Diagnostic Failure in Invasive Fungal Infections: Causes, Clinical Consequences, and Mitigation Strategies

Diagnostic failure in invasive fungal infections (IFIs) remains a relevant and underrecognized cause of mortality, morbidity, delayed therapy, unnecessary antifungal exposure, and pharmacological selective pressure. Although major advances have been achieved in biomarkers, rapid diagnostic tests, molecular methods, imaging studies, and microbiological identification, timely diagnosis continues to be influenced by the interaction among host factors, pathogen-related factors, diagnostic tools, and healthcare system–related factors. This narrative review analyzes diagnostic failure in IFIs as a dynamic process that includes delayed, incorrect, and incomplete diagnosis. It examines its determinants and consequences in high-risk populations—critically ill patients, patients with hematologic diseases or hematopoietic stem cell transplant recipients, and neonates—as well as in invasive candidiasis, aspergillosis, mucormycosis, cryptococcosis, endemic mycoses, and infections caused by rare or emerging fungi. It also reviews how delayed sampling, decontextualized interpretation of biomarkers, incomplete microbiological identification, absence of antifungal susceptibility testing when clinically relevant, and fragmentation between clinical and laboratory teams contribute to adverse outcomes. Finally, it proposes a diagnostic-centered antifungal stewardship framework (AFSP-Dx) based on syndromic bundles, population-specific diagnostic algorithms, 48–72 h reassessment, and auditable indicators intended to support earlier recognition, more precise therapeutic decisions, and rational antifungal use.