ERJ Open Res. 2024 Feb 12;10(1):00722-2023. doi: 10.1183/23120541.00722-2023. eCollection 2024 Jan.

ABSTRACT

BACKGROUND: Our objective was to evaluate the short-, medium- and long-term benefits of home-based pulmonary rehabilitation (PR) on the physical and affective components of dyspnoea in people with fibrotic idiopathic interstitial pneumonias (f-IIPs). Anxiety and depressive symptoms, fatigue, health-related quality of life and exercise tolerance were also assessed.

METHODS: Data on 166 individuals with f-IIPs who enrolled in an 8-week home-based PR programme (weekly supervised 90-min session) were retrospectively analysed. Assessments included the Dyspnoea-12 (D-12) questionnaire, Hospital Anxiety and Depression Scale, Fatigue Assessment Scale, Visual Simplified Respiratory Questionnaire and 6-min stepper test, and were performed at home at short, medium (6 months) and long (12 months) term.

RESULTS: Among the 166 individuals with f-IIPs who enrolled in PR, 75 (45%) and 91 (55%) participants had a diagnosis of idiopathic pulmonary fibrosis and fibrosing non-specific interstitial pneumonia, respectively, and 87 (52%) participants concluded a full year of follow-up. In the total group, both physical and affective components of dyspnoea were improved, at short, medium and long term, after PR. Overall, half of the participants reached the minimally important difference of 3 points of the D-12 questionnaire at the end of PR, and at the 6- and 12-month follow-ups. Anxiety and depressive symptoms, fatigue and health-related quality of life were also improved, while the short-term benefits in exercise tolerance were not maintained 1 year after PR.

CONCLUSION: An individualised home-based PR programme resulted in short-, medium- and long-term improvements in both physical and affective components of dyspnoea assessed by the D-12 questionnaire.

PMID:38348242 | PMC:PMC10860206 | DOI:10.1183/23120541.00722-2023

Front Immunol. 2024 Jan 25;15:1326922. doi: 10.3389/fimmu.2024.1326922. eCollection 2024.

ABSTRACT

Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma-associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging- and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissues from 38 SSc-ILD and 18 healthy controls and found that markers (GDF15, COMP, and CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found that epithelial and fibroblast senescence signatures had a 3.6- and 3.7-fold enrichment, respectively, in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, and NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in the lung tissue and found that, independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis.

PMID:38348044 | PMC:PMC10859856 | DOI:10.3389/fimmu.2024.1326922

J Clin Pharmacol. 2024 Feb 12. doi: 10.1002/jcph.2408. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a continuous, progressive, and lethal age-related respiratory disease. It is characterized by condensed and rigid lung tissue, which leads to a decline in the normal functioning of the lungs. The pathophysiology of IPF has still not been completely elucidated, so current strategies are lagging behind with respect to improving the condition of patients with IPF and increasing their survival rate. The desire for a better understanding of the pathobiology of IPF and its early detection has led to the identification of various biomarkers associated with IPF. The use of drugs such as pirfenidone and nintedanib as a safe and effective treatment alternative have marked a new chapter in the treatment of IPF. However, nonpharmacological therapies, involving long-term oxygen therapy, transplantation of the lungs, pulmonary rehabilitation, ventilation, and palliative care for cough and dyspnea, are still considered to be beneficial as supplementary methods for IPF therapy. A major risk factor for IPF is aging, with associated hallmarks such as telomere attrition, senescence, epigenetic drift, stem cell exhaustion, loss of proteostasis, and mitochondrial dysfunction. These are promising earmarks for the development of potential therapy for the disease. In this review, we have discussed current and emerging novel therapeutic strategies for IPF, especially for targets associated with age-related mechanisms.

PMID:38346921 | DOI:10.1002/jcph.2408

Chin Med J Pulm Crit Care Med. 2023 Jun;1(2):67-76. doi: 10.1016/j.pccm.2023.05.002. Epub 2023 Jun 19.

