Exacerbation Of Idiopathic Pulmonary Fibrosis Research Articles

Mitochondrial DNA in bronchoalveolar lavage fluid is associated with the prognosis of idiopathic pulmonary fibrosis: a single cohort study

BackgroundExtracellular mitochondrial DNA (mtDNA) is released from damaged cells and increases in the serum and bronchoalveolar lavage fluid (BALF) of idiopathic pulmonary fibrosis (IPF) patients. While increased levels of serum mtDNA have been reported to be linked to disease progression and the future development of acute exacerbation (AE) of IPF (AE-IPF), the clinical significance of mtDNA in BALF (BALF-mtDNA) remains unclear. We investigated the relationships between BALF-mtDNA levels and other clinical variables and prognosis in IPF.MethodsExtracellular mtDNA levels in BALF samples collected from IPF patients were determined using droplet-digital PCR. Levels of extracellular nucleolar DNA in BALF (BALF-nucDNA) were also determined as a marker for simple cell collapse. Patient characteristics and survival information were retrospectively reviewed.ResultsmtDNA levels in serum and BALF did not correlate with each other. In 27 patients with paired BALF samples obtained in a stable state and at the time of AE diagnosis, BALF-mtDNA levels were significantly increased at the time of AE. Elevated BALF-mtDNA levels were associated with inflammation or disordered pulmonary function in a stable state (n = 90), while being associated with age and BALF-neutrophils at the time of AE (n = 38). BALF-mtDNA ≥ 4234.3 copies/µL in a stable state (median survival time (MST): 42.4 vs. 79.6 months, p < 0.001) and ≥ 11,194.3 copies/µL at the time of AE (MST: 2.6 vs. 20.0 months, p = 0.03) were associated with shorter survival after BALF collection, even after adjusting for other known prognostic factors. On the other hand, BALF-nucDNA showed different trends in correlation with other clinical variables and did not show any significant association with survival time.ConclusionsElevated BALF-mtDNA was associated with a poor prognosis in both IPF and AE-IPF. Of note, at the time of AE, it sharply distinguished survivors from non-survivors. Given the trends shown by analyses for BALF-nucDNA, the elevation of BALF-mtDNA might not simply reflect the impact of cell collapse. Further studies are required to explore the underlying mechanisms and clinical applications of BALF-mtDNA in IPF.

Lipocalin-2 as a prognostic marker in patients with acute exacerbation of idiopathic pulmonary fibrosis

BackgroundLipocalin-2 (LCN2) is a secretory glycoprotein upregulated by oxidative stress; moreover, patients with idiopathic pulmonary fibrosis (IPF) have shown increased LCN2 levels in bronchoalveolar lavage fluid (BALF). This study aimed to determine whether circulatory LCN2 could be a systemic biomarker in patients with IPF and to investigate the role of LCN2 in a bleomycin-induced lung injury mouse model.MethodsWe measured serum LCN2 levels in 99 patients with stable IPF, 27 patients with acute exacerbation (AE) of IPF, 51 patients with chronic hypersensitivity pneumonitis, and 67 healthy controls. Further, LCN2 expression in lung tissue was evaluated in a bleomycin-induced lung injury mouse model, and the role of LCN2 was investigated using LCN2-knockout (LCN2 -/-) mice.ResultsSerum levels of LCN2 were significantly higher in patients with AE-IPF than in the other groups. The multivariate Cox proportional hazards model showed that elevated serum LCN2 level was an independent predictor of poor survival in patients with AE-IPF. In the bleomycin-induced lung injury mouse model, a higher dose of bleomycin resulted in higher LCN2 levels and shorter survival. Bleomycin-treated LCN2 -/- mice exhibited increased BALF cell and protein levels as well as hydroxyproline content. Moreover, compared with wild-type mice, LCN2-/- mice showed higher levels of circulatory 8-isoprostane as well as lower Nrf-2, GCLC, and NQO1 expression levels in lung tissue following bleomycin administration.ConclusionsOur findings demonstrate that serum LCN2 might be a potential prognostic marker of AE-IPF. Moreover, LCN2 expression levels may reflect the severity of lung injury, and LCN2 may be a protective factor against bleomycin-induced acute lung injury and oxidative stress.

