Background Acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is a lethal condition with mortality exceeding 50% at 3 months, driven by hyperinflammation. Elevated interleukin-6 (IL-6) is associated with poor outcomes. Tocilizumab (TCZ), an IL-6 receptor antagonist, may modulate this harmful inflammation. Objectives To evaluate the efficacy and safety of tocilizumab combined with corticosteroids in AE-IPF. Design Retrospective, propensity score-matched, case-control study. Methods Thirty-nine AE-IPF patients from a registry (NCT03666234) were included. Thirteen received tocilizumab (8 mg/kg) plus methylprednisolone, matched 1:2 to 26 receiving conventional therapy. The primary outcome was 3-month all-cause mortality or lung transplantation. Secondary outcomes included changes in ground-glass opacity (GGO) scores and inflammatory biomarkers. Results Baseline characteristics were balanced. A GGO score ≥18 predicted higher mortality (HR 5.01, 95% CI 1.47–17.14; p=0.01). In univariable analysis, TCZ was associated with a lower but non-significant risk of the 90-day composite endpoint compared with conventional therapy (unadjusted HR 0.39, 95% CI 0.13–1.18; p=0.095). In an exploratory multivariable Cox model adjusting for baseline GGO score and inflammatory markers, TCZ was associated with a significant risk reduction (adjusted HR 0.20, 95% CI 0.05–0.72; p=0.014). In exploratory subgroup analyses, TCZ was associated with marked risk reductions in high-risk subgroups: GGO score ≥18 (HR 0.07, 95% CI 0.01–0.36; p=0.002), moderate oxygenation impairment (HR 0.12, 95% CI 0.02–1.00; p=0.05), and elevated inflammatory markers (HR 0.26, 95% CI 0.08–0.82; p=0.021). Tocilizumab also reduced GGO scores (p=0.009). Severe infections occurred in 23.1% (3/13) of the tocilizumab group between post-treatment days 12 and 30. Conclusion In this small, propensity-matched cohort, while the primary unadjusted analysis did not reach statistical significance, multivariable adjustment revealed a significant survival benefit signal associated with TCZ, particularly in patients with extensive ground-glass opacities or hyperinflammation. These findings suggest that TCZ may offer clinical advantages for specific high-risk AE-IPF subgroups, warranting validation in larger prospective trials.

Pulmonary intravascular large B-cell lymphoma (PIVLBCL) is an extremely rare subtype of extranodal diffuse large B-cell lymphoma (DLBCL). This hematologic malignancy exhibits nonspecific radiological features, including ground glass opacities (GGOs), often leading to misdiagnosis as interstitial lung disease (ILD). We present a 51-year-old female hairdresser with progressive dyspnea and 20 years of occupational hair dye exposure. Initially, she was misdiagnosed with chronic bronchitis due to a persistent dry cough. Then her initial chest CT demonstrated diffuse bilateral GGOs with isolated diffusion capacity of the lungs for carbon monoxide (DLCO) reduction (46.1% predicted) and normal spirometry, which led to a second misdiagnosis as hypersensitivity pneumonitis (HP). Despite initial improvement with corticosteroids, respiratory deterioration occurred during tapering. Finally, transbronchial lung cryobiopsy (TBCB) confirmed PIVLBCL, showing intravascular lymphoid proliferation (CD20+/BCL-6+/Ki-67≈80%). The R-CHOP chemotherapy treatment led to a complete remission for her, and the DLCO improved to 68% of the predicted value at the 6-month follow-up. A literature review of 75 PIVLBCL patients revealed that fever (74.7%) and dyspnea (65.3%) were the predominant presentations. GGOs were observed in 54.7% of cases, with frequent misdiagnosis as ILD (31.8%) or pneumonia (31.8%). TBCB provided definitive diagnostic evidence, demonstrating its clinical utility in resolving ambiguous pulmonary opacities. Clinicians should maintain high suspicion for PIVLBCL when encountering diffuse GGOs with isolated DLCO reduction, even without classic risk factors.

