Daily Respiratory Research Analysis
Three high-impact studies advance respiratory medicine this week: a multicentre randomized trial shows immunoguided CMV prophylaxis is noninferior to standard care in lung transplant recipients while reducing antiviral exposure; a translational study reports that ultralow-dose dextromethorphan augments pirfenidone’s antifibrotic effects in pulmonary fibrosis via redox modulation and shows clinical signals; and a large community study characterizes one-year outcomes after Omicron infection, linki
Summary
Three high-impact studies advance respiratory medicine this week: a multicentre randomized trial shows immunoguided CMV prophylaxis is noninferior to standard care in lung transplant recipients while reducing antiviral exposure; a translational study reports that ultralow-dose dextromethorphan augments pirfenidone’s antifibrotic effects in pulmonary fibrosis via redox modulation and shows clinical signals; and a large community study characterizes one-year outcomes after Omicron infection, linking reinfections to persistent long COVID with measurable functional deficits.
Research Themes
- Immunoguided antiviral prophylaxis in lung transplantation
- Redox-targeted adjunct therapy in pulmonary fibrosis
- Long COVID epidemiology and functional outcomes after Omicron
Selected Articles
1. Safety and efficacy of immunoguided prophylaxis for cytomegalovirus disease in low-risk lung transplant recipients in Spain: a multicentre, open-label, randomised, phase 3, noninferiority trial.
In a multicentre phase 3 randomized noninferiority trial (n=150), immunoguided CMV prophylaxis (3 months of valganciclovir followed by CMV-specific T‑cell–guided discontinuation) was noninferior to standard 6‑month prophylaxis for preventing CMV disease through 18 months (18.7% vs 16.0%; RD −0.03). The approach reduces antiviral exposure without compromising efficacy.
Impact: This RCT provides practice-changing evidence that immune-guided prophylaxis can safely reduce antiviral use in lung transplantation without increasing CMV disease.
Clinical Implications: Centers can consider adopting CMV cell-mediated immunity assays to tailor valganciclovir duration, potentially lowering drug toxicity (e.g., neutropenia) and costs while maintaining CMV control.
Key Findings
- Immunoguided prophylaxis was noninferior to standard prophylaxis for 18‑month CMV disease incidence (18.7% vs 16.0%; risk difference −0.03, 95% CI −0.15 to 0.06).
- The strategy inherently reduces valganciclovir exposure by halving universal prophylaxis duration (3 vs 6 months).
- Trial conducted across seven centers with randomized, open-label design and predefined noninferiority margin (7%).
Methodological Strengths
- Randomized multicentre phase 3 noninferiority design with predefined margin
- Objective clinical endpoints and extended follow-up to 18 months
Limitations
- Open-label design may introduce performance bias
- Conducted in CMV-seropositive, lower-risk recipients; generalizability to higher-risk populations is uncertain
Future Directions: Cost-effectiveness analyses, validation across diverse risk strata and regions, and operational pathways for integrating CMV-specific T‑cell assays into routine post-transplant care.
BACKGROUND: The standard prophylaxis treatment for cytomegalovirus (CMV) disease in CMV-seropositive lung transplant recipients is six months of prophylaxis with valganciclovir followed by six months of pre-emptive therapy. This protocol is associated with adverse events and risk of resistance. We have previously shown that prophylaxis can be suspended in CMV-seropositive kidney transplant recipients receiving thymoglobulin without increasing the risk of CMV disease and reducing the incidence of neutropenia. The objective of the current study is to demonstrate that immunoguided prophylaxis is effective and safe in seropositive lung transplant recipients. METHODS: A phase III, multicentre, randomised, open-label, noninferiority clinical trial was conducted in adult lung transplant recipients. Patients were randomised (1:1) to two groups: (1) immunoguided prophylaxis (IP), consisting of 3 months of universal prophylaxis followed by CMV-specific cell-mediated immunity-guided discontinuation, or (2) standard prophylaxis (SP), consisting of 6 months of prophylaxis followed by pre-emptive therapy, both for a total of 12 months. The noninferiority margin was 7%. The primary and secondary efficacy endpoints were CMV disease and asymptomatic CMV replication at month 18. The primary and secondary safety endpoints were incidence of neutropenia (defined as neutrophil count <1500 cells/μL), incidence of rejection and number of days of valganciclovir prophylaxis. This trial was registered in EudraCT (2018-003300-39) and ClinicalTrials.gov (NCT03699254). This trial has been completed. FINDINGS: Patients were recruited between April 2019 and December 2021 in seven Spanish centres. A total of 150 patients were randomised (75 patients per group). Incidence of CMV disease at month 18 did not differ among groups (18·7% [14 patients] vs. 16·0% [12 patients]; risk difference [RD] -0·03 [95% CI -0·15% to 0·06%]; INTERPRETATION: Immunoguided prophylaxis was noninferior to the standard of care in preventing CMV disease in lung transplant recipients. It could be considered for implementing in clinical practice in CMV-seropositive lung transplant recipients upon considering the study limitations. FUNDING: Carlos III Health Institute, the SATOT Research Grant, the CIBER (Biomedical Network Research Centre Consortium), the Ministry of Science and Innovation, and the European Union.
