Phytomedicine. 2022 Mar 11;100:154040. doi: 10.1016/j.phymed.2022.154040. Online ahead of print.

ABSTRACT

BACKGROUND: The Shuangshen Pingfei formula (SSPF), a classic Chinese medicine derivative formula, has been shown to exert therapeutic effects on idiopathic pulmonary fibrosis (IPF). However, the quality control compounds of SSPF remain unclear.

PURPOSE: To select and confirm Q-markers of SSPF based on network pharmacology, cytobiology, animal-based pharmacodynamics, and phytochemical and pharmacokinetic analyses.

METHODS: A compound-target network was constructed based on previous research. In addition, high-degree compounds of SSPF were chosen as potential Q-marker candidates. Animal and cytological experiments were performed to verify key targets of IPF. Haematoxylin-eosin and Masson's trichrome staining were used to observe lung tissue pathology. Cytokine levels in the bronchoalveolar lavage fluid (BALF) were measured using ELISA kits. Gene and protein expression levels were determined using PCR and western blotting, respectively. The contents of Q-marker candidates in different batches of SSPF were then determined for traceability research, and the quality consistency of SSPF was objectively evaluated using principal component analysis (PCA). Finally, pharmacokinetic research was performed, and candidates with desirable metabolite and bioavailability parameters were confirmed as Q-markers of SSPF.

RESULTS: The compound-target network included 56 compounds and 14 therapeutic targets. Animal experiments showed that SSPF attenuates lung fibrosis. SSPF decreased CC motif chemokine 2 (CCL2) and CC chemokine receptor type 2 (CCR2) levels in the BALF and downregulated the gene and protein expression of IPF therapy-related molecules, such as 5-hydroxytryptamine receptor 2A (HTR2A), CCL2, and CCR2, in the lungs. Cell experiments showed that nine Q-marker candidates in SSPF regulated the expression of CCL2 and CCR2, as predicted. Phytochemical analysis and PCA indicated that the qualities of SSPF in the nine batches were relatively stable. Pharmacokinetic studies demonstrated that mangiferin, salvianolic acid B, tanshinone IIA, naringin, and glycyrrhizic acid could be effectively absorbed into rat plasma, which ensured desirable bioavailability and confirmed their roles as Q-markers to represent anti-pulmonary fibrotic activity.

CONCLUSION: Our study is an integrated strategy, based on network pharmacology with experimental verification and phytochemical and pharmacokinetic analyses that provides a novel approach for Q-marker selection and validation of SSPF for IPF treatment.

PMID:35334302 | DOI:10.1016/j.phymed.2022.154040

Expert Opin Ther Pat. 2022 Mar 25. doi: 10.1080/13543776.2022.2058874. Online ahead of print.

ABSTRACT

INTRODUCTION: Nucleoside triphosphate diphosphohydrolases (NTPDases), alkaline phosphatases (APs), and ecto-nucleotide pyrophosphatases/phosphodiesterases (NPPs) are nucleotidases found on the cell surface. It is a promising therapeutic target for a range of disorders, including fibrosis, tumour metastasis, pruritus, inflammation, multiple sclerosis, and autoimmune diseases. As a result, therapeutic intervention including selective inhibitors of NPPs is required.

AREA COVERED: Many chemical substances, including pyrazole, pyridine and bicyclic compounds have demonstrated promising inhibitory potential for ecto-nucleotide pyrophosphatase/phosphodiesterases. The chemistry and clinical applications of NPPs inhibitors patented between 2015 and 2020 are discussed in this review.

EXPERT OPINION: : In recent years, there has been a lot of effort put into finding effective and selective inhibitors of NPPs. Despite the fact that a variety of synthetic inhibitors have been created, only a few investigations on their in vivo activity have been published. In addition to IOA-289 which has passed Phase Ia clinical trials; potent ATX inhibitor compounds such as BLD-0409, IPF and BBT-877 have been placed in phase I clinical studies. Some of the most promising ATX inhibitors in recent years are closely related analogs of previously known inhibitors, such as PF-8380. Knowledge of the structure activity relationship of such promising inhibitors can potentially translate into the discovery of more potent and effective inhibitors of NPP with a variety of structural characteristics and favourable therapeutic activities.

