Childhood interstitial lung diseases (chILD) are a heterogeneous group of rare disorders. In 2013, the American Thoracic Society (ATS) developed a guideline regarding the classification, evaluation, and management of children <2 years old with chILD. The current guideline provides updated recommendations regarding genetic testing, chest imaging, lung biopsy, and lung transplant referral. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach was used to form clinical questions, summarize evidence, and develop recommendations, following ATS policies and procedures. A multidisciplinary panel with expertise in chILD formulated recommendations addressing diagnostic tools and referral for lung transplant evaluation. Rapid and broad genetic testing is recommended for infants with chILD and respiratory failure (strong recommendation). Chest CT remains an important part of the diagnostic evaluation (conditional recommendation). Surgical lung biopsy is recommended when there is urgency to identify a specific chILD disorder and genetic testing is not feasible, timely, or inconclusive, to identify histopathologic 'treatable traits', or to inform prognosis (strong recommendation). Referral for lung transplant evaluation is recommended for children with specific chILD disorders with predictably poor outcomes (strong recommendation). Repeat chest CT to aid decision-making, prognosis, and/or change therapies is suggested for children with chILD diagnosed before age 2 years (conditional recommendation). This guideline provides evidence-based recommendations for genetic testing, chest imaging, lung biopsy, and referral for lung transplant evaluation to improve the diagnostic evaluation and management of children <2 years with chILD. Implementing this guideline will hopefully increase genetic testing for chILD, inform the diagnostic evaluation and disease monitoring of chILD, and identify future research priorities for chILD.
Severe bacterial pneumonia is a leading cause of death worldwide, and mortality rates remain unacceptably high despite appropriate antibiotic treatment. Macrophage membrane-coated nanoparticles (MΦ-NPs) are biomimetic constructs engineered to neutralize bacterial toxins, pathogen-associated molecular patterns, and proinflammatory cytokines. To evaluate the therapeutic potential of MΦ-NPs for the treatment of severe bacterial pneumonia. We evaluated the therapeutic potential of MΦ-NPs using in vitro models of infection involving human lung endothelial and epithelial cells, as well as primary human neutrophils, and in vivo murine models of Pseudomonas aeruginosa (PA) and methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. MΦ-NPs demonstrated potent cytoprotective and anti-inflammatory activity in vitro, without impairing neutrophil antimicrobial function. In both PA and MRSA pneumonia models, MΦ-NP treatment significantly improved survival, reduced bacterial burden, lowered proinflammatory cytokines, and preserved lung architecture. Quantitative proteomics further revealed suppression of inflammatory, coagulation, and fibrotic pathways associated with poor outcomes in human pneumonia and ARDS. These findings establish MΦ-NPs as a promising host-directed therapeutic strategy for mitigating the deleterious inflammatory sequelae of severe bacterial pneumonia.
Interleukin-33 (IL-33) is a key orchestrator of broad-spectrum downstream host-response mechanisms, including inflammation, tissue homeostasis, and repair. Dysregulation of IL-33 signaling is associated with several pathological conditions. The FRONTIER program comprised four phase 2 signal-finding studies of tozorakimab, an anti-IL-33 human immunoglobulin G1 monoclonal antibody, in diabetic kidney disease (FRONTIER-1), moderate-to-severe atopic dermatitis (FRONTIER-2), moderate-to-severe asthma (FRONTIER-3), and moderate-to-severe chronic obstructive pulmonary disease and chronic bronchitis (FRONTIER-4). This analysis assessed the safety data from these clinical studies. FRONTIER-1-4 were randomized, double-blind, placebo-controlled studies evaluating the efficacy, safety, pharmacokinetics, and immunogenicity of tozorakimab in adults. Participants received subcutaneous tozorakimab (FRONTIER-1, 30-300 mg; FRONTIER-2, 60-600 mg; FRONTIER-3, 300-600 mg; FRONTIER-4, 600 mg) or placebo every 4 weeks for 4-7 doses, with follow-up periods ranging from 24-36 weeks from the first dose. Safety (adverse events [AEs], serious AEs, and AEs of special interest) and immunogenicity endpoints from the FRONTIER studies were summarized. In total, 1076 patients were included in this analysis (tozorakimab, n=738; placebo, n=338). Deaths occurred only in FRONTIER-1, in similar proportions between treatment groups (tozorakimab, 0.9%; placebo, 0.8%), and were unrelated to tozorakimab. The proportion of participants experiencing at least one treatment-emergent AE (TEAE) or serious TEAEs was generally similar between tozorakimab and placebo groups. The proportion of participants experiencing AEs of special interest, including events of progression of heart failure, was low (tozorakimab, 0.0-1.5%; placebo, 0.0-0.8%), with no meaningful differences between groups; the frequency of injection-site reactions was however higher in tozorakimab than in placebo recipients (tozorakimab, 1.2-20.9%; placebo, 0.0-4.9%). No clinically significant trends were observed in laboratory or vital-sign parameters, and immunogenicity was low. Tozorakimab was well tolerated across a range of inflammatory diseases, with no safety concerns identified.