Involvement of necroptotic cell death in macrophages in progression of bleomycin and LPS-induced acute exacerbation of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is the severe form of interstitial pneumonias. Acute exacerbation (AE) of IPF is characterized by progressive lung fibrosis with the irreversible lung function decline and inflammation, and is often fatal with poor prognosis. However, the physiological and molecular mechanisms in AE of IPF are still not fully understood. In this study, we investigated the mechanism underlying AE of IPF, using bleomycin (BLM) and lipopolysaccharide (LPS) (BLM+LPS)-treated mice. The mice were treated with a single dose of 1.5 mg/kg BLM (on day 0) and/or 0.5 mg/kg LPS (on day 14), and maintained for another 7 days (total 21 days). Administration of BLM+LPS more severely aggravated the respiratory function, fibrosis, and inflammation in the lungs, together with the elevated interleukin-6 level in bronchoalveolar lavage fluid, than the control or BLM alone-treated mice. Moreover, the terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay demonstrated that subsequent treatment with LPS elevated cell death in the lungs of BLM-administered mice. Furthermore, the expression levels of mixed lineage kinase domain-like protein (MLKL), a marker of necroptotic cell death, and CD68-positive macrophages were increased, and most of them were co-stained in the lungs of BLM+LPS-treated mice. These results, taken together, indicate that BLM+LPS treatment showed more exacerbated the respiratory function with extensive fibrosis and inflammation than treatment with BLM alone in mice. Fibrosis and inflammation in AE of IPF seen in BLM+LPS-administered mice included an increase in macrophages and their necroptotic cell death.

Infectious respiratory pathogens among patients with acute exacerbation of idiopathic pulmonary fibrosis during the coronavirus disease 2019 pandemic in Japan

BackgroundFew studies have investigated the prevalence of pathogens in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF), specifically, the interactions between respiratory pathogens and AE-IPF during the coronavirus disease 2019 (COVID-19) pandemic. ObjectivesWe aimed to analyze pathogens in patients with AE-IPF between September 2020 and December 2022. MethodsThis retrospective observational study was conducted at our hospital between September 2020 and December 2022. In patients with AE-IPF, pre-hospitalization polymerase chain reaction (PCR) tests for respiratory pathogens, including severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), were performed using multiplex PCR or Smart Gene assay with nasopharyngeal swab specimens. Microbiological assays, including Gram staining, sputum cultures, blood cultures, and urinary antigen tests for Streptococcus pneumoniae and Legionella pneumophila, were also performed. ResultsForty-nine patients with AE-IPF were included. The median age was 75 years old and 42 (86%) were male. Only one of the 49 patients (2%) was positive for SARS-CoV-2. Two of 28 patients (7%) were positive for human rhinovirus/enterovirus. No bacteria were detected in sputum culture, blood culture, or urinary antigen tests. ConclusionsThe detection frequency of SARS-CoV-2 infection in patients with AE-IPF was lower than that of human rhinovirus/enterovirus. Continuous analysis for the presence of pathogens is necessary for appropriate infection control because respiratory viruses may increase as the coronavirus pandemic subsides.

Design of the STRIVE-IPF trial- study of therapeutic plasma exchange, rituximab, and intravenous immunoglobulin for acute exacerbations of idiopathic pulmonary fibrosis

BackgroundAcute 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.MethodsThe 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.DiscussionThe 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 registrationClinicalTrials.gov identifier: NCT03286556.

Acute Exacerbation of Idiopathic Pulmonary Fibrosis With Concurrent Cardiac Amyloidosis: A Technetium Pyrophosphate Study.

