Sarcoidosis Vasc Diffuse Lung Dis. 2022;39(2):e2022021. doi: 10.36141/svdld.v39i2.12534. Epub 2022 Jun 29.

ABSTRACT

INTRODUCTION: Idiopathic pulmonary fibrosis (IPF) is a chronic disease with a peculiar (typical) HRCT pattern, but biopsy can demonstrate usual interstitial pneumonia in patients with atypical patterns. It is unknown how progression pattern varies among different radiographic presentations of IPF. We sought to investigate the longitudinal radiographic evolution and survival of typical and non-typical patterns.

MATERIALS AND METHODS: One-hundred-twenty-three patients diagnosed with IPF in 2 tertiary referral hospitals were included in the study. Longitudinal evolution of non-typical patterns was considered. The HRCT visual fibrosis score was used as a reliable evaluation tool of disease progression. HRCTs were scored by 2 senior chest radiologists with ILD expertise. The primary endpoint was the evolution of the presentation pattern to probable or typical. The secondary endpoint was lung transplant (LTx)-free survival from the time of diagnosis.

RESULTS: Average interval between HRCTs was 16±5 months; average follow-up after the 2nd HRCT was 17±11 months. Four out of 45 (8.9%) patients with probable pattern "evolved" to a typical pattern of IPF, while 5 out of 31 (16.1%) with indeterminate/alternative pattern "evolved" to probable pattern. An average HRCT fibrosis score increase of 9±11% was observed with typical (n=49), 6±5% with probable (n=43) and 7±8% (n=31) with indeterminate/alternative presentation pattern. LTx-free survival and lung function declines did not show any difference related to presentation HRCT patterns.

CONCLUSIONS: The evolution of a non-typical UIP pattern to a typical one is infrequent. All presentation HRCT patterns of IPF evolve in similar way and are associated with comparable survival time.[/sc].

PMID:36118536 | PMC:PMC9437754 | DOI:10.36141/svdld.v39i2.12534

Respirology. 2022 Sep 18. doi: 10.1111/resp.14363. Online ahead of print.

ABSTRACT

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry.

METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021.

RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/μl than patients with monocyte count ≥0.95 K/μl (HR [<0.60 vs. ≥0.95 K/μl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/μl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02).

CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

PMID:36117239 | DOI:10.1111/resp.14363

J Infect Chemother. 2022 Sep 13:S1341-321X(22)00265-3. doi: 10.1016/j.jiac.2022.09.006. Online ahead of print.

ABSTRACT

Acute exacerbations due to COVID-19 vaccination in patients with interstitial lung disease (ILD) have been reported, but their incidence is unknown. We investigated the incidence of exacerbations of ILD and respiratory symptoms due to the mRNA COVID-19 vaccines. A questionnaire survey was conducted on adverse reactions to the mRNA COVID-19 vaccination in 545 patients with ILD attending our hospital and retrospectively examined whether the eligible patients actually developed acute exacerbations of ILD induced by the vaccine. Of the 545 patients, 17 (3.1%) patients were aware of the exacerbation of respiratory symptoms, and four (0.7%) patients developed an acute ILD exacerbation after vaccination. Of the four patients who experienced exacerbations, two had collagen vascular disease-associated ILD, one had nonspecific interstitial pneumonia, another had unclassifiable idiopathic pneumonia, and none had idiopathic pulmonary fibrosis. Four patients were treated using steroid pulse therapy with a steroid taper, and two of the four also received intravenous cyclophosphamide pulse therapy. Tacrolimus was started in one patient with myositis-associated interstitial lung disease. Eventually, all patients exhibited improvement with immunosuppressive treatment and were discharged. COVID-19 vaccination for patients with ILD should be noted for developing acute exacerbations of ILD with low incidence, although manageable with early diagnosis and treatment.