PMID:35333684 | DOI:10.1080/13543776.2022.2058874

Thorax. 2022 Mar 24:thoraxjnl-2021-218440. doi: 10.1136/thoraxjnl-2021-218440. Online ahead of print.

ABSTRACT

INTRODUCTION: The gender-age-physiology (GAP) index is an easy-to-use baseline mortality prediction model in idiopathic pulmonary fibrosis (IPF). The GAP index does not incorporate exercise capacity parameters such as 6 min walk distance (6MWD) or exertional hypoxia. We evaluated if the addition of 6MWD and exertional hypoxia to the GAP index improves survival prediction in IPF.

METHODS: Patients with IPF were identified at a tertiary care referral centre. Discrimination and calibration of the original GAP index were assessed. The cohort was then randomly divided into a derivation and validation set and performance of the GAP index with the addition of 6MWD and exertional hypoxia was evaluated. A final model was selected based on improvement in discrimination. Application of this model was then evaluated in a geographically distinct external cohort.

RESULTS: There were 562 patients with IPF identified in the internal cohort. Discrimination of the original GAP index was measured by a C-statistic of 0.676 (95% CI 0.635 to 0.717) and overestimated observed risk. 6MWD and exertional hypoxia were strongly predictive of mortality. The addition of these variables to the GAP index significantly improved model discrimination. A revised index incorporating exercise capacity parameters was constructed and performed well in the internal validation set (C-statistic: 0.752; 95% CI 0.701 to 0.802, difference in C-statistic compared with the refit GAP index: 0.050; 95% CI 0.004 to 0.097) and external validation set (N=108 (C-statistic: 0.780; 95% CI 0.682 to 0.877)).

CONCLUSION: A simple point-based baseline-risk prediction model incorporating exercise capacity predictors into the original GAP index may improve prognostication in patients with IPF.

PMID:35332096 | DOI:10.1136/thoraxjnl-2021-218440

iScience. 2022 Mar 3;25(4):104022. doi: 10.1016/j.isci.2022.104022. eCollection 2022 Apr 15.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a life-threatening disease resulting from dysregulated repair responses to lung injury. Excessive extracellular matrix deposition by expanding myofibroblasts and fibrotic lung fibroblasts (fLfs) has been implicated in the pathogenesis of PF, including IPF. We explored fLfs' microRNA-34a (miR-34a) expression from IPF tissues. Basal miR-34a levels were decreased with reduced binding of p53 to the promoter DNA and 3'UTR mRNA sequences. Overexpression of miR-34a in fLfs increased p53, PAI-1, and reduced pro-fibrogenic markers. The regulatory effects of miR-34a were altered by modifying the p53 expression. Precursor-miR-34a lung transduction reduced bleomycin-induced PF in wild-type mice. fLfs treated with caveolin-1 scaffolding domain peptide (CSP) or its fragment, CSP7, restored miR-34a, p53, and PAI-1. CSP/CSP7 reduced PDGFR-β and pro-fibrogenic markers, which was abolished in fLfs following blockade of miR-34a expression. These peptides failed to resolve PF in mice lacking miR-34a in fLfs, indicating miR-34a-p53-feedback induction required for anti-fibrotic effects.

PMID:35330685 | PMC:PMC8938287 | DOI:10.1016/j.isci.2022.104022

J Pers Med. 2022 Mar 16;12(3):474. doi: 10.3390/jpm12030474.

ABSTRACT

BACKGROUND: Mechanical ventilation brings the risk of ventilator-induced lung injury, which can lead to pulmonary fibrosis and prolonged mechanical ventilation.

METHODS: A retrospective analysis of patients with acute respiratory distress syndrome (ARDS) who received open lung biopsy between March 2006 and December 2019.

RESULTS: A total of 68 ARDS patients receiving open lung biopsy with diffuse alveolar damage (DAD; the hallmark pathology of ARDS) were analyzed and stratified into non-fibrosis (n = 56) and fibrosis groups (n = 12). The duration of ventilator usage and time spent in the intensive care unit and hospital stay were all significantly higher in the fibrosis group. Hospital mortality was higher in the fibrosis than in the non-fibrosis group (67% vs. 57%, p = 0.748). A multivariable logistic regression model demonstrated that mechanical power at ARDS diagnosis and ARDS duration before biopsy were independently associated with histological fibrosis at open lung biopsy (odds ratio 1.493 (95% CI 1.014-2.200), p = 0.042; odds ratio 1.160 (95% CI 1.052-1.278), p = 0.003, respectively).

