Occup Environ Med. 2023 Jun;80(6):e1. doi: 10.1136/oemed-2022-108404corr1.

NO ABSTRACT

PMID:37172959 | DOI:10.1136/oemed-2022-108404corr1

Medicine (Baltimore). 2023 May 12;102(19):e33722. doi: 10.1097/MD.0000000000033722.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a debilitating condition, with a life expectancy of 2 to 5 years after diagnosis. Pirfenidone is a drug that has been shown to reduce the decline in forced vital capacity (FVC). We sought to identify whether different patterns on high-resolution computed tomography (HRCT) have different clinical effects through a retrospective comparison of baseline values and changes in pulmonary function tests (PFTs) after treatment with pirfenidone. We retrospectively analyzed data from IPF patients treated with pirfenidone at Nanjing Drum Tower Hospital in Jiangsu Province, China. According to the HRCT pattern, the patients were divided into usual interstitial pneumonitis (UIP) and possible UIP groups. Baseline clinical characteristics and changes every 6 months in the PFTs during the follow-up period were compared between the 2 groups. A total of 65 consecutive patients were enrolled. According to the HRCT pattern, patients were clustered into the UIP group (n = 46) and possible UIP group (n = 19). No difference was observed in the baseline PFTs ratio between the 2 groups. The FVC values of the 2 groups were not significantly different at the initial treatment and at 6 and 12 months after pirfenidone treatment (P = .081, 0.099, and 0.236, respectively). The improvement in % diffusion capacity of the lung for carbon monoxide (%DLCO) was higher in the possible UIP group after 6 and 12 months of pirfenidone treatment (P = .149, 0.026, and 0.025, respectively). The annual decrease in FVC was not significantly different between the 2 groups, and the annual decrease in %DLCO in the UIP group was significantly higher than that in patients with the possible UIP type (-7.767 ± 12.797 vs 0.342 ± 20.358, P < .05). These results indicate that patients with IPF with a possible UIP pattern on HRCT showed indications of a good response to pirfenidone.

PMID:37171315 | DOI:10.1097/MD.0000000000033722

Med Sci Sports Exerc. 2023 May 12. doi: 10.1249/MSS.0000000000003208. Online ahead of print.

ABSTRACT

PURPOSE: Cerebral hypoxia may exacerbate the perception of fatigue. We previously demonstrated that exercise-related hypoxemia, a hallmark of fibrotic interstitial lung disease (f-ILD), dose-dependently impairs cerebral oxygenation in these patients. It is unknown whether normalizing cerebral oxygenation with O2 supplementation would be associated with positive changes in a relevant patient-centered outcome during exercise in f-ILD, such as improved perceived fatigue.

METHODS: Fourteen patients (12 males, 72 ± 8 years, 8 with idiopathic pulmonary fibrosis, lung diffusing capacity for carbon monoxide = 44 ± 13% predicted) performed a constant-load (60% peak work rate) cycle test to symptom limitation (Tlim) breathing medical air. Fourteen controls cycled up to Tlim of an age- and sex-matched patient. Patients repeated the test on supplemental O2 (fraction of inspired O2 = 0.41 ± 0.08) for the same duration. Near-infrared spectroscopy and the rating-of-fatigue (ROF) scale respectively assessed prefrontal cortex oxygenation and perceived fatigue.

RESULTS: Patients showed severe exertional hypoxemia (Tlim O2 saturation by pulse oximetry = 80 ± 8%); they had poorer cerebral oxygenation [e.g. oxy-deoxyhemoglobin difference (HbDiff) = -3.5 ± 4.7 (range: -17.6 to +1.9) vs + 1.9 ± 1.7 μmol from rest] and greater fatigue (ROF = 6.2 ± 2.0 vs 2.6 ± 2.3) vs controls under air (p < 0.001). Reversal of exertional hypoxemia with supplemental O2 led to improved HbDiff (+1.7 ± 2.4 μmol from rest; no longer differing from controls) and lower ROF scores (3.7 ± 1.2; p < 0.001 vs air) in patients. There was a significant correlation between O2-induced changes in HbDiff and ROF scores throughout exercise in f-ILD (rrepeated-measures correlation = -0.51; p < 0.001).

