Daily Respiratory Research Analysis
Analyzed 183 papers and selected 3 impactful papers.
Summary
Three impactful respiratory studies stood out today: a multicountry prospective cohort evaluated a rapid 3‑gene host-response cartridge (MTB‑HR) for tuberculosis screening and prognosis among household contacts; an international multicohort study linked pleural fluid neutrophil extracellular traps (NETs) to disease severity, 1‑year mortality, and septations in pleural infection; and single‑cell/translational work uncovered fibrosis‑associated macrophage subsets that coordinate iron metabolism to drive pulmonary fibrosis.
Research Themes
- Host-response molecular diagnostics for TB screening and prognosis
- Neutrophil extracellular traps as biomarkers in pleural infection
- Macrophage-driven iron metabolism in pulmonary fibrosis
Selected Articles
1. Diagnostic and prognostic accuracy of the Mycobacterium tuberculosis host response 3-gene cartridge among tuberculosis household contacts in Mozambique, Tanzania, and Zimbabwe: a prospective, longitudinal, diagnostic and prognostic accuracy cohort study.
In a 3‑country, 2‑year prospective cohort of 2,079 TB household contacts, the MTB‑HR 3‑gene cartridge achieved strong diagnostic discrimination (AUROC 0.86) and short‑term prognostic performance for incident TB (AUROC 0.80 at 1–6 months), with higher PPV than current tools. Although it did not meet WHO target product profile thresholds, results support MTB‑HR as a triage and prevention aid in household contact management.
Impact: This large, pragmatic, multicountry prospective study evaluates a deployable host‑response cartridge in a high‑priority population, addressing the diagnostic and prognostic gap beyond sputum tests and potentially informing TB screening and preventive therapy pathways.
Clinical Implications: MTB‑HR could be integrated as a triage test to prioritize further diagnostic workup and to target preventive therapy among high‑risk contacts, particularly within 6 months of testing, while acknowledging current TPP gaps and the need for local cost‑effectiveness assessments.
Key Findings
- Diagnostic AUROC for MTB‑HR within 30 days of TB diagnosis was 0.86 (95% CI 0.79–0.92).
- Prognostic AUROCs for incident TB were 0.80 (1–6 months), 0.64 (6–12 months), and 0.71 (1–12 months).
- At 6 months, the positive predictive value (PPV) for incident TB was 7.5% and exceeded existing tests.
- The assay did not meet 2025 WHO target product profile thresholds for screening/prognosis.
Methodological Strengths
- Prospective, longitudinal, multicountry design with predefined diagnostic and prognostic endpoints.
- Blinded endpoint adjudication and AUROC‑based discrimination analyses with optimized cutoffs.
Limitations
- Did not achieve WHO TPP benchmarks; PPV remains modest in absolute terms.
- Performance declined over longer prediction windows (6–12 months), requiring interval re‑testing strategies.
Future Directions: Evaluate MTB‑HR integration with targeted preventive therapy algorithms, cost‑effectiveness in different settings, and combined strategies with radiography or AI triage; optimize thresholds for various epidemiologic contexts.
BACKGROUND: Tuberculosis elimination is constrained by symptom-based and sputum-dependent diagnostic strategies, which miss asymptomatic disease and are difficult to deploy in community settings. Household contacts of people with tuberculosis are a priority population for screening and preventive therapy, but existing tests have poor prognostic ability. We aimed to evaluated host-response assays for screening and prognostic use in household contacts of people with tuberculosis. METHODS: In this prospective, longitudinal, diagnostic and prognostic accuracy study, we recruited people aged 10 years and older who lived with a person diagnosed with tuberculosis in Mozambique, Tanzania, or Zimbabwe. Household contacts who had taken antimycobacterial antibiotics within the past 4 weeks were excluded. Participants had real-time Cepheid Xpert Mycobacterium tuberculosis Host Response (MTB-HR) testing and clinical, radiological, and microbiological tuberculosis screening every 6 months for up to 24 months. The primary outcomes were the diagnostic accuracy of MTB-HR obtained within 30 days of a confirmed or likely tuberculosis diagnosis at any baseline or follow-up visit, and the prognostic ability of MTB-HR for incident tuberculosis using MTB-HR results obtained 1-6 months, 6-12 months, and 1-12 months before incident tuberculosis diagnosis. Tuberculosis diagnoses were established by an endpoint review committee and we assessed discrimination using the area under the receiver operating characteristic (AUROC) curve. The study was registered with ClinicalTrials.gov (NCT04781257) and is completed. FINDINGS: Between March 8, 2021, and March 23, 2023, we screened 2109 household contacts and enrolled 2079 for analysis (1294 [62·2%] female and 785 [37·8%] male). In the diagnostic analysis (41 household contacts with tuberculosis), the AUROC was 0·86 (95% CI 0·79-0·92). The prognostic analysis included 29 people with incident tuberculosis during the 1-6-month interval, 19 people for the 6-12-month interval, and 39 people for the 1-12-month interval, yielding AUROCs of 0·80 (0·71-0·89), 0·64 (0·53-0·76), and 0·71 (0·62-0·79), respectively, at optimised cutoffs. For the 6-month prediction at the optimised cutoff, the positive predictive value was 7·5% (95% CI 4·9-11·4). INTERPRETATION: MTB-HR did not meet the 2025 WHO target product profile criteria for screening or prognostic use; however, its positive predictive value for incident tuberculosis was higher than that of currently used tests. These findings support a potential role for MTB-HR in screening and prevention strategies. FUNDING: The second European and Developing Countries Clinical Trials Partnership (EDCTP2) programme.
