Daily Respiratory Research Analysis
A double-blind RCT showed that interferon-α nasal spray halved COVID-19 incidence in adult cancer patients without added safety concerns. Two mechanistic and translational studies advanced respiratory science: human nasal organoid assays accurately predicted real-world monoclonal antibody efficacy against SARS-CoV-2, and a JCI study uncovered an ARG1–ornithine–collagen immune–mesenchymal circuit driving lung fibrosis, nominating ARG1 as a therapeutic target.
Summary
A double-blind RCT showed that interferon-α nasal spray halved COVID-19 incidence in adult cancer patients without added safety concerns. Two mechanistic and translational studies advanced respiratory science: human nasal organoid assays accurately predicted real-world monoclonal antibody efficacy against SARS-CoV-2, and a JCI study uncovered an ARG1–ornithine–collagen immune–mesenchymal circuit driving lung fibrosis, nominating ARG1 as a therapeutic target.
Research Themes
- Prophylaxis for respiratory viral infections in immunocompromised hosts
- Human-relevant organoid models to predict antiviral antibody efficacy
- Immunometabolic circuits driving lung fibrosis as drug targets
Selected Articles
1. Interferon-α Nasal Spray Prophylaxis Reduces COVID-19 in Cancer Patients: A Randomized, Double-Blinded, Placebo-Controlled Trial.
In 433 adult cancer patients, daily interferon-α nasal spray reduced COVID-19 incidence from 14.4% to 8.3% (RR 0.60), with consistent benefit in per-protocol analysis and subgroups (<65 years, female, vaccinated). There was no reduction in severity or hospitalization, and safety was favorable.
Impact: This is a rigorously designed, double-blind RCT in a high-risk population demonstrating a simple, low-cost prophylactic strategy against COVID-19. It can inform infection prevention policies for immunocompromised patients.
Clinical Implications: Clinicians may consider IFN-α nasal spray as an adjunct prophylaxis to reduce COVID-19 incidence in adult cancer patients, especially those <65 years, female, or vaccinated, while noting it did not reduce severity or hospitalization.
Key Findings
- COVID-19 incidence was 8.3% with IFN-α vs 14.4% with placebo (RR 0.60; 95% CrI 0.33–0.97).
- Per-protocol analysis: 7.7% vs 16.0% (RR 0.50; 95% CrI 0.26–0.84).
- No differences in severity, hospitalization, or mortality; safety was acceptable.
- Benefits were consistent in subgroups: age <65 years, female sex, and vaccinated.
Methodological Strengths
- Multicenter, randomized, double-blind, placebo-controlled design with prespecified endpoints
- Subgroup and per-protocol analyses with Bayesian credible intervals; self-collection standardized
Limitations
- No reduction in severity/hospitalization; study likely underpowered for hard outcomes
- Outcome ascertainment relied on participant self-swabbing and testing
Future Directions: Larger trials powered for hospitalization and mortality, evaluation in other immunocompromised groups, dosing optimization, and combination with vaccines/antivirals.
2. Myeloid-mesenchymal crosstalk drives ARG1-dependent profibrotic metabolism via ornithine in lung fibrosis.
This study identifies an ARG1–ornithine–proline/collagen axis in lung fibrosis driven by myeloid cells and regulated by a P2RX4–IL-6 immune–mesenchymal circuit. Pharmacologic ARG1 inhibition and myeloid Arg1 deletion reduced collagen in precision-cut IPF human lung slices and murine models, nominating ARG1 as a therapeutic target.
Impact: It elucidates a druggable immunometabolic mechanism of fibrosis with validation in human IPF tissue and multiple in vivo systems, providing a clear translational path to ARG1-targeted therapies.
Clinical Implications: ARG1 inhibition could modulate collagen synthesis by depriving fibroblasts of ornithine/proline substrate; biomarkers in the P2RX4–IL-6–ARG1 axis may stratify patients for antifibrotic strategies.
Key Findings
- Myeloid ARG1 produces ornithine that fuels fibroblast proline and collagen synthesis.
- In mouse lungs, macrophages predominated as ARG1+ cells; in IPF lung, neutrophils were the main ARG1+ myeloid cells.
- Small-molecule ARG1 inhibition reduced ornithine and collagen in precision-cut IPF lung slices and murine fibrosis.
- Macrophage-specific Arg1 deletion confirmed antifibrotic effects; P2RX4-dependent fibroblast IL-6 was required to induce myeloid ARG1, defining a crosstalk circuit.
Methodological Strengths
- Convergent evidence across human precision-cut lung slices, high-dimensional imaging, pharmacology, and genetic KO models
- Mechanistic dissection of purinergic signaling (P2RX4) and cytokine (IL-6) regulation of ARG1
Limitations
- Translational gap remains: clinical efficacy of ARG1 inhibition in IPF is untested
- Potential off-target effects of small-molecule inhibitors not fully characterized
Future Directions: Early-phase clinical trials of ARG1 inhibitors in IPF; development of biomarkers for P2RX4–IL-6–ARG1 activity; cell-type–specific targeting strategies.
3. Organoid-based neutralization assays reveal a distinctive profile of SARS-CoV-2 antibodies and recapitulate the real-world efficacy.
Human nasal organoid neutralization assays showed that several class 3 anti–SARS-CoV-2 mAbs (for example, VIR-7831) are underestimated by standard cell-line assays, yet their efficacy aligns with clinical outcomes when tested in organoids. The organoid system captures low ACE2 and high TMPRSS2 expression, recapitulating in vivo protection, including for S2-directed mAbs.
Impact: It resolves a key discrepancy between in vitro neutralization and clinical efficacy, providing a more predictive platform for evaluating monoclonal antibodies against evolving variants and informing regulatory and clinical decisions.
Clinical Implications: For antibody selection and authorization, organoid-based assays may better predict real-world performance than cell-line assays, guiding which mAbs to advance or retain against emerging variants.
Key Findings
- Class 3 mAbs that do not block RBD–ACE2 (including VIR-7831) are substantially underestimated by cell-line assays.
- Nasal organoids with low ACE2 and high TMPRSS2 recapitulate real-world protection and in vivo effects, including S2 mAbs.
- Organoid-based neutralization correlates with clinical efficacy, outperforming conventional cell-line readouts.
Methodological Strengths
- Use of human nasal organoids with physiologic ACE2/TMPRSS2 expression profiles
- Direct comparison to conventional assays and alignment with real-world clinical outcomes across mAb classes
Limitations
- Preclinical platform without randomized clinical validation for each antibody
- Variant coverage and breadth of tested antibodies, while broad, may not capture all future evolution
Future Directions: Prospective correlation studies linking organoid assay results to clinical outcomes for newly authorized mAbs and variants; standardization and regulatory acceptance frameworks.