Journal of Clinical Medicine

Research

18 pages, 3143 KiB

Open AccessArticle

Evaluation of Regional Pulmonary Ventilation in Spontaneously Breathing Patients with Idiopathic Pulmonary Fibrosis (IPF) Employing Electrical Impedance Tomography (EIT): A Pilot Study from the European IPF Registry (eurIPFreg)

by Ekaterina Krauss, Daniel van der Beck, Isabel Schmalz, Jochen Wilhelm, Silke Tello, Ruth C. Dartsch, Poornima Mahavadi, Martina Korfei, Eckhard Teschner, Werner Seeger and Andreas Guenther

J. Clin. Med. 2021, 10(2), 192; https://doi.org/10.3390/jcm10020192 - 7 Jan 2021

Cited by 9 | Viewed by 3061

Abstract

Objectives: In idiopathic pulmonary fibrosis (IPF), alterations in the pulmonary surfactant system result in an increased alveolar surface tension and favor repetitive alveolar collapse. This study aimed to assess the usefulness of electrical impedance tomography (EIT) in characterization of regional ventilation in IPF. [...] Read more.

Objectives: In idiopathic pulmonary fibrosis (IPF), alterations in the pulmonary surfactant system result in an increased alveolar surface tension and favor repetitive alveolar collapse. This study aimed to assess the usefulness of electrical impedance tomography (EIT) in characterization of regional ventilation in IPF. Materials and methods: We investigated 17 patients with IPF and 15 healthy controls from the University of Giessen and Marburg Lung Center (UGMLC), Germany, for differences in the following EIT parameters: distribution of ventilation (TID), global inhomogeneity index (GI), regional impedance differences through the delta of end-expiratory lung impedance (dEELI), differences in surface of ventilated area (SURF), as well as center of ventilation (CG) and intratidal gas distribution (ITV). These parameters were assessed under spontaneous breathing and following a predefined escalation protocol of the positive end-expiratory pressure (PEEP), applied through a face mask by an intensive care respirator (EVITA, Draeger, Germany). Results: Individual slopes of dEELI over the PEEP increment protocol were found to be highly significantly increased in both groups (p < 0.001) but were not found to be significantly different between groups. Similarly, dTID slopes were increasing in response to PEEP, but this did not reach statistical significance within or between groups. Individual breathing patterns were very heterogeneous. There were no relevant differences of SURF, GI or CGVD over the PEEP escalation range. A correlation of dEELI to FVC, BMI, age, or weight did not forward significant results. Conclusions: In this study, we did see a significant increase in dEELI and a non-significant increase in dTID in IPF patients as well as in healthy controls in response to an increase of PEEP under spontaneous breathing. We propose the combined measurements of EIT and lung function to assess regional lung ventilation in spontaneously breathing subjects. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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14 pages, 538 KiB

Open AccessArticle

Prevalence of Novel Myositis Autoantibodies in a Large Cohort of Patients with Interstitial Lung Disease

by Sofia A. Moll, Mark G. J. P. Platenburg, Anouk C. M. Platteel, Adriane D. M. Vorselaars, Montse Janssen Bonàs, Claudia Roodenburg-Benschop, Bob Meek, Coline H. M. van Moorsel and Jan C. Grutters

J. Clin. Med. 2020, 9(9), 2944; https://doi.org/10.3390/jcm9092944 - 11 Sep 2020

Cited by 16 | Viewed by 3744

Abstract

Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in [...] Read more.

Connective tissue diseases (CTDs) are an important secondary cause of interstitial lung disease (ILD). If a CTD is suspected, clinicians are recommended to perform autoantibody testing, including for myositis autoantibodies. In this study, the prevalence and clinical associations of novel myositis autoantibodies in ILD are presented. A total of 1194 patients with ILD and 116 healthy subjects were tested for antibodies specific for Ks, Ha, Zoα, and cN1A with a line-blot assay on serum available at the time of diagnosis. Autoantibodies were demonstrated in 63 (5.3%) patients and one (0.9%) healthy control (p = 0.035). Autoantibodies were found more frequently in females (p = 0.042) and patients without a histological and/or radiological usual interstitial pneumonia (UIP; p = 0.010) and a trend towards CTD-ILDs (8.4%) was seen compared with other ILDs (4.9%; p = 0.090). The prevalence of antibodies specific for Ks, Ha, Zoα, and cN1A was, respectively, 1.3%, 2.0%, 1.4%, and 0.9% in ILD. Anti-Ha and Anti-Ks were observed in males with unclassifiable idiopathic interstitial pneumonia (unclassifiable IIP), hypersensitivity pneumonitis (HP), and various CTD-ILDs, whereas anti-cN1A was seen in females with antisynthetase syndrome (ASS), HP, and idiopathic pulmonary fibrosis (IPF). Anti-Zoα was associated with CTD-ILD (OR 2.5; 95%CI 1.11–5.61; p = 0.027). In conclusion, a relatively high prevalence of previously unknown myositis autoantibodies was found in a large cohort of various ILDs. Our results contribute to the awareness that circulating autoantibodies can be found in ILDs with or without established CTD. Whether these antibodies have to be added to the standard set of autoantibodies analysed in conventional myositis blot assays for diagnostic purposes in clinical ILD care requires further study. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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11 pages, 2189 KiB

