BMC Pulm Med. 2021 Feb 5;21(1):51. doi: 10.1186/s12890-021-01418-5.

ABSTRACT

BACKGROUND: Malnutrition and altered body composition are well-documented in chronic pulmonary diseases; however, investigation of nutritional status in interstitial lung disease (ILD) is limited. This study aimed to describe the nutritional status of ILD patients within three diagnostic groups and explore the relationship between nutritional status and quality of life (QoL).

METHODS: Consecutive patients attending an ILD clinic within a tertiary referral hospital in Sydney, Australia were studied. Weight, body-mass-index, anthropometrics, handgrip strength (HGS), subjective global assessment and QoL questionnaires (EQ-5D-5L and King's-Brief Interstitial-Lung-Disease 'K-BILD') were collected. Associations between nutritional status and QoL were analysed.

RESULTS: Ninety participants were recruited and categorised: (1) Idiopathic Pulmonary Fibrosis (IPF) (2) Connective-Tissue Disease associated-ILD (CTD-ILD) or (3) Other (non-IPF/non-CTD ILD). Median age was 66.5 (18) years. Four-percent of patients were underweight and 50% were overweight or obese. Median HGS was 71%-(25.3) of predicted and was correlated to all measures of QoL including EQ-5D health-state index (r = 0.376, p < 0.0001), patient-reported EQ-5D-5L Visual Analogue Score (r = 0.367, p < 0.0001) and K-BILD total score (r = 0.346, p = 0.001). Twenty-three percent of the variance in K-BILD total score (F = 12.888, p < 0.0001) was explained by HGS (ß = 0.273, p = 0.006) and forced vital capacity % predicted (ß = 0.331, p = 0.001).

CONCLUSIONS: Although a small number of ILD patients were malnourished, a large proportion of the cohort were overweight or obese. Handgrip strength was compromised and correlated to QoL. Future research with a larger cohort is required to explore the role of HGS as a predictor of QoL.

PMID:33546667 | PMC:PMC7863253 | DOI:10.1186/s12890-021-01418-5

Am J Respir Crit Care Med. 2021 Feb 5. doi: 10.1164/rccm.202010-3994ED. Online ahead of print.

NO ABSTRACT

PMID:33545013 | DOI:10.1164/rccm.202010-3994ED

Thorax. 2021 Feb 4:thoraxjnl-2020-215135. doi: 10.1136/thoraxjnl-2020-215135. Online ahead of print.

ABSTRACT

BACKGROUND: Exercise-induced hypoxaemia is a hallmark of chronic fibrotic interstitial lung disease (f-ILD). It remains unclear whether patients' severe hypoxaemia may exaggerate locomotor muscle fatigue and, if so, to what extent oxygen (O2) supplementation can ameliorate these abnormalities.

METHODS: Fifteen patients (12 males, 9 with idiopathic pulmonary fibrosis) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) while breathing medical air. Fifteen age-matched and sex-matched controls cycled up to patients' Tlim. Patients repeated the exercise test on supplemental O2 (42%±7%) for the same duration. Near-infrared spectroscopy assessed vastus lateralis oxyhaemoglobin concentration ((HbO2)). Pre-exercise to postexercise variation in twitch force (∆Tw) induced by femoral nerve magnetic stimulation quantified muscle fatigue.

RESULTS: Patients showed severe hypoxaemia (lowest O2 saturation by pulse oximetry=80.0%±7.6%) which was associated with a blunted increase in muscle (HbO2) during exercise vs controls (+1.3±0.3 µmol vs +4.4±0.4 µmol, respectively; p<0.001). Despite exercising at work rates ∼ one-third lower than controls (42±13 W vs 66±13 W), ∆Tw was greater in patients (∆Tw/external work performed by the leg muscles=-0.59±0.21 %/kJ vs -0.25±0.19 %/kJ; p<0.001). Reversal of exertional hypoxaemia with supplemental O2 was associated with a significant increase in muscle (HbO2), leading to a reduced decrease in ∆Tw in patients (-0.33±0.19 %/kJ; p<0.001 vs air). Supplemental O2 significantly improved leg discomfort (p=0.005).

CONCLUSION: O2 supplementation during exercise improves leg muscle oxygenation and fatigue in f-ILD. Lessening peripheral muscle fatigue to enhance exercise tolerance is a neglected therapeutic target that deserves clinical attention in this patient population.

PMID:33542089 | DOI:10.1136/thoraxjnl-2020-215135

Eur Respir J. 2021 Feb 4:2004507. doi: 10.1183/13993003.04507-2020. Online ahead of print.