PMID:36113847 | PMC:PMC9468306 | DOI:10.1016/j.jiac.2022.09.006

Ann Transl Med. 2022 Aug;10(16):896. doi: 10.21037/atm-22-3700.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a disease with a very poor prognosis. The search for new IPF biomarkers is particularly urgent due to the uncertainty of the mechanisms and treatment. Studies have shown that chromatin regulators (CRs) are involved in the development of IPF and are associated with tumor immunity. However, there are no studies on immune-related CRs in IPF. Therefore, we conducted a systematic study to analyze the expression levels and immune correlation of CRs in IPF tissues and normal tissues and to explore their potential as diagnostic biomarkers.

METHODS: GSE53845, GSE179781 and GSE24206 datasets from Gene Expression Omnibus (GEO) database were merged into an integrated dataset as the training set; GSE70866 was used as the validation dataset. The cr-related differentially expressed genes (DEGs) between normal and IPF tissues were identified using the "Limma" software package. Weighted gene co-expression network analysis (WGCNA) was performed using the "WGCNA" package to screen eigengenes, which were intersected with DEGs to identify hub genes. The "ggcorrplot" package was used to analyze the correlation between hub genes and immunity, and immune-related hub genes were defined as immHub. A logistic regression model was constructed using immHub as the independent variable and whether the diagnosis was IPF as the dependent variable.

RESULTS: One hundred and sixty-nine DEGs were identified between IPF and normal tissues. wGCNA identified 3 key modules in brown, green and yellow genes that were present in all 3 modules and met module membership (MM) >0.8 and gene significance (GS) >0.5 were called signature genes (n=390). Four intersecting genes were obtained by intersecting DEGs with signature genes (PADI4, IGFBP7, GADD45A, and SETBP1) all associated with immunity were defined as immHub genes Logistic regression models were constructed based on immHub genes. The area under the curve (AUC) of the ROC curve is used to evaluate the diagnostic accuracy of the logistic regression model for IPF. The AUC in the ROC analysis was 0.771 for the training dataset, and 0.759 for the validation dataset.

CONCLUSIONS: PADI4, IGFBP7 and GADD45A may be biomarkers for IPF, which will provide assistance in the diagnosis, treatment and prognostic assessment of IPF patients, and provide an important basis for future studies on the relationship between CRs genes and IPF.

PMID:36111015 | PMC:PMC9469143 | DOI:10.21037/atm-22-3700

Cureus. 2022 Aug 11;14(8):e27905. doi: 10.7759/cureus.27905. eCollection 2022 Aug.

ABSTRACT

Aspergillus which is normally found as a colonizer in healthy individuals can manifest in various forms in patients with diseased lung or immunocompromised status. Aspergilloma is one such manifestation whereby the fungus makes its way into preexisting cavities in the lung, the most common underlying etiology being old tuberculous cavities, especially in countries with high TB prevalence. However, we hereby report two cases of Aspergillus infestation as aspergilloma in cavities because of extremely rare causes, namely pulmonary thromboembolism and idiopathic pulmonary fibrosis, respectively.

PMID:36110440 | PMC:PMC9464319 | DOI:10.7759/cureus.27905

ACS Pharmacol Transl Sci. 2022 Aug 11;5(9):819-828. doi: 10.1021/acsptsci.2c00149. eCollection 2022 Sep 9.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and fatal lung disease. Rho-associated protein kinases (ROCK) 1/2 are promising therapeutic targets for the treatment of IPF. However, a single inhibition of each of them is insufficient to prevent bleomycin-induced lung fibrosis. The current work reported that bleomycin-induced lung fibrosis can be reduced by dual inhibition of ROCK1/2 with compound 1. We evaluated the dual-selective ROCK1/2 inhibition activity of compound 1, its toxicity, and its preliminary efficacy on bleomycin-induced lung fibrosis. In vitro, compound 1 served as the ROCK1/2 inhibitor with half-maximal inhibitory concentration (IC50) values of 165 ±10.4 nM for ROCK1 and 16.1 ± 2.82 nM for ROCK2. In NIH/3T3 cells, compound 1 inhibited the mRNA expression of COL 1A1 and α-SMA. At therapeutic levels, compound 1 exhibited neither hepatic nor cardiac toxicity, also no CYP450 enzyme inhibition. In vivo, compound 1 had good pharmacokinetic properties, and its oral administration reduced bleomycin-induced pulmonary fibrosis in rats. All the outcomes prove the drug-like characteristics of compound 1 for the treatment of IPF.

