Zhongguo Zhong Yao Za Zhi. 2024 Dec;49(23):6399-6406. doi: 10.19540/j.cnki.cjcmm.20240904.402.

ABSTRACT

To investigate the therapeutic effect of Fuzheng Tongluo Granules on idiopathic pulmonary fibrosis(IPF) and its mechanism. Seventy-two SD rats were randomly divided into the control group, model group, pirfenidone group(162 mg·kg~(-1)), and low-, medium-and high-dose of Fuzheng Tongluo Granules groups(2.63, 5.25, 10.5 g·kg~(-1)). Rat model of IPF was induced by a single non-invasive tracheal intubation drip of bleomycin(BLM). The corresponding drugs were given daily by gavage after the 2nd day of modeling, and body mass was recorded. On the 28th day, the samples were collected and weighed, and the lung coefficients were calculated. The pathological changes in the lung tissue were observed by HE and Masson staining, and the hydroxyproline(HYP) content of the lung tissue was detected by alkaline hydrolysis. The contents of tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), and interleukin-18(IL-18) of the lung tissue were determined by ELISA. The expression of collagen type Ⅰ(collagen Ⅰ) and α-smooth muscle actin(α-SMA) was observed by immunohistochemistry. The expression levels of NOD-, LRR-and pyrin domain-containing 3(NLRP3), cysteine-requiring aspartate protease type 1(caspase-1), gasdermin D-N(GSDMD-N), and apoptosis-associated speck-like protein containing a CARD(ASC) in the lung tissue were detected by Western blot. Immunofluorescence co-localization was used to observe the expression of GSDMD and CD68. The results show that compared with the control group, the model group showed increased lung coefficient, Ashcroft score, Szapiel score, HYP, TNF-α, IL-1β, and IL-18 content in the lung tissue and elevated protein expression levels of NLRP3, caspase-1, GSDMD-N, and ASC. The expression levels of GSDMD and CD68 were increased, and there was a high degree of co-localization between GSDMD and CD68. Compared with those in the model group, the lung coefficient, Ashcroft score, and Szapiel score decreased in all drug administration groups, and the content of HYP, TNF-α, IL-1β, and IL-18 decreased. The protein expression levels of NLRP3, caspase-1, GSDMD-N, and ASC decreased, and the expression levels of GSDMD and CD68 were reduced. There was a high degree of co-localization between GSDMD and CD68. In summary, Fuzheng Tongluo Granules can effectively reduce pulmonary fibrosis and inflammation levels in rats with IPF, and the mechanism may be related to the down-regulation of the NLRP3/caspase-1/GSDMD pathway to inhibit macrophage pyroptosis.

PMID:39805786 | DOI:10.19540/j.cnki.cjcmm.20240904.402

Zhongguo Zhong Yao Za Zhi. 2024 Dec;49(24):6803-6812. doi: 10.19540/j.cnki.cjcmm.20240821.501.

ABSTRACT

This study systematically retrieved the clinical studies in the treatment of idiopathic pulmonary fibrosis(IPF) with traditional Chinese medicine(TCM) and employed evidence mapping to summarize the overall research status and deficiencies of TCM in treating IPF. CNKI, VIP, SinoMed, Wanfang, PubMed, Web of Science, Cochrane Library, and EMbase were searched for the relevant studies published from inception to February 20, 2024. The distribution characteristics of the evidence were analyzed and presented through charts combined with words. A total of 323 studies were included, including 295 randomized controlled trials(RCTs) and 28 Meta-analysis. The number of publications in this field rose with fluctuations, yet the proportion of core papers was low, and the research lacked the attention of foreign researchers. There were scant cross-regional collaboration between researchers and insufficient attention from relevant departments. The included RCT generally had low quality, with small sample sizes, short treatment courses, and insufficient attention to acute exacerbation and complications of IPF. In addition, few studies employed TCM alone, and the TCM syndromes remained to be standardized. A considerable number of outcome indicators were involved in the publications, while the majority of them failed to emphasize the disparity between primary and secondary outcome indicators. There were diverse reference standards for the comprehensive indicators among the outcome indicators, and insufficient attention was paid to long-term prognosis and health economic indicators. The included Meta-analysis concluded that TCM had potential clinical efficacy in treating IPF. However, the methodological credibility grading and the GRADE grading results of outcome indicators were low. The results suggested that TCM demonstrated certain advantages in the treatment of IPF, while the quality of the included studies was not high. In the future, clinical research protocols should be standardized and registered. Multicenter, large-sample, and follow-up clinical studies should be conducted. The research reports should refer to relevant reporting standards to improve the quality and generate high-level evidence, thus providing a reference for the clinical application of TCM in the treatment of IPF.

