Daily Respiratory Research Analysis
Three papers stand out today: a national French cohort characterizes severe adult Mycoplasma pneumoniae during the 2023–24 outbreak and links severity to delayed use of active antibiotics; the first perinatal controlled human infection model shows Neisseria lactamica safely colonizes pregnant individuals but does not sustain transmission to infants; and an in vivo cotton rat model demonstrates EV-D68 associates with extracellular vesicles to disseminate systemically and reach the CNS.
Summary
Three papers stand out today: a national French cohort characterizes severe adult Mycoplasma pneumoniae during the 2023–24 outbreak and links severity to delayed use of active antibiotics; the first perinatal controlled human infection model shows Neisseria lactamica safely colonizes pregnant individuals but does not sustain transmission to infants; and an in vivo cotton rat model demonstrates EV-D68 associates with extracellular vesicles to disseminate systemically and reach the CNS.
Research Themes
- Outbreak characterization and antibiotic timing in atypical pneumonia
- Selective transmission in the perinatal respiratory microbiome
- Extracellular vesicle-mediated viral dissemination beyond the respiratory tract
Selected Articles
1. Mycoplasma pneumoniae infection in adult inpatients during the 2023-24 outbreak in France (MYCADO): a national, retrospective, observational study.
In a national cohort of 1,309 hospitalized adults during France’s 2023–24 M. pneumoniae epidemic, 32% met a severe composite outcome (ICU admission or in-hospital death) and 2% died. Severity was associated with comorbidities, atypical CT patterns, inflammatory/hematologic indices, and notably lack of pre-admission use of an antibiotic active against M. pneumoniae, supporting macrolide-active empiric therapy during epidemics.
Impact: This study provides timely, practice-informing evidence that delayed active therapy contributes to severe outcomes during a national M. pneumoniae outbreak and highlights atypical imaging presentations.
Clinical Implications: During M. pneumoniae epidemics, consider macrolides as first-line empiric therapy or reassess β-lactam monotherapy early; triage using risk factors (hypertension, obesity, chronic liver disease, bilateral CT involvement, systemic inflammation) and do not exclude M. pneumoniae based on imaging alone.
Key Findings
- 32.4% had severe outcomes (31.7% ICU admission; 2.1% in-hospital mortality) during the epidemic.
- Severity associated with hypertension, obesity, chronic liver failure, extra-respiratory manifestations, consolidation/bilateral CT involvement, elevated inflammatory markers, lymphopenia or neutrophilia.
- Not receiving an antibiotic active against M. pneumoniae before admission was linked to severe outcomes.
- Atypical radiological presentations were common, indicating imaging alone cannot rule out M. pneumoniae.
Methodological Strengths
- Large, multi-center national cohort with standardized data extraction across 76 hospitals
- Multivariable logistic regression to adjust for confounders
Limitations
- Retrospective design susceptible to residual confounding and selection bias
- Antibiotic exposure timing and diagnostic heterogeneity may influence associations
Future Directions: Prospective interventional studies testing macrolide-first strategies during epidemics; improved rapid diagnostics; surveillance of macrolide resistance and host factors underpinning severe disease.