PMID:36110377 | PMC:PMC9469187 | DOI:10.1021/acsptsci.2c00149

Am J Respir Cell Mol Biol. 2022 Sep 15. doi: 10.1165/rcmb.2022-0252OC. Online ahead of print.

ABSTRACT

The gain-of-function minor allele of the MUC5B promoter (rs35705950) is the strongest risk factor for idiopathic pulmonary fibrosis (IPF), a devastating fibrotic lung disease that leads to progressive respiratory failure in adults. We have previously demonstrated that Muc5b overexpression in mice worsens lung fibrosis following bleomycin exposure and have hypothesized that excess Muc5b promotes endoplasmic reticulum (ER) stress and apoptosis, stimulating fibrotic lung injury. Here, we report that ER stress pathway members ATF4 and ATF6 co-express with MUC5B in epithelia of the distal IPF airway and honeycomb cyst, and this is more pronounced in carriers of the gain-of-function MUC5B promoter variant. Similarly, in mice exposed to bleomycin, Muc5b expression is temporally associated with markers of ER stress. Using bulk and single cell RNA sequencing (scRNA-seq) in bleomycin-exposed mice, we found that pathologic ER-stress associated transcripts Atf4 and Ddit3 were elevated in alveolar epithelia of SFTPC-Muc5b transgenic (SFTPC-Muc5bTg) mice relative to wild type mice. Activation of the ER stress response inhibits protein translation for most genes by phosphorylation of Eif2α, which prevents guanine exchange by Eif2B, and facilitates translation of Atf4. The integrated stress response inhibitor (ISRIB), facilitates interaction of phosphorylated Eif2α with Eif2B, overcoming translation inhibition associated with ER stress and reducing Atf4 translation. We found that a single dose of ISRIB diminished Atf4 translation in SFTPC-Muc5bTg mice following bleomycin injury. Moreover, ISRIB resolved the exaggerated fibrotic response of SFTPC-Muc5bTg mice to bleomycin. In summary, we demonstrate that MUC5B/Muc5b expression is associated with pathologic ER stress and that restoration of normal translation with a single dose of ISRIB promotes lung repair in bleomycin-injured Muc5b-overexpressing mice.

PMID:36108173 | DOI:10.1165/rcmb.2022-0252OC

Lakartidningen. 2022 Sep 14;119:22033.

ABSTRACT

This article presents updated data regarding exercise training among persons with chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF). Persons with stable COPD and IPF can improve quality of life, physical capacity and dyspnea after a period of exercise training. Persons with COPD exacerbation can improve quality of life and physical capacity, and decrease hospital re-admissions, if they start physical activity directly after the exacerbation. Persons with stable COPD and IPF should be recommended aerobic and muscle strengthening training. For those with balance impairments balance training is also recommended. Persons with COPD exacerbation should be recommended activities of daily living (ADL) followed by muscle strengthening training and then aerobic training in the early recovery phase. Diagnosis-specific advice includes individually tailored exercise training, physical activity recommendations, breathing techniques, and that oxygen saturation during exercise should be ≥88 percent in COPD and ≥85 percent in IPF.

PMID:36106741

Am J Transl Res. 2022 Aug 15;14(8):5660-5668. eCollection 2022.

ABSTRACT

OBJECTIVE: To study the clinical efficacy of acetylcysteine combined with pirfenidone in patients with pulmonary fibrosis (PF).

