Diagnosis of Invasive Aspergillosis: Use of the Galactomannan Assay

Abstract

Invasive aspergillosis is the cause of severe morbidity and mortality in immunocompromised patients. Given the challenges of fungal cultures, non-culture surrogates are crucial to the timely diagnosis of invasive aspergillosis (IA) to initiate expedited treatment. The Platelia™ Aspergillus EIA (Bio-Rad, Hercules, California) is a double-sandwich ELISA that detects the galactomannan (GM) of the fungal cell wall and was cleared by the FDA for use in serum and bronchoalveolar fluid (BAL) in 2003 and 2011, respectively. The population in which GM has been studied the most and has shown the greatest accuracy is that of hematologic malignancy. The optimal optical density index (ODI) cutoff to define test positivity in the serum is still a matter of debate because this value influences test performance. Using a lower ODI threshold (≥0.5 vs. ≥1 vs. ≥1.5) optimizes sensitivity at the expense of specificity and vice versa using a higher ODI threshold. One must be alert to the potential for false-positive results, particularly if a ODI cutoff of 0.5 is used in the serum. False positives can occur due to medications, i.e., piperacillin/tazobactam, though there is increasing evidence that newer formulations are less cross-reactive with GM, and false-positive results occur in the presence of other molds that cross-react with GM. As the use of mold-active antifungal prophylaxis increases, one must be aware that GM may not perform as well due to lower pre-test probability of IA and lower test sensitivity. Emerging evidence indicates that use of GM in combination with other tests, e.g., Aspergillus PCR or lateral flow device (LFD), may enhance diagnostic accuracy beyond GM alone; however, further validation of these diagnostics in combination are required before routine implementation can be recommended. BAL GM performs better than serum as it is significantly more sensitive, though the optimal ODI cutoff is also debated (≥0.5 vs. ≥1).False-positive results can be due to use of medications, as with serum GM. False negatives can occur with the use of certain agents which decrease the viscosity of the BAL fluid, and use of such agents need to be considered by the clinician when evaluating a test result. Again, BAL GM, in conjunction with other tests, e.g., PCR and LFD, are promising, but further studies are needed. GM in other fluids, i.e., CSF, urine, and tissue, may be useful, but the studies are very limited. In summary, when employed in the right clinical context and interpreted appropriately, serum and BAL GM can facilitate the diagnosis and early treatment of IA. While there are significant limitations and the landscape is evolving, the test has an important role in clinical practice today.