BACKGROUND: An epidemic of Mycoplasma pneumoniae infection has been observed in France since September, 2023. We aimed to describe the characteristics of adults hospitalised for M pneumoniae infection and identify factors associated with severe outcomes of infection. METHODS: MYCADO is a retrospective observational study including adults hospitalised for 24 h or more in 76 hospitals in France for a M pneumoniae infection between Sept 1, 2023, and Feb 29, 2024. Clinical, laboratory, and imaging data were collected from medical records. We identified factors associated with severe outcomes of infection, defined as a composite of intensive care unit (ICU) admission or in-hospital death, using multivariable logistic regression. FINDINGS: 1309 patients with M pneumoniae infection were included: 718 (54·9%) were men and 591 (45·1%) were women; median age was 43 years (IQR 31-63); 288 (22·0%) had chronic respiratory failure; 423 (32·3%) had cardiovascular comorbidities; and 105 (8·0%) had immunosuppression. The most common symptoms were cough (1098 [83·9%]), fever (1023 [78·2%]), dyspnoea (948 [72·4%]), fatigue (550 [42·0%]), expectorations (473 [36·1%]), headache (211 [16·1%]), arthromyalgia (253 [19·3%]), ear, nose, and throat symptoms (202 [15·4%]), diarrhoea (138 [10·5%]), and vomiting (132 [10·1%]). 156 (11·9%) of 1309 patients had extra-respiratory manifestations, including 36 (2·8%) with erythema multiforme, 19 (1·5%) with meningoencephalitis, 44 (3·4%) with autoimmune haemolytic anaemia, and 17 (1·3%) with myocarditis. The median hospital stay was 8 days (IQR 6-11). 424 (32·4%) patients had a severe outcome of infection, including 415 (31·7%) who were admitted to the ICU and 28 (2·1%) who died in hospital. Those more likely to present with severe outcomes of infection were patients with hypertension, obesity, chronic liver failure, extra-respiratory manifestations, pulmonary alveolar consolidation or bilateral involvement on CT scan, as well as elevated inflammatory markers, lymphopenia or neutrophilic polynucleosis, and those who did not versus did receive any antibiotic active against M pneumoniae before admission. INTERPRETATION: This national, observational study highlighted unexpected, atypical radiological presentations, a high proportion of transfers to the ICU, and an association between severity and delayed administration of effective antibiotics. This should remind clinicians that no radiological presentation can rule out M pneumoniae infection, and encourage them to reassess patients early after prescribing a β-lactam, or even to discuss prescribing macrolides as first-line treatment in the context of an epidemic. FUNDING: None. TRANSLATION: For the French translation of the abstract see Supplementary Materials section.
2. Enterovirus D68 infection in cotton rats results in systemic inflammation with detectable viremia associated with extracellular vesicle and neurologic disease.
In immunocompetent cotton rats, EV-D68 respiratory infection led to viremia and extra-respiratory organ involvement with inflammation, and EV-D68 was physically associated with extracellular vesicles purified from plasma. Intraperitoneal infection and direct EV-associated virus delivery enabled CNS detection and neurologic signs, providing the first in vivo evidence that EVs facilitate EV-D68 dissemination beyond the respiratory tract.
Impact: This work reveals a plausible mechanism linking respiratory EV-D68 infection to systemic and CNS disease via extracellular vesicles and delivers practical animal models to evaluate anti-dissemination strategies.
Clinical Implications: While preclinical, these findings suggest therapeutic avenues targeting extracellular vesicle biogenesis or uptake to limit EV-D68 dissemination and AFM risk; they also refine pathogenesis models for testing antivirals or vaccines.
Key Findings
- EV-D68 was detected in blood and extra-respiratory organs following respiratory infection, indicating systemic dissemination with accompanying inflammation.
- Virus was physically associated with extracellular vesicles purified from plasma.
- Intraperitoneal infection and EV-associated virus delivery led to CNS detection and neurologic signs in young cotton rats.
- Provides first in vivo experimental support that EVs mediate EV-D68 dissemination beyond the respiratory tract.
Methodological Strengths
- Use of immunocompetent animal model with both respiratory and intraperitoneal infection routes
- Biochemical isolation of plasma extracellular vesicles demonstrating virus association
Limitations
- Preclinical animal model limits direct generalizability to humans
- Strain- and species-specific effects not fully explored; lack of interventional blockade experiments
Future Directions: Test pharmacologic or genetic inhibition of EV biogenesis/uptake to curb dissemination; validate across EV-D68 clades and in human biospecimens; integrate with AFM clinical cohorts.
Enterovirus D68 (EV-D68) is a non-polio enterovirus that causes respiratory illness and is linked to acute flaccid myelitis (AFM) in infants and children. Recent demonstration of association of EV-D68 with extracellular vesicles (EVs) released from infected cells in vitro suggests a role for these vesicles in non-lytic dissemination of virus beyond the respiratory tract. We previously reported the permissiveness of cotton rat (Sigmodon hispidus) to infection with different EV-D68 strains of clades A and B, but did not investigate the virus association with EVs. We present a model of acute respiratory infection with a clinical isolate of EV-D68 of clade B3 in immunocompetent cotton rats featuring systemic dissemination of the virus. EV-D68 was detected in circulation and organs outside of the respiratory tract with the inflammatory response accompanying dissemination. Further analysis demonstrated that the virus was associated with extracellular vesicles purified from plasma. We also present a model of intraperitoneal infection with EV-D68 in young cotton rats featuring dissemination of the virus to spinal cord and brain with associated clinical signs of neurologic disease. EV-D68-associated with EVs produced in cotton rat cells and injected intraperitoneally into young cotton rats also resulted in detection of virus in the CNS. Our results provide the first in vivo experimental support for the notion that respiratory infection with EV-D68 generates virus associated with extracellular vesicles that disseminate outside the respiratory tract. These models of infection could be used to investigate the role of EVs-associated EV-D68 in the pathogenesis of EV-D68 infection and to assess therapeutic interventions.
