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What do you know about triggering receptor expressed on myeloid cells-1 (TREM-1)? It looks like it might be a useful biomarker for predicting severe sepsis and stratifying the risk of poor outcomes in common (globally) childhood infections, including meningitis, pneumonia, dengue and malaria. It is a transmembrane receptor expressed by innate immune cells, and it is a crucial mediator in septic shock. It acts by linking with Toll-like receptors to amplify the inflammatory response to pathogens. This is a remarkable multi-country, prospective cohort study by the Spot Sepsis Investigator Group carried out in Bangladesh, Vietnam, Laos, Cambodia and Indonesia in seven hospitals, which act as the first point of healthcare contact in rural populations. Chandna A, et al (The Lancet Child & Adolescent Health 2025;9 (9):634–635. https://doi.org/10.1016/S2352-4642(25)00 183-X) have examined 3423 children aged 1–59 months presenting with community-acquired acute febrile illness that had lasted no more than 14 days. They followed up on all, but 18 (0.5%) children who were recruited. The primary outcome measure was severe febrile illness (death or receipt of organ support) within 2 days of being recruited into the study. They examined a number of endothelial activation and immune activation markers (see paper). They also collected data on the WHO danger signs, the Liverpool quick Sequential Organ Failure Assessment (LqSOFA) score and the Systemic Inflammatory Response Syndrome (SIRS) score. Severe febrile illness developed in 133 (3.9%) of 3405 participants (22 deaths, 111 received organ support; weighted prevalence 0.34% (95% CI 0.28% to 0.41%)). Soluble TREM-1 (sTREM-1) showed the highest prognostic accuracy to identify patients who would progress to severe febrile illness (area under the curve 0.86 (95% CI 0.82 to 0.90)). More importantly, this marker was better at predicting severe sepsis compared with the clinical scores (WHO danger signs (0.75 (0.71 to 0.80); p<0.0001), LqSOFA (0.74 (0.69 to 0.78); p<0.0001) and SIRS (0.63 (0.58 to 0.68); p<0.0001)). Even combining the WHO danger signs together with sTREM-1 made no difference to the accuracy in identifying clinical deterioration of severe sepsis compared with sTREM-1 alone (p=0.24). Sensitivity for identifying progression to severe febrile illness was greater for sTREM-1 (0.80 (95% CI 0.73 to 0.85)) than for WHO danger signs (0.72 (0.66 to 0.79); numbers needed to treat (NNT)=3000), whereas specificities were comparable (0.81 (0.78 to 0.83) for sTREM1 vs 0.79 (0.76 to 0.82) for WHO danger signs). The accompanying editorial (Atreya MR and Lanziotti VS. The Lancet Child & Adolescent Health 2025;9 (9):615–617. https://doi.org/10.1016/S2352-4642(25)00 210-X.) highlights the importance of this work but does emphasise the issues of resources and cost, potential later presentation to healthcare influencing outcomes and availability of laboratory testing. Clearly, this marker needs further exploration in a number of settings. They also emphasised that they performed a pre-planned sensitivity analysis stratified by site, nutritional status and confirmed infection. Among patients meeting WHO pneumonia criteria, two other markers, angiopoietin-2 and soluble FLT-1 (a gene which encodes vascular endothelial growth factor 1), showed similar prognostic accuracy. In the future, we may well be talking about sTREM-1-based triage strategy for improving early recognition of risk of poor outcomes in children presenting with febrile illness.