PMID:39805768 | DOI:10.19540/j.cnki.cjcmm.20240821.501

Chest. 2025 Jan 11:S0012-3692(25)00005-4. doi: 10.1016/j.chest.2025.01.001. Online ahead of print.

ABSTRACT

BACKGROUND: Pulmonary rehabilitation (PR) is a beneficial intervention for people with interstitial lung disease (ILD), however the effect of PR on survival is unclear. This study compared the survival outcomes in people with ILD who were allocated to PR versus those who were allocated to control in two published randomised controlled trials (RCTs).

RESEARCH QUESTION: Does participation in PR impact survival among people with ILD?

STUDY DESIGN AND METHODS: The combined data from the two previous RCTs of PR in ILD were included. Time from start of PR until date of death, lung transplantation or censoring was calculated. Kaplan-Meir and Cox proportional hazard regression analysis were used to assess the impact of PR on survival. Baseline variables of age at time of PR, gender, FVC, 6-minute walk distance (6MWD), exertional nadir SpO2 and diagnosis of idiopathic pulmonary fibrosis (IPF) were included as covariates.

RESULTS: Of the 182 participants with ILD (87 IPF, 109 males, mean (SD) age 69(10), FVC%pred 76(19), TLCO%pred 48(16)), death occurred in 62%, 6% were transplanted, 20% were alive and 12% were lost to follow-up. Median survival for those who completed PR was 6.1 years (95% CI 4.4 to 7.9) compared to 4.7 years (95%CI 3.4 to 6.0) for those in the control group, however this was not significantly different (log rank p=0.7). After adjusting for baseline variables, at 5 years, completion of PR was associated a 44% lower risk of mortality (HR 0.56 (0.36-0.88), p=0.01). At 10 years, no difference in survival was observed between the PR and control group.

INTERPRETATION: Participation in PR among people with ILD may impact survival at 5 years. Along with clinical improvements following PR, the potential for a survival benefit further strengthens the importance of PR in the standard care of people with ILD.

PMID:39805518 | DOI:10.1016/j.chest.2025.01.001

Lancet Respir Med. 2025 Jan 10:S2213-2600(24)00364-3. doi: 10.1016/S2213-2600(24)00364-3. Online ahead of print.

ABSTRACT

BACKGROUND: Bronchiectasis is a disease with a global impact, but most published data come from high-income countries. We aimed to describe the clinical characteristics of patients with bronchiectasis in China.

METHODS: The Chinese Bronchiectasis Registry (BE-China) is a prospective, observational cohort enrolling patients from 111 hospitals in China. Data on demographics, comorbidities, and aetiological testing results were collected from adult patients with bronchiectasis at baseline and annual follow-up. Patients who met the inclusion criteria (age ≥18 years; received chest high-resolution CT in the past year showing bronchiectasis affecting one or more lung lobes; and clinical history consistent with bronchiectasis, including chronic cough, daily sputum production, and history of exacerbations) were included. Patients with known cystic fibrosis were excluded. To investigate variations according to different economic regions, two groups were compared based on whether per capita disposable income of residents was greater than US$5553. Clinical characteristics were compared with the European (EMBARC) registry and other national registries.

FINDINGS: Between Jan 10, 2020, and March 31, 2024, 10 324 patients from 97 centres were included in the study. Among 9501 participants with available data, the most common cause of bronchiectasis was post-infective disease (4101 [43·2%] patients), followed by idiopathic (2809 [29·6%] patients). 6676 (70·0%) of 9541 patients with available data had at least one exacerbation in the year before enrolment and 5427 (57·2%) of 9489 patients with available data were hospitalised at least once due to exacerbations. Treatments commonly used in high-income countries, such as inhaled antibiotics and macrolides, were infrequently used in China. Implementation of airway clearance in China was scarce, with only 1177 (12·2%) of 9647 patients having used at least one method of airway clearance. Compared with upper-middle-income regions, patients from lower-middle-income regions were younger (61·0 years [SD 14·0] vs 63·9 years [14·2]) with a higher proportion of pulmonary comorbidities (521 [17·8%] of 2922 patients vs 639 [8·6%] of 7402 with chronic obstructive pulmonary disease and 194 [6·6%] of 2922 patients vs 364 [4·9%] of 7402 patients with asthma), a higher tuberculosis burden (442 [16·0%] of 2768 patients vs 715 [10·6%] of 6733 patients), more severe radiological involvement (1160 [42·4%] of 2736 patients vs 2415 [35·4%] of 6816 patients with cystic bronchiectasis), more exacerbations (median 1·4 [IQR 0-2] in both groups; mean 1·4 [SD 1·6] vs 1·2 [1·4] in the previous year) and hospitalisations (1662 [60·6%] of 2743 patients vs 3765 [55·8%] of 6746 patients hospitalised at least once in the previous year), and poorer quality of life (median 57·4 [IQR 53·5-63·1] vs 58·7 [54·8-64·8] assessed by the Bronchiectasis Health Questionnaire).