3. Controlled human infection model of Neisseria lactamica in late pregnancy investigating mother-to-infant transmission in the UK: a single-arm pilot trial.
In this first perinatal CHIM, 71% of inoculated pregnant participants became colonized with N. lactamica without sustained transmission to their infants, despite evidence of Moraxella catarrhalis strain sharing in mother-infant pairs. Maternal anti-N. lactamica IgG increased, and no serious adverse reactions occurred, indicating feasibility and safety while challenging assumptions of passive maternal-to-infant respiratory commensal transfer.
Impact: Establishes the feasibility and safety of a perinatal CHIM and provides evidence that respiratory commensal transmission is selective, informing future microbiome-targeted interventions.
Clinical Implications: Immediate clinical change is not indicated; however, peripartum inoculation to shape infant microbiomes may require alternative strategies, timing, or organisms given the lack of sustained infant colonization observed.
Key Findings
- 71% (15/21) of inoculated pregnant participants were colonized by N. lactamica.
- No sustained transmission of the inoculated N. lactamica strain to infants was observed.
- Maternal anti-N. lactamica IgG titres increased in 88% of colonized mothers; infant titres did not rise.
- Strain sharing was observed for Moraxella catarrhalis in 38% of mother-infant pairs; no serious adverse reactions occurred.
Methodological Strengths
- Controlled human infection model with strain-level microbiology and paired serology
- First feasibility and safety data for perinatal CHIM in pregnancy
Limitations
- Single-arm pilot with small sample size and limited demographic diversity
- Follow-up duration and environmental factors may limit detection of transient infant colonization
Future Directions: Randomized designs comparing strains, doses, and timing; exploration of alternative commensals; longer infant follow-up; integration with safety/ethics frameworks for perinatal CHIMs.
BACKGROUND: The infant respiratory microbiome is derived largely from the mother and is associated with downstream health and disease. Manipulating maternal respiratory flora peripartum to influence the infant microbiome has not previously been investigated. Neisseria lactamica is a harmless pharyngeal commensal that correlates inversely with Neisseria meningitidis carriage and disease. Intranasal N lactamica inoculation is a safe and well characterised controlled human infection model (CHIM) in non-pregnant healthy adults. We hypothesised that N lactamica inoculation in pregnancy induces mother-to-infant N lactamica transmission postnatally. METHODS: In this single-arm trial, 21 healthy pregnant female participants aged 18 years or older were inoculated at 36-38 weeks' gestation with 10 FINDINGS: Between Oct 25, 2021, and March 7, 2022, 31 adult female participants (median age 33·5 years [range 23·1-39·9]; 26 [84%] were White, British) were screened and enrolled, of whom seven were already colonised with N lactamica. After exclusion of three participants, 21 participants were inoculated, of whom 15 (71%) became N lactamica-colonised, and no sustained N lactamica Y92-1009 transmission to their infants was observed. Conversely, non-Y92-1009 N lactamica strain sharing was observed in four (57%) of seven uninoculated mother-sibling pairs, and Moraxella catarrhalis strain sharing in nine (38%) of 24 mother-infant pairs completing the study. Anti-N lactamica serum IgG titres increased in seven (88%) of eight N lactamica Y92-1009-colonised female participants, but none of their infants (where paired sera were available). There were no serious adverse reactions to the inoculum. INTERPRETATION: As the world's first perinatal CHIM, this trial demonstrates that this model in pregnancy is feasible, and that N lactamica Y92-1009 can safely and efficiently colonise pregnant individuals. Lack of sustained mother-to-infant N lactamica transmission, despite evidence supporting mother-to-infant M catarrhalis and sibling-to-mother N lactamica transmission, challenges conventional perceptions of infants as passive recipients of maternal microbes, suggesting that respiratory commensal transmission is selective and microbe-specific. FUNDING: Medical Research Council and National Institute for Health Research Southampton Biomedical Research Centre.