ABSTRACT

Interstitial lung diseases (ILD) comprise a large and heterogeneous group of disorders of known and unknown etiology characterised by diffuse damage of the lung parenchyma. In the past years, it has become evident that patients with different types of ILD are at risk of developing progressive pulmonary fibrosis known as pulmonary fibrosing ILD (PF-ILD). This is a phenotype behaving similar to idiopathic pulmonary fibrosis, the archetypical example of progressive fibrosis. PF-ILD is not a distinct clinical entity but describes a group of ILD with a similar clinical behavior. This phenotype may occur in diseases displaying distinct etiologies and different biopathology during their initiation and development. Importantly, these entities may have the potential for improvement or stabilisation prior to entering in the progressive fibrosing phase. The crucial questions are (1) why a subset of patients develops a progressive and irreversible fibrotic phenotype even with appropriate treatment, and (2) what the pathogenic mechanisms driving progression possibly are. We here provide a framework highlighting putative mechanisms underlying progression, including genetic susceptibility, aging, epigenetics, the structural fibrotic distortion, the aberrant composition and stiffness of the extracellular matrix, and the emergence of distinct profibrotic cell subsets. Understanding the cellular and molecular mechanisms behind PF-ILD will provide the basis for identifying risk factors and appropriate therapeutical strategies.

PMID:33542060 | DOI:10.1183/13993003.04507-2020

Clin Chest Med. 2021 Mar;42(1):59-70. doi: 10.1016/j.ccm.2020.11.006.

ABSTRACT

Group 3 pulmonary hypertension (PH) is a known sequelae of chronic lung disease. Diagnosis and classification can be challenging in the background of chronic lung disease and often requires expert interpretation of numerous diagnostic studies to ascertain the true nature of the PH. Stabilization of the underlying lung disease and adjunctive therapies such as oxygen remain the mainstays of therapy, as there are no Food and Drug Administration-approved therapies for group 3 PH. Referral to PH centers for individualized management and clinical trial enrollment is paramount.

PMID:33541617 | DOI:10.1016/j.ccm.2020.11.006

Theranostics. 2021 Jan 9;11(7):3244-3261. doi: 10.7150/thno.54217. eCollection 2021.

ABSTRACT

Rationale: (Myo)fibroblasts are the ultimate effector cells responsible for the production of collagen within alveolar structures, a core phenomenon in the pathogenesis of idiopathic pulmonary fibrosis (IPF). Although (myo)fibroblast-targeted therapy holds great promise for suppressing the progression of IPF, its development is hindered by the limited drug delivery efficacy to (myo)fibroblasts and the vicious circle of (myo)fibroblast activation and evasion of apoptosis. Methods: Here, a dual small interfering RNA (siRNA)-loaded delivery system of polymeric micelles is developed to suppress the development of pulmonary fibrosis via a two-arm mechanism. The micelles are endowed with (myo)fibroblast-targeting ability by modifying the Fab' fragment of the anti-platelet-derived growth factor receptor-α (PDGFRα) antibody onto their surface. Two different sequences of siRNA targeting protein tyrosine phosphatase-N13 (PTPN13, a promoter of the resistance of (myo)fibroblasts to Fas-induced apoptosis) and NADPH oxidase-4 (NOX4, a key regulator for (myo)fibroblast differentiation and activation) are loaded into micelles to inhibit the formation of fibroblastic foci. Results: We demonstrate that Fab'-conjugated dual siRNA-micelles exhibit higher affinity to (myo)fibroblasts in fibrotic lung tissue. This Fab'-conjugated dual siRNA-micelle can achieve remarkable antifibrotic effects on the formation of fibroblastic foci by, on the one hand, suppressing (myo)fibroblast activation via siRNA-induced knockdown of NOX4 and, on the other hand, sensitizing (myo)fibroblasts to Fas-induced apoptosis by siRNA-mediated PTPN13 silencing. In addition, this (myo)fibroblast-targeting siRNA-loaded micelle did not induce significant damage to major organs, and no histopathological abnormities were observed in murine models. Conclusion: The (myo)fibroblast-targeting dual siRNA-loaded micelles offer a potential strategy with promising prospects in molecular-targeted fibrosis therapy.

PMID:33537085 | PMC:PMC7847691 | DOI:10.7150/thno.54217

Int J Chron Obstruct Pulmon Dis. 2021 Jan 28;16:167-177. doi: 10.2147/COPD.S286360. eCollection 2021.