INTERPRETATION: The clinical characteristics of patients with bronchiectasis in China show differences compared with cohorts in Europe and India. Bronchiectasis is more severe with a higher burden of exacerbations in lower-income regions. The management of patients with bronchiectasis in China urgently needs standardisation and improvement.

FUNDING: National Natural Science Foundation of China, Innovation Program of the Shanghai Municipal Education Commission, Program of the Shanghai Municipal Science and Technology Commission, and Program of the Shanghai Shenkang Development Center.

TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PMID:39805296 | DOI:10.1016/S2213-2600(24)00364-3

Ann Gastroenterol. 2025 Jan-Feb;38(1):80-84. doi: 10.20524/aog.2024.0932. Epub 2024 Dec 12.

ABSTRACT

BACKGROUND: The risk of gastrointestinal (GI) cancer after lung transplantation (LTx) in sarcoidosis patients is not well defined. Given the cancer risks linked to sarcoidosis and organ transplantation, this study investigated the incidence of GI de novo malignancies (DNM), comparing LTx recipients with sarcoidosis or idiopathic pulmonary fibrosis (IPF).

METHODS: We analyzed data from the United Network for Organ Sharing registry, including adults with sarcoidosis or IPF who underwent LTx between May 2005 and December 2018. The primary outcome was the incidence of GI DNM by March 2023.

RESULTS: Of 7996 lung transplant recipients, 108 (1.35%) developed GI malignancies post-transplantation. Among these, 662 patients (9%) had sarcoidosis and 7334 (91%) had IPF. Sarcoidosis patients showed a non-significant trend toward a higher risk of GI malignancies compared to those with IPF (subhazard ratio 1.72, 95% confidence interval 0.90-3.29; P=0.099), with no observed difference in the risk of non-GI cancers.

CONCLUSIONS: The overall incidence of GI DNM following LTx is low, and sarcoidosis does not appear to increase the risk of GI cancers compared to IPF. This finding suggests that enhanced GI cancer screening beyond standard guidelines may not be warranted in this population, allowing for targeted surveillance of more prevalent malignancies in sarcoidosis patients post-LTx.

PMID:39802287 | PMC:PMC11724385 | DOI:10.20524/aog.2024.0932

Int J Gen Med. 2025 Jan 6;18:21-32. doi: 10.2147/IJGM.S498350. eCollection 2025.

ABSTRACT

OBJECTIVE: To evaluate the effectiveness and safety of traditional Chinese medicine (TCM) ion introduction therapy in the treatment of patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF).

METHODS: This study adopts a prospective cohort study design, with 60 AE-IPF patients as the research subjects. Divided into an exposed group and a non exposed group, with 30 cases in each group, based on the frequency of TCM ion introduction treatment as the exposure factor. Follow-up for 1 year to observe the acute exacerbation of the patient. The main indicator is the annual incidence of acute exacerbation, and the secondary indicators are hospitalization time, readmission rate, time to first acute exacerbation, mortality rate, all-cause mortality rate, inflammatory indicators, quality of life, etc.

RESULTS: 51 patients completed a one-year clinical observation, including 27 in the exposed group and 24 in the non exposed group. Compared to the non exposed group, significant differences were observed in the annual incidence of acute exacerbation [incidence rate ratios (IRR) = 0.556, 95% CI: 0.315, 0.980; P = 0.035] and hospitalization time (P = 0.040), readmission rate (IRR = 0.533, 95% CI: 0.288, 0.988; P = 0.037), time to first acute exacerbation (P = 0.045), and quality of life (P < 0.05). However, there was no statistically significant difference in mortality rate and all-cause mortality rate between the two groups (P > 0.05).

CONCLUSION: Compared to the non exposed group, TCM ion introduction can reduce the annual incidence of acute exacerbation of IPF patients. Hospitalization time, readmission rate, time to first acute exacerbation, quality of life improved, but mortality rate and all-cause mortality rate did not improve.

