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Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease with a high incidence of acute exacerbation and an increasing mortality rate. Currently, treatment methods and effects are limited. Therefore, we conducted a meta-analysis of the incidence of acute exacerbation in patients with IPF, hoping to provide reference for the prevention and management of IPF. We systematically searched the PubMed, Embase, Cochrane Library and Web of Science databases. From the creation of the database to the cohort study on April 3, 2023, we collected studies on the incidence of acute exacerbation of IPF patients, and used Stata software (version 16.0) for meta analysis. We used the Newcastle Ottawa Quality Assessment Scale (NOS) to assess the risk of bias for each study. We calculated the incidence of acute exacerbation in IPF patients and analyzed the risk factors for acute exacerbation in IPF patients and prognostic factors for overall survival from the initial IPF diagnosis. A total of ten cohort studies on the incidence of AE-IPF were included, including 11,855 IPF patients. The results showed that the incidence of acute exacerbation within one year was 9%; the incidence of acute exacerbation within 2 years is 13%; the incidence of acute exacerbation within 3 years is 19%; the incidence of acute exacerbation within 4 years is 11%. In addition, one study reported an acute exacerbation rate of 1.9% within 30 days. The incidence of acute exacerbation within ten years reported in one study was 9.8%. Mura et al.'s article included a retrospective cohort study and a prospective cohort study. The prospective cohort study showed that the incidence of acute exacerbation within 3 years was 18.6%, similar to the results of the retrospective cohort study meta-analysis. Our system evaluation and meta-analysis results show that the incidence of AE-IPF is relatively high. Therefore, sufficient attention should be paid to the research results, including the management and prevention of the disease, in order to reduce the risk of AE. Trial registration: PROSPERO, identifier CRD42022341323.

Despite their profound clinical impact and high mortality, acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) still lack any effective or standardized treatment strategies. This manuscript describes the rationale and design of a randomized, multicenter, open-label Phase III clinical trial evaluating the efficacy of intravenous immunoglobulin (IVIG) compared with usual care in hospitalized patients with AE-IPF. This trial will enroll 196 patients across eight different sites in Greece. Inclusion criteria are designed to identify patients with AE-IPF according to the American Thoracic Society definition, while excluding those with cardiac decompensation or pulmonary embolism. The primary endpoint is a composite of all-cause in-hospital mortality or the need for intubation. Secondary endpoints include all-cause mortality at 30 and 90 days, hospital readmission or a new AE-IPF episode within 90 days, and the change in the PaO /FiO ratio from hospital admission to discharge. Based on the concept that patients with IPF frequently demonstrate impaired cellular and humoral immunity, and inflammation and/or immune dysregulation may contribute to AE-IPF pathogenesis, there is a strong rationale for evaluating the therapeutic usefulness of IVIG in this setting. Retrospective data indicate that IVIG could provide clinical benefit in AE-IPF, potentially through its anti-inflammatory and immunomodulatory effects. In this trial, IVIG will be administered as an adjunct to usual care, which includes pulse corticosteroids, broad-spectrum antibiotics, prophylactic anticoagulation, and oxygen therapy. This intervention has the potential to significantly influence current treatment strategies for AE-IPF. https://clinicaltrials.gov/, identifier NCT07299695.

Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a life-threatening condition characterized by uncontrolled inflammation and progressive fibrosis, with limited effective therapies. Kangxianhuanji Formula (KHF), a traditional herbal prescription, has been used clinically for AE-IPF, but its molecular mechanisms remain unclear. This study aimed to elucidate the pharmacological mechanisms and active constituents of KHF. A bleomycin-induced AE-IPF mouse model was established to evaluate the therapeutic effects of KHF using histopathology, immunofluorescence, and inflammatory assessments. Network pharmacology was applied to predict targets, followed by drug affinity responsive target stability (DARTS) to identify direct binding proteins. Quantitative proteomics was used to validate target-related protein expression and pathway changes . Liquid chromatography-tandem mass spectrometry (LC-MS/MS) and molecular docking were used for compound-target analysis, and mechanistic validation was performed in macrophages using the glucose transporter 1 (GLUT1, encoded by SLC2A1) inhibitor STF-31 and cellular thermal shift assay (CETSA). KHF markedly alleviated lung injury in AE-IPF mice, as shown by reduced collagen deposition, decreased levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-α), and high mobility group box 1 (HMGB1), and suppression of abnormal proliferation of alveolar type II epithelial cells. Network pharmacology suggested involvement of glycolysis-related pathways, including PI3K-Akt and HIF-1α signaling. DARTS and proteomics consistently identified GLUT1 as a core target. KHF inhibited glycolytic reprogramming, reflected by reduced expression of GLUT1, HIF-1α, and hexokinase 2 (HK2), along with decreased lactate production. LC-MS/MS and molecular docking identified rutin as a key GLUT1-targeting compound, which was further confirmed by CETSA. In macrophages, rutin showed anti-inflammatory and anti-glycolytic effects, and co-treatment with STF-31 showed no additive effects, suggesting a GLUT1-dependent mechanism. KHF exerts anti-inflammatory and anti-fibrotic effects in AE-IPF, partly by modulating GLUT1-mediated glycolysis and regulating the GLUT1/HIF-1α axis, with rutin as a key bioactive component. These findings support the clinical application of KHF and highlight GLUT1-centered metabolic pathways as potential therapeutic targets.

