Daily Respiratory Research Analysis

BACKGROUND: Critically ill patients with acute respiratory distress syndrome (ARDS) and sepsis exhibit distinct inflammatory phenotypes with divergent clinical outcomes, but the underlying molecular mechanisms remain poorly understood. These phenotypes, derived from clinical data and protein biomarkers, were associated with metabolic differences in a pilot study. METHODS: We performed integrative multi-omics analysis of blood samples from 160 ARDS patients in the ROSE trial, randomly selecting 80 patients from each latent class analysis-defined inflammatory phenotype (Hyperinflammatory and Hypoinflammatory) with phenotype probability >0.9. Untargeted plasma metabolomics and whole blood transcriptomics at Day 0 and Day 2 were analyzed using multi-modal factor analysis (MEFISTO). The primary outcome was 90-day mortality, with validation in an independent critically ill sepsis cohort (EARLI). RESULTS: Multi-omics integration revealed four molecular signatures associated with mortality: (1) enhanced innate immune activation coupled with increased glycolysis (associated with Hyperinflammatory phenotype), (2) hepatic dysfunction and immune dysfunction paired with impaired fatty acid beta-oxidation (associated with Hyperinflammatory phenotype), (3) interferon program suppression coupled with altered mitochondrial respiration (associated with Hyperinflammatory phenotype), and (4) redox impairment and cell proliferation pathways (not associated with inflammatory phenotype). These signatures persisted through Day 2 of trial enrollment. Within-phenotype analysis revealed distinct mortality-associated pathways in each group. All molecular signatures were validated in the independent EARLI cohort. CONCLUSIONS: Inflammatory phenotypes of ARDS reflect distinct underlying biological processes with both phenotype-specific and phenotype-independent pathways influencing patient outcomes, all characterized by mitochondrial dysfunction. These findings suggest potential therapeutic targets for precise treatment strategies in critical illness. FUNDING: This work is the result of NIH funding.

BACKGROUND: Respiratory syncytial virus (RSV) is a leading cause of infant hospitalisation, particularly in infants younger than 6 months. On Aug 12, 2024, Scotland introduced a maternal vaccination programme with bivalent RSV prefusion F (RSVpreF) vaccine, offered from 28 weeks' gestation. Although clinical trials have shown high efficacy of maternal RSVpreF vaccination, this study assessed RSVpreF vaccine effectiveness in a real-world setting, to inform policy and programme delivery. METHODS: We did a retrospective, nested case-control study with a cohort sensitivity analysis. The source population comprised all singleton livebirths in Scotland between Aug 12, 2024, and March 31, 2025, as recorded in the Scottish Linked Pregnancy and Baby Dataset (SLiPBD). Within this population, cases were defined as infants aged 90 days or younger with an RSV-related hospital admission for lower respiratory tract infection (LRTI; first event only) and an RSV-positive PCR test within 14 days before or 2 days after hospital admission, within the study period up to March 31, 2025. At the time of hospital admission, cases were matched to ten controls each (1:10 case:control ratio) from the source population by ISO week of birth and gestational age at birth, with controls defined as infants with no previous RSV-positive test or RSV-related hospital admission at the time of matching. Linked datasets on maternal RSV vaccination and RSV-related hospital admissions were accessed through the recently established Scottish Infectious Respiratory Surveillance Platform. Infants were classified as vaccinated if the RSV vaccine was received more than 14 days before delivery, suboptimally immunised if received 0-14 days before delivery, and unvaccinated if not received during pregnancy. The study outcome was RSV-related LRTI hospital admissions among infants aged 90 days or younger. Vaccine effectiveness against RSV-related LRTI hospital admissions was estimated with adjusted conditional logistic regression comparing vaccination status among cases and controls, adjusting for infant sex and birthweight, maternal ethnicity, maternal age and Scottish Index of Multiple Deprivation at infant birth, maternal smoking status at the first antenatal appointment, and parity. From this model, adjusted vaccine effectiveness was calculated as 100 × (1 - adjusted odds ratio). FINDINGS: During the study period, 27 565 singleton livebirths were recorded in the SLiPBD. 13 842 (50·2%) of the 27 565 pregnant women received the RSVpreF vaccine, 12 747 (92·1%) of whom were vaccinated more than 14 days before delivery. 354 infants aged 90 days or younger had an RSV-related LRTI hospital admission during the study period (cases), with 3511 matched controls. 33 controls later became cases. Among the 354 cases, 43 (12·1%) were vaccinated (>14 days before delivery) against RSV, compared with 1518 (43·2%) of the 3511 controls. Suboptimal immunisation (≤14 days before delivery) occurred in 18 (5·1%) cases and 205 (5·8%) controls. Median gestational age at vaccination was 31 weeks (IQR 28-34) among cases and 30 weeks (28-33) among controls. Adjusted vaccine effectiveness against RSV-associated LRTI hospital admission was 82·2% (95% CI 75·1-87·3; p<0·0001) in vaccinated infants compared with unvaccinated infants, which translated to 219 (95% CI 189-243) RSV-related LRTI hospital admissions averted during the study period. Adjusted vaccine effectiveness remained high among infants born preterm (<37 weeks' gestation; 89·9% [55·3-97·7]; p=0·0025), as well as for term-born infants (≥37 weeks' gestation; 81·5% [73·9-87·0]; p<0·0001). In a sensitivity analysis using a matched cohort approach in the same source population, adjusted vaccine effectiveness against RSV-associated LRTI hospital admission was 81·0% (68·6 to 88·5; p<0·0001). INTERPRETATION: This national population-based study provides evidence that maternal RSV vaccination substantially reduces the risk of RSV-related LRTI hospital admission in infants aged 90 days or younger, including in preterm infants. Maternal RSV vaccination programmes should be scaled up globally, with high coverage, to offer the potential to avert many RSV-associated infant hospitalisations. FUNDING: None.