CONCLUSIONS: Supplemental O2 improved cerebral oxygenation during exercise in f-ILD, which was moderately associated with lower ratings of perceived fatigue. Reversing cerebral hypoxia with O2 supplementation may thus have positive effects on patients' disablement beyond those expected from lower ventilation and dyspnea in this patient population.

PMID:37170955 | DOI:10.1249/MSS.0000000000003208

Ter Arkh. 2023 Apr 26;95(3):230-235. doi: 10.26442/00403660.2023.03.202073.

ABSTRACT

Progressive pulmonary fibrosis is a major problem in respiratory medicine. Currently, there are no reliable biomarkers for early diagnosis of progressive pulmonary fibrosis, which leads to delayed diagnosis.

AIM: To determine the role of serum biomarkers CA-19-9 and CA-125 and the possibilities of capillaroscopy of the nail fold in the diagnosis of progressive pulmonary fibrosis.

MATERIALS AND METHODS: The study included 43 patients with interstitial changes in the lungs. Based on the presence/absence of signs of progression over the previous 12 months, patients were divided into 2 groups. All patients underwent forced spirometry, body plethysmography, diffusion test, CT, lung ultrasound, capillaroscopy of the nail fold, study of serum concentrations of CA-19-9 and CA-125.

RESULTS: In the group of patients with a progressive fibrotic phenotype of Interstitial lung diseases, a greater severity of capillaroscopic changes and a higher level of CA-19-9 were revealed. Correlation of these parameters with changes according to CT scan data (Warrick test) and lung ultrasound was shown.

CONCLUSION: The data obtained demonstrate the possibilities of non-invasive diagnosis of progressive fibrosing interstitial lung diseases and require further research and prospective follow-up to assess the diagnostic and prognostic role of the studied biomarkers, as well as to determine their place in clinical practice.

PMID:37167144 | DOI:10.26442/00403660.2023.03.202073

Ter Arkh. 2023 Apr 26;95(3):224-229. doi: 10.26442/00403660.2023.03.202087.

ABSTRACT

AIM: To study demographic, clinical, serological and morphological features of interstitial pneumonia with autoimmune features (IPAF), compare survival in IPAF and interstitial lung disease in connective tissue diseases (CTD-ILD), and identify predictors of mortality and transformation to CTD in the IPAF group.

MATERIALS AND METHODS: The IPAF group included 48 patients (75.0% women, median age 57.5 years), CTD-ILD - 49 patients (79.6% women, median age 60.0 years). The analysis of demographic, clinical, laboratory and instrumental data was performed, as well as comparison of survival with the Kaplan-Meier method and the log-rank test in the IPAF and CTD-ILD groups. In the IPAF group, predictors of mortality and the development of CTD were studied with multivariate regression analysis.

RESULTS: Duration of observation period did not differ significantly in the IPAF and CTD-ILD groups (40.0 and 37.0 months, respectively). Clinical criteria of IPAF were observed in 25 (52.1%) patients, serological - in 44 (91.7%), morphological - in 44 (91.7%). Mortality in the IPAF group was significantly higher than in the CTD-ILD group (29.2 and 6.1%, respectively; p=0.023). The presence of diabetes mellitus, CT-pattern of usual interstitial pneumonia, and an initial low forced vital capacity value were independent predictors of mortality in the IPAF group. During the observation period, the development of CTD was noted in 4 (8.3%) patients with IPAF. The independent predictor of the CTD development was the increased C-reactive protein level.

CONCLUSION: IPAF is characterized by a lower survival rate compared to CTD-ILD, and a relatively low risk of CTD transformation.

PMID:37167143 | DOI:10.26442/00403660.2023.03.202087

J Asthma Allergy. 2023 May 4;16:473-479. doi: 10.2147/JAA.S409042. eCollection 2023.