METHODS: A total of 114 PF patients admitted from January 2018 to January 2019 were retrospectively analyzed. Among them, 64 patients treated with acetylcysteine combined with pirfenidone were classified into a research group, and the other 50 treated with acetylcysteine combined with budesonide were assigned into a control group. The clinical efficacy and total effectiveness rate of the two groups were compared after 6 months of therapy. The quality of life (QoL) in the two groups before and after treatment was evaluatedusing Asthma Therapy Assessment Questionnaire for idiopathic pulmonary fibrosis patients (ATAQ-IPF). The 2-year survival of the two groups was compared. Additionally, the incidence of adverse reactions was compared between the two groups. The changes in forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), inflammatory factors, and PF markers were compared between the two groups before and after therapy.

RESULTS: There were no significant differences in clinical efficacy or total effectiveness rate (all P > 0.05), serum IL-4, INFγ or IL-6 expression (all P > 0.05), as well as FEV1 and FVC levels (all P > 0.05) after therapy between two groups. After therapy, the research group showed significantly lower PCIII and HA levels, lower ATAQ-IPF scores, and lower total incidence of adverse reactions than the control group (all P < 0.05). In addition, a higher 2-year survival rate was observed in the research group than in the control group (P=0.025).

CONCLUSION: Acetylcysteine combined with pirfenidone can reduce adverse reactions and improve the QoL and survival time of patients.

PMID:36105040 | PMC:PMC9452344

Am J Transl Res. 2022 Aug 15;14(8):5905-5914. eCollection 2022.

ABSTRACT

OBJECTIVE: To determine the effect of Qingfei Huaxian Decoction combined with prednisone acetate on serum inflammatory factors and pulmonary function in patients with idiopathic pulmonary fibrosis (IPF).

METHODS: The clinical data of 118 patients with IPF treated in Wuhan Hospital of Traditional Chinese Medicine from June 2019 to August 2021 were retrospectively analyzed. Among the patients, 56 patients treated with prednisone acetate were assigned to the control group, and the remaining 62 patients treated with Qingfei Huaxian Decoction combined with prednisone acetate were assigned to the observation group. The efficacy and incidence of adverse reactions were compared between the two groups, and forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-18 (IL-18), hyaluronic acid (HA) and laminin (LN) in the two groups were evaluated before and after therapy. Logistic regression was conducted to analyze the risk factors impacting the treatment efficacy in patients.

RESULTS: After therapy, the observation group showed significantly higher efficacy than the control group. Compared with the control group, the observation group showed significantly higher levels of FEV1, FVC and FEV1/FVC, significantly lower levels of HA and LN, and a significantly higher IL-12 level (all P < 0.05). Therapeutic regimen, IL-6, IL-12, IL-18 and HA were independent risk factors impacting the efficacy of treatment in patients (P < 0.05).

CONCLUSION: Qingfei Huaxian Decoction combined with prednisone acetate has greater treatmetn efficacy in patients with IPF by improving the serum inflammatory factors and pulmonary function.

PMID:36105016 | PMC:PMC9452306

Stat Med. 2022 Sep 14. doi: 10.1002/sim.9574. Online ahead of print.

ABSTRACT

Personalized medicine aims to tailor medical decisions based on patient-specific characteristics. Advances in data capturing techniques such as electronic health records dramatically increase the availability of comprehensive patient profiles, promoting the rapid development of optimal treatment rule (OTR) estimation methods. An archetypal OTR estimation approach is the outcome weighted learning, where OTR is determined under a weighted classification framework with clinical outcomes as the weights. Although outcome weighted learning has been extensively studied and extended, existing methods are susceptible to irregularities of outcome distributions such as outliers and heavy tails. Methods that involve modeling of the outcome are also sensitive to model misspecification. We propose a contrast weighted learning (CWL) framework that exploits the flexibility and robustness of contrast functions to enable robust OTR estimation for a wide range of clinical outcomes. The novel value function in CWL only depends on the pairwise contrast of clinical outcomes between patients irrespective of their distributional features and supports. The Fisher consistency and convergence rate of the estimated decision rule via CWL are established. We illustrate the superiority of the proposed method under finite samples using comprehensive simulation studies with ill-distributed continuous outcomes and ordinal outcomes. We apply the CWL method to two datasets from clinical trials on idiopathic pulmonary fibrosis and COVID-19 to demonstrate its real-world application.