Background Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) affect a significant proportion of patients with IPF. There are limited data to inform therapeutic strategies for AE-IPF, despite its high mortality. We discuss the rationale and design of STRIVE-IPF, a randomized, multi-center, open-label Phase IIb clinical trial to determine the efficacy of combined therapeutic plasma exchange (TPE), rituximab, and intravenous immunoglobulin (IVIG), in comparison to treatment as usual (TAU), among patients with acute IPF exacerbations. Methods The STRIVE-IPF trial will randomize 51 patients among five sites in the United States. The inclusion criteria have been designed to select a study population with AE-IPF, as defined by American Thoracic Society criteria, while excluding patients with an alternative cause for a respiratory decompensation. The primary endpoint of this trial is six-month survival. Secondary endpoints include supplement oxygen requirement and six-minute walk distance which will be assessed immediately prior to treatment and after completion of therapy on day 19, as well as at periodic subsequent visits. Discussion The experimental AE-IPF therapy proposed in this clinical trial was adapted from treatment regimens used in other antibody-mediated diseases. The regimen is initiated with TPE, which is expected to rapidly reduce circulating autoantibodies, followed by rituximab to reduce B-cells and finally IVIG, which likely has multiple effects, including affecting feedback inhibition of residual B-cells by Fc receptor occupancy. We have reported potential benefits of this experimental therapy for AE-IPF in previous anecdotal reports. This clinical trial has the potential to profoundly affect current paradigms and treatment approaches to patients with AE-IPF. Trial registration ClinicalTrials.gov identifier: NCT03286556.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease with poor prognosis, nomogram model for its prognosis and acute exacerbation was constructed. Methods Two hundred and sixty eight patients with IPF were grouped with different severity according to fibrosis area, serum Club cell secretory protein 16(CC16) was compared between these groups. All patients were randomly divided into training and testing sets. COX regression and LASSO algorithm were used to screen featured characteristics. Then nomogram models were constructed, ROC curve, calibration curve and decision curve analysis(DCA) were conducted to evaluate the performance of model. Expression of CC16 were detected in fibrotic human lung tissues, bronchoalveolar lavage fluid (BALF) and Bleomycin(BLM)-treated mouse lung tissues and serums. Results Serum CC16 gradually increased with the severity of fibrosis, and was especially high in AE-IPF group. CC16 and diffusion capacity for carbon monoxide (DLCO) were screened as characteristic variables to construct nomogram model for IPF prognosis. The survival was significantly lower in high-risk group scored by the model. The area under ROC curves(AUCs) for 1-year and 2-year mortality prediction were 0.866 and 0.916, respectively. This model performed better than gender-age-physiology (GAP) index for predicting 2-year and 3-year mortality. Another nomogram model for acute exacerbation of IPF based on CC16, Krebs von den Lungen-6(KL-6) and DLCO was developed, the AUC was 0.815. Expression of CC16 obviously up-regulated in fibrotic lung tissues, BALF and BLM-treated mice lung tissues and serums. Conclusions The nomogram model based on CC16 performed good predictive ability for prognosis and acute exacerbation of IPF.

Background Urban air pollution is involved in the progress of idiopathic pulmonary fibrosis (IPF). Its potential role on the devastating event of Acute Exacerbation of IPF (AE-IPF) needs to be clarified. This study examined the association between long-term personal air pollution exposure and AE- IPF risk taking into consideration inflammatory mediators and telomere length (TL). Methods All consecutive IPF-patients referred to our Hospital from October 2013-June 2019 were included. AE-IPF events were recorded and inflammatory mediators and TL measured. Long-term personal air pollution exposures were assigned to each patient retrospectively, for O 3 , NO 2 , PM 2.5 [and PM 10 , based on geo-coded residential addresses. Logistic regression models assessed the association of air pollutants’ levels with AE-IPF and inflammatory mediators adjusting for potential confounders. Results 118 IPF patients (mean age 72 ± 8.3 years) were analyzed. We detected positive significant associations between AE-IPF and a 10 μg/m 3 increase in previous-year mean level of NO 2 (OR = 1.52, 95%CI:1.15–2.0, p  = 0.003), PM 2.5 (OR = 2.21, 95%CI:1.16–4.20, p  = 0.016) and PM 10 (OR = 2.18, 95%CI:1.15–4.15, p  = 0.017) independent of age, gender, smoking, lung function and antifibrotic treatment. Introduction of TL in all models of a subgroup of 36 patients did not change the direction of the observed associations. Finally, O 3 was positively associated with %change of IL-4 ( p  = 0.014) whilst PM 2.5 , PM 10 and NO 2 were inversely associated with %changes of IL-4 ( p  = 0.003, p  = 0.003, p  = 0.032) and osteopontin ( p  = 0.013, p  = 0.013, p  = 0.085) respectively. Conclusions Long-term personal exposure to increased concentrations of air pollutants is an independent risk factor of AE-IPF. Inflammatory mediators implicated in lung repair mechanisms are involved.