PMID:39801926 | PMC:PMC11721691 | DOI:10.2147/IJGM.S498350

Expert Rev Respir Med. 2025 Jan 12. doi: 10.1080/17476348.2025.2453657. Online ahead of print.

ABSTRACT

INTRODUCTION: Interstitial lung disease (ILD) is a broad group of conditions characterized by fibrosis of the lung parenchyma. Idiopathic pulmonary fibrosis (IPF) is the most common subvariant. IPF is marked by considerable symptom burden of dyspnea, cough and fatigue that is often refractory to optimal disease-directed treatment.

AREAS COVERED: In this narrative review, we searched MEDLINE for articles related to the current evidence regarding management of chronic dyspnea, cough, and fatigue as three of the most prevalent and distressing symptoms associated with IPF and other ILDs. Each symptom shares common features of multi-factorial etiology and a lack of safe and effective pharmacological therapies. Both corticosteroids and opioids have been utilized in this context, yet there is insufficient evidence of therapeutic benefit and considerable risk of harms. Whilst some may benefit from symptom-directed pharmacological management, usage must be carefully monitored. Use of non-pharmacological strategies, such as breathing techniques and speech therapy represent low risk and low-cost option, yet broader validation of these therapies' effectiveness is needed.

EXPERT OPINION: Symptom management in IPF and other ILDs requires an iterative and individualized approach. Leveraging the expertise of multidisciplinary teams within an integrated care setting is an important opportunity to maximize health outcomes.

PMID:39800565 | DOI:10.1080/17476348.2025.2453657

Exp Eye Res. 2025 Jan 10:110238. doi: 10.1016/j.exer.2025.110238. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease linked to aging. This study investigates potential connections between IPF and age-related eye problems using a bleomycin-induced IPF mouse model. Intratracheal administration of bleomycin induces rapid lung injury in mice, followed by IPF with characteristics of cellular senescence. IPF-injured mice had reduced amplitudes of scotopic ERG and immunostaining of visual arrestin, suggesting declined rod-related visual function. Interestingly, the mice's eyes also showed increased susceptibility to Staphylococcus aureus infections, reminiscent of the aging eyes. To determine whether an early onset of aging contributes to the eye disorders, we examined complement and senescence markers in the retina. In bleomycin-injury IPF mice, DNA damage-related senescence marker γH2AX was found in the retinal out nuclear layer where photoreceptors are located. Additionally, IPF mice displayed elevated levels of C3b, a complement fragment resulting from C3 activation that occurs frequently in aging eyes. These findings underscore the potential of IPF as a valuable mouse model for investigating early-onset age-related ocular disorders.

PMID:39800285 | DOI:10.1016/j.exer.2025.110238

J Clin Med. 2025 Jan 6;14(1):291. doi: 10.3390/jcm14010291.

ABSTRACT

Chronic cough is a distressing and prevalent symptom in interstitial lung disease (ILD), significantly impairing quality of life (QoL) and contributing to disease progression, particularly in idiopathic pulmonary fibrosis (IPF). It is associated with physical discomfort, psychological distress, and social isolation and is often refractory to conventional therapies. The pathophysiology of cough in ILD is complex and multifactorial, involving neural hypersensitivity, structural lung changes, inflammatory processes, and comorbid conditions such as gastroesophageal reflux disease (GERD). Evaluating cough in ILD relies on subjective and objective tools to measure its severity, frequency, and impact on daily life, although standardization of these measures remains challenging. Management strategies span pharmacological interventions, including neuromodulators such as opiates, antifibrotic agents, pharmacologic and surgical GERD treatments, and non-pharmacological approaches like behavioral therapies, cough suppression techniques, and pulmonary rehabilitation and physiotherapy. Emerging treatments, such as P2X3 receptor antagonists and airway hydration therapies, offer promising avenues but require further investigation through robust clinical trials. This review aims to demonstrate the importance of addressing cough in ILD as a significant symptom and present objective and subjective methods of quantifying coughs, while providing insights into effective and emerging therapeutic options. By highlighting these potential therapies, we hope to guide healthcare practitioners in considering them through a thorough evaluation of benefits and risks on a case-by-case basis, with relevance both in the U.S. and internationally.

PMID:39797373 | DOI:10.3390/jcm14010291

J Clin Med. 2025 Jan 3;14(1):247. doi: 10.3390/jcm14010247.