Genetic testing is standard of care in Non-small Cell Lung Cancer(NSCLC). Few studies evaluate concurrent Endobronchial Ultrasound-Transbronchial Needle Aspiration(EBUS-TBNA) and liquid biopsy for Next Generation Sequencing(NGS). Compare diagnostic yield differences for detecting clinically relevant mutations via NGS in concurrent EBUS-TBNA and liquid biopsies. Prospective observational cohort study of NSCLC patients undergoing concurrent biopsies. Yield differences, receiver operating characteristic (ROC) and kappa statistics were calculated for clinically relevant mutations. Of 199 subjects, diagnostic yield for EGFR was 9.5% in EBUS-TBNA and 7.0% in blood with yield difference 2.5%(95% CI: 3.4%, 8.5%, p = 0.36). For clinically relevant targets, there were 79(39.7%) from EBUS-TBNA and 49(29.6%) from blood with yield difference 15.1%(95% CI: 5.5%, 24.2%, p = 0.001). ROC statistics for detection of clinically relevant mutations (where tissue results were the gold standard) included: sensitivity 0.53 (95% CI: 0.42, 0.64), specificity: 0.95(95% CI: 0.90,0.98), positive predictive value: 0.89 (95% CI: 0.77, 0.96), negative predictive value: 0.74 (95% CI: 0.65, 0.81), and kappa statistic: 0.51 (95% CI: 0.39, 0.63). There were 37 (18.6%) participants with mutations in tissue only and 7(3.5%) with mutations in blood only, while 42(21.1%) had mutations reported from both sources. EBUS-TBNA was more likely to detect mutations than blood. However, some patients had mutations in blood only, suggesting blood testing is complementary. Strategies are needed to improve NGS turnaround time(TAT) and QNS definition.
Continuous positive airway pressure (CPAP) is the first‑line treatment for moderate-to-severe obstructive sleep apnea (OSA), while mandibular advancement devices (MAD) are an established alternative for CPAP-intolerant patients. Differences in efficacy and adherence may affect overall clinical effectiveness. This prospective non-randomized study (First Line Obstructive Sleep Apnea Treatment (FLOSAT)) evaluated the clinical effectiveness of MAD therapy as first-line treatment option compared to second-line CPAP therapy. Moderate-to-severe OSA patients received three months of MAD therapy, followed by a wash-out period and three months of CPAP therapy. The primary outcome was mean disease alleviation (MDA), a measure combining efficacy and adherence, analyzed using a modified intention-to-treat approach. Ninety-four patients (86% male, age: 52±12 years, body mass index: 28·1±3·4 kg/m2) were included. The averaged individual MDA was 49·9±26·1% with MAD and 49·1±34·5% with CPAP, demonstrating non-inferiority of MAD compared to CPAP (p = 0·4). The apnea/hypopnea index (AHI) decreased significantly from 24·2(18·1; 32·3)/h at baseline to 8·4(5·4; 12·9)/h with MAD and to 4·1(2·2; 11·5)/h with CPAP (both p < 0·001). Nightly adherence was significantly higher with MAD (6·7(5·2;7·3) hours/night) than with CPAP (5·4(2·0;6·5); p < 0·05). In this study, 51% of patients preferred MAD compared to 42% for CPAP. MAD therapy achieved good efficacy and high adherence, resulting in non-inferior effectiveness compared to CPAP. However, the sequential, non-randomized design limits interpretation because treatment effects cannot be separated from potential order or period effects. Furthermore, MDA has not been validated against patient-important outcomes and therefore does not establish clinical non-inferiority.