ABSTRACT

Tissue inhibitors of metalloproteases (TIMPs) have caught the attention of many scientists due to their role in various physiological and pathological processes. TIMP-1, 2, 3, and 4 are known members of the TIMPs family. TIMPs exert their biological effects by, but are not limited to, inhibiting the activity of metalloproteases (MMPs). The balance between MMPs and TIMPs is critical for maintaining homeostasis of the extracellular matrix (ECM), while the imbalance between MMPs and TIMPs can lead to pathological changes, such as cancer. In this review, we summarized the current knowledge of TIMP-1 in several pulmonary diseases namely, acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), pneumonia, asthma, chronic obstructive pulmonary disease (COPD), cystic fibrosis, and pulmonary fibrosis. Considering the potential of TIMP-1 serving as a non-invasive diagnostic and/or prognostic biomarker, we also reviewed the circulating TIMP-1 levels in translational and clinical studies.

PMID:38343891 | PMC:PMC10857872 | DOI:10.1016/j.pccm.2023.05.002

medRxiv. 2024 Jan 25:2024.01.24.24301742. doi: 10.1101/2024.01.24.24301742. Preprint.

ABSTRACT

RATIONALE: Neutrophil counts in bronchoalveolar lavage fluid in idiopathic pulmonary fibrosis are associated with worse outcomes; however, the underlying mechanisms are unknown. Neutrophil extracellular trap formation is associated with worse outcomes in several chronic lung diseases however, there is an unknown role in idiopathic pulmonary fibrosis.

OBJECTIVES: To determine the relationship between neutrophil extracellular trap formation in the lungs of idiopathic pulmonary fibrosis patients and clinical outcomes.

METHODS: In a discovery cohort of 156 patients with idiopathic pulmonary fibrosis, we measured neutrophil extracellular trap markers in bronchoalveolar lavage fluid, including extracellular DNA, DNA-myeloperoxidase complexes, calprotectin, and neutrophil elastase. We assessed the correlation of these markers with baseline pulmonary function and survival. In a subset of 50 patients, label-free quantitative proteomics was performed to identify the source of extracellular DNA. A validation cohort of 52 patients was similarly assessed.

MEASUREMENTS AND MAIN RESULTS: Neutrophil extracellular trap markers in the discovery cohort were significantly correlated with worse pulmonary function (p<0.03). Higher levels of these markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79-2.19). Proteomics revealed a significant correlation between extracellular DNA levels and proteins related to neutrophil extracellular trap formation. The validation cohort showed that extracellular DNA levels were associated with reduced pulmonary function (p=0.04) and trend towards worse survival (hazard ratio=2.16).

CONCLUSIONS: Neutrophil extracellular trap formation markers were associated with disease severity and worse survival in idiopathic pulmonary fibrosis. These findings suggest neutrophil extracellular trap formation contributes to lung injury and decreased survival and may represent a potential therapeutic target.

PMID:38343853 | PMC:PMC10854325 | DOI:10.1101/2024.01.24.24301742

J Imaging Inform Med. 2024 Jan 11. doi: 10.1007/s10278-023-00914-w. Online ahead of print.

ABSTRACT

We previously validated Fibresolve, a machine learning classifier system that non-invasively predicts idiopathic pulmonary fibrosis (IPF) diagnosis. The system incorporates an automated deep learning algorithm that analyzes chest computed tomography (CT) imaging to assess for features associated with idiopathic pulmonary fibrosis. Here, we assess performance in assessment of patterns beyond those that are characteristic features of usual interstitial pneumonia (UIP) pattern. The machine learning classifier was previously developed and validated using standard training, validation, and test sets, with clinical plus pathologically determined ground truth. The multi-site 295-patient validation dataset was used for focused subgroup analysis in this investigation to evaluate the classifier's performance range in cases with and without radiologic UIP and probable UIP designations. Radiologic assessment of specific features for UIP including the presence and distribution of reticulation, ground glass, bronchiectasis, and honeycombing was used for assignment of radiologic pattern. Output from the classifier was assessed within various UIP subgroups. The machine learning classifier was able to classify cases not meeting the criteria for UIP or probable UIP as IPF with estimated sensitivity of 56-65% and estimated specificity of 92-94%. Example cases demonstrated non-basilar-predominant as well as ground glass patterns that were indeterminate for UIP by subjective imaging criteria but for which the classifier system was able to correctly identify the case as IPF as confirmed by multidisciplinary discussion generally inclusive of histopathology. The machine learning classifier Fibresolve may be helpful in the diagnosis of IPF in cases without radiological UIP and probable UIP patterns.