ABSTRACT

BACKGROUND: In the two fibrotic hypersensitivity pneumonitis (fHP) diagnostic guidelines, the multidisciplinary discussion (MDD) is required to be performed in diagnosis of fHP, as in idiopathic pulmonary fibrosis (IPF) diagnostic guideline. Although some patients with fHP can improve disease condition during antigen avoidance, which can facilitate the diagnosis of fHP, it is unclear if MDD is necessary in all patients with suspected fHP who improved an antigen avoidance.

OBJECTIVE: To investigate the diagnosis of fHP via MDD with positive antigen avoidance tests (AATs) and the clinical diagnosis with positive AATs.

METHODS: A single-center, retrospective study was conducted. Between 2012 and 2019, patients with fHP were enrolled in the study. Patients in the MDD diagnostic group consisted of patients diagnosed with MDD, including histopathology findings and positive ATTs, and patients in the clinical diagnostic group were diagnosed by two respiratory physicians and had positive ATTs.

RESULTS: AAT was performed on 72 of 219 patients, and 58 had positive AATs. The study included 37 patients in the MDD diagnosis group and 21 patients in the clinical diagnosis group. No significant differences in overall survival (OS) were detected between the two groups (HR: 1.99 [95% CI: 0.82‒4.83], p = 0.127). The conducting MDD was not a risk factor for OS; only <79% forced vital capacity was a risk factor in the multivariate Cox hazard regression analysis. No significant difference in annual changes of forced vital capacity, diffusion of the lung for carbon monoxide and Krebs von den Lungen-6 between the MDD diagnostic and the clinical diagnostic groups were observed (p = 0.41, 0.79, and 0.81, respectively).

CONCLUSION: In patients with positive AATs, the disease progression of the MDD diagnostic and the clinical diagnostic groups were similar. Therefore, MDD could not be necessary in all patients with suspected fHP who had positive AATs.

PMID:37168674 | PMC:PMC10166106 | DOI:10.2147/JAA.S409042

J Community Hosp Intern Med Perspect. 2023 Mar 10;13(2):46-48. doi: 10.55729/2000-9666.1166. eCollection 2023.

ABSTRACT

Constrictive pericarditis most commonly results from fibrosis and adhesions of the parietal and visceral pericardium due to long-standing inflammation. Common etiologies include idiopathic, post-surgical, radiation injury and infectious etiologies including tuberculosis. Traumatic hemopericardium is a rare cause of constrictive pericarditis but atraumatic hemopericardium causing constrictive pericarditis has not been reported in the literature to date. We present a case of constrictive pericarditis from an atraumatic hemopericardium after systemic thrombolysis for a massive pulmonary embolism.

PMID:37168070 | PMC:PMC10166214 | DOI:10.55729/2000-9666.1166

BMC Public Health. 2023 May 11;23(1):868. doi: 10.1186/s12889-023-15733-5.

ABSTRACT

BACKGROUND: Due to the inadequacy of published evidence, association of telomere length (TL), obesity and tobacco smoking with idiopathic pulmonary fibrosis (IPF) remains unclear. The aim of the study was to explore whether these exposures genetically affected the risk of the disease.

METHODS: Genetic variants from genome-wide association studies for TL, body mass index (BMI), body fat percentage (BFP) and tobacco smoking (including maternal smoking) were used as instrumental variables. Inverse-variance weighted were mainly adopted to determine the genetic association of these exposures with IPF. All analyses were conducted by R-software (version 3.6.1).

RESULTS: Firstly, longer TL was associated with the decreased risk of IPF (OR = 0.475 per SD increase in TL, 95%CI = 0.336 ~ 0.670, P<0.001). Secondly, higher levels of BMI and BFP were related to the increased risk of the disease (OR = 1.425 per SD increase in BMI level, 95%CI = 1.114 ~ 1.823, P = 0.005; OR = 1.702 per SD increase in BFP level, 95%CI = 1.202 ~ 2.409, P = 0.003). Thirdly, maternal smoking was implicated in the increased risk of the disease (OR = 13.183 per SD increase in the prevalence of maternal smoking, 95%CI = 1.820 ~ 95.484, P = 0.011).

CONCLUSION: TL should be a genetic risk factor for IPF. Obesity and exposure to tobacco smoking as a fetus might also contribute to the development of this fibrotic diseases. These findings should be verified by future studies.

