Lancet Microbe. 2024 Feb 28:S2666-5247(24)00003-X. doi: 10.1016/S2666-5247(24)00003-X. Online ahead of print.

ABSTRACT

Antimicrobial resistance (AMR) threatens human, animal, and environmental health. Acknowledging the urgency of addressing AMR, an opportunity exists to extend AMR action-focused research beyond the confines of an isolated biomedical paradigm. An AMR learning system, AMR-X, envisions a national network of health systems creating and applying optimal use of antimicrobials on the basis of their data collected from the delivery of routine clinical care. AMR-X integrates traditional AMR discovery, experimental research, and applied research with continuous analysis of pathogens, antimicrobial uses, and clinical outcomes that are routinely disseminated to practitioners, policy makers, patients, and the public to drive changes in practice and outcomes. AMR-X uses connected data-to-action systems to underpin an evaluation framework embedded in routine care, continuously driving implementation of improvements in patient and population health, targeting investment, and incentivising innovation. All stakeholders co-create AMR-X, protecting the public from AMR by adapting to continuously evolving AMR threats and generating the information needed for precision patient and population care.

PMID:38461831 | DOI:10.1016/S2666-5247(24)00003-X

BMJ Open Respir Res. 2024 Mar 9;11(1):e002226. doi: 10.1136/bmjresp-2023-002226.

ABSTRACT

PURPOSE: Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the primary cause of death in patients with IPF, characterised by diffuse, bilateral ground-glass opacification on high-resolution CT (HRCT). This study proposes a three-dimensional (3D)-based deep learning algorithm for classifying AE-IPF using HRCT images.

MATERIALS AND METHODS: A novel 3D-based deep learning algorithm, SlowFast, was developed by applying a database of 306 HRCT scans obtained from two centres. The scans were divided into four separate subsets (training set, n=105; internal validation set, n=26; temporal test set 1, n=79; and geographical test set 2, n=96). The final training data set consisted of 1050 samples with 33 600 images for algorithm training. Algorithm performance was evaluated using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, receiver operating characteristic (ROC) curve and weighted κ coefficient.

RESULTS: The accuracy of the algorithm in classifying AE-IPF on the test sets 1 and 2 was 93.9% and 86.5%, respectively. Interobserver agreements between the algorithm and the majority opinion of the radiologists were good (κw=0.90 for test set 1 and κw=0.73 for test set 2, respectively). The ROC accuracy of the algorithm for classifying AE-IPF on the test sets 1 and 2 was 0.96 and 0.92, respectively. The algorithm performance was superior to visual analysis in accurately diagnosing radiological findings. Furthermore, the algorithm's categorisation was a significant predictor of IPF progression.

CONCLUSIONS: The deep learning algorithm provides high auxiliary diagnostic efficiency in patients with AE-IPF and may serve as a useful clinical aid for diagnosis.

PMID:38460976 | DOI:10.1136/bmjresp-2023-002226

Respir Investig. 2024 Mar 8;62(3):388-394. doi: 10.1016/j.resinv.2024.02.012. Online ahead of print.

ABSTRACT

BACKGROUND: The antifibrotic agents pirfenidone and nintedanib have been shown to be effective in patients with idiopathic pulmonary fibrosis (IPF). However, discontinuation of antifibrotic drugs is a major clinical concern because of the lack of alternative treatment options. Therefore, we identified factors that may be useful for predicting the termination of antifibrotic agents.

METHODS: We retrospectively recruited 280 IPF patients treated with antifibrotic drugs between 2009 and 2018 from seven regional core hospitals in Gunma prefecture, Japan.

