We define adherent, difficult-to-treat asthma as 'true severe asthma.' In preschool children, evidence for add-on long-acting beta-agonists (LABA) to inhaled corticosteroids (ICS) in those with persistent uncontrolled disease despite high-dose ICS remains limited. We evaluated clinical outcomes of ICS-LABA therapy in this population.

This retrospective observational study (2021-2024) included children aged 6-72 months with severe, uncontrolled asthma despite medium- to high-dose ICS and verified adherence, who were initiated on LABA therapy. Primary outcomes were severe exacerbations (systemic corticosteroid use, hospitalizations, and uncontrolled symptoms). Secondary outcomes included PICU admissions and spontaneously reported adverse events. Outcomes 6 months before and after LABA initiation were compared using generalized estimating equations (GEE), adjusting for seasonality, age, sex, and atopy.

Fifty-three children were included (mean age 38.8 ± 17.6 months, 41.5% male, atopy 49.1%). LABA initiation was associated with a substantial reduction in clinical burden: hospitalizations declined from 41.5% to 3.8% (p < 0.001), systemic corticosteroid use from 86.8% to 52.8% (p < 0.001), and daily symptoms from 86.8% to 37.7% (p < 0.001). PICU admissions decreased from 9.4% to 0%. These associations remained significant after adjustment for covariates (p < 0.001). No adverse events were spontaneously reported by patients or caregivers during the follow-up period; however, systematic adverse event surveillance was not conducted.

In adherent preschool children with true severe asthma, LABA initiation was associated with observed improvements in clinical outcomes. Still, prospective controlled studies with systematic safety surveillance are warranted.

Early-onset asthma (EOA) significantly increases the risk of chronic obstructive pulmonary disease (COPD), yet the causal mechanisms and molecular mediators underlying this progression remain poorly understood. Multi-omics integration provides a powerful framework for prioritizing potential mediating proteins and disease-specific therapeutic candidates.

This study integrated large-scale genetic and proteomic data using Mendelian randomization (MR) approaches to investigate the progression from EOA to COPD. Proteome-wide MR evaluated protein quantitative trait loci (pQTLs) in relation to EOA and COPD risk, with mediation analysis evaluating their roles and single-cell transcriptomics defining the cell-type-specific expression of the mediating proteins. Finally, colocalization, multi-tissue expression quantitative trait loci (eQTLs), and druggability assessment were used to prioritize potential disease-specific therapeutic targets.

Evidence from genetic instruments supports a causal relationship between EOA and COPD. Proteome-wide analyses of 7847 pQTLs identified 339 proteins with potential effects on EOA and 389 on COPD. Six proteins, KREMEN1, BLMH, CNTN5, IL1RN, MIA, and PILRA, showed statistically significant mediation effects in the EOA-to-COPD pathway. PILRA strongly colocalized at shared genetic loci between the two diseases and was significantly downregulated in macrophages from COPD patients. For disease-specific targets, immune-tissue eQTL validation supported ITPKA in EOA. Integration of druggability assessment with multi-tissue eQTL analyses prioritized FES, CCN3, NMI, and NMT1 as promising therapeutic candidates for COPD.

These findings provide genetic evidence supporting a causal relationship between EOA and COPD, reveal putative mediating proteins, and prioritize therapeutic candidates with translational potential, offering new insights into pathogenesis, prevention, and intervention.

Pleuroparenchymal fibroelastosis (PPFE) is a rare interstitial lung disease (ILD) associated with systemic autoimmune rheumatic diseases (SARDs). Its clinical characteristics and outcomes in SARDs remain poorly defined.

To describe demographics, imaging patterns, and outcomes in SARD-associated PPFE.

Patients diagnosed with PPFE and SARDs at Mayo Clinic (2000-2024) were included. PPFE diagnosis was confirmed by high-resolution computed tomography, and SARD diagnoses were established by rheumatologists.