Amyloidosis presents a diagnostic challenge, particularly when concomitant with severe conditions like acute exacerbations of idiopathic pulmonary fibrosis (IPF). In this report, we detail the case of a 73-year-old patient with acute exacerbation of IPF and simultaneous emergence of cardiac amyloidosis. The patient's clinical journey began with persistent exertional dyspnea, progressing to hypoxemia on admission. Chest CT scans showed extensive ground-glass opacities, consolidations, and pre-existing honeycombing-like cysts and reticular shadows, accompanied by a right-sided pleural effusion. The therapeutic strategy for acute exacerbation of IPF encompassed methylprednisolone pulse therapy, tacrolimus, and nintedanib, augmented with intravenous immunoglobulin and recombinant thrombomodulin. Concurrently, heart failure with preserved ejection fraction was managed with a pharmacological trio: empagliflozin, diuretics, and eplerenone. A hypertrophied heart and low limb voltage prompted an investigation for cardiac amyloidosis, which 99mTechnetium pyrophosphate (99mTc-PYP) scintigraphy confirmed, yielding a probable diagnosis. Following steroid tapering, the patient was discharged home. This case prompted an investigation into the potential role of amyloidosis in pulmonary pathology. Our retrospective review of 10 patients, including four with cardiac amyloidosis, who underwent 99mTc-PYP scintigraphy, revealed a nonsignificant yet notable trend of increased pulmonary accumulation in cardiac amyloidosis cases (median (interquartile range): 5.4×104 (5.3-13.1×104) vs. 3.6×104 (2.4-5.1×104), p=0.0667). Notably, the pulmonary counts in this patient exceeded the negative cohort's mean values, hinting at a possible contribution of amyloid deposition to pulmonary pathology. This study, pioneering in evaluating lung field accumulation of 99mTc-PYP in cardiac amyloidosis, may provide novel insights into the influence of amyloidosis on pulmonary conditions.

Novel 3D-based deep learning for classification of acute exacerbation of idiopathic pulmonary fibrosis using high-resolution CT

PurposeAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is the primary cause of death in patients with IPF, characterised by diffuse, bilateral ground-glass opacification on high-resolution CT (HRCT). This study proposes...

Clinical manifestations and prognostic factors analysis of patients hospitalised with acute exacerbation of idiopathic pulmonary fibrosis and other interstitial lung diseases

BackgroundAcute exacerbation (AE) is a life-threatening condition taking place not only in idiopathic pulmonary fibrosis (IPF) but also in interstitial lung diseases (ILD) other than IPF (non-IPF ILD). This study...

Baseline Blood Levels of Mucin-1 Are Associated with Crucial On-Treatment Adverse Outcomes in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Pirfenidone.

Mucin-1 is a multi-functional glycoprotein expressed by type II alveolocytes and may be detectable in the circulation following pulmonary fibrosis. The prognostic utility of baseline pre-treatment blood levels of mucin-1 in patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotics has not yet been fully established. We retrospectively studied a cohort of patients (from two hospitals) with IPF who were receiving pirfenidone for >12 weeks. Baseline blood mucin-1 levels were measured via sandwich enzyme-linked immunosorbent assays. We investigated the performance of mucin-1 levels in longitudinally predicting the risks of acute exacerbation of IPF (AE-IPF) and severe adverse outcomes (SAO), including lung transplantation and death. Seventy patients were included; 20 developed AE-IPF; and 31 had SAO during the follow-up period. Patients with baseline mucin-1 levels ≥2.5 ng/mL had enhanced risks of AE-IPF (adjusted hazard ratio [aHR], 14.07; 95% confidence interval [CI], 4.26-46.49) and SAO within 2 years (aHR, 7.87; 95% CI, 2.86-21.70) and anytime during the follow-up (aHR, 4.68; 95% CI, 2.11-10.39). The risks increased across subgroups with increasing mucin-1 levels. Patients in the "mucin-1 ≥ 2.5" group also exhibited an accelerated decline in DLCO. This study supports baseline blood mucin-1 levels as a biomarker for IPF that predicts adverse outcomes during pirfenidone treatment.

Impact of Acute Exacerbation of Idiopathic Pulmonary Fibrosis on Lung Transplant Outcomes.

Acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) are acute, significant respiratory deteriorations in patients with IPF and can lead to increased morbidity and mortality. It remains unclear how AE-IPF impacts lung transplant (LTX) outcomes. All adult patients who were listed for LTX between July 2005 and October 2020 at the Loyola University Medical Center with a diagnosis of IPF were included. Pretransplant characteristics and posttransplant outcomes were gathered via retrospective chart review. The primary outcome was short- and long-term survival for patients transplanted during stable IPF versus those with AE-IPF. One hundred fifty-nine patients were included in this study, 17.6% of whom were transplanted during AE-IPF. AE-IPF patients were more likely to have higher oxygen needs pretransplant, have higher lung allocation score, and were more likely to be intubated or be on extracorporeal membrane oxygenation as compared with stable IPF patients. Survival by AE status at transplant did not differ at 90 d or 1 y posttransplantation. There were also no significant differences in rates of severe primary graft dysfunction or acute rejection within 1 y. Patients with AE-IPF were more likely to have higher oxygenation requirements and higher lung allocation score at the time of LTX than those with stable IPF. Despite this, there were no differences in survival at 90 d, 1 y, or 3 y, or differences in incidence of severe primary graft dysfunction or acute cellular rejection. Transplantation of patients with AE-IPF has clinical outcomes comparable with transplantation of patients with stable IPF. This contrasts with previous studies examining LTX in patients with AE-IPF.

The Impact of Chronic Comorbidities on Outcomes in Acute Exacerbations of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis is a chronic progressive lung disease of unknown cause with a high associated mortality. We aimed to compare the impact of chronic medical conditions on hospital outcomes of patients with acute exacerbations of idiopathic pulmonary fibrosis (AE-IPF). This was a retrospective cohort study using the NIS database from 2016 to 2018. We included patients aged 60 and older hospitalized in academic medical centers with the diagnoses of IPF and acute respiratory failure. We examined factors associated with hospital mortality and length of stay (LOS) using survey-weighted multivariate logistic and negative binomial regression. Out of 4975 patients with AE-IPF, 665 (13.4%) did not survive hospitalization. There was no difference in the mean age between survivors and non-survivors. Patients were more likely to be male, predominantly white, and have Medicare coverage. Most non-survivors were from households with higher median income. Hospital LOS was longer among non-survivors than survivors (9.4 days vs. 9.8 days; p < 0.001). After multivariate-logistic regression, diabetes was found to be protective (aOR 0.62, 95% CI 0.50-0.77; p < 0.0001) while chronic kidney disease (CKD) conferred a significantly higher risk of death after AE-IPF (aOR 6.85, 95% CI 1.90-24.7; p = 0.00). Our multivariate adjusted negative binomial regression model for LOS identified obesity (IRR 0.85, 95% CI 0.76-0.94; p ≤ 0.00) and hypothyroidism (IRR 0.90, 95% CI 0.83-0.98; p = 0.02) to be associated with shorter hospital LOS. Our results suggest that CKD is a significant contributor to hospital mortality in AE-IPF, and diabetes mellitus may be protective. Obesity and hypothyroidism are linked with shorter hospital LOS among patients hospitalized with AE-IPF in US academic medical centers.

The Prevalence of COVID-19 Infection in Patients Presented with Acute Exacerbation of Asthma, COPD and Idiopathic Pulmonary Fibrosis at the Emergency Department of Al-Shaab Teaching Hospital from July 2021 to November 2021

