Inborn Errors of Immunity in Neonatal and Pediatric Intensive Care Units: Clinical Spectrum and Diagnostic Outcomes.

Abstract

Introduction: Inborn errors of immunity (IEI) may manifest with infections, immune dysregulation, syndromic features, and multisystem involvement. Critically ill neonates and children admitted to intensive care units (ICUs) with severe or atypical presentations may harbor underlying IEI, posing significant diagnostic challenges. This study aimed to evaluate the clinical characteristics, consultation indications, immunological findings, warning signs, and diagnostic outcomes of patients assessed for suspected IEI in neonatal and pediatric intensive care units.

Methods: We retrospectively reviewed patients from the neonatal intensive care unit (NICU) and pediatric intensive care unit (PICU) of our hospital who were referred to the Department of Pediatric Immunology and Allergy because of clinical and/or laboratory suspicion of IEI between January 2017 and September 2025. Consultation indications, final diagnoses, IEI categories, and traditional Jeffrey Modell Foundation (JMF) and additional warning signs were evaluated. The diagnostic performance of individual warning signs for confirmed IEI was assessed, and the incremental contribution of additional warning signs beyond the traditional JMF criteria was examined at the patient level.

Results: A total of 172 patients were referred from the NICU and PICU, corresponding to 0.8% and 2.6% of all admissions, respectively; 40 (23.3%) were diagnosed with IEI. Syndromic features with systemic involvement were the most frequent indication for consultation in the NICU, whereas severe infection/sepsis predominated in the PICU. Combined immunodeficiencies with syndromic features were most frequent in the NICU, while predominantly antibody deficiencies were most common in the PICU. Deep-seated infection/septicemia, chronic diarrhea/enteropathy, and syndromic features were significantly associated with confirmed IEI, with ORs of 2.21 (95% CI, 1.08-4.53), 2.57 (95% CI, 1.08-6.07), and 2.41 (95% CI, 1.06-5.48), respectively. Overall, 38/40 (95.0%) patients with IEI fulfilled at least one traditional JMF warning sign. Both JMF-negative patients with IEI had at least one additional warning sign; therefore, considering traditional and additional warning signs together retrospectively identified all 40 patients with IEI in this referral cohort. Mortality among patients with IEI was 32.5%.

Conclusion: IEI was diagnosed in 23.3% of critically ill patients referred for immunological evaluation because of suspected IEI. Deep-seated infection/septicemia, chronic diarrhea/enteropathy, and syndromic features were significantly associated with confirmed IEI. Traditional JMF warning signs identified most patients with IEI; however, additional warning signs captured two IEI patients who did not fulfill any traditional JMF criteria. These findings support considering additional non-infectious and syndromic manifestations alongside traditional warning signs when evaluating critically ill children for IEI.