RESULTS: At four months, the short-term discontinuation group exhibited a significantly worse prognosis in the pirfenidone group and a poorer prognosis in the nintedanib group compared to that in the continuation group. The discontinuation group of pirfenidone at 4 months exhibited lower albumin and higher C-reactive protein (CRP) levels in the sera compared to the group that continued treatment for more than 4 months. In multivariate analysis, the Glasgow prognostic score (GPS), well known as a predictor of cancer prognosis, which comprises serum CRP and albumin levels, predicted early discontinuation and prognosis in the pirfenidone group, whereas the body mass index (BMI) predicted early discontinuation of nintedanib. A high GPS, with both albumin <3.5 g/dL and CRP >1.0 mg/dL, was associated with a poorer prognosis in the pirfenidone group.

CONCLUSION: GPS and BMI were significant factors for short-term pirfenidone and nintedanib discontinuation, respectively. Initial evaluation of GPS and BMI prior to antifibrotic therapy may contribute to less interrupted IPF management, thus leading to better prognostic outcomes in patients with IPF.

PMID:38460356 | DOI:10.1016/j.resinv.2024.02.012

Drug Saf. 2024 Mar 9. doi: 10.1007/s40264-024-01400-0. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary toxicity has been associated with drug use. This is often not recognized in clinical practice, and underestimated.

OBJECTIVE: We aimed to establish whether polymorphisms in certain genes corresponding with a metabolic pathway of drug(s) used are associated with pulmonary toxicity in patients with suspected drug-induced interstitial lung disease (DI-ILD).

METHODS: This retrospective observational study explored genetic variations in three clinically relevant cytochrome P450 (CYP) iso-enzymes (i.e., CYP2D6, CYP2C9, and CYP2C19) in a group of patients with a fibroticinterstitial lung disease, either non-specific interstitial pneumonia (n = 211) or idiopathic pulmonary fibrosis (n = 256), with a suspected drug-induced origin.

RESULTS: Of the 467 patients, 79.0% showed one or more polymorphisms in the tested genes accompanied by the use of drug(s) metabolized by a corresponding affected metabolic pathway (60.0% poor metabolizers and/or using two or more drugs [likely DI-ILD], 37.5% using three or more [highly likely DI-ILD]). Most commonly used drugs were statins (63.1%) with a predominance among men (69.4 vs 47.1%, p < 0.0001). Nitrofurantoin, not metabolized by the tested pathways, was prescribed more frequently among women (51.9 vs 4.5%, p < 0.00001).

CONCLUSIONS: In our cohort with suspected DI-ILD, 79% carried one or more genetic variants accompanied by the use of drugs metabolized by a corresponding affected pathway. In 60%, the diagnosis of DI-ILD was likely, whereas in 37.5%, it was highly likely, based on CYP analyses. This study underlines the importance of considering both drug use and genetic make-up as a possible cause, or at least a contributing factor, in the development and/or progression of fibrotic lung diseases.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT00267800, registered in 2005.

PMID:38460070 | DOI:10.1007/s40264-024-01400-0

Nat Biotechnol. 2024 Mar 8. doi: 10.1038/s41587-024-02143-0. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is an aggressive interstitial lung disease with a high mortality rate. Putative drug targets in IPF have failed to translate into effective therapies at the clinical level. We identify TRAF2- and NCK-interacting kinase (TNIK) as an anti-fibrotic target using a predictive artificial intelligence (AI) approach. Using AI-driven methodology, we generated INS018_055, a small-molecule TNIK inhibitor, which exhibits desirable drug-like properties and anti-fibrotic activity across different organs in vivo through oral, inhaled or topical administration. INS018_055 possesses anti-inflammatory effects in addition to its anti-fibrotic profile, validated in multiple in vivo studies. Its safety and tolerability as well as pharmacokinetics were validated in a randomized, double-blinded, placebo-controlled phase I clinical trial (NCT05154240) involving 78 healthy participants. A separate phase I trial in China, CTR20221542, also demonstrated comparable safety and pharmacokinetic profiles. This work was completed in roughly 18 months from target discovery to preclinical candidate nomination and demonstrates the capabilities of our generative AI-driven drug-discovery pipeline.

PMID:38459338 | DOI:10.1038/s41587-024-02143-0

Front Immunol. 2024 Feb 22;15:1293883. doi: 10.3389/fimmu.2024.1293883. eCollection 2024.