Background: The ongoing global pandemic of COVID-19 has raised concerns about its impact on patients with pre-existing respiratory conditions. Understanding the association between COVID-19 and chronic lung diseases such as asthma, chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) is crucial for early detection and appropriate management. Studying the prevalence rates of COVID-19 in this specific patient population will contribute to the existing knowledge and inform healthcare strategies for better patient care. The objective of this study is to assess the prevalence of COVID-19 infection in patients who presented with acute exacerbation of asthma, COPD and IPF. Method: This cross-sectional descriptive hospital-based study was conducted at Al-Shaab Teaching Hospital in Sudan and included adult Sudanese patients with exacerbation of asthma, COPD, or IPF who presented in the ER from February 2021 to July 2021. A representative sample of 345 patients was selected using a convenience, non-randomized sampling technique. Data were collected using a structured questionnaire and analyzed using SPSS version 26. Ethical clearance and approval were obtained for the study. Results: The study included 175 (50.7%) patients with asthma, 116 (33.6%) with IPF and 54 (15.7%) with COPD. The overall prevalence of COVID-19 among the patients was 58 (16.8%). Among the three groups, the highest prevalence of COVID-19 was observed in 22 (40.7%) patients with COPD, followed by 16 (13.8%) patients with IPF and 20 (11.4%) asthmatic patients (p value &lt; 0.05). In the asthmatic patients, the most common age groups affected were 25-34 years and 35-44 years, while in COPD and IPF patients, the prevalence was higher among patients aged 55 years and above (p value &lt; 0.05). Additionally, the prevalence of COVID-19 in COPD and IPF patients was significantly higher among males than females (p value &lt; 0.05). Conclusion: The prevalence of COVID-19 among patients with pre-existing respiratory conditions, such as asthma, COPD and IPF, is considerable, with the highest prevalence observed in patients with COPD. Furthermore, this study found that age and gender are associated factors with the prevalence of COVID-19 in these patient populations. These findings contribute to our understanding of the association between COVID-19 and chronic lung diseases, providing valuable information for early detection and appropriate management. The results of this study can inform healthcare strategies and contribute to better patient care in this specific patient population.

Prognostic factors associated with mortality in acute exacerbations of idiopathic pulmonary fibrosis: A systematic review and meta-analysis

BackgroundAcute exacerbations of idiopathic pulmonary fibrosis (AE-IPF) increases mortality risk, but which factors increase mortality is unknown. We aimed to perform a prognostic review of factors associated with mortality in patients with IPF. Study designand methods: We searched MEDLINE, EMBASE, and CINAHL for studies that reported on the association between any prognostic factor and AE-IPF. We assessed risk of bias using the QUIPS tool. We conduced pairwise meta-analyses using REML heterogeneity estimator, and GRADE approach to assess the certainty of the evidence. ResultsWe included 35 studies in our analysis. We found that long-term supplemental oxygen at baseline (aHR 2.52 [95 % CI 1.68 to 3.80]; moderate certainty) and a diagnosis of IPF compared to non-IPF ILD (aHR 2.19 [95 % CI 1.22 to 3.92]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. A diffuse pattern on high resolution computed tomography (HRCT) compared to a non-diffuse pattern (aHR 2.61 [95 % CI 1.32 to 2.90]; moderate certainty) is associated with a higher risk of death in patients with AE-IPF. We found that using corticosteroids prior to hospital admission (aHR 2.19 [95 % CI 1.26 to 3.82]; moderate certainty) and those with increased neutrophils (by % increase) in bronchoalveolar lavage (BAL) during the exacerbation is associated with a higher risk of death (aHR 1.02 [1.01 to 1.04]; moderate certainty). InterpretationOur results have implications for healthcare providers in making treatment decisions and prognosticating the clinical trajectory of patients, for researchers to design future interventions to improve patient trajectory, and for guideline developers in making decisions about resource allocation.

Safety and efficacy of CT-guided percutaneous microwave ablation for stage I non-small cell lung cancer in patients with comorbid idiopathic pulmonary fibrosis.