Acute exacerbations (AEs) occur both in patients with idiopathic pulmonary fibrosis (IPF) and non-IPF fibrotic interstitial lung disease (fILD). These events confer high morbidity and mortality, with a lack of proven effective therapeutic interventions. The objective of this state-of-the-art document is to summarize latest evidence since the 2016 international working group report on AE-IPF, expanding it across the spectrum of all fILDs. A comprehensive literature review on the epidemiology, associated and risk factors, prognosis, and management of AE-fILD is summarized. In addition to revising the AE definition and diagnostic criteria for broad application across different fILDs, a conceptual framework for acute respiratory worsening (ARW) has been proposed to encompass a variety of acute respiratory deteriorations, both related and unrelated to AE. This allows structured evaluation in both clinical and research settings. The proposed revised definition for AE-fILD is an acute respiratory event characterized by increased respiratory symptoms or signs and associated with radiologic or histologic features consistent with diffuse alveolar damage (with or without superimposed organizing pneumonia) in a patient with known or newly diagnosed fILD. On the other hand, ARW refers to a heterogeneous group of clinical events with acute symptom worsening not attributable to DAD in patients with fILD, such as pulmonary edema, bronchitis, and pneumonia, although severe pneumonia can trigger AE-fILD. Additionally, we discuss considerations for inclusion of AE as a clinical trial endpoint, as well as research priorities for advancing knowledge on the pathogenic mechanisms, event prediction, risk stratification, and development of drugs and supportive treatments.
Lung cancer is the leading cause of cancer death in the United States and disproportionately affects Black adults. Lung cancer screening (LCS) remains narrowly focused on cigarette smoking, often excluding other tobacco use, and low provider referral rates continue to limit screening uptake. Addressing these gaps is critical to advancing screening equity. We surveyed 100 Black adults (aged 50 + years) with a 20 + year history of tobacco use who either currently used or had quit within the past 15 years. The survey assessed tobacco use characteristics, cessation intentions, tobacco product harm perceptions, LCS-related quit motivations, and LCS knowledge and beliefs. We compared characteristics, beliefs, and experiences by LCS status (56% screened) using a quasi case-control approach. LCS uptake varied by insurance status (p = 0.03), tobacco risk perceptions (p = 0.037), past-year quit attempts (p = 0.005), and lung cancer beliefs, including early detection knowledge (p < 0.001). Screening experiences were associated with health care discrimination and LCS-related risk perceptions. Among adults reporting past-year use of combustible tobacco products other than cigarettes, unscreened adults were more likely than screened adults to report current use (22.7% vs. 5.4%; p = 0.01). Participants most identified social media (48.0%), followed by magazines/newspapers (31.0%) and local news (29.0%), as trusted sources of information on early lung cancer detection. Expanding LCS eligibility to include non-cigarette combustible tobacco use-while addressing structural barriers, provider recommendations, gaps in screening knowledge, risk perception, and culturally responsive communication-are essential for improving the reach, implementation, and equity of LCS in Black communities.
