Defining the diagnosis of invasive aspergillosis

Invasive aspergillosis (IA) is a leading cause of death in severely immunocompromised patients. Delayed diagnosis remains a major impediment to successful treatment of IA. Conventional diagnostic methods based on use of histology and culture remain the cornerstone of diagnosis of IA. However, they have a low yield, and performance of them is frequently precluded in patients with cytopenia and/or underlying comorbidities. In recent years, efforts have been directed toward identifying non-culture-based markers for early, reliable diagnosis of IA by detection of Aspergillus components such as galactomarman (GM), 1,3-beta-D-glucan, and DNA. Studies of profoundly neutropenic hematopoietic stem cell transplant recipients on fluconazole prophylaxis have shown high sensitivity (67-100%) and specificity (86-99%) rates for the GM assay. However, the performance of the GM assay in other settings, including pediatric patients, patients receiving mould-active antifungal prophylaxis, patients with GvHD and recipients of solid organ transplants, is suboptimal. Other factors, such as the pretest probability of infection, sequestration of Aspergillus lesions, the patient's immune status, the presence of anti-GM antibodies, antibacterial therapy, and diet, may also affect both the performance and interpretation of the GM assay. A colorimetric assay for the detection of 1,3-beta-D-glucan, an integral cell-wall component of most pathogenic fungi, has shown promising sensitivity (55-100%) and specificity (52-100%) in limited studies. Polymerase chain reaction (PCR) analysis of Aspergillus DNA is also a promising method for early detection of IA and other opportunistic fungal infections. The sensitivity of PCR is excellent, but its low level of specificity for invasive infections can be problematic. Multiple unresolved issues accompany the use of PCR for diagnosis of IA, including the sample type, amplification strategy, protocol, and primer selection, and account for the lack of a standardized, commercially available assay. Comparative prospective evaluation of non-culture-based assays would facilitate their incorporation into pre-emptive strategies for the optimal management of IA. Combinations of nonculture-based assays could enhance their performance and broaden the spectrum of detectable fungi. Clearly, there is a need for innovation in this area. Preclinical studies suggest that detection of secondary metabolites for Aspergillus and use of novel immunolabeling approaches to positron emission tomography are potentially new avenues for the development of novel diagnostics. In view of the evolving epidemiology of opportunistic mould infections, developing diagnostic strategies to distinguish between pulmonary aspergillosis and other lung mycoses is another important future research direction.