ABSTRACT

Fibrotic diseases, such as idiopathic pulmonary fibrosis (IPF) and systemic scleroderma (SSc), are commonly associated with high morbidity and mortality, thereby representing a significant unmet medical need. Interleukin 11 (IL11)-mediated cell activation has been identified as a central mechanism for promoting fibrosis downstream of TGFβ. IL11 signaling has recently been reported to promote fibroblast-to-myofibroblast transition, thus leading to various pro-fibrotic phenotypic changes. We confirmed increased mRNA expression of IL11 and IL11Rα in fibrotic diseases by OMICs approaches and in situ hybridization. However, the vital role of IL11 as a driver for fibrosis was not recapitulated. While induction of IL11 secretion was observed downstream of TGFβ signaling in human lung fibroblasts and epithelial cells, the cellular responses induced by IL11 was quantitatively and qualitatively inferior to that of TGFβ at the transcriptional and translational levels. IL11 blocking antibodies inhibited IL11Rα-proximal STAT3 activation but failed to block TGFβ-induced profibrotic signals. In summary, our results challenge the concept of IL11 blockade as a strategy for providing transformative treatment for fibrosis.

PMID:38455057 | PMC:PMC10917968 | DOI:10.3389/fimmu.2024.1293883

Eur Respir J. 2024 Mar 7:2301181. doi: 10.1183/13993003.01181-2023. Online ahead of print.

ABSTRACT

BACKGROUND: Lung cancer is a fatal complication of idiopathic pulmonary fibrosis (IPF) with a poor prognosis. However, the association between individual exposure to air pollutants and lung cancer development in patients with IPF is unknown. This study aimed to assess the effect of individual exposure to nitrogen dioxide (NO2) on lung cancer development in patients with IPF.

METHODS: We enrolled 1085 patients from the IPF cohort (mean age: 65.6 years, male: 80.6%). We estimated individual-level long-term exposures to NO2 at the patient's residential addresses using a national-scale exposure prediction model based on the data from air quality regulatory monitoring stations. To evaluate the association between NO2 levels and lung cancer development in IPF, we used an individual- and area-level covariates adjusted model as our primary model.

RESULTS: The estimated average annual NO2 concentration was 23.1 parts per billion (ppb). During a follow-up of 4.3 years (median), 86 patients (7.9%) developed lung cancer. NO2 concentration was associated with lung cancer development in an unadjusted model (hazard ratio [HR], 1.219; p=0.042), while a marginal association was found in the primary model (HR 1.280; p=0.084). When NO2 concentration was divided by the median value (21.0 ppb), exposure to high NO2 levels (≥ 21.0 ppb) was associated with a 2.0-fold increase in the risk of lung cancer development (HR, 2.023; p=0.047) in the primary model.

CONCLUSION: Individual exposure to high NO2 levels may increase the risk of lung cancer development in patients with IPF.

PMID:38453259 | DOI:10.1183/13993003.01181-2023

Int J Tuberc Lung Dis. 2024 Mar 1;28(3):130-135. doi: 10.5588/ijtld.23.0428.

ABSTRACT

<sec id="st1"><title>INTRODUCTION</title>To determine the frequency of TB among patients with interstitial lung diseases (ILDs).</sec><sec id="st2"><title>METHODS</title>We performed a comprehensive search in the PubMed/Medline, EMBASE and Scopus databases up to 1 August 2023 of studies reporting on the prevalence of TB among patients with ILDs.</sec><sec id="st3"><title>RESULTS</title>Twelve studies comprising 3,817 patients with ILD were found: the pooled prevalence of TB among ILD patients was 11.0% (95% CI 5.4-21.0). In the subgroup analysis, the TB rate among patients with silicosis and idiopathic pulmonary fibrosis (IPF) was respectively 35.6% (95% CI 32.6-38.8) and 4.4% (95% CI 3.6-5.3) (P = 0.00). The frequency of TB among ILD patients was higher in high TB burden countries than in low/intermediate-burden countries: 26.3%, 95% CI 17.7-37.3 vs. 4.9%, 95% CI 3.3-7.2; P = 0.00.</sec><sec id="st4"><title>CONCLUSIONS</title>This study shows the frequency of TB among ILD patients. The meta-analysis reveals a significantly increased prevalence of TB among ILD patients with silicosis compared to IPF, and among individuals in high TB burden countries than in those with low/intermediate burden. The study results can help physicians and policymakers make efficient decisions for prompt screening and anti-TB treatment initiation in ILD patients.</sec>.

