Daily Respiratory Research Analysis
Analyzed 58 papers and selected 3 impactful papers.
Summary
Three impactful respiratory-focused studies span clinical evidence synthesis and human immunogenetics. A meta-analysis supports macrolides as adjunct therapy improving asthma control and reducing severe exacerbations with no increase in serious harms. Human genetic data reveal heterozygous DOCK2 variants impair antiviral immunity, and a meta-analysis shows oropharyngeal and respiratory muscle training modestly reduce OSA severity.
Research Themes
- Adjunct anti-inflammatory strategies in asthma
- Host genetic determinants of respiratory viral susceptibility
- Non-CPAP physiological therapies for obstructive sleep apnea
Selected Articles
1. Heterozygous variants in DOCK2 leading to susceptibility to viral illnesses.
Across three families, heterozygous DOCK2 variants within the ELMO1-binding domain impaired protein stability and function, causing defects in Rac1 activation and Toll-like receptor signaling and predisposing to severe RSV, SARS-CoV-2, and HPV infections. Interferon-α led to complete resolution of refractory warts in one patient, suggesting a therapeutic avenue.
Impact: This study reframes DOCK2 deficiency beyond autosomal recessive disease by demonstrating pathogenic heterozygous variants with mechanistic validation, directly relevant to severe respiratory viral infections.
Clinical Implications: Consider genetic evaluation for DOCK2 variants in patients with otherwise unexplained severe RSV or SARS-CoV-2 infections. Type I interferon therapy may be a rational option in selected DOCK2-related phenotypes.
Key Findings
- Identified three novel heterozygous DOCK2 variants in six individuals with severe viral infections (HPV, RSV, SARS-CoV-2).
- All variants localized to the ELMO1-binding domain and reduced DOCK2 expression, ELMO1 binding, Rac1 activation, and select Toll-like receptor signaling.
- Weekly interferon-α resolved refractory warts in one patient, indicating therapeutic potential.
Methodological Strengths
- Functional validation in primary patient cells and overexpression systems demonstrating mechanistic impact.
- Systematic exome screening across three independent cohorts (n=1,109) to identify additional cases.
Limitations
- Small number of affected individuals limits genotype–phenotype generalizability.
- Clinical therapeutic evidence is anecdotal (single-patient IFN-α response).
Future Directions: Prospective multicenter registries to define penetrance and spectrum; functional rescue studies; interventional trials testing type I interferon or pathway-targeted therapies in DOCK2-associated susceptibility.
BACKGROUND: Inborn errors of immunity (IEIs) are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals. OBJECTIVE: We investigated how three novel heterozygous variants in DOCK2 contribute to impaired anti-viral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal recessive disease. METHODS: After identifying the first DOCK2 variant, we screened 1,109 exomes from three cohorts of patients with a history of at least one severe respiratory, bloodborne, or soft tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary peripheral blood mononuclear cells and in cell-based overexpression systems. RESULTS: Six individuals from three unrelated families, aged 3 months to 50 years, caried one of three heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or SARS-CoV-2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in one patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency. CONCLUSIONS: These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2-ELMO1 interactions impair protein stability and anti-viral immunity, revealing a previously unrecognized IEI affecting otherwise healthy individuals.
2. Macrolides for asthma: a systematic review and meta-analysis of randomized trials.
Across 19 RCTs (n=1825), macrolides improved asthma control (ACQ-6 MD -0.23) and likely reduced severe exacerbations (IRR 0.75) with minimal differences in serious adverse events. Benefits were similar in T2-high and T2-low phenotypes.
Impact: High-quality synthesis directly informing forthcoming guideline recommendations and supporting macrolides as an adjunct for both T2-high and T2-low asthma.
Clinical Implications: Macrolides may be considered as adjunct therapy to reduce exacerbations and improve control, particularly in severe or difficult-to-treat asthma, with careful stewardship to mitigate antimicrobial resistance.
Key Findings
- Improved asthma control (ACQ-6 MD -0.23; high certainty) and likely reduced severe exacerbations (IRR 0.75; moderate certainty).
- Quality of life gains were modest (AQLQ MD 0.11), with higher proportions achieving MID improvements on both ACQ and AQLQ.
- No increase in serious adverse events or mortality; effects consistent across T2-high and T2-low phenotypes.
