Daily Ards Research Analysis
A multicenter RCT showed that antenatal betamethasone reduces severe neonatal respiratory morbidity in late preterm twin pregnancies, with an increased risk of neonatal hypoglycemia. Mechanistic work revealed the SARS‑CoV‑2 S2 subunit directly inhibits pulmonary surfactant function, offering a biophysical basis for surfactant dysfunction in COVID‑19 ARDS. A large cohort identified two physiologic latent classes of sepsis-associated AHRF distinguished by lung mechanics and mortality, suggesting a
Summary
A multicenter RCT showed that antenatal betamethasone reduces severe neonatal respiratory morbidity in late preterm twin pregnancies, with an increased risk of neonatal hypoglycemia. Mechanistic work revealed the SARS‑CoV‑2 S2 subunit directly inhibits pulmonary surfactant function, offering a biophysical basis for surfactant dysfunction in COVID‑19 ARDS. A large cohort identified two physiologic latent classes of sepsis-associated AHRF distinguished by lung mechanics and mortality, suggesting a distinct physiologic axis beyond biomarker subphenotypes.
Research Themes
- Antenatal corticosteroids and neonatal respiratory outcomes in twins
- Physiologic subphenotyping in sepsis-associated AHRF/ARDS
- Viral–surfactant biophysical interactions in COVID-19 ARDS
Selected Articles
1. Antenatal Corticosteroid in Twin-Pregnant Women at Risk of Late Preterm Delivery: A Randomized Clinical Trial.
In late preterm twin pregnancies, antenatal betamethasone reduced severe neonatal respiratory morbidity compared with placebo (RR 0.64), with additional reductions in CPAP ≥2 hours and transient tachypnea. Benefits were time-dependent (delivery 12 hours to <7 days after first dose), while neonatal hypoglycemia increased.
Impact: This is a large, multicenter, randomized, placebo-controlled trial addressing a key evidence gap for twins at risk of late preterm delivery and may inform guideline updates.
Clinical Implications: Consider antenatal betamethasone for women with twin pregnancies at risk of late preterm delivery, particularly when delivery is anticipated within 12 hours to 7 days, with vigilant neonatal glucose monitoring.
Key Findings
- Severe neonatal respiratory morbidity was lower with betamethasone vs placebo (4.8% vs 7.5%; RR 0.64, 95% CI 0.42–0.98).
- CPAP use ≥2 hours (RR 0.58, 95% CI 0.35–0.95) and transient tachypnea of the newborn (RR 0.47, 95% CI 0.25–0.89) were reduced.
- Benefit was observed only when delivery occurred 12 hours to <7 days after first betamethasone dose.
- Neonatal hypoglycemia increased with betamethasone (15.6% vs 11.7%; RR 1.33, 95% CI 1.01–1.75).
Methodological Strengths
- Multicenter, randomized, placebo-controlled, intention-to-treat analysis
- Pre-registered trial with clearly defined primary and exploratory outcomes and adequate sample size
Limitations
- Generalizability beyond Korean university centers is uncertain
- Increased neonatal hypoglycemia and limited long-term neonatal follow-up reported
Future Directions: Assess long-term neurodevelopmental and metabolic outcomes; evaluate optimal timing for twins; and stratify by chorionicity and mode of delivery.