PMID:38454180 | DOI:10.5588/ijtld.23.0428

Br J Cancer. 2024 Mar 7. doi: 10.1038/s41416-024-02631-9. Online ahead of print.

ABSTRACT

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a malignancy with a 5-year survival rate of 12%. The abundant mesenchyme is partly responsible for the malignancy. The antifibrotic therapies have gained attention in recent research. However, the role of pirfenidone, an FDA-approved drug for idiopathic pulmonary fibrosis, remains unclear in PDAC.

METHODS: Data from RNA-seq of patient-derived xenograft (PDX) models treated with pirfenidone were integrated using bioinformatics tools to identify the target of cell types and genes. Using confocal microscopy, qRT-PCR and western blotting, we validated the signalling pathway in tumour cells to regulate the cytokine secretion. Further cocultured system demonstrated the interplay to regulate stroma fibrosis. Finally, mouse models demonstrated the potential of pirfenidone in PDAC.

RESULTS: Pirfenidone can remodulate multiple biological pathways, and exerts an antifibrotic effect through inhibiting the secretion of PDGF-bb from tumour cells by downregulating the TGM2/NF-kB/PDGFB pathway. Thus, leading to a subsequent reduction in collagen X and fibronectin secreted by CAFs. Moreover, the mice orthotopic pancreatic tumour models demonstrated the antifibrotic effect and potential to sensitise gemcitabine.

CONCLUSIONS: Pirfenidone may alter the pancreatic milieu and alleviate fibrosis through the regulation of tumour-stroma interactions via the TGM2/NF-kB/PDGFB signalling pathway, suggesting potential therapeutic benefits in PDAC management.

PMID:38454166 | DOI:10.1038/s41416-024-02631-9

PLoS One. 2024 Mar 7;19(3):e0299912. doi: 10.1371/journal.pone.0299912. eCollection 2024.

ABSTRACT

PURPOSE: In chronic thromboembolic pulmonary hypertension (CTEPH), fibrosis of thrombi in the lumen of blood vessels and obstruction of blood vessels are important factors in the progression of the disease. Therefore, it is important to explore the key genes that lead to chronic thrombosis in order to understand the development of CTEPH, and at the same time, it is beneficial to provide new directions for early identification, disease prevention, clinical diagnosis and treatment, and development of novel therapeutic agents.

METHODS: The GSE130391 dataset was downloaded from the Gene Expression Omnibus (GEO) public database, which includes the full gene expression profiles of patients with CTEPH and Idiopathic Pulmonary Arterial Hypertension (IPAH). Differentially Expressed Genes (DEGs) of CTEPH and IPAH were screened, and then Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) functional enrichment analyses were performed on the DEGs; Weighted Gene Co-Expression Network Analysis (WGCNA) to screen the key gene modules and take the intersection genes of DEGs and the key module genes in WGCNA; STRING database was used to construct the protein-protein interaction (PPI) network; and cytoHubba analysis was performed to identify the hub genes.

RESULTS: A total of 924 DEGs were screened, and the MEturquoise module with the strongest correlation was selected to take the intersection with DEGs A total of 757 intersecting genes were screened. The top ten hub genes were analyzed by cytoHubba: IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4.