2. Pleural fluid neutrophil extracellular traps are associated with disease severity and risk of one-year mortality in pleural infection. An observational, international, multicohort study (TORPIDS-3).
Across five datasets in three countries, higher pleural fluid NETs were independently associated with higher RAPID severity, greater 1‑year mortality risk, and more extensive sonographic septations in pleural infection; findings were robust across validation cohorts. Citrullinated fibrin also tracked septation severity, supporting thromboinflammatory biology in complicated empyema.
Impact: Provides externally validated, clinically actionable biomarker data linking NET burden to severity, mortality, and septations, enabling risk stratification and potentially guiding decisions on intrapleural enzyme therapy and early aggressive management.
Clinical Implications: NET quantification could augment RAPID-based risk stratification to identify patients needing early drainage optimization, intrapleural fibrinolytics, or closer follow‑up; it also supports exploration of NET‑targeting adjuncts.
Key Findings
- Each 10‑unit increase in NETs associated with higher RAPID severity (OR 1.13; validation OR 1.29).
- Higher NETs predicted increased 1‑year mortality (HR 1.15) independent of RAPID score.
- NETs associated with greater likelihood and extent of sonographic septations (OR 1.17).
- Citrullinated fibrin correlated with septation severity (OR 1.10).
Methodological Strengths
- Discovery and external validation across independent multicountry cohorts.
- Multivariable modeling with clinically relevant outcomes (RAPID score, 1‑year mortality, septations).
Limitations
- Observational design precludes causal inference; assay standardization for NETs may vary.
- Heterogeneity in local management protocols could influence outcomes (e.g., drainage practices).
Future Directions: Prospective interventional studies incorporating NET‑guided management and trials of NET‑targeting strategies alongside intrapleural enzyme therapy.
BACKGROUND: Influx of large numbers of neutrophils is characteristic of pleural infection; however, neutrophil behaviour is understudied. We designed an observational multicohort study with the aims to discover and validate the association between neutrophil extracellular traps (NETs), disease severity, one-year survival, and the extent of sonographic septations. METHODS: We analysed five independent datasets across three countries. The PILOT cohort (UK, n=215) was used as a discovery cohort for the association of NETs with disease severity with validation in four independent cohorts across three countries (UK, Greece, Italy, n=100). The PILOT cohort was further analysed to assess the association of NETs with one-year survival and the development and extent of sonographic septations. A separate cohort (the Oxford-Osler cohort, UK, n=30) was used to assess the relationship between NETs and the need for intrapleural enzyme therapy (IET) as rescue treatment. RESULTS: A ten-unit increase in NETs was associated with 13% higher odds of being into a higher RAPID Score group (OR=1.13, 95% CI: 1.02-1.27, p=0.02), and this association remained robust in the independent validation cohort (OR=1.29, 95% CI: 1.11-1.40, p=0.0005). A ten-unit increase in NETs was also associated with a 15% higher risk of one-year mortality (HR=1.15, 95% CI: 1.01-1.32, p=0.04) independent of the RAPID Score, and a 17% higher likelihood of sonographic septations (OR=1.17, 95% CI: 1.01-1.37, p=0.04). Citrullinated fibrin was associated with septation severity (OR=1.10, 95% CI: 1.04-1.16, p=0.00005). CONCLUSIONS: Pleural fluid NETs are a biomarker of disease severity and one-year mortality, in pleural infection. Future studies are required to assess the combination of NET-targeting strategies in combination with existing treatments.