Fifteen of 62 patients with PPFE had SARDs with majority having systemic sclerosis (SSc)(n= 7, 46%). Median age at PPFE diagnosis was 57.2 years; 80% were female; 40% were ever-smokers; 40% required supplemental oxygen; 5 had pulmonary hypertension. Coexisting ILD patterns included UIP (26.7%) and NSIP (20%). Coexisting ILD patterns included usual interstitial pneumonia (26.7%) and nonspecific interstitial pneumonia (20%). Three patients died, including two with SSc.

Systemic sclerosis was the most frequently observed SARD among patients with PPFE, and may coexist with other ILD patterns; recognition may inform risk stratification, multidisciplinary evaluation, and longitudinal follow-up.

Preterm infants, often gavage-fed due to immaturity, may benefit from interventions that hasten the move to breastfeeding. Olfactory stimulation may increase appetite and speed up the transition to full oral feeding, potentially shortening hospital stay and improving outcomes for both infants and families.

To evaluate the benefits and harms of olfactory stimulation for reducing morbidity and promoting development in hospitalized preterm infants.

We searched MEDLINE, Embase, CENTRAL, CINAHL, Epistemonikos, two trial registries, and conference abstracts up to 2 April 2025. We checked the reference lists of included studies and systematic reviews on olfactory or sensory stimulation.

We included randomized controlled trials (RCTs) and quasi-RCTs evaluating olfactory stimulation with different odorants (maternal breast milk, food-associated odors, or non-food-associated odors) in preterm infants (born before 37 weeks' gestation). Eligible controls were no intervention, placebo, or standard care (considered together) or another odorant. We excluded studies combining olfactory stimulation with taste, as another review will focus on combined sensory stimulation.

Our critical outcomes were apnea, intermittent hypoxemia, duration of hospital stay, time to full oral feeding, and exclusive breastfeeding. Our important outcomes included blindness and sensorineural deafness requiring amplification.

We used the Cochrane risk of bias tool (RoB 2) to assess risk of bias in the included studies.

We conducted meta-analyses using fixed-effect models to calculate risk ratios (RRs) for dichotomous data and mean differences (MDs) for continuous data, each with its 95% confidence interval (CI). We assessed the certainty of evidence using GRADE.

We included 14 trials enrolling 1087 neonates. The types of olfactory stimulation under investigation were maternal breast milk (9 studies); food-associated odors such as cinnamon, vanilla, or anise (5 studies); and non-food-associated odors such as rose or parents' scent (3 studies). Three studies evaluated two different odorants. Gestational age and bodyweight varied widely. The comparators were placebo, no intervention, and standard care. Eleven studies aimed to assess the effect of olfactory stimulation on infant feeding outcomes such as time to full oral feeding, weight gain, length of hospital stay, or a combination of these outcomes. Three studies aimed to assess the effect of olfactory stimulation on apnea prevention, oxygen saturation, or both. We identified five ongoing trials.

No studies reported apnea as a dichotomous outcome, intermittent hypoxemia, exclusive breastfeeding, or major neurodevelopmental disability for any of the comparisons. We downgraded the certainty of evidence for limitations in study design, imprecision, and indirectness. Olfactory stimulation with maternal breast milk versus no intervention, placebo, or standard care The evidence is very uncertain about the effect of olfactory stimulation with maternal breast milk on the mean number of daily apnea episodes (MD -0.50, 95% CI -1.27 to 0.27; 1 study, 26 participants; very low-certainty evidence) and duration of hospital stay in days (MD -0.18, 95% CI -0.64 to 0.27; I² = 0%; 4 studies, 270 participants; very low-certainty evidence). Olfactory stimulation with maternal breast milk may result in a slight reduction in time to full oral feeding in days (MD -1.68, 95% CI -3.25 to -0.11; I² = 30%; 3 studies, 204 participants; low-certainty evidence). Olfactory stimulation with food-associated odors versus no intervention, placebo, or standard care Olfactory stimulation with food-associated odors may result in a slight reduction in the mean number of daily apnea episodes (MD -1.99, 95% CI -2.69 to -1.29; I² = 58%; 2 studies, 62 participants; low-certainty evidence). The evidence is very uncertain about the effect of olfactory stimulation with food-associated odors on duration of hospital stay in days (MD -2.65, 95% CI -6.18 to 0.89; I² = 20%; 3 studies, 185 participants; very low-certainty evidence) and time to full oral feeding in days (MD -2.06, 95% CI -5.16 to 1.04; I² = 36%; 3 studies, 185 participants; very low-certainty evidence). Olfactory stimulation with non-food-associated odors versus no intervention, placebo, or standard care Olfactory stimulation with non-food-associated odors may result in a slight reduction in duration of hospital stay in days (MD -3.23, 95% CI -5.50 to -0.97; I² = 0%; 2 studies, 94 participants; low-certainty evidence). The evidence is very uncertain about the effect of olfactory stimulation with non-food-associated odor on the mean number of daily apnea episodes (MD -2.13, 95% CI -2.28 to -1.98; 1 study, 60 participants; very low-certainty evidence) and time to full oral feeding (mean 21 (standard deviation 3.1) days in the intervention group and mean 21 (standard deviation 15.6) days in the control group; 1 study, 27 participants; very low-certainty evidence).