BACKGROUND: After a prolonged period of low detection rates, Mycoplasma pneumoniae resurged in China, during September to November, 2023, raising global concern. This study aims to gain a better understanding of the genetic mechanisms underlying the 2023 increase in cases and the evolutionary dynamics of the epidemic populations, which has been previously hampered due to limited genomic data of this pathogen. METHODS: We sequenced 685 M pneumoniae isolates, including 248 isolates from 11 Chinese provinces and municipalities in 2023 and 437 isolates from Beijing (2013-22). By analysing these isolates and 436 publicly global sequences, we reconstructed the pathogen's evolutionary history using time-calibrated phylogenies and effective population size inference. We investigated potential genomic variations contributing to the 2023 resurgence through genome-wide association study and conducted phylogeographic analysis of the 2023 isolates across China. FINDINGS: Two macrolide-resistant epidemic clusters (T1-2-EC1 and T2-2-EC2) were responsible for the 2023 resurgence in China. Both clusters, having acquired the 23S ribosomal RNA A2063G mutation conferring macrolide resistance, emerged in approximately 1997 and 2014, respectively, and subsequently outcompeted their predecessor populations. This coincided with China's large-scale adoption of azithromycin for paediatric community-acquired pneumonia around the early 2000s. Aside from macrolide resistance, T1-2-EC1 independently acquired 17 clade-specific mutations and T2-2-EC2 four clade-specific mutations, which could further explain their increased competitiveness. Whole-genome analysis revealed no resurgence-specific mutations in the 2023 isolates. Phylogeographic analysis showed rapid mixing of T1-2-EC1 isolates between different sampled regions within China. INTERPRETATION: Our study provides evidence that the 2023 resurgence in China is a continuation of the pre-COVID epidemic, rather than emergence of novel variants. The high prevalence of macrolide resistance and rapid intranational spread emphasise the urgent need for enhanced global surveillance of this pathogen. FUNDING: National Key Research and Development Program of China, National Natural Science Foundation of China for Key Programs of China Grants, and Beijing High-Level Public Health Technical Talent Project.