In this study, sTREM-1, a cell surface receptor expressed on myeloid cells associated with neutrophil and monocyte response amplification,15 was superior to ten other biomarkers of endothelial or immune activation in predicting mortality in febrile children aged 2 months to 5 years presenting to the emergency department of a regional hospital in Uganda. The AUROC was 0.893 in the derivation cohort and 0.901 in the validation cohort, very similar to the previously reported AUROC of 0.87 in predicting death within 28 days in 507 consecutive febrile adults presenting to four outpatient clinics in Tanzania.14 Similar to the adult study, discrimination was independent of aetiology and comparable in children with and without malaria. Taken together, this suggests that multiple life-threatening infections share common pathways of injury that are independent of pathogen, age, and geographic location.6–8, 12,13,16 We derived and validated cutoffs of sTREM-1 as the basis for the development of a rapid test (i.e.: lateral flow) that could be used as a simple triage tool at the community level in low-resource settings. Cutoffs associated with LR- of 0.10 and LR + of 10 allowed us to classify more than half of the children into a green zone considered to be at low risk of death of less than 1%, whereas less than 10% of children were classified into a red zone considered to be at high risk of death of 25% or more. Approximately 40% remained in an intermediate risk category, with an estimated risk of death of 3 to 5%.
The majority of paediatric infections are self-limited, and few are life threatening. In the absence of critical illness, many febrile syndromes can be treated conservatively.17 However, we currently lack effective tools to identify children at risk of progression to severe illness – a priority that is not addressed by pathogen-based diagnostics. This results in increased mortality in those with life-threatening infections,18 while paradoxically causing harm,19 misallocation of scarce resources related to over-admission and antimicrobial treatment, and added risk of nosocomial infection in children with milder self-limited infections.20
Our results suggest that a rapid triage test based on finger-prick blood sample using sTREM-1 as a disease severity marker could be used as a simple, objective and clinically meaningful risk-stratification tool that could facilitate an integrated approach to manage fever syndromes at the community level, where no medically qualified health professionals may be available to triage children based on clinical criteria. Children in the red zone according to the rapid triage test, who are at high risk of death, could be urgently referred and prioritized for hospital care, children in the yellow intermediate risk zone could be referred with lower priority for monitoring, diagnostic workup and management depending on the clinical course, whereas children in the green zone could be considered for management at the community level. This strategy could decrease the referral of children with uncomplicated or self-limited infections who are unlikely to benefit from admission, investigation, and urgent supportive care. Collectively this could result in task-shifting from scarce, highly trained health care professionals in centralized health units to community health workers, decrease the pressure on health care facilities and professionals, enhance appropriate resource allocation and potentially decrease sepsis-related mortality in children. The strategy of using a rapid point of care test such as a lateral flow test to triage febrile children at the community level has multiple attributes, including ease-of-use, speed, cost, cultural acceptability, gender equity in access to care, and evidence-based decision-making, that would support their implementation and scalability.
Our study has several limitations. First, this is a single centre study and our results will need to be replicated by independent groups in different settings. However, our results are very similar to those derived in consecutive febrile adults presenting for outpatient care in Tanzania,14 supporting the generalizability of our findings. Second, our study was complicated, as is common in low resource settings,21 by children who absconded or were transferred, for whom vital status could not be definitely ascertained. Plasma was also missing, but in less than 2% of children. We used multiple imputation to account for missing vital status and consider the missing at random assumption of the multiple imputation model given the observed data plausible.22 Third, calibration was only modest in the external validation, as the predicted mortality for children in the red zone was lower than observed in this cohort. However, this does not alter the suggested strategy for triage: children in the red zone would be at high risk of death, regardless of the actual risk of 1 in 4 in the derivation cohort, or 1 in 3 in the validation cohort. Fourth, even though we derived and validated the use of sTREM-1 and suitable cutoffs the basis of a rapid test for prospective risk stratification of febrile children in a prospective cohort study, randomized trials will be required to establish that the addition of a rapid triage test to current standard of care at the community level will improve outcomes of febrile children in low-resource settings. Strengths of our study include its prospective design that distinguish it from prior retrospective cohorts studies that modelled mortality in children in resource-limited African settings,6,23 direct comparison of multiple candidate markers of disease severity at the earliest time point of healthcare presentation, the large sample size with a sufficient number of outcome events, the confirmatory nature of our results, with a discrimination nearly identical to what was previously reported in febrile adults in Tanzania14 as well as other smaller studies conducted in children (Supplementary Table 10)6,24−37, the robustness of results in internal and external validation, and the biological plausibility of the observed association.15
In conclusion, sTREM-1, a severity marker with a pathophysiologic link to sepsis, measured at clinical presentation, accurately predicted mortality in febrile children with either malaria or non-malarial aetiology, in a regional hospital in Uganda. Simple risk-stratification based on a rapid sTREM-1 test could enhance triage and improve outcomes in resource-limited settings.