The incidence of idiopathic pulmonary fibrosis (IPF) is rising globally. Existing meta-analyses and Mendelian randomization (MR) studies have yielded inconsistent findings with uncertain evidence quality.

This study aimed to synthesize available evidence and assess its credibility for potential risk factors of IPF.

We systematically searched 8 databases and selected meta-analyses and MR studies related to IPF risk factors from inception to March 11, 2025. We assessed the quality of meta-analyses using the AMSTAR-2 tool and evaluated MR studies using the STROBE-MR guidelines. We categorized the evidence into four levels and performed pooled analysis for risk factors reported in at least two MR studies.

A total of 8 meta-analyses were included, reporting 22 associations, mainly involving genetics, infections, occupational and environmental exposures, lifestyle, and clinical variables. According to the grading of evidence credibility, 12 were rated as suggestive associations, and 10 as weak associations. The overall credibility of the evidence is relatively low. The 36 MR studies investigated a total of 124 associations, with evidence grading showed 13 as robust, 90 as possible, 17 as suggestive, and 4 as insufficient. The pooled analysis identified 108 associations covering lifestyle, diet and nutrition, anthropometric indices, biomarkers, and clinical variables. The quality level of the included meta-analyses was low and critically low, while the MR studies strictly adhered to STROBE-MR, demonstrating good reporting quality.

This umbrella review uncovers the evidence regarding the associations between IPF risk and factors such as genetics, viral infections, occupational and environmental exposures, lifestyle, and clinical variables through a comprehensive analysis of meta-analyses and MR studies. These findings provide an evidence base for IPF risk factor research and support clinical decisions and public health strategies.

CRD42024575341.

Although the COVID pandemic has gradually subsided, many patients have experienced complicated long-term symptoms, collectively known as "long-COVID", which is commonly associated with persistent discomfort and decrease in quality of life. Individuals with immune-mediated inflammatory diseases, such as inflammatory bowel disease (IBD), are particularly vulnerable in the context of COVID infection, while the influence from "long-COVID" remains unrevealed. This cross-sectional study aims to assess health-related quality of life (HRQoL) among IBD patients with long COVID and to identify factors associated with HRQoL impairment.

A cross-sectional survey was conducted from September 16 to October 10, 2023, among 235 IBD patients who had been treated at Nanjing BenQ Medical Center and Nanjing Jinling Hospital. The survey collected demographic data, COVID-19-related information, and HRQoL assessments using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ). Statistical analyses, including Chi-square tests, non-parametric tests, and multivariate linear regression, were employed to identify factors associated with long COVID and HRQoL.

Among 235 participants, 221 (94.04%) reported COVID-19 infection and 15 of 221 (6.79%) met the study definition of long COVID. Vaccination status differed by long-COVID status in an exploratory unadjusted comparison (p = 0.033); this finding was based on only 15 cases and was not adjusted for confounding. Participants with long COVID had a lower median SIBDQ score than those without long COVID (43.00 vs. 53.00; p = 0.009). In the multivariable model, any post-COVID-19 symptoms and symptom duration were entered as nested indicators. A duration of ≥ 4 weeks was associated with an additional 8.52-point lower SIBDQ score beyond the association of any post-COVID-19 symptoms (B=-8.52; 95% CI, -13.85 to -3.18; p = 0.002).

Participants meeting the study definition of long COVID reported lower HRQoL than those without long COVID. However, because validated IBD activity measures were not collected, the observed difference cannot be separated from the possible effect of underlying IBD activity. The vaccination finding is exploratory. Larger prospective studies with standardized disease-activity assessment are required to confirm these associations.