CONCLUSIONS: Our findings indicate that prompt action aimed at staving off injurious mechanical stretching of lung parenchyma and subsequent progression to fibrosis may have a positive effect on clinical outcomes.

PMID:35330473 | DOI:10.3390/jpm12030474

J Pers Med. 2022 Feb 28;12(3):373. doi: 10.3390/jpm12030373.

ABSTRACT

The most common idiopathic interstitial lung disease (ILD) is idiopathic pulmonary fibrosis (IPF). It can be identified by the presence of usual interstitial pneumonia (UIP) via high-resolution computed tomography (HRCT) or with the use of a lung biopsy. We hypothesized that a CT-based approach using handcrafted radiomics might be able to identify IPF patients with a radiological or histological UIP pattern from those with an ILD or normal lungs. A total of 328 patients from one center and two databases participated in this study. Each participant had their lungs automatically contoured and sectorized. The best radiomic features were selected for the random forest classifier and performance was assessed using the area under the receiver operator characteristics curve (AUC). A significant difference in the volume of the trachea was seen between a normal state, IPF, and non-IPF ILD. Between normal and fibrotic lungs, the AUC of the classification model was 1.0 in validation. When classifying between IPF with a typical HRCT UIP pattern and non-IPF ILD the AUC was 0.96 in validation. When classifying between IPF with UIP (radiological or biopsy-proved) and non-IPF ILD, an AUC of 0.66 was achieved in the testing dataset. Classification between normal, IPF/UIP, and other ILDs using radiomics could help discriminate between different types of ILDs via HRCT, which are hardly recognizable with visual assessments. Radiomic features could become a valuable tool for computer-aided decision-making in imaging, and reduce the need for unnecessary biopsies.

PMID:35330373 | DOI:10.3390/jpm12030373

J Clin Med. 2022 Mar 14;11(6):1609. doi: 10.3390/jcm11061609.

ABSTRACT

BACKGROUND: Interstitial lung disease (ILD) is associated with high rates of comorbidities and non-infectious lung disease mortality. Against this background, we aimed to evaluate the prognostic capacity of lung function and cardiopulmonary exercise testing (CPET) in patients with ILD.

MATERIALS AND METHODS: A total of 183 patients with diverse ILD entities were included in this monocentric analysis. Prediction models were determined using Cox regression models with age, sex, body mass index (BMI), and all parameters from pulmonary function testing and CPET. Kaplan-Meier curves were plotted for selected variables.

RESULTS: The median follow-up period was 3.0 ± 2.5 years. Arterial hypertension (57%) and pulmonary hypertension (38%) were the leading comorbidities. The Charlson comorbidity index score was 2 ± 2 points. The 3-year and 5-year survival rates were 68% and 50%, respectively. VO2peak (mL/kg/min or %pred.) was identified as a significant prognostic parameter in patients with ILD. The cut-off value for discriminating mortality was 61%.

CONCLUSION: The present analyses consistently revealed the high prognostic power of VO2peak %pred. and other parameters evaluating breathing efficacy (VÉ/VCO2 @AT und VÉ/VCO2 slope) in ILD patients. VO2peak %pred., in contrast to the established prognostic values FVC %pred., DLCO/KCO %pred., and GAP, showed an even higher prognostic ability in all statistical models.

PMID:35329935 | DOI:10.3390/jcm11061609

Int J Mol Sci. 2022 Mar 19;23(6):3323. doi: 10.3390/ijms23063323.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by irreversible scarring of the distal lung. IPF is best described by its histopathological pattern of usual interstitial pneumonia (UIP), characterized by spatial heterogeneity with alternating interstitial fibrosis and areas of normal lung, and temporal heterogeneity of fibrosis characterized by scattered fibroblastic foci (FF), dense acellular collagen and honeycomb changes. FF, comprising aggregated fibroblasts/myofibroblasts surrounded by metaplastic epithelial cells (EC), are the cardinal pathological lesion and their presence strongly correlates with disease progression and mortality. We hypothesized that the EC/FF sandwich from patients with UIP/IPF has a distinct molecular signature which could offer new insights into the crosstalk of these two crucial actors in the disease. Laser capture microdissection with RNAseq was used to investigate the transcriptome of the EC/FF sandwich from IPF patients versus controls (primary spontaneous pneumothorax). Differentially expressed gene analysis identified 23 up-regulated genes mainly related to epithelial dysfunction. Gene ontology analysis highlighted the activation of different pathways, mainly related to EC, immune response and programmed cell death. This study provides novel insights into the IPF pathogenetic pathways and suggests that targeting some of these up-regulated pathways (particularly those related to secreto-protein/mucin dysfunction) may be beneficial in IPF. Further studies in a larger number of lung samples, ideally from patients with early and advanced disease, are needed to validate these findings.