ABSTRACT

BACKGROUND: Combined pulmonary fibrosis and emphysema (CPFE) is an underrecognized syndrome characterized by chronic, progressive disease with a dismal prognosis. Frequent co-morbidities with a higher incidence than in idiopathic pulmonary fibrosis or emphysema alone are pulmonary hypertension (WHO group 3) in 47-90% of the patients and lung cancer in 46.8% of the patients.

OBJECTIVE: Review current evidence and knowledge concerning diagnosis, risk factors, disease evolution and treatment options of CPFE.

METHODS: We searched studies reporting CPFE in original papers, observational studies, case reports, and meta-analyses published between 1990 and August 2020, in the PubMed, Embase, Cochrane Library, Wiley Online Library databases and Google Scholar using the search terms [CPFE], [pulmonary fibrosis] OR [IPF] AND [emphysema]. Bibliographies of retrieved articles were searched as well. Further inclusion criteria were publications in English, French, German and Italian, with reference to humans. In vitro data and animal data were not considered unless they were mentioned in studies reporting predominantly human data.

RESULTS: Between May 1, 1990, and September 1, 2020, we found 16 studies on CPFE from the online sources and bibliographies. A total of 890 patients are described in the literature. Although male/female ratio was not reported in all studies, the large majority of patients were male (at least 78%), most of them were current or former heavy smokers.

CONCLUSION: CPFE is a syndrome presenting with dyspnea on exertion followed by disruptive cough and recurrent exacerbations. The disease may progress rapidly, be aggravated by pulmonary hypertension WHO group 3 and is associated with an increased risk of lung cancer. Smoking and male sex are important risk factors. There is a need for more research on CPFE especially relating to etiology, influence of genetics, treatment and prevention options. Antifibrotic therapy might be an interesting treatment option for these patients.

PMID:33536752 | PMC:PMC7850450 | DOI:10.2147/COPD.S286360

Br J Radiol. 2021 Feb 4:20201159. doi: 10.1259/bjr.20201159. Online ahead of print.

ABSTRACT

OBJECTIVES: To determine whether the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for usual interstitial pneumonia (UIP) provide better diagnostic agreement compared to the 2011 guidelines.

METHODS: Cohort for this cross-sectional study (single center, nonacademic) was recruited from a multidisciplinary team discussion (MDD) from July 2010 until November 2018, with clinical suspicion of fibrosing interstitial lung disease (n= 325). Exclusion criteria were technical HRCT issues, known connective tissue disease (rheumatoid arthritis, systemic sclerosis, poly-or dermatomyositis), exposure to pulmonary toxins or lack of working diagnosis after MDD. Four readers with varying degrees in HRCT interpretation independently categorized 192 HRCTs, according to both the previous and current ATS/ERS/JRS/ALAT radiological criteria. An inter-rater variability analysis (Gwet's second-order agreement coefficient, AC2) was performed.

RESULTS: The resulting Gwet's AC2 for the 2011 and 2018 ATS/ERS/JRS/ALAT radiological criteria is 0.62 (±0.05) and 0.65 (±0.05), respectively. We report only minor differences in agreement level among the readers. Distribution according to the 2011 guidelines is as follows: 57.3% 'UIP pattern', 24% 'possible UIP pattern', 18.8% 'inconsistent with UIP pattern' and for the 2018 guidelines: 59.6% 'UIP', 14.5% 'probable UIP', 15.9% 'indeterminate for UIP' and 10% 'alternative diagnosis'.

CONCLUSIONS: No statistically significant higher degree of diagnostic agreement is observed when applying the revised 2018 ATS/ERS/JRS/ALAT radiological criteria for UIP compared to those of 2011. The inter-rater variability for categorizing the HRCT patterns is moderate for both classification systems, independent of experience in HRCT interpretation. The major advantage of the current guidelines is the better subdivision in the categories with a lower diagnostic certainty for UIP.

ADVANCES IN KNOWLEDGE: - In 2018, a revision of the 2011 ATS/ERS/JRS/ALAT radiological criteria for UIP was published, part of diagnostic guidelines for idiopathic pulmonary fibrosis.- The inter-rater agreement among radiologist is moderate for both classification systems, without a significantly higher degree of agreement when applying the revised radiological criteria.

PMID:33539231 | DOI:10.1259/bjr.20201159

Eur Respir Rev. 2021 Feb 2;30(159):200193. doi: 10.1183/16000617.0193-2020. Print 2021 Mar 31.