PMID:37170112 | DOI:10.1186/s12889-023-15733-5

Ter Arkh. 2023 Apr 26;95(3):255-259. doi: 10.26442/00403660.2023.03.202075.

ABSTRACT

The authors of the article prove the need to include a new name for the disease - "Progressive Fibrosing Lung Disease" into clinical practice. Recognition of the fact that some lung diseases end in a fibrosing process, which does not have any significant differences depending on the initial disease that led to fibrosis, will expand the indications for earlier prescription of antifibrotic drugs, which will undoubtedly improve the prognosis in this extremely severe category of patients.

PMID:37167148 | DOI:10.26442/00403660.2023.03.202075

Inflamm Res. 2023 May 11. doi: 10.1007/s00011-023-01739-7. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive chronic interstitial lung disease with limited therapeutic options. Cuproptosis is a recently proposed novel form of programmed cell death, which has been strongly implicated in the development of various human diseases. However, the prognostic and therapeutic value of cuproptosis-related genes (CRGs) in IPF remains to be elucidated.

METHODS: In the present study, weighted gene co-expression network analysis (WGCNA) was employed to identify the key CRGs associated with the development of IPF. The subsequent GSEA, immune cell correlation analysis, and single-cell RNA-Seq analysis were conducted to explore the potential role of the identified CRGs in IPF. In addition, ROC curves and survival analysis were used to assess the prognostic value of the key CRGs in IPF. Moreover, we explored the molecular mechanisms of participation of identified key CRGs in the development of pulmonary fibrogenesis through in vivo and in vitro experiments.

RESULTS: The expression level of cyclin-dependent kinase inhibitor 2A (CDKN2A) is upregulated in the lung tissues of IPF patients and associated with disease severity. Notably, CDKN2A was constitutively expressed by fibrosis-promoting M2 macrophages. Decreased CDKN2A expression sensitizes M2 macrophages to elesclomol-induced cuproptosis in vitro. Inhibition of CDKN2A decreases the number of viable macrophages and attenuates bleomycin-induced pulmonary fibrosis in mice.

CONCLUSION: These findings indicate that CDKN2A mediates the resistance of fibrosis-promoting M2 macrophages to cuproptosis and promotes pulmonary fibrosis in mice. Our work provides fresh insights into CRGs in IPF with potential value for research in the pathogenesis, diagnosis, and a new therapy strategy for IPF.

PMID:37166466 | DOI:10.1007/s00011-023-01739-7

Elife. 2023 May 11;12:e85092. doi: 10.7554/eLife.85092. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) consists of fibrotic alveolar remodeling and progressive loss of pulmonary function. Genetic and experimental evidence indicate that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF pathogenesis. Loss of alveolar type 2 (AT2) stem cells or mutations that either impair their self-renewal and/or impair their differentiation into AT1 cells can serve as a trigger of pulmonary fibrosis. Recent reports indicate increased YAP activity in respiratory epithelial cells in IPF lungs. Individual IPF epithelial cells with aberrant YAP activation in bronchiolized regions frequently co-express AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating 'indeterminate' states of differentiation and suggesting that aberrant YAP signaling might promote pulmonary fibrosis. Yet, Yap and Taz have recently also been shown to be important for AT1 cell maintenance and alveolar epithelial regeneration after Streptococcus pneumoniae induced injury. To investigate how epithelial Yap/Taz might promote pulmonary fibrosis or drive alveolar epithelial regeneration, we inactivated the Hippo pathway in AT2 stem cells resulting in increased nuclear Yap/Taz and found that this promotes their alveolar regenerative capacity and reduces pulmonary fibrosis following bleomycin injury by pushing them along the AT1 cell lineage. Vice versa, inactivation of both Yap1 and Wwtr1 (encoding Taz) or Wwtr1 alone in AT2 cells stem cells impaired alveolar epithelial regeneration and resulted in increased pulmonary fibrosis upon bleomycin injury. Interestingly, inactivation of only Yap1 in AT2 stem cells promoted alveolar epithelial regeneration and reduced pulmonary fibrosis. Together, these data suggest that epithelial Yap promotes, and epithelial Taz reduces pulmonary fibrosis suggesting that targeting Yap but not Taz mediated transcription might help promote AT1 cell regeneration and treat pulmonary fibrosis.