ABSTRACT

Background: Antibodies against Ku have been described in patients with various connective tissue diseases. The objective of this study was to describe the clinical, functional, and imaging characteristics of interstitial lung disease in patients with anti-Ku antibodies. Methods: This single-center, retrospective observational study was conducted at a tertiary referral institution. Patients with positive anti-Ku antibodies and interstitial lung disease identified between 2007 and 2022 were included. Clinical, immunological, functional, and imaging data were systematically reviewed. Results: Nineteen patients (ten females) with a mean age of 59 ± 12.6 years were included. The most frequent associated diagnosis was systemic sclerosis (42%), followed by rheumatoid arthritis (26%), Sjögren syndrome, undifferentiated connective tissue disease, and overlap between systemic sclerosis and idiopathic inflammatory myopathy (scleromyositis). Imaging revealed frequent septal and intralobular reticulations and ground-glass opacities, with nonspecific interstitial pneumonia as the predominant pattern (53%). The mean forced vital capacity was 82% ± 26 of the predicted value, and the mean diffusing capacity for carbon monoxide was 55% ± 21. Over the first year of follow-up, the mean annual forced vital capacity decline was 140 mL/year (range: 0-1610 mL/year). The overall survival rate was 82% at 5 years and 67% at 10 years. Conclusions: Most patients with interstitial lung disease and anti-Ku antibodies presented with dyspnea, a mild-to-moderate restrictive ventilatory pattern, and reduced diffusing capacity for carbon monoxide. The CT pattern was heterogeneous but was consistent with nonspecific interstitial pneumonia in half of the patients.

PMID:39797328 | DOI:10.3390/jcm14010247

Int J Mol Sci. 2025 Jan 4;26(1):382. doi: 10.3390/ijms26010382.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and devastating lung disorder. In response to transforming growth factor-β (TGF-β), normal lung cells proliferate and differentiate into myofibroblasts, which are instrumental in promoting disease progression. Small interfering RNA (siRNA) targeting heat shock protein 47 (HSP47) has been demonstrated to alleviate IPF by blocking collagen synthesis and secretion. Exosomes (EXOs) have been investigated for drug delivery due to their superior carrier properties. However, their loading efficiency has been a limiting factor in widely application as drug carriers. In this study, an ultrasonic microfluidic method was employed to enhance the loading efficiency of siHSP47 into EXOs, achieving 31.1% efficiency rate. EXOs were isolated from human embryonic kidney cells (293F) and loaded with siHSP47 (EXO-siHSP47). The findings indicated that EXO-siHSP47 penetrated the collagen barrier and effectively silenced HSP47 expression in activated fibroblasts in vitro. Western blotting and immunofluorescence analyses confirmed that EXO-siHSP47 significantly reduced the secretion and deposition of extracellular matrix (ECM) proteins. Wound healing and Transwell migration assays demonstrated that EXO-siHSP47 inhibited fibroblast differentiation and migration. In conclusion, 293F-derived EXOs loaded with siHSP47 present a promising therapeutic strategy for IPF.

PMID:39796239 | DOI:10.3390/ijms26010382

Eur J Med Res. 2025 Jan 10;30(1):20. doi: 10.1186/s40001-024-02256-x.

ABSTRACT

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.

PMID:39794841 | DOI:10.1186/s40001-024-02256-x

Gene. 2025 Jan 9:149223. doi: 10.1016/j.gene.2025.149223. Online ahead of print.

NO ABSTRACT

PMID:39794204 | DOI:10.1016/j.gene.2025.149223

Ecotoxicol Environ Saf. 2025 Jan 9;289:117679. doi: 10.1016/j.ecoenv.2025.117679. Online ahead of print.

ABSTRACT

AIM: Identifying the common functional single-nucleotide polymorphisms (SNPs) that can both affect the susceptibility to idiopathic pulmonary fibrosis (IPF) and silicosis.

METHODS: We first integrated the genome-wide association studies (GWASs) of IPF and silicosis to obtain the shared SNPs. Following this, functional expression quantitative trait locus (eQTL)-SNPs were identified by the GTEx database. This was followed by the validation of the correlation between these eQTL-SNPs and silicosis susceptibility through an additional case-control study including 194 silicosis cases and 235 healthy controls.

RESULTS: A total of 10 eQTL-SNPs that may affect silicosis susceptibility (P < 0.05) were obtained after the integration of the GWASs of IPF and silicosis, and a series of rigorous selection principles. Subsequently, the results of integrating the validation stage and the screening stage indicated that the variant T allele of rs1620530 located in the MAD1L1 (additive model: OR= 1.56, 95 % CI = 1.21-2.01, P = 0.001) and the variant G allele of rs2070063 located in the SERTAD2 (additive model: OR= 1.60, 95 % CI = 1.24-2.06, P < 0.001) were associated with increased silicosis susceptibility. The joint analysis indicated the risk of developing silicosis was higher in individuals who carried more unfavorable alleles of rs1620530 and rs2070063.

