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Clinical Signs Associated With Mortality and Sepsis in Young Infants: A Systematic Review and Meta-Analysis
Sophie Driker1, Sitarah Mathias2,3, Alastair Fung4,5
1Department of Pediatrics, Division of Newborn Medicine, Brigham and Women's Hospital, Boston, Massachusetts.
Insights
Identifying clinical signs like abnormal cry and feeding difficulties in infants can help predict sepsis and mortality. This research supports better diagnosis in resource-limited settings.
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.
Importance:
Early and accurate identification of clinical warning signs in young infants may help avert sepsis morbidity and mortality in resource-limited settings.
Objective:
To systematically review evidence on the association and accuracy of clinical signs to diagnose sepsis or predict mortality in young infants aged 0 to 59 days to inform management in settings with limited laboratory diagnostics.
Data Sources:
MEDLINE, Embase, CINAHL, Global Index Medicus, and Cochrane CENTRAL Register were searched from inception through May 2023, with updated searches on September 5, 2024. An umbrella search of systematic reviews was conducted in January 2024.
Study Selection:
Included studies reported data on 24 infant clinical signs informed by current World Health Organization (WHO) Integrated Management of Childhood Illness (IMCI) and hospital-based algorithms for the care of sick young infants reporting odds ratios (OR), risk ratios, or sensitivity and specificity.
Data Extraction And Synthesis:
Data were extracted independently by 2 reviewers. Quality assessment used the Newcastle-Ottawa, Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2), and Quality Assessment of Prognostic Accuracy Studies (QUAPAS) scales. OR data were pooled using random-effects models. Data analysis was performed from July to September 2025.
Main Outcomes And Measures:
OR of all-cause mortality, culture-confirmed sepsis, or clinical sepsis (with access to laboratory investigations).
Results:
Of 7641 studies, 52 studies with 140 885 participants were included. A total of 16 clinical signs were significantly associated with mortality, 11 with culture-confirmed sepsis, and 13 with clinical sepsis. For mortality, the 5 strongest associations were weak, abnormal, or absent cry (OR, 20.48; 95% CI, 6.59-63.67); not able to feed at all (OR, 18.32; 95% CI, 6.00-55.97); not feeding well (OR, 13.39; 95% CI, 6.97-25.72); drowsiness or unconsciousness (OR, 12.46; 95% CI, 6.06-25.62); and prolonged capillary refill (OR, 12.06; 95% CI, 2.77-52.53). The top 5 signs associated with culture-confirmed sepsis were not feeding well (OR, 4.52; 95% CI, 1.10-18.59); prolonged capillary refill (OR, 3.59; 95% CI, 2.05-6.28); lethargy (OR, 3.44; 95% CI, 1.89-6.26); drowsiness or unconsciousness (OR, 3.07; 95% CI, 2.01-4.68); and feeding intolerance (OR, 2.95; 95% CI, 1.67-5.21).
Conclusions And Relevance:
All current WHO IMCI clinical signs were significantly associated with mortality or culture-confirmed sepsis. Several signs not in IMCI were identified that may improve identification of life-threatening illness in young infants in resource-limited settings where clinical sign algorithms are the primary diagnostic tool.
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