Experts discuss key clinical signs to help identify sepsis risk in young infants

Sepsis remains a leading and persistent cause of morbidity and mortality among young infants worldwide, particularly those aged younger than 60 days. However, new evidence shows that current World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) clinical signs reliably identify infants at risk, according to Sophie Driker, MPH, research assistant at Brigham and Women's Hospital, and Anne CC Lee, MD, MPH, Levinger Family Professor of Pediatrics at Warren Alpert Medical School of Brown University.

According to Driker despite substantial progress over recent decades, global declines in neonatal mortality have slowed. Neonatal deaths fell from 5.2 million in 1990 to 2.3 million in 2023, but progress has stalled since 2015 and has lagged behind reductions in postneonatal under-5 mortality. As a result, 65 countries are not on track to meet the Sustainable Development Goal target for neonatal mortality by 2030. Serious bacterial infections—including sepsis, meningitis, and pneumonia—remain major drivers of death and long-term disability, with an estimated 6.3 million cases of neonatal sepsis annually and approximately 200,000 associated deaths, disproportionately affecting low- and middle-income countries (LMICs).

Lee explained that the context of care for young infants differs markedly by setting. In high-income countries, clinicians typically rely on laboratory diagnostics such as blood cultures and imaging to confirm sepsis. In contrast, most infants in LMICs are evaluated in community or primary care settings, often by health workers without access to diagnostic tests or specialized pediatric training. To address this gap, the WHO introduced the IMCI strategy in 1995.

IMCI, now implemented in more than 100 countries, uses a checklist of 7 clinical signs to identify infants who require referral or antibiotic treatment. Previous evidence has shown this checklist to have approximately 80% sensitivity and specificity for identifying infants needing hospitalization or antibiotics.

Building on this foundation, Driker described a systematic review and meta-analysis designed to assess the diagnostic performance of individual clinical signs associated with infant sepsis and mortality. The review evaluated 24 clinical signs drawn from WHO algorithms and other major studies. After screening more than 7,000 records, the researchers included 52 studies comprising data on more than 140,000 infants from 30 countries.

All 7 signs currently included in the IMCI checklist were significantly associated with mortality or culture-confirmed sepsis. Poor feeding emerged as one of the strongest predictors, with a 13-fold increase in mortality risk and a 5-fold increase in odds of sepsis. Neurologic signs—including lethargy, drowsiness, unconsciousness, and weak or absent cry—were also strongly associated with adverse outcomes, as was hypothermia.

The analysis also identified potentially valuable signs not currently included in IMCI. Prolonged capillary refill demonstrated strong associations with mortality and sepsis and relatively high sensitivity, suggesting it could improve diagnostic accuracy. Central cyanosis was also associated with severe outcomes, though its rarity and subjectivity may limit practicality in primary care.

Lee emphasized that future research should focus on prospective studies to test the feasibility and reliability of incorporating new signs into IMCI, as well as exploring alternative approaches such as weighted scoring systems or predictive models, while maintaining feasibility in resource-limited settings.

No relevant disclosures.

Reference

Driker S, Mathias S, Fung A, et al. Clinical signs associated with mortality and sepsis in young infants: a systematic review and meta-analysis. JAMA Pediatr. 2026. doi:10.1001/jamapediatrics.2025.5967