Olfactory stimulation with maternal breast milk compared to no intervention, placebo, or standard care may result in a slight reduction in time to full oral feeding, but the evidence is very uncertain about its effect on frequency of apnea episodes and duration of hospital stay. Olfactory stimulation with food-associated odors compared to no intervention, placebo, or standard care may result in a slight reduction in frequency of apnea episodes, but the evidence is very uncertain about its effect on duration of hospital stay and time to full oral feeding. Olfactory stimulation with non-food-associated odors compared to no intervention, placebo, or standard care may result in a slight reduction in duration of hospital stay, but the evidence is very uncertain about its effect on frequency of apnea episodes and time to full oral feeding. Future studies should be more rigorous in their design, report using TIDieR (Template for Intervention Description and Replication) checklists, have larger sample sizes, and measure outcomes such as apnea (number of infants with ≥ 1 episode), intermittent hypoxemia (number of infants with ≥ 1 episode), exclusive breastfeeding, and major neurodevelopmental disabilities.

Dedicated funding for this review can be found in the 'Sources of support' section.

Protocol: https://doi.org/10.1002/14651858.CD016074.

This is a protocol for a Cochrane Review (intervention). The objectives are as follows: To evaluate the benefits and harms of singing for chronic respiratory diseases in adults compared to all studied comparison groups.

Systemic sclerosis (SSc) is a heterogeneous autoimmune disease in which interstitial lung disease (ILD) is a major determinant of mortality. Given that certain chemokines and adhesion molecules may be involved in the inflammation, subsequent vascular injury, and fibrosis observed in SSc, their circulating levels in peripheral blood may reflect the disease processes ranging from inflammation to vascular damage and fibrotic remodeling. However, the potential of these biomarkers to identify patient subgroups with divergent pulmonary trajectories remains to be elucidated.

We performed a retrospective analysis of prospectively collected data from patients with early severe SSc (diffuse cutaneous SSc irrespective of ILD status or limited cutaneous SSc with ILD; disease duration <5 years) who were enrolled in a multicenter cohort. Serum levels of five chemokines and four soluble adhesion molecules were quantified at baseline. Patients were classified based on these biomarker profiles using k-means clustering. Changes in pulmonary function were compared among clusters using relative changes in percent vital capacity (%VC).

Patients (n = 92) were classified into three clusters: Cluster 1 (n = 37) with elevated sICAM-1 and sE-selectin; Cluster 2 (n = 13) with elevated CCL2, CXCL8, and sP-selectin; and Cluster 3 (n = 42) with no distinctive biomarker pattern. Cluster 3 showed stable %VC and served as the reference group. Cluster 1 showed early decline (one-year difference: -8.41%; 95% CI: -12.62 to -4.20; p < 0.001) that attenuated by year two. In contrast, Cluster 2 showed progressive decline (two-year difference: -7.77%; 95% CI: -15.25 to -0.29; p = 0.042). These biomarker-defined patterns were consistent with a vasculopathic-fibrotic profile in Cluster 1 and an inflammatory-vascular profile in Cluster 2.

Serum chemokine and adhesion molecule profiles may help stratify early severe SSc into biologically distinct subgroups with different pulmonary trajectories, supporting their potential utility for early risk stratification in SSc-ILD.