To evaluate the safety and efficacy of microwave ablation (MWA) for stage I non-small cell lung cancer (NSCLC) in patients with idiopathic pulmonary fibrosis (IPF). A retrospective single-center cohort study was conducted in patients with clinical stage I NSCLC who underwent CT-guided MWA from Nov 2016 to Oct 2021. The patients were divided into the IPF group and the non-IPF group. The primary endpoints were 90-day adverse events and hospital length of stay (HLOS). The secondary endpoints included overall survival (OS) and progression-free survival (PFS). A total of 107 patients (27 with IPF and 80 without IPF) were finally included for analysis. No procedure-related acute exacerbation of IPF or death occurred post-MWA. The rates of adverse events were similar between the groups (48.6% vs. 47.7%; p = 0.998). The incidence of grade 3 adverse events in the IPF group was higher than that in the non-IPF group without a significant difference (13.5% vs. 4.6%; p = 0.123). Median HLOS was 5days in both groups without a significant difference (p = 0.078). The 1-year and 3-year OS were 85.2%/51.6% in the IPF group, and 97.5%/86.4% in the non-IPF group. The survival of patients with IPF was significantly poorer than the survival of patients without IPF (p < 0.001). There was no significant difference for PFS (p = 0.271). MWA was feasible in the treatment of stage I NSCLC in patients with IPF. IPF had an adverse effect on the survival of stage I NSCLC treated with MWA. CT-guided microwave ablation is a well-tolerated and effective potential alternative treatment for stage I non-small cell lung cancer in patients with idiopathic pulmonary fibrosis. • Microwave ablation for stage I non-small cell lung cancer was well-tolerated without procedure-related acute exacerbation of idiopathic pulmonary fibrosis and death in patients with idiopathic pulmonary fibrosis. • No differences were observed in the incidence of adverse events between patients with idiopathic pulmonary fibrosis and those without idiopathic pulmonary fibrosis after microwave ablation (48.6% vs. 47.7%; p = 0.998). • The 1-year and 3-year overall survival rates (85.2%/51.6%) in the idiopathic pulmonary fibrosis group were worse than those in the non- idiopathic pulmonary fibrosis group (97.5%/86.4%) (p < 0.001).

Serum heme oxygenase-1 as a prognostic biomarker in patients with acute exacerbation of interstitial lung disease

Serum heme oxygenase (HO)-1 level has been reported as a clinically reliable diagnostic biomarker for acute exacerbation of interstitial lung disease (ILD); however, its utility for predicting mortality among these patients is unclear. Serum HO-1 levels of patients newly diagnosed with acute exacerbation of ILD were measured at the time of initiating steroid pulse therapy. The relationship between serum HO-1 and various other serum biomarkers, change in HRCT findings, and disease prognosis at 12 weeks after diagnosis of acute exacerbation was evaluated in 51 patients, of whom 17 (33%) had idiopathic pulmonary fibrosis (IPF). Serum HO-1 was higher in patients with acute exacerbation of IPF than in patients with acute exacerbation of other ILDs. Serum HO-1 levels were higher in patients who died within these 12 weeks than in survivors. Among age, sex, comorbidities, IPF diagnosis, HRCT findings, and blood biomarkers, serum HO-1 was a primary predictor of 12-week mortality. In 41 patients who underwent repeat HRCT, serum HO-1 was higher in patients with honeycomb progression than in those without. Serum HO-1 measurement could be useful for evaluating disease mortality and morbidity of patients with acute exacerbation of ILDs.

Pulse versus non-pulse corticosteroid therapy in patients with acute exacerbation of idiopathic pulmonary fibrosis.

Corticosteroids are commonly used for the treatment of acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF); however, the optimal initial dose of corticosteroids remains uncertain due to a lack of sufficient evidence. We evaluated whether the administration of a pulse dose of corticosteroids resulted in improved survival outcomes compared with conventional non-pulse dose of corticosteroids. We retrospectively analysed 238 patients with AE-IPF treated with corticosteroids at a tertiary referral hospital between January 2013 and December 2021. Based on whether a pulse dose of corticosteroids (methylprednisolone of ≥250 mg/day or equivalent) was administered within 7 days of hospitalization for AE-IPF, the patients were divided into the pulse and non-pulse regimen groups. The survival outcomes were compared between the two groups using multivariable regression and propensity score-matched analyses. Among the 238 patients, 59 patients received pulse dose of corticosteroids, whereas 179 patients received conventional non-pulse dose of corticosteroids. After adjusting for the confounding factors related to the baseline clinical and radiographic severity, compared with the conventional non-pulse regimen, the pulse regimen of corticosteroids did not reduce the risk of mortality at the 3-month (aHR 0.84, 95% CI 0.45-1.38) or 12-month (aHR 0.96, 95% CI 0.60-1.25) follow-ups. Propensity score-matched analysis revealed similar results. The survival outcomes of patients with AE-IPF who received a pulse dose of corticosteroids did not differ from those of patients who received conventional non-pulse dose of corticosteroids. Further prospective studies are required to establish the optimal initial dose of corticosteroids for the treatment of AE-IPF.