BACKGROUND AND OBJECTIVE:The treatment of anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD) remains a significant clinical challenge. To compare the effectiveness and safety of upadacitinib (UPA) versus tofacitinib (TOFA) upon 6-month lung transplantation-free survival in newly diagnosed MDA5+DM-ILD patients. METHODS:This multi-centre cohort study in China enrolled MDA5+DM-ILD patients treated from January 2020 to February 2025. Prevalent/incident new users and non-inferior design along with inverse probability treatment weighting (IPTW) were implemented to emulate randomized controlled trial. RESULTS:In the eligible cohort, a total of 106 patients were treated with UPA and 328 with TOFA. The crude 6-month lung transplantation-free survival rates were 71.7% (76/106) in the UPA group and 67.4% (221/328) in the TOFA group. In the IPTW-adjusted cohort, UPA showed a trend toward higher survival than TOFA (p = 0.067), with a weighted risk difference of 10.3% (95% confidence interval -0.4% to 20.2%) meeting the non-inferiority margin (non-inferiority p = 0.003). Sensitivity and subgroup analyses showed consistent results, with potentially greater benefit of UPA in incident JAK inhibitor users (as first-line treatment), monotherapy recipients (without combination with other immunosuppressants except steroid), and those with rapidly progressive ILD. Safety profiles were comparable between groups. CONCLUSION:UPA was found to be non-inferior to TOFA in improving 6-month lung transplantation-free survival among patients with MDA5+DM-ILD, with comparable safety.

This prospective study aimed to compare the prognostic value of [18F]FAPI-42 (fibroblast activation protein inhibitor) and [18F]FDG PET/CT in patients with idiopathic pulmonary fibrosis (IPF). Fifty-two patients with IPF underwent dual-tracer PET/CT. Whole-lung total uptake (wlTU) was quantified for [18F]FAPI-42 and [18F]FDG. PET parameters were correlated with percent predicted forced vital capacity (FVC

Idiopathic pulmonary fibrosis (IPF) is a serious and progressive lung disease characterized by devastating and progressive fibrosis. Treatment is unsatisfactory. There is accumulating evidence that transplantation of mesenchymal stem cell derived exosomes (MSC-EXOs) protects against IPF. This study aimed to investigate the protective effects of EXOs isolated from human induced pluripotent stem cell-derived MSCs (iPSC-MSC-EXOs) on pulmonary fibrosis and explore the underlying mechanisms. Exosomes were isolated from bone marrow-MSCs (BM-MSCs) and iPSC-MSCs and subsequently identified. A mouse model of pulmonary fibrosis was established by tracheal injection of bleomycin (BLM) followed by transplantation of BM-MSC-EXOs or iPSC-MSC-EXOs via tail vein injection. Pulmonary function and fibrosis were assessed by pulmonary function tests (PFT) and Masson trichrome staining, respectively. Mice lung fibroblasts (LFs) were treated with BM-MSC-EXOs or iPSC-MSC-EXOs in the presence of TGF-β1 in vitro. Compared with BM-MSC-EXOs, iPSC-MSC-EXO treatment significantly enhanced pulmonary function and decreased the fibrosis and lactate level in a mouse model of BLM-induced pulmonary fibrosis. In vitro, iPSC-MSC-EXOs exerted a superior protective efficacy against TGF-β1-induced LF activation via downregulation of the lactate level. Further analysis revealed a higher protein level of TRIM31 in iPSC-MSC-EXOs than BM-MSC-EXOs. Mechanistically, exosomal TRIM31 from iPSC-MSC-EXOs inhibited LF activation via downregulation of glycolysis by mediating ubiquitination of hexokinase 2 (HK2). Furthermore, knockdown of TRIM31 reduced the protective effects of iPSC-MSC-EXOs on pulmonary fibrosis in BLM-treated mice. Our study showed that TRIM31 delivered by iPSC-MSC-EXOs exerted anti-pulmonary fibrotic effects by alleviating LF activation via regulation of HK2 ubiquitination. This study provides a potential therapeutic strategy for patients with IPF.

Background Idiopathic pulmonary fibrosis (IPF) is a progressive disease with limited therapeutic options. Mesenchymal stromal cells (MSCs) have shown promise in preclinical models of lung fibrosis. Methods We conducted an open-label, multicenter, dose-escalation phase I trial (NCT06230822) to assess the safety and preliminary efficacy of intravenous human umbilical cord-derived MSCs (UC-MSCs; VUM02) in patients with IPF. Nine patients were enrolled in three dose cohorts (0.5, 1.0, and 2.0 × 10⁸ cells per infusion, three infusions every 3 days) following a “3 + 3” design. Results No dose-limiting toxicities occurred. Seventy-four adverse events were recorded, most grade 1–2; only 13 events in four patients were considered possibly or probably related to UC-MSCs. Six serious adverse events occurred in five patients, all deemed unrelated to the investigational product. In the high-dose cohort, forced vital capacity (FVC) showed a numerical increase of 57 mL (+ 2.36%) at week 24 compared with baseline. Carbon monoxide diffusion capacity (DLCO % predicted) increased by 7.39% in the low-dose cohort at week 24. Exploratory immunological and plasma proteomic analyses suggested immunomodulatory effects and identified ribosomal protein S23 (RPS23) as a candidate biomarker that consistently decreased after treatment. Conclusions Multiple intravenous infusions of UC-MSCs up to 2 × 10⁸ cells were well tolerated in patients with IPF. Preliminary efficacy signals, particularly the numerical FVC improvement in the high-dose group, warrant further investigation in larger controlled trials. Trial registration: ClinicalTrials.gov NCT06230822.