PMID:38343230 | DOI:10.1007/s10278-023-00914-w

Cancers (Basel). 2024 Jan 26;16(3):538. doi: 10.3390/cancers16030538.

ABSTRACT

The accurate selection of the recipient is a crucial aspect in the field of lung transplantation (LTX), especially if patients were previously affected by oncological disease. The aim of this bicentric retrospective study was to evaluate short- and long-term outcomes in patients with previous oncological disease or unknown neoplasia found on native lungs submitted to LTX, compared to a control group. A total of 433 patients were included in the analysis, 31 with malignancies (Group 1) and 402 without neoplastic disease (Group 2). The two groups were compared in terms of short- and long-term outcomes. Patients in Group 1 were older (median age 58 years vs. 50 years, p = 0.039) and mostly affected by idiopathic pulmonary fibrosis (55% vs. 40% p = 0.002). Even though in Group 1 a lower rate of late post-operative complications was found (23% vs. 45%, p = 0.018), the median overall survival (OS) was lower compared to the control group (10 months vs. 29 months, p = 0.015). LTX represents a viable therapeutic option for patients with end-stage lung disease and a history of neoplastic disease. However, every case should be carefully debated in a multidisciplinary setting, considering oncological (histology, stage, and proper disease free-interval) and clinical factors (patient's age and comorbidities). A scrupulous post-transplant follow-up is especially mandatory in those cases.

PMID:38339288 | PMC:PMC10854809 | DOI:10.3390/cancers16030538

Int J Mol Sci. 2024 Jan 26;25(3):1562. doi: 10.3390/ijms25031562.

ABSTRACT

The COVID-19 pandemic has had a significant impact on the health and economy of the global population. Even after recovery from the disease, post-COVID-19 symptoms, such as pulmonary fibrosis, continue to be a concern. This narrative review aims to address pulmonary fibrosis (PF) from various perspectives, including the fibrotic mechanisms involved in idiopathic and COVID-19-induced pulmonary fibrosis. On the other hand, we also discuss the current therapeutic drugs in use, as well as those undergoing clinical or preclinical evaluation. Additionally, this article will address various biomarkers with usefulness for PF prediction, diagnosis, treatment, prognosis, and severity assessment in order to provide better treatment strategies for patients with this disease.

PMID:38338840 | PMC:PMC10855955 | DOI:10.3390/ijms25031562

J Clin Med. 2024 Jan 30;13(3):797. doi: 10.3390/jcm13030797.

ABSTRACT

Hypersensitivity pneumonitis (HP) is a diffuse parenchymal lung disease (DLPD) characterized by complex interstitial lung damage with polymorphic and protean inflammatory aspects affecting lung tissue targets including small airways, the interstitium, alveolar compartments and vascular structures. HP shares clinical and often radiological features with other lung diseases in acute or chronic forms. In its natural temporal evolution, if specific therapy is not initiated promptly, HP leads to progressive fibrotic damage with reduced lung volumes and impaired gas exchange. The prevalence of HP varies considerably worldwide, influenced by factors like imprecise disease classification, diagnostic method limitations for obtaining a confident diagnosis, diagnostic limitations in the correct processing of high-resolution computed tomography (HRCT) radiological parameters, unreliable medical history, diverse geographical conditions, heterogeneous agricultural and industrial practices and occasionally ineffective individual protections regarding occupational exposures and host risk factors. The aim of this review is to present an accurate and detailed 360-degree analysis of HP considering HRCT patterns and the role of the broncho-alveolar lavage (BAL), without neglecting biopsy and anatomopathological aspects and future technological developments that could make the diagnosis of this disease less challenging.