PMID:37166104 | DOI:10.7554/eLife.85092

Bioorg Chem. 2023 Apr 20;137:106539. doi: 10.1016/j.bioorg.2023.106539. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disease with a median survival of only 3-5 years. Due to the lack of effective therapy, IPF threatens human health. Recently, increasing reports have indicated that Rho-associated coiled-coil protein kinases (ROCKs) play important roles in the development of IPF and might represent a novel target for the treatment of IPF. Herein, a new series of selective ROCK2 inhibitors based on indoline were designed and synthesized. Structural modification resulted in optimized compound 9b with an IC50 value of 6 nM against ROCK2 and the inhibition of collagen gel contraction. Cellular assays demonstrated that 9b could significantly suppress the expression of collagen I and α-SMA, and inhibited ROCK signaling pathway. Oral administration of compound 9b (10 mg/kg) exerted more significant anti-pulmonary fibrosis effects than nintedanib (100 mg/kg) and KD025 (100 mg/kg) in a bleomycin-induced IPF rat model, suggesting that 9b could serve as a potential lead compound for the treatment of IPF.

PMID:37163811 | DOI:10.1016/j.bioorg.2023.106539

Aging Dis. 2023 Dec 11. doi: 10.14336/AD.2022.1226. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive and highly lethal inflammatory interstitial lung disease characterized by aberrant extracellular matrix deposition. Macrophage activation by cytokines released from repetitively injured alveolar epithelial cells regulates the inflammatory response, tissue remodeling, and fibrosis throughout various phases of IPF. Our previous studies demonstrate that nuclear factor of activated T cells cytoplasmic member 3 (NFATc3) regulates a wide array of macrophage genes during acute lung injury pathogenesis. However, the role of NFATc3 in IPF pathophysiology has not been previously reported. In the current study, we demonstrate that expression of NFATc3 is elevated in lung tissues and pulmonary macrophages in mice subjected to bleomycin (BLM)-induced pulmonary fibrosis and IPF patients. Remarkably, NFATc3 deficiency (NFATc3+/-) was protective in bleomycin (BLM)-induced lung injury and fibrosis. Adoptive transfer of NFATc3+/+ macrophages to NFATc3+/- mice restored susceptibility to BLM-induced pulmonary fibrosis. Furthermore, in vitro treatment with IL-33 or conditioned medium from BLM-treated epithelial cells increased production of CCL2 and CXCL2 in macrophages from NFATc3+/+ but not NFATc3+/- mice. CXCL2 promoter-pGL3 Luciferase reporter vector showed accentuated reporter activity when co-transfected with the NFATc3 expression vector. More importantly, exogenous administration of recombinant CXCL2 into NFATc3+/- mice increased fibrotic markers and exacerbated IPF phenotype in BLM treated mice. Collectively, our data demonstrate, for the first time, that NFATc3 regulates pulmonary fibrosis by regulating CCL2 and CXCL2 gene expression in macrophages.

PMID:37163433 | DOI:10.14336/AD.2022.1226

medRxiv. 2023 Apr 29:2023.04.29.23289296. doi: 10.1101/2023.04.29.23289296. Preprint.

ABSTRACT

RATIONALE: Changes in peripheral blood cell populations have been observed but not detailed at single-cell resolution in idiopathic pulmonary fibrosis (IPF).

OBJECTIVES: To provide an atlas of the changes in the peripheral immune system in stable and progressive IPF.

METHODS: Peripheral blood mononuclear cells (PBMCs) from IPF patients and controls were profiled using 10x Chromium 5' single-cell RNA sequencing (scRNA-seq). Flow cytometry was used for validation. Protein concentrations of Regulatory T-cells (Tregs) and Monocytes chemoattractants were measured in plasma and lung homogenates from patients and controls.