The burden of interstitial lung diseases (ILDs) in China is rising, yet large-scale, subtype-specific epidemiological data remain limited. We retrospectively analyzed 7,195 hospitalized patients at the First Affiliated Hospital of Guangzhou Medical University (January 2016—June 2024), including 6,824 ILD cases and 371 pneumonia controls. Clinical data included demographics, smoking, BMI, geographic region, and serum KL-6 levels. Among the 6,824 ILD patients, autoimmune-related ILD was the most prevalent subtype (34.33

Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that occurs primarily in the elderly. Although senescence of lung fibroblasts (LFs) contributes to IPF development, the potential mechanisms underlying LF senescence are not fully understood. This study aimed to delineate the role and underlying mechanisms of miR-205-5p in regulating LF senescence in patients with IPF. The LFs from IPF patients (IPF-LFs) and age-matched controls (Control-LFs) were isolated and cultured. Senescence of LFs was determined by senescence-associated β-galactosidase (SA-β-gal) staining. Mitochondrial morphology of LFs was evaluated by MitoTracker staining and transmission electron microscope. The expression of miR-205-5p was examined by RT-PCR. Compared with Control-LFs, IPF-LFs exhibited increased cellular senescence with higher expression of SA-β-gal, p21 and p16 as well as decreased proliferative capacity. Importantly, IPF-LFs had decreased mitochondrial fission, evidenced by elongated mitochondria and downregulation of mitochondrial fission regulator 1-like protein (MTFR1L). The expression of miR-205-5p was much higher in IPF-LFs than Control-LFs. Notably, upregulation of miR-205-5p in Control-LFs led to increased cellular senescence, whereas downregulation rescued IPF-LF senescence. Mechanistically, miR-205-5p downregulated mitochondrial fission in LFs via MTFR1L, leading to mitochondrial dysfunction and cellular senescence. Taken together, our study illustrated that miR-205-5p serves as a critical regulator of cellular senescence of LFs isolated from IPF patients via mediation of mitochondrial dynamics.

Pulmonary fibrosis (PF) is a life-threatening disease characterized by persistent fibroblast activation and excessive extracellular matrix deposition, leading to irreversible lung scarring and respiratory failure. Although epigenetic regulation has been increasingly implicated in PF, the contribution of RNA modifications, particularly N6-methyladenosine (m6A), remains poorly understood. In this study, we identify circPTK2, a fibroblast-specific circular RNA that is significantly upregulated in PF patients and experimental models. We demonstrate that its m6A-modified form (circPTK2-m+), but not the unmethylated isoform (circPTK2-m-) or its linear parental transcript, acts as a critical driver of fibroblast activation during PF progression. Silencing circPTK2-m+ or disrupting its m6A methylation effectively attenuates fibroblast activation and alleviates fibrosis in vitro and in vivo. Mechanistically, elevated m6A writer METTL3 and reader RBMX cooperatively promote the alternative splicing of methylated PTK2 pre-mRNA to generate circPTK2-m+, while another m6A reader EIF4A3 facilitates its nuclear export. In the cytoplasm, circPTK2-m+ functions as a competing endogenous RNA, sequestering miR-484 and miR-125a-3p to relieve repression of YAP1 and FYN, thereby synergistically enhancing STAT3 activation and promoting a profibrotic transcriptional program. Collectively, these findings reveal a previously unrecognized role of m6A modification in PF pathogenesis and establish circPTK2-m+ as a promising therapeutic target for PF intervention.

