Prospective evaluation of a combination of fungal biomarkers for the diagnosis of invasive fungal disease in high‐risk haematology patients

Abstract

We prospectively evaluated a combination of fungal biomarkers in adult haematology patients with focus on their clinical utility at different time points during the course of infection. In total, 135 patients were monitored once to twice weekly for serum (1-3)-ß-d-glucan (BG), galactomannan (GM), bis-methyl-gliotoxin and urinary d-arabinitol/l-arabinitol ratio. In all, 13 cases with proven or probable invasive fungal disease (IFD) were identified. The sensitivity of BG and GM at the time of diagnosis (TOD) was low, but within 2 weeks from the TOD the sensitivity of BG was 92%. BG >800 pg/mL was highly specific for IFD. At a pre-test probability of 12%, both BG and GM had negative predictive values (NPV) >0.9 but low positive predictive values (PPV). In a subgroup analysis of patients with clinically suspected IFD (pre-test probability of 35%), the NPV was lower, but the PPV for BG was 0.86 at cut-off 160 pg/mL. Among IFD patients, 91% had patterns of consecutively positive and increasing BG levels. Bis-methyl-gliotoxin was undetectable in 15 patients with proven, probable and possible IA. To conclude, BG was the superior fungal marker for IFD diagnosis. Quantification above the limit of detection and graphical evaluation of the pattern of dynamics are warranted in the interpretation of BG results.

Aspergillus fumigatus and Aspergillosis in 2019

“…This test is the most extensively used in clinics, has been validated in clinical studies, and has been endorsed in microbiological criteria for diagnosis of IA in all published guidelines (25,93,94). In addition, the decrease in GM values also can be used to monitor the efficacy of a treatment (109).…”

“…Currently, there is not a single serological diagnosis which is 100% reliable for the diagnosis of IA (111,(148)(149)(150). A combination of diagnostic tests significantly increased the detection rate (109,148,(151)(152)(153). Importantly, the performance of molecular diagnostic assays is hampered by the lack of a gold standard for diagnosis in the case of possible or probable IPA and the inability of these tests to distinguish between the different stages of the disease, from colonization to chronic noninvasive infection to IPA, all of which can coexist in the patient at risk.…”

Gliotoxin and bis(methylthio)gliotoxin are not reliable as biomarkers of invasive aspergillosis

“…The additional component separation gained by combining UHPLC and QTOF‐MS increases the specificity and makes misidentification significantly less likely. Indeed, all studies that failed to identify bmGT in patient samples after the initial study by Vidal‐García et al used some form of liquid chromatography–mass spectrometry. Other alternative detection methods, such as a fluorescently labelled aptamer structure‐switching assay, have been developed using spiked samples, but have yet to be evaluated in human samples.…”

“…Vidal‐García et al found bmGT to have a better sensitivity in serum than GM. However, several other studies failed to replicate these results, both in an animal model of IPA and in samples from patients with IPA . Furthermore, results from a mouse model suggest different kinetics and sensitivities of GT and bmGT depending on the host's immune status, whereby bmGT was only detected in lungs from a chronic granulomatous disease model (CGD), but not in bronchoalveolar lavage fluid (BALf) or serum from mice with CGD, neutropenia or after steroid treatment .…”

Use of (1→3)‐β‐d‐glucan for diagnosis and management of invasive mycoses in HIV‐infected patients

“…Examples of which include the use of galactomannan in the diagnosis of invasive aspergillosis and cryptoccocal antigen for diagnosis of cryptococcosis. (1→3)‐β‐ d ‐glucan (BDG), a component of several fungal cell walls, provides another surrogate marker for the diagnosis of IFIs . Since its first assay developed in Japan in 1985, BDG has been recommended to diagnose probable IFIs by the European Organization for Research and Treatment of Cancer, the Mycoses Study Group, the European Society of Clinical Microbiology and Infectious Diseases, the Infectious Diseases Society of America and the American Society for Microbiology …”