The global impact of pulmonary tuberculosis (PTB) is compounded by a limited understanding of modifiable risk factors. While caffeine is the most consumed psychoactive substance, its causal relationship with PTB and the underlying immunological mechanisms remain unknown.

A three-tiered approach was used: 1) two-sample Mendelian randomization (TSMR) was used to analyze 486 metabolites and 731 immune cells for PTB causality (inverse variance weighting was the primary method with reverse MR and Bonferroni correction), 2) single-cell RNA sequencing (scRNA-seq) and bulk RNA-seq were integrated (Seurat, Gene set enrichment analysis, and pseudotime analysis) to characterize CD39⁺ Tregs traits in lungs with PTB using, 3) core genes (LASSO) regression and eQTL-based genetic analyses uniquely) were validated in THP-1 macrophages, C3HeB/FeJ mice, and patients with PTB via FCM, WB, RT-qPCR, and multiplex immunohistochemistry.

Based on TSMR, eight metabolites (including caffeine) and nine immune subsets (including activated CD4⁺ Tregs) were linked to PTB (P < 0.05). Caffeine increased the risk of PTB via CD39⁺CD4⁺ Tregs (mediated proportion = 10.4%, P = 0.046). ScRNA-seq analysis of PTB lungs revealed elevated CD4⁺ Tregs with high caffeine responsiveness and CD39/ADORA2A overexpression. Validation in models revealed that core genes (PSMC5, BAG1, and AGPAT5) exhibited differential expression with PTB (P < 0.05) and good diagnostic efficacy (AUC > 0.7).

We first identified a causal association between genetically predicted caffeine levels and PTB risk at the genetic level. We further uncovered a CD39-adenosine-based Treg activation mechanism underlying this association, and identified PSMC5 as a potential therapeutic target for host-directed therapy. These findings inform PTB pathogenesis and host-directed therapy.

Vitamin D and iron metabolism are increasingly recognized as potential modulators of airway inflammation, yet their interrelationship in pediatric asthma remains unclear. This study investigated the associations of serum vitamin D, ferritin, and eosinophilic inflammation with acute asthma exacerbations in children and explored their potential interaction.

This single-center retrospective study included 120 children with asthma, comprising 60 with acute exacerbation and 60 in clinical remission. Serum 25-hydroxyvitamin D [25(OH)D], ferritin, interleukin-6 (IL-6), and eosinophil-related indices were measured. Group comparisons, Spearman correlation analysis, univariate and multivariable logistic regression, restricted cubic spline analysis, and decision curve analysis were performed.

Compared with the remission group, children with acute exacerbation had significantly higher ferritin levels (median 145 vs. 82 ng/mL, P < 0.001) and eosinophil percentage (6.0% vs. 4.7%, P < 0.001), but lower vitamin D levels (18.6 ± 7.2 vs. 24.3 ± 8.7 ng/mL, P = 0.021). In multivariable logistic regression, ferritin (OR = 1.13, 95% CI 1.07-1.18) and eosinophil percentage (OR = 2.01, 95% CI 1.34-2.70) remained independently associated with acute exacerbation, whereas vitamin D was not statistically significant after adjustment, although the association remained directionally inverse (OR = 0.92, 95% CI 0.84-1.02). No significant interaction between ferritin and vitamin D was observed, but interaction testing was limited by sample size. Restricted cubic spline analysis suggested an inverse linear association between vitamin D level and exacerbation risk. The combined model including ferritin, eosinophil percentage, and vitamin D showed high apparent discrimination (AUC = 0.973, 95% CI 0.952-0.994), although this finding should be interpreted cautiously because of overfitting risk.

Ferritin and eosinophil percentage were independent risk factors for acute asthma exacerbation in children. Vitamin D showed an inverse association in unadjusted and dose-response analyses but was not an independent predictor after multivariable adjustment. These findings support a possible link between metabolic and inflammatory pathways in childhood asthma, but larger studies are needed for validation.