PMID:38337490 | PMC:PMC10856167 | DOI:10.3390/jcm13030797

ACS Biomater Sci Eng. 2024 Feb 9. doi: 10.1021/acsbiomaterials.3c01499. Online ahead of print.

ABSTRACT

Fibrosis has been characterized as a global health problem and ranks as one of the primary causes of organ dysfunction. Currently, there is no cure for pulmonary fibrosis, and limited therapeutic options are available due to an inadequate understanding of the disease pathogenesis. The absence of advanced in vitro models replicating dynamic temporal changes observed in the tissue with the progression of the disease is a significant impediment in the development of novel antifibrotic treatments, which has motivated research on tissue-mimetic three-dimensional (3D) models. In this review, we summarize emerging trends in preparing advanced lung models to recapitulate biochemical and biomechanical processes associated with lung fibrogenesis. We begin by describing the importance of in vivo studies and highlighting the often poor correlation between preclinical research and clinical outcomes and the limitations of conventional cell culture in accurately simulating the 3D tissue microenvironment. Rapid advancement in biomaterials, biofabrication, biomicrofluidics, and related bioengineering techniques are enabling the preparation of in vitro models to reproduce the epithelium structure and operate as reliable drug screening strategies for precise prediction. Improving and understanding these model systems is necessary to find the cross-talks between growing cells and the stage at which myofibroblasts differentiate. These advanced models allow us to utilize the knowledge and identify, characterize, and hand pick medicines beneficial to the human community. The challenges of the current approaches, along with the opportunities for further research with potential for translation in this field, are presented toward developing novel treatments for pulmonary fibrosis.

PMID:38335198 | DOI:10.1021/acsbiomaterials.3c01499

Biochem Genet. 2024 Feb 9. doi: 10.1007/s10528-023-10650-z. Online ahead of print.

ABSTRACT

There is a potential link between rheumatoid arthritis (RA) and idiopathic pulmonary fibrosis (IPF). The aim of this study is to investigate the molecular processes that underlie the development of these two conditions by bioinformatics methods. The gene expression samples for RA (GSE77298) and IPF (GSE24206) were retrieved from the Gene Expression Omnibus (GEO) database. After identifying the overlapping differentially expressed genes (DEGs) for RA and IPF, we conducted functional annotation, protein-protein interaction (PPI) network analysis, and hub gene identification. Finally, we used the hub genes to predict potential medications for the treatment of both disorders. We identified 74 common DEGs for further analysis. Functional analysis demonstrated that cellular components, biological processes, and molecular functions all played a role in the emergence and progression of RA and IPF. Using the cytoHubba plugin, we identified 7 important hub genes, namely COL3A1, SDC1, CCL5, CXCL13, MMP1, THY1, and BDNF. As diagnostic indicators for RA, SDC1, CCL5, CXCL13, MMP1, and THY1 showed favorable values. For IPF, COL3A1, SDC1, CCL5, CXCL13, THY1, and BDNF were favorable diagnostic markers. Furthermore, we predicted 61 Chinese and 69 Western medications using the hub genes. Our research findings demonstrate a shared pathophysiology between RA and IPF, which may provide new insights for more mechanistic research and more effective treatments. These common pathways and hub genes identified in our study offer potential opportunities for developing more targeted therapies that can address both disorders.