MEASUREMENTS AND MAIN RESULTS: Thirty-eight PBMC samples from 25 patients with IPF and 13 matched controls yielded 149,564 cells that segregated into 23 subpopulations, corresponding to all expected peripheral blood cell populations. Classical monocytes were increased in progressive and stable IPF compared to controls (32.1%, 25.2%, 17.9%, respectively, p<0.05). Total lymphocytes were decreased in IPF vs controls, and in progressive vs stable IPF (52.6% vs 62.6%, p=0.035). Tregs were increased in progressive IPF (1.8% vs 1.1%, p=0.007), and were associated with decreased survival (P=0.009 in Kaplan-Meier analysis). Flow cytometry analysis confirmed this finding in an independent cohort of IPF patients. Tregs were also increased in two cohorts of lung scRNA-seq. CCL22 and CCL18, ligands for CCR4 and CCR8 Treg chemotaxis receptors, were increased in IPF.

CONCLUSIONS: The single-cell atlas of the peripheral immune system in IPF, reveals an outcome-predictive increase in classical monocytes and Tregs, as well as evidence for a lung-blood immune recruitment axis involving CCL7 (for classical monocytes) and CCL18/CCL22 (for Tregs).

PMID:37163015 | PMC:PMC10168511 | DOI:10.1101/2023.04.29.23289296

Inflammation. 2023 May 9. doi: 10.1007/s10753-023-01825-2. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) seriously threatens human life and health, and no curative therapy is available at present. Nintedanib is the first agent approved by the US Food and Drug Administration (FDA) in order to treat IPF; however, its mechanism of inhibition of IPF is still elusive. According to recent studies, nintedanib is a potent inhibitor. It can antagonize platelet-derived growth factor (PDGF), basic fibroblast growth factor (b-FGF), vascular endothelial growth factor (VEGF), etc., to inhibit pulmonary fibrosis. Whether there are other signaling pathways involved in IPF remains unknown. This study focused on investigating the therapeutic efficacy of nintedanib in bleomycin-mediated pulmonary fibrosis (PF) mice through PI3K/Akt/mTOR pathway. Following the induction of pulmonary fibrosis in C57 mice through bleomycin (BLM) administration, the mice were randomized into five groups: (1) the normal control group, (2) the BLM model control group, (3) the low-dose Nintedanib administration model group, (4) the medium-dose nintedanib administration model group, and (5) the high-dose nintedanib administration model group. For lung tissues, morphological changes were found by HE staining and Masson staining, ELISA method was used to detect inflammatory factors, alkaline water method to estimate collagen content, and western blotting for protein levels. TUNEL staining and immunofluorescence methods were used to analyze the effect of nintedanib on lung tissue and the impacts and underlying mechanisms of bleomycin-induced pulmonary fibrosis. After 28 days, bleomycin-treated mice developed significant pulmonary fibrosis. Relative to bleomycin-treated mice, nintedanib-treated mice had markedly reduced degrees of PF. In addition, nintedanib showed lung-protective effects by up-regulating antioxidant levels, down-regulating inflammatory protein expression, and reducing collagen accumulation. We demonstrated that nintedanib ameliorated bleomycin-induced lung injury by inhibiting the P13K/Akt/mTOR pathway as well as apoptosis. In addition, significant improvement in pulmonary fibrosis was seen after nintedanib (30/60/120 mg/kg body weight/day) treatment through a dose-dependent way. Histopathological results further corroborated the effect of nintedanib treatment on remarkably attenuating bleomycin-mediated mouse lung injury. According to our findings, nintedanib restores the antioxidant system, suppresses pro-inflammatory factors, and inhibits apoptosis. Nintedanib can reduce bleomycin-induced inflammation by downregulating PI3K/Akt/mTOR pathway, PF, and oxidative stress (OS).

PMID:37160579 | DOI:10.1007/s10753-023-01825-2

Ann Am Thorac Soc. 2023 May 9. doi: 10.1513/AnnalsATS.202302-174OC. Online ahead of print.