Neutrophil-to-Lymphocyte Ratio in Acute Exacerbation of Idiopathic Pulmonary Fibrosis

Background: This study aimed to clarify the prognostic value of the neutrophil-to-lymphocyte ratio (NLR) in patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF). Methods: Eighty-six patients diagnosed with AE-IPF were included in this single-center retrospective study. The NLR was calculated by dividing the peripheral neutrophil count by the peripheral lymphocyte count. The cut-off values of the NLR for predicting 90-day survival were determined using receiver operating characteristic curve analysis. Oxygenation deterioration on days 4 and 8 relative to that on day 1 was clinically defined. The prognostic value of NLR was evaluated using Cox proportional hazard regression analysis. Results: The cut-off value of day-1, day-4, and day-8 NLRs for predicting 90-day survival was 12.13, 14.90, and 10.56, respectively. A higher day-1 NLR was a significant predictor of a poor prognosis in univariate and multivariate analyses. Survival was significantly better in patients without oxygenation deterioration on days 4 and 8 than in those with deterioration. Day-4 and day-8 NLR could predict 90-day survival in patients without oxygenation deterioration. Conclusions: Day-1 NLR was a useful predictor of 90-day survival in AE-IPF. Further, monitoring day-4 and day-8 NLRs and evaluating oxygenation deterioration may be useful for managing AE-IPF.

Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis: An exploratory randomized controlled trial

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is an important occurrence in the natural history of idiopathic pulmonary fibrosis (IPF), associated with high hospitalization rates, high mortality and poor prognosis. At present, there is no effective treatment for AE-IPF. Chinese herbal medicine has some advantages in treating IPF, but its utility in AE-IPF is unclear. ObjectiveThe treatment of AE-IPF with Kangxian Huanji Granule (KXHJ), a compound Chinese herbal medicine, lacks an evidence-based justification. This study explores the efficacy and safety of KXHJ in patients with AE-IPF. Design, setting, participants and interventionsWe designed a randomized, double-blind, placebo-controlled, exploratory clinical trial. A total of 80 participants diagnosed with AE-IPF were randomly assigned to receive KXHJ or a matching placebo; the treatment included a 10 g dose, administered twice daily for 4 weeks, in addition to conventional treatment. Participants were followed up for 12 weeks after the treatment. Main outcome measuresThe primary endpoints were treatment failure rate and all-cause mortality. Secondary endpoints included the length of hospitalization, overall survival, acute exacerbation rate, intubation rate, the modified British Medical Research Council (mMRC) score, and the St George’s Respiratory Questionnaire for IPF (SGRQ-I) score. ResultsThe rate of treatment failure at 4 weeks was lower in the intervention group compared to the control group (risk ratio [RR]: 0.22; 95% confidence interval [CI]: 0.051 to 0.965, P = 0.023). There was no significant difference in all-cause mortality at 16 weeks (RR: 0.75; 95% CI: 0.179 to 3.138; P > 0.999) or in the acute exacerbation rate during the 12-week follow-up period (RR: 0.69; 95% CI: 0.334 to 1.434; P = 0.317). The intervention group had a shorter length of hospitalization than the control group (mean difference [MD]: –3.30 days; 95% CI, –6.300 to –0.300; P = 0.032). Significant differences in the mean change from baseline in the mMRC (between-group difference: –0.67; 95% CI: –0.89 to –0.44; P < 0.001) and SGRQ-I score (between-group difference: –10.36; 95% CI: –16.483 to –4.228; P = 0.001) were observed after 4 weeks, and also in the mMRC (between-group difference: –0.67; 95% CI: –0.91 to –0.43; P < 0.001) and SGRQ-I (between-group difference: –10.28; 95% CI, –15.838 to –4.718; P < 0.001) at 16 weeks. The difference in the adverse events was not significant. ConclusionKXHJ appears to be effective and safe for AE-IPF and can be considered a complementary treatment in patients with AE-IPF. As a preliminary exploratory study, our results provide a basis for further clinical research. Trial registrationChinese Clinical Trial Registry (ChiCTR1900026289).Please cite this article as: Li JS, Zhang HL, Guo W, Wang L, Zhang D, Zhao LM, Zhou M. Efficacy and safety of Kangxian Huanji Granule as adjunctive treatment in acute exacerbation of idiopathic pulmonary fibrosis: an exploratory randomized controlled trial. J Integr Med. 2023; Epub ahead of print.