3. Distinct fibrosis-associated macrophage subsets coordinate iron metabolism in pulmonary fibrosis.
Human BALF scRNA‑seq and histology identified SPP1/APOE macrophages enriched in fibrotic foci and increased in PPF/IPF, splitting into SLC40A1+ and HAMP+ subsets controlled by epithelial IL‑8 and type II AEC‑derived IL‑10. These subsets coordinate iron uptake/export and intracellular accumulation, driving SPP1+ myofibroblast transition and fibrosis via iron‑dependent pathways and TGF‑β1 from ferroptotic fibroblasts.
Impact: Reveals a mechanistic iron‑handling axis in human fibrosis driven by discrete macrophage subsets with plausible, targetable nodes (SLC40A1, HAMP, IL‑8/IL‑10 balance, ferroptosis‑TGF‑β1 crosstalk), advancing therapeutic concept development in progressive pulmonary fibrosis.
Clinical Implications: Supports exploring iron metabolism–modulating therapies (e.g., ferroportin/ferrohepcidin pathways), cytokine milieu modulation (IL‑8/IL‑10), and ferroptosis‑TGF‑β1 interventions as adjuncts to current antifibrotics in PPF/IPF.
Key Findings
- SPP1/APOE macrophages accumulate in fibrotic foci and are increased in PPF and IPF.
- Two fibrosis‑associated macrophage subsets (SLC40A1+ and HAMP+) are controlled by IL‑10/IL‑8 balance and coordinate iron export vs intracellular accumulation.
- Macrophage‑orchestrated iron handling promotes SPP1+ myofibroblast transition; ferroptotic fibroblasts secrete TGF‑β1 to further drive fibrosis.
Methodological Strengths
- Human patient–derived BALF single‑cell RNA‑seq integrated with histological spatial localization.
- Mechanistic linkage across epithelial–immune–stromal compartments (cytokines, iron handling, fibroblast fate).
Limitations
- Exact patient numbers per ILD subgroup and longitudinal causality are not detailed in the abstract.
- Functional perturbation and in vivo interventional validation are needed to confirm therapeutic tractability.
Future Directions: Interventional studies targeting SLC40A1/HAMP axis, modulation of IL‑8/IL‑10 signaling, and ferroptosis‑TGF‑β1 pathways; spatial multi‑omics and longitudinal sampling to map causal dynamics.
Pulmonary fibrosis has a poor prognosis due to challenges in early diagnosis and therapeutic intervention. Current treatments remain largely ineffective due to an incomplete understanding of the complex pathology, including the interactions between fibroblasts and profibrotic immune cells within fibrotic lungs. To elucidate the dynamics of fibrosis, we performed single-cell RNA sequencing (scRNA-seq) on bronchoalveolar lavage fluid (BALF) obtained from patients with interstitial lung disease (ILD). We identified the SPP1- and APOE-expressing macrophage population that is commonly present across ILDs. Histological analysis showed that this macrophage population accumulated at the center of fibrotic foci. Furthermore, the ratio of this macrophage population was increased in both progressive pulmonary fibrosis (PPF) and idiopathic pulmonary fibrosis (IPF). Transcriptomic analysis further divided this macrophage population into two subsets: SLC40A1+ or HAMP+ fibrosis-associated macrophages. We found that the relative balance of IL-10 and IL-8 regulated SLC40A1 and HAMP expression within fibrosis-associated macrophages. Additionally, histological analysis revealed that bronchial epithelium expressed IL-8, while type II alveolar epithelial cells expressed IL-10 in the fibrotic lung. SLC40A1+ fibrosis-associated macrophages localized to CD31+ perivascular regions and mediated the uptake and degradation of the hemoglobin-haptoglobin complex. This dual pathway-providing iron via SLC40A1 and intracellular iron accumulation via HAMP-facilitated the transition of fibroblasts into SPP1+ myofibroblasts. Moreover, ferroptotic fibroblasts secreted TGF-β1, which further contributes to fibrotic progression. In conclusion, aberrant iron metabolism orchestrated by fibrosis-associated macrophages may contribute to fibrosis by facilitating the transition of myofibroblasts. These findings provide mechanistic insight into the progression of autonomous pulmonary fibrosis.