ABSTRACT

RATIONALE: Cough is a commonly reported symptom in idiopathic pulmonary fibrosis (IPF) that negatively impacts patient-reported quality of life. However, both the burden of cough at diagnosis and the behaviour of cough over time have not been systematically described in patients with IPF.

OBJECTIVES: By utilising data prospectively collected as part of the PROFILE study we sought to assess cough burden and the impact that this has on quality of life within a cohort of patients with newly diagnosed IPF. We also re-examined the previously described relationship between cough and mortality and the association of cough with the MUC5B promoter polymorphism.

METHODS: The PROFILE study is a multicentre, prospective, observational, longitudinal cohort study of incident IPF. Leicester cough questionnaire (LCQ) scores were recorded at baseline in 632 subjects and then repeated 6 monthly in a subset (n=216) of the cohort.

RESULTS: The median LCQ at diagnosis was 16.1 (inter-quartile range 6.5). LCQ scores remained stable over the subsequent year in the majority of patients. There was a weak association between LCQ score and baseline lung function with worse cough related quality of life associating with more severe physiological impairment. Cough scores were not associated with subsequent mortality after correcting for baseline lung function. Furthermore, there was no relationship between LCQ score and MUC5B promotor polymorphism status.

CONCLUSION: The burden of cough in IPF is high. Although cough is weakly associated with disease severity at baseline, cough-specific QoL as measured by the LCQ, confers no prognostic value. Cough-specific QoL burden remains relatively stable over time and does not associate with MUC5B promotor polymorphism.

PMID:37159951 | DOI:10.1513/AnnalsATS.202302-174OC

Am J Respir Crit Care Med. 2023 May 9. doi: 10.1164/rccm.202212-2342CI. Online ahead of print.

ABSTRACT

Pulmonary hypertension frequently complicating the course of patients with fibrotic interstitial lung disease is associated with significantly increased morbidity and mortality. The availability of multiple medications to treat pulmonary arterial hypertension has resulted in these agents being used beyond their original indication, including in patients with interstitial lung disease. Whether pulmonary hypertension in the context of interstitial lung disease is an adaptive response not to be treated, or a maladaptive phenomenon amenable to therapy, has been uncertain. While some studies have suggested benefit, there have been others demonstrating harm. This concise review will provide an overview of prior studies and the issues that have plagued drug development for a patient population in dire need of treatment options. More recently, there has been a paradigm shift with the largest study to date demonstrating benefit, resulting in the first approved therapy in the USA for patients with interstitial lung disease complicated by pulmonary hypertension. A pragmatic management algorithm in the context of changing definitions, comorbid contributors and an available treatment option is provided, as are considerations for future clinical trials.

PMID:37159942 | DOI:10.1164/rccm.202212-2342CI

JAMA. 2023 May 9;329(18):1554-1555. doi: 10.1001/jama.2022.23955.

NO ABSTRACT

PMID:37159046 | DOI:10.1001/jama.2022.23955

JAMA. 2023 May 9;329(18):1567-1578. doi: 10.1001/jama.2023.5355.

ABSTRACT

IMPORTANCE: There is a major need for effective, well-tolerated treatments for idiopathic pulmonary fibrosis (IPF).

OBJECTIVE: To assess the efficacy and safety of the autotaxin inhibitor ziritaxestat in patients with IPF.

DESIGN, SETTING, AND PARTICIPANTS: The 2 identically designed, phase 3, randomized clinical trials, ISABELA 1 and ISABELA 2, were conducted in Africa, Asia-Pacific region, Europe, Latin America, the Middle East, and North America (26 countries). A total of 1306 patients with IPF were randomized (525 patients at 106 sites in ISABELA 1 and 781 patients at 121 sites in ISABELA 2). Enrollment began in November 2018 in both trials and follow-up was completed early due to study termination on April 12, 2021, for ISABELA 1 and on March 30, 2021, for ISABELA 2.

INTERVENTIONS: Patients were randomized 1:1:1 to receive 600 mg of oral ziritaxestat, 200 mg of ziritaxestat, or placebo once daily in addition to local standard of care (pirfenidone, nintedanib, or neither) for at least 52 weeks.