PMID:35328744 | DOI:10.3390/ijms23063323

Int J Mol Sci. 2022 Mar 18;23(6):3316. doi: 10.3390/ijms23063316.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by an excess deposition of extracellular matrix in the pulmonary interstitium. Caveolin-1 scaffolding domain peptide (CSP) has been found to mitigate pulmonary fibrosis in several animal models. However, its pathophysiological role in IPF is obscure, and it remains critical to understand the mechanism by which CSP protects against pulmonary fibrosis. We first studied the delivery of CSP into cells and found that it is internalized and accumulated in the Endoplasmic Reticulum (ER). Furthermore, CSP reduced ER stress via suppression of inositol requiring enzyme1α (IRE1α) in transforming growth factor β (TGFβ)-treated human IPF lung fibroblasts (hIPF-Lfs). Moreover, we found that CSP enhanced the gelatinolytic activity of TGFβ-treated hIPF-Lfs. The IRE1α inhibitor; 4µ8C also augmented the gelatinolytic activity of TGFβ-treated hIPF-Lfs, supporting the concept that CSP induced inhibition of the IRE1α pathway. Furthermore, CSP significantly elevated expression of MMPs in TGFβ-treated hIPF-Lfs, but conversely decreased the secretion of collagen 1. Similar results were observed in two preclinical murine models of PF, bleomycin (BLM)- and adenovirus expressing constitutively active TGFβ (Ad-TGFβ)-induced PF. Our findings provide new insights into the mechanism by which lung fibroblasts contribute to CSP dependent protection against lung fibrosis.

PMID:35328736 | DOI:10.3390/ijms23063316

Cancers (Basel). 2022 Mar 11;14(6):1445. doi: 10.3390/cancers14061445.

ABSTRACT

PBT has a unique depth-dose curve with a Bragg peak that enables one to reduce the dose to normal lung tissue. We prospectively enrolled 54 patients with non-small cell lung cancer treated with definitive PBT. The inclusion criteria were forced expiratory volume in 1 s (FEV1) ≤ 1.0 L or FEV1 ≤ 50% of predicted or diffusing capacity of the lungs for carbon monoxide (DLco) ≤ 50%, or pulmonary fibrosis. The primary endpoint was grade ≥ 3 pulmonary toxicity, and secondary endpoints were changes in pulmonary function and quality of life. The median age was 71.5 years (range, 57-87). Fifteen (27.8%) and fourteen (25.9%) patients had IPF and combined pulmonary fibrosis and emphysema, respectively. The median predicted forced vital capacity (FVC), FEV1, and DLco were 77% (range, 42-104%), 66% (range, 31-117%), and 46% (range, 23-94%), respectively. During the follow-up (median, 14.7 months), seven (13.0%) patients experienced grade ≥ 3 pulmonary toxicity. Seven months after the completion of PBT, patients with IPF or non-IPF interstitial lung disease (ILD) experienced a decrease in the FVC but the decrease in DLco was not significant. Under careful monitoring by pulmonologists, PBT could be a useful treatment modality for lung cancer patients with poor lung function or pulmonary fibrosis.

PMID:35326594 | DOI:10.3390/cancers14061445

Cells. 2022 Mar 19;11(6):1050. doi: 10.3390/cells11061050.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a fatal disease with incompletely understood aetiology and limited treatment options. Traditionally, IPF was believed to be mainly caused by repetitive injuries to the alveolar epithelium. Several recent lines of evidence, however, suggest that IPF equally involves an aberrant airway epithelial response, which contributes significantly to disease development and progression. In this review, based on recent clinical, high-resolution imaging, genetic, and single-cell RNA sequencing data, we summarize alterations in airway structure, function, and cell type composition in IPF. We furthermore give a comprehensive overview on the genetic and mechanistic evidence pointing towards an essential role of airway epithelial cells in IPF pathogenesis and describe potentially implicated aberrant epithelial signalling pathways and regulation mechanisms in this context. The collected evidence argues for the investigation of possible therapeutic avenues targeting these processes, which thus represent important future directions of research.

