Clinical Warning Signs in Detecting Inborn Errors of Immunity in Children: A Diagnostic Accuracy Systematic Review

Area of Science:

• Pediatric Immunology
• Diagnostic Accuracy
• Clinical Decision Making

Background:

• Early recognition of inborn errors of immunity (IEI) is critical for patient outcomes.
• The diagnostic accuracy of established clinical warning signs for pediatric IEI remains uncertain.

Purpose of the Study:

• To evaluate the diagnostic accuracy of individual and combined clinical warning signs for identifying IEI in children.
• To assess the effectiveness of established criteria in diagnosing pediatric IEI.

Main Methods:

• Systematic literature search of MEDLINE and EMBASE (inception–May 2024) for studies on IEI warning signs in children (0–18 years).
• Included studies reporting sensitivity and specificity with physician-confirmed IEI as the reference standard.
• Data synthesis using descriptive methods and bivariate random-effects models; risk of bias assessed with QUADAS-2.

Main Results:

• Twelve studies (approx. 7,000 participants) were included, showing high heterogeneity in diagnostic performance.
• Individual warning signs generally had high specificity but low sensitivity; family history, persistent thrush, deep-seated abscesses, and failure to thrive were highly specific but insensitive.
• Infection-based signs offered a more balanced profile, while combinations like the Jeffrey Modell Foundation (JMF) criteria improved sensitivity but had variable specificity; up to one-third of children with IEI did not meet JMF criteria.

Conclusions:

• Traditional warning signs for pediatric IEI possess good rule-in but poor rule-out value.
• Sole reliance on these signs may lead to delayed or missed diagnoses, especially for non-infectious IEI.
• Development of context-specific criteria and decision-support tools is essential for comprehensive IEI diagnosis and timely referral.