MAIN OUTCOMES AND MEASURES: The primary outcome was the annual rate of decline for forced vital capacity (FVC) at week 52. The key secondary outcomes were disease progression, time to first respiratory-related hospitalization, and change from baseline in St George's Respiratory Questionnaire total score (range, 0 to 100; higher scores indicate poorer health-related quality of life).

RESULTS: At the time of study termination, 525 patients were randomized in ISABELA 1 and 781 patients in ISABELA 2 (mean age: 70.0 [SD, 7.2] years in ISABELA 1 and 69.8 [SD, 7.1] years in ISABELA 2; male: 82.4% and 81.2%, respectively). The trials were terminated early after an independent data and safety monitoring committee concluded that the benefit to risk profile of ziritaxestat no longer supported their continuation. Ziritaxestat did not improve the annual rate of FVC decline vs placebo in either study. In ISABELA 1, the least-squares mean annual rate of FVC decline was -124.6 mL (95% CI, -178.0 to -71.2 mL) with 600 mg of ziritaxestat vs -147.3 mL (95% CI, -199.8 to -94.7 mL) with placebo (between-group difference, 22.7 mL [95% CI, -52.3 to 97.6 mL]), and -173.9 mL (95% CI, -225.7 to -122.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, -26.7 mL [95% CI, -100.5 to 47.1 mL]). In ISABELA 2, the least-squares mean annual rate of FVC decline was -173.8 mL (95% CI, -209.2 to -138.4 mL) with 600 mg of ziritaxestat vs -176.6 mL (95% CI, -211.4 to -141.8 mL) with placebo (between-group difference, 2.8 mL [95% CI, -46.9 to 52.4 mL]) and -174.9 mL (95% CI, -209.5 to -140.2 mL) with 200 mg of ziritaxestat (between-group difference vs placebo, 1.7 mL [95% CI, -47.4 to 50.8 mL]). There was no benefit with ziritaxestat vs placebo for the key secondary outcomes. In ISABELA 1, all-cause mortality was 8.0% with 600 mg of ziritaxestat, 4.6% with 200 mg of ziritaxestat, and 6.3% with placebo; in ISABELA 2, it was 9.3% with 600 mg of ziritaxestat, 8.5% with 200 mg of ziritaxestat, and 4.7% with placebo.

CONCLUSIONS AND RELEVANCE: Ziritaxestat did not improve clinical outcomes compared with placebo in patients with IPF receiving standard of care treatment with pirfenidone or nintedanib or in those not receiving standard of care treatment.

TRIAL REGISTRATION: ClinicalTrials.gov Identifiers: NCT03711162 and NCT03733444.

PMID:37159034 | DOI:10.1001/jama.2023.5355

Presse Med. 2023 May 6:104166. doi: 10.1016/j.lpm.2023.104166. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive devastating lung disease with substantial morbidity. It is associated with cough, dyspnea and impaired quality of life. If left untreated, IPF has a median survival of 3 years. IPF affects ∼3 million people worldwide, with increasing incidence in older patients. The current concept of pathogenesis is that pulmonary fibrosis results from repetitive injury to the lung epithelium, with fibroblast accumulation, myofibroblast activation, and deposition of matrix. These injuries, in combination with innate and adaptive immune responses, dysregulated wound repair and fibroblast dysfunction, lead to recurring tissue remodeling and self-perpetuating fibrosis as seen in IPF. The diagnostic approach includes the exclusion of other interstitial lung diseases or underlying conditions and depends on a multidisciplinary team-based discussion combining radiological and clinical features and well as in some cases histology. In the last decade, considerable progress has been made in the understanding of IPF clinical management, with the availability of two drugs, pirfenidone and nintedanib, that decrease pulmonary lung function decline. However, current IPF therapies only slow disease progression and prognosis remains poor. Fortunately, there are multiple clinical trials ongoing with potential new therapies targeting different disease pathways. This review provides an overview of IPF epidemiology, current insights in pathophysiology, diagnostic and therapeutic management approaches. Finally, a detailed description of current and evolving therapeutic approaches is also provided.

PMID:37156412 | DOI:10.1016/j.lpm.2023.104166