CONCLUSIONS: The rs1620530 and rs2070063 may affect the silicosis susceptibility by regulating the expression of the MAD1L1 and SERTAD2, respectively. Further biological experiments are warranted to elucidate the underlying biological mechanisms between these two SNPs and the increased susceptibility to silicosis.

PMID:39793288 | DOI:10.1016/j.ecoenv.2025.117679

JAMA Health Forum. 2025 Jan 3;6(1):e244874. doi: 10.1001/jamahealthforum.2024.4874.

ABSTRACT

IMPORTANCE: The prevalence of pharmacies owned by integrated insurers and pharmacy benefit managers (PBMs), or insurer-PBMs, is of growing regulatory concern. However, little is known about the role of these pharmacies in Medicare, in which pharmacy network protections may influence market dynamics.

OBJECTIVE: To evaluate the prevalence of insurer-PBM-owned pharmacies and the extent to which insurer-PBMs steer patients to pharmacies they own in Medicare.

DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study used Medicare Part D claims data on prescription fills for a 20% random sample of US beneficiaries enrolled from January 1 through December 31, 2021. Data were analyzed from March to November 2024.

EXPOSURES: Prescription fills.

MAIN OUTCOMES AND MEASURES: The main outcome was the share of spending filled by insurer-PBM-owned pharmacies overall, by pharmacy type (specialty and nonspecialty), and by drug class. For the top 100 specialty and nonspecialty molecules by claim volume, 2 quantities were identified for 4 major insurer-PBMs (Cigna, CVS, Humana, and UnitedHealth Group): share of the index firm's insurer claims filled by its owned pharmacies and share of other firms' insurer claims filled by the index firm's owned pharmacies. Differences between these quantities were assessed to evaluate the degree to which insurer-PBMs steered patients to their own pharmacies.

RESULTS: Among 10 455 726 patients (54.8% women; mean [SD] age, 71.8 [10.7] years), 34.1% of all pharmacy and 37.1% of specialty pharmacy spending occurred through Cigna, CVS, Humana, or UnitedHealth Group pharmacies. Among specialty molecules, market shares varied by drug class (antivirals: 18.5%; antipsychotics: 29.5%; cancer: 32.5%; disease-modifying antirheumatic drugs: 41.1%; multiple sclerosis: 64.8%; pulmonary arterial hypertension and idiopathic pulmonary fibrosis: 89.7%). Across molecule-firm combinations, a 19.8 (95% CI, 18.0-21.6)-percentage point and 13.9 (95% CI, 13.1-14.7)-percentage point greater share of claims were filled at insurer-PBM-owned pharmacies than would be expected without steering for specialty and nonspecialty categories, respectively.

CONCLUSIONS AND RELEVANCE: This cross-sectional study found that insurer-PBM firms represented an important portion of the Medicare Part D market, especially for certain drug classes, and that insurer-PBM firms steered patients to their own pharmacies, despite certain pharmacy network protections in Medicare. These findings underscore the need to understand the impacts of insurer-PBM and pharmacy integration on medication access and costs for Medicare patients.

PMID:39792403 | DOI:10.1001/jamahealthforum.2024.4874

ACS Nano. 2025 Jan 10. doi: 10.1021/acsnano.4c15130. Online ahead of print.

ABSTRACT

For idiopathic pulmonary fibrosis (IPF), interleukin 11 (IL-11) is a pivotal cytokine that stimulates the transformation of fibroblasts into myofibroblasts, thus accelerating the progression of pulmonary fibrosis. Here, we develop an innovative inhalable small interfering RNA (siRNA) delivery system termed PEI-GBZA, which demonstrates impressive efficiency in loading siIL-11 targeting IL-11 (siIL-11) and substantially suppresses the differentiation of fibroblasts into myofibroblasts and epithelial-mesenchymal transition (EMT), reduces neutrophil and macrophage recruitment, and ultimately relieves the established fibrotic lesions in the IPF model. PEI-GBZA is prepared by modifying low-molecular-weight polyethylenimine (PEI) with 4-guanidinobenzoic acid (GBZA). The resulting PEI-GBZA may effectively encapsulate siIL-11 through a variety of interactions such as hydrophobic, hydrogen bonding, and electrostatic interactions, creating stable carrier/siIL-11 nanoparticles (PEI-GBZA/siIL-11 NPs). Upon inhalation, PEI-GBZA/siIL-11 NPs demonstrate effective retention in fibrotic lesions, leading to a marked mitigation of disease progression in a bleomycin-induced pulmonary fibrosis model. Impressively, this inhalation therapy exhibits negligible systemic toxicity. This work provides a universal and noninvasive RNA therapeutic delivery platform that holds significant promise for respiratory diseases. The potential for clinical application of this platform is substantial, offering a frontier for the treatment of IPF and potentially other pulmonary disorders.