ABSTRACT

Pulmonary fibrosis is a progressive interstitial lung disease of unknown aetiology with a poor prognosis. Studying genetic diseases associated with pulmonary fibrosis provides insights into the pathogenesis of the disease. Hermansky-Pudlak syndrome (HPS), a rare autosomal recessive disorder characterised by abnormal biogenesis of lysosome-related organelles, manifests with oculocutaneous albinism and excessive bleeding of variable severity. Pulmonary fibrosis is highly prevalent in three out of 10 genetic types of HPS (HPS-1, HPS-2 and HPS-4). Thus, genotyping of individuals with HPS is clinically relevant. HPS-1 tends to affect Puerto Rican individuals due to a genetic founder effect. HPS pulmonary fibrosis shares some clinical features with idiopathic pulmonary fibrosis (IPF), including dyspnoea, cough, restrictive lung physiology and computed tomography (CT) findings of fibrosis. In contrast to IPF, HPS pulmonary fibrosis generally affects children (HPS-2) or middle-aged adults (HPS-1 or HPS-4) and may be associated with ground-glass opacification in CT scans. Histopathology of HPS pulmonary fibrosis, and not IPF, shows vacuolated hyperplastic type II cells with enlarged lamellar bodies and alveolar macrophages with lipofuscin-like deposits. Antifibrotic drugs approved as treatment for IPF are not approved for HPS pulmonary fibrosis. However, lung transplantation has been performed in patients with severe HPS pulmonary fibrosis. HPS pulmonary fibrosis serves as a model for studying fibrotic lung disease and fibrosis in general.

PMID:33536261 | DOI:10.1183/16000617.0193-2020

Stem Cell Res Ther. 2021 Feb 3;12(1):96. doi: 10.1186/s13287-020-02083-x.

ABSTRACT

BACKGROUND: Previous reports have identified that human bone marrow mesenchymal stem cell-derived extracellular vesicles (BMSC-EVs) with their cargo microRNAs (miRNAs) are a promising therapeutic approach for the treatment of idiopathic pulmonary fibrosis (IPF). Therefore, we explored whether delivery of microRNA-186 (miR-186), a downregulated miRNA in IPF, by BMSC EVs could interfere with the progression of IPF in a murine model.

METHODS: In a co-culture system, we assessed whether BMSC-EVs modulated the activation of fibroblasts. We established a mouse model of PF to evaluate the in vivo therapeutic effects of BMSC-EVs and determined miR-186 expression in BMSC-EVs by polymerase chain reaction. Using a loss-of-function approach, we examined how miR-186 delivered by BMSC-EVs affected fibroblasts. The putative relationship between miR-186 and SRY-related HMG box transcription factor 4 (SOX4) was tested using luciferase assay. Next, we investigated whether EV-miR-186 affected fibroblast activation and PF by targeting SOX4 and its downstream gene, Dickkopf-1 (DKK1).

RESULTS: BMSC-EVs suppressed lung fibroblast activation and delayed IPF progression in mice. miR-186 was downregulated in IPF but enriched in the BMSC-EVs. miR-186 delivered by BMSC-EVs could suppress fibroblast activation. Furthermore, miR-186 reduced the expression of SOX4, a target gene of miR-186, and hence suppressed the expression of DKK1. Finally, EV-delivered miR-186 impaired fibroblast activation and alleviated PF via downregulation of SOX4 and DKK1.

CONCLUSION: In conclusion, miR-186 delivered by BMSC-EVs suppressed SOX4 and DKK1 expression, thereby blocking fibroblast activation and ameliorating IPF, thus presenting a novel therapeutic target for IPF.

PMID:33536061 | PMC:PMC7860043 | DOI:10.1186/s13287-020-02083-x

Int J Cancer. 2021 Feb 3. doi: 10.1002/ijc.33499. Online ahead of print.