Open AccessArticle

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis—Part B

by Canay Caliskan, Benjamin Seeliger, Benedikt Jäger, Jan Fuge, Tobias Welte, Oliver Terwolbeck, Julia Freise, Coline H. M. van Moorsel, Yingze Zhang and Antje Prasse

J. Clin. Med. 2020, 9(6), 1993; https://doi.org/10.3390/jcm9061993 - 25 Jun 2020

Cited by 8 | Viewed by 2978

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive disease with high mortality. CC-chemokine ligand 18 (CCL18) is predictive of survival in IPF. We described correlation of CCL18 serum levels with the genotype of rs2015086 C > T polymorphism the CCL18-gene, which was associated with survival in a pre-antifibrotic cohort (Part-A). Herein (Part-B), we aimed to validate these findings and to study the effects of antifibrotics. Two cohorts were prospectively recruited, cohort-A (n = 61, pre-antifibrotic) and cohort B (n = 101, received antifibrotics). Baseline CCL18 serum level measurement by enzyme-linked immunosorbent assay (ELISA, serially in cohort B) and genotyping of rs2015086 was performed and correlated with clinical outcomes. The CT genotype was present in 15% and 31% of patients. These patients had higher CCL18 levels compared to the TT-genotype (cohort-A: 234 vs. 115.8 ng/mL, p < 0.001; cohort B: 159.5 vs. 120 ng/mL, p = 0.0001). During antifibrotic therapy, CCL18 increased (p = 0.0036) regardless of rs2015086-genotype and antifibrotic-agent. In cohort-A, baseline CCL18-cutoff (>120 ng/mL) and CT-genotype were associated with mortality (p = 0.041 and p = 0.0051). In cohort-B, the CCL18-cutoff (>140 ng/mL) was associated with mortality (p = 0.003) and progression (p = 0.004), but not the CT/CC-genotype. In conclusion, we validated the correlation between rs2015086-genotype and CCL18 serum levels, which was predictive of (progression-free)-survival in two prospective validation cohorts. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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11 pages, 1019 KiB

Open AccessArticle

Genetic Variation in CCL18 Gene Influences CCL18 Expression and Correlates with Survival in Idiopathic Pulmonary Fibrosis: Part A

by Ivo A. Wiertz, Sofia A. Moll, Benjamin Seeliger, Nicole P. Barlo, Joanne J. van der Vis, Nicoline M. Korthagen, Ger T. Rijkers, Henk J.T. Ruven, Jan C. Grutters, Antje Prasse and Coline H.M. van Moorsel

J. Clin. Med. 2020, 9(6), 1940; https://doi.org/10.3390/jcm9061940 - 21 Jun 2020

Cited by 21 | Viewed by 3156

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of [...] Read more.

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease, characterized by fibroblast proliferation and extracellular matrix deposition. CC-chemokine ligand 18 (CCL18) upregulates the production of collagen by lung fibroblasts and is associated with mortality. This study was designed to evaluate the influence of single nucleotide polymorphisms (SNPs) in the CCL18 gene on CCL18 expression and survival in IPF. Serum CCL18 levels and four SNPs in the CCL18 gene were analyzed in 77 Dutch IPF patients and 349 healthy controls (HCs). CCL18 mRNA expression was analyzed in peripheral blood mononuclear cells (PBMCs) from 18 healthy subjects. Survival analysis was conducted, dependent on CCL18-levels and -genotypes and validated in two German IPF cohorts (Part B). IPF patients demonstrated significantly higher serum CCL18 levels than the healthy controls (p < 0.001). Both in IPF patients and HCs, serum CCL18 levels were influenced by rs2015086 C > T genotype, with the highest CCL18-levels with the presence of the C-allele. Constitutive CCL18 mRNA-expression in PBMCs was significantly increased with the C-allele and correlated with serum CCL18-levels. In IPF, high serum levels correlated with decreased survival (p = 0.02). Survival was worse with the CT-genotype compared to the TT genotype (p = 0.01). Concluding, genetic variability in the CCL18-gene accounts for differences in CCL18 mRNA-expression and serum-levels and influences survival in IPF. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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12 pages, 869 KiB