CONCLUSION: IL-1B, CXCL8, CCL22, CCL5, CCL20, TNF, IL-12B, JUN, EP300, and CCL4 have diagnostic and therapeutic value in CTEPH disease, especially playing a role in chronic thrombosis. The discovery of NF-κB, AP-1 transcription factors, and TNF signaling pathway through pivotal genes may be involved in the disease progression process.

PMID:38451963 | DOI:10.1371/journal.pone.0299912

J Clin Invest. 2024 Mar 7:e173371. doi: 10.1172/JCI173371. Online ahead of print.

ABSTRACT

The appearance of senescent cells in age-related diseases has spurred the search for compounds that can target senescent cells in tissues ("senolytics"). However, a major caveat with current senolytic screens is the use of cell lines as targets where senescence is induced in vitro, which does not necessarily reflect the identity and function of pathogenic senescent cells in vivo. Here, we developed a new pipeline leveraging a fluorescent murine reporter that allows for isolation and quantification of p16Ink4a+ cells in diseased tissues. By high-throughput screening in vitro, precision cut lung slice (PCLS) screening ex vivo, and phenotypic screening in vivo, we identified a HSP90 inhibitor (XL888) as a potent senolytic in tissue fibrosis. XL888 treatment eliminated pathogenic p16Ink4a+ fibroblasts in a murine model of lung fibrosis and reduced fibrotic burden. Finally, XL888 preferentially targeted p16INK4a-high human lung fibroblasts isolated from patients with idiopathic pulmonary fibrosis (IPF), and reduced p16INK4a+ fibroblasts from IPF PCLS ex vivo. This study provides proof of concept for a platform where p16INK4a+ cells are directly isolated from diseased tissues to identify compounds with in vivo and ex vivo efficacy in mouse and human respectively and provides a senolytic screening platform for other age-related diseases.

PMID:38451724 | DOI:10.1172/JCI173371

Cureus. 2024 Feb 4;16(2):e53578. doi: 10.7759/cureus.53578. eCollection 2024 Feb.

ABSTRACT

We present an interesting case of mediastinal small cell carcinoma (MSCC), an exceedingly rare entity, comorbid with idiopathic pulmonary fibrosis (IPF). A 66-year-old female was first seen in the pulmonology office for abnormal chest computed tomography (CT) findings of right apical bronchiectasis and subpleural fibrotic changes with focal pleural thickening along the fissures, along with a right lower lobe nodule. Pulmonary function testing (PFT) showed an obstructive pattern with modest bronchodilator response, although subsequent PFT showed a worsening restrictive pattern with a worsening DLCO. On a follow-up CT one year later, a soft tissue density with peripheral calcification was found in the anterior mediastinum, later found to be hypermetabolic on a PET scan. Radiographically, fibrosis worsened with the appearance of worsening diffuse bilateral coarse reticular interstitial changes with lower lobe predominance, honeycombing, and areas of ground-glass opacity. A biopsy of the mediastinal lesion showed a high-grade neuroendocrine tumor. Cam5.2, insulinoma-associated protein-1, synaptophysin, and thyroid transcription factor-1 immunostains were positive. She underwent four cycles of chemotherapy with cisplatin and etoposide with a total of 60 Gy of radiation. Mediastinal mass started to decrease in size. Her respiratory status, imaging, and PFTs continued to show evidence of IPF progression. Prednisone resulted in modest clinical and radiographic response. Steroid-sparing therapy with mycophenolate mofetil, although effective, had to be discontinued due to GI bleeding. Anti-fibrotic therapy was deferred due to evidence showing a lack of clinical improvement. We discuss the existing evidence available on IPF management and proceed to highlight the deficiencies in existing data available on the management of IPF and MSCC in these patients. Most of the cases of MSCC reported in the past have managed MSCC using guidance from treatment practices for small cell lung cancer. No reported cases discuss or describe the management of IPF and MSCC in the very rare cohort of patients our case represents.

PMID:38449967 | PMC:PMC10915904 | DOI:10.7759/cureus.53578

Zhonghua Jie He He Hu Xi Za Zhi. 2024 Mar 12;47(3):252-258. doi: 10.3760/cma.j.cn112147-20231020-00251.