Yes-associated protein (YAP)-mediated fibroblast mechanoactivation is an important driver of fibrosis in idiopathic pulmonary fibrosis (IPF). To characterize the role of ADAM with Thrombospondin motifs 14 (ADAMTS14) in YAP-mediated fibroblast mechanoactivation and pulmonary fibrosis. We disrupted ADAMTS14 expression in primary human lung fibroblasts (HLFs) and demonstrated its role in YAP nuclear translocation and fibroblast activation. We confirmed the in vivo relevance of ADAMTS14 in an IPF patient cohort using transcriptomic studies. ADAMTS14-deficient fibroblasts were further characterized in mechanistic studies combining advanced microscopy, unbiased proteomics, and co-immunoprecipitation with functional mechanobiology assays to delineate substrate-matrix interactions. An unbiased siRNA screen identified ADAMTS14 as a regulator of YAP-mediated fibroblast activation and pro-fibrotic activity. Transcriptomic analyses of patient samples with fibrotic lung disease identified an ADAMTS14-expressing fibroblast population characterized by excessive collagen matrix synthesis and located within fibroblastic foci of IPF patients. Disruption of ADAMTS14 expression in IPF patient-derived HLFs reduced pro-fibrotic gene expression and attenuated the response to TGFβ. Mechanistically, we identified collagen V as a novel functionally relevant ADAMTS14 substrate essential for matrix stability. ADAMTS14-deficient fibroblasts produced an unstable extracellular matrix, leading to disorganized focal adhesions, impaired force transmission, and reduced focal adhesion-FAK-AKT signaling. We identify a novel ADAMTS14-collagen V-focal adhesion axis as a potential driver of fibroblast activation in IPF, linking extracellular proteolytic matrix remodeling to focal adhesion dynamics and YAP-mediated mechanoactivation. This feed-forward circuit provides a new mechanistic framework for pulmonary fibrosis and identifies potential novel therapeutic targets.
Hyperinflammatory and hypoinflammatory phenotypes previously identified in sepsis and ARDS may enable precision therapies, but their clinical relevance and translational modeling in severe pneumonia remain incompletely characterized. To examine biomarker-defined hyperinflammatory and hypoinflammatory phenotypes in critically ill patients with pneumonia (pulmonary sepsis), test whether the biomarkers that define these phenotypes identify subgroups and outcomes in a mouse model of bacterial pneumonia, and determine whether the mouse phenotypes respond differently to therapeutic interventions. We performed latent class analysis (LCA) in a cohort of 548 ICU patients with pulmonary sepsis to identify inflammatory phenotypes and test the association of these phenotypes with clinical outcomes using validated classifier models. We developed a mouse model of pneumococcal pneumonia which recapitulates key aspects of these phenotypes and tested responses to dexamethasone and IL-6 receptor blockade. Two phenotypes were identified in patients with pulmonary sepsis: a hyperinflammatory phenotype with more lung injury and increased mortality, and a hypoinflammatory phenotype with more favorable outcomes. Despite uniform pathogen exposure and baseline conditions, LCA identified two phenotypes in the mice with divergent trajectories (lung injury and mortality). Therapeutic benefit from anti-inflammatory interventions was observed exclusively in the more inflamed mice. By integrating clinical data from human studies and experimental findings in a clinically relevant mouse model, this study provides a translational framework for developing phenotype-targeted therapies for critical illness, with the goal of improving patient outcomes.
Chronic rhinosinusitis (CRS) is a common comorbidity in bronchiectasis. Previous studies suggested that bronchiectasis with CRS is associated with elevated type 2 biomarkers, representing an "eosinophilic bronchiectasis" phenotype. However, whether the association with type 2 inflammation exists in rare aetiologies of bronchiectasis such as primary ciliary dyskinesia (PCD) or immune deficiency is unknown. Our aim was to explore the prevalence of CRS with and without nasal polyposis (CRSwNP and CRSnNP), their impact on bronchiectasis outcomes, and their association with type 2 inflammatory biomarkers in patients with bronchiectasis of various aetiologies. Using data from the EMBARC bronchiectasis registry, we classified patients with bronchiectasis as having no CRS, CRSnNP or CRSwNP. Regression models were used to test the effect of CRS on symptom scores and long-term outcomes. Multivariate models were created for elevated "type 2 biomarkers", defined as elevated blood eosinophil count or total IgE. Among 16 640 people with bronchiectasis, 2703 (20.9%) had CRSnNP and 1223 (7.3%) had CRSwNP. CRSwNP and CRSnNP were associated with worse symptoms and more frequent exacerbations, but lower hospitalisations and mortality. Type 2 biomarkers were elevated in people with comorbid CRSwNP in idiopathic bronchiectasis, but not in bronchiectasis secondary to PCD or immune deficiency. In multivariable analysis, CRSwNP was independently associated with elevated type 2 biomarkers. CRS and nasal polyposis are common comorbidities in bronchiectasis, associated with worse symptoms and exacerbations. Elevated type 2 biomarkers are associated with CRS, but this finding is dependent on the aetiology of bronchiectasis.
