The fatal triad in pcr-negative pediatric autopsies: A focus on aspiration, occult sepsis, and underlying immune dysfunction

Abstract

Background: To identify plausible pathophysiological mechanisms underlying death in pediatric autopsy cases with negative culture and PCR results in which the cause of death remained undetermined despite comprehensive evaluation.

Methods: Autopsy reports, histopathology, microbiology, perimortem procalcitonin (PCT), and anthropometric data were retrospectively reviewed (Jan 1, 2020-Dec 31, 2024). Three composite indices captured patterns consistent with aspiration-related respiratory failure, culture-negative systemic inflammation/multiorgan dysfunction, and immune or immunometabolic insufficiency. Associations with cause-of-death classification were assessed using logistic regression and ROC-AUC analyses.

Findings: Among 266 cases (median age 4 months [IQR: 1-9]; 63.6% <6 months), a pulmonary infection pattern was identified in 68.8%, and aspiration findings in 19.9%, with aspiration markedly enriched in neonates (47.4%). A high aspiration score was strongly associated with deaths labelled as undetermined (AUC: 0.832; adjusted OR: 4.87, 95% CI: 2.44-9.71; p < 0.001). In children with PCT > 2 ng/mL, a multiorgan inflammatory pattern was present in 17.7% and was highly predictive of an infectious death phenotype despite negative microbiology (AUC: 0.887; OR: 6.91, 95% CI: 3.01-15.84; p < 0.001). A distinct subgroup (8.2%) showed low PCT with marked lymphoid depletion, consistent with impaired host immune response, and this pattern independently predicted classification as cause of death unknown (AUC: 0.794; OR: 5.42, 95% CI: 2.09-14.06; p < 0.001).

Interpretation: Deaths in PCR-negative pediatric autopsies frequently cluster around three host-response-driven mechanisms: aspiration-related respiratory collapse, systemic inflammation with multiorgan dysfunction, and immune or immunometabolic insufficiency. Recognition of these organ-level patterns may improve pathophysiological interpretation at autopsy and may identify actionable targets for prevention, including aspiration risk mitigation, timely management of culture-negative sepsis, and earlier identification of vulnerable immune and nutritional states in living children.

Keywords: Aspiration; Culture-negative sepsis; Immunodeficiency; Pediatric autopsy; Sudden unexpected child death.