Confronting the “lethal duo” in the ICU: early identification of Aspergillus–Mucorales co-infection using a clinical-immuno-inflammatory signature

Background Co-infection with Aspergillus and Mucorales in the intensive care unit (ICU) represents a devastating syndrome with high mortality that is frequently clinically occult. Clinically distinguishing this co-infection from invasive pulmonary aspergillosis (IPA) is challenging but critical for tailoring precise antifungal strategies. Methods We conducted a single-center, retrospective observational study involving 93 critically ill patients (75 with Aspergillus infection and 18 with co-infection) admitted between 2017 and 2025. We compared clinical characteristics, inflammatory markers, and immunophenotypes between groups. A three-stage variable selection strategy integrating univariable regression pre-screening, multi-algorithm importance ranking (LASSO, Ridge, and Random Forest), and clinical applicability filtering was employed to identify predictors for a multivariable logistic regression nomogram. Results The co-infection group exhibited substantially higher ICU mortality than the sole Aspergillus group, although the difference did not reach statistical significance (72.2% vs. 53.3%, p = 0.24).Kaplan–Meier analysis demonstrated that initiation of amphotericin B within <7 days of diagnosis or strong clinical suspicion was significantly associated with improved survival (log-rank p < 0.0001). A three-stage variable selection strategy integrating univariable regression, multi-algorithm importance ranking (LASSO, Ridge, and Random Forest), and clinical applicability filtering identified four key predictors. The resulting multivariable logistic regression nomogram — incorporating NK cell count, C-reactive protein, corticosteroid use history, and Gram-positive bacterial co-infection — demonstrated robust discrimination (AUC = 0.878, 95% CI: 0.789–0.967), with good calibration (Hosmer–Lemeshow p = 0.849) and stability on internal validation (cross-validated AUC = 0.860). Conclusion Aspergillus and Mucorales co-infection constitutes a distinct, high-mortality clinical entity in the ICU. The developed nomogram, integrating clinical, immunological, and inflammatory features, may facilitate the early identification of high-risk patients and guide timely initiation of Mucorales -active therapy to improve prognosis.