ABSTRACT

Cyclic GMP-AMP synthase (cGAS) is a DNA receptor that produces the second messenger cyclic GMP-AMP (cGAMP). cGAMP activates stimulator of interferon genes (STING), which initiates a signaling cascade leading to immune and inflammatory responses. This intricate molecular pathway plays a pivotal role in the pathogenesis and progression of diverse respiratory ailments, including respiratory infection, lung cancer, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, asthma, and acute lung injury. Consequently, the cGAS-STING signaling pathway has emerged as a promising novel therapeutic target, opening up new avenues for the diagnosis and treatment of respiratory disorders. This review focuses on recent advances in our understanding of the cGAS-STING signaling pathway and its intricate involvement in respiratory system diseases.

PMID:38448178 | DOI:10.3760/cma.j.cn112147-20231020-00251

Zhonghua Jie He He Hu Xi Za Zhi. 2024 Mar 12;47(3):201-206. doi: 10.3760/cma.j.cn112147-20230805-00048.

ABSTRACT

Objective: To summarize and analyze the clinical features, treatment, and prognosis of pulmonary artery stenosis post-lung transplantation. Methods: A 62-year-old male patient was admitted to the hospital with a cough and chest tightness of over a year's duration, which had worsened in the last two months, leading to the diagnosis of idiopathic pulmonary fibrosis. The clinical data were observed and reviewed post-left allograft single lung transplantation. Literature searches were conducted using the keywords "lung transplantation" "stenosis, pulmonary artery" and "postoperative complications" in CNKI, Wanfang Medical Network, and PubMed databases up to December 2022. Results: On January 26, 2022, a left allograft single lung transplantation was performed under general anesthesia. Postoperatively, extracorporeal membrane oxygenation and mechanical ventilation were successfully weaned off at 22 hours and 2 days, respectively, with transfer from the intensive care unit 12 days after surgery. PaO2 and PaCO2 were 50 mmHg and 40 mmHg after deoxygenation. Both pulmonary CT angiography and ventilatory-perfusion imaging indicated stenosis of the left pulmonary anastomosis. Balloon dilation and pulmonary artery stenting were performed, with PaO2 and PaCO2 improving to 87 mmHg and 42 mmHg, respectively. The patient was discharged 102 days post-surgery, and was followed up for 1 year, with a good prognosis. Additionally, 36 related articles were retrieved, encompassing 69 cases with a median age of 53 years (38.5-59.0 years). Of these, 27.54% (19/69) were diagnosed with idiopathic pulmonary fibrosis, 46.38% (32/69) underwent single lung transplantation, with the primary clinical symptom being hypoxemia in 71.01% (49/69) cases. Left pulmonary artery anastomotic stenosis was observed in 43.48% (30/69), with 65.22% (45/69) being diagnosed in the late postoperative period. Interventional therapy was performed to 44.93% (31/69), with a mortality rate of 21.74% (15/69). Conclusions: The primary clinical manifestation of post-lung transplantation pulmonary artery stenosis is hypoxemia and can be diagnosed by pulmonary artery CT angiography, transesophageal echocardiography, and pulmonary angiography. Early diagnosis can significantly reduce mortality, and interventional therapy is an effective treatment for severe pulmonary artery stenosis post-lung transplantation.

PMID:38448168 | DOI:10.3760/cma.j.cn112147-20230805-00048

Bioorg Med Chem Lett. 2024 Mar 4:129690. doi: 10.1016/j.bmcl.2024.129690. Online ahead of print.

