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

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.