PMID:36104931 | DOI:10.1002/sim.9574

Pneumologie. 2022 Sep;76(9):614-621. doi: 10.1055/a-1895-9360. Epub 2022 Sep 14.

ABSTRACT

Rheumatoid arthritis-associated interstitial lung disease (RA-ILD) is of high clinical relevance. It not only affects the quality of life but also makes a significant contribution to the mortality rate of patients with rheumatoid arthritis. RA-ILD can present with all known radiological and histopathological patterns seen in other interstitial pneumonias. Among these pneumonias, diffuse alveolar damage (DAD), followed by usual interstitial pneumonia (UIP) has the worst prognosis. In addition, acute exacerbation of RA-ILD, which can occur at any time during the disease, is highly lethal. An algorithm for the diagnosis and treatment of RA-ILD is pending and will be addressed in the following article. In addition to immunosuppressants and disease-modifying antirheumatic drugs (DMARD), antifibrotics have recently gained importance in the therapy of RA-ILD.

PMID:36104017 | DOI:10.1055/a-1895-9360

Turk Thorac J. 2022 Sep 14. doi: 10.5152/TurkThoracJ.2022.22017. Online ahead of print.

ABSTRACT

OBJECTIVE: Our study aimed to evaluate clinical, functional, and prognostic features and to determine the prognosis of idiopathic pulmonary fibrosis, connective tissue disease-associated interstitial lung diseases, and interstitial pneumonia with autoimmune features.

MATERIAL AND METHODS: Sixty-nine cases with interstitial lung diseases were recruited in this study prospectively. Demographic features, symptoms, radiological findings, functional measurements, and immunological markers were recorded twice (at the time of initial admission and in the 12th month). Twenty-four of 69 cases were idiopathic pulmonary fibrosis, 32 were connective tissue diseaseassociated interstitial lung diseases, and 13 were interstitial pneumonia with autoimmune features .

RESULTS: Most of the patients with idiopathic pulmonary fibrosis were male, while there were more female patients in connective tissue disease-associated interstitial lung diseases and interstitial pneumonia with autoimmune features groups. Female patients (65.0%) predominated in connective tissue disease-associated interstitial lung diseases group (P <.001). There was no significant difference in the mean ages of the disease groups, yet connective tissue disease-associated interstitial lung diseases patients were generally younger (min- max: 34-82 years). In the idiopathic pulmonary fibrosis group, only low titers of antinuclear antibody positivity were found. Antinuclear antibody positivity in the connective tissue disease-associated interstitial lung diseases group and interstitial pneumonia with autoimmune features group was high (P = .001). The long-term survival of idiopathic pulmonary fibrosis, connective tissue disease-associated interstitial lung diseases, and interstitial pneumonia with autoimmune features patients were 37%, 40 months (median) (95% CI, 5.193- 74.807), 48.6%, 80 months (median) (95% CI, 57.032-102.968), 30.8%, 46 months (median) (95% CI, 26.624-65.376), respectively.

CONCLUSION: Although a consensus report describing interstitial lung diseases with autoimmune features has been published, diagnostic criteria for this group are still vague. Since the interstitial pneumonia with autoimmune features group had the worst results in terms of functional loss and survival rates, the follow-up parameters and follow-up algorithm should be established for this group. Clinical and immunological evaluation of the interstitial pneumonia with autoimmune features group should include detailed parameters because of follow-up and to estimate survival.

PMID:36101983 | DOI:10.5152/TurkThoracJ.2022.22017

Tuberc Respir Dis (Seoul). 2022 Sep 13. doi: 10.4046/trd.2022.0116. Online ahead of print.