Open AccessArticle

Short-Term Effects of Comprehensive Pulmonary Rehabilitation and its Maintenance in Patients with Idiopathic Pulmonary Fibrosis: A Randomized Controlled Trial

by Inga Jarosch, Tessa Schneeberger, Rainer Gloeckl, Michael Kreuter, Marion Frankenberger, Claus Neurohr, Antje Prasse, Julia Freise, Juergen Behr, Wolfgang Hitzl, Andreas R. Koczulla and Klaus Kenn

J. Clin. Med. 2020, 9(5), 1567; https://doi.org/10.3390/jcm9051567 - 21 May 2020

Cited by 33 | Viewed by 4614

Abstract

The recommendation for pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) is weak with low-quality evidence. Therefore, the aim of this study is to investigate short-term PR effects and their maintenance after a 3-month follow-up. Fifty-four IPF patients were randomized into a group [...] Read more.

The recommendation for pulmonary rehabilitation (PR) in idiopathic pulmonary fibrosis (IPF) is weak with low-quality evidence. Therefore, the aim of this study is to investigate short-term PR effects and their maintenance after a 3-month follow-up. Fifty-four IPF patients were randomized into a group receiving a 3-week comprehensive, inpatient PR (n = 34, FVC: 74 ± 19% pred.) or usual care (UC) (n = 17, FVC: 72 ± 20%pred.). Outcomes were measured at baseline (T1), after intervention (T2), and 3 months after T2 (T3). A 6-min walk distance (6MWD) was used as the primary outcome and chronic respiratory disease questionnaire (CRQ) scores as the secondary outcome. Change in 6MWD from T1 to T2 (Δ = 61 m, 95% CI (18.5–102.4), p = 0.006) but not from T1 to T3 (∆ = 26 m, 95% CI (8.0–61.5), p = 0.16) differed significantly between groups. Higher baseline FVC and higher anxiety symptoms were significant predictors of better short-term 6MWD improvements. For the change in CRQ total score, a significant between-group difference from T1 to T2 (∆ = 3.0 pts, 95% CI (0.7–5.3), p = 0.01) and from T1 to T3 (∆ = 3.5 pts, 95% CI (1.5–5.4), p = 0.001) was found in favour of the PR group. To conclude, in addition to the short-term benefits, inpatient PR is effective at inducing medium-term quality of life improvements in IPF. PR in the early stages of the disease seems to provoke the best benefits. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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Review

Jump to: Research, Other

13 pages, 305 KiB

Open AccessFeature PaperReview

Telomeres in Interstitial Lung Disease

by Carmel J. W. Stock and Elisabetta A. Renzoni

J. Clin. Med. 2021, 10(7), 1384; https://doi.org/10.3390/jcm10071384 - 30 Mar 2021

Cited by 27 | Viewed by 4975

Abstract

Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive [...] Read more.

Interstitial lung diseases (ILD) encompass a group of conditions involving fibrosis and/or inflammation of the pulmonary parenchyma. Telomeres are repetitive DNA sequences at chromosome ends which protect against genome instability. At each cell division, telomeres shorten, but the telomerase complex partially counteracts progressive loss of telomeres by catalysing the synthesis of telomeric repeats. Once critical telomere shortening is reached, cell cycle arrest or apoptosis are triggered. Telomeres progressively shorten with age. A number of rare genetic mutations have been identified in genes encoding for components of the telomerase complex, including telomerase reverse transcriptase (TERT) and telomerase RNA component (TERC), in familial and, less frequently, in sporadic fibrotic ILDs. Defects in telomerase result in extremely short telomeres. More rapidly progressive disease is observed in fibrotic ILD patients with telomere gene mutations, regardless of underlying diagnosis. Associations with common single nucleotide polymorphisms in telomere related genes have also been demonstrated for various ILDs. Shorter peripheral blood telomere lengths compared to age-matched healthy individuals are found in a proportion of patients with fibrotic ILDs, and in idiopathic pulmonary fibrosis (IPF) and fibrotic hypersensitivity pneumonitis (HP) have been linked to worse survival, independently of disease severity. Greater susceptibility to immunosuppressant-induced side effects in patients with short telomeres has been described in patients with IPF and with fibrotic HP. Here, we discuss recent evidence for the involvement of telomere length and genetic variations in the development, progression, and treatment of fibrotic ILDs. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