Post-COVID-19 symptoms are common following COVID-19, but risk factors of persistent symptoms in patients with asthma and chronic obstructive lung disease (COPD) remain unclear. We aimed to assess the frequency and risk factors of post-COVID-19 symptoms in patients with asthma and COPD. In this cross-sectional study, we used data from the Swedish PRAXIS study collected in 2022. The cohort included randomly selected adult patients with a diagnosis of asthma or COPD in medical records from central Sweden's primary and secondary care. Participants completed a comprehensive questionnaire, and their responses were analysed. We used logistic regression and adjusted for age and lung disease diagnoses. Among 494 patients with confirmed COVID-19, 59% (289/494) reported post-COVID-19 symptoms. Risk factors for post-COVID-19 symptoms included severe acute infection (adjusted odds ratio aOR: 8.91, 95% confidence interval [CI]: 3.49-22.8), higher age (aOR:1.25, 95% CI: 1.09-1.45), female sex (aOR: 1.52, 95% CI: 1.04-2.21), and obesity [BMI ≥ 30] (aOR: 2.24, 95% CI: 1.44-3.47)). Anxiety/depression (aOR:1.79, 95% CI: 1.13-2.80) and chronic pain (aOR: 3.61, 95% CI: 1.95-6.69) were also significant risk factors. Patients with asthma or COPD had a high prevalence of post-COVID-19 symptoms compared to other studies. Several demographic and clinical factors were associated with post-COVID-19 symptoms, which could help identify patients at increased risk.

Postacute sequelae of COVID-19 or "PASC" is a common but heterogeneous condition associated with significant morbidity. Although its pathogenesis remains poorly understood, proposed underlying mechanisms include altered host immune and inflammatory responses and altered coagulation. We measured 57 circulating plasma biomarkers mapping eight biological pathways (axonal injury, inflammation, antiviral immune responses, immune regulation/innate immune activation, tissue damage and repair, endothelial dysfunction, coagulation, and microbial translocation) in a cohort of 356 participants attending with PASC. Using principal component analysis (PCA) and unsupervised clustering, we identified six distinct inflammatory clusters within this PASC cohort, three of which were characterized by elevated biomarkers related to tissue damage and repair, coagulation, axonal injury, and antiviral immune responses. These three "highly inflamed" clusters were associated with reported cardiovascular and respiratory symptoms in fully adjusted analysis. These data suggest a link between distinct host immune responses and different clinical PASC phenotypes.

The human genome encodes thousands of long non-coding RNAs (lncRNAs) that regulate innate immunity and viral life cycles, yet their roles in viral entry remain understudied. Here, we conducted a genome-wide CRISPR interference screen to identify lncRNAs that regulate SARS-CoV-2 entry. We identified two lncRNAs that modulate angiotensin-converting enzyme 2 (ACE2) dependent viral entry through distinct mechanisms. Our findings suggest that the RP11-314A20.5 locus acts as a cis-regulatory element that modulates the expression of neighboring genes, including MED11 and CXCL16, linking this genomic region to host pathways associated with SARS-CoV-2 entry and COVID-19 severity. In contrast, CNPY2-AS1 functions in trans as a central regulator coupling cellular redox homeostasis to innate immune signaling. Mechanistically, CNPY2-AS1 associates with thioredoxin reductase 1 (TXNRD1), a key enzyme that limits reactive oxygen species. Loss of CNPY2-AS1 disrupts redox balance, triggering ligand-independent STAT1 activation and IRF7-mediated interferon and inflammatory responses. This dysregulated program has dual effects: induction of the interferon-stimulated gene PLSCR1 restricts viral entry by reducing cell-surface ACE2, while concurrent cytokine activation recapitulates features of pathological inflammation in severe COVID-19. Consistently, clinical datasets show reduced CNPY2-AS1 expression in patients with fatal disease. Together, these findings reveal distinct lncRNA-mediated mechanisms regulating SARS-CoV-2 entry and identify CNPY2-AS1 as a critical integrator of redox metabolism and innate antiviral immunity.

Pregnancy requires coordinated immune adaptation to maintain fetal tolerance while preserving antiviral defense. However, the temporal dynamics of maternal cellular immunity and maternal-fetal antibody transfer after SARS-CoV-2 infection during pregnancy remain incompletely defined.

