Background: Early recognition of inborn errors of immunity (IEI), formerly primary immunodeficiencies, is crucial, yet the diagnostic accuracy of widely promoted clinical “warning signs” in children is uncertain. Objective: To assess the diagnostic accuracy of clinical warning signs and established criteria for identifying pediatric IEI. Methods: We searched MEDLINE and EMBASE (inception-May 2024) for studies reporting sensitivity and specificity of individual or combined warning signs in children (0-18 years) with suspected IEI. The reference standard was physician-confirmed IEI. Data were synthesized descriptively and, where appropriate, using bivariate random-effects models. Risk of bias was assessed with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. Results: Twelve studies (∼7000 participants, 8 countries) met inclusion criteria. Diagnostic performance was highly heterogeneous, and pooled estimates are exploratory. Overall, most individual warning signs showed high specificity but low sensitivity; family history of IEI and signs such as persistent thrush, deep-seated abscesses, and failure to thrive were generally highly specific but insensitive. Infection-based signs such as recurrent pneumonia or need for intravenous antibiotics provided a more balanced but still imperfect profile. Combinations of signs, including the Jeffrey Modell Foundation threshold of 2 or more warning signs, improved sensitivity in some settings but with variable specificity, and up to one-third of children with IEI did not meet any Jeffrey Modell Foundation warning-sign criteria. Conclusions: Traditional warning signs have good rule-in but poor rule-out value for pediatric IEI. Reliance on these signs alone risks delayed or missed diagnoses, particularly for noninfectious IEI phenotypes. Context-specific criteria and decision-support tools are needed to better capture the breadth of IEI presentations and support timely referral.
Clinical Warning Signs in Detecting Inborn Errors of Immunity in Children: A Diagnostic Accuracy Systematic Review
Comberiati, Pasquale;Peroni, Diego;
2026-01-01
Abstract
Background: Early recognition of inborn errors of immunity (IEI), formerly primary immunodeficiencies, is crucial, yet the diagnostic accuracy of widely promoted clinical “warning signs” in children is uncertain. Objective: To assess the diagnostic accuracy of clinical warning signs and established criteria for identifying pediatric IEI. Methods: We searched MEDLINE and EMBASE (inception-May 2024) for studies reporting sensitivity and specificity of individual or combined warning signs in children (0-18 years) with suspected IEI. The reference standard was physician-confirmed IEI. Data were synthesized descriptively and, where appropriate, using bivariate random-effects models. Risk of bias was assessed with the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies 2) tool. Results: Twelve studies (∼7000 participants, 8 countries) met inclusion criteria. Diagnostic performance was highly heterogeneous, and pooled estimates are exploratory. Overall, most individual warning signs showed high specificity but low sensitivity; family history of IEI and signs such as persistent thrush, deep-seated abscesses, and failure to thrive were generally highly specific but insensitive. Infection-based signs such as recurrent pneumonia or need for intravenous antibiotics provided a more balanced but still imperfect profile. Combinations of signs, including the Jeffrey Modell Foundation threshold of 2 or more warning signs, improved sensitivity in some settings but with variable specificity, and up to one-third of children with IEI did not meet any Jeffrey Modell Foundation warning-sign criteria. Conclusions: Traditional warning signs have good rule-in but poor rule-out value for pediatric IEI. Reliance on these signs alone risks delayed or missed diagnoses, particularly for noninfectious IEI phenotypes. Context-specific criteria and decision-support tools are needed to better capture the breadth of IEI presentations and support timely referral.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