PMID:39791575 | DOI:10.1021/acsnano.4c15130

BMC Pulm Med. 2025 Jan 9;25(1):11. doi: 10.1186/s12890-024-03433-8.

ABSTRACT

BACKGROUND: This study aims to compare Lung Ultrasound (LUS) findings with High-Resolution Computerized Tomography (HRCT) and Pulmonary Function Tests (PFTs) to detect the severity of lung involvement in patients with Usual Interstitial Pneumonia (UIP) and Non-Specific Interstitial Pneumonia (NSIP).

METHODS: A cross-sectional study was conducted on 35 UIP and 30 NSIP patients at a referral hospital. All patients underwent LUS, HRCT, and PFT. LUS findings such as B-lines, pleural fragmentation, and pleural thickening were compared with HRCT-based lung involvement and PFT parameters.

RESULTS: In UIP patients, B-lines > 18 and pleural fragmentation significantly differentiated between < 50% and > 50% HRCT involvement. A logistic regression model showed that B-lines > 18 (OR = 39, p = 0.04) and pleural fragmentation (OR = 22, p = 0.037) independently predicted > 50% HRCT involvement. ROC analysis of the model revealed 84.2% sensitivity and 84.5% specificity. Furthermore, the crude number of B-lines (OR = 1.2, p = 0.038) and > 50% HRCT involvement (OR = 9.5, p = 0.045) independently predicted severe DLCO impairment, with a sensitivity of 94.7% and specificity of 84.5%. Linear regression showed that each additional B-line was associated with a 0.4% decrease in DLCO (Beta = -0.377, p = 0.043), independent of patient diagnosis. In NSIP patients, no significant correlation was observed between LUS findings and > 50% HRCT involvement (p > 0.05), though B-line numbers and pleural thickening increased in cases with severe DLCO impairment (p < 0.05).

CONCLUSIONS: LUS shows promise as a sensitive, radiation-free alternative to HRCT in monitoring the severity of UIP. It is particularly valuable in predicting the extent of lung involvement and severe DLCO impairment in UIP patients but has limited application in NSIP.

PMID:39789530 | DOI:10.1186/s12890-024-03433-8

Lung. 2025 Jan 9;203(1):25. doi: 10.1007/s00408-024-00778-z.

ABSTRACT

PURPOSE: In the INBUILD trial in patients with progressive pulmonary fibrosis (PPF), nintedanib slowed the decline in forced vital capacity (FVC) versus placebo, with a safety profile characterised mainly by gastrointestinal events. INBUILD-ON, the open-label extension of INBUILD, assessed the safety of nintedanib during longer-term treatment. Data on FVC were collected.

STUDY DESIGN AND METHODS: Adverse events and changes in FVC in INBUILD-ON were assessed descriptively in all patients and in two subgroups: patients who received nintedanib in INBUILD and continued nintedanib in INBUILD-ON ("continued nintedanib" group) (n = 212) and patients who received placebo in INBUILD and initiated nintedanib in INBUILD-ON ("initiated nintedanib" group) (n = 222). Changes in FVC were based on observed values.

RESULTS: Median exposure to nintedanib in INBUILD-ON was 22.0 months. Diarrhoea was the most frequent adverse event. Amongst patients who had diarrhoea, 90.0% experienced only events of mild or moderate severity. Adverse events led to discontinuation of nintedanib at a rate of 16.7 per 100 patient-years. Serious and fatal adverse events were reported at rates of 37.2 and 9.5 per 100 patient-years. Mean (SE) changes in FVC from baseline to week 48 were - 71.6 (16.1) mL [- 128.5 (25.5) mL in continued nintedanib group (n = 106), - 14.8 (18.2) mL in initiated nintedanib group (n = 106)].

CONCLUSION: The safety profile of nintedanib in INBUILD-ON was consistent with that in INBUILD. Change in FVC in INBUILD-ON was consistent with decline in FVC in the nintedanib group of INBUILD. These results support the use of nintedanib in the long-term treatment of PPF.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov; NCT03820726; registered January 29, 2019.

PMID:39789408 | DOI:10.1007/s00408-024-00778-z

Sci Rep. 2025 Jan 9;15(1):1479. doi: 10.1038/s41598-025-85135-7.