ABSTRACT

Autotaxin is a secreted lysophospholipase D which is a member of the ectonucleotide pyrophosphatase/phosphodiesterase family converting extracellular lysophosphatidylcholine and other non-choline lysophospholipids, such as lysophosphatidylethanolamine and lysophosphatidylserine, to the lipid mediator lysophosphatidic acid. Autotaxin is implicated in various fibroproliferative diseases including interstitial lung diseases such as idiopathic pulmonary fibrosis and hepatic fibrosis, as well as in cancer. In this study, we present an effort of identifying ATX inhibitors that bind to allosteric ATX binding sites using the Enalos Asclepios KNIME Node. All the available PDB crystal structures of ATX were collected, prepared, and aligned. Visual examination of these structures led to the identification of four crystal structures of human ATX co-crystallized with four known inhibitors. These inhibitors bind to five binding sites with five different binding modes. These five binding sites were thereafter used to virtually screen a compound library of 14,000 compounds to identify molecules that bind to allosteric sites. Based on the binding mode and interactions, the docking score, and the frequency that a compound comes up as a top-ranked among the five binding sites, 24 compounds were selected for in vitro testing. Finally, two compounds emerged with inhibitory activity against ATX in the low micromolar range, while their mode of inhibition and binding pattern were also studied. The two derivatives identified herein can serve as "hits" towards developing novel classes of ATX allosteric inhibitors.

PMID:38447786 | DOI:10.1016/j.bmcl.2024.129690

Respir Res. 2024 Mar 6;25(1):113. doi: 10.1186/s12931-024-02731-3.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with different disease trajectories. Progression (PF-ILD) occurs in up to 50% of patients and is associated with increased mortality.

METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for disease trajectories in different ILD. The course of disease was classified as significant (absolute forced vital capacity FVC decline > 10%) or moderate progression (FVC decline 5-10%), stable disease (FVC decline or increase < 5%) or improvement (FVC increase ≥ 5%) during time in registry. A second definition for PF-ILD included absolute decline in FVC % predicted ≥ 10% within 24 months or ≥ 1 respiratory-related hospitalisation. Risk factors for progression were determined by Cox proportional-hazard models and by logistic regression with forward selection. Kaplan-Meier curves were utilised to estimate survival time and time to progression.

RESULTS: Within the EXCITING-ILD registry 28.5% of the patients died (n = 171), mainly due to ILD (n = 71, 41.5%). Median survival time from date of diagnosis on was 15.5 years (range 0.1 to 34.4 years). From 601 included patients, progression was detected in 50.6% of the patients (n = 304) with shortest median time to progression in idiopathic NSIP (iNSIP; median 14.6 months) and idiopathic pulmonary fibrosis (IPF; median 18.9 months). Reasons for the determination as PF-ILD were mainly deterioration in lung function (PFT; 57.8%) and respiratory hospitalisations (40.6%). In multivariate analyses reduced baseline FVC together with age were significant predictors for progression (OR = 1.00, p < 0.001). Higher GAP indices were a significant risk factor for a shorter survival time (GAP stage III vs. I HR = 9.06, p < 0.001). A significant shorter survival time was found in IPF compared to sarcoidosis (HR = 0.04, p < 0.001), CTD-ILD (HR = 0.33, p < 0.001), and HP (HR = 0.30, p < 0.001). Patients with at least one reported ILD exacerbation as a reason for hospitalisation had a median survival time of 7.3 years (range 0.1 to 34.4 years) compared to 19.6 years (range 0.3 to 19.6 years) in patients without exacerbations (HR = 0.39, p < 0.001).

CONCLUSION: Disease progression is common in all ILD and associated with increased mortality. Most important risk factors for progression are impaired baseline forced vital capacity and higher age, as well as acute exacerbations and respiratory hospitalisations for mortality. Early detection of progression remains challenging, further clinical criteria in addition to PFT might be helpful.

PMID:38448953 | DOI:10.1186/s12931-024-02731-3

BMC Pulm Med. 2024 Mar 6;24(1):117. doi: 10.1186/s12890-024-02936-8.

ABSTRACT

BACKGROUND: Sex difference in the incidence rate of idiopathic pulmonary fibrosis (IPF) indicates that estrogen has a certain protective effect on the disease. Nevertheless, there is a dearth of study investigating the association between factors pertaining to endogenous estrogen exposure level, such as age at menarche (AAM) in women, and IPF. Our study intended to employ Mendelian randomization (MR) method to elucidate the causal association between AAM and IPF.