ABSTRACT

Environmental exposure to air pollution is known to have adverse effects on various organs. Air pollution has greater effects on the pulmonary system as the lungs are directly exposed to contaminants in the air. Here, we review the associations of air pollution with the development, morbidity, and mortality of pulmonary diseases. Short- and long-term exposure to air pollution have been shown to increase mortality risk even at concentrations below the current national guidelines. Ambient air pollution has been shown to be associated with lung cancer. Particularly long-term exposure to particulate matter with a diameter < 2.5 μm (PM2.5) has been reported to be associated with lung cancer even at low concentrations. In addition, exposure to air pollution has been shown to increase the incidence risk of chronic obstructive pulmonary disease (COPD) and has been correlated with exacerbation and mortality of COPD. Air pollution has also been linked to exacerbation, mortality, and development of asthma. Exposure to nigrogen dioxide (NO2) has been demonstrated to be related to increased mortality in patients with idiopathic pulmonary fibrosis (IPF). Additionally, air pollution increases the incidence of infectious diseases, such as pneumonia, bronchitis, and tuberculosis. Furthermore, emerging evidence supports a link between air pollution and coronavirus disease 2019 (COVID-19) transmission, susceptibility, severity and mortality. In conclusion, the stringency of air quality guidelines should be increased and further therapeutic trials are required in patients at high risk of adverse health effects of air pollution.

PMID:36097730 | DOI:10.4046/trd.2022.0116

Mol Biol Rep. 2022 Sep 12. doi: 10.1007/s11033-022-07820-4. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is the key feature of majority of idiopathic interstitial pneumonias (IIPs) as well as many patients with post-COVID-19. The pathogenesis of pulmonary fibrosis is a complex molecular process that involves myriad of cells, proteins, genes, and regulatory elements. The non-coding RNA mainly miRNA, circRNA, and lncRNA are among the key regulators of many protein coding genes and pathways that are involved in pulmonary fibrosis. Identification and molecular mechanisms, by which these non-coding RNA molecules work, are crucial to understand the molecular basis of the disease. Additionally, elucidation of molecular mechanism could also help in deciphering a potential diagnostic/prognostic marker as well as therapeutic targets for IIPs and post-COVID-19 pulmonary fibrosis. In this review, we have provided the latest findings and discussed the role of these regulatory elements in the pathogenesis of pulmonary fibrosis associated with Idiopathic Interstitial Pneumonia and Covid-19.

PMID:36097114 | DOI:10.1007/s11033-022-07820-4

Am J Respir Crit Care Med. 2022 Sep 12. doi: 10.1164/rccm.202206-1075OC. Online ahead of print.

ABSTRACT

RATIONALE: Relatives of patients with familial interstitial pneumonia are at increased risk for pulmonary fibrosis, and develop preclinical pulmonary fibrosis (PrePF).

OBJECTIVES: We defined the incidence and progression of new onset PrePF; its relationship to survival among first degree relatives of families with familial interstitial pneumonia.

METHODS: This is a cohort study of family members with familial interstitial pneumonia who were initially screened with a questionnaire and chest HRCT scan, and approximately 4 years later, the evaluation was repeated. 493 asymptomatic first-degree relatives of patients with familial interstitial pneumonia were evaluated at baseline, and 296 (60%) of the original subjects participated in subsequent evaluation.

RESULTS: The median interval between HRCTs was 3.9 years (IQ range 3.5-4.4). 252 subjects who agreed to repeat evaluation were originally determined not to have PrePF at baseline; 16 developed PrePF. A conservative estimate of the annual incidence of PrePF is 1,023 per 100, 000 person years (95% CI 511-1831). Of 44 subjects with PrePF at baseline, 38.4% subjects had worsening dyspnea compared to 15.4% of those without PrePF (P=0.002). Usual interstitial pneumonia (UIP) by HRCT (P< 0.0002) and baseline quantitative fibrosis score (P<0.001) are also associated with worsening dyspnea. PrePF at the initial screen is associated with decreased survival (P< 0.001).