ABSTRACT

Automated tools for quantification of idiopathic pulmonary fibrosis (IPF) can aid in ensuring reproducibility, however their complexity and costs can differ substantially. In this retrospective study, two automated tools were compared in 45 patients with biopsy proven (12/45) and imaging-based (33/45) IPF diagnosis (mean age 74 ± 9 years, 37 male) for quantification of pulmonary fibrosis in CT. First, a tool that identifies multiple characteristic lung texture features was applied to measure multi-texture fibrotic lung (MTFL) by combining the amount of ground glass, reticulation, and honeycombing. Opacity-based fibrotic lung (OFL) was measured by a second tool that performs a simpler binary classification of tissue into either normal or opacified lung and was originally developed for quantifying pneumonia. Differences in quantification of MTFL and OFL were assessed by Mann-Whitney U-test and Pearson correlation (r). Also, correlation with spirometry parameters (percent predicted total lung capacity (TLC), percent predicted vital capacity (VC), percent predicted forced expiratory volume in 1 s (FEV1), diffusing capacity of the lungs for carbon monoxide (DLCO), partial pressure of oxygen (PO2) and carbon dioxide (PCO2)) were assessed by r. The prognostic values for 3-year patient survival of OFL, LSS and MTFL were investigated by multivariable Cox-proportional-hazards (CPH) models including sex, age and TLC and including sex, age and VC. Also, Kaplan-Meier analysis with log rank test between subgroups separated by median OFL and MTFL were conducted. No significant difference between OFL and MTFL was observed (median and interquartile range: OFL = 29% [20-38%], MTFL = 31% [19-45%]; P = 0.44). For OFL significant correlation was observed to MTFL (r = 0.93, P < 0.01) and VC (r=-0.50, P = 0.03). For MTFL no significant correlation to spirometry parameters was found. The total time for one analysis was lower for the automated MTFL (MTFL: 313 ± 25s vs. OFL: 612 ± 61s, P < 0.001). Both analyses were significant predictors in the multivariable CPH analysis including TLC (hazard-ratios: MTFL 1.03 [1.01-1.06], P = 0.02; OFL 1.03 [1.00-1.06], P = 0.03). No parameter was a significant predictor in the CPH models including VC (hazard-ratios: MTFL 1.01 [0.98-1.04], P = 1; OFL 1.01 [0.97-1.05], P = 1). OFL showed significance in Kaplan-Meier analysis (MTFL: P = 0.17; OFL: P = 0.03). Using a simple opacity-based quantification of pulmonary fibrosis in IPF patients displayed similar results and prognostic value compared to a more complex multi-texture based analysis.

PMID:39789082 | DOI:10.1038/s41598-025-85135-7

Eur Respir J. 2025 Jan 9:2400615. doi: 10.1183/13993003.00615-2024. Online ahead of print.

ABSTRACT

RATIONALE: Although a relationship between the Gas6/AXL pathway and pulmonary fibrosis (PF) has been suggested, the precise mechanisms and clinical implications of the AXL pathway in idiopathic pulmonary fibrosis (IPF) are still unclear.

METHODS: Constitutive and conditional AXL-knockout mice were generated and injected with bleomycin (BLM) to induce pulmonary fibrosis. The expression of AXL and macrophage subtypes in BLM-injected mice and patients with IPF was analysed using flow cytometry. The therapeutic effects of the AXL inhibitors were examined.

RESULTS: AXL-deficient mice were resistant to BLM-induced pulmonary fibrosis and had a lower degree of M2-like macrophage differentiation than wild-type mice. Interestingly, AXL expression in monocytes was enhanced according to the progression of BLM-induced pulmonary fibrosis (PF), and these results were especially prominent in Ly6Chigh monocytes. Gene silencing or inhibitor treatment with AXL inhibited the differentiation of M2-like macrophages during bone marrow-derived macrophage (BMDMs) differentiation. These results were confirmed through experiments using AXLfl/flLysMCre+ mice and systems with depletion and reconstitution of macrophages. In line with these results, patients with severe IPF had higher AXL expression in monocytes, high GAS6 levels, and an enhanced population of M2-like macrophages than those with mild IPF. Lastly, treatment with AXL inhibitors ameliorated BLM-induced PF and improved survival rate.

CONCLUSIONS: The AXL pathway in classical monocytes contributed to PF progression through the induction of M2-like macrophage differentiation. Therefore, targeting AXL may be a promising therapeutic option for PF.

PMID:39788632 | DOI:10.1183/13993003.00615-2024