PMID:38334875 | DOI:10.1007/s10528-023-10650-z

Cells. 2024 Jan 26;13(3):238. doi: 10.3390/cells13030238.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a fatal lung disease of unknown origin, with a median patient survival time of ~3 years after diagnosis without anti-fibrotic therapy. It is characterized by progressive fibrosis indicated by increased collagen deposition and high numbers of fibroblasts in the lung. It has been demonstrated that CCL18 induces collagen and αSMA synthesis in fibroblasts. We aimed to identify the CCL18 receptor responsible for its pro-fibrotic activities.

METHODS: We used a random phage display library to screen for potential CCL18-binding peptides, demonstrated its expression in human lungs and fibroblast lines by PCR and immunostaining and verified its function in cell lines.

RESULTS: We identified CCR6 (CD196) as a CCL18 receptor and found its expression in fibrotic lung tissue and lung fibroblast lines derived from fibrotic lungs, but it was almost absent in control lines and tissue. CCL18 induced receptor internalization in a CCR6-overexpressing cell line. CCR6 blockade in primary human lung fibroblasts reduced CCL18-induced FGF2 release as well as collagen-1 and αSMA expression. Knockdown of CCR6 in a mouse fibroblast cell line abolished the induction of collagen and α-smooth muscle actin expression.

CONCLUSION: Our data indicate that CCL18 triggers pro-fibrotic processes via CCR6, highlighting its role in fibrogenesis.

PMID:38334630 | PMC:PMC10854834 | DOI:10.3390/cells13030238

ACG Case Rep J. 2024 Feb 8;11(2):e01282. doi: 10.14309/crj.0000000000001282. eCollection 2024 Feb.

ABSTRACT

Nintedanib is a medication that has been increasingly used for treatment of idiopathic and progressive pulmonary fibrosis. In this case series, we describe 3 patients with colitis symptoms associated with nintedanib use. Nintedanib discontinuation resulted in symptomatic resolution in all patients. Budesonide decreased symptoms in 1 patient. Clinicians should be vigilant in taking a thorough medication history and include nintedanib as a cause for gastrointestinal symptoms including colitis.

PMID:38333722 | PMC:PMC10852397 | DOI:10.14309/crj.0000000000001282

J Pathol. 2024 Feb 9. doi: 10.1002/path.6253. Online ahead of print.

ABSTRACT

Pulmonary fibrosis, especially idiopathic pulmonary fibrosis (IPF), portends significant morbidity and mortality, and current therapeutic options are suboptimal. We have previously shown that type I collagen signaling through discoidin domain receptor 2 (DDR2), a receptor tyrosine kinase expressed by fibroblasts, is critical for the regulation of fibroblast apoptosis and progressive fibrosis. However, the downstream signaling pathways for DDR2 remain poorly defined and could also be attractive potential targets for therapy. A recent phosphoproteomic approach indicated that PIK3C2α, a poorly studied member of the PI3 kinase family, could be a downstream mediator of DDR2 signaling. We hypothesized that collagen I/DDR2 signaling through PIK3C2α regulates fibroblast activity during progressive fibrosis. To test this hypothesis, we found that primary murine fibroblasts and IPF-derived fibroblasts stimulated with endogenous or exogenous type I collagen led to the formation of a DDR2/PIK3C2α complex, resulting in phosphorylation of PIK3C2α. Fibroblasts treated with an inhibitor of PIK3C2α or with deletion of PIK3C2α had fewer markers of activation after stimulation with TGFβ and more apoptosis after stimulation with a Fas-activating antibody. Finally, mice with fibroblast-specific deletion of PIK3C2α had less fibrosis after bleomycin treatment than did littermate control mice with intact expression of PIK3Cα. Collectively, these data support the notion that collagen/DDR2/PIK3C2α signaling is critical for fibroblast function during progressive fibrosis, making this pathway a potential target for antifibrotic therapy. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:38332727 | DOI:10.1002/path.6253