Polymyxin B-immobilised fibre column treatment for acute exacerbation of idiopathic pulmonary fibrosis patients with mechanical ventilation: a nationwide observational study

BackgroundThe prognosis for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is poor, and there is no established treatment. Hence, we aimed to investigate the effectiveness of a polymyxin B-immobilised fibre column (PMX) for the treatment of AE-IPF.MethodsData were retrospectively collected from the Japanese Diagnosis Procedure Combination database from 1 July 2010 to 31 March 2018. We identified adult patients with idiopathic pulmonary fibrosis who received high-dose methylprednisolone (mPSL) therapy and mechanical ventilation upon admission. Eligible patients (n = 5616) were divided into those receiving PMX treatment combined with high-dose mPSL (PMX group, n = 199) and high-dose mPSL alone (mPSL alone group, n = 5417). To compare outcomes between the two groups, we applied a stabilised inverse probability of treatment weighting (IPTW) using propensity scores. The primary outcome was in-hospital mortality, and the secondary outcomes were 14- and 28-day mortality and length of hospital stay.ResultsThe in-hospital mortality rates of the PMX and mPSL alone groups were 79.9% and 76.4%, respectively. The results did not significantly differ between the two groups after performing a stabilised IPTW. The odds ratio of the PMX group compared with the mPSL alone group was 1.56 (95% confidence interval 0.80–3.06; p = 0.19). The 14- and 28-day mortality and length of hospital stay (secondary outcomes) also did not significantly differ between the two groups.ConclusionsIn AE-IPF patients using mechanical ventilation, the treatment outcome was not significantly better for PMX combined with high-dose mPSL than for high-dose mPSL alone.

Myeloid Heterogeneity Mediates Acute Exacerbations of Pulmonary Fibrosis.

Epidemiological evidence indicates that exposure to particulate matter is linked to the development of idiopathic pulmonary fibrosis (IPF) and increases the incidence of acute exacerbations of IPF. In addition to accelerating the rate of lung function decline, exposure to fine particulate matter (particulate matter smaller than 2.5 μm [PM2.5]) is a risk factor for increased mortality in subjects with IPF. In this article, we show that exposure to PM2.5 mediates monocyte recruitment and fibrotic progression in mice with established fibrosis. In mice with established fibrosis, bronchoalveolar lavage cells showed monocyte/macrophage heterogeneity after exposure to PM2.5. These cells had a significant inflammatory and anti-inflammatory signature. The mixed heterogeneity of cells contributed to the proinflammatory and anti-inflammatory response. Although monocyte-derived macrophages were recruited to the lung in bleomycin-injured mice treated with PM2.5, recruitment of monocytes expressing Ly6Chi to the lung promoted progression of fibrosis, reduced lung aeration on computed tomography, and impacted lung compliance. Ly6Chi monocytes isolated from PM2.5-exposed fibrotic mice showed enhanced expression of proinflammatory markers compared with fibrotic mice exposed to vehicle. Moreover, IPF bronchoalveolar lavage cells treated ex vivo with PM2.5 showed an exaggerated inflammatory response. Targeting Ly6Chi monocyte recruitment inhibited fibrotic progression in mice. Moreover, the adoptive transfer of Ly6Chi monocytes exacerbated established fibrosis. These observations suggest that enhanced recruitment of Ly6Chi monocytes with a proinflammatory phenotype mediates acute exacerbations of pulmonary fibrosis, and targeting these cells may provide a potential novel therapeutic target to protect against acute exacerbations of IPF.