challenges to clinicians and patients. AEs of ILD are variable in presentation but may result in rapid progression of ILD, respiratory failure and death. However, in many cases AEs of ILD may go unrecognised so that their true impact and response to therapy is unknown. The potential for home monitoring to facilitate early, and accurate, identification of AE and/or ILD progression has gained interest. With increasing evidence available, there is a need for a systematic review on home monitoring of patients with ILD to summarise the existing data. The aim of this review was to systematically evaluate the evidence for use of home monitoring for early detection of exacerbations and/or progression of ILD.

METHOD: We searched Ovid-EMBASE, MEDLINE and CINAHL using Medical Subject Headings (MeSH) terms in accordance with the PRISMA guidelines (PROSPERO registration number CRD42020215166).

RESULTS: 13 studies involving 968 patients have demonstrated that home monitoring is feasible and of potential benefit in patients with ILD. Nine studies reported that mean adherence to home monitoring was >75%, and where spirometry was performed there was a significant correlation (r=0.72-0.98, p<0.001) between home and hospital-based readings. Two studies suggested that home monitoring of forced vital capacity might facilitate detection of progression in idiopathic pulmonary fibrosis.

CONCLUSION: Despite the fact that individual studies in this systematic review provide supportive evidence suggesting the feasibility and utility of home monitoring in ILD, further studies are necessary to quantify the potential of home monitoring to detect disease progression and/or AEs.

PMID:34938799 | PMC:PMC8685510 | DOI:10.1183/23120541.00441-2021

Eur Respir Rev. 2021 Dec 22;30(162):210177. doi: 10.1183/16000617.0177-2021. Print 2021 Dec 31.

ABSTRACT

The presence of clinical, serological and/or radiological features suggestive, but not confirmatory, of a defined connective tissue disease in patients with interstitial lung disease is a relatively frequent occurrence. In 2015, the European Respiratory Society and the American Thoracic Society proposed classification criteria for the interstitial pneumonia with autoimmune features (IPAF) research entity to capture such patients in a standardised manner, with the intention of nurturing clinical research. This initiative resulted in the publication of several series of IPAF patients, with significant variation between cohorts in clinical characteristics, outcome and the application of IPAF criteria in patient selection. From this increasing body of published work, it has become apparent that revision of IPAF criteria is now required in order to justify the eventual designation of IPAF as a standalone diagnostic term, as opposed to a provisional entity put forward as a basis for clinical research. This review covers the current state of IPAF, conclusions that can and cannot be drawn from the IPAF evidence base, and ongoing uncertainties that require further expert group consideration.

PMID:34937706 | DOI:10.1183/16000617.0177-2021

Respirology. 2021 Dec 21. doi: 10.1111/resp.14194. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is one of the most common forms of interstitial lung diseases. While studies have been conducted in other countries to determine the epidemiological burden of IPF, there is limited information in Australia. Our study aimed to address this gap and generate the first estimates for the mortality, incidence and prevalence of IPF in Australia.

METHODS: Estimates were generated by utilizing the novel Mortality Incidence Analysis Model (MIAMOD) method and software based on the illness-death model. Data inputs included population estimates and mortality data from the Australian Bureau of Statistics (ABS) for the period 1997-2015 and participant data from the Australian IPF Registry (AIPFR). Projections were estimated for a 10-year period up to 2025.

RESULTS: Overall crude and age-standardized estimates for mortality were 5.9 and 6.3 per 100,000 population; incidence, 10.4 and 11.2 per 100,000 population; and prevalence, 32.6 and 35.1 per 100,000 population. Crude and age-standardized mortality, incidence and prevalence increased over the study period; however, they demonstrated a decreasing trend over the projected period. Persons older than 70 years constituted 9% of the population; however, they accounted for approximately 82%-83% of all deaths, incident and prevalent cases. All estimates were higher in males than in females.

CONCLUSION: Our study provides the first estimates for incidence, prevalence and mortality of IPF in Australia. By reporting national estimates for IPF, our study addresses an information gap important for policy, planning and to help optimize the allocation of resources for the management of patients with IPF.

PMID:34935240 | DOI:10.1111/resp.14194

Am J Gastroenterol. 2021 Dec 21. doi: 10.14309/ajg.0000000000001577. Online ahead of print.

ABSTRACT

INTRODUCTION: Gastroesophageal reflux has been associated with idiopathic pulmonary fibrosis (IPF). Mean nocturnal baseline impedance (MNBI) is a marker of esophageal mucosal integrity, whereas postreflux swallow-induced peristaltic wave (PSPW) index reflects esophageal chemical clearance. Both metrics offer novel ways to assess reflux burden on multichannel intraluminal impedance-pH testing (MII-pH), but their role in extraesophageal reflux remains unclear. We aimed to evaluate the relationship between these novel metrics and lung function decline in patients with IPF.

METHODS: Adults with IPF undergoing prelung transplant MII-pH were enrolled. All patients completed pulmonary function testing (PFT) at the time of MII-pH and at the 1-year follow-up. MNBI was calculated by averaging baseline impedance at three 10-minute intervals (1 AM/2 AM/3 AM). PSPW index was the proportion of all reflux episodes, followed by a peristaltic swallow within 30 seconds. Univariate (Student t-test/Pearson correlation) and multivariable (general linear regression) analyses were performed.

RESULTS: One hundred twenty-five subjects (mean age = 61.7 years, 62% men) were included. Forced expiratory volume in one second and forced vital capacity declined more significantly over 12 months in subjects with lower distal MNBI, proximal MNBI, and PSPW index (all P < 0.05). On multivariable analyses adjusting for age, sex, proton pump inhibitor use, and baseline lung function, distal MNBI (β = -10.86, P = 0.024; β = -8.03, P = 0.045), proximal MNBI (β = -13.5, P = 0.0068; β = -9.80, P = 0.025), and PSPW index (β = -18.1, P = 0.010; β = -12.55, P = 0.050) remained predictive of greater forced expiratory volume in one second and forced vital capacity decline.

DISCUSSION: Low distal MNBI, proximal MNBI, and PSPW index independently predicted more severe lung function decline over 1 year in patients with IPF. These impedance metrics may have prognostic value and support a role for reflux in IPF pathogenesis.

PMID:34934030 | DOI:10.14309/ajg.0000000000001577

J Heart Lung Transplant. 2021 Nov 15:S1053-2498(21)02584-5. doi: 10.1016/j.healun.2021.11.008. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients.

METHODS: Individuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review.

RESULTS: Of 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres.

CONCLUSIONS: There is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.

PMID:34933798 | DOI:10.1016/j.healun.2021.11.008