Background/Objectives: The study evaluates the effectiveness of mandibular advancement device (MAD) treatment in drug-induced sleep endoscopy (DISE) preselected adults with moderate-to-severe obstructive sleep apnea (OSA). Methods: It is a retrospective observational cohort study without a control arm/treatment, including 182 patients with an apnea-hypopnea index (AHI) ≥ 15 events/h of sleep (Level-1 polysomnography) from six Belgian hospitals. After DISE preselection, a custom-made MAD (EVO, ProSomnus, Pleasanton, CA, USA) was titrated to symptom relief or physiological limits. Level-3 home polygraphy with MAD was performed within five months. The primary outcome was change in AHI from baseline. Secondary outcomes included percentage change in AHI, change in OSA severity category, snoring loudness and Epworth Sleepiness Scale (ESS) scores. Analysis of covariance methods adjusting for baseline AHI were employed. Exploratory analyses compared outcome measures by OSA severity at baseline. 'Success' equaled AHI < 10 with ≥50% improvement. Results: Mean AHI significantly decreased from 24.4 to 7.1 (p < 0.0001) with a significant mean percent decrease by 68.6% (p < 0.0001), improving more (p < 0.0001) in severe cases. Mean change in snoring loudness improved significantly from a mean of 7.1 to 1.7 (p < 0.0001), improving more (p = 0.049) in moderate cases. Mean change from baseline in overall ESS score was -1.7 (p < 0.0001). Greater improvements were observed in participants with elevated baseline ESS scores. MAD significantly (p = 0.03) improved OSA category: moderate OSA cases improved by a mean of 1.4 levels, severe cases by a mean of 2.1 levels (p < 0.0001). A total of 75.8% of participants achieved 'Success'. Conclusions: In this retrospective multicenter cohort, MAD therapy was associated with significant reductions in AHI, snoring loudness, and ESS scores among DISE-preselected adults with moderate-to-severe OSA. Because treatment outcomes were assessed using Level-3 home polygraphy, the findings should be interpreted as real-world effectiveness outcomes obtained within the Belgian clinical care pathway.
Cardiac sarcoidosis (CS) is a granulomatous inflammatory disease that frequently progresses to irreversible myocardial fibrosis and lethal conduction abnormalities. While mTORC1-dependent macrophage activation has been implicated in this process, exactly how granulomatous inflammation is mechanistically converted into fibrotic remodeling at the level of macrophage effector function remains unknown. We employed a mouse model with myeloid-specific Tsc2 deletion that recapitulates key features of human cardiac sarcoidosis. Single-cell RNA sequencing, histopathology, bioinformatic analyses, in vitro functional studies in murine and human macrophages, and in vivo pharmacologic inhibition were integrated to define macrophage-intrinsic mechanisms driving granuloma-associated cardiac fibrosis. Constitutive mTORC1 activation induced a fibrogenic macrophage (FibMac) population in the heart characterized by expression of Cd63, Spp1, Gpnmb, and Fabp5 and arising through a TGF-β-dependent monocyte-to-FibMac differentiation process. We identified matrix metalloproteinase 12 (MMP12) as macrophage-intrinsic inducer and dominant effector of this program. Recombinant MMP12 was sufficient to enforce fibrogenic macrophage differentiation, promote macrophage clustering and epithelioid features in both mouse and human macrophages. Conversely, selective MMP12 inhibition disrupted granuloma architecture, reduced fibroblast activation, and attenuated myocardial fibrosis in vivo, with concomitant improvement of cardiac conduction. In human CS tissue, MMP12 colocalized with FibMac markers within granulomas, and reanalysis of published human fibrosis datasets revealed MMP12 expression within analogous fibrogenic macrophage populations. Our findings uncover MMP12 as a macrophage-intrinsic inducer and sustainer that links fibrogenic macrophage identity to granuloma architecture and cardiac fibrosis in sarcoidosis. Targeting this effector axis provides a therapeutic strategy distinct from upstream mTORC1 inhibition.