J Pathol. 2024 Feb 9. doi: 10.1002/path.6256. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine-1-phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF-β signaling. Hence, decreasing lung S1P represents a potential therapeutic strategy for IPF. S1P is degraded by the intracellular enzyme S1P lyase (SPL). Here we find that a knock-in mouse with a missense SPL mutation mimicking human disease resulted in reduced SPL activity, increased S1P, increased TGF-β signaling, increased lung fibrosis, and higher mortality after injury compared to wild type (WT). We then tested adeno-associated virus 9 (AAV9)-mediated overexpression of human SGPL1 (AAV-SPL) in mice as a therapeutic modality. Intravenous treatment with AAV-SPL augmented lung SPL activity, attenuated S1P levels within the lungs, and decreased injury-induced fibrosis compared to controls treated with saline or only AAV. We confirmed that AAV-SPL treatment led to higher expression of SPL in the epithelial and fibroblast compartments during bleomycin-induced lung injury. Additionally, AAV-SPL decreased expression of the profibrotic cytokines TNFα and IL1β as well as markers of fibroblast activation, such as fibronectin (Fn1), Tgfb1, Acta2, and collagen genes in the lung. Taken together, our results provide proof of concept for the use of AAV-SPL as a therapeutic strategy for the treatment of IPF. © 2024 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

PMID:38332723 | DOI:10.1002/path.6256

Respir Med. 2024 Feb 7;223:107542. doi: 10.1016/j.rmed.2024.107542. Online ahead of print.

ABSTRACT

BACKGROUND: Antifibrotic therapy is widely used for patients with progressive fibrotic interstitial lung disease (ILD), regardless of etiology. There is an urgent need for a simple, inexpensive, and repeatable biomarker to evaluate disease severity and mortality risk.

METHODS: This retrospective multicohort study assessed the neutrophil-lymphocyte ratios (NLRs) of 416 patients with ILD who received antifibrotic therapy (Hamamatsu cohort, n = 217; Seirei cohort, n = 199). The mortality risk vs. NLR relationship was evaluated at therapy initiation and 1 year. The optimal NLR cutoff of 2.7 was selected according to the mortality risk.

RESULTS: Survival was shorter in patients with high NLR than with low NLR (median: 2.63 vs. 4.01 years). The NLR classification results (cutoff: 2.7) were longitudinally preserved in >70 % of the patients, and patients with consistently high NLR had a higher risk of mortality than others (median, 2.97 vs. 4.42 years). In multivariate analysis, high NLR was significantly associated with mortality independent of age, sex, forced vital capacity, lung diffusing capacity for carbon monoxide (DLCO), or the gender-age-physiology (GAP) index. A combined GAP index-NLR assessment classified mortality risk into four groups. Subset analyses revealed that NLR assessment was more applicable to patients without advanced disease, not taking steroids, and with idiopathic pulmonary fibrosis (IPF) than to patients with advanced disease, taking steroids, and patients with Non-IPF.

CONCLUSION: High NLR was associated with an increased mortality risk in patients with ILDs receiving antifibrotic therapy. Assessment of NLR may help predict disease severity and mortality risk in antifibrotic therapy.

PMID:38331228 | DOI:10.1016/j.rmed.2024.107542

Korean J Intern Med. 2024 Feb 8. doi: 10.3904/kjim.2023.273. Online ahead of print.

ABSTRACT

BACKGROUND/AIMS: The prognosis of patients with idiopathic pulmonary fibrosis (IPF) and respiratory failure requiring mechanical ventilation is poor. Therefore, mechanical ventilation is not recommended. Recently, outcomes of mechanical ventilation, including those for patients with IPF, have improved. The aim of this study was to investigate changes in the use of mechanical ventilation in patients with IPF and their outcomes over time.

METHODS: This retrospective, observational cohort study used data from the National Health Insurance Service database. Patients diagnosed with IPF between January 2011 and December 2019 who were placed on mechanical ventilation were included. We analyzed changes in the use of mechanical ventilation in patients with IPF and their mortality using the Cochran- Armitage trend test.