IMPORTANCE: Recent guidelines have recommended corticosteroid injection in women with singleton pregnancies at risk of late preterm delivery. However, the effectiveness of antenatal corticosteroid administration in women with twin pregnancies at risk of late preterm delivery has not been evaluated, and studies on this population are lacking. OBJECTIVE: To evaluate whether antenatal betamethasone administration reduces the risk of neonatal respiratory morbidity in late preterm twin neonates. DESIGN, SETTING, AND PARTICIPANTS: In this multicenter randomized trial, twin-pregnant women at 34 weeks 0 days to 36 weeks 5 days of gestation at risk of late preterm delivery were enrolled across 8 university-based clinical centers in Korea. Data were collected between May 2018 and July 2024. Intention-to-treat analysis was performed. INTERVENTION: The participants received 2 injections of betamethasone or placebo after randomization (1:1). MAIN OUTCOMES AND MEASURES: The primary outcome was perinatal death within 72 hours after birth or severe neonatal respiratory morbidity. The exploratory outcomes were mild neonatal respiratory morbidities, other neonatal respiratory morbidities, other neonatal complications, or maternal complications. RESULTS: A total of 812 participants were randomized and analyzed, with 410 in the intervention group (median [IQR] age, 35 [33-37] years) and 402 in the placebo group (median [IQR] age, 35 [32-38] years). Among 1620 neonates (818 in the intervention group and 802 in the placebo group), there were no perinatal deaths in either group, and severe neonatal respiratory morbidity occurred in 99 neonates (6.1%), with lower risk in the betamethasone group than in the placebo group (39 [4.8%] vs 60 [7.5%]; relative risk [RR], 0.64 [95% CI, 0.42-0.98]). For the exploratory outcomes, continuous positive airway pressure use for 2 hours or more (RR, 0.58 [95% CI, 0.35-0.95]) and transient tachypnea of the newborn (RR, 0.47 [95% CI, 0.25-0.89]) were lower in the betamethasone group. The risk of primary outcome and mild respiratory morbidities was reduced only in neonates delivered between 12 hours or more and less than 7 days after the first betamethasone administration. The risk of neonatal hypoglycemia was increased in the betamethasone group (128 [15.6%] vs 94 [11.7%]; RR, 1.33 [95% CI, 1.01-1.75]), but the risk of neonatal sepsis or maternal chorioamnionitis did not differ between the 2 groups. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, antenatal betamethasone administration in women with twin pregnancies at risk of late preterm delivery significantly reduced the risk of neonatal respiratory morbidity. The outcomes from this study could serve as a valuable reference in clinical management of twin pregnancies at risk of late preterm delivery. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03547791.
2. Biophysical mechanisms of SARS-CoV-2-induced surfactant inhibition.
Using constrained drop surfactometry and AFM, the SARS‑CoV‑2 S2 subunit—but not S1—directly impaired pulmonary surfactant films by reducing dynamic surface activity and inducing monolayer domain fusion. These data provide a mechanistic basis for surfactant dysfunction in COVID‑19 ARDS and inform optimization of surfactant therapies.
Impact: First biophysical delineation of differential S1 vs S2 effects on pulmonary surfactant function links viral protein structure to surfactant failure, offering translational targets.
Clinical Implications: Surfactant replacement strategies for COVID‑19 ARDS may need to counter S2-mediated inhibition (e.g., formulations resistant to S2 effects or adjuncts that preserve surface activity).
Key Findings
- Recombinant S2, but not S1, selectively inhibited pulmonary surfactant films.
- S2 reduced dynamic surface activity and caused domain fusion in surfactant monolayers.
- Combined constrained drop surfactometry and AFM enabled direct biophysical characterization on natural bovine surfactant.
Methodological Strengths
- Orthogonal biophysical techniques (constrained drop surfactometry and AFM)
- Controlled comparison of S1 vs S2 on natural surfactant preparations
Limitations
- In vitro system using bovine surfactant without in vivo validation
- Physiological concentrations and interactions with whole virions or airway milieu were not assessed
Future Directions: Validate findings in animal models and human samples; test surfactant formulations resistant to S2; explore pharmacologic blockers of S2–surfactant interactions.
Surfactant replacement has been studied as a supportive therapy for managing COVID-19-induced acute respiratory distress syndrome. The clinical applications require biophysical understanding of the molecular mechanisms behind SARS-CoV-2-induced surfactant inhibition. Although SARS-CoV-2 is known to attack alveolar type II epithelial cells, it is unknown whether the virus can directly interact with the pulmonary surfactant film adsorbed at the alveolar surface. The virus utilizes its spike (S) protein, consisting of two functional subunits (S1 and S2), to bind to the host cell membrane and mediate subsequent membrane fusion. We hypothesize that these two subunits may differentially interact with pulmonary surfactant, resulting in distinct effects on surfactant inhibition. The biophysical impact of recombinant S1 and S2 subunit proteins on a bovine-extracted natural pulmonary surfactant film was investigated with combined constrained drop surfactometry and atomic force microscopy. Our findings revealed that the S2 subunit, in contrast to the S1 subunit, selectively induces surfactant inhibition, evidenced by its capacity in reducing dynamic surface activity and causing domain fusion in surfactant monolayers. These results contribute novel insights into the biophysical mechanisms underlying surfactant inhibition in SARS-CoV-2-induced acute respiratory distress syndrome and may hold translational implications for advancing surfactant therapy to manage COVID-19.