CONCLUSIONS: The incidence of PrePF in this at-risk population is at least 100-fold higher than that reported for sporadic idiopathic pulmonary fibrosis (IPF). While PrePF and IPF represent distinct entities, our study demonstrates that PrePF, like IPF, is progressive and associated with decreased survival.

PMID:36094461 | DOI:10.1164/rccm.202206-1075OC

Chest. 2022 Sep 8:S0012-3692(22)03709-6. doi: 10.1016/j.chest.2022.08.2233. Online ahead of print.

ABSTRACT

BACKGROUND: Functional capacity, as measured by the 6-minute walk test (6MWT), is often reduced in fibrotic interstitial lung disease (ILD). This study evaluated longitudinal changes and prognostic significance of 6MWT parameters and explored change in oxygenation status as a physiological criterion to define disease progression in patients with fibrotic ILD.

RESEARCH QUESTIONS: What are the trajectories and prognostic value of 6MWT parameters in patients with fibrotic ILD?

STUDY DESIGN AND METHODS: Using prospective registries in Australia and Canada, patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic ILD were stratified by the presence of criteria for progressive pulmonary fibrosis (PPF). Cumulative incidence of exertional and resting hypoxemia and changes in 6-minute walk distance (6MWD) and composite indices (distance-saturation product and distance-saturation-oxygen product) were determined, with prognostic significance evaluated at the time of meeting criteria for PPF. New-onset exertional or resting hypoxemia was evaluated as another potential criterion for PPF.

RESULTS: IPF/PPF (n=126) and non-IPF/PPF (n=227) had similar cumulative incidence of exertional hypoxemia and annualized decline in 6MWD and composite indices, which varied across each PPF criterion. IPF/non-PPF (n=231) and non-IPF/non-PPF (n=531) had significantly lower incidence of hypoxemia than IPF/PPF, with annualized increase in 6MWD and composite indices in non-IPF/non-PPF. Exertional or resting hypoxemia at the time of meeting criteria for PPF was independently associated with reduced transplant-free survival in IPF and non-IPF, adjusting for patient demographics and lung function. Adding new-onset exertional or resting hypoxemia as a physiological criterion reduced the median time to development of PPF from 11.2 to 6.7 months in IPF and 11.7 to 5.6 months in non-IPF in patients who eventually met both definitions (p<0.001 for both).

INTERPRETATION: Patients with IPF/PPF and non-IPF/PPF have comparable deterioration in functional capacity. Oxygenation status provides prognostic information in PPF and may assist in defining disease progression in fibrotic ILD.

PMID:36089070 | DOI:10.1016/j.chest.2022.08.2233

Toxicol Appl Pharmacol. 2022 Sep 7:116228. doi: 10.1016/j.taap.2022.116228. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis, a condition with likely genetic and environmental etiology, is relatively more prevalent with poor prognosis in human males. However, the underlying mechanisms for these gender-associated differences in the severity of fibrosis remain unknown. Here, we tested the hypothesis that the transcriptomic repertoire of myeloid cells determines the higher susceptibility of male mice to bleomycin (BLM)-induced lung fibrosis. Adult mice were oropharyngeally challenged with saline or BLM. Lung injury, inflammation, and fibrosis was assessed, and airspace myeloid-cells were subjected to RNA-sequencing. As compared with the female mice, the male mice manifested significantly increased lung injury, inflammation, proinflammatory cytokines (IL-6, IL-1β, IL-7, and IP-10), and fibrosis in response to BLM challenge. Interestingly, several pro-inflammatory and extracellular matrix-associated genes were significantly up-regulated in male myeloid-cells compared to female myeloid-cells in the saline-control group. Similarly, BLM-challenge resulted in greater pro-inflammatory and pro-fibrotic transcriptomic changes in male compared to female myeloid cells. On the other hand, anti-inflammatory and regulatory cytokine, Il10 and Ifng respectively, were uniquely upregulated in female but not in male myeloid cells when compared to their respective saline-control groups. Further, cross-sex bone marrow transplantation experiments revealed that male hematopoietic progenitor cells (HPCs) increased the granulocytic infiltration in female mice while female HPCs decreased the granulocytic infiltration in male mice post-BLM challenge. These findings suggest that there are inherent transcriptomic differences between the male and female lung myeloid cells and that the pro-inflammatory nature of male myeloid cells is sufficient to increase the susceptibility of female mice to BLM-induced inflammation.