METHODS: Our study utilized AAM as a measure of endogenous estrogen exposure and investigated its causal effect on the risk of IPF through MR. We employed the inverse variance weighted (IVW) method to assess the causal relationship between AAM and IPF risk, with supplementary analyses conducted using the weighted median estimator (WME) and MR-Egger method. Several sensitivity analyses were performed to assess the dependability of MR estimates.

RESULTS: A total of 9 selected single nucleotide polymorphisms (SNPs) significantly associated with AAM were selected as instrumental variables. The IVW method showed that genetically later AAM was associated with an increased risk of IPF (odds ratio [OR] = 1.0014, 95%confidence interval [CI] = 1.0005-1.0023, p = 0.001). The median weighting method and the MR-Egger method obtained similar estimates, and no heterogeneity or pleiotropy was found, indicating that the results were robust.

CONCLUSIONS: Our MR study suggested a causal relationship between a later onset of menarche and a heightened susceptibility to IPF.

PMID:38448907 | DOI:10.1186/s12890-024-02936-8

Thorax. 2024 Mar 6:thorax-2023-221148. doi: 10.1136/thorax-2023-221148. Online ahead of print.

ABSTRACT

BACKGROUND: Fibrotic interstitial lung diseases (fILDs) are a heterogeneous group of lung diseases associated with significant morbidity and mortality. Despite a large increase in the number of clinical trials in the last 10 years, current regulatory-approved management approaches are limited to two therapies that prevent the progression of fibrosis. The drug development pipeline is long and there is an urgent need to accelerate this process. This manuscript introduces the concept and design of an innovative research approach to drug development in fILD: a global Randomised Embedded Multifactorial Adaptive Platform in fILD (REMAP-ILD).

METHODS: Description of the REMAP-ILD concept and design: the specific terminology, design characteristics (multifactorial, adaptive features, statistical approach), target population, interventions, outcomes, mission and values, and organisational structure.

RESULTS: The target population will be adult patients with fILD, and the primary outcome will be a disease progression model incorporating forced vital capacity and mortality over 12 months. Responsive adaptive randomisation, prespecified thresholds for success and futility will be used to assess the effectiveness and safety of interventions. REMAP-ILD embraces the core values of diversity, equity, and inclusion for patients and researchers, and prioritises an open-science approach to data sharing and dissemination of results.

CONCLUSION: By using an innovative and efficient adaptive multi-interventional trial platform design, we aim to accelerate and improve care for patients with fILD. Through worldwide collaboration, novel analytical methodology and pragmatic trial delivery, REMAP-ILD aims to overcome major limitations associated with conventional randomised controlled trial approaches to rapidly improve the care of people living with fILD.

PMID:38448221 | DOI:10.1136/thorax-2023-221148

Am J Respir Crit Care Med. 2024 Mar 6. doi: 10.1164/rccm.202402-0290VP. Online ahead of print.

NO ABSTRACT

PMID:38445949 | DOI:10.1164/rccm.202402-0290VP

Occup Ther Health Care. 2024 Mar 5:1-15. doi: 10.1080/07380577.2024.2324256. Online ahead of print.

ABSTRACT

This case-control study examined cognitive function in patients with mild idiopathic pulmonary fibrosis (IPF), in comparison with controls or moderate-to-severe IPF. Ten mild IPF, 10 moderate-to-severe IPF, and 16 controls were enrolled, and performance on seven different cognitive function tests was compared in each group. IPF showed decreased cognitive function compared to controls in verbal memory, cognitive flexibility and information processing speed. As the scores were lower even in mild IPF, this study suggests that cognitive function declines early in the disease process of IPF. Thus, occupational therapy for IPF should require an assessment of cognitive function and assistance appropriate to the client's function.

PMID:38440879 | DOI:10.1080/07380577.2024.2324256