16 pages, 326 KiB

Open AccessReview

Progression in the Management of Non-Idiopathic Pulmonary Fibrosis Interstitial Lung Diseases, Where Are We Now and Where We Would Like to Be

by Tinne Goos, Laurens J. De Sadeleer, Jonas Yserbyt, Geert M. Verleden, Marie Vermant, Stijn E. Verleden and Wim A. Wuyts

J. Clin. Med. 2021, 10(6), 1330; https://doi.org/10.3390/jcm10061330 - 23 Mar 2021

Cited by 12 | Viewed by 4284

Abstract

A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness [...] Read more.

A significant proportion of patients with interstitial lung disease (ILD) may develop a progressive fibrosing phenotype characterized by worsening of symptoms and pulmonary function, progressive fibrosis on chest computed tomography and increased mortality. The clinical course in these patients mimics the relentless progressiveness of idiopathic pulmonary fibrosis (IPF). Common pathophysiological mechanisms such as a shared genetic susceptibility and a common downstream pathway—self-sustaining fibroproliferation—support the concept of a progressive fibrosing phenotype, which is applicable to a broad range of non-IPF ILDs. While antifibrotic drugs became the standard of care in IPF, immunosuppressive agents are still the mainstay of treatment in non-IPF fibrosing ILD (F-ILD). However, recently, randomized placebo-controlled trials have demonstrated the efficacy and safety of antifibrotic treatment in systemic sclerosis-associated F-ILD and a broad range of F-ILDs with a progressive phenotype. This review summarizes the current pharmacological management and highlights the unmet needs in patients with non-IPF ILD. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

Other

Jump to: Research, Review

10 pages, 266 KiB

Open AccessPerspective

Towards the Essence of Progressiveness: Bringing Progressive Fibrosing Interstitial Lung Disease (PF-ILD) to the Next Stage

by Laurens J. De Sadeleer, Tinne Goos, Jonas Yserbyt and Wim A. Wuyts

J. Clin. Med. 2020, 9(6), 1722; https://doi.org/10.3390/jcm9061722 - 3 Jun 2020

Cited by 17 | Viewed by 3473

Abstract

Although only recently introduced in the ILD community, the concept of progressive fibrosing interstitial lung disease (PF-ILD) has rapidly acquired an important place in the management of non-idiopathic pulmonary fibrosis fibrosing ILD (nonIPF fILD) patients. It confirms a clinical gut feeling that an [...] Read more.

Although only recently introduced in the ILD community, the concept of progressive fibrosing interstitial lung disease (PF-ILD) has rapidly acquired an important place in the management of non-idiopathic pulmonary fibrosis fibrosing ILD (nonIPF fILD) patients. It confirms a clinical gut feeling that an important subgroup of nonIPF fILD portends a dismal prognosis despite therapeutically addressing the alleged triggering event. Due to several recently published landmark papers showing a treatment benefit with currently available antifibrotic drugs in PF-ILD patients, endorsing a PF-ILD phenotype has vital therapeutic consequences. Importantly, defining progressiveness is based on former progression, which has proven to be a rather moderate predictor of future progression. As fibrosis extent >20% and the presence of honeycombing have superior predictive properties regarding future progression, we advocate immediate initiation of antifibrotic treatment in the presence of these risk factors. In this perspective, we describe the historical context wherein PF-ILD has emerged, determine the currently employed PF-ILD criteria and their inherent limitations and propose new directions to mature its definition. Finally, while ascertaining progression in a nonIPF fILD patient clearly demonstrates the need for (additional) therapy, in the future, therapeutic decisions should be taken after assessing which pathway is ultimately driving the progression. Although not readily available, pathophysiological insight and diagnostic means are emergent to go full steam ahead in this novel direction. Full article

(This article belongs to the Special Issue The New Perspective in Pulmonary Fibrosis)

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