Non-invasive diagnosis of invasive fungal disease with cell-free DNA PCR

Invasive fungal disease (IFD) is a major cause of morbidity and mortality in the immunocompromised population. Early diagnosis is challenging due to the low sensitivity and non-specificity of non-invasive fungal biomarkers, the need for invasive specimen collection, and the limitations of culture and histopathology. Detection of circulating fungal cell-free DNA (cfDNA) in plasma and serum by polymerase chain reaction (PCR) represents a novel testing modality for rapid and accurate diagnosis of IFD. In this review, we summarize the performance characteristics of fungal cfDNA PCR for the diagnosis of invasive aspergillosis, mucormycosis, and Pneumocystis pneumonia. We discuss a testing algorithm that incorporates fungal cfDNA and the added diagnostic value of invasive specimen collection when non-invasive mold cfDNA PCR is performed first. Lastly, we discuss the role of diagnostic stewardship in fungal cfDNA PCR testing.