Clinical Signs Associated With Mortality and Sepsis in Young Infants: A Systematic Review and Meta-Analysis

Area of Science:

• Neonatal Medicine
• Pediatric Infectious Diseases
• Diagnostic Accuracy Studies

Background:

• Early identification of clinical warning signs in young infants is crucial for averting sepsis-related morbidity and mortality, especially in resource-limited settings.
• Current diagnostic approaches often lack laboratory support, necessitating reliance on clinical signs.

Purpose of the Study:

• To systematically review the evidence on the association and accuracy of clinical signs for diagnosing sepsis or predicting mortality in infants aged 0-59 days.
• To inform management strategies in settings with limited laboratory diagnostics.

Main Methods:

• A comprehensive search of multiple databases (MEDLINE, Embase, CINAHL, Global Index Medicus, Cochrane CENTRAL) was conducted up to May 2023, with updated searches in September 2024.
• Included studies reported data on 24 infant clinical signs, utilizing odds ratios (OR), risk ratios, or sensitivity and specificity.
• Data extraction and quality assessment were performed using established scales (Newcastle-Ottawa, QUADAS-2, QUAPAS), with OR data pooled using random-effects models.

Main Results:

• 52 studies involving 140,885 participants were included. 16 clinical signs were significantly associated with mortality, 11 with culture-confirmed sepsis, and 13 with clinical sepsis.
• The strongest predictors of mortality included abnormal cry (OR, 20.48), inability to feed (OR, 18.32), not feeding well (OR, 13.39), drowsiness/unconsciousness (OR, 12.46), and prolonged capillary refill (OR, 12.06).
• Key signs associated with culture-confirmed sepsis included not feeding well (OR, 4.52), prolonged capillary refill (OR, 3.59), lethargy (OR, 3.44), drowsiness/unconsciousness (OR, 3.07), and feeding intolerance (OR, 2.95).

Conclusions:

• All current World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) clinical signs showed significant associations with mortality or sepsis.
• Several signs not currently included in IMCI algorithms were identified as potentially improving the identification of life-threatening illnesses in young infants.
• These findings can enhance diagnostic algorithms for sick young infants in resource-limited settings where clinical signs are the primary diagnostic tool.