PMID:35326501 | DOI:10.3390/cells11061050

Cells. 2022 Mar 18;11(6):1031. doi: 10.3390/cells11061031.

ABSTRACT

Cell-based therapies hold great promise in re-establishing organ function for many diseases, including untreatable lung diseases such as idiopathic pulmonary fibrosis (IPF). However, many hurdles still remain, in part due to our lack of knowledge about the disease-driving mechanisms that may affect the cellular niche and thereby possibly hinder the function of any transplanted cells by imposing the disease phenotype onto the newly generated progeny. Recent findings have demonstrated increased ciliation of lung cells from IPF patients, but how this affects ciliated cell function and the airway milieu is not well-known. Here, we performed single-cell RNA sequencing on primary ciliated (FOXJ1+) cells isolated from IPF patients and from healthy control donors. The sequencing identified multiple biological processes, such as cilium morphogenesis and cell signaling, that were significantly changed between IPF and healthy ciliated cells. Ferritin light chain (FTL) was downregulated in IPF, which suggests that iron metabolism may be affected in the IPF ciliated cells. The RNA expression was confirmed at the protein level with histological localization in lung tissue, prompting future functional assays to reveal the potential role of FTL. Taken together, our data demonstrate the importance of careful analyses in pure cell populations to better understand the IPF disease mechanism.

PMID:35326483 | DOI:10.3390/cells11061031

Cells. 2022 Mar 14;11(6):986. doi: 10.3390/cells11060986.

ABSTRACT

In this review article, we will first provide a brief overview of the ErbB receptor-ligand system and its importance in developmental and physiological processes. We will then review the literature regarding the role of ErbB receptors and their ligands in the maladaptive remodeling of lung tissue, with special emphasis on idiopathic pulmonary fibrosis (IPF). Here we will focus on the pathways and cellular processes contributing to epithelial-mesenchymal miscommunication seen in this pathology. We will also provide an overview of the in vivo studies addressing the efficacy of different ErbB signaling inhibitors in experimental models of lung injury and highlight how such studies may contribute to our understanding of ErbB biology in the lung. Finally, we will discuss what we learned from clinical applications of the ErbB1 signaling inhibitors in cancer in order to advance clinical trials in IPF.

PMID:35326439 | DOI:10.3390/cells11060986

Cells. 2022 Mar 12;11(6):984. doi: 10.3390/cells11060984.

ABSTRACT

Over the past decades, a better understanding of the genetic and molecular alterations underlying several respiratory diseases has encouraged the development of new therapeutic strategies. Gene therapy offers new therapeutic alternatives for inherited and acquired diseases by delivering exogenous genetic materials into cells or tissues to restore physiological protein expression and/or activity. In this review, we review (1) different types of viral and non-viral vectors as well as gene-editing techniques; and (2) the application of gene therapy for the treatment of respiratory diseases and disorders, including pulmonary arterial hypertension, idiopathic pulmonary fibrosis, cystic fibrosis, asthma, alpha-1 antitrypsin deficiency, chronic obstructive pulmonary disease, non-small-cell lung cancer, and COVID-19. Further, we also provide specific examples of lung-targeted therapies and discuss the major limitations of gene therapy.

PMID:35326434 | DOI:10.3390/cells11060984

Antioxidants (Basel). 2022 Mar 8;11(3):523. doi: 10.3390/antiox11030523.