3. Two Physiologic Latent Classes of Acute Hypoxemic Respiratory Failure in Sepsis Are Distinguished by Lung Mechanics and Gas Exchange.
In 882 ventilated sepsis patients with AHRF, two physiologic latent classes emerged. Class 1 had lower static compliance, impaired ventilation, and higher 30‑day mortality independent of sepsis severity, and included more women and persons with obesity. These classes were distinct from ARDS qualification and biomarker-based subphenotypes.
Impact: Reveals a physiologic axis of heterogeneity in sepsis-associated AHRF that is not captured by ARDS criteria or biomarker subphenotypes, informing precision respiratory care.
Clinical Implications: Physiologic subtyping by lung mechanics and gas exchange may aid risk stratification and tailoring of ventilatory strategies in sepsis-related AHRF beyond current ARDS labels.
Key Findings
- Two physiologic latent classes were identified in sepsis-associated AHRF.
- Class 1 had lower static compliance and impaired ventilation vs class 2.
- Class 1 showed higher 30-day mortality (adjusted risk difference 0.12, p<0.001) independent of sepsis severity.
- Classes were not primarily determined by ARDS qualification or prior hyperinflammatory biomarker subphenotypes; class 1 included more women and individuals with obesity.
Methodological Strengths
- Prospective sepsis cohort with rigorous latent class analysis
- Mortality association adjusted for illness severity (APACHE) and comparison with biomarker-based subphenotypes
Limitations
- Single metropolitan area; external validation needed
- Observational design cannot establish treatment effects or causality
Future Directions: External validation and assessment of treatment-modifying effects across classes, including ventilatory settings, PEEP responsiveness, and proning benefit.
OBJECTIVES: Physiologic subtypes of acute hypoxemic respiratory failure (AHRF) may confer a differential response to treatments, particularly therapeutic strategies that are specific to pulmonary organ failure. We sought to identify physiologic latent classes of sepsis-associated AHRF defined by respiratory mechanics, oxygenation, ventilation, and radiographic patterns of lung injury, and to determine the association between class membership and 30-day mortality. DESIGN: We performed latent class analysis of patients with AHRF newly requiring mechanical ventilation enrolled in a prospective cohort of patients with sepsis from 2011 to 2020. We used logistic regression adjusted for Acute Physiology and Chronic Health Evaluation to determine the association between class membership and 30-day mortality and examined the distribution of patients classified as "hyperinflammatory" by previously described biomarker-based subphenotyping paradigms. SETTING: Philadelphia, Pennsylvania, United States. PATIENTS: Eight hundred eighty-two patients. MEASUREMENTS AND MAIN RESULTS: We identified two physiologic latent classes. Class 1 (n = 390) was characterized by low static compliance and impaired ventilation when compared with class 2 (n = 432). Mortality at 30 days was higher in the more physiologically severe class 1 when compared with class 2 (adjusted risk difference 0.12, p < 0.001) despite a similar severity of sepsis. Class 1 also contained a higher proportion of female patients and patients with obesity. CONCLUSIONS: We identified two physiologic latent classes of sepsis-associated AHRF. Relative to class 2, class 1 was distinguished by low compliance, impaired ventilation, and higher 30-day mortality independent of the severity of sepsis. The higher percentage of female patients and patients with obesity in class 1 suggests a potential role for body composition in class determination. Physiologic classes were not primarily determined by qualification for acute respiratory distress syndrome or previously described biomarker-based subphenotypes, suggesting a distinct physiologic "axis" of heterogeneity.