Methodological Strengths
- Prospective registration (PROSPERO) and GRADE assessment with PRISMA-consistent methodology.
- Use of individual patient data models for asthma control and QoL alongside random-effects meta-analysis for exacerbations and harms.
Limitations
- Heterogeneity in macrolide agents, dosing, and duration across trials.
- Modest effect sizes for QoL and potential publication bias cannot be fully excluded.
Future Directions: Head-to-head RCTs comparing macrolides and biologics or small molecules in defined endotypes, with antimicrobial resistance monitoring and long-term outcomes.
BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear. OBJECTIVE: As part of upcoming AAAAI/ACAAI JTFPP guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma. METHODS: We systematically searched MEDLINE, EMBASE, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides to placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects ANCOVA models addressed asthma control and asthma-related quality of life (QoL). Random effects meta-analyses addressed severe exacerbations and harms. We used the GRADE approach to evaluate certainty of evidence. PROSPERO (CRD42023408677). RESULTS: Nineteen trials enrolled 1825 participants. Compared to placebo, macrolides improve asthma control (ACQ-6; 0-6; lower better; between-group mean difference [MD]: -0.23 [95%CI -0.32 to -0.13]; 40.6% vs. 21.6% improving by minimally important difference [MID] of 0.5 points; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95%CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95%CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve QoL (AQLQ; 1-7; higher better; MD: 0.11 [95%CI -0.06 to 0.29]; 47.6% vs. 42.4% improving by MID of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with T2-high versus T2-low asthma. CONCLUSION: Macrolides likely reduce severe exacerbations and improve asthma control and QoL with little to no difference in serious harms among patients with T2-high or T2-low asthma.
3. Efficacy of therapies based on muscle strength training among individual with Obstructive Sleep Apnea - a systematic review and meta-analysis.
Across 13 RCTs (n=429), oropharyngeal training and respiratory muscle training significantly reduced AHI, while generic resistance training did not. Daytime sleepiness (ESS) changes were inconsistent, supporting these modalities as physiological adjuncts to standard OSA care.
Impact: Synthesizes RCT evidence showing specific muscle-based interventions can reduce physiological OSA severity, informing non-CPAP adjunct strategies.
Clinical Implications: Offer oropharyngeal and/or respiratory muscle training as adjuncts for patients intolerant to CPAP or seeking additional AHI reduction, while standardizing protocols and monitoring adherence.
Key Findings
- Oropharyngeal training significantly reduced AHI (MD approximately -7.6 events/h).
- Respiratory muscle training significantly reduced AHI (MD approximately -4.7 events/h).
- Generic resistance training alone showed no significant effect on AHI; ESS improvements were inconsistent across modalities.
Methodological Strengths
- Restriction to randomized controlled trials with modality-specific random-effects meta-analyses.
- Clear separation of intervention types (OT, RMT, RT) enabling modality-specific inference.
Limitations
- Heterogeneity in program content, intensity, and duration; limited long-term follow-up.
- ESS and other patient-important outcomes were inconsistently reported.
Future Directions: Standardized, multicenter RCTs with longer follow-up to assess sustained effects on AHI, symptoms, cardiovascular outcomes, and adherence; head-to-head comparisons versus other adjuncts.
BACKGROUND: Exercise modalities that target upper-airway and respiratory muscles may modify obstructive sleep apnea (OSA) severity. OBJECTIVE: To synthesize randomized controlled trials (RCTs) of resistance training (RT), oropharyngeal training (OT), and respiratory muscle training (RMT) on OSA severity (apnea-hypopnea index, AHI) and daytime sleepiness (Epworth Sleepiness Scale, ESS). METHODS: PubMed, EBSCO, and Scopus were searched (1 Jan 2015-31 Jan 2025). Of 1,805 records identified, 13 RCTs (n=429) met eligibility. Random-effects meta-analyses were performed within modality. RESULTS: OT reduced AHI (mean difference, MD -7.55 events·h CONCLUSIONS: When analyzed within modality, OT and RMT are associated with reductions in AHI, whereas RT alone does not demonstrate a significant effect. Symptom change measured by ESS was not consistently observed. These findings support OT and RMT as adjunctive options for reducing physiological OSA severity, while underscoring the need for standardized protocols, longer follow-up, and patient-important outcomes.