Following the COVID-19 pandemic, the clinical patterns of pediatric respiratory infections have undergone significant changes, with increasing attention on the immunological imprint left by Post-Acute Sequelae of SARS-CoV-2 infection (PASC), commonly known as Long COVID. A perplexing clinical phenomenon has been observed: some children with a history of Long COVID exhibit a disproportionately severe inflammatory response and extensive lung injury when encountering common community-acquired pneumonia, such as that caused by Mycoplasma pneumoniae or Streptococcus pneumoniae, inconsistent with their pathogen load. This review aims to dissect this phenomenon and proposes the "Immune Priming and Two-Hit" model as its core pathophysiological framework. This model posits that the Long COVID state constitutes the "first hit," establishing a "primed" or "hyper-reactive" immune baseline through viral persistence, trained immunity-induced monocyte reprogramming, and sustained endothelial dysfunction. Upon the "second hit" of a bacterial infection, this primed immune system triggers a dysregulated, synergistically amplified inflammatory cascade. The mechanisms involve the exponential release of cytokines such as Interleukin-6 (IL-6), IL-1β, and Tumor Necrosis Factor-α (TNF-α), inflammation-mediated immunothrombosis, and excessive activation of Neutrophil Extracellular Trap formation (NETosis), ultimately leading to severe outcomes like Acute Respiratory Distress Syndrome (ARDS) and necrotizing pneumonia. Consequently, identifying and defining this "Hyper-inflammatory endotype" is of critical clinical importance. We define it as an "endotype" to emphasize the distinct, host-determined pathophysiological mechanisms underlying it, rather than merely a collection of clinical manifestations. By monitoring biomarkers such as ferritin, D-dimer, lactate dehydrogenase (LDH), and lymphocyte counts, clinicians may be able to perform early risk stratification of these children. This approach not only facilitates a shift in therapeutic strategy from purely antimicrobial therapy to "host-directed therapy"-emphasizing the necessity of early, adequate corticosteroid use and consideration of anticoagulation-but also provides a new theoretical basis and intervention window for preventing long-term sequelae such as pulmonary fibrosis.

Long COVID poses a significant public health challenge. However, population-level trends and associated factors in the general US population during the post-pandemic era are not fully characterized.

To analyze trends in long COVID prevalence among US adults from 2022 to 2024, identify associated demographic and socioeconomic factors, and assess its impact on daily activities.

We analyzed data from three cycles (2022-2024) of the National Health Interview Survey, a repeated cross-sectional, nationally representative survey. COVID-19 infection, long COVID, and daily activity limitation were determined through participant self-report. Daily activity limitation was assessed in 2023-2024. Multivariable Poisson regression identified factors associated with: (1) long COVID history and (2) significant activity limitation among those with current symptoms. All analyses incorporated survey weights to produce nationally representative estimates. Data analysis was conducted in October 2025.

The study included 88,731 adults (median age 47 years; 51.4% female and 48.6% male; 61.7% non-Hispanic White, 17.6% Hispanic, 11.8% non-Hispanic Black, and 8.9% non-Hispanic other). In the overall population, the prevalence of ever long COVID increased from 7.0% (95% CI, 6.6-7.3%) in 2022 to 8.4% (95% CI, 8.0-8.8%) in 2023, plateauing at 8.3% (95% CI, 7.9-8.7%) in 2024, while for current long COVID the prevalence remained stable (3.4% [95% CI, 3.1-3.6%] in 2022, 3.6% [95% CI, 3.3-3.9%] in 2023, and 3.3 [95% CI, 3.1-3.6%] in 2024). Among adults with prior COVID-19 infection, prevalence of both ever and current long COVID declined significantly, from 17.7 to 13.7% and from 8.6 to 5.5%, respectively. Long COVID was more common among women, adults in middle age (35-64 years), Hispanic or non-Hispanic White individuals, those who were widowed/separated/divorced, people with lower educational attainment, and individuals with incomes below the federal poverty threshold. Among those with current long COVID, 19.8% reported significant activity limitation, and this limitation was more common among older adults and individuals with lower incomes.

From 2022 to 2024, long COVID continued to impose a substantial public health burden, with clear demographic and socioeconomic disparities. These findings underscore the necessity for continued surveillance and targeted support for high-risk groups.