ABSTRACT

Bleomycin (BLM) administration is associated with multifunctional proteins inflammations and induction of idiopathic pulmonary fibrosis (IPF). Lemna minor L. extract, a free-floating monocot macrophyte possesses antioxidant and anti-inflammatory potential. The aim of the study was to examine the protective effect of L. minor extract on lung protein oxidation and oxidative stress modulation by BLM-induced pulmonary fibrosis in Balb/c mice. For this purpose, the protein carbonyl content, advanced glycation end product, nitroxide protein oxidation (5-MSL), and lipid peroxidation (as MDA and ROS), in lung cells were examined. The histological examinations, collagen deposition, and quantitative measurements of IL-1β, IL-6, and TNF in lung tissues and blood were investigated. Intraperitoneal, BLM administration (0.069 U/mL; 0.29 U/kg b.w.) for 33 days, caused IPF induction in Balb/c mice. Pulmonary combining therapy was administered with L. minor at dose 120 mg/mL (0.187 mg/kg b.w.). L. minor histologically ameliorated BLM induced IPF in lung tissues. L. minor significantly modulated (p < 0.05) BLM-alterations induced in lung hydroxyproline, carbonylated proteins, 5-MSL-protein oxidation. Oxidative stress decreased levels in antioxidant enzymatic and non-enzymatic systems in the lung were significantly regulated (p < 0.05) by L. minor. L. minor decreased the IL-1β, IL-6, and TNF-α expression in lung tissues and plasma. The L. minor improves the preventive effect/defense response in specific pulmonary protein oxidation, lipid peroxidation, ROS identifications, and cytokine modulation by BLM-induced chronic inflammations, and could be a good antioxidant, anti-inflammatory, and anti-fibrotic alternative or IPF prevention involved in their pathogenesis.

PMID:35326173 | DOI:10.3390/antiox11030523

Antioxidants (Basel). 2022 Feb 28;11(3):492. doi: 10.3390/antiox11030492.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF), a severe and deadly form of lung fibrosis, is widely regarded as a disease of aging. We previously demonstrated that aged mice with persistent lung fibrosis and IPF lung myofibroblasts exhibit deficient Nrf2-mediated antioxidant responses. Tecfidera is an orally administered FDA-approved drug for the treatment of multiple sclerosis, where the active pharmaceutical ingredient is dimethyl fumarate (DMF), an active Nrf2 activator. However, no studies have evaluated the efficacy of DMF for age-associated persistent lung fibrosis. Here, we demonstrate that in IPF lung fibroblasts, DMF treatment inhibited both TGF-β-mediated pro-fibrotic phenotypes and led to a reversal of established pro-fibrotic phenotypes. We also evaluated the pre-clinical efficacy of lung-targeted (inhaled) vs. systemic (oral) delivery of DMF in an aging murine model of bleomycin-induced persistent lung fibrosis. DMF or vehicle was administered daily to aged mice by oral gavage or intranasal delivery from 3-6 weeks post-injury when mice exhibited non-resolving lung fibrosis. In contrast to systemic (oral) delivery, only lung-targeted (inhaled) delivery of DMF restored lung Nrf2 expression levels, reduced lung oxidative stress, and promoted the resolution of age-dependent established fibrosis. This is the first study to demonstrate the efficacy of lung-targeted DMF delivery to promote the resolution of age-dependent established lung fibrosis.

PMID:35326142 | DOI:10.3390/antiox11030492

Nat Commun. 2022 Mar 23;13(1):1558. doi: 10.1038/s41467-022-29064-3.

ABSTRACT

Idiopathic pulmonary fibrosis is an incurable disease of unknown etiology. Acute exacerbation of idiopathic pulmonary fibrosis is associated with high mortality. Excessive apoptosis of lung epithelial cells occurs in pulmonary fibrosis acute exacerbation. We recently identified corisin, a proapoptotic peptide that triggers acute exacerbation of pulmonary fibrosis. Here, we provide insights into the mechanism underlying the processing and release of corisin. Furthermore, we demonstrate that an anticorisin monoclonal antibody ameliorates lung fibrosis by significantly inhibiting acute exacerbation in the human transforming growth factorβ1 model and acute lung injury in the bleomycin model. By investigating the impact of the anticorisin monoclonal antibody in a general model of acute lung injury, we further unravel the potential of corisin to impact such diseases. These results underscore the role of corisin in the pathogenesis of acute exacerbation of pulmonary fibrosis and acute lung injury and provide a novel approach to treating this incurable disease.

PMID:35322016 | DOI:10.1038/s41467-022-29064-3

J Med Econ. 2022 Mar 24:1-35. doi: 10.1080/13696998.2022.2054203. Online ahead of print.