We enrolled 52 pregnant women with laboratory-confirmed SARS-CoV-2 infection and stratified them by infection-to-delivery interval: <90 days, 90-120 days, and >120 days. Maternal peripheral blood mononuclear cells were analyzed by multiparametric flow cytometry. Basal and Omicron BA.5.2 antigen-induced IFN-γ production by CD3⁺, CD4⁺, and CD8⁺ T cells were assessed, and SARS-CoV-2-specific S1/RBD IgM and IgG levels were measured in paired maternal and cord blood by ELISA.

Baseline characteristics and major perinatal outcomes were broadly comparable among groups. Maternal T cells retained antigen-inducible IFN-γ responses, with the strongest responses observed in the 90-120-day group. Immune phenotyping revealed interval-associated remodeling of adaptive T-cell subsets, γδ T-cell receptor phenotypes, NK-cell subsets, and selected B-cell compartments. Cord blood IgM remained consistently low, providing no immunological evidence of intrauterine SARS-CoV-2 infection. In contrast, maternal and cord blood IgG levels were positively correlated, indicating preserved transplacental IgG transfer without clear time-dependent changes in transfer efficiency.

These results extend current understanding of post-infection immune adaptation during pregnancy and provide an immunological basis for future longitudinal studies aimed at defining the timing and durability of maternal and neonatal immune protection.

Available seasonal influenza vaccines, most of which are still produced in eggs, have several limitations. Messenger RNA (mRNA) technology has emerged as a transformative approach capable of overcoming some of these shortcomings. This overview synthesizes clinical trials evaluating the immunogenicity, efficacy, and safety of standalone and combination mRNA influenza vaccines. Moderna's mRNA-1010 (now approved in the United States) and Pfizer's modified-nucleoside RNA candidate (modRNA) represent the most advanced standalone platforms, while Moderna's combination influenza and COVID-19 vaccine, mRNA-1083, was recently granted European authorization. Following iterative platform optimization, these vaccines induce robust humoral and cell-mediated responses, especially against influenza A strains, characterized by extended germinal center reactions, continuous somatic hypermutation, enhanced Fc-mediated effector functions, and strong T helper 1 engagement. In phase III relative efficacy trials, an optimized mRNA-1010 formulation achieved superiority over standard-dose vaccines with a relative efficacy of 26.6% (95% CI: 16.7%, 35.4%) in adults aged ≥50 years. Pfizer's first-generation quadrivalent modRNA candidate showed 34.5% (95% CI: 7.4%, 53.9%) relative efficacy against a standard-dose comparator in younger adults aged 18-64 years, but failed to demonstrate non-inferiority in older adults (≥65 years), showing a relative efficacy of -5.8% (95% CI: -47.2%, 23.8%). However, whether mRNA platforms offer incremental benefits over enhanced formulations (such as high-dose, adjuvanted, or recombinant vaccines), which are the preferred options in some countries for older adults, remains to be established. The safety profile aligns with licensed COVID-19 mRNA vaccines; although reactogenicity is higher than with conventional vaccines, adverse reactions are predominantly mild-to-moderate and transient. Operationally, transitioning to single-dose pre-filled syringes alongside expanding refrigerated stability data significantly mitigates historical cold-chain bottlenecks. However, while standalone and combination mRNA platforms represent a major technological advance, real-world implementation challenges may affect their broader global health impact.

The N-terminal domain (NTD) of the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Spike harbors a neutralizing antibody supersite and is a recurrent site of antigenic change. However, how sequence variability across pre- and post-vaccination immune landscapes reshapes antibody recognition remains incompletely characterized.

Clinical-genomic surveillance was combined with structural modeling and molecular dynamics to identify antigenically relevant NTD changes and probe their structural impact on the neutralizing antibody interface. SARS-CoV-2 profiles were compared across two periods reflecting contrasting immune contexts: a pre-vaccination period dominated by B.1.1.33 and a post-vaccination period dominated by the Omicron sublineage BQ.1.1. A local cohort (n=126) supported descriptive characterization. An expanded cohort integrating local and GISAID genomes with harmonized clinical metadata (n=534; 401 pre-vaccination, 133 post-vaccination) was used to prioritize candidate loci by their association with clinical severity.