PMID:36087614 | DOI:10.1016/j.taap.2022.116228

Int Immunopharmacol. 2022 Sep 7;112:109208. doi: 10.1016/j.intimp.2022.109208. Online ahead of print.

ABSTRACT

Pulmonary fibrosis is common in the development of inflammatory lung diseases with no effective clinical drug treatment currently. As an essential redox enzyme, thioredoxin (Trx) has been reported to be involved in pulmonary fibrosis, but the mechanism is to be revealed. Therefore, in bleomycin-indued pulmonary fibrosis model in C57 mice, Trx activity and nitrated Trx were examined.,p38-MAPK apoptosis pathway was determined in lung tissues. Additionally, before BLM administration, C57/BL6 mice were treated with aminoguanidine (AG, a peroxynitrite scavenger), recombinant human Trx-1 (rhTrx-1), or SIN-1 (a peroxynitrite donor) nitrated Trx-1 (N-Trx-1). In bleomycin (BLM)-induced pulmonary fibrosis model in C57/BL6 mice, we observed that nitrated Trx increased, while its activity decreased, with the increase of alveolar epithelial cells (AECs)apoptosis by p38-MAPK pathway. We demonstrated that AG or rhTrx-1, but not N-Trx-1 significantly reduced pulmonary fibrosis. Taken together, the results above revealed that blockade of Trx-1 nitration, or supplementation of exogenous rhTrx-1, might represent novel therapies to attenuate pulmonary fibrosis in idiopathic pulmonary fibrosis patients.

PMID:36087509 | DOI:10.1016/j.intimp.2022.109208

BMC Pulm Med. 2022 Sep 9;22(1):340. doi: 10.1186/s12890-022-02134-4.

ABSTRACT

BACKGROUND: Different clinical predictors of physical activity (PA) have been described in idiopathic pulmonary fibrosis (IPF), but studies are lacking evaluating the potential role of muscle strength and anxiety and depression symptoms in PA limitation. Moreover, little is known about the impact of changes in PA in the course of the disease. The aim of the present study was to investigate the relationship between baseline PA and a wide range of variables in IPF, to assess its longitudinal changes at 12 months and its impact on progression free-survival.

METHODS: PA was assessed by accelerometer and physiological, clinical, psychological factors and health-related quality of life were evaluated in subjects with IPF at baseline and at 12 month follow-up. Predictors of PA were determined at baseline, evolution of PA parameters was described and the prognostic role of PA evolution was also established.

RESULTS: Forty participants with IPF were included and 22 completed the follow-up. At baseline, subjects performed 5765 (3442) daily steps and spent 64 (44) minutes/day in moderate to vigorous PA. Multivariate regression models showed that at baseline, a lower six-minute walked distance, lower quadriceps strength (QMVC), and a higher depression score in the Hospital Anxiety and Depression scale were associated to lower daily step number. In addition, being in (Gender-Age-Physiology) GAP III stage, having a BMI ≥ 25 kg/m2 and lower QMVC or maximum inspiratory pressure were factors associated with sedentary behaviour. Adjusted for age, gender and forced vital capacity (FVC) (%pred.) a lower progression-free survival was evidenced in those subjects that decreased PA compared to those that maintained, or even increased it, at 12 months [HR 12.1 (95% CI, 1.9-78.8); p = 0.009].

CONCLUSION: Among a wide range of variables, muscle strength and depression symptoms have a predominant role in PA in IPF patients. Daily PA behaviour and its evolution should be considered in IPF clinical assessment and as a potential complementary indicator of disease prognosis.

PMID:36085057 | DOI:10.1186/s12890-022-02134-4