Background This study aimed to investigate risk factors for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) based on baseline high-resolution computed tomography (HRCT). Methods This prospective observational study enrolled patients with IPF treated at the General Hospital of Ningxia Medical University between January 2019 and January 2021. HRCT-derived quantitative parameters at baseline were analyzed. Results A total of 102 patients [92 (90.2%) males with a mean age of 67 years] with IPF were included, with a median follow-up of 32 (24-40.5) months. AE occurred in 30 (29.4%) IPF patients. Multivariable logistic regression analysis identified Doppler transthoracic echocardiography suggestive of pulmonary hypertension (PH) (13.43; 95% CI: 4.18–41.09; P  < 0.001), honeycombing (OR 1.08; 95% CI: 1.02–1.14; P  = 0.013), and whole lung volume (OR 0.99; 95% CI: 0.99-1.00; P  = 0.037) as independent risk factors for AE-IPF. The combination of PH, honeycombing, whole lung volume, and the percentage of predicted forced vital capacity (FVC% pred) showed a high area under the curve from receiver operating characteristic curves of 0.888, with a sensitivity of 90% and specificity of 78%. Conclusions This study emphasizes that quantitative CT parameters (honeycombing, whole lung volume) may serve as risk factors for AE-IPF. The combination of honeycombing, whole lung volume, FVC% pred, and PH may aid in predicting AE-IPF.

Idiopathic pulmonary fibrosis (IPF) represents a chronic progressive fibrotic interstitial lung disease of unknown cause with an ominous prognosis. It remains an unprecedent clinical challenge due to its delayed diagnosis and unpredictable clinical course. The need for accurate diagnostic, prognostic and predisposition biomarkers in everyday clinical practice becomes more necessary than ever to ensure prompt diagnoses and early treatment. The identification of such blood biomarkers may also unravel novel drug targets against IPF development and progression. So far, the role of diverse blood biomarkers, implicated in various pathogenetic pathways, such as in fibrogenesis (S100A4), extracellular matrix remodelling (YKL-40, MMP-7, ICAM-1, LOXL2, periostin), chemotaxis (CCL-18, IL-8), epithelial cell injury (KL-6, SP-A, SP-D), autophagy and unfolded protein response has been investigated in IPF with various results. Moreover, the recent progress in genetics in IPF allows for a better understanding of the underlying disease mechanisms. So far, the causative mutations in pulmonary fibrosis include mutations in telomere-related genes and in surfactant-related genes, markers that could act as predisposition biomarkers in IPF. The aim of this review is to provide a comprehensive overview from the bench to bedside of current knowledge and recent insights on biomarkers in IPF, and to suggest future directions for research. Large-scale studies are still needed to confirm the exact role of these biomarkers.

Objective To develop and validate a diagnosis model to inform risk stratified decisions for idiopathic pulmonary fibrosis patients experiencing acute exacerbations (AE-IPF). Methods In this retrospective cohort study performed from 1 January 2016 to 31 December 2022, we used data from the West China Hospital of Sichuan University for model development and validation. Blood test results and the underlying diseases of patients were collected through the HIS system and LIS system. An algorithm for filtering candidate variables based on least absolute shrinkage and selection operator (LASSO) regression. Logistic regression was performed to develop the risk model. Multiple imputation handled missing predictor data. Model performance was assessed through calibration and diagnostic odds ratio. Results 311 and 133 participants were included in the development and validation cohorts, respectively. 3 candidate predictors (29 parameters) were included. A logistic regression analysis revealed that dyspnea, percentage of CD4 +   T-lymphocytes, and percentage of monocytes are independent risk factors for AE-IPF. Nomographic model was constructed using these independent risk factors, and the C-index was 0.69. For internal validation, the C-index was 0.69, and that indicated good accuracy. Diagnostic odds ratio was 5.40. Meanwhile, in mild, moderate, and severe subgroups, AE positivity rates were 0.37, 0.47, and 0.81, respectively. The diagnostic model can classify patients with AE-IPF into different risk classes based on dyspnea, percentage of CD4 +   T-lymphocytes, and percentage of monocytes. Conclusion A diagnosis model was developed and validated that used information collected from HIS system and LIS system and may be used to risk stratify idiopathic pulmonary fibrosis patients experiencing acute exacerbations.

Glucocorticoid (GC) hormone has been commonly used to treat systemic inflammation and immune disorders. However, the side effects associated with long-term use of high-dose GC hormone limit its clinical application seriously. GC hormone that can specifically target the lung might decrease the effective dosage and thus reduce GC-associated side effects. In this study, we successfully prepared human lung-targeting liposomal methylprednisolone crosslinked with nanobody (MPS-NSSLs-SPANb). Our findings indicate that MPS-NSSLs-SPANb may reduce the effective therapeutic dosage of MPS, achieve better efficacy, and reduce GC-associated side effects. In addition, MPS-NSSLs-SPANb showed higher efficacy and lower toxicity than conventional MPS.