The Early versus Delayed Enteral Nutrition (EDEN) trial found no significant difference in mortality between trophic and full enteral nutrition strategies in acute respiratory distress syndrome (ARDS) patients. Heterogeneity of treatment effect (HTE) has been identified in prior ARDS trials. We previously identified intestine-derived incretin hormones (glucose-dependent insulinotropic peptide [GIP] and glucagon-like peptide [GLP]-1 as potential predictive biomarkers in the response to nutrition. To investigate incretins as biomarkers predictive of HTE in EDEN. GIP, GLP-1, and host immune response biomarkers were measured from pre-intervention EDEN plasma samples. We investigated HTE with 60-day mortality as a primary outcome by testing interaction of treatment with circulating incretin levels in analyses adjusted for demographics, severity of illness, diabetes mellitus, and circulating interleukin-6, and assessed mortality by treatment arm across incretin tertiles. We additionally tested for HTE by de novo ARDS subphenotypes and by risk of mortality. 889 participants were included (452 randomized to trophic and 437 to full enteral nutrition). GIP predicted HTE to enteral nutrition strategies (adjusted interaction p-value 0.01) with lower mortality from trophic feeds (14.1% vs 27.2% in full) in patients in the highest GIP tertile but similar mortality in other tertiles. GLP-1, ARDS subphenotypes, and baseline risk of mortality did not predict HTE. GIP was unique among incretins in predicting HTE to enteral nutrition strategies in EDEN. Further studies are needed to validate our findings as GIP might serve as a biomarker to guide level of enteral nutrition for ARDS patients.
Tissue autoregulation to match local blood flow to metabolic demands requires both a high enough upstream mean arterial pressure (MAP) and perfusion pressure difference between this MAP and the downstream arteriolar critical closing pressure to drive blood flow into the capillaries whose downstream capillary pressure is approximated as mean systemic filling pressure. The closing pressure to mean systemic pressure difference represents a vascular waterfall such that increases or decreases in mean systemic filling pressure below closing pressure do not alter tissue flow. Tissues autoregulate their blood flow by altering upstream local vasomotor tone to increase or decrease closing pressure. In vasoplegia, like septic shock vascular tone is decreased, often decreasing closing pressure to approximating mean systemic filling pressure. Such conditions abolish autoregulation even if MAP and cardiac output are not decreased. Effective resuscitation from septic shock requires restoration of local vascular waterfalls. Often initial fluid resuscitation and vasopressor infusion restore vascular waterfalls and tissue blood flow. But often it does not. There are few readily available real-time quantitative estimates of tissue perfusion. Presently only capillary refill time (CRT) minors tissue blood flow changes. If initial resuscitation to target MAP values does not restore tissue perfusion and CRT is > 3 seconds, then potentially a vasopressor test to increase MAP to > 75 mmHg may be studied. If vasopressor-induced increases in MAP decreases CRT to < 3 seconds, then it can be continued. If not, then return to prior levels to minimize iatrogenic vasopressor risk. This paper lists unanswered questions that need studying.
The Cystic Fibrosis Foundation organised a multidisciplinary committee to develop this Position Paper to outline current knowledge and best practices in reproductive health care for individuals with cystic fibrosis. Working groups reviewed the literature and provided relevant guidance on reproductive health services, fertility, contraception, preconception and pregnancy, and cystic fibrosis transmembrane conductance regulator (CFTR) modulator exposure in utero and during lactation. Findings included: (1) reproductive health-care provision should be standardised, and education should begin at cystic fibrosis diagnosis and revisited annually; (2) contraception is safe overall, but underutilised in those with cystic fibrosis compared with the general population; (3) fertility might be improving with CFTR modulators for females with cystic fibrosis, but not for males with cystic fibrosis-assisted reproductive technologies are still required for males to achieve biological parenthood; (4) pregnancy requires close monitoring and unique screening for diabetes; and (5) CFTR modulator exposure in utero has implications for infant monitoring and cystic fibrosis screening results in newborns.
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