RESULTS: Between 2011 and 2019, 1,227 patients with IPF were placed on mechanical ventilation. The annual number of patients with IPF with and without mechanical ventilation increased over time. However, the ratio was relatively stable at approximately 3.5%. The overall hospital mortality rate was 69.4%. There was no improvement in annual hospital mortality rate. The overall 30-day mortality rate was 68.7%, which did not change significantly. The overall 90-day mortality rate was 85.3%. The annual 90-day mortality rate was decreased from 90.9% in 2011 to 83.1% in 2019 (p = 0.028).

CONCLUSIONS: Despite improvements in intensive care and ventilator management, the prognosis of patients with IPF receiving mechanical ventilation has not improved significantly.

PMID:38326962 | DOI:10.3904/kjim.2023.273

Clin Rheumatol. 2024 Mar;43(3):1145-1154. doi: 10.1007/s10067-024-06873-z. Epub 2024 Feb 7.

ABSTRACT

OBJECTIVES: Myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) are associated with distinctive dermatomyositis (DM) clinical phenotypes. The aim of this study is to explicate the clinical and immunological features of MSAs-negative DM patients.

METHODS: A total of 515 individuals diagnosed with DM was screened from 2013 to 2022 and 220 DM patients were enrolled in this retrospective cohort. Clinical and laboratory data of these patients were analyzed.

RESULTS: MSAs-negative DM patients were categorized into two groups: MAAs-negative (MSAs (-)/MAAs (-)) group and MAAs-positive (MSAs (-)/MAAs (+)) group. The percentage of Raynaud's phenomenon (P=0.026) was higher in the MSAs (-)/MAAs (+) DM patients than the MSAs-positive DM patients and MSAs (-)/MAAs (-) DM patients. The proportion of rapidly progressive interstitial lung disease (RP-ILD) in the MSAs-negative DM patients was lower than that in the MSAs-positive group. The MSAs (-)/MAAs (+) group had a higher proportion of organizing pneumonia and usual interstitial pneumonia (P=0.011), and elevated eosinophils in their bronchoalveolar lavage fluid (P=0.008). Counts of lymphocytes (P=0.001) and CD16+CD56+ natural killer (NK) cells (P=0.012) were higher in the MSAs-negative group. Additionally, the percentage of CD4+TNFα+ (P=0.040), CD4+IFNγ+ (P=0.037), and CD4+IL-2+ (P=0.018) cells among total CD4+ T cells were higher in the MSA-negative DM patients compared with the MSAs-positive DM patients. Besides, MSAs-negative patients demonstrated a more favorable prognosis than MSAs-positive patients. Multivariable regression analysis identified advanced onset age, higher level of carcinoembryonic antigen (CEA), and RP-ILD as risk factors for mortality in DM patients.

CONCLUSIONS: Compared with MSAs-positive group, MSAs-negative DM patients suffered less from organ involvement compared with MSAs-positive group and tend to have better prognosis. Key Points MSAs-negative DM patients exhibited distinct characteristics in comparison with MSAs-positive DM patients: • The MSAs (-)/MAAs (+) DM patients demonstrated a higher prevalence of organizing pneumonia (OP) and usual interstitial pneumonia (UIP), and elevated eosinophil counts in bronchoalveolar lavage fluid. • CEA levels were lower in MSAs-negative patients compared with MSAs-positive patients. • Elevated counts of lymphocytes and CD16+CD56+ NK cells were identified in the MSAs-negative patients. Additionally, proportions of CD4+TNFα+, CD4+IFNγ+, and CD4+IL-2+ cells among total CD4+ T cells were higher in the MSAs-negative DM patients compared with DM MSAs-positive DM patients. • MSAs-negative DM patients had a more favorable prognosis than MSAs-positive DM patients. A multivariable regression analysis revealed the advanced onset age, high CEA levels, and RP-ILD were risk factors for mortality in DM patients.

