Assessment of the clinical utility of serial β-d-glucan concentrations in patients with persistent neutropenic fever

Abstract

The performance of the Fungitell assay was investigated in 100 patients with haematological malignancy undergoing chemotherapy who developed antibiotic-unresponsive neutropenic fever (AUNF). Serum beta-D-glucan (BG) concentrations were significantly elevated on the first day of AUNF and all subsequent alternate days to day 10 in 38 patients who developed an invasive fungal infection (IFI) compared to 42 patients remaining free of such infections. The mean and median values of BG were 171.9+/-29.6 and 95.8 pg ml(-1), respectively, for patients with IFI and 64.4+/-17.1 and 32.9 pg ml(-1) for patients with only AUNF (P<0.0001). The differences remained significant over the 10 days despite antifungal therapy. The occurrence of > or =2 sequential concentrations of > or =80 pg ml(-1) ('positive' test) was found to give the best overall option for diagnosis, with an accuracy of 81.3%, sensitivity of 86.8%, positive predictive value of 76.7% and negative predictive value of 86.5%. Of the patients with an IFI, 78% developed a positive test at or before the clinical diagnosis was made -- this occurred at a mean (range) of 1.25 (-14 to +14) days prior to the IFI diagnosis. By starting sampling of blood from the first day of neutropenia rather than from the first day of AUNF, 50% of the patients with subsequent IFI would have been identified 5 days earlier. Increasing sampling to daily from alternate-day frequency did not further improve this earlier timing of an IFI diagnosis. A greater proportion of patients with persistent high levels of BG without overt IFI had severe enterocyte damage or mucositis than those with lower levels of BG without IFI (P=0.002). If the results of the initial BG test had been acted on to change antifungal therapy, discontinuation would have been inappropriate in 30% of patients and would have delayed definitive antifungal therapy. Although the findings for the cohort of patients studied are very useful, there is inter-patient variability in the test's performance. An holistic diagnostic approach is therefore necessary to interpret the test results optimally. Future studies should address this in further detail as well as the impact of empirical antifungal drug use and patient outcome.

ECIL recommendations for the use of biological markers for the diagnosis of invasive fungal diseases in leukemic patients and hematopoietic SCT recipients

“…21 The prerequisite of two consecutive positive tests for IFD diagnosis was investigated in four studies and resulted in a specificity approaching 100% and a lower sensitivity ranging between 45 and 65%. 17,19,23,26 The diagnostic performance of BG was similar in IC and IA, while utility in other less common IFD could not be assessed because of lacking data. Few data on the timing of BG positivity compared with conventional diagnostic tools are available: one study suggested that BG detection might precede IFD diagnosis according to the EORTC/MSG criteria.…”

“…Overall, the results of cohort studies tend to exhibit a larger variability of test performance when compared with case-control studies. Different cutoffs for positivity have been investigated in seven studies, 17,[19][20][21][22]24,26 suggesting that the optimal cutoff if compared with the recommended value may be lower for the Wako and Maruha assays 19,26 and higher for the Fungitec-G assay. 21 The prerequisite of two consecutive positive tests for IFD diagnosis was investigated in four studies and resulted in a specificity approaching 100% and a lower sensitivity ranging between 45 and 65%.…”

“…As the design of these studies was very variable, only 10 (4 case-control and 6 cohort studies) [17][18][19][20][21][22][23][24][25][26] were considered appropriate for analysis on the basis of the following parameters: type of population (hematological patients), sample size (X20 IFD cases and X50 non-IFD controls) and reference standard of IFD (definition according to the EORTC/MSG criteria). 10 Whereas sensitivity, specificity, positive and negative predictive values derived from these analyses in hematological patients were variable (Table 3), no major differences were observed among the different assays.…”

Evidence for the detection of non-endotoxin pyrogens by the whole blood monocyte activation test

“…the surface glycans, e.g., β(1-3) and β(1-6) glucans such as zymosan, laminarin, lichenan, and curdlan interfere with the lAl-test (Vassallo and limper, 1999). the rabbit test does not mirror the human situation regarding pro-inflammatory cytokine release upon stimulation with glucans, as the concentration of glucan needed to induce fever in rabbits (about 100 µg/ml -300 µg/ml) is far higher than for humans (0.01 µg/ml -0.1 µg/ml) (Nakagawa et al, 2002;ellis et al, 2008;Obayashi et al, 1995). this high amount of Human whole blood was stimulated with the LPS, LTA, and zymosan or fungal spores, and IL-1β release was determined by ELISA at the given time points.…”

Serum (1 → 3)-β-D-glucan levels (Fungitell assay) is not useful as a screening test for recipients of an allogeneic HSCT while on immunoglobulin replacement

“…1,2 Recent publications have described the serial measurement of serum (1-3)-b-D-glucan levels with the Fungitell assay as a useful tool for early diagnosis of invasive fungal infections in patients receiving conventional chemotherapy. 3,4 Our experience with two patients receiving prophylactic immunoglobulin replacement during allo-HSCT questions the use of (1-3)-b-D-glucan levels as a screening tool for this patient cohort.…”