ABSTRACT

AIMS: While nintedanib treatment has been shown to slow the progression of idiopathic pulmonary fibrosis (IPF) in patients across varying levels of lung function, the effect of treatment timing on outcomes has not been examined. We assessed hospitalization risk and medical costs among patients with IPF based on the timing of nintedanib initiation after IPF diagnosis.

MATERIALS AND METHODS: This retrospective administrative claims study included data from 04/01/2014-09/30/2019 for patients aged ≥40 years who initiated nintedanib within 1 year of IPF diagnosis. Patients were assigned to study cohorts based on the time from IPF diagnosis to nintedanib initiation. All-cause hospitalization and all-cause medical costs were modeled using marginal structural models including inverse probability weights to adjust for both baseline and time-varying characteristics.

RESULTS: Of 11,195 patients diagnosed with IPF during the identification period, 449 met the study selection criteria (mean age 72.3 years, 68% male, mean follow-up time 13.3 months). Adjusted hospitalization risk and medical costs both varied significantly by timing of nintedanib initiation (p < 0.001 and p = 0.020, respectively). Adjusted weighted hospitalization risk was higher among untreated vs treated patients in months 2-3, months 4-6, and months 7-12 after diagnosis (hazard ratio [95% CI] 1.97 [1.09-3.56], p = 0.026; 2.62 [1.22-5.63], p = 0.014; and 5.57 [2.31-13.45], p < 0.001, respectively). Medical costs were 69% higher for patients initiating treatment in months 2-3 vs month 1 (cost ratio [95% CI] 1.69 [1.20-2.38], p = 0.003).

LIMITATIONS: Disease severity could not be assessed because clinical data were unavailable; however, proxies such as oxygen use were included to adjust for between-cohort differences in disease severity.

CONCLUSIONS: Patients who initiate nintedanib promptly after IPF diagnosis may have reduced hospitalization risk and medical costs compared with those who start treatment later. Additional studies are warranted to improve understanding of the impact of prompt antifibrotic therapy on patient outcomes.

PMID:35321616 | DOI:10.1080/13696998.2022.2054203

Rev Med Chil. 2021 Oct;149(10):1512-1515. doi: 10.4067/s0034-98872021001001512.

ABSTRACT

We report a 68-year-old woman with a history of idiopathic pulmonary fibrosis, who had immediate skin reactions associated with the use of pirfenidone in two opportunities. In the evaluation by immunology, an allergy to pirfenidone was diagnosed. Given the urgent need for the drug, a desensitization procedure was started. The dose of the medication was increased progressively, previous premedication with cetirizine, ranitidine and montelukast. After this procedure the patient was able to tolerate the treatment with pirfenidone without cutaneous reactions.

PMID:35319642 | DOI:10.4067/s0034-98872021001001512

Andes Pediatr. 2021 Oct;92(5):667-676. doi: 10.32641/andespediatr.v92i5.3708.

ABSTRACT

Left ventricular non-compaction (LVNC) and restrictive cardiomyopathies (RCM) are rare diseases with high morbidity and mortality in the pediatric age group, particularly the restrictive. They can be diagnosed at any age even in fetal life, in isolation or association with other cardiomyopathies or congenital heart disease. The causes may be genetic, neuromuscular, metabolic, storage, or idiopathic disorders. The main morphological characteristic of LVNC is the presence of a non-compact myocar dium with numerous prominent trabeculations and deep recesses, which may results in myocardial dysfunction, malignant arrhythmias and thromboembolism. On the other hand, in RCM there is an abnormal myocardial stiffness, which generates a restrictive ventricular filling and atrial dilatation secondary. Clinically it manifested by severe diastolic dysfunction, pulmonary hypertension, arrhyth mias and sudden death. For both cardiomyopathies, the Doppler color echocardiography, electro cardiography and Holter monitoring of arrhythmias are the gold standard for diagnosis and follow up. Cardiac resonance adds information on functional assessment and quantification of myocardial fibrosis. The therapy is oriented to improve symptoms and quality of life. Patients with severe forms of LVNC and RCM may require extracorporeal ventricular support and cardiac transplantation, even in early stages of the disease. The pediatrician plays an important role in the early recognition of these pathologies for timing to referral as well as in the follow-up and screening for complications. The objective of this review is to update the clinical, genetic, diagnostic, therapeutic issues and prognostic of the LVNC and RCM.

PMID:35319572 | DOI:10.32641/andespediatr.v92i5.3708