2. Add-On Dextromethorphan Improves the Effects of Pirfenidone in Bleomycin-Treated Mice and Patients With Pulmonary Fibrosis.
In bleomycin-treated mice, ultralow-dose dextromethorphan (DM) alone or added to pirfenidone (PFD) reduced fibrosis and hydroxyproline, with benefits even when started 2 weeks after injury. Mechanistically, DM suppressed NOX4/ROS and increased SOD, restoring redox balance. In patients, adding DM to PFD attenuated pulmonary function decline and improved HRCT scores compared with PFD alone.
Impact: This translational work identifies a low-toxicity, repurposable adjunct that enhances antifibrotic efficacy via redox modulation, addressing a key unmet need in IPF.
Clinical Implications: If validated in controlled trials, adding ultralow-dose dextromethorphan to pirfenidone could improve outcomes in pulmonary fibrosis with minimal additional toxicity.
Key Findings
- In vivo, DM (alone/with PFD) reduced fibrotic area and hydroxyproline; efficacy persisted when initiated 2 weeks post-bleomycin.
- In vitro, DM restored redox balance by suppressing NOX4-derived ROS and upregulating SOD, limiting myofibroblast activation.
- Clinically, add-on DM improved HRCT scores and attenuated pulmonary function decline compared with PFD alone.
Methodological Strengths
- Integrated mechanistic (cell), preclinical (mouse), and clinical evaluation
- Consistent antifibrotic effects aligned with redox pathway modulation
Limitations
- Clinical component appears nonrandomized with unspecified sample size, limiting causal inference
- Generalizability and optimal dosing require confirmation in controlled trials
Future Directions: Conduct randomized controlled trials to confirm efficacy and safety, define dosing, and validate redox biomarkers as pharmacodynamic readouts.
BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis is a progressive interstitial lung disease characterised by excessive activation of myofibroblasts. However, currently available antifibrotic drugs exhibit limited efficacy. The dysregulation of redox processes plays a significant role in the pathogenesis of idiopathic pulmonary fibrosis. Dextromethorphan (DM) is used in the treatment of various inflammation-related diseases. This study aimed to investigate the effectiveness of the combination of DM and pirfenidone (PFD) in treating idiopathic pulmonary fibrosis in both animal models and humans. METHODS: In a bleomycin-induced pulmonary fibrosis mouse model, the anti-fibrotic effects of DM and/or PFD were assessed by evaluating fibrotic area, hydroxyproline levels, and fibrotic markers. In a transforming growth factor-β1-induced cell model, proliferation, migration, fibrosis markers, and oxidative stress were analysed to elucidate the mechanisms underlying the anti-fibrotic actions of DM and/or PFD. Finally, the efficacy of DM combined with PFD in patients with pulmonary fibrosis was evaluated by comparing pulmonary imaging scores and pulmonary function before and after treatment in the PFD group and the PFD + DM group. RESULTS: We observed that even ultralow doses of DM, either alone or in combination with PFD, demonstrated substantial protective effects in mice. Notably, administration of DM or combined drugs at 2 weeks after bleomycin modelling still showed anti-fibrotic effects. In vitro, DM monotherapy and combination therapy restored the redox balance by suppressing nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 4/reactive oxygen species production and upregulating superoxide dismutase, contributing to their anti-fibrotic mechanisms. In the clinical study, add-on DM improved PFD in mitigating pulmonary function decline and improving chest high-resolution computed tomography imaging scores. CONCLUSIONS: Ultralow doses of dextromethorphan significantly alleviate pulmonary fibrosis in bleomycin-treated mice through restoring the redox balance. Add-on DM improves the effects of PFD in both bleomycin-treated mice and patients with pulmonary fibrosis. TRIAL REGISTRATION: ChiCTR2000037602.
