Olfactomedin-4 elevation in pediatric acute respiratory distress syndrome

Neutrophils play a key role in acute respiratory distress syndrome (ARDS). The neutrophil marker olfactomedin-4 (OLFM4) has been implicated with worse outcomes in pediatric sepsis; however, OLFM4 has not been studied in pediatric ARDS. Therefore, we performed a secondary analysis of a prospective cohort of children with Berlin-defined ARDS with plasma collected on <i>day 0</i> of ARDS, testing for an association between OLFM4 and 28-day mortality, 7-day dialysis-free survival, and 28-day ventilator-free days (VFDs), adjusting for age, ARDS etiology, immunocompromised status, and arterial partial pressure of oxygen ([Formula: see text])/fraction of inspired oxygen ([Formula: see text]). We also tested the ability of LPS and histones to affect OLFM4 expression in vitro. In 333 children with ARDS (21% nonsurvivors), OLFM4 was higher in nonsurvivors, in severe ARDS, in hyperinflammatory ARDS, and in those with multiple organ failures. In multivariable regression, OLFM4 was associated with higher mortality, higher probability of dialysis by <i>day 7</i>, and fewer VFDs. In stratified analyses, the association between OLFM4 and worse outcomes did not differ between infectious and noninfectious ARDS. In vitro, OLFM4 expression increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. Overall, OLFM4 was associated with worse outcomes in pediatric ARDS. Histone H3 could induce OLFM4 expression in neutrophils, thus linking damage-associated molecular patterns to neutrophil polarization, which may represent a possible targetable pathway in pediatric ARDS.<b>NEW & NOTEWORTHY</b> Olfactomedin-4 (OLFM4) was associated with higher mortality, higher probability of dialysis by <i>day 7</i>, and fewer ventilator-free days (VFDs) in a pediatric acute respiratory distress syndrome (ARDS) cohort. In vitro, OLFM4 increased following H3 exposure in undifferentiated neutrophils, which was partly mitigated by toll-like receptor (TLR) antagonism. OLFM4 appears to be a marker, and potentially a mediator, of pathological inflammation and end-organ damage in ARDS.