ABSTRACT

Patients with idiopathic pulmonary fibrosis (IPF) are at higher risk of developing lung cancers including squamous cell lung carcinoma (SCC), which typically carries a poor prognosis. Although the molecular basis of cancer development subsequent to IPF has not been fully investigated, we recently reported two epigenetic phenotypes characterized by frequent and infrequent DNA hypermethylation in SCC, and an association of the infrequent hypermethylation phenotype with IPF-associated SCCs. Here, we conducted targeted exon sequencing in SCCs with and without IPF using the Human Lung Cancer Panel to investigate the genetic basis of IPF-associated SCC. SCCs with and without IPF displayed comparable numbers of total mutations (137 ± 22 vs 131 ± 27, P = .5), nonsynonymous mutations (72 ± 14 vs 69 ± 16, P = .5), indels (3.0 ± 3.5 vs 3.0 ± 3.9, P = 1) and synonymous mutations (62 ± 9.1 vs 60 ± 12, P = .5). Signature 1 was the predominant signature in SCCs with and without IPF. SETD2 and NFE2L2 mutations were significantly associated with IPF (44% vs 13%, P = .03 for SETD2; 38% vs 10%, P = .04 for NFE2L2). MYC amplification, assessed by copy number variant analysis, was also significantly associated with IPF (18.8% vs 0%, P = .04). Mutations in TP53 and CDKN2A were observed relatively frequently in SCCs with frequent hypermethylation (P = .02 for TP53 and P = .06 for CDKN2A). Survival analysis revealed that the SETD2 mutation was significantly associated with worse prognosis (P = .04). Collectively, we found frequent involvement of SETD2 and NFE2L2 mutations and MYC amplification in SCCs with IPF, and an association of a SETD2 mutation with poorer prognosis.

PMID:33533494 | DOI:10.1002/ijc.33499

Oncoimmunology. 2020 Sep 22;9(1):1824631. doi: 10.1080/2162402X.2020.1824631.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) patients have a high risk of developing lung cancer, with few treatment options available. Pirfenidone, an antifibrotic agent approved for the treatment of IPF, has been demonstrated to suppress the TGFβ signaling and modulate the expression of immune-related genes. However, for lung cancer patients with comorbid IPF, whether pirfenidone has any synergetic effect with immune checkpoint inhibitors has not been investigated. In this study, we showed that pirfenidone monotherapy attenuated tumor growth with an increased T cell inflammatory signature in tumors. Co-administration of pirfenidone with PD-L1 blockades significantly delayed the tumor growth and increased survival, compared with the effect of either treatment alone. Combination therapy promoted gene expression with a unique signature associated with innate and adaptive immune response resulted in the infiltration of immune cells and optimal T cell positioning. Furthermore, we showed a great benefit of combination therapy in alleviating the pulmonary fibrosis and reducing the tumor growth in a tumor-fibrosis model. Our results collectively demonstrated that pirfenidone facilitated antitumor immunity and enhanced the efficacy of PD-L1 blockades. It may act as an adjuvant to immunotherapy in cancer treatment, particularly, in lung cancer patients with preexisting IPF.

PMID:33457101 | PMC:PMC7781712 | DOI:10.1080/2162402X.2020.1824631

Breathe (Sheff). 2020 Sep;16(3):200086. doi: 10.1183/20734735.0086-2020.

ABSTRACT

An acute exacerbation of idiopathic pulmonary fibrosis (AEIPF) is a potentially fatal complication of an already debilitating disease. Management is currently centred on delivering excellent supportive care and identifying reversible triggers. Despite growing international awareness and collaboration, no effective therapies have been identified. Corticosteroids are often the mainstay of treatment; however, the evidence base for their use is poor. Here, we review our current understanding of the disease process and how to manage it, with a focus on the role of corticosteroid therapy.

PMID:33447274 | PMC:PMC7792795 | DOI:10.1183/20734735.0086-2020

2021 Aug 11. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2021 Jan–.

ABSTRACT

Acute interstitial pneumonia (AIP - also known as Hamman-Rich syndrome) is an acute, rapidly progressive idiopathic pulmonary disease that often leads to fulminant respiratory failure and acute respiratory distress syndrome (ARDS). It can be distinguished clinically from other types of interstitial pneumonia by the rapid onset of respiratory failure in a patient without preexisting lung disease. Louis Hamman and Arnold Rich first described it in 1935 as a fulminating diffuse interstitial fibrosis of the lungs. In 1986, Katzenstein introduced the term AIP differentiating it from the group of chronic interstitial pneumonia. The American Thoracic Society (ATS) and European Respiratory Society (ERS) classify AIP under major idiopathic interstitial pneumonia, compared to other rare or unclassified idiopathic interstitial pneumonia.

PMID:32119316 | Bookshelf:NBK554429

2025 Apr 15. LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012–.

ABSTRACT

Pirfenidone is an orally available pyridinone derivative that inhibits collagen formation and is used to treat idiopathic pulmonary fibrosis. Elevations in serum enzyme levels during pirfenidone therapy are not uncommon, but it has yet to be implicated in cases of clinically apparent liver injury with jaundice.

PMID:31644078 | Bookshelf:NBK548769