In adjusted models, age remained independently associated with severity in both periods, whereas sex did not. In the pre-vaccination cohort, Spike S in the NTD was associated with greater severity, without phylogenetic segregation by outcome. This association is exploratory and was used to prioritize an antigenically located NTD change for structural analysis. Q23K was regionally concentrated in Espírito Santo (57.4%) relative to other Brazilian states (2.7%) and international genomes (1.4%). In the post-vaccination cohort, an overlapping deletion event (ORF9b -29/N -33) was associated with non-severe disease, but should be interpreted cautiously given metadata heterogeneity, cohort structure, and the nature of the locus. However, in this period clinical outcome and sequencing source were partially confounded. A source-stratified sensitivity analysis restricted to GISAID-only samples showed the association persisted, but could not rule out a source- or pipeline-dependent indel-calling artifact, so the finding is reported as exploratory. Although Q23K itself did not persist, adjacent NTD changes (T19I/A27S/D24 -26) became recurrent post-vaccination, indicating remodeling of the same antigenic neighborhood rather than persistence of a single mutation. Structural modeling and molecular dynamics of the NTD-antibody 1 -87 complex supported reorganization of the modeled antibody-antigen interface, with redistribution of supersite contacts rather than loss of structural compatibility.

These findings link NTD variability across immune contexts to structural reorganization of the modeled antibody-antigen interface and support integrating genomic surveillance with structural analysis to prioritize antigenically relevant changes for functional testing.

Bispecific antibodies targeting two inflammatory pathways are entering respiratory medicine at an unprecedented pace. TSLP/IL-13 bispecifics have progressed into mid-to-late-stage clinical development, with two distinct molecules (lunsekimig and CM512) in Phase II/III and Phase II trials, respectively. Preclinical and early clinical signals indicate that alarmin blockade may extend beyond classical type 2 immunity, offering therapeutic potential in mixed and non-type 2 inflammatory phenotypes. Yet this molecular acceleration risks outpacing our capacity to deploy these agents rationally. No biomarker-guided framework currently exists to determine which patients require dual-pathway versus single-pathway blockade, or which target pair best matches a given patient's inflammatory endotype. The central clinical tension is whether the incremental benefit of dual-pathway neutralization justifies any increase in immunosuppressive risk. In this Perspective, we argue that the bispecific antibody race may deliver more molecules than necessary unless the field simultaneously builds biomarker-guided matching frameworks. Limited clinical support, drawn mainly from single-target agents such as tezepelumab (efficacy across eosinophil strata) and itepekimab (benefit in former smokers with COPD independent of eosinophils), together with biological rationale, suggests that alarmin blockade may hold promise in mixed and non-type 2 phenotypes; dedicated dual-alarmin trials in these populations remain needed.

Chronic obstructive pulmonary disease (COPD) and atherosclerosis frequently coexist, but their shared immune mechanisms remain incompletely understood.

We integrated single-cell RNA-sequencing datasets from COPD lungs and atherosclerotic lesions to characterize immune-cell composition, intercellular communication, and overlapping upregulated genes. Cell-type-specific sc-eQTL data from oneK1K were further combined with FinnGen GWAS summary statistics for COPD and coronary atherosclerosis using Mendelian randomization.

Both diseases showed a macrophage/monocyte-centered immune architecture, with macrophages serving as major communication hubs. Among overlapping genes evaluated genetically, HSPA1B showed consistent associations across both diseases. Genetically predicted HSPA1B expression in classical monocytes was positively associated with COPD and coronary atherosclerosis, whereas expression in non-classical monocytes showed inverse associations. NK cell-specific HSPA1B expression was also positively associated with COPD.

COPD and atherosclerosis share myeloid-centered immune features, and HSPA1B may represent a cell-state-dependent immune signal linking pulmonary and vascular inflammation.