PMID:38326675 | DOI:10.1007/s10067-024-06873-z

Respir Res. 2024 Feb 8;25(1):81. doi: 10.1186/s12931-024-02705-5.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive disease associated with high mortality. Low muscle mass, frailty and sarcopenia lead to functional impairment that negatively impact quality of life and survival but are not used in clinical practice. We aimed to determine the association of Fat-free mass index (FFMI) and frailty with lung function, exercise tolerance and survival in patients with IPF. In this study, 70 patients with IPF underwent assessment of body composition, lung function, 6-min walk distance (6MWD) testing, hand grip strength, quality of life (QoL) assessment by St. George's Respiratory questionnaire (SGRQ) and frailty assessment using the SHARE-FI tool. FFMI was calculated using pectoralis muscle cross-sectional area (PM-CSA) on CT chest images and the lowest quartile defined reduced muscle mass. Sarcopenia was defined as low FFMI and handgrip strength. Regression analyses were conducted to determine predictive value of frailty, low FFMI and sarcopenia on clinical outcomes. The Cox proportional hazards model was used to analyze the impact of FFMI and frailty score on survival. The mean age was 70 years with moderate impairment in lung function (mean ppFVC 68.5%, ppDLCO 45.6%). Baseline forced vital capacity (p < 0.001), diffusion capacity of lung for carbon monoxide (p = < 0.01), 6WMD (p < 0.05) were significantly lower in frail patients compared to non-frail patients. BMI was found to closely correlate with FFMI (r = 0.79, p < 0.001), but not with frailty score (r = - 0.2, p = 0.07). Frailty was a significant predictor of FVC, DLCO, 6MWD, SGRQ scores when adjusted for age and gender. Muscle mass and sarcopenia were significant predictors of FVC, DLCO, but not 6MWD or QoL scores. Multivariate cox-proportional hazards ratio model adjusting for age and gender showed that frailty was significantly associated with increased mortality (HR = 2.6, 95% CI 1.1-6.1). Low FFMI (HR = 1.3, 95% CI 0.6-2.8), and sarcopenia (HR = 2.1, 95% CI 0.8-5.3), though associated with a trend to increased mortality, were not statistically significant. Frailty is associated with lower lung function and higher mortality in patients with IPF. Longitudinal evaluations are necessary to further determine the associations between low FFMI, sarcopenia and frailty with outcomes in IPF.

PMID:38326848 | PMC:PMC10851557 | DOI:10.1186/s12931-024-02705-5

Am J Pathol. 2024 Feb 5:S0002-9440(24)00041-5. doi: 10.1016/j.ajpath.2024.01.010. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease for which there is no curative therapy available. Repetitive alveolar epithelial injury repair, myofibroblast (MYF) accumulation and excessive collagen deposition are key pathological features of IPF, eventually leading to cellular hypoxia and respiratory failure. The precise mechanism driving this complex maladaptive process remains inadequately understood. WSB1 (WD repeat and SOCS box containing 1) is an E3 ubiquitin ligase, the expression of which is strongly associated with hypoxia, and forms a positive feedback loop with HIF-1α under anoxic condition. In this study, we explored the expression, cellular distribution and function of WSB1 in bleomycin (BLM)-induced mouse lung injury and fibrosis. WSB1 expression was highly induced by BLM injury and correlated with the progression of lung fibrosis. Significantly, conditional deletion of Wsb1 in adult mice ameliorated BLM-induced pulmonary fibrosis. Phenotypically, Wsb1-deficient mice exhibited reduced lipofibroblast (LIF) to MYF transition, but enhanced alveolar type 2 (AT2) proliferation and differentiation into AT1 following BLM injury. Proteomic analysis of mouse lung tissues identified Caveolin 2 as a potential downstream target of WSB1, contributing to BLM-induced epithelial injury repair and fibrosis. Our findings unravel a vital role for WSB1 induction in lung injury repair, thus highlighting it as a potential therapeutic target for pulmonary fibrosis.

PMID:38325552 | DOI:10.1016/j.ajpath.2024.01.010