3. Health outcomes one year after Omicron infection among 12,789 adults: a community-based cross-sectional study.
In 12,789 adults one year after Omicron infection, long COVID affected 7.8% (persistent 5.1%), with fatigue and post-exertional malaise most common and brain fog rarely resolving. Reinfections substantially increased odds of long COVID (OR 2.59 for one; 6.17 for ≥2). Persistent long COVID was associated with reduced muscle strength, exercise capacity, HRQoL, and higher rates of abnormal lung function.
Impact: This large, population-based study quantifies persistent long COVID burden after Omicron and links reinfection to risk, informing surveillance, prevention, and rehabilitation strategies.
Clinical Implications: Prioritize vaccination/boosters and reinfection prevention, screen for persistent deficits with standardized tools, and target rehabilitation for strength, endurance, and respiratory function in long COVID.
Key Findings
- Long COVID prevalence at one year was 7.8%, with 5.1% persistent symptoms; fatigue and post-exertional malaise predominated, and brain fog rarely resolved (4.2%).
- Reinfections markedly increased long COVID risk (OR 2.592 for one reinfection; 6.171 for ≥2).
- Persistent long COVID showed lower muscle strength, impaired exercise capacity, worse HRQoL, and higher proportions of abnormal lung function.
Methodological Strengths
- Large stratified multistage random sample with matched subset for objective testing
- Comprehensive assessment across physical, mental, laboratory, and functional domains
Limitations
- Cross-sectional design limits causal inference and temporal dynamics
- Self-reported symptoms and single-region sample may introduce recall or selection biases
Future Directions: Prospective longitudinal cohorts to define trajectories, biomarker-driven endotypes, and randomized rehabilitation trials targeting persistent deficits.
BACKGROUND: Characterizing the paradigm and impact of long COVID is crucial for addressing this worldwide health challenge. This study aimed to investigate the prevalence of long COVID one year after primary Omicron infection and characterize differences in long-term health consequence between participants with persistent long COVID and those who fully recovered. METHODS: This a community-based cross-sectional study conducted from December 2023 to March 2024 at the China-Japan Friendship Hospital and 16 administrative districts in Beijing. 12,789 participants infected with Omicron between December 2022 and January 2023 were recruited through stratified multistage random sampling and included in the final analysis. Of them, 376 participants with persistent long COVID and 229 without long COVID were matched for further physical examinations. The primary outcome was the prevalence of long COVID one year after infection. Secondary outcomes included muscle strength, exercise capacity, health-related quality of life (HRQoL), mental health, work status, laboratory tests, and examinations. FINDINGS: Among 12,789 participants (media [IQR] age, 48.4 [37.3 to 61.4] years; 7817 females [61.1%]), 995 of them (7.8%) experienced long COVID within one year, with 651 (5.1%) having persistent symptoms. Fatigue (598/995 [60.1%]) and post-exertional malaise (367/995 [36.9%]) were the most common symptoms. Brain fog had the lowest resolution proportion as 4.2% within one year. The odds of long COVID increased with reinfections (odds ratios for one reinfection 2.592 [95% CI: 2.188 to 3.061]; two or more: 6.171 [3.227 to 11.557]; all p < 0.001). Participants with persistent long COVID had markedly lower muscle strength (upper-limb: 26.9 ± 12.4 vs. 29.1 ± 14.5 Kg; lower-limb: 40.0 [27.0 to 62.0] vs. 43.0 [28.0 to 59.0] s), worse exercise capacity and poorer HRQoL, and meaningful difference in laboratory tests results compared to those without long COVID. They also exhibited significantly higher proportions of abnormal lung function (FEV INTERPRETATION: The considerable health burden of long COVID and the progression of neurological symptoms following Omicron infection warrant close monitoring. Utilizing professional questionnaires and developing reliable diagnostic tools are necessary for improving diagnosis and treatment of long COVID. FUNDING: This work was supported by Beijing Research Center for Respiratory Infectious Diseases (BJRID2024-012), Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (2022-I2M-CoV19-005/CIFMS 2021-I2M-1-048), the National Natural Science Foundation of China (82241056/82200114/82200009), the New Cornerstone Science Foundation.