Objectives: Patients with interstitial lung disease (ILD) and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection are at high risk of severe coronavirus disease 2019. It is unclear whether anti-viral cellular and humoral immunity is impacted in patients with ILD in the presence of immune disorders and immunosuppressive therapy. This results in poor control of viral infections following SARS-CoV-2 infection. We aimed to highlight the clinical management of patients with ILD with regard to the adjustment of anti-inflammatory therapy during SARS-CoV-2 infection. Methods: We compared viral clearance, antibody levels, and T-cell immune response between healthy controls and patients with connective tissue disease-related ILD (CTD-ILD) or interstitial pneumonia with autoimmune features (IPAF). Results: Patients with ILD exhibited a higher viral load than the control group (1.58 × 106 vs. 2.37 × 103 copies/mL, p = 0.018), as well as a significantly lower level of neutralizing antibodies against the wild-type (WT) virus (7.01 vs. 625.6, p < 0.0001) and Omicron BA.5 (7.19 vs. 128.4, p < 0.001). Similarly, a lower virus-specific T-cell (VST) immune response was observed 14 days post-symptom onset in the ILD group (CD4+ VSTs: 0.018 vs. 0.082, p = 0.005; CD8+ VSTs: 0.0008 vs. 0.047, p = 0.004). The ILD group had no other heightened inflammatory biomarkers compared with the control group. Conclusions: Our study provides novel evidence of the underlying interaction between virus clearance and host immune status and sheds light on the clinical management of patients with ILD with regard to the adjustment of anti-inflammatory therapy during SARS-CoV-2 infection.

BACKGROUND:Exosome liquid biopsies might be a good supplement for early diagnosis of interstitial lung disease (ILD), especially those challenging cases such as connective tissue disease-ILD (CTD-ILD). METHODS:We developed a circulating exosomal proteomic signature to identify novel biomarkers of ILDs combined with high-resolution CT (HRCT) examination and a new method that makes exosome testing clinically feasible. Blood-derived exosomes were extracted and characterized using a centrifugal microfluidic disc system (Exo-CMDS)-based chemiluminescence immunoassay before being subjected to proteomic analysis by mass spectrometry. Significantly differentially expressed proteins (DEPs) were identified and validated in > 600 clinical samples (collected at three hospitals) by comparing the ILD and disease/healthy control groups. Multivariable logistic regression (LR) analysis was implemented to test the diagnostic performance of the selected biomarkers either alone or in combination. RESULTS:Candidate biomarkers KL-6, CAPN2, SP-B were selected from the top DEPs. An LR model that combined exosomal KL-6/CAPN2/SP-B levels performed well in both the discovery (AUC = 0.987, 95%CI = 0.975-0.998) and validation (AUC = 0.936, 95%CI = 0.911-0.960) sets. The LR model based on the three biomarkers exhibited markedly better diagnostic performance (AUC = 0.880, 95%CI = 0.834-0.925) in serum-KL-6-negative ILD, than the conventional serum-KL-6-based method and could also accurately diagnose connective tissue disease associated-ILD (CTD-ILD) in the context of CTD. CONCLUSION:The circulating exosomal protein detection system used in this study represents a valuable tool for identifying promising exosomal biomarkers for ILD and holds promise for improving the diagnosis and prognosis of patients with ILD in the future.

Objective To compare the effectiveness and safety of tofacitinib (TOF) versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5+DM-ILD). Methods Adult Chinese patients with newly-diagnosed MDA5+DM-ILD (ILD course<3 months) from five tertiary referral centres between April 2014 and January 2023 were included for this retrospective cohort study. The primary effectiveness endpoint was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results : In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the TOF group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients’ lung transplantation-free survival rate within 1 year was significantly higher in the TOF group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed the hazard ratio of TOF versus CNI for 1-year survival was 0.72 (95% CI, 0.56 to 0.94, p=0.013). The adjusted difference of survival rate was 9.3% (95%CI 2.8% to 15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients less than 60 years old, without RPILD, or with baseline PaO 2 /FiO 2 ≥300 mmHg might benefit more from TOF. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion In this large multi-centre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5+DM-ILD.

Objective: To compare the effectiveness and safety of tofacitinib versus calcineurin inhibitor (CNI) as initial immunosuppressive regimen for anti-melanoma differentiation-associated gene 5-positive dermatomyositis with interstitial lung disease (MDA5(+)DM-ILD). Methods: Adult Chinese patients with newly diagnosed MDA5(+)DM-ILD (ILD course <3 months) from five tertiary referral centres between April 2014 and January 2023 were included in this retrospective cohort study. The primary effectiveness end-point was lung transplantation-free survival within 1 year. Propensity score-based inverse probability of treatment weighting (IPTW) was applied for adjustment in this real-world study. Results: In the eligible cohort, a total of 94 (32.4%) and 105 (46.7%) patients died or underwent lung transplantation within 1 year in the tofacitinib group (n=290) and the CNI group (n=225), respectively. After adjustment by IPTW, patients' lung transplantation-free survival rate within 1 year was significantly higher in the tofacitinib group compared to the CNI group (log-rank p=0.013). Multivariable Cox analysis performed in the IPTW dataset revealed that the hazard ratio of tofacitinib versus CNI for 1-year survival was 0.72 (95% CI 0.56-0.94; p=0.013). The adjusted difference of survival rate was 9.3% (95% CI 2.8-15.8%). Alternative analytic strategies yielded consistent results in sensitivity analyses. Patients aged <60 years, without rapidly progressive ILD, or with baseline arterial oxygen tension/inspiratory oxygen fraction >= 300 mmHg might benefit more from tofacitinib. Opportunistic infection was the major treatment-related serious adverse event, with generally comparable incidence (42.4% versus 45.3%). Conclusion: In this large multicentre cohort study, tofacitinib showed significantly more benefits for 1-year lung transplantation-free survival than calcineurin inhibitors in MDA5(+)DM-ILD.

