Daily Respiratory Research Analysis
Three studies stand out today: a massive U.S. target-trial emulation shows nirmatrelvir/ritonavir (Paxlovid) substantially reduces COVID-19 hospitalization and death, including among vaccinated and older adults; a Catalonia-wide infant cohort demonstrates strong real-world effectiveness of single-dose nirsevimab against RSV-related hospital and PICU admissions; and a mechanistic influenza study identifies early neutrophil recruitment and function as key determinants of viral control and lung inf
Summary
Three studies stand out today: a massive U.S. target-trial emulation shows nirmatrelvir/ritonavir (Paxlovid) substantially reduces COVID-19 hospitalization and death, including among vaccinated and older adults; a Catalonia-wide infant cohort demonstrates strong real-world effectiveness of single-dose nirsevimab against RSV-related hospital and PICU admissions; and a mechanistic influenza study identifies early neutrophil recruitment and function as key determinants of viral control and lung inflammation, with adoptive transfer restoring protection.
Research Themes
- Real-world effectiveness of COVID-19 antivirals
- Population-level RSV immunoprophylaxis in infants
- Neutrophil-mediated control of respiratory viral infections
Selected Articles
1. Deficient neutrophil responses early in influenza infection promote viral replication and pulmonary inflammation.
In a comparative murine model, early neutrophil recruitment and effector function (NETs, ROS) determined influenza control and survival. Adoptive transfer of competent neutrophils restored viral clearance and dampened inflammatory mediators, implicating early neutrophil competence as a key moderator of disease.
Impact: This mechanistic study pinpoints early neutrophil competence as causal in influenza outcomes and provides an actionable host-targeted concept for timing and modulation of innate responses.
Clinical Implications: Therapies enhancing early neutrophil recruitment/function or timing immunomodulation to avoid late neutrophil-driven injury could improve outcomes in severe influenza and possibly other respiratory viral infections.
Key Findings
- A self-resolving PR8 dose was lethal in A/J mice with higher viral loads, marked neutrophilia, and vascular leak vs. B6 mice.
- A/J neutrophils exhibited reduced NET release and ROS generation early after infection.
- Adoptive transfer of B6 neutrophils into A/J mice enhanced viral clearance and reduced CXCL1 and IL-6 dissemination; A/J neutrophils did not.
- B6 neutrophils showed greater in vitro viral killing capacity than A/J neutrophils.
Methodological Strengths
- Head-to-head comparison of genetically distinct mouse strains with differing outcomes
- Adoptive neutrophil transfer demonstrating causality for early neutrophil function in viral control
Limitations
- Mouse models may not fully recapitulate human influenza pathophysiology
- Specific molecular determinants of neutrophil functional differences were not identified
Future Directions: Define molecular regulators of early neutrophil competence, test timed host-directed therapies, and validate findings in human cohorts or ex vivo human systems.
2. Effect of nirmatrelvir/ritonavir (Paxlovid) on hospitalization among adults with COVID-19: An electronic health record-based target trial emulation from N3C.
In a target trial emulation of 703,647 U.S. patients during the Omicron era, Paxlovid reduced hospitalization by 39% and death by 61%, with larger absolute benefit in adults ≥65 years and effectiveness regardless of vaccination status. Notably, treatment disparities were observed across racial/ethnic and socially vulnerable groups.
Impact: The study provides robust, contemporary, real-world effectiveness estimates using advanced causal inference on a national scale, directly informing clinical and public health policy.
Clinical Implications: Paxlovid should be prioritized for older adults and high-risk patients regardless of vaccination, while addressing inequities in access to ensure broad benefit.
Key Findings
- Target trial emulation with clone-censor-weight on 703,647 EHR records estimated 39% lower hospitalization risk and 61% lower mortality with Paxlovid.
- Absolute risk reduction was greatest in adults ≥65 years; effectiveness observed in both vaccinated and unvaccinated.
- Significant disparities in Paxlovid treatment rates among Black, Hispanic/Latino patients and socially vulnerable communities.
Methodological Strengths
- Nationwide, multi-site dataset with large sample size (703,647) during Omicron era
- Rigorous target trial emulation using clone-censor-weight and IPCW to address time-related biases
Limitations
- Observational design may be affected by unmeasured confounding despite advanced adjustment
- EHR-based definitions and prescription capture may miss out-of-network treatments
Future Directions: Prospective pragmatic trials on access strategies, dosing/timing optimization in older adults, and interventions to mitigate treatment disparities.
3. Effectiveness of Nirsevimab Immunoprophylaxis Against Respiratory Syncytial Virus-related Outcomes in Hospital Care Settings: A Seasonal Cohort Study of Infants in Catalonia, Spain.
In 15,341 infants <6 months in Catalonia, single-dose nirsevimab markedly reduced RSV bronchiolitis-related hospitalization (HR 0.26), PICU admission (HR 0.15), and emergency visits (HR 0.46), with similar benefits for all-cause bronchiolitis. Sensitivity analyses with matching supported robustness.
Impact: This provides high-quality real-world effectiveness data at regional scale for RSV immunoprophylaxis, directly informing roll-out decisions and healthcare resource planning.
Clinical Implications: Nirsevimab should be integrated into seasonal RSV prevention strategies for young infants to prevent hospital and PICU burden.
Key Findings
- Adjusted HRs for RSV bronchiolitis outcomes with nirsevimab: hospitalization 0.26, PICU 0.15, ED visits 0.46.
- All-cause bronchiolitis also reduced: hospitalization HR 0.45, PICU HR 0.23, ED visits HR 0.49.
- Sensitivity analyses using matching supported the effectiveness estimates.
Methodological Strengths
- Large population-based seasonal cohort (N=15,341) with Cox models and calendar time scale
- Sensitivity analyses including matching to address confounding
Limitations
- Retrospective observational design may be prone to residual confounding
- Effect estimates compared to a catch-up cohort may reflect temporal differences in RSV circulation
Future Directions: Evaluate duration of protection, cost-effectiveness across seasons, and equity in coverage; assess synergistic strategies with maternal vaccination.