Introduction:Tropheryma whipplei (TW) is a bacterium associated with Whipple's disease (WD). It primarily affects the small intestine, heart and eyes, but some studies have explored its relationship with parenchymal disease. With technological advances, next-generation technology has enabled detection of TW in bronchoalveolar lavage (BALF),especially in patients with interstitial lung disease (ILD). Case series:We describe three patients with ILD that was progressive, despite aggressive treatment. Next generation sequecning of BALF revealed the presence of TW, confirmed by polymerase chain reaction (PCR). Periodic acid-Schiff (PAS)-positive macrophages were identified in duodenal biopsy specimens from one patient. All three patients were prescribed doxycycline and hydroxychloroquine, as well as pharmacotherapy for ILD. During 3-6 months follow-up, TW was not detected in BALF and ILD was stable. Conclusion:We report TW detection in BALF of 3 ILD patients, indicating its potential role as a disease-modifying pathogen in ILD progression. These cases underscore the impact of lung microbiome disturbances on ILD pathophysiology and highlight therapeutic implications.

Purpose This study aimed to investigate the respiratory physiological changes resulting from short-term inspiratory resistance training (R-IMT) and inspiratory threshold training (T-IMT) in patients with chronic obstructive pulmonary disease (COPD) and to compare the mechanisms of the two training methods. Patients and methods A total of 75 stable patients with COPD combined with inspiratory muscle weakness were randomly allocated to three groups: R-IMT (n = 26), T-IMT (n = 24), and control (n = 25). Before and after 8 weeks of inspiratory muscle training(IMT), cardiopulmonary exercise tests were conducted to assess respiratory patterns, respiratory central drive, exercise tolerance, and ventilation efficiency. Results After 8 weeks of IMT, Inspiratory muscle strength, represented by MIP (maximum inspiratory mouth pressure) and exercise capacity increased during exercise in both IMT groups (P < 0.05). In the R-IMT group, inspiratory time (Ti) prolonged (P < 0.05), tidal volume (Vt) increased (P < 0.05), ventilation efficiency (represented by ventilation-center coupling) increased (P < 0.05) during exercise. Conversely, the T-IMT group did not exhibit any of these changes after IMT (P > 0.05). Conclusion In summary, the improvement in exercise tolerance was associated with an increase in inspiratory muscle reserve in both R-IMT and T-IMT. However, only R-IMT was associated with deeper and slower breathing, as well as improved ventilation efficiency.

Nodular panniculitis is a non-suppurative, autoimmune disease that originates in fat lobules, the etiology of which is not clear.It lacks typical clinical symptoms, and the imaging findings of lung involvement are variable and non-specific.Imaging presentations of nodular panniculitis are similar to those of hematogenous disseminated pulmonary tuberculosis and sarcoidosis, leading to the difficulties in differential diagnosis.Skin biopsy provides an opportunity for the definite diagnosis of nodular panniculitis.However, it is challenging to diagnose nodular panniculitis, especially the rare cases of nodular panniculitis with lung involvement.This paper reports the diagnosis and treatment of a patient with nodular panniculitis complicated with airway central pulmonary interstitial fibrosis, and reviews the relevant literatures, aiming to improve the understanding of the disease.

In recent clinical trials, fibrotic interstitial lung disease (ILD) that shares the similar physiopathologic mechanism and behavior with those of idiopathic pulmonary fibrosis (IPF) have been uniformly termed as progressive fibrosing ILD (PF-ILD). However, there is no consensus on the definition and diagnostic criteria of PF-ILD." Idiopathic Pulmonary Fibrosis (an Update) and Progressive Pulmonary Fibrosis in Adults: An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline (2022 Edition)" unifies the process of ILD with progressive exacerbation of fibrosis other than idiopathic pulmonary fibrosis, and newly termed as progressive pulmonary fibrosis (PPF). They also clarify the diagnostic criteria, and anti-fibrosis treatment of PPF.This article thoroughly interprets this guideline for PPF.